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Biomedical subjects

I M Modlin

Publications and source records attributed to I M Modlin.

At least 181 records · Page 10Linked to original sources
PubMed1990

Pepsinogen release and acid secretion from human and guinea pig gastric mucosa compromised by hypoxia, endotoxin, or critical illness.

Despite blockade and neutralization of gastric acid, acute gastric lesions cause substantial morbidity and mortality in critically ill patients. Pepsinogen release in response to noxious stimuli such as hypoxia and endotoxin might contribute to mucosal damage. Guinea pig fundic mucosa was mounted in Ussing chambers. Acid secretion, pepsinogen release, potential difference (PD), and resistance were monitored. Gassing with room air or nitrogen diminished acid secretion and PD but increased pepsinogen release 9.7- and 15.5-fold, respectively (both p less than 0.001). Similarly, endotoxin (0.01 and 0.1 units/ml) dose-dependently inhibited acid secretion and PD but increased pepsinogen release 3.3- and 6.1-fold (both p less than 0.05). Endotoxic and air-gassed tissues were edematous with scattered cellular damage by light and transmission electron microscopy; nitrogen-exposed membranes appeared necrotic. Pepsin release may therefore have resulted from cell damage rather than exocytosis. Intragastric peptic activity in critically ill H2-receptor-blocked patients (n = 20) was 5490 +/- 1701 U/ml. The gastric juice of H2-blocked convalescing surgical patients (n = 20) contained 315 +/- 101 U/ml (p less than 0.0001). Occult blood correlated with intragastric peptic activity (r = 0.59, p less than 0.0001) but not with gastric pH (r = 0.04, p = 0.6). These data suggest that the complex of pathophysiologic abnormalities common in critical illness causes substantial pepsin release. Efflux of this potent mucolytic barrier breaker may damage gastric mucosa in severely stressed patients.

Animals↗
PubMed1990

Effects of cholecystokinin and cholinergic receptor blockade on guinea pig pepsinogen secretion.

Although cholecystokinin (CCK) has been reported to stimulate pepsinogen secretion, this action has been poorly characterized. To assess the ability of CCK to regulate mammalian pepsinogen secretion, guinea pig fundic mucosa was incubated in Ussing chambers with CCK-8, carbamylcholine, and pentagastrin, and with cholinergic and CCK antagonists. CCK-8 stimulated pepsinogen secretion at 10(-10) M, with an ED50 of 10(-9) M and maximally (26-fold over basal) at 10(-8) M. Carbachol stimulated pepsinogen and acid secretion with an ED50 of 3 x 10(-7) M and maximally at 10(-6) M. Pentagastrin (10(-9) M-10(-6) M) did not affect acid or pepsinogen secretion, whereas gastrin-I (10(-6) M) stimulated acid secretion slightly but did not alter pepsinogen secretion. L364, 718 (10(-5) M), a specific CCK peripheral receptor antagonist, abolished all pepsigogic effects of 3 x 10(-9) M CCK-8 without altering basal acid or pepsinogen secretion or mucosal electric characteristics. L364,718-treated tissues unresponsive to CCK-8 nevertheless secreted pepsinogen and acid in response to 3 x 10(-7) M carbachol identically to control carbachol-treated preparations. Atropine (10(-5) M) blocked the response to 3 x 10(-7) M carbachol without inhibiting 10(-9) M CCK stimulation. These results support a specific receptor-mediated role for cholecystokinin in the physiologic regulation of guinea pig pepsinogen secretion.

Animals↗
PubMed1990

A novel micromethod for pancreatic acinar secretion. Time course of CCK stimulation and its inhibition by L-364,718.

Dispersed acini have proven to be particularly valuable in the study of pancreatic enzyme secretion. Complex time course studies or experiments requiring large numbers of replicates have proven difficult, however, with currently available techniques. Using a custom-designed incubation chamber, a miniaturized incubation method has been devised, which allows for continuous oxygenation of acini in 96-well microtiter plates and rapid separation of medium from acini by vacuum filtration. The filtrates from individual wells are collected into the wells of a second microtiter plate for pancreatic enzyme measurement. Using the above method, the dose response and time course of cholecystokinin (CCK-8)-stimulated amylase secretion was investigated. During a 1-h incubation, unstimulated amylase secretion was 4.1 +/- 0.3% of total acini content. Response to CCK was very sensitive, being detected at 10(-13) M (p less than 0.05), half-maximal at 10(-11) M CCK (14.0 +/- 0.6%, p less than 0.001) and maximal at 10(-9) M CCK (24.8 +/- 1.0%, p less than 0.001). In the time course experiments, an increase in amylase secretion was detected by 2.5 min and continued to increase steadily to a plateau at 40 min, with both submaximal (10(-11) M) and maximal (10(-9) M) CCK concentrations. The potent and specific CCK-receptor antagonist, L-364,718, caused a dose-dependent decrease in CCK-stimulated amylase secretion, with a half-maximal effect at 10(-10) M. The receptor antagonist, L-364,718, at 10(-8) M completely abolished CCK-stimulated amylase secretion. This microtechnique provides a simple, reliable, and reproducible method for the study of dispersed pancreatic acini.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1990

From Prout to the proton pump--a history of the science of gastric acid secretion and the surgery of peptic ulcer.

Prior to the 17th century, there was considerable confusion regarding the process of digestion. Although some physicians were certain that it was initiated by acid in the stomach, both the source and the nature of the acid were unclear. In the early 19th century, Prout confirmed the active secretion of hydrochloric acid by the stomach and related it to the symptoms of dyspepsia. Jacob Helm and, subsequently, Beaumont studied digestion in humans with gastric fistulas and each commented extensively on the physiologic manifestation of digestion. The role of the vagus nerves in the control of gastric acid secretion was identified in the early and mid-19th century by Brodie, and subsequently elaborated upon by Pavlov. By the early 20th century, Latarjet and Jaboulay in France, performing operations for abdominal pain and tabes, reported the effects of vagotomy on acid secretion and gastric motility. In 1943, Dragstedt, in the United States, reported the cure of duodenal peptic ulcer disease by supradiaphragmatic vagotomy. He later observed the substantial delays in emptying of the stomach, which necessitated the introduction of concomitant gastric drainage procedures, such as gastrojejunostomy and pyloroplasty. In 1902, Bayliss and Starling had described the existence of a chemical regulator of function--secretin--which they termed a hormone. Shortly thereafter, Edkins reported results of studies that supported the presence of an acid regulatory hormone, gastrin, in the antrum of the stomach. Unfortunately, controversy marred this observation, and the action of gastrin was for more than 30 years ascribed to histamine. Komarov, in 1938, confirmed the existence of gastrin and its stimulatory effects on acid secretion. Physiologic recognition of the roles of vagal stimulation and antral gastrin in the secretion of acid from the stomach resulted in the development of the operation of vagotomy and antrectomy for peptic ulcer disease. Studies of the pylorus and the motility of the stomach resulted in an appreciation of the genesis of the postgastrectomy syndromes. By the middle of the 20th century, a clear appreciation of the morphologic characteristics of the parietal cell and its ability to secrete hydrochloric acid was under way. The complex metabolic process of the cell was correlated with the major morphologic transformation necessary to generate secretion of hydrochloric acid. The development of sophisticated research technology allowed the appreciation of the complex intracellular processes necessary to allow the generation of a 2.5 million-fold gradient of hydrogen ion secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphatases↗
PubMed1990

The adenoma to carcinoma sequence.

The frequent coexistence of adenoma with primary carcinoma of the colon and their association with higher incidences of both synchronous and metachronous carcinomas offers only circumstantial evidence that adenomas are premalignant lesions. Detailed histopathologic investigations, however, have documented the transition from adenoma to carcinoma. Although the common, minute adenomatous polyp has a low potential of malignancy, the risk increases with size, villous architecture and degree of epithelial dysplasia. Furthermore, the association of dysplasia, which shares many adenomatous features with carcinoma in patients with chronic ulcerative colitis, and the inevitable development of adenomatous polyps followed by carcinoma of the colon and rectum in patients with familial polyposis further support this concept. Most colorectal malignant lesions, therefore, are believed to progress through the adenoma to carcinoma sequence. Moreover, histochemical investigations have demonstrated that abnormalities of DNA content, enzyme activities, CEA expression and mucin composition are shared by both adenoma and carcinoma. Thus, the malignancy potential of adenoma of the colon and rectum is reflected not only in the overt histologic transition to carcinoma, but in the disruption of the genetic and biochemical control mechanisms of cellular function as well.

Adenoma↗
PubMed1990

Recurrent hemorrhage from an invaginated Meckel's diverticulum in a 78-year-old man.

Complications arising from Meckel's diverticulum are uncommon in adults and are seldom, if ever, seen in the elderly. When they do occur in adults, intestinal obstruction or inflammation is the usual mode of presentation, hemorrhage being much less common. The patient described in this case report was 78 yr old, presented initially with iron deficiency anemia and, later, developed severe acute hemorrhage. The cause of the hemorrhage was ulceration at the tip of an invaginated Meckel's diverticulum. The ulceration was not peptic in origin, as is usually the case in similar presentations in children, no ectopic oxyntic mucosa being detected in the diverticulum of our patient. In previous reports, invaginated Meckel's diverticula have always been accompanied by intussusception, and abdominal pain has been an important part of the symptom complex in such patients. Our patient had no abdominal pain, and no intussusception was noted at surgery. This case emphasizes the need for considering a Meckel's diverticulum as the source of acute or chronic hemorrhage, irrespective of the patient's age. The utility of radionuclide blood pool imaging in arriving at a diagnosis in these cases is discussed.

Aged↗
PubMed1990

Evaluation of the occult blood test in screening for colorectal neoplasms. A prospective study using flexible endoscopy.

Survival rates from colorectal cancer will rise only when polyps and cancers are found at an earlier, curable stage. Consequently, the purpose of the present study was to compare the yield of colonic neoplasms from flexible sigmoidoscopy and colonoscopy with that from occult blood testing. Results from 474 flexible sigmoidoscopies and 1,115 colonoscopies were prospectively recorded during a four-year study period. Colorectal polyps were found in 111 (23.4%) patients undergoing flexible sigmoidoscopy and 325 (29.1%) patients undergoing colonoscopy. Among the 436 patients with polyps, the occult blood test was negative in 282 (64.7%). Among the 51 patients with colorectal cancers, the occult blood test was negative in 20 (39.1%). Thus, testing for occult blood missed the majority of polyps and a large percentage of the carcinomas. These data indicate that lower gastrointestinal endoscopy is superior to occult blood testing as a screening test for detecting colorectal polyps or cancers. Furthermore, given the high incidence of neoplasia in this patient population, the authors suggest that colonoscopy become the screening test of choice for colorectal cancer.

Colonic Polyps↗
PubMed1990

Inhibition of parietal cell H+ secretion by transforming growth factor alpha: a possible autocrine regulatory mechanism.

Transforming growth factor-alpha (TGF alpha) and TGF alpha/epidermal growth factor receptor messenger ribonucleic acid have recently been demonstrated in isolated parietal cells. The aim of this study was to investigate the effects of TGF alpha on basal and stimulated secretion in vitro with the isolated rabbit parietal cell model. Acid secretion was assessed indirectly with cell uptake of carbon 14-labeled aminopyrine [( 14C]AP). TGF alpha (10(-11) to 10(-7) mol/L) had no effect on unstimulated [14C]AP uptake. TGF alpha dose dependently inhibited histamine (10(-5) to 10(-6) mol/L)-stimulated but not forskolin (10(-5) to 10(-7) mol/L)-stimulated [14C]AP uptake. This effect on histamine-stimulated activation was reversed by pertussis toxin (200 ng/ml) before incubation. TGF alpha had no effect on carbachol (10(-5) to 10(-6) mol/L)-stimulated [14C]AP uptake. Specific HCO3-buffer studies demonstrated that these observations were independent of extracellular buffer and possible TGF alpha effects on intracellular pH. Our data indicate that TGF alpha inhibits acid secretion by specifically uncoupling histamine/cyclic adenosine monophosphate transduction at the guanosine triphosphate-binding protein. TGF alpha, unlike epidermal growth factor, has no effect on carbachol stimulation, which suggests a qualitative difference between the biologic actions of TGF alpha and epidermal growth factor. Possible autocrine-paracrine modulation of histamine stimulation by TGF alpha invokes a novel regulatory mechanism of parietal cell secretion.

Aminopyrine↗
PubMed1989

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↗
PubMed1989

Pancreastatin: a novel peptide inhibitor of parietal cell signal transduction.

The direct inhibition of secretion by pancreastatin was investigated in rabbit isolated parietal cells. Pancreastatin exerted no influence on basal aminopyrine uptake. Pancreastatin inhibited histamine stimulated aminopyrine uptake through a decrease in intracellular cAMP. Pancreastatin inhibition of histamine stimulated uptake was blocked in the presence of pertussis toxin. Pancreastatin also inhibited the carbachol stimulated increase in aminopyrine accumulation. However, the effects of pancreastatin on carbachol stimulation were not reversed by pertussis toxin. Pancreastatin did not alter the carbachol induced increase in cytosolic free calcium. Thus, pancreastatin appears to inhibit parietal cell signal transduction at multiple points along the second messenger pathways.

Aminopyrine↗
PubMed1989

Cholecystokinin augmentation of 'surgical' pancreatitis. Benefits of receptor blockade.

The management of acute pancreatitis has not changed appreciably throughout several decades. Recent evidence has suggested that cholecystokinin (CCK) may play an important role in pancreatic disease. Investigations into the precise role of CCK in acute pancreatitis have been hampered by the lack of a specific CCK receptor antagonist. Using a newly described, highly potent and specific CCK receptor antagonist, L-364,718, the effect of CCK in two models of acute "surgical" pancreatitis was examined: (1) the bile salt ductal perfusion model in the rat and (2) a traumatic model in the guinea pig. At a suboptimal dose for pancreatic enzyme secretion (25 pmol/kg/h), CCK was found to potentiate the severity of the ensuing pancreatitis in both models. Continuous CCK receptor blockade with L-364,718 (25 nmol/kg/h) improved biochemical, morphologic, and survival indexes. This study suggests that physiologic levels of CCK play an important permissive role in the evolution of acute pancreatitis. The use of L-364,718 as an investigative probe or therapeutic tool for acute pancreatitis is worthy of further consideration.

Acute Disease↗
PubMed1989

The colon, anorectum, and spinal cord patient. A review of the functional alterations of the denervated hindgut.

As humans have become more mechanized, the number of persons sustaining spinal cord injuries resulting in quadriplegia or paraplegia has increased. Because colorectal function is modulated by a combination of neural, hormonal, and luminal influences, many of the normal regulatory mechanisms remain intact in patients with spinal cord injuries. Management of these patients, however, requires an understanding of altered function in the denervated hindgut. The foregut and midgut are innervated by parasympathetic fibers in the vagus and sympathetic fibers from the lower six thoracic vertebra. In contrast, the hindgut is innervated by parasympathetic fibers arising from the sacral plexus and sympathetic fibers from the lumbar spinal column. Consequently, in most spinal cord injuries, the foregut and midgut remain normally innervated whereas the hindgut looses input from cerebral and spinal cord sources. In high cord lesions this results in decreased colonic motility. In low cord injuries there is loss of inhibitory influences that normally down-regulate left colonic and rectosigmoid sphincter activity. This increased motility causes a loss of left colonic compliance and increases left colonic transit, thus leading to chronic constipation. At the same time in both high and low cord injuries, reflex activity of the anorectum is left unregulated by cerebral input. Once stimulated by distention, the rectum spontaneously evacuates its contents. Thus, fecal impaction and incontinence in these patients principally results from loss of inhibitory influences on rectosigmoid sphincter activity and on rectal reflex activity.

Animals↗
PubMed1989

Does vasoactive intestinal polypeptide mediate the pathophysiology of bowel obstruction?

We hypothesized that bioactive peptides might be released into the portal circulation and mediate pathophysiologic alterations accompanying small bowel obstruction. We studied this question in a subacute canine small bowel obstruction model using 50 percent diameter occlusion. Control animals underwent sham laparotomy. Vasoactive intestinal peptide (VIP), peptide YY, and gastrin were measured in portal and systemic plasma by specific radioimmunoassays at 24-hour intervals as the obstruction progressed to completion over 5 days. All peptides in both groups demonstrated portal and peripheral gradients. In control dogs, peptide concentrations did not change postoperatively but VIP increased markedly in obstructed dogs, demonstrating a median portal level of 95 pmol/liter at 96 hours compared with 31.5 pmol/liter in control animals. These portal VIP levels are known to cause hypersecretion and splanchnic vasodilation in experimental models. The release of vasoactive compounds such as VIP may mediate local pathophysiology in human small bowel obstruction. A similar explanation of the systemic effects is consistent with the known cardiopulmonary bioactivity of VIP.

Animals↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

Cyclosporine inhibits protein kinase C-dependent signals in human peripheral blood lymphocytes.

T helper lymphocyte activation is thought to occur when the T3T1 receptor is activated by antigen, and a calcium signal and stimulus to protein kinase C appear to be essential for interleukin-2 production and lymphocyte proliferation. Previous work from our lab has demonstrated that the calcium signal is unaffected by cyclosporine. In this report, a macrophage and T suppressor/cytotoxic-depleted population of human peripheral blood mononuclear cells is stimulated with Sepharose beads bound to OKT3 monoclonal antibody and Sepharose-OKT3 plus a phorbol ester (a stimulus to protein kinase C). Cyclosporine inhibits both the Sepharose/OKT3-mediated and Sepharose/OKT3/phorbol myristic acetate-mediated mitogenesis. Cyclosporine inhibits either protein kinase C or protein kinase C-dependent intracellular signals necessary for T helper activation and proliferation.

Antibodies, Monoclonal↗
PubMed1989

Nonoperative management of adult blunt splenic trauma. Criteria for successful outcome.

Nonoperative management of blunt splenic trauma in adults is controversial despite numerous reports advocating this mode of therapy. Blunt splenic trauma is frequently managed without operation at our institution and, to define criteria that may predict a successful outcome, a retrospective review (1980 to 1988) of all adult splenic injuries was undertaken. Splenic injuries were documented by scintillation studies, CAT scanning, or at laparotomy. Sixty of 252 (24%) splenic injuries were initially treated without operation, which included bed rest, ICU monitoring, frequent physical exams, nasogastric tube, serial hematocrits, and follow-up splenic imaging. Five patients (5 of 60) failed nonoperative management and required interval laparotomy. Reasons for failure included blood loss greater than four units, enlarging splenic defect, or increasing peritoneal signs. Parameters predicting a successful outcome were localized trauma to the left flank or abdomen, hemodynamic stability, transfusion requirements less than four units, rapid return of GI function, age less than 60 years, and early resolution of splenic defects on imaging studies. No morbidity or deaths resulted from delayed operative intervention. In carefully selected adult patients, blunt splenic trauma may be successfully managed without operation.

Adolescent↗