Biomedical subjects
T W Meade
Publications and source records attributed to T W Meade.
Antithrombin III and arterial disease.
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Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life.
OBJECTIVE: To determine whether reduced fetal and infant growth are associated with higher plasma fibrinogen and factor VII concentrations in adult life. DESIGN: Follow up study of men born during 1920-30 whose weights at birth and at 1 year had been recorded by health visitors, and men born during 1935-43 whose size at birth had been measured in detail. SETTING: Hertfordshire and Preston, England. SUBJECTS: 591 men born in east Hertfordshire who still lived there and 148 men born in Preston who still lived in or close to the city. MAIN OUTCOME MEASURES: Plasma fibrinogen and factor VII concentrations. RESULTS: Among men in Hertfordshire mean plasma fibrinogen and factor VII concentrations fell with increasing weight at 1 year (from 3.21 g/l in men of less than or equal to 18 lb to 2.93 g/l in men greater than or equal to 27 lb and from 122% of standard to 103%; p less than 0.001, p less than 0.005 respectively). The trends were independent of cigarette smoking, alcohol consumption, body mass index, and social class. Neither plasma fibrinogen nor factor VII concentration was related to birth weight. In men in Preston, however, fibrinogen concentration fell progressively as the ratio of placental weight to birth weight decreased (p = 0.01). CONCLUSIONS: Reduced growth in fetal life and infancy is strongly related to high plasma concentrations of the haemostatic factors fibrinogen and factor VII. This may be a persisting response to impaired liver development during a critical early period.
Spinal manipulation and mobilisation for back and neck pain.
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Chorionic villus sampling.
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Hageman factor and risk of myocardial infarction in middle-aged men.
In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.
Involvement of plasma fibrinogen in coronary artery disease.
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Thrombosis and cardiovascular disease.
It was only quite recently that the thrombotic component in myocardial infarction and sudden coronary death was generally acknowledged. When attention was eventually paid to it, interest initially centered primarily on platelet function. There is, of course, no doubt about the central role of platelet adhesion and aggregation in thrombogenesis, but still no generally accepted measure of platelet function has been shown to be associated with the later onset of ischemic heart disease (IHD). Epidemiologically, the assessment of coagulability has been more rewarding. Several prospective studies have now shown a strong relationship between the plasma fibrinogen level and the incidence of IHD and stroke. Epidemiologic and laboratory studies have also implicated factor VII and extrinsic pathway activity in the onset of IHD. Other components of the hemostatic system that are probably involved include factor VIII activity and the fibrinolytic system. It is increasingly clear that lipoproteins exert a major influence on coagulability as well as their better known role in atherogenesis. Any further polarization of hypotheses for IHD as being purely atherogenic or purely thrombogenic is therefore counterproductive. At the same time, antithrombotic measures for primary prevention need to be evaluated as thoroughly as lipid-lowering regimens. If thrombosis is seen as the final arterial event in virtually all major episodes of IHD, the indications for antithrombotic agents in primary prevention may be wider than those for lipid-lowering regimens. It is therefore necessary to establish as quickly as possible not only the preventive effectiveness of antithrombotic measures, including low-dose aspirin and low-intensity oral anticoagulation, but also the relative effectiveness and safety of antithrombotic and lipid-modifying regimens.
Genetic factors determining thrombosis and fibrinolysis.
Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation in plasma levels of these proteins not accounted for by environmental factors. We previously investigated the DNA variation at the fibrinogen gene locus and showed that BclI restriction fragment length polymorphism (RFLP) of the beta-fibrinogen gene is associated with between-person differences in plasma fibrinogen levels. This RFLP is unlikely to be the functional base change itself, since it lies downstream of the gene. The rate-limiting step in the production of the mature fibrinogen molecule in the human hepatoma cell-line HepG2 is the synthesis of the beta-polypeptide chain, which in turn is influenced by the amount of messenger (mRNA) available. One possibility is that BclI RFLP is in linkage disequilibrium with a base change in the region of the beta-gene controlling synthesis of its mRNA and ultimately of fibrinogen protein. We identified a base change in the 5'-flanking region of the beta-fibrinogen gene that is in linkage disequilibrium with the BclI RFLP, that is associated with plasma fibrinogen levels, and that may be involved in control of fibrinogen gene expression. For the factor VII gene, we identified a polymorphism, detected after Msp I digestion of polymerase chain reaction (PCR)-amplified genomic DNA, that is strongly associated with factor VII coagulant activity (factor VIIc). The base change that creates the Msp I polymorphism is a G to A substitution, leading to the replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele. In a sample of 284 men from the United Kingdom the frequency of the Gln allele (M2 loss of cutting site) is 0.1, and individuals of genotype Arg/Gln have factor VIIc levels 22% below the sample mean. In this sample, the Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. Three individuals homozygous for the Gln allele had both low factor VIIc and low factor VII protein concentrations. The conformation of the factor VII Gln may be different from that of the Arg protein, affecting its intracellular processing, secretion, turnover in plasma, or activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Hormone replacement therapy and cardiovascular disease.
Oestrogen alone probably confers a degree of protection against ischaemic heart disease and stroke and is appropriate for women requiring hormone replacement therapy (HRT) who have undergone hysterectomy. However, the cardiovascular effects of the progestogens used with oestrogen in the much larger number of women who have not undergone hysterectomy are unknown. Some widely used progestogens have adverse effects on lipoprotein levels and may raise blood pressure. The antithrombin III level may be involved in determining the response to oestrogen in different settings. The indications for HRT and the effects of different formulations on cardiovascular disease constitute one of the most pressing but complex issues in present-day medical practice. These questions can only be satisfactorily answered by the randomised controlled trials that should have been initiated several years ago and the feasibility of which is only now being investigated.
How common are polycystic ovaries in normal women and what is their significance for the fertility of the population?
OBJECTIVE: We wished to determine the prevalence of polycystic ovaries (PCO) and relate morphological appearance to fertility. DESIGN: We sent postal invitations to a random sample of women born in the years 1952-1969 from a list of a single Group Practice to attend for reproductive history questionnaire, examination, ultrasound scan of the ovaries and hormone measurements within 5 days of the onset of menstruation. SUBJECTS: Of 1065 women potentially available for study, 571 (54%) replied of whom 353 (62%) agreed to participate. One hundred and ninety (18%) completed the study, 163 were deferred (57 because of current or very recent pregnancy, 106 because of inconvenience at time approached), and 18 additional women volunteered. MEASUREMENTS: Prevalence of polycystic ovaries, ovarian size and morphology, menstrual history, features of androgen excess, fertility status, serum hormone levels. RESULTS: The prevalence of PCO was 22% (41/190). PCO and non-PCO women were similar with respect to age, body mass index, oral contraceptive pill (OCP) usage, acne, and menstrual pattern but hirsutism (Ferriman and Gallwey score > 7) was significantly (P = 0.006) more frequent among PCO women. Proven prior fertility was the same in PCO (56%) and non-PCO (64%) women and an equal proportion in each group had not yet tested their fertility. Of those women with previously proven fertility, self-perceived difficulty in conception occurred in similar proportions of women with and without PCO. Unresolved primary or secondary infertility (2.5-4%) was similar in both groups. Ovarian volume (each ovary separately) was larger in women with PCO irrespective of current OCP usage. Serum levels of oestradiol and FSH were similar in PCO and non-PCO women, but LH was distributed around a higher median in PCO women. Median testosterone and androstenedione levels were the same in PCO and non-PCO women. CONCLUSIONS: The prevalence of polycystic ovarian morphology is high but, in this sample of women, was accompanied by minimal clinical manifestations and apparently no deleterious effects on earlier fertility. An isolated finding of polycystic ovaries may be a normal variation and should not necessarily imply altered fertility potential.
Strenuous exercise, plasma fibrinogen, and factor VII activity.
OBJECTIVE: To assess the effect of physical activity on plasma fibrinogen and factor VII activity and thus on the risk of ischaemic heart disease. DESIGN: Cross sectional survey. SETTING: Ten group practices in the Medical Research Council's General Practice Research Framework. PATIENTS: 3967 men aged 45-69 attending screening clinics for the thrombosis prevention trial. METHODS: Structured interview to elicit the intensity and frequency of physical exercise during past month. Measurement of fibrinogen, factor VII activity, cholesterol concentration, blood pressure, and other indices of ischaemic heart disease risk. RESULTS: Strenuous exercise was associated with significantly lower fibrinogen concentrations than mild exercise, implying a difference of about 15% in the risk of ischaemic heart disease. Strenuous exercise was also associated with lower cholesterol concentrations. More frequent strenuous exercise was associated with lower factor VII activity. CONCLUSIONS: With the recognition of plasma fibrinogen as a strong index of ischaemic heart disease risk the results of this and other studies suggest a pathway through which the protective effect of strenuous exercise may partly be mediated and they provide doctors and patients with a valuable incentive towards prevention, particularly in those whose risk of ischaemic heart disease is substantially due to raised fibrinogen concentrations.
Proceedings of the National Heart, Lung, and Blood Institute Workshop on Hemostasis, Thrombosis, and Cardiovascular Diseases. Overview and research opportunities.
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Haemostatic changes that constitute the hypercoagulable state.
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Antithrombin III and arterial disease.
Cross-sectional studies suggest that both low and high antithrombin III levels are associated with the risk of arterial disease, principally ischaemic heart disease (IHD). The prospective relation between antithrombin III and subsequent death from arterial disease has been investigated in 893 men in the Northwick Park Heart Study. Antithrombin III levels were directly correlated with high rather than low levels of factor VII activity and of plasma fibrinogen. There were more deaths from arterial disease in the low and high thirds of the antithrombin III distribution than in the middle third.
Strategies for prevention of osteoporosis and hip fracture.
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Hormone replacement therapy in general practice.
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Purification and characterization of factor VII 304-Gln: a variant molecule with reduced activity isolated from a clinically unaffected male.
Factor VII (FVII) is the plasma serine protease zymogen which, on binding to its cellular receptor tissue factor (TF), initiates blood coagulation. A 47-year-old man with no clinical bleeding tendency was found to have undetectable plasma FVII activity when tested in a one-stage assay using rabbit brain TF, but 0.3 U/mL using recombinant human TF and 1.04 U/mL FVII antigen. Variant FVII purified from his plasma showed an identical migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis to wild-type zymogen. By enzyme kinetic analysis the Km of the variant using FX as a substrate was 12-fold higher than that of normal FVII. Also, the variant FVII was unable to compete with wild-type FVII for limited rabbit TF binding sites. A ligand blot procedure was used to directly demonstrate reduced binding of recombinant human TF to the variant FVII compared with normal FVII. Genetic analysis of leukocyte DNA showed a G to A mutation in the propositus' gene at codon 304 that results in the substitution of a glutamine for an arginine residue in the catalytic domain of the protease. We conclude that this region of the FVII molecule is important for its function.