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Biomedical subjects

C J Packard

Publications and source records attributed to C J Packard.

At least 127 records · Page 7Linked to original sources
PubMed1992

Post-prandial lipoprotein metabolism in nephrotic syndrome.

Post-prandial lipaemia was investigated in a group of nine subjects with nephrotic syndrome by following the concentrations of triglyceride and retinyl palmitate in the d < 1.006 g ml-1 fraction of plasma after a standard oral fat load containing vitamin A. Lipoprotein lipase and hepatic triglyceride lipase activities were measured in post-heparin plasma. Subjects with other renal disease but insignificant proteinuria acted as controls. The time course of the lipaemic response was similar in both groups although individual patients demonstrated a prolonged lipaemia. Overall, there were no significant differences in the rise in triglyceride at 6 h (nephrotic--median 2.53 mmol l-1; range 0.87-4.76 vs. control 1.88; 0.38-4.12, P = 0.34), the peak concentration of retinyl palmitate (nephrotic 0.87 mg dl-1; 0.27-2.16 vs. control 0.65; 0.24-1.89, P = 0.97) or the areas under the curve from 0-24 h for triglyceride (nephrotic 10.5 mmol. h l-1; 2.9-43.6 vs. control 9.7; 4.3-27.0, P = 1.0) or retinyl palmitate (5.5 mg.h dl-1; 1.0-23.4 vs. 4.3; 1.5-12.4, P = 0.7). At baseline, the particles in the d < 1.006 g ml-1 fraction of plasma from nephrotic subjects had a higher free cholesterol:phospholipid ratio but this difference was no longer apparent 6 h after the test meal. There were no differences in total heparin-releasable lipase, lipoprotein lipase or hepatic triglyceride lipase activities between the two groups. These data suggest that impaired clearance of chylomicrons is not a major contributor to nephrotic hyperlipidaemia in man.

Adult↗
PubMed1992

Effects of cholestyramine and acipimox on subfractions of plasma low density lipoprotein. Studies in normolipidaemic and hypercholesterolaemic subjects.

Two independent studies were designed to investigate the separate and combined effects of acipimox and cholestyramine on plasma low density lipoprotein subfractions. In the first study, normolipidaemic subjects were given cholestyramine (16 g day-1, 4 weeks), followed, after an 8-week wash-out period, by acipimox (750mg day-1, 4 weeks). In the second study, moderately hypercholesterolaemic subjects were prescribed acipimox (1250mg day-1, 10 weeks), followed by acipimox in combination with low dose cholestyramine (12g day-1) for a further 10 weeks. In the normal subjects, cholestyramine decreased total LDL mass (density (d) = 1.019-1.063g ml-1) by selectively reducing the largest, least dense LDL-I (d 1.025-1.034 g ml-1, P less than 0.05) and LDL-II (d 1.034-1.044 g ml-1, P less than 0.005) subfractions. The small, dense LDL-III (d 1.044-1060 g ml-1) showed a variable response to the resin. In the same subjects acipimox produced no overall change in total LDL mass but showed a tendency to redistribute LDL towards LDL-I (+10%) and LDL-II (+10%) in a manner related to the changes in plasma triglyceride (TG) (TG vs. LDL-III r = 0.75, P less than 0.05). In the hypercholesterolaemic subjects acipimox induced a substantial redistribution of LDL subfractions (LDL-I +84% P less than 0.05; LDL-III -50%) without affecting total LDL mass. The addition of cholestyramine produced a significant decrease in total LDL mass which was again confined to the LDL-I (-28%) and LDL-II (-23%) subfractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Plasma triglyceride and low density lipoprotein metabolism.

This study examines the relationship between plasma triglyceride and low density lipoprotein (LDL) levels by measuring the turnover of the native and 1,2 cyclohexanedione-treated lipoprotein in 25 healthy adults. Plasma triglyceride showed a strong positive correlation with circulating LDL apoprotein (apo LDL) mass. In order to achieve a satisfactory fit to the kinetic data it was necessary to postulate the existence of two plasma apo LDL pools (A and B). When subjects were grouped in quintiles on the basis of circulating apo LDL mass, pool A predominated in those in the lowest quintile. The fractional catabolic rate (FCR) of apo LDL from this pool was high (FCR = 0.57 +/- 0.06 pools day-1). As plasma triglyceride and apo LDL mass rose, apoprotein accumulated in the more slowly metabolized pool B as a result of an increase in the rate of input of apo LDL into the latter. The fractional clearance rate of protein from this pool remained unchanged at 0.26 +/- 0.04 pools day-1. Synthesis of apo LDL into pool B correlated with plasma triglyceride (r = 0.553, P less than 0.01), suggesting that the protein in this pool was derived from large, triglyceride-rich very low density lipoprotein.

Adult↗
PubMed1992

Plasma lipids, lipoproteins and post-heparin lipases in ponies with hyperlipaemia.

The metabolic origins of equine hyperlipaemia were investigated by analysing the concentration and composition of plasma lipoproteins in 18 ponies with the condition. The mean concentrations of cholesterol, triglyceride and very low density lipoproteins (VLDL) were increased by 4-, 52- and 19-fold, respectively, compared with a control group of 18 healthy ponies. These increases were due to the appearance of a buoyant VLDL fraction (VLDL1) not present in healthy ponies. The mean diameter of VLDL1 particles was 44% greater than control VLDL, and the particles were enriched in triglyceride and free cholesterol and depleted of cholesteryl esters, phospholipid and protein. The apolipoprotein (apo) B-100 content of VLDL1 was reduced and the ratio of apoB-100 to apoB-48 particles was 1:1, compared with 2:1 in control VLDL. The VLDL1 was also enriched in apoE, but had normal complements of apoC-II and apoC-III. The conventional VLDL (called VLDL2), LDL and HDL fractions were moderately enriched with triglyceride, and HDL contained increased amounts of apoE, apoC-II and apoC-III. The activities of lipoprotein lipase and hepatic lipase, the enzymes responsible for the catabolism of VLDL and their remnants, were increased by 2- and 3-fold, respectively, in response to the increased concentrations of their substrates. The composition of VLDL1 suggested that the liver was maximising the secretion of triglyceride by producing larger number of VLDL particles that accommodated a greater mass of triglyceride by having apoB-48 rather than apoB-100 as their structural protein. Plasma free fatty acid (FFA) concentrations were elevated in 17 of the 18 ponies, suggesting that increased FFA flux might be the stimulus for hepatic triglyceride synthesis and VLDL secretion. We conclude that overproduction, rather than defective catabolism, of VLDL was the cause of the hyperlipidaemia and that lipid lowering agents which reduce VLDL synthesis, by decreasing adipose lipolysis and FFA flux, are candidates for the management of hyperlipaemia.

Animals↗
PubMed1992

Selective measurement of lipoprotein lipase and hepatic triglyceride lipase in heparinized plasma from horses.

Affinity chromatography on heparin sepharose was used to identify 2 lipolytic enzymes in heparinized plasma from horses. One enzyme was typical of hepatic triglyceride lipase (HTGL), because it was resistant to inactivation by high concentrations of NaCl, and it did not require the addition of serum for activity. The other enzyme was identified as lipoprotein lipase (LPL), because of its inactivation at NaCl concentrations in excess of 0.2M, and its dependency on addition of serum as a source of apolipoprotein C-II activator. The enzymes were purified by 347-(HTGL) and 442- (LPL) fold, with yields of 54 and 58%, respectively. The partially purified enzymes were used to design incubation conditions that gave optimal activities for each enzyme in vitro. A selective assay was then developed for direct measurement of LPL and HTGL activities in heparinized plasma from horses. Analysis of HTGL took advantage of the almost complete inactivation of LPL when serum cofactor was excluded from the assay at the NaCl concentration that gave optimal HTGL activity. Prior incubation of heparinized plasma with sodium dodecyl sulfate to inhibit HTGL was necessary for measurement of LPL, because HTGL retained 67% of its activity at the NaCl concentration required for optimal LPL activity. Activity of each enzyme was measured in heparinized plasma from 12 Shetland ponies. The mean activity +/- SD for LPL was 3.22 +/- 1.04 mumol of fatty acids/ml of heparinized plasma/h (mumol of FA/ml/h. The mean activity for HTGL was 4.9 +/- 1.56 mumol of FA/ml/h. The performance of the assay was assessed by replicate analysis of pools of each enzyme with high and low activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Restriction fragment length polymorphisms in the Apo B gene in relation to coronary heart disease in a southern Asian population.

We have examined DNA polymorphisms associated with the apolipoprotein B gene in 95 Sri Lankan males with ischaemic heart disease and 95 matched controls. For polymorphisms detected using the XbaI or MspI enzymes the allele frequency in Sri Lankans contrasted markedly from that in Caucasians. Overall, there was no significant association of any allele studied with coronary disease cases in this sample. There was, however, a significant difference observed between the XbaI allele frequency in normotriglyceridaemic or normocholesterolaemic CHD cases compared with the allele frequency in the controls.

Alleles↗
PubMed1991

Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24.

Familial combined hyperlipidaemia (FCHL) is a common inherited disorder of lipid metabolism with a prevalence of 0.5-2.0% (refs 1, 2). It is estimated to cause 10% of premature coronary heart disease. The underlying metabolic and genetic defects in FCHL have not been identified, but a population study has suggested an association between FCHL and an XmnI restriction fragment length polymorphism (RFLP) within the apolipoprotein AI-CIII-AIV gene cluster. Here we confirm this association and show that it results from linkage disequilibrium between FCHL and the 6.6-kilobase (kb) allele of the XmnI RFLP. Subsequent analysis in seven FCHL families, ascertained through a proband carrying the 6.6 kb XmnI allele, demonstrated linkage to the AI-CIII-AIV cluster on 11q23-q24, zeta = 6.86 with no recombinants. This assignment will facilitate the identification of the mutation that causes hyperlipidaemia in these families.

Apolipoprotein A-I↗
PubMed1991

Metabolism of apolipoprotein B-containing lipoproteins in subjects with nephrotic-range proteinuria.

Although hyperlipidemia is a well recognized complication of the nephrotic syndrome, the precise disturbances of lipoprotein metabolism which cause the elevated plasma lipid and lipoprotein concentrations have not been clearly defined in humans. This study examines the metabolism of apolipoprotein B-containing lipoproteins in patients with nephrotic-range proteinuria and in healthy controls. Two radioiodinated tracers of very low density lipoproteins (VLDL1, Sf60 to 400, and VLDL2, Sf20 to 60), were used to trace the metabolism of apolipoprotein B through the delipidation cascade from very low density lipoproteins (VLDL) to low density lipoproteins (LDL). The data from the apoB specific radioactivity curves and the pool sizes of apoB in four subfractions were analyzed by a multicompartmental modeling procedure using the SAAM 30 program. The main findings in the nephrotic group were: 1.) a consistent decrease in the fractional rate of apoB transfer from VLDL1----VLDL2 (median values-nephrotic 0.92 pools/day vs. controls 3.66, P less than 0.02) and from VLDL2----IDL (1.49 vs. 2.74, P less than 0.05); 2.) increased secretion of apoB into VLDL2 (14.5 mg/kg/day vs. 4.2, P less than 0.02); 3.) a trend towards decreased removal of IDL and LDL attributable to a defect in LDL receptor-mediated removal as previously shown (Metabolism 39:187-192, 1990). These findings suggest that catabolic defects of the apo B-containing lipoproteins are as important as increased hepatic synthesis in the pathogenesis of nephrotic hyperlipidemia in humans.

Apolipoproteins B↗
PubMed1991

The isolation, characterisation and quantification of the equine plasma lipoproteins.

Plasma lipoproteins were isolated from eight Thoroughbred horses and eight Shetland ponies on the basis of particle size by gel filtration chromatography and according to density using rate-zonal ultracentrifugation. Three major classes corresponding to very low density lipoproteins (VLDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) were identified and characterised by their lipid and apolipoprotein compositions. The particle size distributions of each class were determined by electron microscopy and non-denaturing polyacrylamide gradient gel electrophoresis. HDL was found to dominate the equine lipoprotein spectrum, accounting for 61 per cent of the total plasma lipoprotein mass (VLDL 24 per cent, LDL 15 per cent). The VLDL class was isolated as a single population of particles that were triglyceride rich and cholesterol, phospholipid and protein poor. Equine LDL was characteristically cholesterol rich and was found to be polydisperse comprising three subfractions that were discrete with respect to particle size and lipid composition. The HDL class was composed of homogeneous particles that were typically protein rich. Apolipoprotein (apo) B was the major protein of VLDL and LDL, and presented two components on polyacrylamide gel electrophoresis with molecular weights in the region of human apoB-100 and a third in VLDL similar to that of apoB-48. ApoA-I was the predominant protein in equine HDL. Although there were no breed differences in the physical or chemical properties of each lipoprotein class, the Shetland ponies had higher plasma triglyceride and VLDL concentrations than their Thoroughbred counterparts.

Animals↗
PubMed1991

Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipemic subjects.

This study examined apolipoprotein (apo) B metabolism in normolipemic subjects homozygous for the apo E2 (n = 4), apo E3 (n = 5), or apo E4 (n = 5) phenotype. Radioiodinated very low density lipoprotein (VLDL1) (ultracentrifuge flotation rate [Sf] 60-400) and VLDL2 (Sf 20-60) were injected into volunteers and the conversion of apo B was followed through intermediate density lipoprotein (IDL) to low density lipoprotein (LDL). Subjects homozygous for E3 converted approximately 50% of LVDL2 to LDL, the remainder being lost by direct catabolism. Those with the E2 phenotype produced less VLDL1, but converted more of it to VLDL2 (compared to E3 subjects). They displayed a characteristic dyslipidemia with the presence of slowly catabolized VLDL1 and VLDL2 remnants. LDL levels were low owing to increased direct catabolism of VLDL2 and IDL and a reduced efficiency of delipidation; only 25% of VLDL2 apo B was directed to LDL production. In contrast, E4 subjects converted more VLDL2 apo B to LDL than E3 subjects. About 70% of VLDL2 apo B was found in LDL; direct catabolism of VLDL and IDL was reduced as was the fractional catabolic rate of LDL (0.2 vs. 0.26 in E3 subjects). These changes in the VLDL----IDL----LDL metabolic cascade can in part be explained by alterations in hepatic LDL receptors with E2 subjects having higher and E4 subjects lower activities than those in E3 homozygotes.

Adult↗
PubMed1991

A comparison of commercial kits for the measurement of lipoprotein(a).

Five commercial kits for the assay of lipoprotein(a) were investigated and two of these, the Immuno Enzyquick and Biopool TintElize, both enzyme-linked immunoassays, were studied in detail. Whilst there was a strong correlation between the results obtained using the two methods there was a significant difference between the absolute values. In view of its higher precision at low levels and robust performance, the Enzyquick kit (Immuno Ltd) was selected for use in this laboratory.

Enzyme-Linked Immunosorbent Assay↗
PubMed1990

An investigation of the relationships between body condition and plasma lipid and lipoprotein concentrations in 24 donkeys.

Obese donkeys are susceptible to a hyperlipaemic crisis characterised by high plasma triglyceride concentrations. In this study, the relationships between the body condition of 24 donkeys and their basal lipid metabolism were investigated. Plasma cholesterol, triglyceride and lipoprotein cholesterol concentrations were measured in healthy donkeys classified according to their body condition as thin, ideal or obese. There were significant differences between the groups in the concentrations of triglyceride and very low density lipoprotein (VLDL), which increased in concentration with body condition (P less than 0.05). Cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) concentrations were similar in all the groups. Triglyceride and VLDL concentrations were positively correlated with body weight (r = 0.82) and plasma free fatty acid concentration (r = 0.48). There were no significant differences in basal plasma concentrations of insulin or cortisol. These results suggest that obesity in donkeys is associated with changes in lipid and lipoprotein metabolism that might predispose the animals to hyperlipaemia.

Animals↗
PubMed1990

Postprandial lipemia, fenofibrate and coronary artery disease.

This report describes the response of patients with severe coronary artery disease to a dynamic fat load test and monitors the change induced by fenofibrate therapy. The presence of disease was associated with prolonged and exaggerated hypertriglyceridemia following the meal and with lower basal HDL cholesterol and HDL subfraction masses. A further indicator of risk was the persistence of increased amounts of retinyl palmitate in the plasma of severely affected individuals 24 h after its ingestion with the meal. These observations are consistent with the proposal that the clearance of chylomicrons and their remnants is impaired in coronary atherosclerosis. Fenofibrate reduced alimentary lipemia following the fat load in both normo- and hypercholesterolemic subjects. This was associated with a 10% rise in plasma HDL cholesterol levels. The improvement in chylomicron catabolism probably derived from a 37% increase (P less than 0.001) in lipoprotein lipase activity induced by fenofibrate. Hepatic lipase on the other had was only slightly affected by treatment.

Adult↗
PubMed1990

Genetic variation in the cholesteryl ester transfer protein and apolipoprotein A-I genes and its relation to coronary heart disease in a Sri Lankan population.

The influence of variation in the genes for cholesteryl ester transfer protein and apolipoprotein A-I was investigated in 95 patients with coronary heart disease and 95 matched control subjects of South East Asian extraction. Restriction fragment length polymorphisms (RFLPs) linked to the cholesteryl ester transfer protein gene TaqIA and TaqIB, and to the apolipoprotein A-I gene SstI, were examined to investigate the extent of genetic variation at these loci. None of the alleles defined by these RFLPs were associated with increased coronary risk. Analysis of the data by division of high density lipoprotein-cholesterol levels into tertiles showed a trend of a higher frequency of B1 allele (presence of the TaqIB site) with reduced high density lipoprotein levels. The B1 allele was more frequent in control subjects, with low high density lipoprotein levels (P less than 0.02), but not in coronary heart disease patients. The differences became significant for both groups (P less than 0.05) when the data of non-smokers were analysed separately.

Apolipoprotein A-I↗
PubMed1990

Rapid isolation of low density lipoprotein (LDL) subfractions from plasma by density gradient ultracentrifugation.

High resolution density gradient ultracentrifugation (DGUC) and non-denaturing gradient gel electrophoresis (GGE) indicate that low density lipoprotein (LDL) in both normal and hyperlipidaemic subjects is composed of overlapping particle populations. A new centrifugation procedure has been developed which permits the separation of LDL subspecies directly from plasma within 24 h. The profiles obtained were analogous to those seen on gradient gel electrophoresis. LDL was divided into 3 fractions. The plasma concentration of LDL-I seen in young females was twice that in men (85.6 +/- 28.8 vs. 42.3 +/- 25.7 mg/dl, P less than 0.005). LDL-II was not significantly different in any group while LDL-III was specifically elevated in coronary artery disease (CAD) patients (207.1 +/- 92.6 mg/dl in CAD vs. 87.4 +/- 79.6 mg/dl in normal men, P less than 0.05). The presence of small, dense LDL detected either by density gradient centrifugation or gel electrophoresis was associated with raised triglyceride (TG) and low high density lipoprotein (HDL) cholesterol and may be a risk marker for coronary artery disease.

Adolescent↗
PubMed1990

Low-density lipoprotein metabolism in the nephrotic syndrome.

Hyperlipidemia is a consistent feature of the nephrotic syndrome. In this study, low-density lipoprotein (LDL) metabolism has been investigated in nine patients with nephrotic syndrome and varying degrees of proteinuria. In subjects with moderate proteinuria (less than 10 g/d), total plasma cholesterol values were elevated to approximately 160% of normal due mainly to an increase in circulating LDL cholesterol. Metabolic studies showed that a defect in LDL clearance via the receptor pathway was responsible for its accumulation. The total amount of LDL apolipoprotein catabolized by this mechanism was only 55% of the value seen in controls; 60% more LDL was channelled into alternative, receptor-independent, catabolic pathways. Heavier proteinuria was associated with substantial increases in plasma triglyceride and very-low-density lipoprotein (VLDL) levels. The defect in LDL catabolism was aggravated by oversynthesis of the lipoprotein, which expanded the plasma LDL pool to 250% of normal. These observations indicate that the hyperlipidemia of the nephrotic syndrome is multifactorial in origin. The altered catabolism of LDL may be important in predisposing these subjects to premature atherosclerosis.

Adult↗