Biopsy Strategies for Endoscopic Surveillance of Pre‐malignant Gastric Lesions

Background: Endoscopic surveillance of pre‐malignant gastric lesions may add to gastric cancer prevention. However, the appropriate biopsy regimen for optimal detection of the most advanced lesions remains to be determined. Therefore, we evaluated the yield of endoscopic surveillance by standardized and targeted biopsy protocols. Materials and Methods: In a prospective, multi‐center study, patients with intestinal metaplasia (IM) or dysplasia (DYS) underwent a surveillance gastroscopy. Both targeted biopsies from macroscopic lesions and 12 non‐targeted biopsies according to a standardized protocol (antrum, angulus, corpus, cardia) were obtained. Appropriate biopsy locations and the yield of targeted versus non‐targeted biopsies were evaluated. Results: In total, 112 patients with IM (n = 101), or low‐grade (n = 5) and high‐grade DYS (n = 6) were included. Diagnosis at surveillance endoscopy was atrophic gastritis (AG) in one, IM in 77, low‐grade DYS in two, high‐grade DYS in three, and gastric cancer in one patient. The angulus (40%), antrum (35%) and lesser curvature of the corpus (33%) showed the highest prevalence of pre‐malignant conditions. Non‐targeted biopsies from the lesser curvature had a significantly higher yield as compared to the greater curvature of the corpus in diagnosing AG and IM (p = .05 and p = .03). Patients with extensive intragastric IM, which was also present at the cardia were at high risk of a concurrent diagnosis of dysplasia or gastric cancer. High‐grade DYS was detected in targeted biopsies only. Conclusions: At surveillance endoscopies, both targeted and non‐targeted biopsies are required for an appropriate diagnosis of (pre‐)malignant gastric lesions. Non‐targeted biopsies should be obtained in particular from the antrum, angulus and lesser curvature of the corpus.     

Lipid Alterations During the Fermentation of Dill Pickles

Analyses of various lipid fractions of sections of cucumbers and of good and bloated dill pickles showed that marked changes occur in all lipid fractions during fermentation. The most striking difference noted was the decrease in the phospholipid fraction. A nearly fourfold increase in free fatty acid, as well as a marked increase in the neutral fat fatty acids and unsaponifiables, occurred. Gas chromatographic analyses of the methyl esters of fatty acids from the various lipid fractions yielded further interesting data. From the analyses, 41 esters were identified; however, 16 of the esters accounted for at least 95% of the acids. Among the marked changes were the increases in linoleic and linolenic acids in good pickles, in contrast to the increase in oleic acid in the bloated pickles. The presence of tridecenoic acid in cucumbers, and its absence in pickles; and the absence of caproic, caprylic, and capric acids in cucumbers, and its presence in pickles, were interesting. The data demonstrated that the lipid alterations that occur during fermentation of cucumbers are analogous to those previously reported for the sauerkraut fermentation.     

A comparison of lysosomal acid hydrolase activities in human gastric antrum and in different regions of the porcine stomach

Lysosomes are known to be implicated in many disease states in both humans and animals. In order to assess the possible role of lysosomes in the aetiology of human gastric ulceration, lysosomal enzyme levels and some of their properties were determined in human gastric antrum and in three discrete porcine gastric regions. Of the four regions investigated, the strongest similarity emerged between the enzymes of the porcine pyloric gland area and those of the human antrum. These data suggest that the pyloric gland is an appropriate model tissue for a comparative in vitro study of lysosomal involvement in human gastric ulceration.     

MIF mRNA在胃窦胃癌组织中的表达及其与幽门螺杆菌感染的关系

目的:探讨胃窦胃癌组织中人巨噬细胞移动抑制因子MIF mRNA的表达,并分析其与幽门螺杆菌感染的关系,分析二者在胃窦胃癌发生中的相关性。方法:选取2013年1月至2014年12月于我院收治的胃窦胃癌患者30例作为观察组,另随机选择10例胃窦胃炎患者作为对照组,采用14C-尿素呼气试验(UBT)检测各组患者有无幽门螺杆菌感染,定量逆转录PCR检测观察组患者及对照组患者组织中MIF mRNA表达。统计分析不同组织中MIF mRNA表达与幽门螺杆菌感染之间的关系。结果:观察组组织中MIF mRNA的表达为(1.09±0.11),高于对照组组织的(0.21±0.08),差异具有统计学意义(P0.05)。进一步亚组分析,观察组合并幽门螺杆菌感染组织中MIF mRNA的表达为(1.24±0.14),高于非幽门螺杆菌感染者的(1.09±0.11),差异具有统计学意义(P0.05)。结论:MIF mRNA在胃窦胃癌组织中高表达,幽门螺杆菌感染促进了MIF mRNA的表达,共同促进了胃窦胃癌的发生发展。     

Helicobacter suis causes severe gastric pathology in mouse and mongolian gerbil models of human gastric disease

Background

“Helicobacter (H.) heilmannii” type 1 is the most prevalent gastric non-H. pylori Helicobacter species in humans suffering from gastric disease. It has been shown to be identical to H. suis, a bacterium which is mainly associated with pigs. To obtain better insights into the long-term pathogenesis of infections with this micro-organism, experimental infections were carried out in different rodent models.

Methodology/Principal Findings

Mongolian gerbils and mice of two strains (BALB/c and C57BL/6) were infected with H. suis and sacrificed at 3 weeks, 9 weeks and 8 months after infection. Gastric tissue samples were collected for PCR analysis, histological and ultrastructural examination. In gerbils, bacteria mainly colonized the antrum and a narrow zone in the fundus near the forestomach/stomach transition zone. In both mice strains, bacteria colonized the entire glandular stomach. Colonization with H. suis was associated with necrosis of parietal cells in all three animal strains. From 9 weeks after infection onwards, an increased proliferation rate of mucosal epithelial cells was detected in the stomach regions colonized with H. suis. Most gerbils showed a marked lymphocytic infiltration in the antrum and in the forestomach/stomach transition zone, becoming more pronounced in the course of time. At 8 months post infection, severe destruction of the normal antral architecture at the inflamed sites and development of mucosa-associated lymphoid tissue (MALT) lymphoma-like lesions were observed in some gerbils. In mice, the inflammatory response was less pronounced than in gerbils, consisting mainly of mononuclear cell infiltration and being most severe in the fundus.

Conclusions/Significance

H. suis causes death of parietal cells, epithelial cell hyperproliferation and severe inflammation in mice and Mongolian gerbil models of human gastric disease. Moreover, MALT lymphoma-like lesions were induced in H. suis-infected Mongolian gerbils. Therefore, the possible involvement of this micro-organism in human gastric disease should not be neglected.     

Urea, fluorofamide, and omeprazole treatments alter helicobacter colonization in the mouse gastric mucosa

BACKGROUND: Helicobacter pylori is a causative agent of gastric and duodenal ulcers and gastric cancer. Its urease enzyme allows survival in acid conditions and drives bacterial intracellular metabolism. We aimed to investigate the role of urease in determining the intragastric distribution of Helicobacter species in vivo. MATERIALS AND METHODS: The C57BL/6 mouse model of gastritis was used for infection with Helicobacter felis (CS1) or H. pylori (SS1). Urease-modulating compounds urea and/or fluorofamide (urease inhibitor) were administered to mice over 7 days. Concurrent gastric acid inhibition by omeprazole was also examined. Bacterial distribution in the antrum, body, antrum/body, and body/cardia transitional zones was graded "blindly" by histologic evaluation. Bacterial colony counts on corresponding tissue were also conducted. RESULTS: Urease inhibition by fluorofamide decreased H. pylori survival in most gastric regions (p < .05); however, there were no marked changes to H. felis colonization after this treatment. There was a consistent trend for decreased antral colonization, and an increase in antrum/body transitional zone and body colonization with excess 5% or 6% (w/v) urea treatment. Significant reductions of both Helicobacter species were observed with the co-treatment of urea and fluorofamide (p < .05). Collateral treatment with omeprazole did not alter H. pylori colonization patterns caused by urea/fluorofamide. CONCLUSIONS: Urease perturbations affect colonization patterns of Helicobacter species. Combined urea and fluorofamide treatment reduced the density of both Helicobacter species in our infection model.     

Immunohistochemical and in situ hybridization studies of β-microseminoprotein in the human gastric mucosa

β-Microseminoprotein is a 10-kDa disulphide-rich protein with unknown function which is present in the mucus of the airways, gastrointestinal tract and urogenital tract. In this paper, an investigation of the distribution of β- microseminoprotein in the human stomach is reported. Immunohistochemistry and in situ hybridization were used. β- Microseminoprotein was found to be localized mainly in the antrum part of the stomach and in two types of cells. Cells of the most abundant type (designated M-cells) were the neutral mucin-containing cells in the bottom part of the gastric glands and the surface epithelium. Virtually all these cells contained both β-microseminoprotein mRNA and protein product. Cells of the second type (designated E-cells) were found in a zone one-third up from the bottom of the gastric glands, where gastric endocrine cells are located. The E-cells were fewer than the M-cells and usually solitary. They seemed to have a high concentration of protein compared with their low mRNA level. The majority of the E-cells contained chromogranin A and gastrin. The observations made have implications for the understanding of the differentiation of the mucosal cells in the antrum of the stomach and form a basis for future studies of β- microseminoprotein in gastric disease.     

The Best Gastric Site for Obtaining a Positive Rapid Urease Test

Background Rapid urease tests (RUTs) provide a simple, sensitive method of detecting Helicobacter pylori infection.
Objectives. Our aim, therefore, was to determine whether the yield of detecting H. pylori infection by RUT varied depending on the site of gastric biopsy.
Materials and Methods. Gastric biopsies were obtained from 50 patients for RUT by use of hp fast (GI Supply, Camp Hill, PA). Biopsies were taken from the prepyloric greater curve antrum, from the gastric angle, and from the greater curve in mid-corpus. One biopsy specimen was placed in the RUT gel, and the biopsy from the adjacent mucosa was placed in formalin for subsequent histological evaluation by using the Genta stain. RUTs were examined and scored at intervals of 5, 10, 15, 30, and 45 minutes and after 1, 2, 4, and 24 hours.
Results. Fifty patients were entered in the test (150 RUTs), 32 having H. pylori infection. There were no false-positive RUTs (specificity, 100%). The gastric angle site was positive in 100%. The prepyloric site was positive in 87%, and the corpus site was positive in 84.4% ( p < .052 for angle or prepyloric antrum versus corpus). The most common pattern was for all to be positive (74%). The median time to positivity was similar with angle and prepyloric sites (37.5 and 60 minutes, respectively, p = not significant) and shorter than the corpus biopsy (180 minutes); ( p < .05 for angle or prepyloric antrum versus corpus).
Conclusion. The maximum probability for detecting H. pylori infection using a RUT is to obtain a biopsy from the gastric angle. To prevent missing a positive result when intestinal metaplasia is present, we recommend that (at a minimum) biopsies be taken from both the angle and the corpus.     

Nonessential amino acids are not necessary to stimulate net muscle protein synthesis in healthy volunteers

The present study was performed to test the hypothesis that orally administered essential amino acids, in combination with carbohydrate, will stimulate net muscle protein synthesis in resting human muscle in vivo. Four volunteers ingested 500 mL of a solution containing 13.4 g of essential amino acids and 35 g sucrose (EAA). Blood samples were taken from femoral arterial and venous catheters over a 2-hour period following the ingestion of EAA to measure arteriovenous concentrations of amino acids across the muscle. Two muscle biopsies were taken during the study, one before administration of the drink and one approximately 2 hours after consumption of EAA. Serum insulin increased from normal physiologic levels at baseline (9.2 +/- 0.8 microU/mL) and peaked (48 +/- 7.1 microU/mL) 30 minutes after EAA ingestion. Arterial essential amino acid concentrations increased approximately 100 to 400% above basal levels between 10 and 30 minutes following drink ingestion. Net nitrogen (N) balance changed from negative (-495 +/- 128 nmol/mL) prior to consumption of EAA to a peak positive value (416 +/- 140 nmol/mL) within 10 minutes of ingestion of the drink. EAA resulted in an estimated positive net N uptake of 307.3 mg N above basal levels over the 2-hour period. Muscle amino acid concentrations were similar prior to and 2 hours following ingestion of EAA. We conclude that ingestion of a solution composed of carbohydrates to stimulate insulin release and a small amount of essential amino acids to increase amino acid availability for protein synthesis is an effective stimulator of muscle protein anabolism.     

Clarithromycin Resistance of Helicobacter pylori Strains Isolated from Children’ Gastric Antrum and Fundus as Assessed by Fluorescent In‐situ Hybridization and Culture on Four‐Sector Agar Plates

Aim: To assess validity of culture on four‐sector agar plates and fluorescent in‐situ hybridization (FISH) test, and clarithromycin resistance rate in Helicobacter pylori strains isolated from children in the last 10 years. Methods: In the last 5 years, gastric biopsy specimens from antrum and fundus were taken from 89 consecutive children (median age 9 years) with H. pylori gastritis and from 21 controls. Culture was performed on 176 gastric biopsies (89 from antrum, 87 from fundus) on four‐sector agar plates, and FISH test with DNA ProbeMix^®. After its validity was evaluated, FISH test was applied on additional 119 biopsies from 68 children (68 from the antrum, 51 from the fundus) stored in the Pathology archive in the previous 5 years. Results: Culture was positive in 157 of 176 biopsies (sensitivity: 89.2%, 95% confidence interval (CI) 85–94). In 33 of 89 children (37%) resistant strains were found in one or both gastric sites. FISH test was positive in 148 of 176 biopsies from infected children (sensitivity 84.1%, 95%CI 79–89) and in none of 42 biopsies from controls (specificity 100%). When applied on archive biopsies, FISH test was positive in 96 of 119 (80.7%, 95%CI 74–88). Total children harboring resistant strains in the last 10 years, as assessed by FISH test, were 66 of 157 (42%). Mixed infection with both sensitive and resistant strains were found in 40 children (25%) and in 12 of them resistant strains were in the fundus only. Conclusions: Culture on four‐sector agar plates and FISH test had a high sensitivity and specificity and showed co‐presence of sensitive and resistant strains. In one‐third of children with mixed infection, the resistant strains were in the fundus only. Clarithromycin resistance should be assessed in biopsies both from the antrum and the fundus, utilizing antral biopsies only can underestimate its prevalence.     

Is Antrum or Corpus the Best Site for Culture of Helicobacter pylori?

Background Isolating Helicobacter pylori on culture media and performing antibiotic susceptibility testing is potentially the most useful tool for guiding antibiotic therapy, especially when antimicrobial resistance is suspected. The aim of this study was to determine whether the yield of H. pylori culture was related to the site from which the gastric specimen was obtained either before or after therapy.
Methods. Gastric mucosal biopsies from the antrum and the corpus of the stomach were cultured. H. pylori status was determined by histological assessment using the Genta stain.
Results. Fifty-two patients with documented H. pylori infection were studied: Twenty-three were tested before antibiotic therapy and 29 after therapy had failed. In 47 patients (90%), both antral and corpus culture specimens were positive. In 5 patients (10%), only one site was positive, with three false-negative antral and two false negative corpus cultures. The overall sensitivity of culture in detecting H. pylori infection was 95% (95% confidence interval = 89–98%) and was not significantly different for the antrum or corpus, either before or after therapy.
Conclusion. Culture of gastric biopsies from either the antrum or the corpus has an excellent diagnostic yield even in patients who failed antimicrobial therapy.     

幽门螺杆菌感染与门脉高压性胃病的发病关系

为了解门脉高压性胃病 (portalhypertensivegastropathyPHG)与幽门螺杆菌 (HP)感染的关系 ,选门脉高压性胃病胃窦粘膜 30例 ,免疫组化SP法 (链霉菌抗生物素蛋白—过氧化酶法 ,Streplavidin Peroxidase,SP)抗HP抗体染色 ,并以慢性乙型肝炎并胃病 2 0例及非肝病胃病 2 1例胃窦粘膜作对照。结果显示 ,30例门脉高压性胃病阳性2 2例 ,占 73.3% ;2 0例慢乙肝组阳性 11例 ,占 5 5 % ;2 1例非肝病组阳性 11例 ,占 5 2 .38%。门脉高压组HP感染阳性率与慢乙肝组、非肝病组相比差异无显著性 (P >0 .0 5 )。可见HP感染虽不是门脉高压性胃病的发生原因 ,但在治疗中短期加用杀HP的药物是必要的。     

PRMT5 acts as a tumor suppressor by inhibiting Wnt/β-catenin signaling in murine gastric tumorigenesis

Previous studies have demonstrated the in vitro oncogenic role of protein arginine methyltransferase 5 (PRMT5) in gastric cancer cell lines. The in vivo function of PRMT5 in gastric tumorigenesis, however, is still unexplored. Here, we showed that Prmt5 deletion in mouse gastric epithelium resulted in spontaneous tumorigenesis in gastric antrum. All Prmt5-deficient mice displayed intestinal-type gastric cancer within 4 months of age. Of note, 20% (2/10) of Prmt5 mutants finally developed into invasive gastric cancer by 8 months of age. Gastric cancer caused by PRMT5 loss exhibited the increase in Lgr5⁺ stem cells, which are proposed to contribute to both the gastric tumorigenesis and progression in mouse models. Consistent with the notion that Lgr5 is the target of Wnt/β-catenin signaling, whose activation is the most predominant driver for gastric tumorigenesis, Prmt5 mutant gastric cancer showed the activation of Wnt/β-Catenin signaling. Furthermore, in human gastric cancer samples, PRMT5 deletion and downregulation were frequently observed and associated with the poor prognosis. We propose that as opposed to the tumor-promoting role of PRMT5 well-established in the progression of various cancer types, PRMT5 functions as a tumor suppressor in vivo, at least during gastric tumor formation.     

Measurement variability and diagnostic sensitivity of gastric mucosal inflammatory cell morphometry

OBJECTIVE: To assess the variability and sensitivity of morphometric measures of gastric mucosal lymphocyte and plasma cells to determine a systematic procedure for evaluating the density of these mononuclear inflammatory cells (MNC). STUDY DESIGN: Gastric biopsies of antrum (n = 3), incisura angularis (n = 2) and corpus (n = 3) from two controls and three patients with Helicobacter pylori-related gastritis (antral, diffuse or multifocal gastritis) were considered. In each biopsy, three fields from each of three sections were selected. In each field, stromal area was obtained by subtracting gland area (GA) from total area, and MNC were counted. Results were expressed as MNC/total mm2 and MNC/stromal mm2. Correlations with GA, coefficients of variation (CV), discriminant power analysis and analysis of variance were performed. RESULTS: Correlations always existed between GA and MNC/total mm2 and rarely between GA and MNC/stromal mm2. CV of MNC/stromal mm2 were lower (18%) than those of MNC/total mm2 (30%). High sensitivity (95.4%) and specificity (95.8%) were found for MNC/stromal mm2 but not for MNC/total mm2. Differences in MNC/stromal mm2 existed in all subjects (P < .0001). Highly significant differences in MNC/stromal mm2 were also found between normal and inflammatory states, gastric sites and sections. CONCLUSION: In contrast to MNC/total mm2, MNC/stromal mm2 is an unbiased estimate of MNC density. The following sampling procedure is proposed: two biopsies from each gastric site, two sections from each biopsy and two microscopic fields from each section.     

Glucagon-like peptide-1 relaxes gastric antrum through nitric oxide in mice

Glucagon-like-peptide-1 (GLP-1) is a proglucagon-derived peptide expressed in the intestinal enteroendocrine-L cells and released after meal ingestion. GLP-1 reduces postprandial glycemia not only by its hormonal effects, but also by its inhibitory effects on gastrointestinal motility. Recently, we showed that GLP-1 acts in the enteric nervous system of mouse intestine. Therefore our working hypothesis was that GLP-1 may have also a direct influence on the gastric mechanical activity since the major part of experimental studies about its involvement in the regulation of gastric motility have been conducted in in vivo conditions. The purposes of this study were (i) to examine exogenous GLP-1 effects on mouse gastric mechanical activity using isolated whole stomach; (ii) to clarify the regional activity of GLP-1 using circular muscular strips from gastric fundus or antrum; (iii) to analyze the mechanism of action underlying the observed effects; (iv) to verify regional differences of GLP-1 receptors (GLP-1R) expression by RT-PCR. In the whole stomach GLP-1 caused concentration-dependent relaxation significantly anatagonized by exendin (9-39), an antagonist of GLP-1R and abolished by tetrodotoxin (TTX) or N_ω-nitro-l-arginine methyl ester (l-NAME), inhibitor of nitric oxide (NO) synthase. GLP-1 was without any effect in fundic strips, but it induced concentration-dependent relaxation in carbachol-precontracted antral strips. The effect was abolished by TTX or l-NAME. RT-PCR analysis revealed a higher expression of GLP-1R mRNA in antrum than in fundus. These results suggest that exogenous GLP-1 is able to reduce mouse gastric motility by acting peripherally in the antral region, through neural NO release.     

Incorporation of radioactive proline and fucose in gastric mucosal biopsies. Correlation with histological findings

Human gastric mucosal biopsies incorporate in vitro radioactive proline and fucose into macromolecular glycoproteins (mucin). Differences were found between the incorporation pattern of antral and fundic mucosae according to their pathology, confirmed by histology. Antral mucosae with abnormal histology showed a significantly higher incorporation of proline than normal samples. Fucose incorporation was also increased. Similar results were found with fundic biopsies. The ratio of total fucose to total proline incorporated into mucin secreted during incubation also increased significantly in these samples. Biochemical analyses on the other hand showed no significant change. The results suggest a breakdown in the processing, storage and secretory processes of mucin-type glycoproteins in pathological mucosae, but not in their biosynthesis. The mucosal samples could be classified as A or B types according to their proline and fucose incorporation: A mucosae have a lower proline incorporation than B mucosae (greater than 380 cpm/micrograms DNA for the antrum and greater than 200 cpm/micrograms DNA for the fundus). These results confirm the possibility of studying abnormal mucus secretion using gastric biopsy samples.     

Human intrinsic factor secretion: immunocytochemical demonstration of membrane-associated vesicular transport in parietal cells

The human gastric parietal cell synthesizes and secretes intrinsic factor (IF) and acid. In contrast to the cellular mechanisms of acid secretion, little is known about the mechanisms of IF secretion. To elucidate these mechanisms we obtained gastric secretions and sequential fundic biopsies from three subjects before and after pentagastrin stimulation (6 microgram/Kg s.c.). IF was localized in the biopsies using an ultrastructural immunoperoxidase technique using a well-characterized, monospecific antibody to human IF. IF output was quantified using a specific radioimmunoassay in concurrently obtained gastric secretions. Before stimulation, IF was associated with tubulovesicles scattered throughout the cytoplasm and with some in rough endoplasmic reticulum (RER). The tubulovesicles associated with IF migrated to the periphery of the secretory canaliculi within 8 min of stimulation. IF was present on secretory microvilli between 8 and 30 min when IF output in gastric juice was at its maximum. The cessation of IF secretion coincided with the depletion of IF associated with tubulovesicles. IF appeared in the perinuclear space and RER as the IF associated with tubulovesicles was secreted. These observations indicate that IF secretion depends upon membrane-associated vesicular transport and provides support for a membrane translocation-fusion hypothesis to explain the morphologic changes that occur in the parietal cell during secretion.     

Short-term exposure to testosterone propionate leads to rapid bill color and dominance changes in zebra finches

Testosterone (T) can influence both male-male competition and mate choice displays. In zebra finches, female mate choice is based in part on bill color, and bill color has been shown to be enhanced by long-term testosterone supplementation. However, it is not clear whether bill color plays a role in male-male interactions and how bill color responds to shorter-term changes in T. We tested whether a single injection of testosterone propionate (TP) would influence male-male dominance interactions and lead to rapid (over a three-day period) changes in bill color. In addition, we tested whether bill color predicted aggression and dominance. We allowed birds in triads to establish hierarchies and then injected either dominant or subordinate individuals with TP, in addition to establishing sham control triads. We found that red chroma, but not hue, predicted aggressiveness of males. Exposure to TP led both dominant and subordinate birds to increase dominance scores over three days, longer than the < 24 h period in which injected TP stays active. In addition, exposure to TP increased red chroma and hue in three days showing the dynamic nature of allocation of pigments to the bill. Our results suggest that zebra finches can modulate T and bill color levels over short time periods and these changes may occur through positive feedback between T-levels and dominance.     

Interstitital cells of Cajal in the human stomach: distribution and relationship with enteric innervation

Interstitial cells of Cajal (ICC) are distributed throughout the gastrointestinal muscle coat with a region-specific location, and are considered to be pace-maker and/or mediators of neurotransmission. Little is known about their shape, size, distribution and relationships with excitatory and inhibitory nerves in human stomach. With this aim, we labeled the ICC, using c-Kit immunohistochemistry, followed by a quantitative analysis to evaluate the distribution and area occupied by these cells in the circular and longitudinal muscle layers and at the myenteric plexus level in the human fundus, corpus and antrum. Furthermore, by NADPH-d histochemistry and substance P (SP) immunohistochemistry, we labeled and quantified nitric oxide (NO)-producing and SP-containing nerves and evidenced their relationships with the ICC in these three gastric regions. In the fundus, the ICC appeared as bipolar cells and in the corpus and antrum they mainly appeared as multipolar cells, with highly ramified processes. The networks formed by ICC differed in the three gastric regions. The ICC number was significantly higher and cell area smaller in the fundus compared to the corpus and antrum. The area occupied by the ICC was significantly higher at the myenteric plexus level compared with circular and longitudinal muscle layers. Everywhere, NADPH-d-positive nerves were more numerous than SP-positive ones. Both kinds of fibers were closely apposed to the ICC in the corpus and antrum. In conclusion, in the human stomach, the ICC have region-specific shape, size and distribution and in the corpus and antrum have close contact with both inhibitory and excitatory nerves. Presumably, as suggested for laboratory mammals, these differences are in relationship with the motor activities peculiar to each gastric area.