Large variability in plasma efavirenz concentration in Papua New Guinea HIV/AIDS patients associated with high frequency of CYP2B6 516T allele.

Papua New Guinea (PNG) has a high HIV/AIDS prevalence and very high frequency of the CYP2B6 c.516G>T (rs3745274) variant. We have conducted the first investigation of the impact of c.516G>T and patient demographics on plasma efavirenz (EFV) and 8-hydroxyefavirenz (8OH-EFV) concentrations, metabolic ratio (8OH-EFV/EFV) (MR), and their association with adverse effects, in PNG patients with HIV/AIDS. For 156 PNG patients with HIV/AIDS taking EFV 600 mg/day (for 3-156 months), plasma EFV and 8OH-EFV concentrations were quantified, CYP2B6 c.516G>T genotyped, and demographic and self-reported adverse effects data recorded. Genotype differences in EFV and 8OH-EFV concentrations, MR, and percent within therapeutic range (1000-4000 ng/ml) were examined, in addition to EFV and 8OH-EFV concentration differences between patients experiencing adverse effects. CYP2B6 c.516T allele frequency was 53%. Plasma EFV (p < 0.0001), 8OH-EFV (p < 0.01), and MR (p < 0.0001) differed significantly between genotypes, with genotype explaining 38%, 10%, and 50% of variability, respectively. Plasma EFV concentrations were significantly higher in T/T (median = 5168 ng/ml) than G/G (1036 ng/ml, post hoc p < 0.0001) and G/T (1502 ng/ml, p < 0.0001) genotypes, with all patients above therapeutic range (n = 23) being T/T genotype (p < 0.0001). EFV and 8OH-EFV concentrations were not significantly higher in patients experiencing adverse effects. In PNG HIV/AIDS population where the 516T frequency is very high, it explains a substantial portion of variability (38%) in EFV disposition; however, at least for the patients receiving EFV long term, this does not translate into significant side effects.

Corticosterone Preexposure Increases NF-κB Translocation and Sensitizes IL-1ß Responses in BV2 Microglia-Like Cells.

Corticosterone (CORT), a critical mediator of the hypothalamus pituitary adrenal axis in rodents, is a stress hormone that is classically viewed as possessing immune-suppressive properties. CORT is now appreciated to also mediate the neuroimmune-priming effect of stress to innate-immune stimulation, and hence serves as a mechanistic link to the neuroimmune involvement in stress-related disorders. However, these dichotomous actions of CORT remain poorly defined. This study investigated the conditions and concentration dependency of CORT's actions required to prime the innate-immune system. Here, we measured the effect of CORT pretreatment on the downstream pro-inflammatory responses of BV2 mouse microglia-like cells stimulated by lipopolysaccharide (LPS). We quantified the concentration-dependent CORT-mediated attenuation and enhancement of LPS-stimulated inflammatory response. A high physiological concentration (500 nM) of CORT attenuated LPS-induced inflammatory IL-1ß cytokine production in a glucocorticoid receptor-dependent manner. However, a low concentration (50 nM) of CORT increased expression and release of IL-1ß in a mineralocorticoid receptor-dependent manner, with accompanied increases in NF-κB translocation and changes to related gene transcription. These results suggest that a mild elevation in CORT may cause selective adaptations in microglia-like cells to overrespond to a second immune challenge in a non-classical manner, thus partially explaining both pro- and anti-inflammatory effects of CORT reported in the literature.

Association of innate immune single-nucleotide polymorphisms with the electroencephalogram during desflurane general anaesthesia.

The electroencephalogram (EEG) records the electrical activity of the brain and enables effects of anaesthetic drugs on brain functioning to be monitored. Identification of genes contributing to EEG variability during anaesthesia is important to the clinical application of anaesthesia monitoring and may provide an avenue to identify molecular mechanisms underlying the generation and regulation of brain oscillations. Central immune signalling can impact neuronal activity in the brain and accumulating evidence suggests an important role for cytokines as neuronal modulators. We tested 21 single-nucleotide polymorphisms (SNPs) in immune-related genes for associations with three anaesthesia-induced EEG patterns; spindle amplitude, delta power and alpha power, during general anaesthesia with desflurane in 111 patients undergoing general, gynaecological or orthopaedic surgery. Wide inter-patient variability was observed for all EEG variables. MYD88 rs6853 (p = 6.7 × 10(-4)) and IL-1ß rs1143627 in conjunction with rs6853 (p = 1.5 × 10(-3)) were associated with spindle amplitude, and IL-10 rs1800896 was associated with delta power (p = 1.3 × 10(-2)) suggesting involvement of cytokine signalling in modulation of EEG patterns during desflurane anaesthesia. BDNF rs6265 was associated with alpha power (p = 3.9 × 10(-3)), suggesting differences in neuronal plasticity might also influence EEG patterns during desflurane anaesthesia. This is the first study we are aware of that has investigated genetic polymorphisms that may influence the EEG during general anaesthesia.