A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.

Association between egg consumption and cardiovascular disease events, diabetes and all-cause mortality.

PURPOSE: The association between egg consumption and cardiovascular disease (CVD) or type 2 diabetes (T2D) remains controversial. We investigated the association between egg consumption and risk of CVD (primary outcome), T2D and mortality in the Caerphilly prospective cohort study (CAPS) and National Diet and Nutritional Survey (NDNS). METHODS: CAPS included 2512 men aged 45-59 years (1979-1983). Dietary intake, disease incidence and mortality were updated at 5-year intervals. NDNS included 754 adults aged 19-64 years from 2008 to 2012. RESULTS: Men free of CVD (n = 1781) were followed up for a mean of 22.8 years, egg consumption was not associated with new incidence of CVD (n = 715), mortality (n = 1028) or T2D (n = 120). When stroke (n = 248), MI (n = 477), heart failure (n = 201) were investigated separately, no associations between egg consumption and stroke and MI were identified, however, increased risk of stroke in subjects with T2D and/or impaired glucose tolerance (IGT, fasting plasma glucose ≥ 6.1 mmol/L), adjusted hazard ratios (95% CI) were 1.0 (reference), 1.09 (0.41, 2.88), 0.96 (0.37, 2.50), 1.39 (0.54, 3.56) and 2.87 (1.13, 7.27) for egg intake (n) of 0 ≤ n ≤ 1, 1 < n ≤ 2, 2 < n ≤ 3, 3 < n < 5, and n ≥ 5 eggs/wk, respectively (P = 0.01). In addition, cross-sectional analyses revealed that higher egg consumption was significantly associated with elevated fasting glucose in those with T2D and/or IGT (CAPS: baseline P = 0.02 and 5-year P = 0.04; NDNS: P = 0.05). CONCLUSIONS: Higher egg consumption was associated with higher blood glucose in subjects with T2D and/or IGT. The increased incidence of stroke with higher egg consumption among T2D and/or IGT sub-group warrants further investigation.

Vitamin D intake and risk of CVD and all-cause mortality: evidence from the Caerphilly Prospective Cohort Study.

OBJECTIVE: Prospective data on the associations between vitamin D intake and risk of CVD and all-cause mortality are limited and inconclusive. The aim of the present study was to investigate the associations between vitamin D intake and CVD risk and all-cause mortality in the Caerphilly Prospective Cohort Study. DESIGN: The associations of vitamin D intake with CVD risk markers were examined cross-sectionally at baseline and longitudinally at 5-year, 10-year and >20-year follow-ups. In addition, the predictive value of vitamin D intake for CVD events and all-cause mortality after >20 years of follow-up was examined. Logistic regression and general linear regression were used for data analysis. SETTING: Participants in the UK. SUBJECTS: Men (n 452) who were free from CVD and type 2 diabetes at recruitment. RESULTS: Higher vitamin D intake was associated with increased HDL cholesterol (P=0·003) and pulse pressure (P=0·04) and decreased total cholesterol:HDL cholesterol (P=0·008) cross-sectionally at baseline, but the associations were lost during follow-up. Furthermore, higher vitamin D intake was associated with decreased concentration of plasma TAG at baseline (P=0·01) and at the 5-year (P=0·01), but not the 10-year examination. After >20 years of follow-up, vitamin D was not associated with stroke (n 72), myocardial infarctions (n 142), heart failure (n 43) or all-cause mortality (n 281), but was positively associated with increased diastolic blood pressure (P=0·03). CONCLUSIONS: The study supports associations of higher vitamin D intake with lower fasting plasma TAG and higher diastolic blood pressure.

Associations between dairy consumption and body weight: a review of the evidence and underlying mechanisms.

As the incidence of obesity is reaching 'epidemic' proportions, there is currently widespread interest in the impact of dietary components on body-weight and food intake regulation. The majority of data available from both epidemiological and intervention studies provide evidence of a negative but modest association between milk and dairy product consumption and BMI and other measures of adiposity, with indications that higher intakes result in increased weight loss and lean tissue maintenance during energy restriction. The purported physiological and molecular mechanisms underlying the impact of dairy constituents on adiposity are incompletely understood but may include effects on lipolysis, lipogeneis and fatty acid absorption. Furthermore, accumulating evidence indicates an impact of dairy constituents, in particular whey protein derivatives, on appetite regulation and food intake. The present review summarises available data and provides an insight into the likely contribution of dairy foods to strategies aimed at appetite regulation, weight loss or the prevention of weight gain.

Aspirin and cancer survival: a systematic review and meta-analyses of 118 observational studies of aspirin and 18 cancers.

BACKGROUND: Despite the accumulation of research papers on aspirin and cancer, there is doubt as to whether or not aspirin is an acceptable and effective adjunct treatment of cancer. The results of several randomised trials are awaited, and these should give clear evidence on three common cancers: colon, breast and prostate. The biological effects of aspirin appear likely however to be of relevance to cancer generally, and to metastatic spread, rather than just to one or a few cancers, and there is already a lot of evidence, mainly from observational studies, on the association between aspirin and survival in a wide range of cancers. AIMS: In order to test the hypothesis that aspirin taking is associated with an increase in the survival of patients with cancer, we conducted a series of systematic literature searches to identify clinical studies of patients with cancer, some of whom took aspirin after having received a diagnosis of cancer. RESULTS: Three literature searches identified 118 published observational studies in patients with 18 different cancers. Eighty-one studies report on aspirin and cancer mortality and 63 studies report on all-cause mortality. Within a total of about a quarter of a million patients with cancer who reported taking aspirin, representing 20%-25% of the total cohort, we found aspirin to be associated with a reduction of about 20% in cancer deaths (pooled hazard ratio (HR): 0.79; 95% confidence intervals: 0.73, 0.84 in 70 reports and a pooled odds ratio (OR): 0.67; 0.45, 1.00 in 11 reports) with similar reductions in all-cause mortality (HR: 0.80; 0.74, 0.86 in 56 studies and OR: 0.57; 0.36, 0.89 in seven studies). The relative safety of aspirin taking was examined in the studies and the corresponding author of every paper was written to asking for additional information on bleeding. As expected, the frequency of bleeding increased in the patients taking aspirin, but fatal bleeding was rare and no author reported a significant excess in fatal bleeds associated with aspirin. No author mentioned cerebral bleeding in the patients they had followed. CONCLUSIONS: There is a considerable body of evidence suggestive of about a 20% reduction in mortality in patients with cancer who take aspirin, and the benefit appears not to be restricted to one or a few cancers. Aspirin, therefore, appears to deserve serious consideration as an adjuvant treatment of cancer, and patients with cancer, and their carers, have a right to be informed of the available evidence.

Aspirin, salicylates, and cancer.

Evidence from a wide range of sources suggests that individuals taking aspirin and related non-steroidal anti-inflammatory drugs have reduced risk of large bowel cancer. Work in animals supports cancer reduction with aspirin, but no long-term randomised clinical trials exist in human beings, and randomisation would be ethically unacceptable because vascular protection would have to be denied to a proportion of the participants. However, opportunistic trials of aspirin, designed to test vascular protection, provide some evidence of a reduction in cancer, but only after at least 10 years. We summarise evidence for the potential benefit of aspirin and natural salicylates in cancer prevention. Possible mechanisms of action and directions for further work are discussed, and implications for clinical practice are considered.

The survival advantage of milk and dairy consumption: an overview of evidence from cohort studies of vascular diseases, diabetes and cancer.

OBJECTIVES: To conduct a detailed evaluation, with meta-analyses, of the published evidence on milk and dairy consumption and the incidence of vascular diseases and diabetes. Also to summarise the evidence on milk and dairy consumption and cancer reported by the World Cancer Research Fund and then to consider the relevance of milk and dairy consumption to survival in the UK, a typical Western community. Finally, published evidence on relationships with whole milk and fat-reduced milks was examined. METHODS: Prospective cohort studies of vascular disease and diabetes with baseline data on milk or dairy consumption and a relevant disease outcome were identified by searching MEDLINE, and reference lists in the relevant published reports. Meta-analyses of relationships in these reports were conducted. The likely effect of milk and dairy consumption on survival was then considered, taking into account the results of published overviews of relationships of these foods with cancer. RESULTS: From meta-analysis of 15 studies the relative risk of stroke and/or heart disease in subjects with high milk or dairy consumption was 0.84 (95% CI 0.76, 0.93) and 0.79 (0.75, 0.82) respectively, relative to the risk in those with low consumption. Four studies reported incident diabetes as an outcome, and the relative risk in the subjects with the highest intake of milk or diary foods was 0.92 (0.86, 0.97). CONCLUSIONS: Set against the proportion of total deaths attributable to the life-threatening diseases in the UK, vascular disease, diabetes and cancer, the results of meta-analyses provide evidence of an overall survival advantage from the consumption of milk and dairy foods.

Dairy Foods and Body Mass Index over 10-Year: Evidence from the Caerphilly Prospective Cohort Study.

The association between dairy product consumption and body mass index (BMI) remains controversial. The aim of the present study was to investigate the association between total dairy, milk, cheese, cream and butter consumption and BMI change over a 10-year follow-up by using long-term follow-up cohort data from the Caerphilly Prospective Cohort Study (CAPS). The CAPS included 2512 men aged 45⁻59 years at baseline, who were followed up at 5-year intervals for over 20-year. A semi-quantitative food frequency questionnaire estimated the intake of dairy consumption, including milk, cheese, cream and butter at baseline, 5-year and 10-year follow-up. In total, men free of cardiovascular disease, diabetes and cancer (n = 1690) were included in current analysis. General linear regression and logistic regression were used for data analysis. The results showed higher cheese consumption was associated with lower BMI at the 5-year follow-up (p = 0.013). There was no evidence that higher consumption of total dairy, milk, cream and butter were significantly associated with BMI during the over the 10-year following-up. This study suggest that cheese consumption have beneficial effects on lowering BMI, which needs further investigation.

Systematic review update of observational studies further supports aspirin role in cancer treatment: Time to share evidence and decision-making with patients?

BACKGROUND: Evidence is growing that low-dose aspirin used as an adjuvant treatment of cancer is associated with an increased survival and a reduction in metastatic spread. We therefore extended up to August 2017 an earlier systematic search and meta-analyses of published studies of low-dose aspirin taken by patients with a diagnosis of cancer. METHODS: Searches were completed in Medline and Embase to August 2017 using a pre-defined search strategy to identify reports of relevant studies. References in all the selected papers were scanned. Two reviewers independently applied pre-determined eligibility criteria and extracted data on cause-specific cancer deaths, overall mortality and the occurrence of metastatic spread. Meta-analyses were then conducted for different cancers and heterogeneity and publication bias assessed. Sensitivity analyses and attempts to reduce heterogeneity were conducted. RESULTS: Analyses of 29 studies reported since an earlier review up to April 2015 are presented in this report, and these are then pooled with the 42 studies in our earlier publication. Overall meta-analyses of the 71 studies are presented, based on a total of over 120 thousand patients taking aspirin. Ten of the studies also give evidence on the incidence of metastatic cancer spread. There are now twenty-nine observational studies describing colorectal cancer (CRC) and post-diagnostic aspirin. Pooling the estimates of reduction by aspirin which are reported as hazard ratios (HR), gives an overall HR for aspirin and CRC mortality 0.72 (95% CI 0.64-0.80). Fourteen observational studies have reported on aspirin and breast cancer mortality and pooling those that report the association with aspirin as a hazard ratio gives HR 0.69 (0.53-0.90). Sixteen studies report on aspirin and prostate cancer mortality and a pooled estimate yields an HR of 0.87 (95% CI 0.73-1.05). Data from 12 reports relating to other cancers are also listed. Ten studies give evidence of a reduction in metastatic spread; four give a pooled HR 0.31 (95% CI 0.18, 0.54) and five studies which reported odds ratio of metastatic spread give OR 0.79 (0.66 to 0.95). CONCLUSION: Being almost entirely from observational studies, the evidence of benefit from aspirin is limited. There is heterogeneity between studies and the results are subject to important biases, only some of which can be identified. Nevertheless, the evidence would seem to merit wide discussion regarding whether or not it is adequate to justify the recommendation of low-dose therapeutic aspirin, and if it is, for which cancers?

Healthy living and cancer: evidence from UK Biobank.

CONTEXT: UK Biobank is a prospective study of half a million subjects, almost all aged 40-69 years, identified in 22 centres across the UK during 2006-2010. OBJECTIVE: A healthy lifestyle has been described as 'better than any pill, and no side effects [5]. We therefore examined the relationships between healthy behaviours: low alcohol intake, non-smoking, healthy BMI, physical activity and a healthy diet, and the risk of all cancers, colon, breast and prostate cancers in a large dataset. METHOD: Data on lifestyle behaviours were provided by 343,150 subjects, and height and weight were measured at recruitment. 14,285 subjects were diagnosed with cancer during a median of 5.1 years of follow-up. RESULTS: Compared with subjects who followed none or a single healthy behaviour, a healthy lifestyle based on all five behaviours was associated with a reduction of about one-third in incident cancer (hazard ratio [HR] 0.68; 95% confidence intervals [CI] 0.63-0.74). Colorectal cancer was reduced in subjects following the five behaviours by about one-quarter (HR 0.75; 95% CI 0.58-0.97), and breast cancer by about one-third (HR 0.65; 95% CI 0.52-0.83). The association between a healthy lifestyle and prostate cancer suggested a significant increase in risk, but this can be attributed to bias consequent on inequalities in the uptake of the prostate specific antigen screening test. CONCLUSIONS: Taken together with reported reductions in diabetes, vascular disease and dementia, it is clearly important that every effort is taken to promote healthy lifestyles throughout the population, and it is pointed out that cancer and other screening clinics afford 'teachable moments' for the promotion of a healthy lifestyle.

Milk and dairy consumption, diabetes and the metabolic syndrome: the Caerphilly prospective study.

OBJECTIVES: To report a negative association between milk or dairy consumption and the metabolic syndrome and to examine associations within the Caerphilly cohort. SETTING: A representative sample of men aged 45-59 years in Caerphilly, UK. PARTICIPANTS AND DATA: Data on fasting blood glucose and plasma insulin, fasting plasma triglycerides and high-density lipoprotein cholesterol, body mass index, and blood pressure were used to define the metabolic syndrome in terms of levels of two or more variates within the top 10%. The clinical importance of the syndrome was assessed from 20-year incidence of diabetes, vascular events and deaths. The relationships between the syndrome and the consumption of milk and dairy products was examined using data from both a semiquantitative food frequence questionnaire, and from a 7-day weighed intake record which had been kept by a 1:3 subsample of the men. MAIN RESULTS: There were 2,375 men without diabetes in the cohort. The prevalence of the metabolic syndrome was 15%. Men with the syndrome had significantly increased risks of a subsequent ischaemic heart disease event, death or diabetes. Negative relationships were shown between both the consumption of milk and dairy produce, and the syndrome. Adjusted odds ratio in men who regularly drank a pint of milk or more daily was 0.38 (0.18 to 0.78) and that for dairy food consumption was 0.44 (0.21 to 0.91). Milk intake showed no significant trend with incident diabetes. CONCLUSIONS: The consumption of milk and dairy products is associated with a markedly reduced prevalence of the metabolic syndrome, and these items therefore fit well into a healthy eating pattern.

Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies.

BACKGROUND: Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. OBJECTIVES: We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. METHODS: Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. RESULTS: Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79-0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76-0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available. CONCLUSIONS AND IMPLICATIONS: The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin. SYSTEMATIC REVIEW PROTOCOL NUMBER: CRD42015014145.

Systematic Review and Meta-Analysis of Randomised Trials to Ascertain Fatal Gastrointestinal Bleeding Events Attributable to Preventive Low-Dose Aspirin: No Evidence of Increased Risk.

BACKGROUND: Aspirin has been shown to lower the incidence and the mortality of vascular disease and cancer but its wider adoption appears to be seriously impeded by concerns about gastrointestinal (GI) bleeding. Unlike heart attacks, stroke and cancer, GI bleeding is an acute event, usually followed by complete recovery. We propose therefore that a more appropriate evaluation of the risk-benefit balance would be based on fatal adverse events, rather than on the incidence of bleeding. We therefore present a literature search and meta-analysis to ascertain fatal events attributable to low-dose aspirin. METHODS: In a systematic literature review we identified reports of randomised controlled trials of aspirin in which both total GI bleeding events and bleeds that led to death had been reported. Principal investigators of studies in which fatal events had not been adequately described were contacted via email and asked for further details. A meta-analyses was then performed to estimate the risk of fatal gastrointestinal bleeding attributable to low-dose aspirin. RESULTS: Eleven randomised trials were identified in the literature search. In these the relative risk (RR) of 'major' incident GI bleeding in subjects who had been randomised to low-dose aspirin was 1.55 (95% CI 1.33, 1.83), and the risk of a bleed attributable to aspirin being fatal was 0.45 (95% CI 0.25, 0.80). In all the subjects randomised to aspirin, compared with those randomised not to receive aspirin, there was no significant increase in the risk of a fatal bleed (RR 0.77; 95% CI 0.41, 1.43). CONCLUSIONS: The majority of the adverse events caused by aspirin are GI bleeds, and there appears to be no valid evidence that the overall frequency of fatal GI bleeds is increased by aspirin. The substantive risk for prophylactic aspirin is therefore cerebral haemorrhage which can be fatal or severely disabling, with an estimated risk of one death and one disabling stroke for every 1,000 people taking aspirin for ten years. These adverse effects of aspirin should be weighed against the reductions in vascular disease and cancer.

Fibrinogen, viscosity and white blood cell count predict myocardial, but not cerebral infarction: evidence from the Caerphilly and Speedwell cohort.

Fibrinogen, plasma viscocity, and the white blood cell count predict ischaemic heart disease, but there is less certainty for their predictive power for ischaemic stroke. Studying stroke and ischaemic heart disease in the same cohort prospectively allows comparison of predictive strengths. The Caerphilly and Speedwell cohorts consist of a population sample of 4,860 men aged 45-59 years at recruitment who had baseline measurements of fibrinogen, plasma viscosity, and white blood cell counts. After 15-19 years of follow-up, men in the two cohorts experienced 312 ischaemic strokes and 557 ischaemic heart disease events. Mean fibrinogen, plasma viscosity and white blood cell counts differed significantly after adjustment for confounding factors between men with and without ischaemic heart disease, 0.25 g/l (95% CIs 0.1 8-0.32); 0.036 cp (95% CIs 0.027-0.044); 0.67 x 10(9)/l (95% CIs 0.50-0.84) respectively. The same measurements showed no significant differences after adjustment for the same confounding factors for men with and without ischaemic stroke, 0.05 g/l (95% CIs -0.04-0.14); 0.008 cp (95% CIs -0.003-0.019); 0.16 x 10(9)/l (95% CIs -0.06-0.38) respectively.

Is type A behavior really a trigger for coronary heart disease events?

OBJECTIVE: The purpose of this study was to compare chronic with acute mechanisms by which Type A might predict incident coronary heart disease (CHD). METHOD: The study included 2394 men aged 50 to 64 years who were assessed for CHD, Type A behavior, and CHD risk factors. Type A was assessed using the Jenkins Activity Survey (JAS), the Bortner scale, and the Framingham scale. Further examinations were completed at 5 and 9 years for incident CHD. RESULTS: After 9 years, there was no increased risk of CHD associated with any Type A score. Nevertheless, high Bortner scores were associated with increased risk of incident CHD at 5 years and high JAS and Bortner scores were associated with a decreased risk between 5 and 9 years. Further analysis of Type A scores on time to first coronary event found strong inverse associations for all type A scores (JAS = 205 -0.49 months to first event, 95% CI = -0.20, -0.78, p =.001) (Bortner = 176 -0.27 months; 95% CI = -0.10, -0.44; p =.002) (Framingham = 0.44 -0.0011 months; 95% CI = -0.0002, -0.0019; p =.01). CONCLUSIONS: The data show Type A is a strong predictor of when incident coronary heart disease (or coronary event) will occur rather than if it will occur. These findings suggest that Type A increases exposure to potential triggers, rather than materially affecting the process of atherosclerosis.

Does dairy food intake predict arterial stiffness and blood pressure in men?: Evidence from the Caerphilly Prospective Study.

Arterial stiffness is an independent predictor of cardiovascular disease events and mortality, and like blood pressure, may be influenced by dairy food intake. Few studies have investigated the effects of consumption of these foods on prospective measures of arterial stiffness. The present analysis aimed to investigate the prospective relationship between milk, cheese, cream, and butter consumption and aortic pulse wave velocity, augmentation index, systolic and diastolic blood pressure, as well as cross-sectional relationships between these foods and systolic and diastolic blood pressure and metabolic markers using data from the Caerphilly Prospective Study. Included in this cohort were 2512 men, aged 45 to 59 years, who were followed up at 5-year intervals for a mean of 22.8 years (number follow-up 787). Augmentation index was 1.8% lower in subjects in the highest quartiles of dairy product intake compared with the lowest (P trend=0.021), whereas in the highest group of milk consumption systolic blood pressure was 10.4 mm Hg lower (P trend=0.033) than in nonmilk consumers after a 22.8-year follow-up. Cross-sectional analyses indicated that across increasing quartiles of butter intake, insulin (P trend=0.011), triacylglycerol (P trend=0.023), total cholesterol (P trend=0.002), and diastolic blood pressure (P trend=0.027) were higher. Across increasing groups of milk intake and quartiles of dairy product intake, glucose (P trend=0.032) and triglyceride concentrations (P trend=0.031) were lower, respectively. The present results confirm that consumption of milk predicts prospective blood pressure, whereas dairy product consumption, excluding butter, is not detrimental to arterial stiffness and metabolic markers. Further research is needed to better understand the mechanisms that underpin these relationships.

Sleep disturbance and daytime sleepiness predict vascular dementia.

BACKGROUND: Disturbed sleep is common throughout the community and is associated with an increase in daytime sleepiness, both of which, in turn are associated with an increased risk of ischaemic vascular disease. The hypothesis that sleep disturbances are predictive of dementia, and in particular vascular dementia was tested in a large community-based cohort of older men. METHODS: A questionnaire on sleep disturbances was administered to 1986 men aged 55-69 years in the Caerphilly Cohort Study and 10 years later the men were examined clinically for evidence of dementia or cognitive impairment with no dementia (CIND). FINDINGS: Approximately 20% of the men reported disturbed sleep and 30% reported 'severe' daytime sleepiness. Ten years later 1,225 men (75% of the surviving men in the cohort) were tested and 268 (22%) were found to be cognitively impaired with 93 (7.6%) showing clear evidence of dementia and the remaining 175 (14.3%) showing evidence of CIND. After adjustment for possible confounding, including cognitive function and the taking of sleeping tablets at baseline, sleep disturbances appeared to be predictive of dementia and CIND of vascular origin, while there was no suggestion of prediction of non-vascular cognitive impairment by sleep. Prediction of vascular dementia appeared to be particularly strong for daytime sleepiness, with an adjusted OR of 4.44 (95% CI 2.05 to 9.61). Further adjustments for psychological distress at baseline reduced the size of the relationships, but the ORs remain large, consistent with a direct positive effect of sleep disturbance on vascular dementia. INTERPRETATION: Sleep disturbances, and in particular severe daytime sleepiness, appear to be strongly predictive of vascular dementia, but have no predictive power for non vascular dementia.