PubMed Health⌕ Search

Biomedical subjects

C J Packard

Publications and source records attributed to C J Packard.

At least 145 records · Page 8Linked to original sources
PubMed1990

Polymorphisms in the gene coding for cholesteryl ester transfer protein are related to plasma high-density lipoprotein cholesterol and transfer protein activity.

1. Cholesteryl ester transfer protein activity may have a physiological effect on high-density lipoprotein levels. 2. We examined restriction fragment length polymorphisms associated with the cholesteryl ester transfer protein gene and the apolipoprotein AI gene in a group of 60 unrelated subjects selected from an initial survey of 5000 subjects on the basis of their high-density lipoprotein levels being high or low at the extremes of the distribution. The activities of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase (phosphatidylcholine-sterol acyltransferase, EC 2.3.1.43) were also determined. Analysis by selection of those with a low high-density lipoprotein cholesterol level (less than or equal to 1.1 for males, less than or equal to 1.2 for females) gave 32 individuals with 24% B2 alleles. Selection of subjects with a high-density lipoprotein cholesterol level (less than or equal to 2 mmol/l) gave 17 with 62% B2 alleles. 3. The group with low levels of high-density lipoprotein cholesterol had higher activity of cholesteryl ester transfer protein and significantly elevated triacylglycerol levels when compared with the group with high levels of high-density lipoprotein cholesterol. 4. A further significant finding was the correlation of the MspI restriction fragment length polymorphism detected by the apolipoprotein AI gene with lecithin:cholesterol acyltransferase activity.

Adult↗
PubMed1990

Acipimox in combination with low dose cholestyramine for the treatment of type II hyperlipidaemia.

1. This study was designed to examine the effects of acipimox 250 mg three times daily and cholestyramine 4 g three times daily on plasma lipids and lipoproteins in 28 hypercholesterolaemic individuals in a prospective double-blind placebo controlled parallel group fashion. 2. Combined treatment with the two agents produced a mean reduction of 27% in plasma total cholesterol and a 32% fall in LDL cholesterol. Plasma triglyceride was reduced by 13% due to a 38% decrement in VLDL cholesterol. 3. In comparison treatment with cholestyramine alone resulted in a 12% fall in plasma cholesterol and a 15% fall in LDL cholesterol. In this group triglycerides and VLDL showed no significant change. 4. Studies of HDL subfraction mass showed that the addition of acipimox to resin therapy produced a mean increment of 45% in HDL2. 5. These results demonstrate the effectiveness of such a well tolerated low dosage combination therapy.

Cholesterol↗
PubMed1990

The relationship between serum cholesterol and serum thyrotropin, thyroxine and tri-iodothyronine concentrations in suspected hypothyroidism.

The relationship between serum cholesterol, thyrotropin, thyroxine and tri-iodothyronine was investigated in 1018 female patients over 40 years of age with suspected hypothyroidism. The correlation between serum thyrotropin and cholesterol (r = 0.398) and between thyroxine and cholesterol (r = -0.217) were both highly significant (P less than 0.001), but the correlation between tri-iodothyronine and cholesterol (r = -0.011) was not significant. Only in patients with a serum thyrotropin in excess of 40 mU/L was there a clinically appreciable increase in the serum cholesterol. In 139 patients treated for hypothyroidism by thyroxine replacement there was a highly significant correlation (P less than 0.001) between the decrease in serum thyrotropin and cholesterol (r = 0.593). The correlation between increase in serum thyroxine and decrease in cholesterol (r = -0.401) was also highly significant (P less than 0.001), but there was an even stronger correlation between the increase in serum tri-iodothyronine and the decrease in serum cholesterol (r = -0.529).

Aged↗
PubMed1990

Effect of insulin therapy on metabolic fate of apolipoprotein B-containing lipoproteins in NIDDM.

Non-insulin-dependent diabetic (NIDDM) subjects exhibit abnormalities in their plasma lipid and lipoprotein profiles that increase the risk of ischemic heart disease. This study was designed to examine the metabolic behavior of very-low-density (VLDL), intermediate-density (IDL), and low-density (LDL) lipoproteins in NIDDM patients before treatment and after 4 wk of insulin therapy. Basal turnover studies of 131I-labeled VLDL1 (svedberg units [Sf] 60-400) and 131I-labeled VLDL2 (Sf 20-60) apolipoprotein B (apoB) were conducted in a group of seven NIDDM patients who had been off oral therapy for 1 wk. The subjects exhibited higher than normal transport rates for VLDL1 and a diminished input of apoB into the VLDL2 density range. These observations are concordant with the hypothesis that NIDDM patients overproduce VLDL triglyceride but not apoB. VLDL1 and VLDL2 were converted to IDL and ultimately to LDL at approximately normal rates, although the delipidation pathway by which apoB-containing particles were processed exhibited different properties from that seen in control subjects. Insulin therapy reduced plasma triglyceride by 38%, and this was associated with a 41% fall in VLDL1 mass (P less than 0.01). VLDL2 was less affected (19% reduction, P less than 0.05), IDL was unchanged, and LDL fell 17% (P less than 0.05). Repeat metabolic studies revealed that the major effects of insulin were to reduce VLDL1-apoB transport (from 811 to 488 mg/day) and increase the direct input of VLDL2 into the plasma (from 182 to 533 mg/day, P less than 0.05). These alterations in VLDL production led to normalization of apoB kinetics in IDL and LDL. The fractional catabolic rate of LDL increased 19% (P less than 0.05), whereas direct input into this fraction, which had been high before treatment, was reduced. Postheparin plasma lipoprotein lipase (LPL) and hepatic lipase levels were unaffected by insulin, although the hormone did increase LPL in adipose tissue. This lack of effect on lipase activities correlated well with the observation that the rates of catabolism of apoB in VLDL1, VLDL2, and IDL were not significantly affected by insulin therapy.

Aged↗
PubMed1989

The Xba1 polymorphism of the apolipoprotein B gene influences the degradation of low density lipoprotein in vitro.

This study examines the influence of variation in the apolipoprotein B (apoB) gene, the major protein of low-density lipoprotein (LDL), on the LDL degradation rate in vitro. Previously we have shown (Demant et al. (1988) J. Clin. Invest. 82, 797-802) that there is an association between the fractional catabolic rate of LDL in vivo and the apoB polymorphism detected using the Xba1 restriction enzyme. Subjects with genotype X1X1 (X1 = absence of cutting site) cleared LDL more rapidly from the plasma compartment than those with the X2X2 genotype. In this study, the LDL degradation rate on dermal fibroblasts was measured for 33 individuals of genotype X1X1 or X2X2. These were subdivided into three groups: (1) young normolipidaemic, (2) older normolipidaemic and (3) older hypercholesterolaemic subjects, because age is known to markedly affect the plasma LDL concentration and may independently influence the population of LDL particles under study. In all experiments, the degradation rate of one type of LDL was compared directly in the cell culture dish with that from an individual of the alternate genotype by labelling them separately with the two iodine isotopes 125I and 131I. In the group of young normals (mean cholesterol 5.03 mmol/l, mean age 31 years), no significant difference was observed between the degradation rates of LDL derived from X1X1 individuals versus X2X2. However, in the older group of normals (mean cholesterol 5.4 mmol/l, mean age 48 years), LDL from subjects with X1X1 genotype was catabolised 17% faster than that from X2X2 subjects (P less than 0.001). A similar result was seen in hypercholesterolaemics (mean cholesterol 8.3 mmol/l, mean age 57 years) with LDL isolated from X1X1 subjects being degraded 22% more rapidly than that from X2X2 subjects. This in vitro evidence adds further weight to the hypothesis that genetic variation in the apoB gene leads to structural changes in LDL than alter its potential for degradation via the LDL receptor.

Adult↗
PubMed1989

Effect of combined therapy with bezafibrate and cholestyramine on low-density lipoprotein metabolism in type IIa hypercholesterolemia.

This study was designed to examine the influence of combined therapy with bezafibrate and cholestyramine on plasma lipids and on the metabolism of low-density lipoprotein (LDL). Twenty-one type II hyperlipidemic subjects were treated with bezafibrate alone or in combination with cholestyramine. A 17% fall in plasma cholesterol was seen with bezafibrate, and addition of cholestyramine produced an additional 9% reduction in this lipid. The effectiveness of the combination therapy was mediated through a 47% decrement in very-low-density lipoprotein (VLDL) cholesterol, a 37% reduction in LDL cholesterol, and a 15% increase in the level of that lipid in high-density lipoprotein (HDL). Plasma triglyceride fell 43% when bezafibrate was given alone, and did not change further when cholestyramine was added. The metabolism of LDL was examined in nine individuals to determine the mechanism underlying these changes. No significant modification in LDL synthetic rate was incurred with either drug regimen, whereas the fractional catabolic rate of LDL via the receptor pathway rose by 66% with bezafibrate alone and by 79% (compared to baseline) following the addition of cholestyramine. Plasma HDL rose during bezafibrate therapy due to an increase in the HDL3 subfraction. Compositional analysis of LDL showed a reduction in cholesterol ester and an increase in triglyceride and phospholipid during combined drug therapy. These results demonstrate that combined therapy with bezafibrate and cholestyramine markedly improves the lipoprotein profile in type II hyperlipidemia. The drugs appear to be complementary in their actions upon the LDL receptor pathway.

Adult↗
PubMed1988

Comparative cellular uptake and cytotoxicity of a complex of daunomycin-low density lipoprotein in human squamous lung tumour cell monolayers.

In an attempt to target cytotoxic drugs to tumour cells daunomycin-low density lipoprotein (LDL) complexes were synthesised. Human squamous lung tumour cells in vitro have large numbers of high affinity cell surface LDL receptors (Vmax = 19 ng LDL/micrograms cell protein per 24 hr; Km = 23 micrograms/ml). Cellular uptake of daunomycin and LDL-daunomycin was rapid and approached equilibrium by approximately 3 hr. Intracellular daunomycin concentrations were similar at each time point regardless of whether free drug or the complex was used. The degree of intracellular drug metabolism differed markedly with significantly higher production of daunomycinol following exposure to free daunomycin for 90 min. Daunomycin and LDL-daunomycin were equally cytotoxic in vitro (respective clonogenic ID90s of 1 microgram/ml and 0.7 microgram/ml). Fluorescence microscopy indicated that both free daunomycin and LDL-daunomycin have a punctate, granular distribution within the cytoplasm.

Carcinoma, Squamous Cell↗
PubMed1988

Very low density lipoprotein apolipoprotein B metabolism in humans.

The human plasma lipoproteins encompass a broad spectrum of particles of widely varying physical and chemical properties whose metabolism is directed by their protein components. Apolipoprotein B100 (apo B100) is the major structural protein resident in particles within the Svedberg flotation range 0-400. The largest of these, the very low density lipoprotein (VLDL), rich in triglyceride, are metabolised by sequential delipidation through a transient intermediate density lipoprotein (IDL) to cholesterol-rich low density lipoproteins (LDL). Several components contribute to the regulation of this process, including (a) the lipolytic enzymes lipoprotein lipase and hepatic lipase (b), apolipoproteins B, CII, CIII and E, and (c) the apolipoprotein B/E or LDL receptor. Lipoprotein lipase acts primarily on large VLDL of Sf 60-400. Hepatic lipase on the other hand seems to be critical for the conversion of smaller particles (Sf 12-60) to LDL (Sf 0-12). Although most apo B100 flux is directed to the production of the delipidation end product LDL, along the length of the cascade there is potential for direct removal of particles from the system, probably via the actions of cell membrane receptors. This alternative pathway is particularly evident in hypertriglyceridaemic subjects, in whom the delipidation process is retarded. VLDL metabolism shows inter subject variability even in normal individuals. In this regard, apolipoprotein E plays an important role. Normolipidaemic individuals homozygous for the apo E2 variant exhibit gross disturbances in the transit of B protein through the VLDL-IDL-LDL chain.

Apolipoproteins B↗
PubMed1988

Thyroid dysfunction and hypercholesterolaemia in the general population of Glasgow, Scotland.

As part of a screening programme for coronary heart disease risk factors, fasting plasma cholesterol was measured in 2,250 people from the east-end of Glasgow. Plasma thyrotropin (TSH) was measured in the 90 individuals (4% of the population studied) who had a cholesterol level greater than or equal to 8.0 mmol/l. Four had unequivocal biochemical evidence of hypothyroidism-TSH greater than 34 mU/l and a low plasma thyroxine (T4) less than or equal to 45 nmol/l. A further 8 were found to have raised TSH levels suggesting they may have subclinical hypothyroidism. These data indicate that thyroid dysfunction may make a significant contribution to hypercholesterolaemia in the general population.

Adult↗
PubMed1988

Influence of etofibrate on low density lipoprotein metabolism.

This study examined the effect of single dose etofibrate (1.0 g/day) on plasma lipids and lipoproteins in a group of eleven hypercholesterolemic individuals. The drug lowered plasma triglyceride and cholesterol by 32% and 14%, respectively (P less than 0.005). The cholesterol reduction came from a decrement in both VLDL and LDL. The cholesterol content of HDL did not change although its mass as determined by analytical ultracentrifugation rose by 29%. LDL metabolism was followed before and during drug therapy. Treatment increased catabolism of this lipoprotein by 14%, without affecting synthesis. The increased clearance resulted from activation (64%) of the LDL receptor pathway. There was a reciprocal decrease in the amount of lipoprotein channelled into the receptor-independent route.

Adult↗
PubMed1988

Catabolic rate of low density lipoprotein is influenced by variation in the apolipoprotein B gene.

This study examines the potential influence of genetic variation on the metabolism of LDL. Restriction fragment length polymorphisms (RFLP) of the gene coding for apo B were identified using the endonucleases Xba I, Eco RI, and Msp I in a group of 19 subjects with moderate hyperlipidemia. There was a significant association between the Xba I polymorphism and the total fractional clearance rate (FCR) of LDL. The individuals with the X1X1 genotype had, on average, a 22% higher FCR (P less than 0.025) than those with the genotype X2X2 (X2 allele = presence of Xba I cutting site). This difference was attributable to increased clearance by the receptor-mediated pathway of LDL catabolism. In this group of subjects, there was no association of LDL kinetic parameters and RFLPs of the LDL receptor gene or the AI- CIII- AIV gene cluster. The data suggest that variation in apo B itself, presumably acting through variable binding to the LDL receptor, makes a significant contribution to the rate of catabolism of LDL.

Adult↗
PubMed1988

Receptors in the regulation of lipoprotein metabolism.

Mamalian cholesterol metabolism is governed by two key features of the steroid nucleus: it is poorly soluble in plasma and it cannot be degraded in animal tissues. Cells which require the lipid import it through their cytoplasmic membranes in the form of solubilized lipid-protein complexes, and a similar export mechanism is essential in order to maintain cellular homeostasis. The translocation is mediated by high affinity receptors which, under normal circumstances, operate in close synchrony. Changes in the nature of the lipoprotein ligand or the cell itself may disturb this balance and lead to the pathological sterol accumulation which characterizes artherosclerosis lesions. All body tissues engage in this traffic in cholesterol but the liver is the single most important organ since it has the capacity both to synthesize large quantities of the lipid and to excrete it from the body via a variety of receptors designed to maintain peripheral sterol levels within safe limits.

Cholesterol↗
PubMed1988

Lipoprotein metabolism in hepatic lipase deficiency: studies on the turnover of apolipoprotein B and on the effect of hepatic lipase on high density lipoprotein.

Hepatic lipase deficiency produces significant distortion in the plasma lipoprotein profile. Particles with reduced electrophoretic mobility appear in very low density lipoprotein (VLDL). Intermediate density lipoprotein (IDL) increases markedly in the circulation and plasma low density lipoprotein (LDL) levels fall. At the same time there is a mass redistribution within the high density lipoprotein (HDL) spectrum leading to dominance in the less dense HDL2 subfraction. The present study examines apolipoprotein B turnover in a patient with hepatic lipase deficiency. The metabolism of large and small very low density lipoproteins was determined in four control subjects and compared to the pattern seen in the patient. Absence of the enzyme did not affect the rate at which large very low density lipoproteins were converted to smaller particles within this density interval (i.e., of VLDL). However, subsequent transfer of small very low density lipoproteins to intermediate density particles was retarded by 50%, explaining the abnormal accumulation of VLDL in the patient's plasma. Despite this, intermediate density particles accumulated to a level 2.4-times normal because their subsequent conversion to low density lipoprotein has been almost totally inhibited. Consequently, the plasma concentration of low density lipoprotein was only 10% of normal. On the basis of these observations, hepatic lipase appears to be essential for the conversion of small very low density and intermediate density particles to low density lipoproteins. The pathways of direct plasma catabolism of these species were not affected by the enzyme defect. In vitro studies were performed by adding purified hepatic lipase to the patient's plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗