Cholecystokinin receptor antagonists.
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Animals↗
Biomedical subjects
I M Modlin
Publications and source records attributed to I M Modlin.
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↗
Colonoscopic detection of early colorectal cancers. Impact of a surgical endoscopy service.
The Surgical Endoscopy Service has been aggressively evaluating gastrointestinal symptoms with colonoscopy and screening asymptomatic patients with flexible sigmoidoscopy in hopes of finding early curable colorectal cancers. The purpose of this study was to compare the stages of colorectal cancers resected during the 18-month period prior to (Pre-SES) and during the first 18 months (Post-SES) after the creation of the Surgical Endoscopy Service. In addition, the yield of lesions that would have been obtained by depending upon patient symptoms or occult blood testing were determined. A total of 361 colonoscopies were performed Pre-SES and 874 colonoscopies Post-SES; 26 patients underwent resection of colorectal cancers Pre-SES and 32 Post-SES. Whereas early colorectal cancers (Dukes' A and B1) were found in only three patients (12%) Pre-SES period, early cancers were found in 13 (41%) Post-SES. Doubling the number of colonoscopies produced a fourfold increase in the number of early lesions. Furthermore, disseminated cancers (D lesions) dropped from 19% Pre-SES to 3% Post-SES. Among the total 58 patients, 43% of the A lesions and 40% of the B1 lesions were asymptomatic. Even more alarming, 86% of the A lesions, 50% of the B1 lesions, 31% of the B2 lesions, and 14% of the C2 lesions were occult blood negative. Indeed, only the D lesions were uniformly occult blood positive. This study demonstrates that aggressive colonoscopy detects early colorectal cancers. Moreover, patient symptoms or occult blood testing will fail to indicate the majority of early colorectal cancers.
Aged↗
Bleeding colonic ulcers secondary to atheromatous microemboli after left heart catheterization.
Atheromicroembolism after aortic or cardiac catheterization is frequently found at autopsy but rarely recognized in life, perhaps because many cases are asymptomatic. We report two patients who, after left heart catheterization, developed gastrointestinal hemorrhage from a solitary colonic ulcer caused by occlusive atheromicroemboli in submucosal vessels. We briefly review the spectrum and pathogenesis of atheromicroembolic injury to the gastrointestinal tract. Atheromicroemboli, which occlude vessels too small to be visualized by angiography, should be considered in the differential diagnosis of gastrointestinal bleeding in patients who have undergone aortic instrumentation.
Aged↗
Prostaglandin E analogue inhibition of intrinsic factor release.
In many mammalian species (including humans) the parietal cell secretes both acid and intrinsic factor (IF). The aim of this study was to examine the direct effect of prostaglandin E analogues on basal and stimulated IF release in isolated, enriched rabbit parietal cells. The effects of graded concentrations (10(-12) to 10(-6) M) of 16,16-dimethyl prostaglandin E2 (DMPGE2) and 16-methyl,16-hydroxyl prostaglandin E1 (misoprostol) on submaximal histamine-stimulated (10(-6) M) secretion were tested. Both analogues failed to alter basal release of IF or aminopyrine accumulation (indirect measure of acid secretion). Increasing concentrations of DMPGE2 resulted in a dose-dependent inhibition of IF release (22 +/- 8% decrease at 10(-9) M; p less than 0.05) and a maximal effective response at 10(-7) M (54 +/- 9%; p less than 0.005). Dose-dependent inhibition of IF secretion was also observed with increasing concentrations of misoprostol, with a 22 +/- 7% decrease at 10(-9) M (p less than 0.05) and maximal effective inhibition at 10(-6) M (47 +/- 8%; p less than 0.01). Misoprostol and DMPGE2 inhibition of acid secretion paralleled IF release. Prostaglandin analogues appear to block IF release potently in histamine-stimulated parietal cells.
Alprostadil↗
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↗
Gastric cancer in Connecticut: outlook for improved survival.
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Adenocarcinoma↗
Postoperative follow-up for colorectal cancer: who are we kidding?
The results of treatment of colorectal cancer have improved little over the last 40 years. This reflects both the advanced age of the patients and the advanced stage of the disease at diagnosis. Currently, extensive multimodality, periodic evaluation of patients is advocated following potentially curative resections in the hope that colorectal cancer recurrence will be identified when metastases are isolated and curable. Such efforts, however, have failed to make any substantial impact on survival. At this time, the identification of colorectal cancer at an earlier than usual stage appears to be the only means by which survival can be improved. Despite this, substantially more effort and resources are devoted to the postoperative follow-up of patients with colorectal cancer than to the identification of early curable colorectal cancer. In the current economic climate and with limited medical resources, it may be more appropriate to aim primarily at identifying early curable lesions by more routine colonscopy.
Antineoplastic Combined Chemotherapy Protocols↗
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↗
A novel protein kinase activity in rabbit gastric gland cytosol.
A novel protein kinase activity was characterized from the cytosolic fraction of isolated rabbit gastric glands. The kinase phosphorylated a major 33,000 Da endogenous protein (pp33) and was stimulated by Zn2+ and Mn2+ with Kact of 1.0 and 7.5 mM, respectively. Mg2+ and Ca2+ failed to stimulate any pp33 kinase activity. The kinase utilized both ATP and GTP as phosphate donors with a Km of 10 microM for both. The pp33 protein displayed an isoelectric point of 7.5 to 7.8 and was phosphorylated predominantly on threonine residues. The kinase activity is clearly differentiable from all reported kinase activities and appeared to be enriched in rabbit gastric fundic mucosa. The results indicate that gastric fundic mucosa contains a novel protein kinase activity.
Animals↗
Percutaneous angioplasty for peripheral arterial occlusive disease. Correlates of clinical success.
We reviewed 142 percutaneous transluminal angioplasties (PTAs) in the iliac (n = 94) and femoropopliteal (n = 48) positions of 107 patients. Emphasis was placed on the ultimate clinical outcome, which was determined from a pool of clinical, hemodynamic, and angiographic data. Limb-threatening ischemia was the indication for intervention in 53% of the cases. The median follow-up interval was 17 months. Overall success was achieved in 50% of cases in both iliac and femoral positions at one year after PTA. The following factors were found to correlate with a successful clinical outcome: PTA for claudication vs limb-threatening ischemia (P less than .001); focal as opposed to diffuse stenosis or occlusion (P less than .02); immediate return of distal pulses (P less than .001); the absence of diabetes (P less than .05); and the presence of a patent outflow tract (P less than .001). Treatment results with PTA will vary widely according to the nature of the patient population and the criteria for determining success.
Aged↗
Role of endoscopy in the diagnosis of early gastric cancer.
Early gastric cancer (EGC) is characterized by tumor invasion limited to the submucosa, with or without regional lymph node involvement, and five-year survival rates in excess of 90%. Although infrequently reported in the United States, EGC represents 35% of gastric cancers in Japan. A retrospective analysis of all patients with gastric cancer (1972 through 1985) was performed to determine the frequency and most efficacious diagnostic modalities in this group of patients. Early gastric cancer was identified in 6% (17/302) of all these patients and in 28% (17/61) of patients undergoing curative resection. A review of presenting historical, physical, laboratory, radiologic, and endoscopic findings identified fiberoptic endoscopy as the most sensitive diagnostic procedure. Increased use of endoscopy in patients with persistent nonspecific gastrointestinal tract complaints may increase the number of patients seen with EGC.
Aged↗
The role of flexible sigmoidoscopy in the preoperative screening of patients with inguinal hernia. A high yield of neoplasms.
Disagreement persists as to whether all patients with inguinal hernia should undergo screening examinations for colorectal cancers before hernia repair. The purpose of this study was to prospectively evaluate the effectiveness of flexible sigmoidoscopy (FS) as a screening examination for these patients. In an 18-month period, 110 patients with inguinal hernia (99% men) with an average age of 63 +/- 10 years underwent FS. Diverticulosis was found in 36% of the patients, colorectal polyps in 26%, and colorectal cancers in 3.6%. Occult blood was found in the stool of only 11% of these patients and, thus, was an ineffective screening test. These results suggest that FS is an effective means of screening for premalignant and malignant colorectal lesions in patients with inguinal hernias.
Colonic Neoplasms↗
Screening for colorectal neoplasms. A comparison of the fecal occult blood test and endoscopic examination.
Testing for occult blood in stool is used frequently as a screening technique for colorectal carcinomas, but no study has ever shown an improved survival rate for colorectal carcinoma in patients screened by this method. Consequently, the authors have prospectively compared the sensitivity of endoscopy and occult blood testing in finding colorectal neoplasms. During the first year of the Surgical Endoscopy Service, 585 patients underwent sigmoidoscopy or colonoscopy. Seventy-nine patients (13.5 percent) were excluded from the study because their occult blood status was not recorded. Patients averaged 63 + 10 years of age and 98 percent were men. Of the 348 patients with occult blood negative stools 55.5 percent underwent colonoscopy and 44.5 percent underwent sigmoidoscopy. Polyps were found in 25.6 percent of these patients, colorectal carcinomas in 2.6 percent, and diverticulosis 36.2 percent. Of the 158 patients with occult blood positive stool, 76.5 percent underwent colonoscopy and 23.4 percent underwent sigmoidoscopy. Polyps were discovered in 39.0 percent of these patients, colorectal carcinomas in 10.1 percent, and diverticulosis in 43.0 percent. Thus, the occult blood test was negative in 59 percent of patients with polyps and 36 percent with colorectal cancers. These data indicate that lower gastrointestinal endoscopy is superior to occult blood testing in detecting colorectal neoplasms. These results further suggest that using the occult blood test as a screening test for colorectal neoplasms will result in a significant number of these lesions being missed at an early curable stage.
Aged↗
Superior mesenteric artery syndrome following ileal J-pouch anal anastomosis. An iatrogenic cause of early postoperative obstruction.
This is the first case report of the superior mesenteric artery syndrome developing in a patient following total proctocolectomy and ileal J-pouch anal anastomosis. In addition, this is the first demonstration of this syndrome using abdominal CT scan. A 22-year-old veteran underwent total proctocolectomy for left-sided ulcerative colitis because of failure of medical therapy. At operation an ileal J-pouch anal anastomosis was constructed. Following operation, the patient developed an intestinal obstruction. Abdominal CT scan demonstrated scant retroperitoneal fatty tissue, massive dilatation of the duodenum proximal to the midline, and tapered narrowing of the duodenum between the superior mesenteric artery and aorta. These findings indicated superior mesenteric artery syndrome: arteriomesenteric obstruction of the duodenum. Based on the experience of this case, the authors believe that compression of the duodenum by the superior mesenteric artery may be a common but unsuspected cause of prolonged postoperative ileus or early postoperative obstruction following ileal pouch anal anastomosis.
Adult↗
Prostaglandin inhibition of acid is cAMP dependent.
Prostaglandin E (PGE) potently inhibits acid secretion stimulated by histamine, but not by acetylcholine or gastrin, and is accompanied by decreased intracellular cAMP. Adenylate cyclase receptor systems are composed of three complex proteins: cell receptor, nucleotide binding protein, and the catalytic subunit. The exact mechanism of PGE interaction with this complex remains unclear and elucidation of this site of action is the purpose of this study. We utilized molecular probes directed at the various components of adenylate cyclase. Cholera toxin alters the stimulatory subunit of the nucleotide binding proteins (Ns), rendering it resistant to normal deactivation, whereas N-ethylmaleimide (NEM) blocks the inhibitory subunit (Ni). Forskolin acts as a direct activator of the catalytic subunit of adenylate cyclase and 8-bromo-cAMP acts as a cyclic AMP mimetic. We measured in vitro acid secretion in isolated parietal cells by the assessment of [14C]aminopyrine (AP) accumulation. The PGE1 analog (miso) and the PGE2 analog (DMPG) were incubated in graded doses (10(-11) to 10(-6) M) with histamine (10(-6) M). Miso (10(-7) M) reduced AP accumulation to 21 +/- 8% of histamine alone (100%) and DMPG (10(-6) M) reduced AP to 61 +/- 9% (P less than 0.005 for both). AP accumulation stimulated by 8-Br-cAMP (10(-6) M) and forskolin (10(-6) M) was not significantly affected by either PGE analog (P greater than 0.05) suggesting that the site of PGE interaction is proximal to the activation of the catalytic subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
8-Bromo Cyclic Adenosine Monophosphate↗
Somatostatin and analogs lack splanchnic vasoconstrictive effects in anesthetized pigs.
Due to an apparently selective vasoconstrictive effect on the splanchnic circulation, somatostatin (SRIF) has been advocated for the treatment of variceal hemorrhage. The present study was designed to compare and contrast the systemic and splanchnic hemodynamic effects of SRIF and two of its long-acting analogs (SMS 201,995 and L 363,568) with those of Pitressin. Anesthetized pigs were subjected to laparotomy for placement of an electromagnetic flowmeter on the main trunk of the superior mesenteric artery (SMA). Systemic hemodynamic parameters of arterial blood pressure and cardiac output were monitored with thermodilution catheters. Portal venous blood was collected for measurement of plasma levels of SMS 201,995 and L 363,568 and for determination of gastrin levels during infusion of the latter analog. Experimental drugs were administered via an aortic cannula in a range (5-10 mg/kg bolus and 5-10 mg/kg/min continuous infusion) of dosages. At the higher dosages, SRIF, SMS 201,995, and L 363,568 decreased SMA blood flow (mean% +/- SD) 5.6 +/- 2.2, 1.6 +/- 4.4, and 8.0 +/- 3.8 after 10 min. None of the values achieved significance when compared to variation in baseline determinations. Pitressin (0.25 units, intravenously) produced a consistent and highly significant (P less than 0.001) reduction-in SMA flow after 5 min. Pharmacologic levels of SMS 201,995 and L 363,568 were reliably achieved in portal blood and the latter produced significant reduction (P less than 0.05) in portal venous levels of gastrin. SRIF and its long-acting analogs produced no significant splanchnic nor systemic hemodynamic effects in this model.
Anesthesia↗
A specific histamine-stimulated phosphoprotein in isolated parietal cells.
Histamine-stimulated phosphorylation was studied in isolated rabbit parietal cells. Secretion of acid, as assessed by aminopyrine uptake, was linear at 15 min of stimulation with histamine. By utilizing two dimensional gels, a specific 30,000-Da protein (pp30) was identified whose phosphorylation was prominently stimulated by histamine after 15 min of incubation. The pp30 protein displayed an isoelectric point of 6.0. Furthermore, cAMP-dependent pp30 phosphorylation could also be demonstrated in vitro in a preparation of parietal cell cytosol. The results suggest that pp30 may represent an important histamine-stimulated cAMP-dependent phosphoprotein involved in the initiation or maintenance of parietal cell secretion.
Aminopyrine↗