RESUMEN
BACKGROUND AND OBJECTIVES: Despite effective combination antiretroviral therapy (cART), adolescents with perinatally acquired HIV (PHIV) exhibit cognitive impairment, of which structural changes could be the underlying pathophysiological mechanism. Prior MRI studies found lower brain volumes, more white matter (WM) hyperintensities (WMH) volume, lower WM integrity, and differences in cerebral blood flow (CBF). However, these findings may be confounded by adoption status, as the large portion PHIV adolescents have been adopted. Adoption has been associated with malnutrition and neglect which in turn may have affected brain development. We investigated the long-term effects of PHIV on the brain, while minimizing the confounding effect of adoption status. METHODS: We determined whole brain gray matter (GM) and WM volume with 3D T1-weighted scans; total WMH volume with fluid-attenuated inversion recovery (FLAIR); CBF in the following regions of interest (ROIs): WM, GM and subcortical GM with arterial spin labeling (ASL); and whole brain WM microstructural markers: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) with diffusion tensor imaging (DTI) in cART treated PHIV adolescents visiting our outpatient clinic in Amsterdam and controls matched for age, sex, ethnic origin, socio-economic status, and adoption status. We assessed differences in neuroimaging parameters between PHIV adolescents and controls using linear regression models adjusted for age and sex and applied multiple comparisons correction. RESULTS: 35 PHIV adolescents and 38 controls were included with a median age (years) of 14.9 (IQR: 10.7-18.5) and 15.6 (IQR:11.1-17.6), respectively with a similar rate of adoption. We found a lower overall FA (beta = -0.012; p<0.014, -2.4%), higher MD (beta = 0.014, p = 0.014, 1.3%) and higher RD (beta = 0.02, p = 0.014, 3.3%) in PHIV adolescents vs. adoption-matched controls, but no differences in AD. We found comparable GM, WM and WMH volume, and CBF in ROIs between PHIV adolescents and controls. We did not find an association between cognitive profiles and WM microstructural markers in PHIV adolescents. DISCUSSION: Irrespective of adoption status, PHIV adolescents exhibited subtle lower WM integrity. Our findings may point towards early-acquired WM microstructural alterations associated with HIV.
RESUMEN
Most flavors used in e-liquids are generally recognized as safe for oral consumption, but their potential effects when inhaled are not well characterized. In vivo inhalation studies of flavor ingredients in e-liquids are scarce. A structure-based grouping approach was used to select 38 flavor group representatives (FGR) on the basis of known and in silico-predicted toxicological data. These FGRs were combined to create prototype e-liquid formulations and tested against cigarette smoke (CS) in a 5-week inhalation study. Female A/J mice were whole-body exposed for 6 h/day, 5 days/week, for 5 weeks to air, mainstream CS, or aerosols from (1) test formulations containing propylene glycol (PG), vegetable glycerol (VG), nicotine (N; 2% w/w), and flavor (F) mixtures at low (4.6% w/w), medium (9.3% w/w), or high (18.6% w/w) concentration or (2) base formulation (PG/VG/N). Male A/J mice were exposed to air, PG/VG/N, or PG/VG/N/F-high under the same exposure regimen. There were no significant mortality or in-life clinical findings in the treatment groups, with only transient weight loss during the early exposure adaptation period. While exposure to flavor aerosols did not cause notable lung inflammation, it caused only minimal adaptive changes in the larynx and nasal epithelia. In contrast, exposure to CS resulted in lung inflammation and moderate-to-severe changes in the epithelia of the nose, larynx, and trachea. In summary, the study evaluates an approach for assessing the inhalation toxicity potential of flavor mixtures, thereby informing the selection of flavor exposure concentrations (up to 18.6%) for a future chronic inhalation study.