Xanthelasma palpebrarum and corneal arcus in octogenarians.
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Aged↗
Biomedical subjects
J Davignon
Publications and source records attributed to J Davignon.
Effect of fenofibrate treatment on type III hyperlipoproteinemia.
The effect of treatment with fenofibrate was investigated in nine patients (seven men) presenting with type III hyperlipoproteinemia. This therapy produced a statistically significant decrease in serum triglyceride, cholesterol, apolipoproteins B, CII, CIII, and E levels. Particular attention was focused on lipoproteins containing apolipoprotein B. The concentration of particles recognized by monoclonal antibodies (BL3, BL5, and BL7), associated with atherosclerotic disease, was lowered by the treatment. The most dramatic decrease was observed for lipoproteins LpE:B and LpCIII:B, which are particularly enhanced in type III hyperlipoproteinemia.
Adult↗
Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia.
We found a large deletion (more than 10 kilobases) in the gene for the low-density-lipoprotein receptor in 63 percent of French Canadians with heterozygous familial hypercholesterolemia. The deletion also occurred in homozygous form in four of seven French Canadian homozygotes. The deletion removes the promoter and first exon of the gene, and it abolishes the production of messenger RNA for the low-density-lipoprotein receptor. The high frequency of this mutation is presumably related to a founder effect among the 8000 ancestors of present-day French Canadians, who have had relatively little cross-breeding with groups of other national origins. This deletion has not been observed in any other ethnic group. It can be detected by analysis of genomic DNA from blood leukocytes, thus allowing direct diagnosis of familial hypercholesterolemia in a majority of affected French Canadians.
Adult↗
Apolipoprotein E polymorphism and plasma cholesterol response to probucol.
Probucol has been shown to be an effective and well-tolerated cholesterol-lowering drug. However, response in terms of cholesterol reduction has been shown to vary significantly among individuals. The purpose of this study was to assess the role of apolipoprotein E polymorphism in determining this variation. A retrospective study of 89 hypercholesterolemic type II patients who had been treated with probucol (1 g/d) and for whom the apolipoprotein E phenotype was known was carried out. The patients were first grouped into those with heterozygous familial hypercholesterolemia (FH) and those considered to have other forms of hypercholesterolemia (non-FH). Further subclassification of the individuals in both groups as IIa or IIb, allowed the definition of four diagnostic classes, FH IIa or IIb and non-FH IIa or IIb. Among these classes there was no significant heterogeneity for the relationship between response and age or sex. After correction for between-class heterogeneity in duration of probucol treatment, comparison of individuals with the apo E3/3 phenotype with those carrying the epsilon 4 allele showed significant differences in cholesterol reduction both absolute change and percent change. Further contrasts between diagnostic and apo E genotype stratifications of these data showed that the FH patients carrying the epsilon 4 allele had the greatest reduction in cholesterol level.
Adult↗
[The predictive value of apolipoproteins in atheroma].
During the last three decades studies on the pathogenesis of atheroma have highlighted successively lipids, lipoproteins and apolipoproteins. The undisputed role of cholesterol has been widened by taking into account the nature and composition of lipoproteins in addition to their plasma levels. The concept of relative atherogenicity of lipoproteins and a better understanding of the role played by apolipoproteins have thrown more light on the formation of atheromatous plaques in the absence of hyperlipidaemia. On this point must be mentioned studies that associate LDL apo-B with coronary risk, and apo-A1 abnormalities which predispose to atheromatosis. More recently, attention has been focused on apo-E as a genetic factor that may interact with the environment to modulate blood cholesterol and triglyceride levels and secondarily influence individual tendencies to develop atherosclerosis. The three major forms of apo-E (E2, E3, E4) are encoded by three alleles (E2, E3, E4) and act on the same locus of chromosome 19 to determine 6 apo-E phenotypes in the population. We now know that the E2 allele is associated with lower levels, and the E4 allele with higher levels, of LDL-cholesterol than the E3 allele. E4 is a risk factor which predisposes to coronary atherosclerosis. It follows that the E2 allele should have protective powers, provided no other factor, ecological or hereditary, intervenes to foster the development of an atherogenic hypertriglyceridaemia.
Alleles↗
Medical management of hyperlipidemia and the role of probucol.
Recent experimental and epidemiologic evidence has dispelled all doubts about the need to treat patients with hyperlipidemia. Therapy should focus on 3 areas: control of concomitant risk factors for atherosclerosis, reduction of lipid levels through diet and, if response to diet proves inadequate, administration of lipid-lowering agents. There are 4 categories of first-line drugs: resins, fibrates, nicotinic acid and probucol. Probucol has a sustained effect, additive to that of a lipid-lowering diet; it can reduce total serum cholesterol and cause xanthoma regression even in patients with receptor-defective homozygous familial hypercholesterolemia. It is effective when used alone and has an additive effect when combined with resins or nicotinic acid. Compared with many other lipid-lowering medications, it is well tolerated. Although the combination of probucol and clofibrate may cause a significant decrease in high density lipoproteins, there is no evidence that this decrease carries any adverse consequences for the underlying disease process.
Adult↗
Severe hypoalphalipoproteinemia induced by a combination of probucol and clofibrate.
Observation of a markedly depressed HDL-cholesterol (5 mg/dL) in a patient with familial hypercholesterolemia (FH) receiving probucol (1 g/day) and clofibrate (2 g/day) prompted a review of all cases treated by this combination at our lipid clinic. Hypoalphalipoproteinemia (HDL-C less than 15 mg/dL) developed in 19 of 28 (70%) hyperlipidemic subjects who received this combination for an average of 1.5 years. This effect was sustained and reversible; it did not occur on either drug alone and was manifested on average 17 weeks after the combination was started. Plasma triglycerides increased significantly in most of those patients susceptible to this reduction in HDL-C. Plasma apolipoprotein A-I was decreased 82%, in proportion to the HDL-C fall, whereas apo A-II was lowered 65%. Since apo C-III concentrations tended to be high, the apo A-I/C-III ratio was markedly depressed. Apo E levels were unchanged and apo B levels reflected the high LDL concentrations of the underlying disease. An intermediate response was observed in subjects whose HDL-C remained well above 15 mg/dL on the combination. No deleterious side-effects could be attributed directly to the administration of the combined drugs in this high-risk group. One patient actually showed complete regression of xanthelasma and extensor tendon xanthomas of the finger on the combination. A parallel is drawn with Fish-Eye disease and the presence of the apolipoprotein A-I Milano variant, where similar HDL-C levels are observed in the absence of an increased atherogenic risk. It is mandatory to monitor plasma HDL-C in hypercholesterolemic patients treated with this combination, otherwise the pronounced HDL-deficiency could go unnoticed.
Apolipoproteins↗
Effect of indomethacin treatment on prostaglandin excretion and tissue phospholipid fatty acid composition in rats bearing mammotropic pituitary tumor, MtT-F4.
The hypothesis that hormonal changes induced by the mammotropic pituitary tumor, MtT-F4, might accelerate the conversion of n-6 fatty acids to prostaglandins, resulting in a partial depletion of n-6 fatty acids was examined. In tumor-bearing rats, the administration of indomethacin induced a 50% reduction of the urinary prostaglandin levels, but exerted no significant effect on the fatty acid composition of the tissue phospholipids. It is concluded that the observed depletion of n-6 fatty acids in tumor-bearing rats is not caused by an increased production of prostaglandins.
6-Ketoprostaglandin F1 alpha↗
Risks for hyperlipidemia.
The predisposition for the development of hyperlipidemia rests almost equally on genetic and environmental factors and their interplay. Because one of the least understood factors is the duration of exposure to risk, the authors have chosen to review here some of the genetic factors and some of the relatively long-term environmental factors, such as diet and drug therapies, that are known to increase the risk of hyperlipidemia and likely the predisposition to cardiovascular disease.
Adrenergic beta-Antagonists↗
Tendon xanthomas associated with cholestanolosis and hyperapobetalipoproteinemia.
Large Achilles tendon xanthomas of the type found in severe familial hypercholesterolemia were the first manifestation of cholestanolosis (cerebrotendinous xanthomatosis) in our patient, an otherwise asymptomatic normolipidemic 21-year-old woman. Extensive laboratory investigation disclosed the presence of hyperapobetalipoproteinemia which did not resolve with the administration of probucol. Immunofluorescent studies revealed marked accumulation of apolipoprotein B in a xanthoma excised from the tricipital area. This was in contrast to the spotty and weak fluorescence observed in a tuberous xanthoma, from the same anatomical area and histologically otherwise identical, obtained from a patient with heterozygous familial hypercholesterolemia. Hyperapobetalipoproteinemia has been reported before in association with sitosterolemia but not with cholestanolosis. We suggest that cholestanol, like sitosterol, may interfere with the normal uptake and degradation of low-density lipoproteins by peripheral cells.
Adult↗
Plasma carnitine and lipid-lowering drugs.
Oral carnitine has been reported to have a lipid-lowering effect with concomitant elevation of high density lipoprotein cholesterol (HDL-C) levels in normo- and hyperlipidemic individuals. Unexpectedly, basal carnitine concentrations were found to be abnormally high in subjects receiving a combination of probucol (1 g/day) and clofibrate (2 g/day), and who also had reduced HDL-C levels. Changes in plasma carnitine levels were found to correlate with clofibrate therapy and to be readily reversible with cessation of this drug. These increases of circulating carnitine were not accompanied by a rise in HDL-C.
Carnitine↗
Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation.
The structural gene locus for apolipoprotein E (apo E) is polymorphic. Three common alleles (epsilon 2, epsilon 3, epsilon 4) code for three major isoforms in plasma and determine six apo E phenotypes that may be identified by isoelectric focusing on polyacrylamide. To establish what fraction of the inherited variation in a normal plasma lipid and lipoprotein profile is attributable to the segregation of the common alleles at the apo E gene locus, we have estimated the average apo E allelic effects on plasma cholesterol (C), triglycerides, very low-density lipoprotein (VLDL)-C, VLDL-apo B, low-density lipoprotein (LDL)-C, LDL-apo B, and high-density lipoprotein (HDL)-C in a representative sample of normolipidemic individuals from Ottawa, Canada. Data from published studies were also analyzed by the same statistical procedures. As much as 16% of the genetic variance (8.3% of the total variance) for LDL-C could be accounted for by the apo E gene locus. After correction for differences in age, sex, height, and weight, it was found that the epsilon 2 allele lowered and the epsilon 4 allele raised total cholesterol, LDL-C, and LDL-apo B. No other gene has been identified that contributes as much to normal cholesterol variability. Analysis of these data and those of others also indicates that the apo E locus imparts a differential susceptibility to a variety of factors that promote hyperlipidemia. The hypothesis is proposed that the epsilon 2 allele protects against coronary heart disease (CHD) and, hence, gives a reproductive advantage that is balanced by a predisposition to CHD when the epsilon 2 is combined with a second, independent causative factor to give a reproductive disadvantage. A similar mechanism is proposed for the maintenance of the epsilon 4 allele in the population.
Adult↗
An application of a model for a genotype-dependent relationship between a concomitant (age) and a quantitative trait (LDL cholesterol) in pedigree data.
In most genetic studies in humans the variability in a quantitative trait is adjusted for variability in concomitants (age, sex, etc) using a single regression equation prior to analyses of pedigree data. To illustrate an alternative approach, a single locus genetic model was tested. This model incorporates genotypic effects on the level of the trait, the variability in the trait, and the relationship between a concomitant and the trait. In this study, the model was applied to measures of age and low-density lipoprotein (LDL) cholesterol in a large kindred with familial hypercholesterolemia. The application of this model to 322 individuals in four generations provided evidence that genotypic variation at a single locus influences LDL levels early in life, the rate of increase of LDL with age and the phenotypic variance. A model with genotype-dependent slope and variance fit the data significantly better than a model with slope and variance independent of genotype. The inclusion of age-specific genotypic differences contributed to identification of high-risk individuals, to statistical support for a major locus, and to evidence for genetic determination of the tracking of LDL levels. Models that incorporate genotype-specific concomitant effects have the potential to represent more realistically the relationship between genotypic variability and quantitative phenotypic variation than models that assume that these effects do not exist.
Adolescent↗
Distribution of apolipoprotein E phenotypes in Friedreich's ataxia.
Allelic polymorphism at the apolipoprotein E (apo E) gene locus (alleles epsilon 2, epsilon 3, and epsilon 4) is responsible for the existence of 6 discrete electrophoretic phenotypes of plasma apo E. Since the presence of the epsilon 2 allele in the genotype tends to be associated with higher triglyceride levels, a study was undertaken to determine if a higher frequency of this allele could account for the presence of higher plasma triglycerides in subsets of patients with Friedreich's Ataxia. The frequency of the apo E phenotypes was determined in 37 subjects with Friedreich's Ataxia and compared with that of 102 normolipidemic and 102 hyperlipidemic individuals. There was no increased prevalence of the E3/2 phenotype and the epsilon 2 allele in the Friedreich's sample as is found in a hyperlipidemic sample. Furthermore, the epsilon 2 subset did not have significantly higher plasma triglycerides than the non-epsilon 2 subset and the hypothesis was rejected. On the other hand, there was a trend for a decreased frequency of the E4/3 phenotype in the Friedreich's sample relative to the hyperlipidemic group but the difference did not reach statistical significance. The apo E phenotype distribution was also measured in a smaller sample of Charlevoix-Saguenay disease; this led to the discovery of two siblings with the relatively rare E2/2 phenotype and unexpectedly low levels of plasma lipid and lipoprotein concentrations. Plasma apolipoprotein E concentrations in both diseases were within the normal range except for subjects bearing the E2/2 phenotype.
Adolescent↗
Plasma cholesteryl sulfate in Friedreich's ataxia.
Alteration of membrane fluidity and anomalies of membrane structural proteins have been suspected in Friedreich's ataxia. Plasma lecithin:cholesterol acyltransferase (LCAT) activity is also lowered in this disease, presumably because of a substrate effect. The membrane-stabilizing effect of cholesteryl sulfate (CS) and its inhibitory effect on LCAT activity prompted us to measure this substance in the plasma of Friedreich's ataxia patients as well as in normal subjects and in patients with Charlevoix-Saguenay disease. Plasma cholesteryl sulfate concentrations were significantly higher in Friedreich's ataxia, with levels above the upper limit of normal in nearly half of the cases. This increase was unrelated to age, sex or plasma cholesterol levels, but closely associated with the severity of the disease and thus considered to be secondary. A similar phenomenon (except the association with severity) was observed in Charlevoix-Saguenay ataxia. Levels also tended to be higher in first-degree relatives of Friedreich cases. The significance of these findings is discussed in the light of recent knowledge and experimental data obtained in this laboratory on rats made deficient in essential fatty acids. The highest concentrations of CS observed in Friedreich's ataxia (1097 micrograms/dL, 6 times the normal mean) was only 25% as high as the concentrations reported to inhibit LCAT activity.
Adolescent↗
The lipid content of the diabetic kidney of the rat.
Rats were made diabetic by intravenous administration of streptozotocin, 100 mg/kg. Six groups of animals were studied: normal; animals given a supplement of 100% corn oil margarine; insulin-treated normoglycemic diabetic; hyperglycemic nonacidotic diabetic; ketoacidotic diabetic; and NH4Cl acidotic. The kidneys were removed from anesthetized animals. The renal cortex was separated from the medulla, freeze-clamped, and homogenized. Total lipids were extracted and measured gravimetrically. Lipid fractions were determined by thin-layer chromatography. Fatty acids of triacylglycerols and of phospholipids were analyzed by gas chromatography. Plasma triacylglycerols were elevated in hyperglycemic nonacidotic rats and more so in ketoacidotic animals. Total kidney lipids were 18% higher in nonacidotic hyperglycemic rats and 56% higher in ketoacidotic diabetic rats. This was due to accumulation of triacylglycerols while the phospholipid and cholesterol fractions did not change. Examination of long-chain fatty acids of kidney cortex triacylglycerols revealed that palmitate rose in a significant fashion while linoleate fell. This pattern was similar in all three groups of diabetic animals. The present data characterize the lipid content of the experimental rat diabetic kidney. They establish that the accumulation of lipids in the renal cortex during diabetes is related to triacyclgycerols and their palmitate content. Our study also provides a clear profile of plasma triacylglycerols during diabetes mellitus in the rat.
Ammonium Chloride↗
Isolation and characterization of apolipoprotein B-48 and B-100 very low density lipoproteins from type III hyperlipoproteinemic subjects.
Two major species of human apolipoprotein (apo) B have been identified, apo B-48 and apo B-100, which are the predominant forms in chylomicrons and very low density lipoproteins (VLDL), respectively. Due to defective hepatic clearance, apo B-48 containing lipoproteins accumulate in the plasma of subjects with type III hyperlipoproteinemia. In the present study, we have used immunoaffinity chromatography to separate type III VLDL into a nonretained (apo B-48 VLDL) and a retained (apo B-100 VLDL) fraction. To achieve complete separation, as determined by electrophoresis and radioimmunoassay, it was necessary to employ two different insolubilized anti-apo B-100 monoclonal antibodies because of immunochemical heterogeneity within the apo B-100 VLDL fraction. The ability to separate apo B-100 VLDL from apo B-48 VLDL shows that the two apo B species are found on different particles. The apo B-48 VLDL had an electrophoretic mobility similar to chylomicrons, whereas the apo B-100 VLDL migrated similarly to total type III VLDL. Both fractions showed a concentration of particles with diameters approximately 100 nm, with apo B-48 VLDL being somewhat more heterogeneous in particle size. The two fractions were qualitatively similar in apolipoprotein composition but apo B-48 VLDL was enriched in apo E, relative to apo B-100 VLDL. Apo B-48 VLDL was enriched in cholesterol esters and deficient in triglycerides and phospholipids when compared with apo B-100 VLDL. The existence of immunochemical heterogeneity in the apo B-100 VLDL may reflect different functional subpopulations of particles within this fraction.
Apolipoprotein B-100↗
Rapid measurement of erythrocyte osmotic fragility.
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Autoanalysis↗