J J Series

Royal United Hospital Bath NHS Trust, Bath, England, United Kingdom

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Publications (13)41.07 Total impact

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    ABSTRACT: In this study the frequencies of the genotypes of four restriction fragment length polymorphisms in the apolipoprotein B gene (XbaI, EcoRI, PvuII and MspI) are compared between groups of normolipidaemic and diet resistant hypercholesterolaemic individuals as possible markers for the influence of this gene on plasma cholesterol levels. In the first part of the study genotypes of all four markers were determined in 92 normolipidaemic (mean cholesterol 5.6 + 0.8 mmol/l) and 79 diet resistant hypercholesterolaemic (mean cholesterol 7.8 + 0.7 mmol/l) individuals seen in a local health centre screening programme for coronary heart disease risk factors. No significant difference was seen in the frequencies of the EcoRI and PvuII genotypes between the two groups. There was significant enrichment of both the XbaI X2 (presence of cutting site) allelic frequency and of the MspI M1M2 (M2 absence of cutting site, rarer allele) genotype frequency in the hypercholesterolaemic group. In the second part of the study an independent larger group of individuals, seen in a multicentre screening programme across the city of Glasgow, were genotyped for the two potentially significant polymorphic sites (XbaI and MspI). From this second screening programme 188 age matched normolipidaemic males (mean cholesterol 5.0 +/- 0.8 mmol/l) were compared with 186 males who were still hypercholesterolaemic (mean 8.2 +/- 0.6 mmol/l) after three months dietary intervention. The hypercholesterolaemic individuals in this second study did not show a significant enrichment of the XbaI X2 allele but again showed a highly significant enrichment of the MspI M1M2 genotype. This genetic effect may relate directly to the charge change from arginine to glutamine at amino acid 3611 caused by the MspI mutation or to an as yet unknown functionally significant mutation in linkage disequilibrium with this site.
    Clinica Chimica Acta 05/1993; 215(1):89-98. · 2.85 Impact Factor
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    ABSTRACT: In this study the frequencies of the genotypes of four restriction fragment length polymorphisms in the apolipoprotein B gene (XbaI, EcoRI, PvuII and MspI) are compared between groups of normolipidaemic and diet resistant hypercholesterolaemic individuals as possible markers for the influence of this gene on plasma cholesterol levels. In the first part of the study genotypes of all four markers were determined in 92 normolipidaemic (mean cholesterol 5.6 + 0.8 mmol/l) and 79 diet resistant hypercholesterolaemic (mean cholesterol 7.8 + 0.7 mmol/l) individuals seen in a local health centre screening programme for coronary heart disease risk factors. No significant difference was seen in the frequencies of the EcoRI and PvuII genotypes between the two groups. There was significant enrichment of both the XbaI X2 (presence of cutting site) allelic frequency and of the MspI M1M2 (M2 absence of cutting site, rarer allele) genotype frequency in the hypercholesterolaemic group. In the second part of the study an independent larger group of individuals, seen in a multicentre screening programme across the city of Glasgow, were genotyped for the two potentially significant polymorphic sites (XbaI and MspI). From this second screening programme 188 age matched normolipidaemic males (mean cholesterol ) were compared with 186 males who were still hypercholesterolaemic (mean ) after three months dietary interven-
    Clinica Chimica Acta. 04/1993;
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    ABSTRACT: 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.
    European Journal of Clinical Investigation 03/1992; 22(2):96-104. · 3.37 Impact Factor
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    ABSTRACT: 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.
    British Journal of Clinical Pharmacology 08/1990; 30(1):49-54. · 3.58 Impact Factor
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    ABSTRACT: 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).
    Annals of Clinical Biochemistry 04/1990; 27 ( Pt 2):110-3. · 1.92 Impact Factor
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    ABSTRACT: 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.
    Biochimica et Biophysica Acta 07/1989; 1003(2):183-8. · 4.66 Impact Factor
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    ABSTRACT: 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.
    Metabolism 03/1989; 38(2):153-8. · 3.10 Impact Factor
  • Progress in clinical and biological research 02/1989; 314:39-47.
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    ABSTRACT: We have investigated changes in serum interleukin 6 (IL-6) in patients undergoing elective cholecystectomy. Serum IL-6 increased in all patients within 1.5 hour of incision, reaching a maximum between 1.5-4 hours after incision (median 50 U/ml; range 22-79 U/ml). The maximum serum IL-6 correlated with the length of the operation (r = 0.95). Serum C-reactive protein was not detectable until 8-12 hours post-incision, but maximum serum C-reactive protein did not correlate with maximum serum IL-6 concentration or length of operation. There was no consistent increase in plasma interleukin 1 or tumour necrosis factor following surgery. Serum IL-6 is an early marker of tissue damage and may be of value in the study of the metabolic response to injury.
    Lymphokine research 02/1989; 8(2):123-7.
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    ABSTRACT: 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.
    Journal of Clinical Investigation 10/1988; 82(3):797-802. · 12.81 Impact Factor
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    ABSTRACT: A method for separating IL-1 from plasma inhibitors by silica extraction has been developed and coupled to a highly sensitive bioassay using the LBRM TG6 cell line and the I1-2 dependent HT2A cell line. Using this assay we have detected IL-1 activity in plasma from patients undergoing elective surgery.
    Journal of Immunological Methods 05/1988; 108(1-2):33-7. · 2.23 Impact Factor
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    ABSTRACT: 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.
    Clinica Chimica Acta 04/1988; 172(2-3):217-21. · 2.85 Impact Factor
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    ABSTRACT: 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.
    Atherosclerosis 03/1988; 69(2-3):233-9. · 3.71 Impact Factor