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Purpose To investigate associations of total dietary choline intake and its major dietary form, phosphatidylcholine, with type 2 diabetes risk. Methods We included 2332 men aged 42–60 years at baseline in 1984–1989 from the Kuopio Ischaemic Heart Disease Risk Factor Study in eastern Finland. Dietary intakes were assessed with 4-d food recording at baseline. Type 2 diabetes diagnosis was based on self-administered questionnaires, fasting and 2-h oral glucose tolerance test blood glucose measurements, or by record linkage to national health registries. Multivariable-adjusted Cox proportional hazards regression models were used for statistical analysis. Results During the mean 19.3-year follow-up, 432 men had type 2 diabetes diagnosis. After multivariable adjustments, those in the highest vs. lowest choline intake quartile had 25% (95% CI 2–43%) lower relative risk (P trend across quartiles = 0.02) and those in the highest vs. lowest phosphatidylcholine quartile had 41% (95% CI 22–55%) lower relative risk (P trend Conclusions Higher choline intake, especially phosphatidylcholine, was associated with lower type 2 diabetes risk among men.

Background Moderate egg intake has been associated with better cognitive performance in observational studies. This association may be due to the rich content of choline, especially phosphatidylcholine, in eggs because choline has been suggested to have a role in the prevention of cognitive decline. Objectives We investigated the associations of dietary choline intake with the risk of incident dementia and with cognitive performance in middle-aged and older men in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Methods A population-based sample of 2497 dementia-free men aged 42-60 y was examined in 1984-1989. A subset of 482 men completed 5 different cognitive performance tests 4 y later. Dementia and Alzheimer disease diagnoses were retrieved from Finnish health registers. Dietary intakes were assessed with the use of 4-d food records at baseline. Cox regression and ANCOVA were used for the analyses. All analyses were also stratified by the apolipoprotein E phenotype (APOE-e4 compared with other phenotypes). These data were available for 1259 men. Results The mean ± SD total choline intake was 431 ± 88 mg/d, of which 188 ± 63 mg/d was phosphatidylcholine. During a 21.9-y follow-up, 337 men were diagnosed with dementia. Those in the highest compared with the lowest phosphatidylcholine intake quartile had 28% (95% CI: 1%, 48%; P-trend = 0.02 across quartiles) lower multivariable-adjusted risk of incident dementia. Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning. For example, higher intakes were associated with better performance in verbal fluency and memory functions. The APOE phenotype had little or no impact on the associations. Conclusion Higher phosphatidylcholine intake was associated with lower risk of incident dementia and better cognitive performance in men in eastern Finland. This trial was registered at clinicaltrials.gov as NCT03221127.

Background: Epidemiologic studies suggest inverse associations between consumption of egg, a major source of dietary cholesterol, and stroke. However, the evidence of the relation remains limited, especially among carriers of apolipoprotein E4 (apoE4), which influences cholesterol metabolism. Objective: The aim of this study was to investigate associations of egg and cholesterol intakes with risk of stroke and with the major stroke risk factor, blood pressure, inmiddle-aged and older men from eastern Finland and whether apoE phenotype could modify these associations. Methods: A total of 1950 men aged 42-60 y in 1984-1989 were included at the baseline examinations of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on apoE phenotype were available for 1015 men. Dietary intakes were assessed with 4-d food records at baseline and incident stroke events were assessed by record linkage to hospital discharge registries. Cox proportional hazards regression analyses were used to estimate associations with stroke risk. Associations with baseline blood pressure were evaluated with ANCOVA. Results: During the mean +/- SD follow-up of 21.2 +/- 7.2 y, there were 217 incidences of any stroke: 166 of ischemic stroke and 55 of hemorrhagic stroke. Comparing the highest egg intake quartile with the lowest, the multivariable-adjusted HRs were 0.81 for total stroke (95% CI: 0.54, 1.23; P-trend = 0.32), 0.84 for ischemic stroke (95% CI: 0.53, 1.34; P-trend = 0.44), and 0.75 for hemorrhagic stroke (95% CI: 0.32, 1.77; P-trend = 0.40). The respective HRs for the highest cholesterol intake quartile compared with the lowest were 0.86 (95% CI: 0.57, 1.32; P-trend = 0.42), 0.74 (95% CI: 0.46, 1.20; P-trend = 0.32), and 1.10 (95% CI: 0.45, 2.66; P-trend = 0.75). Diastolic blood pressure was 1.6 mm Hg (P-trend = 0.04) lower in the highest egg intake quartile compared with the lowest, but there were no associations with systolic blood pressure or with cholesterol intake. ApoE phenotype (32% had apoE4 phenotype) did not modify the associations. Conclusion: Neither egg nor cholesterol intakes were associated with stroke risk in this cohort, regardless of apoE phenotype. This trial was registered at www.clinicaltrials.gov as NCT03221127.

Background: Several publications have described differences in cross-sectional comparisons of gut microbiota between patients with Parkinson's disease and control subjects, with considerable variability of the reported differentially abundant taxa. The temporal stability of such microbiota alterations and their relationship to disease progression have not been previously studied with a high-throughput sequencing based approach. Methods: We collected clinical data and stool samples from 64 Parkinson's patients and 64 control subjects twice, on average 2.25 years apart. Disease progression was evaluated based on changes in Unified Parkinson's Disease Rating Scale and Levodopa Equivalent Dose, and microbiota were characterized with 16S rRNA gene amplicon sequencing. Findings: We compared patients to controls, and patients with stable disease to those with faster progression. There were significant differences between microbial communities of patients and controls when corrected for confounders, but not between timepoints. Specific bacterial taxa that differed between patients and controls at both timepoints included several previously reported ones, such as Roseburia, Prevotella and Bifidobacterium. In progression comparisons, differentially abundant taxa were inconsistent across methods and timepoints, but there was some support for a different distribution of enterotypes and a decreased abundance of Prevotella in faster-progressing patients. Interpretation: The previously detected gut microbiota differences between Parkinson's patients and controls persisted after 2 years. While we found some evidence for a connection between microbiota and disease progression, a longer follow-up period is required to confirm these findings. (C) 2019 The Authors. Published by Elsevier B.V.

Background Previous studies investigating protein intake in relation to mortality have provided conflicting results. Objective We investigated the associations of dietary protein and protein sources with risk of disease death in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Methods The study population consisted of 2641 Finnish men, aged 42-60 y at baseline in 1984-1989. We estimated protein intakes with 4-d dietary records at baseline and collected data on disease deaths from the national Causes of Death Register. Cox proportional hazards regression models were used to estimate HRs and 95% CIs. Results During the average follow-up of 22.3 y, we observed 1225 deaths due to disease. Higher intakes of total protein and animal protein had borderline statistically significant associations with increased mortality risk: multivariable-adjusted HR (95% CI) in the highest compared with the lowest quartile for total protein intake = 1.17 (0.99, 1.39; P-trend across quartiles = 0.07) and for animal protein intake = 1.13 (0.95, 1.35; P-trend = 0.04). Higher animal-to-plant protein ratio (extreme-quartile HR = 1.23; 95% CI: 1.02, 1.49; P-trend = 0.01) and higher meat intake (extreme-quartile HR = 1.23; 95% CI: 1.04, 1.47; P-trend = 0.01) were associated with increased mortality. When evaluated based on disease history at baseline, the association of total protein with mortality appeared more evident among those with a history of type 2 diabetes, cardiovascular disease, or cancer (n = 1094) compared with those without disease history (n = 1547) (P-interaction = 0.05 or 0.07, depending on the model). Intakes of fish, eggs, dairy, or plant protein sources were not associated with mortality. Conclusions Higher ratio of animal to plant protein in diet and higher meat intake were associated with increased mortality risk. Higher total protein intake appeared to be associated with mortality mainly among those with a predisposing disease. This trial was registered at clinicaltrials.gov as NCT03221127.

Recent dairy product studies have suggested that fermented rather than non-fermented dairy products might provide benefits on cardiovascular health, but the evidence is inconclusive. Therefore, we investigated whether fermented and non-fermented dairy products have distinct associations with the risk of incident CHD in a population with high dairy product intake. The present study included a total of 1981 men, aged 42–60 years, from the Kuopio Ischaemic Heart Disease Risk Factor Study, with no CHD at baseline. Dietary intakes were assessed with instructed 4-d food records. We used Cox’s proportional hazards regression model to estimate the associations with the risk of CHD. Fatal and non-fatal CHD events were ascertained from national registries. During a mean follow-up of 20·1 years, 472 CHD events were recorded. Median intakes were 105 g/d for fermented (87 % low-fat products) and 466 g/d for non-fermented dairy products (60 % low-fat products). After adjusting for potential confounders, those in the highest (v. lowest) intake quartile of fermented dairy products had 27 % (95 % CI 5, 44; P-trend=0·02) lower risk of CHD. In contrast, those in the highest intake quartile of non-fermented dairy products had 52 % (95 % CI 13, 104; P-trend=0·003) higher risk of CHD. When analysed based on fat content, low-fat (P-trend=0·03), but high-fat fermented dairy and low-fat or high-fat non-fermented dairy products had no association. These results suggest that fermented and non-fermented dairy products can have opposite associations with the risk of CHD.

The cardioprotective properties of linoleic acid (LA), a major n-6 (ω-6) polyunsaturated fatty acid (PUFA), have been recognized, but less is known about its associations with other causes of death. Relatively little is also known about how the minor n-6 PUFAs-γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA)-relate to mortality risk.We investigated the associations of serum n-6 PUFAs, an objective biomarker of exposure, with risk of death in middle-aged and older men and whether disease history modifies the associations.We included 2480 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y at baseline in 1984-1989. The stratified analyses by baseline disease status included 1019 men with a history of cardiovascular disease (CVD), cancer, or diabetes and 1461 men without a history of disease.During the mean follow-up of 22.4 y, 1143 deaths due to disease occurred. Of these, 575 were CVD deaths, 317 were cancer deaths, and 251 were other-cause deaths. A higher serum LA concentration was associated with a lower risk of death from any cause (multivariable-adjusted HR for the highest compared with the lowest quintile: 0.57; 95% CI: 0.46, 0.71; P-trend 0.001) and with deaths due to CVD (extreme-quintile HR: 0.54; 95% CI: 0.40, 0.74; P-trend 0.001) and non-CVD or noncancer causes (HR: 0.48; 95% CI: 0.30, 0.76; P-trend = 0.001). Serum AA had similar, although weaker, inverse associations. Serum GLA and DGLA were not associated with risk of death, and none of the fatty acids were associated with cancer mortality. The results were generally similar among those with or without a history of major chronic disease (P-interaction 0.13).Our findings showed an inverse association of a higher biomarker of LA intake with total and CVD mortality and little concern for risk, thus supporting the current dietary recommendations to increase LA intake for CVD prevention. The finding of an inverse association of serum AA with the risk of death needs replication in other populations.

Vitamin D3 has via its metabolites 25-hydroxyvitamin D3 (25(OH)D3) and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) direct effects on the transcriptome and the epigenome of most human cells. In the VitDbol study we exposed 35 healthy young adults to an oral vitamin D3 dose (2000μg) or placebo and took blood samples directly before the supplementation as well as at days 1, 2 and 30. Within 24h the vitamin D3 intake raised the average serum levels of both 25(OH)D3 and 1,25(OH)2D3 by approximately 20%. However, we observed large inter-individual differences in these serum levels, reflected by the average ratios between 25(OH)D3 and 1,25(OH)2D3 concentrations ranging from 277 to 1365. Interestingly, average serum parathyroid hormone (PTH) levels increased at day 1 by some 10% but then decreased within the following four weeks to levels 5% below baseline. In peripheral blood mononuclear cells (PBMCs) that were isolated at the same time points we determined vitamin D-modulated chromatin accessibility by FAIRE-qPCR at selected genomic loci. This method is well suited to evaluate both short-term and long-term in vivo effects of vitamin D on the epigenome of human subjects. The differential vitamin D responsiveness of the VitDbol study participants was determined via individual changes in their PTH levels or chromatin accessibility in relation to alterations in 25(OH)D3 concentrations. This led to the segregation of the subjects into 14 high, 11 mid and 10 low responders. In summary, the vitamin D responsiveness classification provides additional information compared to a vitamin D status assessment based on single 25(OH)D3 serum measurements. The study was registered at Clinicaltrials.gov (NCT02063334).

Background Depression is a major public health challenge worldwide, and polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, have been found to inversely associate with the risk of depression. However, only few cross-sectional studies have investigated the association between dihomo-γ-linolenic acid (DGLA), an n-6 PUFA with anti-inflammatory effects, and depression. The aims of the present study were to examine an association between serum DGLA and the risk of depression, and to study whether the potential association is mediated via inflammation. Methods A 20-year prospective Kuopio Ischaemic Heart Disease Risk Factor (KIHD) follow-up study was conducted from 1984 to 1989 with 2179 middle-aged and older Finnish men (42–60 years old at baseline). The baseline concentrations of serum fatty acids, including DGLA, were determined. A hospital discharge diagnosis of depression was used as the main outcome and obtained from linkage to National Hospital Discharge Register. Serum C-reactive protein (CRP) levels were measured to assess inflammation. Results An inverse association between serum DGLA concentration and incidence of depression was found after adjustment for several potential confounders (Hazard ratio HR 0.53, CI 0.36–0.79, P=0.002). The association between DGLA and depression was not dependent on inflammation (P-interaction=0.618). Limitations Our findings may not be generalizable to individuals below middle-age or women. Moreover, we were unable to consider cases with mild depression in the longitudinal setting. Conclusions Higher serum DGLA concentrations may predict lower risk of develop depression in elderly men. Further studies are warranted to address potential mechanisms as mechanism behind this association remains unclear., final draft, peerReviewed

International audience; BACKGROUND:Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.OBJECTIVE:We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.METHODS:Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.RESULTS:There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.CONCLUSIONS:Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.

BACKGROUND The role of n-6 (ω-6) polyunsaturated fatty acids (PUFAs) in type 2 diabetes (T2D) is inconclusive. In addition, little is known about how factors involved in PUFA metabolism, such as zinc, may affect the associations. OBJECTIVES We investigated the associations of serum n-6 PUFAs and activities of enzymes involved in PUFA metabolism, Δ5 desaturase (D5D) and Δ6 desaturase (D6D), with T2D risk to determine whether serum zinc concentrations could modify these associations. DESIGN The study included 2189 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y and free of T2D at baseline in 1984-1989. T2D was assessed by self-administered questionnaires, by fasting and 2-h oral-glucose-tolerance test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline, and by record linkage to the hospital discharge registry and the reimbursement register on diabetes medication expenses. Multivariate-adjusted Cox proportional hazards regression models were used to analyze associations. RESULTS During the average follow-up of 19.3 y, 417 men developed T2D. Those with higher estimated D5D activity (extreme-quartile HR: 0.55; 95% CI: 0.41, 0.74; P-trend < 0.001) and higher concentrations of total n-6 PUFAs (HR: 0.54; 95% CI: 0.41, 0.73; P-trend < 0.001), linoleic acid (LA; HR: 0.52; 95% CI: 0.39, 0.70; P-trend < 0.001), and arachidonic acid (AA; HR: 0.62; 95% CI: 0.46, 0.85; P-trend = 0.007) had a lower risk and those with higher concentrations of γ-linolenic acid (GLA; HR: 1.28; 95% CI: 0.98, 1.68; P = 0.021) and dihomo-γ-linolenic acid (DGLA; HR: 1.38; 95% CI: 1.04, 1.84; P-trend = 0.005) and higher D6D activity had a higher (HR: 1.50; 95% CI: 1.14, 1.97; P-trend < 0.001) multivariate-adjusted risk of T2D. Zinc mainly modified the association with GLA on T2D risk, with a higher risk observed among those with serum zinc concentrations above the median (P-interaction = 0.04). CONCLUSIONS Higher serum total n-6 PUFA, LA, and AA concentrations and estimated D5D activity were associated with a lower risk of incident T2D, and higher GLA and DGLA concentrations and estimated D6D activity were associated with a higher risk. In addition, a higher serum zinc concentration modified the association of GLA on the risk of T2D.

Fish intake and the long-chain omega-3 polyunsaturated fatty acids (PUFAs) in fish have been suggested to lower the risk of cognitive decline. We assessed whether serum long-chain omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) are associated with performance on neuropsychological tests in an older population and whether exposure to methylmercury, mainly from fish, or apolipoprotein-E4 (Apo-E4) phenotype can modify the associations.A total of 768 participants from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study were included. Cognitive function was measured using five neuropsychological tests: the Trail Making Test, the Verbal Fluency Test, the Selective Reminding Test, the Visual Reproduction Test and the Mini Mental State Exam. Multivariate-adjusted analysis of covariance and linear regression were used to analyze the cross-sectional associations.We found statistically significant associations between serum EPA+DPA+DHA and better performance in the Trail Making Test and the Verbal Fluency Test. The individual associations with EPA and DHA were similar with the findings with EPA+DPA+DHA, although the associations with DHA were stronger. No associations were observed with serum DPA. Pubic hair mercury content was associated only with a worse performance in the Trail Making Test, and mercury had only little impact on the associations between the serum PUFAs and cognitive performance. Apo-E4 phenotype did not modify the associations with PUFAs or mercury.Higher serum long-chain omega-3 PUFA concentrations were associated with better performance on neuropsychological tests of frontal lobe functioning in older men and women. Mercury exposure or Apo-E4 phenotype had little impact on cognitive performance.

Background: A Finnish joint research effort Kuopio Birth Cohort (KuBiCo) seeks to evaluate the effects of genetics, epigenetics and different risk factors (medication, nutrition, lifestyle factors and environmental aspects) during pregnancy on the somatic and psychological health status of the mother and the child. Methods: KuBiCo will ultimately include information on 10,000 mother-child pairs who have given their informed consent to participate in this cohort. Identification of foetal health risk factors that can potentially later manifest as disease requires a repository of relevant biological samples and a flexible open up-to-date data handling system to register, store and analyse biological, clinical and questionnaire-based data. KuBiCo includes coded questionnaire-based maternal background data gathered before, during and after the pregnancy and bio-banking of maternal and foetal samples that will be stored in deep freezers. Data from the questionnaires and biological samples will be collected into one electronic database. KuBiCo consists of several work packages which are complementary to each other: Maternal, foetal and placental metabolism and omits; Paediatrics; Mental wellbeing; Prenatal period and delivery; Analgesics and anaesthetics during peripartum period; Environmental effects; Nutrition; and Research ethics. Discussion: This report describes the set-up of the KuBiCo and descriptive analysis from 3532 parturients on response frequencies and feedback to KuBiCo questionnaires gathered from June 2012 to April 2016. Additionally, we describe basic demographic data of the participants (n = 1172). Based on the comparison of demographic data between official national statistics and our descriptive analysis, KuBiCo represents a cross-section of Finnish pregnant women.

Low concentrations of serum 25-hydroxyvitamin D [25(OH)D] have been postulated to associate with an increased prevalence of depression. As there are a limited number of publications on this issue, we examined the association between serum 25(OH)D and depression in a general middle-aged or older population. A population-based cross-sectional study. A total of 1602 men and women from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in Eastern Finland, aged 53-73 y in 1998-2001, were analysed. Depressive symptoms were assessed with the DSM-III depression scale, and those individuals who had scores over 4 (range 0-12) or had reported undergoing current antidepressant therapy, were considered as suffering from depression. Associations were estimated in serum 25(OH)D tertiles using logistic regression. Among the participants, 183 subjects (11.4%) were considered to have depression. The mean age of the subjects was 62.6 years (SD 6.4, range 53.4- 73.8 years). The mean serum 25(OH)D concentration was 43.8 nmol/L (SD 17.7, range 8.5-112.8 nmol/L), concentrations

SCOPE: Higher egg intake was previously associated with a lower risk of developing type 2 diabetes (T2D) in the prospective, population‐based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in eastern Finland. Potential compounds that can explain this association are explored using nontargeted LC‐MS‐based metabolic profiling. METHODS AND RESULTS: Two hundred and thirty‐nine baseline serum samples from the KIHD are analyzed in four groups: subjects with higher (mean intake one egg per day) or lower (mean intake two eggs per week) egg intake who developed T2D (cases) or remained heatlhy (controls) during the mean follow‐up of 19.3 years. Different serum profiles of subjects who had either higher or lower egg intakes, and of those who developed type 2 diabetes or remained healthy, are observed. The higher baseline tyrosine level predicts higher odds of T2D (OR 1.94; 95% CI 1.45, 2.60; p < 0.001; FDR 0.023) along with an unknown hexose‐containing compound (OR 2.13; 95% CI 1.57, 2.88; p < 0.001; FDR 0.005). Certain predominant metabolites in T2D cases are correlated positively with ones in the lower‐egg‐intake group and negatively with ones in the higher‐egg‐intake group. CONCLUSION: Our current findings may underline some potential metabolites that can explain how egg intake is associated with a lower risk of T2D.

BACKGROUND The prevalence of type 2 diabetes (T2D) is increasing around the world. Eggs are a major source of cholesterol, which has been associated with elevated blood glucose and an increased risk of T2D. However, there are limited and conflicting data from prospective population studies on the association between egg consumption and risk of T2D. OBJECTIVE We investigated the association between egg consumption and risk of incident T2D in middle-aged and older men from eastern Finland. DESIGN The study included 2332 men aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Dietary intakes were assessed with 4-d food records at baseline. Incident T2D was assessed by self-administered questionnaires; by fasting and 2-h oral-glucose-tolerance-test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline; and by record linkage to a hospital discharge registry and reimbursement register of diabetes medication expenses. Cox proportional hazards regression analyses were used to estimate associations with the risk of incident T2D. Associations with the metabolic risk markers at baseline and at the 4-y examinations were analyzed by ANCOVA. RESULTS During an average follow-up of 19.3 y, 432 men developed T2D. After adjustment for potential confounders, those in the highest compared with the lowest egg intake quartile had a 38% (95% CI: 18%, 53%; P-trend across quartiles

Background The associations of n-6 polyunsaturated fatty acids (PUFA) with metabolic syndrome have been poorly explored. We investigated the associations of the serum n-6 PUFA and the activities of enzymes involved in the PUFA metabolism, delta-5-desaturase (D5D) and delta-6-desaturase (D6D) with risk of incident metabolic syndrome. We also investigated whether zinc, a cofactor for these enzymes, modifies these associations. Methods A prospective follow-up study was conducted on 661 men who were aged 42–60 years old at baseline in 1984–1989 and who were re-examined in 1998–2001. Results Men in the highest versus the lowest serum total omega-6 PUFA tertile had a 70% lower multivariate-adjusted risk of incident metabolic syndrome [odds ratio (OR) = 0.30; 95% confidence interval (CI) = 0.18–0.51, Ptrend < 0.001]. Inverse associations were also observed for linoleic acid, arachidonic acid and D5D activity. By contrast, men in the highest tertile of D6D activity had an 84% higher risk (OR = 1.84; 95% CI = 1.15–2.94, Ptrend = 0.008). Similar associations were observed with many of the metabolic syndrome components at the re-examinations. Most associations were attenuated after adjustment for body mass index. Finally, the associations of D6D and LA were stronger among those with a higher serum zinc concentration. Conclusions Higher serum total n-6 PUFA, linoleic acid and arachidonic acid concentrations and D5D activity were associated with a lower risk of developing metabolic syndrome and higher D6D activity was associated with a higher risk. The role of zinc also needs to be investigated in other populations.

Article, The roles of different dietary proteins in the aetiology of type 2 diabetes (T2D) remain unclear. We investigated the associations of dietary proteins with the risk of incident T2D in Finnish men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study. The study included 2332 men aged 42–60 years at the baseline examinations in 1984–1989. Protein intakes were calculated from 4-d dietary records. Incident T2D was determined by self-administered questionnaires, fasting blood glucose measurements, 2-h oral glucose tolerance tests, and with national registers. The multivariable-adjusted risk of T2D on the basis of protein intakes was compared by the Cox proportional hazard ratios (HR). During the mean follow-up of 19·3 years, 432 incident T2D cases were identified. Total, animal, meat or dairy product protein intakes were not associated with risk of T2D when the potential confounders were accounted for. Plant (multivariable-adjusted extreme-quartile HR 0·65; 95 % CI 0·42, 1·00; P trend 0·04) and egg (HR 0·67; 95 % CI 0·44, 1·00; P trend 0·03) protein intakes were associated with a decreased risk of T2D. Adjustments for BMI, plasma glucose and serum insulin slightly attenuated associations. Replacing 1 % energy from carbohydrates with energy from protein was associated with a 5 % (95 % CI 0, 11) increased risk of T2D, but adjustment for fibre intake attenuated the association. Replacing 1 % of energy from animal protein with energy from plant protein was associated with 18 % (95 % CI 0, 32) decreased risk of T2D. This association remained after adjusting for BMI. In conclusion, favouring plant and egg proteins appeared to be beneficial in preventing T2D., final draft, peerReviewed

Article, Vitamin D has been suggested to have a role in various neurovascular diseases, but the data regarding headache is inconclusive. Our aim was to investigate the associations between serum 25-hydroxyvitamin D [25(OH)D], a marker for vitamin D status, and risk of frequent headache. The study population consisted of 2601 men from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) from eastern Finland, aged 42–60 years in 1984–1989. The cross-sectional associations with prevalence of self-reported frequent headache (defined as weekly or daily headaches) were estimated with multivariable-adjusted odds ratios. The average serum 25(OH) concentration was 43.4 nmol/L (SD 18.9, min-max 7.8–136.1 nmol/L). A total of 250 men (9.6%) reported frequent headache. The average serum 25(OH)D concentration among those with frequent headache was 38.3 nmol/L (SD 18.8) and 43.9 nmol/L (SD 18.9) among those without frequent headache, after adjustment for age and year and month of blood draw (P for difference, published version, peerReviewed

Background Previous studies assessing the role of dietary factors in depression have mainly focused on nutrients, while the association between dietary patterns and depression is less studied. Objective The aim was to assess the role of dietary patterns in depression in both cross-sectional and prospective analyses. Design The study population consisted of 1003 Finnish middle-aged or older men from the Kuopio Ischemic Heart Disease Risk Factor Study. Food consumption was assessed by food frequency questionnaire in 1991–1993 and dietary patterns from 25 predefined food groups were extracted by factor analysis. Depressive symptoms were assessed with the self-administered Human Population Laboratory Depression Scale, cut-off point of five or more indicating elevated depressive symptoms. Results Altogether 72 (7.2%) subjects had elevated depressive symptoms. Three dietary patterns were identified: “prudent”, “Western” and “mixed”. In cross-sectional analysis, after adjustments for age, examination year, BMI, smoking, alcohol consumption, education, marital status, leisure-time physical activity , history of mental illness and cardiovascular disease the prudent dietary pattern was associated with a 25% lower prevalence of elevated depressive symptoms (OR: 0.75; 95% CI: 0.57, 0.99; P =0.036), whereas the Western dietary pattern was associated with increased prevalence of elevated depressive symptoms (OR: 1.41; 95% CI: 1.08, 1.84; P =0.011). In the prospective analysis (16.5 follow-up years), the prudent dietary pattern was inversely associated with the risk of getting a hospital discharge diagnosis of depression (HR: 0.66; 95% CI 0.47, 0.93; P =0.018). Conclusions Adherence to healthy dietary pattern is associated with lower risk of getting a hospital discharge diagnosis of depression.

Background Although higher intakes of fruit, berries, and vegetables (FBV) have been associated with reduced risk of type 2 diabetes (T2D) in some observational studies, the evidence is limited and inconclusive. Objective We assessed the relation of FBV intake and T2D incidence in Finnish men. Design We studied 2332 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study who were aged 42-60 y and free of T2D or impaired fasting glucose at baseline in 1984-1989. Food intake was assessed with 4-d food recording. T2D was assessed by using self-administered questionnaires, a fasting blood glucose measurement, a 2-h oral-glucose-tolerance test, and record linkage to a reimbursement register on diabetes medication expenses. In the Cox proportional hazards model, HRs for T2D were computed for the highest compared with lowest quartiles of FBV intake adjusted for age, examination year, body mass index, waist-to-hip ratio, smoking, education, physical activity, family history of diabetes, and energy and alcohol intakes. Results During the mean follow-up time of 19.3 y, 432 new cases of T2D occurred. For the total FBV intake (with the exclusion of potatoes and fruit and berry juices), the extreme-quartile multivariable-adjusted HR for T2D was 0.76 (95% CI: 0.57, 1.02; P-trend = 0.15). In the analysis for FBV components, berries had a corresponding HR of 0.65 (95% CI: 0.49, 0.88; P-trend = 0.003), whereas no significant associations were shown for fruit, fruit and berry juices, and vegetables. Conclusion Fruit and vegetables, particularly berries, may reduce risk of T2D in men.

Background Zinc is an immunomodulatory trace element suggested to be beneficial in the augmentation of antidepressant therapy. Cross-sectional studies have also suggested an association between low dietary zinc and depression. This study examined the association between dietary zinc intake and depression in a prospective setting in initially depression-free men during a 20-year follow-up. Methods The study formed a part of the population-based Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study, and comprised 2317 Finnish men aged 42–61 years. Zinc intake was assessed at baseline by a 4-d food record. Baseline depression severity was recorded with the Human Population Laboratory Depression Scale. In the prospective setting, depression was defined as having received a hospital discharge diagnosis of unipolar depressive disorder. Individuals who at baseline had elevated depressive symptoms were excluded (n=283). Results Altogether, 60 (2.7%) individuals received a hospital discharge diagnosis of depression during the 20-year follow-up. In Cox regression analysis adjusted for age, baseline depression severity, smoking, alcohol use, physical exercise and the use of dietary supplements, belonging to the lowest tertile of energy-adjusted zinc intake was not associated with an increased depression risk (RR 1.06, 95% CI 0.59–1.90). Limitations These observations may not be generalizable to women, or to individuals with a depression level not warranting hospitalization. Conclusions Our findings suggest that a low dietary zinc intake may not longitudinally precede depression in men. Dietary zinc intake may not have relevance for the prevention of depression in middle-aged men with a sufficient dietary zinc intake.

Background There is little information about the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with the risk of cognitive decline in general populations or in carriers of apolipoprotein E ɛ4 (APO-E4), a major risk factor for dementia. Objective We investigated the associations of cholesterol and egg intakes with incident dementia, Alzheimer disease (AD), and cognitive performance in middle-aged and older men from Eastern Finland. Design A total of 2497 dementia-free men, aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, were included in the study. Information on the apolipoprotein E (Apo-E) phenotype was available for 1259 men. Data on cognitive performance tests at the 4-y re-examinations were available for 480 men. Dietary intakes were assessed with the use of 4-d food records at baseline. Dementia and AD diagnoses were based on Finnish health registers. Cox regression and ANCOVA were used for the analyses. Results During the 21.9-y follow-up, 337 men were diagnosed with dementia, and 266 men were diagnosed with AD. Neither cholesterol nor egg intake was associated with a higher risk of incident dementia or AD. For example, when evaluated continuously, each intake of 100 mg cholesterol/d was associated with a multivariable-adjusted HR of 0.90 (95% CI: 0.79, 1.02) for incident dementia, and each additional 0.5 egg (27 g)/d was associated with an HR of 0.89 (95% CI: 0.78, 1.01). However, egg intake was associated with better performance on neuropsychological tests of the frontal lobe and executive functioning, the Trail Making Test, and the Verbal Fluency Test. The Apo-E4 phenotype did not modify the associations of cholesterol or egg intake (P-interactions > 0.11). Conclusions Neither cholesterol nor egg intake is associated with an increased risk of incident dementia or AD in Eastern Finnish men. Instead, moderate egg intake may have a beneficial association with certain areas of cognitive performance.

Importance: The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. Objective: To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA; 22:6ω-3) and plant-derived α-linolenic acid (ALA; 18:3ω-3) for incident CHD. Data Sources: A global consortium of 19 studies identified by November 2014. Study Selection: Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD. Data Extraction and Synthesis: Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes. Main Outcomes and Measures: Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). Results: The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. Conclusions and Relevance: On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.

Objective The aim of this study was to investigate associations of serum zinc with incident metabolic syndrome and its components in middle-aged and older Finnish men. Methods An 11-y prospective follow-up study conducted among 683 men from the Kuopio Ischaemic Heart Disease Risk Factor Study who were 42 to 60 y old at baseline in 1984 to 1989. The main outcome was incident metabolic syndrome, defined by the National Cholesterol Education Program (NCEP) criteria. Other outcomes were the individual components of the NCEP metabolic syndrome: Fasting blood glucose, serum triacylglycerols, serum high-density lipoprotein (HDL) cholesterol, hypertension, and waist circumference. Results During the average follow-up of 11 y, 139 men (20.4%) developed metabolic syndrome. Those in the highest tertile of serum zinc had 84% higher risk (95% confidence interval 12 to 201%, P trend across tertiles = 0.015) to develop metabolic syndrome compared with those in the lowest tertile, after adjustment for several potential confounders. The association between serum zinc and incident metabolic syndrome was attenuated by adjustment for waist circumference, serum HDL cholesterol, or hypertension. Serum zinc was also directly associated with higher waist circumference and hypertension and inversely associated with HDL cholesterol at the 11 y examinations. Conclusions We found a direct association between serum zinc and incidence of metabolic syndrome in middle-aged and older eastern Finnish men. Further studies are warranted to explore the mechanisms.

Background Studies of gender difference in type 2 diabetes have been inconclusive. We investigated gender difference in type 2 diabetes and the contribution of body iron, as assessed by serum ferritin to this difference. Methods We performed cross-sectional ( n = 1707) and prospective ( n = 1506) analyses in males and females aged 53–73 years in 1998–2001. Type 2 diabetes diagnosis was determined by questionnaire, blood glucose measurements and record linkage to type 2 diabetes registers. Gender difference in type 2 diabetes and serum ferritin contribution to the difference was examined in multivariable logistic and Cox regression models. Gender difference in fasting plasma glucose and insulin and homeostasis model assessment of insulin resistance was examined in linear regression analysis. Results In the cross-sectional analysis, a total of 201 type 2 diabetes cases were observed (males = 111 [55.2%] vs. female = 90 [44.8%], P = 0.032), and in adjusted models, males had higher odds of type 2 diabetes (OR = 1.61, 95% CI 1.10 to 2.34); higher fasting plasma glucose (β = 0.28, 95% CI 0.15 to 0.41), fasting plasma insulin (β = 0.73, 95% CI 0.26 to 1.19) and homeostasis model assessment of insulin resistance (β = 0.11, 95% CI 0.04 to 0.17). In the prospective analysis, males had increased risk of type 2 diabetes (HR = 1.46, 95% CI 1.03 to 2.07). With serum ferritin introduction (100 µg/L, log-transformed) into the models, the type 2 diabetes prevalence (OR = 1.35, 95% CI 0.91 to 1.99) and incidence (HR = 1.38, 95% CI 0.96 to 1.97) were appreciably attenuated. Conclusions These data suggest a gender difference in type 2 diabetes, with a higher prevalence and increased type 2 diabetes risk in males. Body iron explains about two-fifths and one-fifth of the gender difference in type 2 diabetes prevalence and incidence, respectively.

Article, Background Vegetarian and vegan diets have become more popular among adolescents and young adults. However, few studies have investigated the nutritional status of vegans, who may be at risk of nutritional deficiencies. Objective To compare dietary intake and nutritional status of Finnish long-term vegans and non-vegetarians. Methods Dietary intake and supplement use were estimated using three-day dietary records. Nutritional status was assessed by measuring biomarkers in plasma, serum, and urine samples. Vegans’ (n = 22) data was compared with those of sex- and age-matched non-vegetarians (n = 19). Results All vegans adhered strictly to their diet; however, individual variability was marked in food consumption and supplementation habits. Dietary intakes of key nutrients, vitamins B12 and D, were lower (P < 0.001) in vegans than in non-vegetarians. Nutritional biomarker measurements showed lower concentrations of serum 25-hydroxyvitamin D3 (25(OH)D3), iodine and selenium (corrected for multiple comparisons, P < 0.001), Vegans showed more favorable fatty acid profiles (P < 0.001) as well as much higher concentrations of polyphenols such as genistein and daidzein (P < 0.001). Eicosapentaenoic acid proportions in vegans were higher than expected. The median concentration of iodine in urine was below the recommended levels in both groups. Conclusions Long-term consumption of a vegan diet was associated with some favorable laboratory measures but also with lowered concentrations of key nutrients compared to reference values. This study highlights the need for nutritional guidance to vegans., published version, http://purl.org/eprint/status/PeerReviewed

Fish or fish oil consumption has been associated with lower blood pressure. Fish may also contain methylmercury, which has been associated with cardiovascular diseases and higher blood pressure. Our aim was to study the associations of serum long-chain n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA), mainly reflecting fish or fish oil intake, and hair mercury concentration with blood pressure. Data were available for 848 men and 909 women from the Kuopio Ischaemic Heart Disease Risk Factor Study, aged 53-73 years. We excluded participants with ischemic heart disease, stroke, diabetes or hypertension treatment, leaving 396 men and 372 women. Log-transformed values were used to study the associations. The mean serum concentrations were 1.63% (s.d. 0.91) for EPA, 0.77% (s.d. 0.16) for DPA and 2.73% (s.d. 0.90) for DHA of all serum fatty acids. Multivariate-adjusted serum EPA+DPA+DHA was associated with lower systolic blood pressure (β = -4.50, 95% confidence interval (CI) -8.02 - -0.99) and pulse pressure (β = -4.41, 95% CI -6.95 - -1.87), but not with diastolic blood pressure (β = -0.45, 95% CI -2.31-1.52). The associations were similar with EPA, DPA and DHA evaluated individually. The mean hair mercury concentration was 1.42 μg g(-1) (s.d. 1.54). Hair mercury was not associated with blood pressure and it did not modify the association between PUFA and blood pressure. These results suggest that higher serum long-chain n-3 PUFA concentration has a modest inverse association with blood pressure in older men and women.

Aims: Childhood psychosocial problems have been associated with poor alcohol habits in adulthood. The purpose of this study was to investigate further the association in men by using information from historical health records. Methods: As part of the epidemiological FinDrink Study, we examined the association between childhood psychosocial problems and total ethanol consumption, binge drinking, and abstinence in later life among Finnish men. The participants were a sample from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD), a population-based cohort study in eastern Finland. The data on childhood psychosocial factors were collected from health records (n = 952, 35.5% of the entire study sample), mainly from the 1930s to the 1950s. Questionnaire data on alcohol consumption were obtained from the baseline examinations of the KIHD cohort in 1984—1989. Results: Controlling for age and examination year, the men who had been considered psychosocially disadvantaged by elementary school nurses had a 2.72-fold (95% confidence interval 1.30—5.65) risk of bingeing on fortified wine in later life. After adjustment for adulthood behavioural and socioeconomic factors the association (odds ratio 3.71, 95% confidence interval 1.56—8.84) appeared even stronger. Childhood psychosocial problems also contributed to abstinence, but did not appear to increase the total amount of ethanol consumed. Conclusions: Psychosocial problems observed in boys seem to contribute to different alcohol habits in later life. However, the factors eventually involved in the manifestation of problematic drinking patterns through the life course still require further research.

To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] concentration, a marker of vitamin D status, and risk of all-cause and cardiovascular mortality in a general older population with relatively low average serum 25(OH)D concentrations.The study population included 552 men and 584 women aged 53-73 years who were free of CVD and cancer at baseline in 1998-2001 from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. Deaths were ascertained by a computer linkage to the national cause of death register. All deaths that occurred from the study entry to December 31, 2008, were included. Cox proportional hazards regression models were used to analyze the association between serum 25(OH)D and risk of death.The mean serum 25(OH)D concentration was 43.7 nmol/L (SD 17.8), with a strong seasonal variation. During the average follow-up of 9.1 years, 87 participants died, 35 from cardiovascular disease (CVD). After multivariable-adjustments, the hazard ratios (HR) for all cause death in the tertiles of serum 25(OH)D were 1, 1.68 (95% CI: 0.92, 3.07) and 2.06 (95% CI: 1.12, 3.80), p for trend = 0.02.Our study supports the accumulating evidence from epidemiological studies that vitamin D deficiency is associated with increased risk of death. Large-scale primary prevention trials with vitamin D supplementation are warranted.

Depression and cardiovascular disease (CVD) are closely associated, but the mechanisms underlying this connection are unclear. Regardless of the low cholesterol levels observed in depression, a small particle size of low-density lipoproteins (LDL), as well as elevated apolipoprotein B (ApoB) levels, are related to increased CVD risk, even when levels of LDL cholesterol are low. We examined the association between elevated depressive symptoms and compositional changes in serum LDL particles in a sample of 2,456 middle-aged Finnish men. Depressive symptoms were assessed with the 18-item Human Population Laboratory Depression Scale, and the study population was divided into two groups (elevated depressive symptoms, n = 269; non-depressed, n = 2,187). The levels of serum total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), triglycerides (TG), and ApoB were determined. The LDL-C/ApoB ratio, a marker of compositional changes in LDL particle size, was calculated. The group with elevated depressive symptoms had lowered levels of serum TC (P = 0.028) and LDL-C (P = 0.008). No differences were observed in the LDL-C/ApoB ratio. The likelihood for belonging to the group with elevated depressive symptoms increased 10% for each 0.5 mmol/l decrease in the levels of TC (P = 0.002) or LDL-C (P = 0.001) in regression models adjusted for age, examination years, marital and socioeconomic status, energy expenditure, body mass index, CVD history, alcohol consumption, smoking, and the use of lipid-lowering, antidepressant and antipsychotic medications. Our findings suggest that greater small-particle LDL levels are not associated with depression, and are thus unlikely to underlie the association between cardiovascular risk and depression.

Background— Atrial fibrillation (AF) is a common cardiac arrhythmia. Regular fish consumption has been shown to reduce the risk of AF in some but not all studies. Long-chain n-3 polyunsaturated fatty acids (PUFAs) from fish have been suggested to account for these beneficial effects. We tested this hypothesis by studying the association between the serum long-chain n-3 PUFAs eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid and risk of AF in men. Methods and Results— A total of 2174 men from the prospective population-based Kuopio Ischemic Heart Disease Risk Factor Study, 42 to 60 years old and free of AF at baseline in 1984 to 1989, were studied. During the average follow-up time of 17.7 years, 240 AF events occurred. In the Cox proportional hazards model, the multivariable-adjusted hazard ratio in the highest (>5.33%) versus the lowest (P for trend=0.07). Evaluated individually, only serum docosahexaenoic acid was associated with the risk of AF (hazard ratio in the highest versus the lowest quartile 0.62, 95% confidence interval 0.42 to 0.92, P for trend=0.02). Exclusion of subjects (n=233) with myocardial infarction or congestive heart failure either at baseline or that preceded the AF event during follow-up slightly strengthened the associations. Serum intermediate chain-length n-3 PUFA, α-linolenic acid, or hair methylmercury concentration were not associated with the risk. Conclusions— An increased concentration of long-chain n-3 PUFAs in serum, a marker of fish or fish oil consumption, may protect against AF. Serum docosahexaenoic acid concentration had the greatest impact.

Intake of lignans has been assessed in different study populations, but so far none of the studies has compared the daily intake of lignans and the urinary excretion of plant and enterolignans. We assessed the intake of lariciresinol, pinoresinol, secoisolariciresinol and matairesinol in 100 Finnish men consuming their habitual omnivorous diet, and measured the 24 h urinary excretion of plant and enterolignans to compare the intake and metabolism. Dietary determinants of lignan intake and their urinary excretion were also determined. The mean intake of lignans was 1224 (sd 539) μg/d, of which lariciresinol and pinoresinol covered 78 %. Almost half (47 %) of the intake of lignans was explained by the intake of rye products, berries, coffee, tea and roots. The urinary excretion of plant lignans corresponded to 17 % and enterolignans to 92 % of the intake of lignans. The urinary excretion of plant lignans was explained 14 % by the intake of rye products and intake of coffee, and consequently 3–7 % by the intake of water-insoluble fibre. The urinary excretion of enterolactone was explained 11 % by the intake of vegetables and rye products, 14 % by the intake of water-soluble fibre and only 4 % by the intake of lariciresinol. Although the assessed intake of lignans corresponded well with the urinary excretion of lignans, the enterolactone production in the human body depended more on the dietary sources of lignans than the absolute intake of lignans.

We studied the metabolism of berry anthocyanins to phenolic acids in six human subjects by giving them bilberry-lingonberry puree with and without oat cereals. Puree + cereals contained 1435 micromol of anthocyanins and 339 micromol of phenolic acids. The urinary excretion of measured 18 phenolic acids increased 241 micromol during the 48 h follow-up after the puree + cereals supplementation. The excretion peak of dietary phenolic acids was observed at 4-6 h after the puree + cereals supplementation and 2 h earlier after the supplementation of the puree alone. Homovanillic and vanillic acids were the most abundant metabolites, and they were partly produced from anthocyanins. No gallic acid, a fragmentation product of delphinidin glycosides, was detected, and only a very low amount of malvidin glycosides was possibly metabolized to syringic acid. Although anthocyanins were partly fragmented to phenolic acids, still a large part of metabolites remained unknown.

The role of flavonoids in CVD, especially in strokes, is unclear. Our aim was to study the role of flavonoids in CVD. We studied the association between the intakes of five subclasses (flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins), a total of twenty-six flavonoids, on the risk of ischaemic stroke and CVD mortality. The study population consisted of 1950 eastern Finnish men aged 42–60 years free of prior CHD or stroke as part of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up time of 15·2 years, 102 ischaemic strokes and 153 CVD deaths occurred. In the Cox proportional hazards model adjusted for age and examination years, BMI, systolic blood pressure, hypertension medication, serum HDL- and LDL-cholesterol, serum TAG, maximal oxygen uptake, smoking, family history of CVD, diabetes, alcohol intake, energy-adjusted intake of folate, vitamin E, total fat and saturated fat intake (percentage of energy), men in the highest quartile of flavonol and flavan-3-ol intakes had a relative risk of 0·55 (95 % CI 0·31, 0·99) and 0·59 (95 % CI 0·30, 1·14) for ischaemic stroke, respectively, as compared with the lowest quartile. After multivariate adjustment, the relative risk for CVD death in the highest quartile of flavanone and flavone intakes were 0·54 (95 % CI 0·32, 0·92) and 0·65 (95 % CI 0·40, 1·05), respectively. The present results suggest that high intakes of flavonoids may be associated with decreased risk of ischaemic stroke and possibly with reduced CVD mortality.

Mercury is a heavy metal that exists naturally in the environment. Major sources include the burning of fossil fuels (especially coal) and municipal waste incineration. Mercury can exist in several forms, with the most hazardous being organic methylmercury. In waterways (lakes, rivers, reservoirs, etc.), mercury is converted to methylmercury, which then accumulates in fish, especially in large predatory fish. Fish and fish products are the major--if not the only--source of methylmercury in humans. Mercury has long been recognized as a neurotoxin for humans, but in the last 10 years, its potentially harmful effects on cardiovascular diseases (CVD) have raised a cause for concern, mostly due to the proposed role of mercury in oxidative stress propagation. Some epidemiological studies have indeed found an association between increased levels of mercury in the body and risk of CVD. There are several plausible mechanisms to explain the association; these are discussed in this review. We also review the epidemiological studies that have investigated the association between mercury and CVD.

Background Depression is a major global public health concern. The aetiology of depression is partly unclear; however, intake of nutrients, such as magnesium, have been suggested to affect depressive symptoms and modify depression risk. Methods This research is a part of the Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study, conducted on a sample of 2320 Eastern Finnish men aged 42–61 years old at the baseline. Magnesium intake was assessed by a 4-day food record. Hospital discharge diagnosis of unipolar depressive disorder was used as an outcome variable. Results Participants in the middle tertile of dietary magnesium intake had a statistically significantly decreased risk of getting a hospital discharge diagnosis of depression compared to participants in the lowest tertile of magnesium intake (HR 0.49, CI 0.25–0.95, P =0.035) in the prospective setting after multivariable adjustments. In addition, an inverse association between magnesium intake and the risk of depression was found when the combined middle and highest tertiles of magnesium intake were compared with the lowest tertile (HR 0.53, CI 0.29–0.95, P =0.033). Limitations Our findings may not be generalizable to individuals below middle-age or women. Moreover, we were unable to consider cases with mild depression in the longitudinal setting. Conclusions The results of this study suggest that magnesium intake may have an effect on the risk to develop depression. Further studies are needed to investigate whether sufficient magnesium intake could have implications for prevention or treatment of depression.

Long-chain omega-3 polyunsaturated fatty acids (PUFAs) from fish have been shown to lower blood pressure. However, there is little information about the association with orthostatic hypotension, for which hypertension is a risk factor. We investigated the associations between serum long-chain omega-3 PUFAs and orthostatic hypotension in 1666 middle-aged or older men and women free of cardiovascular disease (CVD), diabetes or hypertension in 1998-2001 in the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) in eastern Finland. We also investigated the associations with mercury exposure, a major source of which is fish, and which has been associated with higher CVD risk in KIHD. Orthostatic hypotension was defined as decrease in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 1 min of standing. Orthostatic hypotension was found in 146 participants (8.8%). The mean serum concentrations were 1.67% (s.d. 0.92) for eicosapentaenoic acid, 0.79% (s.d. 0.16) for docosapentaenoic acid (DPA) and 2.78 (s.d. 0.92) for docosahexaenoic acid of all serum fatty acids. The mean pubic hair mercury concentration was 1.5 μg g(-1) (s.d. 1.6). We did not find statistically significant associations between the serum long-chain omega-3 PUFAs or pubic hair mercury and risk of orthostatic hypotension, except for DPA. Those in the highest vs. the lowest serum DPA tertile had multivariate-adjusted 41% lower odds for orthostatic hypotension (95% confidence interval 7-63%, P-trend=0.02). Serum long-chain omega-3 PUFAs or mercury exposure were not associated with the risk of orthostatic hypotension, except for the inverse association with DPA.

Objectives Zinc may play a role in the development of type 2 diabetes (T2D), because it is involved in antioxidant and anti-inflammatory activities. However, the role of zinc in the etiology of T2D has been poorly investigated. This study was conducted to study the association of serum zinc on T2D risk in middle-aged and older Finnish men. Methods This was a 20-year prospective follow-up study on 2220 Finnish men from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) who were 42 to 60 years old at baseline in 1984–1989. The main outcome was incident T2D. Serum zinc, body mass index (BMI), fasting blood glucose (FBG), serum insulin, C-reactive protein (CRP) and, in a subset of 751 participants, insulin-like growth factor-binding protein-1 (IGFBP-1), were measured. Also, the homeostatic model assessment (HOMA) was used to quantify insulin resistance (HOMA-IR), beta-cell function (HOMA-β) and insulin sensitivity (HOMA-IS). Results At baseline, serum zinc was associated with higher BMI, serum insulin, HOMA-IR, HOMA-β and IGFBP-1 and lower HOMA-IS. During the average follow-up of 19.3 years, 416 men developed T2D. Men in the highest quartile of serum zinc had 60% higher risk (95% CI 20–113%; P-trend

Background: In general populations, the effects of dietary cholesterol on blood cholesterol concentrations are modest. However, the relation is stronger in those with an ɛ4 allele in the apolipoprotein E gene (APOE). There is little information on the association between cholesterol intake and the risk of coronary artery disease (CAD) among those with the ApoE4 phenotype. Objective: We investigated the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with carotid intima-media thickness and the risk of incident CAD in middle-aged and older men from eastern Finland. Design: The study included 1032 men aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on common carotid artery intima-media thickness (CCA-IMT) were available for 846 men. Dietary intakes were assessed with 4-d food records. Associations with incident CAD and baseline CCA-IMT were analyzed by using Cox regression and ANCOVA, respectively. Results: The ApoE4 phenotype was found in 32.5% of the men. During the average follow-up of 20.8 y, 230 CAD events occurred. Egg or cholesterol intakes were not associated with the risk of CAD. Each 1 additional egg (55 g)/d was associated with a multivariable-adjusted HR of 1.17 (95% CI: 0.85, 1.61) in the ApoE4 noncarriers and an HR of 0.93 (95% CI: 0.50, 1.72) in the ApoE4 carriers (P-interaction = 0.34). Each 100-mg/d higher cholesterol intake was associated with an HR of 1.04 (95% CI: 0.89, 1.22) in the ApoE4 noncarriers and an HR of 0.95 (95% CI: 0.73, 1.25) in the ApoE4 carriers (P-interaction = 0.81). Egg or cholesterol intakes were also not associated with increased CCA-IMT. Conclusion: Egg or cholesterol intakes were not associated with increased CAD risk, even in ApoE4 carriers (i.e., in highly susceptible individuals).

To investigate the associations of serum long-chain omega-3 polyunsaturated fatty acids (PUFA) and hair mercury with future blood pressure in an ageing population.Prospective study with baseline measurements in 1998-2001 and follow-up measurements in 2005-2008. The linear relationships (β) of baseline serum fatty acids and hair mercury with future systolic and diastolic blood pressure and pulse pressure were analyzed with multiple linear regression models, using log-transformed values.181 men and 200 women aged 53-73 y from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) population in Eastern Finland, who were free of cardiovascular disease, diabetes or hypertension at baseline.Total serum esterified and nonesterified fatty acids and pubic hair mercury were used as markers for exposure. Anthropometric and other lifestyle and health-related data were collected.The mean serum concentrations were 1.67% (SD 0.92) for eicosapentaenoic acid (EPA), 0.79% (SD 0.16) for docosapentaenoic acid (DPA) and 2.78 (SD 0.92) for docosahexaenoic acid (DHA), of all serum fatty acids. The mean hair mercury concentration was 1.5 µg/g (SD 1.6). We did not find statistically significant associations between the baseline serum long-chain omega-3 PUFA concentrations or hair mercury content and future blood pressure. Hair mercury did not modify the associations with the long-chain omega-3 PUFAs, either.Higher serum long-chain omega-3 PUFA concentration, a biomarker of fish or fish oil consumption, may not have an impact on future blood pressure in an ageing population.

The authors analyzed data from a prospective, community-based cohort to assess the risk of incident type 2 diabetes mellitus associated with coffee and sweetened beverage consumption. They included 12,204 nondiabetic, middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) Study (1987-1999). Consumption of each beverage was assessed by food frequency questionnaire and classified into categories of cups per day. They found an inverse association, after adjusting for potential confounders, between increased coffee consumption and risk of type 2 diabetes mellitus in men (for > or =4 cups (> or =0.95 liter)/day compared with almost never: hazard ratio = 0.77, p(trend) = 0.02) with no significant association in women (hazard ratio = 0.89, p(trend) = 0.32) using a combination of self-report of physician-diagnosed diabetes, diabetes treatment, and a fasting or nonfasting blood glucose test. When self-reported diabetes or diabetes treatment alone was used, a stronger and significant inverse association was seen in men and women. Sweetened beverage consumption (men: hazard ratio = 1.03, p(trend) = 0.94; women: hazard ratio = 1.01, p(trend) = 0.58) showed no consistent association with the incidence of type 2 diabetes mellitus. In summary, increased coffee consumption was significantly associated with a decreased risk of diagnosed type 2 diabetes mellitus in community-based US adults.

Background and aim Homocysteine, a methionine metabolite, is suggested to be a risk factor for cardiovascular diseases (CVD). To date, the effects of dietary intake of methionine, the key amino acid in homocysteine metabolism, on CVD have not been studied. Our aim was to examine the effects of dietary methionine intake on the risk of acute coronary events. Methods and results We examined the effects of dietary methionine intake, assessed with 4-d food record, on acute coronary events in a prospective cohort study consisting of 1981 coronary disease free men from eastern Finland, aged 42–60 years at baseline in 1984–89, in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. During an average follow-up time of 14.0 years, 292 subjects experienced an acute coronary event. In a Cox proportional hazards model adjusting for age, examination years, BMI, urinary nicotine metabolites and protein intake (excluding methionine) the relative risks of acute coronary event in the three highest quarters of dietary methionine intake were 1.31 (95% CI: 0.92, 1.86), 1.31 (95% CI: 0.88, 1.96) and 2.08 (95% CI: 1.31, 3.29) as compared with the lowest quarter. Further adjustments did not change the results. However, opposite association was observed with total protein intake, which tended to decrease the risk. Conclusions The main finding of this study is that long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior CHD. More prospective research is needed to confirm the role of dietary methionine in the development of CVD, and whether its effects are independent of homocysteine.

Background Homocysteine and folate have been suggested to have opposite effects on the risk of stroke, although the results are controversial. Design and methods The purpose of this study was to assess the effects of serum total homocysteine (tHcy) and serum folate levels on the risk of stroke in a prospective cohort study. The subjects were 1015 men aged 46–64 years and free of prior stroke, examined in 1991–1993 in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. Results At baseline the mean serum tHcy concentration was 10.9 μmol/l (SD 3.4). During an average follow-up time of 9.6 years, 49 men experienced a stroke, of which 34 were ischaemic. In Cox proportional hazards models, men in the highest tHcy third had a risk factor-adjusted hazard rate ratio (RR) of 2.77 [95% confidence interval (CI): 1.23–6.24] for any stroke and 2.61 (95% CI: 1.02–6.71) for ischaemic stroke, compared with men in the lowest third. The mean baseline serum folate concentration was 10.4 nmol/l (SD 4.1). Men in the highest third of serum folate (> 11.2 nmol/l) had an adjusted RR for any stroke of 0.35 (95% CI: 0.14–0.87) and for ischaemic stroke of 0.40 (95% CI: 0.15–1.09), compared with men in the lowest third. Conclusion Elevated serum tHcy is associated with increased risk of all strokes and ischaemic strokes in middle-aged eastern Finnish men free of prior stroke. On the other hand, high serum folate concentration may protect against stroke.

Despite extensive research, the cardiovascular effects of coffee consumption in humans remain controversial. Our aim was to investigate the excretion of coffee phenols and the effects of filtered coffee consumption on oxidative stress and plasma homocysteine (tHcy) concentration in humans. The study consisted of a multiple-dose clinical supplementation trial and a single-dose study. In the long-term trial, 43 healthy nonsmoking men optionally consumed daily either no coffee, 3 cups (450 mL), or 6 cups (900 mL) of filtered coffee for 3 weeks, while in the short-term study 35 subjects consumed a single dose of 0, 1 (150 mL), or 2 cups (300 mL) of coffee. Long-term consumption of coffee increased the urinary excretion of caffeic and ferulic acid. The change in the total excretion of phenolic acids in 3 and 6 cups groups represented 3.8 and 2.5% of the amount ingested daily. Plasma tHcy concentrations increased nonsignificantly, but the consumption of coffee had neither short-nor long-term effects on lipid peroxidation or the activity of measured antioxidant enzymes. In conclusion, the consumption of filtered coffee does not have any detectable effects on lipid peroxidation in healthy nonsmoking men. The effect of coffee consumption on tHcy concentrations needs further investigation.

Objective— Mercury has been suggested to have negative effects on cardiovascular health. We investigated the effects of high mercury content in hair on the risk of acute coronary events and cardiovascular and all-cause mortality in men from eastern Finland. Methods and Results— The population-based prospective Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) cohort of 1871 Finnish men aged 42 to 60 years and free of previous coronary heart disease (CHD) or stroke at baseline was used. During an average follow-up time of 13.9 years, 282 acute coronary events and 132 cardiovascular disease (CVD), 91 CHD, and 525 all-cause deaths occurred. Men in the highest third of hair mercury content (>2.03 μg/g) had an adjusted 1.60-fold (95% CI, 1.24 to 2.06) risk of acute coronary event, 1.68-fold (95% CI, 1.15 to 2.44) risk of CVD, 1.56-fold (95% CI, 0.99 to 2.46) risk of CHD, and 1.38-fold (95% CI, 1.15 to 1.66) risk of any death compared with men in the lower two thirds. High mercury content in hair also attenuated the protective effects of high-serum docosahexaenoic acid plus docosapentaenoic acid concentration. Conclusions— High content of mercury in hair may be a risk factor for acute coronary events and CVD, CHD, and all-cause mortality in middle-aged eastern Finnish men. Mercury may also attenuate the protective effects of fish on cardiovascular health.

Cocoa powder is rich in polyphenols and, thus, may contribute to the reduction of lipid peroxidation. Our aim was to study the effects of long-term ingestion of chocolate, with differing amounts of polyphenols, on serum lipids and lipid peroxidation ex vivo and in vivo. We conducted a 3 week clinical supplementation trial of 45 nonsmoking, healthy volunteers. Participants consumed 75 g daily of either white chocolate (white chocolate, WC group), dark chocolate (dark chocolate, DC group), or dark chocolate enriched with cocoa polyphenols (high-polyphenol chocolate, HPC group). In the DC and HPC groups, an increase in serum HDL cholesterol was observed (11.4% and 13.7%, respectively), whereas in the WC group there was a small decrease (-2.9%, p < 0.001). The concentration of serum LDL diene conjugates, a marker of lipid peroxidation in vivo, decreased 11.9% in all three study groups. No changes were seen in the total antioxidant capacity of plasma, in the oxidation susceptibility of serum lipids or VLDL + LDL, or in the concentration of plasma F2-isoprostanes or hydroxy fatty acids. Cocoa polyphenols may increase the concentration of HDL cholesterol, whereas chocolate fatty acids may modify the fatty acid composition of LDL and make it more resistant to oxidative damage.

Heavy coffee consumption has been associated with increased coronary heart disease (CHD) risk although many studies have not observed any relation. We studied the effect of coffee consumption, assessed with a 4-d food record, on the incidence of nonfatal acute myocardial infarction or coronary death in a cohort of 1971 men who were 42 to 60 y old and free of symptomatic CHD at baseline in 1984-1989. During a mean follow-up of 14 y, 269 participants experienced an acute coronary event. After adjustment for age, smoking, exercise ischemia, diabetes, income, and serum insulin concentration, the rate ratios (95% CIs) in daily nondrinkers and light (375 mL or less), moderate (reference level), and heavy (814 mL or more) drinkers were 0.84 (0.41-1.72), 1.22 (0.90-1.64), 1.00, and 1.43 (1.06-1.94). To address time dependence of the effect, the analysis was repeated for 75 CHD events that occurred during the first 5 y; the respective rate ratios were 0.42 (0.06-3.10), 2.00 (1.16-3.44), 1.00, and 2.07 (1.17-3.65). Further adjustment for serum HDL and LDL cholesterol concentration, diastolic blood pressure, maximal oxygen uptake, and waist-hip ratio slightly increased the rate ratio for heavy coffee intake. Neither the brewing method (boiling vs. filtering) nor the serum LDL cholesterol concentration had any impact on the risk estimates for coffee intake. In conclusion, heavy coffee consumption increases the short-term risk of acute myocardial infarction or coronary death, independent of the brewing method or currently recognized risk factors for CHD.

Several cross-sectional studies have focused on the low blood folate levels of depressed patients. However, no published studies have examined the association between dietary folate and current symptoms of depression in a general population. We investigated the association between dietary folate, cobalamin, pyridoxine and riboflavin and current symptoms of depression in a cross-sectional general population study. We recruited 2682 men aged between 42 and 60 y from eastern Finland. Those who had a previous history of psychiatric disorder were excluded (n = 146, 5.6% of the cohort). Depressive symptoms were assessed with the 18-item Human Population Laboratory Depression Scale. Those who scored 5 or more at baseline were considered to have elevated depressive symptoms (n = 228, 9.3% of the cohort). The participants were grouped into thirds according to their dietary folate intake. Those in the lowest third of energy-adjusted folate intake had a higher risk of being depressed [odds ratio (OR) 1.67, 95% CI = 1.19-2.35, P = 0.003] than those in the highest folate intake third. This increased risk remained significant after adjustment for smoking habits, alcohol consumption, appetite, BMI, marital status, education, adulthood socioeconomic status and total fat consumption (OR = 1.46, 95% CI = 1.01-2.12, P = 0.044). There were no associations between the intake of cobalamin, pyridoxine or riboflavin, and depression. These results indicate that nutrition may have a role in the prevention of depression.

Background— Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT). Methods and Results— The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol ≥5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, P =0.014), in men by 33% (95% CI, 4 to 62, P =0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, P =0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P =0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol. Conclusions— These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.