The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

Research on apolipoprotein E (APOE) has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD). However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area

The pharmacokinetics of the interstitial space in humans

BACKGROUND: The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. METHODS: The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphine-6-glucuronide, morphine-3-glucuronide, inulin and β-lactam antibiotics with a range of protein binding (amoxicillin, piperacillin, cefatrizine, ceforanide, flucloxacillin, dicloxacillin). A PBPK data set was developed for extracellular solutes based on the literature for interstitial organ volumes. The program PKQuest was used to generate the PBPK model predictions. The pharmacokinetics of the protein (albumin) bound β-lactam antibiotics were characterized by two parameters: 1) the free fraction of the solute in plasma; 2) the interstitial albumin concentration. A new approach to estimating the capillary permeability is described, based on the pharmacokinetics of the highly protein bound antibiotics. RESULTS: About 42% of the total body water is extracellular. There is a large variation in the organ distribution of this water – varying from about 13% of total tissue water for skeletal muscle, up to 70% for skin and connective tissue. The weakly bound antibiotics have flow limited capillary-tissue exchange kinetics. The highly protein bound antibiotics have a significant capillary permeability limitation. The experimental pharmacokinetics of the 11 solutes is well described using the new PBPK data set and PKQuest. CONCLUSIONS: Only one adjustable parameter (systemic clearance) is required to completely characterize the PBPK for these extracellular solutes. Knowledge of just this systemic clearance allows one to predict the complete time course of the absolute drug concentrations in the major organs. PKQuest is freely available

Editorial [in Language and Intercultural Communication]

We begin this 22nd volume of Language and Intercultural Communication by announcing that Hans Ladegaard is joining me as joint Editor-in-Chief of the journal. Hans is a long-standing member of IALIC, and for some time was a loyal member of the Association Committee, then the journal’s Editorial Board. Our partnership moving forward will, amongst other things, ensure the continuation of the symbiotic relationship which has endured between the association and the journal since their inception in 2000. On this note, I am compiling this first issue of the New Year still in the continuing warm afterglow of the 21st IALIC conference, which was hosted this year – again virtually – by the Universidad de Los Andes, in Bogota, Columbia

Quantitative Methods

The first two sections of this chapter are concerned with identifying quantitative tools for capturing the complex benefits of reading. Rhiannon Corcoran, Josie Billington and Megan Watkins explain the processes (experimental and hypothesis-driven) by which they have discriminated clinical outcomes measures and indicators of psychological health and well-being appropriate to those engaging with literary reading who are experiencing mental health difficulties, including self-harm. Mette Steenberg, Charlotte Christiansen and Nikolai Ladegaard recount the challenges they encountered in trying to replicate the use of these measures in relation to a Danish-reading programme and the implications for standardising ‘reading for health’. In the final section, Donald Kuiken explicates the objectives of empirical phenomenology—to bring to clarity and coherence, as systematically as possible the full complexity of categories of lived experience—and offers a rationale for numeric formalisation of phenomenological procedures that facilitate the identification and articulation of different types of reading experience. Using a specific exemplary study, Kuiken reviews the distinctive contributions of numerically aided phenomenological methods to studies of reading experience, with particular attention to design factors (such as suspension of concern with explanation) that facilitate fresh revelation and clarification of different ‘species’ of reading experience