Shelly Sun

Greater Tenofovir-Associated Renal Function Decline with Protease Inhibitor-Based versus Nonnucleoside Reverse-Transcriptase Inhibitor-Based Therapy

BACKGROUND Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. METHODS We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. RESULTS Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. CONCLUSIONS Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.

Transforming Growth Factor-β Signaling Pathway in Patients With Kawasaki Disease

Background—Transforming growth factor (TGF)-&bgr; is a multifunctional peptide that is important in T-cell activation and cardiovascular remodeling, both of which are important features of Kawasaki disease (KD). We postulated that variation in TGF-&bgr; signaling might be important in KD susceptibility and disease outcome. Methods and Results—We investigated genetic variation in 15 genes belonging to the TGF-&bgr; pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands. We analyzed transcript abundance patterns using microarray and reverse transcriptase–polymerase chain reaction for these same genes, and measured TGF-&bgr;2 protein levels in plasma. Genetic variants in TGFB2, TGFBR2, and SMAD3 and their haplotypes were consistently and reproducibly associated with KD susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A SMAD3 haplotype associated with KD susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338) (P=0.000022; odds ratio, 1.50; 95% confidence interval, 1.25 to 1.81). Pathway analysis using all 15 genes further confirmed the importance of the TGF-&bgr; pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-&bgr;2 plasma protein levels changed dynamically over the course of the illness. Conclusions—These studies suggest that genetic variation in the TGF-&bgr; pathway influences KD susceptibility, disease outcome, and response to therapy, and that aortic root and coronary artery Z scores can be used for phenotype/genotype analyses. Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis.

Evidence for Insulin Suppression of Baseline Luteinizing Hormone in Women with Polycystic Ovarian Syndrome and Normal Women

CONTEXT In women with polycystic ovarian syndrome (PCOS), the relationship of insulin to LH secretion and responses to GnRH remains unresolved. A rigorous analytical examination of this relationship has not been performed. OBJECTIVE Our objective was to determine the relationship of basal LH secretion and responses to GnRH, insulin, and other endocrine variables in normal and PCOS women. DESIGN In PCOS and normal women, mean composite 12-h LH secretion was analyzed for correlating factors. LH responses to varying doses of GnRH during a fixed rate of insulin infusion and LH responses to a fixed dose of GnRH during varying doses of insulin infusion were analyzed for contributing factors. PATIENTS AND SETTING Eighteen PCOS and 21 normal women underwent studies of frequent blood sampling and GnRH stimulation before and during insulin infusion at the General Clinical Research Center, University of California, San Diego. MAIN OUTCOME MEASURES Group mean composite 12-h LH levels were assessed with respect to other endocrine variables. In addition, LH responses to GnRH with or without insulin infusion were assessed. RESULTS In normal women, insulin negatively predicted mean LH. In PCOS, the combined effect of body mass index (negative) and testosterone (positive) predicted LH. The best predictor of LH was body mass index and insulin combined. Basal LH and LH responses to GnRH were unaltered by insulin infusion in normal women. These measures were reduced during insulin infusion in PCOS women. CONCLUSIONS In PCOS, insulin infusion suppresses pituitary response to GnRH. In normal women, insulin negatively correlates with mean LH and suppresses GnRH response at a high infusion rate.

Increases in Plasma Carotenoid Concentrations in Response to a Major Dietary Change in the Women's Healthy Eating and Living Study

Background: Cohort studies suggest that higher circulating carotenoid concentrations through food sources may reduce breast cancer events. Other intervention studies have not achieved the level of change in circulating carotenoids required to properly test this hypothesis. Methods: In a randomized trial of 2,922 breast cancer survivors, we examined blood and self-reported diet at baseline and 1 year. Intensive telephone counseling encouraged a plant-based diet in the intervention group. Diet was measured via 24-hour recalls, and a panel of plasma carotenoid concentrations was assessed at both time points. Results: The study intervention was associated with a 51% increase in total carotenoid concentration, from 2.272 ± 1.294 to 3.440 ± 2.320 μmol/L, achieved mainly by marked increases in targeted carotenoids: α-carotene, β-carotene, and lutein. For each of these targeted carotenoids, the proportion of the intervention sample remaining below the cutpoint for the lowest baseline quartile decreased by one third to one half. After 1 year of study, half of the intervention group was in the highest baseline quartile. No change in distribution was observed in comparison group. Intervention participants achieved this change by both dietary pattern and vegetable juice consumption. Participants who chose to change dietary pattern without consuming significant quantities of vegetable juice achieved 75% of the level of change observed in other intervention participants. Conclusions: Innovative telephone counseling intervention and dietary targets in the Womens Healthy Eating and Living study were associated with the level of change in circulating carotenoid concentration necessary to test the diet and breast cancer hypothesis suggested by cohort studies. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1886–92)

Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease.

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US–UK KD patients (aneurysm+: n=111, aneurysm−: n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm−: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (−/T) and haplotypes containing MMP-3 rs3025058 (−/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4 × 10−5) that conferred increased risk of aneurysm formation in US–UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation.

Abacavir and tenofovir disoproxil fumarate co-administration results in a nonadditive antiviral effect in HIV-1-infected patients.

Objectives:To evaluate a potential pharmacodynamic/pharmacokinetic interaction between abacavir (ABC) and tenofovir disoproxil fumarate (TDF). Design and methods:This randomized trial compared 7 days of ABC or TDF monotherapy, separated by a 35-day washout, with 7 days of ABC + TDF dual-therapy in treatment-naive, HIV-1-infected patients. During each 7-day course, the slope of the phase I viral decay was estimated and steady-state intracellular concentrations of carbovir triphosphate (CBV-TP), deoxyguanosine triphosphate (dGTP), tenofovir diphosphate (TFV-DP) and deoxyadenosine triphosphate (dATP) were determined. Results:Twenty-one participants were randomized to initial monotherapy with ABC (n = 11) or TDF (n = 10). The addition of TDF did not increase the slope of viral decay compared to ABC alone (−0.15 log10 per day vs. −0.16 log10 per day, respectively). No decrease in CBV-TP or TFV-DP between monotherapy and dual-therapy was observed. However, intracellular dATP concentrations increased between monotherapy and dual-therapy [median dATP (fmol/106 cells) 3293 vs. 4638; P = 0.08], although this difference was significant only among patients randomized to TDF [median dATP (fmol/106 cells) 3238 vs. 4534; P = 0.047]. A lower TFV-DP-to-dATP ratio was associated with reduced viral decay during dual-therapy (ρ = −0.529; P = 0.045). Conclusion:In this study, the viral decay during ABC and TDF dual-therapy was similar to that during ABC therapy alone, suggesting a nonadditive antiviral effect. This negative pharmacodynamic interaction was not explained by changes in CBV-TP or TFV-DP concentrations. Rather, modest increases in endogenous dATP pools were associated with reduced antiviral potency of TDF during co-administration with ABC.

Insulin-Like Growth Factor I, Insulin-Like Growth Factor I Binding Protein 1, Insulin, Glucose, and Leptin Serum Levels Are Not Influenced by a Reduced-Fat, High-Fiber Diet Intervention

The Womens Healthy Eating and Living study is a dietary intervention aimed at increasing vegetables, fruit, and fiber, and reducing fat intake in breast cancer survivors. In a subsample of this study, we measured five interrelated factors: free circulating insulin-like growth factor I (IGF-I),

Individuals With Chronic Traumatic Brain Injury Improve Walking Speed and Mobility With Intensive Mobility Training

OBJECTIVE To determine the feasibility and impact of different dosages of Intensive Mobility Training (IMT) on mobility, balance, and gait speed in individuals with chronic traumatic brain injury (TBI). DESIGN Prospective, single group design with 3-month follow-up. SETTING University research laboratory. PARTICIPANTS Volunteer sample of participants with chronic TBI (N=10; ≥3 mo post-TBI; able to ambulate 3.05 m with or without assistance; median age, 35.4 y; interquartile range, 23.5-46 y; median time post-TBI, 9.91 y; interquartile range, 6.3-14.2 y). Follow-up data were collected for all participants. INTERVENTIONS Twenty days (5 d/wk for 4 wk), with 150 min/d of repetitive, task-specific training equally divided among balance; gait training; and strength, coordination, and range. MAIN OUTCOME MEASURES Pain and fatigue were recorded before and after each session to assess feasibility. Treatment outcomes were assessed before training (pre), after 10 sessions (interim), after 20 sessions (post), and at 3-months follow-up and included the Berg Balance Scale and gait speed. RESULTS Participants averaged 150.1±2.7 minutes per session. Median presession and postsession pain scores were 0 (out of 10) for 20 sessions; median presession fatigue scores ranged from 0 to 2.5 (out of 10); and postsession scores ranged from 3 to 5.5 (out of 10). Four outcome measures demonstrated significant improvement from the pretest to interim, with 7 out of 10 participants exceeding the minimal detectable change (MDC) for fast walking speed. At the posttest, 2 additional measures were significant, with more participants exceeding the MDCs. Changes in fast walking speed and Timed Up and Go test were significant at follow-up. CONCLUSIONS Limited fluctuations in pain and fatigue scores indicate feasibility of IMT in this population. Participants demonstrated improvements in walking speed, mobility, and balance postintervention and maintained gains in fast walking speed and mobility at 3 months.

Pilot study to show the feasibility of a multicenter trial of home-based assessment of people over 75 years old

This report describes a pilot study to evaluate feasibility of new home-based assessment technologies applicable to clinical trials for prevention of cognitive loss and Alzheimer disease. Methods: Community-dwelling nondemented individuals ≥75 years old were recruited and randomized to 1 of 3 assessment methodologies: (1) mail-in questionnaire/ live telephone interviews (MIP); (2) automated telephone with interactive voice recognition (IVR); and (3) internet-based computer Kiosk (KIO). Brief versions of cognitive and noncognitive outcomes were adapted to the different methodologies and administered at baseline and 1-month. An Efficiency measure, consisting of direct staff-to-participant time required to complete assessments, was also compared across arms. Results: Forty-eight out of 60 screened participants were randomized. The dropout rate across arms from randomization through 1-month was different: 33% for KIO, 25% for IVR, and 0% for MIP (Fisher Exact Test P=0.04). Nearly all participants who completed baseline also completed 1-month assessment (38 out of 39). The 1-way ANOVA across arms for total staff-to-participant direct contact time (ie, training, baseline, and 1-month) was significant: F (2,33)=4.588; P=0.017, with lowest overall direct time in minutes for IVR (Mn=44.4; SD=21.5), followed by MIP (Mn=74.9; SD=29.9), followed by KIO (Mn=129.4; SD=117.0). Conclusions: In this sample of older individuals, a higher dropout rate occurred in those assigned to the high-technology assessment techniques; however, once participants had completed baseline in all 3 arms, they continued participation through 1 month. High-technology home-based assessment methods, which do not require live testers, began to emerge as more time-efficient over the brief time of this pilot, despite initial time-intensive participant training.

Interlaboratory Measurement Differences in Intracellular Carbovir Triphosphate Concentrations in HIV-Infected Patients: Sources of Variability in Processing, Shipping, and Quantitation

D inhibitors (NRTIs) form the backbone of most potent antiretroviral (ARV) regimens. The quantity of dideoxynucleotide analog triphosphates (ddNTPs) produced appears to be tightly regulated by a number of host cellular factors. Differences in nucleoside drug metabolism may explain, in part, the significant interindividual variability observed in intracellular ddNTP concentrations with several NRTIs, including zidovudine (ZDV), lamivudine (3TC), tenofovir disoproxil fumarate (TDF), and abacavir (ABC). However, the issue of measurement error due to variability during specimen processing and ddNTP quantitation should be considered when interpreting clinical nucleotide concentrations obtained in different laboratories despite similar analytical methodologies. Abacavir is biotransformed intracellularly to carbovir (CBV) triphosphate (TP), the active moiety that competes with endogenous guanosine triphosphate (dGTP) for incorporation by viral reverse transcriptase (RT). Large variations in the intracellular half-life of CBV-TP have been reported, ranging from 3.3 to 21 hours. This degree of variability may complicate the evaluation of NRTI exposures in vivo. For example, Hawkins et al determined the intracellular pharmacokinetics of 15 HIV-infected individuals on stable ABCand TDF-containing regimens to evaluate a potential pharmacologic explanation for the high rates of early virologic failure observed with triple-NRTIonly regimens containing ABC, TDF, and 3TC. The median intracellular CBV-TP concentrations and half-lives ranged from 88 to 200 fmol/10 cells and 12 to 19 hours, respectively, with a high degree of intrasubject variability (fold variability,