Genetic Risk as a Marker of Amyloid-β and Tau Burden in Cerebrospinal Fluid.

BACKGROUND: The search for a biomarker of Alzheimer's disease (AD) pathology (amyloid-β (Aβ) and tau) is ongoing, with the best markers currently being measurements of Aβ and tau in cerebrospinal fluid (CSF) and via positron emission tomography (PET) scanning. These methods are relatively invasive, costly, and often have high screening failure rates. Consequently, research is aiming to elucidate blood biomarkers of Aβ and tau. OBJECTIVE: This study aims to investigate a case/control polygenic risk score (PGRS) as a marker of tau and investigate blood markers of a combined Aβ and tau outcome for the first time. A sub-study also considers plasma tau as markers of Aβ and tau pathology in CSF. METHODS: We used data from the EDAR*, DESCRIPA**, and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts in a logistic regression analysis to investigate blood markers of Aβ and tau in CSF. In particular, we investigated the extent to which a case/control PGRS is predictive of CSF tau, CSF amyloid, and a combined amyloid and tau outcome. The predictive ability of models was compared to that of age, gender, and APOE genotype ('basic model'). RESULTS: In EDAR and DESCRIPA test data, inclusion of a case/control PGRS was no more predictive of Aβ, and a combined Aβ and tau endpoint than the basic models (accuracies of 66.0%, and 73.3% respectively). The tau model saw a small increase in accuracy compared to basic models (59.6%). ADNI 2 test data also showed a slight increase in accuracy for the Aβ model when compared to the basic models (61.4%). CONCLUSION: We see some evidence that a case/control PGRS is marginally more predictive of Aβ and tau pathology than the basic models. The search for predictive factors of Aβ and tau pathologies, above and beyond demographic information, is still ongoing. Better understanding of AD risk alleles, development of more sensitive assays, and studies of larger sample size are three avenues that may provide such factors. However, the clinical utility of possible predictors of brain Aβ and tau pathologies must also be investigated.*'Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response'**'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease'.Multiple funders listed on paper

Circulating Proteomic Signatures of Chronological Age

To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10−46) and pleiotrophin (0.012 [0.005], p = 3.88 × 10−41). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10−5). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and agin

Aboriginal-mainstream partnerships: Exploring the challenges and enhancers of a collaborative service arrangement for Aboriginal clients with substance use issues

Background: Partnerships between different health services are integral to addressing the complex health needs of vulnerable populations. In Australia, partnerships between Aboriginal community controlled and mainstream services can extend health care options and improve the cultural safety of services. However, although government funding supports such collaborations, many factors can cause these arrangements to be tenuous, impacting the quality of health care received. Research was undertaken to explore the challenges and enhancers of a government initiated service partnership between an Aboriginal Community Controlled alcohol and drug service and three mainstream alcohol rehabilitation and support services. Methods. Sixteen staff including senior managers (n=5), clinical team leaders (n=5) and counsellors (n=6) from the four services were purposively recruited and interviewed. Interviews were semi-structured and explored staff experience of the partnership including the client intake and referral process, shared client care, inter-service communication and ways of working. Results & discussion. Communication issues, partner unfamiliarity, 'mainstreaming' of Aboriginal funding, divergent views regarding staff competencies, client referral issues, staff turnover and different ways of working emerged as issues, emphasizing the challenges of working with a population with complex issues in a persistent climate of limited resourcing. Factors enhancing the partnership included adding a richness and diversity to treatment possibilities and opportunities to explore different, more culturally appropriate ways of working. Conclusion: While the literature strongly advises partnerships be suitably mature before commencing service delivery, the reality of funding cycles may require partnerships become operational before relationships are adequately consolidated. Allowing sufficient time and funding for both the operation and relational aspects of a partnership is critical, with support for partners to regularly meet and workshop arrangements. Documentation that makes clear and embeds working arrangements between partners is important to ameliorate many of the issues that can arise. Given the historical undercurrents, flexible approaches are required to focus on strengths that contribute to progress, even if incremental, rather than on weaknesses which can undermine efforts. This research offers important lessons to assist other services collaborating in post-colonial settings to offer treatment pathways for vulnerable populations. © 2013 Taylor et al.; licensee BioMed Central Ltd

Polarized secretion of Leukemia Inhibitory Factor

<p>Abstract</p> <p>Background</p> <p>The direction of cytokine secretion from polarized cells determines the cytokine's cellular targets. Leukemia inhibitory factor (LIF) belongs to the interleukin-6 (IL-6) family of cytokines and signals through LIFR/gp130. Three factors which may regulate the direction of LIF secretion were studied: the site of stimulation, signal peptides, and expression levels. Stimulation with IL-1β is known to promote IL-6 secretion from the stimulated membrane (apical or basolateral) in the human intestinal epithelial cell line Caco-2. Since LIF is related to IL-6, LIF secretion was also tested in Caco-2 following IL-1β stimulation. Signal peptides may influence the trafficking of LIF. Two isoforms of murine LIF, LIF-M and LIF-D, encode different signal peptides which have been associated with different locations of the mature protein in fibroblasts. To determine the effect of the signal peptides on LIF secretion, secretion levels were compared in Madin-Darby canine kidney (MDCK) clones which expressed murine LIF-M or LIF-D or human LIF under the control of an inducible promoter. Low and high levels of LIF expression were also compared since saturation of the apical or basolateral route would reveal specific transporters for LIF.</p> <p>Results</p> <p>When Caco-2 was grown on permeable supports, LIF was secreted constitutively with around 40% secreted into the apical chamber. Stimulation with IL-1β increased LIF production. After treating the apical surface with IL-1β, the percentage secreted apically remained similar to the untreated, whereas, when the cells were stimulated at the basolateral surface only 20% was secreted apically. In MDCK cells, an endogenous LIF-like protein was detected entirely in the apical compartment. The two mLIF isoforms showed no difference in their secretion patterns in MDCK. Interestingly, about 70% of murine and human LIF was secreted apically from MDCK over a 400-fold range of expression levels within clones and a 200,000-fold range across clones.</p> <p>Conclusion</p> <p>The site of stimulation affected the polarity of LIF secretion, while, signal peptides and expression levels did not. Exogenous LIF is transported in MDCK without readily saturated steps.</p

Acyloxylation of Cyclic Enones: Synthesis of Densely Oxygenated Guaianolides

The α′-acyloxylation of cyclic enones with linear carboxylic acids is described. The reaction is promoted by KMnO4 in the presence of a carboxylic acid and its corresponding carboxylic anhydride. The optimization of the reaction has been carried out using the statistical methodology known as design of experiments. The optimized reaction conditions have been evaluated in terms of substrate scope and compatibility with different functional groups. The methodology has been applied to the synthesis of densely oxygenated guaianes and guaianolides

Circulating Proteomic Signatures of Chronological Age.

To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 × 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging

Portrait of cadet, E. N. C. Snow

This is a circa 1863 portrait of cadet E. N. C. Snow, a University of Alabama class of 1865 student

Community development through partnership: Promoting health in an urban indigenous community in New Zealand.

Abstract Indigenous people who have been dispossessed of their lands and resources bear a disproportionate burden of health problems. Programmes aimed at improving their health status must operate within the context of colonisation history and the contemporary cultural renaissance whereby indigenous populations are asserting their rights to self-determination. Community development strategies incorporating empowerment as both means and end are consistent with the aspirations of the renaissance and re¯ect the principles of the Ottawa Charter for Health Promotion. This paper describes a formative and process evaluation of a community development partnership for health promotion between a health group and an urban Maori community in New Zealand. Key issues encountered related to trust, prioritisation of health, and appropriate research paradigms. Most signi®cant among these was trust, or more speci®cally, distrust among Maori engendered by historical and contemporaneous experiences of contact with Europeans. Ultimately, the partnership achieved what it set out to do when the Maori partners took over the running of their own health groups and health programme. Building upon a detailed literature review and data from the evaluation, the paper oers a list of recommended procedures for the development of partnerships, applicable to health and other domains. Recommendations encompass preparatory steps, the formation of a partnership committee, programme planning and development, and the appointment of a community-based liaison worker. A conclusion of the research and premise underpinning the recommendations is that devolution of power is a key aspect of organisational process underlying successful partnerships involving professional groups and indigenous people.