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Cholesterol is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (

Obese individuals have elevated platelet activation and arterial stiffness, but the strength and temporality of the relationship between these factors remain unclear. We aimed to determine the effect of increased arterial stiffness on circulating platelet activity in overweight/obese young adults. This analysis included 92 participants (mean age 40 years, 60 women) in the Slow Adverse Vascular Effects of excess weight (SAVE) trial, a clinical trial examining the effects of a lifestyle intervention with or without sodium restriction on vascular health in normotensive overweight/obese young adults. Carotid-femoral (cf), brachial-ankle (ba) and femoral-ankle (fa) pulse wave velocity (PWV) served as measures of arterial stiffness and were measured at baseline and 6, 12 and 24 months follow-up. Platelet activity was measured as plasma β-thromboglobulin (β-TG) at 24 months. Higher plasma β-TG was correlated with greater exposure to elevated cfPWV (p = 0.02) and baPWV (p = 0.04) during the preceding two years. After adjustment for serum leptin, greater exposure to elevated baPWV remained significant (p = 0.03) and exposure to elevated cfPWV marginally significant (p = 0.054) in predicting greater plasma β-TG. Greater arterial stiffness, particularly central arterial stiffness, predicts greater platelet activation in overweight/obese individuals. This relationship might partly explain the association between increased arterial stiffness and incident atherothrombotic events.

SummaryObjective Maternal blood leptin levels are positively associated with adiposity. Recent studies suggest that leptin is also abundantly produced by the placenta and may function as a regulator of foetal growth. Our goal was to examine mid-pregnancy levels of leptin in maternal blood in relation to birthweight for gestational age (BW/GA) and timing of delivery after accounting for maternal prepregnancy body mass index (prepreg-BMI) and pregnancy complications. Patients Data were from 1304 subcohort mother/infant pairs who participated in the Pregnancy Outcomes and Community Health (POUCH) Study (1998–2004). Measurements Leptin levels, measured at 16–27 weeks' gestation, were log-transformed. Geometric mean (GMean) leptin levels were estimated by weighted linear regression with gestational age at blood draw as a covariate. GMean was re-transformed to the original scale for reporting. Results Using the GMeans leptin in mothers of term appropriate-for-gestational age (AGA) neonates as the referent (25·2 μg/l), we observed lower levels in mothers of preterm-AGA (21·9 μg/l), term small-for-gestational age (SGA) (20·3 μg/l) and preterm-SGA neonates (21·7 μg/l). Results were largely unchanged after adjustment for prepreg-BMI. Leptin levels were higher in mothers who delivered large-for-gestational age (LGA) neonates, both preterm (33·6 μg/l) and term (29·1 μg/l), but the GMeans were markedly attenuated after adjustment for prepreg-BMI. Conclusion The association between BW/GA and maternal leptin levels after adjustment for prepreg-BMI may represent: (i) a residual effect of maternal adiposity that is not fully captured by BMI; and/or (ii) variation in placental leptin levels entering the maternal circulation. In conclusion, mid-pregnancy maternal blood leptin levels may be an early indicator of foetal growth status.

Diets low in omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and high in omega-3 (n-3) PUFAs may protect against breast cancer development. Associations of PUFA intake with mammographic density, an intermediate marker of breast cancer risk, have been inconsistent; however, prior studies have relied on self-reported dietary PUFA intake. We examined the association between circulating erythrocyte n-6 and n-3 PUFAs with mammographic density in 248 postmenopausal women who were not taking exogenous hormones. PUFAs in erythrocytes were measured by gas-liquid chromatography, and mammographic density was assessed quantitatively by planimetry. Spearman's correlation coefficients and generalized linear models were used to evaluate the relationships between PUFA measures and mammographic density. None of the erythrocyte n-6 or n-3 PUFA measures were associated with percent density or dense breast area.

Background: Despite the prevalence of severe obesity, particularly among women and African-American women, there is little data on CV risk factor differences across the BMI spectrum including extreme obesity. Methods: Participants were 1200 black and white postmenopausal women sampled from the Women’s Health Initiative Observational Study according to BMI categories and waist circumference tertiles: 300 black and 300 white women with BMI 40-65 kg/m 2 and 75 black and 75 white women in BMI categories 8.5-2 . Using stored baseline serum, total and high molecular-weight (HMW) adiponectin, leptin, ghrelin and insulin were measured by immunoassay; plasma lipoproteins and subclasses were measured by NMR spectroscopy. Race-ethnicity differences were tested in linear regression models adjusted for age, diabetes, BMI, waist, hip, hormone therapy and lipid-lowering medication. Results: Compared with white women, black women had lower levels of total and HMW adiponectin and ghrelin, and higher levels of insulin and leptin. Despite similar levels of total LDL particles (LDL-P), black women had lower levels of small LDL-P and higher levels of large LDL-P and larger mean LDL size. Levels of large HDL particles (HDL-P) and small HDL-P were also similar for black and white women, but black women had lower levels of total and medium HDL-P and larger mean HDL particle size. Black women also had lower levels of total, large, medium and small VLDL particles (VLDL-P) which increased little across BMI category, such that mean levels of total or large VLDL-P among black women with BMI≥ 40 kg/m 2 were lower than white women of normal BMI (2 ) (Figure). Among white, but not black women, total LDL-P was higher and total HDL-P was lower with higher BMI category (Figure). Conclusions: Among postmenopausal women of similar BMI and waist circumference, black women have lower levels of ghrelin and total and HMW adiponectin, but better lipoprotein levels that are less related to obesity compared with white women.

ObjectivePre-pregnancy obesity has been associated with adverse birth outcomes. Poor essential fatty acid (EFA) and micronutrient status during pregnancy may contribute to these associations. We assessed the associations between pre-pregnancy BMI and nutritional patterns of maternal micronutrient and EFA status during mid-pregnancy.DesignA cross-sectional analysis from a prospective cohort study. Women provided non-fasting blood samples at ≤20 weeks’ gestation that were assayed for red cell EFA; plasma folate, homocysteine and ascorbic acid; and serum retinol, 25-hydroxyvitamin D, α-tocopherol, soluble transferrin receptors and carotenoids. These nutritional biomarkers were employed in a factor analysis and three patterns were derived: EFA, Micronutrients and Carotenoids.SettingThe Antidepressant Use During Pregnancy Study, Pittsburgh, PA, USA.SubjectsPregnant women (n 129).ResultsAfter adjustment for parity, race/ethnicity and age, obese pregnant women were 3·0 (95 % CI 1·1, 7·7) times more likely to be in the lowest tertile of the EFA pattern and 4·5 (95 % CI 1·7, 12·3) times more likely to be in the lowest tertile of the Carotenoid pattern compared with their lean counterparts. We found no association between pre-pregnancy obesity and the Micronutrient pattern after confounder adjustment.ConclusionsOur results suggest that obese pregnant women have diminished EFA and carotenoid concentrations.

Introduction: Obesity is linked to the development of insulin resistance (IR) and type 2 diabetes. Weight loss achieved by lifestyle modification could improve insulin sensitivity (IS). However, weight loss is difficult to maintain, and individuals often weight cycle, potentially placing them at greater risk for adverse health outcomes. Objective: The purpose of this secondary analysis was to examine how long-term changes in weight are associated with changes in factors related to the development of diabetes (IR and IS) among obese adults enrolled in a 24-month behavioral weight loss trial. Methods: The sample (N=66) included non-diabetic adults who lost and regained at least 10 lbs during the 24-month trial. All participants received standard behavioral weight loss treatment during the first 18 months. Assessments were conducted at baseline, 6, 12, 18, and 24 months. IR was assessed using the homeostatic model assessment (HOMA), and IS was assessed using the quantitative insulin sensitivity check for insulin sensitivity (QUICKI). Linear mixed modeling was used to examine the association between % changes in weight and % changes in fasting insulin, HOMA, and QUICKI. All models were adjusted for time, age, gender, race, % change in energy intake, and % change in physical activity. Results: The sample was 80% female and 86% White. At baseline, the mean (±SD) values were: age, 48.4±7.4 years; BMI, 34.5±4.4 kg/m 2 ; energy intake, 2176.8±603.8 kcal/day; physical activity, 11.4±13.6 MET- hr/week; plasma insulin, 16.9±6.0 μU/mL; HOMA, 4.1±1.7; and QUICKI, 0.3±.02. On average, compared to baseline, participants experienced an 11% decrease in weight (p Conclusion: In this unique sample of participants who weight cycled during a 24-month trial, weight loss improved metabolic outcomes; however, this was partially attenuated when weight was regained. These results reveal the effects of changes in weight on metabolic outcomes and highlight the importance of sustaining healthy lifestyle changes that support weight loss maintenance and improved metabolic outcomes.

Introduction: Although marine n-3 fatty acids are believed to be cardioprotective through their anti-arrhythmic, anti-thrombotic, anti-atherogenic and other effects, results from recent meta-analyses of marine n-3 fatty acids on cardiovascular disease (CVD) are controversial. We performed a meta-analysis of marine n-3 fatty acids on CVD outcomes in randomized clinical trials (RCTs) to test the hypothesis that marine n-3 fatty acids are anti-atherogenic. We also tested the hypothesis that such benefit is dose-dependent. Methods: A systematic review of English language articles using PubMed, EMBASE and Cochrane Library through Aug 2012 was performed selecting RCTs evaluating the effect of marine n-3 fatty acids intake for 2 years or more on cardiovascular diseases, coronary disease, arteriosclerosis, cardiac imaging techniques, and carotid artery ultrasound. Descriptive and quantitative information was extracted. Odds ratios were calculated for cardiac event outcome. Correlation coefficients were obtained from studies of which outcome is intima-media thickness (IMT) and coronary lumen diameter (CD). We converted the estimates into a single effect size; the log odds ratio and its corresponding standard error. Results: Of 14,236 citations retrieved, 13 studies were selected, including studies reporting IMT (n=3) and CD (n=2) and major CVD events (n=8). Overall, marine n-3 fatty acids significantly reduced atherosclerotic CVD (RR 0.94: 95%CI 0.90 to 0.99, p Conclusions: The result of our meta-analysis supports a modest anti-atherogenic effect of marine n-3 fatty acids. This benefit may be proportional to the amount of marine n-3 fatty acids consumed.

Cholesterol metabolism is implicated in the etiology of Alzheimer’s disease (AD) and amyloid production in the brain. While brain cholesterol cannot be measured directly in vivo, the oxysterol, 24S-hydroxycholesterol (24-OHC), is the predominant metabolite of brain cholesterol and can be measured in the blood. The aim of this review is to evaluate plasma 24-OHC as a potential biomarker of AD risk and discuss factors related to its levels in the brain and blood. This systematic review examines studies published between 1950 and June 2012 that examined the relationship between plasma 24-OHC, cognition, brain structure, and dementia using the following key words (“24S-hydroxycholesterol” or “24-hydroxycholesterol”) and (“Brain” or “Cognitive”). We found a total of 28 studies of plasma 24-OHC and neurodegenerative disease, including a subset of 12 that used dementia as a clinical endpoint. These studies vary in the direction of the observed associations. Results suggest plasma 24-OHC may be higher in the early stages of cognitive impairment and lower in more advanced stages of AD when compared to cognitively normal controls. Measures of 24-OHC in the blood may be an important potential marker for cholesterol metabolism in the brain and risk of AD. Further studies of plasma 24-OHC and dementia must account for the stage of disease, establish the temporal trends in oxysterol concentrations, and employ neuroimaging modalities to assess the structural and metabolic changes occurring in the brain prior to the onset of cognitive impairment.

Anesthetics are believed to produce anesthesia through the reversible inhibition of synaptic transmission but how this is accomplished is unknown. Based on earlier studies of anesthetic-enzyme-phospholipid interaction, we surmised that anesthetics may inhibit synaptic transmission by increasing synaptic membrane lateral pressure thereby inhibiting phospholipid hydrolysis, membrane transduction and synaptic transmission. As a first approximation towards investigating this concept, we hypothesized that anesthetics modulate the rate of phospholipase C hydrolysis of a lipid monolayer through its effects on surface pressure. The relationship between the hydrolysis rate of a monolayer of dipalmitoylphosphatidylcholine [14C-choline] (DPPC) by phospholipase C (Plase C) and monolayer surface pressure (SP) as altered by either halothane, isoflurane, or by physical compression at 37°C was studied. The decline in surface 14C-activity as the [14C]choline diffuses into the Krebs-Ringer bicarbonate buffer aqueous subphase is estimated as the rate of DPPC hydrolysis measured by the initial slope method. DPPC hydrolysis was about 300 cpm/min and constant between SP of 0 to 20 dynes/cm. Higher SP between 25 and 30 dyne/cm, whether induced by halothane, isoflurane or physical compression, increased the rate of hydrolysis by 5-fold to a peak rate of about 1600 cpm/min at 25–30 dynes/cm. At a SP above 32 dynes/cm, DPPC hydrolysis abruptly ceased. We conclude that anesthetics can reversibly inhibit synaptic transmission through their effects on synaptic membrane lateral pressure. We also speculate that membrane lateral pressure may be a highly sensitive means of controlling membrane function through alteration in membrane lipid composition, membrane enzyme activity, receptor affinity and ion channel permeability.

Epoxyeicosatrienoic acids (EETs), normally present in brain and blood, appear to be released from atherosclerotic vessels in large amounts. Once intravascular, EETs can constrict renal arteries in vivo and dilate cerebral and coronary arteries in vitro. Whether EETs in blood will alter cerebral blood flow (CBF) in vivo is unknown. In the present study, the chemical synthesis of four EET regioisomers was optimized, and their identity and structural integrity established by chromatographic and mass spectral methods. The chemically labile EETs were converted to a sodium salt, complexed with albumin, and infused into anesthetized rats via the common carotid. The objective was to test whether sustained, high levels of intravascular EETs alter CBF. The CBF (cortical H2 clearance) was measured before and 30 min after the continuous infusion of 14,15-(n = 5), 11,12-(n = 5), 8,9-(n = 7) and 5,6-EET (unesterified or as the methyl ester, n = 5 for each). Neither the CBF nor the systemic blood pressure was affected by EETs. Because the infusions elevated the plasma concentrations of EETs about 700-fold above normal levels (1.0 nM), it is unlikely that EETs released from atherosclerotic vessels will alter CBF.

Male and female F-344 rats were fed for 1 week choline-devoid or control choline-supplemented diets containing either 5% corn oil and 10% partially hydrogenated vegetable oils (PHO diets) or 15% corn oil (CO diets). HPLC/second derivative UV spectrophotometric analyses, combined with on-line atmospheric pressure ionization mass spectrometry, were used to determine whether conjugated diene isomers of linoleic acid (CLA), present in the diets, were assimilated into liver and adipose tissue lipids. The CLA content in the PHO diets was an order of magnitude greater than that in the CO diets. CLA were detected in the adipose tissue of all rats but in the liver of only rats fed the PHO diets. In adipose tissue, the CLA levels clearly reflected those present in the diets, and no sex differences, or differences between rats fed the choline-devoid or control diets were noted. In addition to CLA, conjugated linolenic and eicosatrienoic acids, arising probably from desaturation and elongation of CLA, were detected in the liver. The results provide evidence that the conjugated dienes detected in liver lipids of rats fed a PHO-containing choline-devoid diet are of dietary origin and do not reflect lipid peroxidation.

Breast milk lipids from 13 lactating women in Southern Nigeria who were moderate to severely malnourished and whose mean body mass index (BMI) was 20.2 (± 1.9) and (16.4 (± 1.2)), respectively were separated into various neutral lipid and phospholipid fractions and analyzed for their fatty acid compositions. There were no differences in the content of free fatty acids, diglycerides, triglycerides or the major phospholipid classes between the two groups of women. Three saturated fatty acids (12:0, 14:0, and 16:0) and oleic acid accounted for more than three-fourths of the total fatty acids in the triglyceride fractions. Lauric acid (12:0) and myristic acid (14:0), intermediate-chain length fatty acids which are readily digested, absorbed and oxidized by newborn infants, comprised an unusually high proportion (approximately 40%) of the fatty acids of the total breast milk lipids. While the breast milk of all the mothers we studied contained moderate levels of linoleic acid [18:2(n-6)], they were markedly deficient in another essential fatty acid, namely α-linolenic acid [18:3(n-3)]. A lack of α-linolenic acid could result in a deficiency of docosahexaenoic acid [22:6(n-3)] in the central nervous system of the infants being nursed by these mothers.

In this study, the efficacy of concurrent treatment of experimental acute otitis media with ibuprofen and ampicillin was evaluated in chinchillas with respect to clearance of the effusion, presence of mucosal inflammation, and modulation of biochemical markers. Forty chinchillas were infected with non-typable Haemophilus influenzae and randomly assigned to treatment with either IM ampicillin (control) or ampicillin plus ibuprofen beginning on day 2 post inoculation. On days 5 and 10, animals from each group were killed, effusions recovered for biochemical assay, and the middle ears prepared for histological study. Differences in outcome measures favoring the control group were observed at the 5 day endpoint. However, at the 10 day endpoint, mucosal thickness was significantly less, the number of effusion free ears greater, and the concentrations of free fatty acids and thromboxane less in the animals treated with the combined therapy when compared to the control group. These results suggest that the addition of ibuprofen to ampicillin for the treatment of acute otitis media alters disease pathogenesis in this infectious model.

Bone mineral density (BMD) has been inversely associated with subclinical and clinical cardiovascular disease (CVD) in population studies, but the potential mechanisms underlying this relationship are unclear. To test if there is a genetic basis underlying this association, we determined the phenotypic and genetic correlations between BMD and carotid artery ultrasound measures in families. Dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were used to measure BMD in 461 individuals with African ancestry belonging to seven large, multigenerational families (mean family size 66; 3414 total relative pairs). Carotid artery ultrasound was used to measure adventitial diameter (AD) and intima-media thickness (IMT). Phenotypic and genetic correlations between BMD and carotid measures were determined using pedigree-based maximum likelihood methods. We adjusted for potential confounding factors, including age, sex, body weight, height, menopausal status, smoking, alcohol intake, walking for exercise, diabetes, hypertension, serum lipid and lipoprotein levels, inflammation markers, and kidney function. We found statistically significant phenotypic (ρ = -0.19) and genetic (ρG = -0.70) correlations (p 0.05 for both) between lumbar spine BMD and AD in fully adjusted models. There was also a significant genetic correlation between trabecular BMD at the radius and IMT in fully adjusted models (ρG = -0.398; p 0.05). Our findings indicate that the previously observed association between osteoporosis and CVD in population-based studies may be partly mediated by genetic factors and that the pleiotropic effects of these genes may operate independently of traditional risk pathways.

To describe patterns of weight loss and regain and their effect on the pro-inflammatory cytokines IL-6 and TNF-α, and anti-inflammatory cytokines adiponectin and IL-10 during a 24-month weight loss trial.Participants were obese adults (N=66) who lost and regained ≥ 10lb during a 24-month clinical trial of behavioral weight loss treatment. Measurements of cytokines and weight were conducted at baseline, 6, 12, 18, and 24 months. Linear mixed modeling was used to determine percent change in weight and cytokines from baseline.The sample was predominantly female (80.3%) and White (86.4%), with a mean age of 48.4 ± 7.3 years and mean BMI of 34.5 ± 4.4 kg/m(2). At baseline, men had higher waist circumference, body weight, and energy intake, and lower percent body fat and adiponectin. The largest decrease in weight was observed at 6 months with a mean 11% decrease (p.0001).A significant gender-by-weight change interaction on percent change in adiponectin was observed [b(se)=0.9 (0.2), p=.0003], with men having a larger increase in adiponectin with weight loss compared to women. There was a significant effect of weight gain over time with increases in IL-6 [b(se)=0.9 (0.3), p=.001].Overall, weight loss was significantly associated with improvements in adiponectin and IL-6. Those improvements remained at 24 months, following weight regain. The association between weight change and adiponectin was different between genders. Implementing strategies that support sustained weight loss can help prevent a state of chronic systemic inflammation and its associated adverse effects.

Objective To compare maternal lipid and lipoprotein concentrations between small for gestational age (SGA) infants and infants with normal growth born at term. Study design This was a case-control study nested within a large (n = 5337) prospective multicenter cohort of pregnant women followed to delivery. SGA cases (n = 323) were all term infants with birth weight below the 10th percentile for their gestational age and sex. Controls (n = 671) were selected at random from term infants with birth weight between the 25th and 75th percentiles. Plasma samples obtained at 24-26 weeks were analyzed for lipoproteins using a recently developed nuclear magnetic resonance-based procedure that distinguishes high-density lipoprotein (HDL) and low-density lipoprotein particles of different sizes. Apolipoprotein A-1 and C-II levels were analyzed using turbidimetric methods. Results Compared with controls, mothers of SGA cases had significantly higher mean concentrations of total HDL particles, medium and small HDL particles, and apolipoprotein A-1, with evidence of a dose–response relationship across quartiles of the control distribution. aORs for the highest quartiles were 2.8 (95% CI, 1.7-4.5) for total HDL particles and 3.1 (95% CI, 1.9-5.0) for apolipoprotein A-1. Conclusion Our results suggest that the higher HDL particle and apolipoprotein A-1 concentrations in mothers of SGA cases may reflect defective placental transport of HDL, which could compromise cholesterol uptake by the developing fetus.

The serum level of LOX-1 ligand containing ApoB (LAB) may reflect atherogenicity better than LDL cholesterol (LDLC), total LDL particles and usual measurement of oxidized LDL. The association between LAB and intima-media thickness (IMT) of carotid artery was investigated by ultrasound in US and Japan men.Participants were 297 US Caucasian and 310 Japanese men, aged 40-49 years without past history of cardiovascular disease. Serum LAB levels were measured by ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody.Serum LAB levels [median (interquartile range), μg/L] were 1321 (936, 1730) in US Caucasians and 940 (688, 1259) in Japanese. For Caucasian men, average IMT was higher in higher LAB quartile, which was 0.653, 0.667, 0.688, and 0.702 mm, respectively (p for trend = 0.02). Linear regression analysis showed serum LAB was significantly associated with IMT after adjustment for LDLC or total LDL particles in addition to other traditional or novel risk factors for atherosclerosis such as C-reactive protein. However, there was no significant relationship between LAB and IMT in Japanese men.Serum LAB, a new candidate biomarker for residual risk, was associated with an increased carotid IMT in US Caucasian men independently of various risk factors; however, ethnic difference should be clarified in the future.

Limited data are available about risk factors for the progression of aortic stiffness in healthy population. We examined several risk factors as possible independent predictors of aortic stiffness progression among a population-based sample of US men.A total of 240 men (40-49 years) free of CVD at baseline from the Pittsburgh site of the ERA JUMP study were evaluated. Aortic stiffness was measured as carotid-femoral pulse wave velocity at baseline and after 4.6 ± 0.2 (mean ± SD) years of follow-up. Progression of aortic stiffness was evaluated as relative annual change in carotid-femoral pulse wave velocity (% change/year). Using linear regression, both baseline potential risk factors and their annual changes were evaluated as possible risk factors for aortic stiffness progression. Baseline age, follow-up time, race, heart rate, and medications use were forced in all models.During follow-up, relative to baseline level, aortic stiffness increased 0.3% ± 5.3% per year. In final models, the independent predictors of degree of aortic stiffness progression were lower levels of adiponectin (P = 0.03), higher levels of systolic blood pressure (P = 0.03), greater annual change in systolic blood pressure (P = 0.04), and alcohol consumption ≥ 2 times/week (P = 0.02). Adiponectin levels within the third (9.8 μg/Ml ≤ adiponectin13.0 μg/mL) and the fourth (adiponectin ≥ 13.0 μg/mL) quartiles were associated with an improvement in relative annual aortic stiffness progression (P = 0.02, P = 0.01, respectively) compared to levels within the first quartile (adiponectin ≤ 7.0 μg/mL).Among apparently healthy men, lower levels of baseline adiponectin could be a novel marker for greater risk of aortic stiffness progression. Longitudinal research is required to evaluate whether adiponectin change over time would have similar association with aortic stiffness progression.

To determine the short-term efficacy of oral glucosamine supplementation by evaluating structural lesions in the knee joints, as assessed using 3T magnetic resonance imaging (MRI).This study was designed as a randomized, double-blind, placebo-controlled trial. Recruitment was performed via mass mailings and an arthritis registry in southwestern Pennsylvania. In total, 201 participants with mild-to-moderate pain in one or both knees, as defined by a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score ≥25 and ≤100, were enrolled. Of these subjects, 69.2% had a Kellgren/Lawrence grade ≥2 in at least 1 knee. Participants received 24 weeks of treatment with 1,500 mg glucosamine hydrochloride in beverage form or a placebo beverage. The primary outcome was decreased worsening of cartilage damage on 3T MRI of both knees, assessed according to a validated scoring system, the Whole-Organ MRI Score (WORMS). Secondary outcomes included change in bone marrow lesion (BML) scores in all knees and change in excretion of urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II).The adjusted odds ratio (OR) for the likelihood of decreased cartilage damage over 24 weeks in any WORMS-scored subregion of the knee in the glucosamine treatment group compared to the control group was 0.938 (95% confidence interval [95% CI] 0.528, 1.666). Compared to subjects treated with glucosamine, control subjects showed more improvement in BMLs (adjusted OR 0.537, 95% CI 0.291, 0.990) but no difference in worsening BMLs (adjusted OR 0.691, 95% CI 0.410, 1.166) over 24 weeks. There was no indication that treatment with glucosamine decreased the excretion of urinary CTX-II (β = -0.10, 95% CI -0.21, 0.002).The results of this short-term study provide no evidence of structural benefits (i.e., improvements in MRI morphologic features or urinary CTX-II excretion) from glucosamine supplementation in individuals with chronic knee pain.

Objectives: RCT results of effect of fish oil on aortic stiffness are inconclusive. The aim of this study is to examine the differential association of EPA and DHA with aortic stiffness measured as cfPWV in Korean men in South Korea where fish intake is much higher than in the US (70 g/day vs. 7 g/day, respectively), and in White and Japanese American men. Methods: The ERA JUMP Study is a population-based study of atherosclerosis in men aged 40-49 free of CVD in Japan, Korea, and the US. The study examined cfPWV in 298 Koreans, 298 Japanese Americans and 263 Whites in 2002-07 using an automated waveform analyzer (VP2000, Omron, Japan). Serum EPA and DHA were measured using gas chromatography. Other variables including BP, heart rate, lipids, BMI, smoking and alcohol were measured using standardized methods. Multiple regression analysis was used to examine the association of each of EPA and DHA with cfPWV after adjusting for confounders. Results: Mean (SD) cfPWV (cm/sec) in Koreans was significantly lower than the other two groups (810 (130), 863 (213), and 902 (208), for Koreans, Whites, and Japanese Americans, respectively). Mean (SD) EPA (%) in Koreans was significantly higher than that in the other two groups (1.9 (1.0), 0.8 (0.6), and 1.0 (0.9) for Koreans, Whites, and Japanese Americans, respectively). Similarly mean (SD) DHA (%) in Koreans was significantly higher than that in the other two groups (4.8 (1.4), 2.4 (1.2), and 3.2 (1.4) for Koreans, Whites, and Japanese Americans, respectively). Multiple regression analyses showed that cfPWV in Koreans had a significant inverse association with EPA after adjusting for age, systolic BP, and heart rate, which remained after further adjusting for other potential confounders ( Table ). In contrast cfPWV in Koreans did not have a significant association with DHA. Meanwhile cfPWV in Whites or Japanese Americans did not have a significant association with either EPA or DHA. Table Multivariate adjusted association of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with aortic stiffness measured as carotid-femoral Pulse Wave Velocity Koreans in South Korea (n=298) Whites (n=263) Japanese Americans (n=280) Standardized beta P Standardized beta P Standardized beta P EPA Model I −0.141 0.010 0.018 0.759 −0.078 0.213 Model II −0.138 0.012 0.035 0.536 −0.013 0.827 Model III −0.150 0.007 0.037 0.529 −0.037 0.528 DHA Model I −0.086 0.112 0.012 0.840 −0.066 0.239 Model II −0.084 0.124 0.050 0.397 −0.039 0.696 Model III −0.089 0.103 0.052 0.392 −0.009 0.881 Model I: adjusted for age, systolic blood pressure and heart rate Model II: further adjusted for body mass index, current smoking, alcohol drinking, and medication for blood pressure Model III: further adjusted for LDL-C, HDL-C, triglycerides, diabetes, medication for lipid Conclusions: Our results suggest that high levels of EPA observed in Koreans have a favorable effect on aortic stiffness.

Objective: Aortic stiffness, a significant marker of vascular aging, is independently associated with CVD and all-cause mortality. Limited data are available about risk factors for the progression of aortic stiffness in healthy population. We examined several baseline risk factors as possible independent predictors of aortic stiffness progression among US men. Design: Participants were a population-based sample of black and white men aged 40–49 from the Pittsburgh site of the ERA JUMP Study, who were free of CVD at baseline. Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using an automated waveform analyzer at baseline and after 4.6±0.21(mean±SD) years of follow-up. Progression of cfPWV was evaluated as: 1) occurrence of progression (defined as ≥ 75th percentile of the change in cfPWV since baseline (≥ 118.5 cm/s increase); and 2) severity of progression as the difference between the natural-log cfPWV at follow-up and the natural-log cfPWV at baseline. Systolic BP (SBP), BMI, visceral adiposity, lipids, glucose, insulin, adiponectin, PAI-1, fibrinogen, CRP, alcohol drinking, and smoking status at baseline were evaluated as possible risk factors for occurrence and severity of cfPWV progression. Stepwise logistic and linear regression models were utilized as appropriate. In univariate analysis, risk factors found to be associated with cfPWV progression at a P value ≤ 0.25 were eligible for stepwise regression analysis. Variables were dropped from models at a P value > 0.1. Age at baseline, follow-up time, race, heart rate, and medication use were forced in all models. Results: A total of 240 men (White:82.5%, Black:17.5%) who were 45.0±2.9 years old at baseline, were included in this analysis. During follow-up, cfPWV progressed in 125 participants (52.0%) with a median increase of 113.5 cm/s (Q1=46.0, Q3=204.5). Final models revealed that independent predictors of the occurrence of cfPWV progression were lower levels of adiponectin (OR: 0.46, 95%CI: 0.23, 0.95, P=0.04), higher levels of SBP (OR: 1.03, 95%CI: 1.002, 1.06, P=0.04) and drinking alcohol ≥ 2 times/week (OR: 1.92, 95%CI: 1.01, 3.64, P=0.046) at baseline. Similarly, adiponectin (β=−0.097(SE=0.04), P=0.02) and drinking alcohol ≥ 2times/week (β=0.084(SE=0.04), P=0.02) were also independent predictors of severity of cfPWV progression. No significant interactions were found between these predictors and race. Conclusions: Independent of age at baseline, follow-up time, race, heart rate and medication use, lower levels of adiponectin, higher levels of SBP and drinking alcohol ≥2 times/week at baseline are associated with greater progression in aortic stiffness among relatively young middle-aged US men.

A commercially available partially hydrogenated fat was analyzed for fatty acids containing conjugated dienes. The fatty acids were isolated by high-performance liquid chromatography (HPLC), and analyzed with a photodiode array detector and an atmospheric-pressure ionization mass spectrometer. Conventional and second-derivative ultraviolet (UV) spectra of the peaks eluting from the HPLC were recorded with the photodiode array detector, and peaks displaying second-derivative UV spectra characteristic of the conjugated diene chromophore were analyzed by mass spectrometry. The UV and mass spectra of the fatty acids with conjugated dienes, present in the partially hydrogenated fat, were identical to those of reference preparations of linoleic acid isomers with conjugated dienes. The results obtained emphasize that care must be exercised in the interpretation of clinical and experimental data concerning the detection of conjugated dienes in tissues or body fluids of humans and experimental animals. The conjugated dienes may not reflect an ongoing process of lipid peroxidation, but may be of dietary origin.

The increased cardiovascular risk experienced by patients (particularly women) with insulin-dependent diabetes mellitus (IDDM) is not fully explained by conventional risk factors including lipid and lipoprotein concentrations. To determine if plasma lipid peroxide concentrations are relevant to these observations, levels of thiobarbituric acid reactive substances (TBARS) were measured in 56 young adult subjects with IDDM (mean age, 33 years; duration, 24 years) and 56 age- and sex-matched healthy controls. The TBARS concentration was significantly higher in women with diabetes than in female controls (7.4 v 4.5 nmol/mL, P = .001), but not in men with IDDM (5.1 v 5.3 nmol/mL). Diabetic men showed a significant correlation between triglyceride and TBARS concentrations (P < .01), a finding not seen in diabetic women. Furthermore, there was a correlation between glycemic control (hemoglobin A1 [HBA1]) and TBARS in diabetic men, but not in women (P < .01). These findings raise the possibility that the relatively greater increase in cardiovascular disease risk seen in IDDM women compared with men may relate to their increased degree of lipid peroxidation, which is independent of their degree of glycemic control.

Serum fatty acids had been studied for more than 30 years. In the investigations of the relation with the risks of coronary heart disease, fatty acids were examined in either serum total lipids or in one or two lipid fractions, the results were not conclusive. The purpose of this study was to report serum fatty acid compositions in total lipids (TL) and in lipid fractions: cholesterol esters (CE), phospholipids (PL), and triglycerides (TG). One hundred and four postmenopausal women who were living in Allegheny Country, Pennsylvania, USA and not taking hormone replacement therapy at the time of their first year clinic visit after cessation of menses were selected to be studied. Fifteen fatty acids in TL, CE, PL, and TG were measured and identified by capillary gas chromatography. A aliquot control serum was measured repeatedly for assessment of quality control. The coefficient of variation for common fatty acids was 8.2% for stearic acid in TL, 12.4% for palmitic acid in PL, 9.1% for oleic acid in CE, and 4.5% for palmitic acid in TG. We report results from both quantitative (mg/dl) and qualitative (mole %) analyses. The weight of fasting serum total fatty acids were 366.6 mg/dl in TL, 80.6 mg/dl in CE, 107.8 mg/dl in PL, and 56.9 mg/dl in TG. The p/s ratios of serum fatty acids were 1.33, 3.57, 0.64, and 0.51 in TL, CE, PL, and TG, respectively. Fatty acid distributions from both quantitative and qualitative measurements are to be evaluated for the relation with coronary heart disease.

Epidemiological studies suggested thatn-6 fatty acids, especially linoleic acid (LA), have beneficial effects on CHD, whereas somein vitrostudies have suggested thatn-6 fatty acids, specifically arachidonic acid (AA), may have harmful effects. We examined the association of serumn-6 fatty acids with plasminogen activator inhibitor-1 (PAI-1). A population-based cross-sectional study recruited 926 randomly selected men aged 40–49 years without CVD during 2002–2006 (310 Caucasian, 313 Japanese and 303 Japanese-American men). Plasma PAI-1 was analysed in free form, both active and latent. Serum fatty acids were measured with gas-capillary liquid chromatography. To examine the association between totaln-6 fatty acids (including LA and AA) and PAI-1, multivariate regression models were used. After adjusting for confounders, totaln-6 fatty acids, LA and AA, were inversely and significantly associated with PAI-1 levels. These associations were consistent across three populations. Among 915 middle-aged men, serumn-6 fatty acids had significant inverse associations with PAI-1.

Background and Purpose— Recent studies reported the differential effect of docosahexaenoic (DHA) and eicosapentaenoic acids (EPA). We examined the differential association of DHA and EPA with carotid intima-media thickness (IMT) in Japanese individuals in Japan and in U.S. white individuals and explored whether DHA or EPA contributes to the difference in IMT between the two groups. Methods— A population-based cross-sectional study in 608 Japanese and U.S. white men aged 40 to 49 was conducted to assess IMT, serum DHA, EPA, and other cardiovascular risk factors. Results— Japanese compared to U.S. whites had significantly lower IMT (mean±SD, 618±81 and 672±94 μm for Japanese and whites, respectively; P 2-fold higher levels of DHA and EPA. DHA, but not EPA, had an inverse association with IMT in both Japanese and U.S. whites. The inverse association remained only in Japanese men after adjusting for risk and other factors. The significant difference in multivariable-adjusted IMT became nonsignificant after further adjusting for DHA (mean difference, 17 μm; 95% CI, −8 to 43; P =0.177) but not EPA. In this multivariable-adjusted model, DHA but not EPA was a significant predictor of IMT ( P =−0.032 versus 0.863, respectively). Conclusions— These data suggest that DHA may have a more potent antiatherogenic effect than EPA, especially in levels observed in the Japanese, independent of risk factors.

We recently reported that Japanese had higher liver fat at a lower level of BMI compared with non-Hispanic whites (NHW).We hypothesize that ethnic difference in fat storage capacity contributes to this ethnic difference in liver fat.To examine this, we assessed liver fat among 244 Japanese-American aged 40-49, using regional computed-tomography images, along with metabolic variables.Despite the similar BMI between Japanese-Americans and NHW men, Japanese-Americans had more liver fat (liver to spleen attenuation ratio: 1.03 ± 0.22 for Japanese-Americans, and 1.07 ± 0.15 for NHW men; p0.05) and tended to have a greater disposition for fatty liver with an increase in BMI than NHW, indicating a clear difference between the two groups. In addition, liver fat is less in Japanese-Americans compared with Japanese men (1.03 ± 0.22 vs. 1.01 ± 0.16; p0.05), despite of a much higher BMI. These ethnic differences support the hypothesis that higher fat storage capacity indeed seems to be associated with less liver fat. In all the groups, liver fat content strongly correlated with triglycerides, homeostasis model assessment-insulin resistance, and C-reactive protein (CRP). Nevertheless, these metabolic variables were worse in Japanese-Americans, despite of less liver fat, compared with Japanese. Moreover, CRP levels were least among Japanese with highest liver fat, and highest among NHW men with least liver fat, despite of a strong positive association between CRP and fatty liver within each population.Fat content in the liver is intermediate for Japanese-Americans compared with Japanese and NHW men, which supports the hypothesis of less fat storage capacity among Japanese, closely linked to ethnic difference in predisposition to fatty liver.

Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extrarenal factors.In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR less than 60 mL/min/1.73 m) and examined the influence of extrarenal factors on GFR estimates among HIV-infected men.Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs 5%, P0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC, whereas it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR estimates. Higher serum albumin levels and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were associated with lower eGFRSCR. HIV viral load, hepatitis C coinfection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared with eGFRSCR. Differences between these GFR-estimating methods may be the result of the effects of extrarenal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.

Background: Skeletal muscle adipose tissue (AT) infiltration, or myosteatosis, appears to be greater in African compared with European ancestry individuals and may play a role in type 2 diabetes mellitus (T2DM), a disease that disproportionally affects African ancestry populations. Inflammation is one mechanism that may link myosteatosis with increased T2DM risk, but studies examining the relationship between inflammation and myosteatosis are lacking.To examine these associations, we measured skeletal muscle subcutaneous AT, intermuscular AT, and skeletal muscle density using quantitative computed tomography and serum markers of inflammation in 471 individuals from 8 Afro-Caribbean multigenerational families [mean family size 67; mean age 43 years; mean body mass index (BMI) 28 kg/m(2)].After removing the variation attributable to significant covariates, heritabilities of inflammation markers [C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)] ranged from 33% (TNFα) to 40% (CRP); all P0.01. Higher CRP, IL-6, and TNF-α were associated with lower subcutaneous AT around skeletal muscle (r=-0.13 to -0.19, P0.05). Higher CRP was additionally associated with lower skeletal muscle density, indicative of greater intramuscular AT (r=-0.10, P0.05), hyperinsulinemia (r=0.12, P0.05), and increased homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.17, P0.01).Our findings suggest that heredity may play a significant role in the determination of several markers of inflammation in African ancestry individuals. Higher concentrations of CRP appear to be associated with greater skeletal muscle AT infiltration, lower subcutaneous AT, hyperinsulinemia, and insulin resistance. Longitudinal studies are needed to further evaluate the relationship between inflammation with changes in skeletal muscle AT distribution with aging and the incidence of T2DM.

Adiponectin and leptin are adipokines that influence bone metabolism in vitro and in animal models. However, less is known about the longitudinal association of leptin and adiponectin with fracture. We tested the hypothesis that low leptin and high adiponectin levels are each individually associated with fracture risk in a prospective cohort study in Memphis and Pittsburgh among 3075 women and men aged 70 to 79 years from the Health Aging and Body Composition (Health ABC) study. There were 406 incident fractures (334 nonvertebral and 72 vertebral) over a mean of 6.5 ± 1.9 years. Cox regression was used to estimate the hazard ratios for fracture. Sex modified the association between adiponectin and fracture (p = .025 for interaction). Men with the highest adiponectin level (tertile 3) had a 94% higher risk of fracture [hazard ratio (HR) = 1.94; 95% confidence interval (CI) 1.20-3.16] compared with the lowest tertile (tertile 1; p = .007 for trend) after adjusting age, race, body mass index (BMI), education, diabetes, weight change, and hip bone mineral density (BMD). Among women, after adjusting for age and race, this association was no longer significant (p = .369 for trend). Leptin did not predict fracture risk in women (p = .544 for trend) or men (p = .118 for trend) in the multivariate models. Our results suggest that adiponectin, but not leptin, may be a novel risk factor for increased fracture risk independent of body composition and BMD and that these relationships may be influenced by sex. More research is needed to understand the physiologic basis underlying these sex differences.

Rat livers were flushed and stored ex vivo in Krebs-Henseleit buffer at 37 degrees C for 3 hr or in University of Wisconsin solution at 2 degrees C for 48 hr. After this they were perfused with recirculated Krebs-Henseleit solution at 37 degrees C for 1 hr. Levels of phospholipids (PL), free fatty acids (FFA), and conjugated dienes were determined at various times during ischemia and after 1 hr of reperfusion. After 3 hr warm ischemia, total PL content decreased by about 30% primarily because of decreases in phosphatidylcholine and phosphatidylethanolamine. One hour of reperfusion normalized PL levels. Total PL content was unchanged up to 48 hr of cold ischemia because of offsetting alterations in levels of PL classes. FFA accumulation during warm ischemia was about half that during cold ischemia. Conjugated diene concentration increased fivefold during warm ischemia but was unchanged during cold ischemia. Low PL levels and FFA accumulation along with production of conjugated dienes suggest that lipid oxidation is a major mechanism of PL degradation during warm, but not cold, ischemia of the liver.

D-dimer and von Willebrand factor (vWF) are associated with atherosclerosis. We recently reported that in a post-World War II birth cohort, Japanese men in Japan had lower levels of atherosclerosis than white men in the United States (U.S.). We examined whether the differences in D-dimer and vWF levels are associated with differences in atherosclerosis between the two populations.Population-based samples of 99 Japanese and 100 white American men aged 40-49 years were examined for coronary artery calcification (CAC), carotid intima-media thickness (IMT), D-dimer, vWF, and other factors using a standardized protocol. When compared to white American men,Japanese had similar levels of D-dimer (0.22 +/- 0.28 vs. 0.19 +/- 0.24 microg/L, respectively, P = 0.39) but significantly higher levels of vWF (124.1 +/- 36.6 vs. 91.3 +/- 48.8%, respectively, P0.01). Japanese as compared to white American men had significantly lower prevalence of CAC (13.1 vs. 28.0%, P0.01, respectively) and significantly lower IMT (0.61 +/- 0.07 vs. 0.66 +/- 0.08 mm, P0.01, respectively). Japanese men had a significant positive association of D-dimer with the prevalence of CAC and a negative association of vWF with IMT, whereas white American men did not have any significant associations.In men aged 40-49 years, Japanese as compared to white Americans had similar levels of D-dimer and higher levels of vWF although Japanese had a significantly lower prevalence of CAC and IMT. These haemostatic factors are unlikely to explain the difference in atherosclerosis in these populations.

Although the role of Wnt/beta-catenin signaling in liver growth and development is well established, its contribution in non-neoplastic hepatic pathologies has not been investigated. Here, we examine the role of beta-catenin in a murine model of diet-induced liver injury. Mice with hepatocyte-specific beta-catenin deletion (KO) and littermate controls were fed the steatogenic methionine and choline-deficient (MCD) diet or the corresponding control diet for 2 weeks and characterized for histological, biochemical, and molecular changes. KO mice developed significantly higher steatohepatitis and fibrosis on the MCD diet compared with wild-type mice. Both wild-type and KO livers accumulated triglyceride on the MCD diet but, unexpectedly, higher hepatic cholesterol levels were observed in KO livers on both control and MCD diets. Gene expression analysis showed that hepatic cholesterol accumulation in KO livers was not attributable to increased synthesis or uptake. KO mice had lower expression of bile acid synthetic enzymes but exhibited higher hepatic bile acid and serum bilirubin levels, suggesting defects in bile export. Therefore, loss of beta-catenin in the liver leads to defective cholesterol and bile acid metabolism in the liver and increased susceptibility to developing steatohepatitis in the face of metabolic stress.

The relation between cholesteryl ester transfer protein (CETP) levels and atherosclerosis is controversial. We examined whether the serum CETP levels were associated with subclinical atherosclerosis, independent of its most common gene variant, in a sample of Japanese men. A population-based cross-sectional study of 250 Japanese men aged 40 to 49 years was conducted to assess the intima-media thickness of the carotid artery, coronary artery calcium, serum CETP levels, and the CETP D442G gene variant. Compared with the lowest CETP quartile, the multivariate adjusted odds ratio for coronary artery calcium was 0.77 (95% confidence interval 0.18 to 3.36), 0.96 (95% confidence interval 0.27 to 3.40), and 3.49 (95% confidence interval 1.05 to 11.6) with increasing CETP quartiles. The serum CETP quartiles were also positively associated with the intima-media thickness of the carotid artery (adjusted mean 602, 616, 615, and 646 mum for the lowest to top quartile, respectively). The findings remained unchanged after additional adjustment for the CETP D442G gene variant. No significant difference was found in the prevalence of coronary artery calcium or in the mean intima-media thickness of the carotid artery between participants with and without the CETP D442G gene variant.

Cardiovascular disease (CVD) is the leading cause of death in type 1 diabetes mellitus (T1D). Pulse pressure, a measure of arterial stiffness, is elevated in T1D and associated with CVD. Free fatty acids (FFAs), elevated in women and abdominal adiposity, are also elevated in T1D and CVD. We thus examined the association of fasting FFAs with pulse pressure and coronary artery calcification (CAC, a marker of coronary atherosclerotic burden) in an adult population (n = 150) of childhood-onset T1D and whether any such associations varied by abdominal adiposity and sex. Mean age and diabetes duration were 42 and 33 years, respectively, when CAC, visceral abdominal adiposity (VAT), and subcutaneous abdominal adiposity (SAT) were determined by electron beam tomography. Free fatty acids were determined by in vitro colorimetry. Pulse pressure was calculated as systolic blood pressure minus diastolic blood pressure. Free fatty acids were log transformed before analyses, and all analyses were controlled for serum albumin. Free fatty acids were associated with pulse pressure in women (r = 0.24, P = .04), but not in men (r = 0.07, P = .55). An interaction for the prediction of pulse pressure was noted between FFAs and both VAT (P = .03) and SAT (P = .008) in women, but only a marginal interaction with SAT (P = .09) and no interaction for VAT (P = .40) with FFAs were observed in men. In multivariable linear regression analysis allowing for serum albumin, age, height, heart rate, albumin excretion rate, hemoglobin A(1c), high-density lipoprotein cholesterol, hypertension medication use, FFAs, SAT, and the interaction between FFAs and SAT, the interaction between FFAs and SAT remained associated with pulse pressure in women (FFAs, P = .04; interaction term, P = .03), but not men (FFAs, P = .32; interaction term, P = .32). FFAs showed no association with log-transformed CAC. Although FFAs were not associated with CAC in either sex, they were associated with pulse pressure in women and their effect appeared to vary by abdominal adiposity, particularly SAT. This finding might help explain the loss of the sex difference in CVD in T1D.

Previous investigations have documented a reduced activity of the sodium-potassium-stimulated adenosine triphosphatase enzyme (Na+,K+ ATPase) in platelet membranes of allergic subjects. The purpose of this study was to determine if the reduced Na+,K+ ATPase activity was due to an enzyme inhibitor. Na+,K+ ATPase activity of a particulate fraction of sonicated platelets was determined by spectrophotometry in asymptomatic adults with and without allergy. The Na+,K+ ATPase level (mean, nanomoles per microgram of protein per minute; +/- STD) of allergic subjects (0.9 +/- 1.3) was lower (p less than 0.001) than that of nonallergic subjects (3.9 +/- 1.6). In contrast, when the same platelet fractions were frozen before assay, Na+,K+ ATPase was higher (p less than 0.005) in allergic subjects (6.0 +/- 1.4) than in nonallergic subjects (3.6 +/- 2.0). An inhibitor of canine kidney Na+,K+ ATPase was detected in the buffer in which these platelet fractions were frozen, allergic subjects (0.5% +/- 0.4% inhibition per microgram of protein) compared to nonallergic subjects (0.04% +/- 0.08%; p less than 0.005). The level of inhibition correlated positively with the postfreezing increase in platelet membrane Na+,K+ ATPase, suggesting a freezing-induced displacement of an inhibitor from the membrane. Plasma from these same subjects inhibited Na+,K+ ATPase activity of normal platelets, allergic subjects (70% +/- 31% inhibition) compared to nonallergic subjects (13% +/- 16%; p less than 0.001). These data suggest that the transport-enzyme defect observed in platelets from allergic subjects was due to a circulating Na+,K+ ATPase inhibitor. In vivo Na+,K+ ATPase inhibition in allergy could have profound effects on intracellular cation concentrations and broad implications for pathogenesis.

Background: Although obesity is strongly associated with diabetes, the greater prevalence of diabetes in persons of African ancestry than in those of other ancestries cannot be explained simply by differences in total or central adiposity. Objective: We examined whether skeletal muscle composition is associated with diabetes in 1249 men of African ancestry aged ≥40 y. Design: Anthropometry and fasting serum glucose were measured, and lower-leg skeletal muscle composition was assessed with peripheral quantitative computerized tomography (pQCT). Results: The prevalence of diabetes in this population was high (21%). We observed an age-associated adipose tissue remodeling in skeletal muscle and greater intermuscular (IMAT) and lesser subcutaneous (SAT) adipose tissue area with advancing age (P < 0.0001). Multivariate stepwise logistic regression identified more IMAT and less SAT to be significantly associated with a greater prevalence of diabetes. Even among normal-weight men [body mass index (BMI; in kg/m 2 ) < 25], diabetic men had significantly (P = 0.01) more IMAT than did those without diabetes. Greater IMAT was also associated with a greater prevalence of hyperglycemia in men with a family history of diabetes than in those without such history (P for interaction = 0.02). Conclusions: These findings underscore the independent associations of subcutaneous and intermuscular fat among men of African ancestry, an effect that may be modified by a family history of diabetes. Further studies are needed to identify the genetic and physiologic mechanisms that influence the distribution and remodeling of adipose tissue in skeletal muscle with aging.

Both platelet activating factor and eicosanoids participate in the cerebrovascular response to ischemia. Eicosanoids also modulate cerebrovascular tone under normal physiologic circumstances, but a similar role for platelet activating factor has not been investigated. Therefore, using 16 rats, we studied the effects of the platelet activating factor receptor blockers BN 52021 (10 mg/kg, n = 4 or 30 mg/kg, n = 2) and WEB 2086 (5 mg/kg, n = 6) on global cerebral blood flow and the cerebral metabolic rate for oxygen and compared them with the effect of indomethacin (10 mg/kg, n = 4). Neither antagonist altered cerebral blood flow (112 +/- 16 and 107 +/- 14 ml/100 g/min at baseline versus 108 +/- 16 and 105 +/- 18 ml/100 g/min after BN 52021 and WEB 2086, respectively). In contrast, indomethacin significantly (p less than 0.05) decreased cerebral blood flow from 106 +/- 8 to 69 +/- 4 ml/100 g/min. No treatment altered the cerebral metabolic rate for oxygen compared with baseline. These data suggest that in normal rat brain, concentrations of platelet activating factor, unlike those of eicosanoids, are subthreshold and do not modulate cerebral blood flow or the cerebral metabolic rate for oxygen.

Very few studies have comprehensively defined the genetic and environmental influences on body fat storage in the arms and legs and their association with diabetes, especially in families of African heritage. We analyzed body fat distribution by dual-energy x-ray absorptiometry (percentage total fat, percentage trunk fat, percentage arm fat, and percentage leg fat) and fasting serum glucose in 471 individuals (mean age, 43 years) from 8 multigenerational Afro-Caribbean families (mean family size = 51; 3535 relative pairs). Diabetes was inversely associated with percentage leg fat (P = .009) and, to some extent, positively associated with percentage arm fat independent of age, sex, and body size (P = .08), but not with anthropometric or dual-energy x-ray absorptiometric measures of total and central adiposity. Furthermore, percentage leg fat was inversely, whereas percentage arm fat was positively, associated with body mass index, waist circumference, and serum glucose (P.01). Residual heritability (h2r) for arm and leg fat was significant (P.01) and high: 62% (for percentage arm fat) and 40% (for percentage leg fat). Moreover, sex-specific h2r for leg fat was considerably higher (P = .02) in women than in men (h2r values, 58% vs 17%, respectively). Genetic correlation (rho(G)) between arm and leg fat was -0.61 (P.01), suggesting that only 37% of the covariation between these 2 adipose tissue depots may be due to shared genetic influences. This study provides new evidence for a strong genetic and sex contribution to upper and lower body fat, with relatively little covariation between these traits due to shared genes. Our findings also suggest that, in this population, leg fat is associated with diabetes independent of overall adiposity.

This unblinded, randomized, Phase I clinical trial was conducted to determine whether lycopene supplementation lowered serum prostate specific antigen (PSA), surrogate endpoint for prostate cancer initiation or progression, in men with elevated prostate cancer risk. Afro-Caribbean men (n=81) with high-grade prostatic intraepithelial neoplasia, atypical foci or repeated non-cancerous biopsies, ascertained in a population-based screening program, were randomized to four months intervention with 30 mg/day lycopene (Lyc-O-Mato) plus a multivitamin, or to multivitamin, only. Serum PSA and lycopene were compared at randomization, 1, and 4 mo using two-sided chi2 and t-tests for independent samples. Treatment groups were similar at baseline. Serum lycopene levels approximately doubled in the lycopene intervention group. Serum PSA declined during the first month of treatment, but returned to randomization level by month 4. The PSA response was nearly identical in both treatment groups. No adverse effects attributed to lycopene supplementation were documented. We conclude that the PSA lowering response to antioxidant supplementation observed in previous 3-wk studies in men awaiting prostatectomy may have been a transient response, perhaps not specific to lycopene. Lowering of serum PSA may not be an appropriate endpoint for the long-term studies needed to evaluate lycopene supplementation for reducing prostate cancer initiation or progression.

Objective The aim of the study was to describe longitudinal changes in serum lipids among HIV-infected men receiving highly active antiretroviral therapy (HAART) with long-term follow-up. Methods A total of 304 HIV-infected men who initiated HAART and who had serum lipid measurements prior to and for up to 7 years after HAART initiation were identified from the Multicenter AIDS Cohort Study (MACS). Mean levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were examined at biannual time-points. Results Significant lipid changes were seen within 0.5 years of HAART initiation but increases in TC (+1.09 mmol/L), LDL-C (+0.57 mmol/L), HDL-C (+0.16 mmol/L) and non-HDL-C (+0.91 mmol/L) reached peak levels 2–3 years after HAART initiation. Declines in serum TC, LDL-C and non-HDL-C in subsequent years occurred concurrently with a substantial increase in use of lipid-lowering medications (from 1% usage pre-HAART to 43% 6–7 years after HAART initiation) but the proportion of men who either were treated with cholesterol-lowering medication or had elevated cholesterol levels (>5.18 mmol/L) did not change during the 2–7-year interval after HAART. Mean HDL-C also decreased after 2–3 years and was low (

Coronary heart disease incidence and mortality remain very low in Japan despite major dietary changes and increases in risk factors that should have resulted in a substantial increase in coronary heart disease rates (Japanese paradox). Primary genetic effects are unlikely, given the substantial increase in coronary heart disease in Japanese migrating to the United States. For men aged 40-49 years, levels of total cholesterol and blood pressure have been similar in Japan and the United States throughout their lifetimes. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery calcification, and intima-media thickness of the carotid artery in men aged 40-49 years are similar in Japan and the United States. They conducted a population-based study of 493 randomly selected men: 250 in Kusatsu City, Shiga, Japan, and 243 White men in Allegheny County, Pennsylvania, in 2002-2005. Compared with the Whites, the Japanese had a less favorable profile regarding many risk factors. The prevalence ratio for the presence of a coronary calcium score ofor =10 for the Japanese compared with the Whites was 0.52 (95% confidence interval: 0.35, 0.76). Mean intima-media thickness was significantly lower in the Japanese (0.616 mm (standard error, 0.005) vs. 0.672 (standard error, 0.005) mm, p0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations.

Adiponectin, an adipose-specific protein, is negatively associated with adiposity, insulin sensitivity, and diabetes. Very few studies have examined the role of heredity in the regulation of adiponectin and its association with body fat among individuals of African heritage. Thus, we measured fasting serum adiponectin levels by radioimmunoassay and body composition by dual-energy x-ray absorptiometry (DEXA) in 402 individuals aged 18 to 103 years belonging to 7 multigenerational families of African heritage in the relatively homogeneous island population of Tobago. Heritability of adiponectin was 33.2% (P < .01), and age, sex, and body mass index explained 23.4% of the variance in adiponectin. Sex-specific heritability was significant in men (heritability, 34%; P < .05), but not in women. The inverse associations between body mass index and percentage of body fat and adiponectin, independent of age and height, were much stronger in women (all P values

It has been notoriously difficult to successfully cryopreserve swine embryos, a task that has been even more difficult for in vitro-produced embryos. The first reproducible method of cryopreserving in vivo-produced swine embryos was after centrifugation and removal of the lipids. Here we report the adaptation of a similar process that permits the cryopreservation of in vitro-produced somatic cell nuclear transfer (SCNT) swine embryos. These embryos develop to the blastocyst stage and survive cryopreservation. Transfer of 163 cryopreserved SCNT embryos to two surrogates produced 10 piglets. Application of this technique may permit national and international movement of cloned transgenic swine embryos, storage until a suitable surrogate is available, or the long-term frozen storage of valuable genetics.

Meat products are generally low in omega-3 (n-3) fatty acids, which are beneficial to human health. We describe the generation of cloned pigs that express a humanized Caenorhabditis elegans gene, fat-1, encoding an n-3 fatty acid desaturase. The hfat-1 transgenic pigs produce high levels of n-3 fatty acids from n-6 analogs, and their tissues have a significantly reduced ratio of n-6/n-3 fatty acids (P < 0.001).

Background Elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels were associated with higher incidence of type II diabetes. Elucidating the determinants of PAI-1 in various ethnicities may help to understand the susceptibility to developing diabetes. The aim of our study was to compare PAI-1 levels between Americans and the Japanese in the post-war generation and to elucidate the determinants of the PAI-1 levels. Methods We conducted a cross-sectional study on a total of 198 men aged 40–49 in the US (Body mass index (BMI): 27.0 ± 3.3 kg/m 2 ) and Japan (BMI: 23.3 ± 3.1 kg/m 2 ). Examination included physique measurement (BMI and waist girth), blood analysis (lipid profiles, glucose, insulin, C-reactive protein, and PAI-1), and life-style assessment by self-administered questionnaires. Results PAI-1 levels were significantly lower in American than in Japanese men, even after adjustment for age, waist girth, cigarette smoking, habitual alcohol drinking, and other factors. In the Americans, waist girth, insulin, and cigarette smoking were significantly associated with PAI-1 levels, while waist girth and triglycerides were significantly associated with PAI-1 levels in the Japanese. Conclusions PAI-1 levels were significantly lower in American than in Japanese men and the determinants of PAI-1 levels differ for American and Japanese men aged 40–49.

Background The Women’s Health Initiative (WHI) clinical trial found no reduction in coronary heart disease events among hormone therapy (HT) users despite an improvement in lipid levels. We hypothesized that a lack of benefit of HT on atherosclerosis would be better explained by the lipoprotein subclasses than by standard lipid levels. To test this hypothesis, we evaluated differences in coronary calcification, lipids, and lipoprotein subclasses among HT users and nonusers in a longitudinal study of the menopause. Methods Lipoprotein subclasses determined by nuclear magnetic resonance spectroscopy and coronary artery calcification (CAC) determined by electron beam computed tomography were compared between HT users (49%) and nonusers among 243 women, approximately 8 years postmenopausal, from the Healthy Women Study. Results The distribution of CAC scores was not significantly different between HT users and nonusers. As expected, HT users had higher levels of large high-density lipoprotein (HDL) particles and large very low-density lipoprotein (VLDL) particles. However, despite lower low-density lipoprotein (LDL) cholesterol levels among HT users, there were no significant differences between HT users and nonusers in any LDL subclass measures, including particle size or concentration. Regardless of HT use, women with CAC had higher levels of large VLDL and small LDL particles, higher LDL particle concentration, and smaller mean LDL size compared with women with no detectable CAC. Conclusions Compared with nonusers, HT users had higher levels of VLDL particles (triglycerides) and did not have a better LDL subclass distribution, which may explain the failure of HT to be associated with a difference in CAC in our study or with a reduction in coronary heart disease risk in randomized clinical trials.