Diffuse axonal injury predicts neurodegeneration after moderate-severe traumatic brain injury

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials

Diffuse axonal injury predicts neurodegeneration after moderate–severe traumatic brain injury

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer’s disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate–severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials

The effect of blast-furnace slag particle size on the hydration of slag-Portland cement grouts at elevated temperatures

The UK nuclear industry has historically used a unique specification of cement powder that differs from construction industry requirements. However, the slags that complied with this specification have become unavailable. The material now used to meet the requirements of the specification is a blend of standard construction industry ground granulated blast-furnace slag (GGBS), which has high fineness, with Calumite which is a coarser slag powder. Both materials have very similar chemical compositions, and the main reason for blending is to control the particle size distribution (PSD) to replicate the performance of the previous supply. The effect of changing the PSD on the performance properties of the cement paste was investigated. Isothermal conduction calorimetry at elevated temperatures was carried out to monitor the heat of hydration; it was found that the peak heat and total heat evolution increased with an increase in GGBS content. It was also found that Calumite contributes very little to the hydration reaction and thus behaves similarly to an inert filler. As the GGBS content was decreased, the fluidity of the pastes increased up to a certain point, but decreased again for systems dominated by very coarse particles, indicating that there is an optimum balance between the finer and coarser slag particles within this cementing system

Process-related patterns in dioxin emissions: a simplified assessment procedure applied to coke combustion in sinter plant

Analyses for dioxins present in the windlegs of sinter plant using coke breeze as fuel which were carried out originally to monitor the 17 targeted isomers have been re-examined in order to establish the variation in isomer profiles with location of the sampling point relative to the beginning of the sinter strand. The analysis has been carried out using peak height as a measure of isomer abundance to allow assessment of a large number of peaks reasonably rapidly. It is found that the isomer profiles of the tetra- to heptachlorodibenzofurans, which dominate sinter plant emissions in the exhaust gases from the majority of the bed are similar. However, analysis shows that whilst some isomers contribute a similar percentage of the isomer group at the beginning of the strand, there are more, which vary significantly from the mean. Ways in which this localised difference in isomer distribution could arise are discussed

Distinct patterns of neurodegeneration after TBI and in Alzheimer's disease

Introduction Traumatic brain injury (TBI) is a dementia risk factor, with Alzheimer's disease (AD) more common following injury. Patterns of neurodegeneration produced by TBI can be compared to AD and aging using volumetric MRI. Methods A total of 55 patients after moderate to severe TBI (median age 40), 45 with AD (median age 69), and 61 healthy volunteers underwent magnetic resonance imaging over 2 years. Atrophy patterns were compared. Results AD patients had markedly lower baseline volumes. TBI was associated with increased white matter (WM) atrophy, particularly involving corticospinal tracts and callosum, whereas AD rates were increased across white and gray matter (GM). Subcortical WM loss was shared in AD/TBI, but deep WM atrophy was TBI-specific and cortical atrophy AD-specific. Post-TBI atrophy patterns were distinct from aging, which resembled AD. Discussion Post-traumatic neurodegeneration 1.9–4.0 years (median) following moderate-severe TBI is distinct from aging/AD, predominantly involving central WM. This likely reflects distributions of axonal injury, a neurodegeneration trigger. Highlights We compared patterns of brain atrophy longitudinally after moderate to severe TBI in late-onset AD and healthy aging. Patients after TBI had abnormal brain atrophy involving the corpus callosum and other WM tracts, including corticospinal tracts, in a pattern that was specific and distinct from AD and aging. This pattern is reminiscent of axonal injury following TBI, and atrophy rates were predicted by the extent of axonal injury on diffusion tensor imaging, supporting a relationship between early axonal damage and chronic neurodegeneration

An Exercise in Reverse Engineering for Safety-Critical Systems: An Experience for the Classroom

Since the Y2K crisis, reverse engineering has become a major area of work in industrial software application development, but lacks emphasis in US academia. This issue is exemplified by the high demand for software systems in new and expanding software application areas, which has resulted in systems being implemented before the requirements and design phases have been completed. Towards the maintenance of such systems, it is necessary to conducted reverse engineering for the derivation of software documentation for requirements and high-level and low-level design. When this scenario exists in the domain of safety-critical system, particularly in the aviation industry, reverse engineering takes on greater value because such software systems have to undergo development regulations and certification restrictions. This work reports on the pedagogical revelations gained from conducting reverse engineering on a software system that was developed and deployed for use in managing the assignment of commercial aircrafts to airport terminal gates. The software system incorporated genetic algorithms solutions and was implemented on a high-speed multi-processor system. The reverse engineering methodology applied was based on the RTCA DO-178C Software Considerations in Airborne Systems and Equipment Certification specification for onboard avionic software systems

Traumatic brain injury: a comparison of diffusion and volumetric magnetic resonance imaging measures

Cognitive impairment after traumatic brain injury remains hard to predict. This is partly because axonal injury, which is of fundamental importance, is difficult to measure clinically. Advances in MRI allow axonal injury to be detected after traumatic brain injury, but the most sensitive approach is unclear. Here, we compare the performance of diffusion tensor imaging, neurite orientation dispersion and density-imaging and volumetric measures of brain atrophy in the identification of white-matter abnormalities after traumatic brain injury. Thirty patients with moderate-severe traumatic brain injury in the chronic phase and 20 age-matched controls had T1-weighted and diffusion MRI. Neuropsychological tests of processing speed, executive functioning and memory were used to detect cognitive impairment. Extensive abnormalities in neurite density index and orientation dispersion index were observed, with distinct spatial patterns. Fractional anisotropy and mean diffusivity also indicated widespread abnormalities of white-matter structure. Neurite density index was significantly correlated with processing speed. Slower processing speed was also related to higher mean diffusivity in the corticospinal tracts. Lower white-matter volumes were seen after brain injury with greater effect sizes compared to diffusion metrics; however, volume was not sensitive to changes in cognitive performance. Volume was the most sensitive at detecting change between groups but was not specific for determining relationships with cognition. Abnormalities in fractional anisotropy and mean diffusivity were the most sensitive diffusion measures; however, neurite density index and orientation dispersion index may be more spatially specific. Lower neurite density index may be a useful metric for examining slower processing speed

Alginate inhibits iron absorption from ferrous gluconate in a randomized controlled trial and reduces iron uptake into Caco-2 cells

Previous in vitro results indicated that alginate beads might be a useful vehicle for food iron fortification. A human study was undertaken to test the hypothesis that alginate enhances iron absorption. A randomised, single blinded, cross-over trial was carried out in which iron absorption was measured from serum iron appearance after a test meal. Overnight-fasted volunteers (n=15) were given a test meal of 200g cola-flavoured jelly plus 21 mg iron as ferrous gluconate, either in alginate beads mixed into the jelly or in a capsule. Iron absorption was lower from the alginate beads than from ferrous gluconate (8.5% and 12.6% respectively, p=0.003). Sub-group B (n=9) consumed the test meals together with 600 mg calcium to determine whether alginate modified the inhibitory effect of calcium. Calcium reduced iron absorption from ferrous gluconate by 51%, from 11.5% to 5.6% (p=0.014), and from alginate beads by 37%, from 8.3% to 5.2% (p=0.009). In vitro studies using Caco-2 cells were designed to explore the reasons for the difference between the previous in vitro findings and the human study; confirmed the inhibitory effect of alginate. Beads similar to those used in the human study were subjected to simulated gastrointestinal digestion, with and without cola jelly, and the digestate applied to Caco-2 cells. Both alginate and cola jelly significantly reduced iron uptake into the cells, by 34% (p=0.009) and 35% (p=0.003) respectively. The combination of cola jelly and calcium produced a very low ferritin response, 16.5% (p<0.001) of that observed with ferrous gluconate alone. The results of these studies demonstrate that alginate beads are not a useful delivery system for soluble salts of iron for the purpose of food fortification

Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function

Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (P = 0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered

Effectiveness of UK optometric enhanced eye care services: a realist review of the literature

PURPOSE: UK demographic and legislative changes combined with increasing burdens on National Health Service manpower and budgets have led to extended roles for community optometrists providing locally-commissioned enhanced optometric services (EOS). This realist review's objectives were to develop programme theories that implicitly or explicitly explain quality outcomes for eye care provided by optometrists via EOS and to test these theories by investigating the effectiveness of services for cataract, glaucoma, and primary eye care. METHODS: The review protocol was published on PROSPERO, and RAMESES publication standards were followed. Programme theories were formulated via scoping literature searches and expert consultation. The searching process involved all relevant electronic databases and grey literature, without restrictions on study design. Data synthesis focussed on questioning the integrity of each theory by considering supportive and refuting evidence from the source literature. RESULTS: Good evidence exists for cataract, glaucoma and primary eye care EOS that: with appropriate training, accredited optometrists manage patients commensurate with usual care standards; genuine partnerships can exist between community and hospital providers for cataract and glaucoma EOS; patient satisfaction with all three types of service is high; cost-effectiveness of services is unproven for cataract and primary eye care, while glaucoma EOS cost-effectiveness depends on service type; contextual factors may influence service success. CONCLUSIONS: The EOS reviewed are clinically effective and provide patient satisfaction but limited data is available on cost-effectiveness