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Urine Eicosanoids in the Metabolic Abnormalities, Telmisartan, and HIV Infection (MATH) Trial.
Le CN, Hulgan T, Tseng CH, Milne GL, Lake JE
(2017) PLoS One 12: e0170515
MeSH Terms: Adipose Tissue, Adult, Angiotensin II Type 1 Receptor Blockers, Anthropometry, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Benzimidazoles, Benzoates, Body Fat Distribution, Eicosanoids, Female, HIV Infections, Humans, Inflammation, Lipodystrophy, Male, Middle Aged, Oxidative Stress, Pilot Projects, Prospective Studies, Sex Factors, Telmisartan, Waist-Hip Ratio
Show Abstract · Added December 11, 2019
OBJECTIVES - Arachidonic acid metabolites (eicosanoids) reflect oxidative stress and vascular health and have been associated with anthropometric measures and sex differences in cross-sectional analyses of HIV-infected (HIV+) persons. Telmisartan is an angiotensin receptor blocker and PPAR-γ agonist with potential anti-inflammatory and metabolic benefits. We assessed telmisartan's effects on urine eicosanoids among HIV+ adults with central adiposity on suppressive antiretroviral therapy enrolled in a prospective clinical trial.
METHODS - Thirty-five HIV+ adults (15 women; 20 men) completed 24 weeks of open-label oral telmisartan 40mg daily. Lumbar computed tomography quantified visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue. Urine F2-isoprostane (F2-IsoP), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB-M) were quantified at baseline and 24 weeks using gas/liquid chromatography-mass spectroscopy. Mann-Whitney-U tests compared sub-group differences; Spearman's rho assessed correlations between clinical factors and eicosanoid levels.
RESULTS - Median PGE-M increased on telmisartan (p<0.01), with greater changes in men (+4.1 [p = 0.03] vs. +1.0 ng/mg cr in women; between-group p = 0.25) and participants losing >5% VAT (+3.7 ng/mg cr, p<0.01) and gaining >5% SAT (+1.7 ng/mg cr, p = 0.04). Median baseline F2-IsoP and TxB-M were slightly higher in women (both between-group p = 0.08) and did not change on telmisartan.
CONCLUSIONS - Urine PGE-M increased with 24 weeks of telmisartan in virally suppressed, HIV+ adults with central adiposity. Associations with favorable fat redistribution suggest increased PGE-M may reflect a beneficial response.
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MeSH Terms
Characterization of a caveolin-1 mutation associated with both pulmonary arterial hypertension and congenital generalized lipodystrophy.
Han B, Copeland CA, Kawano Y, Rosenzweig EB, Austin ED, Shahmirzadi L, Tang S, Raghunathan K, Chung WK, Kenworthy AK
(2016) Traffic 17: 1297-1312
MeSH Terms: Caveolae, Caveolin 1, Child, Preschool, Echocardiography, Female, Fibroblasts, Humans, Hypertension, Pulmonary, Lipodystrophy, Congenital Generalized, Microscopy, Fluorescence, Mutation
Show Abstract · Added February 21, 2017
Congenital generalized lipodystrophy (CGL) and pulmonary arterial hypertension (PAH) have recently been associated with mutations in the caveolin-1 ( CAV1 ) gene, which encodes the primary structural protein of caveolae. However, little is currently known about how these CAV1 mutations impact caveolae formation or contribute to the development of disease. Here, we identify a heterozygous F160X CAV1 mutation predicted to generate a C-terminally truncated mutant protein in a patient with both PAH and CGL using whole exome sequencing, and characterize the properties of CAV1 , caveolae-associated proteins and caveolae in skin fibroblasts isolated from the patient. We show that morphologically defined caveolae are present in patient fibroblasts and that they function in mechanoprotection. However, they exhibited several notable defects, including enhanced accessibility of the C-terminus of wild-type CAV1 in caveolae, reduced colocalization of cavin-1 with CAV1 and decreased stability of both 8S and 70S oligomeric CAV1 complexes that are necessary for caveolae formation. These results were verified independently in reconstituted CAV1 mouse embryonic fibroblasts. These findings identify defects in caveolae that may serve as contributing factors to the development of PAH and CGL and broaden our knowledge of CAV1 mutations associated with human disease.
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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11 MeSH Terms
Mitochondrial genomics and antiretroviral therapy-associated metabolic complications in HIV-infected Black South Africans: a pilot study.
Sinxadi PZ, Dave JA, Samuels DC, Heckmann JM, Maartens G, Levitt NS, Wester CW, Haas DW, Hulgan T
(2013) AIDS Res Hum Retroviruses 29: 1031-9
MeSH Terms: Adult, African Continental Ancestry Group, Anti-HIV Agents, Cross-Sectional Studies, DNA, Mitochondrial, Female, Genetic Predisposition to Disease, Genetic Variation, Genome, Mitochondrial, HIV Infections, HIV-Associated Lipodystrophy Syndrome, Humans, Hypertriglyceridemia, Male, Metabolic Diseases, Pilot Projects, Polyneuropathies, South Africa
Show Abstract · Added December 12, 2013
Studies suggest that mitochondrial DNA (mtDNA) haplogroups are associated with antiretroviral therapy (ART)-related metabolic complications and distal sensory polyneuropathy (DSP), but there have been few studies in persons of African descent. We explored such associations in South African adults. Clinical and laboratory data and DNA specimens from a cross-sectional study were used. Sequencing and Phylotree determined African mtDNA subhaplogroups. Wilcoxon and regression analyses determined associations between mtDNA subhaplogroups and ART-related complications. The 171 participants represented six major haplogroups: L0 (n=78), L1 (n=3), L2 (n=30), L3 (n=53), L4 (n=1), and L5 (n=6). Analyses were restricted to 161 participants representing L0, L2, and L3: 78% were female; the median age was 36 years. All had been exposed to thymidine analogues, 42% were on lopinavir/ritonavir (lopinavir/r), and 58% were on either efavirenz or nevirapine. Median (IQR) ART duration was 22 (14-36) months. Median fasting triglycerides were 1.60 (1.13-1.75) and 1.04 (0.83-1.45) mmol/liter among L3e1 (n=22) and other subhaplogroups, respectively (p=0.003). Subhaplogroup L3e1 [adjusted OR (aOR) 3.16 (95% CI: 1.11-8.96); p=0.03] and exposure to lopinavir/r [aOR 2.98 (95% CI: 1.02-8.96); p=0.05] were independently associated with hypertriglyceridemia, after adjusting for age, sex, and ART duration. There were no significant associations between mtDNA haplogroups and cholesterol, dysglycemia, hyperlactatemia, or lipoatrophy, or DSP. Subhaplogroup L3e1 and lopinavir/r exposure were independently associated with hypertriglyceridemia in black South Africans on ART. This is the first report to link an African mtDNA variant with hypertriglyceridemia. If replicated, these findings may provide new insights into host factors affecting metabolic complications.
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18 MeSH Terms
European mitochondrial DNA haplogroups and metabolic changes during antiretroviral therapy in AIDS Clinical Trials Group Study A5142.
Hulgan T, Haubrich R, Riddler SA, Tebas P, Ritchie MD, McComsey GA, Haas DW, Canter JA
(2011) AIDS 25: 37-47
MeSH Terms: Absorptiometry, Photon, Adolescent, Adult, Aged, Antiretroviral Therapy, Highly Active, Clinical Trials, Phase III as Topic, DNA, Mitochondrial, Female, HIV Infections, HIV Protease Inhibitors, HIV-1, HIV-Associated Lipodystrophy Syndrome, Haplotypes, Humans, Male, Middle Aged, Retrospective Studies, Reverse Transcriptase Inhibitors, Sequence Analysis, DNA, Young Adult
Show Abstract · Added December 10, 2013
BACKGROUND - Mitochondrial DNA (mtDNA) influences metabolic diseases and perhaps antiretroviral therapy (ART) complications. We explored associations between European mtDNA haplogroups and metabolic changes among A5142 participants.
METHODS - Seven hundred and fifty-seven ART-naive patients were randomized to one of three class-sparing ART regimens including efavirenz and/or lopinavir/ritonavir with or without nucleoside reverse transcriptase inhibitors (NRTIs). Nonrandomized NRTIs included stavudine, tenofovir, or zidovudine, each with lamivudine. Fasting lipid profiles and whole-body dual-energy X-ray absorptiometry (DEXA) were performed. Nine European mtDNA haplogroups were determined for 231 self-identified non-Hispanic white individuals. Metabolic changes from baseline to 96 weeks were analyzed by haplogroup.
RESULTS - Median age was 39 years, 9% were women, and 37, 32, and 30 were randomized to NRTI-containing regimens with either efavirenz or lopinavir/ritonavir, and an NRTI-sparing regimen, respectively. Among NRTI-containing regimens, 51% included zidovudine, 28% tenofovir, and 21% stavudine. Compared with other haplogroups, mtDNA haplogroup I (N = 10) had higher baseline non-HDL cholesterol [160 mg/dl (interquartile range 137-171) vs. 120 mg/dl (104-136); P = 0.005], a decrease in non-HDL cholesterol over 96 weeks [-14% (-20 to 6) vs. +25% (8 to 51); P < 0.001], tended to have more baseline extremity fat, and had more extremity fat loss by DEXA [-13% (-13 to 12) vs. +9% (-13 to 26); P = 0.08] and lipoatrophy (50 vs. 20%; P = 0.04). Haplogroup W (N = 5; all randomized to NRTI-sparing regimens) had the greatest increase in extremity fat [+35.5% (26.8 to 54.9); P = 0.02].
CONCLUSIONS - Lipids and extremity fat were associated with European mtDNA haplogroups in this HIV-infected population. These preliminary results suggest that mitochondrial genomics may influence metabolic parameters before and during ART.
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20 MeSH Terms
Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment.
Haubrich RH, Riddler SA, DiRienzo AG, Komarow L, Powderly WG, Klingman K, Garren KW, Butcher DL, Rooney JF, Haas DW, Mellors JW, Havlir DV, AIDS Clinical Trials Group (ACTG) A5142 Study Team
(2009) AIDS 23: 1109-18
MeSH Terms: Absorptiometry, Photon, Adult, Benzoxazines, Female, HIV Infections, HIV Protease Inhibitors, HIV-1, HIV-Associated Lipodystrophy Syndrome, Humans, Lipid Metabolism, Lopinavir, Male, Pyrimidinones, Ritonavir
Show Abstract · Added March 13, 2015
BACKGROUND - The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection.
METHODS - Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids.
RESULTS - Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25-39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12-24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5-14) in the NRTI-sparing arm (P < or = 0.023 for all comparisons). Varying the definition of lipoatrophy (> or =10 to > or =40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32-33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11-13%) in the NRTI-sparing arm.
CONCLUSION - Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.
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14 MeSH Terms
Hemochromatosis gene polymorphisms, mitochondrial haplogroups, and peripheral lipoatrophy during antiretroviral therapy.
Hulgan T, Tebas P, Canter JA, Mulligan K, Haas DW, Dubé M, Grinspoon S, Robbins GK, Motsinger AA, Kallianpur AR, AIDS Clinical Trials Group 384 and A5005s Study Teams
(2008) J Infect Dis 197: 858-66
MeSH Terms: Absorptiometry, Photon, Adult, Anti-Retroviral Agents, DNA, Mitochondrial, Female, Genotype, HIV Infections, HIV-1, HIV-Associated Lipodystrophy Syndrome, Hemochromatosis, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide
Show Abstract · Added December 10, 2013
BACKGROUND - Antiretroviral therapy (ART)-associated lipoatrophy involves mitochondrial dysfunction. Iron metabolism impacts mitochondrial function and oxidative stress. Mitochondrial haplogroups and hemochromatosis gene (HFE) polymorphisms have been associated with ART-induced neuropathy. We assessed relationships between these variants and lipoatrophy.
METHODS - The AIDS Clinical Trials Group 384 study randomized ART-naive individuals to receive didanosine-stavudine or zidovudine-lamivudine, combined with efavirenz and/or nelfinavir. Substudy A5005s evaluated fat distribution by dual-energy X-ray absorptiometry (DEXA). We characterized HFE polymorphisms 845G>A and 187C>G and European mitochondrial haplogroups in A5005s participants who consented to genetic analyses.
RESULTS - Among 96 participants (58% were white, and 10% were female) with baseline and 48 or 64 week DEXA data, the median limb fat change was -8.8% (interquartile range, -28.7% to +15.6%). HFE 187C/G heterozygotes (n = 23) had less limb fat loss than 187C/C homozygotes (n = 71) (+6.1% vs. -12.5%; P = .02) and were less likely to develop lipoatrophy after adjustment for age, sex, race, and ART randomization (odds ratio, 0.31; 95% confidence interval, 0.10-0.95; P = .04). Among non-Hispanic white participants, median limb fat change was +26.1% among 5 participants with mitochondrial haplogroup J, compared with -9.7% among 49 participants with other mitochondrial haplogroups (P = .07).
CONCLUSIONS - HFE 187C>G and, possibly, mitochondrial haplogroup J gave relative protection against lipoatrophy during ART in A5005s. These associations should be replicated in other studies.
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14 MeSH Terms
The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults.
Noor MA, Parker RA, O'Mara E, Grasela DM, Currie A, Hodder SL, Fiedorek FT, Haas DW
(2004) AIDS 18: 2137-44
MeSH Terms: Adult, Analysis of Variance, Atazanavir Sulfate, Cross-Over Studies, Double-Blind Method, Energy Metabolism, Fatty Acids, Nonesterified, Glycogen, HIV Protease Inhibitors, HIV Seronegativity, Humans, Insulin Resistance, Lipids, Lipodystrophy, Lopinavir, Oligopeptides, Pyridines, Pyrimidinones
Show Abstract · Added March 13, 2015
BACKGROUND - Therapy with some HIV protease inhibitors (PI) contributes to insulin resistance and type 2 diabetes mellitus, by inhibition of insulin-sensitive glucose transporters. Atazanavir (ATV) is a new PI with substantially less in vitro effect on glucose transport than observed with other PI, including lopinavir (LPV) or ritonavir (RTV).
METHODS - Randomized, double-blind, crossover study of the effect of 5 days of administering ATV, lopinavir/ritonavir (LPV/r) or placebo on insulin-stimulated glucose disposal in 30 healthy HIV-negative subjects. Each subject was studied on two of three possible treatments with a wash-out period between treatments.
RESULTS - The mean insulin-stimulated glucose disposal (mg/min per kg body weight) per unit insulin (microU/ml) (M/I) was 9.88, 9.80 and 7.52 for placebo, ATV and LPV/r, respectively (SEM, 0.84 for all). There was no significant difference between ATV and placebo. The M/I for LPV/r was 23% lower than that for ATV (P = 0.010) and 24% lower than that for placebo (P = 0.008). The mean glycogen storage rates were 3.85, 4.00 and 2.54 mg/min per kg for placebo, ATV and LPV/r, respectively (SEM, 0.39 for all). There was no significant difference between ATV and placebo. The glycogen storage rate for LPV/r was 36% lower than ATV (P = 0.003) and 34% lower than placebo (P = 0.006).
CONCLUSIONS - ATV given to healthy subjects for 5 days did not affect insulin sensitivity, while LPV/r induced insulin resistance. This observation is consistent with differential in vitro effects of these PI on glucose transport. Further data are needed to assess clinical implications for body composition.
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18 MeSH Terms
Enhanced bone formation in lipodystrophic PPARgamma(hyp/hyp) mice relocates haematopoiesis to the spleen.
Cock TA, Back J, Elefteriou F, Karsenty G, Kastner P, Chan S, Auwerx J
(2004) EMBO Rep 5: 1007-12
MeSH Terms: Animals, Bone and Bones, Hematopoiesis, Extramedullary, Lipodystrophy, Mice, Mice, Inbred C57BL, PPAR gamma, RNA, Messenger, Spine, Spleen
Show Abstract · Added November 14, 2013
The peroxisome proliferator-activated receptor gamma (PPARgamma) controls adipogenesis and metabolism. We demonstrate here that the absence of PPARgamma in fat has potent osteogenic activities, which affect haematopoiesis. The congenital absence of PPARgamma in fat of lipodystrophic PPARgamma(hyp/hyp) mice, strongly enhanced bone mass and consequentially reduced the bone-marrow cavity. Consistent with this, PPARgamma(hyp/hyp) mice had a significant decrease in bone marrow cellularity and resorted to extramedullary haematopoiesis in the spleen to maintain haematopoiesis. Our data indicate that antagonizing PPARgamma activity in fat could be an effective way to combat osteoporosis and suggest that haematopoietic function should be scrutinized in lipodystrophic subjects.
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10 MeSH Terms
Serum leptin level is a regulator of bone mass.
Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson C, Nakao K, Capeau J, Karsenty G
(2004) Proc Natl Acad Sci U S A 101: 3258-63
MeSH Terms: Animals, Bone Density, Brain, Cerebral Ventricles, Homeostasis, Humans, Infusions, Parenteral, Leptin, Lipodystrophy, Mice, Mice, Obese, Mice, Transgenic
Show Abstract · Added November 14, 2013
Leptin is a powerful inhibitor of bone formation in vivo. This antiosteogenic function involves leptin binding to its receptors on ventromedial hypothalamic neurons, the autonomous nervous system and beta-adrenergic receptors on osteoblasts. However, the mechanisms whereby leptin controls the function of ventromedial hypothalamic antiosteogenic neurons remain unclear. In this study, we compared the ability of leptin to regulate body weight and bone mass and show that leptin antiosteogenic and anorexigenic functions are affected by similar amounts of leptin. Using a knock-in of LacZ in the leptin locus, we failed to detect any leptin synthesis in the central nervous system. However, increasing serum leptin level, even dramatically, reduced bone mass. Conversely, reducing serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass. Congruent with these results, the high bone mass of lipodystrophic mice could be corrected by restoring serum leptin level, suggesting that leptin is an adipocyte product both necessary and sufficient to control bone mass. Consistent with the high bone mass phenotype of lipodystrophic mice, we observed an advanced bone age, an indirect reflection of premature bone formation, in lipodystrophic patients. Taken together, these results indicate that adipocyte-derived circulating leptin is a determinant of bone formation and suggests that leptin antiosteogenic function is conserved in vertebrates.
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12 MeSH Terms
Membranous lipodystrophy. A case report.
Sami S, Liu G, Hornicek F, Cates JM, Mankin HJ
(2002) J Bone Joint Surg Am 84: 630-3
MeSH Terms: Adult, Female, Humans, Lipodystrophy
Added March 15, 2013
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4 MeSH Terms