Adiposity associated DNA methylation signatures in adolescents are related to leptin and perinatal factors.

Epigenetics links perinatal influences with later obesity. We identifed differentially methylated CpG (dmCpG) loci measured at 17 years associated with concurrent adiposity measures and examined whether these were associated with hsCRP, adipokines, and early life environmental factors. Genome-wide DNA methylation from 1192 Raine Study participants at 17 years, identified 29 dmCpGs (Bonferroni corrected p < 1.06E-07) associated with body mass index (BMI), 10 with waist circumference (WC) and 9 with subcutaneous fat thickness. DmCpGs within Ras Association (RalGDS/AF-6), Pleckstrin Homology Domains 1 (RAPH1), Musashi RNA-Binding Protein 2 (MSI2), and solute carrier family 25 member 10 (SLC25A10) are associated with both BMI and WC. Validation by pyrosequencing confirmed these associations and showed that MSI2 , SLC25A10 , and RAPH1 methylation was positively associated with serum leptin. These were  also associated with the early environment; MSI2 methylation (ß = 0.81, p = 0.0004) was associated with pregnancy maternal smoking, SLC25A10 (CpG2 ß = 0.12, p = 0.002) with pre- and early pregnancy BMI, and RAPH1 (ß = -1.49, p = 0.036) with gestational weight gain. Adjusting for perinatal factors, methylation of the dmCpGs within MSI2, RAPH1, and SLC25A10 independently predicted BMI, accounting for 24% of variance. MSI2 methylation was additionally associated with BMI over time (17 years old ß = 0.026, p = 0.0025; 20 years old ß = 0.027, p = 0.0029) and between generations (mother ß = 0.044, p = 7.5e-04). Overall findings suggest that DNA methylation in MSI2, RAPH1, and SLC25A10 in blood may be robust markers, mediating through early life factors.

Features of the metabolic syndrome in late adolescence are associated with impaired testicular function at 20 years of age.

STUDY QUESTION: Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood? SUMMARY ANSWER: Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder. WHAT IS KNOWN ALREADY: Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function. STUDY DESIGN, SIZE, DURATION: The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years; 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).At 17 and 20 years of age, fasting blood samples were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA >4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk. MAIN RESULTS AND THE ROLE OF CHANCE: Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P < 0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P < 0.05 after adjustment for age, BMI, abstinence and a history of cryptorchidism, varicocele, cigarette smoking, alcohol and drug use), compared to those without an elevated sTNFR1. Multivariable regression analysis, adjusting for confounders, demonstrated that men in the high-risk metabolic cluster at 20 years had a lower serum testosterone and inhB (P = 0.003 and P = 0.001, respectively). A HOMA-IR > 4 was associated with a lower serum testosterone (P = <0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015). LIMITATIONS, REASONS FOR CAUTION: This study is limited by the sample size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment. WIDER IMPLICATIONS OF THE FINDINGS: Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018.

Maternal smoking and low family income during pregnancy as predictors of the relationship between depression and adiposity in young adults.

There is an increasing incidence of overweight/obesity and mental health disorders in young adults and the two conditions often coexist. We aimed to investigate the influence of antenatal and postnatal factors that may underlie this association with a focus on maternal prenatal smoking, socio-economic status and gender. Data from the Western Australian Pregnancy Cohort (Raine) Study (women enrolled 1989-1991) including 1056 offspring aged 20 years (cohort recalled 2010-2012) were analyzed (2015-2016) using multivariable models for associations between offspring depression scores (DASS-21 Depression-scale) and body mass index (BMI), adjusting for pregnancy and early life factors and offspring behaviours. There was a significant positive relationship between offspring depression-score and BMI independent of gender and other psychosocial covariates. There was a significant interaction between maternal prenatal smoking and depression-score (interaction coefficient=0.096; 95% CI: 0.006, 0.19, P=0.037), indicating the relationship between depression-score and BMI differed according to maternal prenatal smoking status. In offspring of maternal prenatal smokers, a positive association between BMI and depression-score (coefficient=0.133; 95% CI: 0.05, 0.21, P=0.001) equated to 1.1 kg/m2 increase in BMI for every 1standard deviation (8 units) increase in depression-score. Substituting low family income during pregnancy for maternal prenatal smoking in the interaction (interaction coefficient=0.091; 95% CI: 0.01, 0.17, P=0.027) showed a positive association between BMI and depression score only among offspring of mothers with a low family income during pregnancy (coefficient=0.118; 95% CI: 0.06, 0.18, P<0.001). There were no significant effects of gender on these associations. Whilst further studies are needed to determine whether these associations are supported in other populations, they suggest potentially important maternal behavioural and socio-economic factors that identify individuals vulnerable to the coexistence of obesity and depression in early adulthood.

Fat mass and obesity-associated obesity-risk genotype is associated with lower foetal growth: an effect that is reversed in the offspring of smoking mothers.

Fat mass and obesity-associated (FTO) gene variants are associated with childhood and adult obesity; however, the influence of FTO polymorphisms on foetal growth is unknown. Associations between the FTO variant rs9939609 and the foetal growth trajectories, maternal pregnancy weight gain, anthropometric measures at birth and body mass index (BMI) at age 14 years were assessed in 1079 singleton-birth Australian Caucasians. Analyses were repeated in 3512 singleton-birth Dutch Caucasians. The rs9939609 obesity-risk AA genotype was associated with symmetrical intrauterine growth restriction; an effect reversed in mothers who smoked during pregnancy. The effect increased over time and was modified by maternal smoking for head circumference (P = 0.007), abdominal circumference (P = 0.007), femur length (P = 0.02) and estimated foetal weight (P = 0.001). The modification of the association between the AA genotype and birth anthropometrics by maternal smoking was consistent across birth weight (P = 0.01) and birth length (P = 0.04) and neonatal day 2 anthropometry. Consistent associations were replicated in the Generation R cohort. Maternal pregnancy weight gain matched the pattern of birth weight and was independent of placental weight. In adolescents, the AA genotype was associated with increased BMI-adjusted-for-age in males (P = 0.00009), but no effect was detected in females. A variant in the FTO gene influences foetal growth trajectories in the third trimester, early postnatal growth and adiposity in adolescence. Maternal smoking during pregnancy reversed the direction of association of rs9939609 on foetal growth, which was probably mediated by maternal energy intake. The detection of genetic variants associated with foetal growth has the potential to identify novel molecular mechanisms underlying growth and targeted early life intervention.

Hospital admissions and length of stay for coronary disease in an Aboriginal cohort.

BACKGROUND AND AIMS: Coronary disease (CHD)-related hospital admission is more common among indigenous than non-indigenous Australians. We aimed to identify predictors of hospital admission potentially useful in planning prevention programs. METHODS AND RESULTS: Length of stay (LOS), interval between, and number of recurrent admissions were modelled with proportional hazards or negative binomial models using lifestyle data recorded in 1988-1989 among Aborigines (256 women, 258 men, aged 15-88years) linked to hospital records to 2002. Among 106 Aborigines with CHD, hypertension (hazard ratio (HR) 1.69, 95% CI 1.05-2.73); smoking (HR 1.90, 95% CI 1.02-3.53); consuming processed meat >4 times/month (HR 1.81, 95% CI 1.01-3.24); >6 eggs/week (HR 1.73, 95% CI 1.03-2.94); and lower intake of alcohol (HR 0.54, 95% CI 0.35-0.83) predicted LOS. Eating eggs (HR 1.05, 95% CI 1.01-1.09) and bush meats > or =7 times/month (HR 0.46, 95% CI 0.23-0.92) predicted interval between recurrent admissions. Hypertension (IRR 4.07; 95% CI 1.32-12.52), being an ex-drinker (IRR 6.60, 95% CI 2.30-19.00), eating red meat >6 times/week (IRR 0.98, 95% CI 0.97-0.99), bush meats >7 times/month (IRR 0.26, 95% CI 0.10-0.67), and adding salt to meals (IRR 3.16, 95% CI 1.12-8.92) predicted number of admissions. CONCLUSION: Hypertension, alcohol drinking, smoking, and diet influence hospital admissions for CHD in Aboriginal Australians.

Changes in cognitive measures associated with a lifestyle program for treated hypertensives: a randomized controlled trial (ADAPT).

Cognitive changes are reported infrequently in programs targeting cardiovascular risk. We examined self-efficacy, behavioral barriers and health beliefs in a lifestyle program for drug-treated hypertensives that aimed to reduce blood pressure, antihypertensive drug needs and cardiovascular risk. In a randomized controlled trial, we compared usual care (controls) and a 4-month program focusing on weight loss, diet and exercise. Outcomes were assessed at baseline, 4 months and 1-year follow-up. Of 241 individuals randomized, 102/123 in the program and 90/118 of controls completed follow-up. In the program group, dietary barriers fell by 14% at 4 months (controls 2%, P = 0.025) and by 8% at follow-up (controls 3%, P = 0.010). Exercise barriers fell by 11% at 4 months (controls 3%, P = 0.020) and 17% (controls 4%, P = 0.002) at follow-up. Dietary self-efficacy improved by 3% at 4 months (controls -1%, P = 0.003) and by 2% at follow-up (controls -1%, P = 0.051). Exercise self-efficacy increased by 8% at 4 months (controls 3%, P < 0.001) and by 5% at follow-up (controls 3%, P = 0.130). Changes in cognitive variables predicted changes in health-related behaviors at 4 months and follow-up. A cognitively based lifestyle program in treated hypertensives is associated with improvements in cognitive measures in the shorter and longer term.

The frequency of high-grade intraepithelial neoplasia in anal/perianal warts is higher than previously recognized.

A retrospective review of the prevalence of intraepithelial neoplasia (IN) in surgically removed perianal/anal warts from December 1995 to December 2004 was undertaken in patients referred to the Sexual Health Clinic at Royal Perth Hospital. Data were analysed from 115 men and 38 women, 29 of whom had HIV infection (27 men and two women). Perianal/anal IN within the warts was found in 78% (52% high grade) of men with HIV infection. In men without HIV infection, the overall rate of IN within warts was 33% (20% high grade). The IN rate was 8.3% for HIV-negative women (2.8% high grade). Rates of IN within perianal/anal warts in men with or without HIV infection are higher than previously reported, and suggest the likelihood of a substantial increase in the future incidence of anal cancer. The association between IN and genital warts needs to be further studied.

Alcohol intake and incidence of coronary disease in Australian aborigines.

AIMS: To examine risk for coronary heart disease (CHD) and cardiovascular disease (CVD) in relation to alcohol in a cohort of Australian Aborigines. METHODS: In 1988-1989, alcohol intake, drinking pattern, and beverage preference were elicited by interviewer-administered questionnaire in Western Australian Aborigines (258 men, 256 women) and cardiovascular outcomes ascertained through linkage to mortality and hospital admission records to 2002. RESULTS: In proportional hazards models, risk for CHD, relative to lifetime abstainers, was significantly increased in ex-drinkers [Hazard ratio (HR) 2.29, 95% CL 1.23, 4.27], those drinking 41-60 g/day in men or 21-40 g/day in women (HR 2.80, 95% CL 1.04, 7.53), and those drinking >150 g/day for men or >100 g/day for women (HR 2.25, 95% CL 1.03, 4.90) with a J-shaped relationship. Low-to-moderate drinkers had lower waist girth, exercised more, and had a lower prevalence of overweight and smoking than at-risk drinkers. A preference for wine was associated with lower HR (0.28, 95% CL 0.10, 0.95). With CVD, only ex-drinkers showed significantly increased risk (HR 1.87, 95% CL 1.20, 2.91). CONCLUSIONS: More favourable health-related behaviours in low-to-moderate drinkers suggest that lower risk could be mediated by lifestyle, as proposed in other populations.

Perinatal and childhood origins of cardiovascular disease.

BACKGROUND: Features of the metabolic syndrome comprise a major risk for cardiovascular disease and will increase in prevalence with rising childhood obesity. We sought to identify early life influences on development of obesity, hypertension and dyslipidemia in children. METHODS AND RESULTS: Cluster analysis was used on a subset of a longitudinal Australian birth cohort who had blood samples at age 8 (n=406). A quarter of these 8-year-olds fell into a cluster with higher body mass index, blood pressure (BP), more adverse lipid profile and a trend to higher serum glucose resembling adult metabolic syndrome. There was a U-shaped relationship between percentage of expected birth weight (PEBW) and likelihood of being in the high-risk cluster. The high-risk cluster had elevated BP and weight as early as 1 and 3 years old. Increased likelihood of the high-risk cluster group occurred with greatest weight gain from 1 to 8 years old (odds ratio (OR)=1.4, 95% confidence interval (CI)=1.3-1.5/kg) and if mothers smoked during pregnancy (OR=1.82, CI=1.05-3.2). Risk was lower if children were breast fed for >/=4 months (OR=0.6, 95% CI=0.37-0.97). Newborns in the upper two quintiles for PEBW born to mothers who smoked throughout pregnancy were at greatest risk (OR=14.0, 95% CI=3.8-51.1) compared to the nadir PEBW quintile of non-smokers. CONCLUSION: A U-shaped relationship between birth weight and several components of the metabolic syndrome was confirmed in a contemporary, well-nourished Western population of full-term newborns, but post-natal weight gain was the dominant factor associated with the high-risk cluster. There was a prominence of higher as well as lowest birth weights in those at risk. Future health programs should focus on both pre- and post-natal factors (reducing excess childhood weight gain and smoking during pregnancy), and possibly the greatest benefits may arise from targeting the heaviest, as well as lightest newborns, especially with a history of maternal smoking during pregnancy.

Health-related behaviours as predictors of mortality and morbidity in Australian Aborigines.

OBJECTIVE: To examine predictors of coronary heart disease (CHD) and all-cause mortality in Aboriginal Australians. METHOD: In 1988-89, a survey of Western Australian Aborigines (256 women, 258 men) aged 15-88 years documented diet, alcohol and smoking habits. Linkage to mortality and hospital admissions to the end of 2002 provided longitudinal data for modelling of coronary heart disease endpoints and all-cause mortality using Cox regression. RESULTS: Coronary heart disease risk increased with smoking (HR 2.62, 95% CI: 1.19, 5.75), consumption of processed meats >once/week (HR 2.21, 95% CI: 1.05, 4.63), eggs >twice/week (HR 2.59, 95% CI: 1.11, 6.04) and using spreads on bread (HR 3.14. 95% CI: 1.03, 9.61). All-cause mortality risk was lower with exercise >once/week (HR 0.51, 95% CI 0.26, 1.05), increased in ex-drinkers (HR 3.66, 95% CI: 1.08, 12.47), heavy drinkers (HR 5.26, 95% CI: 1.46, 7.52) and with consumption of take away foods >nine times/month (HR 1.78, 95% CI 0.96, 3.29). Greater alcohol intake, smoking and adverse dietary choices clustered in 53% of men and 56% of women and increased risk of coronary heart disease (HR 2.1, 95% CI: 1.1, 4.0) and all-cause mortality (HR 2.3, 95% CI: 1.2, 4.2). CONCLUSION: Lifestyle in Aboriginal Australians predicts coronary heart disease and all-cause mortality. Clustering of adverse behaviours is common and increases risk of coronary heart disease and death.

Alcohol intake and incidence of coronary disease in Australian aborigines.

AIMS: To examine risk for coronary heart disease (CHD) and cardiovascular disease (CVD) in relation to alcohol in a cohort of Australian Aborigines. METHODS: In 1988-1989, alcohol intake, drinking pattern, and beverage preference were elicited by interviewer-administered questionnaire in Western Australian Aborigines (258 men and 256 women) and cardiovascular outcomes ascertained through linkage to mortality and hospital admission records to 2002. RESULTS: In proportional hazards models, risk for CHD, relative to lifetime abstainers, was significantly increased in ex-drinkers [Hazard ratio (HR), 2.29; 95% confidence intervals (CI), 1.23-4.27], those drinking 41-60 g/day in men or 21-40 g/day in women (HR 2.80; 95% CI, 1.04-7.53) and those drinking >150 g/day for men or >100 g/day for women (HR, 2.25; 95% CI, 1.03-4.90) with a J-shaped relationship. Low-to-moderate drinkers had lower waist girth, exercised more and had a lower prevalence of overweight and smoking than at-risk drinkers. A preference for wine was associated with lower HR (0.28; 95% CI, 0.10-0.95). With CVD, only ex-drinkers showed significantly increased risk (HR, 1.87; 95% CI, 1.20-2.91). CONCLUSIONS: More favourable health-related behaviours in low-to-moderate drinkers suggest that lower risk could be mediated by lifestyle, as proposed in other populations.

Predictors of body mass index and associations with cardiovascular risk factors in Australian children: a prospective cohort study.

OBJECTIVE: To examine predictors of body mass index (BMI) at the age of 8 y in a prospective study of Australian children. DESIGN: Longitudinal survey of a cohort of Australian children followed from the 16th week of gestation to 8 y. SUBJECTS: In total, 741 boys and 689 girls who attended the survey as 8 y olds. MEASUREMENTS: Weight and height, blood pressure measured by automated oscillometry, fasting blood lipids and glucose. Questionnaire assessment of activity and diet. RESULTS: Proportions of overweight including obesity in boys and girls were, respectively, 22 and 25% at 1 y, 14 and 14% at 3 y, 13 and 18% at 5 y and 15 and 20% at 8 y. At the age of 1, 3, 6 and 8 y, children with overweight including obesity showed significantly more adverse cardiovascular risk factors. Blood pressure (BP) was significantly higher by 2/3 mmHg (systolic/diastolic) at 1 y, 3/2 mmHg at 3 y, 4/2 mmHg at 5 y and 6/2 mmHg at 8 y; HDL was significantly lower (P=0.002) by 8% and triglycerides were significantly higher by 27% (P<0.001). In multivariate regression, BMI at the age of 8 y was significantly predicted positively by birth weight, mother's BMI and hours spent in watching television at the time of the survey of 6 y olds. Mothers being ex-smokers or non smokers and children being 'slightly active' and 'active' negatively predicted BMI in 8 y olds. In a subset of 298 children with information about fathers, paternal BMI was an additional independent predictor. Maternal or paternal overweight including obesity each independently increased risk of overweight including obesity at the age of 8 y three-fold. A food factor with consumption of cereals and breads as the major components derived from a Food Frequency Questionnaire in a subset of 340 children was also an independent negative predictor of BMI in multivariate models. CONCLUSION: The increasing rate of overweight including obesity, particularly in girls, is associated with an increase in cardiovascular risk factors very early in life. Improvement of health-related behaviours within the family and a focus on promotion of activity in children should be priorities in achieving weight control.

A randomized trial of interactive group sessions achieved greater improvements in nutrition and physical activity at a tiny increase in cost.

OBJECTIVE: Weight gain may follow altered eating habits and decreased physical activity in couples beginning to live together. Mutual support and willingness to accept changes in lifestyle at this stage may facilitate positive responses to health promotion. We aimed to compare the effects of a diet and physical activity program in couples using a randomized controlled trial. STUDY DESIGN AND SETTING: Couples were randomized to a control group or to one of two intervention groups in whom the program was either delivered mainly by mail or with a combination of mail-outs and interactive group sessions. RESULTS: Diets, physical fitness, and blood cholesterol improved up to 12 months after beginning the 4-month program, mainly in the interactive group. In that group, at the end of the program, the estimated cost was 445.30 dollars (111.33 dollars/month) per participant per unit change in outcome variables, only 0.03 dollars per participant per month more than the group receiving the program mainly by mail. One year after beginning the program, costs per participant per month were 38.37 dollars in the interactive group and 38.22 dollars in the group receiving the program mainly by mail-out. CONCLUSION: The changes observed in cardiovascular risk factors could translate to a substantial cost-savings relating to health.

Maternal fish oil supplementation in pregnancy reduces interleukin-13 levels in cord blood of infants at high risk of atopy.

BACKGROUND AND OBJECTIVES: The epidemiological association between higher dietary n-3 polyunsaturated fatty acids (PUFA) and lower prevalence of asthma, has led to interest in the role of early dietary modification in allergic disease prevention. In this study we examined the effects of maternal n-3 (PUFA)-rich fish oil supplementation on cord blood (CB) IgE and cytokine levels in neonates at risk of developing allergic disease. METHODS: In a randomized double-blind, placebo-controlled trial, 83 atopic pregnant women received either fish oil capsules (n = 40) containing 3.7 g n-3 PUFA/day or placebo capsules (n = 43) from 20 weeks gestation until delivery. CB cytokine levels (IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, TNF-alpha and IFN-gamma) and total IgE levels were measured and compared between the two groups. Fatty acid composition of red cell membranes was analysed by gas chromatography and the relationships among PUFA, cytokine and IgE levels were examined. RESULTS: Maternal fish oil supplementation resulted in a significant increase in n-3 PUFA levels (P < 0.001) in neonatal erythrocyte membranes. Neonates whose mothers had fish oil supplementation had significantly lower plasma IL-13 (P < 0.05) compared to the control group. There was also a significant inverse relationship between levels of n-3 PUFA in neonatal cell membranes and plasma IL-13. There was no difference in levels of IgE and the other cytokines measured. CONCLUSIONS: This study provides preliminary evidence that increasing neonatal n-3 PUFA levels with maternal dietary supplementation can achieve subtle modification of neonatal cytokine levels. Further assessment of immune function and clinical follow-up of these infants will help determine if there are any significant effects on postnatal immune development and expression of allergic disease.

Factorial study of the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity.

BACKGROUND: Dyslipidaemia may account for increased risk of cardiovascular disease in central obesity. Pharmacotherapy is often indicated in these patients, but the optimal approach remains unclear. We investigated the effects of atorvastatin and fish oil on plasma lipid and lipoprotein levels, including remnant-like particle-cholesterol and apolipoprotein C-III, in dyslipidaemic men with visceral obesity. METHODS: We carried out a 6-week randomized, placebo-controlled, 2 x 2 factorial intervention study of atorvastatin (40 mg day(-1)) and fish oil (4 g day(-1)) on plasma lipids and lipoproteins in 52 obese men (age 53 +/- 1 years, BMI 33.7 +/- 0.55 kg m(-2)) with dyslipidaemia and insulin resistance. Treatment effects were analysed by general linear modelling. RESULTS: Atorvastatin had significant main effects in decreasing triglycerides (-0.38 +/- 0.02 mmol L(-1), P = 0.002), total cholesterol (-1.89 +/- 0.17 mmol L(-1), P = 0.001), LDL-cholesterol (-1.78 +/- 0.14 mmol L(-1), P = 0.001), remnant-like particle-cholesterol (-0.08 +/- 0.04 mmol L(-1), P = 0.035), apolipoprotein B (-49 +/- 4 mg dL(-1), P = 0.001), apolipoprotein C-III (-12.6 +/- 6.1 mg L(-1), P = 0.044) and in increasing HDL-cholesterol (+0.10 +/0- 0.04 mmol L(-1), P = 0.007). Fish oil had significant main effects in decreasing triglycerides (-0.38 +/- 0.11 mmol L(-1), P = 0.002) and in increasing HDL-cholesterol (+0.07 +/- 0.04 mmol L(-1), P = 0.041). There were no significant changes in weight or insulin resistance during the study. CONCLUSIONS: Atorvastatin and fish oil have independent and additive effects in correcting dyslipidaemia in viscerally obese men. Improvement in abnormalities in remnant lipoproteins may occur only with use of atorvastatin. Combination treatment with statin and fish oil may, however, offer an optimal therapeutic approach for globally correcting dyslipidaemia in obesity.

P2Y receptor-induced EDHF vasodilatation is of primary importance for the regulation of perfusion pressure in the peripheral circulation of the rat.

Extracellular nucleotides have been shown to induce vasodilatation of conductance arteries by release of the endothelium-derived hyperpolarizing factor (EDHF). As small resistance arteries are of greater importance for blood pressure regulation, a whole rat mesenteric arterial bed preparation was used in the present study when evaluating the physiological relevance for EDHF in mediating nucleotide dilatation. Dilatory responses were examined after pre-contraction with noradrenaline in the presence of 10 mM indomethacin. Adenosine-5'-O-thiodiphosphate (ADPbetaS), adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced vasodilatation (pEC50=6.5-7 and E(max)=40-70%), while uridine diphosphate (UDP) was ineffective. Endothelium-derived hyperpolarizing factor was studied in the presence of 0.5 mM Nvarpi-nitro-L-arginine (L-NOARG). ADPbetaS and UTP induced strong and potent EDHF-dilatations, while ATP only had a weak effect (E(max)=25%). After P2X1 receptor desensitization with 10 microM alphabeta-methylene-adenosine triphosphate, the ATP response was significantly increased (E(max)=65%). Putatively, this could be because of simultaneous activation of both endothelial P2Y receptors and P2X1 receptors on smooth muscle cells, which resulted in the release of EDHF and subsequent hyperpolarization, and depolarization, respectively. Nitric oxide (NO) was studied in the presence of 60 mM K+. ADPbetaS, ATP and UTP induced weak NO dilatations, suggesting a minor role for NO as compared with EDHF. In conclusion, extracellular nucleotides stimulate dilatation by activating P2Y(1) and P2Y(2)/P2Y(4) receptors, but not P2Y(6) receptors. The dilatory responses are mediated primarily by EDHF in the peripheral vascular bed.

Effects of regular ingestion of black tea on haemostasis and cell adhesion molecules in humans.

OBJECTIVE: To assess the effects in humans of regular ingestion of black tea on haemostasis-related variables and cell adhesion molecules. DESIGN: Twenty-two subjects were recruited from the general population to a randomised-controlled crossover study. Subjects stopped drinking tea, apart from that provided, for the duration of the study. During a 4-week baseline period all subjects drank 5 cups/day (250 ml) of hot water. The effects of 5 cups/day of black tea for 4 weeks were then compared with hot water. Platelet aggregation in response to three doses of collagen and ADP, plasma concentrations of coagulation and fibrinolytic factors (fibrinogen, factor VII, tPA, PAI-1) and plasma concentrations of cell adhesion molecules (soluble P-selectin, E-selectin, ICAM-1, VCAM-1) were assessed twice, one week apart, at the end of each period. Twenty-four hour urinary concentration of 4-O-methylgallic acid (4OMGA), assessed once at the end of each period, was used as a marker of black tea polyphenol intake. RESULTS: The 24 h urinary excretion of 4OMGA was increased during regular ingestion of black tea in comparison to hot water (P<0.0001). Black tea resulted in lower soluble P-selectin (P=0.01) in comparison to hot water, but did not influence other adhesion molecules. Soluble P-selectin was significantly correlated with mean collagen-stimulated platelet aggregation at baseline (r=0.61, P=0.003), and during regular ingestion of hot water (r=0.70, P<0.0001) and black tea (r=0.51, P=0.01). However, platelet aggregation was not different between the black tea and hot water periods for collagen- or ADP-stimulated aggregation at any dose. Coagulation and fibrinolytic factors were also not different between periods. CONCLUSIONS: The effect of black tea on soluble P-selectin provides a potential mechanism for cardiovascular benefits of regular ingestion of tea. SPONSORSHIP: This study was supported by grants from the Tea Trade Health Research Association and the National Heart Foundation of Australia.

Family lifestyle and parental body mass index as predictors of body mass index in Australian children: a longitudinal study.

OBJECTIVE: To investigate associations between body mass index (BMI) and family characteristics, including lifestyle, in parents and offspring from Australian families. DESIGN AND SUBJECTS: Longitudinal survey of 219 families of Australian children who had been surveyed 3-yearly between the ages of 9 and 18 y. MEASUREMENTS: Socio-economic status, weight and height, diet from 3 day records or food frequency questionnaires, alcohol consumption, smoking habits and physical fitness in offspring (bicycle ergometry in 18-y-olds). RESULTS: In 18-y-olds, in models examining offspring's lifestyle variables, BMI was predicted negatively by physical fitness (P=0.012), and positively by alcohol intake (P=0.046) in sons while, in daughters, only a negative association with physical fitness was significant. In models including parental characteristics, BMI in 18-y-old sons and daughters was significantly predicted by mothers' and fathers' BMI, independently of offsprings' alcohol intake, smoking, physical fitness and parents' education, and, in daughters, by fathers' alcohol intake. These models explained 48% of variance in daughters and 33% in sons. In both sons and daughters, BMI over the 9 y of the survey was consistently higher in offspring with overweight or obese fathers (P=0.033 for sons, P=0.024 for daughters) or mothers (P=0.031 for sons, P=0.037 for daughters). Physical fitness at the ages of 12, 15 and 18 y was negatively related to fathers' obesity in daughters and mothers' obesity in sons. Obesity in fathers was associated with a four-fold increase in risk of obesity at the age of 18 y in both sons and daughters with an independent eight-fold increase in risk for daughters if mothers were obese. Birthweight was unrelated to overweight or obesity in the 18-y-olds. Alcohol intake in sons related significantly to alcohol intake in either parent while, for daughters, there was a significant association only with fathers' alcohol consumption. In daughters, fat intake was positively associated with fat intake score in both fathers and mothers. CONCLUSION: Parental overweight or obesity may identify children at risk for a range of unhealthy behaviours. Promotion of a healthy lifestyle targeting overweight families, particularly in lower socio-economic groups, should be a priority.

Red wine polyphenols, in the absence of alcohol, reduce lipid peroxidative stress in smoking subjects.

Phenolic compounds in red wine can exert antioxidant effects on in vitro lipoprotein oxidation. This has led to speculation that red wine consumption mediates unique anti-atherosclerotic effects compared to other alcoholic beverages. However, studies assessing the effects of red wine consumption on lipoprotein oxidation ex vivo have not been conclusive. The recent identification of the F2-isoprostanes as oxidative products of arachidonic acid has provided a reliable measure of in vivo lipid peroxidation. This randomized trial investigated changes in plasma and urinary F2-isoprostane concentrations following red wine, white wine, or dealcoholized red wine consumption in humans. Eighteen male smokers consumed, in random order, red wine, white wine, or dealcoholized red wine, for two weeks with one week washout between beverages. Plasma and urinary F2-isoprostane concentrations were measured before and after each beverage. Serum gamma-glutamyl transpeptidase (gamma-GT) and urinary 4-O -methylgallic acid were measured as markers of alcohol consumption and phenolic acid absorption, respectively. Plasma F2-isoprostanes (p < .05) decreased significantly with dealcoholized red wine but not with the alcohol-containing beverages. Urinary excretion of F2-isoprostanes showed a similar trend. gamma-GT decreased significantly with dealcoholized red wine and increased with both alcohol-containing beverages (p < .01). Urinary excretion of 4-O-methylgallic acid increased significantly (p < .001) in the 24 h urine samples following red wine or dealcoholized red wine ingestion, but not with white wine. Serum urate increased and beta-carotene decreased with both alcoholic beverages relative to dealcoholized red wine. There was no change in the antioxidants alpha- and gamma-tocopherol or vitamin C with any of the beverages. The results suggest that polyphenols in dealcoholized red wine can reduce in vivo lipid peroxidation as measured by F2-isoprostanes in smoking subjects. However, no reduction in lipid peroxidation was observed following red or white wine consumption, suggesting that any protective effects of wine drinking on cardiovascular disease are unlikely to be related to inhibition of lipid oxidation.

Non pharmacologic therapy and lifestyle factors in hypertension.

Lifestyle factors are now recognised to be key determinants of both the rise in blood pressure with ageing and the cardiovascular disease associated with essential hypertension. This paper summarises recent evidence for independent or additive effects of different aspects of diet and behavioural factors on blood pressure levels and some related cardiovascular risk factors. The influence of single nutrients, fats, fibre, protein, antioxidants, caffeine, complex dietary patterns, physical activity, alcohol and smoking will be considered against a background of obesity and psychological factors contributing to blood pressure elevation.