Adaptive preconditioning in neurological diseases -­ therapeutic insights from proteostatic perturbations

International audienceIn neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson´s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses - and the molecular pathways they recruit - might be exploited for therapeutic gai

Transient ischaemic attack (TIA) knowledge in general practice: a cross-sectional study of Western Adelaide general practitioners

Extent: 9p.Background: With evidence to support early assessment and management of TIAs, the role of the general practitioner (GP) needs to be considered in developing a TIA service in Western Adelaide. We thus aimed to determine GP knowledge of TIA assessment and management and identify perceived barriers, in order to tailor subsequent GP education and engage primary care in the co-ordinated care of TIA patients. Findings: A self-administered questionnaire was mailed to all GPs (n = 202) in the Adelaide Western General Practice Network. Response frequencies were calculated for all variables, and associations examined by univariate analysis. 32 GPs responded. All respondents correctly identified early risk of stroke following a TIA. Difficulty accessing neurological expertise was identified as a barrier (40.6 %), as was a lack of GP knowledge (18.8 %). Areas for improvement included access to neurologists (36.7 %), relevant guidelines and education (43.3 %). Conclusions: Diagnosis of TIA is difficult and this study highlights the need for further education and practical guidelines for GPs. With this training, GPs could be better equipped to assess and manage TIAs effectively in the community in consultation with stroke physicians.Elaine Stephanie Leung, Monica Anne Hamilton-Bruce, Cate Price and Simon A. Kobla

Individual patient information to select patients for different radiation techniques

Background and purpose: Proton therapy is an emerging technique in radiotherapy which results in less dose to the normal tissues with similar target dose than photon therapy, the current standard. Patient-level simulation models support better decision making on which patients would benefit most. Materials and methods: A simulation model was developed tracking individual patients' status regarding the primary tumour and multiple complications. As a proof of principle, the model was populated based on information from a cohort of 1013 head and neck cancer patients. Dose-volume parameters for photon and proton radiation treatment plans were then fed into the model to compare outcomes in terms of length and quality of life and select patients that would benefit most. Results: The illustrative model could adequately replicate the outcomes of photon therapy in the cohort. Improvements from proton therapy varied considerably between patients. The model projects medium-term outcomes for specific individuals and determines the benefits of applying proton rather than photon therapy. Conclusions: While the model needs to be fed with more and especially recent data before being fully ready for use in clinical practice, it could already distinguish between patients with high and low potential benefits from proton therapy. Benefits are highest for patients with both good prognosis and high expected damage to adjacent organs. The model allows for selecting such patients a priori based on patient relevant outcomes. (C) 2016 Elsevier Ltd. All rights reserved

Strategies for determining heteroaggregation attachment efficiencies of engineered nanoparticles in aquatic environments

Heteroaggregation of engineered nanoparticles (ENPs) with suspended particulate matter (SPM) ubiquitous in natural waters often dominates the transport behaviour and overall fate of ENPs in aquatic environments. In order to provide meaningful exposure predictions and support risk assessment for ENPs, environmental fate and transport models require quantitative information about this process, typically in the form of the so-called attachment efficiency for heteroaggregation αhetero. The inherent complexity of heteroaggregation-encompassing at least two different particle populations, various aggregation pathways and several possible attachment efficiencies (α values)-makes its theoretical and experimental determination challenging. In this frontier review we assess the current state of knowledge on heteroaggregation of ENPs with a focus on natural surface waters. A theoretical analysis presents relevant equations, outlines the possible aggregation pathways and highlights different types of α. In a second part, experimental approaches to study heteroaggregation and derive α values are reviewed and three possible strategies are identified: I) monitoring changes in size, ii) monitoring number or mass distribution and iii) studying indirect effects, such as sedimentation. It becomes apparent that the complexity of heteroaggregation creates various challenges and no single best method for its assessment has been developed yet. Nevertheless, many promising strategies have been identified and meaningful data can be derived from carefully designed experiments when accounting for the different concurrent aggregation pathways and clearly stating the type of α reported. For future method development a closer connection between experiments and models is encouraged. © 2020 The Royal Society of Chemistry

Mysterious α6-containing nAChRs: function, pharmacology, and pathophysiology

Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (α2-α10) and three beta (β2, β3, and β4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although α4β2- and α7-nAChRs are the two major functional nAChR types in the CNS, α6*-nAChRs are abundantly expressed in the midbrain dopaminergic (DAergic) system, including mesocorticolimbic and nigrostriatal pathways, and particularly present in presynaptic nerve terminals. Recently, functional and pharmacological profiles of α6*-nAChRs have been assessed with the use of α6 subunit blockers such as α-conotoxin MII and PIA, and also by using α6 subunit knockout mice. By modulating DA release in the nucleus accumbens (NAc) and modulating GABA release onto DAergic neurons in the ventral tegmental area (VTA), α6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, α6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinson's disease (PD). Thus, α6*-nAChRs may hold promise for future clinical treatment of human disorders, such as nicotine addiction and PD. In this review, we mainly focus on the recent advances in the understanding of α6*-nAChR function, pharmacology and pathophysiology