Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma – a study of the United Kingdom Children's Cancer Study Group

The administration of 13-cis-retinoic acid (13-cisRA), following myeloablative therapy improves 3-year event-free survival rates in children with high-risk neuroblastoma. This study aimed to determine the degree of inter-patient pharmacokinetic variation and extent of metabolism in children treated with 13-cisRA. 13-cis-retinoic acid (80 mg m−2 b.d.) was administered orally and plasma concentrations of parent drug and metabolites determined on days 1 and 14 of courses 2, 4 and 6 of treatment. Twenty-eight children were studied. The pharmacokinetics of 13-cisRA were best described by a modified one-compartment, zero-order absorption model combined with lag time. Mean population pharmacokinetic parameters included an apparent clearance of 15.9 l h−1, apparent volume of distribution of 85 l and absorption lag time of 40 min with a large inter-individual variability associated with all parameters (coefficients of variation greater than 50%). Day 1 peak 13-cisRA levels and exposure (AUC) were correlated with method of administration (P<0.02), with 2.44- and 1.95-fold higher parameter values respectively, when 13-cisRA capsules were swallowed as opposed to being opened and the contents mixed with food before administration. Extensive accumulation of 4-oxo-13-cisRA occurred during each course of treatment with plasma concentrations (mean±s.d. 4.67±3.17 μM) higher than those of 13-cisRA (2.83±1.44 μM) in 16 out of 23 patients on day 14 of course 2. Extensive metabolism to 4-oxo-13-cisRA may influence pharmacological activity of 13-cisRA

Taking a Feminist Disability Studies Approach to Fundamental British Values: Do “Fundamental” “British” Values Encourage the Appreciation of Marginalized Identity Groups, or Lead to the Performance of Inclusion?

In this article, Fundamental British Values (FBV) are understood as a token attempt toward societal inclusion and empowerment of all citizens. Rather than providing meaningful routes for all individuals to be included in British citizenship, FBV are built on foundations of “inclusionism” — the inclusion of marginalized identity groups in society, on the premise that existing social structures are not threatened. Disabled women’s responses to sociocultural stereotypes surrounding disability and gender are interpreted through a feminist disability studies lens. Empirical data, gathered within a larger research project which examined disabled women’s responses to the representation of disabled women in Anglo-American advertising, are drawn on and connections are made between the growing trend of promoting diversity in advertising, and superficial approaches to diversity and empowerment of all citizens, enacted in FBV. Two key themes underpin this critical discussion: participant resistance to “pity” narratives surrounding the portrayal of disabled women in advertising and disabled women’s navigation of “belonging” in exclusionary environments

Mesenchymal derived exosomes enhance recovery of motor function in a monkey model of cortical injury

BACKGROUND: Exosomes from mesenchymal stromal cells (MSCs) are endosome-derived vesicles that have been shown to enhance functional recovery in rodent models of stroke. OBJECTIVE: Building on these findings, we tested exosomes as a treatment in monkeys with cortical injury. METHODS: After being trained on a task of fine motor function of the hand, monkeys received a cortical injury to the hand representation in primary motor cortex. Twenty-four hours later and again 14 days after injury, monkeys received exosomes or vehicle control. Recovery of motor function was followed for 12 weeks. RESULTS: Compared to monkeys that received vehicle, exosome treated monkeys returned to pre-operative grasp patterns and latency to retrieve a food reward in the first three-five weeks of recovery. CONCLUSIONS: These results provide evidence that in monkeys exosomes delivered after cortical injury enhance recovery of motor function