Ghrelin expression in hyperplastic and neoplastic proliferations of the enterochromaffin-like (ECL) cells

Ghrelin, a recently discovered peptide isolated from the gastric corpus mucosa, is believed to be important in the regulation of growth hormone secretion and has been shown to increase appetite and food intake as well. It may also have other gastrointestinal and cardiac functions. Because a cell of origin for ghrelin has not been convincingly identified in the gastric mucosa thus far, we studied the immunohistochemical expression of ghrelin in proliferative lesions of the enterochromaffin-like (ECL) cells—a cell that is not only exclusively confined to the gastric corpus mucosa but is its dominant endocrine cell type as well. Formalin-fixed, paraffin embedded tissues from three cases of gastric ECL cell hyperplasia and five ECL carcinoids (three with coexisting foci of diffuse, linear, and micronodular hyperplasia) were immunohistochemically stained for ghrelin, using a commercially available antibody. The Sevier-Munger stain for ECL cells and immunohistochemical stains for chromogranin, gastrin, serotonin, somatostatin, and vesicular monoamine transporter-2 (VMAT-2) were performed on parallel sections for correlation with the ghrelin staining results. All ECL cell carcinoids and hyperplastic lesions were positive for both the Sevier-Munger and the immunohistochemical stains for chromogranin and VMAT-2. Immunoreactivity for ghrelin was seen in 4/5 ECL carcinoids, all cases of ECL cell hyperplasia, as well as in all areas with linear and micronodular hyperplasia adjacent to the ECL cell carcinoids. In each instance, such staining was confined to the Sevier-Munger, and VMAT-2 positive cells only. Our findings indicate that the ECL cells are either the ghrelin-producing cells of the gastric mucosa or acquire the capability to synthesize ghrelin during proliferative states encompassing the entire hyperplasia to neoplasia spectrum. In view of the orexigenic and other known actions of ghrelin, the functional and/or biologic significance of ghrelin production in such ECL cell proliferations needs to be investigated further.     

Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors

The vesicular monoamine transporter 2 (VMAT2) facilitates the ATP-dependent accumulation of biogenic amine inside the secretory granules of endocrine cells and neurons and was demonstrated in the histamine-producing enterochromaffin-like (ECL) cells of the stomach. In the present investigation, VMAT2 immunohistochemistry was tested in 85 endocrine tumors, of which 60 were well differentiated gastrointestinal and pancreatic growths, 5 poorly differentiated (neuro)endocrine carcinomas (PDEC) and 1 mixed PDEC/ECL cell carcinoma of the stomach, 12 pheochromocytomas/paragangliomas, 3 adrenocortical lesions, 2 parathyroid and 2 lung neuroendocrine tumors. Extensive and intense VMAT2 immunoreactivity was observed in 16 of 16 gastric ECL cell tumors, 6 of 6 adrenal pheochromocytomas, 2 of 2 chromaffin paragangliomas and in 3 of the 4 carotid body paragangliomas investigated. Rare VMAT2-positive cells were observed in 12 of 21 intestinal enterochromaffin (EC) cell tumors, in 9 of 11 pancreatic neuroendocrine tumors, and in the mixed PDEC/ ECL cell carcinoma of the stomach (differentiated cells only). No VMAT2 immunoreactivity was observed in five gastrin, four somatostatin and three enteroglucagon/peptideYY tumors of the gastrointestinal tract, in six gastric PDECs, in three adrenocortical growths, and two parathyroid and two lung neuroendocrine tumors. These data support VMAT2 immunohistochemistry as being a useful tool for the diagnosis of gastric ECL cell tumors, separating them from all other endocrine tumors arising in the gastroduodenal area i.e., gastrin, somatostatin, EC cell and PDEC tumors, all of which proved essentially negative. Received: 28 June 1999 / Accepted: 20 October 1999     

两种方法检测血清甲胎蛋白(AFP)的比较

目的对电化学发光免疫法与微粒子酶联免疫法检测血清甲胎蛋白作对比分析.方法随机抽取150份临床送检的标本,用电化学发光免疫法与微粒子酶联免疫法测试甲胎蛋白的含量,对测试数据进行相关性试验、线性试验、精密度试验、回收试验.结果两法无显著性差异(P＞0.05),但电化学发光免疫法的线性范围较宽(1-980ng/ml),重复性较好(批内CV值3.4%,批间CV值3.5%),回收率较高(97.2%).结论电化学发光免疫法检测血清甲胎蛋白优于微粒子酶联免疫法检测血清甲胎蛋白     

Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections

After Helicobacter pylori eradication was introduced and largely eliminated the need for maintenance therapy for peptic ulcer disease, gastroesophageal reflux disease (GERD) became the main indication for prolonged gastric acid inhibition. The drug effect on GERD depends on the degree of acid inhibition, thus the efficacious proton pump inhibitors are preferred. The proton pump inhibitors have few immediate side effects, the main concern being the profound hypoacidity and hypergastrinaemia they induce. In short-term, hypergastrinaemia causes rebound hyperacidity, possibly worsening GERD and reducing the efficacy of histamine H₂ blockers. In the long-term, hypergastrinaemia causes enterochromaffin-like cell hyperplasia and carcinoids. Since enterochromaffin-like cells may be important in gastric carcinogenesis, iatrogenic hypergastrinaemia may predispose to carcinoma. Gastric hypoacidity also increases gut bacterial infections, and the barrier function of acid against viral and prion infections requires further assessment.     

Clinical consequences of controversies in gastric physiology

Abstract

Studies on the regulation of gastric acid secretion started more than 100 years ago at an early phase of experimental physiology. In nearly the whole last century there were disputes about the interpretation of the findings: the interaction between the three principle gastric acid secretagogues acetylcholine, gastrin and histamine, the cell producing the relevant histamine which turned out to be the ECL cell, the ability of the ECL cell to divide and thus develop into tumours, the classification of gastric carcinomas and the mechanism for Helicobacter pylori carcinogenesis. The elucidation of the central role of the ECL cell and thus its main regulator, gastrin, solve all these controversies, and gives a solid base for handling upper gastrointestinal diseases.     

G‐cell hyperplasia of the stomach induces ECL‐cell proliferation in the pyloric glands in a paracrinal manner

An inhibitory mechanism toward gastrin hypersecretion is significantly different between G‐cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G‐cell, d ‐cell and ECL‐cell density in a case of G‐cell hyperplasia. The 70‐year‐old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G‐cells in the pyloric glands was quantified on the surgical specimens and G‐cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL‐cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G‐cell density. Somatostatin immunoreactive cells (d ‐cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G‐cell hyperplasia could induce ECL‐cell proliferation in a paracrinal manner. In addition, relatively non‐prominent endocrinological features in the G‐cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL‐cells in the pyloric glands.     

Advances in understanding the molecular basis of the first steps in color vision

Serving as one of our primary environmental inputs, vision is the most sophisticated sensory system in humans. Here, we present recent findings derived from energetics, genetics and physiology that provide a more advanced understanding of color perception in mammals. Energetics of cis–trans isomerization of 11-cis-retinal accounts for color perception in the narrow region of the electromagnetic spectrum and how human eyes can absorb light in the near infrared (IR) range. Structural homology models of visual pigments reveal complex interactions of the protein moieties with the light sensitive chromophore 11-cis-retinal and that certain color blinding mutations impair secondary structural elements of these G protein-coupled receptors (GPCRs). Finally, we identify unsolved critical aspects of color tuning that require future investigation.     

Gastric Carcinoids of Argyrophil ECL Cells

Histochemical and ultrastructural studies were carried out in four gastric carcinoids, two of which were associated with atrophic gastritis and pernicious anemia. All tumors showed intense argyrophilia and vesicular granules resembling those of endocrine enterochromaffinlike (ECL) cells in normal human gastric mucosa. Tumor cells were found to be unreactive to all the 18 available antiserums to gut hormones, including gastrin, somatostatin, glucagon, and pancreatic polypeptide. The tumors were interpreted as ECL cell argyrophil carcinoids with various degrees of differentiation and atypia.     

Significance of platelet and monocyte activation for therapeutic immunoglobulin-induced thromboembolism

Objectives

Thromboembolic events (TEE) in patients receiving infusions of intravenous immunoglobulin (IVIG) products have recently been associated with contaminating factor XIa. We studied whether platelet and monocyte activation could also be involved.

Methods

Twenty IVIG samples from five manufacturers were tested for the induction of visible whole blood clot formation. A selection of TEE-associated and not associated lots was further analyzed for effects on thromboelastometry, platelet activation and adhesion, as well as monocyte tissue factor surface expression. Pure factor XIa was included for comparison. Western blotting was applied to analyze anti-CD154-reactive proteins in IVIG.

Results

In whole blood, IVIG enhanced macroscopic clotting additively with factor XIa. In monocytes, all IVIG products induced the FcγRII-dependent tissue factor expression to a similar extent, which was not affected by addition of factor XIa. Testing platelet aggregation, IVIG strengthened the ADP and TRAP-6-elicited response. Furthermore, IVIG increased platelet-monocyte adhesion and annexin V binding to platelet microvesicles, and promoted platelet adhesion to IVIG-coated surfaces. The strongest effects were observed with TEE-associated lots. CD154-related proteins were detected in all IVIG products. CD154-related high molecular weight complexes were particularly found in the TEE-associated IVIG. In platelet aggregation, recombinant soluble CD154 enhanced aggregate formation and stability.

Conclusion

Our data demonstrate that IVIG modulate platelet and monocyte activation and can thereby affect the hemostatic balance. These effects are either additive to or independent from factor XIa. CD154-related proteins are assumed to be involved in these interactions, the mechanism of which needs to be elucidated in further studies.