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Biomedical subjects

M J Zdon

Publications and source records attributed to M J Zdon.

At least 19 recordsLinked to original sources

Follicular neoplasms of the thyroid: predictors of malignancy?

Follicular neoplasms of the thyroid present a therapeutic challenge. Initial limited thyroidectomy may result in some patients requiring completion thyroidectomy for malignancy. In the current study we examined age, gender, race, time from nodule discovery to operation in months, history of radiation exposure, tumor size (cm), and cell type in patients with follicular neoplasms identified at the time of thyroidectomy in two socioeconomically diverse settings from 1993 through 2000 to identify possible factors associated with a greater chance of malignancy. Of 36 follicular lesions identified in 35 patients seven (19%) were malignant on permanent section. Hurthle cell histology was present in six of 36 lesions. Mean age of patients with benign lesions was 47 +/- 13 versus 50 +/- 15 in malignant cases (P > 0.05). Benign lesions measured 2.6 +/- 1.2 cm versus 3.1 +/- 1.7 cm in malignant (P > 0.05). Other factors found not to be significant included gender and time nodule was present (12.8 +/- 19 months benign vs 11.8 +/- 20 months malignant) (P > 0.05). Hurthle cell histology was associated with a 50 per cent malignancy rate (three of six) versus 13 per cent (four of 30) with non-Hurthle cell histology (P < 0.05). Two patients with exposure to radiation fallout had malignancies in lesions of one and 2 cm (P < 0.05). Patients from a socioeconomically disadvantaged setting had a malignancy rate of 50 per cent (six of 12) compared with a malignancy rate of 3 per cent (one of 24) from a socioeconomically affluent population (P < 0.05). In conclusion Hurthle cell histology and exposure to radiation fallout were associated with significantly higher rates of malignancy in follicular neoplasms and should be taken into account when deciding on the initial extent of thyroidectomy. The difference in malignancy rates observed between socioeconomic settings while significant requires further investigation.

Adolescent↗

Update on colorectal cancer.

An estimated 129,400 new cases of colorectal cancer occurred in the United States during 1999. The lifetime risk of developing this cancer is 2.5 to 5 percent in the general population but two to three times higher in persons who have a first-degree relative with colon cancer or an adenomatous polyp. Between 70 and 90 percent of colorectal cancers arise from adenomatous polyps, whereas only 10 to 30 percent arise from sessile adenomas. Tumors or polyps that develop proximal to the splenic flexure carry a poorer prognosis than those that arise more distally, in part because of delayed diagnosis secondary to later development of symptoms. The Dukes system is the classic staging method for colorectal cancer; the TNM staging system is more detailed and therefore more useful for surgical purposes. Although screening guidelines vary, most agree that colorectal cancer screening should begin at 50 years of age in patients without a personal or family history of colorectal cancer.

Algorithms↗

Decreased parietal cell acid secretion after vagotomy is not associated with altered gastric prostaglandin levels.

In a previous investigation we demonstrated that after vagotomy there is a decreased ability of parietal cells to use intracellular cyclic adenosine monophosphate (cAMP). Prostaglandins are present in gastric mucosa and have been demonstrated to be inhibitors of in vivo and in vitro acid secretion through a cAMP-mediated mechanism. In the present study we have examined in vitro acid secretion and prostaglandin E2 levels in rabbits 8 weeks after vagotomy and pyloroplasty compared with control animals to investigate the possible role of prostaglandins in postvagotomy-impaired cAMP use. In vitro acid secretion was assessed in isolated gastric glands by 14C-labeled aminopyrine uptake and prostaglandin E2-generating capacity measured by high-pressure liquid chromatography. After vagotomy, there was a decrease in basal aminopyrine uptake (p less than 0.05), as well as that simulated by histamine and 8-bromo-cAMP (p less than 0.007). No differences were observed in prostaglandin E2 levels in either gastric glands or intact fundic mucosa (p greater than 0.5). These data suggest that impaired cAMP use observed in parietal cells after vagotomy is not the result of alterations in gastric prostaglandin levels.

Aminopyrine↗

Hyperparathyroidism and cellular mechanisms of gastric acid secretion.

Patients with hyperparathyroidism appear to be a particular risk for peptic ulcer disease. To test the hypothesis that hypercalcemia or parathyroid hormone plays a role in promoting ulcer disease, we studied the effect of varying concentrations of extracellular calcium on acid secretion using in vitro isolated rabbit gastric glands. Acid secretion was assessed by the accumulation of carbon 14-labeled aminopyrine (14C-AP). Glands were incubated with varying calcium concentrations in the unstimulated state and with histamine or carbachol (10(-7) to 10(-4) mol/L) in 1 or 2 mmol/L calcium medium. The effect of parathyroid hormone was also examined under identical conditions. Compared to 1 mmol/L standard calcium medium, unstimulated 14C-AP accumulation was significantly inhibited (p less than 0.05) at both lower (0.33 mmol/L) and higher (2 and 2.5 mmol/L) calcium concentrations. Accumulation of 14C-AP in response to histamine stimulation was unaffected by alteration of extracellular calcium (p greater than 0.2). Carbachol-stimulated 14C-AP accumulation was significantly augmented (p less than 0.01) by an increase in calcium concentration from 1 to 2 mmol/L. The addition of parathyroid hormone (10(-7) to 10(-4) mmol/L) alone or in combination with carbachol or histamine (10(-6) mmol/L) incubation did not alter 14C-AP accumulation. These data suggest that elevations in extracellular calcium play an active role in the potentiation of cholinergic-mediated gastric gland acid secretion and may thereby play a role in hyperparathyroid-related ulcer disease.

Aminopyrine↗

A micromethod for the assay of cellular secretory physiology: application to rabbit parietal cells.

A micromethod for investigating secretory physiology in isolated cells was evaluated. The method utilized a specially designed polycarbonate incubation chamber to provide constant oxygenation to cells incubating in a 96-well microtiter plate. Cells were rapidly separated from media by vacuum filtration. Isolated parietal cells were utilized to demonstrate the versatility of the method for assay of intracellular accumulation of [14C]-aminopyrine, secretion of intrinsic factor into the medium, and assay of intracellular cAMP. Histamine stimulated the uptake of [14C]aminopyrine and intrinsic factor secretion in a sustained and linear fashion. At the end of the 2-h period uptake of aminopyrine and secretion of intrinsic factor were increased 17- and 5-fold, respectively. This response to histamine was accompanied by a rapid and sustained 3-fold rise in intracellular cyclic AMP. In contrast, carbamylcholine caused a transient increase in [14C]aminopyrine accumulation and intrinsic factor secretion which was most pronounced during the first 10 min and had almost ceased by 30 min. Carbamylcholine had no effect on intracellular cAMP levels. This new method, which can handle 400 replicates using parietal cells from the fundic mucosa of a single rabbit, is suitable for studying the time course of intracellular events which accompany general secretory processes.

Aminopyrine↗

cAMP- and calcium-mediated modulation of intrinsic factor secretion in isolated rabbit gastric glands.

We have studied the role of cAMP-mediated and calcium-mediated secretagogues in stimulating secretion of intrinsic factor (IF) from parietal cells in isolated rabbit gastric glands. The magnitudes of IF release caused by maximally stimulating doses of the following agents were compared: histamine (5 x 10(-5) M), forskolin (10(-5) M), 8-bromo-cAMP (10(-3) M), pentagastrin (10(-7) M), carbachol (10(-5) M), and the calcium ionophore A23187 (10(-3) M). Each agent was tested simultaneously in gastric glands prepared from the same animal so as to minimize the effects of variations between preparations. Gastric glands were incubated 30 min alone (unstimulated) or with each of the secretagogues. IF release into the culture medium was measured using an assay based on the binding of IF to 57Co-cyanocobalamin. Results were expressed as percentages IF release above unstimulated levels. Three cAMP-mediated agents significantly (P less than 0.05) stimulated IF secretion above unstimulated levels: histamine (439 +/- 33%), forskolin (769 +/- 385%), and 8-bromo-cAMP (1483 +/- 362%). Two agents thought to act through calcium-dependent mechanisms significantly (P less than 0.05) stimulated IF release: carbachol (79 +/- 25%) and pentagastrin (16 +/- 6%). A23187 did not increase IF release above unstimulated levels (P greater than 0.05). In this study, cAMP-mediated secretagogues stimulated significantly (P less than 0.05) more IF release than carbachol or pentagastrin. This study supports the hypothesis that both cAMP- and calcium-mediated mechanisms participate in regulating IF release.

8-Bromo Cyclic Adenosine Monophosphate↗

Decreased parietal cell secretory capacity following vagotomy and pyloroplasty.

Although vagotomy reduces acid secretion in vivo, the effects of vagotomy at the level of the parietal cell are not known. In the present study we examined the in vitro secretory characteristics of parietal cells in rabbits 8 weeks following vagotomy compared to unoperated and sham-operated controls. Acid secretion was assessed by the uptake of [14C]aminopyrine (AP) in isolated gastric glands. Also, gastric fundus histology, mucosal thickness, parietal cell density, and gastric gland somatostatin content were examined. Basal AP uptake was decreased following vagotomy (8 +/- 0.4 pmole/mg dry wt) compared to controls (21 +/- 2) (P less than 0.001). Increase in AP uptake by the cholinergic agonist carbachol was unaffected after vagotomy (P greater than 0.5) suggesting intact muscarinic receptors and calcium second messenger system. Increase in AP uptake was significantly reduced following vagotomy by the cyclic AMP-mediated agonist histamine (P less than 0.05) and the cyclic AMP mimetic 8-bromo cyclic AMP (P less than 0.001) suggesting an alteration in the ability of the parietal cell to utilize cAMP following vagotomy. There were no discernible differences in histology, mucosal thickness, or parietal cell number in vagotomized animals compared to controls (P greater than 0.5). There was a significant increase in gastric gland somatostatin content following vagotomy (37 +/- 10 fmole/mg dry wt) compared to control (14 +/- 1.5) (P = 0.025). These results suggest that there is a decrease in the capacity of parietal cells to secrete acid following vagotomy. In addition, the decrease in cAMP utilization following vagotomy suggests that the cAMP second messenger system is dependent, at least in part, on an intact vagus nerve.

8-Bromo Cyclic Adenosine Monophosphate↗

Hypergastrinemia after vagotomy is not associated with decreased gastric somatostatin.

Although hypergastrinemia occurs after vagotomy, the mechanisms responsible are not understood. Somatostatin (SRIF) is a peptide that inhibits gastrin release, is present within the gastric fundus and antrum, and is under vagal control. In this study we have investigated the hypothesis that hypergastrinemia is associated with a decrease in gastric SRIF. We examined tissue levels of SRIF in gastric mucosa and muscle wall in rabbits undergoing vagotomy and pyloroplasty compared with sham-operated controls. We also compared the release of SRIF from gastric glands in response to vasoactive intestinal peptide and calcitonin gene-related peptide. Vagotomy resulted in an increase in gastrin compared with controls in both antrum (1062 +/- 176 pmol/gm vs 484 +/- 48 pmol/gm) and plasma (236 +/- 72 pmol/L vs 29 +/- 4 pmol/L; p less than 0.05). This was accompanied by an increase in the number of gastrin cells (25 +/- 4 vs 9 +/- 3; p less than 0.05). No significant differences were observed in gastric SRIF levels in either the fundus or antrum (p greater than 0.5). In addition, there were no differences in the release of SRIF from gastric glands of vagotomized animals compared with controls in response to vasoactive intestinal peptide and calcitonin gene-related peptide (p greater than 0.5). These data suggest that the elevations in plasma and antral gastrin levels after vagotomy are not a result of alterations in gastric SRIF.

Animals↗

Detection of early gastric cancer in an aggressive endoscopy unit.

Early Gastric Cancer (EGC) is defined as tumor invasion limited to the mucosa and submucosa, irrespective of regional lymph node involvement. These patients have five-year survival rates in excess of 90 per cent. Although frequently seen in Japan, the detection of ECG remains uncommon in the United States. Twenty-two patients with EGC over a 15-year period were reviewed. EGC was identified in 0.5 per cent (1/207) of all gastric cancers before the widespread use of endoscopy (1972-1979) in our institution and in 16.5 per cent (21/127) of such patients after endoscopy began to replace barium contrast studies (1980-1987). Radiographic studies were performed initially in 14 out of 22 patients with EGC, and in ten patients were reported as normal. Endoscopy was used to make the diagnosis of EGC in 21 of 22 patients. Nineteen of the 22 patients are currently alive and free of disease (86%) with a mean follow-up of 3.4 years (range 6 months to 12 years). Our experience has paralleled that of the Japanese in that, with the adoption of fiberoptic endoscopy as the first-line diagnostic modality in patients with GI complaints, the detection of EGC has significantly increased.

Adult↗

Identification and characterization of a cytosolic 30 kDa histamine stimulated phosphoprotein in parietal cell cytosol.

Histamine stimulated acid secretion is mediated by an increase in intracellular cAMP. Cytosolic protein phosphorylation stimulated by histamine was investigated in isolated rabbit parietal cells. Histamine stimulated the phosphorylation of a 30 kDa phosphoprotein with an isoelectric point of 5.6. Cimetidine completely inhibited histamine-stimulated pp30 phosphorylation. However, omeprazole had no effect on the phosphorylation of pp30. Forskolin and 8-bromo-cAMP also stimulated the phosphorylation of pp30. The results suggest that pp30 is a histamine-stimulated, cAMP-dependently phosphorylated protein substrate in parietal cell cytosol.

Animals↗

Pepsin release by prostaglandin E1 analogue. A potential therapeutic problem.

Prostaglandins Inhibit gastric acid secretion and are independently "cytoprotective" for gastric mucosa. They are currently under clinical Investigation for the treatment of peptic ulcers. The effects of the prostaglandin E1 analogue misoprostol on pepsinogen and acid secretion were tested in isolated rabbit gastric glands and enriched parietal cells. Pepsinogen concentrations were measured by iodine 125-labeled albumin digestion and acid secretion indirectly by carbon 14-tagged aminopyrine uptake. Misoprostol inhibited histamine-stimulated acid secretion in parietal cells with 50% inhibition at 10(-9) mol/L and maximally (78% inhibition) at 10(-7) mol/L. In contrast, however, misoprostol strongly stimulated pepsinogen secretion by gastric glands with a half-maximal effect at 10(-8) mol/L and maximal stimulation of 227% at 10(-6) mol/L. It is possible that this release of pepsin could compromise the action of prostaglandins in promoting ulcer healing.

Alprostadil↗

Characteristics of the spontaneous gastric endocrine tumor of mastomys.

Mastomys is a rodent which has been reported to develop spontaneous antral endocrine tumors with acid hypersecretion and duodenal ulceration. This study documents the establishment of a breeding colony and the characterization of the tumors and their possible secretagogues. Parietal cell secretory characteristics were studied using isolated gastric glands (IGG) of both normal (n = 5) and tumor-bearing animals. Tumors (n = 6) and control gastric tissue samples were examined by light transmission microscopy and immunohistochemistry. Gastrin was measured by radioimmunoassay in both plasma and tissue. IGG were prepared by collagenase dispersion and acid sequestration assessed by [14C]AP accumulation. Secretory mechanisms of this species were identified by establishment of a histamine dose-response curve and use of 8-bromo-cAMP. Receptor and proton pump inhibitions were assessed using cimetidine (10(-5)M) and the H/K ATPase inhibitor omeprazole (10(-5]. Both reduced [14C]AP accumulation significantly (P less than 0.05). 8-Bromo-cAMP and histamine significantly stimulated [14C]AP accumulation (P less than 0.05). Although parietal cells were substantially increased in tumor animals as compared to controls, the physiological parameters of acid secretion appeared normal in both and were comparable to other species which have been studied. Tumors were Grimelius positive and contained diffuse electron-dense granules. Immunohistochemistry was negative for gastrin, bombesin, serotonin, neuron-specific enolase, calcitonin, and pancreatic polypeptide. Tumor histamine-like immunoreactivity was, however, positive. Normal stomach contained 1001 +/- 185 compared to less than 0.5 pmole/g gastrin in tumors. Plasma gastrin was normal in both groups (29 +/- 5) as compared to 26 +/- 8 pmole/liter. This study characterizes a spontaneous gastric endocrine tumor which is associated with apparent parietal cell hyperplasia and reports of increased acid secretion and duodenal ulceration. The observations are consistent with the elaboration by the tumor of a nongastrin acid-trophic secretagogue.

Aminopyrine↗

Gastric somatostatin release: evidence for direct mediation by calcitonin gene-related peptide and vasoactive intestinal peptide.

It has previously been demonstrated that somatostatin (SRIF) directly inhibits parietal cell secretion. However, the significance of SRIF as a paracrine agent and mechanisms of local gastric SRIF release are not clear. Vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) are neuropeptides which have been localized in the gastric fundus and have been demonstrated to inhibit gastric acid secretion in vivo. The present study examines the hypothesis that CGRP and VIP act via the release of gastric fundic SRIF. The study utilized rabbit isolated gastric glands prepared by collagenase digestion. Glands were incubated alone, or with 10(-10)-10(-6) M CGRP or 10(-10)-10(-6) M VIP for 30 min. Supernatant SRIF was measured using a specific radioimmunoassay. Unstimulated SRIF release was 101 +/- 16 fmole/ml. CGRP (10(-7) and 10(-6) M) and VIP (10(-7) and 10(-6) M) resulted in significant SRIF release. The maximum release of SRIF by CGRP (506 +/- 113 fmole/ml) was significantly greater than that by VIP (293 +/- 33 fmole/ml) (P less than 0.05). However, both these concentrations of SRIF are comparable to the ID50 concentration (4.5 X 10(-10) M) for SRIF inhibition of acid secretion by isolated parietal cells as assessed by [14C]aminopyrine accumulation. These results are consistent with the hypothesis that CGRP and VIP inhibition of acid secretion may be mediated, at least in part, by the local release of SRIF from the gastric fundus. These data further support the significance of paracrine interactions in the modulation of cellular secretory function.

Animals↗

Lack of peptide YY immunoreactivity in adenomatous colonic polyps: evidence in favor of an adenoma-carcinoma sequence.

The aim of endoscopic polypectomy is to prevent colorectal cancer, as it is assumed that most, if not all, large bowel cancers are derived from adenomatous polyps. While it is now recognized that colonic endocrine cells, like other mucosal epithelial cells, have an endodermal origin, they are relatively sparse components of large bowel tumors. Peptide YY (PYY) is the most abundant endocrine regulatory peptide localized to the distal bowel. Endocrine cells, like the other cells of the mucosal epithelia, are derived from a common stem cell in the base of the crypts. The presence of endocrine peptides may thus be viewed as a marker for cellular differentiation in the gut. PYY was therefore measured in colonic carcinomas and adenomatous polyps, as its absence would be evidence in favor of genetic alterations in epithelial stem cell maturation. PYY concentrations in extracts of surgically removed colonic carcinomas (n = 22) from all regions were very low compared with those of adjacent normal bowel. Similarly, PYY concentrations in extracts of polyps (n = 39) obtained during endoscopic polypectomy were also very low when compared with those of adjacent normal mucosa. These varied between 1 and 11% of the normal epithelial content, depending upon the region. Low PYY levels appeared to reflect the malignant potential of these lesions: highest in tubular polyps, lower in villous polyps, and lowest in carcinomas. The very low concentrations of PYY in adenomatous polyps, like those of colonic cancer, are consistent with epithelial dysplasia and the incomplete formation of mucosal endocrine cells. These findings support the hypothesis of an adenoma to carcinoma sequence in colonic cancer.

Adenoma↗

Epidermal growth factor (EGF) inhibits both intrinsic factor secretion and acid secretion in histamine-stimulated isolated gastric glands.

Epidermal growth factor (EGF) is a polypeptide present in mammalian salivary glands which has been shown to have mitogenic and gastric acid inhibitory properties in vivo. The mechanisms of action of EGF at the level of the parietal cell are not clear. In the present study, we have examined the effects of EGF on both acid and macromolecular (intrinsic factor, IF) secretion stimulated by the cyclic AMP-mediated agonist histamine using the rabbit isolated gastric gland model. Acid secretion was assessed by the accumulation of [14C]aminopyrine (AP) in glands and IF in the supernatants by the binding of [57Co]cyanocobalamin. Histamine (10(-6) to 5 x 10(-5) M) resulted in a 4-6 fold increase in [14C]AP and IF (P less than 0.05). EGF alone (10(-8) M, 10(-7) M) had no significant effect on basal [14C]AP accumulation or IF secretion (P less than 0.05). EGF (10(-7) M) significantly inhibited the histamine dose-response curve for [14C]AP and IF, but a relatively greater inhibition was observed at higher histamine concentration. These data demonstrate that EGF inhibits both acid and IF secretion in vitro at concentrations consistent with those observed in vivo. The observations further support the hypothesis that EGF may play a role in the regulation of parietal cell secretion.

Aminopyrine↗

Pancreastatin: a novel peptide inhibitor of parietal cell secretion.

Pancreastatin is a recently identified 49-amino-acid peptide found in gastrointestinal tract and gastric mucosa. Its biologic effects on gastric function are unknown. The aim of this study was to determine the effects of pancreastatin [33-49] (the synthetic C-terminal fragment) on acid secretion and somatostatin release in vitro. Isolated rabbit gastric glands were prepared by means of collagenase digestion. Acid secretion was assessed indirectly with use of 14C-aminopyrine (AP) uptake by glands, and somatostatin release from D cells was measured with radioimmunoassay. Pancreastatin alone (10(-10) to 10(-6) mol/L) had no effect on 14C-AP uptake compared with unstimulated glands. In contrast, pancreastatin inhibited with histamine-(10(-6), 10(-5) mol/L; p less than 0.005) and carbachol-(10(-5), 10(-4) mol/L; p less than 0.001) stimulated 14C-AP uptake in a dose-dependent manner. Neither forskolin-(10(-6), 10(-4) mol/L; p greater than 0.50) or 8-Br-cAMP-(10(-5), 10(-4) mol/L; p greater than 0.30) stimulated 14C-AP uptake were influenced by pancreastatin. Pancreastatin had no effect on somatostatin release from glands. These data suggest that pancreastatin probably acts at receptor or membrane level, inhibiting both histamine- and carbachol-stimulated 14C-AP uptake. These effects are not mediated by D cell somatostatin release. It is possible that pancreastatin acts as a paracrine or endocrine inhibitory regulator of parietal cell secretion.

8-Bromo Cyclic Adenosine Monophosphate↗

A calmodulin dependent protein kinase in parietal cells.

An enriched population of isolated rabbit gastric parietal cells, from the fundic mucosa of New Zealand White rabbit, contained an active cytosolic calmodulin-dependent protein kinase activity with a prominent 100 kDa substrate (pp100). The latter focused as a doublet with isoelectric point of 6.8-7.0. The pp100 protein was phosphorylated only on threonine residues on a single tryptic peptide. Trifluoperazine inhibited the pp100 kinase activity with a KI of 10-15 microM. Addition of exogenous calmodulin was able to restore activity to uninhibited levels. A protein band with a molecular weight and phosphopeptide map identical to pp100, phosphorylated by calcium-dependent kinase, was also observed in rabbit pancreatic cytosol. The data suggest that a type III calmodulin-dependent kinase is present in parietal cell cytosol.

Animals↗