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Biomedical subjects

M C Geokas

Publications and source records attributed to M C Geokas.

At least 37 records · Page 2Linked to original sources
PubMed1985

Effect of Pseudomonas aeruginosa exotoxin-A on the synthesis and secretion of proteins in isolated rat pancreatic acini.

Exposure of isolated rat dispersed pancreatic acini to increasing concentrations (10 to 1000 ng/ml) of purified exotoxin-A from Pseudomonas aeruginosa resulted in a progressive inhibition of 3H-leucine incorporation into "cellular" (those remaining in the cells) and "secretory" (those released into the medium) proteins. With each concentration of exotoxin-A, magnitude of reduction was found to be greater for the "secretory" proteins than that observed for the "cellular" proteins. Thus, in the presence of 250 ng/ml of exotoxin-A, a dose that produced maximal inhibition in protein synthesis, 3H-leucine incorporation into "cellular" and "secretory" proteins was found to be decreased by about 19 and 50%, respectively, when compared with the corresponding basal controls. Release of trypsinogen, chymotrypsinogen and amylase from the isolated pancreatic acini was also inhibited by high doses of exotoxin-A. However, whereas the exotoxin concentration of 1000 ng/ml, caused a near complete inhibition of chymotrypsinogen release, trypsinogen and amylase secretion were decreased by 40 and 50%, respectively. It is concluded that in isolated pancreatic acini, exotoxin-A inhibits the synthesis and secretion of proteins.

ADP Ribose Transferases↗
PubMed1985

Nicotine stimulation of protein secretion from isolated rat pancreatic acini.

The secretion of amylase and trypsinogen from isolated rat pancreatic acini was greatly stimulated by 3-25 mM nicotine. In the presence of 12.5 mM nicotine, a concentration used in the study, amylase and trypsinogen release was increased by 95 and 400%, respectively, when compared with the corresponding control and showed further a preferential release of trypsinogen. A 90-min time course release of the enzymes revealed that in the presence of nicotine trypsinogen-to-amylase ratio remained two- to threefold elevated over that of the control throughout the incubation period. The nicotine-induced stimulation of trypsinogen and amylase release from the acini could not be blocked by 2.5 mM cycloheximide, a dose that inhibited overall acinar protein synthesis by about 85%. When isolated acini were incubated with [3H]leucine in the presence of nicotine, the released proteins revealed a fourfold higher radioactivity (dpm/microgram acinar DNA) than the control. Cycloheximide dramatically decreased this increment. The rate of release of 3H-pulse-labeled proteins from the acini was greatly accelerated by nicotine. It is concluded that nicotine stimulates the secretion of preformed zymogen granules and newly synthesized proteins from dispersed rat pancreatic acini in vitro.

Amylases↗
PubMed1985

Biochemical changes in the pancreas of rats with chronic renal failure.

Chronic renal failure (CRF) was produced in female Sprague-Dawley rats by 7/8 nephrectomy. Creatinine clearance was depressed significantly (P less than 0.005) and blood urea nitrogen (BUN) increased in CRF rats when compared with the sham-operated (S) controls. CRF caused no apparent change in body weight but significantly increased pancreatic weight as well as increased DNA, RNA, and protein content. Pancreatic protein-to-DNA and RNA-to-DNA ratios were also found to be significantly higher in CRF rats than in the S controls. Trypsin-like activity and immunoreactive cationic trypsinogen levels were both increased in the pancreas of CRF rats, but not in their serum. On the other hand, protease inhibitory activity in the pancreas and serum was significantly decreased by CRF. The ability of the dispersed pancreatic acini isolated from CRF rats to incorporate [3H]-leucine into protein, in the absence and presence of 0.25 nM cholecystokinin octapeptide (CCK-8), was found to be lower than in the controls. Furthermore, discharge of both trypsinogen and chymotrypsinogen induced by CCK-8 was markedly reduced from acini of CRF rats as compared with the S controls. In contrast, lactate dehydrogenase (LDH) was released more readily from pancreatic acini of CRF. It is concluded that mild CRF produces hyperplasia and hypertrophy of the pancreas and lowers the responsiveness of acini to CCK-8 with respect to synthesis and secretion of proteins.

Animals↗
PubMed1985

Acute pancreatitis.

The exocrine pancreas secretes into the gut on demand more than 20 proteins that are indispensable for digestion. In-vivo autodigestion is prevented by an array of natural safeguards. In acute pancreatitis, inappropriate intrapancreatic activation and release of pancreatic hydrolases occur, but the pathogenetic mechanism of autodigestion is unclear. The release of proteases, lipase and colipase, phospholipase A, vasoactive peptides, and other agents probably accounts for the edema, tissue destruction, fat necrosis, metabolic abnormalities, and complications. Ethyl alcohol abuse, gallstones, trauma, and other common and rare conditions can induce pancreatitis. The patient's outcome can be predicted by certain prognostic signs. Ultrasonography and computerized tomography are invaluable diagnostic tools and magnetic resonance imaging appears promising. Hemodynamic monitoring, intensive care with colloid and crystalloid infusions, correction of electrolyte abnormalities, judicious use of antibiotics, peritoneal lavage, drainage of pancreatic exudation fluids, and surgical intervention require a team approach, especially in patients with multiple complications. Additional research is needed into the pathogenetic mechanism of autodigestion and the design of specific therapies.

Abscess↗
PubMed1985

The aging gastrointestinal tract, liver, and pancreas.

This article summarizes the age-related structural and functional alterations in the esophagus, stomach, small and large intestines, liver, pancreas, and vermiform appendix. Also considered are the possible relationships of these changes with the disturbance of homeostatic mechanisms and proneness to certain diseases in the aged.

Adolescent↗
PubMed1984

Effect of ethanol on cholecystokinin-induced enzyme secretion from isolated rat pancreatic acini.

Cholecystokinin octapeptide (CCK8)-stimulated amylase release in isolated rat pancreatic acini was inhibited over 30% by 600 mM ethanol. The configuration of the dose-response curve for CCK8, however, in the presence of ethanol was similar to that of the control. Amylase release elicited by maximal concentrations of CCK8 (300 pM) was inhibited by increasing concentrations of ethanol (0.3 to 1.3 M), and this inhibition was concentration dependent. In addition, the binding of [125I]CCK33 to specific membrane receptors on acini was inhibited by ethanol in a dose-dependent manner. A positive correlation between the inhibitory effects of ethanol on CCK binding and CCK-induced amylase release was observed. Furthermore, these inhibitory effects of ethanol were reversible. Basal amylase release, however, was increased 20-50% by ethanol between the concentrations of 0.3 and 1.3 M; higher concentrations caused a leakage of amylase from the acini both in the absence and presence of 300 pM CCK8. This is confirmed by 51Cr release from prelabeled acini which revealed no significant damage to acinar cell membrane between 0.3 and 1.6 M ethanol, but significant damage to acini at higher concentrations. These data suggest that the 600 mM ethanol-induced inhibition of CCK action in acini is due to reversible perturbation of the acinar cell membrane.

Amylases↗
PubMed1984

Ethanol and the pancreas.

The acute and chronic effects of ethanol on pancreatic structure and function are discussed. Acute necrotizing, acute edematous, acute relapsing, chronic relapsing, and painless pancreatitis have an established association with ethanol abuse. The management of these disorders is outlined.

Alcoholic Intoxication↗
PubMed1984

Effects of food intake and cholecystokinin on plasma trypsinogen levels in dogs.

Concentrations of plasma immunoreactive anionic and cationic trypsin(ogen) were monitored in unanesthetized dogs to investigate diurnal variation, response to food intake, and effects of cholecystokinin octapeptide (CCK-8) plus secretin administration. Identical meals were consumed at the beginning and end of a 24-h period. Plasma levels of both trypsin(ogen)s increased significantly within 30 min of feeding. Second-meal responses were much larger than those following the first meal. Plasma cationic trypsin(ogen) was also elevated during the normal feeding period when food was withheld and dogs in adjacent cages were fed. Small, irregular variations in plasma trypsin(ogen)s occurred during the interdigestive period when blood was sampled every 2 h. CCK-8 plus secretin, in doses shown previously to stimulate exocrine secretion of enzymes submaximally, increased plasma levels of both trypsin(ogen)s dose dependently. Most (greater than 80%) of the immunoreactive cationic trypsin(ogen) in plasma before and after feeding and following CCK-8 was in proenzyme form. We conclude that plasma levels of pancreatic trypsinogens are increased by food intake and low doses of CCK-8. Furthermore, cephalic mechanisms appear to play an important role in mediating the response to food intake.

Animals↗
PubMed1982

Plasma immunoreactive anionic pancreatic trypsin in cystic fibrosis.

Previous data from this laboratory have shown good correlation between plasma cationic trypsin(ogen) and levels of pancreatic function in older cystic fibrosis (CF) patients with and without malabsorption. In the present study a radioimmunoassay for human anionic trypsin(ogen) has been employed in the assessment of pancreatic function in older patients with CF. Immunoreactive anionic trypsin(ogen) levels correlated poorly with pancreatic function due to an apparent elevation of this enzyme in many older CF patients with malabsorption (CF + M). When plasma from three older CF + M patients is examined for the molecular size of the apparent immunoreactive material detected, no free anionic trypsinogen is observed. Instead, a broad peak of apparent immunoreactive material appears in the gammaglobulin region. However, only free anionic trypsinogen could be detected in plasma from two CF patients without malabsorption (CF - M), who had not received pancreatic enzyme supplements. It appears possible that a human plasma immunoglobulin G (IgG) to porcine pancreatic enzyme in the CF + M patients might interfere in the assay by binding TLCK--anionic trypsin tracer. It is unclear why such an effect does not appear to occur in the cationic trypsin(ogen) assay. The results of the current study suggest that, for assessment of pancreatic insufficiency in CF, the radioimmunoassay for cationic trypsin(ogen) is more useful than the presently available radioimmunoassay for the anionic form.

Adolescent↗
PubMed1982

Plasma pancreatic trypsinogens in chronic renal failure and after nephrectomy.

The kidney has previously been shown to be a major site for the plasma clearance of pancreatic trypsinogens in the rat. This study investigated plasma concentrations of anionic and cationic trypsinogen in chronic renal failure and anephric patients. Plasma concentrations were significantly elevated in both groups of patients. Hemodialysis did not change their plasma levels. The plasma levels of anionic and cationic trypsinogens were highly correlated in patients and normal subjects; however, the relative concentrations of anionic trypsinogen were significantly higher in renal failure patients. This suggests that in patients with renal failure the secondary clearance mechanisms for these plasma proteins more efficiently clear cationic molecules. In normal dogs, intravenous infusion of synthetic octapeptide of cholecystokinin (CCK-8) resulted in small transitory increases in plasma trypsinogen levels. After nephrectomy, basal levels of anionic and cationic trypsinogen were elevated, and intravenous infusion of CCK-8 resulted in prolonged, high levels of plasma trypsinogens.

Animals↗
PubMed1982

Peptide radioimmunoassays in clinical medicine.

The radioimmunoassay technique, first developed for the determination of hormones, has been applied to many substances of biologic interest by clinical and research laboratories around the world. It has had an enormous effect in medicine and biology as a diagnostic tool, a guide to therapy, and a probe for the fine structure of biologic systems. For instance, the assays of insulin, gastrin, secretin, prolactin, and certain tissue-specific enzymes have been invaluable in patient care. Further refinements of current methods, as well as the emergence of new immunoassay techniques, are expected to enhance precision, specificity, reliability, and convenience of the radioimmunoassay in both clinical and research laboratories.

Acid Phosphatase↗
PubMed1981

Plasma immunoreactive pancreatic cationic trypsinogen in cystic fibrosis: a sensitive indicator of exocrine pancreatic dysfunction.

Plasma immunoreactive cationic trypsin(ogen) levels were determined in 32 control subjects and 43 patients with varying degrees of pancreatic insufficiency including 35 with cystic fibrosis (CF) and eight with Shwachman's syndrome. In six CF infants less than 2 years of age, plasma trypsin(ogen) levels were significantly elevated (97.3 +/- 62.2 ng/ml) above the normal range for nine controls (7.0 +/- 5.9 ng/ml; P less than 0.025). Four of these infants had steatorrhea, three of whom had undetectable duodenal trypsin activity after stimulation with secretin-cholecystokinin. In two CF infants, molecular size fractionation by gel filtration of plasma followed by radioimmunoassay of the column fractions demonstrated that trypsinogen was the only immunoreactive species in the circulation. In contrast, in older CF patients with steatorrhea (mean age, 15.3 +/- 4.6 years), plasma cationic trypsin(ogen) levels were undetectable or low (1.1 +/- 1.7 ng/ml). This finding clearly distinguished them from older CF patients without steatorrhea (mean age, 14.3 +/- 3.9 years) in whom cationic trypsin(ogen) levels were significantly higher (23.3 +/- 17.6 ng/ml; P less than 0.01). The mean trypsin(ogen) concentration in the older CF patients without steatorrhea did not differ from the mean value for 23 normal subjects of similar age. Plasma cationic trypsin(ogen) levels in two Schwachman's patients with steatorrhea (0.19 and 0.86 ng/ml) were significantly lower than the values found in six Shwachman's patients without steatorrhea (5.9 +/- 2.3 ng/ml; P less than 0.025). Furthermore, in nine older CF patients and eight Schwachman's patients, circulating trypsin(ogen) levels were highly correlated with duodenal trypsin output after secretin-cholecystokinin stimulation (r = 0.946, P less than 0.01; r = 0.899, P less than 0.01, respectively). These results suggest that in CF infants high levels of circulating trypsin(ogen) persist even in those with Shwachman's syndrome, however, circulating trypsin(ogen) accurately reflects residual pancreatic function.

Adolescent↗
PubMed1981

Ethanol, the liver, and the gastrointestinal tract.

Ethanol is easily absorbed from the intestine and diffuses quickly throughout body water. The bulk of ethanol is metabolized in the liver, where alcohol dehydrogenase, a complex mixture of isoenzymes, oxidizes ethanol to acetaldehyde. Ethanol abuse produces functional and structural changes in the gastrointestinal tract, such as in the stomach, small intestine, liver, and pancreas. Accumulating evidence suggests direct toxicity of ethanol and possibly of acetaldehyde. Fatty liver, alcoholic hepatitis, liver cirrhosis, acute and chronic gastritis, deranged structure and function of the small intestine, acute and chronic pancreatitis, and pancreatic lithiasis are some of the sequelae of ethanol abuse. Recent investigations have enhanced our understanding of the functional and structural changes of the gastrointestinal tract produced by the abuse of ethanol.

Alcoholism↗
PubMed1981

Immunoreactive forms of cationic trypsin in plasma and ascitic fluid of dogs in experimental pancreatitis.

A canine model of bile-induced pancreatitis has been employed to investigate time-dependent changes in the molecular forms of trypsin in blood and ascitic fluid in this disease. The distribution of immunoreactive trypsin as trypsinogen and trypsin bound to plasma inhibitors in ascitic fluid and plasma during the course of the disease has been investigated by means of a radioimmunoassay for canine pancreatic cationic trypsin. In addition, trypsinlike amidase activity was determined in plasma and ascitic fluid using Z-Gly-Gly-Arg-beta-Nap as substrate. Early plasma and ascitic fluid samples in four dogs that died contained primarily trypsinogen, while extensive activation of trypsinogen to alpha 2-macroglobulin and alpha 1-protease inhibitor-bound trypsin occurred in the course of the disease. A fifth dog survived and showed little activation of trypsinogen. In the four dogs that died, the levels of trypsinlike amidase activity in the ascitic fluid were substantial throughout the course of the disease. The plasma levels of trypsinlike activity in these animals were much lower, but increased during the disease process. The dog that survived had lower concentrations of trypsinlike activity in ascitic fluid and plasma. These results suggest that activation of trypsinogen resulting in inhibitor-bound forms of trypsin in ascitic fluid and plasma is important in the pathogenesis of acute pancreatitis.

Amidohydrolases↗
PubMed1980

Interaction of chymotrypsinogens with alpha 1-protease inhibitor.

In a previous report [Largman, C., Brodrick, J.W., Geokas, M.C., Sischo, W.M., & Johnson, J.H. (1979) J. Biol. Chem. 254, 8516-8523] it was demonstrated that human proelastase 2 and alpha 1-protease inhibitor react slowly to form a complex that is stable to denaturation with sodium dodecyl sulfate and beta-mercaptoethanol and that the zymogen can be recovered from the isolated complex following dissociation by hydroxylamine. The present report demonstrates that bovine chymotrypsinogen A reacts with human alpha 1-protease inhibitor in a very similar manner. The rate of complex formation was measured by two methods. In the first, the reaction was followed by determining the loss of the inhibitory activity of alpha 1-protease inhibitor as a function of time. A second-order rate constant for complex formation formation (pH 7.6, 36 degrees C) of 12.9 +/- 2.4 M-1s-1 was obtained. In the second procedure, the reaction of fluorescein isothiocyanate labeled chymotrypsinogen A with alpha 1-protease inhibitor was measured by fluorescence polarization. A second-order rate constant (pH 7.6, 37 degrees C) of 13.9 +/- 2.1 M-1s-1 was obtained. The rate of complex formation is approximately 10(-5) of that measured for the reaction of bovine chymotrypsin with alpha 1-protease inhibitor. Dissociation of the complex was not observed after dilution or the addition of excess bovine alpha-chymotrypsin. As judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis experiments, human chymotrypsinogens I and II react with alpha 1-protease inhibitor at rates that are approximatley equivalent to that determined for bovine chymotrypsinogen A. In contrast, bovine trypsinogen reacts very slowly with alpha 1-protease inhibitor, at a rate that is at most 10(-2) of that of bovine chymotrypsinogen A. These results suggest that zymogens react with alpha 1-protease inhibitor by virtue of partially formed active sites and that the potential active-site specificity of the zymogen in part determines the rate of complex formation.

Animals↗