Community environment, cognitive impairment and dementia in later life: results from the Cognitive Function and Ageing Study

Background: Few studies have investigated the impact of the community environment, as distinct from area deprivation, on cognition in later life. This study explores cross-sectional associations between cognitive impairment and dementia and environmental features at the community level in older people. Method: The postcodes of the 2424 participants in the year-10 interview of the Cognitive Function and Ageing Study in England were mapped into small area level geographical units (Lower-layer Super Output Areas) and linked to environmental data in government statistics. Multilevel logistic regression was conducted to investigate associations between cognitive impairment (defined as MMSE3 in GMS-AGECAT) and community level measurements including area deprivation, natural environment, land use mix and crime. Sensitivity analyses tested the impact of people moving residence within the last two years. Results: Higher levels of area deprivation and crime were not significantly associated with cognitive impairment and dementia after accounting for individual level factors. Living in areas with high land use mix was significantly associated with a nearly 60% reduced odds of dementia (OR: 0.4; 95% CI: 0.2, 0.8) after adjusting for individual level factors and area deprivation, but there was no linear trend for cognitive impairment. Increased odds of dementia (OR: 2.2, 95% CI: 1.2, 4.2) and cognitive impairment (OR: 1.4, 95% CI: 1.0, 2.0) were found in the highest quartile of natural environment availability. Findings were robust to exclusion of the recently relocated. Conclusion: Features of land use have complex associations with cognitive impairment and dementia. Further investigations should focus on environmental influences on cognition to inform health and social policies

A longitudinal study of muscle rehabilitation in the lower leg after cast removal using Magnetic Resonance Imaging and strength assessment

Acknowledgements We thank the A&E nurses and plaster technicians for identifying suitable patients, the MRI radiographers for performing the scanning, Dr Scott Semple for invaluable help in some of the pilot studies and Mr E. C. Stevenson for constructing the footrest used in the scanner. We are very grateful to the dedicated patients themselves who gave considerable amounts of time to come in for scanning, exercise and assessment during the course of this study.Peer reviewedPublisher PD

Prevalence of dementia in East Asia: a synthetic review of time trends.

OBJECTIVE: This study aims to synthesise evidence on time trends of dementia prevalence in East Asian countries including Japan, China, South Korea and Taiwan and assess the impact of the societal changes on future prevalence. METHOD: Relevant reviews and recent nationwide studies in East Asia were identified to investigate changes in prevalence of dementia over time taking into account the potential impact of methodological factors and study designs. RESULTS: The robust evidence that has been interpreted to suggest a substantial increasing trend over time is less compelling once fundamental differences in study methods and populations across individual surveys are considered. In Japan, longitudinal studies in small areas suggest the potential increase of prevalence after 2000. Increasing trends in China, South Korea and Taiwan over the last 20-30 years are based on the literature review without adjustment for methodological differences. Economic development and huge societal changes alongside the rise of non-communicable disease in East Asia could lead to increasing prevalence of dementia in the future once those cohorts with high risk of dementia reached their older age. CONCLUSION: Current evidence is not sufficient to suggest increasing trends of dementia prevalence in East Asia. Longitudinal studies with representative samples and stable methodology are needed to provide fundamental information of the epidemiology of dementia and identify important risk factors in East Asian societies.There is no specific funding contributing to this study. Yu-Tzu Wu received a PhD scholarship from the Cambridge Trust, University of Cambridge. Fiona E. Matthews was supported by the Medical Research Council [grant number U105292687].This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1002/gps.4297/abstract

Dementia: time trends and policy responses.

In recent years, dementia has been considered a public health priority and become a topic of major political interest. Recent reviews and studies have reported with varying degrees of alarm an impending and existing "dementia epidemic" with increasing predicted trends in prevalence and enormous numbers of people with dementia particularly in low- and middle-income countries (LMICs). However, robust evidence from dementia research in high-income countries suggests stable or decreased prevalence over the last decades. Current evidence is not sufficient to suggest increasing trends of prevalence in LMICs once variation in methodological factors and study populations are taken into account. Changes in diagnostic methods over the last decades substantially influence the identification of dementia cases with systematic difference between the resulting individual prevalence studies. Potential geographical variations at the country level might indicate potential risk factors at population levels or systematic difference in clinical application of dementia diagnosis. Although it is important and necessary to use information from dementia research for evidence-based policymaking, over-interpretation of results without carefully considering underlying factors could exaggerate the findings and influence policy planning in ways which do not serve current and future population best. Planning of dementia policy needs to take full cognisance of the provenance of the data being used and be integrated with policies which optimise health across the lifecourse.Yu-Tzu Wu received a PhD scholarship from the Cambridge Trust, University of Cambridge. Fiona E. Matthews was supported by the Medical Research Council [grant number U105292687].This is the accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.maturitas.2014.06.02

Community environment, cognitive impairment and dementia in later life: results from the Cognitive Function and Ageing Study

Background: Few studies have investigated the impact of the community environment, as distinct from area deprivation, on cognition in later life. This study explores cross-sectional associations between cognitive impairment and dementia and environmental features at the community level in older people. Method: The postcodes of the 2424 participants in the year-10 interview of the Cognitive Function and Ageing Study in England were mapped into small area level geographical units (Lower-layer Super Output Areas) and linked to environmental data in government statistics. Multilevel logistic regression was conducted to investigate associations between cognitive impairment (defined as MMSE3 in GMS-AGECAT) and community level measurements including area deprivation, natural environment, land use mix and crime. Sensitivity analyses tested the impact of people moving residence within the last two years. Results: Higher levels of area deprivation and crime were not significantly associated with cognitive impairment and dementia after accounting for individual level factors. Living in areas with high land use mix was significantly associated with a nearly 60% reduced odds of dementia (OR: 0.4; 95% CI: 0.2, 0.8) after adjusting for individual level factors and area deprivation, but there was no linear trend for cognitive impairment. Increased odds of dementia (OR: 2.2, 95% CI: 1.2, 4.2) and cognitive impairment (OR: 1.4, 95% CI: 1.0, 2.0) were found in the highest quartile of natural environment availability. Findings were robust to exclusion of the recently relocated. Conclusion: Features of land use have complex associations with cognitive impairment and dementia. Further investigations should focus on environmental influences on cognition to inform health and social policies

Economic Evaluation Plan (EEP) for A Very Early Rehabilitation Trial (AVERT): An international trial to compare the costs and cost-effectiveness of commencing out of bed standing and walking training (very early mobilization) within 24 h of stroke onset with usual stroke unit care

Rationale: A key objective of A Very Early Rehabilitation Trial is to determine if the intervention, very early mobilisation following stroke, is cost-effective. Resource use data were collected to enable an economic evaluation to be undertaken and a plan for the main economic analyses was written prior to the completion of follow up data collection. Aim and hypothesis To report methods used to collect resource use data, pre-specify the main economic evaluation analyses and report other intended exploratory analyses of resource use data. Sample size estimates: Recruitment to the trial has been completed. A total of 2,104 participants from 56 stroke units across three geographic regions participated in the trial. Methods and design: Resource use data were collected prospectively alongside the trial using standardised tools. The primary economic evaluation method is a cost-effectiveness analysis to compare resource use over 12 months with health outcomes of the intervention measured against a usual care comparator. A cost-utility analysis is also intended. Study outcome: The primary outcome in the cost-effectiveness analysis will be favourable outcome (modified Rankin Scale score 0-2) at 12 months. Cost-utility analysis will use health-related quality of life, reported as quality-adjusted life years gained over a 12 month period, as measured by the modified Rankin Scale and the Assessment of Quality of Life. Discussion: Outcomes of the economic evaluation analysis will inform the cost-effectiveness of very early mobilisation following stroke when compared to usual care. The exploratory analysis will report patterns of resource use in the first year following stroke

Heat shock protein 27 is a potential indicator for response to YangZheng XiaoJi and chemotherapy agents in cancer cells

Heat shock protein 27 (HSP27) is a member of the heat shock protein family which has been linked to tumour progression and, most interestingly, to chemotherapy resistance in cancer patients. The present study examined the potential interplay between HSP27 and YangZheng XiaoJi, a traditional Chinese medicine used in cancer treatment. A range of cell lines from different tumour types including pancreatic, lung, gastric, colorectal, breast, prostate and ovarian cancer (both wild-type and resistant) were used. Levels and activation of HSP27 and its potential associated signalling pathways were evaluated by protein array and western blotting. Knockdown of HSP27 in cancer cells was achieved using siRNA. Localisation and co-localisation of HSP27 and other proteins were carried out by immunofluorescence. Cell growth and migration were evaluated in their response to a range of chemotherapeutic agents. The present study first identified, by way of protein array, that YangZheng XiaoJi was able to inhibit the phosphorylation of HSP27 protein in cancer cells. We further demonstrated that HSP27, which is co-localised with caspase-9, can be blocked from localising in focal adhesions and co-localising with caspase-9 by YangZheng XiaoJi. The study also demonstrated that YangZheng XiaoJi was able to sensitise cancer cells including those cells that were resistant to chemotherapy, to chemotherapeutic agents. Finally, knocking down HSP27 markedly reduced the migration of cancer cells and increased the sensitivity of cancer cells to the inhibitory effect on cellular migration by YangZheng XiaoJi. YangZheng XiaoJi can act as an agent in first sensitising cancer cells to chemotherapy and secondly to overcome, to some degree, chemoresistance when used in an appropriate fashion in patients who have active HSP2

Structural basis for DNA strand separation by a hexameric replicative helicase

Hexameric helicases are processive DNA unwinding machines but how they engage with a replication fork during unwinding is unknown. Using electron microscopy and single particle analysis we determined structures of the intact hexameric helicase E1 from papillomavirus and two complexes of E1 bound to a DNA replication fork end-labelled with protein tags. By labelling a DNA replication fork with streptavidin (dsDNA end) and Fab (5′ ssDNA) we located the positions of these labels on the helicase surface, showing that at least 10 bp of dsDNA enter the E1 helicase via a side tunnel. In the currently accepted ‘steric exclusion’ model for dsDNA unwinding, the active 3′ ssDNA strand is pulled through a central tunnel of the helicase motor domain as the dsDNA strands are wedged apart outside the protein assembly. Our structural observations together with nuclease footprinting assays indicate otherwise: strand separation is taking place inside E1 in a chamber above the helicase domain and the 5′ passive ssDNA strands exits the assembly through a separate tunnel opposite to the dsDNA entry point. Our data therefore suggest an alternative to the current general model for DNA unwinding by hexameric helicases

The clinical and biological implications of the focal adhesion kinase pathway in ShenLingLan mediated suppression of cellular migration of ovarian cancer cells

The incidence of ovarian cancer in the UK has increased by almost twenty percent since the 1970’s and the majority of cases are not diagnosed until the late stages, when metastasis is more likely to have occurred. Focal Adhesion Kinase (FAK) is one of the key protein complexes which is integral to cell migration and has been linked to a variety of solid tumours. ShenLingLan (SLDM) is a traditional herbal medicine which has been formulated for the treatment of solid tumours. This study aimed to establish the impact of SLDM on FAK in ovarian cancer cells in vitro and transcript levels of FAK in an ovarian cancer cohort. FAK and paxillin phosphorylation events stimulated by SLDM treatment were identified using a Kinexus™ antibody based protein array. The impact of SLDM on cell attachment and migration was evaluated using Electric cell-substrate impedance sensing (ECIS), whilst the changes in focal adhesion complex localisation were assessed using immunofluorescence. In an ovarian cancer cohort, differences in FAK and paxillin transcript levels were assessed against key clinical parameters such as differentiation, stage and survival outcome. SLDM treatment of ovarian cancer cells in vitro resulted in the suppression of FAK and paxillin phosphorylation at several sites, which appeared to manifest as decreased cellular attachment and migration in a range of immortalised ovarian cancer cells. Increased FAK and paxillin transcript copies were observed in high grade and poorly differentiated ovarian tumours as well as in tumours from patients with ovarian cancer related incidence. SLDM has a profound effect on the migratory and adhesive properties of ovarian cancer cells, potentially via inhibitory effects on the activation of the FAK pathway, which is aberrant in clinical ovarian cancers