63 results on '"Gebhard RL"'
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2. Thyroid hormone differentially augments biliary sterol secretion in the rat. I. The isolated-perfused liver model.
- Author
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Gebhard, RL, primary, Stone, BG, additional, Andreini, JP, additional, Duane, WC, additional, Evans, CD, additional, and Prigge, W, additional
- Published
- 1992
- Full Text
- View/download PDF
3. Sclerotherapy for actively bleeding esophageal varices in male alcoholics with cirrhosis. Veterans Affairs Cooperative Variceal Sclerotherapy Group.
- Author
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Hartigan PM, Gebhard RL, and Gregory PB
- Subjects
- Alcoholism complications, Endoscopy, Digestive System, Esophageal and Gastric Varices complications, Esophageal and Gastric Varices diagnosis, Follow-Up Studies, Gastrointestinal Hemorrhage diagnosis, Gastrointestinal Hemorrhage etiology, Gastrointestinal Hemorrhage mortality, Hospital Mortality, Hospitalization, Humans, Liver Cirrhosis, Alcoholic diagnosis, Liver Cirrhosis, Alcoholic mortality, Male, Middle Aged, Retrospective Studies, Single-Blind Method, Treatment Outcome, Esophageal and Gastric Varices therapy, Gastrointestinal Hemorrhage therapy, Liver Cirrhosis, Alcoholic complications, Sclerotherapy methods
- Abstract
Background: Male alcoholics hospitalized with actively bleeding esophageal varices were treated with sclerotherapy or sham sclerotherapy and the outcomes during the index hospitalization were compared., Methods: The 87 patients were a subset of 253 patients enrolled in a prospective, randomized, single-blind, multicenter, controlled trial conducted in 12 VA medical centers. The patients (44 sclerotherapy, 43 sham therapy) were actively bleeding from esophageal varices at either randomization endoscopy (49) or follow-up endoscopy (38). Events and resource use during the index hospitalization were recorded., Results: In 40 (91%) of the sclerotherapy and 26 (60%) of the sham therapy patients, bleeding was stopped during the endoscopy session (p < 0.001). During the hospitalization, 10 (25%) sclerotherapy and 21 (49%) sham therapy patients died (p = 0.04, relative risk 2.17, 95% CI [1.02, 4.61]); 9 sclerotherapy and 22 sham therapy patients rebled (p = 0.005). The median transfusion requirement was higher for sham therapy (8 vs 4 units, p = 0.001), the number of median ICU hours was greater (101 vs 55, p < 0.001), and more patients in this group required shunt surgery (6 vs 0, p = 0.01)., Conclusion: Sclerotherapy, compared to no sclerotherapy, stops hemorrhage from actively bleeding esophageal varices and reduces use of resources. Sclerotherapy significantly increased hospital survival.
- Published
- 1997
- Full Text
- View/download PDF
4. Oral acetylsalicylic acid induces biliary cholesterol secretion in the rat.
- Author
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Prigge WF and Gebhard RL
- Subjects
- Administration, Oral, Animals, Bile chemistry, Cholesterol Esters analysis, Diet, Fat-Restricted, Hydroxymethylglutaryl CoA Reductases analysis, Hypothyroidism metabolism, Male, Microsomes, Liver enzymology, Rats, Rats, Sprague-Dawley, Triiodothyronine pharmacology, Aspirin pharmacology, Bile metabolism, Cholesterol metabolism, Liver metabolism
- Abstract
Several agents can alter biliary cholesterol secretion, critical for cholesterol excretion and gallstone formation. Although salicylate effects on bile formation and gallstones have been studied, biliary lipid secretion has not been measured during oral aspirin treatment. We examined whether oral acetylsalicylic acid affects bile lipid secretion. Three groups of young rats were fed chow for 3 wk. Two of the groups then received aspirin at either 1.67 or 3.33 g/kg diet for 4 d. Serum, hepatic, and bile lipids were measured, as were enzymes of cholesterol synthesis and esterification. With oral aspirin, bile cholesterol secretion increased by 42% and hepatic cholesteryl ester content decreased by 40%. Serum cholesterol and hepatic free cholesterol did not change. To evaluate mechanisms of the cholesterol hypersecretion, hypothyroid animals fed low-fat or fish oil diets and repleted with triiodothyronine were also studied. Aspirin stimulated cholesterol secretion to a degree similar to triiodothyronine. An additive response was seen in fish oil-fed rats. Aspirin did not appear to have a primary action on 3-hydroxy-3-methylglutaryl-CoA reductase or acyl CoA:cholesterol acyltransferase activities, and had no direct effect on esterification of cholesterol by isolated hepatocytes. Aspirin may directly increase cholesterol transport into bile or have cell membrane effects which alter cholesterol transport. It remains to be determined whether the observed alterations in bile cholesterol secretion are specific to the rat or also apply to humans.
- Published
- 1997
- Full Text
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5. Gallstones in chronic spinal cord injury: is impaired gallbladder emptying a risk factor?
- Author
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Ketover SR, Ansel HJ, Goldish G, Roche B, and Gebhard RL
- Subjects
- Adult, Female, Gallbladder physiopathology, Humans, Male, Middle Aged, Risk Factors, Ultrasonography, Cholelithiasis diagnostic imaging, Cholelithiasis physiopathology, Gallbladder diagnostic imaging, Spinal Cord Injuries physiopathology
- Abstract
Objective: To confirm that spinal cord injured persons are susceptible to gallstones and to evaluate the role of gallbladder stasis as a risk factor., Study Design: Twenty-nine subjects with chronic spinal cord injury underwent fasting ultrasonography to determine the incidence of gallstones and to quantitate gallbladder emptying response to a 20g fat liquid meal. Gallbladder emptying fraction was compared to that of healthy subjects studied concurrently., Results: Gallstones or sludge were found in 6 spinal cord injured men, a minimal prevalence of 21%. Four additional subjects had prior cholecystectomy for stones, giving a potential maximal prevalence of 30%. Four of the 6 subjects had gallstone risk factors of diabetes, obesity, and/or family history. Gallbladder stasis was not apparent in chronic spinal cord injured subjects. Only 5 subjects had poor gallbladder emptying, and 4 of them had diabetes and/or obesity., Conclusions: The study confirms an increased prevalence of gallstones after spinal cord injury. However, gallbladder stasis did not appear to be etiologic, and most gallstones were associated with conventional risk factors. The results do not support a general policy of gallstone screening or prophylactic therapy after spinal cord injury.
- Published
- 1996
- Full Text
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6. The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss.
- Author
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Gebhard RL, Prigge WF, Ansel HJ, Schlasner L, Ketover SR, Sande D, Holtmeier K, and Peterson FJ
- Subjects
- Adult, Dietary Fats pharmacology, Female, Gallbladder Emptying drug effects, Humans, Male, Middle Aged, Obesity pathology, Obesity physiopathology, Reference Values, Time Factors, Cholelithiasis etiology, Diet, Reducing adverse effects, Gallbladder Emptying physiology, Obesity diet therapy, Weight Loss
- Abstract
Obese persons are at risk for cholesterol gallstones because their bile is saturated with cholesterol. The risk increases during rapid weight loss by means of certain very-low-calorie diets or gastric bypass surgery. Gallstone risk factors during rapid weight loss include increased bile cholesterol saturation index and gallbladder stasis. Obese subjects were randomized to one of two low-calorie liquid diets for rapid weight loss: a 520-kcal diet with less than 2 g fat/d, and a 900-kcal diet with 30 g fat/d (including one 10-g fat meal to stimulate maximal gallbladder emptying). Bile and blood lipids, saturation index, leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity, and ultrasonographic gallbladder emptying were measured repeatedly during dietary treatment. Both diets produced comparable weight loss of 22%. Bile cholesterol saturation index increased during both diets (26%), but fell to 15% below prediet level after weight loss. Compared with subjects' maximal gallbladder emptying fraction of 66%, the 520-kcal diet provided poor gallbladder emptying (35%), whereas the 10-g fat meal of the 900-kcal diet provided maximal emptying. Gallstones developed in four of six 520-kcal subjects and none of seven 900-kcal subjects (P = .021), an unanticipated difference that resulted in premature study termination for ethical reasons. Blood lipids and HMG CoA reductase activity in mononuclear leukocytes fell at week 8 during both diets, but recovered while weight was still being lost. The findings suggest that gallstone risk during rapid weight loss may be reduced by maintenance of gallbladder emptying with a small amount of dietary fat. Ultimately, weight loss reduced bile cholesterol saturation and improved highdensity lipoprotein (HDL) levels.
- Published
- 1996
- Full Text
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7. Thyroid hormone is required for dietary fish oil to induce hypersecretion of biliary cholesterol in the rat.
- Author
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Prigge WF, Ketover SR, and Gebhard RL
- Subjects
- Animals, Cholesterol blood, Dietary Fats metabolism, Drug Synergism, Fish Oils metabolism, Hydroxymethylglutaryl CoA Reductases metabolism, Liver drug effects, Liver enzymology, Male, Rats, Rats, Sprague-Dawley, Thyroid Hormones metabolism, Antithyroid Agents pharmacology, Bile metabolism, Cholesterol metabolism, Dietary Fats pharmacology, Fish Oils pharmacology, Methimazole pharmacology, Phospholipids metabolism, Thyroid Hormones pharmacology
- Abstract
In the rat, both fish oil diet and thyroid hormone replacement are reported to augment bile cholesterol secretion out of proportion to bile flow or secretion of other bile lipids. We sought common mechanisms for these effects and evaluated the role of phospholipid fatty acid composition in the process. Methimazole-treated hypothyroid rats were fed low-fat chow or chow supplemented with 10% corn oil or fish oil, and were studied before and after thyroid hormone treatment. Serum, hepatic, and bile lipids were measured, phospholipid fatty acid composition determined, and hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity assayed. Fish oil diet stimulated cholesterol secretion into bile only after thyroid hormone was given, and this action was synergistic with that of thyroid hormone. Reduced serum cholesterol in fish oil-treated rats was associated with increased biliary cholesterol secretion and diminished hepatic cholesterol content. This suggests that augmented biliary cholesterol secretion may contribute to the fish oil-induced reduction of serum cholesterol. No definite relationship between hepatic or biliary phospholipid fatty acid composition and biliary secretion was apparent, although high bile cholesterol secretion was associated with a low percentage of hepatic and bile phospholipid linoleic acid.
- Published
- 1995
- Full Text
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8. Gallbladder emptying stimuli in obese and normal-weight subjects.
- Author
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Stone BG, Ansel HJ, Peterson FJ, and Gebhard RL
- Subjects
- Adult, Body Mass Index, Body Weight, Female, Humans, Male, Gallbladder Emptying physiology, Obesity physiopathology
- Abstract
Gallbladder stasis may be an important factor in the pathogenesis of cholesterol-gallstone formation in some individuals. We investigated gallbladder function in a group of nondieting, gallstone-free, healthy subjects with normal (22 +/- 1 kg/m2) and high (36 +/- 1 kg/m2) body mass indexes. Fasting gallbladder volume (28.2 +/- 4.4 ml) and residual volume after maximal emptying (8.4 +/- 2.3 ml) in high-body-mass index subjects were not significantly different from those of normal-body-mass index subjects (20.5 +/- 2.5 ml and 4.2 +/- 1.3 ml, respectively). The percentage of gallbladder emptying (71% +/- 5%) and the rate of gallbladder emptying (-1.9 +/- 0.3 x 10(-2) min-1) in high-body-mass index subjects in response to a maximal emptying stimulus was similar to the percentage of emptying (78% +/- 6%) and rate of emptying (-2.3 +/- 0.6 x 10(-2) min-1) in normal-body-mass index subjects. A liquid meal containing less than 1 gm fat, 14 gm protein and 6 gm carbohydrate resulted in both a decreased rate of gallbladder emptying and an increased residual gallbladder emptying and an increased residual gallbladder volume in both groups. The addition of 10 or 20 gm (but not 4 gm) of fat to the liquid meal restored gallbladder emptying to the maximal-stimulus level. These results demonstrate that gallbladder emptying in response to a single liquid meal stimulus is not altered in obesity and that dose-response relationships to fat are similar in obese and normal-weight individuals.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
- Full Text
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9. Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition on human gut mucosa.
- Author
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Gebhard RL, Ewing SL, Schlasner LA, Hunninghake DB, and Prigge WF
- Subjects
- Anticholesteremic Agents adverse effects, Cell Division drug effects, Humans, Hypercholesterolemia drug therapy, Hypercholesterolemia enzymology, Hypercholesterolemia pathology, Intestinal Mucosa enzymology, Intestinal Mucosa pathology, Jejunum drug effects, Jejunum enzymology, Jejunum pathology, Lovastatin adverse effects, Male, Middle Aged, Mitotic Index, Simvastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Intestinal Mucosa drug effects, Lovastatin analogs & derivatives
- Abstract
Mevalonic acid is an important biochemical intermediate in cholesterol synthesis and other processes involved in cell replication. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the enzyme which catalyzes mevalonic acid synthesis. To determine whether a potent competitive inhibitor of this enzyme, the drug simvastatin, may have an adverse effect on enterocyte cell replication and cholesterol metabolism, small intestinal biopsies from nine hypercholesterolemic subjects were obtained before and during treatment with simvastatin as a lipid-lowering agent. Histologic review of biopsies in a blinded manner detected no change in ratio of villous length to crypt length or in mitotic index which might indicate altered cell replication. Similarly, no significant change in measured activity of HMG-CoA reductase activity was observed. In spite of the high exposure of jejunal mucosal cells to this potent competitive inhibitor of a key enzyme, no adverse effect on growth could be detected.
- Published
- 1991
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10. Effect of probucol on blood cholesterol and basal and lovastatin-induced 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in mice.
- Author
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Gebhard RL, Prigge WF, Andreini JP, and Freeman ML
- Subjects
- Animals, Enzyme Induction, Intestinal Mucosa enzymology, Mice, Microsomes, Liver enzymology, Receptors, LDL drug effects, Sterol O-Acyltransferase analysis, Cholesterol blood, Hydroxymethylglutaryl CoA Reductases analysis, Lovastatin pharmacology, Probucol pharmacology
- Abstract
The drug probucol is known to reduce levels of blood cholesterol and to have antioxidant effects on lipoproteins that may alter their metabolism. While studying probucol feeding in mice, we observed that the drug lowered total hepatic, but not gut, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase activities during the diurnal cycle. Hepatic fatty acyl:cholesterol acyl transferase activity and cholesterol content were not measurably affected by probucol. Probucol also abolished the induction of HMG CoA reductase activity that resulted from feeding of lovastatin, when activity was measured in microsomes washed free of drugs. These effects are consistent with previous reports that probucol increases fractional clearance of lipoprotein cholesterol by the liver. The findings raise the possibility that some patients with hypercholesterolemia may benefit from combined therapy with lovastatin plus probucol.
- Published
- 1991
11. The diet pill that worked.
- Author
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Gebhard RL and Albrecht J
- Subjects
- Humans, Male, Middle Aged, Appetite Depressants adverse effects, Bezoars etiology, Deglutition Disorders etiology, Dietary Fiber adverse effects
- Published
- 1990
- Full Text
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12. Cryptosporidial carriage without symptoms in the acquired immunodeficiency syndrome (AIDS)
- Author
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Janoff EN, Limas C, Gebhard RL, and Penley KA
- Subjects
- Adult, Humans, Male, Acquired Immunodeficiency Syndrome complications, Carrier State diagnosis, Cryptosporidiosis diagnosis, Cytomegalovirus Infections diagnosis, Diarrhea etiology
- Published
- 1990
- Full Text
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13. Hepatic and intestinal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in genetically diabetic mice.
- Author
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Gebhard RL, Levine AS, Prigge WF, Brown DM, Handwerger BS, and Morley JE
- Subjects
- Animals, Body Weight, Diabetes Mellitus genetics, Insulin Resistance, Mice, Mice, Inbred C57BL, Mice, Obese, Diabetes Mellitus enzymology, Diabetes Mellitus, Experimental enzymology, Hydroxymethylglutaryl CoA Reductases isolation & purification, Intestines enzymology, Liver enzymology, Obesity
- Abstract
Cholesterol synthesis rate, as determined by 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, is characterized in the major organs of genetically diabetic mice. Both C57BL/Ks db+/db+ and C57BL/6 ob+/ob+ mice are hyperinsulinemic and insulin-resistant. These animals demonstrate loss of the circadian rhythm of hepatic reductase activity and a tendency for increased intestinal activity. As a result, proportionally more endogenous cholesterol synthesis occurs in intestinal mucosa than liver in genetically diabetic animals. Thus, the alterations in activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase which are observed in animal models of diabetes are the result of diminished insulin effect rather than insulin level.
- Published
- 1983
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14. Effect of exorphins on gastrointestinal function, hormonal release, and appetite.
- Author
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Morley JE, Levine AS, Yamada T, Gebhard RL, Prigge WF, Shafer RB, Goetz FC, and Silvis SE
- Subjects
- Adult, Female, Glutens metabolism, Glutens pharmacology, Humans, Intestines physiology, Male, Middle Aged, Pancreatic Hormones metabolism, Appetite drug effects, Gastrointestinal Hormones metabolism, Gastrointestinal Motility drug effects, Intestines drug effects, Peptides pharmacology
- Abstract
Peptic digestion of gluten results in the production of substances having opiatelike activity in bio- and receptor assays. These substances have been termed exorphins. In this study, we determined the effect of gluten, hydrolyzed gluten, and hydrolyzed gluten plus the opiate blocker naloxone on a variety of hormonal parameters, gastrointestinal transit time, small bowel mucosal integrity, and satiety. Hydrolyzed gluten prolonged intestinal transit time, and this effect was reversed by concomitant administration of naloxone. Hydrolyzed gluten also produced a naloxone-reversible increase in plasma somatostatinlike activity, which may have been responsible for the delayed transit time. No effects of the "exorphins" could be demonstrated on serum gastrin, cortisol, carbohydrate metabolism, or small bowel mucosal integrity. Although a number of studies have suggested a role for endogenous opiates in appetite regulation, we could not demonstrate any effect of "exorphins" on the amount of calories ingested nor on the perception of satiety. This study defines a potential role for small opiatelike peptides in foodstuffs in the regulation of intestinal function.
- Published
- 1983
15. Gluten-sensitive enteropathy.
- Author
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Struber W, Falchuk ZY, and Gebhard RL
- Subjects
- Absorption, Alkaline Phosphatase analysis, Antibody Formation, Antibody Specificity, Carbon Radioisotopes, Chromatography, Affinity, Culture Techniques, Epithelial Cells, Epithelium immunology, Histocompatibility Antigens, Immunoglobulin A biosynthesis, Immunoglobulin M biosynthesis, Intestinal Diseases genetics, Intestinal Mucosa immunology, Intestine, Small pathology, Jejunum enzymology, Leucine metabolism, Glutens, Intestinal Diseases immunology
- Abstract
Gluten-sensitive enteropathy is a disease characterized by villous atrophy related to the ingestion of wheat protein, gluten. In the present series of studies it was shown that gluten ingestion in affected patients is promptly followed by a local immune reaction involving the production of antigluten antibodies. An in vitro model of gluten enteropathy involving the organ culture of biopsy tissue has been developed which has led to the conclusion that gluten is not directly toxic to the gastrointestional mucosa but, instead, brings about tissue damage through the activation of an endogenous mechanism, presumably the immune system. An additional insight into the pathogenesis of gluten-sensitive enteropathy is afforded by the fact that some 90% of patients carry the HL-A8 histocompatibility type. This may be a marker for the presence of an abnormal immune response gene or may determine the presence of abnormal gluten-protein receptor sites on epithelial cells. Either of these abnormalities could result in a propensity to respond immunologically to gluten, with destructive consequences.
- Published
- 1975
16. Clinical and endoscopic findings in patients early in the course of clostridium difficile-associated pseudomembranous colitis.
- Author
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Gebhard RL, Gerding DN, Olson MM, Peterson LR, McClain CJ, Ansel HJ, Shaw MJ, and Schwartz ML
- Subjects
- Adult, Aged, Clostridium isolation & purification, Diarrhea microbiology, Enterocolitis, Pseudomembranous pathology, Enterocolitis, Pseudomembranous physiopathology, Feces analysis, Female, Humans, Male, Middle Aged, Sigmoidoscopy, Clostridium Infections complications, Enterocolitis, Pseudomembranous complications
- Abstract
Endoscopic and clinical features are reported for 39 patients detected early in the course of pseudomembranous colitis. Disease was detected early by virtue of careful surveillance in patients in whom diarrhea developed. Early proctosigmoidoscopic findings in pseudomembranous colitis are illustrated. Clinical presentation includes development of fever, leukocytosis, abdominal pain, and even an ileus picture on radiography in addition to diarrhea.
- Published
- 1985
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17. The effects of several weeks of ethanol consumption on ethanol kinetics in normal men and women.
- Author
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Holtzman JL, Gebhard RL, Eckfeldt JH, Mottonen LR, Finley DK, and Eshelman FN
- Subjects
- Adult, Cimetidine pharmacology, Ethanol pharmacology, Female, Humans, Kinetics, Male, Microsomes, Liver enzymology, Oxidation-Reduction, Ranitidine pharmacology, Sex Factors, Ethanol metabolism
- Abstract
We examined in normal men and women the effects of chronic ethanol consumption and the coadministration of cimetidine and ranitidine on the kinetics of ethanol. We found that the consumption of 45 gm ethanol per day for 3 weeks increased the apparent volume of distribution of ethanol in men from 732 to 884 ml/kg (P less than 0.01) but had no such effect in women (697 ml/kg before ethanol and 746 ml/kg after chronic ethanol consumption). This combined therapy had no effect on the rate of ethanol disappearance in either sex. In men the rate of disappearance was 165 mg/L/hr before and 168 mg/L/hr after chronic consumption, while in women the respective values were 209 and 203 mg/L/hr. The addition of either cimetidine or ranitidine had no effect on either parameter compared with values observed on day 22 of the study. In view of the known inhibitory effects of cimetidine on cytochrome P-450-dependent enzymes, our data suggest that this enzyme system does not metabolize a significant fraction of ingested ethanol in subjects who have consumed moderate doses of alcohol for several weeks.
- Published
- 1985
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18. The effect of severe zinc deficiency on activity of intestinal disaccharidases and 3-hydroxy-3-methylglutaryl coenzyme A reductase in the rat.
- Author
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Gebhard RL, Karouani R, Prigge WF, and McClain CJ
- Subjects
- Animals, Ileum enzymology, Intestinal Mucosa enzymology, Jejunum enzymology, Male, Rats, Rats, Inbred Strains, Sucrase metabolism, Trehalase metabolism, Zinc metabolism, beta-Galactosidase metabolism, Alkaline Phosphatase metabolism, Glycoside Hydrolases metabolism, Hydroxymethylglutaryl CoA Reductases metabolism, Intestine, Small enzymology, Zinc deficiency
- Abstract
Specific activities of five enzymes were measured in intestinal mucosa of zinc-deficient rats and compared to activities in appropriate zinc-sufficient controls. Three disaccharidases were found to be significantly reduced in zinc deficiency. Alkaline phosphatase, a zinc metalloenzyme, also showed reduced activity. Activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis, was elevated. It is possible that impaired carbohydrate digestion (reflected in disaccharidase activity) and even defective lipid absorption (reflected in reductase activity) may contribute to the poor nutrition and diarrhea of zinc deficiency.
- Published
- 1983
- Full Text
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19. In vivo regulation of canine intestinal 3-hydroxy-3-methylglutaryl coenzyme A reductase by cholesterol, lipoprotein, and fatty acids.
- Author
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Gebhard RL and Prigge WF
- Subjects
- Animals, Cholesterol pharmacology, Cholestyramine Resin pharmacology, Dogs, Fatty Acids pharmacology, Hydroxycholesterols pharmacology, Organ Culture Techniques, Cholesterol biosynthesis, Fatty Acids metabolism, Hydroxymethylglutaryl CoA Reductases metabolism, Ileum enzymology, Intestinal Mucosa enzymology, Lipoproteins metabolism
- Abstract
Thirty-Vella-isolated ileal segments in dogs were used to study the regulation of intestinal cholesterol synthesis. This excluded fistula enabled independent in vivo manipulation of luminal and vascular influences on mucosal cells. Segments were studied repeatedly and each animal served as its own control. Cholesterol synthesis rate was assessed by measuring mucosal activity of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Luminal cholesterol and 25-hydroxycholesterol were shown to reduce HMG CoA reductase activity to 64 +/- 7% and 42 +/- 4%, respectively, of control within 4 hr. Reductase activity in the excluded segment also responded to alterations in serum cholesterol produced by cholesterol or cholestyramine feeding. Similarly, in vitro studies showed that lipoprotein cholesterol inhibited HMG CoA reductase in mucosa from the excluded segment but not in mucosa from intact bowel. In contrast to sterols, fatty acids stimulated HMG CoA reductase activity by luminal contact. These findings suggest that the cholesterol needs of canine intestinal epithelial cells are acutely balanced by absorption and synthesis of cholesterol. Mucosal cells may also utilize lipoprotein cholesterol under certain conditions, perhaps via low density lipoprotein receptors. Fatty acid absorption stimulated cholesterol synthesis in the absence of luminal cholesterol, perhaps to facilitate chylomicron formation.
- Published
- 1981
20. Efficacy of routine fiberoptic endoscope cleaning and disinfection for killing Clostridium difficile.
- Author
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Hughes CE, Gebhard RL, Peterson LR, and Gerding DN
- Subjects
- Clostridium drug effects, Clostridium isolation & purification, Clostridium Infections prevention & control, Disinfectants pharmacology, Hydrogen-Ion Concentration, Microbial Sensitivity Tests, Aldehydes pharmacology, Disinfection methods, Endoscopes, Equipment Contamination prevention & control, Glutaral pharmacology, Sterilization methods
- Abstract
We have evaluated a standard procedure for cleaning and disinfection of endoscopes for efficacy in eradicating a spore-forming bacterial organism, Clostridium difficile. Initially, 23 endoscopes were cultured for the presence of C. difficile after hanging in storage for at least 24 hours after cleaning and disinfection. All cultures were negative. Subsequently, endoscopes used in 15 patients who had stool cultures positive for C. difficile were cultured immediately after use and again after cleaning and disinfection with 2% alkaline glutaraldehyde for 5 min. Ten of 15 (67%) endoscopes were culture positive for C. difficile immediately after use. After cleaning and disinfection, all of the endoscopes were culture negative except one, which yielded two negative cultures and two cultures showing late growth of rare C. difficile colonies, but contamination could not be ruled out. In vitro exposure to 2% alkaline glutaraldehyde for 5 min resulted in 99% or greater killing of C. difficile spores. We conclude that cleaning and a minimum of 5 min of disinfection with 2% alkaline glutaraldehyde are likely to be effective in killing C. difficile vegetative organisms and spores on endoscopes.
- Published
- 1986
- Full Text
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21. TRH and histidyl-proline diketopiperazine inhibit cholesterol synthesis in dog intestine.
- Author
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Gebhard RL, Morley JE, Prigge WF, Goodman MW, and Prasad C
- Subjects
- Animals, Dogs, Hydroxymethylglutaryl CoA Reductases metabolism, Ileum drug effects, Intestinal Mucosa drug effects, Organ Culture Techniques, Cholesterol biosynthesis, Ileum metabolism, Intestinal Mucosa metabolism, Peptides, Cyclic pharmacology, Piperazines pharmacology, Thyrotropin-Releasing Hormone pharmacology
- Abstract
Low concentrations of thyrotropin-releasing hormone and one of its metabolites, histidyl-proline diketopiperazine, are shown to have an inhibitory effect on the activation of 3-hydroxy-3-methylglutaryl coenzyme A reductase which occurs during organ culture of canine intestinal mucosa. Somatostatin and vasoactive intestinal polypeptide, in contrast, are shown to have no effect. Thyrotropin-releasing hormone, recently shown to be present in gut mucosa, may be a physiological regulator of intestinal cholesterol synthesis. Histidyl-proline diketopiperazine, an active metabolite of the hormone, is possibly the active agent since its inhibitory effect was observed at a concentration as low as 10(-12) M. These observations demonstrate an effect on intestinal metabolism by a neurotransmitter-like hormone at potentially physiologic concentrations.
- Published
- 1981
- Full Text
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22. A balloon designed for endoscopic variceal sclerotherapy.
- Author
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Sievert CE Jr, Gebhard RL, and Silvis SE
- Subjects
- Animals, Dogs, Endoscopy methods, Esophageal and Gastric Varices physiopathology, Female, Male, Endoscopes, Esophageal and Gastric Varices therapy, Sclerosing Solutions therapeutic use
- Published
- 1984
- Full Text
- View/download PDF
23. An in vitro model of gluten-sensitive enteropathy. Effect of gliadin on intestinal epithelial cells of patients with gluten-sensitive enteropathy in organ culture.
- Author
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Falchuk ZM, Gebhard RL, Sessoms C, and Strober W
- Subjects
- Adolescent, Adult, Aged, Alkaline Phosphatase metabolism, Celiac Disease pathology, Child, Disaccharidases metabolism, Gastrointestinal Diseases, Gliadin pharmacology, Glutens pharmacology, Humans, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Intestinal Mucosa ultrastructure, Jejunum drug effects, Jejunum pathology, Jejunum ultrastructure, Microscopy, Electron methods, Middle Aged, Models, Biological, Organ Culture Techniques, Celiac Disease metabolism, Gliadin metabolism, Glutens metabolism, Jejunum metabolism
- Abstract
Jejunal biopsy specimens from patients with gluten-sensitive enteropathy (GSE) (obtained during gluten challenge) as well as from normal individuals and patients with other gastrointestinal abnormalities were cultured in vitro for 48 h in the presence or absence of a peptic-tryptic digest (P-T digest) of gliadin. In the absence of gliadin the alkaline phosphatase activity in the biopsy specimens obtained from normal control individuals increased from an initial value of 384 +/- 83 U to a 48 h value of 561 +/- 151 U (mean +/- SD) (difference significant at P < 0.01). The initial alkaline phosphatase activity of specimens obtained from patients with GSE was strikingly lower than that of normals, 117 +/- 79 U, and increased to a 48 h value of 399 +/- 203 U (difference significant at P < 0.01). The biochemical change in cultured biopsy specimens of GSE patients correlated with increases in the length and regularity of brush borders of epithelial cells as seen with the electron microscope. In the presence of a P-T digest of gliadin, the alkaline phosphatase activity of biopsy specimens of control individuals increased from an initial value of 384 +/- 83 U to a 48 h value of 578 +/- 156 U. In contrast, the alkaline phosphatase activity of biopsy specimens of patients with GSE in exacerbation showed a markedly diminished increase in activity during 48 h of culture; in this case the initial activity was 117 +/- 79 U and the final activity was 203 +/- 93 U. This inhibitory effect on increase of alkaline phosphatase activity during organ culture was specific in that a P-T digest of casein (a protein not toxic in vivo to patients with GSE) had no effect on alkaline phosphatase increases in culture. Finally, these results obtained with biopsy specimens taken from patients with GSE in exacerbation were compared with results obtained from patients with GSE in remission. Alkaline phosphatase activity of specimens obtained from the latter group of patients also increased during culture but in this instance P-T digest of gliadin in the culture medium had no significant inhibitory effect. In conclusion, the inhibitory effect of gliadin on intestinal epithelial cells in organ culture represents an in vitro model of gluten-sensitive enteropathy. Inasmuch as this effect of gliadin is not seen in cultures of specimens taken from patients in remission, it appears that gliadin is not directly toxic to GSE jejunal mucosa per se, but rather toxicity requires the participation of an endogenous effector mechanism which must first be stimulated in vivo.
- Published
- 1974
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24. Acute viral enteritis and exacerbations of inflammatory bowel disease.
- Author
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Gebhard RL, Greenberg HB, Singh N, Henry P, Sharp HL, Kaplan L, and Kapikian AZ
- Subjects
- Acute Disease, Adolescent, Adult, Antibodies, Viral analysis, Child, Colitis, Ulcerative immunology, Crohn Disease immunology, Humans, Middle Aged, Norwalk virus immunology, Rotavirus immunology, Rotavirus Infections complications, Colitis, Ulcerative complications, Crohn Disease complications, Enteritis complications, Virus Diseases complications
- Abstract
In order to determine whether or not acute viral gastroenteritis predisposes to exacerbations of inflammatory bowel disease, patients with Crohn's disease and ulcerative colitis were observed longitudinally. Assessment of disease activity was correlated with evidence for viral infection by serology and stool antigen testing. Disease exacerbations were rarely associated with rotavirus, Norwalk agent, or adenovirus infection, primarily because these infection rates were very low. However, the few patients having these viral infections often had relapse symptoms.
- Published
- 1982
25. Filiform polyposis in Crohn's colitis mimicking toxic megacolon.
- Author
-
Antonow DR, Gebhard RL, Dykoski RK, and Sumner HW
- Subjects
- Adult, Colitis diagnosis, Colon diagnostic imaging, Colon pathology, Diagnosis, Differential, Humans, Male, Megacolon, Toxic diagnosis, Radiography, Colonic Neoplasms diagnosis, Crohn Disease diagnosis, Intestinal Polyps diagnosis
- Abstract
A patient with filiform polyposis in Crohn's colitis is reported. Unlike previous reports of filiform polyposis, this patient's colitis was of rapid onset and antedated development of pseudopolyps by a short duration. Additionally, unlike previous reports, the disease process was quite aggressive. The extensive degree of fissuring found throughout the bowel wall may have produced the unusually shaped polyps and caused the toxic colonic atony.
- Published
- 1981
- Full Text
- View/download PDF
26. Malabsorption--a cause of geriatric nutritional failure.
- Author
-
Gebhard RL
- Subjects
- Aged, Biological Transport, Celiac Disease complications, Digestion, Ethanol adverse effects, Exocrine Pancreatic Insufficiency complications, Giardiasis complications, Humans, Intestinal Absorption, Intestines microbiology, Malabsorption Syndromes etiology, Malabsorption Syndromes physiopathology, Protein-Losing Enteropathies complications, Whipple Disease complications, Malabsorption Syndromes diagnosis
- Published
- 1983
27. Simvastatin, a competitive inhibitor of HMG-CoA reductase, lowers cholesterol saturation index of gallbladder bile.
- Author
-
Duane WC, Hunninghake DB, Freeman ML, Pooler PA, Schlasner LA, and Gebhard RL
- Subjects
- Adult, Aged, Bile analysis, Bile metabolism, Clinical Trials as Topic, Gallbladder metabolism, Humans, Hypercholesterolemia drug therapy, Hypercholesterolemia metabolism, Lipids analysis, Lovastatin therapeutic use, Male, Middle Aged, Random Allocation, Simvastatin, Time Factors, Anticholesteremic Agents therapeutic use, Bile drug effects, Cholesterol metabolism, Gallbladder drug effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lovastatin analogs & derivatives
- Abstract
We tested the possibility that simvastatin, a competitive inhibitor of HMG-CoA reductase related to mevinolin, might alter cholesterol saturation of gallbladder bile. Ten patients with Type IIa or IIb hypercholesterolemia underwent bile sampling before, and again after, treatment with 20 or 40 mg per day simvastatin for 7 to 13 weeks. Mean cholesterol saturation index of gallbladder bile fell from 1.01 to 0.77 during simvastatin treatment (p less than 0.01). This finding strongly suggests that treatment with HMG-CoA reductase inhibitors will not predispose to development of cholesterol gallstones. Indeed, it raises the possibility that such inhibitors might have a future role to play in treatment of gallstones.
- Published
- 1988
- Full Text
- View/download PDF
28. Influence of dietary ascorbic acid upon enzymes of sterol biosynthesis in the guinea pig.
- Author
-
Holloway DE, Peterson FJ, Prigge WF, and Gebhard RL
- Subjects
- Animals, Ascorbic Acid analysis, Ascorbic Acid pharmacology, Body Weight, Cholesterol blood, Guinea Pigs, Intestinal Mucosa enzymology, Liver analysis, Male, Ascorbic Acid Deficiency enzymology, Cholesterol 7-alpha-Hydroxylase metabolism, Diet, Hydroxymethylglutaryl CoA Reductases metabolism, Steroid Hydroxylases metabolism
- Published
- 1981
- Full Text
- View/download PDF
29. Lovastatin treatment inhibits sterol synthesis and induces HMG-CoA reductase activity in mononuclear leukocytes of normal subjects.
- Author
-
Stone BG, Evans CD, Prigge WF, Duane WC, and Gebhard RL
- Subjects
- Adult, Aged, Enzyme Induction drug effects, Humans, Leukocytes, Mononuclear metabolism, Lipids blood, Lovastatin administration & dosage, Microsomes enzymology, Middle Aged, Hydroxymethylglutaryl CoA Reductases biosynthesis, Leukocytes, Mononuclear drug effects, Lovastatin pharmacology, Sterols biosynthesis
- Abstract
The mechanism by which competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase decrease serum cholesterol is incompletely understood. The few available data in humans suggest that chronic administration of the competitive inhibitor, lovastatin, decreases serum cholesterol with little or no change in total body sterol synthesis. To further define the effect of lovastatin on cholesterol synthesis in normal subjects, we investigated the effect of a single oral dose of lovastatin and a 4-week treatment period of lovastatin on mononuclear leukocyte (ML) sterol synthesis as a reflection of total body sterol synthesis. In parallel, we measured serum lipid profiles and HMG-CoA reductase activity in ML microsomes that had been washed free of lovastatin. ML sterol synthesis did not significantly decrease (23 +/- 5%, mean +/- SEM) at 3 h after a single 40-mg dose of lovastatin. With a single oral 80-mg dose, ML sterol synthesis decreased by 57 +/- 10% (P less than 0.05) and remained low for the subsequent 6 h. With both doses, total HMG-CoA reductase enzyme activity in microsomes prepared from harvested mononuclear leukocytes was induced 4.8-fold (P less than 0.01) over baseline values. Both the 20-mg bid dose and the 40-mg bid dose of lovastatin administered for a 4-week period decreased serum cholesterol by 25-34%. Lovastatin at 20 mg bid decreased ML sterol synthesis by 23 +/- 6% (P less than 0.02) and increased ML HMG-CoA reductase 3.8 times (P less than 0.001) the baseline values. Twenty four hours after stopping lovastatin, ML sterol synthesis and HMG-CoA reductase enzyme activity had returned to the baseline values. The higher dose of lovastatin (40 mg bid) decreased ML sterol synthesis by 16 +/- 3% (P less than 0.05) and induced HMG-CoA reductase to 53.7 times (P less than 0.01) the baseline value at 4 weeks. Stopping this higher dose effected a rebound in ML sterol synthesis to 140 +/- 11% of baseline (P less than 0.01), while HMG-CoA reductase remained 12.5 times baseline (P less than 0.01) over the next 3 days. No rebound in serum cholesterol was observed. From these data we conclude that in normal subjects lovastatin lowers serum cholesterol with only a modest effect on sterol synthesis. The effect of lovastatin on sterol synthesis in mononuclear leukocytes is tempered by an induction of HMG-CoA reductase enzyme quantity, balancing the enzyme inhibition by lovastatin.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1989
30. Abnormal cholesterol metabolism in renal clear cell carcinoma.
- Author
-
Gebhard RL, Clayman RV, Prigge WF, Figenshau R, Staley NA, Reesey C, and Bear A
- Subjects
- Adenocarcinoma enzymology, Adenocarcinoma ultrastructure, Cholesterol Esters metabolism, Cholesterol, HDL metabolism, Cytosol enzymology, Fatty Acids metabolism, Humans, Kidney Neoplasms enzymology, Kidney Neoplasms ultrastructure, Microsomes enzymology, Adenocarcinoma metabolism, Cholesterol metabolism, Kidney Neoplasms metabolism
- Abstract
The clear cell form of renal cell carcinoma is known to derive its histologic appearance from accumulations of glycogen and lipid. We have found that the most consistently stored lipid form is cholesteryl ester. Clear cell cancer tissue contained 8-fold more total cholesterol and 35-fold more esterified cholesterol than found in normal kidney. Cholesteryl ester appeared to be formed intracellularly since it was not membrane-bound and since oleate was the predominant form, as opposed to linoleate in lipoprotein cholesteryl esters. The cholesterol in clear cell tumors did not appear to be a result of excessive synthesis from acetate since HMG-CoA reductase (EC 1.1.1.34) activity was lower in cancer tissue than in normal kidney (2.9 +/- 0.8 vs. 7.2 +/- 1.2 pmol/mg of protein per min). In contrast, intracellular activity of fatty acyl-coenzyme A:cholesterol acyl transferase (ACAT, EC 2.3.1.26) was higher in tumor tissue than in normal kidney (2405 +/- 546 vs. 1326 +/- 301 pmol/mg of protein per 20 min) while cytosolic cholesteryl ester hydrolase activity appeared normal. Cholesteryl ester storage in clear cell renal cancer may be a result of a primary abnormality in ACAT activity or it may be a result of reduced release of free cholesterol (relative to cell content) with a secondary elevation in ACAT activity.
- Published
- 1987
31. Transport of circulating serum cholesterol by human renal cell carcinoma.
- Author
-
Clayman RV, Figenshau RS, Prigge WF, Forstrom L, and Gebhard RL
- Subjects
- Adosterol, Adrenal Glands metabolism, Biological Transport, Carcinoma, Renal Cell diagnostic imaging, Cholesterol Esters metabolism, Humans, Iodine Radioisotopes, Kidney metabolism, Kidney Neoplasms diagnostic imaging, Liver metabolism, Preoperative Care, Radionuclide Imaging, Carcinoma, Renal Cell metabolism, Cholesterol blood, Kidney Neoplasms metabolism
- Abstract
Clear cell renal cancer contains a large quantity of cholesterol ester (300-mg./gm. protein). To determine whether abnormalities in cholesterol transport could account for this sterol accumulation, the uptake, release, and imaging capabilities of intravenously injected 131I-6-iodomethyl-29-norcholesterol, a cholesterol analogue, were studied preoperatively in five patients with clear cell renal cancer. At surgery, samples of the liver, tumor, adrenal, and non-tumor kidney were obtained for analysis. 131I-sterol uptake by the tumor, when normalized for cholesterol content, was less than for adrenal, liver or kidney. In contrast, release of preloaded 131I-sterol from the human tumors was consistently slower than for normal kidney. The reduced release of free cholesterol from renal cancer cells may, in part, be responsible for the accumulation of cholesterol in human renal cancer.
- Published
- 1987
- Full Text
- View/download PDF
32. Shingles esophagitis: endoscopic diagnosis in two patients.
- Author
-
Gill RA, Gebhard RL, Dozeman RL, and Sumner HW
- Subjects
- Aged, Biopsy, Esophagitis pathology, Herpes Zoster pathology, Humans, Male, Skin Diseases, Infectious complications, Skin Diseases, Infectious diagnosis, Thorax, Esophagitis diagnosis, Esophagoscopy, Herpes Zoster diagnosis
- Published
- 1984
- Full Text
- View/download PDF
33. Clostridium difficile-associated diarrhea and colitis in adults. A prospective case-controlled epidemiologic study.
- Author
-
Gerding DN, Olson MM, Peterson LR, Teasley DG, Gebhard RL, Schwartz ML, and Lee JT Jr
- Subjects
- Adult, Aged, Anti-Bacterial Agents adverse effects, Clostridium isolation & purification, Cross Infection diagnosis, Cytotoxins analysis, Diarrhea diagnosis, Endoscopy, Enterocolitis, Pseudomembranous diagnosis, Feces microbiology, Female, Humans, Male, Middle Aged, Prospective Studies, Clostridium Infections diagnosis, Cross Infection etiology, Diarrhea etiology, Enterocolitis, Pseudomembranous etiology
- Abstract
In a one-year period, 149 adult cases of Clostridium difficile-associated diarrhea and colitis were compared with 148 diarrhea-free controls. Eighty-seven percent were nosocomial and 75% were on surgical services. Endoscopy revealed pseudomembranes in 51% of the 109 cases in which stool cytotoxin was present, compared with 11% of the 40 cases that were culture-positive but cytotoxin-negative. Cases diagnosed only by stool culture showed essentially no differences from controls, 21% of whom had asymptomatic stool colonization. We estimate that only 20% of these cases had diarrhea due to C difficile. Compared with controls, cases diagnosed by the presence of cytotoxin or pseudomembranes were found to have been hospitalized longer at diarrhea onset, to have had more antecedent infections, and to have received clindamycin, multiple antimicrobials, and therapeutic antimicrobials more often than controls, but controls received prophylactic antimicrobials more frequently than cases. Cultures of the environment, patients, and personnel failed to detect a mechanism of acquisition.
- Published
- 1986
34. Inhibition of mammary carcinogenesis in rats by dietary restriction.
- Author
-
Sinha DK, Gebhard RL, and Pazik JE
- Subjects
- 9,10-Dimethyl-1,2-benzanthracene, Animals, Body Weight, DNA biosynthesis, Estrogens analysis, Female, Mammary Neoplasms, Experimental chemically induced, Rats, Rats, Inbred Strains, Diet, Reducing, Mammary Neoplasms, Experimental prevention & control
- Abstract
Mammary tumors were induced by 7,12-dimethylbenz[a]anthracene (DMBA) in Sprague-Dawley female rats kept under different dietary restrictions. Starting at 40 days of age, 4 groups of rats were either full-fed or fed 25%, 50% or 80% of their daily ration. At 55 days of age DMBA was given by intravenous injection. Rats were continued on the restricted diet until 150 days after carcinogen treatment. Rats on 25% diet lost weight rapidly and the experiment had to be terminated. Rats on the 50% diet maintained a lower body weight throughout the experiment; only 12% developed tumors. Rats on the 80% diet lost weight initially, but at the termination of the experiment, there was no significant difference in body weight between this group and the full-fed controls. Of the rats on 80% diet, 34% developed tumors, compared to 92% tumor incidence in the full-fed controls. Vaginal smears were normal in the animals fed the 80% diet, while some irregularity was observed in the 50% group. Breeding capability in rats on the 80% diet was not affected, since there was no observable difference in the pregnancy rate between these animals and their controls. There was also no difference in plasma level of estrogen between the 80% diet group and the full-fed controls at the time of carcinogen treatment. [3H]Thymidine labelling index was significantly affected by 50% restriction of diet while there was no significant change in the 80% group.
- Published
- 1988
- Full Text
- View/download PDF
35. In vitro studies of ulcerative ileojejunitis.
- Author
-
Klaeveman HL, Gebhard RL, Sessoms C, and Strober W
- Subjects
- Adult, Atrophy, Biopsy, Carbon Radioisotopes, Celiac Disease pathology, Enteritis immunology, Enteritis pathology, HLA Antigens, Humans, Leucine metabolism, Male, Organ Culture Techniques, Remission, Spontaneous, Alkaline Phosphatase biosynthesis, Celiac Disease complications, Enteritis metabolism, Glutens adverse effects, Ileum immunology, Ileum metabolism, Immunoglobulin A biosynthesis, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Jejunum immunology, Jejunum metabolism, Jejunum pathology, Ulcer metabolism
- Abstract
A patient with ulcerative ileojejunitis was studied by determination of HL-A phenotype, by measurement of jejunal IgA synthesis using a labeled amino acid incorporation technique, and by in vitro organ culture. The patient carried the HL-A8 phenotype in common with 87.5% of patients with gluten-sensitive enteropathy. During a period of exposure to dietary gluten, jejunal tissue from the patient exhibited in high IgA synthetic rate. In organ culture of the jejunal biopsy specimen there was an increase in alkaline phosphatase activity in the absence, but not in the presence, of gluten peptides. The synthetic rate value and the organ culture behavior are similar to those observed in patients with gluten-sensitive enteropathy in exacerbation. During a period in which the patient was not exposed to dietary gluten, including prolonged period of intravenous alimentation, jejunal IgA synthesis and organ culture behavior were studied repeatedly. In contrast to patients with gluten-sensitive enteropathy in remission (i.e., on a gluten-free diet), jejunal IgA synthesis did not decline. However, in organ culture in the patients tissue now behaved like that of other patients with gluten-sensitive enteropathy in remission: alkaline phosphatase activity increased during culture in the presence and absence of gluten peptides. These studies support the concept that ulcerative ileojejunitis is a complication of gluten-sensitive enteropathy in which escape from control by gluten restriction has occurred. They suggest that ulcerative ileojejunitis due to a supervening pathological process which is, at least in part, immunological in nature.
- Published
- 1975
36. Diurnal rhythm of HMG CoA reductase activity in canine intestine is independent of luminal contents.
- Author
-
Gebhard RL, Sievert CE, and Prigge WF
- Subjects
- Animals, Biopsy, Dogs, Eating, Gastrointestinal Contents, Circadian Rhythm, Hydroxymethylglutaryl CoA Reductases metabolism, Ileum enzymology, Intestinal Mucosa enzymology
- Abstract
Activity of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34) measured in isolated segments of canine intestinal mucosa showed a distinct diurnal rhythm. Total activity changed over a twofold range with a peak occurring during midday, shortly after feeding. Since the isolated segments had no contact with luminal contents, the rhythm was not directly related to food components or bile salts. Humoral or neural influences must mediate the rhythm. The diurnal rhythm persisted for at least 3-5 mo, but was lost by 10 mo following formation of the isolated segment, possibly because of mucosal involution.
- Published
- 1986
- Full Text
- View/download PDF
37. Relative secretion of cholesterol-4-14C in the bile and upper and lower small intestinal washings of the bile fistula rabbit.
- Author
-
Buchwald H, Gebhard RL, and Varco RL
- Subjects
- Animals, Biliary Fistula, Ileum metabolism, Jejunum metabolism, Rabbits, Time Factors, Cholesterol metabolism, Intestinal Mucosa metabolism
- Published
- 1974
38. Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension.
- Author
-
Archer SL, Johnson GJ, Gebhard RL, Castleman WL, Levine AS, Westcott JY, Voelkel NF, Nelson DP, and Weir EK
- Subjects
- Animals, Hypertension, Pulmonary prevention & control, Male, Rats, Rats, Inbred Strains, Dietary Fats, Unsaturated pharmacology, Fatty Acids analysis, Fish Oils pharmacology, Hypertension, Pulmonary etiology, Hypoxia complications, Lung analysis, Phospholipids analysis
- Abstract
The effects of dietary polyunsaturated fats on chronic hypoxic pulmonary hypertension were assessed in rats fed fish oil, corn oil, or a lower fat, "high-carbohydrate" diet (regular) beginning 1 mo before the start of hypoxia (0.4 atm, n = 30 for each). Mean pulmonary arterial pressures were lower in the chronically hypoxic rats fed fish oil (19.7 +/- 1.8 mm Hg) than in the rats fed corn oil (25.3 +/- 1.6 mm Hg) or regular diets (27.5 +/- 1.5 mm Hg, P less than 0.05). The fish oil diet increased lung eicosapentaenoic acid 50-fold and depleted lung arachidonic acid 60% (P less than 0.0001 for each). Lung thromboxane B2 and 6-ketoprostaglandin F1 alpha levels were lower, and platelet aggregation, in response to collagen, was reduced in rats fed fish oil. Chronically hypoxic rats fed fish oil had lower mortality rates than the other hypoxic rats. They also had lower blood viscosity, as well as less right ventricular hypertrophy and less peripheral extension of vascular smooth muscle to intra-acinar pulmonary arteries (P less than 0.05 for each). The mechanism by which dietary fish oil decreases pulmonary hypertension and vascular remodeling during chronic hypoxia remains uncertain. The finding that a fish oil diet can reduce the hemodynamic and morphological sequelae of chronic hypoxia may have therapeutic significance.
- Published
- 1989
- Full Text
- View/download PDF
39. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity in the human gastrointestinal tract.
- Author
-
Gebhard RL, Stone BG, and Prigge WF
- Subjects
- Biopsy, Cholesterol pharmacology, Humans, Hydroxycholesterols pharmacology, Intestinal Mucosa drug effects, Intestinal Mucosa enzymology, Organ Culture Techniques, Tissue Distribution, Digestive System enzymology, Hydroxymethylglutaryl CoA Reductases metabolism
- Abstract
Activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34) was measured in intestinal mucosa of the human gastrointestinal tract. Activity was highest in gastric mucosa (18.2 pmol per mg per min) and there was a constant low level in the small bowel and colon (approximately 10 pmol per mg per min). Phosphorylation/dephosphorylation modulation of intestinal reductase activity was demonstrated in normal mucosa. Expressed jejunal reductase activity was significantly higher in celiac sprue mucosa and mucosa from defunctionalized intestine of jejunoileal bypass patients. Enzyme activity also increased during 24-hr mucosal organ culture in the absence of exogenous cholesterol. Addition to the culture medium of pure cholesterol or 25-hydroxycholesterol dissolved in a small volume of ethanol suppressed the culture-induced increase to 86 +/- 3% and 69 +/- 5% of paired controls, respectively. This evidence suggests that a moderate degree of feedback regulation of intestinal cholesterol synthesis by luminal sterol occurs in man. Mucosal HMG-CoA reductase activity was also measured in patients with hyperlipoproteinemia. Patients with either predominant hypercholesterolemia or predominant hypertriglyceridemia lipid profiles had "normal" expressed reductase activity, but feedback regulation by free cholesterol could not be demonstrated in either group under these conditions.
- Published
- 1985
40. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis.
- Author
-
Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, and Lee JT Jr
- Subjects
- Adult, Aged, Clinical Trials as Topic, Colitis etiology, Costs and Cost Analysis, Diarrhea etiology, Female, Humans, Male, Middle Aged, Prospective Studies, Random Allocation, Clostridium Infections drug therapy, Colitis drug therapy, Diarrhea drug therapy, Metronidazole therapeutic use, Vancomycin therapeutic use
- Abstract
101 patients with Clostridium-difficile-associated diarrhoea or colitis were prospectively randomised to 10-day oral courses of metronidazole, 250 mg four times a day, or vancomycin, 500 mg four times a day. 7 did not complete the protocol and were dropped from analysis. Pseudomembranous colitis (PMC) was diagnosed after endoscopy in 33 patients. Of the remaining patients without PMC, 38 had both C difficile culture and cytotoxin and 23 had only culture evidence of C difficile. 52 evaluable patients received vancomycin and 42 received metronidazole. There were two treatment failures with metronidazole and none with vancomycin (p = 0.20); and two relapses with metronidazole versus six with vancomycin (p = 0.17). Treatment in 1 patient in each group was discontinued because of drug intolerance. Response and relapse rates of the 33 patients with PMC were no different from those of the remaining patients. Pharmacy cost for the dosage used was $387.48 to $520.00 for vancomycin and $11.84 for metronidazole. Metronidazole and vancomycin have equivalent efficacy and relapse rates and are tolerated to a similar extent by patients with C-difficile-related diarrhoea and colitis, but metronidazole is considerably more economical.
- Published
- 1983
- Full Text
- View/download PDF
41. Dermatitis herpetiformis. Immunologic concomitants of small intestinal disease and relationship to histocompatibility antigen HL-A8.
- Author
-
Gebhard RL, Falchuk ZM, Katz SI, Sessoms C, Rogentine GN, and Strober W
- Subjects
- Adult, Aged, Alkaline Phosphatase analysis, Carbon Radioisotopes, Celiac Disease genetics, Dermatitis Herpetiformis genetics, Female, Glutens metabolism, Humans, Immunoglobulin A biosynthesis, Intestinal Absorption, Intestinal Mucosa enzymology, Intestinal Mucosa metabolism, Jejunum enzymology, Jejunum metabolism, Leucine metabolism, Male, Middle Aged, Sucrase analysis, Trehalase analysis, Celiac Disease immunology, Dermatitis Herpetiformis immunology, Histocompatibility Antigens, Intestinal Diseases immunology
- Abstract
In the present study the relation between the gluten-sensitive intestinal lesion observed in dermatitis herpetiformis (DH) and in gluten-sensitive enteropathy (coeliac sprue) (GSE) was analyzed. Jejunal IgA synthesis in DH was estimated from the extent of incorporation of [(14)C]leucine into IgA in jejunal biopsy specimens during short-term in vitro culture. Patients with DH have significantly elevated incorporation values as compared to normal control individuals (18,880+/-13,614 vs. 5,830+/-3,190 cpm/mg tissue protein/ 90 min) (P < 0.02) and the degree of elevation correlates well with the degree of morphologic abnormality. Thus patients with DH are similar to patients with GSE where elevated local mucosal IgA synthesis has also been observed. By using both morphologic and immunologic criteria for evaluating intestinal status, patients with DH and intestinal disease were distinguished from patients with DH free of intestinal disease. Of the eight patients in the former group, seven carried HL-A8 (87.5%), an incidence which is strikingly similar to that observed in patients with GSE alone (88.5%). In contrast, of the seven patients in the latter group (without gastro-intestinal disease) two had HL-A8, an incidence (27%) not significantly different from that in the normal population (20%) (P > 0.1).Thus, both in respect to local mucosal increase in IgA synthetic rates and in respect to the association with HL-A8, the intestinal lesion of DH is similar to that of GSE.
- Published
- 1974
- Full Text
- View/download PDF
42. Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers.
- Author
-
Hohmann EL, Elde RP, Rysavy JA, Einzig S, and Gebhard RL
- Subjects
- Animals, Bone Development drug effects, Bone and Bones blood supply, Chromatography, High Pressure Liquid, Dogs, Fluorescent Antibody Technique, Neurons physiology, Radioimmunoassay, Swine, Vasoactive Intestinal Peptide pharmacology, Bone and Bones innervation, Periosteum physiology, Vasoactive Intestinal Peptide physiology
- Abstract
Neural control of bone metabolism and growth has been suggested, although the identity of participating neurons and neurotransmitters effecting this control has not been established. Immunohistochemical studies demonstrated a system of vasoactive intestinal peptide (VIP)-immunoreactive nerve fibers that innervate periosteum and bone in several mammalian species. Thoracic sympathetic chain ganglionectomy resulted in an ipsilateral loss of VIP-immunoreactive fibers in the periosteum of ribs, whereas dorsal root ganglionectomy had no effect. Injection of fast blue into rib periosteum labeled a population of VIP-immunoreactive sympathetic postganglionic neurons. Thus, postganglionic sympathetic neurons may provide an important means by which VIP regulates bone mineralization.
- Published
- 1986
- Full Text
- View/download PDF
43. Time course of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and messenger ribonucleic acid, biliary lipid secretion, and hepatic cholesterol content in methimazole-treated hypothyroid and hypophysectomized rats after triiodothyronine administration: possible linkage of cholesterol synthesis to biliary secretion.
- Author
-
Day R, Gebhard RL, Schwartz HL, Strait KA, Duane WC, Stone BG, and Oppenheimer JH
- Subjects
- Animals, Cholesterol biosynthesis, Cholesterol blood, Hydroxymethylglutaryl CoA Reductases genetics, Hypothyroidism chemically induced, Lipid Metabolism, Liver enzymology, Male, Methimazole pharmacology, Rats, Rats, Inbred Strains, Bile metabolism, Cholesterol metabolism, Hydroxymethylglutaryl CoA Reductases metabolism, Hypophysectomy, Hypothyroidism metabolism, Liver metabolism, RNA, Messenger metabolism, Triiodothyronine pharmacology
- Abstract
In an effort to define the mechanism by which thyroid hormone increases the synthesis of hepatic cholesterol, we have investigated both in hypophysectomized and methimazole-treated hypothyroid rats the time course of T3 effects on plasma cholesterol concentration, total hepatic cholesterol, the rate of biliary secretion of cholesterol, bile acids, and phospholipids, and the activity and mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, the rate-limiting enzyme in the hepatic synthesis of cholesterol. A single dose of 200 micrograms T3 was estimated to maintain at least 90% nuclear occupancy for the ensuing 54 h of the experiment. In both preparations the relative rise in biliary secretion of cholesterol exceeded that of other biliary constituents and preceded by 12 h an increase in HMG-CoA reductase enzyme activity and its mRNA. The level of total hepatic cholesterol remained constant throughout the experiment. We interpret these findings to suggest that T3-stimulated cholesterol synthesis is mediated by an antecedent T3-induced rise in biliary cholesterol secretion. We postulate that biliary cholesterol secretion is augmented by an intrahepatic shift of cholesterol and depletion of the hepatic sampling center responsible for the feedback regulation of cholesterol synthesis. The level of HMG CoA reductase mRNA appeared to govern enzyme activity in both preparations, but the ratio of mRNA to hepatic enzyme activity was substantially greater in the methimazole-treated compared with the hyphophysectomized animals.
- Published
- 1989
- Full Text
- View/download PDF
44. Hormonal regulation of canine intestinal cholesterol synthesis.
- Author
-
Goodman MW, Prigge WF, and Gebhard RL
- Subjects
- Alkaline Phosphatase metabolism, Animals, Dogs, Ileum enzymology, In Vitro Techniques, Sucrase metabolism, Glucagon pharmacology, Hydroxymethylglutaryl CoA Reductases metabolism, Insulin pharmacology, Intestinal Mucosa enzymology
- Abstract
Hormonal regulation of intestinal cholesterol synthesis was studied both in vitro and in vivo. Cholesterol synthesis rate was determined by measurement of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 1.1.1.34) activity and by incorporation [14C]acetate into sterol. In vitro studies utilized organ culture of canine ileal mucosa. During 6-h culture, reductase activity was stimulated sevenfold. Insulin (10-6 M) augmented this rise to 144 +/- 7% of th control activity, while 10(-8) M glucagon, 10(-3) M adenosine 3',5'-cyclic monophosphate, and 3-isobutyl-1-methylxanthine suppressed activity (final reductase activity was 83 +/- 3%, 75 +/- 4%, and 41 +/- 3%, respectively, of cultured control values). In vivo studies utilized dogs with isolated Thiry-Vella ileal fistulas. In vivo, insulin doubled reductase activity while glucagon led to a 42 +/- 9% suppression. It is concluded that insulin and glucagon may be potential physiological regulators of intestinal cholesterol synthesis. The glucagon effect may be mediated by cyclic nucleotides.
- Published
- 1981
- Full Text
- View/download PDF
45. Intestinal HMG-CoA reductase activity is low in hypercholesterolemic patients and is further decreased with lovastatin therapy.
- Author
-
Freeman ML, Prigge WF, Hunninghake DB, Duane WC, and Gebhard RL
- Subjects
- Bile analysis, Cholestyramine Resin therapeutic use, Female, Humans, Hypercholesterolemia drug therapy, Jejunum enzymology, Male, Middle Aged, Hydroxymethylglutaryl CoA Reductases metabolism, Hypercholesterolemia enzymology, Intestinal Mucosa enzymology, Lovastatin therapeutic use
- Abstract
Significant cholesterol synthesis occurs in gut mucosa of animals and humans. However, the role of gut synthesis in hypercholesterolemia and the effect of drugs on this function have not been defined. We obtained jejunal biopsies and bile samples from 21 Type II hypercholesterolemic subjects (mean serum cholesterol = 331 mg/dl) on a low fat diet after an over-night fast. Whole gut mucosal homogenate was assayed for activity of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-determining enzyme of cholesterol synthesis. Mean reductase activity (pmol/mg per min) was 5.5 +/- 1.0 (n = 21) in hypercholesterolemic subjects versus 11.3 +/- 1.0 in 52 normal subjects (P less than 0.01). This is consistent with the hypothesis that the primary defect in these patients is not excessive cholesterol synthesis but decreased low density lipoprotein (LDL) clearance. It implies that high LDL levels down-regulate gut reductase activity. After treatment of 7 patients with lovastatin (40-80 mg/day for at least 6-13 weeks), gut reductase activity decreased from 7.7 +/- 2.6 to 3.6 +/- 0.5 (P less than 0.05), in biopsies obtained 12 hr after the last drug dose. Inhibition of reductase activity by this drug was detected 12 hr after a dose, and the enzyme was not measurably induced during 6-13 weeks of therapy. In keeping with the decrease in serum cholesterol (332----239 mg/dl) and mucosal reductase activity during lovastatin therapy, mean gallbladder bile cholesterol saturation index also decreased (1.045 +/- 0.112 vs. 0.883 +/- 0.109, n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1988
46. Antibodies to viral gastroenteritis viruses in Crohn's disease.
- Author
-
Greenberg HB, Gebhard RL, McClain CJ, Soltis RD, and Kapikian AZ
- Subjects
- Adolescent, Adult, Complement Fixation Tests, Female, Humans, Male, Middle Aged, Radioimmunoassay, Antibodies, Viral analysis, Crohn Disease microbiology, Gastroenteritis microbiology, RNA Viruses immunology, Rotavirus immunology, Viruses, Unclassified immunology
- Abstract
Antibody prevalence and titer to rotavirus and Norwalk virus were studied in Crohn's disease patients and in age-, sex-, and time-matched controls. There were no significant antibody differences between the groups studied.
- Published
- 1979
47. Abnormal intestinal permeability to sugars in diabetes mellitus.
- Author
-
Mooradian AD, Morley JE, Levine AS, Prigge WF, and Gebhard RL
- Subjects
- Adult, Aged, Diabetes Mellitus, Type 1 drug therapy, Humans, Insulin therapeutic use, Male, Middle Aged, Diabetes Mellitus, Type 1 physiopathology, Diabetes Mellitus, Type 2 physiopathology, Disaccharides, Intestinal Absorption, Lactulose urine, Rhamnose urine
- Abstract
A test of intestinal mucosal function which utilizes the differential permeability of L-rhamnose and lactulose has been reported to be helpful in the diagnosis of gluten-sensitive enteropathy. We have applied this test to 48 male subjects with diabetes mellitus to evaluate its usefulness as a screening test in diabetic patients and to further study sugar absorption in these individuals. Total urinary lactulose excretion in the 13 healthy control subjects was 54.5 +/- 8.5 mg/5 h, while excretion by diabetic patients was increased at 116.1 +/- 15.7 mg/5 h (p less than 0.01). Similarly, total L-rhamnose excretion by diabetic patients was significantly higher (139.7 +/- 14.3 mg/5 h vs 84.3 +/- 18.4 mg/5 h, p less than 0.05). The ratio of percent urinary excretion for lactulose/L-rhamnose (L/R ratio) for diabetic patients (0.197 +/- 0.024) was not different from the control subjects (0.151 +/- 0.2). Nine out of 48 diabetic patients studied had lactulose/L-rhamnose ratios higher than the mean plus two standard deviations of the control group, which might lead to the diagnosis of small bowel mucosal disease. Although we may have been detecting subclinical mucosal disease or gluten sensitive enteropathy in a subgroup, it appears that this test of intestinal mucosal function should be interpreted with caution in diabetic patients.
- Published
- 1986
- Full Text
- View/download PDF
48. Regulation of cholesterol synthesis in cultured canine intestinal mucosa.
- Author
-
Gebhard RL and Cooper AD
- Subjects
- Animals, Bile Acids and Salts pharmacology, Biological Transport, Active, Cholesterol pharmacology, Cycloheximide pharmacology, Dogs, Hydroxymethylglutaryl CoA Reductases metabolism, Intestinal Absorption, Intestinal Mucosa drug effects, Lipid Metabolism, Lipoproteins pharmacology, Organ Culture Techniques, Cholesterol biosynthesis, Intestinal Mucosa metabolism
- Abstract
The regulation of intestinal cholesterol synthesis was studied utilizing canine ileal mucosa maintained in organ culture for 6 h. Viability was monitored by light and electron microscopy, measurement of cellular enzymes, and the ability to actively transport a glucose analogue. The activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.4.3.4), the rate-limiting enzyme of cholesterol synthesis, increased 4-fold during a 6-h culture. A parallel increase occurred in the rate of acetate incorporation into digitonin-precipitable sterols during this period. This increase could be prevented by the addition of cycloheximide to the culture. Pure cholesterol, 7-ketocholesterol, and 25-hydroxycholesterol, when present during the last 4 h of culture, also caused significant suppression of the rise in HMG-CoA reductase activity (final HMG-CoA reductase with the three sterols was 77 +/- 4%, 68 +/- 5%, and 58 +/- 3% of control postculture value). Bile salts at low, nontoxic concentrations also inhibited the increase of enzyme activity (2 mM taurocholate = 63 +/- 3% of control, 0.5 mM taurochenodeoxycholate = 76 +/- 6% of control). In contrast, dog lipoproteins separated by ultracentrifugation failed to significantly affect intestinal cholesterol synthesis in these short term organ cultures.
- Published
- 1978
49. Recent advances in diagnosis and treatment of cholestatic jaundice.
- Author
-
Gebhard RL and Vennes JA
- Subjects
- Bile Acids and Salts therapeutic use, Biopsy, Needle, Cholangiography, Cholelithiasis drug therapy, Cholestasis blood, Diagnosis, Differential, Humans, Liver pathology, Tomography, X-Ray Computed, Ultrasonography, Cholestasis diagnosis, Cholestasis therapy
- Published
- 1980
50. Subacute combined degeneration of the spinal cord with cystinuria.
- Author
-
De Myer W and Gebhard RL
- Subjects
- Adolescent, Cystinuria metabolism, Cystinuria pathology, Humans, Intestinal Absorption, Intestinal Mucosa pathology, Male, Spinal Cord Diseases metabolism, Spinal Cord Diseases pathology, Syndrome, Cystinuria complications, Spinal Cord Diseases complications
- Abstract
An 18-year-old man had noticed increasing difficulty in walking for 4 years. Examination disclosed spastic paraparesis and posterior column signs suggestive of subacute combined degeneration of the spinal cord. Urinalysis, urinary thin-layer chromatography, and intestinal biopsy disclosed typical cystinuria. Pernicious anemia and other known enteropathies were excluded. Although this could be a chance association of cystinuria and subacute combined degeneration, one other paper has reported a cystinuria patient with similar neurologic findings. A chance association between cystinuria and nonpernicious anemia subacute combined degeneration of the spinal cord should occur only once in 120 million individuals. Thus, identification of only a few more cases would suggest a pathogenetic link between the two disorders. These observations emphasize the need to search for neurologic signs in patients with cystinuria and to screen the urine of patients with spinal cord signs of obscure origin for cystinuria.
- Published
- 1975
- Full Text
- View/download PDF
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