Publications
Department of Medicine faculty members published more than 3,000 peer-reviewed articles in 2022.
2013
BACKGROUND
In HIV-infected women, urine concentrations of novel tubulointerstitial injury markers, interleukin-18 (IL-18) and kidney injury marker-1 (KIM-1), are associated with kidney function decline and all-cause mortality. We hypothesized that HIV-infected individuals with preserved kidney filtration function would have more extensive kidney injury, as determined by urine injury markers, compared to the uninfected controls, and that risk factors for tubulointerstitial injury would differ from risk factors for albuminuria.
METHODS
In this cross-sectional study, we compared urine concentrations of IL-18, KIM-1 and albumin-to-creatinine ratio (ACR) in 908 HIV-infected and 289 HIV-uninfected women enrolled in the Women's Interagency HIV Study, utilizing stored urine specimens from visits between 1999 and 2000.
RESULTS
After multivariate-adjusted linear regression analysis, mean urine concentrations were higher in HIV-infected individuals by 38% for IL-18 (P<0.0001), 12% for KIM-1 (P=0.081) and 47% for ACR (P<0.0001). Higher HIV RNA level (15% per 10-fold increase; P<0.0001), lower CD4(+) lymphocyte count (8% per doubling; P=0.0025), HCV infection (30%; P=0.00018) and lower high-density lipoprotein (5% per 10 mg/dl; P=0.0024) were each associated with higher IL-18 concentrations. In contrast, hypertension (81%; P<0.0001) and diabetes (47%; P=0.018) were among the strongest predictors of higher ACR, though HIV RNA level (15% per 10-fold increase; P=0.0004) was also associated with higher ACR.
CONCLUSIONS
HIV-infected women had more extensive tubulointerstitial and glomerular injury than uninfected women, but the associated factors differed among the urine biomarkers. Combinations of urinary biomarkers should be investigated to further characterize early kidney injury in HIV-infected women.
View on PubMed2013
Mefenamic acid (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug, is metabolized into the chemically-reactive MFA-1-O-acyl-glucuronide (MFA-1-O-G), MFA-acyl-adenylate (MFA-AMP), and the MFA-S-acyl-coenzyme A (MFA-CoA), all of which are electrophilic and capable of acylating nucleophilic sites on biomolecules. In this study, we investigate the nonenzymatic ability of each MFA acyl-linked metabolite to transacylate amino and thiol functional groups on the acceptor biomolecules Gly, Tau, l-glutathione (GSH), and N-acetylcysteine (NAC). In vitro incubations with each of the MFA acyl-linked metabolites (1 μM) in buffer under physiologic conditions with Gly, Tau, GSH, or NAC (10 mM) revealed that MFA-CoA was 11.5- and 19.5-fold more reactive than MFA-AMP toward the acylation of cysteine-sulfhydryl groups of GSH and NAC, respectively. However, MFA-AMP was more reactive toward both Gly and Tau, 17.5-fold more reactive toward the N-acyl-amidation of taurine than its corresponding CoA thioester, while MFA-CoA displayed little reactivity toward glycine. Additionally, mefenamic acid-S-acyl-glutathione (MFA-GSH) was 5.6- and 108-fold more reactive toward NAC than MFA-CoA and MFA-AMP, respectively. In comparison with MFA-AMP and MFA-CoA, MFA-1-O-G was not significantly reactive toward all four bionucleophiles. MFA-AMP, MFA-CoA, MFA-1-O-G, MFA-GSH, and mefenamic acid-taurine were also detected in rat in vitro hepatocyte MFA (100 μM) incubations, while mefenamic acid-glycine was not. These results demonstrate that MFA-AMP selectively reacts with the amino functional groups of glycine and lysine nonenzymatically, MFA-CoA selectively reacts nonenzymatically with the thiol functional groups of GSH and NAC, and MFA-GSH reacts with the thiol functional group of GSH nonenzymatically, all of which may potentially elicit an idiosyncratic toxicity in vivo.
View on PubMed2013
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Effects of cellular activation on anti-HIV-1 restriction factor expression profile in primary cells.
2013
Expression of cell-intrinsic antiviral factors suppresses HIV-1 replication. We hypothesized that cellular activation modulates host restriction and susceptibility to HIV-1 infection. We measured the gene expression of 34 antiviral factors in healthy peripheral blood mononuclear cells (PBMC). Cellular activation induced expression of interferon-stimulated gene 15 (ISG15), tripartite motif 5α (TRIM5α), bone marrow stromal cell antigen 2 (BST-2)/tetherin, and certain apolipoprotein B mRNA editing enzyme 3 (APOBEC3) family members. Expression of RTF1, RNA polymerase II-associated factor 1 (PAF1), TRIM11, TRIM26, and BST-2/tetherin correlated with decreased HIV-1 infectivity. This report demonstrates synchronous effects of activation-induced antiviral genes on HIV-1 infectivity, providing candidates for pharmacological manipulation.
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