Altered cerebrovascular response to acute exercise in patients with Huntington’s Disease

Objective. To determine whether a single session of exercise is sufficient to induce cerebral adaptations in individuals with Huntington’s disease, and explore the time dynamics of any acute cerebrovascular response. Methods. In this case-control study we employed arterial-spin labelling magnetic resonance imaging in 19 HD gene-positive participants (32-65 years old, 13 males) and 19 controls (29-63 years old, 10 males) matched for age, gender, body mass index and self-reported activity levels, to measure global and regional perfusion in response to 20-minutes of moderate intensity cycling. Cerebral perfusion was measured at baseline and 15-, 40- and 60-minutes after exercise cessation. Results. Relative to baseline, cerebral perfusion increased in HD patients yet was unchanged in control participants in the precentral gyrus, middle frontal gyrus and hippocampus 40 minutes after exercise cessation (+15 to +32.5% change in HD participants, -7.7 to 0.8% change in controls). CAG repeat length predicted the change in the precentral gyrus, and the intensity of the exercise intervention predicted hippocampal perfusion change in HD participants. In both groups, exercise increased hippocampal blood flow 60-minutes after exercise cessation. Conclusions. Here we demonstrate the utility of acute exercise as a clinically sensitive experimental paradigm to modulate the cerebrovasculature. Twenty minutes of aerobic exercise induced transient cerebrovascular adaptations in the hippocampus and cortex selectively in HD participants and likely represents latent neuropathology not evident at rest

Hippocampal blood flow is increased after 20 min of moderate-intensity exercise

Long-term exercise interventions have been shown to be a potent trigger for both neurogenesis and vascular plasticity. However, little is known about the underlying temporal dynamics and specifically when exercise-induced vascular adaptations first occur, which is vital for therapeutic applications. In this study, we investigated whether a single session of moderate-intensity exercise was sufficient to induce changes in the cerebral vasculature. We employed arterial spin labeling magnetic resonance imaging to measure global and regional cerebral blood flow (CBF) before and after 20 min of cycling. The blood vessels’ ability to dilate, measured by cerebrovascular reactivity (CVR) to CO2 inhalation, was measured at baseline and 25-min postexercise. Our data showed that CBF was selectively increased by 10–12% in the hippocampus 15, 40, and 60 min after exercise cessation, whereas CVR to CO2 was unchanged in all regions. The absence of a corresponding change in hippocampal CVR suggests that the immediate and transient hippocampal adaptations observed after exercise are not driven by a mechanical vascular change and more likely represents an adaptive metabolic change, providing a framework for exploring the therapeutic potential of exercise-induced plasticity (neural, vascular, or both) in clinical and aged populations

A multi-agency project of the Western Australian Salinity Action Plan supported by the Natural Heritage Trust

Land Monitor is a multi-agency project of the Western Australian Salinity Action Plan supported by the Natural Heritage Trust. It will provide land managers and administrators with baseline salinity and vegetation data for monitoring changes over time, and land height data from which contours accurate to two metre intervals can be produced. The Project will also provide estimates of areas at risk from secondary or future salinisation. Land Monitor will cover the 18 million hectares of agricultural area of south-west, Western Australia. Sequences of calibrated Landsat Thematic Mapper satellite images integrated with landform information derived from height data, ground truthing and other existing mapped data sets are used as the basis for monitoring changes in salinity and woody vegetation. Heights are derived on a 10m grid from stereo aerial photography flown at 1:40,000 scale, using soft-copy automatic terrain extraction (image correlation) techniques. Proposed Land Monitor products include salinity maps, predicted salinity maps, enhanced imagery, vegetation status maps and spectral / temporal statistics. These products will be available in a range of formats and scales, from paddock, farm to catchment and shire scales to suit customer needs

The Land Monitor Project

The Land Monitor Project is providing information over the southwest agricultural region of WA. It is assembling and processing sequences of Landsat TM data, a new highresolution digital elevation model (DEM) and other spatial data to provide monitoring information on the area of salt-affected land, and on changes in the area and status of perennial vegetation over the period 1988-2000. Land Monitor is a multi-agency project of the Western Australian Salinity Action Plan supported by the Natural Heritage Trust. The Project will also providing estimates of areas at risk from secondary or future salinisation, based on the historical salinity maps and a set of landform variables derived from the high resolution DEM. Sequences of calibrated Landsat Thematic Mapper satellite images integrated with landform information derived from height data, ground truthing and other existing mapped data are used as the basis for monitoring changes in salinity and woody vegetation. Procedures for accurate registration and calibration were developed by CSIRO Mathematical and Information Sciences (CMIS), as were the data integration procedures for salinity mapping and prediction. For the DEM, heights are derived on a 10m grid from stereo aerial photography flown at 1:40,000 scale, using soft-copy automatic terrain extraction (image correlation) techniques. Land Monitor products include: high resolution DEMs; calibrated sequences of Landsat imgery; present and historical salinity maps; predicted salinity maps; maps of change in vegetation status and spectral/temporal statistics. These products are available in a range of formats and scales, from paddock to catchment and shire scales to suit customer needs

Framework, principles and recommendations for utilising participatory methodologies in the co-creation and evaluation of public health interventions

Background: Due to the chronic disease burden on society, there is a need for preventive public health interventions to stimulate society towards a healthier lifestyle. To deal with the complex variability between individual lifestyles and settings, collaborating with end-users to develop interventions tailored to their unique circumstances has been suggested as a potential way to improve effectiveness and adherence. Co-creation of public health interventions using participatory methodologies has shown promise but lacks a framework to make this process systematic. The aim of this paper was to identify and set key principles and recommendations for systematically applying participatory methodologies to co-create and evaluate public health interventions. Methods: These principles and recommendations were derived using an iterative reflection process, combining key learning from published literature in addition to critical reflection on three case studies conducted by research groups in three European institutions, all of whom have expertise in co-creating public health interventions using different participatory methodologies. Results: Key principles and recommendations for using participatory methodologies in public health intervention co-creation are presented for the stages of: Planning (framing the aim of the study and identifying the appropriate sampling strategy); Conducting (defining the procedure, in addition to manifesting ownership); Evaluating (the process and the effectiveness) and Reporting (providing guidelines to report the findings). Three scaling models are proposed to demonstrate how to scale locally developed interventions to a population level. Conclusions: These recommendations aim to facilitate public health intervention co-creation and evaluation utilising participatory methodologies by ensuring the process is systematic and reproducible

Alterations in the metabolic and cardiorespiratory response to exercise in Huntington's Disease

Background: Limited data suggests that an altered metabolic and cardiorespiratory exercise response may affect exercise performance in individuals with Huntington's disease (HD). There is no clear exploration of the response in individuals at different stages of the disease or in relation to genetic markers. This study aimed to examine the exercise response and recovery of HD participants, and the relationship to genetic and clinical markers. Method: HD gene-positive participants (n = 31; 9 pre-manifest; 22 manifest HD) and a healthy control group (n = 29) performed an incremental exercise test until exhaustion. Performance, cardiorespiratory, metabolic and perceptual responses to exercise were determined from a maximal cycle ergometer test throughout the exercise test and during a recovery period. Results: During sub-maximal exercise, metabolic (lactate levels, oxygen uptake) and cardiorespiratory markers (heart rate) were elevated in HD participants compared to controls. Lactate elevation was specific to pre-manifest HD participants. Work capacity was reduced in both pre-manifest and manifest HD participants with tests terminated with no difference in metabolic, perceptual or cardiorespiratory markers. Submaximal oxygen uptake was correlated with motor score, whilst peak measures were unrelated to genetic or clinical markers. Heart rate recovery was attenuated in pre-manifest and manifest HD participants. Conclusions: Our findings confirm metabolic and cardiorespiratory deficits reduce exercise performance and affect recovery from an early stage in HD, with submaximal deficits related to phenotypic expression. Exercise capacity appears to be limited by an altered movement economy, thus clinicians should consider an altered exercise response and recovery may affect prescription in HD

Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS - Neurofilament as a Surrogate of Disease Progression

This work was supported by National MS Society (USA) under the Promise 2010 initiative and the MS Society of Great Britain and Northern Ireland as part of exploratory analysis for the UK MS Clinical Trial Network. VL is supported by Italian Minister of Health grant for young researcher 2008

OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes

Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA ‘plus’ phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability

Simultaneous genetic analysis of means and covariance structure: Pearson-Lawley selection rules

The object of this paper is to indicate that the Pearson-Lawley selection rules form a plausible general theory for the simultaneous genetic analysis of means and covariance structure. Models are presented based on phenotypic selection and latent selection. Previously presented quantitative genetic models to decompose means and covariance structure simultaneously are reconsidered as instances of latent selection. The selection rules are very useful in the context of behavior genetic modeling because they lead to testable models and a conceptual framework for explaining variation between and within groups by the same genetic and environmental factors. © 1994 Plenum Publishing Corporation

SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice

Background: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. Results: Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1−/−) mice. Conclusions: These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation