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Many measures have been proposed to summarize the prognostic ability of the Cox proportional hazards (CPH) survival model, although none is universally accepted for general use. By contrast, little work has been done to summarize the prognostic ability of the stratified CPH model; such measures would be useful in analyses of individual participant data from multiple studies, data from multi-centre studies, and in single study analysis where stratification is used to avoid making assumptions of proportional hazards. We have chosen three measures developed for the unstratified CPH model (Schemper and Henderson's V , Harrell's C-index and Royston and Sauerbrei's D), adapted them for use with the stratified CPH model and demonstrated how their values can be represented over time. Although each of these measures is promising in principle, we found the measure of explained variation V very difficult to apply when data are combined from several studies with differing durations of participant follow-up. The two other measures considered, D and the C-index, were more applicable under such circumstances. We illustrate the methods using individual participant data from several prospective epidemiological studies of chronic disease outcomes.

Background—There is increasing interest in the predictive value of C-reactive protein (CRP) and fibrin D-dimer in the prediction of ischemic heart disease (IHD). We assessed their joint and independent associations with IHD in a large combined analysis of 2 population cohorts.Methods and Results—Men aged 49 to 66 years from the general populations of Caerphilly and Speedwell were studied between 1982 and 1988 and re-examined for new IHD events at fixed intervals of ≈105 months (Caerphilly) and 75 months (Speedwell). 3213 men had CRP and D-dimer measured at baseline and 351 (11%) had a new IHD event. Mean levels of CRP and D-dimer were significantly higher among men in whom IHD developed. The relative odds of IHD in men in the top 20% of the distribution of CRP was 2.97 (95% CI, 2.04, 4.32) and for D-dimer was 2.40 (95% CI, 1.69, 3.40); CRP and D-dimer had additive effects on risk of IHD. Multivariate analysis reduced the size of the relative odds, which remained significant for D-dimer.Conclusions—Both inflammatory and thrombogenic markers are important (and potentially additive) predictors of coronary risk.

Aims We compare the predictive values of plasma lipids (total and HDL-cholesterol, triglycerides) and three haemostatic/inflammatory risk markers for subsequent ischaemic heart disease (IHD). Methods and results Two UK populations totalling 4860 men were screened for evidence of IHD between 1979 and 1983. Men were followed over 10 years and validated coronary events were recorded. Risk estimates were made using relative odds, receiver operating characteristic (ROC) curves and deciles of risk. Regression dilution effects were also examined. By 10 years, 525 men had a coronary event (fatal, non-fatal or silent myocardial infarction, MI). Two alternative multivariate models were compared – a lipid model (total, HDL-cholesterol, triglyceride) and a haemostatic/inflammatory model (fibrinogen, viscosity and white cell count). `Correction' for regression dilution increased relative odds for most risk factors. In the distribution of predicted risk, using established risk factors in conjunction with either lipid or haemostatic/inflammatory factors, the deciles of risk analysis showed that the observed 10-year risk of IHD was 34–35% in men in the top tenth, compared to 2–3% in the lowest tenth of the distribution. Conclusion At the 10 years' follow-up, major, haemostatic/inflammatory risk factors showed a graded relationship to incident IHD that was at least as strong as that given by plasma lipids. Haemostatic/inflammatory factors provide possible additional targets for intervention.

Objective: To examine the optimal intensity of leisure time physical activity (LTPA) to decrease the risk of all cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in a population sample of middle aged British men. Design: Prospective study of middle aged men with an 11 year follow up. Setting: A whole population sample of men from Caerphilly, South Wales, UK. Subjects: 1975 men aged 49–64 years without historical or clinical evidence of CHD at baseline examination. Main outcome measures: All cause, CVD, and CHD mortality. Results: Total (cumulative) LTPA had a graded, significant relation with all cause, CVD, and CHD mortality but no trend with cancer deaths. When different intensities of activity were considered, light and moderate intensity LTPA had inconsistent and non-significant relations with all cause, CVD, or CHD mortality whether adjusted only for age or for other cardiovascular risk factors. In contrast a significant dose–response relation was found for heavy intensity LTPA for all cause, CVD, and CHD mortality fully adjusted for other risk factors. Conclusions: These data suggest that, in a population of men without evidence of CHD at baseline, only leisure exercise classified as heavy or vigorous was independently associated with reduced risk of premature death from CVD.

Apolipoproteins B, A–I and Lp(a) have been proposed as independent predictors of subsequent ischaemic heart disease (IHD) improving on the prediction obtained by routine lipid measurements. In this report we have investigated the relative predictive ability of apolipoproteins and plasma lipids in a prospective study of middle aged men. 2398 men aged 49–65 years from the general population of Caerphilly, South Wales, UK were screened for evidence of IHD. After an overnight fast 2225 men each provided a venous blood sample on which plasma lipids, apolipoproteins B, A–I, A–II, and lipoprotein (a) (Lp(a)) were measured. Over a follow-up period of nearly 9 years, 282 (12%) men developed major IHD. Multiple logistic regression analysis showed that after adjusting for standard cardiovascular risk factors other than lipids there was a strong trend (standardised relative odds (SRO) = 1·20; P = 0·009) for incidence of IHD to increase with apolipoprotein B. However, on further adjusting for total cholesterol this trend largely disappeared (SRO = 1·05; P = 0·57). Similarly, a trend for incidence of IHD to increase with decreasing apolipoprotein A–I (SRO = 1·18; P = 0·02) disappeared when HDL cholesterol was added to the model. Levels of apolipoprotein A–II were not related to risk of subsequent IHD. Incidence of IHD was effectively constant over nearly 90% of the range of Lp(a). Only among the 5% of men with Lp(a) greater than 70 mg dL−1 was the risk of IHD significantly (P = 0·04) greater than among men with Lp(a) less than 10 mg dL−1. Apolipoproteins B and A–I do not improve on the prediction of risk of IHD provided by total and HDL cholesterol, respectively. Apolipoprotein A–II was not related to risk of IHD. Lp(a) may be independently associated with incident IHD among the 5–10% of men with the highest levels.

Background There is much interest in reported associations between serum C-reactive protein and incident ischaemic heart disease. It is uncertain what this association represents. We aimed to assess the effect of confounding from a number of different sources in the Caerphilly Prospective Heart Disease Study and in particular whether the low grade inflammation indicated by C-reactive protein may be the mechanism whereby non-circulating risk factors may influence pathogenesis of ischaemic heart disease. Methods Plasma specimens collected during 1979–83 from 1395 men with sufficient sample remaining were assayed for serum C-reactive protein by ELISA. Subsequent mortality and incident ischaemic heart disease events were ascertained from death certificates, hospital records and electrocardiographic changes at 5-yearly follow-up examinations. Results There was a positive association between C-reactive protein and incident ischaemic heart disease (P

Objectives: To investigate the effect of Chlamydia pneumoniae infection on future development of ischaemic heart disease and mortality. Design: Prospective longitudinal study. Setting: Caerphilly, South Wales. Subjects: Plasma specimens were collected during 1979-83 from 1773 men aged 45-59 years. These were tested for IgG and IgA antibodies to C pneumoniae (TW183) by microimmunofluorescence. Outcome measures: 13 year mortality and incident ischaemic heart disease events were ascertained from death certificates, hospital records, and electrocardiographic changes at follow up every 4 to 5 years. Results: 642 men (36.2%) had IgG antibodies at a titre of Conclusion: This is the first prospective demonstration of an association between IgA antibodies to C pneumoniae, a putative marker of chronic infection, and subsequent risk of death from ischaemic heart disease. In contrast to earlier case-control studies, IgG antibodies were not associated with either prevalent or incident ischaemic heart disease.

The relationships of three measurements of the factor VIII/von Willebrand factor (VWF) complex (factor VIII activity, FVIIIc (one-stage assay); VWF antigen, VWF Ag (ELISA); and VWF activity, VWF act, measured by a recently-developed ELISA) to major ischaemic heart disease (IHD) events were studied in 1997 men aged 49-65 years, in the second phase of the Caerphilly Heart Study. These variables were related using logistic regression analysis to myocardial infarction or IHD death, which occurred in 129 men during an average follow-up period of 61 months. All three measurements were highly correlated (r = 0.63-0.77), and each was significantly associated with incident major IHD on univariate analyses (relative odds in highest fifth compared to lowest fifth, 1.68-1.90; P = 0.028-0.006) and on multivariate analyses adjusting for major IHD risk factors and for baseline IHD. Neither FVIIIc nor VWF act was significantly related to incident IHD following adjustment for VWF Ag. We therefore suggest that the associations between these three measurements of the factor VIII/VWF complex and incident IHD might have at least three explanations: VWF Ag is a marker of arterial endothelial disturbance; VWF act promotes platelet adhesion/aggregation and hence the platelet component of arterial thrombosis; and FVIIIc promotes fibrin formation and hence the fibrin component of arterial thrombosis.

The Caerphilly and Speedwell studies have previously reported the predictive power of heat-precipitation, nephelometric, fibrinogen for 10-year incidence of ischaemic heart disease. A Clauss, clotting time, fibrinogen was also measured at baseline, but has not previously been reported. The predictive power of the two assays is compared. Both methods were employed on fasting blood samples from a total of 4391 men aged 45–63 years. Over the following 10 years 533 (12%) developed major ischaemic heart disease. Nephelometric fibrinogen was higher by 0.33 g/l among the men who developed disease; clottable fibrinogen was higher by 0.20 g/l. This difference is statistically significant (P = 0.01). Relative odds of developing heart disease increased steadily to 3.53 (P < 0.0001) in the 20% of men with the highest nephelometric fibrinogen; for clottable fibrinogen the corresponding relative odds increased to 2.24 (P < 0.0001). When both measures of fibrinogen were included in logistic regression models together with age and smoking habit, the trend for incidence to increase with increasing nephelometric fibrinogen remained highly significant (P < 0.0001), whereas for the Clauss fibrinogen the trend almost entirely disappeared (P = 0.37). We conclude that functional assays of clottable fibrinogen may not reflect all of the mechanisms which mediate the association between fibrinogen and cardiovascular disease and that assays of both ‘heat precipitable’ and ‘clottable’ fibrinogen should be included in all future prospective studies.

SummaryPlasma levels of fibrin D-dimer, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI) have been associated with ischaemic heart disease (IHD). However their associations with incident IHD in samples of the general population are not established. D-dimer antigen, tPA antigen and PAI activity were measured in stored, fasting plasma samples from 1,998 men aged 45-65 examined between 1984 and 1988, during the first re-examination of the Caerphilly Study cohort. These variables were related to major IHD events (myocardial infarction or IHD death) which occurred in 129 men during a follow-up period which averaged 61 months. Mean fibrin D-dimer was higher in men who developed IHD events (90 vs. 71 ng/ml; age-adjusted logarithmic mean difference 0.21; 95% CI 0.11, 0.30; p

Antioxidant flavonols and their major food source, black tea, have been associated with a lower risk of ischemic heart disease (IHD) and stroke in Dutch men. We investigated whether flavonol intake predicted a lower rate of IHD in 1900 Welsh men aged 45-59 y, who were followed up for 14 y. Flavonol intake, mainly from tea to which milk is customarily added, was not related to IHD incidence [relative risk (RR), highest compared with lowest quartile: 1.0; 95% CI: 0.6, 1.6; P for trend = 0.996; n = 186] but was weakly positively related to IHD mortality (RR: 1.6; 95% CI: 0.9, 2.9; P = 0.119; n = 131) and cancer mortality (RR: 1.3; 95% CI: 0.7, 2.3; P = 0.150; n = 104) and strongly related to total mortality (RR: 1.4; 95% CI: 1.0, 2.0; P = 0.014; n = 334). Men with the highest consumption of tea (> 1.2 L, or > 8 cups/d) had an RR of 2.4 (95% CI: 1.5, 3.9) of dying in the follow-up period compared with men consuming < 300 mL/d (< 2 cups/d). We conclude that intake of antioxidant flavonols is not inversely associated with IHD risk in the United Kingdom. Possibly, flavonols from tea to which milk is added are not absorbed; experimental evidence suggests that adding milk to tea abolishes the plasma antioxidant-raising capacity of tea. The apparent association between tea consumption and increased mortality in this population merits further investigation.

Aims To use the ten year follow-up of the Caerphilly and Speedwell studies to assess the contributions of fibrinogen and viscosity to the prediction of risk of ischaemic heart disease. Methods and Results Caerphilly and Speedwell are prospective studies based on representative samples of middleaged males. Ischaemic heart disease morbidity and mortality were defined using hospital notes, repeat electrocardiographs and death certificates. There were 603 incident events among the 4860 men. Age-adjusted relative odds of ischaemic heart disease increased to 3 3 and 3-4 in the 20% of men with the highest levels of fibrinogen and viscosity, respectively. After standardizing for the major cardiovascular risk factors, these relative odds were 2-2 (95% confidence interval I-6 to 31) for fibrinogen and 2-3 (95% confidence interval 1-7 to 3-2) for viscosity. When fibrinogen and viscosity were entered jointly, both remained significant (/>

The indole alkaloid ibogaine (NIH 10567, Endabuse) is currently being examined for its potential utility in the treatment of cocaine and opioid addiction. However, a clearly defined molecular mechanism of action for ibogaine's putative anti-addictive properties has not been delineated. Radioligand binding assays targeting over 50 distinct neurotransmitter receptors, ion channels, and select second messenger systems were employed to establish a broad in vitro pharmacological profile for ibogaine. These studies revealed that ibogaine interacted with a wide variety of receptors at concentrations of 1-100 microM. These included the mu, delta, kappa, opiate, 5HT2, 5HT3, and muscarinic1 and 2 receptors, and the dopamine, norepinephrine, and serotonin uptake sites. In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [3H]MK-801 and [3H]bactrachotoxin A 20-alpha-benzoate binding (BTX-B), respectively. This broad spectrum of activity may in part be responsible for ibogaine's putative anti-addictive activity.

The binding of HIV-1 envelope glycoprotein, gp120, to the CD4 receptor is an important step in productive infection. The development of agents which interrupt this binding phenomenon should be of therapeutic interest. The present study characterizes a whole cell gp120/CD4 radioligand binding assay (radioligand binding assay) modified for use in a high volume screening format. Modifications include the use of human CD4 receptor stably expressed in a Chinese hamster ovary cell line and the gentle fixation (paraformaldehyde) of the CD4 receptor just prior to assay. Binding of [125I]gp120 to fixed CD4 was of high affinity (KD = 6 nM), saturable, reversible, and specific. The kinetics of binding were identical to those of viable (non-fixed) CD4 receptor. [125I]gp120 binding was inhibited by unlabeled recombinant gp120, soluble CD4, and the anti-CD4 monoclonals OKT4A and LEU3A. A number of compounds reported to inhibit gp120 binding and/or gp120 induced syncytium formation were also active in this assay. This modified radioligand binding assay was developed to initiate a rational and extensive screening program to assist in the identification of potential chemotherapeutic agents based on their ability to inhibit gp120 binding to host cells.

Factors influencing compliance with dietary advice were investigated in the Diet and Reinfarcation Trial (DART). In terms of achieved intakes, smokers had a lower mean P/S ratio and fibre intake than non-smokers; manual workers had a lower mean fibre intake than non-manual workers; and obese men had a higher percentage of energy from fat and lower P/S ratio than non-obese men. However the effect of the advice (difference in intakes of those advised and thosen not advised) was similar in smokers and non-smokers and was similar in all social classes. The effect of fat advice was less among obese men than among non-obese men, probably as a result of weight-reducing advice given to all overweight men. Fat advice tended to have a greater effect among those who gave up smoking after their heart attack than among non-smokers and those who continued to smoke but the difference was not statistically significant. This suggests that advice on diet and smoking can be given simultaneously and still be effective.

As part of two large heart surveys, associations between traffic noise exposure and cardiovascular risk factors were studied. The Caerphilly sample (small town, total sample) consisted of 2512 men aged 45 to 59 years and the Speedwell sample (suburb of a major city, random sample) of 2030 men of same age group. Both studies have a prospective design; cross-sectional results are presented here. Acoustic measurements were carried out in both areas. Among the possible risk factors for ischaemic heart disease studied were blood pressure, blood coagulation, blood lipids and other biochemical factors. Statistically significant noise effects were detected for systolic blood pressure, total cholesterol, HDL cholesterol, total triglycerides, blood viscosity, platelet count and glucose level, although not all of these were consistent with noise being a risk factor for heart disease. In a subsample, the additional influence of work noise as determined by noise dosimetry was studied in 255 men, taking the use of ear protection into account. The associations between traffic noise and risk factors were more pronounced in men who also were exposed to high work noise levels.

Summary A large prospective epidemiological study of middle-aged men has been in progress in South Wales over the last two decades. Information on medication use has been collected and shows a large increase in the number of men taking garlic preparations over this time. The group of men who take garlic are similar to the non-users in many ways but significant differences include lower levels of smoking, higher levels of alcohol consumption, some better dietary habits and a higher proportion with a history of hypertension.

We have previously reported that plasma fibrin D-dimer (a marker of turnover of cross-linked fibrin) showed a strong and independent association with incident ischaemic heart disease (IHD) in the Caerphilly Study cohort of 1,998 men aged 49-65. To establish the specificity of this finding, we assayed plasma samples from this cohort with a more specific assay for fibrin D-dimer: this showed an association with incident IHD which was at least as strong and independent as that for the original assay (odds ratio, OR for top fifth compared to bottom fifth 3.79; 95% CI 1.77-8.10; p0.0001). To establish potential causes of the increased fibrin turnover, we also assayed several potential markers of coagulation activation or thrombotic tendency (prothrombin fragment F1+2, thrombin-antithrombin complexes, factor VIIc, activated partial thromboplastin time [APTT] and activated protein C resistance): none of these variables were associated with incident IHD in this cohort. We suggest that further studies are required to establish the causes of increased cross-linked fibrin turnover, which is associated with incident IHD in the general population when measured by a specific assay.

Several studies have suggested that men with raised plasma triglycerides (TGs) in combination with adverse levels of other lipids may be at special risk of subsequent ischemic heart disease (IHD). We examined the independent and combined effects of plasma lipids at 10 years of follow-up. We measured fasting TGs, total cholesterol (TC), and high density lipoprotein cholesterol (HDLC) in 4362 men (aged 45 to 63 years) from 2 study populations and reexamined them at intervals during a 10-year follow-up. Major IHD events (death from IHD, clinical myocardial infarction, or ECG-defined myocardial infarction) were recorded. Five hundred thirty-three major IHD events occurred. All 3 lipids were strongly and independently predictive of IHD after 10 years of follow-up. Subjects were then divided into 27 groups (ie, 3 3 ) by the tertiles of TGs, TC, and HDLC. The number of events observed in each group was compared with that predicted by a logistic regression model, which included terms for the 3 lipids (without interactions) and potential confounding variables. The incidence of IHD was 22.6% in the group with the lipid risk factor combination with the highest expected risk (high TGs, high TC, and low HDLC) and 4.7% in the group with the lowest expected risk ( P

Over the past decade, high throughput screening (HTS) has become the focal point for discovery programs within the pharmaceutical industry. The role of this discipline has been and remains the rapid and efficient identification of lead chemical matter within chemical libraries for therapeutics development. Recent advances in molecular and computational biology, i.e., genomic sequencing and bioinformatics, have resulted in the announcement of publication of the first draft of the human genome. While much work remains before a complete and accurate genomic map will be available, there can be no doubt that the number of potential therapeutic intervention points will increase dramatically, thereby increasing the workload of early discovery groups. One current drug discovery paradigm integrates genomics, protein biosciences and HTS in establishing what the authors refer to as the "gene-to-screen" process. Adoption of the "gene-to-screen" paradigm results in a dramatic increase in the efficiency of the process of converting a novel gene coding for a putative enzymatic or receptor function into a robust and pharmacologically relevant high throughput screen. This article details aspects of the identification of lead chemical matter from HTS. Topics discussed include portfolio composition (molecular targets amenable to small molecule drug discovery), screening file content, assay formats and plating densities, and the impact of instrumentation on the ability of HTS to identify lead chemical matter.

Apolipoproteins B, A-I and Lp(a) have been proposed as independent predictors of subsequent ischaemic heart disease (IHD) improving on the prediction obtained by routine lipid measurements. In this report we have investigated the relative predictive ability of apolipoproteins and plasma lipids in a prospective study of middle aged men. 2398 men aged 49-65 years from the general population of Caerphilly, South Wales, UK were screened for evidence of IHD. After an overnight fast 2225 men each provided a venous blood sample on which plasma lipids, apolipoproteins B, A-I, A-II, and lipoprotein (a) (Lp(a)) were measured. Over a follow-up period of nearly 9 years, 282 (12%) men developed major IHD. Multiple logistic regression analysis showed that after adjusting for standard cardiovascular risk factors other than lipids there was a strong trend (standardised relative odds (SRO) = 1.20; P = 0.009) for incidence of IHD to increase with apolipoprotein B. However, on further adjusting for total cholesterol this trend largely disappeared (SRO = 1.05; P = 0.57). Similarly, a trend for incidence of IHD to increase with decreasing apolipoprotein A-I (SRO = 1.18; P = 0.02) disappeared when HDL cholesterol was added to the model. Levels of apolipoprotein A-II were not related to risk of subsequent IHD. Incidence of IHD was effectively constant over nearly 90% of the range of Lp(a). Only among the 5% of men with Lp(a) greater than 70 mg dL-1 was the risk of IHD significantly (P = 0.04) greater than among men with Lp(a) less than 10 mg dL-1. Apolipoproteins B and A-I do not improve on the prediction of risk of IHD provided by total and HDL cholesterol, respectively. Apolipoprotein A-II was not related to risk of IHD. Lp(a) may be independently associated with incident IHD among the 5-10% of men with the highest levels.

Objective: To describe the pattern of polypharmacy (PP) among older men and to relate medication use to personal, social and medical information. Methods: Information on medication use, both prescribed and `over the counter' (OTC), was collected from 1906 men, aged 56–75 years, observed on up to four occasions since 1979 in a community survey – the Caerphilly prospective study. On each visit, a variety of questionnaires regarding personal, social and medical factors were completed, and a brief medical examination was conducted. Medication use was related to some of the questionnaire information and biological measurements collected in order to identify factors associated with PP. Results: A quarter of the men (475/1906) reported using three or more prescription-only medicines (PoMs), with 9% (163) using five or more (major PP). PP was related to increasing age, lower social class, not being in employment, smoking and obesity (high body mass index). Men with a medical history, especially of high blood pressure, angina, heart attack, or hospital admission in the last 5 years, comprised a large proportion of those on major PP. Higher levels of PoM use by this group had been apparent over the previous 14 years. Men on PP reported lower levels of self-rated health and higher rates of non-PoM use. Cardiovascular and, to a lesser extent, central nervous and respiratory system drugs were the main medicines used by men on major PP. Conclusions: PP is common among men aged 56–75 years in Caerphilly, South Wales. It is related to many personal, social and medical factors, and associated with lower self-rated health status and greater use of non-PoMs. Cardiovascular medicines are the main contributor to major PP. Those on PP require regular review and, where possible, PP should be reduced as it has many potential adverse effects.

The relationships of three measurements of the factor VIII/von Willebrand factor (VWF) complex (factor VIII activity, FVIIIc (one-stage assay); VWF antigen, VWF Ag (ELISA); and VWF activity, VWF act, measured by a recently-developed ELISA) to major ischaemic heart disease (IHD) events were studied in 1997 men aged 49-65 years, in the second phase of the Caerphilly Heart Study. These variables were related using logistic regression analysis to myocardial infarction or IHD death, which occurred in 129 men during an average follow-up period of 61 months. All three measurements were highly correlated (r = 0.63-0.77), and each was significantly associated with incident major IHD on univariate analyses (relative odds in highest fifth compared to lowest fifth, 1.68-1.90; P = 0.028-0.006) and on multivariate analyses adjusting for major IHD risk factors and for baseline IHD. Neither FVIIIc nor VWF act was significantly related to incident IHD following adjustment for VWF Ag. We therefore suggest that the associations between these three measurements of the factor VIII/VWF complex and incident IHD might have at least three explanations: VWF Ag is a marker of arterial endothelial disturbance; VWF act promotes platelet adhesion/aggregation and hence the platelet component of arterial thrombosis; and FVIIIc promotes fibrin formation and hence the fibrin component of arterial thrombosis.

Baseline cognitive function was established for a study of pre-symptomatic cognitive decline in 1870 men from the general population aged 55-69 years as part of the third examination of the Caerphilly Study. Cognitive assessment included the AH4, a four choice serial reaction time task, a modified CAMCOG, MMSE, NART and various memory tests. Distributions and relationships with age, social class, education and mood at time of testing are presented for a younger population than has previously been available. Multiple linear regression showed cognitive function to be independently associated with all four factors. The age effect was equivalent to one half of a standard deviation (SD) in CRT and AH4 scores. Only the NART score was not associated with age, supporting the use of NART score as an estimate of pre-morbid IQ. The largest age adjusted differences between men with low and normal mood were for the AH4 (3 points, t = 5.6, p0.0001) and the CAMCOG (2 points, t = 5.8, p0.0001). The smallest age adjusted effect of mood was for the CRT (33 ms, t = 2.14, p = 0.32) and the MMSE (0.4 points, t = 2.97, p = 0.003). Age, mood and education adjusted social class effects were very large ranging between around 0.5 SD for the CRT, and 1.0 SD for the AH4 and NART, respectively. For educational status age, mood and social class adjusted differences were also substantial with tests for trend showing the largest differences for the NART (t = 12, p0.0001) and modified CAMCOG (t = 10.6, p0.0001) with the smallest differences for the CRT (t = 2.73, p = 0.006).

OBJECTIVE—To assess the role of cytomegalovirus (CMV) infection in primary ischaemic heart disease. METHODS—Plasma specimens collected during 1979-83 from men in Caerphilly, south Wales, were analysed for IgG antibodies to CMV by enzyme linked immunosorbent assay and latex tests. Incident ischaemic heart disease events were ascertained after five and 10 years from death certificates, hospital records, and ECG changes; 195 incident ischaemic heart disease cases were compared with 216 controls of a similar age drawn from the rest of the cohort. RESULTS—164 cases (84%) and 180 controls (83%) were seropositive for CMV. Optical density, an indicator of CMV antibody titre, was similar for cases and controls. Among controls, seropositivity was not associated with age, socioeconomic status currently or in childhood, smoking, height, body mass index, blood pressure, total cholesterol, fibrinogen, plasma viscosity, or leucocyte count. The unadjusted odds ratio relating CMV seropositivity to incident ischaemic heart disease was 1.06 (95% confidence interval 0.63 to 1.79) and was little changed (1.11, 0.63 to 1.97) after adjustment for age, smoking, body mass index, systolic blood pressure, total cholesterol, and socioeconomic status currently and in childhood. CONCLUSIONS—CMV infection is unlikely to be a strong risk factor for development of myocardial infarction in middle aged men. Keywords: cytomegalovirus; coronary artery disease; atherosclerosis

Plasma levels of fibrin D-dimer, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI) have been associated with ischaemic heart disease (IHD). However their associations with incident IHD in samples of the general population are not established. D-dimer antigen, tPA antigen and PAI activity were measured in stored, fasting plasma samples from 1,998 men aged 45-65 examined between 1984 and 1988, during the first re-examination of the Caerphilly Study cohort. These variables were related to major IHD events (myocardial infarction or IHD death) which occurred in 129 men during a follow-up period which averaged 61 months. Mean fibrin D-dimer was higher in men who developed IHD events (90 vs. 71 ng/ml; age-adjusted logarithmic mean difference 0.21; 95% CI 0.11, 0.30; p0.0001). This association remained after adjusting for baseline IHD and for other risk factors including fibrinogen: the adjusted relative odds of IHD in the highest fifth of D-dimer were 3.5 (95% CI 1.8, 6.9; p = 0.0003). Mean tPA antigen was also higher in men who developed IHD (12.6 vs. 11.6 ng/ml; mean difference 0.9; 95% CI 0.2, 1.7; p = 0.02); however this difference largely disappeared after adjusting for other risk factors. PAI activity was not associated with risk of IHD.

To use the ten year follow-up of the Caerphilly and Speedwell studies to assess the contributions of fibrinogen and viscosity to the prediction of risk of ischaemic heart disease.Caerphilly and Speedwell are prospective studies based on representative samples of middle-aged males. Ischaemic heart disease morbidity and mortality were defined using hospital notes, repeat electro-cardiographs and death certificates. There were 603 incident events among the 4860 men. Age-adjusted relative odds of ischaemic heart disease increased to 3.3 and 3.4 in the 20% of men with the highest levels of fibrinogen and viscosity, respectively. After standardizing for the major cardiovascular risk factors, these relative odds were 2.2 (95% confidence interval 1.6 to 3.1) for fibrinogen and 2.3 (95% confidence interval 1.7 to 3.2) for viscosity. When fibrinogen and viscosity were entered jointly, both remained significant (P0.01) predictors. Incidence of ischaemic heart disease increased with increasing fibrinogen at every level of viscosity, and vice versa. Interactions with lipids were also examined. There was no support for the suggestion that risk is independent of cholesterol level when fibrinogen is low.Fibrinogen and viscosity are powerful, long term and independent predictors of the risk of ischaemic heart disease.

We investigated whether the consumption of fruit and vegetables lowered cancer mortality in a cohort of 2112 Welsh men ages 45-69 years (The Caerphilly Study), which was followed-up for 13.8 years. At baseline (between 1979 and 1983), participants completed a 56-item food frequency questionnaire from which the consumption of fruit and vegetables was calculated. Relative risks (RR) were estimated with Cox proportional hazard analysis, with death from various types of cancer as a dependent variable, and fruit, vegetables, vitamin C, beta-carotene, dietary fiber, and potential confounders as independent variables. Mean consumption of vegetables and fruit at baseline was 118 g/day and 83 g/day, respectively. During follow-up 114 men died from cancer, including 51 men who died from respiratory tract cancer and 45 men who died from digestive tract cancer. Fruit consumption and the intake of dietary fiber were inversely related to respiratory tract cancer, but after adjustment for potential confounders including age, smoking, and social class, the association with fruit consumption became nonsignificant. Vegetable and fruit consumption was, independently from other risk factors, inversely related to mortality from cancer of the digestive tract (P for trend = 0.021), mainly due to an inverse association with fruit consumption (RR for the highest quartile versus the lowest was 0.3; 95% CI, 0.1-0.8). Vitamin C, beta-carotene, and dietary fiber were not significantly associated with cancers of the digestive tract. Vegetable and fruit consumption was also inversely related to all-cause cancer mortality, and the strongest association was observed for fruit consumption (RR in the highest versus lowest quartile was 0.5; 95% CI, 0.3-1.0). Consumption of vegetables and particularly the consumption of fruit could considerably lower the risk of dying from cancer in middle-aged men.

Objective: To determine the relationships between birthweight, the incidence of coronary heart disease, and arange of coronary heart disease risk factors that operate during adult life. Design: Cohort study with a 10-year follow-up period. Setting: The town of Caerphilly, South Wales, and five adjacent villages. Subjects: 1,258 men aged 45–59 at time of recruitment between 1979 and 1983. Main outcome measures: All deaths, coronary heart disease deaths, non-fatal CHD events. Results: The validity of the birthweight data was supported by the strong graded associations between birthweightand anthropometric measures in adulthood, particularly height, body mass index, triceps skinfold thickness and percentage body fat. An inverse relationship was found between birthweight and incident fatal and non-fatal CHD, ( P =0.01), though no relationship was found between birthweight and all-cause mortality. Amongst the major CHD risk factors, only fibrinogen shows a statistically significant relationship with birthweight ( P =0.008), fibrinogen levels being lower among the men with lower birthweights. When social and biological variables are included in models relating incident CHD and birthweight, the relationship between birthweight and incident fatal and non-fatal CHD remains essentially unchanged. Conclusion: A graded association between low birthweight and later CHD has been demonstrated in this cohort. This inverse association cannot be explained by the measured social or behavioural variables, or by other risk factors operating in adult life.

OBJECTIVES--The goal of this study was to investigate whether the deficit of male births found among the offspring of Danish physiotherapists exposed to shortwave radiation during the first month of their pregnancy could be confirmed among the offspring of physiotherapists from Switzerland. METHODS--A self-administrated questionnaire was mailed (two mailings) to all of the 2846 female members of the Swiss Federation of Physiotherapists. It included questions on the gender and birth-weight of all children of the physiotherapists, as well as on the use of shortwave or microwave equipment during the first month of each pregnancy. The response rate was 79.5%, and the analysis was based on 1781 pregnancies. RESULTS--The gender ratio (the number of males per number of females x 100) was 107 with a 95% confidence interval (95% CI) of 89-127 for the 508 pregnancies exposed to shortwave radiation and 101 (95% CI 90-113) for the 1273 unexposed pregnancies. There was no trend in the gender ratio with increasing intensity or duration of exposure. The prevalence of low birthweight (< or = 2500 g) was not related to exposure to shortwave radiation for either the boys or the girls. CONCLUSIONS--No atypical gender ratio was found for the children of female physiotherapists from Switzerland who had been exposed to shortwave radiation at the beginning of pregnancy. The findings of the Danish study could not be confirmed.

BACKGROUND The relative importance of HDL2 and HDL3 cholesterol as risk factors for ischemic heart disease (IHD) is still uncertain. Their associations with the incidence of IHD in the Caerphilly and Speedwell prospective studies are described. METHODS AND RESULTS The two studies have a common core protocol and are based on a total of 4860 middle-aged men from the general population. The first follow-up was at a nearly constant interval of 5.1 years in Caerphilly and 3.2 years in Speedwell: 251 major IHD events had occurred. Lipid levels were measured on fasting samples. Different laboratories were used by the two studies. Each laboratory used ultracentrifugation to separate HDL2 and HDL3. Both subfractions were inversely associated with risk of IHD. Standardized relative odds of developing major IHD were 0.95 (95% confidence interval [CI], 0.80 to 1.14) for HDL2 cholesterol and 0.83 (95% CI, 0.68 to 1.00) for HDL3 cholesterol in Caerphilly and 0.76 (95% CI, 0.57 to 1.01) for HDL2 and 0.64 (95% CI, 0.49 to 0.83) for HDL3 in Speedwell. The association with incident IHD appeared to be stronger for HDL3 in both areas. No linear combination of the two subfractions was a better predictor of IHD than total HDL cholesterol alone. CONCLUSIONS In British men, both HDL2 and HDL3 cholesterol are inversely associated with the incidence of IHD. However, the prediction of the risk of IHD from total HDL cholesterol alone could not be improved upon by measurement of the two HDL subfractions. The relative value of the two HDL subfractions as predictors of risk is still unresolved. The uncertainty may be due, at least in part, to problems associated with their measurement.

OBJECTIVE--To investigate the predictive value of fasting insulin concentrations for subsequent fatal or non-fatal ischaemic heart disease at five year follow up and to examine the associations between insulin and other indicators of risk. DESIGN--A prospective population study among 2512 men aged 45 to 59 at recruitment. SETTING--A whole population sample of men resident in Caerphilly, South Wales. MEASUREMENTS--At recruitment fasting blood samples were taken for measurement of plasma lipids and serum insulin. Men were re-examined at a five year follow up and ischaemic heart disease events during this period were assessed from hospital notes, death certificates, and electrocardiograms. MAIN RESULTS--Diabetic men and those men with a fasting blood glucose of > or = 8 mmol/l were excluded from all analyses. In a univariate analysis the incidence of ischaemic heart disease increased with increasing concentration of fasting insulin, such that for men in the top 20% of the insulin distribution the odds of developing ischaemic heart disease were 1.87 relative to men in the bottom 20%. On multivariate analysis this relation disappeared on adjusting for plasma triglycerides, body mass index, and evidence of ischaemic heart disease at recruitment. CONCLUSION--In this population in South Wales there was no evidence that the fasting insulin concentration is an independent risk factor for ischaemic heart disease. The univariate association between insulin and incident disease was almost entirely explained by the association of both with triglycerides and body mass index.

Objective—To assess the roles of plasma triglyceride and high density lipoprotein (HDL) cholesterol concentrations in predicting ischaemic heart disease. Design—Two prospective cohort studies with common core protocols. Setting and participants—Both cohorts are 100% samples of middle aged men. In Caerphilly the 2512 men were living within a defined area. In Speedwell the 2348 men were registered with local general practitioners. Main outcome measures—Fasting blood samples were taken at initial examination and plasma lipid concentrations were measured. Major ischaemic heart disease events were assessed from hospital notes, death certificates, and electrocardiograms. Results—At first follow up, after an average of 5·1 years in Caerphilly and 3·2 years in Speedwell, 251 major ischaemic heart disease events had occurred. Men with triglyceride concentrations in the top 20% of the distribution had a relative odds value for ischaemic heart disease of 2·3 (95% confidence interval (95% CI) 1·3 to 4·1) compared with men in the bottom 20%, after adjusting for both plasma total and HDL cholesterol, and non-lipid risk factors. Men in the lowest 20% of the distribution of HDL cholesterol concentration had a relative odds value of 1·7 (95% CI 1·0 to 2·8) compared with the top 20%, after adjustment was made for total cholesterol and triglyceride concentrations, and non-lipid risk factors. These relations were not caused by β blockers, which were being taken by 5% of the men. Conclusions—Plasma triglyceride concentration predicts major ischaemic events after allowance is made for total and HDL cholesterol concentrations and other risk factors. In these populations, triglyceride is a more important predictor than total cholesterol concentration.

Only two studies have specifi-cally tackled the issue of whether large bloodpressure reactions to brief hand immersion incold water are associated with increased risk forcoronary heart disease. In one, the magnitudeof diastolic reactions to the cold pressor testwas reported to be the most significant singlepredictor of 20 year incident coronary heartdisease in a sample of 279 middle aged men.

Objective A long term review of women after hysterectomy with a history of pre-invasive carcinoma of the cervix. Design 193 women had cervical intra-epithelial neoplasia and two had adenocarcinoma in situ either at hysterectomy or at previous cone biopsy. These were followed up by annual cytology. Setting South Glamorgan Health Authority. Subjects Of 195 women who had a hysterectomy, 143 have been followed up cytologically for more than 10 years and 43 for more than 20 years: a total of 2800 women years of experience. Main outcome measures Timing of abnormal smears. Results A detailed reviw of the five women with abnormal smears. The estimated percentage of women who remain negative is 98% at five years, 98.4%, at 10 years and 96.5 % at 20 years. Conclusion Cytological screening ofall women who had a hysterectomy with a history of CIN is indicated for the first two years after hysterectomy. Thereafter the estimated incidence of 0.7 per 1000 women years is higher than the general population but it is not a sufficient reason to screen more frequently. We recommend screening for the carcinoma of the vagina to be every three years which is the same screening frequency as for cervical carcinoma in the general population.

Levels of risk factors for ischaemic heart disease (IHD)were compared in employed men, and in men who were not employed at the time of examination. The men were aged 45-59 years and were participants in the Caerphilly Heart Disease Study. In order to minimize the effet of IHD on employment status, only men who were either free of IHD or had evidence of asymptomatic disease were included in the analysis. Data from 2031 men were available of whom 1712 were employed. Of men who were not in employment, 52% were current cigarette smokers compared with 42% of employed men, and a lower proportion (10%)of men not employed had never smoked (18% 0f employed men), the employed men were 2cm taller but the groups had identical body mass corrected for height (BMI), and only very small differences were found in blood pressure and blood lipids.Differnces in some of the haemostatic factors were large suggesting that "not employed" men may have a higher risk of thrombosis. These differences were not removed by controlling for the effects of social class, age, height and smoking habit.

Ascorbic acid blood levels were estimated in 828 elderly people living in the community. 297 subjects with low blood levels were admitted to a 2-year controlled trial of vitamin C. Despite a rise in plasma and leucocyte levels, vitamin C produced no apparent benefit in terms of mortality, morbidity or mental senescence. On following up all those who were originally seen, it was found that a higher proportion of deaths occurred among subjects whose leucocyte levels were below 15 mug/10(8) cells than among the rest. This association was especially marked in the men; it was not due to smoking and was probably attributable to an effect of ill-health on blood levels, either directly or through impairment of appetite.

The 1916 painters and the 1948 electricians who resided in the Canton of Geneva at the time of the 1970 census were identified and followed up to 1984. During the study period 121 disability pensions were awarded to painters and 59 to electricians. Age standardised incidence of disability per 1000 man-years at risk was higher among painters than among electricians for all neuropsychiatric causes (1.23/1000 and 0.68/1000, respectively) and for all other causes (5.50/1000 and 3.41/1000, respectively). No case of presenile dementia was diagnosed among painters. There was inadequate evidence to indicate that the higher risk of neuropsychiatric disability for painters might have been due to their occupational exposure to organic solvents. A possible toxic effect of these substances on the central nervous system was confounded with alcoholism which was associated with disability from neuropsychiatric disease in 12 of 20 painters and in only one of 10 electricians. Mortality and incidence of cancer were assessed among both cohorts and compared with the expected figures calculated from Geneva rates. Among painters there was a significant increase in overall mortality (O = 254, E = 218.5), in mortality from all cancers (O = 96, E = 75.4), and in incidence from all cancers (O = 159, E = 132.0). For the specific cancer sites, there was a significant excess risk for lung cancer (mortality: O = 40, E = 23.0), which was possibly related to occupational exposure to asbestos and to zinc chromate, although cigarette smoking was not controlled. The significant excesses of biliary tract cancer and of bladder cancer were in accordance with previous observations among painters from other countries. There was also a significant increase in incidence from testicular cancer (O=5, E=1.6), which has not been reported before. For causes of death other than cancer the excesses for alcoholism (O=5, E=0.8). for liver cirrhosis (O=14, E=8.8), for motor vehicle accidents (O=12, E=5.9), and for cerebrovascular disease when allowing for ten years of latency (O=8, E=4.0), were consistent with a probable increased risk of alcohol abuse. Among electricians overall mortality was similar to that expected (O=137, E=139.0). No significant excess risk was found for all cancers or for any specific cancer site. Because of the small number of expected deaths the statistical power was low for the assessment of a possible risk for leukaemia or for brain tumour.

A randomised controlled study was carried out of the effect on growth of the provision of free milk supplements to schoolchildren aged 7 and 8. In selecting children for this study, the aim was to identify those whose socioeconomic circumstances might place them at a disadvantage for growth. Five hundred and eighty-one-children were selected from schools where a high proportion of the pupils received free school meals, and from families with four or more children. The subjects were randomly allocated to receive a third of a pint (190 ml) of free milk daily for six school terms or to a control group. The mean difference in height gain at the end of twenty-one-and-a-half months was 3% or 2.93 mm (P less than 0.05) in favour of the children provided with free milk. The mean difference in weight gain was 130 g (P greater than 0.05) in their favour. The height and weight gain associated with the provision of free mild was very small in the study population, and it is therefore likely that the benefit to growth of providing free milk for the whole unselected population of schoolchildren of these ages would be even smaller.

There is a large excess in prescribing costs by GPs in Wales compared with England. This excess amounts to about 30%, equivalent at present to over pounds 11 m a year. The pattern of drug prescribing by GPs and of patient consultation was studied in random samples of electors in Cardiff and Bristol. Overall, more subjects in Cardiff had received prescriptions, and the average number of scripts for each person was higher than in England in the same period. The pattern for consultations was similar. For both prescriptions and consultations the rates were higher in Wales and the difference from those in England seemed to be greater for women than for men. There was no consistent difference between the two cities in the proportions of those who had consulted who received a script, nor was there any evidence that subjects in Cardiff received more prescriptions without a consultation. In both cities similar proportions of subjects bought drugs from chemists without a prescription.