Effects of Training Intensity on Locomotor Performance in Individuals With Chronic Spinal Cord Injury: A Randomized Crossover Study

Background. Many physical interventions can improve locomotor function in individuals with motor incomplete spinal cord injury (iSCI), although the training parameters that maximize recovery are not clear. Previous studies in individuals with other neurologic injuries suggest the intensity of locomotor training (LT) may positively influence walking outcomes. However, the effects of intensity during training of individuals with iSCI have not been tested. Objective. The purpose of this pilot, blinded-assessor randomized trial was to evaluate the effects of LT intensity on walking outcomes in individuals with iSCI. Methods. Using a crossover design, ambulatory participants with iSCI \u3e1 year duration performed either high- or low-intensity LT for ≤20 sessions over 4 to 6 weeks. Four weeks following completion, the training interventions were alternated. Targeted intensities focused on achieving specific ranges of heart rate (HR) or ratings of perceived exertion (RPE), with intensity manipulated by increasing speeds or applying loads. Results. Significantly greater increases in peak treadmill speeds (0.18 vs 0.02 m/s) and secondary measures of metabolic function and overground speed were observed following high- versus low-intensity training, with no effects of intervention order. Moderate to high correlations were observed between differences in walking speed or distances and differences in HRs or RPEs during high- versus low-intensity training. Conclusion. This pilot study provides the first evidence that the intensity of stepping practice may be an important determinant of LT outcomes in individuals with iSCI. Whether such training is feasible in larger patient populations and contributes to improved locomotor outcomes deserves further consideration

Implementation of wearable sensing technology for movement: Pushing forward into the routine physical rehabilitation care field

While the promise of wearable sensor technology to transform physical rehabilitation has been around for a number of years, the reality is that wearable sensor technology for the measurement of human movement has remained largely confined to rehabilitation research labs with limited ventures into clinical practice. The purposes of this paper are to: (1) discuss the major barriers in clinical practice and available wearable sensing technology; (2) propose benchmarks for wearable device systems that would make it feasible to implement them in clinical practice across the world and (3) evaluate a current wearable device system against the benchmarks as an example. If we can overcome the barriers and achieve the benchmarks collectively, the field of rehabilitation will move forward towards better movement interventions that produce improved function not just in the clinic or lab, but out in peoples\u27 homes and communities

High intensity variable stepping training in persons with motor incomplete spinal cord injury: a case series

Background and Purpose: Previous data suggest that large amounts of high intensity stepping training in variable contexts (tasks and environments) may improve locomotor function, aerobic capacity and treadmill gait kinematics in individuals post-stroke. Whether similar training strategies are tolerated and efficacious for patients with other acute-onset neurological diagnoses, such as motor incomplete spinal cord injury (iSCI) is unknown, particularly with potentially greater, bilateral impairments. This case series evaluated the feasibility and preliminary short and long-term efficacy of high intensity variable stepping practice in ambulatory participants >1 year post-iSCI. Case Series Description: Four participants with iSCI (neurological levels C5-T3) completed up to 40 1-hr sessions over 3–4 months. Stepping training in variable contexts was performed at up to 85% maximum predicted heart rate, with feasibility measures of patient tolerance, total steps/session, and intensity of training. Clinical measures of locomotor function, balance, peak metabolic capacity and gait kinematics during graded treadmill assessments were performed at baseline and post-training, with >1 year follow-up. Outcomes: Participants completed 24–40 sessions over 8–15 weeks, averaging 2222±653 steps/session, with primary adverse events of fatigue and muscle soreness. Modest improvements in locomotor capacity where observed at post-training, with variable changes in lower extremity kinematics during treadmill walking. Discussion: High intensity, variable stepping training was feasible and tolerated by participants with iSCI although only modest gains in gait function or quality were observed. The utility of this intervention in patients with more profound impairments may be limited

Defects in Stratum Corneum Desquamation Are the Predominant Effect of Impaired ABCA12 Function in a Novel Mouse Model of Harlequin Ichthyosis.

Harlequin Ichthyosis is a severe skin disease caused by mutations in the human gene encoding ABCA12. Here, we characterize a novel mutation in intron 29 of the mouse Abca12 gene that leads to the loss of a 5' splice donor site and truncation of the Abca12 RNA transcript. Homozygous mutants of this smooth skin or smsk allele die perinatally with shiny translucent skin, typical of animal models of Harlequin Ichthyosis. Characterization of smsk mutant skin showed that the delivery of glucosylceramides and CORNEODESMOSIN was defective, while ultrastructural analysis revealed abnormal lamellar bodies and the absence of lipid lamellae in smsk epidermis. Unexpectedly, mutant stratum corneum remained intact when subjected to harsh chemical dissociation procedures. Moreover, both KALLIKREIN 5 and -7 were drastically decreased, with retention of desmoplakin in mutant SC. In cultured wild type keratinocytes, both KALLIKREIN 5 and -7 colocalized with ceramide metabolites following calcium-induced differentiation. Reducing the intracellular levels of glucosylceramide with a glucosylceramide synthase inhibitor resulted in decreased secretion of KALLIKREIN proteases by wild type keratinocytes, but not by smsk mutant keratinocytes. Together, these findings suggest an essential role for ABCA12 in transferring not only lipids, which are required for the formation of multilamellar structures in the stratum corneum, but also proteolytic enzymes that are required for normal desquamation. Smsk mutant mice recapitulate many of the pathological features of HI and can be used to explore novel topical therapies against a potentially lethal and debilitating neonatal disease

Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103)

Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (\u3e 60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability. AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test. One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients a parts per thousand yen60 years old (median 66; range 60-74) had a significantly higher BuCL versus those \u3c 60 years old (median 50; range 18-60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p \u3e 0.34). Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients

Organic Cation Transporter 3 and the Dopamine Transporter Differentially Regulate Catecholamine Uptake in the Basolateral Amygdala and Nucleus Accumbens

Regional alterations in kinetics of catecholamine uptake are due in part to variations in clearance mechanisms. The rate of clearance is a critical determinant of the strength of catecholamine signaling. Catecholamine transmission in the nucleus accumbens core (NAcc) and basolateral amygdala (BLA) is of particular interest due to involvement of these regions in cognition and motivation. Previous work has shown that catecholamine clearance in the NAcc is largely mediated by the dopamine transporter (DAT), but clearance in the BLA is less DAT‐dependent. A growing body of literature suggests that organic cation transporter 3 (OCT3) also contributes to catecholamine clearance in both regions. Consistent with different clearance mechanisms between regions, catecholamine clearance is more rapid in the NAcc than in the BLA, though mechanisms underlying this have not been resolved. We compared the expression of DAT and OCT3 and their contributions to catecholamine clearance in the NAcc and BLA. We found DAT protein levels were ~ 4‐fold higher in the NAcc than in the BLA, while OCT3 protein expression was similar between the two regions. Immunofluorescent labeling of the two transporters in brain sections confirmed these findings. Ex vivo voltammetry demonstrated that the magnitude of catecholamine release was greater, and the clearance rate was faster in the NAcc than in the BLA. Additionally, catecholamine clearance in the BLA was more sensitive to the OCT3 inhibitor corticosterone, while clearance in the NAcc was more cocaine sensitive. These distinctions in catecholamine clearance may underlie differential effects of catecholamines on behavioral outputs mediated by these regions

Stepwise Regression and Latent Profile Analyses of Locomotor Outcomes Poststroke

Background and purpose: Previous data suggest patient demographics and clinical presentation are primary predictors of motor recovery poststroke, with minimal contributions of physical interventions. Other studies indicate consistent associations between the amount and intensity of stepping practice with locomotor outcomes. The goal of this study was to determine the relative contributions of these combined variables to locomotor outcomes poststroke across a range of patient demographics and baseline function. Methods: Data were pooled from 3 separate trials evaluating the efficacy of high-intensity training, low-intensity training, and conventional interventions. Demographics, clinical characteristics, and training activities from 144 participants >1-month poststroke were included in stepwise regression analyses to determine their relative contributions to locomotor outcomes. Subsequent latent profile analyses evaluated differences in classes of participants based on their responses to interventions. Results: Stepwise regressions indicate primary contributions of stepping activity on locomotor outcomes, with additional influences of age, duration poststroke, and baseline function. Latent profile analyses revealed 2 main classes of outcomes, with the largest gains in those who received high-intensity training and achieved the greatest amounts of stepping practice. Regression and latent profile analyses of only high-intensity training participants indicated age, baseline function, and training activities were primary determinants of locomotor gains. Participants with the smallest gains were older (≈60 years), presented with slower gait speeds (<0.40 m/s), and performed 600 to 1000 less steps/session. Conclusions: Regression and cluster analyses reveal primary contributions of training interventions on mobility outcomes in patients >1-month poststroke. Age, duration poststroke, and baseline impairments were secondary predictors

White Matter Microstructure and Structural Networks in Treatment-Resistant Schizophrenia Patients After Commencing Clozapine Treatment: A Longitudinal Diffusion Imaging Study

This study investigates changes on white matter microstructure and neural networks after 6 months of switching to clozapine in schizophrenia patients compared to controls, and whether any changes are related to clinical variables. T1 and diffusion-weighted MRI images were acquired at baseline before commencing clozapine and after 6 months of treatment for 22 patients with treatment-resistant schizophrenia and 23 controls. The Tract-based spatial statistics approach was used to compare changes over time between groups in fractional anisotropy (FA). Changes in structural network organisation weighted by FA and number of streamlines were assessed using graph theory. Patients displayed a significant reduction of FA over time (p<0.05) compared to controls in the genu and body of the corpus callosum and bilaterally in the anterior and superior corona radiata. There was no correlation between FA change in patients and changes in clinical variables or serum level of clozapine. There was no changes in structural network organisation between groups (F(7,280)=2.80;p = 0.187). This longitudinal study demonstrated progressive focal FA abnormalities in key anterior tracts, but preserved brain structural network organisation in patients. The FA reduction was independent of any clinical measures and may reflect progression of the underlying pathophysiology of this malignant form of schizophrenia illness