Functional range of motion of the cervical spine in cervical fusion patients during activities of daily living.

Following cervical spine fusion there is a reduction in maximum range of motion (ROM) but how this impacts activity of daily living (ADLs) and quality of life is unknown. This study's purpose is to quantify maximum and functional cervical spine ROM in patients with multi-level cervical fusion (>3 levels) compared to controls during ADLs and to correlate functional range of motion with scores from patient reported outcomes measures (PROs) including the Comparative Pain Scale (CPS), Fear Avoidance Belief Questionnaire (FABQ), and Neck Disability Index (NDI). An inertial measurement unit (IMU) system quantified ROM during ADLs in the extension/flexion, lateral bending, and axial rotation directions of motion. The reliability of this system was compared to standard optical motion tracking. Fourteen participants (8 females, age = 60.0 years (18.7) (median, (interquartile range)) with a history of multi-level cervical fusion (years post-op 0.9 (0.7)) were compared to 16 controls (13 females, age = 52.1 years (15.8)). PROs were collected for each participant. Fusion participants had significantly decreased maximum ROM in all directions of motion. Fusion participants had decreased ROM for some ADLs (backing up a car, using a phone, donning socks, negotiating stairs). CPS, FABQ, and NDI scores were significantly increased in fusion participants. Reductions in two activities (backing up a car, stair negotiation) correlated with a combination of increased PRO scores. Cervical fusion decreases maximum ROM and is correlated with increased PROs in some ADLs, however there is minimal impact on functional ROM. Investigation into velocity and acceleration may yield categorization of pathologic movement.

A Portable System for Remote Rehabilitation Following a Total Knee Replacement: A Pilot Randomized Controlled Clinical Study.

Rehabilitation has been shown to improve functional outcomes following total knee replacement (TKR). However, its delivery and associated costs are highly variable. The authors have developed and previously validated the accuracy of a remote (wearable) rehabilitation monitoring platform (interACTION). The present study's objective was to assess the feasibility of utilizing interACTION for the remote management of rehabilitation after TKR and to determine a preliminary estimate of the effects of the interACTION system on the value of rehabilitation. Specifically, we tested post-operative outpatient rehabilitation supplemented with interACTION (n = 13) by comparing it to a standard post-operative outpatient rehabilitation program (n = 12) using a randomized design. Attrition rates were relatively low and not significantly different between groups, indicating that participants found both interventions acceptable. A small (not statistically significant) decrease in the number of physical therapy visits was observed in the interACTION Group, therefore no significant difference in total cost could be observed. All patients and physical therapists in the interACTION Group indicated that they would use the system again in the future. Therefore, the next steps are to address the concerns identified in this pilot study and to expand the platform to include behavioral change strategies prior to conducting a full-scale randomized controlled trial. Trial registration: ClinicalTrials.gov NCT02646761 "interACTION: A Portable Joint Function Monitoring and Training System for Remote Rehabilitation Following TKA" 6 January 2016.

Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan: mouse proof-of-concept.

5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR's pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.

Adaptation of a clinical fixation device for biomechanical testing of the lumbar spine.

In-vitro biomechanical testing is widely performed for characterizing the load-displacement characteristics of intact, injured, degenerated, and surgically repaired osteoligamentous spine specimens. Traditional specimen fixture devices offer an unspecified rigidity of fixation, while varying in the associated amounts and reversibility of damage to and "coverage" of a specimen - factors that can limit surgical access to structures of interest during testing as well as preclude the possibility of testing certain segments of a specimen. Therefore, the objective of this study was to develop a specimen fixture system for spine biomechanical testing that uses components of clinically available spinal fixation hardware and determine whether the new system provides sufficient rigidity for spine biomechanical testing. Custom testing blocks were mounted into a robotic testing system and the angular deflection of the upper fixture was measured indirectly using linear variable differential transformers. The fixture system had an overall stiffness 37.0, 16.7 and 13.3 times greater than a typical human functional spine unit for the flexion/extension, axial rotation and lateral bending directions respectively - sufficient rigidity for biomechanical testing. Fixture motion when mounted to a lumbar spine specimen revealed average motion of 0.6, 0.6, and 1.5° in each direction. This specimen fixture method causes only minimal damage to a specimen, permits testing of all levels of a specimen, and provides for surgical access during testing.

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept.

Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HTExt) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HTExt beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) elevates 5-HTExt beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment-resistant depression (TRD). However, sustained, stable 5-HTExt elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HTExt elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5-HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HTExt beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HTExt spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HTExt beyond the SSRI effect and represent a novel treatment for TRD.

Differential regulation of microtubule severing by APC underlies distinct patterns of projection neuron and interneuron migration.

Coordinated migration of distinct classes of neurons to appropriate positions leads to the formation of functional neuronal circuitry in the cerebral cortex. The two major classes of cortical neurons, interneurons and projection neurons, utilize distinctly different modes (radial versus tangential) and routes of migration to arrive at their final positions in the cerebral cortex. Here, we show that adenomatous polyposis coli (APC) modulates microtubule (MT) severing in interneurons to facilitate tangential mode of interneuron migration, but not the glial-guided, radial migration of projection neurons. APC regulates the stability and activity of the MT-severing protein p60-katanin in interneurons to promote the rapid remodeling of neuronal processes necessary for interneuron migration. These findings reveal how severing and restructuring of MTs facilitate distinct modes of neuronal migration necessary for laminar organization of neurons in the developing cerebral cortex.