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Biomedical subjects

A H Smelt

Publications and source records attributed to A H Smelt.

At least 37 records · Page 2Linked to original sources
PubMed1999

The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding?

OBJECTIVE: In order to determine whether screening of thyroid function is justified in patients with hypercholesterolaemia, we determined the prevalence of subclinical hypothyroidism at different levels of total plasma cholesterol in middle-aged men and women. DESIGN AND METHODS: 1200 participants were selected from a population based cross sectional study on risk factors for cardiovascular diseases. The participants were divided into three groups: total plasma cholesterol < 5 mmol/l, total plasma cholesterol 5-8 mmol/l, total plasma cholesterol > 8 mmol/l. Each group was comparable in size and sex distribution. Subclinical hypothyroidism was defined as plasma TSH levels higher than 4 mU/l, in the presence of normal free thyroxine (FT4(4)) concentration. RESULTS: Plasma samples of a total of 1191 participants were analyzed. The overall prevalence of subclinical hypothyroidism was 1.9% in men and 7.6% in women of middle age. In women the prevalence of subclinical hypothyroidism increased from 4.0 percent in the lowest, to 10.3 percent in the highest cholesterol stratum (P = 0.02). In men, the mean prevalence was 1.8 percent and roughly similar in the various strata. After age correction, an increase of 1 mU/l TSH in women was associated with an increase of 0.09 mmol/l total plasma cholesterol (95% confidence interval (CI) 0.02-0.16 mmol/l). A similar trend was found in men (0.16 mmol/l, 95% CI -0.02-0.34 mmol/l). CONCLUSIONS: In the population, the prevalence of subclinical hypothyroidism is up to 10 percent in middle aged women with high levels of total plasma cholesterol and may justify case-finding. In these women approximately 0.5 mmol/l of total plasma cholesterol can be attributed to the subclinical thyroid dysfunction. In men a similar correlation between thyroid dysfunction and total plasma cholesterol is seen, but the prevalence of thyroid dysfunction is considerably lower.

Cholesterol↗
PubMed1999

Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism.

More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158-->Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors, suggesting a multifactorial etiology. To elucidate these additional risk factors, we analyzed normolipidemic and hyperlipidemic apoE2 homozygotes. Hyperinsulinemia was observed in 27 of 49 apoE2 homozygotes and associated with elevated lipid levels: hyperinsulinemic apoE2 homozygotes had type III hyperlipoproteinemia 6 times more often than apoE2 homozygotes with normal insulin levels (odds ratio 6.2, P=0.02). We screened the normolipidemic and hyperlipidemic apoE2 homozygotes for common variants in candidate genes involved in lipolysis-the APOA1-C3-A4 gene cluster, lipoprotein lipase, and hepatic lipase-and analyzed for associations with the expression of hyperlipidemia. In the hyperinsulinemic group, the 7 carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol (P(insulin by SstI)<0.001) and VLDL triglyceride (P(insulin by SstI)<0.01) and low levels of HDL (P(insulin by SstI)<0.02). In the normoinsulinemic group, no such relation of the SstI polymorphism with hyperlipidemia was observed. These data provide the first evidence for a combined effect of hyperinsulinemia and the SstI polymorphism on the expression of hyperlipidemia in apoE2 homozygotes.

Adult↗
PubMed1999

Binding of beta-VLDL to heparan sulfate proteoglycans requires lipoprotein lipase, whereas ApoE only modulates binding affinity.

The binding of beta-VLDL to heparan sulfate proteoglycans (HSPG) has been reported to be stimulated by both apoE and lipoprotein lipase (LPL). In the present study we investigated the effect of the isoform and the amount of apoE per particle, as well as the role of LPL on the binding of beta-VLDL to HSPG. Therefore, we isolated beta-VLDL from transgenic mice, expressing either APOE*2(Arg158-->Cys) or APOE*3-Leiden (E2-VLDL and E3Leiden-VLDL, respectively), as well as from apoE-deficient mice containing no apoE at all (Enull-VLDL). In the absence of LPL, the binding affinity and maximal binding capacity of all beta-VLDL samples for HSPG-coated microtiter plates was very low. Addition of LPL to this cell-free system resulted in a 12- to 55-fold increase in the binding affinity and a 7- to 15-fold increase in the maximal binding capacity (Bmax). In the presence of LPL, the association constant (Ka) tended to increase in the order Enull-VLDL<E2-VLDL<E3Leiden-VLDL, whereas Bmax increased in the reverse order: E3Leiden-VLDL approximately E2-VLDL<Enull-VLDL. Addition of LPL resulted in a marked stimulation of both Ka and Bmax for binding of beta-VLDL samples to J774 cells similar to that found for the binding to HSPG-LPL complexes. Our results indicate that both Ka and Bmax for binding of beta-VLDL to HSPG are increased more than 1 order of magnitude on addition of LPL. In addition, for the binding of beta-VLDL to HSPG-LPL complexes, the presence of apoE is not a prerequisite, but results in an increased binding affinity, depending on the apoE isoform used.

Animals↗
PubMed1998

Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset.

Very long chain acyl-coenzyme A (acyl-CoA) dehydrogenase (VLCAD) deficiency is a severe disorder of mitochondrial beta-oxidation in infants. We report adult onset of attacks of painful rhabdomyolysis. Gas chromatography identified strongly elevated levels of tetradecenoic acid, 14:1(n-9), tetradecadienoic acid, 14:2(n-6), and hexadecadienoic acid, 16:2(n-6). Palmitoyl-CoA and behenoyl-CoA dehydrogenase in fibroblasts were deficient. Muscle VLCAD activity was very low. DNA analysis revealed compound heterozygosity for two missense mutations in the VLCAD gene. The relatively mild clinical course may be due to residual enzyme activity as a consequence of the two missense mutations. Treatment with L-carnitine and medium chain triglycerides in the diet did not reduce the attacks of rhabdomyolysis.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1998

Similar response to simvastatin in patients heterozygous for familial hypercholesterolemia with mRNA negative and mRNA positive mutations.

In patients heterozygous for familial hypercholesterolemia, the low-density lipoprotein (LDL) cholesterol lowering effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors may depend on the nature of the mutation in the LDL receptor gene. To test this hypothesis, we compared the response to simvastatin, 20 mg daily for 9 weeks, between heterozygous carriers of functionally different classes of mutations, i.e. mRNA negative or mRNA positive mutations. Out of 116 consecutive, unrelated patients with familial hypercholesterolemia, 27 patients were selected for molecular analyses: 14 patients with mRNA negative and 13 with mRNA positive mutations. Before simvastatin treatment, patients with mRNA negative mutations had higher levels of LDL cholesterol, lower levels of high-density lipoprotein (HDL) cholesterol and significantly more often tendon xanthomas, compared to patients with mRNA positive mutations. Simvastatin reduced the mean fasting LDL cholesterol levels to a similar percentage in the mRNA negative and mRNA positive patients (37, 36%, respectively, 95% CI of difference--8 to 5%, P = 0.2). This effect was similar to the 37% decrease observed in our total series of patients with familial hypercholesterolemia (n = 116). The increase in mean concentration of HDL cholesterol was greater in the mRNA negative group than in the mRNA positive group (16, 0%, respectively, 95%, CI of difference 8-25%, P = 0.002) independent of the response of total triglycerides to simvastatin. The percentage LDL cholesterol lowering response varied among multiple carriers of the same mutation, even in the case of mRNA negative mutations. We conclude that the percentage LDL lowering response to simvastatin treatment was similar in patients with mRNA negative and mRNA positive mutations. Moreover, variation of this response within multiple carriers of the same mutation suggests an influence of additional factors.

Anticholesteremic Agents↗
PubMed1998

Effect of apolipoprotein E variants on lipolysis of very low density lipoproteins by heparan sulphate proteoglycan-bound lipoprotein lipase.

Lipoprotein lipase (LPL) is bound to heparan sulphate proteoglycans (HSPG) at the luminal surface of endothelium. It is the key enzyme involved in the hydrolysis of very low density lipoproteins (VLDL). Prior to lipolysis by LPL, the lipoproteins are considered to interact with vessel wall HSPG. Apolipoprotein (apo) E is thought to mediate this interaction thereby enhancing the stability of the lipoprotein-LPL complex. We hypothesize that apo E mutations may cause a diminished interaction of VLDL with HSPG leading to impaired lipolysis of VLDL by HSPG-bound LPL. In order to test this hypothesis, lipolysis experiments were performed using HSPG-bound LPL. The mean lipolysis rates of VLDL, isolated from the apo E2 (Lys146-->Gln) heterozygotes, apo E2 (Arg158-->Cys) homozygotes and apo E3-Leiden heterozygotes were 92.3 +/- 10.3 (ns), 77.3 +/- 4.2 (P < 0.05) and 76.7 +/- 10.0% (P < 0.05), respectively, of that of control VLDL (100.0 +/- 9.7%). No differences in lipolysis were observed between VLDL from controls and VLDL from the same patients if LPL in solution was used. Thus, compositional differences alone can not explain the differences in lipolysis rates observed with HSPG-bound LPL. In competition experiments, the binding efficiency to HSPG-LPL of VLDL from the apo E2 (Lys146-->Gln) heterozygotes, apo E2 (Arg158-->Cys) homozygotes and apo E3-Leiden heterozygotes was 63 (ns), 41 (P < 0.05) and 35% (P < 0.05), respectively of that of control VLDL (100%). We conclude that VLDL isolated from apo E2 homozygotes and apo E3-Leiden heterozygotes display decreased lipolysis by HSPG-bound LPL due to a defective binding of these lipoproteins to the HSPG-LPL complex.

Adult↗
PubMed1998

Increased risk for endogenous hypertriglyceridaemia is associated with an apolipoprotein C3 haplotype specified by the SstI polymorphism.

BACKGROUND: Hypertriglyceridaemia is a common metabolic disorder frequently found in patients with coronary heart disease. Numerous studies have revealed an association between the SstI polymorphism in the APOC3 gene and increased plasma apoC3 and triglyceride levels. In addition, two different variants within the promoter region have been recently suggested to be the mutations of the APOC3 gene leading to hypertriglyceridaemia. METHODS: In the present study, we have applied haplotype analysis to investigate whether these promoter polymorphisms are involved in the lipid disorders of patients with distinct types of hypertriglyceridaemia: combined hyperlipidaemia (CHL), familial dysbetalipoproteinaemia (FD) and endogenous hypertriglyceridaemia (HTG). RESULTS: The -482 and -455 polymorphisms were significantly more frequent in FD patients (P = 0. 017) and endogenous HTG patients (P < 0.0001) than in CHL patients and a control group. The SstI polymorphism was only significantly more frequent in HTG patients (P < 0.0001). However, we did not find differences in frequencies for these polymorphisms in the APOC3 gene between CHL patients and a control group. Haplotype analysis indicates that the SstI polymorphism arose on the allele containing both promoter polymorphisms. CONCLUSION: The haplotype containing the SstI polymorphism is found five times more frequently among HTG patients (OR 5.28, 95% CI 1.65-16.90), which strongly suggests it is associated with an increased risk for severe hypertriglyceridaemia.

Adult↗
PubMed1998

Graves' hyperthyroidism in a patient with primary sclerosing cholangitis. Coincidence or combined pathogenesis?

Several autoimmune disorders have been associated with the diagnosis of primary sclerosing cholangitis (PSC). We report on a 19-year-old male PSC patient with a history of ulcerative colitis who developed hyperthyroidism consistent with Graves' disease. In contrast to primary biliary cirrhosis, hyperthyroidism appears to be very uncommon in PSC patients. Nevertheless, the rarity of Graves' disease in young males, the presence of a human leucocyte antigen (HLA) phenotype often encountered in both Graves' disease and PSC and the presence of several autoantibodies suggest a common immunogenetic predisposition, rather than mere coincidence, of both diseases in this patient. Since many patients with thyroid disease exhibit mild cholestatic liver function abnormalities but few of them undergo cholangiographic examination, PSC may be underdiagnosed. Physicians should therefore be aware of the potential association between thyroid disease and PSC.

Adult↗
PubMed1997

Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors.

BACKGROUND AND PURPOSE: To estimate the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors ("statins") on stroke ris, we combined the data of the randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors published so far. METHODS: The studies were identified using the Medline CD+ and Current Contents databases from January 1980 through May 1996, inclusive. All studies were evaluated on the use of a placebo control, monotherapy, and double blindness. When the type of stroke or the occurrence of clinical events or adverse effects were incompletely or not reported, the investigators were contacted personally. For each trial, the number of strokes in the treatment arm was compared with the number of strokes expected on all observations under the assumption that drug treatment had no effect. RESULTS: A total of 462 strokes among 20438 participants in 13 trials could be analyzed. A total of 181 strokes were observed in patients randomized to treatment with an HMG-CoA reductase inhibitor and 261 strokes in patients randomized to placebo. A lower than expected number of strokes was observed in the treatment groups of all but one trial (P = .001). Treatment with an HMG-CoA reductase inhibitor led to an overall risk reduction of 31% (odds ratio, 0.69; 95% confidence interval, 0.57 to 0.83). CONCLUSIONS: The combined data suggest that treatment with HMG-CoA reductase inhibitors prevents stroke in middle-aged persons. Because stroke is especially common in older age, these data reinforce the need for clinical trials to evaluate the effect of HMG-CoA reductase inhibitors in preventing stroke in the elderly.

Aged↗
PubMed1997

Lipolysis of very low density lipoproteins by heparan sulfate proteoglycan-bound lipoprotein lipase.

An in vitro assay to study lipolysis of very low density lipoproteins (VLDL) by heparan sulfate proteoglycan (HSPG-bound lipoprotein lipase (LPL) was developed. Optimal conditions for VLDL lipolysis by HSPG-bound LPL were obtained by incubating plastic wells with 0.5 microg HSPG and 1.5 microg LPL, subsequently. Control experiments with heparinase indicate that at least 90% of the LPL activity is derived from LPL bound to heparan sulfate chains. For HSPG-LPL-mediated lipolysis, the apparent Km and Vmax values were 0.36 +/- 0.11 mM VLDL-triglycerides and 1.2 +/- 0.1 microM free fatty acids/min x ng LPL, respectively. The mean intra-assay and inter-assay coefficients of variance were 5% and 8%, respectively.

Animals↗
PubMed1996

Effect of apolipoprotein E and insulin resistance on VLDL particles in combined hyperlipidemic patients.

Apolipoprotein (apo) E2 and high insulin levels are associated with the severity of hypertriglyceridemia in patients with combined hyperlipidemia. To study how these determinants affect very low-density lipoprotein (VLDL) in combined hyperlipidemic patients, we characterized VLDL particles in 106 unrelated patients with combined hyperlipidemia. The study was performed after 9 weeks of standardized dietary intake and after an overnight fast. Patients heterozygous for apoE2 had significantly higher mean levels of VLDL cholesterol by 0.71 mmol/l (95% CI, 0.30 to 1.12 mmol/l, P < 0.005) and VLDL triglycerides by 0.88 mmol/l, (95% CI, 0.30 to 1.47 mmol/l, P < 0.005) compared to patients without apoE2. The VLDL triglyceride content per particle and the calculated diameter of the VLDL particles were similar in both groups, which indicate a higher number of circulating VLDL particles in heterozygous apoE2 carriers. Patients with high fasting insulin levels (> or = 80 pmol/l) had a higher mean serum VLDL triglyceride level by 0.56 mmol/l (95% CI, 0.04 to 1.07 mmol/l, P < 0.05). The calculated VLDL diameter was larger by 3.7 nm (95% CI, 1.2 to 6.2 nm, P < 0.005) and the particles contained more triglycerides by 2.7 weight percent (95% CI, 0.3 to 5.1 weight percent, P < 0.05). These insulin-dependent changes in VLDL particles were only present in the absence of apoE2. In conclusion, patients heterozygous for apoE2 have higher numbers of circulating VLDL particles, whereas patients with high fasting insulin levels have larger, triglyceride enriched VLDL particles.

Adult↗
PubMed1996

Effects of fish oil on oxidation resistance of VLDL in hypertriglyceridemic patients.

In hypertriglyceridemic (HTG) patients the addition of fish oil to the diet causes a marked reduction in the concentration of triglyceride-rich lipoproteins in the serum. To investigate the effects of fish oil on the oxidation resistance of VLDL and LDL in HTG patients, nine male patients received 1 g/d fish oil (containing 55.7% n-3 polyunsaturated fatty acids [PUFAS] and l U alpha-tocopherol/g fish oil) for 6 weeks followed by 5 g/d fish oil for an additional 6 weeks. Cu(2+)-induced oxidation of VLDL and LDL was measured by continuous monitoring of conjugated dienes. Supplementation with 1 g/d fish oil caused hardly any changes in the n-3 PUFA content of lipoproteins or lipoprotein concentrations in serum. However, supplementation with 5 g/d fish oil resulted in a significant increase of n-3 PUFA content in VLDL (from 2.5% to 6.4% of total fatty acids) and LDL (from 3.2% to 6.4% of total fatty acids), decreases in serum triglyceride, VLDL triglyceride, and VLDL cholesterol concentrations of 54%, 56%, and 40%, respectively, and an increase in LDL cholesterol of 23%. The lag times of VLDL and LDL oxidation decreased from 197 to 140 minutes (-29%) and 101 to 86 minutes (-15%), respectively. At the end of the 5 g/d fish oil supplementation the lag times of VLDL and LDL oxidation were correlated with their respective n-3 PUFA content (r = -.67; P < .05 and r = -.79; P < .02, respectively). Before and at the end of supplementation with 5 g/d fish oil the lag times and propagation rates of VLDL oxidation also correlated with the total number of double bonds in all PUFAs of VLDL. We conclude that fish oil supplementation strongly reduces serum concentrations of total triglycerides, VLDL triglycerides, and VLDL cholesterol. However, in HTG patients fish oil supplementation increased the serum LDL cholesterol concentration and the susceptibility of VLDL and LDL to oxidation.

Adult↗
PubMed1995

A placebo-controlled parallel study of the effect of two types of coffee oil on serum lipids and transaminases: identification of chemical substances involved in the cholesterol-raising effect of coffee.

In a randomized double-blind parallel study in 36 subjects the effect on serum cholesterol of a daily dose of 2 g lipid extracted from green Arabica and Robusta coffee beans was studied. Arabica oil elevated serum total cholesterol by 1.1 mmol/L (95% CI for the difference from placebo: 0.41, 1.73 mmol/L); the effect of robusta oil (+0.5 mmol/L) was not statistically significant (95% CI: -0.01, 0.92 mmol/L). Arabica oil also raised plasma triglycerides by 0.8 mmol/L (95% CI: 0.26, 1.25 mmol/L). The effect of robusta oil on triglycerides was +0.14 mmol/L and not significant (95% CI: -0.26, 0.42 mmol/L). In the 12 subjects taking arabica oil an average serum alanine amino-transferase elevation of 18 U/L (95% CI: 9.4, 28.4 U/L) was observed. Because only arabica oil contains kahweol and arabica coffee contains more cafestol than does robusta oil, this is further evidence for the role of diterpenes in the rise of serum cholesterol and alanine aminotransferase after consumption of boiled coffee.

Administration, Oral↗
PubMed1995

Superior sagittal sinus thrombosis and thyrotoxicosis. Possible association in two cases.

BACKGROUND: Superior sagittal sinus thrombosis is an uncommon cerebrovascular accident that is frequently associated with diseases that may contribute to the development of thrombosis through hypercoagulability, stasis of the local blood stream, and abnormalities of the vessel wall. In approximately 25% of cases underlying diseases remain unrecognized. CASE DESCRIPTIONS: Two patients with superior sagittal sinus thrombosis during a thyrotoxic phase of Graves' disease are described. Both patients presented with hemiplegia, seizures, and a large goiter. CONCLUSIONS: The development of superior sagittal sinus thrombosis is multifactorial. Patients with thyrotoxicosis and a large goiter may be predisposed to the development of superior sagittal sinus thrombosis through hypercoagulability and stasis of the local venous blood flow.

Adult↗