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Spontaneous autoimmune peripheral polyneuropathy (SAPP) is a mouse model of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in non-obese diabetic (NOD) mice null for costimulatory molecule, B7-2 gene (B7-2 -/- ). SAPP is a chronic progressive and multifocal inflammatory and demyelinating polyneuropathy of spontaneous onset with secondary axonal degeneration. Insulin-like growth factor 1(IGF-1) is a pleiotropic factor with neuroprotective, regenerative, and anti-inflammatory effects with extensive experience in its preclinical and clinical use. Systemic delivery of recombinant adeno-associated virus serotype 9 (rAAV9) provides robust and widespread gene transfer to central and peripheral nervous systems making it suitable for gene delivery in neurological diseases. A significant proportion of patients with inflammatory neuropathies like CIDP do not respond to current clinical therapies and there is a need for new treatments. In this study, we examined the efficacy IGF-1 gene therapy by systemic delivery with rAAV9 in SAPP model. The rAAV9 construct also contained a reporter gene to monitor the surrogate expression of IGF-1. We found significant improvement in neuropathic disease after systemic delivery of rAAV9/IGF-1 gene at presymptomatic and symptomatic stages of SAPP model. These findings support that IGF-1 treatment (including gene therapy) is a viable therapeutic option in immune neuropathies such as CIDP.

Single crystal 6H-SiC wafers with 4° off-axis [0001] orientation were irradiated with carbon ions and then annealed at 900 °C for different time periods. The microstructure and surface morphology of these samples were investigated by grazing incidence X-ray diffraction (GIXRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Ion irradiation induced SiC amorphization, but the surface was smooth and did not have special structures. During the annealing process, the amorphous SiC was recrystallized to form columnar crystals that had a large amount of twin structures. The longer the annealing time was, the greater the amount of recrystallized SiC would be. The recrystallization volume fraction was accorded with the law of the Johnson-Mehl-Avrami equation. The surface morphology consisted of tiny pieces with an average width of approximately 30 nm in the annealed SiC. The volume shrinkage of irradiated SiC layer and the anisotropy of newly born crystals during annealing process produced internal stress and then induced not only a large number of dislocation walls in the non-irradiated layer but also the initiation and propagation of the cracks. The direction of dislocation walls was perpendicular to the growth direction of the columnar crystal. The longer the annealing time was, the larger the length and width of the formed crack would be. A quantitative model of the crack growth was provided to calculate the length and width of the cracks at a given annealing time., Competing Interests: The authors declare no conflict of interest.

The microstructure evolution of Zr-1.1Nb-1.51Fe-0.26Cu-0.72Ni zirconium alloy, irradiated by 800 keV Kr 2+ ions at 585 K using the IVEM-Tandem Facility at Argonne National Laboratory, was observed by in situ transmission electron microscopy. A number of β-Nb precipitates with a body-centered cubic (BCC) structure were distributed in the as-received zirconium alloy with micrometer-size grains. Kr 2+ ion irradiation induced the growth of β-Nb precipitates, which could be attributed to the segregation of the dissolved niobium atoms in the zirconium lattice and the migration to the existing precipitates. The size of precipitates was increased with increasing Kr 2+ ion fluence. During Kr 2+ iron irradiation, the zirconium crystals without Nb precipitates tended to transform to the nanocrystals, which was not observed in the zirconium crystals with Nb nanoparticles. The existing Nb nanoparticles were the key factor that constrained the nanocrystallization of zirconium crystals. The thickness of the formed Zr-nanocrystal layer was about 300 nm, which was consistent with the depth of Kr 2+ iron irradiation. The mechanism of the precipitate growth and the formation of zirconium nanocrystal was analyzed and discussed.

The microstructural evolution of Dy₂O₃-TiO₂ powder mixtures during ball milling and post-milled annealing was investigated using XRD, SEM, TEM, and DSC. At high ball-milling rotation speeds, the mixtures were fined, homogenized, nanocrystallized, and later completely amorphized, and the transformation of Dy₂O₃ from the cubic to the monoclinic crystal structure was observed. The amorphous transformation resulted from monoclinic Dy₂O₃, not from cubic Dy₂O₃. However, at low ball-milling rotation speeds, the mixtures were only fined and homogenized. An intermediate phase with a similar crystal structure to that of cubic Dy₂TiO₅ was detected in the amorphous mixtures annealed from 800 to 1000 °C, which was a metastable phase that transformed to orthorhombic Dy₂TiO₅ when the annealing temperature was above 1050 °C. However, at the same annealing temperatures, pyrochlore Dy₂Ti₂O₇ initially formed and subsequently reacted with the remaining Dy₂O₃ to form orthorhombic Dy₂TiO₅ in the homogenous mixtures. The evolutionary mechanism of powder mixtures during ball milling and subsequent annealing was analyzed.

Background: Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS., Methods: This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg)., Results: Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups., Conclusion: The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).

Multivariate meta-regression models are commonly used in settings where the response variable is naturally multi-dimensional. Such settings are common in cardiovascular and diabetes studies where the goal is to study cholesterol levels once a certain medication is given. In this setting, the natural multivariate endpoint is Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C), and Triglycerides (TG) (LDL-C, HDL-C, TG). In this paper, we examine study level (aggregate) multivariate meta-data from 26 Merck sponsored double-blind, randomized, active or placebo-controlled clinical trials on adult patients with primary hypercholesterolemia. Our goal is to develop a methodology for carrying out Bayesian inference for multivariate meta-regression models with study level data when the within-study sample covariance matrix S for the multivariate response data is partially observed. Specifically, the proposed methodology is based on postulating a multivariate random effects regression model with an unknown within-study covariance matrix Σ in which we treat the within-study sample correlations as missing data, the standard deviations of the within-study sample covariance matrix S are assumed observed, and given Σ, S follows a Wishart distribution. Thus, we treat the off-diagonal elements of S as missing data, and these missing elements are sampled from the appropriate full conditional distribution in a Markov chain Monte Carlo (MCMC) sampling scheme via a novel transformation based on partial correlations. We further propose several structures (models) for Σ, which allow for borrowing strength across different treatment arms and trials. The proposed methodology is assessed using simulated as well as real data, and the results are shown to be quite promising.

Objective: We compared the variability of LDL-C-lowering responses to treatment with ezetimibe + statins versus statins in hypercholesterolemic patients., Methods: An analysis of patient-level data pooled from 27 double-blind, placebo and/or active-controlled studies in 21,671 patients treated with ezetimibe + statins versus statins on first-line (statin-naïve/wash-out) or second-line (on statin, randomized to ezetimibe versus placebo [add-on] or ezetimibe versus uptitrated statin [uptitrate]) for 6-24 wks. Variances (standard deviation [SD], coefficient of variation [CV], and root mean squared error [RMSE] adjusted for various factors) for % change from baseline in LDL-C were compared., Results: In first-line and second-line add-on studies, the variability (SD, RMSE) of % change from baseline in LDL-C was lower in ezetimibe + statin-treated patients versus statin-treated patients, ±covariates. Differences were small but statistically significant due to the large sample size. In second-line uptitrate studies, ezetimibe + statin treatment resulted in greater unadjusted variability (SD) versus statin therapy, while the adjusted variability (RMSE) was significantly lower. Relative variability (CV=SD/mean) was lower for ezetimibe + statins versus statin therapy for all study types, being more pronounced in second-line add-on and uptitrate studies, attributed to larger mean LDL-C reductions for ezetimibe + statins versus statin groups. When assessed by individual study/type, statin brand, potency or dose, the CVs remained lower for ezetimibe + statins versus statins in second-line studies. The SDs showed no consistent trend for either therapy., Conclusion: In hypercholesterolemic patients, the absolute variability of LDL-C-lowering responses to ezetimibe + statins was not greater versus statins alone and appeared lower when adjusted for other factors. Relative variability was lower in patients treated with statins + ezetimibe. A better understanding of the variability of the LDL-C lowering response may help guide clinicians in making therapeutic decisions., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Adipose tissue inflammation increases with obesity, but adipocyte vs. immune cell contributions are unclear. In the present study, transcriptome analyses were performed on highly-purified subcutaneous adipocytes from lean and obese women, and differentially expressed genes/pathways were determined in both adipocyte and stromal vascular fraction (SVF) samples. Adipocyte but not SVF expression of NOD-like receptor pathway genes, including NLRP3 and PYCARD, which regulate caspase-1-mediated IL-1β secretion, correlated with adiposity phenotypes and adipocyte class II major histocompatibility complex (MHCII) gene expression, but only MHCII remained after adjusting for age and body mass index. IFNγ stimulated adipocyte MHCII, NLRP3 and caspase-1 expression, while adipocyte MHCII-mediated CD4(+) T cell activation, an important factor in adipose inflammation, induced IFNγ-dependent adipocyte IL-1β secretion. These results uncover a dialogue regulated by interactions among T cell IFNγ and adipocyte MHCII and NLRP3 inflammasome activity that appears to initiate and escalate adipose tissue inflammation during obesity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Few clinical studies have focused on the efficacy of lipid-lowering therapies in patients ≥65 years., Methods: After stabilization on atorvastatin 10 mg, hypercholesterolemic subjects ≥65 years at high/very high risk for CHD and not at LDL-C <1.81 mmol/L (with atherosclerotic vascular disease [AVD]) or <2.59 mmol/L (without AVD) were randomized to ezetimibe 10 mg plus atorvastatin 10 mg or uptitration to atorvastatin 20 mg (6 weeks) followed by uptitration to 40 mg (additional 6 weeks). A post-hoc analysis compared between-group differences in percent attainment of individual and combined LDL-C, non-HDL-C and Apo B targets based on recommendations from 2012 European and Canadian Cardiovascular Society (CCS) guidelines for dyslipidemia treatment., Results: Atorvastatin 10 mg plus ezetimibe produced significantly greater attainment of LDL-C, non-HDL-C, and Apo B individual and dual/triple targets vs. atorvastatin 20 mg for the entire cohort and very high-risk groups at 6 weeks. After 12 weeks, very high-risk subjects maintained significantly greater achievement of LDL-C <1.8 mmol/L (47% vs. 35%), non-HDL-C <2.6 mmol/L (63% vs. 53%) and Apo B <0.8 g/L (47% vs. 38%) single targets and dual/triple targets with atorvastatin 10 mg plus ezetimibe vs. atorvastatin 40 mg, while attainment of European target for high-risk subjects was generally similar for both treatments. Achievement of Canadian targets was significantly greater with combination therapy vs. atorvastatin 20 mg (6 weeks) or atorvastatin 40 mg (12 weeks)., Conclusions: Atorvastatin 10 mg plus ezetimibe provided more effective treatment than uptitration to atorvastatin 20/40 mg for attainment of most European and Canadian guideline-recommended lipid targets in older at-risk patients., Trial Registration: ClinicalTrials.gov identifier NCT00418834.

In this paper, we propose a class of Box-Cox transformation regression models with multidimensional random effects for analyzing multivariate responses for individual patient data in meta-analysis. Our modeling formulation uses a multivariate normal response meta-analysis model with multivariate random effects, in which each response is allowed to have its own Box-Cox transformation. Prior distributions are specified for the Box-Cox transformation parameters as well as the regression coefficients in this complex model, and the deviance information criterion is used to select the best transformation model. Because the model is quite complex, we develop a novel Monte Carlo Markov chain sampling scheme to sample from the joint posterior of the parameters. This model is motivated by a very rich dataset comprising 26 clinical trials involving cholesterol-lowering drugs where the goal is to jointly model the three-dimensional response consisting of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG) (LDL-C, HDL-C, TG). Because the joint distribution of (LDL-C, HDL-C, TG) is not multivariate normal and in fact quite skewed, a Box-Cox transformation is needed to achieve normality. In the clinical literature, these three variables are usually analyzed univariately; however, a multivariate approach would be more appropriate because these variables are correlated with each other. We carry out a detailed analysis of these data by using the proposed methodology., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: Treatment response to lipid-lowering therapy can vary in patients with the metabolic syndrome (MetS) due to various patient demographic and baseline characteristics., Objective: This study assessed the relationships between baseline characteristics and changes in lipid variables, high-sensitivity C-reactive protein (hs-CRP) and attainment of prespecified low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) levels in MetS patients treated with ezetimibe/simvastatin and atorvastatin., Methods: This is a post-hoc analysis of a multicenter, double-blind, randomized, 6-week parallel study in >1000 hypercholesterolemic subjects (median age of 59 years) with MetS and moderately high/high coronary heart disease risk who were treated with ezetimibe/simvastatin (10/20 and 10/40 mg) or atorvastatin (10, 20, 40 mg). Factors that could affect these treatments were assessed by multivariate analysis., Results: Increasing age, abdominal obesity (waist circumference ≥ 40/35 inches for men/women), and lower baseline hs-CRP were significant predictors of greater reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, triglycerides, and very-low-density lipoprotein cholesterol but not for changes in HDL-C or apolipoprotein AI; effects of race and baseline triglycerides, non-HDL-C, LDL-C, or HDL-C levels were more limited. Age ≥ 65 years (versus <65 years) was also associated with significantly greater attainment of all LDL-C and non-HDL-C targets, whereas abdominal obesity, gender (female > male) and lower baseline LDL-C, non-HDL-C, triglycerides, and hs-CRP were associated with improved attainment for some of these targets. Blood pressure, fasting glucose, Homeostasis Model Assessment of Insulin Resistance tertiles, and diabetes did not predict response for any efficacy variable. Ezetimibe/simvastatin treatment (versus atorvastatin) was a significant predictor for change in most efficacy variables., Conclusions: Treatment responses to ezetimibe/simvastatin and atorvastatin in at-risk patients with the MetS were related to age (≥ 65 years), abdominal obesity, and lower baseline hs-CRP. Ezetimibe/simvastatin treatment was found to be consistently more effective than atorvastatin at the specified dose comparisons across these subgroups. The clinical value of predictive factors requires further study in outcome trials., (Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Adipose-resident T cells (ARTs) regulate metabolic and inflammatory responses in obesity, but ART activation signals are poorly understood. Here, we describe class II major histocompatibility complex (MHCII) as an important component of high-fat-diet (HFD)-induced obesity. Microarray analysis of primary adipocytes revealed that multiple genes involved in MHCII antigen processing and presentation increased in obese women. In mice, adipocyte MHCII increased within 2 weeks on HFD, paralleling increases in proinflammatory ART markers and decreases in anti-inflammatory ART markers, and preceding adipose tissue macrophage (ATM) accumulation and proinflammatory M1 polarization. Mouse 3T3-L1 and primary adipocytes activated T cells in an antigen-specific, contact-dependent manner, indicating that adipocyte MHCII is functional. HFD-fed MHCII(-/-) mice developed less adipose inflammation and insulin resistance than did wild-type mice, despite developing similar adiposity. These investigations uncover a mechanism whereby a HFD-induced adipocyte/ART dialog involving MHCII instigates adipose inflammation and, together with ATM MHCII, escalates its progression., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In this paper, we propose a class of multivariate random effects models allowing for the inclusion of study-level covariates to carry out meta-analyses. As existing algorithms for computing maximum likelihood estimates often converge poorly or may not converge at all when the random effects are multi-dimensional, we develop an efficient expectation-maximization algorithm for fitting multi-dimensional random effects regression models. In addition, we also develop a new methodology for carrying out variable selection with study-level covariates. We examine the performance of the proposed methodology via a simulation study. We apply the proposed methodology to analyze metadata from 26 studies involving statins as a monotherapy and in combination with ezetimibe. In particular, we compare the low-density lipoprotein cholesterol-lowering efficacy of monotherapy and combination therapy on two patient populations (naïve and non-naïve patients to statin monotherapy at baseline), controlling for aggregate covariates. The proposed methodology is quite general and can be applied in any meta-analysis setting for a wide range of scientific applications and therefore offers new analytic methods of clinical importance., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objective: Statins inhibit cholesterol synthesis but can upregulate cholesterol absorption, with higher doses producing larger effects. Ezetimibe inhibits cholesterol absorption but also upregulates synthesis. We tested whether ezetimibe added to on-going statin therapy would be most effective in lowering LDL-cholesterol (LDL-C) in subjects on high-potency statins and whether these effects would be related to alterations in cholesterol absorption (β-sitosterol) and synthesis (lathosterol) markers., Methods: Hypercholesterolemic subjects (n = 874) on statins received ezetimibe 10 mg/day. Plasma lipids, lathosterol, and β-sitosterol were measured at baseline and on treatment. Subjects were divided into low- (n = 133), medium- (n = 582), and high- (n = 159) statin potency groups defined by predicted LDL-C-lowering effects of each ongoing statin type and dose (reductions of ~20-30%, ~31-45%, or ~46-55%, respectively)., Results: The high-potency group had significantly lower baseline lathosterol (1.93 vs. 2.58 vs. 3.17 μmol/l; p < 0.001) and higher baseline β-sitosterol values (6.21 vs. 4.58 vs. 4.51 μmol/l, p < 0.001) than medium-/low-potency groups. Ezetimibe treatment in the high-potency group produced significantly greater reductions from baseline in LDL-C than medium-/low-potency groups (-29.1% vs. -25.0% vs. -22.7%; p < 0.001) when evaluating unadjusted data. These effects and group differences were significantly (p < 0.05) related to greater β-sitosterol reductions and smaller lathosterol increases. However, LDL-C reduction differences between groups were no longer significant after controlling for placebo effects, due mainly to modest LDL-C lowering by placebo in the high-potency group., Conclusion: Patients on high-potency statins have the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline, and the greatest reduction in absorption markers and the smallest increases in synthesis markers with ezetimibe addition. Therefore, such patients may be good candidates for ezetimibe therapy if additional LDL-C lowering is needed., (Copyright © 2012 Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Patients with dyslipoproteinemia constitute the largest risk group for development of atherosclerosis and cardiovascular disease (CVD). Despite extensive statin use, many patients with CVD risk do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets. This pooled analysis of 27 previously published clinical trials conducted between 1999 and 2008 evaluated the lipid-altering efficacy and factors related to treatment response of ezetimibe combined with statin and statin monotherapy., Methods: Patient-level data were combined from double-blind, placebo-controlled or active comparator studies randomizing adult subjects to ezetimibe 10mg plus statin (n=11,714) versus statin alone (n=10,517) for 6-24 weeks (mean=9 weeks). Association of factors with treatment response, percent change from baseline LDL-C and other lipids, and attainment of guideline-recommended lipid and lipoprotein targets were evaluated., Results: Higher baseline LDL-C, diabetes mellitus, Black race, greater age, and male gender were associated with small but significantly greater percent reductions in LDL-C regardless of treatment. Treatment influenced efficacy, with ezetimibe plus statin producing significantly greater reductions in LDL-C, total-cholesterol, non-HDL-C, ApoB, triglycerides, lipid ratios, hs-CRP; significantly larger increases in HDL-C and ApoA1; and significantly higher achievement of LDL-C (<70mg/dl, <100mg/dl), non-HDL-C (<100mg/dl, <130mg/dl), and ApoB (<80mg/dl, <90mg/dl) targets than statin monotherapy at statin potencies compared (p<0.0001 for all). Differential treatment effects were seen with first-/second-line therapy and statin potency., Conclusion: These results suggest that patient characteristics have a limited influence on response to lipid-lowering therapy and demonstrate the consistent treatment effect of ezetimibe combined with statin and statin monotherapy across a diverse patient population., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: According to prior analyses, extended-release niacin/laropiprant (ERN/LRPT) consistently reduces low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) levels across a wide range of dyslipidemic patient subgroups., Objectives: This analysis examined ERN/LRPT's consistency across four phase III, randomized, double-blind trials in improving other lipid/lipoprotein parameters associated with cardiovascular risk, across several key dyslipidemic patient subgroups., Methods: In three of the studies, the randomized population included patients with primary hypercholesterolemia or mixed hyperlipidemia; in the remaining study, the population included patients with type 2 diabetes mellitus. The lipid-altering consistency of ERN/LRPT's efficacy was evaluated versus the pre-defined comparator (placebo or active control) among key subgroups of sex, race (White, non-White), region (US, ex-US), baseline age (<65 years, ≥65 years), use of statin therapy (yes, no), coronary heart disease (yes, no), risk status (low, multiple, high), and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline LDL-C, HDL-C, and TG levels. The consistency of the treatment effects on lipoprotein(a).[Lp(a)], apolipoprotein B (ApoB), non-HDL-C, ApoA1, and ApoB/ApoA1 ratio was evaluated by examining treatment difference estimates of the percentage change from baseline with 95% confidence intervals., Results: Treatment with ERN/LRPT produced significantly greater improvements in Lp(a), ApoB, non-HDL-C, ApoA1, and ApoB/ApoA1 ratio compared with placebo/active comparator in each study. These effects were generally consistent across key subgroups within each study., Conclusion: ERN/LRPT produced lipid-altering efficacy on the parameters evaluated in four controlled studies; these effects were generally consistent across all examined subgroups. ERN/LRPT represents an effective and reliable therapeutic option for the treatment of dyslipidemia in a wide range of patient types., Clinical Trial Registration: Registered as Clinicaltrials.gov NCT00269204, NCT00269217, NCT00479388, and NCT00485758.

Background: Metabolic syndrome (MetS) and atherosclerotic vascular disease (AVD) are associated with increased coronary heart disease risk., Objective: To assess percent change from baseline in lipids and high-sensitivity C-reactive protein (hs-CRP) levels and the proportion of subjects reaching specified low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (Apo B) single, dual, and triple targets and hs-CRP <2 mg/L among subjects with and without AVD treated with ezetimibe/simvastatin or atorvastatin for 6 weeks., Methods: Adults (N = 1143) with MetS and hypercholesterolemia were randomized to starting and next higher doses of ezetimibe/simvastatin (10/20 or 10/40 mg) or atorvastatin (10, 20, or 40 mg)., Results: Ezetimibe/simvastatin produced significantly greater reductions in evaluated lipids than atorvastatin for most prespecified dose comparisons. More subjects without AVD achieved LDL-C levels <100 mg/dL, non-HDL-C levels <130 mg/dL, and dual LDL-C/non-HDL targets (83%-92% vs 62%-76%) and Apo B <90 mg/dL or triple targets (65%-75% vs 41%-49%) with 40 mg of atorvastatin or 10/20-40 mg of ezetimibe/simvastatin compared with 10 or 20 mg of atorvastatin, respectively. More subjects with AVD achieved LDL-C<70 mg/dL and non-HDL-C<100 mg/dL single and dual targets (65%-80%) and Apo B <80 mg/dL (53%-63%) with 10/20-40 mg of ezetimibe/simvastatin than with 40 mg of atorvastatin (40%-49%). More subjects achieved triple lipid targets with 10/20-40 mg of ezetimibe/simvastatin versus 10-40 mg of atorvastatin (50%-63% vs 24%-40%). Achievement of hs-CRP <2 mg/L was similar across all doses regardless of AVD status., Conclusions: More intensive therapy was required for >80% of subjects to achieve LDL-C <100 mg/dL and non-HDL-C <130 mg/dL and for the majority of subjects to achieve lower levels of LDL-C <70 mg/dL, non-HDL-C <100 mg/dL, and/or Apo B <90 mg/dL. The effect of ezetimibe on cardiovascular risk reduction has yet to be established. (Clintrials.gov no: NCT00409773)., (Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Despite documented benefits of lipid-lowering treatment in women, a considerable number are undertreated, and fewer achieve treatment targets vs. men., Methods: Data were combined from 27 double-blind, active or placebo-controlled studies that randomized adult hypercholesterolemic patients to statin or statin+ezetimibe. Consistency of treatment effect among men (n = 11,295) and women (n = 10,499) was assessed and percent of men and women was calculated to evaluate the between-treatment ability to achieve specified treatment levels between sexes., Results: Baseline lipids and hs-CRP were generally higher in women vs. men. Between-treatment differences were significant for both sexes (all p < 0.001 except apolipoprotein A-I in men = 0.0389). Men treated with ezetimibe+statin experienced significantly greater changes in LDL-C (p = 0.0066), non-HDL-C, total cholesterol, triglycerides, HDL-C, apolipoprotein A-I (all p < 0.0001) and apolipoprotein B (p = 0.0055) compared with women treated with ezetimibe+statin. The odds of achieving LDL-C < 100 mg/dL, apolipoprotein B < 90 mg/dL and the dual target [LDL-C < 100 mg/dL & apoliprotein B < 90 mg/dL] was significantly greater for women vs. men and the odds of achieving hs-CRP < 1 and < 2 mg/L and dual specified levels of [LDL-C < 100 mg/dL and hs-CRP < 2 mg/L] were significantly greater for men vs. women. Women reported significantly more gall-bladder-related, gastrointestinal-related, and allergic reaction or rash-related adverse events (AEs) vs. men (no differences between treatments). Men reported significantly more CK elevations (no differences between treatments) and hepatitis-related AEs vs. women (significantly more with ezetimibe+simvastatin vs. statin)., Conclusions: These results suggest that small sex-related differences may exist in response to lipid-lowering treatment and achievement of specified lipid and hs-CRP levels, which may have implications when managing hypercholesterolemia in women.

Objectives: Correlations between low-density lipoprotein cholesterol (LDL-C), or nonhigh-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (Apo B) change after statin therapy has been initiated in hypercholesterolemic patients. This post-hoc analysis studied the correlation between these parameters in patients with mixed dyslipidemia before and after receiving lipid-lowering treatment., Results: Data from two randomized, double-blind studies of 1112 patients with mixed dyslipidemia receiving treatment (ezetimibe 10 mg, ezetimibe/simvastatin 10/20 mg, fenofibrate 160 mg, ezetimibe + fenofibrate 10/160 mg, or ezetimibe/simvastatin + fenofibrate 10/20/160 mg) were pooled. Correlation analyses and simple linear regression analyses were performed at baseline in untreated patients and after 12 weeks of treatment in the whole pooled population, the treatment groups, and after stratification by baseline triglyceride levels (150-250, ≥ 250 mg/dL) within the treatment groups. Both LDL-C and non-HDL-C were closely correlated with levels of Apo B at baseline, and these correlations improved after treatment. When using the fitted simple linear regression equations, we found that the on-treatment LDL-C and non-HDL-C levels corresponding to an Apo B of 90, 80, and 70 mg/dL were lower than proposed LDL-C and non-HDL-C treatment targets. For TG ≥ 250 mg/dL, the corresponding LDL-C was generally lower than that for triglycerides 150-250 mg/dL, except in the cases with fenofibrate in the treatment., Conclusion: The results of these analyses suggest that achieving goal-specified levels of Apo B in statin-treated patients with mixed dyslipidemia would require more aggressive LDL-C lowering to achieve the greatest reduction in LDL particle number., (Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy with secondary targets of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB). Data were pooled from 27 randomised, double-blind, active or placebo-controlled trials in 21,794 adult hypercholesterolaemic patients (LDL-C 1.81-6.48 mmol/L) receiving ezetimibe/statin or statin for 4-24 weeks. Percentages of patients achieving various targets were calculated among diabetes (n = 6541) and non-diabetes (n = 15,253) subgroups. Significantly more patients with and without diabetes achieved specified levels of LDL-C (< 2.59, < 1.99, < 1.81 mmol/L), non-HDL-C (< 3.37, < 2.59 mmol/L) and apoB (< 0.9, < 0.8 g/L) with ezetimibe/statin versus statin. Patients with diabetes had larger mean per cent reductions in LDL-C and non-HDL-C than non-diabetes patients. A greater percentage of patients achieved both the LDL-C and apoB targets and all three LDL-C, apoB, and non-HDL-C targets with ezetimibe/statin versus statin in both subgroups. Patients with diabetes benefitted at least as much as, and sometimes more than, non-diabetes patients following treatment with ezetimibe/statin.

Objective: Patients with metabolic syndrome (MetS) are at increased risk for cardiovascular disease. Niacin improves lipid abnormalities associated with MetS, but is underused, mainly because of flushing. Laropiprant (LRPT) reduces niacin-induced flushing and, in combination with extended-release niacin (ERN/LRPT), improves lipid levels., Methods: In this post-hoc subgroup analysis of a phase 3 randomized, double-blind, placebo-controlled, 24-week study (n = 1613), we evaluated the efficacy and safety of ERN/LRPT in dyslipidemic patients with MetS. Dyslipidemic patients were randomized 3:2:1 to ERN/LRPT 1 g, ERN 1 g, or placebo. After 4 weeks, active treatment doses were doubled (2 tablets) for 20 weeks., Results: Relative to placebo, ERN/LRPT significantly lowered low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol levels to a similar degree in MetS and non-MetS cohorts. ERN/LRPT significantly (P < .001) lowered triglyceride levels versus placebo in patients with MetS and without MetS (-30.2% vs -22.2%, respectively). The between subgroup difference in triglyceride lowering was not significant. For all lipid parameters, ERN/LRPT and ERN produced similar magnitude changes. ERN/LRPT and ERN produced similar increases in median fasting blood glucose levels versus placebo in patients with MetS (2.0 and 4.0 mg/dL, respectively) and without MetS (4.0 mg/dL for both groups), consistent with a known effect of niacin., Conclusion: In patients with MetS, ERN/LRPT improves multiple lipid parameters associated with increased cardiovascular disease risk. ERN/LRPT numerically improved triglyceride levels more in patients with versus without MetS, which is likely related to greater baseline triglycerides in MetS patients., (Copyright © 2010 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objective: We examined baseline data from a lipid treatment study to assess the relationship between testosterone (T) and the cardiovascular inflammatory marker, high sensitivity C-reactive protein (hsCRP)., Methods: The baseline T, hsCRP, lipid, glycemic, and anthropometric data were obtained from 467 men (mean age: 52 years). Inclusion criteria included low-density lipoprotein cholesterol > or = 3.4 to 4.9 mmol/l and triglycerides < or = 4.0 mmol/l. The baseline hsCRP levels were examined across the following T subgroups: <6.9 nmol/l (moderate to severe hypogonadism), 6.9 to <10.4 nmol/l (mild to moderate hypogonadism), 10.4 to <15 nmol/l (low-normal T), and > or = 15 nmol/l (normal T)., Results: The median hsCRP levels were significantly (p = 0.041) different across the four T subgroups; patients in the lower T subgroups had higher median hsCRP levels than patients in the higher T subgroups. The percentage of men with elevated hsCRP (>2 mg/l) was also significantly (p = 0.038) different across the four T subgroups; 83% of men with T < 6.9 nmol/l had elevated hsCRP compared with 40% with T > or = 15 nmol/l., Conclusions: This analysis demonstrated an inverse relationship between serum T and hsCRP in aging men. Urologists need to be aware that low T levels may not only adversely affect sexual function but also may worsen cardiovascular risk in aging, hypogonadal men.

Objective: We previously examined the inverse relationship between total serum testosterone (T) and the occurrence of the metabolic syndrome in ageing men using baseline data from two lipid treatment studies. We further examined baseline data from a subset of US men participating in one of these two studies to assess the relationship between T and the cardiovascular risk factor lipid, lipoprotein(a) [Lp(a)]., Methods: Baseline T, lipid, glycaemic and anthropometric data were obtained from 107 men (mean age: 55 years). Inclusion criteria included low-density lipoprotein cholesterol > or = 3.4-4.9 mmol/l and triglycerides < or = 4.0 mmol/l. Baseline Lp(a) levels were examined across the following baseline T subgroups: <15 nmol/l (low/low-normal T) and > or = 15 nmol/l (normal T)., Results: There was an overall trend for a higher incidence of clinically significant Lp(a) elevations in men with low T; 17.1% of men in the low/low-normal T subgroup had an Lp(a) level > or = 3 times the upper limit of normal compared to 8.1% in the normal T subgroup., Conclusions: The data from this descriptive analysis suggest that ageing men with low serum T levels may have an increase in marked elevations in Lp(a), which would be expected to be associated with a significant increase in their cardiovascular event risk.

Inflammation is associated with coronary artery disease (CAD), and statins reduce the inflammatory marker C-reactive protein (CRP). The effects of ezetimibe, alone or in combination with statins, on CRP and low-density lipoprotein (LDL) cholesterol were examined in 2 pooled analyses of randomized, placebo-controlled trials of ezetimibe 10 mg/day in patients with hypercholesterolemia: 6 12-week trials as monotherapy (n = 1,372) and 7 6- to 8-week trials as add-on to baseline statin therapy (n = 3,899). Mean percentage changes from baseline in CRP and LDL cholesterol were examined using analysis of variance in patients with CRP < or =10 mg/L. Effects within subgroups (age, gender, race, body mass index, diabetes mellitus, metabolic syndrome, CAD, baseline CRP or lipids, and statin potency) and correlations between CRP and LDL cholesterol were also examined. Reduction in CRP by ezetimibe monotherapy was numerically greater than with placebo (treatment difference 6%, p = 0.09). Added to statin therapy, ezetimibe was associated with a significant additional reduction in CRP (treatment difference 10%, p <0.001). Treatment effects were generally consistent across subgroups for the 2 analyses. With monotherapy and add-on to statin therapy, LDL cholesterol reduction with ezetimibe was significantly greater than with placebo (treatment differences -19% and -23%, respectively, p <0.001). Spearman's correlation coefficients among baseline values and percentage changes from baseline in CRP and LDL cholesterol ranged from -0.007% to 0.13%. In conclusion, the addition of ezetimibe to statin treatment provides significantly enhanced CRP reductions over and above those achieved with statin monotherapy. Correlations between changes in CRP and changes in LDL cholesterol were weakly positive and significant only when ezetimibe was added to statin treatment. The effects of ezetimibe monotherapy are not well defined. The effects of ezetimibe on CRP were consistent across patient subgroups.

Background: Recent evidence suggests that in addition to low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), non-high-density lipoprotein cholesterol (non-HDL-C), some lipoprotein ratios, and C-reactive protein (CRP) are predictive of coronary heart disease (CHD) risk. This post-hoc analysis of two trials comparing single-tablet ezetimibe/simvastatin (EZE/SIMVA) to atorvastatin (ATORVA) or rosuvastatin (ROSUVA) evaluates the proportion of patients attaining LDL-C <70 mg/dL and specific levels of these emerging risk factors., Methods: These were double-blind, 6-week, parallel group trials of hypercholesterolemic patients randomized to milligram equivalent doses of ATORVA versus EZE 10 mg/SIMVA, or to usual starting, next higher, and maximum doses of ROSUVA versus EZE/SIMVA. This analysis examined the percent of patients in prespecified dose comparisons and overall achievement of LDL-C <70 mg/dL and/or Apo-B <90 mg/dL, total cholesterol (TC)/HDL-C <4.0, or Apo-B/Apo-A-I <0.7 among all treated patients, non-HDL-C <100 mg/dL among patients with baseline triglycerides ≥200 mg/dL, or CRP <2.0 mg/L among patients with baseline CRP ≥2.0 mg/L., Results: Within each trial, baseline characteristics were similar among groups. At all dose comparisons, significantly more patients receiving EZE/SIMVA reached LDL-C <70 mg/dL and achieved both LDL-C <70 mg/dL and either Apo-B <90 mg/dL, TC/HDL-C <4.0, or Apo-B/Apo-A-I <0.7 (EZE/SIMVA versus ATORVA) compared to ATORVA and ROSUVA. For most dose comparisons, significantly more patients receiving EZE/SIMVA attained both LDL-C <70 mg/dL and either non-HDL-C <100 mg/dL or CRP <2 mg/L compared to ATORVA or ROSUVA., Conclusion: The greater efficacy related to changes in blood lipids of EZE/SIMVA compared with both ATORVA and ROSUVA extends to changes in many emerging risk factors. Ultimate clinical implications of these findings still need to be defined.

Background: In addition to low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hs-CRP) are considered predictive for cardiovascular disease in type 2 diabetes mellitus (T2DM) patients., Objective: To assess the proportion of T2DM patients with hypercholesterolemia who attained the optional target level of LDL-C (<70 mg/dL) and additionally non-HDL-C (<100 mg/dL), ApoB (<90 mg/dL), and hs-CRP (<2 mg/L), following treatment with ezetimibe/simvastatin (E/S) vs atorvastatin (A)., Methods: This post-hoc analysis of a multicenter, randomized, double-blind, 6-week parallel study assessed the proportion of T2DM patients who attained specified LDL-C levels and non-HDL-C, ApoB, and hs-CRP with usual, recommended starting doses of E/S (10/20 mg) vs A (10 or 20 mg) and next highest doses of E/S (10/40 mg) vs A (40 mg) by logistic regression. Baseline triglyceride and hs-CRP effects were also evaluated., Results: Significantly higher percentages of patients treated with E/S compared to A achieved individual and concurrent target levels of LDL-C (<70 mg/dL), non-HDL-C (<100 mg/dL), and ApoB (<90 mg/dL) at all dose comparisons (P < 0.05 to P < 0.001). Baseline triglyceride levels had no effect on reaching LDL-C levels. Attainment of non-HDL-C (<100 mg/dL), and ApoB (<90 mg/dL) was lower at triglycerides ≥200 mg/dL than <200 mg/dL. Achievement of hs-CRP level (<2 mg/L) was comparable for both treatments. Significantly more patients attained both LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) at all E/S doses compared to A (P < 0.05 to P < 0.001), regardless of baseline CRP levels., Conclusion: E/S provides a therapeutic option to T2DM patients for lowering not only LDL-C, but also non-HDL-C, ApoB, and hs-CRP. These factors may help guide assessment and treatment of cardiovascular disease risk in these patients.

Objective: Natural and synthetic retinoids such as N-(4-hydroxyphenyl)retinamide (4HPR) have been used for prevention and treatment of a variety of cancers; however, relapse usually occurs after treatment is stopped. Furthermore, the retinoid analogues are insoluble in water, making it difficult for systemic administration. The purpose of this study was to develop and evaluate a water-soluble polymeric formulation of 4HPR that can release 4HPR over a period of a few days., Methods: 4HPR was bound to a synthetic polyamino acid poly(L-glutamic acid) (PG). PG-4HPR was evaluated for its release kinetics and in vitro anti-proliferative and in vivo antitumor activities against ovarian cancer cell lines., Results: The release profile of PG-4HPR in phosphate buffered saline at 37 degrees C followed a first order kinetic, with a rate constant of 8.8x10(-3) h(-1). Approximately 60% of 4HPR was released over a period of 100 h. In vitro, both 4HPR and PG-4HPR inhibited proliferation of three ovarian cancer cells lines (SKOV3, OVCA420, and OVCA433) and an immortalized human ovarian epithelium cell line (IOSE) in a time- and dose-dependent manner. Increasing the exposure time of SKOV3 cells to both agents from 1 to 5 days resulted in an increased apoptotic response. In vivo, PG-4HPR demonstrated significantly enhanced antitumor activities compared to 4HPR in both early treatment and later treatment protocols. Treatments with PG-4HPR suppressed the expression of VEGF and reduced blood flow into the tumor., Conclusions: PG-4HPR may have potential applications in the prevention and therapy of ovarian cancers.

Background: We compared the lipid-altering effects of ezetimibe/simvastatin (EZE/SIMVA) co-administered with fenofibrate (FENO) in mixed hyperlipidemic patients with (MetS) versus those without MetS., Methods: A total of 611 patients, 20 to 79 years old, with LDL-C 130-220 mg/dL (100-180 mg/dL for patients with type 2 diabetes [T2D]), triglycerides (TG) 150-500 mg/dL, and no history of CHD or other CHD risk equivalent disease (except for T2D), were randomized in a 1:3:3:3 ratio into one of the following four treatments for 12 weeks: placebo; EZE/SIMVA 10/20 mg; FENO 160 mg; or EZE/SIMVA+FENO. MetS status was determined in 607 patients using National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Percentage change from baseline in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), TG, apolipoproteins A-I and B, and C-reactive protein was assessed in these patients with or without MetS. The primary objective was to evaluate the lipid-altering efficacy of EZE/SIMVA+FENO versus FENO monotherapy in the MetS versus non-MetS subgroups., Results: At baseline, patients with MetS had a higher body mass index (BMI) and TG and lower HDL-C. At Week 12, treatment with EZE/SIMVA, FENO, and EZE/SIMVA + FENO led to similar improvements in lipid parameters in patients with MetS compared to those without MetS. Treatment with EZE/SIMVA + FENO and FENO also led to an increase in LDL particle-size pattern after 12 weeks in both subgroups of patients., Conclusions: This post-hoc analysis suggested that co-administration of EZE/SIMVA+FENO had consistent benefits on the lipid profile in mixed hyperlipidemic patients with or without MetS.

Seizure outcome is frequently described in terms of patients ever attaining remission or being in terminal remission. Outcomes are more complicated and, over many years, repeated remission and relapses may occur. These are difficult to quantify with standard survival techniques used in analysis of remission and relapse. The Markov process, which allows one to track a patient's state (remission or not) over time, provides a suitable approach for studying repeated remission and relapse. In a prospective community-based study of children followed from the point of the initial diagnosis of epilepsy, we examined the probability of repeated remission and relapse over up to three different remission episodes (minimum 1 year each) per patient. The role of epilepsy syndrome was the main determinant of remission-relapse patterns considered in the analysis. Two different Markov models were used, one involving three states and the other seven states. Of 613 children initially recruited into the study, 602 were followed at least 1 year and thus eligible for the analysis. Almost 90% of the cohort experienced a remission; however, almost half then relapsed. Second remissions occurred in 81% of those who relapsed of whom 38% relapsed again. A third remission occurred in 82% of those after a second relapse of whom 58% relapsed yet again. After the first 2 years, approximately 70% of the cohort was in remission, 20% was no longer in remission having relapsed, and 10% had never been in remission. Significant differences were seen by underlying epilepsy syndrome. Children with one of the epileptic encephalopathies were least likely of all syndrome groups ever to remit. Those with symptomatic partial epilepsies were less likely to remit than children with any of the other syndromes, idiopathic partial or generalized, cryptogenic partial, and unclassified. Differences between these last groups became apparent when considering their subsequent remission and relapse histories. These differences were best seen in the seven-state model. For example, idiopathic partial epilepsies were most likely to enter remission and never relapse. By contrast, idiopathic generalized and cryptogenic partial epilepsies were more likely to remit and relapse repeatedly. The Markov approach provides an alternative to standard survival techniques for understanding remission and relapse outcomes in epilepsy. Its advantage is that it allows one to track the individuals' outcome over time even as the condition fluctuates. The technique would also be applicable in virtually any remitting-relapsing disorder.