SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury

Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or “concussion”. The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, “SNTF”, was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here, we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n = 18) were compared to age-matched controls (n = 16) from the Glasgow TBI archive. We also examined brains from an established model of mild TBI at 6, 48 and 72 h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis, and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labeling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co-localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI

Chronic traumatic encephalopathy — confusion and controversies

The term chronic traumatic encephalopathy (CTE) has recently entered public consciousness via media reports and even a Hollywood movie. However, in contrast to general impressions, the incidence of CTE is unknown, the clinical diagnostic criteria have not been agreed upon and the current neuropathological characterization of CTE is acknowledged as preliminary. Additionally, few studies have compared the pathologies of CTE with those of other neurodegenerative disorders or of age-matched controls. Consequently, disagreement continues about the neuropathological aspects that make CTE unique. Furthermore, CTE is widely considered to be a consequence of exposure to repeated head blows, but evidence suggests that a single moderate or severe traumatic brain injury can also induce progressive neuropathological changes. These unresolved aspects of CTE underlie disparate claims about its clinical and pathological features, leading to confusion among the public and health-care professionals alike

Deconstructing tumor heterogeneity: The stromal perspective

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportiv

Jet-induced ground effects on a parametric flat-plate model in hover

The jet-induced forces generated on short takeoff and vertical landing (STOVL) aircraft when in close proximity to the ground can have a significant effect on aircraft performance. Therefore, accurate predictions of these aerodynamic characteristics are highly desirable. Empirical procedures for estimating jet-induced forces during the vertical/short takeoff and landing (V/STOL) portions of the flight envelope are currently limited in accuracy. The jet-induced force data presented significantly add to the current STOVL configurations data base. Further development of empirical prediction methods for jet-induced forces, to provide more configuration diversity and improved overall accuracy, depends on the viability of this STOVL data base. The data base may also be used to validate computational fluid dynamics (CFD) analysis codes. The hover data obtained at the NASA Ames Jet Calibration and Hover Test (JCAHT) facility for a parametric flat-plate model is presented. The model tested was designed to allow variations in the planform aspect ratio, number of jets, nozzle shape, and jet location. There were 31 different planform/nozzle configurations tested. Each configuration had numerous pressure taps installed to measure the pressures on the undersurface of the model. All pressure data along with the balance jet-induced lift and pitching-moment increments are tabulated. For selected runs, pressure data are presented in the form of contour plots that show lines of constant pressure coefficient on the model undersurface. Nozzle-thrust calibrations and jet flow-pressure survey information are also provided

Effectiveness and cost-effectiveness of a universal parenting skills programme in deprived communities : multicentre randomised controlled trial

Objective: To evaluate the effectiveness and cost utility of a universally provided early years parenting programme. Design: Multicentre randomised controlled trial with cost-effectiveness analysis. Setting: Early years centres in four deprived areas of South Wales. Participants: Families with children aged between 2 and 4 years. 286 families were recruited and randomly allocated to the intervention or waiting list control. Intervention: The Family Links Nurturing Programme (FLNP), a 10-week course with weekly 2 h facilitated group sessions. Main outcome measures: Negative and supportive parenting, child and parental well-being and costs assessed before the intervention, following the course (3 months) and at 9 months using standardised measures. Results: There were no significant differences in primary or secondary outcomes between trial arms at 3 or 9 months. With ‘+’ indicating improvement, difference in change in negative parenting score at 9 months was +0.90 (95%CI −1.90 to 3.69); in supportive parenting, +0.17 (95%CI −0.61 to 0.94); and 12 of the 17 secondary outcomes showed a non-significant positive effect in the FLNP arm. Based on changes in parental well-being (SF-12), the cost per quality-adjusted life year (QALY) gained was estimated to be £34 913 (range 21 485–46 578) over 5 years and £18 954 (range 11 664–25 287) over 10 years. Probability of cost per QALY gained below £30 000 was 47% at 5 years and 57% at 10 years. Attendance was low: 34% of intervention families attended no sessions (n=48); only 47% completed the course (n=68). Also, 19% of control families attended a parenting programme before 9-month follow-up. Conclusions: Our trial has not found evidence of clinical or cost utility for the FLNP in a universal setting. However, low levels of exposure and contamination mean that uncertainty remains. Trial registration: The trial is registered with Current Controlled Trials ISRCTN13919732

The genomics of stem rust resistance in wheat

Background: The quality of the parent–child relationship has an important effect on a wide range of child outcomes. The evaluation of interventions to promote healthy parenting and family relationships is dependent on outcome measures which can quantify the quality of parent–child relationships. Between the Mothers’ Object Relations – Short Form (MORS-SF) scale for babies and the Child–parent Relationship Scale (C-PRS) there is an age gap where no validated scales are available. We report the development and testing of an adaptation of the MORS-SF; the MORS (Child) scale and its use in children from the age of 2 years to 4 years. This scale aims to capture the nature of the parent–child relationship in a form which is short enough to be used in population surveys and intervention evaluations. Methods: Construct and criterion validity, item salience and internal consistency were assessed in a sample of 166 parents of children aged 2–4 years old and compared with that of the C-PRS. The performance of the MORS (Child) as part of a composite measure with the HOME inventory was compared with that of the C-PRS using data collected in a randomised controlled trial and the national evaluation of Sure Start. Results: MORS (Child) performed well in children aged 2–4 with high construct and criterion validity, item salience and internal consistency. One item in the C-PRS failed to load on either subscale and parents found this scale slightly more difficult to complete than the MORS (Child). The two measures performed very similarly in a factor analysis with the HOME inventory producing almost identical loadings. Conclusions: Adapting the MORS-SF for children aged 2–4 years old produces a scale to assess parent–child relationships that is easy to use and outperforms the more commonly used C-PRS in several respects

Quantum Conductance Oscillations in Metal/Molecule/Metal Switches at Room Temperature

Conductance switching has been reported in many molecular junction devices, but in most cases has not been convincingly explained. We investigate conductance switching in Pt/stearic acid monolayer/Ti devices using pressure-modulated conductance microscopy. For devices with conductance G>>G_Q or G<<G_Q, where GQ=2e^2/h is the conductance quantum, pressure-induced conductance peaks <30 nm in diameter are observed, indicating the formation of nanoscale conducting pathways between the electrodes. For devices with G~ 1- 2 G_Q, in addition to conductance peaks we also observed conductance dips and oscillations in response to localized pressure. These results can be modeled by considering interfering electron waves along a quantum conductance channel between two partially transmitting electrode surfaces. Our findings underscore the possible use of these devices as atomic-scale switches

Modelling ultrasound-induced mild hyperthermia of hyperplasia in vascular grafts

<p>Abstract</p> <p>Background</p> <p>Expanded polytetrafluoroethylene (ePTFE) vascular grafts frequently develop occlusive neointimal hyperplasia as a result of myofibroblast over-growth, leading to graft failure. ePTFE exhibits higher ultrasound attenuation than native soft tissues. We modelled the selective absorption of ultrasound by ePTFE, and explored the feasibility of preventing hyperplasia in ePTFE grafts by ultrasound heating. Specifically, we simulated the temperature profiles of implanted grafts and nearby soft tissues and blood under ultrasound exposure. The goal was to determine whether ultrasound exposure of an ePTFE graft can generate temperatures sufficient to prevent cell growth on the graft without damaging nearby soft tissues and blood.</p> <p>Methods</p> <p>Ultrasound beams from two transducers (1.5 and 3.2 MHz) were simulated in two graft/tissue models, with and without an intra-graft cellular layer mimicking hyperplasia, using the finite-difference time-domain (FDTD) method. The resulting power deposition patterns were used as a heat source for the Pennes bioheat equation in a COMSOL^®Multiphysics heat transfer model. 50°C is known to cause cell death and therefore the transducer powers were adjusted to produce a 13°C temperature rise from 37°C in the ePTFE.</p> <p>Results</p> <p>Simulations showed that both the frequency of the transducers and the presence of hyperplasia significantly affect the power deposition patterns and subsequent temperature profiles on the grafts and nearby tissues. While neither transducer significantly raised the temperature of the blood, the 1.5-MHz transducer was less focused and heated larger volumes of the graft and nearby soft tissues than the 3.2-MHz transducer. The presence of hyperplasia had little effect on the blood's temperature, but further increased the temperature of the graft and nearby soft tissues in response to either transducer. Skin cooling and blood flow play a significant role in preventing overheating of the native tissues.</p> <p>Conclusions</p> <p>Modelling shows that ultrasound can selectively heat ePTFE grafts and produce temperatures that cause cell death on the graft. The temperature increase in blood is negligible and that in the adjacent soft tissues may be minimized by skin cooling and using appropriate transducers. Therefore, ultrasound heating may have the potential to reduce neointimal hyperplasia and failure of ePTFE vascular grafts.</p

Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players

Chronic traumatic encephalopathy (CTE) is reported at high prevalence in selected autopsy case series of former contact sports athletes. Nevertheless, the contribution of CTE pathology to clinical presentation and its interaction with co-morbid neurodegenerative pathologies remain unclear. To address these issues, we performed comprehensive neuropathology assessments on the brains of former athletes with dementia and considered these findings together with detailed clinical histories to derive an integrated clinicopathological diagnosis for each case. Consecutive, autopsy-acquired brains from former soccer and rugby players with dementia were assessed for neurodegenerative pathologies using established and preliminary consensus protocols. Thereafter, next of kin interviews were conducted to obtain detailed accounts of the patient’s clinical presentation and course of disease to inform a final, integrated clinicopathological diagnosis. Neuropathologic change consistent with CTE (CTE-NC) was confirmed in five of seven former soccer and three of four former rugby players’ brains, invariably in combination with mixed, often multiple neurodegenerative pathologies. However, in just three cases was the integrated dementia diagnosis consistent with CTE, the remainder having alternate diagnoses, with the most frequent integrated diagnosis Alzheimer’s disease (AD) (four cases; one as mixed AD and vascular dementia). This consecutive autopsy series identifies neuropathologic change consistent with preliminary diagnostic criteria for CTE (CTE-NC) in a high proportion of former soccer and rugby players dying with dementia. However, in the majority, CTE-NC appears as a co-morbidity rather than the primary, dementia causing pathology. As such, we suggest that while CTE-NC might be common in former athletes with dementia, in many cases its clinical significance remains uncertain

Evaluation of the effectiveness and cost-effectiveness of Families for Health V2 for the treatment of childhood obesity : study protocol for a randomized controlled trial

Background: Effective programs to help children manage their weight are required. Families for Health focuses on a parenting approach, designed to help parents develop their parenting skills to support lifestyle change within the family. Families for Health V1 showed sustained reductions in overweight after 2 years in a pilot evaluation, but lacks a randomized controlled trial (RCT) evidence base. Methods/design: This is a multi-center, investigator-blind RCT, with parallel economic evaluation, with a 12-month follow-up. The trial will recruit 120 families with at least one child aged 6 to 11 years who is overweight (≥91st centile BMI) or obese (≥98th centile BMI) from three localities and assigned randomly to Families for Health V2 (60 families) or the usual care control (60 families) groups. Randomization will be stratified by locality (Coventry, Warwickshire, Wolverhampton). Families for Health V2 is a family-based intervention run in a community venue. Parents/carers and children attend parallel groups for 2.5 hours weekly for 10 weeks. The usual care arm will be the usual support provided within each NHS locality. A mixed-methods evaluation will be carried out. Child and parent participants will be assessed at home visits at baseline, 3-month (post-treatment) and 12-month follow-up. The primary outcome measure is the change in the children’s BMI z-scores at 12 months from the baseline. Secondary outcome measures include changes in the children’s waist circumference, percentage body fat, physical activity, fruit/vegetable consumption and quality of life. The parents’ BMI and mental well-being, family eating/activity, parent–child relationships and parenting style will also be assessed. Economic components will encompass the measurement and valuation of service utilization, including the costs of running Families for Health and usual care, and the EuroQol EQ-5D health outcomes. Cost-effectiveness will be expressed in terms of incremental cost per quality-adjusted life year gained. A de novo decision-analytic model will estimate the lifetime cost-effectiveness of the Families for Health program. Process evaluation will document recruitment, attendance and drop-out rates, and the fidelity of Families for Health delivery. Interviews with up to 24 parents and children from each arm will investigate perceptions and changes made. Discussion: This paper describes our protocol to assess the effectiveness and cost-effectiveness of a parenting approach for managing childhood obesity and presents challenges to implementation. Trial registration: Current Controlled Trials ISRCTN4503220