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Biomedical subjects

S Tonstad

Publications and source records attributed to S Tonstad.

At least 73 records · Page 4Linked to original sources
PubMed1996

The effect of growth hormone on low-density lipoprotein cholesterol and lipoprotein (a) levels in familial hypercholesterolemia.

Severe elevations of low-density lipoprotein (LDL) cholesterol are not always normalized with conventional drugs. Growth hormone decreases LDL cholesterol levels, in part by augmenting liver LDL receptor activity. This increase may be on the order of magnitude of the increase induced by statins. We investigated the effect of growth hormone in familial hypercholesterolemia (FH) in a randomized, double-blind, placebo-controlled study. Thirty-one men with FH aged 20 to 48 years, of whom 81% had a known LDL receptor gene mutation, discontinued all lipid-lowering drugs 6 weeks before the study. Dietary stabilization continued for 5 more weeks, followed by single-blind placebo injections for 1 week. Thereafter, 16 subjects were allocated to recombinant growth hormone 0.05 IU/kg/d and 15 to placebo injected subcutaneously for 12 weeks. Baseline lipid levels were similar in both groups. One subject in the growth hormone group withdrew after 8 weeks due to shoulder pain. Mean compliance among the rest of the subjects was 98%. The mean change in LDL cholesterol was -0.46 mmol/L (95% confidence interval [CI], -1.00 to 0.09 mmol/L) in the growth hormone group versus 0.08 mmol/L (95% CI, -0.55 to 0.71 mmol/L) in the placebo group (difference not significant). No changes occurred in the levels of other lipids, lipoprotein particles, or apolipoproteins, with the exception of lipoprotein(a) [Lp(a)]. The median changes in Lp(a) were 33% (interquartile range, 2% to 53%) and -15% (interquartile range, -22% to 18%) in the growth hormone and placebo groups, respectively (P = .02). We conclude that the effect of growth hormone on LDL cholesterol levels in FH is less than expected, based on its LDL-catabolic effects, and is counteracted by profound increases in Lp(a) levels, resulting in unchanged levels of apolipoprotein B. Thus, growth hormone is probably not useful as adjunctive therapy in FH.

Adult↗
PubMed1996

Effect of hormone replacement therapy on the susceptibility of low-density lipoprotein to oxidation among postmenopausal hypercholesterolaemic women.

The effect of sequential combined hormone replacement therapy on the susceptibility of low-density lipoprotein to oxidative modification was investigated in a double-blind, randomized placebo-controlled study. Hypercholesterolaemic, postmenopausal women were supplemented with 17 beta-oestradiol and norethisterone acetate (n = 13 subjects) or placebo capsules (n = 15 subjects) for 12 weeks. They were instructed to follow the American Heart Association step one diet. Low-density lipoprotein, isolated before and after treatment, was subjected to copper-catalysed lipid peroxidation. There were no significant differences between low-density lipoprotein from the hormone replacement therapy and placebo groups, as assessed by measuring the lag time for formation of conjugated dienes, the rate of formation and the amount of conjugated dienes formed, the amount of lipid peroxides generated, and the relative electrophoretic mobility at baseline and after treatment. Dietary records showed that the subjects were consuming similar amounts of fat and vitamins. No major differences were found in the fatty acid pattern of low-density lipoprotein from the two groups. In conclusion, the results indicated that hormone replacement therapy with 17 beta-oestradiol sequentially combined with norethisterone acetate in non-smoking, hypercholesterolaemic, postmenopausal women has no protective effect on the susceptibility of low-density lipoprotein to copper-catalysed modification in vitro.

Adult↗
PubMed1996

Validity of selected physical activity questions in white Seventh-day Adventists and non-Adventists.

The validity and reliability of selected physical activity questions were assessed in both Seventh-day Adventist (N = 131) and non-Adventist (N = 101) study groups. Vigorous activity questions similar to those used by others and new questions that measured moderate and light activities were included. Validation was external, comparing questionnaire data with treadmill exercise time, resting heart rate, and body mass index (kg.m-2), and internal, comparing data with other similar questions. Both Adventist and non-Adventist males showed significant age-adjusted correlations between treadmill time and a "Run-Walk-Jog Index" (R = 0.28, R = 0.48, respectively). These correlations increased substantially when restricting analysis to exercise speeds exceeding 3 mph (R = 0.39, R = 0.71, respectively). Frequency of sweating and a vigorous physical activity index also correlated significantly with treadmill time in males. Correlations were generally weaker in females. Moderate- and light-intensity questions were not correlated with physical fitness. Internal correlations R = 0.50-0.78) between the above three vigorous activity questions were significant in all groups, and correlations (R = 0.14-0.60) for light and moderate activity questions were also documented. Test-retest reliability coefficients were high for vigorous activity questions (R = 0.48-0.85) and for one set of moderate activity questions (R = 0.43-0.75). No important differences in validity and reliability were found between Adventist and non-Adventists, but the validity of vigorous activity measures was generally weaker in females.

Adult↗
PubMed1996

Two novel missense mutations in the LDL receptor gene causing familial hypercholesterolemia.

We have employed analysis of single-strand conformation polymorphisms to identify mutations in the low density lipoprotein receptor gene causing familial hypercholesterolemia. Two familial hypercholesterolemia heterozygotes had abnormal single-strand conformation polymorphism patterns of exons 4 and 8. DNA sequencing revealed that the abnormal pattern of exon 4 was due to heterozygosity (G/T) at nucleotide 502. Nucleotide 502 is the first base of codon 147, and the G->T mutation (D147Y) changes this codon from AspGAC to TyrUAC. The abnormal pattern of exon 8 was due to heterozygosity (A/G) at nucleotide 1097. Nucleotide 1097 is the second base of codon 345, and the A->G mutation (Q345R) changes this codon from GlnCAG to ArgCGG. Based upon screening of 437 unrelated familial hypercholesterolemia heterozygotes, both D147Y and Q345R account for about 0.5% of the mutations causing familial hypercholesterolemia in Norway.

Base Sequence↗
PubMed1996

Familial hypercholesterolaemia: a pilot study of parents' and children's concerns.

OBJECTIVE: To assess psychosocial concerns of families with familial hypercholesterolaemia. METHODS: One-hundred-and-fifty-four single or pairs of parents of children age 6 - 16 years responded to a specifically designed questionnaire. One child from each family was interviewed. RESULTS: Eleven percent of parents thought that their quality of life would have been better had they not known about the disease. None agreed totally that they wished the diagnosis had not been made. However, 20% reported familial conflicts and 8% that their child's emotional or social life had been adversely affected. Conflicts and adverse effects were associated with higher scores on the Child Behaviour Checklist (CBCL). Among the children, worry about cardiovascular disease (affirmed by 22%) was related to male sex and CBCL score. RELEVANCE: Most families do not indicate that they have experienced psychosocial problems due to familial hypercholesterolaemia. Parental ratings of the child's behavioural adjustment may identify vulnerable children.

Adolescent↗
PubMed1996

Colestipol tablets in adolescents with familial hypercholesterolaemia.

The objective of this study was to examine palatability and side effects of the new tablet formulation of colestipol. A clinical series of 23 boys and 4 girls aged 10-16 years with heterozygous familial hypercholesterolaemia were given 2-12 g colestipol daily for 6 months in an open study. There were no serious side effects. The median reduction in low density lipoprotein cholesterol level was 20%. All preferred the tablets to resin granules they had tried previously. We conclude that low-dose colestipol tablets appear to be safe and effective, and are preferred by adolescents.

Adolescent↗
PubMed1996

Low dose colestipol in adolescents with familial hypercholesterolaemia.

The effects of orange flavoured colestipol granules, 10 g/day, in 37 boys and 29 girls aged 10-16 years with familial hypercholesterolaemia were examined first in an eight week double blind, placebo controlled protocol, then in open treatment for 44-52 weeks. All patients were on a low fat diet. Low density lipoprotein cholesterol levels were reduced by 19.5% by colestipol v 1.0% by placebo. Levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group, but not the vitamin E/cholesterol and carotenoid/cholesterol ratios or serum concentrations of vitamins A and D. After one year of colestipol, two thirds of the participants remained in the study, of whom half took > or = 80% of the prescribed dose. Those who took > or = 80% of the dose had a greater decrease in serum 25-hydroxyvitamin D levels than those who took < 80%. No adverse effects on weight gain or linear growth velocity were observed. Although low dose colestipol effectively reduces low density lipoprotein cholesterol levels, only a minority of adolescents adhered to the new formulation for one year. Folate and possibly vitamin D supplementation is recommended.

Adolescent↗
PubMed1996

Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and control subjects.

To assess the relationship between risk factors for cardiovascular disease and early atherosclerotic changes in the carotid artery, we measured carotid intima-media thickness by B-mode ultrasonography in 61 boys and 29 girls 10 to 19 years old with familial hypercholesterolemia (FH) and 30 control subjects matched for age and sex. All were nonsmokers, and all the FH adolescents had a known mutation in the LDL receptor gene. Mean intima-media thickness in the far wall of the carotid bulb was greater (P = .03) in the FH group than in the control subjects: 0.54 mm (95% confidence interval [CI], 0.52 to 0.56) versus 0.50 mm (95% CI, 0.47 to 0.52). In the entire group, mean and maximum intima-media thicknesses in the carotid bulb were positively associated with levels of apolipoprotein B and fibrinogen after control for pubertal stage (r = .19 to .24; P < .05), as was male sex. Plasma total homocysteine was similar in the FH and control groups and was associated with mean and maximum intima-media thicknesses in the far wall of the common carotid artery and carotid bulb after control for pubertal stage (r = .22 to .28; P < .05). With the exception of the relation between plasma fibrinogen level and mean carotid bulb intima-media thickness, these associations were essentially unchanged in stepwise multiple linear regression analyses, allowing for the entry of BMI and level of HDL cholesterol into the analysis. Carotid artery plaque was present in 10% of the children with FH versus none of the control subjects. Children with plaque had a higher mean cholesterol-years score than children without plaque. These findings suggest that the classic lipid and hemostatic risk factors as well as plasma total homocysteine are associated with markers of early carotid atherosclerosis from the second decade of life. B-mode ultrasonography may prove to be a useful tool in risk stratification of children with FH.

Adolescent↗
PubMed1996

Relation of total homocysteine and lipid levels in children to premature cardiovascular death in male relatives.

We assessed the relative importance of lipid, apo B, lipoprotein(a) [Lp(a)], and total homocysteine (tHcy) levels in children in relation to premature cardiovascular disease in family members. Parents of 381 girls and 375 boys age 8-12 y completed family history questionnaires. Nonfasting serum lipid and lipoproteins and plasma tHcy and cysteine levels were measured in the children. Serum folate and vitamin B12 levels were determined in a random subsample of 23% of the children, who participated in a food frequency interview. Children whose parents reported hypercholesterolemia had higher total and non-HDL cholesterol and apo B levels than the rest, but these levels were not associated with cardiovascular disease. tHcy levels were similar in girls and boys. tHcy was higher in children whose father, grandfather, or uncle died at age < or = 55 y of myocardial infarction or sudden cardiac arrest (n = 42) than in control children [5.92 mumol/L (95% confidence interval [CI] of 5.47-6.36) versus 5.25 mumol/L (95% CI, 5.16-5.34)], also after adjustment for socioeconomic group. Intake and serum levels of vitamin B12 and folate were within recommended or reference ranges. In a stepwise multiple regression analysis, serum folate (negative correlation), plasma creatinine, and sugar intake as percent of dietary energy (positive correlations) were significantly associated with tHcy (multiple r = 0.44, adjusted r2 = 18%; 95% CI, 5-30%). Our data show that a modest elevation in tHcy in children was related to premature cardiovascular death in their male relatives and may partly account for the contribution of family history to risk of cardiovascular disease. tHcy may be modifiable through the diet, even in children with apparently adequate vitamin nutriture.

Age of Onset↗
PubMed1996

Psychosocial function during treatment for familial hypercholesterolemia.

OBJECTIVE: To determine whether children treated for familial hypercholesterolemia (FH) have greater psychosocial dysfunction compared with their peers. CHILDREN: Children were 86 boys and 66 girls 7-16 years of age attending a lipid clinic. They were screened and instructed to follow a diet low in saturated fat and cholesterol 18 months to 9 years earlier (mean, 4 years), and their mean dietary intake, estimated by a quantitative food frequency questionnaire, was within recommended limits. One-fourth had lost a parent or had a parent who had had cardiovascular disease due to FH (parental disease group). METHODS: Results of the Child Behavior Checklist, Teacher's Report Form, and Youth Self-Report were compared with a population sample. A semistructured interview, the Child Assessment Schedule, was administered to the children with FH and a well-functioning comparison group from the population (epidemiologic cohort; n = 62). RESULTS: Psychosocial scores were similar in the children with FH and the population sample. The Child Assessment Schedule showed that, compared with the epidemiologic cohort, children with FH did not have increased symptoms in any area of function, and scores for family, mood, and expression of anger were lower (less symptomatic). The prevalence of psychiatric diagnoses was 10%, which was not greater than expected. Children from the parental disease group had higher symptom scores in the areas of school and expression of anger than the rest of the children with FH. Their mean Children's Global Assessment Score (CGAS, which gives average children scores of 70-79) was slightly lower (77 vs 79). Belonging to the parental disease group predicted a lower CGAS in multivariate regression analyses, as did male sex, parental divorce, and low parental educational level. These factors explained up to 19% (95% confidence interval, 9%-31%) of the variance in CGAS. CONCLUSIONS: We found that the prevalence of psychosocial dysfunction was not greater than expected in children treated for FH. Psychosocial function within the group was associated with the usual demographic characteristics and with the loss or disease of a parent, beyond the period of bereavement or immediately after the event.

Adolescent↗
PubMed1995

[Diagnosis and treatment of familial hypercholesterolemia in children and adolescents].

The identification and management of hyperlipidemias in children are currently limited to persons regarded as being at very high risk, such as those with familial hypercholesterolemia. Universal screening of children is not recommended, but it is important to screen the subset of children and adolescents at highest risk, i.e. those with a family history of premature cardiovascular disease or familial hypercholesterolemia. Treatment of children and adolescents with hypercholesterolemia requires a multidisciplinary approach. Cholesterol-lowering medication may be required in addition to dietary therapy in children with a history of premature coronary heart disease among close relatives.

Adolescent↗
PubMed1995

Standardization of a flow cytometric method for measurement of low-density lipoprotein receptor activity on blood mononuclear cells.

Flow cytometric methods for measurement of low-density lipoprotein (LDL) receptor activity on peripheral blood mononuclear cells (PBMC) may be used to identify patients with familial hypercholesterolemia (FH). However, cellular LDL receptor activities measured in FH heterozygotes may overlap with those of healthy subjects. Analytical variation is probably responsible for some of this overlap. We have examined several technical details that may affect analytical variation. In each analysis, we included one standard and two control cell preparations. These were cells isolated from three donors and stored in aliquots at -135 degrees C. Use of standard cells reduced between-series analytical variation of the controls by approximately 50%. Preincubation-conditions used to induce the maximum number of receptors, the concentration of fluorochrome 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-perchlorate (DiI)-LDL, labelling time, and conditions during storage of labelled cells before flow cytometry were also examined in order to reduce analytical variation. Having standardized the assay, we found among 20 healthy subjects a median receptor activity of 100% vs. 51% among 26 patients who fulfilled clinical criteria for FH. However, four of the patients showed distinctly normal receptor activities, which may suggest either the presence of some other biochemical defect or that in vivo dysfunctional receptors may be measured as normal in some patients with our assay.

Adult↗
PubMed1995

[Antioxidants and cardiovascular disorders--epidemiologic aspects. Should high risk patients receive supplementation?].

Dietary antioxidants such as vitamin E, vitamin C, beta carotene and flavonoids may retard atherosclerosis by preventing low density lipoprotein oxidation. Observational epidemiological studies, including ecological correlations, case control and prospective studies, indicate that high vitamin E levels may be associated with decreased cardiovascular disease. Beta carotene may be protective among smokers and the elderly. Few studies have been able to show that vitamin C has a protective effect. A handful of intervention studies have examined the effects of vitamin E and beta carotene with mixed results. While few side effects of antioxidant supplementation are known, the results of current, large-scale studies in primary intervention must be awaited before recommendations can be made. Increased intake of fruits and vegetables that are rich in antioxidants is recommended.

Antioxidants↗
PubMed1995

Two novel point mutations in the EGF precursor homology domain of the LDL receptor gene causing familial hypercholesterolemia.

Familial hypercholesterolemia is caused by mutations in the low density lipoprotein (LDL) receptor gene. Analysis of single-strand conformation polymorphisms of exons 10 and 11 of the LDL receptor gene from familial hypercholesterolemia heterozygotes indicated the presence of two mutations, which were characterized by DNA sequencing. One mutation (delta N466) was a 3-bp deletion in exon 10 that deletes Asn in codon 466. The other (intron 11 +1, G-->T) was a splice donor mutation at position +1 of intron 11.

Amino Acid Sequence↗
PubMed1995

Screening for known mutations in the LDL receptor gene causing familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is caused by defective low density lipoprotein (LDL) receptors and is characterized by hypercholesterolemia and premature coronary heart disease. Two strategies can be used to identify the mutation in the LDL receptor gene underlying FH. One strategy is to search for novel mutations by DNA sequencing with or without prior mutation screening. The other strategy is to screen for known mutations. In this study we employed the latter strategy to screen 75 unrelated, Norwegian FH subjects for 38 known mutations. Three of the 38 mutations were detected in our group of FH subjects. Two subjects had FH-Padova, one had FH-Cincinnati-2 and one had FH-Gujerat. When additional unrelated FH heterozygotes were screened for the three mutations, the gene frequencies were 1.3%, 1.0% and 3.0%, respectively. In addition to identifying known mutations we also detected a novel stop codon in codon 541 (S541X). We conclude that screening for known mutations in the LDL receptor gene should be used as a complementary strategy to screening for novel mutations in order to understand the molecular genetics of FH.

Base Sequence↗
PubMed1995

Efficacy of sequential hormone replacement therapy in the treatment of hypercholesterolaemia among postmenopausal women.

OBJECTIVES: To test the efficacy of hormone replacement therapy (HRT) and dietary therapy, compared to dietary therapy, in lowering LDL cholesterol levels among postmenopausal women. DESIGN: A prospective parallel randomized study of sequential 17 beta-oestradiol and norethisterone acetate or placebo for 48 weeks. SETTING: A University outpatient lipid clinic. SUBJECTS: A total of 76 postmenopausal women, aged 43-60 years, with LDL cholesterol levels > or = 4.2 mmol 1-1, treated with a lipid-lowering diet. MAIN OUTCOME MEASURES: Levels of lipids, lipoproteins, apolipoproteins, fibrinogen and glucose tolerance. RESULTS: Adherence to the diet was similar in both groups. Total and LDL cholesterol levels were reduced by 14% (95% CI, 11-17%) and 19% (95% CI, 14-23%), respectively, in the HRT group vs. 3% (95% CI, 0-7%) and 5% (95% CI, 0-11%) in the diet group. HRT reduced the levels of apolipoprotein B and lipoprotein(a). Levels of HDL cholesterol, HDL2, HDL3, triglycerides, lipoprotein populations and apolipoproteins AI and AII remained unchanged. No adverse effects on glucose tolerance or on fibrinogen levels were observed. The reduction in LDL cholesterol was positively correlated with initial levels of LDL cholesterol and negatively correlated with body mass index. CONCLUSIONS: HRT is effective in reducing elevated LDL cholesterol levels, and should be considered in the treatment of hyperlipidaemic postmenopausal women, in addition to dietary therapy.

Adult↗