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1.  An In-Silico Model of Lipoprotein Metabolism and Kinetics for the Evaluation of Targets and Biomarkers in the Reverse Cholesterol Transport Pathway 
PLoS Computational Biology  2014;10(3):e1003509.
High-density lipoprotein (HDL) is believed to play an important role in lowering cardiovascular disease (CVD) risk by mediating the process of reverse cholesterol transport (RCT). Via RCT, excess cholesterol from peripheral tissues is carried back to the liver and hence should lead to the reduction of atherosclerotic plaques. The recent failures of HDL-cholesterol (HDL-C) raising therapies have initiated a re-examination of the link between CVD risk and the rate of RCT, and have brought into question whether all target modulations that raise HDL-C would be atheroprotective. To help address these issues, a novel in-silico model has been built to incorporate modern concepts of HDL biology, including: the geometric structure of HDL linking the core radius with the number of ApoA-I molecules on it, and the regeneration of lipid-poor ApoA-I from spherical HDL due to remodeling processes. The ODE model has been calibrated using data from the literature and validated by simulating additional experiments not used in the calibration. Using a virtual population, we show that the model provides possible explanations for a number of well-known relationships in cholesterol metabolism, including the epidemiological relationship between HDL-C and CVD risk and the correlations between some HDL-related lipoprotein markers. In particular, the model has been used to explore two HDL-C raising target modulations, Cholesteryl Ester Transfer Protein (CETP) inhibition and ATP-binding cassette transporter member 1 (ABCA1) up-regulation. It predicts that while CETP inhibition would not result in an increased RCT rate, ABCA1 up-regulation should increase both HDL-C and RCT rate. Furthermore, the model predicts the two target modulations result in distinct changes in the lipoprotein measures. Finally, the model also allows for an evaluation of two candidate biomarkers for in-vivo whole-body ABCA1 activity: the absolute concentration and the % lipid-poor ApoA-I. These findings illustrate the potential utility of the model in drug development.
Author Summary
Epidemiological studies have shown a strong inverse association between HDL-C and cardiovascular risk and led to the formulation of the “HDL cholesterol hypothesis”: under this hypothesis, interventions raising HDL-C should decrease risk. However, the recent failures of HDL-C raising therapies in improving cardiovascular disease risk in outcomes trials have suggested a need to revise the hypothesis to account for the contrary data. An “HDL flux hypothesis” has emerged: it is not HDL-C level per se which forms the basis for reducing risk, but it is the flux rate of reverse cholesterol transport that drives risk reduction. We propose that, the concentration of HDL cholesteryl ester in plasma simply reflects the ratio of input rate of reverse cholesterol transport into the HDL compartments to its clearance rate. A challenge in identifying targets under the new conceptual framework is the feedback process that occurs between the input rate and the clearance rate of HDL-C. To meet this challenge, we have built a systems model which incorporates the main processes of HDL metabolism to elucidate the relationships between target modulations and the reverse cholesterol transport rate.
doi:10.1371/journal.pcbi.1003509
PMCID: PMC3952822  PMID: 24625468
2.  Cardiovascular Risk Prediction in Diabetic Men and Women using Hemoglobin A1c versus Diabetes as a High Risk Equivalent 
Archives of internal medicine  2011;171(19):1712-1718.
Background
It is unclear whether models which include hemoglobin A1c (HbA1c) levels only for diabetic patients improve ability to predict cardiovascular disease (CVD) risk when compared to the currently recommended classification of diabetes as a cardiovascular risk equivalent.
Methods
24,674 women (including 685 diabetic participants at baseline) and 11,280 men (including 563 diabetic participants at baseline) were followed prospectively for CVD. 125 CVD events occurred in diabetic women (666 in non-diabetic women) and 170 events occurred in diabetic men (1382 in non-diabetic men). Models for CVD risk were generated separately for men and women using the traditional CVD risk factors with the addition of a term for HbA1c levels only for diabetic individuals. In diabetic participants, the resulting predicted risks were compared to classification of diabetes as a cardiovascular risk equivalent (10-year CVD-risk of at least 20%).
Results
In women, the models including HbA1c levels in diabetic participants improved the c-statistic by 0.177 (p <0.001) over the risk equivalence model and showed improved reclassification (NRI of 26.7%, p = 0.001). In men, the improvements were more modest but still statistically significant (c-statistic change of 0.039, p=0.015; NRI of 9.2%, p= 0.042). Including HbA1c levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8%, p = 0.033) but not in men.
Conclusions
In both women and men with baseline diabetes, we observed significant improvements in predictive ability of CVD risk using models incorporating HbA1c levels compared to classification of diabetes as a cardiovascular risk equivalent.
doi:10.1001/archinternmed.2011.351
PMCID: PMC3202025  PMID: 21788538
3.  Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation 
Context.
Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial’s Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant’s perception of change.
Methods.
Men aged 65 years and older, with mobility limitation, total testosterone 100–350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared.
Results.
Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change.
Conclusions.
Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.
doi:10.1093/gerona/glr100
PMCID: PMC3202898  PMID: 21697501
Testosterone; Minimally important difference; Mobility limitation; Older men; Function promoting therapies
4.  Adverse Events Associated with Testosterone Administration 
The New England journal of medicine  2010;363(2):109-122.
Background
Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied.
Methods
Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group.
Results
A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load.
Conclusions
In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy.
doi:10.1056/NEJMoa1000485
PMCID: PMC3440621  PMID: 20592293
5.  Effects of Testosterone Therapy on Muscle Performance and Physical Function in Older Men with Mobility Limitations (The TOM Trial): Design and Methods 
Contemporary clinical trials  2008;30(2):133-140.
The TOM study is the first, single-site, placebo-controlled, randomized clinical trial designed to comprehensively determine the effects of testosterone administration on muscle strength and physical function in older men with mobility limitations. A total of 252 community dwelling individuals aged 65 and older with low testosterone levels and self-reported limitations in mobility and short physical performance battery (SPPB) score between 4 and 9 will be randomized to receive either placebo or testosterone therapy for 6 months. The primary objective is to determine whether testosterone therapy improves maximal voluntary muscle strength as quantified by the one repetition maximum. Secondary outcomes will include measures of physical function (walking, stair climbing and a lifting and lowering task), habitual physical activity and self-reported disability. The effects of testosterone on affect, fatigue and sense of well being will also be assessed. Unique aspects of the TOM Trial include selection of men with self-reported as well as objectively demonstrable functional limitations, community-based screening and recruitment, adjustment of testosterone dose to ensure serum testosterone levels in the target range while maintaining blinding, and inclusion of a range of self-reported and performance-based physical function measures as outcomes. Clinicaltrials.gov identifier: NCT00240981.
doi:10.1016/j.cct.2008.10.005
PMCID: PMC3031114  PMID: 18996225
testosterone; mobility limitations; physical function; strength; aging; sarcopenia; anabolic therapies
6.  Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging 
SUMMARY
Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with β-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.
doi:10.1038/ncpendmet0120
PMCID: PMC2072878  PMID: 16932274
anabolic therapies; androgens; sarcopenia; selective androgen receptor modulators; testosterone

Results 1-6 (6)