Biomedical subjects
Publications and source records attributed to U Syversen.
Chromogranin A (CgA) is a protein localized to the secretory granules of neuroendocrine cells. Determination of CgA in blood is a useful marker for neoplasia and hyperplasia of neuroendocrine cells. Chromogranin A in serum should be the first test used for detecting carcinoids. It is also useful for diagnosing other neuroendocrine tumours, such as oat-cell carcinoma of the lung, pheochromocytoma and neuroblastoma.
Neuroendocrine (NE) differentiation of prostatic adenocarcinomas has received increasing attention in recent years as a result of possible implications on prognosis and therapy. The incidence of NE cells in tumors has been reported from 10% up to 100%. Several studies have shown chromogranin A (CgA) to be the most reliable serum marker of NE differentiation. We have followed 22 patients with prostatic adenocarcinoma over a 2-year period. The patients underwent a palliative transurethral resection of the prostate (TURP) because of urinary outflow obstruction. The prostatic tissue specimens were stained immunohistochemically using antibodies against CgA, chromogranin B (CgB), neuron-specific enolase (NSE), thyroid-stimulating hormone (TSH), serotonin, and somatostatin. In addition, each specimen was stained with hematoxylin & eosin (H & E), and saffran for tumor grading. Blood samples were taken preoperatively and after 1, 3, 6, and 24 months. The serum values of CgA, CgB, pancreastatin (Pst), NSE, and prostate-specific antigen (PSA) were determined from each sample. Carcinomas with groups of CgA-positive cells had higher serum levels of CgA compared to carcinomas with no or only scattered CgA-positive NE cells. During the 2-year period, there were no statistical significant variations in serum levels of CgA, NSE, Pst, and PSA. However, there was a significant increase in serum levels of CgB during the same period, P = 0.002, possibly due to an increase in number of NE cells in tumor or to a relative increase in production of CgB in the NE cells.
The aim of the present study was to examine the correlation between the immunohistochemical findings and the serum markers for neuroendocrine (NE) cells in patients with carcinoma of the prostate. Preoperative serum values of chromogranin A (CgA), chromogranin B (CgB), pancreastatin (Pst), neuron-specific enolase (NSE), and prostatic specific antigen (PSA) were determined in 22 patients. The tissue specimens were obtained by a palliative transurethral resection of the prostate (TURP) because of urinary outflow obstruction. Immunohistochemistry was performed by using antibodies against CgA, CgB, NSE,.serotonin, thyroid-stimulating hormone (TSH), and somatostatin. Tumor cells with NE differentiation were found in 91% of the cases. No patient had elevated serum values of NSE, despite the presence of NSE-positive tumor cells in 77% of the tumors. Neither did CgB in serum correlate with the immunohistochemical findings. Elevated serum values of CgA were found in 59% of patients. A positive correlation between the number of CgA-staining cells and the serum values of CgA was found, as seven out of eight patients with groups of CgA-positive tumor cells had elevated serum values of CgA. We conclude that CgA, in contrast to NSE, CgB, and Pst, seems to be a useful serum marker in predicting the extent of NE differentiation in prostatic tumors.
BACKGROUND: In contrast with the histamine2 (H2) blockers, proton pump inhibitors have not been shown to give rebound hypersecretion of acid. Taking into consideration the hyperplasia of the enterochromaffin-like (ECL) cell provoked by hypergastrinaemia secondary to profound acid inhibition and the central role of histamine from ECL cells in the regulation of acid secretion, the lack of any rebound acid hypersecretion after treatment with proton pump inhibitors has been questioned. AIMS: To reassess the effect of treatment with omeprazole on post-treatment acid secretion. METHODS AND PATIENTS: Basal and pentagastrin stimulated acid secretion were determined in nine patients with reflux oesophagitis before and 14 days after termination of a 90 day treatment period with the proton pump inhibitor omeprazole (40 mg daily). Basal gastrin release were determined before and during omeprazole treatment. Furthermore, biopsy samples from the oxyntic mucosa were taken before and at the end of the treatment period for chemical (histamine and chromogranin A (CgA)) evaluation of the ECL cell mass. RESULTS: A substantial increase in meal stimulated gastrin release during omeprazole treatment resulted in an increased ECL cell mass. Furthermore, CgA in serum increased during omeprazole treatment suggesting that serum CgA may be used as a test to evaluate ECL cell hyperplasia. A significant increase in basal and a marked (50%) and significant increase in pentagastrin stimulated acid secretion were found after treatment with omeprazole. CONCLUSIONS: Increased acid secretion after a conventional treatment period with a proton pump inhibitor is probably due to ECL cell hyperplasia and may have negative consequences for acid related diseases.
Placenta is a neuroendocrine organ, and we therefore wanted to study the occurrence of the general neuroendocrine marker chromogranin A (CgA) and its split product pancreastatin. CgA and pancreastatin-like immunoreactivity (PST-LI) were determined by ELISA and RIA methods, respectively, in homogenates from term placentas, sera from pregnant women, nonpregnant women, umbilical cords, and in amniotic fluids. In placental homogenates, the mean level of CgA was 7.1 +/- 8.6 pmol/g wet wt (mean +/- SD), whereas PST-LI was not detectable. CgA immunoreactivity was demonstrated by immunofluorescence studies of isolated trophoblasts and decidual cells from term placentas. In trophoblasts, CgA was colocalized with human chorionic gonadotropin (hCG) and human placental lactogen. By Northern blotting, a distinct band corresponding to CgA messenger RNA (mRNA) was demonstrated in the placental cell line, whereas, in placental homogenates, a mRNA band of a slightly larger size was found. Median CgA level in maternal sera at term tended to be higher (median: 469 pmol/L, range 61-980 pmol/L, P < 0.1) than at 6-11 weeks (286 pmol/L, 61-653 pmol/L) or in sera from nonpregnant women (306 pmol/L, 204-469 pmol/L). In umbilical cord sera, median CgA level was significantly higher (898 pmol/L, 102-2245 pmol/L, P < 0.05) than in term sera. Median serum level of PST-LI was significantly higher at term (38 pmol/L, 0-131 pmol/L) than at 6-11 weeks (9 pmol/L (0-85 pmol/L, P < 0.05), than in nonpregnant women (6 pmol/L, 0-52 pmol/L, P < 0.05), and in umbilical cord sera (12 pmol/L, 0-76 pmol/L, P < 0.05). In amniotic fluid, median CgA value was significantly higher at term (1163 pmol/L, 714-1673 pmol/L) than at 14-17 weeks (551 pmol/L, 82-980 pmol/L, P < 0.01), whereas median level of PST-LI was significantly higher at 14-17 weeks (32 pmol/L, 6-97 pmol/L) than at term (0 pmol/L, 0-15 pmol/L, P < 0.01). To our knowledge, this is the first report describing the presence of CgA and PST-LI in placenta and amniotic fluid and the occurrence CgA mRNA in placental tissue and in a placental cell line. The presence of CgA in placenta may indicate a physiological role in pregnancy.
OBJECTIVE: To evaluate neuroendocrine differentiation in tumours from patients with colorectal carcinomas by immunostaining with antibodies against human chromogranin A (CgA) and neuron-specific enolase (NSE), and to correlate these finding with serum levels of CgA and pancreastatin-like immunoreactivity (PST-LI). We also investigated the degree of neuroendocrine differentiation found in colorectal carcinomas of different embryonic origins (hindgut and midgut). PATIENTS AND METHODS: The presence of CgA and NSE in tumours from 91 patients with colorectal carcinoma was investigated using immunohistochemistry; levels of CgA and PST-LI in sera from 55 of these patients were determined using radioimmunoassays. RESULTS: Immunostaining for CgA and NSE was found in 15 and 36% of tumours, respectively. One or both markers of neuroendocrine differentiation were demonstrated in 40% of the colorectal carcinomas. In patients who died during the study, 23 and 51% expressed CgA and NSE in their tumours, respectively, while the corresponding values in survivors were 11 and 27% (P = 0.14 and P = 0.025, respectively). The median survival time tended to be lower in patients with neuroendocrine differentiation of their tumours than in those without such differentiation (P = 0.1). The expression of NSE was significantly higher in colorectal carcinomas derived from the midgut than in those of hindgut origin. Elevated serum levels of CgA and PST-LI were found in 38 and 43% of the patients, respectively; 62% had elevated levels of one or both markers. Of the patients with elevated serum levels of CgA or PST-LI, 44% had positive immunohistochemistry for either NSE or CgA compared with 29% of those with normal serum levels of CgA and PST-LI (P = 0.27). Serum levels of CgA were increased in a significantly higher percentage of patients with colorectal carcinomas of midgut than of hindgut origin (63 and 28%, respectively, P = 0.03). Of patients with hindgut-derived carcinomas who died during the study, 64% had raised serum values of CgA compared with 19% of those who survived (P = 0.023). The corresponding figures for PST-LI elevation were 75 and 44%, respectively (P = 0.096). In the midgut group, no difference was demonstrated for these parameters between survivors and non-survivors. CONCLUSION: Neuroendocrine differentiation was demonstrated in 40% of the colorectal carcinomas investigated and was more frequent in midgut-derived carcinomas than in those of hindgut origin. We have shown for the first time that serum levels of CgA and PST-LI are elevated in patients with colorectal carcinomas. In accordance with previous studies, our data support the value of neuroendocrine differentiation as an indicator of poor prognosis; they also suggest a role for serum CgA and PST-LI as prognostic markers.
Chromogranin A (CgA) is a useful marker of neuroendocrine tumors in humans. Here we describe and compare two immunoassay methods for determination of CgA, a radioimmunoassay (RIA) and an enzyme linked immunoassay (ELISA). The detection limit of the ELISA was lower than that of the RIA method (2 ng/ml versus 10 ng/ml, respectively), though the CgA RIA method covered a wider range than the CgA ELISA (10-920 ng/ml versus 2-500 ng/ml, respectively). There was no cross-reactivity with synthetic human and porcine pancreastatin (PST) in the two assays. There was a significant positive correlation between levels of CgA in sera from patients with carcinoid disease, measured by the two methods (r = 0.9, p < 0.0001), and the values were in the same range. Similarly, serum CgA levels in normal controls were also in the same range when assayed by the two methods. A commercially available porcine PST RIA method was evaluated, especially with respect to the influence of Sep-Pak extraction of serum on the levels of pancreastatin-like immunoreactivity (PST-LI). Ten sera from carcinoid patients were treated with Sep-Pak extraction, and levels of PST-LI were determined in non-extracted and extracted sera. There was a significant positive correlation between the concentrations of PST-LI measured in extracted and non-extracted carcinoid sera (r = 0.9, p < 0.002), and the levels were in the same range. There was also a significant positive correlation between levels of CgA and PST-LI in 49 carcinoid sera (r = 0.8, p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Bismuth has been used as symptomatic treatment of dyspepsia for many years. It promotes healing of peptic ulcers and reduces their recurrence. The beneficial effect of bismuth on duodenal ulcer disease is thought to be due to an effect on Helicobacter pylori, although it has a rather weak bactericidal effect on H. pylori in vitro. Eradication of H. pylori in duodenal ulcer patients by a combination of bismuth, tetracycline and metronidazole has been reported to increase the density of somatostatin-producing D cells in the antrum. A reduced D cell density in the antral mucosa of duodenal ulcer patients could explain their exaggerated gastrin release. AIMS/METHODS: To test the possibility that bismuth could affect the neuroendocrine cells independently of the presence of H. pylori or not, we gave rats a diluted tripotassium dicitrato bismuthate solution by gastric gavage for 14 days. RESULTS: Tripotassium dicitrato bismuthate treatment did not affect maximal pentagastrin-stimulated acid secretion or histamine release in isolated rat stomachs or the density of argyrophil cells in the oxyntic and antral mucosa. However, it significantly reduced the duodenal concentration of gastrin and calcitonin gene-related peptide, and the density of G cells in the antrum and duodenum. CONCLUSION: The effect of tripotassium dicitrato bismuthate on the G cell may be of significance for its beneficial effect on duodenal ulcer disease.
All vertebrates secrete gastric acid. Acid denatures the proteins in the food and thus makes them more accessible to proteolytic enzymes, and it kills swallowed micro-organisms. Gastric acid plays an important pathogenetic role in peptic ulcer disease and reflux oesophagitis. In these diseases, drugs that inhibit secretion of gastric acid will heal the lesions and suppress the symptoms. However, both reflux oesophagitis and peptic ulcer tend to recur when the acid-inhibitory treatment is stopped. Therefore, these patients often require long-term treatment with acid-inhibitors. In this overview the potential risks of long-term profound inhibition of acid secretion, raising the pH above 4 for a considerable time, resulting in reduced killing of micro-organisms and secondary hypergastrinaemia, are discussed. Gastrin regulates both the function (production and release of histamine) and growth of the enterochromaffin-like (ECL) cell. Hitherto, the role that this cell plays in gastric carcinogenesis appears to have been underestimated.
Histamine has a central role in the regulation of gastric acid secretion. This histamine is produced by and released from the enterochromaffin-like (ECL) cell which accordingly has a key-regulatory role in the oxyntic mucosa. Gastrin and the vagal nerves stimulate the formation and release of histamine from the ECL cell. Moreover, gastrin and the vagal nerves also stimulate the proliferation of the ECL cell. An increased ECL cell density may partly explain the increased acid secretion in patients with duodenal ulcer, particularly in patients with Zollinger-Ellison syndrome. The reduced potency of histamine-2 blockers in patients with Zollinger-Ellison syndrome is probably due to increased histamine release by an elevated ECL cell mass. Prolonged and profound hypergastrinemia may lead to ECLomas. Moreover, a proportion of diffuse gastric carcinomas may originate from ECL cells.
Gastrin and pancreastatin-like immunoreactivity were determined by radioimmunoassay methods and chromogranin A was determined by enzyme-linked immunoassay in sera from 18 patients with gastrinomas (Zollinger-Ellison syndrome) and in 20 age and sex matched controls. Gastrin serum levels in the gastrinoma patients were in the range 26-80,000 pmol/l, and in the controls 5-31 pmol/l. Chromogranin A serum levels in the gastrinoma group were in the range 6-2,700 ng/ml (mean +/- SEM: 400 +/- 147 ng/ml). The mean value of chromogranin A was significantly higher than in the control group (8 +/- 2 ng/ml, p = 0.008). The serum levels of pancreastatin-like immunoreactivity in the gastrinoma patients were in the range 23-1,994 pg/ml (597 +/- 123 pg/ml). The mean value of pancreastatin-like immunoreactivity in the gastrinoma group was significantly higher than in the control group (104 +/- 25 pg/ml, p = 0.0002). The levels of chromogranin A and pancreastatin-like immunoreactivity were significantly higher in patients with verified metastatic disease (p = 0.04, p = 0.01 respectively). There was a significantly positive correlation between levels of gastrin and pancreastatin-like immunoreactivity (r = 0.7, p = 0.002), while no correlation was found between gastrin and chromogranin A levels or between levels of chromogranin A and pancreastatin-like immunoreactivity. The study demonstrates an elevation of both chromogranin A and pancreastatin-like immunoreactivity in serum of gastrinoma patients. The lack of correlation between gastrin and chromogranin A, however, gives an indication that the gastrinoma cells are not the main source of serum chromogranin A elevation.
Chromogranin A (CgA) is a useful probe of human neuroendocrine neoplasia and exocytotic sympathoadrenal activity, but the application of CgA immunoassays has not been widespread because of limited availability of purified human CgA. Here we describe a rapid, high yield isolation of human CgA. After obtaining and lysing pheochromocytoma chromaffin granules, the soluble core proteins (chromogranins) were depleted of dopamine-beta-hydroxylase by passage over a concanavalin A-Sepharose affinity column, then lyophilized, resuspended in volatile buffer, and gel filtered on Sephacryl S-300. SDS-PAGE-analyzed column fractions contained homogeneous human CgA, which was verified structurally (N-terminal amino acid sequence) and immunologically (radioimmunoassay and immunoblot). The overall 22.6 mg yield of purified CgA represented 5.7% of the starting vesicle core protein. This preparation will be useful in evaluating the sympathoadrenal system and endocrine neoplasia in man.
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