Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer''s disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development.     

Exploring the relationships between housing,neighbourhoods and mental wellbeing for residents of deprived areas

Background  

Housing-led regeneration has been shown to have limited effects on mental health. Considering housing and neighbourhoods as a psychosocial environment, regeneration may have greater impact on positive mental wellbeing than mental ill-health. This study examined the relationship between the positive mental wellbeing of residents living in deprived areas and their perceptions of their housing and neighbourhoods.     

Speaker‐specific kinematic properties of alveolar reductions in English and German

A simultaneous EPG/EMA study of tongue gestures of five speakers was conducted to investigate the kinematic events accompanying alveolar stop reductions in the context of a velar plosive /k/ and in the context of a laryngeal fricative /h/ in two languages, English and German. No systematic language differences could be detected. Alveolar productions before a following /h/ showed only a marginal weakening of the formation of complete occlusion, while alveolar productions before a following /k/ showed a wide range of reductions, including instances of a complete deletion of the alveolar gesture. The extension of movement reduction varied between and within subjects. Importantly, while speakers were consistent with themselves, they employed different articulatory patterns with respect to the timing relationship between movement initiation, overall movement duration, peak velocity as well as closure duration. An attempt is made to relate the observed movement patterns to the dynamic factors of the speech mechanism.     

A systematic review of physiological reactivity to stimuli in autism

Objective: The prevalence of abnormal behavioural responses to a variety of stimuli among individuals with autism has led researchers to examine whether physiological reactivity (PR) is typical in this population. This article reviewed studies assessing PR to sensory, social and emotional, and stressor stimuli in individuals with autism. Methods: Systematic searches of electronic databases identified 57 studies that met our inclusion criteria. Studies were analysed to determine: (a) participant characteristics; (b) physiological measures used; (c) PR to sensory, social and emotional or stressor stimuli; (d) the relation between PR and behavioural or psychological variables and (e) baseline physiological activity. A novel measure of methodological quality suitable for use with non-randomized, non-interventional, psychophysiological studies was also developed and applied. Results: Individuals with autism were found to respond differently than typically developing controls in 78.6%, 66.7% and 71.4% of sensory, social and emotional, and stressor stimulus classes, respectively. However, this extant literature is characterized by variable and inconsistent findings, which do not appear to be accounted for by varying methodological quality, making it difficult to determine what specific factors differentiate individuals with autism who present with atypical PR from those who do not. Conclusions: Despite this uncertainty, individual differences in PR are clearly present in autism, suggesting additional research is needed to determine the variables relating to PR among those with ASD and to examine the possible existence of physiological subtype responders in the population.     

A meta-analysis of amputation versus limb salvage in mangled lower limb injuries—The patient perspective

This meta-analysis evaluates the quality of life in post-traumatic amputees in comparison with limb salvage. Studies included in this meta-analysis had a minimum of 24 months of follow-up and used a validated quality-of-life outcome assessment scale (Short Form-36 or Sickness Impact Profile) for physical and psychological outcomes. Two reviewers performed the search and data extraction independent of each other.A total of 214 studies were identified; 11 fulfilled the inclusion criteria; thus, 1138 patients were available for meta-analysis (769 amputees and 369 cases of reconstruction).The meta-analysis demonstrated that lower limb reconstruction is more acceptable psychologically to patients with severe lower limb trauma compared with amputation, even though the physical outcome for both management pathways was more or less the same.