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Objectives: To study the prospective relationship between serum levels of type II secretory phospholipase A2 (sPLA2) and the risk of future coronary artery disease (CAD) in apparently healthy men and women., Methods and Results: We conducted a prospective nested case-control study among apparently healthy men and women aged 45 to 79 years. Cases (n=1105) were people in whom fatal or nonfatal CAD developed during follow-up. Controls (n=2209) were matched by age, sex, and enrollment time. sPLA2 levels were significantly higher in cases than controls (9.5 ng/mL; interquartile range [IQR], 6.4 to 14.8 versus 8.3 ng/mL; IQR, 5.8 to 12.6; P<0.0001). sPLA2 plasma levels significantly correlated with age, body mass index, systolic blood pressure, high-density lipoprotein (HDL) cholesterol levels, and C-reactive protein (CRP) levels. Taking into account matching for sex and age and adjusting for body mass index, smoking, diabetes, systolic blood pressure, low-density lipoprotein cholesterol, HDL cholesterol, and CRP levels, the risk of future CAD was 1.34 (1.02 to 1.71; P=0.02) for people in the highest sPLA2 quartile, compared with those in the lowest (P for linearity=0.03)., Conclusions: Elevated levels of sPLA2 were associated with an increased risk of future CAD in apparently healthy individuals. The magnitude of the association was similar to that observed between CRP and CAD risk, and both associations were independent.

Background: Plasma fibrinogen may be an independent risk factor for cardiovascular disease. Cigarette smoking is a well-recognized determinant of plasma fibrinogen however it remains unclear how fibrinogen levels relate to the degree and duration of smoking, or to time since smoking cessation., Methods: In a population-based study of 11 059 men and women aged 45-74 years, we examined the cross-sectional relationship between plasma fibrinogen and cigarette smoking habit., Results: Mean fibrinogen concentrations were higher in current smokers compared to non-current smokers (men: 3.13+/-0.77 versus 2.80+/-0.71 g/l, P<0.0001; women: 3.03+/-0.72 versus 2.95+/-0.71 g/l, P=0.01), independent of age, body mass index and hormone replacement therapy in women In men, fibrinogen concentrations declined with years since stopping smoking but remained higher than in life-long non-smokers for 15 years. No relationship between fibrinogen and duration of smoking cessation was observed in women. On multivariate analysis, age, body mass index, use of hormone-replacement therapy, smoking status and pack-years of smoking were independent predictors of plasma fibrinogen., Conclusions: Plasma fibrinogen is strongly associated with cigarette smoking with a dose-response relationship with total pack-years of smoking. In men who stop smoking plasma fibrinogen may remain elevated for several years after cessation.

We typed 247 cases of nasopharyngeal carcinoma (NPC), a disease predominantly of the southern Chinese, and 274 controls from the Chao Shan region of China's Guangdong province for HLA A and B. Besides confirming the established associations with A2, A33, B46 and B58 (positive associations) and A11 (negative association), the results demonstrated a number of rarer alleles with strong negative association with NPC. Our data, combined with those from the previous studies in Southern Chinese, displayed the protective effects for A31 (odds ratio (OR)=0.0; 95% confidence interval (CI)=0-0.11), B13 (OR=0.50; 95% CI=0.35-0.69), B27 (OR=0.49; 95% CI=0.25-0.92), B39 (OR=0.18; 95% CI=0.06-0.48) and B55 (OR=0.32; 95% CI=0.14-0.68), the ORs comparing individuals with or without each allele. Other ethnic groups do not display such large HLA-associated variation in NPC risk. We show that a linked NPC gene with dominant mode of action could not generate such large protective effects. The results provide strong supporting evidence for the existence of a southern Chinese specific, recessive NPC gene closely linked to the HLA region as a major determinant of the Chinese risk for the disease.

Cross-sectional studies investigating the relationship between phytoestrogens in diet, urine, or blood with plasma estradiol and sex hormone binding globulin (SHBG) have been inconclusive. We investigated the relationship among phytoestrogen exposure, polymorphisms in the ESR1, COMT, CYP19, and SHBG genes, and plasma estradiol and SHBG levels in 125 free-living postmenopausal women taking part in a cohort study (European Prospective Investigation of Cancer and Nutrition-Norfolk) using three different markers: dietary, urinary, and serum phytoestrogens. Phytoestrogen levels (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) in spot urine and serum were analyzed by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, respectively. Plasma estradiol and SHBG were measured by immunoassays. Adjusting for age and body mass index, urinary daidzein, genistein, glycitein, and serum daidzein and glycitein were negatively correlated with plasma estradiol (R = -0.199 to -0.277, P <0.03), with particularly strong associations found in the 18 women with CC genotype for ESR1 PvuII polymorphism (R = -0.597 to -0.834, P < 0.03). The negative correlations observed between isoflavones and estradiol in women as a whole became no longer significant when we excluded women with ESR1 PvuII CC genotype, indicating that the correlations observed were due mainly to this group of women. There was no relationship between dietary isoflavones and plasma estradiol and no association was found between any of the dietary, urinary, and serum phytoestrogen and plasma SHBG or between these factors and polymorphisms in CYP19, SHBG, and COMT. We conclude that higher isoflavone exposure is associated with lower plasma estradiol in postmenopausal women and that this preliminary study is suggestive of the involvement of diet-gene interactions.

Introduction: About two-thirds of the excess familial risk associated with breast cancer is still unaccounted for and may be explained by multiple weakly predisposing alleles. A gene thought to be involved in low-level predisposition to the disease is ERBB2 (HER2). This gene is involved in cell division, differentiation, and apoptosis and is frequently amplified in breast tumours. Its amplification correlates with poor prognosis. Moreover, the coding polymorphism I655V has previously been associated with an increased risk of breast cancer., Methods: We aimed to determine if common polymorphisms (frequency >or= 5%) in ERBB2 were associated with breast cancer risk in a white British population. Five single-nucleotide polymorphisms (SNPs) were selected for study: SNP 1 near the promoter, SNP 2 in intron 1, SNP 3 in intron 4, SNP 4 in exon 17 (I655V), and SNP 5 in exon 27 (A1170P). We tested their association with breast cancer in a large case-control study (n = 2192 cases and 2257 controls)., Results: There were no differences in genotype frequencies between cases and controls for any of the SNPs examined. To investigate the possibility that a common polymorphism not included in our study might be involved in breast cancer predisposition, we also constructed multilocus haplotypes. Our set of SNPs generated all existing (n = 6) common haplotypes and no differences were seen in haplotype frequencies between cases and controls (P = 0.44)., Conclusions: In our population, common ERBB2 polymorphisms are not involved in predisposition to breast cancer.

Objective: To investigate the association of red meat and other specific dietary components in predicting the development of inflammatory polyarthritis., Methods: This nested case-control study was conducted within a prospective population-based study of cancer incidence (European Prospective Investigation of Cancer in Norfolk [EPIC-Norfolk]). EPIC-Norfolk recruited 25,630 subjects ages 45-75 years between 1993 and 1997. Dietary intake was assessed at baseline using a 7-day food diary, and the information was analyzed using dietary analysis software. Patients with new cases of inflammatory polyarthritis were identified by linkage with the Norfolk Arthritis Register, a primary care-based inception study of inflammatory polyarthritis, and were matched for age and sex to 2 controls from EPIC-Norfolk. The risk for development of inflammatory polyarthritis was compared between subjects in the highest and lowest tertiles of dietary intake using conditional logistic regression and was expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs)., Results: Between 1993 and 2002, 88 new patients with inflammatory polyarthritis were identified and matched with 176 controls. Among patients, the level of red meat intake was higher (P = 0.04) and that of vitamin C was lower (P = 0.03) compared with intake among controls, but no difference in total energy intake was observed. Patients were more likely to be smokers. After adjusting for total energy intake, smoking, and other possible dietary confounders, subjects with the highest level of consumption of red meat (OR 1.9, 95% CI 0.9-4.0), meat and meat products combined (OR 2.3, 95% CI 1.1-4.9), and total protein (OR 2.9, 95% CI 1.1-7.5) were at an increased risk for inflammatory polyarthritis., Conclusion: A high level of red meat consumption may represent a novel risk factor for inflammatory arthritis or may act as a marker for a group of persons with an increased risk from other lifestyle causes.

Background: The measurement of energy intake in epidemiological studies is difficult. However, it is important that energy intake is assessed if epidemiological analyses are to correspond to isocaloric experiments. The aim of this study was to compare self-reported energy intake, physical activity, and body weight with energy expenditure measured by 4 days of heart rate monitoring with individual calibration of the relationship between heart rate and oxygen consumption., Methods: Volunteer sub-study of 97 men and women (mean ages 54 and 51 years respectively) within the European Investigation into Cancer (EPIC) study in Norfolk (UK). Dietary assessment of energy intake and physical activity was by self-report and weight was measured using standard techniques. Energy expenditure was assessed objectively by recording heart rate for 4 days following a calibration of the relationship between heart rate and oxygen consumption., Results: Self-reported energy intake by 7-day diary (mean 8.5 MJ/day) and food frequency questionnaire (FFQ) (mean 8.8 MJ/day) were significantly lower than objectively measured total energy expenditure (mean 11.2 MJ/day). The deattenuated partial correlations between total energy expenditure were 0.33 (7-day diary), 0.34 (FFQ), 0.50 (physical activity), and 0.56 (weight). Weight accounted for 31% (deattenuated) of the sum of squares about the mean of true energy intake after adjusting for age and sex. With the addition of self-reported physical activity, the model was significantly improved (R2 = 0.57). Adding energy either assessed by the diary or FFQ did not improve the model., Conclusions: The results presented here indicate that to adjust for energy intake, for the purpose of replicating an isocaloric experiment in an observational epidemiological study, one would do considerably better adjusting for weight and physical activity, than adjusting for energy intake estimated from an FFQ.

Multicenter epidemiologic studies provide a unique opportunity to evaluate the association between exposure and disease at the individual and the aggregate levels. The two components can eventually be pooled to corroborate each other, using weights proportional to the intraclass correlation coefficient (ICC), which expresses the amount of between-cohort variability in the exposure variable compared with the total. The greater the ICC, the more the overall estimate will reflect the between-cohort component. Dietary measurements are affected by measurement errors, particularly within a cohort. In 1992-2000, the variability of macronutrient intake distribution before and after calibration for measurement error in the European Prospective Investigation into Cancer and Nutrition was evaluated. A two-level, random-effects model was used. Evaluation of macronutrient densities revealed that energy has a considerable effect on the calibration model, leading to ICC values larger than those for the absolute intakes. Given the shrinkage of the within-center variability, a sizable increase in the ICC was observed for protein in men and women (0.48 and 0.54, respectively) and carbohydrates in men (0.41). Results suggest that the effect of calibration on macronutrient intake variability is greater for the within-cohort component, thus increasing the relative importance of the between-cohort component. After calibration, the two components had a similar weight. This observation has important implications for the analysis of multicenter studies because the between-cohort component provides a large part of the overall heterogeneity.

Levels of plasma DNA concentrations in cancer patients have been shown to be higher than the plasma DNA concentrations found in healthy subjects. The value of plasma DNA levels for development of neoplastic or pulmonary disease was evaluated in a large prospective study. Plasma samples (n = 1,184) were analyzed from 776 controls, 359 cases of cancer (lung, bladder, oral cavity, pharynx, larynx, leukemia) and 49 deaths from chronic obstructive pulmonary disease (COPD), including never smokers and ex-smokers, from 9 countries across Europe. The amount of plasma DNA was variable across the European Prospective Investigation into Cancer and Nutrition (EPIC) centers. High DNA concentrations in some centers might be due to the type of population recruited and/or the treatment of the samples. An elevated and statistically significant odds ratio (OR) was found for COPD deaths (OR = 2.53; 95% CI = 1.06-6.02), while nonsignificant increased ORs were present for oral cancers, cancers of the pharynx and larynx and leukemia. When the analyses were stratified by time since recruitment (below or above 36 months), the increased ORs were limited to the more recent period of recruitment, i.e., a time elapsed between blood drawing and disease onset lower than 36 months. This was particularly true for COPD deaths (OR = 12.7; 95% CI = 1.57-103) and leukemia (OR = 2.37; 95% CI = 1.20-4.67)., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: To determine whether plasma levels of macrophage migration inhibitory factor, a proinflammatory cytokine involved in atherogenesis, are predictive of myocardial infarction or death from coronary artery disease., Methods: We performed a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. We selected men and women who did not report a history of myocardial infarction or stroke at baseline. Baseline concentrations of macrophage migration inhibitory factor were measured among 777 patients who had a myocardial infarction or died of coronary artery disease during follow-up, and 1554 matched controls who remained free of coronary artery disease., Results: Baseline macrophage migration inhibitory factor concentrations were higher in cases than controls (median, 107.4 microg/L vs. 90.7 microg/L, P = 0.001). The risk of myocardial infarction or death from coronary artery disease increased with increasing quartiles of macrophage migration inhibitory factor (P for linearity <0.0001). Patients in the highest quartile had the greatest likelihood of myocardial infarction or death due to coronary artery disease (unadjusted odds ratio [OR] = 1.6; 95% confidence interval [CI]: 1.2 to 2.0). After adjustment for traditional risk factors and C-reactive protein level, the odds ratio decreased slightly (OR = 1.3; 95% CI: 1.0 to 1.7). Upon additional adjustment for white cell count, this association was no longer statistically significant., Conclusion: Prospective data suggest that the relation between macrophage migration inhibitory factor and the risk of myocardial infarction or death due to coronary artery disease in adults without a history of myocardial infarction or stroke is not very strong. However, the data support a regulatory role for macrophage migration inhibitory factor in the process of atherosclerosis., (Copyright 2004 Elsevier Inc.)

Objective: To assess whether starting to smoke in childhood increases the risk of obstructive airways disease (OAD) in adult life., Methods: A retrospective cohort analysis was undertaken of 12 504 current and ex-smokers in the EPIC-Norfolk cohort. The main exposure was starting to smoke during childhood (age <16 years). Three definitions of OAD were used: doctor diagnosed asthma, doctor diagnosed bronchitis/emphysema, and "any OAD" (doctor diagnosed asthma or bronchitis/emphysema, or taking medication used in the treatment of OAD)., Results: Childhood smokers had significantly more pack years of exposure and poorer lung function than subjects who started to smoke in adulthood (>/=16 years). Compared with starting in adulthood, starting to smoke in childhood was associated with a greater risk of bronchitis/emphysema in female smokers (OR 1.79, 95% CI 1.25 to 2.56) and ex-smokers of both sexes (OR 1.29, 95% CI 1.07 to 1.55 in men and OR 1.40, 95% CI 1.05 to 1.85 in women), and of "any OAD" in female smokers (OR 1.72, 95% CI 1.24 to 2.38) and male and female ex-smokers (OR 1.20, 95% CI 1.03 to 1.40 in men and 1.34, 95% CI 1.07 to 1.57 in women). After adjustment for pack years, childhood smoking was associated with poorer lung function (FEV(1) 92.3% predicted in adult smokers and 89.5% in childhood smokers, p = 0.03) and a greater risk of bronchitis/emphysema (adjusted OR 1.55, 95% CI 1.08 to 2.24) and for "any OAD" (OR 1.54, 95% CI 1.10 to 2.13) in female smokers but not in male and female ex-smokers., Conclusion: Starting to smoke in childhood is associated with an increased risk of airways disease because of the extra pack years smoked. In women, childhood smoking is itself an independent risk factor for the development of airways disease.

Objective: To study the role of IL-8 in predicting future coronary artery disease (CAD) in apparently healthy men and women., Methods and Results: A nested case-control study was performed in the prospective EPIC-Norfolk population study. We measured baseline IL-8 concentrations among 785 apparently healthy individuals in whom fatal or nonfatal CAD developed during follow-up and 1570 matched controls. Baseline IL-8 concentrations were higher in cases than in matched controls (3.5 pg/mL versus 3.1 pg/mL, P=0.001). The risk of future CAD increased with increasing quartiles of IL-8 (P linearity <0.0001). Among individuals in the highest IL-8 quartile, the unadjusted odds ratio for future CAD was 1.72 (95% CI, 1.34 to 2.21; P<0.0001). The odds ratio for future CAD was still significant after adjustment for traditional risk factors (OR, 1.58; 95%CI, 1.19 to 2.09; P=0.002) and after additional adjustment for C-reactive protein and white cell count (OR, 1.77; 95% CI, 1.21 to 2.60; P=0.001)., Conclusions: We conclude that among apparently healthy men and women, elevated levels of IL-8 are associated with an increased risk of future CAD. These prospective data support a role for IL-8 in the development of CAD events.

Self-reported diet is prone to measurement error. Analytical models of diet may include several foods or nutrients to avoid confounding. Such multivariate models of diet may be affected by errors correlated among the dietary covariates, which may introduce bias of unpredictable direction and magnitude. The authors used 1993-1998 data from the European Prospective Investigation into Cancer and Nutrition in Norfolk, United Kingdom, to explore univariate and multivariate regression models relating nutrient intake estimated from a 7-day diet record or a food frequency questionnaire to plasma levels of vitamin C. The purpose was to provide an empirical examination of the effect of two different multivariate error structures in the assessment of dietary intake on multivariate regression models, in a situation where the underlying relation between the independent and dependent variables is approximately known. Emphasis was put on the control for confounding and the effect of different methods of controlling for estimated energy intake. The results for standard multivariate regression models were consistent with considerable correlated error, introducing spurious associations between some nutrients and the dependent variable and leading to instability of the parameter estimates if energy was included in the model. Energy adjustment using regression residuals or energy density models led to improved parameter stability., (Copyright 2004 Johns Hopkins Bloomberg School of Public Health)

Introduction: Large trials have shown that angiotensin converting enzyme inhibitor (ACE-I) therapy reduces the risk of myocardial infarction and stroke. Acute vascular events are thought to be initiated by plaque rupture. Animal models of atherosclerosis show an increase in extra cellular matrix when given ACE-I therapy. ACE-I therapy could influence collagen synthesis, one of the major constituents of the atherosclerotic cap., Methods: A nested case-control study was performed within the Huntingdon Aneurysm Screening Project. Subjects were assessed for arterial disease, drug history and smoking. Blood samples were taken for a measure of collagen synthesis, the amino-terminal propeptide of type III procollagen (PIIINP), lipid levels, iron metabolism and cotinine levels., Results: Information was available for 420 subjects. Thirty-five were taking ACE-I therapy and 385 were not. Mean serum PIIINP level was 3.5 microg/l (sd 1.3 microg/l, range: 1.7-16.5 microg/l. There was a marked increase in mean collagen turnover between subjects taking ACE-I therapy compared to those not. Mean PIIINP level for cases and controls was 4.26 microg/l (95% CI: 3.73-4.79 microg/l) versus 3.61 microg/l (95% CI: 3.48-3.75 microg/l). No differences were found for patients taking other antihypertensive drugs. After adjusting for age, weight, height, lipid levels and ferritin, PIIINP levels remained significantly higher in cases than controls: 4.14 microg/l (95% CI: 3.72-4.57 microg/l) versus 3.62 microg/l (95% CI: 3.49-3.75 microg/l) (P-value 0.02)., Discussion: These results suggest that ACE-I therapy up-regulates collagen synthesis, and could improve plaque stabilisation. This may provide an explanation for the decrease in acute vascular events observed in patients on ACE-I therapy.

Data suggest that soy protein, a source of isoflavones, may have favorable effects on cardiovascular risk factors. Women (n = 205), ages 49-65 y, were randomized into this double blind, placebo-controlled trial of 43.5 mg red clover-derived isoflavones/d. A total of 177 women completed the trial. There were no differences between treatments for changes from baseline to 12 mo in total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol, systolic and diastolic blood pressures, fibrinogen, and plasminogen activator inhibitor type 1 (PAI-1) (P >/= 0.1). Interactions between treatment and menopausal status were significant for changes in triglycerides and PAI-1 (P = 0.02 and P = 0.01), and changes were significant among perimenopausal women. In the isoflavone and placebo groups, changes in triglycerides were -0.2 +/- 0.6 and 0.4 +/- 0.6 mmol/L, P = 0.02, and changes in PAI-1 were -3.06 +/- 5.88 and 4.95 +/- 6.25 IU/L, P = 0.004, respectively. Interactions between apolipoprotein E (apoE) genotype and treatment tended to be significant for changes in total and LDL cholesterol (P = 0.06 and P = 0.05), and differences between treatments were significant in E2/E3 women. In the isoflavone and placebo groups, changes in total cholesterol were -0.61 +/- 0.79 and 0.18 +/- 0.79 mmol/L, P = 0.03, and changes in LDL cholesterol were -0.84 +/- 0.79 and -0.04 +/- 0.69 mmol/L, P = 0.02, respectively. Although there were potentially beneficial changes in triglycerides and PAI-1 among perimenopausal women consuming isoflavones, this study suggests that isoflavones alone are not responsible for the well-documented effects of soy protein on blood lipids. A larger study is required to confirm the effect modification by apoE genotype.

Background: Reports suggest a relationship between circulating sex hormone levels and breast cancer risk, but genetic association studies have been inconclusive. We investigated the association between levels of sex hormones and single nucleotide polymorphisms (SNPs) in genes coding for the enzymes that regulate them., Methods: We assayed circulating levels of estradiol, testosterone, estrone, androstenedione, 17alpha-hydroxyprogesterone, and sex hormone-binding globulin (SHBG) in 1975 normal postmenopausal women. Fifteen SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were genotyped in these postmenopausal women and in a breast cancer case-control study. Associations of genotypes with breast cancer risk were evaluated in the case-control study and with hormone levels in the postmenopausal women using multiple linear regression with assay batch, body mass index, parity, peri- or postmenopausal status, and age band as covariates., Results: CYP19 SNPs (rs10046 and [TCT]+/-) were associated with differences in estradiol level (P =.0006 and P =.0003, respectively) and the estradiol : testosterone ratio (P =.000001() and P =.002). SNP rs10046 explained 1.6% of the variance (r2) in the estradiol : testosterone ratio. SHBG SNPs (5' untranslated region [5'UTR] g-a and D356N) were associated with both SHBG levels (P<10(-6) and P =.005) and the estradiol : SHBG ratio (P =().000008() and P =.01). These SNPs explained 2.4% and 0.6% of the variance in SHBG levels, respectively. SNPs in the other genes were not associated with differences in any hormone levels, and none were statistically significantly associated with breast cancer risk., Conclusion: Genetic variation in CYP19 and SHBG contributes to variance in circulating hormone levels between postmenopausal women, but low r2 values may explain why these genes have given inconclusive results in breast cancer case-control studies.

Background: Microalbuminuria is independently associated with increased cardiovascular risk and renal function deterioration in diabetes and hypertension, but the clinical relevance of raised albuminuria in the general population is less certain. We examined the prevalence of microalbuminuria and its relationship to cardiovascular risk factors and cardiovascular morbidity in the UK general population., Methods: Cross-sectional population-based study of 23,964 individuals, aged 40-79 years recruited in 1993-1997 for the EPIC-Norfolk Study. Smoking status, prevalent physician diagnosed diabetes, hypertension, cardiovascular disease and cancer were derived from a health and lifestyle questionnaire. Albumin-to-creatinine ratios were estimated from random spot urine specimens collected at the survey visit, and using these ratios participants were categorized into normoalbuminuria, microalbuminuria (2.5-25 mg/mmol), and macroalbuminuria., Results: The prevalence of microalbuminuria and macroalbuminuria was 11.8% and 0.9% respectively in the total population and significantly higher in women (14.4%) compared with men (8.9%) (P<0.001). Independent determinants of microalbuminuria were age, sex, systolic blood pressure and current smoking. Microalbuminuria was independently associated with cardiovascular morbidity, after adjusting for known cardiovascular risk factors, with odds ratio (95% confidence interval) for prevalent cardiovascular disease of 1.30 (1.12-1.51) in all men and women., Conclusion: Microalbuminuria was present in approximately 12% of this population. It was independently associated with cardiovascular risk factors and prevalent cardiovascular disease. Microalbuminuria may be a useful indicator of high absolute cardiovascular risk in the community but prospective data are needed to establish its independent predictive value for future events.

Subjects of this study consisted of 333 women (aged 45-75 years) drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer and Nutrition-Norfolk study. Using newly developed gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry methods incorporating triply (13)C-labeled standards, seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in 114 spot urines and 97 available serum samples from women who later developed breast cancer. Results were compared with those from 219 urines and 187 serum samples from healthy controls matched by age and date of recruitment. Dietary levels were low, but even so, mean serum levels of phytoestrogens were up to 600 times greater than postmenopausal estradiol levels. Phytoestrogen concentrations in spot urine (adjusted for urinary creatinine) correlated strongly with that in serum, with Pearson correlation coefficients > 0.8. There were significant relationships (P < 0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes. Urinary enterodiol and enterolactone and serum enterolactone were significantly correlated with dietary fiber intake (r = 0.13-0.29). Exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, odds ratios increased by 20-45% [log(2) odds ratio = 1.34 (1.06-1.70; P = 0.013) for urine equol, 1.46 (1.05-2.02; P = 0.024) for serum equol, and 1.22 (1.01-1.48; P = 0.044) for serum daidzein]. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies.

The design of studies aimed at identifying the interaction between genetic and environmental determinants in disease risk is attracting increased attention. In this paper, we study the effect of errors on measuring exposures and the effect of assessing genotype at one locus on the association of a continuous outcome measure with continuous exposures and genotype. The estimation of misclassification errors in assessing genotypes from a separate study is proposed. If the exposure measurement error is substantial, then even relatively small errors in genotyping within limits that are often quoted can have an appreciable effect on interaction estimates. We, thus, consider a method for correcting the measurement errors when the interaction between the exposures and the genetic factor is significant. Finally, we present an epidemiological example to demonstrate the importance of correcting measurement errors., (Copyright 2004 John Wiley & Sons, Ltd.)

Background: It has been suggested that hyperhomocysteinemia (HHcy) is an independent risk factor for peripheral arterial occlusive disease (PAOD). However, the relationship between dietary folate and vitamin B6, cofactors in the metabolism of homocysteine (Hcy), and PAOD is unclear., Aims: To study the relationship between dietary folate and B6 and PAOD., Methods: Case-control population based study of 392 men older than 50 years living in Huntingdon, United Kingdom. PAOD, defined as an ankle-brachial pressure index (ABPI) < 0.9, was present in 86 (22%) of subjects. Folate, vitamin B6, and vitamin B12 intakes were calculated by means of the EPIC (European Prospective Investigation into Cancer) food frequency questionnaire., Results: Daily folate intake was significantly lower in case subjects (mean, 288; 95% confidence interval [CI], 266-309 microg) than in control subjects (324; 95% CI, 313-335 microg). Daily vitamin B6 intake was also lower in case subjects (2.05; 95% CI, 1.92-2.19 mg versus 2.26; 95% CI, 2.19-2.33 mg). Daily folate and vitamin B6 intakes were independent predictors of PAOD after adjusting for age, blood pressure, cholesterol levels, diabetes, and smoking status in a logistic regression model. This model suggests that increasing daily folate intake by 1 standard deviation decreased the risk of PAOD by 46%. A similar increase in daily vitamin B6 intake decreased the risk of PAOD by 29%., Conclusion: In men older than 50 years, dietary folate and B6 intakes are independent predictors of PAOD. Longitudinal studies are required to determine whether dietary modification can reduce the incidence of PAOD in the population.

Microalbuminuria is associated with an increased risk of cardiovascular and renal disease in patients with diabetes and hypertension. The role of microalbuminuria as a predictor of coronary heart disease (CHD) has not been examined in large general-population cohorts, and its prognostic significance in persons with established CHD is uncertain. The authors examined the relation between microalbuminuria and incident CHD (1993-2002) in a population-based British cohort of 22,368 men and women aged 40-79 years without prevalent baseline CHD and evaluated its prognostic significance in 1,596 participants with baseline CHD. Participants were members of the Norfolk, United Kingdom, component of the European Prospective Investigation into Cancer and Nutrition (the EPIC-Norfolk Study). At baseline, participants were categorized into normoalbuminuria, microalbuminuria, and macroalbuminuria groups. During an average of 6.4 years of follow-up, 800 primary CHD events were registered. The age-adjusted incidence of CHD increased significantly across ordered categories of albuminuria (4.3, 4.4, and 5.6/1,000 person-years across tertiles of normoalbuminuria, 7.1/1,000 person-years for microalbuminuria, and 12.2/1,000 person-years for macroalbuminuria; p for trend < 0.001). The multivariate hazard ratio for incident primary CHD was 1.36 (95% confidence interval (CI): 1.12, 1.64) for microalbuminuria and 1.59 (95% CI: 1.10, 2.37) for macroalbuminuria. Among participants with established baseline CHD, the independent risk of all-cause mortality associated with microalbuminuria was 1.61 (95% CI: 1.19, 2.07). Microalbuminuria may be useful in identifying persons at increased risk of CHD and subsequent death in the general population.

The objective of this study was to assess the effect of age, breast size and use of hormone replacement therapy (HRT) on the rate of change of mammographic parenchymal patterns, and the effect of age on the probability of misclassification between patterns. It was designed as a longitudinal study of the members of the treatment arm of a non-randomized screening trial in which subjects were assigned to screening or not by year of birth. The subjects were women in the Kotka district of Finland, each of whom attended for four or five mammographic screens. Participants were all women living in the district who were born in the relevant years and accepted an invitation to screening. A model was fitted to the longitudinal data comprising the observed Wolfe patterns on each woman, with age and breast size as predictors of breast density at first screen, age and HRT use as predictors of change in density at future screens, and age as a predictor of misclassification of true density between favourable (non-dense) and unfavourable (dense) patterns (according to the Wolfe classification). Relevant posterior probability estimates (with 95% credible intervals) were as follows. The probability that a woman of age 43.5 is truly in the favourable state ranged from 0.35 (0.34-0.37) for smallest breast size to 0.74 (0.72-0.76) for the largest. The probability that a woman is truly in the favourable state at first screen increased from 0.37 (0.36-0.38) at age 40 to 0.59 (0.58-0.60) at age 47. The probability that a woman having a later screen who had truly been in the unfavourable state at her previous screen changed to the favourable state increased from 0.12 (0.11-0.13) at age 42 to 0.48 (0.46-0.50) at age 55 for a woman not taking HRT, and from 0.10 (0.09-0.11) to 0.43 (0.40-0.45) at the same ages for a woman taking HRT. The probability that a woman would have changed from being truly in the favourable state to the unfavourable state was 0.003 (0.001-0.003) for any age and HRT use. The probability that a woman truly in a favourable state would be correctly classified rose from 0.87 (0.85-0.89) at age 40 to 0.998 (0.997-0.998) at age 55. The probability that a woman truly in the unfavourable state would be correctly classified decreased from 0.96 (0.95-0.97) to 0.93 (0.91-0.94) between the same ages. The probability of being in a non-dense, favourable state increases with age, as does the rate of change from dense to non-dense patterns. These are consistent with previous work. The probability of non-dense patterns and the rate of change to non-dense patterns are reduced with HRT use. Errors of classification are relatively rare, but are dependent on the age of the subject.

Background: In patients with diabetes or hypertension, raised albuminuria is independently associated with an increased risk of all mortality, cardiovascular morbidity and mortality, and renal insufficiency. The role of albuminuria in the general population is still controversial. We therefore undertook this study to examine the relationship between albuminuria and all-cause, cardiovascular disease (CVD) and non-CVD mortality in the general population., Methods: Prospective population-based cohort study of 20 911 individuals aged 40-79 years recruited in 1993-1997 for the EPIC-Norfolk Study (UK) and followed-up for an average of 6.3 years. Random spot urine specimens were collected at baseline and the albumin-to-creatinine ratio measured. Participants were categorized into normoalbuminuria, microalbuminuria, and macroalbuminuria ordered groups. At follow-up, vital status and cause of death were obtained from the UK Office for National Statistics., Results: During follow-up, 934 deaths were registered. Age-adjusted all-cause mortality rate increased significantly across categories of baseline albuminuria (5.3, 5.2, and 6.3/1000 person years (pyrs) across tertiles of normoalbuminuria, 8.7/1000 pyrs for microalbuminuria, and 18.4/1000 pyrs for macroalbuminuria, P < 0.001 for trend); CVD, 1.6, 1.7, 2.1, 4.3, 12.6/1000 pyrs (P < 0.001); and non-CVD, 3.7, 3.5, 4.2, 4.4, 5.8/1000 pyrs (P = 0.052) respectively. The multivariate hazard ratio for all-cause mortality associated with microalbuminuria was 1.48 (95% CI: 1.20, 1.79), and CVD 2.03 (95% CI: 1.55, 2.67). The association with non-CVD mortality was only significant in men., Conclusions: The significant increased risk of all-cause mortality especially from CVD associated with microalbuminuria, suggest that this may be a useful indicator in identifying those in the population at greatest absolute risk of fatal CVD events alongside conventional CVD risk factors.

Objectives: To examine the relationship between microalbuminuria and incident stroke in the general population., Design: Population-based prospective cohort study., Setting: Participants were recruited in a primary care setting from 35 participating general practice units in Norfolk, UK., Subjects and Main Outcome Measures: The study population consisted of 23,630 individuals aged 40-79 years recruited between 1993 and 1997 for the EPIC-Norfolk Study and followed up for an average of 7.2 years. Random spot urine specimens were collected at baseline and albumin-to-creatinine ratio measured. Participants were categorized into normoalbuminuria, microalbuminuria and macroalbuminuria groups. During follow-up, the main end point was stroke incidence (fatal and nonfatal), ascertained from the UK Office for National Statistics and from the National Health Service Health District database of all hospital admissions., Results: A total of 246 stroke events occurred during follow-up [crude incidence rate of stroke, 1.5 per 1000 person years (pyrs)]. The age-adjusted incidence of stroke increased significantly across categories of baseline albuminuria (0.9, 1.1 and 1.4/1000 pyrs for tertiles of normoalbuminuria, 2.6/1000 pyrs for microalbuminuria, and 6/1000 pyrs for macroalbuminuria in the total population, P < 0.001 for trend). In all women and men, the multivariate hazard ratio [95% confidence interval (CI)] for stroke associated with microalbuminuria was 1.49 (1.13-2.14) and macroalbuminuria 2.43 (1.11-6.26). After stratifying by stroke subtype, microalbuminuria was only independently predictive of ischaemic stroke, with hazard ratio (95% CI) of 2.01 (1.29-3.31)., Conclusion: Microalbuminuria is independently associated with approximately 50% increased risk of stroke in the general population. Microalbuminuria may be useful in identifying those at increased risk of stroke in the general population.

Objective: To investigate the association between habitual fish consumption and a continuous measure of glycaemia., Design: Cross-sectional study., Setting: EPIC-Norfolk, a population-based cohort study of diet and chronic disease., Subjects and Methods: In all, 4500 men and 5509 women, aged 40-78 y, without self-reported diabetes. Diet was assessed by a semiquantitative food frequency questionnaire, and glycaemia was measured by glycated haemoglobin., Results: In women only, in analyses adjusted for age, the HbA(1c) level was positively associated with eating fried fish and inversely associated with eating oily fish (b=0.036, 95% confidence interval (CI): 0.0033, 0.069; and b=-0.046, 95% CI:-0.086, -0.0064 respectively). These associations were attenuated by adjustment for family history of diabetes, smoking status and physical activity level, but the association with fried fish remained statistically significant (b=0.033, 95% CI: 0.00056, 0.066). Adjusting for total energy, alcohol, fruit and vegetable intakes resulted in further attenuation and both associations were no longer statistically significant. In men, there was no evidence that HbA(1c) level was associated with fish consumption., Conclusions: The study found no evidence of an association between fish consumption and HbA(1c) after taking other lifestyle factors into account.

Background: Isoflavone phytoestrogen therapy has been proposed as a natural alternative to hormone replacement therapy (HRT). HRT has a beneficial effect on bone, but few trials in humans have investigated the effects of isoflavones on bone., Objective: The objective of the study was to determine the effect on bone density of a red clover-derived isoflavone supplement that provided a daily dose of 26 mg biochanin A, 16 mg formononetin, 1 mg genistein, and 0.5 mg daidzein for 1 y. Effects on biochemical markers of bone turnover and body composition were also studied., Design: Women aged 49-65 y (n = 205) were enrolled in a double-blind, randomized, placebo-controlled trial; 177 completed the trial. Bone density, body composition, bone turnover markers, and diet were measured at baseline and after 12 mo., Results: Loss of lumbar spine bone mineral content and bone mineral density was significantly (P = 0.04 and P = 0.03, respectively) lower in the women taking the isoflavone supplement than in those taking the placebo. There were no significant treatment effects on hip bone mineral content or bone mineral density, markers of bone resorption, or body composition, but bone formation markers were significantly increased (P = 0.04 and P = 0.01 for bone-specific alkaline phosphatase and N-propeptide of collagen type I, respectively) in the intervention group compared with placebo in postmenopausal women. Interactions between treatment group and menopausal status with respect to changes in other outcomes were not significant., Conclusion: These data suggest that, through attenuation of bone loss, isoflavones have a potentially protective effect on the lumbar spine in women.

Intake of fruits and vegetables is thought to protect against the development of lung cancer. However, some recent cohort and case-control studies have shown no protective effect. We have assessed the relation between fruit and vegetable intake and lung cancer incidence in the large prospective investigation on diet and cancer, the European Prospective Investigation Into Cancer and Nutrition (EPIC). We studied data from 478,021 individuals that took part in the EPIC study, who were recruited from 10 European countries and who completed a dietary questionnaire during 1992-1998. Follow-up was to December 1998 or 1999, but for some centres with active follow-up to June 2002. During follow-up, 1,074 participants were reported to have developed lung cancer, of whom 860 were eligible for our analysis. We used the Cox proportional hazard model to determine the effect of fruit and vegetable intake on the incidence of lung cancer. We paid particular attention to adjustment for smoking. Relative risk estimates were obtained using fruit and vegetable intake categorised by sex-specific, cohort-wide quintiles. After adjustment for age, smoking, height, weight and gender, there was a significant inverse association between fruit consumption and lung cancer risk: the hazard ratio for the highest quintile of consumption relative to the lowest being 0.60 (95% Confidence Interval 0.46-0.78), p for trend 0.0099. The association was strongest in the Northern Europe centres, and among current smokers at baseline, and was strengthened when the 293 lung cancers diagnosed in the first 2 years of follow-up were excluded from the analysis. There was no association between vegetable consumption or vegetable subtypes and lung cancer risk. The findings from this analysis can be regarded as re-enforcing recommendations with regard to enhanced fruit consumption for populations. However, the effect is likely to be small compared to smoking cessation., (Copyright 2003 Wiley-Liss, Inc.)

Introduction: Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were also assessed., Methods: A total of 205 women (age range 49-65 years) with Wolfe P2 or DY mammographic breast patterns were randomly assigned to receive either a red clover-derived isoflavone tablet (26 mg biochanin A, 16 mg formononetin, 1 mg genistein and 0.5 mg daidzein) or placebo. Change in mammographic breast density, serum oestradiol, FSH, LH, menopausal symptoms and lymphocyte tyrosine kinase activity from baseline to 12 months were assessed., Results: A total of 177 women completed the trial. Mammographic breast density decreased in both groups but the difference between the treatment and placebo was not statistically significant. There was a significant interaction between treatment group and oestrogen receptor (ESR1) PvuII polymorphism for the change in estimated percentage breast density (mean +/- standard deviation): TT isoflavone 1.4 +/- 12.3% and TT placebo -9.6 +/- 14.2%; CT isoflavone -5.2 +/- 12.0% and CT placebo -2.8 +/- 10.3%; and CC isoflavone -3.4 +/- 9.7% and CC placebo -1.1 +/- 9.5%. There were no statistically significant treatment effects on oestradiol, FSH, or LH (assessed only in postmenopausal women), or on lymphocyte tyrosine kinase activity. Baseline levels of menopausal symptoms were low, and there were no statistically significant treatment effects on frequency of hot flushes or other menopausal symptoms., Conclusion: In contrast to studies showing that conventional hormone replacement therapies increase mammographic breast density, the isoflavone supplement did not increase mammographic breast density in this population of women. Furthermore, there were no effects on oestradiol, gonadotrophins, lymphocyte tyrosine kinase activity, or menopausal symptoms.

Objective: To examine the relationship between serum lipids and abdominal aortic aneurysms (AAA)., Methods: Two hundred and six males (>50 years) with AAA (> or =30 mm) detected in a population based screening programme were compared with 252 age-matched male controls in a nested case-control study. Smoking status, previous medical and family histories, height, weight, blood pressure, ankle brachial pressure index (ABPI) and non-fasting lipid profile were recorded., Results: Cases were found to have significantly higher LDL cholesterol than controls. LDL cholesterol was an independent predictor of the risk for aneurysms in a logistic regression model adjusting for smoking status, family history of AAA, history of ischaemic heart disease, presence of peripheral vascular disease, use of lipid lowering medication and treatment for hypertension. There was a linear effect with increased levels of LDL cholesterol increasing the risk of having a small aneurysm (test for trend p=0.03)., Conclusion: The highly significant association between LDL cholesterol and small aneurysms suggests that LDL, possibly acting via inflammatory mediated matrix degeneration, could be an initiating factor in the development of AAA. The ability of statin therapy to prevent AAA formation requires further investigation.

We hypothesized that measures of physical activity would have a closer relationship with section modulus (SM), an indicator of bending resistance, than with bone mineral density (BMD) because physical activity might expand the bony envelope, which tends to reduce BMD for a constant bone mineral content. Four hundred twenty-three men and 436 women (mean age 72 years, SD =3) were recruited from a prospective population-based cohort study to a study of hip bone loss. Hip BMD was measured on two occasions 2-5 years apart (mean 2.7, DXA-Hologic 1,000 W). Hip structural analysis (HSA) software was used to calculate SM and BMD from the DXA scans on three narrow regions: the narrow neck (NN), intertrochanter (IT) and shaft (S). A physical activity and lifestyle questionnaire was administered at baseline. Multivariate repeated measures analysis of variance was used to model the associations between personal attributes (weight, height, age), physical activity and lifestyle variables with SM, cross-sectional area (CSA), sub-periosteal diameter (PD) and BMD. Men and women were analysed together after tests for interactions with gender, which were found not to be significant. In all regions female gender was associated with having lower values of all outcomes, and body weight was positively associated with all outcomes, i.e., SM, CSA, PD and BMD ( P<0.0001). Sub-periosteal diameter was positively associated with reported lifetime physical activity (IT and S, P<0.0001). There was a significant decline of BMD with age at the NN and S regions ( P<0.026), and the PD increased with age (NN and S, P<0.019). Previous fracture history was associated with having lower values of BMD, SM and CSA (except for S; P<0.022). Both section modulus and CSA were positively associated with heavy physical activity after age 50 years in all regions ( P<0.019), whereas NN BMD was the only BMD associate of heavy physical activity after 50 ( P=0.036). Time spent per week on recreational activities classified as no impact activity was positively associated with BMD, CSA and SM (multivariate P<0.016). In conclusion, proximal femur diameter is associated positively with reported life-long physical activity. If this is mediated through a loading related effect on sub-periosteal expansion, BMD would be an unsatisfactory outcome measure in physical activity studies since it is inversely related to projected bone area. SM in contrast was associated with several measures of recent physical activity and relates more directly to the bending experienced by the proximal femur in response to a given load. These data are consistent with an effect of mechanical loading to regulate bone strength through an anabolic effect maximal in the subperiosteal cortex, where the highest loading-related strains are experienced.

The focus of this study was to determine the functional capacity of class II transactivator (CIITA), a regulatory factor of major histocompatibility complex (MHC) class II genes, in K-562 cells. We show that CIITA mRNA is present in K-562 cells and the interferon-gamma (IFN-gamma)-inducible CIITA promoter-IV exhibits low levels of basal activity, which is greatly enhanced upon treatment with IFN-gamma. Further study revealed that the CIITA cDNA contains an insertion of genomic sequence, which introduces a stop codon. The truncated coding region of the CIITA transcript in K-562 cells provides a possible explanation for the absence of MHC class II molecules.

Background: Understanding of the impact of depressive and anxiety disorders on functional health status in the context of chronic medical illness has been gained almost exclusively from the study of patient populations., Aims: To compare the impact of major depressive and generalised anxiety disorder with that of chronic medical conditions on functional health in a UK resident population., Method: The functional health of 20,921 study participants was assessed using the Medical Outcomes Study Short Form 36 questionnaire. Depressive and anxiety disorder episode histories and chronic medical conditions were assessed using independent self-completed questionnaires., Results: The degree of physical functional impairment associated with mood disorders was of equivalent magnitude to that associated with the presence of chronic medical conditions or with being some 12 years older., Conclusions: Depressive and anxiety disorders have a profound impact on functional health that is independent of chronic medical illness. Chronic anxiety is associated with physical health limitations in excess of those associated with chronic depression or any of the physical health conditions considered, except for stroke.

Objective: This study describes the associations between sedentary behaviour (television viewing) and participation in vigorous recreational activity with obesity and with biomarkers of cardiovascular disease (CVD) risk profile., Design: Cross-sectional analysis of the EPIC-Norfolk cohort study., Setting: The study is a population-based study of participants living in Norfolk, UK., Subjects: A total of 15 515 men and women aged between 45 and 74 y, recruited through General Practice lists, who completed the detailed physical activity questionnaire., Results: Following exclusion of those with self-reported myocardial infarction, stroke and diabetes, 14 189 participants remained for the analysis. Self-reported television viewing was positively and participation in vigorous activity negatively associated with markers of obesity, blood pressure and plasma lipids. In multiple regression analysis, adjusting for age, alcohol, smoking, treatment for hypertension, vigorous and total physical activity, these associations remained significant. For women who participated in more than 1 h/week of vigorous activity and who watched fewer than 2 h of television each day, the adjusted mean body mass index was 1.92 kg/m(2) less than for women who reported participating in no vigorous activity and who watched more than 4 h of television each day (P<0.001). The equivalent figure for men was 1.44 kg/m(2) (P<0.001). In a similar analysis, with blood pressure as the outcome, mean diastolic blood pressure difference between the extreme groups of vigorous activity and television viewing was 3.6 mmHg in men (P<0.001) and 2.7 mmHg (P=0.001) in women., Conclusions: These data suggest that time spent participating in vigorous recreational physical activity and television viewing, an indicator of a sedentary lifestyle, are associated with obesity and markers of CVD disease risk independent of total reported physical activity. Whether these observations represent the true underlying aetiological relations or are a manifestation of the different precision with which the subdimensions of activity are measured remains uncertain.

The total white blood cell (WBC) count is reported to be an independent predictor of mortality in several prospective studies. We investigated the association between total and differential WBC counts and cigarette smoking habit in a cross-sectional population-based study of 6902 men and 8405 women 39-79 years of age participating between July 1994 and 1997 in the European Prospective Investigation of Cancer (EPIC-Norfolk) study. Main outcome measures included WBC, granulocyte, lymphocyte and monocyte counts measured at a baseline health check and self-reported cigarette smoking habit. The age- and body mass index-adjusted mean total WBC counts were 7.8, 6.4, and 6.2x10(3) per ul (P<0.0001) among male current, former and never smokers, respectively, and 7.4, 6.3 and 6.2x10(3) per ul (P<0.0001), respectively, in women. The greatest absolute and percentage differences between smoking groups were observed for the granulocyte count. Current smoking habit had a stronger effect on mean total WBC counts than cumulative exposure as measured by pack years. Among former smokers mean age- and body mass index-adjusted WBC, granulocyte and lymphocyte counts were inversely related to duration of smoking cessation (P< or =0.02). Smokers who had given up less than 12 months previously had WBC counts substantially lower (6.7 and 6.9x10(3) per ul, respectively, in men and women) than current smokers. In conclusion, the total WBC count and its components (particularly the granulocyte count) are strongly associated with cigarette smoking habit. Smoking cessation may have an almost immediate impact at least on pathophysiologic processes such as inflammation that may be indicated by the WBC count. The apparent almost immediate reversibility of effects of smoking on inflammation, as indicated by the WBC count, may help motivate efforts to stop smoking.

A substantial proportion of the familial risk of breast cancer may be attributable to genetic variants each contributing a small effect. Polymorphisms in DNA repair genes are good candidates for such low penetrance breast cancer susceptibility alleles. Checkpoint kinase 2 (CHEK2) is a kinase in which the yeast counterpart regulates a cell cycle checkpoint and causes cells to arrest proliferation after DNA damage. A rare, protein truncating mutation in the CHEK2 gene has recently been shown to confer a modest risk of breast cancer. The aim of this study was to determine whether common polymorphic variants in CHEK2 are associated with an increase in breast cancer risk. We assessed two variants in CHEK2 using a case control study design (n = 1786 cases and 1828 controls). No differences in genotype frequencies were found between cases and control for either the IVS1 + 38insa or the a1013g polymorphisms (P = 0.3 and 0.2 respectively), and no genotype-specific risk was significantly different from unity. The haplotype frequency distribution in cases and controls were also similar (P = 0.3). We conclude that the CHEK2 polymorphisms IVS + 1a and a1013g do not confer an increased risk of breast cancer. It is also unlikely that other, as yet unidentified, common polymorphisms that affect risk are present in the gene in the British population.

A calibration approach was developed to correct for systematic between-cohort dietary measurement errors in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large multicenter cohort study. To validate the 24-h diet recalls (24-HDRs) as reference measurements for between-cohort calibration, we estimated the agreement between center mean nitrogen (N) and total energy intakes and mean 24-h urinary N. Similar analyses using N and energy intake data from different dietary questionnaires (DQs) used at study baseline were conducted to estimate the effect of the calibration approach. This study was conducted between 1995 and 1999, and involved 1103 volunteers of both genders from 12 centers participating in European Prospective Investigation into Cancer and Nutrition. Pearson's correlation coefficients were weighted for study center sample size. When both genders were considered together (n = 22), the correlation coefficients between the center mean log-transformed urinary estimates and the center mean log-transformed dietary N estimates from the 24-HDRs were 0.86 and 0.94 after exclusion of outliers. The corresponding correlation with the DQs was 0.53. When center mean total energy intakes were regressed on center mean urinary N, the correlation remained slightly higher with 24-HDRs (0.91; 0.95 after exclusion of outliers) than DQs (0.86). When stratified by gender, these correlations were systematically higher in men than women with both dietary methods. The beta regression coefficients were not significantly different from 1 when mean N (or total energy intakes) from 24-HDR or DQ were regressed on urinary estimates, except with N from 24-HDRs in men and, in most cases, after adjustment for age, body mass index, and sex with both genders together. This suggests that overall the systematic bias across centers is of uniform magnitude. Although relatively high correlations were observed between urinary N and both dietary methods in men, the errors in DQs tend to vary in both directions (under- and over-reporting) in contrast with 24-HDRs in women. This observation may have implications on the dietary measurement error characteristics and support the potential benefit of between-cohort calibration.

We aimed to quantify the benefits of detecting ductal carcinoma in situ (DCIS) and of downwards stage-shifting within invasive tumours in mammographic screening. Using data from the Swedish Two-County Trial of breast cancer screening, we examined the 20-year death rates from invasive tumours of stage II or worse, invasive tumours of stage I and DCIS. We then used these rates and their respective incidences in invited (active study population, ASP) and control (passive study population, PSP) arms of the trial, to estimate the numbers of deaths avoided by downward stage-shifting the larger stage II or worse tumours to stage I and the stage I cancers to DCIS. We also studied the association between the mortality reduction achieved and the proportion of DCIS cases detected in the randomised trials of breast cancer screening. In the Swedish Two County Trial, 141 breast cancer deaths were avoided in the ASP compared with the PSP at approximately 20 years of follow-up. Of these, 65% (91/141) were avoided as a result of stage-shifting from invasive stage II or worse to invasive stage I, and 5% (7/141) as a result of stage-shifting from invasive stage I to DCIS. If we assumed that 10% of stage II or worse tumours avoided were shifted not to stage I, but to DCIS, the estimated number of deaths prevented by shifting from invasive disease to in situ was 17, which is 12% of all deaths prevented. When the results of all the randomised trials of breast cancer screening were reviewed, there was no clear association between the percentage of DCIS cases diagnosed and the observed mortality reduction. We conclude that compared with downward stage-shifting of invasive tumours, detection of DCIS plays a small part in saving lives from breast cancer. Treatment decisions in DCIS, as in invasive carcinoma, should take full account of histopathological, clinical and radiological attributes of the tumour.

Objectives: We undertook this study to calculate the cost per life-year gained in the first round of a screening program for abdominal aortic aneurysm (AAA) and to estimate the costs in a subsequent round., Methods: This was an intervention study, with follow-up for ruptured aneurysms. Men older than 50 years were screened for asymptomatic AAA. Outcome measures included cost per life-year saved and number of men needed to be screened to save one life., Results: The incidence of ruptured AAA was 2.6 per 10,000 person- years in the screening group and 7.1 per 10,000 person-years in the control group. Screening is estimated to have prevented 10.8 ruptured AAA and 8 deaths per year, gaining 51 life-years per year for the study population, and to have reduced the incidence of ruptured AAA by 64% (95% CI, 42%-77%). Each life-year gained during the first screening round cost $1107. To save one life, 1000 men need to be screened and 5 elective operations performed. We predict that a second round of screening can be cost neutral., Conclusions: The cost-effectiveness of screening for AAA compares favorably with screening programs for other disorders in adults.

We measured the impact of diet, anthropometry, physical activity and lifestyle variables on rates of hip bone mineral density (BMD) loss in 470 white men and 474 white women aged 67-79 years at recruitment dwelling in the community. The subjects were recruited from a prospective population-based diet and cancer study (EPIC-Norfolk) in Eastern England. Dietary intake was measured at baseline using 7-day food diaries and used to calculate intakes of some 31 nutrients and 22 food groups. Standardised questionnaires were used to collect data on anthropometry, physical activity and lifestyle variables. BMD loss (percent per annum; % p.a.) was measured using dual-energy X-ray absorptiometry performed on two occasions an average of 3 years apart (range 2-5 years). The mean rate of BMD change at the total hip region was -0.17% p.a. (SD 1.3% p.a.) in men and -0.41% p.a. (SD 1.2% p.a.) in women. In both men and women, weight gain protected against (and weight loss promoted) BMD loss ( P<0.0001). Markers of current physical activity were protective. In men, an increase of 1 l/s in FEV(1) was associated with an increase in BMD at an average rate of 0.25% p.a. ( P=0.013). In women, for every ten trips made per day climbing a flight of stairs, BMD increased at a rate of 0.22% p.a. ( P=0.005) and additionally a 10% increase in activities of daily living score was associated with BMD increasing at a rate of 0.12% p.a. ( P=0.011) in women. Nutritional variation appeared to have less impact on BMD loss. In men there was no evidence of an effect of any of the nutrients evaluated. However, in women, low intake of vitamin C was associated with faster rate of BMD loss. Women in the lowest tertile (7-57 mg/day) of vitamin C intake lost BMD at an average rate of -0.65% p.a., which was significantly faster compared to loss rates in the middle (58-98 mg/day) and upper (99-363 mg/day) tertiles of intake, which were -0.31% p.a. and -0.30% p.a., respectively ( P=0.016). There was no effect of fruits and vegetables, combined or separately, on rate of BMD loss. The results confirm that weight maintenance (or gain) and commonly practiced forms of physical activity appear to protect against BMD loss in this age group. Measures such as ensuring good general nutrition to guard against weight loss in the non-overweight elderly and maintenance of physical fitness could be valuable in protecting against BMD loss. The protective effect of vitamin C in women needs to be further investigated in other prospective cohort or intervention studies.

Background: Dietary fibre is thought to protect against colorectal cancer but this view has been challenged by recent prospective and intervention studies that showed no protective effect., Methods: We prospectively examined the association between dietary fibre intake and incidence of colorectal cancer in 519978 individuals aged 25-70 years taking part in the EPIC study, recruited from ten European countries. Participants completed a dietary questionnaire in 1992-98 and were followed up for cancer incidence. Relative risk estimates were obtained from fibre intake, categorised by sex-specific, cohort-wide quintiles, and from linear models relating the hazard ratio to fibre intake expressed as a continuous variable., Findings: Follow-up consisted of 1939011 person-years, and data for 1065 reported cases of colorectal cancer were included in the analysis. Dietary fibre in foods was inversely related to incidence of large bowel cancer (adjusted relative risk 0.75 [95% CI 0.59-0.95] for the highest versus lowest quintile of intake), the protective effect being greatest for the left side of the colon, and least for the rectum. After calibration with more detailed dietary data, the adjusted relative risk for the highest versus lowest quintile of fibre from food intake was 0.58 (0.41-0.85). No food source of fibre was significantly more protective than others, and non-food supplement sources of fibre were not investigated., Interpretation: In populations with low average intake of dietary fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40%.

The European Prospective Investigation into Cancer and Nutrition (EPIC) is an ongoing multi-centre prospective cohort study designed to investigate the relationship between nutrition and cancer, with the potential for studying other diseases as well. The study currently includes 519 978 participants (366 521 women and 153 457 men, mostly aged 35-70 years) in 23 centres located in 10 European countries, to be followed for cancer incidence and cause-specific mortality for several decades. At enrollment, which took place between 1992 and 2000 at each of the different centres, information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire addressing usual diet. Anthropometric measurements were performed and blood samples taken, from which plasma, serum, red cells and buffy coat fractions were separated and aliquoted for long-term storage, mostly in liquid nitrogen. To calibrate dietary measurements, a standardised, computer-assisted 24-hour dietary recall was implemented at each centre on stratified random samples of the participants, for a total of 36 900 subjects. EPIC represents the largest single resource available today world-wide for prospective investigations on the aetiology of cancers (and other diseases) that can integrate questionnaire data on lifestyle and diet, biomarkers of diet and of endogenous metabolism (e.g. hormones and growth factors) and genetic polymorphisms. First results of case-control studies nested within the cohort are expected early in 2003. The present paper provides a description of the EPIC study, with the aim of simplifying reference to it in future papers reporting substantive or methodological studies carried out in the EPIC cohort.

Objective: To evaluate measurement error structure in dietary assessment instruments and to investigate its implications for nutritional studies, using urinary nitrogen excretion as a reference biomarker for protein intake., Design: The dietary assessment methods included different food-frequency questionnaires (FFQs) and such conventional dietary-report reference instruments as a series of 24-hour recalls, 4-day weighed food records or 7-day diaries., Setting: Six original pilot validation studies within the European Prospective Investigation of Cancer (EPIC), and two validation studies conducted by the British Medical Research Council (MRC) within the Norfolk cohort that later joined as a collaborative component cohort of EPIC., Subjects: A sample of approximately 100 to 200 women and men, aged 35-74 years, from each of eight validation studies., Results: In assessing protein intake, all conventional dietary-report reference methods violated the critical requirements for a valid reference instrument for evaluating, and adjusting for, dietary measurement error in an FFQ. They displayed systematic bias that depended partly on true intake and partly was person-specific, correlated with person-specific bias in the FFQ. Using the dietary-report methods as reference instruments produced substantial overestimation (up to 230%) of the FFQ correlation with true usual intake and serious underestimation (up to 240%) of the degree of attenuation of FFQ-based log relative risks., Conclusion: The impact of measurement error in dietary assessment instruments on the design, analysis and interpretation of nutritional studies may be much greater than has been previously estimated, at least regarding protein intake.

The United Kingdom Childhood Cancer Study, a population-based case-control study covering the whole of Great Britain, incorporated a pilot study measuring electric fields. Measurements were made in the homes of 473 children who were diagnosed with a malignant neoplasm between 1992 and 1996 and who were aged 0-14 at diagnosis, together with 453 controls matched on age, sex and geographical location. Exposure assessments comprised resultant spot measurements in the child's bedroom and the family living-room. Temporal stability of bedroom fields was investigated through continuous logging of the 48-h vertical component at the child's bedside supported by repeat spot measurements. The principal exposure metric used was the mean of the pillow and bed centre measurements. For the 273 cases and 276 controls with fully validated measures, comparing those with a measured electric field exposure >/=20 V m(-1) to those in a reference category of exposure <10 V m(-1), odds ratios of 1.31 (95% confidence interval 0.68-2.54) for acute lymphoblastic leukaemia, 1.32 (95% confidence interval 0.73-2.39) for total leukaemia, 2.12 (95% confidence interval 0.78-5.78) for central nervous system cancers and 1.26 (95% confidence interval 0.77-2.07) for all malignancies were obtained. When considering the 426 cases and 419 controls with no invalid measures, the corresponding odds ratios were 0.86 (95% confidence interval 0.49-1.51) for acute lymphoblastic leukaemia, 0.93 (95% confidence interval 0.56-1.54) for total leukaemia, 1.43 (95% confidence interval 0.68-3.02) for central nervous system cancers and 0.90 (95% confidence interval 0.59-1.35) for all malignancies. With exposure modelled as a continuous variable, odds ratios for an increase in the principal metric of 10 V m(-1) were close to unity for all disease categories, never differing significantly from one.

Background: Opposing views have been published on the importance of ultrasound screening for abdominal aortic aneurysms. The Multicentre Aneurysm Screening Study was designed to assess whether or not such screening is beneficial., Methods: A population-based sample of men (n=67800) aged 65-74 years was enrolled, and each individual randomly allocated to either receive an invitation for an abdominal ultrasound scan (invited group, n=33839) or not (control group, n=33961). Men in whom abdominal aortic aneurysms (> or =3 cm in diameter) were detected were followed-up with repeat ultrasound scans for a mean of 4.1 years. Surgery was considered on specific criteria (diameter > or =5.5 cm, expansion > or =1 cm per year, symptoms). Mortality data were obtained from the Office of National Statistics, and an intention-to-treat analysis was based on cause of death. Quality of life was assessed with four standardised scales. The primary outcome measure was mortality related to abdominal aortic aneurysm., Findings: 27147 of 33839 (80%) men in the invited group accepted the invitation to screening, and 1333 aneurysms were detected. There were 65 aneurysm-related deaths (absolute risk 0.19%) in the invited group, and 113 (0.33%) in the control group (risk reduction 42%, 95% CI 22-58; p=0.0002), with a 53% reduction (95% CI 30-64) in those who attended screening. 30-day mortality was 6% (24 of 414) after elective surgery for an aneurysm, and 37% (30 of 81) after emergency surgery., Interpretation: Our results provide reliable evidence of benefit from screening for abdominal aortic aneurysms.

Dense mammographic patterns are a risk factor for breast cancer. In a recent case-control study, dense patterns were observed to be associated with a higher relative risk estimate for the more aggressive grade 3 tumors than for grade 1 or 2 tumors. The present study was designed to ascertain, by reference to odds ratio estimates of relative risk by tumor size and histologic grade, whether this was more likely to be due to increased innate predisposition of dense parenchymal patterns to grade 3 tumors, or to dedifferentiation of cases missed at screening due to dense patterns. If the observation were due entirely to dedifferentiation, then for a given size the relative risk of grade 3 tumors would be the same as for grades 1-2. Size-specific relative risks of grade 3 tumors were higher than those of grade 1-2 tumors. It is concluded that the majority of the enhanced risk of grade 3 tumors is due to enhanced innate predisposition to grade 3 tumors in dense breasts.

Background: Although studies have reported large reductions in the risks of AIDS and death since the introduction of potent anti-retroviral therapies, few have evaluated whether this has been similar for all AIDS-defining diseases. We wished to evaluate changes over time in the risk of specific AIDS-defining diseases, as first events, using data from individuals with known dates of HIV seroconversion., Methods: Using a competing risks proportional hazards model on pooled data from 20 cohorts (CASCADE), we evaluated time from HIV seroconversion to each first AIDS-defining disease (16 groups) and to death without AIDS for four calendar periods, adjusting for exposure category, age, sex, acute infection, and stratifying by cohort. We compared results to those obtained from a cause-specific hazards model., Results: Of 6,941, 2,021 (29%) developed AIDS and 437 (6%) died without AIDS. The risk of AIDS or death remained constant to 1996 then reduced; relative hazard = 0.89 (95% CI: 0.77-1.03); 0.90 (95% CI: 0.81-1.01); and 0.32 (95% CI: 0.28-0.37) for 1979-1990, 1991-1993, and 1997-2001, respectively, compared to 1994-1996. Significant risk reductions in 1997-2001 were observed in all but two AIDS-defining groups and death without AIDS in a competing risks model (with similar results from a cause-specific model). There was significant heterogeneity in the risk reduction across events; from 96% for cryptosporidiosis, to 17% for death without AIDS (P < 0.0001)., Conclusion: These findings suggest that studies reporting a stable trend for particular AIDS diseases over the period 1979-2001 may not have accounted for the competing risks among other events or lack the power to detect smaller trends.

Objective: The aim of this study was to investigate the association between anti-hypertensive drugs, the risk of developing an abdominal aortic aneurysm (AAA), aortic wall stiffness, collagen turnover, and change in aortic diameter. STUDY DESIGN, SETTINGS AND METHODS: Data on present medication, smoking status, and medical history of participants in two population-based aneurysm screening programs in the United Kingdom were collected by use of questionnaire. Aortic elasticity was measured by M-mode ultrasound scanning. A serum radioimmunoassay of the amino-terminal propeptide of type III procollagen was used to assess collagen turnover in one of the patient series., Results: Data from 438 cases with an AAA >29 mm and 5373 controls were analyzed. Calcium-channel blockers were independently associated with AAA. The odds ratio of having an AAA was 2.6 (95% confidence interval [CI], 1.5-4.2) after adjusting for all relevant confounders. Other antihypertensive drugs showed no increased risk. No significant differences in growth rates were found in cases exposed to any of the main antihypertensive drugs. An increased collagen turnover was found in subjects receiving angiotensin-converting enzyme (ACE) inhibitors: 4.26 mg/L (95% CI, 3.73-4.79) compared with 3.62 mg/L (95% CI, 3.49-3.76) for subjects not receiving ACE inhibitors. No differences in type III collagen turnover was found with use of any other antihypertensive drug. The mean aortic wall stiffness was greater for all subjects exposed to calcium-channel blockers, whether with AAA or not: 25.1 arbitrary units (95% CI, 20.0-30.2) vs 19.3 (95% CI, 18.1-20.4)(P =.002). By contrast, the mean stiffness for cases receiving ACE inhibitors was smaller than for those not receiving ACE inhibitors: 19.0 (95% CI, 13.9-24.0) vs 25.2 (95% CI, 23.0-27.4)., Conclusions: Calcium-channel blockers were an independent risk factor for the presence of an AAA and were associated with an increased arterial aortic wall stiffness. ACE inhibitors were associated with decreased stiffness and greater collagen turnover. No significant effects on the growth rate of small aneurysms were detected.