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1.  Significant associations between lipoprotein(a) and corrected apolipoprotein B-100 levels in African-Americans 
Atherosclerosis  2014;235(1):223-229.
Lipoprotein(a), Lp(a), represents an apolipoprotein (apo) B-carrying lipoprotein, yet the relationship between Lp(a) and apoB levels has not been fully explored.
We addressed the relationship between Lp(a) and apoB-containing lipoprotein levels in 336 Caucasians and 224 African-Americans. Our approach takes unique molecular properties of Lp(a) as well as contribution of Lp(a) to the levels of these lipoproteins into account.
Levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apoB and apoB/apoA-1 did not differ across ethnicity. African-Americans had higher levels of Lp(a) and high-density lipoprotein cholesterol and lower triglyceride levels compared to Caucasians. Lp(a) levels were correlated with levels of TC (p<0.005), LDL-C (p<0.001), apoB (p<0.05) or apoB/apoA-1 (p<0.05) in both ethnic groups. These associations remained significant only in African-Americans after adjustments for the contribution of Lp(a)-cholesterol or Lp(a)-apoB. Furthermore, taking Lp(a)-apoB into account, allele-specific apo(a) levels were significantly associated with apoB levels and the apoB/apoA-1 ratio in African-Americans. The latter associations in African-Americans remained significant for allele-specific apo(a) levels for smaller apo(a) sizes (<26 K4 repeats), after controlling for the effects of age, sex, and BMI.
Although TC, LDL-C, and apoB levels were comparable between African-Americans and Caucasians, the associations of these parameters with Lp(a) and allele specific apo(a) levels differed between these two ethnic groups. In African-Americans, apoB and apoB/apoA-1 remained consistently and positively associated with both Lp(a) and allele-specific apo(a) levels after adjustments for the contribution of Lp(a)-apoB. The findings suggest an interethnic difference with a closer relationship between Lp(a) and apoB among African-Americans.
PMCID: PMC4095745  PMID: 24859635
plasma lipids; ethnicity; corrections for the contribution of Lp(a); apo(a) sizes; K4 repeats
2.  Treatment options for hypertriglyceridemia: from risk reduction to pancreatitis 
While there has been considerable focus on the role and treatment of LDL cholesterol levels, a definitive role of triglycerides in the management of cardiovascular disease has been uncertain. Notably, with increasing triglyceride levels, there is a parallel increase in cholesterol levels carried by triglyceride-rich lipoproteins, which has prompted interest in the use of non-HDL cholesterol levels as a tool guiding interventions. Recent studies have provided evidence for an independent role of triglyceride levels as a cardiovascular risk factor, and recently, an Endocrine Society guideline was published for treatment of hypertriglyceridemia. In contrast to the relative uncertainty regarding triglycerides and cardiovascular disease, a role of very high triglyceride levels as a risk factor for pancreatitis has been well known. The present paper summarizes the underlying evidence for a risk role for triglyceride levels in cardiovascular disease and pancreatitis, current treatment recommendations and areas of future research.
PMCID: PMC4028601  PMID: 24840268
Dyslipidemia; Lipoproteins; coronary heart disease; hypolipidemic therapy; lifestyle intervention
3.  Attenuated Age-Impact on Systemic Inflammatory Markers in the Presence of a Metabolic Burden 
PLoS ONE  2015;10(3):e0121947.
The overall burden of chronic disease, inflammation and cardiovascular risk increases with age. Whether the relationship between age and inflammation is impacted by presence of an adverse metabolic burden is not known.
We determined inflammatory markers in humans (336 Caucasians and 224 African Americans) and in mice, representing a spectrum of age, weight and metabolic burden.
In humans, levels of inflammatory markers increased significantly with age in subjects without the metabolic syndrome, (P=0.009 and P=0.037 for C-reactive protein, P<0.001 and P=0.001 for fibrinogen, P<0.001 and P=0.005 for serum amyloid-A, for Caucasians and African Americans, respectively). In contrast, trend patterns of inflammatory markers did not change significantly with age in subjects with metabolic syndrome in either ethnic group, except for fibrinogen in Caucasians. A composite z-score for systemic inflammation increased significantly with age in subjects without metabolic syndrome (P=0.004 and P<0.006 for Caucasians and African Americans, respectively) but not in subjects with metabolic syndrome (P=0.009 for difference in age trend between metabolic syndrome and non-metabolic syndrome). In contrast, no similar age trend was found in vascular inflammation. The findings in humans were paralleled by results in mice as serum amyloid-A levels increased across age (range 2-15 months, P<0.01) and were higher in ob/ob mice compared to control mice (P<0.001).
Presence of a metabolic challenge in mice and humans influences levels of inflammatory markers over a wide age range. Our results underscore that already at a young age, presence of a metabolic burden enhances inflammation to a level that appears to be similar to that of decades older people without metabolic syndrome.
PMCID: PMC4376898  PMID: 25815855
4.  Effects of Sugar-sweetened Beverages on plasma Acylation Stimulating Protein, Leptin & Adiponectin and Metabolic Parameters 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20437.
We determined the effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity.
Design and Methods
32 overweight/obese adults consumed glucose- or fructose-sweetened beverages (25% energy requirement) with their ad libitum diets for 8 weeks, followed by sweetened beverage consumption for 2 weeks with a standardized, energy-balanced diet. Plasma variables were measured at baseline, 2, 8 and 10 weeks, and body adiposity and insulin sensitivity at baseline and 10 weeks.
Fasting and postprandial ASP concentrations increased at 2 and/or 8 weeks. ASP increases correlated with changes in late-evening triglyceride concentrations. At 10 weeks, fasting adiponectin levels decreased in both groups, and decreases were inversely associated with baseline intra-abdominal fat volume. Sugar consumption increased fasting leptin concentrations; increases were associated with body weight changes. 24-h leptin profiles increased during glucose consumption and decreased during fructose consumption. These changes correlated with changes of 24-h insulin levels.
The consumption of fructose and glucose beverages induced changes in plasma concentrations of ASP, adiponectin and leptin. Further study is required to determine if these changes contribute to the metabolic dysfunction observed during fructose consumption.
PMCID: PMC3732502  PMID: 23512943
fructose; glucose; obesity; acylation stimulating protein; leptin; adiponectin
5.  Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor. Results from a novel triple-tracer approach 
Journal of lipid research  1998;39(4):913-924.
To differentiate effects of lovastatin on low density lipoprotein (LDL) receptor activity from effects on LDL metabolic properties, LDL apolipoprotein B (apoB) turnover was studied in eight hyperlipidemic subjects during baseline and lovastatin treatment, in the latter case with LDL tracers isolated during both baseline (C-LDL) and drug treatment (Rx-LDL) conditions. Lovastatin (40 mg/day) significantly lowered total plasma and LDL cholesterol levels (27% and 25%, respectively) as well as plasma triglyceride levels (30%). Using contemporaneous tracers (C-LDL before and Rx-LDL during treatment), lovastatin caused a modest increase in LDL fractional catabolic rate (FCR) (0.410 ± 0.113 vs. 0.339 ± 0.108 pools/day, P < 0.04 by paired t). The increase in LDL tracer FCR was higher when C-LDL tracer isolated during the untreated period was injected during lovastatin treatment (0.496 ± 0.177 vs. 0.339 ± 0.108 pools/day, P < 0.02). These in vivo studies in humans were confirmed by injecting LDL tracers from two patients into five guinea pigs. The C-LDL tracer was cleared consistently faster than the Rx-LDL tracer (0.082 ± 0.018 vs. 0.057 ± 0.015 pools/h, P < 0.001). The results demonstrate three important outcomes of lovastatin treatment in these subjects: LDL receptor activity increased by 49% (P < 0.02); LDL apoB production rate decreased by 17% (P < 0.03), and LDL particle in vivo affinity for the LDL receptor decreased by 15% (P < 0.01). The decrease in LDL particle affinity partially negated the expected effect of increased LDL receptors on LDL clearance. The present study provides an explanation for earlier observations by several investigators using contemporaneous tracers that treatment with HMGCoA reductase inhibitors resulted in only modest increases in low density lipoprotein functional catabolic rate.
PMCID: PMC3988111  PMID: 9555954
HMG-CoA reductase inhibitors; LDL receptor; apolipoprotein B; lipoprotein metabolism; tracer kinetics; lipid-lowering therapy
6.  Obesity and Lifespan Health—Importance of the Fetal Environment 
Nutrients  2014;6(4):1725-1736.
A marked increase in the frequency of obesity at the population level has resulted in an increasing number of obese women entering pregnancy. The increasing realization of the importance of the fetal environment in relation to chronic disease across the lifespan has focused attention on the role of maternal obesity in fetal development. Previous studies have demonstrated that obesity during adolescence and adulthood can be traced back to fetal and early childhood exposures. This review focuses on factors that contribute to early developmental events, such as epigenetic modifications, the potential for an increase in inflammatory burden, early developmental programming changes such as the variable development of white versus brown adipose tissue, and alterations in organ ontogeny. We hypothesize that these mechanisms promote an unfavorable fetal environment and can have a long-standing impact, with early manifestations of chronic disease that can result in an increased demand for future health care. In order to identify appropriate preventive measures, attention needs to be placed both on reducing maternal obesity as well as understanding the molecular, cellular, and epigenetic mechanisms that may be responsible for the prenatal onset of chronic disease.
PMCID: PMC4011063  PMID: 24763115
adipose tissue; pregnancy; metabolic syndrome; birth weight; risk factors; fetal environment; lifespan health
7.  Nanostructured biocomposite films of high toughness based on native chitin nanofibers and chitosan 
Chitosan is widely used in films for packaging applications. Chitosan reinforcement by stiff particles or fibers is usually obtained at the expense of lowered ductility and toughness. Here, chitosan film reinforcement by a new type of native chitin nanofibers is reported. Films are prepared by casting from colloidal suspensions of chitin in dissolved chitosan. The nanocomposite films are chitin nanofiber networks in chitosan matrix. Characterization is carried out by dynamic light scattering, quartz crystal microbalance, field emission scanning electron microscopy, tensile tests and dynamic mechanical analysis. The polymer matrix nanocomposites were produced in volume fractions of 8, 22, and 56% chitin nanofibers. Favorable chitin-chitosan synergy for colloidal dispersion is demonstrated. Also, lowered moisture sorption is observed for the composites, probably due to the favorable chitin-chitosan interface. The highest toughness (area under stress-strain curve) was observed at 8 vol% chitin content. The toughening mechanisms and the need for well-dispersed chitin nanofibers is discussed. Finally, desired structural characteristics of ductile chitin biocomposites are discussed.
PMCID: PMC4235265  PMID: 25478558
chitin nanofibers; chitosan; nanostructured; nanocomposites; mechanical properties
8.  GDF-15 for Prognostication of Cardiovascular and Cancer Morbidity and Mortality in Men 
PLoS ONE  2013;8(12):e78797.
The objective was to evaluate the hypothesis that growth-differentiation factor 15 (GDF-15) is an independent marker of the long-term risk for both cardiovascular disease and cancer morbidity beyond clinical and biochemical risk factors. Plasma obtained at age 71 was available from 940 subjects in the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort. Complete mortality and morbidity data were obtained from public registries. At baseline there were independent associations between GDF-15 and current smoking, diabetes mellitus, biomarkers of cardiac (high-sensitivity troponin-T, NT-proBNP) and renal dysfunction (cystatin-C) and inflammatory activity (C-reactive protein), and previous cardiovascular disease (CVD). During 10 years follow-up there occurred 265 and 131 deaths, 115 and 46 cardiovascular deaths, and 185 and 86 events with coronary heart disease mortality or morbidity in the respective total cohort (n=940) and non-CVD (n=561) cohort. After adjustment for conventional cardiovascular risk factors, one SD increase in log GDF-15 were, in the respective total and non-CVD populations, associated with 48% (95%CI 26 to 73%, p<0.001) and 67% (95%CI 28 to 217%, p<0.001) incremental risk of cardiovascular mortality, 48% (95%CI 33 to 67%, p<0.001) and 61% (95%CI 38 to 89%, p<0.001) of total mortality and 36% (95%CI 19 to 56%, p<0.001) and 44% (95%CI 17 to 76%, p<0.001) of coronary heart disease morbidity and mortality. The corresponding incremental increase for cancer mortality in the respective total and non-cancer disease (n=882) population was 46% (95%CI 21 to 77%, p<0.001) and 38% (95%CI 12 to 70%, p<0.001) and for cancer morbidity and mortality in patients without previous cancer disease 30% (95%CI 12 to 51%, p<0.001). In conclusion, in elderly men, GDF-15 improves prognostication of both cardiovascular, cancer mortality and morbidity beyond established risk factors and biomarkers of cardiac, renal dysfunction and inflammation.
PMCID: PMC3846468  PMID: 24312445
Atherosclerosis  2012;223(1):230-234.
Apolipoprotein E (apoE) has been implicated as conveying increased risk for coronary artery disease (CAD). Previous studies suggest a role of apoE as a modulator of immune response and inflammatory properties. We hypothesized that the presence of apo E4 is associated with an increased inflammatory burden in subjects with CAD as compared to subjects without CAD.
ApoE genotypes, systemic (C-reactive protein [CRP], fibrinogen, serum amyloid-A [SAA]) and vascular inflammatory markers (Lipoprotein-associated phospholipase A2 [Lp-PLA2] and pentraxin-3 [PTX-3]) were assessed in 324 Caucasians and 208 African Americans, undergoing coronary angiography.
For both ethnic groups, Lp-PLA2 index, an integrated measure of Lp-PLA2 mass and activity, increased significantly and stepwise across apoE isoforms (P=0.009 and P=0.026 for African Americans and Caucasians respectively). No differences were found for other inflammatory markers tested (CRP, fibrinogen, SAA and PTX-3). For the top cardiovascular score tertile, apo E4 carriers had a significantly higher level of Lp-PLA2 index in both ethnic groups (P=0.027 and P=0.010, respectively).
The presence of the apo E4 isoform was associated with a higher level of Lp-PLA2 index, a marker of vascular inflammation. Our results suggest that genetic variation at the apoE locus may impact cardiovascular disease risk through enhanced vascular inflammation.
PMCID: PMC3389284  PMID: 22632920
ApoE genotype; inflammation; coronary artery disease; ethnicity
10.  Postprandial Metabolic Responses to Dietary Glycemic Index in Hypercholesterolemic Postmenopausal Women 
Preventive cardiology  2010;13(1):29-35.
Cardiovascular disease is the leading cause of death in postmenopausal women. While diet and lifestyle remain the cornerstones of prevention, a low-fat/high-carbohydrate diet is associated with hyperglycemia and hyperlipemia—atherosclerotic risk factors affected by postprandial conditions. The objective of this study was to examine the acute response of lipids and insulin to a low-fat/high-carbohydrate meal with either a high-glycemic or a low-glycemic index in healthy postmenopausal women. Fifteen healthy postmenopausal women were enrolled in a randomized crossover dietary intervention study. Levels of glucose, triglyceride, free fatty acids (FFAs), and insulin were measured preprandially and for 240 minutes after consumption of the test meals. In response to the high-glycemic compared with the low-glycemic index meal, postprandial insulin levels had a higher peak (65.4 vs 48.1 μU/mL, respectively), the homeostasis model assessment-insulin resistance (HOMA-IR) was significantly higher (P=.014), serum triglyceride levels declined significantly (P<.001), and there was a small reduction in FFA levels, although the difference did not reach statistical significance. The results suggest a postprandial impact of glycemic index on cardiovascular metabolic biomarkers in postmenopausal women and may have implications for dietary glycemic modification of cardiovascular risk in women.
PMCID: PMC3613123  PMID: 20021624
11.  Low serum adiponectin concentrations are associated with insulin sensitivity independent of obesity in Sudanese subjects with type 2 diabetes mellitus 
Prevalence of Type 2 diabetes mellitus among Sudanese population was found to be 3.4% and associated with high rates of complications and obesity. Different adipocytokines are secreted from adipose tissues, among them adiponectin, which was shown to have insulins ensitizing properties and anti-inflammatory, anti-atherogenic effect. The aim of this study was to characterize type 2 diabetes in Sudanese diabetic subjects and controls in respect to hormones influencing or influenced by glucose metabolism.
104 type 2 diabetic patients (45 men and 59 women), and 75 matched control subjects (34 men and 41 women) were studied. Fasting serum samples were used to measure adiponectin, leptin, insulin, proinsulin, ghrelin and glucose. Body mass index, insulin/proinsulin ratio and (HOMA) insulin resistance and beta cell function were also calculated.
Adiponectin serum concentrations were significantly lower in subjects with type 2 diabetes compared with controls subjects (P = 0.002), comparison between males and females did not reach significant levels in both diabetic (P = 0.06) or controls (P = 0.16) groups. In the diabetic group adiponectin correlated positively with serum glucose, negatively with serum proinsulin and HOMA beta cell function (P = 0.03) respectively and serum ghrelin (P = 0.003), but not with BMI, HOMA insulin resistance, insulin or leptin. In controls serum adiponectin correlated negatively with BMI (P = 0.002) but not with other variables.
The findings of this study suggest that, adiponectin concentrations independent on BMI as a measure of adiposity, were mostly linked to insulin sensitivity and not to insulin resistance in Sudanese type 2 diabetic subjects, where race specific regulation mechanisms or different type 2 diabetes phenotype suggested being a major contributory factor in clarification the findings of this study.
PMCID: PMC3667040  PMID: 23497407
Diabetes mellitus; Sudan; Adiponectin; Ghrelin; Leptin
12.  A proposal for an additional clinical trial outcome measure assessing preventive effect as delay of events 
European Journal of Epidemiology  2012;27(12):903-909.
Many effect measures used in clinical trials are problematic because they are differentially understood by patients and physicians. The emergence of novel methods such as accelerated failure-time models and quantile regression has shifted the focus of effect measurement from probability measures to time-to-event measures. Such modeling techniques are rapidly evolving, but matching non-parametric descriptive measures are lacking. We propose such a measure, the delay of events, demonstrating treatment effect as a gain in event-free time. We believe this measure to be of value for shared clinical decision-making. The rationale behind the measure is given, and it is conceptually explained using the Kaplan–Meier estimate and the quantile regression framework. A formula for calculation of the delay of events is given. Hypothetical and empirical examples are used to demonstrate the measure. The measure is discussed in relation to other measures highlighting the time effects of preventive treatments. There is a need to further investigate the properties of the measure as well as its role in clinical decision-making.
PMCID: PMC3539066  PMID: 23224516
Clinical trials; Randomized; Kaplan–Meier survival curves; Preventive measures; Treatment Outcome
13.  Lipoprotein(a): Genotype–Phenotype Relationship and Impact on Atherogenic Risk 
In 2010, more than 45 years after the initial discovery of lipoprotein(a) [Lp(a)] by Kare Berg, an European Atherosclerosis Society Consensus Panel recommended screening for elevated Lp(a) in people at moderate to high risk of atherosclerotic cardiovascular disease (CVD). This recommendation was based on extensive epidemiological findings demonstrating a significant association between elevated plasma Lp(a) levels and coronary heart disease, myocardial infarction, and stroke. In addition to those patients considered to be at moderate to high risk of heart disease, statin-treated patients with recurrent heart disease were also identified as targeted for screening of elevated Lp(a) levels. Taken together, recent findings have significantly strengthened the notion of Lp(a) as a causal risk factor for CVD. It is well established that Lp(a) levels are largely determined by the size of the apolipoprotein a [apo(a)] gene; however, recent studies have identified several other LPA gene polymorphisms that have significant associations with an elevated Lp(a) level and a reduced copy number of K4 repeats. In addition, the contribution of other genes in regulating Lp(a) levels has been described. Besides the strong genetic regulation, new evidence has emerged regarding the impact of inflammation as a modulator of Lp(a) risk factor properties. Thus, oxidized phospholipids that possess a strong proinflammatory potential are preferentially carried on Lp(a) particles. Collectively, these findings point to the importance of both phenotypic and genotypic factors in influencing apo(a) proatherogenic properties. Therefore, studies taking both of these factors into account determining the amount of Lp(a) associated with each individual apo(a) size allele are valuable tools when assessing a risk factor role of Lp(a).
PMCID: PMC3225061  PMID: 21749171
14.  Hard and Transparent Films Formed by Nanocellulose–TiO2 Nanoparticle Hybrids 
PLoS ONE  2012;7(10):e45828.
The formation of hybrids of nanofibrillated cellulose and titania nanoparticles in aqueous media has been studied. Their transparency and mechanical behavior have been assessed by spectrophotometry and nanoindentation. The results show that limiting the titania nanoparticle concentration below 16 vol% yields homogeneous hybrids with a very high Young’s modulus and hardness, of up to 44 GPa and 3.4 GPa, respectively, and an optical transmittance above 80%. Electron microscopy shows that higher nanoparticle contents result in agglomeration and an inhomogeneous hybrid nanostructure with a concomitant reduction of hardness and optical transmittance. Infrared spectroscopy suggests that the nanostructure of the hybrids is controlled by electrostatic adsorption of the titania nanoparticles on the negatively charged nanocellulose surfaces.
PMCID: PMC3462202  PMID: 23049689
15.  Age as a modulator of inflammatory cardiovascular risk factors 
Levels of acute phase reactants are impacted by age. To what extent cardiovascular risk associated with aging is due to an increase in the inflammatory burden is not known. We assessed the relationship with age of inflammatory markers, representing a) systemic (C-reactive protein [CRP], fibrinogen and serum amyloid-A [SAA]) and b) vascular (lipoprotein-associated phospholipase A2 [Lp-PLA2] and pentraxin-3 [PTX-3]) inflammation.
Methods and Results
We determined Lp-PLA2 mass and activity, CRP, fibrinogen, SAA, and PTX-3 levels and other CVD risk factors in 336 Caucasians and 224 African Americans. Levels of systemic inflammatory markers increased significantly with age in both ethnic groups (P<0.05 for all), while trend patterns of vascular inflammatory markers did not change significantly with age for either group. In multivariate regression models adjusting for confounding variables, age remained independently associated with a composite z-score for systemic, but not vascular inflammation (β=0.250, P<0.001 and (β=0.276, P<0.001, for Caucasians and African Americans respectively).
We report an increase in the systemic, but not vascular, inflammatory burden over age. Levels of both categories of inflammatory markers over age were similar across ethnicity after adjustment for confounders. Our results underscore the importance of age in evaluating inflammatory markers to assess cardiovascular risk.
PMCID: PMC3158295  PMID: 21700927
Inflammation; aging; cardiovascular disease; epidemiology
16.  Differential Associations of Serum Amyloid A and Pentraxin-3 with Allele-Specific Lipoprotein(a) Levels in African Americans and Caucasians 
Lipoprotein(a) [Lp(a)] is a CVD risk factor, where inflammation impacts levels differentially across ethnicity. We investigated the effect of systemic [serum amyloid A (SAA)] and vascular [pentraxin-3 (PTX-3)] inflammation on Lp(a) levels across different apo(a) sizes in a bi-ethnic population. Lp(a) and allele-specific apo(a) levels, apo(a) sizes, SAA and PTX-3 levels were determined in 336 Caucasians and 224 African Americans. We dichotomized subjects into 2 groups using the respective median SAA (29.8 and 41.5 mg/dl for Caucasians and African Americans, respectively) or PTX-3 levels (1.6 and 1.1 ng/ml for Caucasians and African Americans, respectively). Among African Americans, but not in Caucasians, Lp(a) levels were increased (146 vs. 117 nmol/l, P=0.024) in the high vs. low SAA group. No difference was seen across PTX-3 groups. Further, among African Americans with smaller (<26 K4 repeats) apo(a) sizes, allele-specific apo(a) levels (111 vs. 79 nmol/l, P=0.020) were increased in the high vs. low SAA group. Again, no difference was seen for PTX-3. We did not find any significant associations between allele-specific apo(a) and SAA or PTX-3 levels among Caucasians with smaller (<26 K4) apo(a) sizes. In conclusion, elevated levels of SAA, but not PTX-3, were significantly associated with higher Lp(a) levels for smaller (<26 K4) apo(a) sizes in African Americans. Our results implicate that a pro-inflammatory stimulus may result in an increased cardiovascular risk through a selective increase in Lp(a) levels among African Americans carrying smaller apo(a) size.
PMCID: PMC3137802  PMID: 21757153
17.  Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women 
The results of short-term studies in humans suggest that, compared with glucose, acute consumption of fructose leads to increased postprandial energy expenditure and carbohydrate oxidation and decreased postprandial fat oxidation. The objective of this study was to determine the potential effects of increased fructose consumption compared to isocaloric glucose consumption on substrate utilization and energy expenditure following sustained consumption and under energy-balanced conditions.
As part of a parallel arm study, overweight/obese male and female subjects, 40–72 y, consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Energy expenditure and substrate utilization were assessed using indirect calorimetry at baseline and during the 10th week of intervention.
Consumption of fructose, but not glucose, led to significant decreases of net postprandial fat oxidation and significant increases of net postprandial carbohydrate oxidation (P < 0.0001 for both). Resting energy expenditure decreased significantly from baseline values in subjects consuming fructose (P = 0.031) but not in those consuming glucose.
Increased consumption of fructose for 10 weeks leads to marked changes of postprandial substrate utilization including a significant reduction of net fat oxidation. In addition, we report that resting energy expenditure is reduced compared to baseline values in subjects consuming fructose-sweetened beverages for 10 weeks.
PMCID: PMC3252467  PMID: 21952692
fructose; fat oxidation; carbohydrate oxidation; energy expenditure; metabolic rate; humans
18.  Regression dilution bias: Tools for correction methods and sample size calculation 
Upsala Journal of Medical Sciences  2012;117(3):279-283.
Random errors in measurement of a risk factor will introduce downward bias of an estimated association to a disease or a disease marker. This phenomenon is called regression dilution bias. A bias correction may be made with data from a validity study or a reliability study.
Aims and methods
In this article we give a non-technical description of designs of reliability studies with emphasis on selection of individuals for a repeated measurement, assumptions of measurement error models, and correction methods for the slope in a simple linear regression model where the dependent variable is a continuous variable. Also, we describe situations where correction for regression dilution bias is not appropriate.
The methods are illustrated with the association between insulin sensitivity measured with the euglycaemic insulin clamp technique and fasting insulin, where measurement of the latter variable carries noticeable random error. We provide software tools for estimation of a corrected slope in a simple linear regression model assuming data for a continuous dependent variable and a continuous risk factor from a main study and an additional measurement of the risk factor in a reliability study. Also, we supply programs for estimation of the number of individuals needed in the reliability study and for choice of its design.
Our conclusion is that correction for regression dilution bias is seldom applied in epidemiological studies. This may cause important effects of risk factors with large measurement errors to be neglected.
PMCID: PMC3410287  PMID: 22401135
Correction methods; measurement errors; regression dilution bias; SAS and R programs
19.  Consumption of fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans 
Prospective studies in humans examining the effects of fructose consumption on biological markers associated with the development of metabolic syndrome are lacking. Therefore we investigated the relative effects of 10 wks of fructose or glucose consumption on plasma uric acid and RBP-4 concentrations, as well as liver enzyme (AST, ALT, and GGT) activities in men and women.
As part of a parallel arm study, older (age 40–72), overweight and obese male and female subjects (BMI 25–35 kg/m2) consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wks. Fasting and 24-h blood collections were performed at baseline and following 10 wks of intervention and plasma concentrations of uric acid, RBP-4 and liver enzyme activities were measured.
Consumption of fructose, but not glucose, led to significant increases of 24-h uric acid profiles (P < 0.0001) and RBP-4 concentrations (P = 0.012), as well as plasma GGT activity (P = 0.04). Fasting plasma uric acid concentrations increased in both groups; however, the response was significantly greater in subjects consuming fructose (P = 0.002 for effect of sugar). Within the fructose group male subjects exhibited larger increases of RBP-4 levels than women (P = 0.024).
These findings suggest that consumption of fructose at 25% of energy requirements for 10 wks, compared with isocaloric consumption of glucose, may contribute to the development of components of the metabolic syndrome by increasing circulating uric acid, GGT activity, suggesting alteration of hepatic function, and the production of RBP-4.
PMCID: PMC3463498  PMID: 22828276
20.  The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a systematic review and meta-analysis 
Hypertriglyceridemia may be associated with important complications. The aim of this study is to estimate the magnitude of association and quality of supporting evidence linking hypertriglyceridemia to cardiovascular events and pancreatitis.
We conducted a systematic review of multiple electronic bibliographic databases and subsequent meta-analysis using a random effects model. Studies eligible for this review followed patients longitudinally and evaluated quantitatively the association of fasting hypertriglyceridemia with the outcomes of interest. Reviewers working independently and in duplicate reviewed studies and extracted data.
35 studies provided data sufficient for meta-analysis. The quality of these observational studies was moderate to low with fair level of multivariable adjustments and adequate exposure and outcome ascertainment. Fasting hypertriglyceridemia was significantly associated with cardiovascular death (odds ratios (OR) 1.80; 95% confidence interval (CI) 1.31-2.49), cardiovascular events (OR, 1.37; 95% CI, 1.23-1.53), myocardial infarction (OR, 1.31; 95% CI, 1.15-1.49), and pancreatitis (OR, 3.96; 95% CI, 1.27-12.34, in one study only). The association with all-cause mortality was not statistically significant.
The current evidence suggests that fasting hypertriglyceridemia is associated with increased risk of cardiovascular death, MI, cardiovascular events, and possibly acute pancreatitis.
Précis: hypertriglyceridemia is associated with increased risk of cardiovascular death, MI, cardiovascular events, and possibly acute pancreatitis
PMCID: PMC3342117  PMID: 22463676
Hypertriglyceridemia; Cardiovascular disease; Pancreatitis; Systematic reviews and meta-analysis
21.  Seasonal variations of insulin sensitivity from a euglycemic insulin clamp in elderly men 
Seasonal variations in hemoglobin-A1c have been reported in diabetic patients, but the underlying mechanisms have not been elucidated.
To study if insulin sensitivity, insulin secretion, and fasting plasma glucose showed seasonal variations in a Swedish population-based cohort of elderly men.
Altogether 1117 men were investigated with a euglycemic insulin clamp and measurements of fasting plasma glucose and insulin secretion after an oral glucose tolerance test. Values were analyzed in linear regression models with an indicator variable for winter/summer season and outdoor temperature as predictors.
During winter, insulin sensitivity (M/I, unit = 100 × mg × min-1 × kg-1/(mU × L-1)) was 11.0% lower (4.84 versus 5.44, P = 0.0003), incremental area under the insulin curve was 16.4% higher (1167 versus 1003 mU/L, P = 0.007). Fasting plasma glucose was, however, not statistically significantly different (5.80 versus 5.71 mmol/L, P = 0.28) compared to the summer season. There was an association between outdoor temperature and M/I (0.57 units increase (95% CI 0.29–0.82, P < 0.0001) per 10°C increase of outdoor temperature) independent of winter/summer season. Adjustment for life-style factors, type 2 diabetes, and medication did not alter these results.
Insulin sensitivity showed seasonal variations with lower values during the winter and higher during the summer season. Inverse compensatory variations of insulin secretion resulted in only minor variations of fasting plasma glucose. Insulin sensitivity was associated with outdoor temperature. These phenomena should be further investigated in diabetic patients.
PMCID: PMC3282240  PMID: 22066936
Insulin secretion; insulin sensitivity; seasonal variation
22.  Lipoprotein(a) An Elusive Cardiovascular Risk Factor 
Lipoprotein (a) [Lp(a)], is present only in humans, Old World nonhuman primates, and the European hedgehog. Lp(a) has many properties in common with low-density lipoprotein (LDL) but contains a unique protein, apo(a), which is structurally different from other apolipoproteins. The size of the apo(a) gene is highly variable, resulting in the protein molecular weight ranging from 300 to 800 kDa; this large variation may be caused by neutral evolution in the absence of any selection advantage. Apo(a) influences to a major extent metabolic and physicochemical properties of Lp(a), and the size polymorphism of the apo(a) gene contributes to the pronounced heterogeneity of Lp(a). There is an inverse relationship between apo(a) size and Lp(a) levels; however, this pattern is complex. For a given apo(a) size, there is a considerable variation in Lp(a) levels across individuals, underscoring the importance to assess allele-specific Lp(a) levels. Further, Lp(a) levels differ between populations, and blacks have generally higher levels than Asians and whites, adjusting for apo(a) sizes. In addition to the apo(a) size polymorphism, an upstream pentanucleotide repeat (TTTTAn) affects Lp(a) levels. Several meta-analyses have provided support for an association between Lp(a) and coronary artery disease, and the levels of Lp(a) carried in particles with smaller size apo(a) isoforms are associated with cardiovascular disease or with preclinical vascular changes. Further, there is an interaction between Lp(a) and other risk factors for cardiovascular disease. The physiological role of Lp(a) is unknown, although a majority of studies implicate Lp(a) as a risk factor.
PMCID: PMC3275911  PMID: 15345512
atherosclerosis; genetics; blacks; lipids
Lipoprotein (a), Lp(a), has many properties in common with low density lipoprotein, LDL, but contains a unique protein apolipoprotein(a), linked to apolipoprotein B-100 by a single disulfide bond. There is a substantial size heterogeneity of apo(a), and generally smaller apo(a) sizes tend to correspond to higher plasma Lp(a) levels, but this relation is far from linear, underscoring the importance to assess allele-specific apo(a) levels. The presence of apo(a), a highly charged, carbohydrate-rich, hydrophilic protein may obscure key features of the LDL moiety and offer opportunities for binding to vessel wall elements. Recently, interest in Lp(a) has increased because studies over the past decade have confirmed and more robustly demonstrated a risk factor role of Lp(a) for cardiovascular disease. In particular, levels of Lp(a) carried in particles with smaller size apo(a) isoforms are associated with CAD. Other studies suggest that pro-inflammatory conditions may modulate risk factor properties of Lp(a). Further, Lp(a) may act as a preferential acceptor for pro-inflammatory oxidized phospholipids transferred from tissues or from other lipoproteins. However, at present only a limited number of agents (e.g. nicotinic acid and estrogen) has proven efficacy in lowering Lp(a) levels. Although Lp(a) has not been definitely established as a cardiovascular risk factor and no guidelines presently recommend intervention, Lp(a)-lowering therapy might offer benefits in subgroups of patients with high Lp(a) levels.
PMCID: PMC3075492  PMID: 21167011
Lipoprotein(a); apo(a) size; allele-specific apo(a) levels; risk factors; ethnicity
24.  Integrated Role of Two Apoliprotein E Polymorphisms on Apolipoprotein B Levels and Coronary Artery Disease in a Biethnic Population 
Apolipoprotein E (ApoE) plays a major role in lipoprotein metabolism and genetic variability of ApoE confers susceptibility to coronary artery disease (CAD). Beyond variability in the coding region, promoter polymorphisms in the ApoE gene impact on ApoE transcription.
We determined the ApoE − 491 A/T promoter polymorphism, ApoE isoforms, lipid and lipoprotein levels, and CAD risk factors in 313 Caucasians and 215 African Americans.
Caucasians had a lower ApoE T allele frequency compared to African Americans (18.1% vs. 32.3%, P < 0.05). Among T/* carriers, ApoB levels were significantly lower in Caucasians, but significantly higher among African Americans, in both cases compared to A/A homozygotes (P = 0.017, and P = 0.012). For a given −491A/T genotype, levels of atherogenic lipoproteins differed across ApoE2/E3/E4 isoforms among African Americans, but not Caucasians, as T/* carriers with ApoE4 had significantly higher ApoB levels compared to T/* carriers with ApoE2 (P = 0.010). Among patients with CAD, Caucasian A/A homozygotes and African American T/* carriers had higher ApoB levels compared to the same genotype without CAD (P = 0.007, P = 0.049, respectively).
We observed an ethnicity-specific variability in ApoB levels across the ApoE − 491 A/T polymorphism and a modulatory impact on this pattern by ApoE2/E3/E4 isoforms.
PMCID: PMC3125560  PMID: 20715976
25.  Usefulness of Apolipoprotein B/Apolipoprotein A-I Ratio to Predict Coronary Artery Disease Independent of the Metabolic Syndrome in African-Americans 
The American journal of cardiology  2010;106(9):1264-1269.
Studies demonstrate that the apolipoprotein B/apolipoprotein A-I (ApoB/apoA-I) ratio predicts cardiovascular risk better than any of the cholesterol indexes. A number of factors that define the metabolic syndrome (MS) differ across African-American and European-American ethnicities. We assessed relationship of the apoB/apoA-I ratio to MS and coronary artery disease (CAD) in 224 African-Americans and 304 European-Americans. The MS was defined by the revised NCEP-ATP III criteria and CAD was assessed as ≥50% stenosis or a continuous cardiovascular score (0–75). European-Americans had higher apoB/apoA-I ratio compared with African-Americans (1.15 vs. 1.07, P=0.008). The apoB/apoA-I ratio was associated with presence of the MS in both European-Americans (OR=5.9; 95% confidence interval (CI), 2.53–13.57; P<0.001) and African-Americans (OR=8.3; 95% CI, 3.52–19.25; P<0.001), and was higher in subjects with MS compared to those without MS (1.21 vs. 1.04, P<0.001 for European-Americans and 1.20 vs. 0.94, P<0.001 for African-Americans). There was a stepwise increase in the prevalence of MS across apoB/apoA-I ratio tertiles in both ethnic groups (χ2=13.1, P<0.001 for European-Americans and χ2=19.6, P<0.001 for African-Americans). In multiple regression analyses, the apoB/apoA-I ratio independently predicted CAD in African-Americans (β=0.242, P=0.011). The cardiovascular score was significantly increased across apoB/apoA-I ratio tertiles in European-American subjects with MS (P=0.001), whereas this association was seen in African-American subjects without MS (P=0.023). In conclusion, the apoB/apoA-I ratio differed across ethnicities and was associated with presence of the MS in both groups. Among African-Americans, elevated apoB/apoA-I ratio independently predicted higher risk for CAD.
PMCID: PMC2975905  PMID: 21029822
apoB/apoA-I ratio; cardiovascular disease; ethnicity

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