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Biomedical subjects

Christopher D Byrne

Publications and source records attributed to Christopher D Byrne.

At least 19 recordsLinked to original sources
PubMed2006

Von Willebrand factor short sequence repeat locus 2 (intron 40) consists of three polymorphic subloci.

Currently, identification of alleles within the short sequence repeat locus (SSR locus) of intron 40 of the von Willebrand factor gene (previously known as VNTR II) is based on the size of PCR products that only predicts a certain number of repeats. Through cloning and sequencing, we demonstrated the complexity of nucleotide sequence structure of this region by describing three polymorphic tetranucleotide repeat subloci SSR 'a', SSR 'b' and SSR 'c' within the same originally described locus: the original TCTA (9-14 repeats), a small TCTA repeat locus (2 or 3 repeats) located at the 5' end and 30 nucleotides upstream from the original locus and a TGTA repeat locus (5 or 6 repeats), adjacent to the 2/3 repeat locus. Sequencing of 54 VWF alleles has revealed 14 different sequence combinations in this region while the size variability in the region only amounts to a 7-allele system. While the determination of VNTR alleles by PCR remains a practical methodology in linkage analysis, this may not be applicable in forensic medicine since not all alleles of identical length based on PCR are the same. Our study reveals the important implication of the identification of SSR 2 subloci and concludes that at least in some situations, there may be a necessity to take into consideration these polymorphic subloci.

Alleles↗
PubMed2006

Percentage of body fat and plasma glucose predict plasma sialic acid concentration in type 2 diabetes mellitus.

Circulating sialic acid is an independent risk factor for cardiovascular disease and is higher in people with type 2 diabetes mellitus. Sialic acid is associated with body mass index, but it is uncertain whether body fat contributes to the higher levels of sialic acid in type 2 diabetes mellitus. Therefore, we have investigated whether the higher levels of sialic acid observed in type 2 diabetes mellitus persist when controlling for fatness. Fasting plasma samples were collected from 24 individuals with type 2 diabetes mellitus and 24 controls. Percentage of body fat was measured by bioelectrical impedance. Plasma sialic acid was quantified by an enzymatic method. Plasma sialic acid was higher in the group with type 2 diabetes mellitus than controls (602 +/- 14 vs 545 +/- 14 mg/L, P = .007). Percentage of body fat was associated with plasma sialic acid concentration in both the control group (r = 0.481, P = .020) and the group with type 2 diabetes mellitus (r = 0.527, P = .007). Fasting glucose was also associated with plasma sialic acid in the group with type 2 diabetes mellitus (r = 0.700, P < .001). Adjustment for percentage of body fat accounted for the higher levels of sialic acid in type 2 diabetes mellitus. Using linear regression, 54.3% of the variation of plasma sialic acid was explained by percentage of body fat and glucose concentrations in the whole group. Seventy-four percent of sialic acid variation was explained by the same model in type 2 diabetes mellitus. In conclusion, this is the first study to show that percentage of body fat predicts plasma sialic acid concentration and contributes toward higher levels of sialic acid in type 2 diabetes mellitus.

Adipose Tissue↗
PubMed2006

Differences in cortisol concentrations in South Asian and European men living in the United Kingdom.

OBJECTIVE: The metabolic syndrome is more prevalent in South Asians in Britain than in the general population. Furthering our understanding of the underlying mechanisms is important because of the increased risk of cardiovascular disease associated with the metabolic syndrome. As it has been proposed that increased activity of the hypothalamic pituitary adrenal axis might underlie the metabolic syndrome, we hypothesized that plasma cortisol levels would be higher in South Asians and that increased cortisol levels would be associated with cardiovascular risk factors comprising the metabolic syndrome. The aim of the study was to examine ethnic differences in cortisol levels and to compare the relationships between cortisol levels and cardiovascular risk factors in men from different ethnic groups. DESIGN: Cross-sectional population-based study, Newcastle upon Tyne, UK. (Newcastle Heart project). Participants One hundred men, 40-67 years old, of European and South Asian (Indian, Pakistani, Bangladeshi) ancestry, with and without cardiovascular risk factors of the metabolic syndrome. MEASUREMENTS: Measurement of plasma cortisol and corticosteroid binding globulin in stored sera. RESULTS: After adjustment for age and the presence of cardiovascular risk factors, mean cortisol was 27% (95% CI, 10%, 40%) lower in South Asians compared to Europeans. Cortisol levels were higher in all men with cardiovascular risk factors than those without. CONCLUSIONS: Cortisol levels are lower in South Asian than in European men resident in the UK. Despite lower cortisol levels in South Asians, the relations between cortisol and cardiovascular risk factors remain strong.

Adult↗
PubMed2006

Effects of VLDL and remnant particles on platelets.

There is a considerable body of evidence supporting an association between hypertriglyceridaemia, a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade. Fibrinolysis is also less efficient when thrombin is generated. Thrombin induces thrombin activatable fibrinolysis inhibitor. Thrombin activatable fibrinolysis inhibitor is a carboxypeptidase that cleaves the carboxylic lysine residues on fibrin, thereby abolishing the critical binding site for tPA-plasminogen decreasing plasmin formation. Thus the evidence is supportive of dysregulated coagulation, and impaired fibrinolysis with a predisposition to atherothrombosis, in conditions such as the metabolic syndrome, in which there are increased concentrations of VLDL and remnant lipoproteins. The purpose of this review is to describe the current evidence supporting a procoagulant state induced by VLDL and remnant lipoproteins. The role of these lipoprotein classes in (1) platelet activation; (2) the intrinsic coagulation cascade, and (3) clot formation and fibrinolysis is discussed.

Blood Coagulation↗
PubMed2006

Low ankle-brachial pressure index predicts increased risk of cardiovascular disease independent of the metabolic syndrome and conventional cardiovascular risk factors in the Edinburgh Artery Study.

OBJECTIVE: To investigate whether a low ankle-brachial pressure index (ABI) predicts increased risk of cardiovascular disease (CVD) independent of the metabolic syndrome and conventional cardiovascular risk factors. RESEARCH DESIGN AND METHODS: The Edinburgh Artery Study is a population-based cohort study in which subjects were followed up until their death or for approximately 15 years. Low ABI at baseline was defined as <0.9; subjects with ABI >1.4 (n = 13) were excluded from the analyses. We used a modified version of the definition of the metabolic syndrome published in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, replacing waist circumference criteria with BMI criteria. Data on relevant parameters were available for 1,467 men and women ages 55-74 years at baseline. Cox proportional hazards models were used to study cardiovascular morbidity and mortality before and after adjusting for potential confounding factors. RESULTS: We determined that 25% of the study population had the metabolic syndrome and that a low ABI was more prevalent among people with than without the metabolic syndrome (24 vs. 15%; P < 0.001). During the follow-up period, there were 226 deaths from CVD and 462 nonfatal cardiovascular events. The hazard ratio (95% CI) for low ABI after adjusting for age, sex, baseline CVD, diabetes, smoking status, LDL cholesterol, and metabolic syndrome was 1.5 (1.1-2.1) for CVD mortality and 1.5 (1.2-1.8) for all CVD outcomes. CONCLUSIONS: Low ABI is associated with increased risk of CVD independent of the metabolic syndrome and other major CVD risk factors.

Aged↗
PubMed2005

Insulin and human chorionic gonadotropin cause a shift in the balance of sterol regulatory element-binding protein (SREBP) isoforms toward the SREBP-1c isoform in cultures of human granulosa cells.

The isoforms of sterol regulatory element-binding proteins (SREBP) (1a, 1c, and 2) are key transcriptional regulators of lipid biosynthesis. We examined their regulation by gonadotropin and insulin in human granulosa cells. After removal of leukocytes, granulosa cells were exposed to hormonal additions for 16 h starting on d 2 of culture. Progesterone, lactate, and IGF binding protein-1 were measured in culture medium and cellular mRNA measured by competitive RT-PCR. Addition of human chorionic gonadotropin (hCG) (100 ng/ml) stimulated progesterone production (7.0-fold, P < 0.001 vs. control), whereas lactate was increased by hCG (1.6-fold, P < 0.001) and insulin (1.4-fold, P < 0.001; 1000 ng/ml). Insulin decreased IGF binding protein-1 production by 85% (P < 0.001). There were no significant effects on the expression of SREBP-1a but significant increases in mRNA for SREBP-1c with insulin (6.3-fold), hCG (10.4-fold) and in combination (15.2-fold; P < 0.01 for all comparisons). No consistent effects on SREBP-2 were observed. The expression of mRNA for fatty acid synthase, a target gene for SREBP-1c, was increased by hCG (24-fold, P = 0.006) and insulin (19-fold, P = 0.024), which also increased the level of cellular, total fatty acid (1.34-fold; P = 0.03). Thus, hCG and insulin cause a switch toward expression of the SREBP-1c isoform with consequent effects on fatty acid synthesis. We suggest that high circulating insulin, associated with clinically defined insulin resistance, may up-regulate SREBP-1c expression in the ovary.

CCAAT-Enhancer-Binding Proteins↗
PubMed2005

Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease.

Interaction between the platelet glycoprotein Ibalpha (GPIbalpha) receptor and its adhesive ligand von Willebrand factor (VWF) has a critical role in the process of hemostasis. Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder that results from gain-of-function mutations in the GPIBA gene. We studied this gene from 5 members of a previously unreported family with a PT-VWD phenotype. We identified a novel in-frame deletion of 27 base pair (bp) in the macroglycopeptide region. This deletion was not found in the unaffected family members or in 50 healthy controls. The patients' platelets expressed normal quantities of GPIb/IX/V complex on their surface and the mutant (Mut) GPIbalpha was expressed at levels indistinguishable from the wild-type (WT) receptor on the surface of transfected Chinese hamster ovary (CHO) beta/IX cells. Analysis of ristocetin-mediated (125)I-VWF binding showed that the Mut receptor binds VWF in the absence of ristocetin and displays an increased sensitivity to lower concentrations of the modulator. This is the first report of a gain-of-function mutation in the GPIbalpha receptor outside the VWF-binding domain in patients with PT-VWD. The mutation provides a molecular basis for the PT-VWD phenotype and supports a role for the macroglycopeptide region in receptor function.

Adult↗
PubMed2004

Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses.

Maternal dietary Fe restriction reduced fasting plasma cholesterol and triglyceride (TG) concentrations in the fetuses, as well as decreased plasma TG levels in the adult offspring. To investigate how maternal Fe restriction was affecting fetal lipid metabolism, we investigated whether there were changes in liver lipid metabolism in the full-term fetuses. There was a approximately 27% (P < 0.05) increase in cholesterol but approximately 29% reduction (P = 0.01) in TG concentrations in the liver of the Fe-restricted fetuses. Hepatic mRNA levels of cholesterol 7alpha hydroxylase and liver X receptor-alpha (LXRalpha) were reduced by approximately 50% (P < 0.01) and approximately 34% (P < 0.01), respectively. As LXRalpha regulates expression of sterol response element binding protein-1c (SREBP-1c) expression, we measured SREBP-1c expression. There was an approximately 43% (P < 0.001) reduction in mRNA levels of SREBP-1c and its response genes, including acetyl-CoA carboxylase by approximately 35% (P = 0.01), fatty acid synthase by approximately 18% (P = 0.05), and diacylglycerol acyltransferase by approximately 19% (P = 0.03). Furthermore, protein levels of CD36 were reduced by approximately 27% (P = 0.02) in Fe-restricted fetuses. In conclusion, changes in liver cholesterol and TG concentrations in Fe-restricted fetuses may be coordinated through reduced expression of heme-containing cholesterol 7alpha hydroxylase and its regulator LXRalpha, mainly via downregulation of expression of genes in bile acid synthesis and fatty acid synthesis pathways.

Animals↗
PubMed2004

High-unsaturated-fat, high-protein, and low-carbohydrate diet during pregnancy and lactation modulates hepatic lipid metabolism in female adult offspring.

Whether a high-unsaturated-fat, high-protein (HFP), and low-carbohydrate (CHO) diet during gestation has long-lasting beneficial effects on lipid metabolism in the offspring was investigated using a mouse model. Female mice were fed either a standard (CHO rich) chow diet or a CHO HFP diet, before and during gestation and lactation. All offspring were weaned onto the same chow until adulthood. Although liver cholesterol concentration and fasting plasma triglyceride (TG), cholesterol, and free fatty acid concentrations were not affected in either male or female HFP offspring, hepatic TG concentration was reduced by approximately 51% (P < 0.05) in the female adult offspring from dams on the HFP diet, compared with females from dams on the chow diet (a trend toward reduced TG concentration was also observed in the male). Furthermore, hepatic protein levels for CD36, carnitine palmitoyltransferase-1 (CPT-1), and peroxisomal proliferator activated receptor-alpha (PPAR-alpha) were increased by approximately 46% (P < 0.001), approximately 52% (P < 0.001), and approximately 14% (P = 0.035), respectively, in the female HFP offspring. Liver TG levels were negatively correlated with protein levels of CD 36 (r = -0.69, P = 0.007), CPT-1 (r = -0.55, P = 0.033), and PPAR-alpha (r = -0.57, P = 0.025) in these offspring. In conclusion, a maternal HFP diet during gestation and lactation reduces hepatic TG concentration in female offspring, which is linked with increased protein levels in fatty acid oxidation.

Animals↗
PubMed2004

Hemodynamic effects of amlodipine, bisoprolol, and lisinopril in hypertensive patients after liver transplantation.

BACKGROUND: Hypertension is common after liver transplantation. There are few published data on optimum treatment. Augmentation index (AIx) is a measure of arterial wave reflection determined by pulse wave analysis. METHODS: Amlodipine was administered to 24 hypertensive liver transplant recipients. Thirteen patients intolerant of or unresponsive to amlodipine were randomized to a crossover study comparing bisoprolol with lisinopril. RESULTS: With amlodipine, systolic blood pressure (SBP) fell from 154+/-2 mm Hg to 130+/-2 mm Hg, and AIx also fell. With bisoprolol, SBP fell from 154+/-2 mm Hg to 142+/-4 mm Hg, but AIx increased. With lisinopril, SBP fell from 154+/-2 mm Hg to 130+/-5 mm Hg, and AIx also fell (P <0.001 throughout). CONCLUSIONS: Amlodipine is an effective treatment for hypertension. The increased AIx with bisoprolol indicates increased wave reflection such that central aortic pressure is reduced less than peripheral SBP. Lisinopril reduces AIx and reduces SBP more than bisoprolol and is the preferred drug.

Adult↗
PubMed2004

Is there disparity between risk and incidence of cardiovascular disease after liver transplant?

BACKGROUND: Hypertension and hypercholesterolemia are recognized complications of liver transplantation, but whether they contribute to the development of cardiovascular disease is uncertain. We aimed first to determine the prevalence of risk factors for coronary heart disease (CHD) after liver transplantation and second to study the effect of liver transplantation on the predicted 10-year risk of developing CHD and the incidence of cardiovascular events in comparison with a matched local population. METHODS: Data on blood pressure, serum lipids, weight, diabetes mellitus, smoking, and incidence of myocardial infarction (MI) and stroke were obtained retrospectively from the case notes of 181 consecutive adult liver transplant recipients (median follow-up 54 months). The Framingham coronary risk equations were used to calculate the 10-year probability of developing CHD. RESULTS: The prevalences of hypertension and hypercholesterolemia after transplantation were 77% and 62%, respectively. The predicted 10-year risk of CHD increased from 6.9% before transplantation to 11.5% at 1 year after transplantation, whereas that of a matched local population was 7%. Compared with a matched nontransplant population, the incidence ratios for MI and stroke were 0.55 (95% confidence interval, 0.01-3.06 ) and 1.45 (95% confidence interval, 0.18-5.22), respectively. No patients died from MI or stroke. CONCLUSIONS: Liver transplant recipients have a high prevalence of risk factors for cardiovascular disease, exceeding that of the general population, and have a higher predicted risk of developing CHD. Despite this, there were no deaths from CHD or stroke during the study period.

Adolescent↗
PubMed2003

Human skeletal muscle PPARalpha expression correlates with fat metabolism gene expression but not BMI or insulin sensitivity.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a key regulator of fatty acid oxidation in skeletal muscle, but few data exist from humans in vivo. To investigate whether insulin sensitivity in skeletal muscle and body mass index (BMI) were associated with skeletal muscle expression of PPARalpha and with important genes regulating lipid metabolism in humans in vivo, we undertook hyperinsulinemic-euglycemic clamps and measured PPARalpha mRNA levels and mRNA levels of lipid regulating PPARalpha response genes in skeletal muscle biopsies. mRNA levels were measured in 16 men, using a novel highly sensitive and specific medium throughput quantitative competitive PCR that allows reproducible measurement of multiple candidate mRNAs simultaneously. mRNA levels of PPARalpha were positively correlated with mRNA levels of CD36 (r = 0.77, P = 0.001), lipoprotein lipase (r = 0.54, P = 0.024), muscle-type carnitine palmitoyltransferase-I (r = 0.54, P = 0.024), uncoupling protein-2 (r = 0.63, P = 0.008), and uncoupling protein-3 (r = 0.53, P = 0.026), but not with measures of insulin sensitivity, BMI, or GLUT4, which plays an important role in insulin-mediated glucose uptake. Thus our data suggest that in humans skeletal muscle PPARalpha expression and genes regulating lipid metabolism are tightly linked, but there was no association between both insulin sensitivity and BMI with PPARalpha expression in skeletal muscle.

Adult↗
PubMed2003

A novel role for CD36 in VLDL-enhanced platelet activation.

Type 2 diabetes is characterized by increased plasma triglyceride levels and a fourfold increase in ischemic heart disease, but the mechanism is unclear. CD36 is a receptor/transporter that binds fatty acids of lipoproteins. CD36 deficiency has been linked with insulin resistance. There is strong evidence of in vivo interaction between platelets and atherogenic lipoproteins suggesting that atherogenic triglyceride-rich lipoproteins, such as VLDL, that are increased in diabetic dyslipidemia are important in this process. This study demonstrates that VLDL binds to the platelet receptor CD36, enhances platelet thromboxane A2 production, and causes increased collagen-mediated platelet aggregation. VLDL enhanced collagen-induced platelet aggregation by 1) shortening the time taken for aggregation to begin (lag time) to 70% of control (P = 0.001); 2) increasing maximum aggregation to 170% of control (P = 0.008); and 3) increasing thromboxane production to 3,318% of control (P = 0.004), where control represents platelets stimulated with collagen (100%). A monoclonal antibody against CD36 attenuated VLDL-enhanced collagen-induced platelet aggregation by 1) inhibiting binding of VLDL to platelets by 75% (P = 0.041); 2) lengthening lag time to 190% (P < 0.001); and 3) decreasing thromboxane production to 8% of control (P < 0.001). In support of this finding, platelets from Cd36-deficient rats showed no increase in aggregation, thromboxane production, and VLDL binding in contrast to platelets from rats expressing CD36. These data suggest that platelet Cd36 has a key role in VLDL-induced collagen-mediated platelet aggregation, possibly contributing to atherothrombosis associated with increased VLDL levels.

Antigens, CD↗
PubMed2002

A novel medium throughput quantitative competitive PCR technology to simultaneously measure mRNA levels from multiple genes.

There is a great demand for technologies to simultaneously measure mRNA levels from multiple genes. Here we report a new quantitative competitive PCR technology and demonstrate simultaneous quantification of mRNA from multiple genes. First, a sequential 2-fold dilution series containing equal amounts of gene-specific standard DNAs for 10-12 genes is prepared. Second, the serially diluted standard DNAs are individually added to equal amounts of tissue-derived cDNA and amplified with gene-specific primers for 19-26 PCR cycles. Each gene/standard DNA pair is amplified individually. All amplified DNA products (n = 80) are resolved by one microplate array diagonal gel electrophoresis using 5% polyacrylamide. Changes in mRNA levels of approximately 15% can be detected by this technology. The mRNA levels from 10-12 genes were simultaneously quantified. mRNA levels were compared in RNA samples from rat liver, kidney and skeletal muscle. This quick, specific, sensitive, reproducible and yet inexpensive technique is ideal for simultaneously studying co-ordinate changes in mRNA levels from multiple genes.

Animals↗