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OBJECTIVE: Ongoing studies are focused on adapting transcranial magnetic stimulation (TMS) for the treatment of major depressive disorder in adolescent humans. Most protocols in adolescent humans to date have delivered daily 10 Hz prefrontal stimulation with mixed results. Novel TMS dosing strategies such as accelerated TMS have recently been considered. There are knowledge gaps related to the potential clinical and pragmatic advantages of accelerated TMS. This pilot study compared the behavioral effects of a standard daily and accelerated low-intensity TMS (LI-TMS) protocol in an adolescent murine model of depression. METHODS: Male adolescent Sprague Dawley rats were placed in transparent plexiglass tubes for 2.5 hours daily for 13 days as part of a study to validate the chronic restraint stress (CRS) protocol. Rats subsequently received 10 minutes of active or sham 10 Hz LI-TMS daily for 2 weeks (standard) or three times daily for 1 week (accelerated). Behavior was assessed using the elevated plus maze and forced swim test (FST). Hippocampal neurogenesis was assessed by injection of the thymidine analogue 5-ethynyl-2′-deoxyuridine at the end of LI-TMS treatment (2 weeks standard, 1 week accelerated), followed by postmortem histological analysis. RESULTS: There were no significant differences in behavioral outcomes among animals receiving once-daily sham or active LI-TMS treatment. However, animals treated with accelerated LI-TMS demonstrated significant improvements in behavioral outcomes compared with sham treatment. Specifically, animals receiving active accelerated treatment showed greater latency to the first immobility behavior (p

Background. While upper body training has been effective for improving aerobic fitness and muscle strength after spinal cord injury (SCI), activity-based therapies intended to activate the paralyzed extremities have been reported to promote neurological improvement. Objective. To compare the effectiveness of intensive whole-body exercise compared with upper body exercise for people with chronic SCI. Methods. A parallel-group randomized controlled trial was conducted. Participants with a range of SCI levels and severity were randomized to either full-body exercise (FBE) or upper body exercise (UBE) groups (3 sessions per week over 12 weeks). FBE participants underwent locomotor training, functional electrical stimulation-assisted leg cycling, and trunk and lower extremity exercises, while UBE participants undertook upper body strength and aerobic fitness training only. The primary outcome measure was the American Spinal Injury Association (ASIA) motor score for upper and lower extremities. Adverse events were systematically recorded. Results. A total of 116 participants were enrolled and included in the primary analysis. The adjusted mean between-group difference was −0.04 (95% CI −1.12 to 1.04) for upper extremity motor scores, and 0.90 (95% CI −0.48 to 2.27) for lower extremity motor scores. There were 15 serious adverse events in UBE and 16 in FBE, but only one of these was definitely related to the experimental intervention (bilateral femoral condyle and tibial plateau subchondral fractures). No significant between-group difference was found for adverse events, or functional or behavioral variables. Conclusions. Full-body training did not lead to improved ASIA motor scores compared with upper body training in people with chronic SCI.

Objective: To conduct a per-protocol analysis on thigh muscle volume outcomes from the Spinal Cord Injury and Physical Activity (SCIPA) Switch-On Trial. Design: Secondary analysis from an assessor-blind randomized, controlled trial. Setting: Four acute/sub-acute hospitals in Australia and New Zealand. Participants: 24 adults (1 female) within four weeks of motor complete or incomplete spinal cord injury (SCI) Intervention: Functional electrical stimulation–assisted cycling (FESC) or passive cycling (PC) 4x/week for 12 weeks. Outcome Measures: Whole thigh and muscle group volumes calculated from manually segmented MR images. Results: 19/24 participants completed ≥ twelve weeks of the intervention. Five participants experienced hypertrophy (4 FESC; 1 PC) and eight attenuation of atrophy (20% (3 FESC; 3 PC). Mean (SD) change for FESC was −2.3% (25.3%) and PC was −14.0% (12.3%). After controlling for baseline muscle volumes, a strong significant correlation was found between mean weekly exercise frequency and quadriceps and hamstring volumes (r=6.25, P=0.006), regardless of mode. Average watts was highly correlated to quadriceps volumes only (r=5.92, P=0.01), while total number of sessions was strongly correlated with hamstring volumes only (r=5.91, P=0.01). Conclusion: This per-protocol analysis of FESC and PC early after SCI reports a partial response in 42% and a beneficial response in 25% of patients who completed 12 weeks intervention, regardless of mode. Strong correlations show a dose–response according to exercise frequency. Characteristics of non-responders are discussed to inform clinical decision-making.

Background After facial nerve injury and surgical repair in rats, recovery of vibrissal whisking is associated with a high proportion of mono-innervated neuro-muscular junctions (NMJs). Our earlier work with Sprague Dawley (SD)/Royal College of Surgeons (RCS) rats, which are blind and spontaneously restore NMJ-monoinnervation and whisking, showed correlations between functional recovery and increase of fibroblast growth factor-2 (FGF2) and brain-derived neurotrophic factor (BDNF) in denervated vibrissal muscles. Methods We used normally sighted rats (Wistar), in which NMJ-polyinnervation is highly correlated with poor whisking recovery, and injected the vibrissal muscle levator labii superioris (LLS) with combinations of BDNF, anti-BDNF, and FGF2 at different postoperative periods after facial nerve injury. Results Rats receiving anti-BDNF+FGF2 showed low NMJ-polyinnervation and best recovery of whisking amplitude. Conclusions Restoration of target reinnervation after peripheral nerve injury requires a complex mixture of trophic factors with a specific time course of availability for each of them.

Parkinson’s disease (PD) is a debilitating and incurable neurodegenerative disorder, characterized by nigrostriatal alpha-synuclein (αSyn) aggregates, dopaminergic neuronal death and motor impairme...

Nanoparticle drug delivery applications have predominantly focused on the entrapment and delivery of hydrophobic molecules with poor water solubility. However, benefits can also be obtained from nanoparticle-based delivery of hydrophilic therapeutics. This study reports on the development of a p(HEMA-ran-GMA)-based nanoparticle synthesized via a spontaneous water-in-oil inverse nanoemulsion to deliver doxorubicin, a water-soluble chemotherapeutic. High drug loading efficiency and sustained release of doxorubicin from Cy5-functionalized p(HEMA-ran-GMA) nanoparticles enabled effective inhibition of the MCF-7 human breast cancer derived cell line. Direct comparative analyses with a hydrophobic PGMA nanoparticle demonstrated enhanced capabilities of the p(HEMA-ran-GMA)-based nanoparticle in vitro. The results suggest that p(HEMA-ran-GMA)-based nanoparticles, which are better suited for hydrophilic drug loading and delivery, may have the potential for the improved therapeutic effect in vivo by enhanced permeation and retention of the nanoparticles by avoidance of off-site side effects of the chemotherapeutic.

The adsorption of serum proteins on the surface of nanoparticles (NPs) delivered into a biological environment has been known to alter NP surface properties and consequently their targeting efficiency. In this paper, we use random copolymer (p(HEMA- ran-GMA))-based NPs synthesized using 2-hydroxyethyl methacrylate (HEMA) and glycidyl methacrylate (GMA). We show that serum proteins bind to the NP and that functionalization with antibodies and peptides designed to facilitate NP passage across the blood-brain barrier (BBB) to bind specific cell types is ineffective. In particular, we use systematic in vitro and in vivo analyses to demonstrate that p(HEMA- ran-GMA) NPs functionalized with HIV-1 trans-activating transcriptor peptide (known to cross the BBB) and α neural/glial antigen 2 (NG2) (known for targeting oligodendrocyte precursor cells (OPCs)), individually and in combination, do not specifically target OPCs and are unable to cross the BBB, likely due to the serum protein binding to the NPs.

Following mild traumatic brain injury (mTBI), further mild impacts can exacerbate negative outcomes. To compare chronic damage and deficits following increasing numbers of repeated mTBIs, a closed-head weight-drop model of repeated mTBI was used to deliver 1, 2 or 3 mTBIs to adult female rats at 24 h intervals. Outcomes were assessed at 3 months following the first mTBI. No gross motor, sensory or reflex deficits were identified (p 0.05), consistent with current literature. Cognitive function assessed using a Morris water maze revealed chronic memory deficits following 1 and 2, but not 3 mTBI compared to shams (p ≤ 0.05). Oxidative damage to DNA was assessed immunohistochemically in the dentate hilus of the hippocampus and splenium of the corpus callosum; no changes were observed. IBA1-positive microglia were increased in size in the cortex following 1 mTBI and in the corpus callosum following 2 mTBI compared to shams (p ≤ 0.05); no changes were observed in the dentate hilus. Glial fibrillary acidic protein (GFAP)-positive astrocyte immunoreactivity was assessed in all three brain regions and no chronic changes were observed. Integrity of myelin ultrastructure in the corpus callosum was assessed using transmission electron microscopy. G ratio was decreased following 2 mTBIs compared to shams (p ≤ 0.05) at post hoc level only. The changing patterns of damage and deficits following increasing numbers of mTBI may reflect dynamic responses to small numbers of mTBIs or a conditioning effect such that increasing numbers of mTBIs do not necessarily result in worsening pathology. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Cover Image for this issue: doi: 10.1111/jnc.14508.

Computational biomechanics analysis of neurologic injuries has so far been focused on the brain. This has resulted in the development of industrially applied computational biomechanics models of the brain and various criteria (such as cumulative strain damage measure, CSDM and maximum principal strain, MPS) to determine the likelihood of brain injuries. In contrast, spinal cord injury (SCI) has attracted relatively little attention from the computational biomechanics research community. This study, addresses this gap by applying computational biomechanics analysis to predict deformations of the cervical spinal cord and the risk of SCI. To do this, a three-dimensional finite element model of the cervical spinal cord was built using data from the Visible Human Project and incorporated into a well-established finite element model of the human body for injury analysis, created by the Global Human Body Models Consortium (GHMBC). The model was applied to simulate well-documented low-speed whiplash-type experiments previously conducted on volunteers by the Japan Automobile Research Institute and University of Tsukuba. The results suggest that direct application of CSDM and MPS criteria and the related injury risk curves leads to overestimation of SCI risk.

Qualitative survey.Examine clinicians' perspectives on adherence to published evidence-based guidelines and clinician-perceived barriers, and facilitators to optimising inpatient bladder management within one Spinal Cord Injury (SCI) service.Surgical Hospital (acute care) and SCI Unit (sub-acute, rehabilitation) in Western Australia (WA).Clinicians reviewed an 'Evidence Matrix' summarising published clinical practice guidelines and recommendations for SCI bladder management. Focus groups examined the extent to which current practice adhered to recommendations and identified perceived barriers and facilitators to optimal management. Data were analysed thematically using a deductive approach.Current management closely mirrors published recommendations. Key facilitators included long-standing prioritisation of rapid progression from urethral indwelling (IDC) to a 6 hourly intermittent catheterisation (IC) protocol; regular competency audits of catheterisation technique; and a Spinal Urology Clinical Nurse Consultant (CNC) position. Barriers included limited resources/staffing; restricted access to Neuro-urology consultation; inter-disciplinary communication gaps; and delays in determining and implementing long-term bladder management.Inpatient SCI bladder care in WA closely emulates published evidence, although adherence at other sites may reveal different practices. Bladder management was found to have been facilitated by a strong culture of practice led by Neuro-urologists, informed by evidence and embraced by Senior Clinicians. Further reduction in duration of initial IDC, provision of early and ongoing Neuro-urology consultations as part of standard care, increased interdisciplinary communication and dedicated SCI Urology theatre lists would further optimise management.

The relationships between various parameters of tissue damage and subsequent functional recovery after spinal cord injury (SCI) are not well understood. Patients may regain micturition control and walking despite large postinjury medullar cavities. The objective of this study was to establish possible correlations between morphological findings and degree of functional recovery after spinal cord compression at vertebra Th8 in rats. Recovery of motor (Basso, Beattie, Bresnahan, foot-stepping angle, rump-height index, and ladder climbing), sensory (withdrawal latency), and bladder functions was analyzed at 1, 3, 6, 9, and 12 weeks post-SCI. Following perfusion fixation, spinal cord tissue encompassing the injury site was cut in longitudinal frontal sections. Lesion lengths, lesion volumes, and areas of perilesional neural tissue bridges were determined after staining with cresyl violet. The numbers of axons in these bridges were quantified after staining for class III β-tubulin. We found that it was not the area of the spared tissue bridges, which is routinely determined by magnetic resonance imaging (MRI), but the numbers of axons in them that correlated with functional recovery after SCI (Spearman’s ρ > 0.8; p

We examined spinal cord injury (SCI) catheterization practices in Australia to understand practice patterns and consistency with research evidence. A national facilitated discussion forum was held during the annual Australian and New Zealand Spinal Cord Society conference attended by 66 conference delegates. Initially, presentations were given on the latest laboratory research examining bladder changes following SCI; an overview of evidence-based recommendations indicating that intermittent catheterization is best practice; and results of a single-center practice audit that demonstrated substantial delay in transition between acute SCI and intermittent catheterization. The ensuing discussion covered current catheterization practices in both inpatient SCI units and the community and highlighted gaps between evidence and practice, with considerable variation in practice between centers and settings. Reported challenges to implementing best practice included social, economic, and resource factors. A disconnect between hospital and community practice was also identified as an important barrier to long-term uptake of intermittent catheterization following acute SCI. The discussion identified 3 proposed activities: (1) explore current practice and bladder health following SCI in greater depth across SCI units and in local communities through audits and standardized biochemical analysis; (2) determine the behavioral drivers of current practice; and (3) develop a knowledge translation strategy to better align practice with current clinical practice guidelines.

Background Following injury to the central nervous system, increased microglia, secretion of pro- and anti-inflammatory cytokines, and altered blood-brain barrier permeability, a hallmark of degeneration, are observed at and immediately adjacent to the injury site. However, few studies investigate how regions remote from the primary injury could also suffer from inflammation and secondary degeneration. Methods Adult female Piebald-Viral-Glaxo (PVG) rats underwent partial transection of the right optic nerve, with normal, age-matched, unoperated animals as controls. Perfusion-fixed brains and right optic nerves were harvested for immunohistochemical assessment of inflammatory markers and blood-brain barrier integrity; fresh-frozen brains were used for multiplex cytokine analysis. Results Immediately ventral to the optic nerve injury, immunointensity of both the pro-inflammatory biomarker inducible nitric oxide synthase (iNOS) and the anti-inflammatory biomarker arginase-1 (Arg1) increased at 7 days post-injury, with colocalization of iNOS and Arg1 immunoreactivity within individual cells. CD11b+ and CD45+ cells were increased 7 days post-injury, with altered BBB permeability still evident at this time. In the lower and middle optic tract and superior colliculus, IBA1+ resident microglia were first increased at 3 days; ED1+ and CD11b+ cells were first increased in the middle and upper tract and superior colliculus 7 days post-injury. Increased fibrinogen immunoreactivity indicative of altered BBB permeability was first observed in the contralateral upper tract at 3 days and middle tract at 7 days post-injury. Multiplex cytokine analysis of brain homogenates indicated significant increases in the pro-inflammatory cytokines, IL-2 and TNFα, and anti-inflammatory cytokine IL-10 1 day post-injury, decreasing to control levels at 3 days for TNFα and 7 days for IL-2. IL-10 was significantly elevated at 1 and 7 days post-injury with a dip at 3 days post-injury. Conclusions Partial injury to the optic nerve induces a complex remote inflammatory response, characterized by rapidly increased pro- and anti-inflammatory cytokines in brain homogenates, increased numbers of IBA1+ cells throughout the visual pathways, and increased CD11b+ and ED1+ inflammatory cells, particularly towards the synaptic terminals. BBB permeability can increase prior to inflammatory cell infiltration, dependent on the brain region.

Question: What is the effect of adding an intensive task-specific hand-training program involving functional electrical stimulation to a combination of usual care plus three 15-minute sessions per week of one-to-one hand therapy in people with sub-acute tetraplegia? Design: A parallel group, randomised, controlled trial. Participants were randomly assigned (1:1) via a computer-generated concealed block randomisation procedure to either a control or experimental intervention. Participants: Seventy people with C2 to T1 motor complete or incomplete tetraplegia within 6 months of injury. Participants were recruited from seven spinal units in Australia and New Zealand. Intervention: Experimental participants received intensive training for one hand. Intensive training consisted of training with an instrumented exercise workstation in conjunction with functional electrical stimulation for 1 hour per day, 5 days per week for 8 weeks. Both groups received usual care and 15minutes of one-to-one hand therapy three times per week without functional electrical stimulation. Outcome measures: The primary outcome was the modified Action Research Arm Test reflecting arm and hand function, which was assessed at the end of the intervention, that is, 11 weeks after randomisation. Secondary outcomes were measured at 11 and 26 weeks. Results: Sixty-six (94%) participants completed the post-intervention assessment and were included in the primary intention-to-treat analysis. The mean modified Action Research Arm Test score for experimental and control participants at the post-intervention assessment was 36.5 points (SD 16.0) and 33.2 points (SD 17.5), respectively, with an adjusted mean between-group difference of 0.9 points (95% CI –4.1 to 5.9). Conclusion: Adding an intensive task-specific hand-training program involving functional electrical stimulation to a combination of usual care plus three 15-minute sessions per week of one-to-one hand therapy does not improve hand function in people with sub-acute tetraplegia. Registration: Australian and New Zealand Trial Registry ACTRN12609000695202 and ClinicalTrials.gov NCT01086930. [Harvey LA, Dunlop SA, Churilov L, Galea MP, Spinal Cord Injury Physical Activity (SCIPA) Hands On Trial Collaborators (2016) Early intensive hand rehabilitation is not more effective than usual care plus one-to-one hand therapy in people with sub-acute spinal cord injury (‘Hands On'): a randomised trial. Journal of Physiotherapy 62: 88–95]

A retrospective audit of assessor accuracy using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) in three multicentre randomised controlled trials (SCIPA: Spinal Cord Injury and Physical Activity) spanning 2010–2014 with standards revised in 2011. To investigate assessor accuracy of neurological classification after spinal cord injury. Australia and New Zealand. ISNCSCI examinations were undertaken by trained clinicians prior to randomisation. Data were recorded manually and ISNCSCI worksheets circulated to panels, consensus reached and worksheets corrected. An audit team used a 2014 computerised ISNCSCI algorithm to check manual worksheets. A second audit team assessed whether the 2014 computerised algorithm accurately reflected pre- and post-2011 ISNCSCI standards. Of the 208 ISNCSCI worksheets, 24 were excluded. Of the remaining 184 worksheets, 47 (25.5%) were consistent with the 2014 computerised algorithm and 137 (74.5%) contained one or more errors. Errors were in motor (30.1%) or sensory (12.4%) levels, zone of partial preservation (24.0%), motor/sensory scoring (21.5%), ASIA Impairment Scale (AIS, 8.3%) and complete/incomplete classification (0.8%). Other difficulties included classification when anal contraction/sensation was omitted, incorrect neurological levels and violation of the ‘motor follows sensory rule in non-testable myotomes’ (7.4%). Panel errors comprised corrections that were incorrect or missed or incorrect changes to correct worksheets. Given inaccuracies in the manual ISNCSCI worksheets in this long-term clinical trial setting, continued training and a computerised algorithm are essential to ensure accurate scoring, scaling and classification of the ISNCSCI and confidence in clinical trials.

Introduction We previously have shown that manual stimulation (MS) of vibrissal muscles for 2 months after facial nerve injury in rats improves whisking and reduces motor end plate polyinnervation. Here, we seek to determine whether discontinuing or delaying MS after facial-facial anastomosis (FFA) leads to similar results. Methods Rats were subjected to FFA and received MS for (1) 4 months (early and continued), (2) the first but not the last 2 months (discontinued), or (3) the last 2 months (delayed). Intact animals and those not receiving MS (no MS) were also examined. Results Early and continued MS restored whisking amplitude to 43°, a value significantly higher compared with the discontinued, delayed, and no MS groups (32°, 24°, and 10°, respectively). Motor end plate polyinnervation occurred in all experimental groups but was significantly higher in the delayed group. Discussion Early and continued MS results in better recovery than when it is either discontinued or delayed. Muscle Nerve 57: 100-106, 2018.

Background Following spinal cord injury (SCI), exercise training provides a wide range of benefits and promotes activity-dependent synaptic plasticity. Whole body vibration (WBV) in SCI patients improves walking and spasticity as well as bone and muscle mass. However, little is known about the effects of timing or frequency of intervention. Objective To determine which WBV-onset improves locomotor and bladder functions and influences synaptic plasticity beneficially. Methods SCI was followed by WBV starting 1, 7, 14, 28 days after injury (WBV1, WBV7, etc.) and continued for 12 weeks. Intact animals and those receiving SCI but no WBV (No WBV), SCI plus WBV twice daily (2×WBV) and SCI followed by passive hindlimb flexion-extension (PFE) served as controls. Locomotor [BBB rating, foot stepping angle (FSA) and rump-height index (RHI)] as well as bladder function were determined at 1, 3, 6, 9, and 12 weeks. Following perfusion fixation at 12 weeks, lesion volume and immunofluorescence for astrogliosis (GFAP), microglia (IBA1) and synaptic vesicles (synaptophysin, SYN) were determined. Results Compared to the No WBV group, the WB7 and WBV14 groups showed significantly faster speeds of BBB score recovery though this effect was temporary. Considering RHI we detected a sustained improvement in the WBV14 and PFE groups. Bladder function was better in the WBV14, WBV28, 2×WBV and PFE groups. Synaptophysin levels improved in response to WBV7 and WBV14, but worsened after WBV28 in parallel to an increased IBA1 expression. Correlation- and principal components analysis revealed complex relationships between behavioural (BBB, FSA, RHI) and morphological (GFAP, IBA1, SYN) measurements. Conclusions WBV started 14 days after SCI provides the most benefit (RHI, bladder); starting at 1day after SCI provides no benefit and starting at 28 days may be detrimental. Increasing the intensity of WBV to twice daily did not provide additional benefit.

Background. Substantial skeletal muscle atrophy after spinal cord injury (SCI) carries significant repercussions for functional recovery and longer-term health. Objective. To compare the efficacy, safety, and feasibility of functional electrical stimulation–assisted cycling (FESC) and passive cycling (PC) to attenuate muscle atrophy after acute SCI. Methods. This multicenter, assessor-blinded phase I/II trial randomized participants at 4 weeks post-SCI to FESC or PC (4 sessions per week, 1 hour maximum per session, over 12 weeks). The primary outcome measure was mean maximum cross-sectional area (CSA) of thigh and calf muscles (magnetic resonance imaging), and secondary outcome measures comprised body composition (dual energy X-ray absorptiometry), anthropometry, quality of life, and adverse events (AEs). Results. Of 24 participants, 19 completed the 12-week trial (10 FESC, 9 PC, 18 male). Those participants completed >80% of training sessions (FESC, 83.5%; PC, 85.9%). No significant between-group difference in postintervention muscle CSA was found. No significant between-group difference was found for any other tissue, anthropometric parameter, or behavioral variable or AEs. Six participants experienced thigh hypertrophy (FESC = 3; PC = 3). Atrophy was attenuated (

Clinical trials evaluating early therapies after spinal cord injury (SCI) are challenging because of the absence of a rapid assessment. The aim of this study was to determine whether the severity and level of SCI could be established from a brief neurological assessment capable of being used in an emergency setting. A brief assessment called the SPinal Emergency Evaluation of Deficits (SPEED) was developed and retrospectively evaluated in a cohort of 118 patients with SCI. Foot motor and sensory function was used to indicate injury severity. C3 dermatome sensation, handgrip strength and location of spinal pain were used to indicate the level of injury. With regard to injury severity, a high proportion of patients (94%) with no foot movement at the time of injury were initially diagnosed as motor complete (American Spinal Injury Association Impairment Scale [AIS] grade A-B), whereas all patients with foot movement were identified as motor incomplete (AIS grade C-D). This was reflected by a good correlation (rs = 0.79) and agreement (κ = 0.85) between the SPEED motor score and the acute hospital assessment. With respect to injury level, the majority of cases with cervical SCI (92%) had no or weak handgrip at the time of paramedic assessment, whereas all cases with thoracolumbar SCI had a strong handgrip. The location of spinal pain was also in accordance with the level of spinal injury. The SPEED assessment appears capable of accurately determining the severity and level of cervical SCI in the first hours post-injury. A neurological assessment that can be performed rapidly after injury is important for clinical trials of early therapy and to identify patients most likely to benefit from intervention.

Retrospective audit.Examine factors associated with urinary tract infection (UTI), UTI incidence and impact on hospital length of stay (LOS) in new, inpatient adult traumatic spinal cord injury (SCI).Western Australian Hospitals managing SCI patients.Data on UTIs, bladder management and LOS were obtained from hospital databases and medical records over 26 months. Adherence to staff-administered intermittent catheterisation (staff-IC) was determined from fluid balance charts.Across the cohort (n = 70) UTI rate was 1.1 starts/100 days; UTI by multi-resistant organisms 0.1/100 days. Having ≥1 UTIs compared with none and longer duration of initial urethral indwelling catheterisation (IDC) were associated with longer LOS (p-values 0.001). For patients with ≥1 UTIs (n = 43/70), longer duration of initial IDC was associated with shorter time to first UTI (1 standard deviation longer [SD, 45.0 days], hazard ratio (HR): 0.7, 95% confidence interval [CI] 0.5-1.0, p-value 0.044). In turn, shorter time to first UTI was associated with higher UTI rate (1 SD shorter [30.7 days], rate ratio (RR): 1.32, 95%CI 1.0-1.7, p-value 0.039). During staff-IC periods (n = 38/70), protocols were followed (85.7% ≤ 6 h apart, 96.1% 8 h), but 26% of IC volumes exceeded 500 mL; occasional volumes 800 mL and interruptions requiring temporary IDC were associated with higher UTI rates the following week (odds ratios (ORs): 1.6, 95%CI 1.1-2.3, p-value 0.009; and 3.9, 95%CI 2.6-5.9, p-value 0.001 respectively).Reducing initial IDC duration and limiting staff-IC volumes could be investigated to possibly reduce inpatient UTIs and LOS.None.

There is a growing need for the development of nanoparticles, with imaging and drug delivery capabilities, to maintain cellular uptake but avoid protein attachment and recognition. In this study we have demonstrated that nanoparticles consisting of a poly(glycidyl methacrylate) (PGMA) core and a mixed brush architecture of methoxypoly(ethylene glycol) and poly(ethylenimine) (mPEG-PEI) on the surface can meet this need. Surface functionalization with PEI alone results in cellular uptake, but rapid protein attachment whereas PEG alone can avoid protein attachment but to the detriment of cellular uptake. A mixed copolymer brush of both PEI and mPEG provides the ideal balance.

Before using nanoparticles for therapeutic applications, it is necessary to comprehensively investigate nanoparticle effects, both in vitro and in vivo. In the associated research article [1] we generate multimodal polymeric nanoparticles functionalized with an antibody, that are designed to deliver an anti-oxidant to astrocytes. Here we provide additional data demonstrating the effects of the nanoparticle preparations on an indicator of oxidative stress in an immortalized Müller cell line in vitro. We provide data demonstrating the use of nanoscale secondary ion mass spectroscopy (NanoSIMS) to identify specific ions in bulk dried NP. NanoSIMS is also used to visualize 40Ca microdomains in the z dimension of optic nerve that has been subjected to a partial optic nerve transection. The associated article [1] describes the use of NanoSIMS to quantify 40Ca microdomains in optic nerve from animals treated with various nanoparticle preparations and provides further interpretation and discussion of the findings.

Lanthanide-doped upconversion nanoparticles are promising dual mode near-infrared (NIR) and magnetic resonance imaging (MRI) bioimaging agents. In this communication we report the utility of NaGdF4:Yb,Er nanoparticles with a functional poly(glycidyl methacrylate) (PGMA) coating, as a biocompatible multimodal formulation for neuronal cell imaging.

Following injury to the central nervous system, axons and myelin distinct from the initial injury site undergo changes associated with compromised function. Quantifying such changes is important to understanding the pathophysiology of neurotrauma; however, most studies to date used 2 dimensional (D) electron microscopy to analyse single sections, thereby failing to capture changes along individual axons. We used serial block face scanning electron microscopy (SBF SEM) to undertake 3D reconstruction of axons and myelin, analysing optic nerves from normal uninjured female rats and following partial optic nerve transection. Measures of axon and myelin dimensions were generated by examining 2D images at 5 µm intervals along the 100 µm segments. In both normal and injured animals, changes in axonal diameter, myelin thickness, fiber diameter, G-ratio and percentage myelin decompaction were apparent along the lengths of axons to varying degrees. The range of values for axon diameter along individual reconstructed axons in 3D was similar to the range from 2D datasets, encompassing reported variation in axonal diameter attributed to retinal ganglion cell diversity. 3D electron microscopy analyses have provided the means to demonstrate substantial variability in ultrastructure along the length of individual axons and to improve understanding of the pathophysiology of neurotrauma.

Myelotomy is a surgical procedure allowing removal of extravasated blood and necrotic tissue that is thought to attenuate secondary injury as well as promote recovery in experimental spinal cord injury (SCI) models and humans. Here we examined in rat whether myelotomy at 48 h after low-thoracic compressive SCI provided any benefit over a 12 week period. Compared to animals receiving SCI alone, myelotomy worsened BBB scores (p

Focus Group.To develop a unified, regional spinal cord injury (SCI) research strategy for Australia and New Zealand.Australia.A 1-day structured stakeholder dialogue was convened in 2013 in Melbourne, Australia, by the National Trauma Research Institute in collaboration with the SCI Network of Australia and New Zealand. Twenty-three experts participated, representing local and international research, clinical, consumer, advocacy, government policy and funding perspectives. Preparatory work synthesised evidence and articulated draft principles and options as a starting point for discussion.A regional SCI research strategy was proposed, whose objectives can be summarised under four themes. (1) Collaborative networks and strategic partnerships to increase efficiency, reduce duplication, build capacity and optimise research funding. (2) Research priority setting and coordination to manage competing studies. (3) Mechanisms for greater consumer engagement in research. (4) Resources and infrastructure to further develop SCI data registries, evaluate research translation and assess alignment of research strategy with stakeholder interests. These are consistent with contemporary international SCI research strategy development activities.This first step in a regional SCI research strategy has articulated objectives for further development by the wider SCI research community. The initiative has also reinforced the importance of coordinated, collective action in optimising outcomes following SCI.

This is a rapid evidence review.The objective of this study was to gain an overview of the volume, nature and findings of studies regarding priorities for spinal cord injury (SCI) research.A worldwide literature search was conducted.Six medical literature databases and Google Scholar were searched for reviews in which the primary aim was to identify SCI research priorities.Two systematic reviews were identified-one of quantitative and one of qualitative studies. The quality of the reviews was variable. Collectively, the reviews identified 31 primary studies; 24 quantitative studies totalling 5262 participants and 7 qualitative studies totalling 120 participants. Despite the difference in research paradigms, there was convergence in review findings in the areas of body impairments and relationships. The vast majority of literature within the reviews focused on the SCI patient perspective.The reviews inform specific research topics and highlight other important research considerations, most notably those pertaining to SCI patients' perspectives on quality of life, which may be of use in determining meaningful research outcome measures. The views of other SCI research stakeholders such as researchers, clinicians, policymakers, funders and carers would help shape a bigger picture of SCI research priorities, ultimately optimising research outputs and translation into clinical practice and health policy change. Review findings informed subsequent activities in developing a regional SCI research strategy, as described in two companion papers.This project was funded by the Victorian Transport Accident Commission and the Australian and New Zealand SCI Network.

Glutamate excitotoxicity contributes to damage following injury to the central nervous system via mechanisms including changes in the expression of receptors, calcium overload, oxidative stress and cell death. Excitotoxicity is triggered by glutamate binding to receptors, including calcium permeable AMPA receptors, which can be upregulated under injury conditions. However, the transcriptional response of AMPA receptor regulatory proteins to excitotoxic conditions is unknown. Here, we use real-time quantitative PCR (RT-qPCR), to determine the effect of prolonged glutamate excitotoxicity on the expression of mRNA encoding for GluR1 and AMPA receptor regulatory proteins in dissociated rat retinal cultures that include neuronal (retinal ganglion cell (RGCs)) and glial (Müller) cell populations. mRNA levels of GluR1 and regulators of the GluR1 subunit of AMPA receptors, including Sap97, Cnih2 and Cnih3, decreased following 6, 24 and 48 h incubation with 5 mM glutamate: related regulators not associated with GluR1 were unaffected. In contrast, GluR1 protein, assessed immunohistochemically, was increased in both RGCs and Müller cells after 24 h glutamate exposure: western blotting analysis was inconclusive. Reductions in mRNA of GluR1 and associated regulators occurred prior to cell death, which was first detected at 24 h, and substantial by 48 h. Exposure to glutamate acutely increased the intracellular calcium concentration in the cultures and by 24 h, reactive oxygen species were increased. Our data suggest a negative feedback mechanism in retinal cells, that down-regulates transcription of genes encoding GluR1 regulatory proteins in response to glutamate exposure. Despite this mechanism, GluR1 protein levels remain increased, and are associated with increased reactive species and cell death. Therapeutic strategies targeting calcium permeable AMPA receptors should take into account that increases in GluR1 protein are not necessarily associated with increases in associated mRNA levels over time.

International audience; Background: Repetitive transcranial magnetic stimulation is increasingly used as a treatment for neurological dysfunction. Therapeutic effects have been reported for low intensity rTMS (LI-rTMS) although these remain poorly understood. Objective: Our study describes for the first time a systematic comparison of the cellular and molecular changes in neurons in vitro induced by low intensity magnetic stimulation at different frequencies. Methods: We applied 5 different low intensity repetitive magnetic stimulation (LI-rMS) protocols to neuron-enriched primary cortical cultures for 4 days and assessed survival, and morphological and biochemical change. Results: We show pattern-specific effects of LI-rMS: simple frequency pulse trains (10 Hz and 100 Hz) impaired cell survival, while more complex stimulation patterns (theta-burst and a biomimetic frequency) did not. Moreover, only 1 Hz stimulation modified neuronal morphology, inhibiting neurite outgrowth. To understand mechanisms underlying these differential effects, we measured intracellular calcium concentration during LI-rMS and subsequent changes in gene expression. All LI-rMS frequencies increased intracellular calcium, but rather than influx from the extracellular milieu typical of depolarization, all frequencies induced calcium release from neuronal intracellular stores. Furthermore, we observed pattern-specific changes in expression of genes related to apoptosis and neurite outgrowth, consistent with our morphological data on cell survival and neurite branching. Conclusions: Thus, in addition to the known effects on cortical excitability and synaptic plasticity, our data demonstrate that LI-rMS can change the survival and structural complexity of neurons. These findings provide a cellular and molecular framework for understanding what low intensity magnetic stimulation may contribute to human rTMS outcomes.

Facial nerve injury is a common clinical trauma involving long-term functional deficits with facial asymmetry leading to associated psychological issues and social hardship. We have recently shown that repair by hypoglossal-facial or facial-facial nerve surgical end-to-end anastomosis and suture [hypoglossal-facial anastomosis (HFA) or facial-facial anastomosis (FFA)] results in collateral axonal branching, polyinnervation of neuromuscular junctions (NMJs) and poor function. We have also shown that another HFA repair procedure using an isogenic Y-tube (HFA + Y-tube) and involving a 10-mm gap reduces collateral axonal branching, but fails to reduce polyinnervation. Furthermore, we have previously demonstrated that manual stimulation (MS) of facial muscles after FFA or HFA reduces polyinnervation of NMJs and improves functional recovery. Here, we examined whether HFA + Y-tube and MS of the vibrissal muscles reduce polyinnervation and restore function. Isogenic Y-tubes were created using abdominal aortas. The proximal hypoglossal nerve was inserted into the long arm and sutured to its wall. The distal zygomatic and buccal facial nerve branches were inserted into the two short arms and likewise sutured to their walls. Manual stimulation involved gentle stroking of the vibrissal muscles by hand mimicking normal whisker movement. We evaluated vibrissal motor performance using video-based motion analysis, degree of collateral axonal branching using double retrograde labeling and the quality of NMJ reinnervation in target musculature using immunohistochemistry. MS after HFA + Y-tube reduced neither collateral branching, nor NMJ polyinnervation. Accordingly, it did not improve recovery of function. We conclude that application of MS after hypoglossal-facial nerve repair using an isogenic Y-tube is contraindicated: it does not lead to functional recovery but, rather, worsens it.

Lampreys are one of two extant representatives of the earliest group of vertebrates, the agnathans or jawless fishes. The single species of the southern hemisphere lamprey family Geotriidae, Geotria australis, possesses the potential for pentachromatic color discrimination opposed to the mono- or dichromacy found in other lampreys. However, little is known of the retinal ganglion cell types that contribute to visual processing in G. australis. A quantitative morphological approach was used to distinguish and describe retinal ganglion cell types in G. australis. The morphology of retinal ganglion cells was revealed by retrograde biocytin labeling from the optic disc. Cells were digitally reconstructed, and somatic area and position and dendritic field size, density, tortuosity, and stratification were subjected to quantitative morphometric analyses. Cluster analysis, in conjunction with similarity profile analysis (SIMPROF), statistically identified five discrete monostratified retinal ganglion cell types, one of which may comprise two subtypes. Two bistratified types were identified separately, including a biplexiform and a bistratified subtype. The use of cluster analysis with SIMPROF provided a robust statistical technique for objectively identifying cell types whose characteristics were similar and significantly different from those of other types and thus provides an objective resolution of the problems posed by "lumpers vs. splitters" when designating cell types. The diversity of retinal ganglion cells suggests that visual information in the lamprey G. australis is processed in parallel streams, as in gnathostomes. These findings, together with the results of previous studies, indicate that the visual system of the lamprey G. australis represents the upper limit of visual complexity in extant agnathans.

We report the synthesis, characterisation and evaluation of the in vitro biocompatibility of polymeric nanoparticles with both magnetic and upconverting fluorescent properties. The particles consist of superparamagnetic iron oxide nanoparticles and upconverting NaYF4:Yb,Er nanoparticles co-encapsulated within a poly(glycidyl methacrylate) sphere. Two different upconverting nanoparticles (10 nm α-NaYF4:Yb,Er and 50 nm β-NaYF4:Yb,Er) were synthesised and the optical and magnetic properties of the composite polymeric nanoparticle systems assessed by near infra-red laser spectroscopy, SQUID magnetometry and proton relaxometry. A live-dead assay was used to assess the viability of PC-12 neural cells incubated with varying concentrations of the nanoparticles. The composite nanoparticles produced no observed impact on cellular viability even at concentrations as high as 1000 μg mL−1. Confocal microscopy revealed uptake of nanoparticles by PC-12 cells and peri-nuclear cytoplasmic localisation. Both particle systems show favourable magnetic properties. However, only the nanospheres containing 50 nm β-NaYF4:Yb,Er were suitable for optical tracking because the presence of iron oxide within the composites imparts a significant quenching of the upconversion emission. This study demonstrates the size and phase of the upconverting nanoparticles are important parameters that have to be taken into account in the design of multimodal nanoparticles using co-encapsulation strategies.

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Despite increased understanding of peripheral nerve regeneration, functional recovery after surgical repair remains disappointing. A major contributing factor is the extensive collateral branching at the lesion site, which leads to inaccurate axonal navigation and aberrant reinnervation of targets.To determine whether the Y tube reconstruction improved axonal regrowth and whether this was associated with improved function.We used a Y-tube conduit with the aim of improving navigation of regenerating axons after facial nerve transection in rats.Retrograde labeling from the zygomatic and buccal branches showed a halving in the number of double-labeled facial motor neurons (15% vs 8%; P.05) after Y tube reconstruction compared with facial-facial anastomosis coaptation. However, in both surgical groups, the proportion of polyinnervated motor endplates was similar (≈ 30%; P.05), and video-based motion analysis of whisking revealed similarly poor function.Although Y-tube reconstruction decreases axonal branching at the lesion site and improves axonal navigation compared with facial-facial anastomosis coaptation, it fails to promote monoinnervation of motor endplates and confers no functional benefit.

Burn injury can lead to abnormal sensory function at both the injury and at distant uninjured sites. Here, we used a mouse model to investigate return of nociceptive function and reinnervation of the skin at the wound and uninjured distant sites following a 3% total burn surface area full-thickness burn injury. We have previously shown that topical application of zinc-metallothionein-IIA (Zn 7 -MT-IIA) accelerates healing following burn injury, and here, we investigated the potential of Zn 7 -MT-IIA to enhance reinnervation and sensory recovery. In all burn-injured animals, there was a significant reduction in nociceptive responses (Semmes-Weinstein filaments) at locations near and distant to the wound up to 8 weeks following injury. Cutaneous nerve reinnervation (assessed using protein gene product 9.5 immunohistochemistry) of the wound center was slow in the epidermis but rapid in the dermis. In the dermis, nerves subsequently degenerated both at the wound center and in distant uninjured areas. In contrast, epidermal nerve densities in the distant uninjured areas returned to normal, uninjured levels. Zn 7 -MT-IIA did not influence return of nociceptive function nor reinnervation. We conclude that burn injury compromises nociceptive function and nerve regeneration both at the injury site and systemically; thus, therapies in addition to Zn 7 -MT-IIA should be explored to return normal sensory function.

This study examined barriers to physical activity reported individuals with spinal cord injury (SCI) and the degree to which these barriers differed across varying degrees of independence. Participants were 65 individuals recruited from the Western Australian Spinal Cord Injury database. Data on physical activity participation and perceived barriers to physical activity participation were collected using a cross-sectional survey and analysed using independent samples t-tests. We found that, regardless of level of ambulation or ability to transfer, few participants reported being physically active. While there were no significant differences in the amount of barriers reported by individuals with different levels of independence, the type of barriers reported varied across groups.

CNS injury is often localized but can be followed by more widespread secondary degenerative events that usually result in greater functional loss. Using a partial transection model in rat optic nerve (ON). we recently demonstrated in vivo increases in the oxidative stress-associated enzyme MnSOD 5 min after injury. However, mechanisms by which early oxidative stress spreads remain unclear. In the present study, we assessed ion distributions, additional oxidative stress indicators, and ion channel immunoreactivity in ON in the first 24 hr after partial transection. Using nanoscale secondary ion mass spectroscopy (NanoSIMS), we demonstrate changes in the distribution pattern of Ca ions following partial ON transection. Regions of elevated Ca ions in normal ON in vivo rapidly decrease following partial ON transection, but there is an increasingly punctate distribution at 5 min and 24 hr after injury. We also show rapid decreases in catalase activity and later increases in immunoreactivity of the advanced glycation end product carboxymethyl lysine in astrocytes. Increased oxidative stress in astrocytes is accompanied by significantly increased immunoreactivity of the AMPA receptor subunit GluR1 and aquaporin 4 (AQP4). Taken together, the results indicate that Ca ion changes and oxidative stress are early events following partial ON injury that are associated with changes in GluR1 AMPA receptor subunits and altered ionic balance resulting from increased AQP4.