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The adaptation of CRISPR/Cas technology for use in mammals has revolutionized genome engineering. In particular with regard to clinical application, efficient expression of Cas9 within a narrow time frame is highly desirable to minimize the accumulation of off-target editing. We developed an effective, aptamer-independent retroviral delivery system for Cas9 mRNAs that takes advantage of a unique foamy virus (FV) capability: the efficient encapsidation and transfer of non-viral RNAs. This enabled us to create a FV vector toolbox for efficient, transient delivery (TraFo) of CRISPR/Cas9 components into different target tissues. Co-delivery of Cas9 mRNA by TraFo-Cas9 vectors in combination with retroviral, integration-deficient single guide RNA (sgRNA) expression enhanced efficacy and specificity of gene-inactivation compared with CRISPR/Cas9 lentiviral vector systems. Furthermore, separate TraFo-Cas9 delivery allowed the optional inclusion of a repair matrix for efficient gene correction or tagging as well as the addition of fluorescent negative selection markers for easy identification of off-target editing or incorrect repair events. Thus, the TraFo CRISPR toolbox represents an interesting alternative technology for gene inactivation and gene editing., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background. Predicting functional outcomes after traumatic spinal cord injury (SCI) is essential for counseling, rehabilitation planning, and discharge. Moreover, the outcome prognosis is crucial for patient stratification when designing clinical trials. However, no valid prediction rule is currently available for bowel outcomes after a SCI. Objective . To generate a model for predicting the achievement of independent, reliable bowel management at 1 year after traumatic SCI. Methods . We performed multivariable logistic regression analyses of data for 1250 patients with traumatic SCIs that were included in the European Multicenter Study about Spinal Cord Injury. The resulting model was prospectively validated on data for 186 patients. As potential predictors, we evaluated age, sex, and variables from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the Spinal Cord Independence Measure (SCIM), measured within 40 days of the injury. A positive outcome at 1 year post-SCI was assessed with item 7 of the SCIM. Results . The model relied on a single predictor, the ISNCSCI total motor score-that is, the sum of muscle strengths in 5 key muscle groups in each limb. The area under the receiver operating characteristics curve (aROC) was 0.837 (95% CI: 0.815-0.859). The prospective validation confirmed high predictive power: aROC = 0.817 (95% CI: 0.754-0.881). Conclusions . We generated a valid model for predicting independent, reliable bowel management at 1 year after traumatic SCI. Its application could improve counseling, optimize patient-tailored rehabilitation planning, and become crucial for appropriate patient stratification in future clinical trials.

A 14-year-old girl with a history of complex congenital heart disease in end-stage heart failure and with cyclic vomiting was admitted to our hospice program in 2012. Before hospice enrollment, she had required intermittent infusions of dexmedetomidine to abort cyclic vomiting episodes after cardiac catheterization procedures. Following a hospital admission in November 2013, she was discharged home in the care of our hospice on a continuous dexmedetomidine infusion. She remained on this infusion at varying doses (range of 0.1-0.38 mcg/kg/hour) for nearly three years, until her death in September 2016. This report describes the palliative use of dexmedetomidine in this patient and difficulties related to the use of this medication during the course of her care.

Background: Accurate predictors of neurological recovery after cervical spinal cord injury are needed. Particularly, to tailor adequate rehabilitation plans. However, objective and quantifiable predictors are sparse., Methods: Within the prospective European Multicenter Study about Spinal Cord Injury (EMSCI) registry, cervical spinal cord injury patients are monitored at fixed follow up visits (2, 4, 12, 24, and 48 weeks after injury) clinically and with ulnar nerve electroneurography. Associations of ulnar nerve compound muscle action potential amplitudes (CMAP) with American Spinal Cord Injury Association (ASIA) impairment scale (AIS) grades over time were analyzed using linear mixed modeling. Applying logistic regression, the prognostic value of within 4-week ulnar nerve CMAP for 1-year AIS was analyzed. To account for missing data, (1) last observation carried forward and (2) multiple imputation methods were applied. For model derivation, our centers' cohort (EMSCI-HD) was analyzed. For model validation the cohort of other centers (EMSCI-nonHD) was used., Results: In the EMSCI-HD cohort, the median age (interquartile range (IQR)) was 52 (34-67) years. 58% were male. The initial AIS distribution was: A = 31%, B = 17%, C = 30%, and D = 22%). In the EMSCI-nonHD cohort, the median age was 49 (32-65) years. Compared to the EMSCI-HD cohort more patients were male (79%, p  = 0.0034). The AIS distribution was: A = 33%, B = 13%, C = 21%, and D = 33%).In complete-case mixed model analyses (EMSCI-HD: n  = 114; EMSCI-nonHD: n  = 508) higher ulnar nerve CMAP were associated with better AIS grades over the entire follow up period. In complete-case logistic regression (EMSCI-HD: n  = 90; EMSCI-nonHD: n  = 444) higher ulnar nerve CMAP was an independent predictor of better AIS grades. The odds ratio for within 4-week ulnar nerve CMAP to predict 1-year AIS grade D versus A-C in the EMSCI-HD cohort was 1.24 per millivolt (confidence interval 1.07-1.44). The model was validated in an independent cervical spinal cord injury (EMSCI-nonHD) cohort (odds ratio 1.09, confidence interval 1.03-1.17)., Conclusions: In cervical spinal cord injury, the consideration of early ulnar nerve CMAP improves prognostic accuracy, which is of particular importance in patients with clinical grading uncertainties., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Study Design: Narrative review by individuals experienced in the recruitment of participants to neurotherapeutic clinical trials in spinal cord injury (SCI)., Objectives: To identify key problems of recruitment and explore potential approaches to overcoming them., Methods: Published quantitative experience with recruitment of large-scale, experimental neurotherapeutic clinical studies targeting central nervous system and using primary outcome assessments validated for SCI over the last 3 decades was summarized. Based on this experience, potential approaches to improving recruitment were elicited from the authors., Results: The rate of recruitment has varied between studies, depending on protocol design and other factors, but particularly inclusion/exclusion criteria. The recruitment rate also ranged over an order of magnitude between individual centers in a given study. In older multicenter studies, average recruitment rate was approximately one person per study center per month. More recent trials experienced lower rates of recruitment and potential reasons for this trend were examined. The current roles and potential of various stakeholder organizations in addressing problems of recruitment were explored. In addition, recent developments in methodology may help reduce the number of subjects required for well-powered studies., Conclusions: Several approaches are emerging to improve clinical trial design, efficacy outcome measures, and quantifiable surrogate markers, all of which should reduce the number of participants required for adequate statistical power. There is a growing sense of cooperation between various stakeholders but more should be done to bring together consumer and provider groups to improve recruitment and the effectiveness and relevance of neurotherapeutic clinical trials.

Purpose: This retrospective analysis aimed to address the efficacy of total nodal irradiation (TNI)-based reconditioning regimens in pediatric patients with graft failure/rejection after allogeneic hematopoietic cell transplantation., Methods and Materials: Thirty-three pediatric patients with malignant (n = 25) and nonmalignant diseases (n = 8) were treated with a TNI-based reconditioning regimen. All patients received a 7-Gy single dose combined with anti-T lymphocyte antibody OKT3 (n = 16), anti-thymocyte globulin (n = 24), fludarabine (n = 31), and/or thiotepa (n = 28), followed by an infusion of peripheral blood stem cells (n = 31) or bone marrow transplant (n = 2). Twenty-eight of 33 patients had haploidentical family donors., Results: After a median of 11 days, engraftment was seen in 32 of 33 children. Two children died 34 days after retransplantation because of either disease relapse or treatment-related multiple organ failure. Severe acute toxicity was reported in only 1 child (systemic inflammatory response syndrome-like reaction; recovery after cortisone treatment). The average follow-up was 60.2 months (range, 1.1-162.5 months). Event-free and overall survival rates at 2/5 years follow-up were 62.0%/58.6% and 65.1%/61.7%, respectively. Despite sustained engraftment, 12 patients died from disease relapse (n = 3), Moschkowitz syndrome (n = 1), or multiple organ failure (n = 8). Follow-up data were available for 18 of 21 survivors, with a median follow-up of 92.8 months (range, 3.6-162.5 months). Hypothyroidism was present in 78.6% of patients, and sex/growth hormonal insufficiencies were reported for 37.5%. Mean forced expiratory volume in 1 second after TNI was 84%; mean vital capacity was 79%. Severe growth failure (<3rd percentile) occurred in 28.6% (height) and 35.7% (weight) of patients. No secondary malignancies were reported., Conclusions: In the high-risk group of patients with graft failure/rejection after allogeneic hematopoietic cell transplantation, the TNI-based reconditioning regimen seems to allow sustained engraftment combined with a favorable toxicity profile, leading to long-term event-free and overall survival. Late toxicity after a median follow-up of over 7.5 years includes growth failure, manageable hormonal deficiencies, and a low risk of decrease of lung function., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The translation of therapeutic interventions to humans with spinal cord injury with the goal of promoting growth and repair in the central nervous system could, inadvertently, drive mechanisms associated with the development of neuropathic pain. A framework is needed to evaluate the probability that a therapeutic intervention for acute spinal cord injury modifies the progression of neuropathic pain. We analyzed a large, longitudinal dataset from the European Multi-Center Study about Spinal Cord Injury (EMSCI) and compared these observations with a previously published Swedish/Danish cohort. A meta-analysis was performed to produce aggregate estimates for the transition period between 1-6 months and the transition period between 1-12 months after injury. A secondary analysis used logistic regression to explore associations between the progression of neuropathic pain and demographics, pain characteristics, and injury characteristics. For overall neuropathic pain, 72% presenting with pain symptoms at one month reported persisting symptoms at six months, and 23% who did not have neuropathic pain at one month later had it develop. From 1-12 months, there was a similar likelihood of pain persisting (69%) and slightly higher rate of pain developing (36%). Characteristics that were significantly associated with the progression of pain included age and sensory and motor preservation. We provide historical benchmarks for estimating the progression of neuropathic pain during the first year after acute SCI. This information will be useful for comparison and evaluating safety during early phase acute spinal cord injury trials.

Impact Statement: Axonal bridging across a lesion in the injured spinal cord requires a growth substrate and guidance cues. Using alginate hydrogels with capillary channels we show that poly-l-ornithine and laminin can be stably bound and improve cell adhesion and neurite growth in vitro , and axon growth in vivo by enhancing host cell infiltration in the injured spinal cord. Filling of coated hydrogels with postnatal astrocytes further increases short-distance axon growth and results in a continuous astroglial substrate across the host/graft interface. Thus, positively charged bioactive molecules can be stably bound to anisotropic capillary alginate hydrogels and early astrocytes further promote tissue integration.

Purpose: To prospectively investigate the role of re-irradiation (re-RT) combined with hyperthermia (HT) in a contemporary cohort of patients affected by recurrent breast cancer (RBC)., Methods: Within the prospective registry HT03, patients with resected RBC and previous irradiation were included. Re-RT was applied to the recurrence region with doses of 50-50.4 Gy, with a boost up to 60-60.4 Gy to the microscopically or macroscopically positive resection margins (R1/R2) region. Concurrent HT was performed at 40-42 ℃. Primary endpoint was LC. Acute and late toxicity, overall survival, cancer-specific survival (CSS), and progression-free survival (PFS) were also evaluated., Results: 20 patients and 21 RBC were analyzed. Median re-RT dose was 50.4 Gy and a median of 11 HT fractions were applied. Re-RT+HT was well tolerated, with three patients who experienced a grade (G) 3 acute skin toxicity and no cases of ≥G3 late toxicity. With a median follow up of 24.7 months, two local relapses occurred. Ten patients experienced regional and/or distant disease progression. Five patients died, four of them from breast cancer. PFS was favorable in patients treated with re-RT+HT for the first recurrence with doses of 60 Gy. A trend towards better CSS was found in patients with negative or close margins and after doses of 60 Gy., Conclusion: Full-dose re-RT+HT for RBC is well tolerated, provides good LC, and seems to be more effective when applied at the time of the first relapse and after doses of 60 Gy. The registry will be continued for validation in a larger cohort and with longer follow-up.

Objective: Determining differences in neurological and functional outcome between adolescents and adults after acute traumatic spinal cord injury (SCI)., Design: Retrospective, multi-center case-control study., Methods: 100 cases of patients under 18 years at accident with acute traumatic cervical SCI admitted to SCI centers participating in the European Multi-center study about SCI (EMSCI) between January 2005 and April 2016 were reviewed. According to their age at accident, age 13 to 17, patients were selected for the adolescent group. After applying in- and exclusion criteria 32 adolescents were included. Each adolescent patient was matched with two adult SCI patients for analysis., Outcome Measures: ASIA Impairment scale (AIS) grade, neurological, sensory, motor level, total motor score, and Spinal Cord Independence Measure (SCIM III) total score., Results: Mean AIS conversion, neurological, motor and sensory levels as well as total motor score showed no significantly statistical difference in adolescents compared to the adult control group after follow up of 6 months. Significantly higher final SCIM scores (p < 0.05) in the adolescent group compared to adults as well as a strong trend for a higher gain in SCIM score (p < 0.061) between first and last follow up was found., Conclusions: Neurological outcome after traumatic cervical SCI is not superior in adolescents compared to adults in this cohort. Significantly higher SCIM scores indicate more functional gain for the adolescent patients after traumatic cervical SCI. Juvenile age appears to be an independent predictor for a better functional outcome., (Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Non-invasive brain-computer interfaces (BCI) represent an emerging technology for enabling persons with impaired or lost grasping and reaching functions due to high spinal cord injury (SCI) to control assistive devices. A major drawback of BCIs is a high rate of false classifications. The robustness and performance of BCIs might be improved using cerebral electrophysiological correlates of error recognition (error-related potentials, ErrPs). As ErrPs have never been systematically examined in subjects with SCI, this study compares the characteristics of ErrPs in individuals with SCI with those of able-bodied control subjects. Methods: ErrPs at FCz and Cz were analyzed in 11 subjects with SCI (9 male, median age 28 y) and in 11 sex- and age-matched controls. Moving a shoulder joystick according to a visual cue, subjects received feedback about the match/mismatch of the performed movement. ErrPs occurring after "error"-feedback were evaluated by comparing means of voltage values within three consecutive time windows after feedback (wP1, wN1, wP2 containing peak voltages P1, N1, P2) using repeated-measurement analysis of variance. Results: In the control group, mean voltage values for the "error" and "correct" feedback condition differed significantly around N1 (FCz: 254 ms, Cz: 252 ms) and P2 (FCz: 347 ms, Cz: 345 ms), but not around P1 (FCz: 181 ms, Cz: 179 ms). ErrPs of the control and the SCI group showed similar morphology, however mean amplitudes of ErrPs were significantly smaller in individuals with SCI compared to controls for wN1 (FCz: control = -1.55 μV, SCI = -0.27 μV, p = 0.02; Cz: control = -1.03 μV, SCI = 0.11 μV, p = 0.04) and wP2 (FCz: control = 2.79 μV, SCI = 1.29 μV, p = 0.011; Cz: control = 2.12 μV, SCI = 0.81 μV, p = 0.003). Mean voltage values in wP1, wN1, and wP2 did not correlate significantly with either chronicity after or level of injury. Conclusion: The morphology of ErrPs in subjects with and without SCI is comparable, however, with reduced mean amplitude in wN1 and wP2 in the SCI group. Further studies should evaluate whether ErrP-classification can be used for online correction of false BCI-commands in individuals with SCI.

Orthopedic care is an important aspect of the overall management of patients with Duchenne muscular dystrophy (DMD). In addition to progressive muscle weakness and loss of function, patients may develop joint contractures, scoliosis, and osteoporosis, causing fractures; all of these necessitate intervention by a multidisciplinary team including an orthopedic surgeon as well as rehabilitation specialists such as physio- and occupational therapists. The causes of these musculoskeletal complications are multifactorial and are related to primary effects on the muscles from the disease itself, secondary effects from weak muscles, and the related side effects of treatments, such as glucocorticoid use that affect bone strength. The musculoskeletal manifestations of DMD change over time as the disease progresses, and therefore, musculoskeletal management needs change throughout the life span of an individual with DMD. In this review, we target pediatricians, neurologists, orthopedic surgeons, rehabilitation physicians, anesthesiologists, and other individuals involved in the management of patients with DMD by providing specific recommendations to guide clinical practice related to orthopedic issues and surgical management in this setting., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

In this article, we outline a comprehensive plan for the psychosocial management of patients with Duchenne muscular dystrophy (DMD) across the life span. In 2010, the Centers for Disease Control and Prevention sponsored the development of multidisciplinary management guidance for DMD, and in 2018, that guidance was updated. In the intervening years, a new emphasis was placed on studying and addressing the psychosocial issues that affect patients with DMD, driven in part by improved patient survival. Once viewed as ancillary to managing the significant medical needs of patients with DMD, it is now standard practice to integrate psychosocial management into the multidisciplinary management of the disease. It is also increasingly recognized that neurodevelopmental disorders in DMD occur at a higher rate than what was previously understood and that these disorders warrant early and intensive intervention. In this article, we expand on the content found in the 2018 DMD Care Considerations., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Within the past 12 months, Dr Gibbons was a consultant for Sarepta Therapeutics and attended an advisory board meeting; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

A large proportion of patients suffering from spinal cord injury (SCI) develop chronic central neuropathic pain. Previously, we and others have shown that sensorimotor training early after SCI can prevent the development of mechanical allodynia. To determine whether training initiated in the subchronic/chronic phase remains effective, correlates of below-level neuropathic pain were analyzed in the hindpaws 5-10 weeks after a moderate T11 contusion SCI (50 kDyn) in adult female C57BL/6 mice. In a comparison of SCI and sham mice 5 weeks post-injury, about 80% of injured animals developed mechanical hypersensitivity to light mechanical stimuli, whereas testing of noxious stimuli revealed hypo-responsiveness. Thermal sensitivity testing showed a decreased response latency after injury. Without intervention, mechanical and thermal hyper-responsiveness were evident until the end of the experiment (10 weeks). In contrast, treadmill training (2 × 15 min/day; 5 × /week) initiated 6 weeks post-injury resulted in partial amelioration of pain behavior and this effect remained stable. Analysis of calcitonin gene-related peptide (CGRP)-labeled fibers in lamina III-IV of the lumbar dorsal horn revealed an increase in labeling density after SCI. This was not due to changes in the number or size distribution of CGRP-labeled lumbar dorsal root ganglion neurons. Treadmill training reduced the CGRP-labeling density in the spinal cord of injured mice, whereas the density of non-peptidergic isolectin-B4 (IB4) + fibers showed no changes in lamina IIi and a slight reduction of sparse IB4 labeling in laminae III-IV. Thus, sensorimotor activity initiated in the subchronic/chronic phase of SCI remains effective in ameliorating pain behavior and influencing structural changes of the nociceptive system.

Following a spinal cord injury (SCI) a growth aversive environment forms, consisting of a fibroglial scar and inhibitory factors, further restricting the already low intrinsic growth potential of injured adult central nervous system (CNS) neurons. Previous studies have shown that local administration of the microtubule-stabilizing drug paclitaxel or epothilone B (Epo B) reduce fibrotic scar formation and axonal dieback as well as induce axonal growth/sprouting after SCI. Likewise, systemic administration of Epo B promoted functional recovery. In this study, we investigated the effects of epothilone D (Epo D), an analog of Epo B with a possible greater therapeutic index, on fibrotic scarring, axonal sprouting and functional recovery after SCI. Delayed systemic administration of Epo D after a moderate contusion injury (150 kDyn) in female Fischer 344 rats resulted in a reduced number of footfalls when crossing a horizontal ladder at 4 and 8 weeks post-injury. Hindlimb motor function assessed with the BBB open field locomotor rating scale and Catwalk gait analysis were not significantly altered. Moreover, formation of laminin positive fibrotic scar tissue and 5-HT positive serotonergic fiber length caudal to the lesion site were not altered after treatment with Epo D. These findings recapitulate a functional benefit after systemic administration of a microtubule-stabilizing drug in rat contusion SCI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

OBJECTIVE To quantify vitamin D 3 (VitD 3 ) concentrations in commercial dog foods and compare those concentrations with Association of American Feed Control Officials (AAFCO) recommendations and manufacturer-reported concentrations. DESIGN Cross-sectional study. SAMPLE 82 commercial dog foods. PROCEDURES Samples of commercially available dog foods were obtained from owners of healthy dogs in the Guelph, ON, Canada, area and owners of dogs that were patients at the Ontario Veterinary College Health Sciences Centre's Mona Campbell Centre for Animal Cancer. For each food, the VitD 3 concentration was determined by high-performance liquid chromatography-tandem mass spectrometry, and adherence to AAFCO and National Research Council recommendations was assessed. Analyzed VitD 3 concentrations were compared with manufacturer-reported VitD 3 concentrations and between wet and dry foods, among AAFCO nutritional adequacy statements (nutrient profiles vs feeding trials and adult maintenance vs all life stages), between foods sold only by veterinarians and those sold over the counter, and between small and large manufacturers. RESULTS The analyzed VitD 3 concentration was below both AAFCO and National Research Council recommendations for one sample and below the assay detection limit for another. Analyzed VitD 3 concentrations did not differ significantly from manufacturer-reported VitD 3 concentrations or between wet and dry foods, among foods with different AAFCO nutritional adequacy statements, between foods sold only by veterinarians and those sold over the counter, or between foods produced by small and large manufacturers. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that manufacturer-reported VitD 3 concentrations were accurate and that dog owners can be confident that VitD 3 intake is adequate for AAFCO-compliant commercial dog foods.

Background: Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery., Objective: This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia., Methods: Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks)., Results: ATI355 was well tolerated up to 1-year follow-up. All patients experienced ≥1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia., Conclusions: ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI.

The causes of degenerative disease of the upper and lower motor neurons are incompletely understood. In this review the current concepts in the clinical and genetic differential diagnostics of motor neuron diseases are presented. Hereditary spastic paraplegia, primary lateral sclerosis, spinal muscular atrophy and amyotrophic lateral sclerosis are explained, structured according to the affection of the upper and/or lower motor neuron. The substantial variability in the presentation and course of motor neuron diseases as well as the lack of specific laboratory tests hinder an early diagnosis. The precise description of the clinical picture, thorough testing of possible differential diagnoses as well as monitoring of the clinical course are essential. Genetic analyses should be offered to patients with a positive family history. Early identification of clinical and genetic subentities of the individual motor neuron diseases is a prerequisite for future neuroprotective interventions.

Background: Degenerative stenotic spondylosis is not an uncommon cause of cervical spondylotic myelopathy (CSM) and cauda equina lesions in the aged population. Limited standardization exists with respect to diagnostic and therapeutic procedures., Objective: Literature review with respect to diagnostic and therapeutic procedures for neurologically relevant cervical and lumbar spinals stenosis., Material and Methods: Comprehensive literature review., Results and Conclusion: Clinical neurological examination and diagnostic imaging are fundamental for the diagnosis of neurologically relevant cervical and lumbar spinal stenosis. Additional laboratory blood and cerebrospinal fluid testing might be required for a differential diagnosis. Neurophysiological testing is reserved for specific clinical problems. The clinical evidence for the efficacy of conservative therapeutic strategies is limited.

Background: Walking disabilities negatively affect inclusion in society and quality of life and increase the risk for secondary complications. It has been shown that external feedback applied by therapists and/or robotic training devices enables individuals with gait abnormalities to consciously normalize their gait pattern. However, little is known about the effects of a technically-assisted over ground feedback therapy. The aim of this study was to assess whether automatic real-time feedback provided by a shoe-mounted inertial-sensor-based gait therapy system is feasible in individuals with gait impairments after incomplete spinal cord injury (iSCI), stroke and in the elderly., Methods: In a non-controlled proof-of-concept study, feedback by tablet computer-generated verbalized instructions was given to individuals with iSCI, stroke and old age for normalization of an individually selected gait parameter (stride length, stance or swing duration, or foot-to-ground angle). The training phase consisted of 3 consecutive visits. Four weeks post training a follow-up visit was performed. Visits started with an initial gait analysis (iGA) without feedback, followed by 5 feedback training sessions of 2-3 min and a gait analysis at the end. A universal evaluation and FB scheme based on equidistant levels of deviations from the mean normal value (1 level = 1 standard deviation (SD) of the physiological reference for the feedback parameter) was used for assessment of gait quality as well as for automated adaptation of training difficulty. Overall changes in level over iGAs were detected using a Friedman's Test. Post-hoc testing was achieved with paired Wilcoxon Tests. The users' satisfaction was assessed by a customized questionnaire., Results: Fifteen individuals with iSCI, 11 after stroke and 15 elderly completed the training. The average level at iGA significantly decreased over the visits in all groups (Friedman's test, p < 0.0001), with the biggest decrease between the first and second training visit (4.78 ± 2.84 to 3.02 ± 2.43, p < 0.0001, paired Wilcoxon test). Overall, users rated the system's usability and its therapeutic effect as positive., Conclusions: Mobile, real-time, verbalized feedback is feasible and results in a normalization of the feedback gait parameter. The results form a first basis for using real-time feedback in task-specific motor rehabilitation programs., Trial Registration: DRKS00011853 , retrospectively registered on 2017/03/23.

Activity dependent plasticity is a key mechanism for the central nervous system (CNS) to adapt to its environment. Whether neuronal activity also influences axonal regeneration in the injured CNS, and whether electrical stimulation (ES) can activate regenerative programs in the injured CNS remains incompletely understood. Using KCl-induced depolarization, in vivo ES followed by ex-vivo neurite growth assays and ES after spinal cord lesions and cell grafting, we aimed to identify parameters important for ES-enhanced neurite growth and axonal regeneration. Using cultures of sensory neurons, neurite growth was analyzed after KCl-induced depolarization for 1-72h. Increased neurite growth was detected after short-term stimulation and after longer stimulation if a sufficient delay between stimulation and growth measurements was provided. After in vivo ES (20Hz, 2× motor threshold, 0.2ms, 1h) of the intact sciatic nerve in adult Fischer344 rats, sensory neurons showed a 2-fold increase in in vitro neurite length one week later compared to sham animals, an effect not observed one day after ES. Longer ES (7h) and repeated ES (7days, 1h each) also increased growth by 56-67% one week later, but provided no additional benefit. In vivo growth of dorsal column sensory axons into a graft of bone marrow stromal cells 4weeks after a cervical spinal cord lesion was also enhanced with a single post-injury 1h ES of the intact sciatic nerve and was also observed after repeated ES without inducing pain-like behavior. While ES did not result in sensory functional recovery, our data indicate that ES has time-dependent influences on the regenerative capacity of sensory neurons and might further enhance axonal regeneration in combinatorial approaches after SCI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Study Design: Prospective observational multicenter study., Objectives: Investigation of content, duration and adjustment of physical therapy for the rehabilitation of ambulation in acute spinal cord injury (SCI)., Setting: European Multicenter Study of SCI (EMSCI)., Methods: Physical therapy interventions during acute in-patient rehabilitation of eighty incomplete SCI patients (AIS B, C, D all lesion levels) were recorded using the SCI - Intervention Classification System. Mobility was documented using the Spinal Cord Independence Measurement (SCIM III), demographics and clinical data were retrieved from the EMSCI database., Results: Overall recovery of locomotor function was categorized into three outcome groups (G1-G3). Of 76 initial wheelchair-using patients, 53.9% remained wheelchair user (G1), 25% regained moderate (G2) and 21.1% good walking (G3) capability. Strength training was the most frequently applied intervention of body function/-structure across all outcome groups (about 30% of all interventions), while interventions focusing on muscle tone and respiration were predominantly applied in wheelchair-dependent patients. Activity-focused interventions of transfer, transition, sitting were trained most intensively in outcome group G1, while walking and swimming were increasingly trained in patients with moderate and good walking outcomes. Physical therapy interventions of assistive and active trainings as well as corresponding training environments changed with the recovery of locomotor function., Conclusions: Physical therapy of locomotor function is targeted to individual patients' conditions and becomes adjusted to the progress of ambulation. Although the involved clinical sites were not following explicitly standardized rehabilitation programs, common patterns can be discerned which may form the basis of prospective standardized programs.

Spinal cord injury (SCI), resulting in para- and tetraplegia caused by the partial or complete disruption of descending motor and ascending sensory neurons, represents a complex neurological condition that remains incurable. Following SCI, numerous obstacles comprising of the loss of neural tissue (neurons, astrocytes, and oligodendrocytes), formation of a cavity, inflammation, loss of neuronal circuitry and function must be overcome. Given the multifaceted primary and secondary injury events that occur with SCI treatment options are likely to require combinatorial therapies. While several methods have been explored, only the intersection of two, cell transplantation and biomaterial implantation, will be addressed in detail here. Owing to the constant advance of cell culture technologies, cell-based transplantation has come to the forefront of SCI treatment in order to replace/protect damaged tissue and provide physical as well as trophic support for axonal regrowth. Biomaterial scaffolds provide cells with a protected environment from the surrounding lesion, in addition to bridging extensive damage and providing physical and directional support for axonal regrowth. Moreover, in this combinatorial approach cell transplantation improves scaffold integration and therefore regenerative growth potential. Here, we review the advances in combinatorial therapies of Schwann cells (SCs), astrocytes, olfactory ensheathing cells (OECs), mesenchymal stem cells, as well as neural stem and progenitor cells (NSPCs) with various biomaterial scaffolds.

There is emerging interest in linking vitamin D status to physiological health and disease states in the dog, as evidenced by the recent increase in publications in this area. This research has most likely been spurred by the studies exploring vitamin D and disease in humans. However, there are important differences in vitamin D intake and metabolism between humans and dogs that should be accounted for. The understanding of basic vitamin D metabolism and the relationship between vitamin D intake and vitamin D status in dogs remains even more limited than current knowledge in humans. This review will summarize current knowledge of vitamin D in the dog, including metabolism and dietary recommendations. Emphasis is placed on the limitations to current knowledge. Studies investigating links between vitamin D and disease will be discussed in light of this knowledge. Suggestions for future research, including the development of reference ranges to define blood vitamin D sufficiency, are provided.

Background: Neuropathic pain (NeuP) is a frequent sequel of spinal cord injury (SCI). The SCI Pain Instrument (SCIPI) was developed as a SCI-specific NeuP screening tool. A preliminary validation reported encouraging results requiring further evaluation in terms of psychometric properties. The painDETECT questionnaire (PDQ), a commonly applied NeuP assessment tool, was primarily validated in German, but not specifically developed for SCI and not yet validated according to current diagnostic guidelines. We aimed to provide convergent construct validity and to identify the optimal item combination for the SCIPI. The PDQ was re-evaluated according to current guidelines with respect to SCI-related NeuP., Methods: Prospective monocentric study. Subjects received a neurological examination according to the International Standards for Neurological Classification of SCI. After linguistic validation of the SCIPI, the IASP-grading system served as reference to diagnose NeuP, accompanied by the PDQ after its re-evaluation as binary classifier. Statistics were evaluated through ROC-analysis, with the area under the ROC curve (AUROC) as optimality criterion. The SCIPI was refined by systematic item permutation., Results: Eighty-eight individuals were assessed with the German SCIPI. Of 127 possible combinations, a 4-item-SCIPI (cut-off-score = 1.5/sensitivity = 0.864/specificity = 0.839) was identified as most reasonable. The SCIPI showed a strong correlation (r sp  = 0.76) with PDQ. ROC-analysis of SCIPI/PDQ (AUROC = 0.877) revealed comparable results to SCIPI/IASP (AUROC = 0.916). ROC-analysis of PDQ/IASP delivered a score threshold of 10.5 (sensitivity = 0.727/specificity = 0.903)., Conclusion: The SCIPI is a valid easy-to-apply NeuP screening tool in SCI. The PDQ is recommended as complementary NeuP assessment tool in SCI, e.g. to monitor pain severity and/or its time-dependent course., Significance: In SCI-related pain, both SCIPI and PainDETECT show strong convergent construct validity versus the current IASP-grading system. SCIPI is now optimized from a 7-item to an easy-to-apply 4-item screening tool in German and English. We provided evidence that the scope for PainDETECT can be expanded to individuals with SCI., (© 2017 European Pain Federation - EFIC®.)

Background: Low blood 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with cancer in dogs. Little research has examined what other factors may affect 25(OH)D concentrations., Objectives: (1) To determine whether the presence of cancer (lymphoma, osteosarcoma, or mast cell tumor [MCT]) in dogs is associated with plasma 25(OH)D concentrations and (2) identify other factors related to plasma 25(OH)D concentrations in dogs., Animals: Dogs newly diagnosed with osteosarcoma (n = 21), lymphoma (n = 27), and MCT (n = 21) presented to a tertiary referral oncology center, and healthy, client-owned dogs (n = 23)., Methods: An observational study design was used. Dietary vitamin D intake, sex, age, body condition score (BCS), muscle condition score (MCS), and plasma concentrations of 25(OH)D, 24,25-dihydroxyvitamin D (24,25(OH) 2 D) (a marker of CYP24A1 activity), as well as ionized calcium (ICa), parathyroid hormone, and parathyroid hormone-related protein concentrations were measured. An analysis of covariance was used to model plasma 25(OH)D concentrations., Results: Cancer type (P = 0.004), plasma 24,25(OH) 2 D concentrations (P < 0.001), and plasma ICa concentrations (P = 0.047) had significant effects on plasma 25(OH)D concentrations. Effects of age, sex, body weight, BCS, MCS, and plasma PTH concentrations were not identified. A significant interaction between ICa and cancer was found (P = 0.005). Plasma 25(OH)D concentrations increased as ICa concentrations increased in dogs with cancer, whereas plasma 25(OH)D concentrations decreased as ICa concentrations increased in healthy dogs., Conclusions and Clinical Importance: Results support a relationship between cancer and altered vitamin D metabolism in dogs, mediated by plasma ICa concentrations. The CYP24A1 activity and plasma ICa should be measured in studies examining plasma 25(OH)D concentrations in dogs., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Grafting of cell-seeded alginate capillary hydrogels into a spinal cord lesion site provides an axonal bridge while physically directing regenerating axonal growth in a linear pattern. However, without an additional growth stimulus, bridging axons fail to extend into the distal host spinal cord. Here we examined whether a combinatory strategy would support regeneration of descending axons across a cervical (C5) lateral hemisection lesion in the rat spinal cord. Following spinal cord transections, Schwann cell (SC)-seeded alginate hydrogels were grafted to the lesion site and AAV5 expressing brain-derived neurotrophic factor (BDNF) under control of a tetracycline-regulated promoter was injected caudally. In addition, we examined whether SC injection into the caudal spinal parenchyma would further enhance regeneration of descending axons to re-enter the host spinal cord. Our data show that both serotonergic and descending axons traced by biotinylated dextran amine (BDA) extend throughout the scaffolds. The number of regenerating axons is significantly increased when caudal BDNF expression is activated and transient BDNF delivery is able to sustain axons after gene expression is switched off. Descending axons are confined to the caudal graft/host interface even with continuous BDNF expression for 8weeks. Only with a caudal injection of SCs, a pathway facilitating axonal regeneration through the host/graft interface is generated allowing axons to successfully re-enter the caudal spinal cord., Statement of Significance: Recovery from spinal cord injury is poor due to the limited regeneration observed in the adult mammalian central nervous system. Biomaterials, cell transplantation and growth factors that can guide axons across a lesion site, provide a cellular substrate, stimulate axon growth and have shown some promise in increasing the growth distance of regenerating axons. In the present study, we combined an alginate biomaterial with linear channels with transplantation of Schwann cells within and beyond the lesion site and injection of a regulatable vector for the transient expression of brain-derived neurotrophic factor (BDNF). Our data show that only with the full combination axons extend across the lesion site and that expression of BDNF beyond 4weeks does not further increase the number of regenerating axons., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Study Design: Retrospective statistical analysis of database., Objective: Spinal cord injury (SCI) clinical trials are challenged to enroll participants, and early trial outcomes have often been equivocal. We hypothesized that a specifically designed novel true linear interval-scaled outcome measure targeted to simultaneously track a broad range of SCI will enable more inclusive enrollment of participants and valid comparisons of functional changes after SCI., Methods: To define a single SCI measurement framework, we used items from existing measures. To evaluate linearity and validity of the measure, we used rigorous psychometric Rasch analysis on two data sets from over 2500 traumatic SCI participants (all levels and severities of SCI) within the EMSCI (European Multicenter study about SCI) database., Results: Volitional performance was found to be the unidimensional construct that would detect and track a treatment effect from a central nervous system-directed therapeutic. Along with early evidence for voluntary neurological control of upper-extremity muscle contractions, volitional performance is best described by goal-directed activities of daily living that are increasingly difficult to re-acquire when activity within more caudal spinal segments is required. Validity of the Spinal Cord Ability Ruler (SCAR) as a linear interval construct was confirmed with Rasch analysis. All measurement items were properly ordered, as well as being precise and stable across clinically relevant groups. Only 5/24 items had some misfit. Targeting was excellent over time after SCI, with few gaps and only modest floor and ceiling effects (3% each)., Conclusions: SCAR is a quantitative linear measure of volitional performance across an inclusive range of tetraplegic and paraplegic SCI.

Objectives: Pressure ulcers impose a major lifetime medical problem to patients with high-grade spinal cord injury (SCI). For patients with stages 3-4 pressure ulcers, plastic surgery is often the only remaining treatment option. Despite considerable flap failure rates of around 30%, only sparse knowledge exists on predictors for flap failure. Hence, identification of predictors for flap failures is needed., Methods: We prospectively enrolled 38 SCI patients with stages 3-4 pressure ulcers scheduled for plastic surgery. Preoperative wound swabs, intraoperative tissue samples and postoperative drainage liquids were microbiologically analyzed. In multivariable logistic regression analyses, bacterial loads of deep tissue cultures of intraoperative samples as well as other clinical variables were analyzed with respect to the prediction of flap failures., Results: The flap failure rate was 27.5%. Bacterial loads of deep tissue cultures were not predictive for flap failure, neither was the colonization with a specific bacterial strain. We observed a considerable fluctuation of microbiological environment from initial swab cultures, intraoperative samples and postoperative drainage fluids. Antibioprophylaxis was sufficient in only 75% of deep tissue cultures and 69% of drainage fluids. Insufficient antibioprophylaxis was associated with a higher flap failure rates (odds ratio 6.3, confidence interval 1.2-41.0)., Conclusion: After inpatient wound conditioning, bacterial load analysis of intraoperative wound tissue cultures is ineffective in order to predict flap failure rates in SCI patients with stages 3-4 pressure ulcers after flap surgery. Instead, insufficient antibioprophylaxis might be a factor contributing to flap failure.

Introduction: To investigate whether MR-defecography can be employed in sensorimotor complete spinal cord injury (SCI) subjects as a potential diagnostic tool to detect defecational disorders associated with neurogenic bowel dysfunction (NBD) using standard parameters for obstructed defecation., Material and Methods: In a prospective single centre clinical trial, we developed MR-defecography in traumatic sensorimotor complete paraplegic SCI patients with upper motoneuron type injury (neurological level of injury T1 to T10) using a conventional 3T scanner. Defecation was successfully induced by eliciting the defecational reflex after rectal filling with ultrasonic gel, application of two lecicarbon suppositories and digital rectal stimulation. Examination was performed with patients in left lateral decubitus position using T2-weighted turbo spin echo sequence in the sagittal plane at rest (TE 89ms, TR 3220ms, FOV 300mm, matrix 512×512, ST 4mm) and ultrafast-T2-weighted-sequence in the sagittal plane with repeating measurements (TE 1.54ms, TR 3.51ms, FOV 400mm, matrix 256×256, ST 6mm). Changes of anorectal angle (ARA), anorectal descent (ARJ) and pelvic floor weakness were documented and measured data was compared to reference values of asymptomatic non-SCI subjects in the literature to assess feasibility., Results: MR-defecography provides evaluable imaging sequences of the induced evacuation phase in SCI patients. Measurement results for ARA, ARJ, hiatal width (H-line) and hiatal descent (M-line) deviate significantly from reference values in the literature in asymptomatic subjects without SCI. The overall mean values in our study for SCI patients were: ARA (rest) 127.3°, ARA (evacuation) 137.6°, ARJ (rest) 2.4cm, ARJ (evacuation) 4.0cm, H-line (rest) 7.6cm, H-line (evacuation) 8.1cm, M-line (rest) 2.6cm, M-line (evacuation) 4.2cm., Conclusions: MR-defecography is feasible in sensorimotor complete SCI patients. Individual MR-defecography findings may help to determine specific therapeutical options for respective patients suffering from severe NBD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Objective: The course of central and peripheral motor recovery after cervical spinal cord injury (SCI) may be investigated by electrophysiological measures. The goal of this study was to compare the 2 over the first year after injury in relation to motor gains., Methods: Compound motor action potentials (CMAPs), motor-evoked potentials (MEPs), and F-waves were recorded from the abductor digiti minimi and CMAP and F-waves from abductor hallucis muscles in 305 patients at about 15 days, 1 month, 3 months, 6 months, and 12 months following an acute traumatic SCI., Results: The MEP amplitudes and F-wave persistences were lower with more severe sensorimotor impairment. They steadily increased in most subgroups within 6 months after SCI. The amplitude of the CMAPs was low for the first 3 months in the most severely affected participants. This was also found for CMAPs from tibial nerve originating well below the cervical lesion level. Improvement in neurophysiological parameters correlated with improved upper extremity motor scores., Conclusion: The results point to a systematic interrelation of corticospinal transmission, spinal motoneuron excitability, and its axon function, respectively. Electrophysiological correlates of neural excitability show distinct spatial and temporal interrelations within central and peripheral motor pathways following acute cervical SCI. A strong secondary deterioration within the peripheral motor system with incomplete or no recovery depends on anatomical distance caudal to lesion and on lesion severity. Electrophysiological assessments may increase the sensitivity of interventional studies in addition to clinical measures.

The anticonvulsant pregabalin promotes neural regeneration in a mouse model of spinal cord injury (SCI). We have also previously observed that anticonvulsants improve motor outcomes following human SCI. The present study examined the optimal timing and type of anticonvulsants administered in a large, prospective, multi-center, cohort study in acute SCI. Mixed-effects regression techniques were used to model total motor scores at 1, 3, 6, and 12 months post injury. We found that early (not late) administration of anticonvulsants significantly improved motor recovery (6.25 points over 1 year). The beneficial effect of anticonvulsants remained significant after adjustment for differences in 1-month motor scores and injury characteristics. A review of a subset of patients revealed that gabapentinoids were the most frequently administrated anticonvulsant. Together with preclinical findings, intervention with anticonvulsants represents a potential pharmacological strategy to improve motor function after SCI., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Palliative sedation is a means of relieving intractable symptoms at the end of life, however, guidelines about its use lack consistency. In addition, ethical concerns persist around the practice. There are reports of palliative sedation in the pediatric literature, which highlight various institutional perspectives., Objectives: This survey of 4786 pediatric providers sought to describe their knowledge of and current practices around pediatric palliative sedation., Methods: Our survey was administered to pediatricians who care for children at the end of life. The survey assessed agreement with a definition of palliative sedation, as well as thoughts about its alignment with aggressive symptom management. Bivariate analyses using χ 2 and analysis of variance were calculated to determine the relationship between responses to closed-ended questions. Open-ended responses were thematically coded by the investigators and reviewed for agreement., Results: Nearly half (48.6%) of the respondents indicated that the stated definition of palliative sedation "completely" reflected their own views. Respondents were split when asked if they viewed any difference between palliative sedation and aggressive symptom management: Yes (46%) versus No (54%). Open-ended responses revealed specifics about the nature of variation in interpretation., Conclusions: Responses point to ambiguity surrounding the concept of palliative sedation. Pediatricians were concerned with a decreased level of consciousness as the goal of palliative sedation. Respondents were split on whether they view palliative sedation as a distinct entity or as one broad continuum of care, equivalent to aggressive symptom management. Institutional-based policies are essential to clarify acceptable practice, enable open communication, and promote further research.

Dissection of the cavernous nerves during radical prostatectomy for prostate cancer eliminates spontaneous erections. Using the rat as an experimental model, we compared the regenerative capacity of autologous nerve grafts and Schwann-cell-seeded nerve guides. After bilateral excision of cavernous nerve segments, cavernous nerves were reconstructed using unseeded silicon tubes, nerve autografts and silicon tubes seeded with either Glial-cell-line-derived (GDNF)-overexpressing or green fluorescent protein (GFP)-expressing Schwann cells (SCs) (16 study nerves per group). Control groups underwent either a sham operation or bilateral excision of cavernous nerve segments without repair. After 12 weeks erectile function was assessed by neurostimulation and intracavernous pressure (ICP) measurement. The reconstructed nerve segments were excised and histologically analyzed. We demonstrated an intact erectile response upon neurostimulation in 25% (4/16) of autologous nerve grafts, in 50% (8/16) of unseeded tubes, in 75% (12/16) of the Schwann-cell-GFP group and in 93.75% (15/16) of the GDNF group. ICP was significantly increased when comparing the Schwann-cell-GFP group with nerve autografts, unseeded conduits and negative controls (P<0.005). In conclusion, Schwann-cell-seeded scaffolds combined with neurotrophic factors are superior to unseeded tubes and autologous nerve grafts. They present a promising therapeutic approach for the repair of erectile nerve gaps., Competing Interests: The authors declare no competing or financial interests., (© 2016. Published by The Company of Biologists Ltd.)

Background and Purpose: Outcome of patients with genitourinary rhabdomyosarcoma has been improved in the past, but organ preservation rates are too low. Conservative surgery with LDR-brachytherapy has been advocated, but LDR-brachytherapy is often not available. We wanted to establish a novel treatment modality combining HDR-brachytherapy and conservative surgery., Material and Methods: We performed an organ preserving tumor resection with intraoperative placement of brachytherapy tubes. Suitable patients were selected following assessment of response to neoadjuvant chemotherapy where organ preserving surgical resection was deemed feasible. In bladder-prostate rhabdomyosarcoma, only tumors located below the bladder neck could be treated by brachytherapy. After surgery, high dose rate brachytherapy was carried out for 30-36Gy total dose., Results: A total of 11 patients were treated up to now (embryonal histology n=10, alveolar histology n=1) with a median follow-up of 18months [4-80]. All patients were IRS group III. There were no significant side effects. One patient had local relapse and was successfully treated with re-excision. All other patients are in the first complete remission. One patient developed a neurogenic bladder and required creation of a Mitrofanoff stoma., Conclusion: Combined conservative surgery and high dose rate brachytherapy is a treatment option for selected rhabdomyosarcoma patients. The paper highlights the essential technical challenges and clearly shows limitations of this treatment approach., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background Approximately 60% of patients suffering from acute spinal cord injury (SCI) develop pain within days to weeks after injury, which ultimately persists into chronic stages. To date, the consequences of pain after SCI have been largely examined in terms of interfering with quality of life. Objective The objective of this study was to examine the effects of pain and pain management on neurological recovery after SCI. Methods We analyzed clinical data in a prospective multicenter observational cohort study in patients with SCI. Using mixed effects regression techniques, total motor and sensory scores were modelled at 1, 3, 6, and 12 months postinjury. Results A total of 225 individuals were included in the study (mean age: 45.8 ± 18 years, 80% male). At 1 month postinjury, 28% of individuals with SCI reported at- or below-level neuropathic pain. While pain classification showed no effect on neurological outcomes, individuals administered anticonvulsant medications at 1 month postinjury showed significant reductions in pain intensity (2 points over 1 year; P < .05) and greater recovery in total motor scores (7.3 points over 1 year; P < .05). This drug effect on motor recovery remained significant after adjustment for injury level and injury severity, pain classification, and pain intensity. Conclusion While initial pain classification and intensity did not reveal an effect on motor recovery following acute SCI, anticonvulsants conferred a significant beneficial effect on motor outcomes. Early intervention with anticonvulsants may have effects beyond pain management and warrant further studies to evaluate the therapeutic effectiveness in human SCI., (© The Author(s) 2016.)

Context/objective: To verify the hypothesis that motor levels (ML) inferred from sensory levels in the upper cervical segments C2-C4 according to the current version of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) are counterintuitive in cases where the most rostral myotomes C5 and C6 are graded as intact., Design: Prospective cohort study of ISNCSCI instructional course participants completing a post-test after the workshop to determine the MLs in two variants of a complete, high cervical spinal cord injury (SCI) case scenario. Both variants were based on the same ISNCSCI sensory and MLs of C2. In the first variant myotomes C5 and C6 were bilaterally graded as intact, while in variant 2 only active movements against gravity were possible (grade 3)., Setting: Eight ISNCSCI instructional courses conducted during the study period from November 2012 until March 2015 in the framework of the European Multicenter Study on Human Spinal Cord Injury (EMSCI- http//emsci.org )., Participants: Ninety-two clinicians from twenty-two SCI centers. Most of the attendees were physicians (58.7%) or physical therapists (33.7%) and had less than one year (44.6%) experience in SCI medicine., Interventions: Not applicable., Outcome Measure: The classification performance described as percentage of correctly determined MLs by the clinicians., Results: Variant 2 (89.13%) was significantly (P < 0.0001) better classified than variant 1 (65.76%). In variant 1 with intact myotomes at C5 and C6, C6 was incorrectly classified as the ML by the clinicians in 33.15% of all cases, whereas in variant 2 with non-intact C5 / C6 myotomes, C6 was rarely chosen (2.17%)., Conclusions: Sensory level deferred MLs in the high cervical region of C2-C4 are counterintuitive whenever the most rostral cervical myotomes are intact. An adjustment of the ML definition in ISNCSCI may be needed.

Study Design: Prospective cohort study., Objectives: Comparison of the classification performance between the worksheet revisions of 2011 and 2013 of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI)., Settings: Ongoing ISNCSCI instructional courses of the European Multicenter Study on Human Spinal Cord Injury (EMSCI). For quality control all participants were requested to classify five ISNCSCI cases directly before (pre-test) and after (post-test) the workshop., Participants: One hundred twenty-five clinicians working in 22 SCI centers attended the instructional course between November 2011 and March 2015. Seventy-two clinicians completed the post-test with the 2011 revision of the worksheet and 53 with the 2013 revision., Interventions: Not applicable., Outcome Measures: The clinicians' classification performance assessed by the percentage of correctly determined motor levels (ML) and sensory levels, neurological levels of injury (NLI), ASIA Impairment Scales and zones of partial preservations., Results: While no group differences were found in the pre-tests, the overall performance (rev2011: 92.2% ± 6.7%, rev2013: 94.3% ± 7.7%; P = 0.010), the percentage of correct MLs (83.2% ± 14.5% vs. 88.1% ± 15.3%; P = 0.046) and NLIs (86.1% ± 16.7% vs. 90.9% ± 18.6%; P = 0.043) improved significantly in the post-tests. Detailed ML analysis revealed the largest benefit of the 2013 revision (50.0% vs. 67.0%) in a case with a high cervical injury (NLI C2)., Conclusion: The results from the EMSCI ISNCSCI post-tests show a significantly better classification performance using the revised 2013 worksheet presumably due to the body-side based grouping of myotomes and dermatomes and their correct horizontal alignment. Even with these proven advantages of the new layout, the correct determination of MLs in the segments C2-C4 remains difficult.

Background: Neurogenic bladder dysfunction represents one of the most common and devastating sequelae of traumatic spinal cord injury (SCI). As early prediction of bladder outcomes is essential to counsel patients and to plan neurourological management, we aimed to develop and validate a model to predict urinary continence and complete bladder emptying 1 y after traumatic SCI., Methods and Findings: Using multivariate logistic regression analysis from the data of 1,250 patients with traumatic SCI included in the European Multicenter Spinal Cord Injury study, we developed two prediction models of urinary continence and complete bladder emptying 1 y after traumatic SCI and performed an external validation in 111 patients. As predictors, we evaluated age, gender, and all variables of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and of the Spinal Cord Independence Measure (SCIM). Urinary continence and complete bladder emptying 1 y after SCI were assessed through item 6 of SCIM. The full model relies on lower extremity motor score (LEMS), light-touch sensation in the S3 dermatome of ISNCSI, and SCIM subscale respiration and sphincter management: the area under the receiver operating characteristics curve (aROC) was 0.936 (95% confidence interval [CI]: 0.922-0.951). The simplified model is based on LEMS only: the aROC was 0.912 (95% CI: 0.895-0.930). External validation of the full and simplified models confirmed the excellent predictive power: the aROCs were 0.965 (95% CI: 0.934-0.996) and 0.972 (95% CI 0.943-0.999), respectively. This study is limited by the substantial number of patients with a missing 1-y outcome and by differences between derivation and validation cohort., Conclusions: Our study provides two simple and reliable models to predict urinary continence and complete bladder emptying 1 y after traumatic SCI. Early prediction of bladder function might optimize counselling and patient-tailored rehabilitative interventions and improve patient stratification in future clinical trials.

Context: We report the case of a 20-year-old woman who underwent tracheal resection with postoperative chin-to-chest suture for 10 days, presenting with severe tetraparesis at our institution. Similar cases have been reported previously, however, not yet in the pathophysiological context of chronic cervical flexion myelopathy (Hirayama syndrome)., Findings: Extensive myelopathy at cervical level is the consequence of the fixed cervical spine position due to chin-to-chest suture. Predominantly affected young individuals (age range from 20-25 years) without evidence of degenerated spine disease suggest a similar mechanism as described in Hirayama syndrome-displacement of the dura with consecutive compression of the spinal cord vasculature., Conclusions: Subacute flexion myelopathy represents a serious complication of operative/postoperative fixed cervical spine positions, warranting particular attention by respective surgeons.

Below-level central neuropathic pain (CNP) affects a large proportion of spinal cord injured individuals. To better define the dynamic changes of the spinal cord neural network contributing to the development of CNP after spinal cord injury (SCI), we characterized the morphological and behavioral correlates of CNP in female C57BL/6 mice after a moderate T11 contusion SCI (50 kdyn) and the influence of moderate physical activity. Compared with sham-operated animals, injured mice developed mechanical allodynia 2 weeks post injury when tested with small-diameter von Frey hair filaments (0.16 g and 0.4 g filament), but presented hyporesponsiveness to noxious mechanical stimuli (1.4 g filament). The mechano-sensory alterations lasted up to 35 days post injury, the longest time point examined. The response latency to heat stimuli already decreased significantly 10 days post injury reaching a plateau 2 weeks later. In contrast, injured mice developed remarkable hyposensitivity to cold stimuli. Animals that underwent moderate treadmill training (2 × 15 minutes; 5 d/wk) showed a significant reduction in the response rate to light mechanical stimuli as early as 6 days after training. Calcitonin gene-related peptide (CGRP) labeling in lamina III-IV of the dorsal horn revealed significant increases in CGRP-labeling density in injured animals compared with sham control animals. Importantly, treadmill training reduced CGRP-labeling density by about 50% (P < 0.01), partially reducing the injury-induced increases. Analysis of IB4-labeled nonpeptidergic sensory fibers revealed no differences between experimental groups. Abnormalities in temperature sensation were not influenced by physical activity. Thus, treadmill training partially resolves signs of below-level CNP after SCI and modulates the density of CGRP-labeled fibers.

Cell transplantation might be one means to improve motor, sensory, or autonomic recovery after traumatic spinal cord injury (SCI). Among the different cell types evaluated to date, bone marrow stromal cells (BMSCs) have received considerable interest due to their potential neuroprotective properties. However, uncertainty exists whether the efficacy of BMSCs after intraspinal transplantation justifies an invasive procedure. In the present study, we analyzed the effect of syngeneic BMSC transplantation following a moderate to severe rat spinal cord injury. Adult Fischer 344 rats underwent a T9 contusion injury (200 kDy) followed by grafting of GFP-expressing BMSCs 3 days postinjury. Animals receiving a contusion injury without cellular grafts or an injury followed by grafts of syngeneic GFP-expressing fibroblasts served as control. Eight weeks posttransplantation, BMSC-grafted animals showed only a minor effect in one measure of sensorimotor recovery, no significant differences in tissue sparing, and no changes in the recovery of bladder function compared to both control groups in urodynamic measurements. Both cell types survived in the lesion site with fibroblasts displaying a larger graft volume. Thus, contrary to some reports using allogeneic or xenogeneic transplants, subacute intraparenchymal grafting of syngeneic BMSCs has only a minor effect on functional recovery.

Appropriate target reinnervation and functional recovery after spinal cord injury depend on longitudinally directed regrowth of injured axons. Anisotropic alginate-based capillary hydrogels (ACH) support peripheral nervous system derived axon growth, which is accompanied by glial supporting cell migration into the ACH. The aim of the present study was to analyze central nervous system (CNS) derived (entorhinal cortex, spinal cord slice cultures) axon regrowth into ACH containing linearly aligned capillaries of defined capillary sizes without and with gelatin constituent. Anisotropic ACH were prepared by ionotropic gel formation using Ba(2+), Cu(2+), Sr(2+), or Zn(2+) ions resulting in gels with average capillary diameters of 11, 13, 29, and 89μm, respectively. Postnatal rat entorhinal cortex or spinal cord slice cultures were placed on top of 500μm thick ACH. Seven days later axon growth and astroglial migration into the ACH were determined. Axon density within capillaries correlated positively with increasing capillary diameters, whereas longitudinally oriented axon outgrowth diminished with increasing capillary diameter. Axons growing into the hydrogels were always accompanied by astrocytes strongly suggesting that respective cells are required to mediate CNS axon elongation into ACH. Overall, midsize capillary diameter ACH appeared to be the best compromise between axon density and orientation. Taken together, ACH promote CNS axon ingrowth, which is determined by the capillary diameter and migration of slice culture derived astroglia into the hydrogel., Statement of Significance: Biomaterials are investigated as therapeutic tools to bridge irreversible lesions following traumatic spinal cord injury. The goal is to develop biomaterials, which promote longitudinally oriented regeneration of as many injured axons as possible as prerequisite for substantial functional recovery. Optimal parameters of the biomaterial have yet to be defined. In the present study we show that increasing capillary diameters within such hydrogels enhanced central nervous system axon regeneration at the expense of longitudinal orientation. Axon ingrowth into the hydrogels was only observed in the presence of glial supporting cells, namely astrocytes. This suggests that alginate-based hydrogels need to be colonized with respective cells in order to facilitate axon ingrowth., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Despite recent progress in enhancing axonal growth in the injured spinal cord, the guidance of regenerating axons across an extended lesion site remains a major challenge. To determine whether regenerating axons can be guided in rostrocaudal direction, we implanted 2mm long alginate-based anisotropic capillary hydrogels seeded with bone marrow stromal cells (BMSCs) expressing brain-derived neurotrophic factor (BDNF) or green fluorescent protein (GFP) as control into a C5 hemisection lesion of the rat spinal cord. Four weeks post-lesion, numerous BMSCs survived inside the scaffold channels, accompanied by macrophages, Schwann cells and blood vessels. Quantification of axons growing into channels demonstrated 3-4 times more axons in hydrogels seeded with BMSCs expressing BDNF (BMSC-BDNF) compared to control cells. The number of anterogradely traced axons extending through the entire length of the scaffold was also significantly higher in scaffolds with BMSC-BDNF. Increasing the channel diameters from 41μm to 64μm did not lead to significant differences in the number of regenerating axons. Lesions filled with BMSC-BDNF without hydrogels exhibited a random axon orientation, whereas axons were oriented parallel to the hydrogel channel walls. Thus, alginate-based scaffolds with an anisotropic capillary structure are able to physically guide regenerating axons., Statement of Significance: After injury, regenerating axons have to extend across the lesion site in the injured spinal cord to reestablish lost neuronal connections. While cell grafting and growth factor delivery can promote growth of injured axons, without proper guidance, axons rarely extend across the lesion site. Here, we show that alginate biomaterials with linear channels that are filled with cells expressing the growth-promoting neurotrophin BDNF promote linear axon extension throughout the channels after transplantation to the injured rat spinal cord. Animals that received the same cells but no alginate guidance structure did not show linear axonal growth and axons did not cross the lesion site. Thus, alginate-based scaffolds with a capillary structure are able to physically guide regenerating axons., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Observational data show that nonsteroidal anti-inflammatory drug (NSAID) use is associated with a lower rate of breast cancer. We evaluated the effect of etodolac, an FDA-approved NSAID reported to inhibit cyclooxygenase (COX) enzymes and the retinoid X receptor alpha (RXR), on rationally identified potential biomarkers in breast cancer. Patients with resectable breast cancer planned for initial management with surgical resection were enrolled and took 400 mg of etodolac twice daily prior to surgery. Protein and gene expression levels for genes related to COX-2 and RXRα were evaluated in tumor samples from before and after etodolac exposure. Thirty subjects received etodolac and 17 subjects were assayed as contemporaneous or opportunistic controls. After etodolac exposure mean cyclin D1 protein levels, assayed by immunohistochemistry, decreased (P = 0.03). Notably, pre- versus post cyclin D1 gene expression change went from positive to negative with greater duration of etodolac exposure (r = -0.64, P = 0.01). Additionally, etodolac exposure was associated with a significant increase in COX-2 gene expression levels (fold change: 3.25 [95% CI: 1.9, 5.55]) and a trend toward increased β-catenin expression (fold change: 2.03 [95% CI: 0.93, 4.47]). In resectable breast cancer relatively brief exposure to the NSAID etodolac was associated with reduced cyclin D1 protein levels. Effect was also observed on cyclin D1 gene expression with decreasing levels with longer durations of drug exposure. Increased COX-2 gene expression was seen, possibly due to compensatory feedback. These data highlight the utility of even small clinical trials with access to biospecimens for pharmacodynamic studies., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Several novel drug- and cell-based potential therapies for spinal cord injury (SCI) have either been applied or will be considered for future clinical trials. Limitations on the number of eligible patients require trials be undertaken in a highly efficient and effective manner. However, this is particularly challenging when people living with incomplete SCI (iSCI) represent a very heterogeneous population in terms of recovery patterns and can improve spontaneously over the first year after injury., Objective: The current study addresses 2 requirements for designing SCI trials: first, enrollment of as many eligible participants as possible; second, refined stratification of participants into homogeneous cohorts from a heterogeneous iSCI population., Methods: This is a retrospective, longitudinal analysis of prospectively collected SCI data from the European Multicenter study about Spinal Cord Injury (EMSCI). We applied conditional inference trees to provide a prediction-based stratification algorithm that could be used to generate decision rules for the appropriate inclusion of iSCI participants to a trial., Results: Based on baseline clinical assessments and a defined subsequent clinical endpoint, conditional inference trees partitioned iSCI participants into more homogeneous groups with regard to the illustrative endpoint, upper extremity motor score. Assuming a continuous endpoint, the conditional inference tree was validated both internally as well as externally, providing stable and generalizable results., Conclusion: The application of conditional inference trees is feasible for iSCI participants and provides easily implementable, prediction-based decision rules for inclusion and stratification. This algorithm could be utilized to model various trial endpoints and outcome thresholds., (© The Author(s) 2015.)

Background: For the translation of noninvasive motor imagery (MI)-based brain-computer interfaces (BCIs) from the lab environment to end users at their homes, their handling must be improved. As a key component, the number of electroencephalogram (EEG)-recording electrodes has to be kept at a minimum. However, due to inter-individual anatomical and physiological variations, reducing the number of electrodes bares the risk of electrode misplacement, which will directly translate into a limited BCI performance of end users. The aim of the study is to evaluate the use of focal transcranial magnetic stimulation (TMS) as an easy tool to individually optimize electrode positioning for a MI-based BCI. For this, the area of MI-induced mu-rhythm modulation was compared with the motor hand representation area in respect to their localization and to the control performance of a MI-based BCI., Methods: Focal TMS was applied to map the motor hand areas and a 48-channel high-resolution EEG was used to localize MI-induced mu-rhythm modulations in 11 able-bodied, right-handed subjects (5 male, age: 23-31). The online BCI performances of the study participants were assessed with a single next-neighbor Laplace channel consecutively placed over the motor hand area and over the area of the strongest mu-modulation., Results: For most subjects, a consistent deviation between the position of the mu-modulation center and the corresponding motor hand areas well above the localization error could be observed in mediolateral and to a lesser degree in anterior-posterior direction. On an individual level, the MI-induced mu-rhythm modulation was at average found 1.6 cm (standard deviation (SD) = 1.30 cm) lateral and 0.31 cm anterior (SD = 1.39 cm) to the motor hand area and enabled a significantly better online BCI performance than the motor hand areas., Conclusion: On an individual level a trend towards a consistent average spatial distance between motor hand area and mu-rhythm modulation center was found indicating that TMS may be used as a simple tool for quick individual optimization of EEG-recording electrode positions of MI-based BCIs. The study results indicate that motor hand areas of the primary motor cortex determined by TMS are not the main generators of the cortical mu-rhythm.