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Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury.
Gant, KL, Guest, JD, Palermo, AE, Vedantam, A, Jimsheleishvili, G, Bunge, MB, Brooks, AE, Anderson, KD, Thomas, CK, Santamaria, AJ, et al
Journal of neurotrauma. 2022;(3-4):285-299
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Abstract
A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (n = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI.
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Scalable culture techniques to generate large numbers of purified human Schwann cells for clinical trials in human spinal cord and peripheral nerve injuries.
Khan, A, Diaz, A, Brooks, AE, Burks, SS, Athauda, G, Wood, P, Lee, YS, Silvera, R, Donaldson, M, Pressman, Y, et al
Journal of neurosurgery. Spine. 2022;(1):135-144
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Abstract
OBJECTIVE Schwann cells (SCs) have been shown to play an essential role in axon regeneration in both peripheral nerve injuries (PNIs) and spinal cord injuries (SCIs). The transplantation of SCs as an adjunctive therapy is currently under investigation in human clinical trials due to their regenerative capacity. Therefore, a reliable method for procuring large quantities of SCs from peripheral nerves is necessary. This paper presents a well-developed, validated, and optimized manufacturing protocol for clinical-grade SCs that are compliant with Current Good Manufacturing Practices (CGMPs). METHODS The authors evaluated the SC culture manufacturing data from 18 clinical trial participants who were recruited for autologous SC transplantation due to subacute SCI (n = 7), chronic SCI (n = 8), or PNIs (n = 3). To initiate autologous SC cultures, a mean nerve length of 11.8 ± 3.7 cm was harvested either from the sural nerve alone (n = 17) or with the sciatic nerve (n = 1). The nerves were digested with enzymes and SCs were isolated and further expanded in multiple passages to meet the dose requirements for transplantation. RESULTS An average yield of 87.2 ± 89.2 million cells at P2 and 150.9 ± 129.9 million cells at P3 with high viability and purity was produced. Cell counts and rates of expansion increased with each subsequent passage from P0 to P3, with the largest rate of expansion between P2 and P3. Larger harvest nerve lengths correlated significantly with greater yields at P0 and P1 (p < 0.05). In addition, a viability and purity above 90% was sustained throughout all passages in nearly all cell products. CONCLUSIONS This study presents reliable CGMP-compliant manufacturing methods for autologous SC products that are suitable for regenerative treatment of patients with SCI, PNI, or other conditions.
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Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent.
Nguyen, A, Chow, DS, Wu, L, Teng, YA, Sarkar, M, Toups, EG, Harrop, JS, Schmitt, KM, Johnson, MM, Guest, JD, et al
Journal of clinical pharmacology. 2021;(9):1232-1242
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Abstract
Riluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A 1-compartment with first-order elimination population pharmacokinetic model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the phase 1 and the ongoing phase 2/3 trials. This change in therapeutic exposure may lead to a biased estimate of the exposure-response relationship when evaluating therapeutic effects. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification that preserves the required therapeutic exposure of riluzole.
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Limited Association between the Total Healthy Eating Index-2015 Score and Cardiovascular Risk Factors in Individuals with Long-Standing Spinal Cord Injury: An Exploratory Study: An Exploratory Study.
Li, J, Demirel, A, Azuero, A, Womack, ED, Kroeger, EN, McLain, A, Yarar-Fisher, C
Journal of the Academy of Nutrition and Dietetics. 2021;(11):2260-2266
Abstract
BACKGROUND The healthy eating index-2015 (HEI-2015) reflects diet quality in reference to the 2015-2020 Dietary Guidelines for Americans (DGA). Little is known regarding its application in individuals with chronic spinal cord injury (SCI). OBJECTIVE To explore the relationship between diet quality as assessed by the HEI-2015 and cardiovascular risk factors among individuals with chronic SCI. DESIGN This is a cross-sectional analysis of baseline data collected from August 2017 through November 2019 for an interventional study that evaluates the effects of a high-protein/low-carbohydrate diet on cardiovascular risk factors in individuals with chronic SCI at the University of Alabama at Birmingham. PARTICIPANTS/SETTING Twenty-four free-living adults with SCI (mean age, 45 ± 12 y; 8F/16M, level of injury: nine cervical, 15 thoracic; mean duration of injury: 20 ± 13 y) were included. MAIN OUTCOME MEASURES Participants underwent a 2-hour oral glucose tolerance test (OGTT) and a dual-energy x-ray absorptiometry scan. Dietary intake was assessed by three, 24-hour multiple-pass dietary recalls to calculate the HEI-2015 using the simple HEI scoring algorithm method. DATA ANALYSIS Multiple linear regression analyses were performed to predict indices of lipid metabolism and glucose homeostasis and C-reactive protein (CRP) from the HEI-2015. Principal component analysis was used to reduce the number of covariates (level of injury, sex, and body fat percentage). RESULTS On average, participants' diets were of low quality (HEI-2015, 47.2 ± 10.8). The regression models for fasting glucose (FG), cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and CRP had moderate to large effect sizes (adjusted R2 ≥ 13%), suggesting good explanatory abilities of the predictors. Small or limited effect sizes were observed for glucose tolerance, fasting insulin, triglycerides, and Matsuda index (adjusted R2 < 13%). The HEI-2015 accounted for a moderate amount of variation in FG (partial omega-squared, ωP2 = 13%). Each 10-point HEI-2015 score increase was associated with a 3.3-mg/dL decrease in FG concentrations. The HEI-2015 accounted for a limited amount of variation in other indices (ωP2 < 5%). CONCLUSIONS Among participants with SCI, higher conformance to the 2015-2020 DGA was 1) moderately associated with better FG homeostasis; and 2) trivially associated with other cardiovascular risk factors. Because of the small sample size, these conclusions cannot be extrapolated beyond the study sample. Future larger studies are warranted to better understand the relationship between diet quality and cardiovascular disease risks in this population.
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Barriers and Facilitators to Lifestyle Intervention Engagement and Weight Loss in People Living With Spinal Cord Injury.
Betts, AC, Ochoa, C, Hamilton, R, Sikka, S, Froehlich-Grobe, K
Topics in spinal cord injury rehabilitation. 2021;(1):135-148
Abstract
Background: Individuals living with spinal cord injury (SCI) have a high prevalence of obesity and unique barriers to healthy lifestyle. Objective: To examine barriers and facilitators to engagement and weight loss among SCI participants enrolled in the Group Lifestyle Balance Adapted for individuals with Impaired Mobility (GLB-AIM), a 12-month intensive lifestyle intervention. Methods: SCI participants (N = 31) enrolled in a wait-list, randomized controlled trial where all participants received intervention between August 2015 and February 2017. Analyses of pooled data occurred in 2020 to examine cross-sectional and prospective associations of hypothesized barriers and facilitators with (1) intervention engagement, comprised of attendance and self-monitoring, and (2) percent weight change from baseline to 12 months. We performed multivariable linear regression on variables associated with outcomes at p < .05 in bivariate analyses and controlled for intervention group. Results: Participants were middle-aged (mean age, 48.26 ± 11.01 years), equally male (50%) and female, White (80.7%), and unemployed (65.6%). In participants who completed baseline surveys (n = 30), dietary self-efficacy explained 26% of variance in engagement (p < .01); among the 12-month study completers (n = 22, 71.0%), relationship issues explained 23% of variance in engagement (p < .01). Money problems, health issues unrelated to SCI, lack of motivation, and experimental group explained 57% of variance in weight loss (p for model < .01), with lack of motivation uniquely explaining 24% of variance (p < .01). Conclusion: Improving engagement and weight loss for persons with SCI in the GLBAIM program may be achieved by addressing lack of motivation, relationship issues, and nutrition self-efficacy.
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Safety of Every-Other-Day Fasting in the Treatment of Spinal Cord Injury: A Randomized Controlled Trial.
Zheng, J, Liu, J, Jiang, Y, Pang, R, Yang, X, Liu, H, Lin, N, Li, Y, Xiong, D, Chen, X, et al
American journal of physical medicine & rehabilitation. 2021;(12):1184-1189
Abstract
Every-other-day fasting is effective for a variety of major human diseases, but the safety of these interventions is uncertain for patients with spinal cord injury. A randomized controlled study was conducted to investigate the safety of every-other-day fasting in patients with spinal cord injury. Participants who met the diagnostic inclusion and exclusion criteria were randomly divided into the control and every-other-day fasting groups. In the every-other-day fasting group, fasting lasted from 09:00 p.m. on day 1 to 06:00 p.m. on the following day (day 2). Dinner on day 2 was restricted to approximately 30% of the average daily calorie intake. The changes in plasma glucose were recorded daily for 2 days and every other day from the third day after every-other-day fasting intervention. The changes in albumin, prealbumin, plasma potassium, serum sodium, blood calcium, body weight, and body mass index were monitored at the baseline and at the end of the every-other-day fasting intervention. The results showed that compared with the control group, the mean blood glucose levels were significantly decreased from the second week after every-other-day fasting intervention. The body weight of patients in the every-other-day fasting group was notably reduced compared with that at baseline, whereas in body mass index, no obvious differences were observed before and after treatment with every-other-day fasting. In general, every-other-day fasting could be considered as a safe approach for individuals with spinal cord injury.
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Carbohydrate Considerations for Athletes with a Spinal Cord Injury.
Ruettimann, B, Perret, C, Parnell, JA, Flueck, JL
Nutrients. 2021;(7)
Abstract
The Paralympic movement is growing in popularity, resulting in increased numbers of athletes with a spinal cord injury (SCI) competing in various sport disciplines. Athletes with an SCI require specialized recommendations to promote health and to maximize performance, as evidenced by their metabolic and physiological adaptations. Nutrition is a key factor for optimal performance; however, scientifically supported nutritional recommendations are limited. This review summarizes the current knowledge regarding the importance of carbohydrates (CHO) for health and performance in athletes with an SCI. Factors possibly affecting CHO needs, such as muscle atrophy, reduced energy expenditure, and secondary complications are analyzed comprehensively. Furthermore, a model calculation for CHO requirements during an endurance event is provided. Along with assessing the effectiveness of CHO supplementation in the athletic population with SCI, the evaluation of their CHO intake from the available research supplies background to current practices. Finally, future directions are identified. In conclusion, the direct transfer of CHO guidelines from able-bodied (AB) athletes to athletes with an SCI does not seem to be reasonable. Based on the critical role of CHOs in exercise performance, establishing recommendations for athletes with an SCI should be the overall objective for prospective research.
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Novel Approaches for Omega-3 Fatty Acid Therapeutics: Chronic Versus Acute Administration to Protect Heart, Brain, and Spinal Cord.
Zirpoli, H, Chang, CL, Carpentier, YA, Michael-Titus, AT, Ten, VS, Deckelbaum, RJ
Annual review of nutrition. 2020;:161-187
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This article reviews novel approaches for omega-3 fatty acid (FA) therapeutics and the linked molecular mechanisms in cardiovascular and central nervous system (CNS) diseases. In vitro and in vivo research studies indicate that omega-3 FAs affect synergic mechanisms that include modulation of cell membrane fluidity, regulation of intracellular signaling pathways, and production of bioactive mediators. We compare how chronic and acute treatments with omega-3 FAs differentially trigger pathways of protection in heart, brain, and spinal cord injuries. We also summarize recent omega-3 FA randomized clinical trials and meta-analyses and discuss possible reasons for controversial results, with suggestions on improving the study design for future clinical trials. Acute treatment with omega-3 FAs offers a novel approach for preserving cardiac and neurological functions, and the combinations of acute treatment with chronic administration of omega-3 FAs might represent an additional therapeutic strategy for ameliorating adverse cardiovascular and CNS outcomes.
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Selenium and copper status - potential signposts for neurological remission after traumatic spinal cord injury.
Seelig, J, Heller, RA, Hackler, J, Haubruck, P, Moghaddam, A, Biglari, B, Schomburg, L
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2020;:126415
Abstract
INTRODUCTION Traumatic Spinal Cord Injury (TSCI) is a severe incident resulting in loss of motor and sensory function caused by complex pathological mechanisms including massive oxidative stress and extensive inflammatory processes. The essential trace elements selenium (Se) and copper (Cu) play crucial roles as part of the antioxidant defense. HYPOTHESIS Remission after TSCI is associated with characteristic dynamics of early changes in serum Cu and Se status. STUDY DESIGN Single-center prospective observational study. PATIENTS AND METHODS Serum samples from TSCI patients were analyzed (n = 52); 21 recovered and showed a positive abbreviated injury score (AIS) conversion within 3 months (G1), whereas 21 had no remission (G0). Ten subjects with vertebral fractures without neurological impairment served as control (C). Different time points (at admission, and after 4, 9, 12, and 24 h) were analyzed for total serum Se and Cu concentrations by total reflection X-ray fluorescence, and for Selenoprotein P (SELENOP) and Ceruloplasmin (CP) by sandwich ELISA. RESULTS At admission, CP and SELENOP concentrations were higher in the remission group (G1) than in the non-remission group (G0). Within 24 h, there were marginal changes in Se, SELENOP, Cu and CP concentrations in the groups of controls (C) and G0. In contrast, these parameters decreased significantly in G1. Binary logistic regression analysis including Cu and Se levels at admission in combination with Se and CP levels after 24 h allowed a prediction for potential remission, with an area under the curve (AUC) of 87.7% (CI: 75.1%-100.0%). CONCLUSION These data indicate a strong association between temporal changes of the Se and Cu status and the clinical outcome after TSCI. The dynamics observed may reflect an ongoing redistribution of the trace elements in favor of a better anti-inflammatory response and a more successful neurological regeneration.
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Well on wheels intervention: Satisfaction with life and health for adults with spinal cord injuries.
Silveira, SL, Ledoux, TA, Johnston, CA, Kalpakjian, C, O'Connor, DP, Cottingham, M, McGrath, R, Tate, D
The journal of spinal cord medicine. 2020;(1):60-68
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Objective/Background: To examine how demographic and injury characteristics identify satisfaction with life (SWL), and assess the differential effects of a wellness intervention by baseline SWL groups.Design: Baseline and longitudinal analysis of a randomized controlled pilot intervention using decision tree regression and linear mixed models.Setting: Community based.Participants: Seventy-two individuals with spinal cord injury (SCI) were randomized to an intervention group (n = 39) or control group (n = 33). Participants were aged 44.1 ± 13.0 years and 13.1 ± 10.6 years post-injury. Most participants were male (n = 50; 69.4%) and had paraplegia (n = 38; 52.7%). Participants were classified as high versus low SWL at baseline using a cutoff score of 20.Interventions: The intervention aimed to increase self-efficacy, and in turn, increase engagement in health-promoting behaviors related to SWL. Six 4-hour in-person workshops were conducted over a 3-month period led by experts and peer-mentors who were available for support.Outcome measure(s): Self-efficacy for health practices, secondary condition severity, health-promoting behaviors, perceived stress, and SWL.Results: At baseline, participants with low SWL were recently injured (<4.5 years), while persons with high SWL were married and younger (<49 years old). Intervention participants with low SWL at baseline significantly improved SWL over time compared to those with high SWL (P = 0.02).Conclusion: Certain injury and demographic characteristics were associated with SWL, and intervention participants with low SWL at baseline improved their SWL over 2 years. Healthcare providers should consider time post-injury, marital status, and age in identifying individuals at risk for low SWL that may benefit from wellness interventions.