The long-chain 3-hydroxyacyl-CoA dehydrogenase of human liver mitochondria.
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3-Hydroxyacyl CoA Dehydrogenases↗
Biomedical subjects
B Middleton
Publications and source records attributed to B Middleton.
Probabilistic diagnosis using a reformulation of the INTERNIST-1/QMR knowledge base. I. The probabilistic model and inference algorithms.
In Part I of this two-part series, we report the design of a probabilistic reformulation of the Quick Medical Reference (QMR) diagnostic decision-support tool. We describe a two-level multiply connected belief-network representation of the QMR knowledge base of internal medicine. In the belief-network representation of the QMR knowledge base, we use probabilities derived from the QMR disease profiles, from QMR imports of findings, and from National Center for Health Statistics hospital-discharge statistics. We use a stochastic simulation algorithm for inference on the belief network. This algorithm computes estimates of the posterior marginal probabilities of diseases given a set of findings. In Part II of the series, we compare the performance of QMR to that of our probabilistic system on cases abstracted from continuing medical education materials from Scientific American Medicine. In addition, we analyze empirically several components of the probabilistic model and simulation algorithm.
Algorithms↗
Probabilistic diagnosis using a reformulation of the INTERNIST-1/QMR knowledge base. II. Evaluation of diagnostic performance.
We have developed a probabilistic reformulation of the Quick Medical Reference (QMR) system. In Part I of this two-part series, we described a two-level, multiply connected belief-network representation of the QMR knowledge base and a simulation algorithm to perform probabilistic inference on the reformulated knowledge base. In Part II of this series, we report on an evaluation of the probabilistic QMR, in which we compare the performance of QMR to that of our probabilistic system on cases abstracted from continuing medical education materials from Scientific American Medicine. In addition, we analyze empirically several components of the probabilistic model and simulation algorithm.
Algorithms↗
A free-text processing system to capture physical findings: Canonical Phrase Identification System (CAPIS).
The task of gathering detailed patient information from free-text medical records presents a significant barrier to clinical research. In this paper, we describe a prototype system for extracting physical examination findings from dictated admission summaries. Our computer program applies a concept-based free-text processing algorithm that identifies user-selected target physical examination findings. We are using the extraction system to enrich an existing clinical database. The system was evaluated by comparing the physical examination findings extracted by our computer program with findings extracted by an independent investigator. Our prototype system was able to recall 92 percent (sensitivity) of the relevant physical findings, with a precision of 96 percent (positive predictive value).
Algorithms↗
A free-text processing system to capture physical findings: Canonical Phrase Identification System (CAPIS).
The task of gathering detailed patient information from free-text medical records presents a significant barrier to clinical research. In this paper, we describe a prototype system for extracting physical examination findings from dictated admission summaries. Our computer program applies a concept-based free-text processing algorithm that identifies user-selected target physical examination findings. We are using the extraction system to enrich an existing clinical database. The system was evaluated by comparing the physical examination findings extracted by our computer program with findings extracted by an independent investigator. Our prototype system was able to recall 92 percent (sensitivity) of the relevant physical findings, with a precision of 96 percent (positive predictive value).
Academic Medical Centers↗
Agents which increase cyclic AMP have diverse effects on low-density-lipoprotein-receptor function in human vascular smooth-muscle cells and skin fibroblasts.
Receptor-mediated binding and metabolism of low-density lipoproteins (LDL) in cultured human vascular smooth-muscle cells and skin fibroblasts are altered by increased cellular cyclic AMP concentrations. However, the LDL receptor does not respond to changes in cyclic AMP concentration in a simple manner. The activation of adenylate cyclase with forskolin, or the addition of membrane-permeant cyclic AMP analogues, initially decreases the expression of the LDL receptor, but is followed by a substantial increase in receptor expression after 24 h. This increase does not occur in the presence of inhibitors of RNA or protein synthesis, and is due to doubling of the Bmax. of the LDL receptor, without alteration of its affinity for LDL. By contrast, elevation of cyclic AMP concentration by inhibition of phosphodiesterases results in decreased receptor expression throughout the 24 h period. These two response patterns are reproducible phenomena, consistently observed in low-passaged cells derived from seven unrelated individuals.
1-Methyl-3-isobutylxanthine↗
Inhibition of acyl coenzyme A: cholesterol acyl transferase by trimethylcyclohexanylmandelate (cyclandelate).
Cyclandelate was an effective inhibitor of rat hepatic acycloenzyme A: cholesterol acyltransferase (ACAT) with a concentration of 80 microM being required for half maximal inhibition. A similar effect was seen with human and rabbit liver microsomal enzymes. The drug did not compete with oleoyl CoA or cholesterol and could be removed from enzyme preparations by washing. It was hydrolysed rapidly by rat liver microsomes to products which were non inhibitory. No hydrolysis of the drug was seen with non hepatic microsomes and the concentration of cyclandelate required to cause half maximal inhibition of ACAT in the transformed mouse macrophage J774 microsomal fraction was less than 30 microM. The possible significance of the differential actions of cyclandelate towards hepatic and extra hepatic ACAT in vivo is discussed.
Acyl Coenzyme A↗
3-Oxothiolase activities and [14C]-2-methylbutanoic acid incorporation in cultured fibroblasts from 13 cases of suspected 3-oxothiolase deficiency.
Cultured fibroblasts from 13 patients with organic aciduria suggesting 3-oxothiolase deficiency were studied by measuring first the capacity of the isoleucine degradative pathways in whole cells, as the incorporation of 1-[14C]-2-methylbutanoic acid into macromolecules, and, second, the activity of 3-oxothiolase in cell homogenates using specific 3-oxoacyl-CoA substrates to identify the different enzymes. Nine patients showed low incorporation by the macromolecular labeling assay, as well as deficiency of 2-methylacetoacetyl-CoA thiolase. In this group of patients, low activity by the macromolecular labeling assay was associated with clinically severe symptoms, and vice versa. Two patients showed reduced macromolecular labeling, but apparently normal 3-oxothiolase. Finally, two patients showed normal activities by either test, the reason for their particular organic aciduria being unknown. In conclusion, occurrence of urinary 2-methyl-3-hydroxybutyric acid and/or tiglyglycine is not an unequivocal indicator of the absence of the thiolase that metabolizes 2-methylacetoacetyl-CoA. Measurement of 1-[14C]-2-methylbutanoic acid incorporation in cultured fibroblasts adds important information in studying possible defects of the isoleucine catabolic pathway.
Acetyl-CoA C-Acyltransferase↗
Chemical synthesis of dual-radiolabelled cyclandelate and its metabolism in rat hepatocytes and mouse J774 cells.
1. The chemical synthesis of 3,3,5-trimethyl[1-3H]cyclohexanol, 3,3,5-trimethyl[2,3-3H]cyclohexanol and 3,3,5-trimethyl[2,3-3H]cyclohexanyl[1-14C]mandelate (cyclandelate) are described. The ratio of 3H/14C radioactivity in the ester was 27:1. 2. Cultured rat hepatocytes accumulated trimethylcyclohexanol rapidly and excreted its glucuronide into the culture medium. Rat hepatocytes also accumulated cyclandelate rapidly, hydrolysing the ester and excreting trimethylcyclohexanol into the medium. This trimethylcyclohexanol then re-entered the cells and was converted to its glucuronide prior to excretion. 3. In contrast, no hydrolysis of cyclandelate was seen on incubation with J774 cells, a transformed mouse macrophage. 4. Similar differences in hydrolytic activity were seen with microsomal fractions prepared from rat liver and J774 cells. Hepatic microsomes caused a rapid hydrolysis of cyclandelate while no hydrolysis was detectable after incubations of over an hour with J774 microsomes. 5. This difference in hydrolytic activity may have important implications for the action of cyclandelate on cholesterol metabolism in extrahepatic tissues.
Animals↗
Cholesterol esterification plays a major role in determining low-density-lipoprotein receptor activity in primary monolayer cultures of rat hepatocytes.
1. We have previously shown that the capacity for specific binding of human 125I-labelled low-density lipoprotein (LDL) to rat hepatocytes increases with time in culture [Salter, Bugaut, Saxton, Fisher & Brindley (1987) Biochem. J. 247, 79-84]. 2. In the present study we show that this up-regulation is accompanied by a rise in the cholesterol ester content of the cells. 3. Inhibition of cholesterol esterification with the drug 58-035 (Sandoz) significantly decreases the time-dependent 'up-regulation' of LDL receptors. 4. Incubation of hepatocytes with LDL itself has little effect on subsequent LDL binding. However, when cholesterol esterification is inhibited, incubation with LDL decreases binding below that attained with the drug alone. 5. Inhibition of cholesterol synthesis with Lovastatin significantly increases LDL binding and antagonizes the effect of 58-035. 6. We conclude that in hepatocytes the rate of cellular cholesterol esterification can become the major determinant of LDL-receptor activity.
Amides↗
The substrate determines the rate and pattern of neutral lipid synthesized by isolated human sebaceous glands.
Lipogenesis from different substrates was determined in isolated human sebaceous glands after 17-20 h in culture. Rates of total lipogenesis were 1003 +/- 141, 842 +/- 90, 481 +/- 57 pmol.h-1 gland-1 +/- SE from acetate, lactate and glucose, respectively, when present as sole substrates: the rate from glucose was significantly lower (P less than 0.01). Squalene synthesis was greatest from acetate at 479 +/- 44 pmol.h-1.gland-1; significantly higher than from lactate (281 +/- 45 pmol.h-1.gland-1) or glucose at 119 +/- 18 pmol.h-1.gland-1. Wax ester plus cholesterol ester synthesis showed similar dependence on substrate but triglyceride synthesis was unaffected. We conclude that the added substrate determines both the rate and pattern of non-polar lipid synthesized by isolated human sebaceous glands.
Acetates↗
Inhibition of cellular cholesterol esterification can decrease low density lipoprotein receptor number in human fibroblasts.
In fibroblasts deprived of exogenous cholesterol to induce low density lipoprotein receptors there is a continuing flux of cholesterol esterification. The structurally unrelated inhibitors of acyl-CoA; cholesterol acyl-transferase, progesterone, trimethylcyclohexanyl mandelate and 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl] propanamide, (58035), could all inhibit this basal rate of esterification within 1h of addition. Exposure of cholesterol-deprived fibroblasts for 17h to progesterone or trimethylcyclohexanyl mandelate caused decreased specific binding and metabolism of low density lipoprotein. The effect was not a direct inhibition of lipoprotein binding; it was time dependent and followed from the reversible inhibition of cholesterol esterification by these two compounds. The irreversible inhibition of esterification by 58035 left the receptor number unaffected. The results indicate that down regulation of low density lipoprotein receptors is initiated by accumulation of cholesterol in a specific intracellular pool. Inhibition of cholesterol esterification by progesterone and trimethylcyclohexanyl mandelate causes accumulation of cholesterol in this pool but 58035 does not.
Amides↗
beta-Ketothiolase deficiency with favourable evolution.
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Acetyl-CoA C-Acyltransferase↗
Is remission of acne due to changes in sebum composition?
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Acne Vulgaris↗
Hyperketotic states due to inherited defects of ketolysis.
From the description of 2 unrelated patients with succinyl-CoA transferase (3-OAT) deficiency and 1 patient with acetoacetyl-CoA thiolase (AAT) deficiency, we have attempted to draw the clinical and metabolic consequences of such defects. The association of recurrent attacks of severe ketoacidosis with blood glucose levels generally high or normal, low lactacidemia and low ammonemia is the most common presentation of these disorders. In 3-OAT deficiency, a potentially fatal disorder, there is a permanent ketosis with the only excretion of 3-hydroxybutyrate, acetoacetate and 3-hydroxyisovalerate. AAT patients usually excrete, in addition to the usual ketone bodies, 2-methyl-3-hydroxybutyrate and tiglylglycine; 2-methyl-acetoacetate may also be present. Both conditions can be identified by enzymatic analysis in cultured fibroblast. These disorders can mimic diabetic ketoacidosis or salicylism and can easily be missed. The knowledge of these ketolytic defects must severely question the complacent diagnosis of 'fasting ketoacidosis' or 'idiopathic ketotic hypoglycemia', mainly when severe metabolic acidosis is present.
Acetoacetates↗
Acetoacetyl CoA thiolase deficiency presenting as ketotic hypoglycemia.
We report two children who presented with hypoglycemia and metabolic acidosis in whom acetoacetyl-CoA thiolase (EC 2.3.1.9) measured in fibroblast homogenates was deficient. Deficiency of this enzyme is normally associated with urinary excretion of 2-methylacetoacetate and in one child the urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine was raised. By contrast, in the other child, the urinary excretion of these metabolites was very low even during ketoacidosis and following an isoleucine load. We suggest that this could be due to deficiency of the extrahepatic isoenzyme, a defect that may be responsible for some of the cases of "ketotic hypoglycemia."
Acetoacetates↗
Cyclandelate. An inhibitor of cholesterol esterification.
In an in vitro study the action of cyclandelate on cholesterol metabolism was investigated. The addition of cyclandelate (100 mumol/L) inhibited the incorporation of acetate into sterol but not into fatty acid in human fibroblasts incubated with the drug for 3 hours. Further exposure of fibroblasts to cyclandelate for 17 hours resulted in a similar inhibition in the uptake and hydrolysis of LDL. Moreover, in the presence of cyclandelate (100 mumol/L), cholesterol esterification was inhibited by 90% in fibroblasts cultured with LDL and in human monocyte derived macrophages cultured with acetyl-LDL. It is likely that the inhibition by cyclandelate of cholesterol esterification in whole cells is due to a direct inhibition of the hepatic microsomal enzyme acyl coenzyme A: cholesterol acyl transferase (ACAT), since addition of the drug in a concentration of 100 mumol/L inhibited by 74% the activity of ACAT derived from rat liver. Furthermore, the intact drug molecule was required for maximal inhibition of microsomal ACAT.
Animals↗
Cyclohexanol and methylcyclohexanols. A family of inhibitors of hepatic HMGCoA reductase in vivo.
Oral dosing of rats with cyclohexanol and methylcyclohexanols resulted in the inhibition of hepatic HMGCoA reductase. Neither cyclohexane or cyclohexane diols exerted any effects. Inhibition was not due to alcohol dehydrogenase mediated changes in redox state since 3,3',5-trimethylcyclohexanol (TMC), a non substrate for alcohol dehydrogenase, was a potent inhibitor of HMGCoA reductase. Following a single dose of TMC there was no alteration in total hepatic HMGCoA reductase activity for more than 6 hr after which the enzyme activity was depressed in a dose-dependent manner. The normal diurnal rhythm of HMGCoA reductase was reduced in amplitude following TMC administration but the phase was unaltered and the t 1/2 for activity decay following the peak of activity was unaffected. Prior to the inhibitory effect of a TMC dose becoming apparent in total HMGCoA reductase activity we found that the expressed activity of the enzyme (after isolation in F- medium to suppress endogenous protein phosphatase) was depressed by 43%. The inhibitory effect of TMC on total HMGCoA reductase activity seen 8 hr or more after dosing was reflected by inhibition of sterol synthesis in liver measured in vivo after [3H]-H2O administration.
Animals↗