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Biomedical subjects

P B Duell

Publications and source records attributed to P B Duell.

At least 19 recordsLinked to original sources
PubMed1998

Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease.

BACKGROUND: The Food and Drug Administration (FDA) has recommended that cereal-grain products be fortified with folic acid to prevent congenital neural-tube defects. Since folic acid supplementation reduces levels of plasma homocyst(e)ine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, we hypothesized that folic acid fortification might reduce plasma homocyst(e)ine levels. METHODS: To test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. RESULTS: Plasma folic acid increased and plasma homocyst(e)ine decreased proportionately with the folic acid content of the breakfast cereal. Cereal providing 127 microg of folic acid daily, approximating the increased daily intake that may result from the FDA's enrichment policy, increased plasma folic acid by 31 percent (P=0.045) but decreased plasma homocyst(e)ine by only 3.7 percent (P= 0.24). However, cereals providing 499 and 665 microg of folic acid daily increased plasma folic acid by 64.8 percent (P<0.001) and 105.7 percent (P=0.001), respectively, and decreased plasma homocyst(e)ine by 11.0 percent (P<0.001) and 14.0 percent (P=0.001), respectively. CONCLUSIONS: Cereal fortified with folic acid has the potential to increase plasma folic acid levels and reduce plasma homocyst(e)ine levels. Further clinical trials are required to determine whether folic acid fortification may prevent vascular disease. Until then, our results suggest that folic acid fortification at levels higher than that recommended by the FDA may be warranted.

Aged↗
PubMed1998

The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocyst(e)ine in fetal metabolism.

OBJECTIVE: Data on fetal blood homocyst(e)ine concentrations are not available. We tested the hypothesis that homocyst(e)ine crosses the maternal/placental/fetal interphases and is sequestered by the fetus. STUDY DESIGN: The concentration of homocyst(e)ine was determined at parturition in peripheral venous plasma from 35 nulliparous healthy pregnant women and umbilical arterial and venous plasma from their conceptus. RESULTS: Findings demonstrated a descending concentration gradient of plasma homocyst(e)ine from maternal vein to umbilical vein and to umbilical artery; the decrease at each interphase approximated 1 micromol/L. The neonate weight and gestational age were inversely related to maternal homocyst(e)ine concentrations. CONCLUSION: The umbilical vein to umbilical artery homocyst(e)ine decrement suggests that uptake of homocyst(e)ine occurs in the fetus. The likely incorporation of homocyst(e)ine into the fetal metabolic cycle may implicate maternal homocyst(e)ine as having a potential nutritional role in the fetus. Further studies are required to explain the role of homocyst(e)ine in fetal metabolism and development.

Adult↗
PubMed1997

Differential effects of subcutaneous estrogen and progesterone on low-density lipoprotein size and susceptibility to oxidation in postmenopausal rhesus monkeys.

OBJECTIVE: To study the differential effects of subcutaneous E2 alone or in combination with P on the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation in naturally postmenopausal diet-controlled rhesus monkeys. DESIGN: Prospective, longitudinal controlled study. SETTING: Oregon Health Sciences University, Portland, Oregon, and Oregon Regional Primate Research Center, Beaverton, Oregon. PATIENT(S): Five naturally postmenopausal rhesus monkeys. INTERVENTION(S): Estradiol was administered subcutaneously for the first 4 weeks, followed by E2 plus P for 4 weeks, followed by a third 4-week washout period. MAIN OUTCOME MEASURE(S): Changes in plasma lipoprotein levels and oxidation of LDL and serum concentrations of E2 and P. RESULT(S): Levels of LDL cholesterol fell after 4 weeks of treatment with E2, compared with baseline. The lag time to half maximal light absorbancy after 4 weeks of E2 treatment was significantly increased compared with baseline. The maximal absorbance values and the slope of the propagation phase after 4 weeks of treatment with E2 were decreased compared with baseline. After 4 weeks of combined E2 and P treatment, all values were comparable to baseline. CONCLUSION(S): These results suggest that subcutaneous E2 therapy appears to enhance LDL resistance to oxidation and that this effect is attenuated by the addition of the P.

Animals↗
PubMed1997

Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease.

Homocysteine is an intermediate compound formed during metabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation. Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12, or betaine, but further research is required to determine the efficacy of this intervention in reducing morbidity and mortality associated with atherosclerotic vascular disease.

Arteriosclerosis↗
PubMed1997

The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes.

Elevated concentration of plasma total homocysteine (tHcy) is a common risk factor for arterial occlusive diseases. Folic acid (FA) supplementation usually lowers tHcy levels, but initial tHcy and vitamin levels, multivitamin use, and polymorphisms in the gene for 5, 10-methylenetetrahydrofolate reductase (MTHFR) may contribute to variability in reduction. We tested the effects of a 3-week daily intake of 1 or 2 mg of FA supplements on tHcy levels in patients with and without coronary heart disease (CHD) who were analyzed for the C677T MTHFR mutation. Prior multivitamin intake and baseline vitamin and tHcy levels were also compared with responsiveness to folate supplementation. Both dosages of FA lowered tHcy levels similarly, regardless of sex, age, CHD status, body mass index, smoking, or plasma creatinine concentration. In non-multivitamin users, FA supplements reduced tHcy by 7% in C/C homozygotes and by 13% or 21% in subjects with one or two copies of the T677 allele, respectively; the corresponding reductions were smaller in users of multivitamins. Moreover, T/T homozygotes had elevated tHcy and increased susceptibility to high levels of tHcy at marginally low plasma folate levels, as well as enhanced response to the tHcy-lowering effects of FA. Although other factors are probably involved in the responsiveness of tHcy levels to FA supplementation, about one third of heterogeneity in responsiveness was attributable to baseline tHcy and folate levels and to multivitamin use.

Alleles↗
PubMed1997

Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels.

The factors responsible for the variability in plasma leptin levels observed among individuals with similar body compositions remain unclear. To examine the impact of dietary variables, we compared the changes in leptin levels induced by fasting and dietary fat restriction with the expected decrease following a significant loss in adipose mass. A 21.4 +/- 3.7% weight loss led to a 76.3 +/- 8.1% decrease in mean plasma leptin level (25.2 +/- 9.3 to 6.1 +/- 3.4 ng/mL, P = 0.0001) in a group of 9 obese males. Despite a weight loss of only 2.6 +/- 0.8%, mean plasma leptin levels fell by 61.9 +/- 25.2% (8.5 +/- 4.5 to 2.4 +/- 0.5 ng/mL, P < 0.01) in 7 nonobese females subjected to 3 days of fasting. Leptin levels in fasted subjects returned to baseline within 12 h of refeeding. Individual high- and low-fat meals given to 19 subjects after an overnight fast had no effect on plasma leptin levels. Reduction in dietary fat content from 37-10% of total calories for 7 weeks was also without effect on plasma leptin levels in these subjects. We conclude that plasma leptin levels primarily reflect total adipose mass, rather than meal consumption or dietary energy source, but that the reduction in leptin levels with ongoing fasting is disproportionate to the reduction in adipose mass. The ability of fasting to deactivate this presumed physiological satiety system may have been advantageous in environments characterized by rapid changes in food availability.

Adult↗
PubMed1996

Inappropriate thyroid gland ablation in patients with generalized resistance to thyroid hormone. A common sequela of a rare disorder.

Generalized resistance to thyroid hormone is one of several rare disorders of thyroid metabolism that can be associated with confusing symptoms and signs. Five cases of generalized resistance to thyroid hormone that were misdiagnosed with thyrotoxicosis, leading to unnecessary thyroid gland ablation and iatrogenic hypothyroidism, are reviewed herein. These cases illustrate the point that a careful review of the history, physical examination, and laboratory data, as well as an understanding of hormonal feedback relationships, will greatly benefit the practitioner in evaluating the patients with thyroid dysfunction. Consultation with an endocrinologist may be helpful to establish the correct diagnosis and avoid unnecessary treatments.

Adult↗
PubMed1996

Prevention of atherosclerosis with dietary antioxidants: fact or fiction?

The notion that oxidation of lipids and lipoproteins may contribute to the pathogenesis of atherosclerosis is supported by a large body of evidence. It is hypothesized that dietary antioxidants may help prevent development and progression of atherosclerosis. The available evidence helps substantiate this hypothesis but is not yet conclusive. The results of several ongoing large randomized intervention trials will provide valuable information about the efficacy and safety of supplemental dietary antioxidants in prevention of atherosclerosis.

Antioxidants↗
PubMed1994

A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-beta (TR beta) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3-binding domain of the TR beta gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (+/- SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 +/- 21 vs. 108 +/- 13; total T3, 4.3 +/- 0.4 vs. 2.4 +/- 0.4 nmol/L; and TSH, 4.5 +/- 1.1 vs. 2.4 +/- 1.1 mU/L. DNA samples from 18 family members were screened for the TR beta mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TR beta expressed in Cos-I cells did not bind T3 (Ka of C446R/wild-type, < 0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild-type TR beta.

Adolescent↗
PubMed1994

The relationship between serum lipoprotein(a) and insulinemia in healthy nondiabetic adult men.

OBJECTIVE: To test the hypothesis that variations in serum insulin concentrations and insulin action may influence serum concentrations of lipoprotein(a) [Lp(a)]. RESEARCH DESIGN AND METHODS: A cross-sectional analysis of fasting serum insulin and Lp(a) concentrations were conducted in a group of 54 healthy adult men 23-61 years of age. Measures of dietary intake, exercise, smoking, alcohol ingestion, body mass index (BMI), fasting plasma lipoprotein lipid concentrations, and serum sex hormone and fasting glucose levels were also determined. RESULTS: The fasting serum concentrations of insulin and Lp(a) were negatively correlated (r = -0.339, P = 0.014) by univariate regression analysis. Several confounding variables were also significantly correlated with Lp(a) concentrations: testosterone (r = 0.348, P = 0.012), strenuous exercise (r = 0.287, P = 0.041), and BMI (r = -0.276, P = 0.050). As expected, these additional variables and serum insulin concentrations were highly interrelated. In a stepwise regression model, the serum insulin level was identified as the single best predictor of Lp(a) levels. Nearly 25% of the heterogeneity in serum concentrations of Lp(a) could be predicted by serum levels of insulin and testosterone, BMI, and the amount of strenuous exercise. CONCLUSIONS: The results of these studies have shown that serum concentrations of insulin and testosterone, BMI, and strenuous exercise appear to account for the majority of predicted nongenetic variability in serum levels of Lp(a). These observations suggest the possibility in this group of healthy men that serum concentrations of Lp(a) may be modulated by a complex interplay between insulin action, obesity, androgen levels, and strenuous exercise.

Adult↗
PubMed1994

Hyperlipidemia.

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Arteriosclerosis↗
PubMed1991

High glucose levels do not directly impair cellular binding of HDL3 or HDL-mediated efflux of cholesterol from human skin fibroblasts.

The excess risk of atherosclerosis that is associated with diabetes mellitus cannot be completely accounted for by other known risk factors. Recent studies have suggested that increased glycation of high density lipoproteins (HDL) at high glucose concentrations causes functional abnormalities that might contribute to accelerated atherosclerosis. Other investigators also have shown that elevated glucose concentrations can stimulate the activity of protein kinase C in cultured cells. Because protein kinase C appears to be involved in HDL receptor-mediated efflux, the hypothesis that a high glucose concentration in vitro might modulate HDL-mediated efflux of cholesterol from human fibroblasts was tested. These studies indicate that a high glucose level alone does not affect the interaction of normal HDL3 with cultured human skin fibroblasts.

Carrier Proteins↗
PubMed1991

Potential role of insulin in the clearance of remnant lipoproteins in dysbetalipoproteinaemia.

Dysbetalipoproteinaemia is a genetic disorder characterized by accumulation of lipoprotein remnant particles in the plasma, accelerated atherosclerosis, and the abnormal apoprotein E2. Uncontrolled diabetes mellitus can aggravate the hyperlipidaemia associated with this disorder, presumably by increasing triglyceride synthesis and reducing very low density lipoprotein catabolism by lipoprotein lipase. This report documents the gradual amelioration of dysbetalipoproteinaemia in uncontrolled diabetes mellitus following therapy with exogenous insulin alone. Although the beneficial effects of insulin therapy in this patient may include inhibition of triglyceride synthesis and improved triglyceride catabolism, we propose that insulin may also stimulate clearance of atherogenic remnant lipoprotein particles.

Adult↗
PubMed1991

Nonenzymatic glycosylation of HDL and impaired HDL-receptor-mediated cholesterol efflux.

Previous studies have shown that nonenzymatic glycosylation of high-density lipoprotein (HDL) inhibits high-affinity binding to cultured cells and the candidate HDL-receptor protein. Because binding of HDL to its receptor is required for HDL-receptor-mediated cholesterol efflux from cells, we hypothesized that glycosylated HDL3 would have reduced ability to remove cholesterol from cells. HDL3 was glycosylated in vitro to achieve up to 40-50% reductions in free-lysine residues. Glycosylated HDL3 had a slightly greater ability than control HDL3 to sequester cholesterol directly from the plasma membrane, as predicted by changes in lipid composition. This process is independent of HDL-receptor binding and should not be influenced by reduced binding of HDL3. In contrast, efflux of intracellular cholesterol from cells, which is HDL-receptor dependent, was reduced 25-40%. The ability of glycosylated HDL3 to diminish cholesterol esterification was significantly reduced, indicating reduced net cholesterol efflux. Steady-state efflux of LDL-derived cholesterol was also markedly reduced. These findings suggest that nonenzymatically glycosylated HDL is functionally abnormal and might contribute to the accelerated development of atherosclerosis in patients with diabetes mellitus.

Carrier Proteins↗