Physical activity for people with dementia: A scoping study

Background: This scoping study aimed to identify how physical activity may benefit people with dementia; how and/or if current service provide these benefits; and what support they need to do so. Methods: Methods included an evidence review using literature; mapping current service provision through a survey; and in-depth interviews with a sample of service providers. Results: The 26 studies included in the review indicated the potential effectiveness of physical activity for people with dementia, including improvements in cognition and mood, behaviour and physical condition. Mechanisms of action and the link with outcomes were poorly defined and implemented. The mapping survey and related interviews showed that service providers were delivering a range of services broadly consistent with the scientific evidence. They tended to take a holistic view of possible benefits, and focused on enjoyment and well-being, more than specific cognitive, physical and behavioural outcomes highlighted in literature. Service providers needed more evidence based information and resources to develop services and realise their potential. Conclusion: Despite potential benefits demonstrated in literature and practice, there is a need for further research to optimise interventions and to consider some neglected issues including delivery at home and in communities; impacts for carers; physical activities through ADLs; and individual needs. Studies are needed which take a more holistic approach to the effects of physical activity, and outcomes should be broader and include mental health and wellbeing

Characterization of transcriptional networks in blood stem and progenitor cells using high-throughput single-cell gene expression analysis

Cellular decision-making is mediated by a complex interplay of external stimuli with the intracellular environment, in particular transcription factor regulatory networks. Here we have determined the expression of a network of 18 key haematopoietic transcription factors in 597 single primary blood stem and progenitor cells isolated from mouse bone marrow. We demonstrate that different stem/progenitor populations are characterized by distinctive transcription factor expression states, and through comprehensive bioinformatic analysis reveal positively and negatively correlated transcription factor pairings, including previously unrecognized relationships between Gata2, Gfi1 and Gfi1b. Validation using transcriptional and transgenic assays confirmed direct regulatory interactions consistent with a regulatory triad in immature blood stem cells, where Gata2 may function to modulate cross-inhibition between Gfi1 and Gfi1b. Single-cell expression profiling therefore identifies network states and allows reconstruction of network hierarchies involved in controlling stem cell fate choices, and provides a blueprint for studying both normal development and human disease

Investigation of Association between PFO Complicated by Cryptogenic Stroke and a Common Variant of the Cardiac Transcription Factor GATA4

Patent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke

Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Normalization of the Lymph Node T Cell Stromal Microenvironment in lpr/lpr Mice Is Associated with SU5416-Induced Reduction in Autoantibodies

The vascular-stromal elements of lymph nodes can play important roles in regulating the activities of the lymphocytes within. During model immune responses, the vascular-stromal compartment has been shown to undergo proliferative expansion and functional alterations. The state of the vascular-stromal compartment and the potential importance of this compartment in a spontaneous, chronic model of autoimmunity have not been well studied. Here, we characterize the vascular expansion in MRL-lpr/lpr lymph nodes and attempt to ask whether inhibiting this expansion can interfere with autoantibody generation. We show that characteristics of vascular expansion in enlarging MRL-lpr/lpr lymph nodes resemble that of the VEGF-dependent expansion that occurs in wild-type mice after model immunization. Surprisingly, treatment with SU5416, an inhibitor of VEGF and other receptor tyrosine kinases, did not have sustained effects in inhibiting vascular growth, but attenuated the anti-dsDNA response and altered the phenotype of the double negative T cells that are expanded in these mice. In examining for anatomic correlates of these immunologic changes, we found that the double negative T cells are localized within ectopic follicles around a central B cell patch and that these T cell-rich areas lack the T zone stromal protein ER-TR7 as well as other elements of a normal T zone microenvironment. SU5416 treatment disrupted these follicles and normalized the association between T zone microenvironmental elements and T cell-rich areas. Recent studies have shown a regulatory role for T zone stromal elements. Thus, our findings of the association of anti-dsDNA responses, double negative T cell phenotype, and altered lymphocyte microenvironment suggest the possibility that lymphocyte localization in ectopic follicles protects them from regulation by T zone stromal elements and functions to maintain autoimmune responses. Potentially, altering the lymphocyte microenvironment that is set up by the vascular-stromal compartment can be a means by which to control undesired autoimmune responses

Effectiveness of balance training exercise in people with mild to moderate severity Alzheimer's disease: protocol for a randomised trial

BACKGROUND: Balance dysfunction and falls are common problems in later stages of dementia. Exercise is a well-established intervention to reduce falls in cognitively intact older people, although there is limited randomised trial evidence of outcomes in people with dementia. The primary objective of this study is to evaluate whether a home-based balance exercise programme improves balance performance in people with mild to moderate severity Alzheimer's disease. METHODS/DESIGN: Two hundred and fourteen community dwelling participants with mild to moderate severity Alzheimer's disease will be recruited for the randomised controlled trial. A series of laboratory and clinical measures will be used to evaluate balance and mobility performance at baseline. Participants will then be randomized to receive either a balance training home exercise programme (intervention group) from a physiotherapist, or an education, information and support programme from an occupational therapist (control group). Both groups will have six home visits in the six months following baseline assessment, as well as phone support. All participants will be re-assessed at the completion of the programme (after six months), and again in a further six months to evaluate sustainability of outcomes. The primary outcome measures will be the Limits of Stability (a force platform measure of balance) and the Step Test (a clinical measure of balance). Secondary outcomes include other balance and mobility measures, number of falls and falls risk measures, cognitive and behavioural measures, and carer burden and quality of life measures. Assessors will be blind to group allocation. Longitudinal change in balance performance will be evaluated in a sub-study, in which the first 64 participants of the control group with mild to moderate severity Alzheimer's disease, and 64 age and gender matched healthy participants will be re-assessed on all measures at initial assessment, and then at 6, 12, 18 and 24 months. DISCUSSION: By introducing a balance programme at an early stage of the dementia pathway, when participants are more likely capable of safe and active participation in balance training, there is potential that balance performance will be improved as dementia progresses, which may reduce the high falls risk at this later stage. If successful, this approach has the potential for widespread application through community based services for people with mild to moderate severity Alzheimer's disease. TRIAL REGISTRATION: The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12608000040369)