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Biomedical subjects

A D Marais

Publications and source records attributed to A D Marais.

At least 19 recordsLinked to original sources
PubMed2006

Concomitant consumption of red wine and polyunsaturated fatty acids in edible oil does not influence the peroxidation status of chylomicron lipids despite increasing plasma catechin concentration.

BACKGROUND AND AIMS: Atherosclerosis may be ameliorated by red wine consumption possibly by providing antioxidants. The effects of red wine on the peroxidation status of chylomicrons (CM) are unknown. The aims were to compare the lipid peroxidation status of oil rich in polyunsaturated fatty acids (PUFA) from a standardised high-fat meal with that of the CM at peak concentrations following ingestion of the meal with and without wine, and to examine the contribution of wine to the antioxidant content of the plasma. METHODS AND RESULTS: Fasted subjects ingested the meal randomly with and without red wine. The peroxidation status was described by conjugated dienes (CD), lipid hydroperoxides (LOOH) and thiobarbituric acid reactive substances (TBARS). CM lag times and the area under the curve (AUC) of CD were determined under oxidative stress. Plasma catechin concentrations and oxygen radical absorbance capacity (ORAC) values were determined. The CM produced with and without wine did not differ in their concentration of CD, LOOH and TBARS. Lag times of CM with and without wine were not significantly different, nor were the AUC. Plasma catechin values increased significantly after consumption of wine with the meal, whereas ORAC values did not. CONCLUSION: Red wine consumption increases plasma catechins, but does not influence lipid peroxidation in postprandial CM.

Adult↗
PubMed2003

Four novel mutations in APOB causing heterozygous and homozygous familial hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is a rare codominant disorder of lipoprotein metabolism characterized by low levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B. Heterozygotes for FHBL have less-than-half normal LDL-cholesterol and apoB concentrations, whereas homozygotes have extremely low or undetectable LDL-cholesterol and apoB levels. These reductions in LDL-cholesterol and apoB have been suggested to provide FHBL subjects with resistance to atherosclerosis. FHBL can be caused by mutations in the APOB gene on chromosome 2. We present four novel mutations and one previously described mutation in APOB causing FHBL in five families. Immunoblotting and DNA sequencing were used to characterize the novel mutation apoB-40.3 (c.5564_5565insC) and the previously reported mutation apoB-80.5 (c.11040T>G). The apoB-6.9 (c.1018_1025del) and apoB-25.8 (c.3600T>A) mutations were identified by DNA sequence analysis, as variants shorter than apoB-31 are not detectable in plasma. A fifth mutation, the splice variant c.82+1G>A, was identified by sequencing and was found in a homozygous subject. In approximately 50% of the FHBL subjects, plasma alanine aminotransferase concentrations were mildly increased, suggestive of fatty liver. All affected FHBL subjects had low to low-normal serum vitamin E concentrations, highlighting the important and recognized relationship between lipid and vitamin E concentrations.

Adolescent↗
PubMed2002

Statins in homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia is a rare disorder resulting in severe premature atherosclerosis. Drug therapy was previously viewed as inadequate for control of the dyslipidemia, so portacaval shunting, plasmapheresis, and liver transplantation were undertaken to treat this condition. Despite these drastic measures, additional cholesterol-lowering treatment may still be required. Furthermore, there is a need for pharmacologic control until additional measures can be undertaken. The statins, an evolving class of cholesterol-modifying drugs, represent a significant development in the treatment of homozygous familial hypercholesterolemia. The experience with statins in this condition is limited, but some insight into their utility has been gained from studies reviewed in this article. It is recommended that high doses of statins be used in combination with other lipid-modifying strategies for the best control of the dyslipidemia of homozygous familial hypercholesterolemia.

Clinical Trials as Topic↗
PubMed2002

Dysbetalipoproteinaemia--clinical and pathophysiological features.

OBJECTIVES: Dysbetalipoproteinaemia (type III hyperlipidaemia, broad-beta disease) is a highly atherogenic genetic disorder of lipoprotein metabolism. It presents with a severe mixed hyperlipidaemia in which the ratio of total cholesterol to triglycerides is typically 2:1. There is a high incidence of atherosclerotic complications and severe hypertriglyceridaemia may cause pancreatitis. Highly effective therapy is available and affected families also benefit from genetic counselling. We present a review of our experience with dysbetalipoproteinaemia at the lipid clinic of Groote Schuur Hospital to enhance awareness of this serious condition, for which the index of suspicion should be raised. DESIGN: Retrospective review of case records, 1969-2001. SETTING: Lipid clinic of Groote Schuur Hospital, Cape Town. SUBJECTS: Patients with dysbetalipoproteinaemia diagnosed by the presence of cholesterol-enriched very-low-density lipoproteins (VLDL) and/or dyslipidaemia associated with homozygosity for apolipoprotein E2 or carriers of the apoE2 (Arg145-->Cys) mutation. RESULTS: One hundred and five patients were identified, 55 of whom were male and 50 female. The age at presentation was 48.8 +/- 11.1 years (mean, standard deviation). Total cholesterol was 12.0 +/- 5.5 mmol/l and plasma triglycerides 8.3 +/- 9.8 mmol/l. The ratio (by mass) of cholesterol to triglycerides within VLDL was 0.52 +/- 0.17, while VLDL cholesterol to plasma triglycerides was 0.33 +/- 0.09. Fifty patients were epsilon 2 homozygotes while 22 carried the apoE2 (Arg145-->Cys) mutation. Palmar crease xanthomas occurred in 20% of patients, cutaneous xanthomas in 18%, and tendon xanthomas in 13%. Coronary artery disease was found in 47% of patients and peripheral vascular disease in 20%. Fibrates were the most commonly used hypolipidaemic agents (48%), while 31% of patients received combination therapy with a fibrate and statin. Statin monotherapy was used in 11% of patients and a few patients were treated with niacin or required no drug therapy. The treated cholesterol was 5.7 +/- 2.4 mmol/l, with plasma triglycerides of 2.7 +/- 1.9 mmol/l. CONCLUSIONS: Dysbetalipoproteinaemia is a highly atherogenic disorder and is extremely responsive to therapy. A significant proportion of dysbetalipoproteinaemia locally is caused by the apoE2 (Arg145-->Cys) mutation and is therefore dominantly inherited. This mutation is particularly prevalent in the black community where dysbetalipoproteinaemia may be undiagnosed in many patients. Patients with severe mixed hyperlipidaemia or clinical stigmata of dyslipidaemia should be assessed at a lipid clinic for a specific diagnosis and initiation of therapy.

Adolescent↗
PubMed2001

Effects of androgen manipulation on postprandial triglyceridaemia, low-density lipoprotein particle size and lipoprotein(a) in men.

Although androgenic hormones decrease HDLC concentration, no direct evidence has linked them to atherosclerosis. The present study was undertaken to extend our ability to assess risk associated with androgen induced lipoprotein(Lp) changes by simultaneously gathering information about postprandial triglyceridaemia (PPT), LDL particle size, HDL and Lp(a) in men either taking exogenous androgens or with suppressed endogenous androgen concentrations. The experimental groups comprised nine male bodybuilders who self-administered anabolic-androgenic steroids (AAS) for a mean period of 6.5 weeks, and 10 healthy men whose testosterone concentration had been reversibly suppressed for 5 weeks using the GnRH agonist triptorelin (Decapeptyl; D-Trp-6-LHRH). A separate group receiving no hormonal treatment provided analytical control (n=7). Lipoprotein size was assessed by gradient gel electrophoresis categorisation (GGE), lipoprotein concentrations by immuno and enzymatic assays and PPT by a standardised oral fat tolerance test (65g /m(2)). Testosterone concentration was significantly reduced on triptorelin from 7.32+/-1.92 to 1.15+/-0.57 ng/ml (P=0.002). High dose AAS use was confirmed by urinalysis. With AAS use, mean HDLC and Lp(a) concentrations and PPT decreased from 0.9+/-0.3 to 0.7+/-0.3 mmol/l (P=0.004), 125+/-128 to 69+/-73 U/l (P=0.008) and 11.6+/-10.0 mmol/l h to 7.5+/-5.4 mmol/l h (P=0.027) respectively. Mean total cholesterol and LDLC were unchanged. LDL size was unchanged in six AAS users, decreased in one but remaining in the normal size range, and increased in two from small LDL to the normal range. Size changes in the latter two subjects were associated with 42 and 58% reductions in PPT respectively. In the triptorelin group, mean total cholesterol, HDLC and Lp(a) were increased from 4.8+/-0.8 mmol/l to 5.2+/-1.0 mmol/l (P=0.039), 1.1+/-0.2 to 1.4+/-0.3 mmol/l (P=0.002) and 278+/-149 to 377+/-222 U/l (P=0.004) respectively. Mean LDLC concentration and PPT were unchanged. LDL particle size increased in four, decreased in two, and was unchanged in four subjects. LDL size decreased in two and showed no change in the other five control subjects. Other lipid measures were unchanged in the control group. Thus, apart from lowering HDLC concentrations, no other potentially atherogenic effects of endogenous androgens or AAS were observed. A suppression of Lp(a) as well as a reduced PPT and increased LDL size in predisposed individuals may be antiatherogenic effects of AAS.

Adult↗
PubMed2001

Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test.

Chylomicron remnant metabolism was studied using a stable isotope breath test in 25 patients with familial hypercholesterolaemia (FH) (10 homozygotes, 15 heterozygotes), and in 15 normolipidaemic controls. A lipid emulsion mimicking the composition of chylomicron remnants and labelled with cholesteryl (13)C-oleate was injected intravenously; (13)CO(2) was measured subsequently in breath using isotope-ratio mass spectrometry. The fractional catabolic rate (pools/h) of the emulsion, derived from a compartmental model, did not differ significantly among the groups: homozygous FH mean 0.20 (S.E.M. 0.05), heterozygous FH 0.12 (0.02), controls 0.16 (0.03). We suggest that the catabolism of chylomicron remnants from plasma is not impaired in FH and that the hepatic uptake of these particles is not dependent on functional LDL receptors.

Adult↗
PubMed2001

The use of simvastatin in analbuminaemia.

Congenital analbuminaemia, a rare disorder associated with defective albumin synthesis, is characterised by hyperlipidaemia. Administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGRI) to analbuminaemic rats have demonstrated no significant effect on plasma lipids, however no published information regarding HMGRI treatment could be found in human subjects. The efficacy, safety and tolerability of Simvastatin was thus investigated in 2 South African patients with analbuminaemia, a 21 year old Caucasian male (H-B) and a 61 year old black male (A-K). In the case of A-K, the lipid profile responded predictably but H-B responded less that expected from general experience with Simvastatin. Both subjects, however, experienced a three- to five-fold increase in creatine kinase. The use of HMGRI's should thus be used cautiously in these patients and it may be advisable to reserve treatment for secondary prevention.

Adult↗
PubMed2001

Chylomicron remnant metabolism in familial dyslipidemias studied with a remnant-like emulsion breath test.

We have developed a stable isotope breath test for the assessment of chylomicron remnant metabolism and report the results from the breath test in human subjects selected for disorders of chylomicron or remnant metabolism. In type I hyperlipemia, the phenotype is extreme hypertriglyceridemia due to a lack of lipoprotein lipase activity, which causes the failure of remnant formation. The type III dyslipidemia phenotype is caused by the inefficient removal of chylomicron remnants from plasma, generally because of homozygosity for apolipoprotein E2 alleles. The breath test was predicted to be abnormal in type III hyperlipemia, whereas a priori in type I hyperlipemia defective remnant clearance was not anticipated. Subjects were injected with lipid emulsions prepared with a composition similar to normal chylomicron remnants. The emulsions contained cholesteryl ester incorporating the stable nonradioactive isotope (13)C in the fatty acid moiety. End exhalation breath was collected at intervals after intravenous injection of the remnant-like emulsions and analyzed for (13)C enrichment by isotope-ratio mass spectrometry. Compared with the group of normolipemic men, the fractional catabolic rate of remnants measured by the breath test was significantly decreased (P = 0.006) in subjects with type III dyslipidemia. In the group with type I hyperlipemia, the fractional catabolic rate was not different (P = 0.233) from the control group. Therefore, the underlying capacity for remnant catabolism was normal in this group of markedly hypertriglyceridemic subjects. By short-circuiting the step of lipolysis, the remnant-like emulsion breath test provides direct information about remnant clearance and metabolism, which should assist in investigations of postprandial lipid metabolism.

Adolescent↗
PubMed2000

Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.

Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P<0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (P<0. 01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r=0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day.

Adolescent↗
PubMed2000

Therapeutic modulation of low-density lipoprotein size.

Small, dense LDL particles have been linked to atherosclerosis, often in a cluster of risk factors and affecting approximately 20% of adults. Over the past year, studies confirmed that small dense LDL is an autosomal dominant trait, influenced mainly by hypertriglyceridaemia and obesity, insulin resistance and diabetes mellitus and some incompletely investigated genetic loci. Compositional and functional differences have been observed in small LDL. Evidence is emerging that lifestyle as well as pharmacological intervention can modulate LDL size, but there is no proof yet that this is of clinical benefit.

Arteriosclerosis↗
PubMed2000

Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis.

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depending on its localization. Decreased plasma LPL activity is associated with the high triglyceride (TG);-low HDL phenotype that is often observed in patients with premature vascular disease. In contrast, in the vessel wall, decreased LPL may be associated with less lipoprotein retention due to many potential mechanisms and, therefore, decreased foam cell formation. To directly assess this hypothesis, we have distinguished between the effects of variations in plasma and/or vessel wall LPL on atherosclerosis susceptibility in apoE-deficient mice. Reduced LPL in both plasma and vessel wall (LPL(+/-)E(-/-)) was associated with increased TG and increased total cholesterol (TC) compared with LPL(+/+)E(-/-) sibs. However despite their dyslipidemia, LPL(+/-)E(-/-) mice had significantly reduced lesion areas compared to the LPL(+/+)E(-/-) mice. Thus, decreased vessel wall LPL was associated with decreased lesion formation even in the presence of reduced plasma LPL activity. In contrast, transgenic mice with increased plasma LPL but with no increase in LPL expression in macrophages, and thus the vessel wall, had decreased TG and TC and significantly decreased lesion areas compared with LPL(+/+)E(-/-) mice. This demonstrates that increased plasma LPL activity alone, in the absence of an increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis. Taken together, these results provide in vivo evidence that the contribution of LPL to atherogenesis is significantly influenced by the balance between vessel wall protein (pro-atherogenic) and plasma activity (anti-atherogenic).

Animals↗
PubMed1999

Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry.

The South African population harbors genes that are derived from varying degrees of admixture between indigenous groups and immigrants from Europe and the East. This study represents the first direct mutation-based attempt to determine the impact of admixture from other gene pools on the familial hypercholesterolemia (FH) phenotype in the recently founded Coloured population of South Africa, a people of mixed ancestry. A cohort of 236 apparently unrelated patients with clinical features of FH was screened for a common mutation causing familial defective apolipoprotein B-100 (FDB) and seven low-density lipoprotein receptor (LDLR) gene defects known to be relatively common in South Africans with FH. Six founder-type 'South African mutations' were responsible for FH in approximately 20% of the study population, while only 1 patient tested positive for the familial defective apolipoprotein B-100 mutation R3500Q. The detection of multiple founder-type LDLR gene mutations originating from European, Indian and Jewish populations provides direct genetic evidence that Caucasoid admixture contributes significantly to the apparently high prevalence of FH in South African patients of mixed ancestry. This study contributes to our knowledge of the biological history of this unique population and illustrates the potential consequences of recent admixture in populations with different disease risks.

Founder Effect↗
PubMed1999

Mutation -59c-->t in repeat 2 of the LDL receptor promoter: reduction in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia.

The low-density lipoprotein receptor (LDLR) plays a major role in cholesterol homeostasis. Mutations in the regulatory region of the LDLR gene, although rare, have been shown to alter transcriptional activity of the gene and can cause familial hypercholesterolaemia (FH). In this study, a transition (c-->t) was identified at nucleotide position -59 within repeat 2 of the LDLR promoter in a South African FH patient of mixed ancestry. By screening 17 family members of the index case for this promoter mutation, two additional single base changes (-124c-->t and-175g-->t) were identified, located at recently described cis- acting regulatory sequences of the LDLR promoter. Both the-59c-->t and the-124c-->t transitions were identified in the normocholesterolaemic son of the index patient. Reporter plasmids containing the normal and mutant promoter fragments were constructed by directional cloning. Transcription studies using a luciferase reporter system demonstrated that the-59c-->t mutation significantly reduces promoter activity in both the presence and absence of sterols ( approximately 40% of normal activity), while the-124c-->t variant increases transcription ( approximately 160%) of the LDLR gene. The intra-familial phenotypic variability observed amongst individuals with the-59c-->t mutation can probably be ascribed to allelic interaction, suggesting that variation in the LDLR promoter region may contribute significantly to the phenotypic expression of FH-related mutations in populations where these mutations prevail.

Adolescent↗
PubMed1999

Effects of anabolic-androgenic steroid use or gonadal testosterone suppression on serum leptin concentration in men.

OBJECTIVE: Serum leptin concentration shows a sexual dimorphism that is not accounted for by gender differences in adiposity. A strong inverse association exists between serum leptin and testosterone concentrations in men, pointing to a likely influence of gonadal sex steroids on serum leptin concentration. The aim of this study was to investigate whether manipulation of sex steroid hormones in men would alter serum leptin concentration independently of changes in fat mass. DESIGN AND METHODS: The effects of sex steroid suppression on serum leptin concentration were investigated in nine healthy men in whom testosterone had been reversibly suppressed for 5 weeks after treatment with intramuscular triptorelin. The effects of sex steroid supplementation were investigated in nine male bodybuilders who self-administered anabolic--androgenic steroids (AAS) for a mean period of 6.5 weeks. A control group received no hormonal treatment. RESULTS: Testosterone concentration was significantly reduced by triptorelin administration (7.32+/- 1.92ng/ml at baseline compared with 1.15+/-0.57ng/ml at 5 weeks, P=0.002). High-dose AAS use was confirmed by urine analysis. Body fat percentage was unaffected by the AAS or triptorelin intervention (P>0.19). Leptin concentration was significantly reduced after one cycle of AAS use (2.40+/-0. 98ng/ml off cycle compared with 1.63+/-0.37ng/ml on cycle, P=0.012), and was significantly increased by triptorelin administration (2. 96+/-1.50ng/ml at baseline compared with 6.63+/-4.67ng/ml at five weeks, P=0.004). No significant change occurred in the control group. CONCLUSION: Androgenic sex hormone supplementation decreases serum leptin concentration, whereas suppression increases serum leptin concentration, independently of changes in body fat mass in healthy men. The sexual dimorphism evident in serum leptin concentration is likely to be due to a suppressive effect of testosterone on serum leptin concentration in males.

Adipose Tissue↗
PubMed1998

Follow-up on primary prevention trials.

Recent primary prevention trials demonstrated that cardiovascular morbidity and mortality benefits are not accompanied by adverse effects on overall mortality and morbidity in cohorts representing plasma cholesterol concentrations observed in the bulk of coronary artery disease. During the past year, further analyses of the West of Scotland Coronary Prevention Study have indicated that benefit requires a 25% reduction of LDL cholesterol and that such treatment is not very expensive when focussed on selected high-risk individuals. The Air Force/Texas Coronary Artery Prevention Study indicated that benefit is seen in individuals with even lower plasma lipid concentration. Although current treatment with lifestyle and lipid modifying drug management is successful in primary prevention, the unpredictable nature of coronary artery disease and the cost of drugs mitigate against direct application of drug management in persons with relatively low risk, but selective treatment should be undertaken in very high-risk settings. Future studies need to examine more specific at risk cohorts, test better targeted lipoprotein modification, test more risk factors and also examine whether changes in vascular function or markers of inflammation will predict a better outcome.

Cholesterol, LDL↗
PubMed1998

HMG-CoA reductase is not the site of the primary defect in phytosterolemia.

Phytosterolemia is an autosomal recessive disorder characterized by the excessive absorption, reduced excretion, and consequent high tissue and plasma levels of plant sterols, by the presence of tendon xanthomas, and by premature atherosclerosis. Low HMG-CoA reductase (HRase) activity and mass have been reported in liver and mononuclear leucocytes and low mRNA levels in liver from phytosterolemic subjects. These results led to the proposal that the primary defect in this condition involves the HRase gene locus. We examined this hypothesis in phytosterolemic subjects and heterozygous parents from four unrelated families. A variable number tandem repeat (VNTR) polymorphism of the HRase gene in the three informative families and a ScrFI restriction fragment length polymorphism (RFLP) within intron 2 of the gene in one of these families, segregated independently of the disease phenotype. Biological parentage was confirmed in the family in whom both polymorphisms failed to segregate with the disorder. These results conclusively exclude the HRase gene locus as the site of the primary defect in phytosterolemia. The study was extended by examining plasma levels of mevalonic acid and lathosterol, both markers of cholesterol biosynthesis, in response to cholestyramine, a bile acid sequestrant that is known to up-regulate HRase. Oral administration of cholestyramine resulted in a substantial (7.7-fold) increase in mevaIonic acid levels in two phytosterolemic subjects, compared with a 2.2-fold rise in their obligate heterozygote parents and a 2.3-fold increase in three healthy control subjects. The lathosterol/cholesterol (L/C) ratio showed a quantitatively similar response. Baseline levels of mevalonate and the L/C ratio were low in the phytosterolemic patients in conformity with reports of reduced cholesterol biosynthesis and HRase activity in this disorder. These functional data provide support for the concept that the primary defect in phytosterolemia does not affect a trans gene locus responsible for the constitutive expression or regulation of HMG-CoA reductase.

Adolescent↗