Temporal changes in tau phosphorylation and related kinase and phosphatases following two models of traumatic brain injury

Published: November 09, 2018A history of traumatic brain injury (TBI) is linked to later neurodegeneration, with a key feature accumulation of hyperphosphorylated tau. Tau is a microtubule stability protein that undergoes frequent cycles of phosphorylation and dephosphorylation due to kinases and phosphatase activity. Hyperphosphorylation of tau destabilizes microtubules interrupting axonal transport, as well as promotes aggregation disturbing synaptic dysfunction. Aberrant phosphorylation of tau post-injury is thought to be a key player in later neurodegeneration. However, it is not known whether type of TBI- a single severe injury compared to repeated mild injuries- affects the time course of tau accumulation or the pattern of changes in kinases and phosphatases that facilitate this phosphorylation. To investigate, male Sprague Dawley rats were subjected to either a single moderate/severe or 3 mild TBIs spaced 5 days apart (rmTBI) utlising the Marmarou impact-acceleration model. Levels of cortical ptau (AT180, pSer422, oligomeric tau), pGSK3β, pCDK5, pERK1/2, pAkt and PP2Ac were evaluated at 24h, 7 days, 1 month and 3 months post-injury, with changes in tau phosphorylation confirmed via immunohistochemistry. A similar time course of AT180 tau phosphorylation was seen irrespective of the nature of the initiating insult, with a spike at 24h post-injury return to baseline and then increasing chronically at 3 months post-injury. In line with this, levels of PP2Ac were decreased at 24h and 3 months post-injury, indicating a potential loss of phosphatase activity. Interestingly, minimal changes were seen in the kinases examined, with a spike in phosphorylation of GSK3β, at the inhibitory Ser site, at 24h and 3 months following rmTBI, but not single moderate severe TBI, suggesting a possible protective effect only post-rmTBI. This study highlights that changes in levels of phosphorylated tau are similar, regardless of the initiating injury, and highlights the need to further understand the driving mechanisms behind this phenomenon.Lyndsey Collins-Praino, Daniel Gutschmidt, Jessica Sharkey, Alina Arulsamy, and Frances Corriga

Distribution of Major Health Risks: Findings from the Global Burden of Disease Study

BACKGROUND: Most analyses of risks to health focus on the total burden of their aggregate effects. The distribution of risk-factor-attributable disease burden, for example by age or exposure level, can inform the selection and targeting of specific interventions and programs, and increase cost-effectiveness. METHODS AND FINDINGS: For 26 selected risk factors, expert working groups conducted comprehensive reviews of data on risk-factor exposure and hazard for 14 epidemiological subregions of the world, by age and sex. Age-sex-subregion-population attributable fractions were estimated and applied to the mortality and burden of disease estimates from the World Health Organization Global Burden of Disease database. Where possible, exposure levels were assessed as continuous measures, or as multiple categories. The proportion of risk-factor-attributable burden in different population subgroups, defined by age, sex, and exposure level, was estimated. For major cardiovascular risk factors (blood pressure, cholesterol, tobacco use, fruit and vegetable intake, body mass index, and physical inactivity) 43%–61% of attributable disease burden occurred between the ages of 15 and 59 y, and 87% of alcohol-attributable burden occurred in this age group. Most of the disease burden for continuous risks occurred in those with only moderately raised levels, not among those with levels above commonly used cut-points, such as those with hypertension or obesity. Of all disease burden attributable to being underweight during childhood, 55% occurred among children 1–3 standard deviations below the reference population median, and the remainder occurred among severely malnourished children, who were three or more standard deviations below median. CONCLUSIONS: Many major global risks are widely spread in a population, rather than restricted to a minority. Population-based strategies that seek to shift the whole distribution of risk factors often have the potential to produce substantial reductions in disease burden

RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts. Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies

Christchurch Women's Hospital: Performance analysis of the base-isolation system during the series of Canterbury earthquakes 2011-2012

Live monitoring data and simple dynamic reduced-order models of the Christchurch Women’s Hospital (CWH) help explain the performance of the base isolation (BI) system of the hospital during the series of Canterbury earthquakes in 2011-2012. A Park-Wen-Ang hysteresis model is employed to simulate the performance of the BI system and results are compared to measured data recorded above the isolation layer and on the 6th story. Simplified single, two and three degree of freedom models (SDOF, 2DOF and 3DOF) show that the CWH structure did not behave as an isolated but as a fixed-base structure. Comparisons of accelerations and deflections between simulated and monitored data show a good match for isolation stiffness values of approximately two times of the value documented in the design specification and test protocol. Furthermore, an analysis of purely measured data revealed very little to no relative motion across the isolators for large events of moment magnitude scale (Mw) 5.8 and 6.0 that occurred within 3 hours of each other on December 23, 2011. One of the major findings is that the BI system during the seismic events on December 23, 2011 did not yield and that the superstructure performed as a fixed-base building, indicating a need to reevaluate the analysis, design and implementation of these structures