Background The CYP4503A5*1 genotype is associated with lower tacrolimus concentrations. Although its effect is important, it incompletely explains the variability in tacrolimus concentrations and has a relatively low minor allele frequency in Caucasians relative to African Americans (AA). Methods We studied clinical and recipient genetic correlates of dose-normalized tacrolimus troughs (n=12,277) in the first 6 months posttransplant using a customized single nucleotide polymorphism chip with 2,722 variants in a large, ethnically diverse (144 AA and 551 non-AA) adult kidney transplant population through a 7-center consortium. Results Over the 6 month study, AAs had consistently lower median (interquartile range) troughs than non-AAs, 6.2 (4.4–8.4) vs 8.3 (6.4–10.4) ng/mL (p<0.0001), in spite of 60% higher daily doses, 8 (5–10) vs 5 (4–7) mg (p<0.0001). The median tacrolimus trough concentration in week one posttransplant was particularly low in AAs [2.1 (1.2–3.5)] compared to non-AAs [5.0 (3.1–8.2) ng/mL](p<0.0001) despite similar initial doses. In single variant analysis, CYP3A5*3 (rs776746) was the top variant (p=2.4x10−33) associated with troughs. After adjustment for CYP3A5*3, clinical factors and race, thirty-nine additional variants were identified (p<0.01, not significant at FDR 20%). In the final multivariant, regression models beginning with these variants and clinical factors, 7 variants were identified in the non-AA and 7 variants in the AA group towards the first trough concentrations. Rs776746 (CYP3A5), rs2239393 (COMT) and diabetes were the only factors common in both populations. Conclusion We identified variants beyond CYP3A5*3 which may further explain pharmacokinetic variability of tacrolimus and demonstrated that important variants differ by race.
This paper reinvestigates the use of transient fluorescence spectroscopy of polar aromatics in solution as a method to determine microscopic solvation dynamics. It is shown that the compounds previously employed as polar fluorescent probes tend to fall into three photophysical classes depending upon: (i) whether the photon induced change in μ occurs simultaneously with photon absorption (ii) whether solvent motion subsequent to photon absorption is required to induce the change in μ; or (iii) whether two excited-state isomers with different μ’s are present simultaneously. The consequence of the different classes on microscopic solvation dynamic measurements is discussed with a molecular example for each class: (i) 4-aminophthalimide, (ii) 4-(9-anthryl)-N, N-dimethylaniline, and (iii) bianthryl, respectively. In addition, we introduce a new transient fluorescence procedure for the determination of solvation dynamics that has advantages over the traditional transient Stokes-shift method. Finally, for the first time, extensive measurements on the solvation dynamics of a polar aprotic solvent have been made. The observed dynamics of the solvent (glycerol triacetate) are highly nonexponential; this has important implications for chemical reactions in similar solvents. Interestingly, the experimentally observed microscopic dynamics are in qualitative agreement with predictions of the dielectric continuum model.
This pilot study suggests that an additional evaluation of choline supplementation as an intervention for memory functioning in children with FASDs is warranted. The observed interaction between age and choline's effect on EI suggests that potential sensitive periods should be considered in future work. This trial was registered at clinicaltrials.gov as NCT01149538.
Purpose To investigate the association of psychosocial distress with risk of stroke mortality and incident stroke in older adults. Methods Data were from the Chicago Health and Aging Project, a longitudinal population-based study conducted in three contiguous neighborhoods on the south side of Chicago, Illinois. Participants were community-dwelling black and non-Hispanic white adults, age 65 and older (N=4,120 for stroke mortality; N=2,649 for incident stroke). Psychosocial distress was an analytically-derived composite measure of depressive symptoms, perceived stress, neuroticism, and life dissatisfaction. Cox proportional hazards models examined the association of distress with stroke mortality and incident stroke over 6 years of follow-up. Results 151 stroke deaths and 452 incident strokes were identified. Adjusting for age, race, and sex, the hazard ratio (HR) for each 1-SD increase in distress was 1.47 (95% confidence interval [CI]=1.28–1.70) for stroke mortality and 1.18 (95% CI, 1.07–1.30) for incident stroke. Associations were reduced following adjustment for stroke risk factors and remained significant for stroke mortality (HR=1.29; 95% CI=1.10–1.52) but not for incident stroke (HR=1.09; 95% CI=0.98–1.21). Secondary analyses of stroke subtypes showed that distress was strongly related to incident hemorrhagic strokes (HR=1.70; 95% CI=1.28–2.25) but not ischemic strokes (HR=1.02; 95% CI=0.91–1.15) in fully adjusted models. Conclusions Increasing levels of psychosocial distress are related to excess risk of both fatal and nonfatal stroke in older black and white adults. Additional research is needed to examine pathways linking psychosocial distress to cerebrovascular disease risk.
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