It has recently become clear that the gut microbiota influence intestinal motility, intestinal barrier function, and mucosal immune function; therefore, the gut microbiota are deeply involved in the maintenance of intestinal homeostasis. The effects of the gut microbiota on the enteric nervous system (ENS) in the adult intestine, however, remain poorly understood. In the current study, we investigated the effects of the gut microbiota on the ENS. Male C57BL/6 SPF mice at 12 weeks of age were given a cocktail of four antibiotics (ABX) orally to induce dysbiosis (ABX mice). As early as six hours after ABX administration, the weight of the cecum of ABX mice increased to be significantly greater than that of vehicle-treated animals; moreover, ABX-induced dysbiosis reduced the density of enteric nerve fibers (marked by tubulin-β3 immunoreactivity) in the lamina propria of the proximal colon to approximately 60% that of control. TAK242, a TLR4 antagonist, significantly lowered the nerve fiber density in the lamina propria of the proximal colonic mucosa to approximately 60% that of vehicle-treated SPF mice. We thus developed and tested the hypothesis that mucosal glia expressing TLR4 are activated by enteric bacteria and release neurotrophic factors that contribute to the maintenance of enteric neural circuits. Neurotrophic factors in the mucosa of the SPF mouse proximal colon were examined immunohistochemically. Ciliary neurotrophic factor (CNTF) was abundantly expressed in the lamina propria; most of the CNTF immunoreactivity was observed in mucosal glia (marked by S100β immunoreactivity). Administration of CNTF (subcutaneously, 0.3 mg/kg, 3 doses, 2 hours apart) to ABX mice significantly increased mucosal nerve fiber density in the ABX mouse proximal colon to nearly control levels. The effect of CNTF on enteric mucosal nerve fibers was examined in isolated preparations of proximal colon of ABX mice. As it did in vivo, exposure to CNTF in vitro significantly increased enteric mucosal nerve fiber density in the ABX-treated colon. In conclusion, our evidence suggests that gut microbiota constitutively activate TLR4 signaling in enteric mucosal glia, which secrete CNTF in response. The resulting bacterial-driven glial release of CNTF helps to maintain the integrity of enteric mucosal nerve fibers.

Neurite outgrowth is the critical step of nervous development. Molecular probes against neurites are essential for evaluation of the nervous system development, compound neurotoxicity, and drug efficacy on nerve regeneration. To obtain a neurite probe, we developed a neurite-SELEX strategy and generated a DNA aptamer, yly12, that strongly binds neurites. The molecular target of yly12 was identified to be neural cell adhesion molecule L1 (L1CAM), a surface antigen expressed in normal nervous system and various cancers. Here, yly12 was successfully applied to image the three-dimensional network of neurites between live cells, as well as the neurite fibers on normal brain tissue section. This aptamer was also found to have an inhibitory effect on neurite outgrowth between cells. Given the advantages of aptamers, yly12 hold great potential as a molecular tool in the field of neuroscientific research. The high efficiency of neurite-SELEX suggests that SELEX against a subcellular structure instead of the whole cells is more effective in obtaining the desired aptamers.

The aim of the present study was to perform immunohistochemical and ultrastructural analysis of gastrin-, synaptophysin (SY)- and atrial natriuretic peptide (ANP)-positive cells in the pylorus of "two kidney, one clip" (2K1C) renovascular hypertension model in rats.

In order to identify neuroendocrine (NE) cells, immunohistochemical reactions were performed with the use of specific antibodies against gastrin, SY and ANP. Gastric NE cells were also examined using an electron microscope.

The present study revealed a twofold increase in the number of gastrin- and SY-positive cells and a significant decrease in the number of ANP-immunoreactive (IR) cells in the pyloric mucosa of 2K1C rats. Test results obtained with an electron microscope confirmed a change in the activity of the stomach endocrine cells of hypertensive rats.

Immunohistochemical and ultrastructural investigations demonstrated the impact of renovascular hypertension on the neuroendocrine system in the rat stomach. The changes in the total number and ultrastructure of DNES cells proved their undeniable role in the modulation of gastric dysfunction, as a consequence of deregulation of homeostasis-maintaining systems.

This review surveys immunocytochemical and histochemical markers of neuronal lineage for application to tissue sections of fetal and neonatal brain. They determine maturation of individual nerve cells as the tissue progresses to mature architecture. From a developmental perspective, neuronal markers are all about timing. These diverse cellular labels may be classified in two ways: 1) time of onset of expression (early; intermediate; late); 2) labeling of subcellular structures or metabolic functions (nucleoproteins; synaptic vesicle proteins; enolases; cytoskeletal elements; calcium-binding; nucleic acids; mitochondria). Apart from these positive markers of maturation, other negative markers are expressed in primitive neuroepithelial cells and early stages of neuroblast maturation, but no longer are demonstrated after initial stages of maturation. These examinations are relevant for studies of normal neuroembryology at the cellular level. In fetal and perinatal neuropathology they provide control criteria for application to malformations of the brain, inborn metabolic disorders and acquired fetal insults in which neuroblastic maturation may be altered. Disorders, in which cells differentiate abnormally, as in tuberous sclerosis and hemimegalencephaly, pose another yet aspect of mixed cellular lineage. The measurement in living patients, especially neonates, of serum and CSF levels of enolases, chromogranins and S-100 proteins as biomarkers of brain damage may potentially be correlated with their corresponding tissue markers at autopsy in infants who do not survive. The neuropathological markers here described can be performed in ordinary hospital laboratories, not just research facilities, and offer another dimension of diagnostic precision in interpreting abnormally developed fetal and postnatal brains.

To assess synaptophysin expression in columnar-lined oesophageal mucosa showing either goblet cells, known as intestinal metaplasia, or with accompanying oxyntic glands or pyloric glands.

Of 159 biopsies, 53 were oesophageal (19 had intestinal metaplasia, 13 oxyntic glands, and 21 pyloric glands), 77 gastric (12 had goblet cells and 27 no goblet cells) and 29 duodenal. Synaptophysin-positive goblet cells were found in all biopsies from the normal duodenum, in 53% of the oesophageal biopsies showing intestinal metaplasia, but only in 8% of gastric biopsies showing intestinal metaplasia. Synaptophysin-positive Paneth cells occurred in all duodenal biopsies, and in nine of the gastric biopsies showing intestinal metaplasia, but in only one of the oesophageal biopsies showing intestinal metaplasia. A continuous synaptophysin-positive neck cell zone was found in all biopsies from the normal antrum, but in none of the oesophageal biopsies with pyloric glands or with chronic antritis.

The paucity or absence of synaptophysin-positive cells in all three phenotypes of Barrett's mucosa might mirror a sequela of chronic inflammation caused by the particular pathogenic bacteria present in the immediate oesophageal microenvironment.

Targeted multiplex imaging mass spectrometry utilizes several different antigen-specific primary antibodies, each directly labeled with a unique photocleavable mass tag, to detect multiple antigens in a single tissue section. Each photocleavable mass tag bound to an antibody has a unique molecular weight and can be readily ionized by laser desorption ionization mass spectrometry. This article describes a mass spectrometry method that allows imaging of targeted single cells within tissue using transmission geometry laser desorption ionization mass spectrometry. Transmission geometry focuses the laser beam on the back side of the tissue placed on a glass slide, providing a 2 μm diameter laser spot irradiating the biological specimen. This matrix-free method enables simultaneous localization at the sub-cellular level of multiple antigens using specific tagged antibodies. We have used this technology to visualize the co-expression of synaptophysin and two major hormones peptides, insulin and somatostatin, in duplex assays in beta and delta cells contained in a human pancreatic islet.

In order to investigate the expression of mRNA and protein for synaptophysin (SYP) in bovine corpus luteum (CL) during different stages of pregnancy, we chose Holstein cows during various pregnancy stages. The CL was divided into two parts, then immunohistochemical streptavidin-perosidase and RT-PCR were used to determine the levels of protein and mRNA for SYP respectively. SYP immunoreactive products mainly located in large luteal cells; much less or no immunoreactivity was found in small luteal cells. The expression levels of SYP were different in various stages of pregnancy. In the CL of mid pregnancy, the levels of protein and mRNA for SYP were both significantly higher than those in early and late stage of pregnancy (P<0.05). After parturition, compared with late stage of pregnancy, the protein level of SYP decreased (P<0.05), but its mRNA increased (P<0.05). In conclusion, SYP has the strongest expression in mid stage of pregnancy, and its regular expression in bovine CL indicates that SYP may play important roles in maintaining the function of bovine CL and in the regulation of production.

Since reports on endocrine cells and their kinetics in the corpus of the human stomach are limited, the aim of this study was to examine the appearance, localization, density, and the relationship among the endocrine cell types in the corpus of the human stomach during prenatal and early postnatal development.

We examined chromogranin A, somatostatin, ghrelin, glucagon, and serotonin expression by immunohistochemistry in 2 embryos, 38 fetuses, and 3 infants in the corpus of human stomach.

Chromogranin A secreting endocrine cells were identified in the corpus at week 10 of gestation. Somatostatin cells were present from the 10th week, ghrelin and serotonin cells from the 11th week, and glucagon cells from the 12th week of gestation. Endocrine cells were present individually or clustered within the glandular base and body during the first trimester, and were present separately within the basal and central parts of glands during the second and third trimesters. Somatostatin cells were the most common type of cells (~46 %) during the first trimester, while ghrelin cells were the most numerous during the second trimester (~34 %), and in infants (~28 %). The percentage of glucagon cells was significant only during the first trimester of pregnancy (5.5 %), and the percentage of serotonin cells was only significant just before birth (4.8 %).

These results show, for the first time, that the largest number of endocrine cells are present in the corpus during the first trimester of prenatal development. Also, these results suggest that secretory products of endocrine cells play a role in the regulation of homeostasis, growth, and differentiation, and in human stomach function.

Neuroendocrine tumours of the pancreas (PNETs) represent 1-2% of all pancreatic tumours. The terms 'islet cell tumours' and 'carcinoids' of the pancreas should be avoided. The aim of this review is to offer an overview of the history and diagnosis of PNETs followed by a discussion of the available treatment options.

A search on PubMed using the keywords 'neuroendocrine', 'pancreas' and 'carcinoid' was performed to identify relevant literature over the last 30 years.

The introduction of a revised classification of neuroendocrine tumours by the World Health Organisation (WHO) in 2000 significantly changed our understanding of and approach to the management of these tumours. Advances in laboratory and radiological techniques have also led to an increased detection of PNETs. Surgery remains the only treatment that offers a chance of cure with increasing number of non-surgical options serving as beneficial adjuncts. The better understanding of the behaviours of PNETs together with improvements in tumour localisation has resulted in a more aggressive management strategy with a concomitant improvement in symptom palliation and a prolongation of survival.

Due to their complex nature and the wide range of therapeutic options, the involvement of specialists from all necessary disciplines in a multidisciplinary team setting is vital to provide optimal treatment of this disease.

The gastro-entero-pancreatic (GEP) system of four reptilian species: turtle (Emys orbicularis), lizards (Lacerta viridis and Lacerta agilis) and snake (Natrix natrix) has been investigated immunohistochemically for the presence and topographic distribution of synaptophysin. Among the studied reptiles, only in turtles were neural, glial and neuroendocrine elements labelled for this marker protein. Semi-quantitative evaluation of the immunolabelled neural structures distributed throughout the gastroenteric wall revealed, with two exceptions, highly significant mean differences between the successive gut segments. Significant mean differences were noted also between myenteric and submucosal neurons immunolabelled in the various gastroenteric regions. Moreover, the comparison of ganglionic perikarya groups showed, at least in the stomach, significant mean differences. The amounts of immunopositive glial cells seemed to vary similarly to those of nerve fibers along the entire gastrointestinal tract. Finally, every "closed" and "open" population of immunopositive epithelial cells showed typical fluctuations along the gut. In addition to the distribution of synaptophysin in the GEP system of turtles, the above findings furnish evidence that this marker protein, which is widespread in mammals, is only occasionally expressed in reptiles and probably in most poikilothermic vertebrates.

Somatostatin is a potent inhibitor of gastrin secretion and gene expression. Menin is a 67-kDa protein product of the multiple endocrine neoplasia type 1 (MEN1) gene that when mutated leads to duodenal gastrinomas, a tumor that overproduces the hormone gastrin. These observations suggest that menin might normally inhibit gastrin gene expression in its role as a tumor suppressor. Since somatostatin and ostensibly menin are both inhibitors of gastrin, we hypothesized that somatostatin signaling directly induces menin. Menin protein expression was significantly lower in somatostatin-null mice, which are hypergastrinemic. We found by immunohistochemistry that somatostatin receptor-positive cells (SSTR2A) express menin. Mice were treated with the somatostatin analog octreotide to determine whether activation of somatostatin signaling induced menin. We found that octreotide increased the number of menin-expressing cells, menin mRNA, and menin protein expression. Moreover, the induction by octreotide was greater in the duodenum than in the antrum. The increase in menin observed in vivo was recapitulated by treating AGS and STC cell lines with octreotide, demonstrating that the regulation was direct. The induction required suppression of protein kinase A (PKA) since forskolin treatment suppressed menin protein levels and octreotide inhibited PKA enzyme activity. Small-interfering RNA-mediated suppression of PKA levels raised basal levels of menin protein and prevented further induction by octreotide. Using AGS cells, we also showed for the first time that menin directly inhibits endogenous gastrin gene expression. In conclusion, somatostatin receptor activation induces menin expression by suppressing PKA activation.

The epithelial linings of the small and large intestine are rapidly turned over and provide an ideal system for exploring links between differentiation and regulation of cell cycle exit. We utilized wild type, p21-/-, p27-/- and p21/p27-/- mice to address contributions of the Cdk inhibitors p21 and p27 to proliferation and differentiation in the mouse gastrointestinal tract. We did not detect any significant differences in proliferation, and all differentiated epithelial cell lineages were represented in all four genotypes. These data indicate that p21 and p27 do not play essential roles in the regulation of normal epithelial renewal in the intestine. These Cdk inhibitors are not needed in vivo for either assembly of Cdk/Cyclin complexes that drive active proliferation, or inhibition of Cdk/Cyclin complexes during cell cycle exit. However, expression of Cyclin D2 and to a lesser degree Cyclin D3 was reduced in p27-/- and p21/p27-/- mice, indicating a unique role for p27 in the regulation of these specific D-type Cyclins in vivo. In the absence of p27, reduced levels of Cyclin D2 and D3 may help to counteract increased proproliferative signals in the intestine.

The intestinal glucagon-like peptides GLP-1 and GLP-2 inhibit intestinal motility, whereas GLP-2 also stimulates growth of the intestinal mucosa. However, the mechanisms of action of these peptides in the intestine remain poorly characterized. To determine the role of the enteric nervous system in the actions of GLP-1 and GLP-2 on the intestine, the glial cell line-derived neurotropic factor family receptor alpha(2) (GFRalpha2) knockout (KO) mouse was employed. The mice exhibited decreased cholinergic staining, as well as reduced mRNA transcripts for substance P-ergic excitatory motoneurons in the enteric nervous system (ENS) (P < 0.05). Examination of parameters of intestinal growth (including small and large intestinal weight and small intestinal villus height, crypt depth, and crypt cell proliferation) demonstrated no differences between wild-type and KO mice in either basal or GLP-2-stimulated mucosal growth. Nonetheless, KO mice exhibited reduced numbers of synaptophysin-positive enteroendocrine cells (P < 0.05), as well as a markedly impaired basal gastrointestinal (GI) transit rate (P < 0.05). Furthermore, acute administration of GLP-1 and GLP-2 significantly inhibited transit rates in wild-type mice (P < 0.05-0.01) but had no effect in GFRalpha2 KO mice. Despite these changes, expression of mRNA transcripts for the GLP receptors was not reduced in the ENS of KO animals, suggesting that GLP-1 and -2 modulate intestinal transit through enhancement of inhibitory input to cholinergic/substance P-ergic excitatory motoneurons. Together, these findings demonstrate a role for GFRalpha2-expressing enteric neurons in the downstream signaling of the glucagon-like peptides to inhibit GI motility, but not in intestinal growth.

In view of the importance of molecular sensing in the function of the gastrointestinal (GI) tract, we assessed whether signal transduction proteins that mediate taste signaling are expressed in cells of the human gut. Here, we demonstrated that the alpha-subunit of the taste-specific G protein gustducin (Galpha(gust)) is expressed prominently in cells of the human colon that also contain chromogranin A, an established marker of endocrine cells. Double-labeling immunofluorescence and staining of serial sections demonstrated that Galpha(gust) localized to enteroendocrine L cells that express peptide YY and glucagon-like peptide-1 in the human colonic mucosa. We also found expression of transcripts encoding human type 2 receptor (hT2R) family members, hT1R3, and Galpha(gust) in the human colon and in the human intestinal endocrine cell lines (HuTu-80 and NCI-H716 cells). Stimulation of HuTu-80 or NCI-H716 cells with the bitter-tasting compound phenylthiocarbamide, which binds hT2R38, induced a rapid increase in the intracellular Ca2+ concentration in these cells. The identification of Galpha(gust) and chemosensory receptors that perceive chemical components of ingested substances, including drugs and toxins, in open enteroendocrine L cells has important implications for understanding molecular sensing in the human GI tract and for developing novel therapeutic compounds that modify the function of these receptors in the gut.

To assess long-term effects of Helicobacter pylori (H pylori) eradication on antral G cell morphology and function in patients with and without duodenal ulcer (DU).

Consecutive dyspeptic patients referred to the endoscopy entered the study. Out of 39 H pylori positive patients, 8 had DU (H pylori +DU) and 31 gastritis (H pylori +G). Control groups consisted of 11 uninfected dyspeptic patients (CG1) and 7 healthy volunteers (CG2). Basal plasma gastrin (PGL), antral tissue gastrin concentrations (ATGC), immunohistochemical and electron microscopic characteristics of G cells were determined, prior to and 6 mo after therapy.

We demonstrated elevated PGL in infected patients compared to uninfected controls prior to therapy. Elevated PGL were registered in all H pylori+patients (H pylori +DU: 106.78+/-22.72 pg/mL, H pylori +G: 74.95+/-15.63, CG1: 68.59+/-17.97, CG2: 39.24+/-5.59 pg/mL, P<0.01). Successful eradication (e) therapy in H pylori+patients lead to significant decrease in PGL (H pylori+DU: 59.93+/-9.40 and H pylori +Ge: 42.36+/-10.28 pg/mL, P<0.001). ATGC at the beginning of the study were similar in infected and uninfected patients and eradication therapy lead to significant decrease in ATGC in H pylori +gastritis, but not in DU patients. In the H pylori +DU patients, the mean number of antral G cells was significantly lower in comparison with all other groups (P<0.01), but after successful eradication was close to normal values found in controls. By contrast, G cell number and volume density were significantly decreased (P<0.01) in H pylori +Ge group after successful eradication therapy (294+/-32 and 0.31+/-0.02, respectively), in comparison to values before eradication (416+/-40 and 0.48+/-0.09). No significant change of the G cell/total endocrine cell ratio was observed during the 6 mo of follow up in any of the groups. A reversible increase in G cell secretory function was seen in all infected individuals, demonstrated by a more prominent secretory apparatus. However, differences between DU and gastritis group were identified.

H pylori infection induces antral G cell hyperfunction resulting in increased gastrin synthesis and secretion. After eradication therapy complete morphological and functional recovery is observed in patients with gastritis. In the DU patients some other factors unrelated to the H pylori infection influence antral G cell morphology and function.

The authors review the application of a variety of neuroendocrine cell markers to identify pancreatic islet cells and tumors. In the past, several empiric histochemical techniques had been used to demonstrate neuroendocrine cells, particularly the Grimelius argyrophilic stain. The development of immunohistochemistry made it possible to demonstrate specific cell products such as regulatory peptides, thus allowing the classification of pancreatic neuroendocrine tumors with a view to clinical symptoms. However, it is not always possible to visualize regulatory peptides in these tumors. It is therefore important to use broad-spectrum neuroendocrine cell markers to identify the neuroendocrine nature. These markers are proteins localized in the secretory granules (core- or membrane-related), in the cytosol, or in the cellular membrane. The markers most commonly used in routine histopathology are the secretory granule proteins chromogranin A and synaptophysin and the cytosolic enzyme neuronspecific enolase. Other new markers (e.g., synaptic vesicle protein 2) are of general diagnostic value. Region-specific antibodies to chromogranin A can be valuable in differentiating between benign and malignant neuroendocrine tumors. Some markers may be related to the functioning characteristics of pancreatic neuroendocrine tumors, such as prohormone convertases. In addition, markers giving further complementary information have been identified, such as five somatostatin receptor subtypes, the expression of which varies markedly in pancreatic neuroendocrine tumors. Antibodies against all somatostatin receptor subtypes are now commercially available, and immunohistochemical investigation of its expression should be routinely applied when considering treatment with somatostatin analogs.

As well as causing chronic gastritis, Helicobacter pylori predisposes patients to peptic ulcer disease and gastric cancer, and induces gastric functional disorders. The aim of our study was to investigate the effects of H. pylori eradication therapy on the morphological and functional recovery of gastric antral and corpus D cells in patients with chronic gastritis during 6 months of follow-up.

Forty consecutive, dyspeptic patients referred for endoscopy (31 with H. pylori infection and nine controls; mean age 49 years; 17 men, 23 women) entered the study. All patients had histological signs of gastritis but no signs of peptic ulcer or gastric cancer. Antrum (n=8) and corpus (n=6) biopsy specimens were collected for routine histology, radioimmunoassay tissue somatostatin levels, immunohistochemistry and electron microscopy, prior to and 6 months after therapy. Basal plasma somatostatin levels were determined prior to eradication, plus 6 weeks and 6 months after therapy. Eradication therapy consisted of amoxicillin, metronidazole and omeprazole.

Basal somatostatin plasma values in antral and corpus tissue were lower in infected patients than in the H. pylori-negative controls at the beginning of the study. A significant increase occurred after successful eradication therapy, together with an increase in the number of D cells in both regions. Changes in the D-cell ultrastructure in antral and corpus mucosa after eradication therapy suggest an increase in somatostatin synthesis and secretion.

The structural and functional restoration of D cells following eradication therapy indicates possible recovery of the diseased mucosa.

As well as causing chronic gastritis, Helicobacter pylori predisposes patients to peptic ulcer disease and gastric cancer, and induces gastric functional disorders. The aim of our study was to investigate the effects of H. pylori eradication therapy on the morphological and functional recovery of gastric antral and corpus D cells in patients with chronic gastritis during 6 months of follow-up.

Forty consecutive, dyspeptic patients referred for endoscopy (31 with H. pylori infection and nine controls; mean age 49 years; 17 men, 23 women) entered the study. All patients had histological signs of gastritis but no signs of peptic ulcer or gastric cancer. Antrum (n=8) and corpus (n=6) biopsy specimens were collected for routine histology, radioimmunoassay tissue somatostatin levels, immunohistochemistry and electron microscopy, prior to and 6 months after therapy. Basal plasma somatostatin levels were determined prior to eradication, plus 6 weeks and 6 months after therapy. Eradication therapy consisted of amoxicillin, metronidazole and omeprazole.

Basal somatostatin plasma values in antral and corpus tissue were lower in infected patients than in the H. pylori-negative controls at the beginning of the study. A significant increase occurred after successful eradication therapy, together with an increase in the number of D cells in both regions. Changes in the D-cell ultrastructure in antral and corpus mucosa after eradication therapy suggest an increase in somatostatin synthesis and secretion.

The structural and functional restoration of D cells following eradication therapy indicates possible recovery of the diseased mucosa.

Tetraspan vesicle membrane proteins (TVPs) are characterized by four transmembrane regions and cytoplasmically located end domains. They are ubiquitous and abundant components of vesicles in most, if not all, cells of multicellular organisms. TVP-containing vesicles shuttle between various membranous compartments and are localized in biosynthetic and endocytotic pathways. Based on gene organization and amino acid sequence similarities TVPs can be grouped into three distinct families that are referred to as physins, gyrins, and secretory carrier-associated membrane proteins (SCAMPs). In mammals synaptophysin, synaptoporin, pantophysin, and mitsugumin29 constitute the physins, synaptogyrin 1-4 the gyrins, and SCAMP1-5 the SCAMPs. Members of each family are cell-type-specifically synthesized resulting in unique patterns of TVP coexpression and subcellular colocalization. TVP orthologs have been identified in most multicellular organisms, including diverse animal and plant species, but have not been detected in unicellular organisms. They are subject to protein modification, most notably to phosphorylation, and are part of multimeric complexes. Experimental evidence is reviewed showing that TVPs contribute to vesicle trafficking and membrane morphogenesis.

Synaptic vesicle protein 2 (SV2) is a glycoprotein identified in the nervous system of several species, including man, but its occurrence in the human neuroendocrine (NE) cell system has not been investigated. By using a monoclonal antibody to SV2, immunoreactivities were demonstrated in NE cell types in human gastrointestinal tract, pancreas, anterior pituitary gland, thyroid, parathyroid, and adrenal medulla, and also in chief cells of gastric oxyntic mucosa. Immunoelectron microscopy of pancreatic islets revealed SV2 immunoreactivity in secretory granules. Comparison of SV2, synaptophysin, and chromogranin A immunoreactivity showed more SV2- and synaptophysin- than chromogranin A-immunoreactive cells in the antrum and pancreas. In the other gastrointestinal regions and in the other endocrine organs more SV2- than synaptophysin-immunoreactive cells were seen. More chromogranin A- than SV2-immunoreactive cells were observed in duodenum, colon, and parathyroid. Various NE tumors were examined and all contained SV2-immunoreactive cells. The staining patterns with the three markers agreed well, except in hindgut carcinoids, which showed strong SV2 immunoreactivity, weak synaptophysin but no chromogranin A immunostaining. In pituitary adenomas more cells were immunoreactive to SV2 than to the other two antibodies. In conclusion, SV2 is recognized as a further broad marker for NE cells and widens the arsenal of diagnostic tools for NE tumors. It is of special importance for identifying hindgut carcinoids.