A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status

Open Access ArticleBACKGROUND: Diagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health. RESULTS: One hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83-0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is 'up-regulated' in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case-control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA 'disease signature', the healthy ageing RNA classifier is diagnostic for AD. CONCLUSIONS: We identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.European CommissionAlzheimer’s Research UKJohn and Lucille van Geest FoundationNational Institute for Health Research (NIHR)European Medical Information Framework (EMIF)Medical Research Council (MRC)Wallenberg FoundationKarolinska InstitutetSwedish Medical Research CouncilSwedish Society for Medical Research (SSMF

Tumor heterogeneity in neoplasms of breast, colon, and skin

<p>Abstract</p> <p>Background</p> <p>Different cell subpopulations in a single tumor may show diverse capacities for growth, differentiation, metastasis formation, and sensitivity to treatments. Thus, heterogeneity is an important feature of tumors. However, due to limitations in experimental and analytical techniques, tumor heterogeneity has rarely been studied in detail.</p> <p>Presentation of the hypothesis</p> <p>Different tumor types have different heterogeneity patterns, thus heterogeneity could be a characteristic feature of a particular tumor type.</p> <p>Testing the hypothesis</p> <p>We applied our previously published mathematical heterogeneity model to decipher tumor heterogeneity through the analysis of genetic copy number aberrations revealed by array CGH data for tumors of three different tissues: breast, colon, and skin. The model estimates the number of subpopulations present in each tumor. The analysis confirms that different tumor types have different heterogeneity patterns. Computationally derived genomic copy number profiles from each subpopulation have also been analyzed and discussed with reference to the multiple hypothetical relationships between subpopulations in origin-related samples.</p> <p>Implications of the hypothesis</p> <p>Our observations imply that tumor heterogeneity could be seen as an independent parameter for determining the characteristics of tumors. In the context of more comprehensive usage of array CGH or genome sequencing in a clinical setting our study provides a new way to realize the full potential of tumor genetic analysis.</p

Strain-dependent host transcriptional responses to toxoplasma infection are largely conserved in mammalian and avian hosts

Toxoplasma gondii has a remarkable ability to infect an enormous variety of mammalian and avian species. Given this, it is surprising that three strains (Types I/II/III) account for the majority of isolates from Europe/North America. The selective pressures that have driven the emergence of these particular strains, however, remain enigmatic. We hypothesized that strain selection might be partially driven by adaptation of strains for mammalian versus avian hosts. To test this, we examine in vitro, strain-dependent host responses in fibroblasts of a representative avian host, the chicken (Gallus gallus). Using gene expression profiling of infected chicken embryonic fibroblasts and pathway analysis to assess host response, we show here that chicken cells respond with distinct transcriptional profiles upon infection with Type II versus III strains that are reminiscent of profiles observed in mammalian cells. To identify the parasite drivers of these differences, chicken fibroblasts were infected with individual F1 progeny of a Type II x III cross and host gene expression was assessed for each by microarray. QTL mapping of transcriptional differences suggested, and deletion strains confirmed, that, as in mammalian cells, the polymorphic rhoptry kinase ROP16 is the major driver of strain-specific responses. We originally hypothesized that comparing avian versus mammalian host response might reveal an inversion in parasite strain-dependent phenotypes; specifically, for polymorphic effectors like ROP16, we hypothesized that the allele with most activity in mammalian cells might be less active in avian cells. Instead, we found that activity of ROP16 alleles appears to be conserved across host species; moreover, additional parasite loci that were previously mapped for strain-specific effects on mammalian response showed similar strain-specific effects in chicken cells. These results indicate that if different hosts select for different parasite genotypes, the selection operates downstream of the signaling occurring during the beginning of the host's immune response. © 2011 Ong et al

Brain white matter structure and information processing speed in healthy older age

Cognitive decline, especially the slowing of information processing speed, is associated with normal ageing. This decline may be due to brain cortico-cortical disconnection caused by age-related white matter deterioration. We present results from a large, narrow age range cohort of generally healthy, community-dwelling subjects in their seventies who also had their cognitive ability tested in youth (age 11 years). We investigate associations between older age brain white matter structure, several measures of information processing speed and childhood cognitive ability in 581 subjects. Analysis of diffusion tensor MRI data using Tract-based Spatial Statistics (TBSS) showed that all measures of information processing speed, as well as a general speed factor composed from these tests (g(speed)), were significantly associated with fractional anisotropy (FA) across the white matter skeleton rather than in specific tracts. Cognitive ability measured at age 11 years was not associated with older age white matter FA, except for the g(speed)-independent components of several individual processing speed tests. These results indicate that quicker and more efficient information processing requires global connectivity in older age, and that associations between white matter FA and information processing speed (both individual test scores and g(speed)), unlike some other aspects of later life brain structure, are generally not accounted for by cognitive ability measured in youth

Converting simulated total dry matter to fresh marketable yield for field vegetables at a range of nitrogen supply levels

Simultaneous analysis of economic and environmental performance of horticultural crop production requires qualified assumptions on the effect of management options, and particularly of nitrogen (N) fertilisation, on the net returns of the farm. Dynamic soil-plant-environment simulation models for agro-ecosystems are frequently applied to predict crop yield, generally as dry matter per area, and the environmental impact of production. Economic analysis requires conversion of yields to fresh marketable weight, which is not easy to calculate for vegetables, since different species have different properties and special market requirements. Furthermore, the marketable part of many vegetables is dependent on N availability during growth, which may lead to complete crop failure under sub-optimal N supply in tightly calculated N fertiliser regimes or low-input systems. In this paper we present two methods for converting simulated total dry matter to marketable fresh matter yield for various vegetables and European growth conditions, taking into consideration the effect of N supply: (i) a regression based function for vegetables sold as bulk or bunching ware and (ii) a population approach for piecewise sold row crops. For both methods, to be used in the context of a dynamic simulation model, parameter values were compiled from a literature survey. Implemented in such a model, both algorithms were tested against experimental field data, yielding an Index of Agreement of 0.80 for the regression strategy and 0.90 for the population strategy. Furthermore, the population strategy was capable of reflecting rather well the effect of crop spacing on yield and the effect of N supply on product grading

Comparing urine samples and cervical swabs for Chlamydia testing in a female population by means of Strand Displacement Assay (SDA)

<p>Abstract</p> <p>Background</p> <p>There has been an increasing number of diagnosed cases of <it>Chlamydia trachomatis </it>in many countries, in particular among young people. The present study was based on a growing request to examine urine as a supplementary or primary specimen in screening for <it>Chlamydia trachomatis </it>in women, with the Becton Dickinson ProbeTec (BDPT) Strand Displacement Assay (SDA). Urine samples may be particularly important in screening young people who are asymptomatic.</p> <p>Methods</p> <p>A total of 603 women aged 15 and older were enrolled from the Sexually Transmitted Infection (STI) clinic at Haukeland University Hospital, Norway, in 2007. Only 31 women were older than 35 years. Cervical swabs and urine samples were tested with BDPT for all participants. In cases of discrepant test results from a given patient, both samples were retested by Cobas TaqManCT and a Polymerase Chain Reaction (PCR)-method (in-house). Prevalence of <it>C. trachomatis</it>, sensitivity, and specificity were estimated by latent class analysis using all test results available. Bootstrap BC confidence intervals (10 000 computations) were estimated for sensitivity and specificity, and their differences in cervix vs. urine tests.</p> <p>Results</p> <p>A total of 1809 specimens were collected from 603 patients. 80 women (13.4%) were positive for <it>C. trachomatis</it>. Among these, BDPT identified 72 and 73 as positive in cervix and urine samples, respectively. Of the 523 <it>C. trachomatis </it>negative women, BDPT identified 519 as negative based on cervical swabs, and 514 based on urine samples. Sensitivity for cervical swabs and urine samples with the BDPT were 89.0% (95% CI 78.8, 98.6) and 90.2% (95% CI 78.1, 95.5), respectively. The corresponding values for specificity were 99.2% (95% CI 98.3, 100) and 98.3% (95% CI 96.4, 100).</p> <p>Conclusions</p> <p>This study indicates that urine specimens are adequate for screening high-risk groups for <it>C. trachomatis </it>by the SDA method (BDPT). Such an approach may facilitate early detection and treatment of the target groups for screening, and be cost-effective for patients and the health services.</p

Solving Nonlinear Parabolic Equations by a Strongly Implicit Finite-Difference Scheme

We discuss the numerical solution of nonlinear parabolic partial differential equations, exhibiting finite speed of propagation, via a strongly implicit finite-difference scheme with formal truncation error $\mathcal{O}\left[(\Delta x)^2 + (\Delta t)^2 \right]$. Our application of interest is the spreading of viscous gravity currents in the study of which these type of differential equations arise. Viscous gravity currents are low Reynolds number (viscous forces dominate inertial forces) flow phenomena in which a dense, viscous fluid displaces a lighter (usually immiscible) fluid. The fluids may be confined by the sidewalls of a channel or propagate in an unconfined two-dimensional (or axisymmetric three-dimensional) geometry. Under the lubrication approximation, the mathematical description of the spreading of these fluids reduces to solving the so-called thin-film equation for the current's shape $h(x,t)$. To solve such nonlinear parabolic equations we propose a finite-difference scheme based on the Crank--Nicolson idea. We implement the scheme for problems involving a single spatial coordinate (i.e., two-dimensional, axisymmetric or spherically-symmetric three-dimensional currents) on an equispaced but staggered grid. We benchmark the scheme against analytical solutions and highlight its strong numerical stability by specifically considering the spreading of non-Newtonian power-law fluids in a variable-width confined channel-like geometry (a "Hele-Shaw cell") subject to a given mass conservation/balance constraint. We show that this constraint can be implemented by re-expressing it as nonlinear flux boundary conditions on the domain's endpoints. Then, we show numerically that the scheme achieves its full second-order accuracy in space and time. We also highlight through numerical simulations how the proposed scheme accurately respects the mass conservation/balance constraint.Comment: 36 pages, 9 figures, Springer book class; v2 includes improvements and corrections; to appear as a contribution in "Applied Wave Mathematics II

Oral health promotion: the economic benefits to the NHS of increased use of sugarfree gum in the UK.

INTRODUCTION: The effect of sugarfree gum (SFG) on the prevention of dental caries has been established for some time. With increased constraints placed on healthcare budgets, the importance of economic considerations in decision-making about oral health interventions has increased. The aim of this study was to demonstrate the potential cost savings in dental care associated with increased levels of SFG usage. METHODS: The analysis examined the amount of money which would hypothetically be saved if the UK 12-year-old population chewed more SFG. The number of sticks chewed per year and the caries risk reduction were modelled to create a dose response curve. The costs of tooth restoration, tooth extraction in primary care settings and under general anaesthetic were considered, and the effects of caries reduction on these costs calculated. RESULTS: If all members of the UK 12-year-old population chewed SFG frequently (twice a day), the potential cost savings for the cohort over the course of one year were estimated to range from £1.2 to £3.3 million and if they chewed three times a day, £8.2 million could be saved each year. Sensitivity analyses of the key parameters demonstrated that cost savings would still be likely to be observed even in scenarios with less significant increases in SFG use. CONCLUSION: This study shows that if levels of SFG usage in the teenage population in the UK could be increased, substantial cost savings might be achieved