Brain Alterations in Aged OVT73 Sheep Model of Huntington's Disease: An MRI Based Approach.

BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1 : 20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity. OBJECTIVE AND METHODS: Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep. RESULTS: Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination. CONCLUSION: This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.

A systems framework for national assessment of climate risks to infrastructure.

Extreme weather causes substantial adverse socio-economic impacts by damaging and disrupting the infrastructure services that underpin modern society. Globally, $2.5tn a year is spent on infrastructure which is typically designed to last decades, over which period projected changes in the climate will modify infrastructure performance. A systems approach has been developed to assess risks across all infrastructure sectors to guide national policy making and adaptation investment. The method analyses diverse evidence of climate risks and adaptation actions, to assess the urgency and extent of adaptation required. Application to the UK shows that despite recent adaptation efforts, risks to infrastructure outweigh opportunities. Flooding is the greatest risk to all infrastructure sectors: even if the Paris Agreement to limit global warming to 2°C is achieved, the number of users reliant on electricity infrastructure at risk of flooding would double, while a 4°C rise could triple UK flood damage. Other risks are significant, for example 5% and 20% of river catchments would be unable to meet water demand with 2°C and 4°C global warming respectively. Increased interdependence between infrastructure systems, especially from energy and information and communication technology (ICT), are amplifying risks, but adaptation action is limited by lack of clear responsibilities. A programme to build national capability is urgently required to improve infrastructure risk assessment.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'.

Turning risk assessment and adaptation policy priorities into meaningful interventions and governance processes.

The UK is one of the first countries in the world to have set up a statutory system of national climate risk assessments followed by a national adaptation programme. Having this legal framework has been essential for enabling adaptation at the government level in a challenging political environment. However, using this framework to create an improvement in resilience to climate change across the country requires more than publishing a set of documents; it requires careful thought about what interventions work, how they can be enabled and what level of risk acceptability individuals, organizations and the country should be aiming for.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'.

Translocation of surface-inoculated Escherichia coli into whole muscle nonintact beef striploins following blade tenderization.

Translocation of Escherichia coli among beef loins processed with a mechanical tenderizer was evaluated. Two beef striploins were inoculated on the lean side with 6.4 to 7.2 ml of a nalidixic acid-resistant E. coli at 8.2 to 10.1 log CFU/ml. Total E. coli inoculated onto striploins ranged from 1.12 × 10(9) to 9.10 × 10(10) CFU. Striploins were passed once (lean side up, anterior end first) through a mechanical blade tenderizer. After the inoculated striploins had been tenderized, uninoculated beef striploins (n = 5) were passed once (lean side up, anterior end first) through the same mechanical tenderizer. This procedure was repeated twice for a total of 12 striploins. Six core samples were taken from each striploin starting with the anterior end. Each core was cut into six sections; sections 1 through 4 represented the top 4 cm of the core sample, and sections 5 and 6 represented the remaining part of the core split in half. After tenderization, E. coli levels were highest (P < 0.05) in loin 1. Loin 2 had higher levels (P < 0.05) than did loins 4, 5, and 6. No differences in E. coli levels (P > 0.05) were found among loins 3, 4, 5, and 6, for which levels were below the limit of detection. Levels of E. coli from section 1 were higher than those for all other sections. Section 2 had higher levels (P < 0.05) than did sections 3, 4, 5, and 6. E. coli recovery from section 6 was higher (P < 0.05) than that from sections 3, 4, and 5. No differences in E. coli recovery (P > 0.05) were found among sections 3, 4, and 5. Data indicate that even after inoculation of E. coli a high initial levels, contamination from one loin to another is quickly reduced to < 10 CFU/g.