Cholinergic and inflammatory phenotypes in transgenic tau mouse models of Alzheimer’s Disease and Frontotemporal Lobar Degeneration

All authors have made a substantial, direct and intellectual contribution to the work, and approved it for publication. This work was funded by NCN grant 2014/15/B/NZ4/05041 and WisTa Laboratories Ltd. CH and CW serve as officers in both WisTa Laboratories Ltd. and TauRx Therapeutics Ltd. The sponsor was involved in the design of the study; in the collection, analysis and interpretation of data; and in the writing of the report. The corresponding authors had full access to all the data and had final responsibility for submission of the report for publication.Peer reviewedPublisher PD

Rescue of synaptosomal glutamate release defects in tau transgenic mice by the tau aggregation inhibitor hydromethylthionine

Glutamatergic neurotransmission, important for learning and memory, is disrupted in different ways in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) tauopathies. We have previously reported that two tau transgenic mouse models, L1 and L66, produce different phenotypes resembling AD and FTD, respectively. The AD-like L1 model expresses the truncated core aggregation domain of the AD paired helical filament (PHF) form of tau (tau296–390) whereas the FTD-like L66 model expresses full-length tau carrying two mutations at P301S/G335D. We have used synaptosomes isolated from these mice to investigate K+-evoked glutamate release and, if abnormal, to determine responsiveness to hydromethylthionine, a tau aggregation inhibitor previously shown to reduce tau pathology in these models. We report that the transgenes in these two mouse lines cause opposite abnormalities in glutamate release. Over-expression of the core tau unit in L1 produces a significant reduction in glutamate release and a loss of Ca²⁺-dependency compared with wild-type control mice. Full-length mutant tau produces an increase in glutamate release that retains normal Ca²⁺-dependency. Chronic pre-treatment with hydromethylthionine normalises both reduced (L1) and excessive glutamate (L66) and restores normal Ca²⁺dependency in L1 mice. This implies that both patterns of impairment are the result of tau aggregation, but that the direction and Ca²⁺-dependency of the abnormality is determined by expression of the disease-specific transgene. Our results lead to the conclusion that the tauopathies need not be considered a single entity in terms of the downstream effects of pathological aggregation of tau protein. In this case, directionally opposite abnormalities in glutamate release resulting from different types of tau aggregation in the two mouse models can be corrected by hydromethylthionine. This may help to explain the activity of hydromethylthionine on cognitive decline and brain atrophy in both AD and behavioural-variant FTD

Long-Term Oxygen Therapy 24 vs 15 h/day and Mortality in Chronic Obstructive Pulmonary Disease

Long-term oxygen therapy (LTOT) >= 15 h/day improves survival in hypoxemic chronic obstructive pulmonary disease ( COPD). LTOT 24 h/day is often recommended but may pose an unnecessary burden with no clear survival benefit compared with LTOT 15 h/day. The aim was to test the hypothesis that LTOT 24 h/day decreases all-cause, respiratory, and cardiovascular mortality compared to LTOT 15 h/day in hypoxemic COPD. This was a prospective, observational, population-based study of COPD patients starting LTOT between October 1, 2005 and June 30, 2009 in Sweden. Overall and cause-specific mortality was analyzed using Cox and Fine-Gray regression, controlling for age, sex, prescribed oxygen dose, PaO2 (air), PaCO2 (air), Forced Expiratory Volume in one second (FEV1), WHO performance status, body mass index, comorbidity, and oral glucocorticoids. A total of 2,249 included patients were included with a median follow-up of 1.1 years (interquartile range, 0.6-2.1). 1,129 (50%) patients died and no patient was lost to follow-up. Higher LTOT duration analyzed as a continuous variable was not associated with any change in mortality rate (hazard ratio [HR] 1.00; (95% confidence interval [CI], 0.98 to 1.02) per 1 h/day increase above 15 h/day. LTOT exactly 24 h/day was prescribed in 539 (24%) patients and LTOT 15-16 h/day in 1,231 (55%) patients. Mortality was similar between the groups for all-cause, respiratory and cardiovascular mortality. In hypoxemic COPD, LTOT 24 h/day was not associated with a survival benefit compared with treatment 15-16 h/day. A design for a registry-based randomized trial (R-RCT) is proposed

“Up the Windsor Road” : social complexity, geographies of emotion, and the rise of Hillsong

This chapter explores the expansion of Hillsong in socio-historical terms, matching its responses to key challenges to contexts and trends in each of the following Hillsong 1.0–4.0 “identities”: as context driven local churchplant; as culture driven regional worship church; as personality-driven transnational network Church; and as brand-driven, technology-mediated Global Church. All these identities co-exist in various localities. The chapter plays particular attention to contextual factors such as Australian public secularism and crises of politics, corporatism and infrastructure, and the consequent development of geographies of emotion and aesthetics which help Hillsong “bridge” into global settings. It is a story not only of the ability of new evangelicalisms to renew and overplant old forms, but of remarkable internal resources of leadership and organization adaptability