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Biomedical subjects

I M Modlin

Publications and source records attributed to I M Modlin.

At least 199 records · Page 11Linked to original sources
PubMed1989

"Pseudoascites" secondary to an amylase-producing serous ovarian cystadenoma. A case study.

Large intraabdominal cystic tumors may mimic ascites. In particular, large ovarian cystadenomas may be mistaken for ascites, and when tapped, may contain an elevated cyst fluid amylase. The amylase from ovarian neoplasms, however, is distinguishable from pancreatic or salivary amylase in that it is more acidic in its isoelectric focusing. Additionally, epithelial cells from the tumor do not contain zymogen granules when examined with electron microscopy. We describe what we think is the third reported case of a patient with "pseudoascites" secondary to an amylase-producing serous cystadenoma.

Adult↗
PubMed1989

Prostaglandin E analogue inhibition of pancreatic enzyme secretion.

The effect of native prostaglandins and their methylated analogues on pancreatic enzyme secretion remains unclear, with previous studies reporting inconsistent results. To determine whether the E series prostaglandins directly influence pancreatic secretion, we studied the effect of rioprostil, a prostaglandin E1 analogue, and 16,16-dimethyl prostaglandin E2 (DMPGE2), a prostaglandin E2 analogue, on enzyme release from dispersed guinea pig pancreatic acini. Basal amylase release (4.3 +/- 0.6% of total acinar content) was not altered by either analogue (10(-10)-10(-5) M). A 50% inhibition of maximal cholecystokinin stimulation (10(-9) M; 28.8 +/- 1.2%) was seen with rioprostil (10(-7) M; 14.6 +/- 1.3%) and DMPGE2 (10(-6) M; 15.9 +/- 0.7%) (both p less than 0.005). Prostaglandin inhibition of carbachol-stimulated amylase was less pronounced. The most effective inhibitory dosage with maximal carbachol (10(-5) M; 30.2 +/- 1.9%) was 10(-6) M for both rioprostil (19.2 +/- 1.6%) and DMPGE2 (22.4 +/- 1.7%) (both p less than 0.005). Incubation of acini with A23187, phorbol ester, and 1-oleoyl-2-acetyl-glycerol resulted in a dose-dependent increase in amylase release that was not altered by maximal concentrations of either prostaglandin analogue. Our results indicate that rioprostil and DMPGE2 can directly inhibit pancreatic acinar secretion. This effect appears to occur before activation of the inositol phospholipid system.

16,16-Dimethylprostaglandin E2↗
PubMed1989

Effects of the CCK receptor antagonist L364,718 on pancreatic growth in adult and developing animals.

Although exogenous administration of cholecystokinin (CCK) or dietary manipulation to increase circulating CCK have previously been shown to promote pancreatic growth, the role of CCK in controlling normal pancreatic development remains unclear. A potent CCK receptor antagonist, L364,718, was administered to rats, guinea pigs, and hamsters to block the effect of endogenous CCK. Animals were given continuous infusions of L364,718 (25 nmol.kg-1.h-1), CCK octapeptide [(CCK-8) 200 pmol.kg-1.h-1], or both CCK-8 and L364,718 for 14 and 28 days. Adult (4-mo-old) and young (4-wk-old) animals were used. CCK-8 and L364,718 were administered via separate, subcutaneously implanted mini-osmotic pumps. Infusions of CCK-8 alone for 28 days resulted in a 21.7% increase in wet pancreatic weight in 4-wk-old rats and a 22.7% increase in 4-wk-old guinea pigs (both P less than 0.001 compared with controls). Similar increases were found in DNA, RNA, and total protein contents. Coadministration of L364,718 totally blocked the trophic effects of exogenously infused CCK-8 in rats and guinea pigs. Administration of L364,718 alone in hamsters, guinea pigs, and rats for 14 and 28 days failed to alter the normal growth of the pancreas gland as measured by these parameters. Although elevated levels of CCK appear to promote a potent trophic response in the growing pancreas, this regulatory peptide does not appear to be an essential trophic factor for the normal growth of the exocrine pancreas in these animals.

Aging↗
PubMed1989

Deoxycholate-stimulated release of peptide YY from the isolated perfused rabbit left colon.

The purpose of this study was 1) to measure the effect of graded concentrations of oleic acid and deoxycholic acid (DCA) on the release of peptide YY (PYY) and enteroglucagon and 2) to test whether DCA-stimulated release of PYY was neurally mediated by blocking neuronal conduction with tetrodotoxin. Studies were performed in isolated left colons from New Zealand White rabbits. Oleic acid in concentrations from 0.22 to 22 mM suspended in 10 mM DCA significantly stimulated release of PYY (P less than 0.01) but resulted in no graded response (Bartlett's test, P = 0.15). Similarly, oleic acid (2.2 mM) suspended with ursodeoxycholic acid (10 mM) produced no increased release of PYY above that achieved by ursodeoxycholic acid alone. In contrast, oleic acid (2.2 and 22 mM suspended with 10 mM DCA) produced a graded release of enteroglucagon during the stimulated period. Deoxycholic acid caused a concentration-dependent release of PYY (1, 3.3, 10, and 25 mM) during the stimulated period. Deoxycholic acid (1 and 10 mM) did not significantly increase enteroglucagon release. Tetrodotoxin blockade had no effect on release of PYY stimulated by 10 mM DCA. Because PYY and enteroglucagon are both found in colonic endocrine cells, these results suggest that the release of PYY and enteroglucagon are mediated by specific secretagogues and not simply caused by noxious effects of the agonists. Also, this study has demonstrated that DCA-stimulated release of PYY is not dependent on neuronally mediated mechanisms.

Animals↗
PubMed1989

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↗
PubMed1989

H2-receptor blockade induces peptide YY and enteroglucagon-secreting gastric carcinoids in mastomys.

Gastric carcinoid tumor formation has been reported with prolonged achlorhydria in both animals and human beings. The hypothesis in this study was that the ablation of parietal cell function in an animal (mastomys) genetically predisposed to gastric neuroendocrine neoplasia would promote and accelerate tumor formation. Loxtidine, an irreversible H2-receptor blocker, was administered at 1 mg/kg/day in drinking water for 4 months to young mastomys (n = 16). After 4 months of treatment, 14 of 16 animals had gastric carcinoids compared with 0 of 16 young control animals and 4 of 16 older control animals. Ultrastructurally, these tumors were characterized by the presence of neurosecretory granules. Serum gastrin levels were elevated (230 +/- 40 pmol/L) in loxtidine-treated animals compared with control animals (26 +/- 8 pmol/L) (p less than 0.05). In addition, both peptide YY (620 +/- 160 pmol/L) and enteroglucagon (500 +/- 147 pmol/L) were significantly elevated compared with control groups (p less than 0.05). Similarly, in tumor tissue, peptide YY (676 +/- 152 pmol/gm) and enteroglucagon (551 +/- 164 pmol/gm) were found in large quantities, whereas gastrin was undetectable. These observations provide substantial support for the possible pathophysiologic role of gut peptides, particularly gastrin, in the generation of endocrine neoplasia. The advent of endocrine tumors after inhibition of a gut secretory cell (parietal) may be of considerable significance in understanding the genesis of endocrine neoplasia. Whether the drug acts as a neoplastic promoter of enterochromaffin-like cells or the tumor development is related to elevation of peptides such as gastrin cannot be established in this study. Long-term H2-receptor blockade with new potent, irreversible agents as an alternative to surgery may have potential grave implications that require careful consideration.

Animals↗
PubMed1989

Malignant diathesis from jejunal-ileal carcinoids.

A facet of carcinoid tumors often not recognized is their close association with other, noncarcinoid malignancies. The clinical course of two patients with multiple ileal-jejunal carcinoids and multiple other noncarcinoid malignancies is described. These patients were found to have elevated circulating levels of gastrin, bombesin, glucagon, enteroglucagon, pancreatic polypeptide, and peptide tyrosine tyrosine. These regulatory peptides have been demonstrated to promote trophic effects on the gastrointestinal tract as well as malignant tumors. We propose that the release of these bioactive hormones into the portal and systemic circulation by carcinoid tumors may play some role in their association with these multiple second tumors.

Adolescent↗
PubMed1989

Dopamine and neurotensin storage in colocalized and noncolocalized neuronal populations.

The effects of reserpine on dopamine (DA) and neurotensin (NT) levels were studied in four different brain regions of the rat. Reserpine (0.5-5.0 mg/kg i.p., 6, 18, 48 and 72 hr) produced a dose- and time-dependent decrease in both DA and NT levels in the prefrontal cortex, a brain region innervated by a mixed DA/NT projection. The effect of reserpine was not mimicked by alpha-methylparatyrosine (200 mg/kg i.p.) pretreatment. Furthermore, the reserpine-induced decline in prefrontal cortex DA and NT levels occurred after gamma-butyrolactone (GBL)-induced inhibition of impulse flow (750 mg/kg i.p.). In contrast, in the nucleus accumbens and striatum, regions which contain colocalized (nucleus accumbens) and intrinsic (striatum and nucleus accumbens) neurotensin perikarya, reserpine produced declines in DA and increases in NT levels. alpha-Methylparatyrosine decreased striatal and nucleus accumbens DA levels without altering NT levels in these structures. GBL produced an increase in DA levels in the nucleus accumbens and striatum while decreasing nucleus accumbens and striatal NT levels. Reserpine attenuated the decline in nucleus accumbens and striatal NT levels produced by GBL. In the periaqueductal grey, a brain region densely innervated by NT which has a small population of DA perikarya, reserpine had no effect on NT levels. Because there is no known colocalization of DA and NT in the striatum, the increases in striatal NT levels after depletion of DA may indicate that striatal DA afferents control the release and/or synthesis of NT within NT cells in the striatum, thus leading to alterations in striatal tissue levels.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Butyrolactone↗
PubMed1989

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↗
PubMed1988

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↗
PubMed1988

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↗
PubMed1988

Advanced rectal cancer. What is the best palliation?

The best treatment of advanced rectal cancer remains uncertain. The aim of this study was to determine the outcome after palliative procedures in patients with advanced rectal cancer. One hundred and three patients treated over a seven-year period were identified, including 30 with local invasion, 18 with local metastases, and 55 with distant metastases. Patients were grouped into two groups: those who underwent palliative resection (68) and those who were treated without rectal resection (55). The nonresected group included patients who underwent diverting colostomies (28) and those who received multimodality therapy without surgery (7). The average age of all patients was 63.1 years. Patients in the nonresected group had more distant disease (68 percent) than the resected group (46 percent). Significant pelvic pain was a more common problem in the nonresected group (15 percent) than in the resected group (4 percent). Similarly, pelvic sepsis was more common in the nonresected group (14 percent) than in the resected group (9 percent). Postoperative mortality was 4.3 percent after palliative resection and 3.8 percent after diverting colostomy. Survival of the resected group at one year was 65 percent and at two years 20 percent. Survival of the nonresected group at one year was 20 percent and at two years 0 percent. Survival in the resected group was significantly (P less than .01) better than the nonresected group but probably can be attributed to the more extensive disease generally present in the patients who did not undergo resection. These results suggest that patients with advanced rectal cancers should undergo palliative resection whenever possible because resection decreases pelvic complications and may improve quality of life.

Adult↗
PubMed1988

Dissociation of pepsinogen and acid secretion in the guinea pig.

In vivo observations have suggested that acid secretion may potentiate pepsinogen release. We measured pepsinogen and acid secretion by guinea pig fundic mucosal sheets stimulated by 10(-4) M histamine, 10(-8) and 10(-9) M cholecystokinin, and 3 x 10(-7) M carbamylcholine and then investigated the effects of 10(-4) M omeprazole on basal, carbachol-stimulated, and cholecystokinin-stimulated secretion. Histamine increased basal acid secretion fivefold (p less than 0.01) without altering pepsinogen secretion. Cholecystokinin did not stimulate acid secretion but increased pepsinogen secretion by factors of 23.1 at 10(-8) M and 9.1 at 10(-9) M (both p less than 0.01). The combination of 10(-4) M histamine and 10(-9) M cholecystokinin increased acid secretion 3.5-fold and pepsinogen secretion 6.4-fold, statistically equivalent to the sum of the effects of histamine and cholecystokinin alone. Carbachol increased acid secretion and pepsinogen secretion by factors of 4.0 and 10.9, respectively (both p less than 0.01). Pretreatment with 10(-4) M omeprazole abolished basal and carbachol-stimulated acid secretion. However, pepsinogen secretion was unaffected (p greater than 0.05). Furthermore, omeprazole-treated tissues increased pepsinogen secretion by factors of 10.0 with 3 x 10(-7) M carbachol and 9.1 with 10(-9) M cholecystokinin (both p less than 0.01). Thus, basal and secretagogue-stimulated pepsinogen secretion appear independent of acid secretion in intact guinea pig mucosa.

Animals↗
PubMed1988

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↗
PubMed1988

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↗
PubMed1988

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↗