Lifetime and 10-year risks of cardiovascular mortality in relation to risk factors in middle and old age: 50-year follow-up of the Whitehall study of London Civil Servants.

BACKGROUND: Cardiovascular disease (CVD)-related mortality has declined substantially in the United Kingdom (UK) in recent decades, but the continued relevance of conventional risk factors for prediction of CVD mortality throughout the life-course is uncertain. We compared the 10-year risks and lifetime risks of CVD mortality associated with conventional risk factors recorded in middle and old age. METHODS: The Whitehall study was a prospective study of 19,019 male London civil servants (mean age 52 years) when enrolled in 1967-1970 and followed-up for 50 years for cause-specific mortality. In 1997, 7044 (83%) survivors (mean age 77 years) were re-surveyed. The 10-year and lifetime risks of CVD mortality were estimated by levels of CVD risk factors recorded in middle-age and old-age, respectively. RESULTS: By July 2020, 97% had died (22%, 51% and 80% before age 70, 80 and 90 years, respectively) and 7944 of 17,673 deaths (45%) were from CVD. The 10-year and lifetime risks of CVD death increased linearly with higher levels of CVD risk factors recorded in middle-age and in old-age. Individuals in the top versus bottom 5% of CVD risk scores in middle age had a 10.3% (95% CI:7.2-13.4) vs 0.6% (0.1-1.2) 10-year risk of CVD mortality, a 61.4% (59.4-65.3) vs 31.3% (24.1-34.5) lifetime risk of CVD mortality and a 12-year difference in life expectancy from age 50 years. The corresponding differences using a CVD risk score in old-age were 11.0% (4.4-17.5) vs 0.8% (0.0-2.2) for 10-year risk and 42.1% (28.2-50.0) vs 30.3% (6.0-38.0) for lifetime risk of CVD mortality and a 6-year difference in life expectancy from age 70 years. CONCLUSIONS: Conventional risk factors remained highly predictive of CVD mortality and life expectancy through the life-course. The findings highlight the relevance of estimation of both lifetime risks of CVD and 10-year risks of CVD for primary prevention of CVD.

Tissue sodium content in patients with systemic lupus erythematosus: association with disease activity and markers of inflammation.

OBJECTIVES: Sodium (Na+) is stored in the skin and muscle and plays an important role in immune regulation. In animal models, increased tissue Na+ is associated with activation of the immune system, and high salt intake exacerbates autoimmune disease and worsens hypertension. However, there is no information about tissue Na+ and human autoimmune disease. We hypothesized that muscle and skin Na+ content is (a) higher in patients with systemic lupus erythematosus (SLE) than in control subjects, and (b) associated with blood pressure, disease activity, and inflammation markers (interleukin (IL)-6, IL-10 and IL-17 A) in SLE. METHODS: Lower-leg skin and muscle Na+ content was measured in 23 patients with SLE and in 28 control subjects using 23Na+ magnetic resonance imaging. Demographic and clinical information was collected from interviews and chart review, and blood pressure was measured. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Plasma inflammation markers were measured by multiplex immunoassay. RESULTS: Muscle Na+ content was higher in patients with SLE (18.8 (16.7-18.3) mmol/L) than in control subjects (15.8 (14.7-18.3) mmol/L; p < 0.001). Skin Na+ content was also higher in SLE patients than in controls, but this difference was not statistically significant. Among patients with SLE, muscle Na+ was associated with SLEDAI and higher concentrations of IL-10 after adjusting for age, race, and sex. Skin Na+ was significantly associated with systolic blood pressure, but this was attenuated after covariate adjustment. CONCLUSION: Patients with SLE had higher muscle Na+ content than control subjects. In patients with SLE, higher muscle Na+ content was associated with higher disease activity and IL-10 concentrations.

Induction of ß-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis.

Tuberculosis is a worldwide health problem, and multidrug-resistant (MDR) and extensively multidrug-resistant (XMDR) strains are rapidly emerging and threatening the control of this disease. These problems motivate the search for new treatment strategies. One potential strategy is immunotherapy using cationic anti-microbial peptides. The capacity of l-isoleucine to induce beta-defensin expression and its potential therapeutic efficiency were studied in a mouse model of progressive pulmonary tuberculosis. BALB/c mice were infected with Mycobacterium tuberculosis strain H37Rv or with a MDR clinical isolate by the intratracheal route. After 60 days of infection, when disease was in its progressive phase, mice were treated with 250 µg of intratracheal l-isoleucine every 48 h. Bacillary loads were determined by colony-forming units, protein and cytokine gene expression were determined by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively, and tissue damage was quantified by automated morphometry. Administration of l-isoleucine induced a significant increase of beta-defensins 3 and 4 which was associated with decreased bacillary loads and tissue damage. This was seen in animals infected with the antibiotic-sensitive strain H37Rv and with the MDR clinical isolate. Thus, induction of beta-defensins might be a potential therapy that can aid in the control of this significant infectious disease.

BMI peak in infancy as a predictor for later BMI in the Uppsala Family Study.

BACKGROUND: The development of obesity through childhood, often characterized by using body mass index (BMI), has received much recent interest because of the rapidly increasing levels of obesity worldwide. However, the extent to which the BMI trajectory in the first year of life (the BMI 'peak' in particular) is associated with BMI in later childhood has received little attention. SUBJECTS: The Uppsala Family Study includes 602 families, comprising mother, father and two consecutive singleton offspring, both of whom were delivered at the Uppsala Academic Hospital, Sweden, between 1987 and 1995. The children's postnatal growth data, including serial measurements of height and weight (from which BMI was calculated), were obtained from health records. All children had a physical examination when they were aged between 5 and 13 years, at which height and weight were again recorded and used to calculate age- and sex-adjusted BMI z-scores. METHODS: Subject-specific growth curves were fitted to the infant BMI data using penalized splines with random coefficients, and from these the location of the BMI peak for each participant was estimated. A multilevel modelling approach was used to assess the relationships between the BMI peak and BMI z-score in later childhood. RESULTS: The BMI peak occurred, on average, slightly later in female children, with a higher BMI peak in male children. Considered separately, both age and BMI at BMI peak were positively associated with later BMI z-score. Considered jointly, both dimensions of BMI peak retained their positive associations. CONCLUSIONS: The growth trajectory associated with higher childhood BMI appears to include a later and/or higher BMI peak in infancy.

Reduced expression and desensitization of adenosine A1 receptor/adenylyl cyclase pathway after chronic (-)N6-phenylisopropyladenosine intake during pregnancy.

Little is known about the G protein-coupled receptor desensitization process during pregnancy. Wistar pregnant rats were treated with (-)N(6)-phenylisopropyladenosine (R-PIA), an adenosine A(1) receptor (A(1)R) agonist, in their drinking water during pregnancy, and the effect on A(1)R/adenylyl cyclase system was studied in both maternal and fetal brain. In maternal brain, binding assays revealed a significant decrease in total receptor numbers in plasma membranes (27%, P<0.05), with no significant changes in receptor affinity. The effect of R-PIA on plasma membranes from fetal brains was more marked, with approximately 42% (P<0.05) of the total receptors detected in control fetuses. Real time reverse transcriptase polymerase chain reaction (RT-PCR) analyses showed that chronic R-PIA treatment during the whole gestational period only decreased significantly mRNA level coding A(1)R in maternal brain (P<0.05). alpha Gi(1,2) and alpha Gi(3) subunits were not affected in mothers or fetuses as revealed by immunoblotting. mRNA levels coding these subunits were also unaffected in mothers and fetuses. On the other hand, forskolin- and forskolin-plus guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S)-stimulated adenylyl cyclase activity was decreased in maternal (P<.01) and fetal brain (P<.001). Furthermore, adenylyl cyclase inhibition elicited by N(6)-cyclohexyladenosine (CHA), a selective A(1)R agonist, was significantly decreased in both maternal (P<0.05) and fetal brain (P<.01), suggesting a desensitization of the A(1)R/adenylyl cyclase pathway. Therefore, these results suggest that R-PIA intake during pregnancy causes desensitization of the A(1)R-mediated inhibitory transduction pathway in both maternal and fetal brain, probably due to the decreased density of A(1)R at the cell surface.

Socioeconomic position and hypertension: a study of urban civil servants in Ghana.

BACKGROUND: The association of socioeconomic position and cardiovascular disease risk factors in low- and middle-income countries has not been as consistent as that reported from high-income countries. METHODS: A cross-sectional study of 1015 participants from seven civil service departments in Accra, Ghana, was conducted in 2006. Hypertension was diagnosed when the mean of a second and third blood pressure reading on each of two visits 3 weeks apart was > or =140/90 mmHg or where participants were already diagnosed and on antihypertensive drugs. Socioeconomic measures considered were education, early life and adult wealth and civil service employment grade. RESULTS: The age-adjusted prevalence of hypertension was lowest in participants of lower socioeconomic position (OR 21.9%; 95% CI 16.3 to 27.5) and highest in those of highest socioeconomic position (OR 31.8%; 95% CI 23.4 to 40.2) with inconsistent patterns among participants in the intermediate socioeconomic groups. Participants in the highest employment grade category were more likely to have hypertension than those in the lowest category (OR 1.91; 95% CI 1.14 to 3.20). There was a positive graded association between adult wealth and hypertension, with more assets associated with a greater risk (p trend 0.008). This trend was partly explained by body mass index differences. Blood pressure control among those with diagnosed hypertension was generally poor across the socioeconomic strata. CONCLUSIONS: In low-income countries such as Ghana, there is a need to promote primary prevention of hypertension across the socioeconomic strata, with a focus on weight control among civil servants of higher socioeconomic position, and better hypertension control in those with hypertension.

Obesity in urban civil servants in Ghana: association with pre-adult wealth and adult socio-economic status.

OBJECTIVE: To investigate the distribution of obesity and its association with pre-adult wealth and adult socio-economic factors in urban Ghanaian civil servants. STUDY DESIGN: Cross-sectional study of urban civil servants. METHODS: A total of 1015 (615 men and 400 women) civil servants aged 25 years and above employed in seven central government ministries and departments in Accra, Ghana were studied (participation rate 82.7%). RESULTS: The prevalence of obesity [body mass index (BMI) > or =30.0 kg/m(2)] was 10% in men and 36% in women. Men of higher pre-adult or current socio-economic position generally had higher mean BMI and waist circumference. In women, however, the mean waist circumference was higher in those of lower socio-economic position (lower education, less pre-adult wealth), but mean BMI did not differ significantly between socio-economic groups. There was a positive graded association between pre-adult and adult levels of wealth (determined by the availability of selected household amenities) and the risk of obesity in men (P-trend=0.003), but weak suggestions of an inverse association between adult level of wealth and obesity in women under 45 years of age. CONCLUSIONS: The high prevalence of obesity in this population indicates the need for appropriate interventions for its prevention and treatment. Programmes and interventions to control obesity need to address different needs of men and women in the various social strata, and must not be limited to adults.

Lifetime reproductive output over two generations in patients with psychosis and their unaffected siblings: the Uppsala 1915-1929 Birth Cohort Multigenerational Study.

BACKGROUND: Schizophrenic patients have fewer offspring than the general population but it is unclear whether (i) this persists for more than one generation, (ii) the reduced fertility is compensated by increased fertility in unaffected relatives, (iii) sociodemographic factors confound or interact with the association, and (iv) patients with affective psychosis have a similar fertility disadvantage. This study measured biological fitness over two generations in patients with schizophrenia or affective psychosis, and their unaffected siblings. METHOD: We conducted a historical cohort study using a Swedish birth cohort of 12 168 individuals born 1915-1929 and followed up until 2002. We compared biological fitness over two generations in patients with schizophrenia (n=58) or affective psychosis (n=153), and their unaffected siblings, with the population, adjusting for a range of sociodemographic variables from throughout the lifespan. RESULTS: Patients with schizophrenia had fewer children [fertility ratio (FR) 0.42, 95% confidence interval (CI) 0.29-0.61] and grandchildren (FR 0.51, 95% CI 0.33-0.80) than the population. Some of this reduction was related to lower marriage rates in schizophrenic patients. The unaffected siblings of schizophrenic patients showed no evidence of any compensatory increase in fitness, but there was a trend towards enhanced fertility among the offspring of schizophrenia patients. Patients with affective psychosis and their relatives did not differ from the general population on any fertility measure. CONCLUSIONS: Schizophrenia, but not affective psychosis, is associated with reduced biological fertility; this disadvantage is partly explained by marital status and persists into the second generation.

Breast-feeding influences on later life--cardiovascular disease.

Current evidence, almost exclusively from observational studies, provides a rather mixed picture. From the few studies that have been able to look at fatal or non-fatal cardiovascular events, there is little indication that breast-feeding is associated with either an increased or decreased risk. With respect to blood pressure, the meta-analyses suggest a small but statistically significant lowering of around 1 mmHg SBP associated with having been breast-fed in infancy. However, there is a strong indication from the meta-analyses that even this small effect may partly be accounted for by publication bias. The strongest evidence for an effect of breast-feeding reviewed in this chapter is for serum lipids, where there is good evidence that being breast-fed is associated with an increase in serum total cholesterol in infancy. In childhood there appears to be no association, while in adults there is some indication of breast-feeding being associated with a small decline in total cholesterol levels. As already outlined at the start of the chapter, this whole area of research is made particularly difficult by the fact that breast-feeding can be defined in many different ways. Some studies use definitions that are equivalent to exclusive breast-feeding prior to weaning, while others define it as having ever been breast-fed. This problem of classification is likely to dilute any real associations that may exist. The other major problem is one of interpretation. A result implying that breast-feeding is a "good thing" for cardiovascular health could equally be construed as evidence for a "bad" effect of bottle-feeding. From these data alone, we cannot convincingly determine which conclusion is correct. This is not simply a philosophical debating point. As discussed above in relation to the interpretation of results from the randomised trial of infant feeding, the issue has implications for all research on this topic. Some progress in this area will be made if studies are conducted which define breast-feeding in a more precise and comparable way, and take account of the composition of alternative infant feeds. This will be most easily done by following up more recent study populations that were originally recruited to look at shorter-term effects of infant feeding on outcomes such as growth. With respect to randomised trial evidence, looking at the cardiovascular disease risk profiles of children (and later adults) who were part of the PROBIT trial in Belarus (see Chapters 5 and 10) is likely to prove fruitful.

Prevalence and socio-economic distribution of hazardous patterns of alcohol drinking: study of alcohol consumption in men aged 25-54 years in Izhevsk, Russia.

AIM: To estimate the prevalence of hazardous drinking and its socio-economic distribution among Russian men. DESIGN: Participants were an age-stratified, population-based random sample of men aged 25-54 years living in Izhevsk, a city in the Urals, Russia. Interviewers administered questionnaires to cohabiting proxy respondents about behavioural indicators of hazardous drinking derived from frequency of hangover, frequency of drinking beverage spirits, episodes in the last year of extended periods of drunkenness during which the participant withdraws from normal life (zapoi), consumption of alcoholic substances not intended to be drunk (surrogates) and socio-economic position. Logistic regression was used to examine associations between socio-economic position and indicators of hazardous drinking in the past year. FINDINGS: Of 1750 men, 79% drank spirits and 8% drank surrogates at least sometimes in the past year; 25% drank spirits and 4% drank surrogates at least weekly and 10% had had an episode of zapoi in the past year. After adjustment for other socio-economic factors, education was strongly associated with indicators of hazardous drinking. Men with the lowest level of education compared to the highest level of education had an odds ratio of surrogate drinking of 7.7 (95% CI 3.2-18.5), of zapoi of 5.2 (2.3-11.8) and of frequent hangover of 3.7 (1.8-7.4). These indicators of hazardous drinking were also independently strongly associated with being unemployed (versus employed) and with levels of household wealth/amenities. Associations of all these variables with daily consumption of beverage spirits were weaker. CONCLUSION: Using a novel range of indicator variables of hazardous drinking, this paper shows that the prevalence of these behaviours is high among working-age men in this Russian city. Moreover, these hazardous behaviours show very clear socio-economic patterns, with particularly high prevalence among those who have had the least education and are not in employment. In contrast, more conventional measures of heavy drinking, based on frequency of consumption of beverage spirits, are less prevalent and show much weaker associations with socio-economic position.

The associations of birthweight, gestational age and childhood BMI with type 2 diabetes: findings from the Aberdeen Children of the 1950s cohort.

AIMS/HYPOTHESIS: The aim of this study was to examine the associations of birthweight, gestational age and childhood BMI (assessed at a mean age of 5 years) with a self-report of a doctor diagnosis of diabetes in middle age. METHODS: We studied a birth cohort of 5,793 individuals who were born between 1950 and 1956 in Aberdeen, Scotland, and who responded to a questionnaire administered in 2000. RESULTS: Birthweight and gestational age were inversely associated with diabetes. These associations remained with additional adjustment for indicators of childhood and adult socioeconomic position, maternal complications of pregnancy, adult smoking, adult BMI and simultaneous adjustment for each other: the adjusted odds ratio per unit increase in birthweight z score was 0.73 (95% CI 0.60-0.88), the odds ratio per week increase in gestational age was 0.91 (95% CI 0.82-1.00) and odds ratio for preterm birth was 2.04 (94% CI 1.18-3.53). The positive association of childhood BMI with diabetes was attenuated on adjustment for adult BMI. CONCLUSIONS/INTERPRETATION: In this population, who were born in the 1950s, poor intrauterine growth and preterm birth are associated with an increased risk of diabetes.

Childhood intelligence, educational attainment and adult body mass index: findings from a prospective cohort and within sibling-pairs analysis.

BACKGROUND: The mechanisms underlying the observed association of childhood intelligence with body mass index (BMI) are unclear and few studies of this association have been prospective in design. METHODS: Prospective study in a birth cohort of 5467 individuals who were born in Aberdeen, Scotland between 1950 and 1956 and who responded to a follow-up survey in 2001. Comparison of associations within sibling pairs of the same family to associations between different families in 643 sibling pairs (1286 individuals) who are participants in the main cohort. RESULTS: Childhood intelligence (age 7 years) and educational attainment were both inversely associated with adult BMI (mean age 48 years): the sex- and age-adjusted mean change in adult BMI per s.d. of intelligence was -0.35 kg/m(2) (95% CI: -0.49, -0.21 kg/m(2)) and per unit increase in educational category (seven categories) was -0.28 kg/m(2) (95% CI: -0.34, -0.22). On adjustment for education the association between childhood intelligence and adult BMI attenuated to the null (-0.03 kg/m(2) (-0.19, 0.13 kg/m(2))); other potential confounding or mediating factors had little or only modest effects on this association. The association between education and adult BMI was not affected by adjustment for childhood intelligence or other potential covariates. The within sibling-pair effect of education on adult BMI (-0.06 kg/m(2) (95% CI: -0.26, 0.14)) was weaker than the effect between different families (-0.37 kg/m(2) (95%CI: -0.58, -0.17)), P-value for difference of within sibling and between family effect=0.03. CONCLUSIONS: The association of childhood intelligence with adult BMI is attenuated to the null on adjustment for educational attainment, whereas the association of educational attainment with adult BMI appears to be independent of childhood intelligence and other measured covariates. However, our family analyses suggest that fixed family and neighbourhood factors, which are closely matched in siblings of a similar age, explain much of the association between greater educational attainment and lower adult BMI.

Birth weight, hypertension and "white coat" hypertension: size at birth in relation to office and 24-h ambulatory blood pressure.

We investigated the association of size at birth with hypertensive status defined by office blood pressure (BP) and 24-h ambulatory BP monitoring in a historical cohort study of 736 men born 1920-1924 and examined at age 70 years. Office BP was measured after 10-min supine rest with a sphygmomanometer, ambulatory BP was recorded with Accutracker 2, and anthropometric and other measurements were taken at a clinic. Birth weight and gestational age were abstracted from the men's birth records. A total of 24% of the men were treated for hypertension at the time of the study. Among not treated subjects, there was a weak positive association of birth weight with daytime and 24-h diastolic ambulatory BP. In subjects treated for hypertension, both office and ambulatory BP were inversely related to birth weight, although these associations were not statistically significant. Birth weight did not show significant association with sustained hypertension (elevated office and daytime ambulatory BPs) but showed a strong and statistically significant inverse association with "white coat" hypertension (elevated office BP and normal daytime ambulatory BP) when adjusted for concurrent body mass index (odds ratios 1.91, 1.59, 1 and 1.21 from lowest to highest quartile of birth weight, P-value for trend 0.035). We conclude that BP measured by 24-h-ambulatory monitoring is not related to birth weight in a pattern previously reported for office BP and that factors related to growth in utero are particularly related to higher risk of "white coat" hypertension.

Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort.

OBJECTIVE: To investigate whether size at birth and rate of fetal growth influence the risk of breast cancer in adulthood. DESIGN: Cohort identified from detailed birth records, with 97% follow up. SETTING: Uppsala Academic Hospital, Sweden. PARTICIPANTS: 5358 singleton females born during 1915-29, alive and traced to the 1960 census. MAIN OUTCOME MEASURES: Incidence of breast cancer before (at age <50 years) and after (> or = 50 years) the menopause. RESULTS: Size at birth was positively associated with rates of breast cancer in premenopausal women. In women who weighed > or =4000 g at birth rates of breast cancer were 3.5 times (95% confidence interval 1.3 to 9.3) those in women of similar gestational age who weighed <3000 g at birth. Rates in women in the top fifths of the distributions of birth length and head circumference were 3.4 (1.5 to 7.9) and 4.0 (1.6 to 10.0) times those in the lowest fifths (adjusted for gestational age). The effect of birth weight disappeared after adjustment for birth length or head circumference, whereas the effects of birth length and head circumference remained significant after adjustment for birth weight. For a given size at birth, gestational age was inversely associated with risk (P=0.03 for linear trend). Adjustment for markers of adult risk factors did not affect these findings. Birth size was not associated with rates of breast cancer in postmenopausal women. CONCLUSIONS: Size at birth, particularly length and head circumference, is associated with risk of breast cancer in women aged <50 years. Fetal growth rate, as measured by birth size adjusted for gestational age, rather than size at birth may be the aetiologically relevant factor in premenopausal breast cancer.

Changes in life expectancy in Russia in the mid-1990s.

BACKGROUND: Between 1987 and 1994, life expectancy in Russia declined substantially. Between 1994 and 1998, this trend reversed, and mortality rates returned to those of the early 1980s. Although the decline in life expectancy has been examined previously, much less is known about the subsequent improvement in mortality rates. We used recently published cause-specific mortality data up to 1998 to clarify this issue. METHODS: Changes in cause-specific death rates at ages 15-74 years were examined. Rates for 1998 were compared with those for 1994 (the year of lowest life expectancy) and for 1991 (the year the Soviet Union broke up). FINDINGS: Death rates among children fell steadily throughout the 1990s, and those in elderly people changed little. The reduction in mortality since 1994 was mainly due to a decrease in the death rate among middle-aged adults, which had increased until 1994. Deaths among those aged 15-30 years, which rose during 1991-94, remained high. Some causes of death, such as stomach cancer and road-traffic accidents, declined throughout the 1990s, whereas others, such as breast and prostate cancers and tuberculosis, increased. The decline in mortality since 1994 was, however, mainly due to a reduction in the rate of deaths from a group of causes associated with alcohol consumption. INTERPRETATION: The changing life expectancy in Russia is a consequence of a complex pattern of trends in different causes of death, some of which have their origins long in the past, and others that result from contemporary circumstances. This study provides further support for the view that alcohol has played an important part in the fluctuations in life expectancy in Russia in the 1990s, although there remains a need for a much better understanding of the factors underlying these continuing changes.

Do socioeconomic disadvantages persist into old age? Self-reported morbidity in a 29-year follow-up of the Whitehall Study.

OBJECTIVES: This study examined (1) the relation of employment grade in middle age to self-reported poor health and functional limitations in old age and (2) whether socioeconomic status at approximately the time of retirement modifies health differentials in old age. METHODS: Survivors of the Whitehall Study cohort of men were resurveyed. Respondents were aged 40 to 69 years when they were originally screened in 1967 to 1970. RESULTS: Compared with senior administrators, men in clerical or manual (low-grade) jobs in middle age had quadruple the odds of poor physical performance in old age, triple the odds of poor general health, and double the odds of poor mental health and disability. At most, 20% of these differences were explained by baseline health or risk factors. Men who moved from low to middle grades before retirement were less likely than those who remained in low grades to have poor mental health. CONCLUSIONS: Socioeconomic status in middle age and at approximately retirement age is associated with morbidity in old age.