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1.  Measurement of Muscle Protein Fractional Synthetic Rate by Capillary Gas Chromatography/Combustion Isotope Ratio Mass Spectrometry 
Biological mass spectrometry  1992;21(10):486-490.
The measurement of skeletal muscle protein fractional synthetic rate using an infusion of (1-13C)leucine and measuring the isotopic abundance of the tracer in skeletal muscle protein by preparative gas chromatography (GC)/ninhydrin isotope ratio mass spectrometry (IRMS) is laborious and subject to errors owing to contamination by 12C. The purpose of this study was to compare muscle (13C)leucine enrichment measured with the conventional preparative GC/ninhydrin IRMS approach to a new, continuous-flow technique using capillary GC/combustion IRMS. Quadriceps muscles were removed from four Sprague–Dawley rats after each was infused at a different rate with (1-13C)leucine for 6–8 h. Muscle leucine enrichment (at.% excess) measured by both methods differed by less than 4%, except at low (13C)leucine enrichments (<0.03 at.% excess). In addition, capillary GC/combustion IRMS was used to assess muscle (13C)leucine enrichment and fractional muscle protein synthesis rate in ten normal young men and women infused with (1,2-13C2)leucine for 12–14 h. This approach reduced the variability of the isotope abundance measure and gave estimates of muscle protein synthesis rate (0.050 ± 0.011% h−1 (mean ± SEM); range = 0.023–0.147% h−1) that agree with published values determined using the standard analytical approach. The measurement of (13C)leucine enrichment from skeletal muscle protein by capillary GC/combustion IRMS provides a simple, acceptable and practical alternative to preparative GC/ninhydrin IRMS.
doi:10.1002/bms.1200211004
PMCID: PMC4003887  PMID: 1420371
2.  Age and sex affect protein metabolism at protein intakes that span the range of adequacy: comparison of leucine kinetics and nitrogen balance data☆ 
The Journal of nutritional biochemistry  2012;24(4):10.1016/j.jnutbio.2012.03.021.
Research suggests that changes in leucine oxidation (leuox) with feeding may reflect adult protein requirements. We evaluated this possibility by assessing the effects of age, sex, and different protein intakes on whole-body leucine kinetics and nitrogen balance. Thirty-four young (n = 18, 22–46 years) and old (n= 16, 63–81 years) men and women completed three 18-day trials with protein intakes of 0.50, 0.75 and 1.00 g protein·kg body weight−1·d−1. Fasting and fed-state leucine kinetics were quantified on day 12 of each trial using a primed, constant infusion of L-[1-13C]leucine. Protein requirement was estimated using classical nitrogen balance measurements and calculations. Leucine kinetics parameters were influenced by age and sex across all protein intakes. With feeding, leuox increased more in old vs. young adults. Independent of age, fasting and fed-state leuox were lower, and net leucine balance (fasting+fed-state) was higher in women vs. men. Among all subjects and protein intakes, nitrogen balance was correlated with fed-state leuox (r=0.39), fed-state leucine balance (r=0.60), net leucine balance (r=0.49) and the change in leuox from the fasting to fed state (r=0.49) (P<.05 for all results). At the highest protein intake, the change in leuox with feeding was inversely correlated with protein requirement (r=−0.39). These findings indicate that leucine kinetics, especially leuox, reflect nitrogen balance-based estimates of the need for dietary protein and generally support the view that protein requirement is comparable between young and old adults.
doi:10.1016/j.jnutbio.2012.03.021
PMCID: PMC3885868  PMID: 22841544
Dietary protein; Protein adequacy; Protein metabolism
3.  Exercise Training Reduces Central Adiposity and Improves Metabolic Indices in HAART-Treated HIV-Positive Subjects in Rwanda: A Randomized Controlled Trial 
As HAART becomes more accessible in sub-Saharan Africa, metabolic syndromes, body fat redistribution (BFR), and cardiovascular disease may become more prevalent. We conducted a 6-month, randomized controlled trial to test whether cardiorespiratory exercise training (CET), improves metabolic, body composition and cardiorespiratory fitness parameters in HAART-treated HIV+ African subjects with BFR. Six months of CET reduced waist circumference (−7.13 ± 4.4 cm, p < 0.0001), WHR (−0.10 ± 0.1, p < 0.0001), sum skinfold thickness (−6.15 ± 8.2 mm, p < 0.0001) and % body fat mass (−1.5 ± 3.3, p < 0.0001) in HIV+BFR+EXS. Hip circumference was unchanged in non-exercise control groups. CET reduced fasting total cholesterol (−0.03 ± 1.11 mM, p < 0.05), triglycerides (−0.22 ± 0.48 mM, p < 0.05) and glucose levels (−0.21 ± 0.71 mM, p < 0.05) (p < 0.0001). HDL-, LDL-cholesterol and HOMA values were unchanged after CET. Interestingly, HIV+ subjects randomized to non-exercising groups experienced increases in fasting plasma glucose levels, whereas HIV seronegative controls did not (p < 0.001). Predicted VO2 peak increased more in the HIV+BFR+EXS than in all other groups (4.7 ± 3.9 ml/kg/min, p < 0.0001). Exercise training positively modulated body composition and metabolic profiles, and improved cardiorespiratory fitness in HAART-treated HIV+ Africans. These beneficial adaptations imply that exercise training is a safe, inexpensive, practical, and effective treatment for evolving metabolic and cardiovascular syndromes associated with HIV and HAART exposure in resource-limited sub-Saharan countries, where treatment is improving, morbidity and mortality rates are declining, but where minimal resources are available to manage HIV- and HAART-associated cardiovascular and metabolic syndromes.
doi:10.1089/aid.2007.0023
PMCID: PMC3936606  PMID: 18275343
4.  Blunted lipolysis and fatty acid oxidation during moderate exercise in HIV-infected subjects taking HAART 
The protease inhibitor (PI) ritonavir (RTV) has been associated with elevated resting lipolytic rate, hyperlipidemia, and insulin resistance/glucose intolerance. The purpose of this study was to examine relationships between lipolysis and fatty acid (FA) oxidation during rest, moderate exercise and recovery, and measures of insulin sensitivity/glucose tolerance and fat redistribution in HIV-positive subjects taking RTV (n = 12), HAART but no PI (n = 10), and HIV-seronegative controls (n = 10). Stable isotope tracers [1-13C]palmitate and [1,1,2,3,3- 2H5]glycerol were continuously infused with blood and breath collection during 1-h rest, 70-min submaximal exercise (50%V̇ O2 peak), and 1-h recovery. Body composition was evaluated using DEXA, MRI, and MRS, and 2-h oral glucose tolerance tests with insulin monitoring were used to evaluate glucose tolerance and insulin resistance. Lipolytic and FA oxidation rates were similar during rest and recovery in all groups; however, they were lower during moderate exercise in both HIV-infected groups [glycerol Ra: HIV + RTV 5.1 ± 1.2 vs. HIV + no PI 5.9 ± 2.8 vs. Control 7.4 ± 2.2 µmol·kg fat-free mass (FFM)−1 · min−1; palmitate oxidation: HIV + RTV 1.6 ± 0.8 vs. HIV + no PI 1.6 ± 0.8 vs. Control 2.5 ± 1.7 µmol·kg FFM·min, P < 0.01]. Fasting and orally-challenged glucose and insulin values were similar among groups. Lipolytic and FA oxidation rates were blunted during moderate exercise in HIV-positive subjects taking HAART. Lower FA oxidation during exercise was primarily due to impaired plasma FA oxidation, with a minor contribution from lower nonplasma FA oxidation. Regional differences in adipose tissue lipolysis during rest and moderate exercise may be important in HIV and warrant further study.
doi:10.1152/ajpendo.00300.2006
PMCID: PMC3935339  PMID: 17106066
human immunodeficiency virus; highly active antiretroviral therapy; ritonavir; lipodystrophy; insulin resistance; metabolic syndrome; mass spectrometry
5.  Pilot Study of Pioglitazone and Exercise Training Effects on Basal Myocardial Substrate Metabolism and Left Ventricular Function in HIV-Positive Individuals with Metabolic Complications 
HIV clinical trials  2013;14(6):303-312.
Background
Individuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether interventions shown to be effective in improving peripheral insulin sensitivity can improve basal myocardial insulin sensitivity and diastolic function in people with HIV and peripheral metabolic complications.
Objective
In a pilot study, we evaluated whether the peroxisome proliferator–activated receptor-gamma (PPAR-γ) agonist pioglitazone or combined endurance and resistance exercise training improves basal myocardial insulin sensitivity and diastolic function in HIV+ adults with peripheral metabolic complications.
Design
Twenty-four HIV+ adults with metabolic complications including peripheral insulin resistance were randomly assigned to 4 months of pioglitazone (PIO; 30 mg/d) or supervised, progressive endurance and resistance exercise training (EXS; 90–120 min/d, 3 d/wk). Basal myocardial substrate metabolism was quantified by radioisotope tracer methodology and positron emission tomography (PET) imaging, and LV function was measured by echocardiography.
Results
Twenty participants completed the study. Neither PIO nor EXS resulted in a detectable improvement in basal myocardial insulin sensitivity or diastolic function. Post hoc analyses revealed sample sizes of more than 100 participants are needed to detect significant effects of these interventions on basal myocardial insulin sensitivity and function.
Conclusions
PIO or EXS alone did not significantly increase basal myocardial insulin sensitivity or LV diastolic function in HIV+ individuals with peripheral metabolic complications.
doi:10.1310/hct1406-303
PMCID: PMC3934557  PMID: 24334183
exercise; HIV; insulin resistance; left ventricular dysfunction; metabolic syndrome
6.  Nutrient Ingestion, Protein Intake, and Sex, but Not Age, Affect the Albumin Synthesis Rate in Humans123 
The Journal of nutrition  2007;137(7):1734-1740.
The aim of this study was to assess the effects of nutrient ingestion, dietary protein intake, age, and sex on the fractional synthesis rate (FSR) of albumin. Thirty-six healthy free-living individuals (8 females and 10 males aged 21–43 y and 9 females and 9 males aged 63–79 y) completed three 18-d periods of controlled feeding with protein intakes of 125% (P125, 1.00 g protein · kg−1 · d−1), 94% (P94, 0.75 g protein · kg−1 · d−1), and 63% (P63, 0.50 g protein · kg−1 · d−1) of the recommended dietary allowance. On d 12 of each trial, postabsorptive (PA) serum albumin concentration was determined and PA and postprandial (PP) albumin FSR were estimated from the rate of L-[1-13C] leucine incorporation into plasma albumin during an 8-h infusion. There were no age-related differences in PA and PP albumin FSR. Albumin FSR was higher PP than PA (P < 0.0001), and the increase in albumin FSR from PA to PP was smaller as dietary protein intake decreased from P125 to P94 and P63 (P < 0.05). Independent of protein intake, males had a higher albumin FSR (P < 0.05) and a greater increase in albumin FSR with feeding (P < 0.05). There was no age or dietary protein effect on serum albumin concentrations, but males had higher albumin concentrations than females (P < 0.0001). These results show that older persons are responsive to nutrient ingestion and dietary protein-related changes in albumin FSR. The greater albumin synthesis rate in males might contribute to a higher albumin concentration set point.
PMCID: PMC3885871  PMID: 17585023
7.  Increased in vivo Amyloid-β42 production, exchange, and irreversible loss in Presenilin Mutations Carriers 
Science translational medicine  2013;5(189):10.1126/scitranslmed.3005615.
Alzheimer’s disease is hypothesized to be caused by an over-production or reduced clearance of amyloid-beta (Aβ) peptide. Autosomal Dominant Alzheimer’s Disease (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related non-carriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer, Pittsburgh compound B (PiB). CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to non-carriers and this was independent of fibrillar amyloid deposits quantified by PET PiB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with pre-existing unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with presenilin mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.
doi:10.1126/scitranslmed.3005615
PMCID: PMC3838868  PMID: 23761040
8.  HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus 
Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60–80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty (fa/fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-α and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs.
doi:10.1152/ajpendo.00167.2007
PMCID: PMC3711823  PMID: 18171911
metabolic syndrome; insulin-signaling pathways; human immunodeficiency virus
9.  Insulin Resistance in HIV Protease Inhibitor–Associated Diabetes 
Background
Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy.
Objective
To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI–associated diabetes.
Design
Cross-sectional evaluation.
Patients
8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir.
Measurements
Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 μM) on rat pancreatic [beta]-cell function in vitro.
Results
In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat [beta]-cells.
Conclusions
The pathogenesis of HIV PI–associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic [beta]-cell function was not impaired by indinavir. HIV PI–associated diabetes mirrors that of non–insulin-dependent diabetes mellitus and impaired insulin action in the periphery.
PMCID: PMC3182110  PMID: 10421244
AIDS; Metabolic complications; Glucose metabolism; Pancreatic [beta]-cells; Insulin release
10.  Serum Leptin Concentrations in Human Immunodeficiency Virus–Infected Men With Low Adiposity 
The product of the obese gene (ob) is the protein leptin, which is synthesized in and secreted from adipocytes. Fasting serum leptin concentrations are closely related to body fat content and are higher in obese than in normal-weight individuals. Leptin may contribute to body weight regulation. Overproduction of leptin in certain pathologic conditions such as acquired immunodeficiency syndrome (AIDS) might in principle contribute to the low body fat content associated with body wasting. We measured fasting serum leptin levels by radioimmunoassay in individuals infected with the human immunodeficiency virus (HIV) and in a group of healthy lean men to determine whether HIV infection increases leptin levels. Thirteen HIV-infected men aged 26 to 50 years with a body mass index (BMI) of 15 to 26 kg/m2 and 4 to 24 kg body fat (7% to 29% body fat) had serum leptin levels (3.4 ± 1.6 ng/mL) that were not elevated compared with the levels in 17 healthy men (4.0 ± 1.4 ng/mL) matched for age (23 to 47 years), BMI (18 to 26 kg/m2), and body fat (5 to 21 kg; 9% to 28%). In both groups of men, serum leptin concentrations were correlated with percent body fat and body fat content (P < .001), and these relationships were not different between the two groups. In both groups, leptin concentrations were not correlated with lean body mass (P ≥ .24). Energy intake in the HIV-infected men, assessed from 3-day intake records, was within the normal range. These findings extend the hypothesis that circulating leptin concentrations directly reflect adipose tissue mass, even in HIV-infected men with low body fat content. These findings do not support the hypothesis that HIV infection is associated with high circulating leptin concentrations, and suggest that low leptin levels do not stimulate food intake in HIV-infected individuals.
PMCID: PMC3176667  PMID: 9054474
11.  Yoga lifestyle intervention reduces blood pressure in HIV-infected adults with cardiovascular disease risk factors 
HIV medicine  2010;11(6):379-388.
People living with human immunodeficiency virus infection (HIV) are at increased risk for developing cardiovascular disease (CVD). Safe and effective interventions for lowering CVD risk in HIV are high priorities.
Objective
We conducted a prospective, randomized, controlled study to evaluate whether a yoga lifestyle intervention improves CVD risk factors, virologic or immunologic status, or quality of life in HIV-infected adults more than in a matched control group.
Methods
Sixty HIV-infected adults with mild-moderate CVD risk were assigned to 20 wks of supervised yoga practice or standard of care treatment. Baseline and week 20 measures were; 2hr-oral glucose tolerance test with insulin monitoring, body composition, fasting serum lipid/lipoprotein profile, resting blood pressures, CD4+ T-cell number and plasma HIV RNA, and the Medical Outcomes Study SF-36 health-related quality of life inventory.
Results
Resting systolic and diastolic blood pressures were reduced more (p=0.04) in the yoga group (−5±2 and −3±1 mmHg) than in the standard of care group (+1±2 and +2±2 mmHg), despite no greater reduction in body weight, fat mass, proatherogenic lipids, or improvements in glucose tolerance or overall quality of life after yoga. Immune and virologic status was not adversely affected.
Conclusion
Among traditional lifestyle modifications, yoga is a low cost, simple to administer, non-pharmacological, popular behavioral intervention that can lower blood pressure in pre-hypertensive HIV-infected adults with mild-moderate CVD risk factors.
doi:10.1111/j.1468-1293.2009.00801.x
PMCID: PMC2889007  PMID: 20059570
complementary or alternative therapy; physical activity; cardiometabolic complications; hypertension
13.  Whole body proteolysis rate is elevated in HIV-associated insulin resistance 
Diabetes  2006;55(10):2849-2855.
Type 2 diabetes (T2DM) is characterized by impaired glucose tolerance (IGT) and insulin resistance with respect to glucose metabolism, but not amino acid metabolism. We examined whether whole body leucine and protein metabolism are dysregulated in HIV-infected people with IGT. Glucose and leucine kinetics were measured under fasting insulin conditions and during euglycemic-hyperinsulinemia using primed constant infusions of 2H2-glucose and 13C-leucine in 10 HIV-seronegative control subjects, 16 HIV+ with normal glucose tolerance, and 21 HIV+IGT. Glucose disposal rate during hyperinsulinemia was lower in HIV+IGT than the other two groups. Absolute plasma leucine levels and rate of appearance (whole body proteolysis) were higher in HIV+IGT at all insulin levels, but declined in response to hyperinsulinemia in parallel to those in the other two groups. HIV+IGT had greater visceral adiposity, fasting serum IL-8 and FFA levels, and higher lipid oxidation rates during the clamp than the other two groups. The findings implicate several factors in the insulin-signaling pathway that may be further dysregulated in HIV+IGT, and support the notion that insulin-signaling pathways for glucose and leucine metabolism may be disrupted by increased proinflammatory adipocytokines (IL-8) and increased lipid oxidation. Increased proteolysis may provide amino acids for gluconeogenesis; exacerbating hyperglycemia in HIV.
doi:10.2337/db06-0255
PMCID: PMC1764855  PMID: 17003352
muscle amino acid metabolism; insulin signaling; adipocytokine; lipotoxicity; substrate partitioning; mass spectrometry; stable isotope tracer methods; HIV=human immunodeficiency virus; AIDS=acquired immunodeficiency syndrome; HAART=highly active antiretroviral therapy; FFM=fat-free mass; T2DM=type 2 diabetes mellitus; BCAA=branched chain amino acids; Rd=rate of disposal; Ra=rate of appearance; IGT=impaired glucose tolerance; FFA=serum free fatty acids; VAT=visceral adipose tissue content; SAT=subcutaneous adipose tissue content; TAT=total adipose tissue content; HOMA=homeostasis model assessment of insulin resistance; RIA=radioimmunoassay; NRTI= nucleoside analog reverse transcriptase inhibitors; NNRTI= non-nucleoside analog reverse transcriptase inhibitor; PI= protease inhibitor
14.  Value of measuring muscle performance to assess changes in lean mass with testosterone and growth hormone supplementation 
European journal of applied physiology  2011;112(3):1123-1131.
We hypothesized that treatment with testosterone (T) and recombinant human growth hormone (rhGH) would increase lean mass (LM) and muscle strength proportionally and an in a linear manner over 16 weeks. This was a multicenter, randomized, controlled, double-masked investigation of T and rhGH supplementation in older (71 ± 4 years) community-dwelling men. Participants received transdermal T at either 5 or 10 g/day as well as rhGH at 0, 3.0 or 5.0 µg/kg/day for 16 weeks. Body composition was determined by dual-energy X-ray absorptiometry (DEXA) and muscle performance by composite one-repetition maximum (1-RM) strength and strength per unit of lean mass (muscle quality, MQ) for five major muscle groups (upper and lower body) at baseline, week 8 and 17. The average change in total LM at study week 8 compared with baseline was 1.50 ± 1.54 kg (P < 0.0001) in the T only group and 2.64 ± 1.7 (P < 0.0001) in the T + rhGH group and at week 17 was 1.46 ± 1.48 kg (P < 0.0001) in the T only group and 2.14 ± 1.96 kg (P < 0.0001) in the T + rhGH group. 1-RM strength improved modestly in both groups combined (12.0 ± 23.9%, P < 0.0001) at week 8 but at week 17 these changes were twofold greater (24.7 ± 31.0%, P < 0.0001). MQ did not significantly change from baseline to week 8 but increased for the entire cohort, T only, and T + rhGH groups by week 17 (P < 0.001). Despite sizeable increases in LM measurements at week 8, tests of muscle performance did not show substantive improvements at this time point.
doi:10.1007/s00421-011-2077-y
PMCID: PMC3448487  PMID: 21748366
Anabolic hormones; Androgen supplementation; Muscle quality; HORMA study
16.  18FDG PET-CT imaging detects arterial inflammation and early atherosclerosis in HIV-infected adults with cardiovascular disease risk factors 
Background
Persistent vascular inflammation has been implicated as an important cause for a higher prevalence of cardiovascular disease (CVD) in HIV-infected adults. In several populations at high risk for CVD, vascular 18Fluorodeoxyglucose (18FDG) uptake quantified using 3D-positron emission-computed tomography (PET-CT) has been used as a molecular level biomarker for the presence of metabolically active proinflammatory macrophages in rupture-prone early atherosclerotic plaques. We hypothesized that 18FDG PET-CT imaging would detect arterial inflammation and early atherosclerosis in HIV-infected adults with modest CVD risk.
Methods
We studied 9 HIV-infected participants with fully suppressed HIV viremia on antiretroviral therapy (8 men, median age 52 yrs, median BMI 29 kg/m2, median CD4 count 655 cells/μL, 33% current smokers) and 5 HIV-negative participants (4 men, median age 44 yrs, median BMI 25 kg/m2, no current smokers). Mean Framingham Risk Scores were higher for HIV-infected persons (9% vs. 2%, p < 0.01). 18FDG (370 MBq) was administered intravenously. 3D-PET-CT images were obtained 3.5 hrs later. 18FDG uptake into both carotid arteries and the aorta was compared between the two groups.
Results
Right and left carotid 18FDG uptake was greater (P < 0.03) in the HIV group (1.77 ±0.26, 1.33 ±0.09 target to background ratio (TBR)) than the control group (1.05 ± 0.10, 1.03 ± 0.05 TBR). 18FDG uptake in the aorta was greater in HIV (1.50 ±0.16 TBR) vs control group (1.24 ± 0.05 TBR), but did not reach statistical significance (P = 0.18).
Conclusions
Carotid artery 18FDG PET-CT imaging detected differences in vascular inflammation and early atherosclerosis between HIV-infected adults with CVD risk factors and healthy HIV-seronegative controls. These findings confirm the utility of this molecular level imaging approach for detecting and quantifying glucose uptake into inflammatory macrophages present in metabolically active, rupture-prone atherosclerotic plaques in HIV infected adults; a population with increased CVD risk.
doi:10.1186/1476-9255-9-26
PMCID: PMC3469335  PMID: 22726233
Pathophysiologic molecular-level biomarker; Atherogenesis; Non-invasive imaging; Infectious disease
17.  In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS 
PLoS ONE  2012;7(6):e38013.
Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer’s disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer’s disease (AD). Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ) peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.
doi:10.1371/journal.pone.0038013
PMCID: PMC3366983  PMID: 22675504
18.  Age-Related Skeletal Muscle Decline Is Similar in HIV-Infected and Uninfected Individuals 
Background.
Skeletal muscle (SM) mass decreases with advanced age and with disease in HIV infection. It is unknown whether age-related muscle loss is accelerated in the current era of antiretroviral therapy and which factors might contribute to muscle loss among HIV-infected adults. We hypothesized that muscle mass would be lower and decline faster in HIV-infected adults than in similar-aged controls.
Methods.
Whole-body 1H-magnetic resonance imaging was used to quantify regional and total SM in 399 HIV-infected and 204 control men and women at baseline and 5 years later. Multivariable regression identified associated factors.
Results.
At baseline and Year 5, total SM was lower in HIV-infected than control men. HIV-infected women were similar to control women at both time points. After adjusting for demographics, lifestyle factors, and total adipose tissue, HIV infection was associated with lower Year 5 SM in men and higher SM in women compared with controls. Average overall 5-year change in total SM was small and age related, but rate of change was similar in HIV-infected and control men and women. CD4 count and efavirenz use in HIV-infected participants were associated with increasing SM, whereas age and stavudine use were associated with decreasing SM.
Conclusions.
Muscle mass was lower in HIV-infected men compared with controls, whereas HIV-infected women had slightly higher SM than control women after multivariable adjustment. We found evidence against substantially faster SM decline in HIV infected versus similar-aged controls. SM gain was associated with increasing CD4 count, whereas stavudine use may contribute to SM loss.
doi:10.1093/gerona/glq228
PMCID: PMC3041474  PMID: 21310810
Sarcopenia; Lipoatrophy; Fat redistribution; Body composition
19.  Decreased Clearance of CNS Amyloid-β in Alzheimer’s Disease 
Science (New York, N.Y.)  2010;330(6012):1774.
Alzheimer’s disease is thought to be caused by an imbalance between amyloid-β (Aβ) production and clearance leading to Aβ accumulation in the Central Nervous System (CNS). Aβ production and clearance are key targets in the development of disease modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. Using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of patients with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared to controls. On average, there were no differences in Aβ42 or Aβ40 production rates. Thus, the common late-onset form of Alzheimer’s disease may involve an overall impairment of Aβ clearance.
doi:10.1126/science.1197623
PMCID: PMC3073454  PMID: 21148344
20.  Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow, and oxygen consumption: a cross-sectional analysis 
Background
In the general population, peripheral metabolic complications (MC) increase the risk for left ventricular dysfunction. Human immunodeficiency virus infection (HIV) and combination anti-retroviral therapy (cART) are associated with MC, left ventricular dysfunction, and a higher incidence of cardiovascular events than the general population. We examined whether myocardial nutrient metabolism and left ventricular dysfunction are related to one another and worse in HIV infected men treated with cART vs. HIV-negative men with or without MC.
Methods
Prospective, cross-sectional study of myocardial glucose and fatty acid metabolism and left ventricular function in HIV+ and HIV-negative men with and without MC. Myocardial glucose utilization (GLUT), and fatty acid oxidation and utilization rates were quantified using 11C-glucose and 11C-palmitate and myocardial positron emission tomography (PET) imaging in four groups of men: 23 HIV+ men with MC+ (HIV+/MC+, 42 ± 6 yrs), 15 HIV+ men without MC (HIV+/MC-, 41 ± 6 yrs), 9 HIV-negative men with MC (HIV-/MC+, 33 ± 5 yrs), and 22 HIV-negative men without MC (HIV-/MC-, 25 ± 6 yrs). Left ventricular function parameters were quantified using echocardiography.
Results
Myocardial glucose utilization was similar among groups, however when normalized to fasting plasma insulin concentration (GLUT/INS) was lower (p < 0.01) in men with metabolic complications (HIV+: 9.2 ± 6.2 vs. HIV-: 10.4 ± 8.1 nmol/g/min/μU/mL) than men without metabolic complications (HIV+: 45.0 ± 33.3 vs. HIV-: 60.3 ± 53.0 nmol/g/min/μU/mL). Lower GLUT/INS was associated with lower myocardial relaxation velocity during early diastole (r = 0.39, p < 0.001).
Conclusion
Men with metabolic complications, irrespective of HIV infection, had lower basal myocardial glucose utilization rates per unit insulin that were related to left ventricular diastolic impairments, indicating that well-controlled HIV infection is not an independent risk factor for blunted myocardial glucose utilization per unit of insulin.
Trial Registration
NIH Clinical Trials NCT00656851
doi:10.1186/1475-2840-10-111
PMCID: PMC3258269  PMID: 22151886
insulin resistance; cardiac metabolism and function; PET-imaging
21.  Increased plasma Gln and Leu Ra and inappropriately low muscle protein synthesis rate in AIDS wasting 
The American journal of physiology  1998;275(4 Pt 1):E577-E583.
Muscle protein wasting occurs in human immunodeficiency virus (HIV)-infected individuals and is often the initial indication of acquired immunodeficiency syndrome (AIDS). Little is known about the alterations in muscle protein metabolism that occur with HIV infection. Nine subjects with AIDS wasting (CD4 < 200/mm3), chronic stable opportunistic infections (OI), and ≥10% weight loss, fourteen HIV-infected men and one woman (CD4 > 200/mm3) without wasting or OI (asymptomatic), and six HIV-seronegative lean men (control) received a constant intravenous infusion of [1-13C]leucine (Leu) and [2-15N]glutamine (Gln). Plasma Leu and Gln rate of appearance (Ra), whole body Leu turnover, disposal and oxidation rates, and [13C]Leu incorporation rate into mixed muscle protein were assessed. Total body muscle mass/fat-free mass was greater in controls (53%) than in AIDS wasting (43%; P = 0.04). Fasting whole body proteolysis and synthesis rates were increased above control in the HIV+ asymptomatic group and in the AIDS-wasting group (P = 0.009). Whole body Leu oxidation rate was greater in the HIV+ asymptomatic group than in the control and AIDS-wasting groups (P < 0.05). Fasting mixed muscle protein synthesis rate was increased in the asymptomatic subjects (0.048%/h; P = 0.01) but was similar in AIDS-wasting and control subjects (0.035 vs. 0.037%/h). Plasma Gln Ra was increased in AIDS-wasting subjects but was similar in control and HIV+ asymptomatic subjects (P < 0.001). These findings suggest that AIDS wasting results from 1) a preferential reduction in muscle protein, 2) a failure to sustain an elevated rate of mixed muscle protein synthesis while whole body protein synthesis is increased, and 3) a significant increase in Gln release into the circulation, probably from muscle. Several interesting explanations for the increased Gln Ra in AIDS wasting exist.
PMCID: PMC3177303  PMID: 9755075
acquired immunodeficiency syndrome-wasting syndrome; immune cell function; amino acid metabolism; metabolic complications; stable isotopes; mass spectrometry; leucine; glutamine
22.  Testosterone Replacement and Resistance Exercise in HIV-Infected Men With Weight Loss and Low Testosterone Levels 
Context
Previous studies of testosterone supplementation in HIV-infected men failed to demonstrate improvement in muscle strength. The effects of resistance exercise combined with testosterone supplementation in HIV-infected men are unknown.
Objective
To determine the effects of testosterone replacement with and without resistance exercise on muscle strength and body composition in HIV-infected men with low testosterone levels and weight loss.
Design and Setting
Placebo-controlled, double-blind, randomized clinical trial conducted from September 1995 to July 1998 at a general clinical research center.
Participants
Sixty-one HIV-infected men aged 18 to 50 years with serum testosterone levels of less than 12.1 nmol/L (349 ng/dL) and weight loss of 5% or more in the previous 6 months, 49 of whom completed the study.
Interventions
Participants were randomly assigned to 1 of 4 groups: placebo, no exercise (n = 14); testosterone enanthate (100 mg/wk intramuscularly), no exercise (n = 17); placebo and exercise (n = 15); or testosterone and exercise (n = 15). Treatment duration was 16 weeks.
Main Outcome Measures
Changes in muscle strength, body weight, thigh muscle volume, and lean body mass compared among the 4 treatment groups.
Results
Body weight increased significantly by 2.6 kg (P<.001) in men receiving testosterone alone and by 2.2 kg (P = .02) in men who exercised alone but did not change in men receiving placebo alone (−0.5 kg; P = .55) or testosterone and exercise (0.7 kg; P = .08). Men treated with testosterone alone, exercise alone, or both experienced significant increases in maximum voluntary muscle strength in leg press (range, 22%–30%), leg curls (range, 18%–36%), bench press (range, 19%–33%), and latissimus pulls (range, 17%–33%). Gains in strength in all exercise categories were greater in men assigned to the testosterone-exercise group or to the exercise-alone group than in those assigned to the placebo-alone group. There was a greater increase in thigh muscle volume in men receiving testosterone alone (mean change, 40 cm3; P<.001 vs zero change) or exercise alone (62 cm3; P = .003) than in men receiving placebo alone (5 cm3; P = .70). Average lean body mass increased by 2.3 kg (P = .004) and 2.6 kg (P<.001), respectively, in men who received testosterone alone or testosterone and exercise but did not change in men receiving placebo alone (0.9 kg; P = .21). Hemoglobin levels increased in men receiving testosterone but not in those receiving placebo.
Conclusion
Our data suggest that testosterone and resistance exercise promote gains in body weight, muscle mass, muscle strength, and lean body mass in HIV-infected men with weight loss and low testosterone levels. Testosterone and exercise together did not produce greater gains than either intervention alone.
PMCID: PMC3173037  PMID: 10683055
23.  Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy 
AIDS (London, England)  2000;14(4):F63-F67.
Background
The use of highly active antiretroviral therapy (HAART) has been associated with multiple metabolic complications whose pathogenesis is poorly understood at the present time.
Methods
We performed a cross-sectional analysis of whole-body, lumbar spine (L1 – L4) and proximal femur bone mineral density in 112 male subjects (HIV-infected patients on HAART that included a protease inhibitor, HIV-infected patients not receiving a protease inhibitor and healthy seronegative adults) using dual energy x-ray absorptiometry.
Results
Men receiving protease inhibitors had a higher incidence of osteopenia and osteoporosis according to World Health Organization definitions: relative risk = 2.19 (95% confidence interval 1.13–4.23) (P = 0.02). Subjects receiving protease inhibitors had greater central : appendicular adipose tissue ratios than the other two groups (P < 0.0001). There was no relationship between the central : appendicular fat ratio and the lumbar spine or proximal femur bone mineral density t- or z- scores, suggesting that osteoporosis and body fat redistribution are independent side effects of HAART.
Conclusions
Osteopenia and osteoporosis are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution.
PMCID: PMC3170993  PMID: 10770534
bone mineral metabolism; bone densitometry; osteoporosis; adiposity; aspartyl protease inhibitors; HIV infection
24.  Reducing plasma HIV RNA improves muscle amino acid metabolism 
We reported (Yarasheski KE, Zachwieja JJ, Gischler J, Crow-ley J, Horgan MM, and Powderly WG. Am J Physiol Endocrinol Metab 275: E577–E583, 1998) that AIDS muscle wasting was associated with an inappropriately low rate of muscle protein synthesis and an elevated glutamine rate of appearance (Ra Gln). We hypothesized that high plasma HIV RNA caused dysregulation of muscle amino acid metabolism. We determined whether a reduction in HIV RNA (≥1 log) increased muscle protein synthesis rate and reduced Ra Gln and muscle proteasome activity in 10 men and 1 woman (22–57 yr, 60–108 kg, 17–33 kg muscle) with advanced HIV (CD4 = 0–311 cells/μl; HIV RNA = 10–375 × 103 copies/ml). We utilized stable isotope tracer methodologies ([13C]Leu and [15N]Gln) to measure the fractional rate of mixed muscle protein synthesis and plasma Ra Gln in these subjects before and 4 mo after initiating their first or a salvage antiretroviral therapy regimen. After treatment, median CD4 increased (98 vs. 139 cells/μl, P = 0.009) and median HIV RNA was reduced (155,828 vs. 100 copies/ml, P = 0.003). Mixed muscle protein synthesis rate increased (0.062 ± 0.005 vs. 0.078 ± 0.006%/h, P = 0.01), Ra Gln decreased (387 ± 33 vs. 323 ± 15 μmol·kg fat-free mass−1·h−1, P = 0.04), and muscle proteasome chymotrypsin-like catalytic activity was reduced 14% (P = 0.03). Muscle mass was only modestly increased (1 kg, P = not significant). We estimated that, for each 10,000 copies/ml reduction in HIV RNA, ~3 g of additional muscle protein are synthesized per day. These findings suggest that reducing HIV RNA increases muscle protein synthesis and reduces muscle proteolysis, but muscle protein synthesis relative to whole body protein synthesis rate is not restored to normal, so muscle mass is not substantially increased.
doi:10.1152/ajpendo.00359.2004
PMCID: PMC3170408  PMID: 15367396
human immunodeficiency virus; metabolic complications; body composition; mass spectrometry; antiretroviral medications; cachexia; lentivirus
25.  The effects of exercise training on quality of life in HAART-treated HIV-positive Rwandan subjects with body fat redistribution 
Objective
Our objective was to examine the effects of exercise training (EXS) on quality of life (QoL) in highly active antiretroviral therapy (HAART)-treated HIV-positive (HIV+) subjects with body fat redistribution (BFR) in Rwanda.
Methods
The effects of a randomised controlled trial of EXS on QoL were measured using World Health Organisation Quality of Life (WHOQOL)-BREF in HIV+ subjects with BFR randomised to EXS (n = 50; BFR + EXS) or no exercise training (n = 50; BFR + noEXS).
Results
At 6 months, scores on the psychological [1.3 (0.3) vs. 0.5 (0.1); P < 0.0001], independence [0.6 (0.1) vs. 0.0 (0.0); P < 0.0001], social relationships [0.6 (0.2) vs. 0.0 (0.0); P < 0.0001] and HIV HAART-specific QoL domains [1.4 (0.2) vs. −0.1 (0.2); P < 0.0001] improved more in BFR + EXS than BFR + noEXS group, respectively. Self-esteem [1.3 (0.8) vs. 0.1 (0.6); P < 0.001], body image [1.5 (0.6) vs. 0.0 (0.5); P < 0.001] and emotional stress [1.6 (0.7) vs. 0.2 (0.5); P < 0.001] improved more in the BFR + EXS group than BFR + noEXS group, respectively. Psychological [1.5 (0.2) vs. 1.1 (0.3); P < 0.0001], social relationship [0.8 (0.2) vs. 0.4 (0.2); P < 0.0001], and HIV HAART-specific well-being [1.8 (0.2) vs. 1.0 (0.0); P < 0.0001] improved more in BFR + EXS female than male subjects.
Conclusions
Exercise training improved several components of QoL in HAART-treated HIV+ African subjects with BFR. Exercise training is an inexpensive and efficacious strategy for improving QoL in HIV+ African subjects, which may improve HAART adherence and treatment initiatives in resource-limited areas of sub-Saharan Africa.
doi:10.1007/s11136-008-9319-4
PMCID: PMC3167195  PMID: 18320351
Africa; HAART; Lipodystrophy; Rwanda

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