Biomedical subjects
L J Miller
Publications and source records attributed to L J Miller.
Complex role of protein kinase C in mediating the supramaximal inhibition of pancreatic secretion observed with cholecystokinin.
Protein kinase C appears to play an important, yet complex role in the supramaximal inhibition of pancreatic acinar cell secretion observed in response to cholecystokinin (CCK). The addition of protein kinase C activation to the concentration-response curve of a partial agonist acting at the CCK receptor (a phenethyl ester analogue of CCK), transforms a curve without supramaximal inhibition to a full agonist curve typical of CCK. This effect can be elicited by low concentrations of phorbol ester (50pM to 1nM 12-0-tetradecanoyl-phorbol-13-acetate) or by hormonal agonists (0.1 microM carbamylcholine, 10pM bombesin, 1pM CCK-8) which activate protein kinase C, but not by agonists acting via alternate second messengers (VIP). Of interest, this effect is dependent on preincubation of the acinar cells with the protein kinase C activator at 37 degrees C, with the effect rapidly reversed by transient exposure of the cells to lower temperature. This is consistent with mediation by a phosphorylation event. However, the requirement for an extended (greater than 15 min) preincubation period when using minimal kinase activation suggests that this phenomenon is more complicated than a simple bimolecular phosphorylation event and likely includes a series of events such as translocation of substrates and/or enzymes involved.
Expression cloning and characterization of the canine parietal cell gastrin receptor.
Gastrin is an important stimulant of acid secretion by gastric parietal cells and is structurally related to the peptide hormone cholecystokinin (CCK). The pharmacologic properties of the parietal cell gastrin receptor are very similar to the predominant CCK receptor in the brain, CCK-B. Neither the gastrin nor the CCK-B receptor have been cloned thus far, making it difficult to resolve whether these two receptors are distinct. We have isolated a clone encoding the canine gastrin receptor by screening a parietal cell cDNA expression library using a radioligand-binding strategy. Nucleotide sequence analysis revealed an open reading frame encoding a 453-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the beta-adrenergic family of G protein-coupled receptors. The expressed recombinant receptor shows the same binding specificity for gastrin/CCK agonists and antagonists as the canine parietal cell receptor. Gastrin-stimulated phosphatidylinositol hydrolysis and intracellular Ca2+ mobilization in COS-7 cells expressing the cloned receptor suggest second-messenger signaling through phospholipase C. Affinity labeling of the expressed receptor in COS-7 cells revealed a protein identical in size to the native parietal cell receptor. Gastrin receptor transcripts were identified by high-stringency RNA blot analysis in both parietal cells and cerebral cortex, suggesting that the gastrin and CCK-B receptors are either highly homologous or identical.
Binding of a phenethyl ester analogue of cholecystokinin to the solubilized pancreatic cholecystokinin receptor: use in ligand-affinity chromatography.
Pancreatic acinar cells have both high and low affinity receptors for cholecystokinin (CCK), yet their membranes appear to possess only a single class of binding sites. Recently, gallbladder membrane CCK receptors were shown to undergo inter-conversion between two affinity states dependent on G protein coupling. Keys for that observation were the differential binding affinities of CCK and a phenethyl ester analogue of CCK (OPE), with the high affinity state binding CCK with higher affinity than OPE, and the low affinity state binding OPE with higher affinity than CCK. Here, we performed analogous experiments using these ligands and both pancreatic membranes and a solubilized preparation. Both preparations were found to have only single affinity states of this receptor. However, the state on membranes had a higher affinity for CCK than for OPE, and that on the solubilized preparation had a higher affinity for OPE than for CCK. This supports the hypothesis that the ternary complex of ligand-receptor-G protein found in membranes represents the high affinity state of this receptor, while the uncoupled form of this receptor after solubilization represents its low affinity state. The high affinity of OPE for the solubilized receptor can be utilized in a purification strategy to follow receptor-bearing fractions and to provide an efficient and specific affinity-binding step.
A historical perspective of gastrointestinal endocrinology--the new age of molecular receptorology.
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The Zollinger-Ellison syndrome. A collective surgical experience.
A retrospective study of 90 surgically treated patients with the Zollinger-Ellison syndrome seen from 1958 through 1990 was performed. Fifteen patients had Zollinger-Ellison syndrome as a manifestation of multiple endocrine neoplasia type I. Preoperative tumor localization was positive in 46% of 54 patients studied. Gastrinomas were identified in 66% of patients, 38% of the tumors being malignant. Postoperative eugastrinemia was achieved in 11% of patients after a variety of surgical procedures. Exploratory laparotomy provides the only chance for cure and identifies the significant prognostic factors associated with long-term patient survival: small tumor size, extrapancreatic primary, and absence of tumor metastases.
Control of human postprandial pancreatic exocrine secretion: a function of the gastroduodenal region.
Regulation of the exocrine pancreatic secretion elicited by a meal in man is incompletely understood. In this study, we attempted to localize in the gastrointestinal tract areas that control postprandial trypsin secretion and to determine the effects of individual components of jejunal chyme on the meal-stimulated trypsin secretion. Trypsin outputs elicited by ingesting a mixed-nutrient meal and diverting it at the ligament of Treitz proximal to an occlusive balloon were compared with those occurring when the same meal was ingested, diverted at the ligament of Treitz, and immediately reinfused distal to the balloon, a procedure that exposed the entire gastrointestinal tract to chyme. Two different meals, one of semielemental and one of complex nutrients, were used with similar results. Trypsin outputs were similar whether or not jejunal chyme was diverted. In addition, no component--exogenous nutrients or endogenous secretions--of chyme reaching the jejunum after a meal further modified the trypsin secretion elicited by the gastroduodenal segment. This finding suggests that the gastroduodenal segment is sufficient to elicit the entire postprandial trypsin output and is the physiologic determinant of meal-stimulated trypsin secretion.
Takayasu's arteritis in Crohn's disease.
This report describes a patient with coexistent Crohn's colitis and Takayasu's arteritis involving the thoracic aorta, superior mesenteric artery, and left hepatic artery. Unlike most previously reported cases of this association, characteristic histopathology is demonstrated. This case is also unusual in that the Takayasu's arteritis presented as aneurysmal disease instead of occlusive disease. We believe that Takayasu's arteritis may represent another of the many extra-intestinal manifestations of inflammatory bowel disease.
Gastrointestinal hormone profile in renal insufficiency.
Fasting serum gastrin, cholecystokinin, glucagon, and gastric inhibitory polypeptide concentrations were simultaneously measured in normal subjects and in patients with different degrees of renal failure. Values of gastrin, cholecystokinin, gastric inhibitory polypeptide, and glucagon were significantly higher in all patients with serum creatinine concentrations greater than 3 mg/dl than in controls (P less than 0.01). The degree of renal insufficiency was significantly correlated (P less than 0.05) with serum concentrations of each hormone, but no significant linear correlation existed among the serum concentrations of different gastrointestinal hormones in individuals. Hemodialysis did not significantly alter predialysis serum gastrin, cholecystokinin, or glucagon concentration, but the serum gastric inhibitory polypeptide concentration decreased by 30% (P less than 0.01) after hemodialysis. The disproportionate increases of hormones with antagonistic actions may alter gastrointestinal function in renal insufficiency.
Analytical characteristics of late-eluting halogenated flame retardants.
The analytical characteristics of halogenated flame retardants were studied. Suitable electron capture gas-liquid chromatographic conditions were developed, and retention times and sensitivity responses were obtained. The behavior of these industrial chemicals through the AOAC multiresidue method for nonfatty foods was studied using fish as the test substrate. Of the 24 flame retardants investigated, 23 were recovered (85-110%) using the AOAC method.
Postprandial duodenal function in man.
Duodenal function was studied in 11 healthy volunteers after intragastric instillation of a mixed semi-elemental meal. The duodenum accepted chyme of varying pH, osmolality, and nutrient concentration; and, as a result of biliary, pancreatic, and enteric secretion as well as absorption, it delivered chyme with nearly constant pH, osmolality, and nutrient concentration to the jejunum. The flow rate and nutrient load of jejunal chyme varied. The duodenum absorbed more carbohydrate than lipid and less protein, taking up each nutrient at a constant rate during most of the postprandial period. The percentage of nutrient load absorbed was greatest in the late postprandial period, when flow rate, nutrient load, and concentrations were low.
Intestinal nutrient influence on the enteroinsular axis.
The gastrointestinal contribution to carbohydrate metabolism includes carbohydrate absorption and the release of gastrointestinal hormones that interact with the endocrine pancreas. To learn the contributions to the enteroinsular axis from different levels of the gastrointestinal tract and different nutrients in chyme, we determined serum concentrations of glucose, gastric inhibitory peptide (GIP), insulin, and glucagon postprandially in six normal subjects who underwent diversion of chyme just proximal to an occlusive balloon at the ligament of Treitz and jejunal infusion of saline or chyme carbohydrate, protein, and lipid, separately or in combination. Postprandial elevations of serum glucose, GIP, and insulin and decrease of serum glucagon were elicited predominantly from the bowel and its contents distal to the ligament of Treitz. In this segment, each chyme nutrient (but especially carbohydrate) significantly stimulated factors affecting carbohydrate metabolism. Protein and lipid were able to block carbohydrate-induced glucagon inhibition. The gastroduodenal segment, although containing several proposed insulinotropic hormones (gastrin, secretin, and cholecystokinin), had no effect on serum glucose of glucagon and stimulated only small insulin and GIP responses.
Gut-thyroid interrelationships.
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Crohn's disease involving the esophagus and colon. Case report.
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Abnormal intestinal bile acid distribution in azotaemic man: a possible role in the pathogenesis of uraemic diarrhoea.
Proximal intestinal bile acids have been studied in 14 ambulatory patients with varying degrees of azotaemia. When compared with normal subjects, the azotaemic patients showed a significant decrease in deoxycholic acid. Analysis of faecal bile acids of a patient with low intestinal deoxycholic acid also showed low deoxycholic acid with a preponderance of primary bile acids, and contrast with faecal bile acids of a normal subject and a patient with normal intestinal deoxycholic acid. It is suggested that impairment of deconjugation or 7alpha-dehydroxylation might be contributing to the low deoxycholic acid observed in azotaemic patients. Unusual bile acids: ursodeoxycholic acid, 3-hydroxy-7-keto-cholanic acid, and 3,12-dihydroxy-7-keto-cholanic acid were also noted in intestinal aspirates of azotaemic patients. The presence of these bile acids in conjunction with low deoxycholic acid correlates with the symptom of diarrhoea in azotaemic patients, and may contribute to the pathogenesis of diarrhoea in these patients.
Interrelationships of psychopathology and adience-abience on the HABGT.
Using two distinctively different populations, 40 hospitalized schizophrenics and 100 outpatient therapy cases, the interrelationships of two measures based on the HABGT, one of psychopathology and the other of perceptual adience-abience, were investigated. The relationships of each of these measures with sex, age, and educational level were examined. Both measures significantly differentiate the psychotic from the non-psychotic population. Although there is a statistically significant correlation between the two measures in each population, it is shown that the commonality between them varies from a considerable degree of commonality in the schizophrenic group to only a limited degree in the outpatient group. Both measures are uncorrelated with sex, age, and level of educational attainment. The study offers additional evidence of the values of these two measures.
Further studies of a measure of adience-abience: reliability.
Previous studies have suggested adequate reliability for a measure of perceptual adience-abience based on the HABGT in view of significant evidence concerning its construct and predictive validity. The present study explored the test-retest reliability of this scale with 40 process schizophrenics over a two-week interval. Reliability was found to be adequate for both males and females (rho equals .84) for the total scale. The four components of the scale were similarly found to be reliable. No subject changed on retest with respect to adient or abient orientation. Interjudge reliability was very high (rho = .912).
Psychopathology scale of the Hutt adaptation of the Bender-Gestalt Test: reliability.
The test-retest reliability of the Hutt Adaptation of the Bender-Gestalt test was explored with a population of 40 process schizophrenics over a two-week interval. The total Psychopathology Scale Score was found to have high retest reliability for both male and female patients (rho = .87 for males and .83 for females). Moreover the three major components for the Scale were found to have high reliability, and fairly high reliabilities were obtained for patients scoring high as well as low on the Scale. Interjudge reliability was also found to be very high (rho = .895), confirming previous studies in this respect. On these grounds, the Scale offers promise both for clinical and research purposes.