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Biomedical subjects

J de Graaf

Publications and source records attributed to J de Graaf.

At least 37 records · Page 2Linked to original sources
PubMed2000

The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia.

We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs. +26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P>0.05). Cu(2+)-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.

Adult↗
PubMed2000

Comparison of the measurement of lipids and lipoproteins versus assay of apolipoprotein B for estimation of coronary heart disease risk: a study in familial combined hyperlipidemia.

We compared in 506 members of families with familial combined hyperlipidaemia (FCH), two approaches to selecting subjects with an apparent increased risk for coronary heart disease: assay of apolipoprotein (apo) B only versus measurement of plasma lipids and lipoproteins. When comparing both criteria, there was an overlap of 81.2% at apo B levels < or = 1250 mg/l and of 86.9% at apo B levels > 1250 mg/l. At apo B < or = 1250 mg/l all subjects were normolipidemic. However, 18.8% of these subjects had sub-normal HDL-cholesterol concentrations (< 0.9 mmol/l) but were not considered to have an increased risk because of very low LDL-cholesterol levels (< 2.5 mmol/l). At apo B concentrations > 1250 mg/l we observed a group with normal plasma lipid levels (13.1%). In this group, defined as normolipidemic hyperapobetalipoproteinemia, and considered to have an increased risk for coronary heart disease, apo B determination was thus most informative. The selection of the subgroup with 'normolipidemic hyperapobetalipoproteinemia' on the basis of the conventional approach could be refined using a cut off limit for plasma triglycerides < 1.5 mmol/l. This limit distinguished optimally between an atherogenic very dense LDL pattern versus a dense and buoyant pattern. Thus, based on the results of our study, the determination of apo B appeared to be, if not superior, at least as effective as the conventional lipid and lipoprotein parameters in classifying subjects at increased risk for coronary heart disease.

Adult↗
PubMed2000

alpha-tocopherol supplementation decreases production of superoxide and cytokines by leukocytes ex vivo in both normolipidemic and hypertriglyceridemic individuals.

BACKGROUND: alpha-Tocopherol plays an important role in protecting LDL against oxidation. However, additional effects of alpha-tocopherol at the intracellular level may contribute to the clinical outcome of intervention studies. OBJECTIVE: We investigated whether alpha-tocopherol influences the inflammatory responses of immune cells in normolipidemic and hypertriglyceridemic subjects. DESIGN: RRR-alpha-Tocopherol was administered for 6 wk at a dose of 600 IU (402 mg)/d to 12 primary hypertriglyceridemic and 8 normolipidemic (fasting triacylglycerol >3.0 and <2.0 mmol/L, respectively) subjects. Cytokine production [tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-8] by mononuclear cells and superoxide production by polymorphonuclear cells and in diluted whole blood were determined before and after the intervention. RESULTS: Cytokine and superoxide production did not differ significantly between hypertriglyceridemic and normolipidemic subjects. alpha-Tocopherol supplementation resulted in a 2- to 3-fold increase in the concentration of alpha-tocopherol in plasma and LDL. Whereas superoxide production in response to phorbol 12-myristate 13-acetate decreased in all subjects, response to oxidized LDL increased in 19 of 20 subjects. Response to opsonized zymosan before alpha-tocopherol supplementation was not significantly different from that after supplementation. Lipopolysaccharide-induced cytokine production by mononuclear cells decreased after supplementation with alpha-tocopherol. CONCLUSIONS: alpha-Tocopherol differentially influences inflammatory responses of immune cells. These effects of alpha-tocopherol may be relevant in chronic inflammatory processes such as atherogenesis.

Cells, Cultured↗
PubMed1998

Defects of lipoprotein metabolism in familial combined hyperlipidaemia.

Familial combined hyperlipidaemia is the most common inherited hyperlipidaemia and is found in up to 10% of patients with premature myocardial infarction. The genetic and metabolic bases of the disorder have not yet been defined. This review discusses the important advances in the past year in our understanding of the different metabolic pathways contributing to the pathogenesis of familial combined hyperlipidaemia.

Adipose Tissue↗
PubMed1997

Effects of ketoconazole on plasma lipids and lipoprotein(a) in familial hypercholesterolaemia, compared with simvastatin.

BACKGROUND: Ketoconazole is an imidazole derivative that is active as a broad-spectrum antifungal agent. It is also an inhibitor of cholesterol production both in vivo and in vitro. METHODS: We compared the effect of low-dose ketoconazole (200 mg/day) or simvastatin (20-40 mg/day) on lipids, lipoproteins and lipoprotein(a) [Lp(a)] in 10 patients with familial hypercholesterolaemia. RESULTS: Ketoconazole reduced serum total cholesterol and low-density lipoprotein (LDL)-cholesterol by 7.6 and 9.7%, respectively. Simvastatin was more effective, the respective changes being -34.4 and -40.6%. Serum triglycerides and high-density lipoprotein (HDL) were unchanged by ketoconazole therapy, whereas simvastatin decreased triglyceride levels by 33.8% and increased HDL-cholesterol levels by 8.7%. Median Lp(a) levels tended to increase during simvastatin and to decrease during ketoconazole therapy. However, due to the wide range of baseline concentrations of Lp(a), these changes were not significant. CONCLUSIONS: Ketoconazole has some hypocholesterolaemic potential, but the effect of simvastatin is much more pronounced. The increase in Lp(a) during simvastatin therapy has been reported earlier, whereas ketoconazole does not exhibit an effect on the level of Lp(a).

Adult↗
PubMed1994

Changes in the low-density lipoprotein profile during 17 beta-estradiol-dydrogesterone therapy in postmenopausal women.

Changes in the low-density lipoprotein (LDL) subfractions, determined with gradient gel electrophoresis (GGE), were prospectively studied during hormone replacement therapy (HRT) in 23 healthy nonhysterectomized postmenopausal women. LDL subfractions were analyzed by densitometric scanning of the gels. We observed significant changes in the LDL subfraction profile toward a smaller particle size (P < .001). These changes could almost completely be attributed to the hormonal treatment regimen (P < .01), and may indicate an effect partially opposite to the other reported changes in the lipid profile.

Dydrogesterone↗
PubMed1994

Frequencies of lipopolysaccharide core types in Escherichia coli strains from bacteraemic patients.

We have investigated the distribution of the various core types (R1, R2, R3, R4 and K-12) in 138 Escherichia coli isolates obtained from positive blood cultures. Rabbit antisera, raised against five rough strains expressing the respective core types, were made monospecific by extensive absorption. The reactivity of the antisera was tested in ELISA with bacterial cells that had been autoclaved for full exposure of core epitopes. One hundred and thirty strains could be typed directly, while eight strains required prior digestion with proteinase K for removal of cross-reactions. Ninety-four of the strains (68%) expressed the R1 type, and 9 (6.5%), 12 (8.7%), 7 (5.1%) and 3 (2.2%) strains expressed the R2, R3, R4 and K-12 core types, respectively. An R1R4 mixed core type, hitherto not yet described, was found in 13 (9.4%) strains. Results obtained with polyclonal antisera were in agreement with those obtained with monoclonal antibodies to the R1, R2 and R3 core types. Core typing may serve as an additional serological marker next to conventional typing of O-, H- and K-antigens.

Antibodies, Bacterial↗
PubMed1993

Low density lipoprotein subfractions increase thromboxane formation in endothelial cells.

Correlations between dyslipidemia and high blood pressure have been shown. It is unclear whether there is a causal relationship but there are indications that blood lipids might have a direct effect on mechanisms regulating the vascular tone. As secretory products of endothelial cells (EC) have been suggested to be involved in blood pressure regulation, we studied the influence of low density lipoprotein subfractions on thromboxane (T) synthesis in human umbilical vein endothelial cells (HUVEC). LDL can be separated into at least three major subfractions. In the present study, subfractions LDL1 (d = 1.030-1.033 g/ml), LDL 2 (d = 1.033-1.040 g/ml), and LDL 3 (d = 1.040-1.045 g/ml) were obtained by density gradient ultracentrifugation. T was measured by a radioimmuno-assay. LDL subfractions induced a dose dependent (10-100 micrograms/ml) increase in T synthesis. Control T concentration was 96 +/- 12 pg/ml. LDL 3 (205 +/- 17 pg/ml, p < 0.01) and LDL 2 (194 +/- 13 pg/ml, p < 0.05) caused a significantly higher T concentration compared to the LDL 1 subfraction (152 +/- 11 pg/ml). These results indicate that LDL 2 and 3- the subfractions with the higher density-might have a more pronounced effect on T synthesis by EC than the other LDL subfractions.

Cells, Cultured↗
PubMed1993

Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects. Normalization after clofibrate treatment.

The influence of different plasma triglyceride concentrations on the heterogeneity of low density lipoprotein (LDL) and on the susceptibility of LDL to copper oxidation was investigated. By density gradient ultracentrifugation, LDL subfractions were isolated from the plasma of 10 normolipidemic control subjects and 12 hypertriglyceridemic patients both before and after clofibrate treatment. In the plasma of control subjects three LDL subfractions were present: LDL1 (d = 1.030-1.033 g/mL), LDL2 (d = 1.033-1.040 g/mL), and LDL3 (d = 1.040-1.045 g/mL). In the plasma of nine moderately hypertriglyceridemic subjects up to five LDL subfractions could be detected: LDL1-LDL3, LDL4 (d = 1.045-1.049 g/mL), and LDL5 (d = 1.049-1.054 g/mL). This polydispersity of LDL was replaced by monodispersity with increasing plasma triglyceride concentrations in three subjects with chylomicronemia, in whom LDL was concentrated in the narrow LDL5 density range. Clofibrate treatment resulted in a lighter LDL subfraction pattern (LDL1-LDL4). In both the control and the moderately hypertriglyceridemic subjects, the small dense LDL subfractions appeared more prone to oxidative modification in vitro than the light LDL subfractions, as measured by the decreased lag time preceding the onset of lipid peroxidation. Furthermore, the dense LDL subfractions were more extensively modified over time, as shown by an increased oxidation rate and a greater number of dienes formed after 6 hours of oxidation. These results suggest an enhanced atherogenic potential of the small, dense LDL subfractions within each LDL subfraction profile. The hypertriglyceridemic LDL subfractions before therapy (LDL3-LDL5) were less resistant to in vitro oxidation than the light, control LDL subfractions (LDL1-LDL3).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Low density lipoprotein subfractions and [Ca2+]i in vascular smooth muscle cells.

Several studies have established that plasma low density lipoprotein (LDL) consists of various discrete subfractions. Using a variety of techniques (analytical ultracentrifugation, equilibrium density gradient ultracentrifugation, and gradient gel electrophoresis), LDL has been fractionated into a maximum of seven subclasses that differ in particle size, density, and physiochemical composition. Recently, a predominance of smaller denser LDL particles has been associated with an increased risk of coronary artery disease. However, other lipoprotein changes, such as elevated triglycerides and lower HDL cholesterol levels, have been shown in patients with a predominance of the smaller denser LDL subfractions. Thus, it is unclear whether the enhanced atherogenic potential is induced by the LDL subfraction pattern per se or by concomitant lipoprotein changes. Because intracellular free Ca2+ is an important second messenger involved in atherogenesis and regulation of vascular tone, we studied the influence of three LDL subfractions (very light [LDL1], 1.030 to 1.033 g/mL; light [LDL2], 1.033 to 1.040 g/mL; and dense [LDL3], 1.040 to 1.045 g/mL) on [Ca2+]i in vascular smooth muscle cells (VSMCs) cultured from rat aorta. LDL subfractions were isolated by density gradient ultracentrifugation from human EDTA-plasma (n = 15). [Ca2+]i was measured by fura 2 fluorescence. Basal [Ca2+]i was 77 +/- 6 nmol/L. Stimulation of VSMCs with dense LDL3 caused a significantly (P < .05) more pronounced increase (+71 +/- 13 nmol/L) compared with LDL1 (+38 +/- 8 nmol/L) and LDL2 (+36 +/- 9 nmol/L). To further investigate the mechanisms leading to the stimulation of [Ca2+]i by LDL subfractions, we incubated VSMCs with the Ca2+ antagonists nifedipine, diltiazem, and verapamil in concentrations up to 10 mumol/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Differences in the low density lipoprotein subfraction profile between oral contraceptive users and controls.

To investigate the effect of low dose oral contraceptives on the low density lipoprotein (LDL) subfraction profile, the distribution of the LDL subfraction patterns in 20 premenopausal women on oral contraceptive (OC) therapy and 41 premenopausal women not taking gonadal hormones was studied. The LDL subfraction patterns were identified by density gradient ultracentrifugation and each individual LDL subfraction pattern was characterized by the relative contribution of three major LDL subfractions: light, LDL1; intermediate, LDL2; and dense, LDL3 to total LDL. Serum lipid and lipoprotein levels were similar in OC users and controls, except for significantly higher triglyceride levels in OC users. As for the LDL subfraction patterns, among the OC users the mean relative contribution of dense LDL3 to total LDL was significantly higher than in the controls (32% +/- 8% vs. 26% +/- 13%, P < 0.05), whereas the relative contribution of light LDL1 to total LDL was significantly lower (27% +/- 8% vs. 34% +/- 10%, P < 0.01), indicating a higher prevalence of the more dense LDL subfraction patterns among OC users. Furthermore, the distribution of the LDL subfraction patterns in OC users (27% LDL1, 41% LDL2, and 32% LDL3) resembled that of men (25% LDL1, 43% LDL2, and 33% LDL3, n = 59). Statistical analysis revealed that OC use was significantly associated with a more dense LDL subfraction pattern, characterized by an increased relative contribution of LDL3 (+6%, P < 0.05) and a decreased relative contribution of LDL1 (-6%, P < 0.01), even after correcting for the influence of lipid and lipoprotein levels, which in controls were shown to have a significant relation to LDL3 and LDL1, respectively. So, independent of the lipid and lipoprotein levels, low dose OC alter the composition of LDL to a heavy, dense LDL subfraction profile, which reportedly has been associated with an increased risk of atherosclerosis.

Cholesterol↗
PubMed1993

The effect of simvastatin treatment on the low-density lipoprotein subfraction profile and composition in familial hypercholesterolaemia.

The effect of simvastatin treatment on the low-density lipoprotein (LDL) subfraction profile was studied in 26 patients with familial hypercholesterolaemia. Before treatment LDL consisted of three LDL subfractions, using density-gradient ultracentrifugation (LDL1, LDL2 and LDL3) present in a relatively narrow density range (d = 1.030-1.045 g/ml). Simvastatin did not influence this profile with respect to the number and density range of the LDL subfractions. However, the composition of the isolated LDL subfractions changed after treatment, as evidenced by the reversal towards normal of the increased cholesterol/protein ratio (mean 1.51 before vs. 1.38 after therapy, p < 0.01; mean 1.36 in normolipidaemic subjects). When the subjects were stratified by their plasma triglyceride levels or the change in plasma triglycerides during simvastatin therapy, a strong dependence of the LDL subfraction profile and its composition on plasma triglyceride levels was observed; increasing plasma triglyceride levels were associated with a more dense LDL subfraction profile, characterized by a high relative contribution of dense LDL3 to total LDL and changes in LDL composition, reflected by a relatively low cholesterol/protein ratio. Our results indicate that in patients with familial hypercholesterolaemia: (1) plasma triglyceride levels have an important role in determining the properties of LDL and (2) simvastatin treatment results in changes in composition of LDL, which may affect the intrinsic metabolic characteristics and thus the atherogenic potential of LDL.

Adolescent↗
PubMed1993

Differences in LDL receptor-mediated metabolism of three low density lipoprotein subfractions by human monocyte-derived macrophages: impact on the risk for atherosclerosis.

The metabolism of three low density lipoprotein (LDL) subfractions by human monocyte-derived macrophages (HMDM) through the LDL receptor pathway was studied. The three LDL subfractions, very light LDL1, light LDL2 and heavy LDL3, were isolated from serum pools of normolipidemic subjects by density gradient ultracentrifugation. The LDL subfractions were shown to differ in molecular size and chemical composition but not in electrophoretic mobility on agarose gel. Cell specific association, cell specific degradation and stimulation of cholesteryl esterification were determined in parallel after incubation of HMDM with increasing amounts of LDL-protein of the three LDL subfractions. The experiments were repeated four times with freshly prepared LDL subfractions. Both the cell specific association and degradation increased more with increasing LDL-protein concentration for LDL1 than for LDL3 (p < 0.001). The results for LDL2 were intermediate between those for LDL1 and LDL3 and differed significantly from both (p < 0.05). For the stimulation of cholesteryl ester formation, the curves for LDL1 and LDL2 increased more with increasing LDL-protein concentration than that for LDL3 (p < 0.001); the results for LDL1 and LDL2 did not differ significantly from each other. These differences between LDL subfractions in cholesteryl esterification were independent of the cholesterol content of the LDL subfractions. The results show that LDL subfractions have different rates of LDL receptor-mediated catabolism by HMDM. As HMDM play an important role in the formation of atherosclerotic plaques, the differences between the LDL subfractions in catabolism by HMDM, may result in differences in atherogenicity between LDL subfractions isolated from normolipidemic subjects.

Analysis of Variance↗
PubMed1992

Both inherited susceptibility and environmental exposure determine the low-density lipoprotein-subfraction pattern distribution in healthy Dutch families.

A lipoprotein profile characterized by a predominance of small, dense, low-density lipoprotein (LDL) particles has been associated with an increased risk of atherosclerosis. To investigate whether genetic factors are involved in determining this heavy LDL subfraction pattern, this study was undertaken with the aim of resolving the effects that major genes, multifactorial heritability, and environmental exposures have on the LDL subfraction pattern. In a random sample of 19 healthy Dutch families including 162 individuals, the distribution of the LDL subfraction pattern was determined by density gradient ultracentrifugation. For each subject a specific LDL subfraction profile was observed, characterized by the relative contribution of the three major LDL subfractions--LDL1 (d = 1.030-1.033 g/ml), LDL2 (d = 1.033-1.040 g/ml), and LDL3 (d = 1.040-1.045 g/ml)--to total LDL. A continuous variable, parameter K, was defined to characterize each individual LDL subfraction pattern. Complex segregation analysis of this quantitative trait, under a model which includes a major locus, polygenes, and both common and random environment, was applied to analyze the distribution of the LDL subfraction pattern in these families. The results indicate that the LDL subfraction pattern, described by parameter K, is controlled by a major autosomal, highly penetrant, recessive allele with a population frequency of .19 and an additional multifactorial inheritance component. The penetrance of the more dense LDL subfraction patterns, characterized by values of K < 0, was dependent on age, gender, and, in women, on oral contraceptive use and postmenopausal status. Furthermore, multiple regression analysis revealed that approximately 60% of the variation in the LDL subfraction pattern could be accounted for by alterations in age, gender, relative body weight, smoking habits, hormonal status in women, and lipid and lipoprotein levels. In conclusion, our results indicate that genetic influences as well as environmental exposure, sex, age and hormonal status in women are important in determining the distribution of the LDL subfraction patterns in this population and that these influences may contribute to the explanation of familial clustering of coronary heart disease.

Adult↗
PubMed1991

Single-spin density-gradient ultracentrifugation vs gradient gel electrophoresis: two methods for detecting low-density-lipoprotein heterogeneity compared.

Single-spin density-gradient ultracentrifugation (DUC) has proven to be a reproducible method for detection of low-density-lipoprotein (LDL) heterogeneity. Recently another method has been described for this: gradient gel electrophoresis (GGE) of serum, a method that might be more suitable for screening. To gain insight into the relationship of GGE to DUC and into their reproducibility, we determined LDL heterogeneity by DUC and GGE in 41 healthy individuals. In 90.2% (n = 37) of the subjects, the number of LDL subfractions found by both methods agreed. In addition, the density and the relative migration distance of the predominant LDL subfraction observed with the respective methods showed a strong correlation (Pearson correlation, r = 0.85, P less than 0.0001). Although it was not possible to compare for all aspects of LDL heterogeneity, these data suggest that GGE is a valid method of analysis for LDL heterogeneity. In screening programs, it may be necessary to store samples. Therefore, we studied in 24 sera the influence of storage at -80 degrees C for one, four, and 12 weeks on the LDL subfraction distribution detected by each method. LDL heterogeneity was maintained during storage under these conditions.

Adult↗
PubMed1990

Exclusion of linkage between the human apolipoprotein B gene and abetalipoproteinemia.

Abetalipoproteinemia (ABLP) is a rare autosomal recessive disease characterized by a lack of plasma apolipoprotein B (apo B). In this report, the hypothesis that ABLP is due to rare mutations in the apo B gene was tested. A total of eight ABLP families were studied. Apo B gene RFLPs were used to establish the haplotypes of the apo B alleles in family members. LOD score analysis was used to study the linkage between the apo B alleles and ABLP. These families were categorized arbitrarily as class I, II, III, or IV because of differences in the results derived from both haplotyping and LOD score analysis. In a class I family, affected siblings, who on the basis of the hypothesis would be expected to have the same apo B alleles, had different ones. LOD score analysis of this family gave an infinite negative number at a recombination fraction (theta) of zero. In two class II families, probands who were the result of consanguineous marriages and who, on the basis of the hypothesis, should be homozygotes for a defective apo B allele, were heterozygotes at this locus. The sum of the LOD scores from these two families was -1.7 at theta = 0. In one class III family, a parent was apparently homozygous for a particular apo B allele and yet not affected. This also contributed negatively to the LOD score. In four class IV families, disease inheritance was compatible with segregation of the apo B alleles. This, however, was not statistically significant (LOD score = 0.97 at theta = 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Abetalipoproteinemia↗