Fibrinogen aptamer functionalized gold-coated iron-oxide nanoparticles for targeted imaging of thrombi.

Targeting of molecular constituents of thrombi with aptamer functionalized core-shell nanoparticles (CSN) allowed for high resolution clot delineation in T2-weighted magnetic resonance imaging. Meanwhile, the gold-coating demonstrated sufficient contrast capabilities in computed tomography (1697 HU µM-1). This targeted CSN formulation could allow for precise imaging of blood clots at low nanomolar concentrations.

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson's-linked neurodegeneration.

A Randomized Controlled Trial of Local Delivery of a Rho Inhibitor (VX-210) in Patients with Acute Traumatic Cervical Spinal Cord Injury.

Acute traumatic spinal cord injury (SCI) can result in severe, lifelong neurological deficits. After SCI, Rho activation contributes to collapse of axonal growth cones, failure of axonal regeneration, and neuronal loss. This randomized, double-blind, placebo-controlled phase 2b/3 study evaluated the efficacy and safety of Rho inhibitor VX-210 (9 mg) in patients after acute traumatic cervical SCI. The study enrolled patients 14-75 years of age with acute traumatic cervical SCIs, C4-C7 (motor level) on each side, and American Spinal Injury Association Impairment Scale (AIS) Grade A or B who had spinal decompression/stabilization surgery commencing within 72 h after injury. Patients were randomized 1:1 with stratification by age (<30 vs. ≥30 years) and AIS grade (A vs. B with sacral pinprick preservation vs. B without sacral pinprick preservation). A single dose of VX-210 or placebo in fibrin sealant was administered topically onto the dura over the site of injury during decompression/stabilization surgery. Patients were evaluated for medical, neurological, and functional changes, and serum was collected for pharmacokinetics and immunological analyses. Patients were followed up for up to 12 months after treatment. A planned interim efficacy-based futility analysis was conducted after ∼33% of patients were enrolled. The pre-defined futility stopping rule was met, and the study was therefore ended prematurely. In the final analysis, the primary efficacy end-point was not met, with no statistically significant difference in change from baseline in upper-extremity motor score at 6 months after treatment between the VX-210 (9-mg) and placebo groups. This work opens the door to further improvements in the design and conduct of clinical trials in acute SCI.

Analysis of human satellite cell dynamics on cultured adult skeletal muscle myofibers.

BACKGROUND: Maintaining stem cells in physiologically relevant states is necessary to understand cell and context-specific signalling paradigms and to understand complex interfaces between cells in situ. Understanding human stem cell function is largely based on tissue biopsies, cell culture, and transplantation into model organisms. METHODS: Here, we describe a method to isolate post-mortem intact human muscle myofibers and culture muscle stem cells within the niche microenvironment to assay cellular dynamics, stem cell identity, stem cell hierarchy, and differentiation potential. RESULTS: We show human myofiber culture maintains complex cell-cell contacts and extracellular niche composition during culture. Human satellite cells can be cultured at least 8 days, which represents a timepoint of activation, differentiation, and de novo human myofiber formation. We demonstrate that adult human muscle stem cells undergo apicobasal and planar cell divisions and express polarized dystrophin and EGFR. Furthermore, we validate that stimulation of the EGFR pathway stimulates the generation of myogenic progenitors and myogenic differentiation. CONCLUSIONS: This method provides proof of principle evidence for the use of human muscle to evaluate satellite cell dynamics and has applications in pre-clinical evaluation of therapeutics targeting muscle repair.

Factors Associated with Recovery in Motor Strength, Walking Ability, and Bowel and Bladder Function after Traumatic Cauda Equina Injury.

Traumatic cauda equina injury (TCEI) is usually caused by spine injury at or below L1 and can result in motor and/or sensory impairments and/or neurogenic bowel and bladder. We examined factors associated with recovery in motor strength, walking ability, and bowel and bladder function to aid in prognosis and establishing rehabilitation goals. The analysis cohort was comprised of persons with acute TCEI enrolled in the Rick Hansen Spinal Cord Injury Registry. Multi-variable regression analysis was used to determine predictors for lower-extremity motor score (LEMS) at discharge, walking ability at discharge as assessed by the walking subscores of either the Functional Independence Measure (FIM) or Spinal Cord Independence Measure (SCIM), and improvement in bowel and bladder function as assessed by FIM-relevant subscores. Age, sex, neurological level and severity of injury, time from injury to surgery, rehabilitation onset, and length of stay were examined as potential confounders. The cohort included 214 participants. Median improvement in LEMS was 4 points. Fifty-two percent of participants were able to walk, and >20% recovered bowel and bladder function by rehabilitation discharge. Multi-variable analyses revealed that shorter time from injury to rehabilitation admission (onset) was a significant predictor for both improvement in walking ability and bowel function. Longer rehabilitation stay and being an older female were associated with improved bladder function. Our results suggest that persons with TCEI have a reasonable chance of recovery in walking ability and bowel and bladder function. This study provides important information for rehabilitation goals setting and communication with patients and their families regarding prognosis.

Increased Prevalence of Chronic Disease in Back Pain Patients Living in Car-dependent Neighbourhoods in Canada: A Cross-sectional Analysis.

OBJECTIVES: Chronic diseases, including back pain, result in significant patient morbidity and societal burden. Overall improvement in physical fitness is recommended for prevention and treatment. Walking is a convenient modality for achieving initial gains. Our objective was to determine whether neighbourhood walkability, acting as a surrogate measure of physical fitness, was associated with the presence of chronic disease. METHODS: We conducted a cross-sectional study of prospectively collected data from a prior randomized cohort study of 227 patients referred for tertiary assessment of chronic back pain in Ottawa, ON, Canada. The Charlson Comorbidity Index (CCI) was calculated from patient-completed questionnaires and medical record review. Using patients' postal codes, neighbourhood walkability was determined using the Walk Score, which awards points based on the distance to the closest amenities, yielding a score from 0 to 100 (0- 50: car-dependent; 50-100: walkable). RESULTS: Based on the Walk Score, 134 patients lived in car-dependent neighborhoods and 93 lived in walkable neighborhoods. A multivariate logistic regression model, adjusted for age, gender, rural postal code, body mass index, smoking, median household income, percent employment, pain, and disability, demonstrated an adjusted odds ratio of 2.75 (95% confidence interval, 1.16 to 6.53) times higher prevalence for having a chronic disease for patients living in a car-dependent neighborhood. There was also a significant dose-related association (p=0.01; Mantel-Haenszel chi-square=6.4) between living in car-dependent neighbourhoods and more severe CCI scores. CONCLUSIONS: Our findings suggest that advocating for improved neighbourhood planning to permit greater walkability may help offset the burden of chronic disease.

The impact of spine stability on cervical spinal cord injury with respect to demographics, management, and outcome: a prospective cohort from a national spinal cord injury registry.

BACKGROUND CONTEXT: Emergent surgery for patients with a traumatic spinal cord injury (SCI) is seen as the gold standard in acute management. However, optimal treatment for those with the clinical diagnosis of central cord syndrome (CCS) is less clear, and classic definitions of CCS do not identify a unique population of patients. PURPOSE: The study aimed to test the authors' hypothesis that spine stability can identify a unique group of patients with regard to demographics, management, and outcomes, which classic CCS definitions do not. STUDY DESIGN/SETTING: This is a prospective observational study. PATIENT SAMPLE: The sample included participants with cervical SCI included in a prospective Canadian registry. OUTCOME MEASURES: The outcome measures were initial hospitalization length of stay, change in total motor score from admission to discharge, and in-hospital mortality. METHODS: Patients with cervical SCI from a prospective Canadian SCI registry were grouped into stable and unstable spine cohorts. Bivariate analyses were used to identify differences in demographic, injury, management, and outcomes. Multivariate analysis was used to better understand the impact of spine stability on motor score improvement. No conflicts of interest were identified. RESULTS: Compared with those with an unstable spine, patients with cervical SCI and a stable spine were older (58.8 vs. 44.1 years, p<.0001), more likely male (86.4% vs. 76.1%, p=.0059), and have more medical comorbidities. Patients with stable spine cervical SCI were more likely to have sustained their injury by a fall (67.4% vs. 34.9%, p<.0001), and have high cervical (C1-C4; 58.5% vs. 43.3%, p=.0009) and less severe neurologic injuries (ASIA Impairment Scale C or D; 81.3% vs. 47.5%, p<.0001). Those with stable spine injuries were less likely to have surgery (67.6% vs. 92.6%, p<.0001), had shorter in-hospital lengths of stay (median 84.0 vs. 100.5 days, p=.0062), and higher total motor score change (20.7 vs. 19.4 points, p=.0014). Multivariate modeling revealed that neurologic severity of injury and spine stability were significantly related to motor score improvement; patients with stable spine injuries had more motor score improvement. CONCLUSIONS: We propose that classification of stable cervical SCI is more clinically relevant than classic CCS classification as this group was found to be unique with regard to demographics, neurologic injury, management, and outcome, whereas classic CCS classifications do not . This classification can be used to assess optimal management in patients where it is less clear if and when surgery should be performed.

A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury and Central Cord Syndrome: Recommendations on the Timing (≤24 Hours Versus >24 Hours) of Decompressive Surgery.

OBJECTIVE: To develop recommendations on the timing of surgical decompression in patients with traumatic spinal cord injury (SCI) and central cord syndrome. METHODS: A systematic review of the literature was conducted to address key relevant questions. A multidisciplinary guideline development group used this information, along with their clinical expertise, to develop recommendations for the timing of surgical decompression in patients with SCI and central cord syndrome. Based on GRADE, a strong recommendation is worded as "we recommend," whereas a weak recommendation is presented as "we suggest." RESULTS: Conclusions from the systematic review included (1) isolated studies reported statistically significant and clinically important improvements following early decompression at 6 months and following discharge from inpatient rehabilitation; (2) in one study on acute central cord syndrome without instability, a marginally significant improvement in total motor scores was reported at 6 and 12 months in patients managed with early versus late surgery; and (3) there were no significant differences in length of acute care/rehabilitation stay or in rates of complications between treatment groups. Our recommendations were: "We suggest that early surgery be considered as a treatment option in adult patients with traumatic central cord syndrome" and "We suggest that early surgery be offered as an option for adult acute SCI patients regardless of level." Quality of evidence for both recommendations was considered low. CONCLUSIONS: These guidelines should be implemented into clinical practice to improve outcomes in patients with acute SCI and central cord syndrome by promoting standardization of care, decreasing the heterogeneity of management strategies, and encouraging clinicians to make evidence-informed decisions.

Effect of older age on treatment decisions and outcomes among patients with traumatic spinal cord injury.

BACKGROUND: Older people are at increased risk of traumatic spinal cord injury from falls. We evaluated the impact of older age (≥ 70 yr) on treatment decisions and outcomes. METHODS: We identified patients with traumatic spinal cord injury for whom consent and detailed data were available from among patients recruited (2004-2013) at any of the 31 acute care and rehabilitation hospitals participating in the Rick Hansen Spinal Cord Injury Registry. Patients were assessed by age group (< 70 v. ≥ 70 yr). The primary outcome was the rate of acute surgical treatment. We used bivariate and multivariate regression models to assess patient and injury-related factors associated with receiving surgical treatment and with the timing of surgery after arrival to a participating centre. RESULTS: Of the 1440 patients included in our study cohort, 167 (11.6%) were 70 years or older at the time of injury. Older patients were more likely than younger patients to be injured by falling (83.1% v. 37.4%; p < 0.001), to have a cervical injury (78.0% v. 61.6%; p = 0.001), to have less severe injuries on admission (American Spinal Injury Association Impairment Scale grade C or D: 70.5% v. 46.9%; p < 0.001), to have a longer stay in an acute care hospital (median 35 v. 28 d; p < 0.005) and to have a higher in-hospital mortality (4.2% v. 0.6%; p < 0.001). Multivariate analysis did not show that age of 70 years or more at injury was associated with a decreased likelihood of surgical treatment (adjusted odds ratio [OR] 0.48, 95% confidence interval [CI] 0.22-1.07). An unplanned sensitivity analysis with different age thresholds showed that a threshold of 65 years was associated with a decreased chance of surgical treatment (OR 0.39, 95% CI 0.19-0.80). Older patients who underwent surgical treatment had a significantly longer wait time from admission to surgery than younger patients (37 v. 19 h; p < 0.001). INTERPRETATION: We found chronological age to be a factor influencing treatment decisions but not at the 70-year age threshold that we had hypothesized. Older patients waited longer for surgery and had a substantially higher in-hospital mortality despite having less severe injuries than younger patients. Further research into the link between treatment delays and outcomes among older patients could inform surgical guideline development.

Metastatic renal cell carcinoma mimicking a schwannoma in a dorsal root ganglion: case report.

Peripheral nerve tumors are soft-tissue tumors that can occur in any nerve throughout the body. The majority of peripheral nerve tumors arise from elements of the nerve sheath with the two most common being neurofibromas and schwannomas. More than 90% of all peripheral nerve tumors are benign. When there is peripheral nerve involvement in metastatic carcinoma, it is often via contiguous spread from the primary mass; hematogenous seeding to a peripheral nerve is seldom seen. In this report the authors describe the even rarer case of metastatic renal cell carcinoma mimicking a schwannoma in a dorsal root ganglion. Cases from the literature show the rarity of this finding and its late clinical appearance. Given that survival in patients with metastatic carcinoma continues to increase, dorsal root ganglion metastasis may become more common over time.

The influence of time from injury to surgery on motor recovery and length of hospital stay in acute traumatic spinal cord injury: an observational Canadian cohort study.

To determine the influence of time from injury to surgery on neurological recovery and length of stay (LOS) in an observational cohort of individuals with traumatic spinal cord injury (tSCI), we analyzed the baseline and follow-up motor scores of participants in the Rick Hansen Spinal Cord Injury Registry to specifically assess the effect of an early (less than 24 h from injury) surgical procedure on motor recovery and on LOS. One thousand four hundred and ten patients who sustained acute tSCIs with baseline American Spinal Injury Association Impairment Scale (AIS) grades A, B, C, or D and were treated surgically were analyzed to determine the effect of the timing of surgery (24, 48, or 72 h from injury) on motor recovery and LOS. Depending on the distribution of data, we used different types of generalized linear models, including multiple linear regression, gamma regression, and negative binomial regression. Persons with incomplete AIS B, C, and D injuries from C2 to L2 demonstrated motor recovery improvement of an additional 6.3 motor points (SE=2.8 p<0.03) when they underwent surgical treatment within 24 h from the time of injury, compared with those who had surgery later than 24 h post-injury. This beneficial effect of early surgery on motor recovery was not seen in the patients with AIS A complete SCI. AIS A and B patients who received early surgery experienced shorter hospital LOS. While the issues of when to perform surgery and what specific operation to perform remain controversial, this work provides evidence that for an incomplete acute tSCI in the cervical, thoracic, or thoracolumbar spine, surgery performed within 24 h from injury improves motor neurological recovery. Early surgery also reduces LOS.

A systematic review of cellular transplantation therapies for spinal cord injury.

Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem/progenitor cells, fate-restricted neural/glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same "type" exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.

Daily smoking and lower back pain in adult Canadians: the Canadian Community Health Survey.

BACKGROUND: Lower back pain (LBP) is one of the primary causes of disability in the Canadian community. However, only a limited number of studies have addressed the association between daily smoking and LBP in Canada. Of the studies that have explored this association, many had small sample sizes and failed to control for confounders. OBJECTIVE: The primary objective of the study was to determine if daily smoking is associated with an increased risk of having LBP. The secondary objectives were to assess the risk for LBP among occasional smokers and to determine the prevalence of LBP in relation to different covariates. DATA AND STUDY DESIGN: Using the Canadian Community Health Survey (cycle 3.1) data, 73,507 Canadians between the ages of 20 and 59 years were identified. LBP status, smoking level, sex, age, body mass index (BMI), level of activity and level of education were assessed in these subjects. METHODS: Stratified analysis and logistic regression analysis were used to detect effect modifications and to adjust for covariates. Population weight and design were taken into consideration. RESULTS: The prevalence of LBP was 23.3% among daily smokers and 15.7% among non-smokers. Age and sex were found to be effect modifiers. The association between LBP and daily smoking was statistically significant in all ages and genders; this association was stronger for younger age groups. The adjusted odds ratio for male daily smokers aged 20 to 29 was 1.87 (95% CI = 1.62, 2.17); findings were similar for women. Occasional smoking slightly increased the odds of having back pain. CONCLUSION: Young Canadian daily smokers are at higher risk for LBP. This study also suggests a positive correlation between smoking dose and the risk of LBP. These findings indicate that smoking behavioral modification may have an impact on reducing back pain especially among young adults.

Nonseminomatous germ cell tumor after chemotherapy with residual mass invading the spine.

Bony metastasis is a rare feature of metastatic nonseminomatous germ cell tumor. A 25 year-old man presented with back pain radiating down both legs, and a subsequent work-up demonstrated a right-sided testicular mass with bilateral retroperitoneal lymphadenopathy and tumor involvement of the L2 vertebra. Radical inguinal orchiectomy confirmed nonseminomatous germ cell tumor, and the patient underwent chemotherapy with a residual mass and vertebral involvement by MRI. Combined vertebral resection with spinal reconstruction and retroperitoneal lymph node dissection demonstrated residual fibrosis. While bony metastasis of nonseminomatous germ cell tumors is rare, resection with spinal reconstruction can be accomplished with acceptable morbidity.

Tumors of the skull base in children: review of tumor types and management strategies.

Although many treatment strategies for skull base tumors in adults have been reported, relatively little has been reported regarding such therapies in the pediatric population. Skull base tumors in children present a therapeutic challenge because of their unique pathological composition, the constraints of the maturing skull and brain, and the small size of the patients. In this review, the authors examine the pediatric skull base lesions that occur in the anterior, middle, and posterior cranial base, focusing on unique pediatric tumors such as encepahalocele, fibrous dysplasia, esthesioneuroblastoma, craniopharyngioma, juvenile nasopharyngeal angiofibroma, cholesteatoma, chordoma, chondrosarcoma, and Ewing sarcoma. They review management strategies that include radio- and chemotherapy, as well as surgical approaches with emphasis on the modifications and complications associated with the procedures as they apply in children. Evidence for the advantages and limitations of radiotherapy, chemotherapy, and surgery as it pertains to the pediatric population will be examined. With a working knowledge of skull base anatomy and special considerations of the developing craniofacial skeleton, neurosurgeons can treat skull base lesions in children with acceptable morbidity and mortality rates. Outcomes in this population may be better than those in adults, in part because of the benign histopathology that frequently affects the pediatric skull base, as well as the plasticity of the maturing nervous system.