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Deniz Konya,
Wei-Lee Liao, Howard Choi,
Dou Yu,
Matthew C Woodard,
Kimberly M Newton,
Allyson M King,
Necmettin M Pamir,
Peter M Black,
Walter R Frontera,
Sunil Sabharwal,
Yang D Teng
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ABSTRACT: Functional improvements after spinal cord injury (SCI) have been reported anecdotally following neurotization, in other words, rerouting nerves proximal to injured cord segments to distal neuromuscular targets, although the underlying mechanisms remain largely unknown.
To test our hypothesis that neurotization-mediated recovery is primarily attributable to CNS neuroplasticity that therefore manifests optimal response during particular therapeutic windows, we anastomosed the T12 intercostal nerve to the ipsilateral L3 nerve root 1-4 weeks after T13-L1 midline hemisection in rats.
While axonal tracing and electromyography revealed limited reinnervation in the target muscles, neurobehavioral function, as assessed by locomotion, extensor postural thrust and sciatic functional index of SCI rats receiving neurotization 7-10 days postinjury (n = 11), recovered to levels close to non-SCI controls with neurotization only (n = 3), beginning 3-5 weeks postanastomosis. Conversely, hindlimb deficits were unchanged in hemisected controls with sham neurotization (n = 7) or 4 weeks-delayed neurotization (n = 3) and in rats that had undergone T13-L1 transection plus bilateral anastomoses (n = 6).
Neurotized SCI animals demonstrated multiparameters of neural reorganization in the distal lumbar cord, including enhanced proliferation of endogenous neural stem cells, increased immunoreactivity of serotonin and synaptophysin, and neurite growth/sprouting, suggesting that anastomosing functional nerves with the nerve stump emerging distal to the hemisection stimulates neuroplasticity in the dysfunctional spinal cord. Our conclusion is validated by the fact that severance of the T13-L1 contralateral cord abolished the postanastomosis functional recovery. Neurotization and its neuroplastic sequelae need to be explored further to optimize clinical strategies of post-SCI functional repair.
Regenerative Medicine 06/2008; 3(3):309-27. · 3.72 Impact Factor
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ABSTRACT: As data elucidating the complexity of spinal cord injury pathophysiology emerge, it is increasingly being recognized that successful repair will probably require a multifaceted approach that combines tactics from various biomedical disciplines, including pharmacology, cell transplantation, gene therapy and material sciences. Recently, new evidence highlighting the benefit of physical activity and rehabilitation interventions during the post-injury phase has provided novel possibilities in realizing effective repair after spinal cord injury. However, before a comprehensive therapeutic strategy that optimally utilizes the benefits of each of these disciplines can be designed, the basic mechanisms by which these various interventions act must be thoroughly explored and important synergistic and antagonistic interactions identified. In examining the mechanisms by which physical activity-based functional recovery after spinal cord injury is effected, endogenous neural stem cells, in our opinion, engender a potentially key role. Multipotent neural stem cells possess many faculties that abet recovery, including the ability to assess the local microenvironment and deliver biofactors that promote neuroplasticity and regeneration, as well as the potential to replenish damaged or eradicated cellular elements. Encouragingly, the functional recovery owing to physical activity-based therapies appears relatively robust, even when therapy is initiated in the chronic stage of spinal cord injury. In this article, we review experimental outcomes related to our hypothesis that endogenous neural stem cells mediate the functional recovery noted in spinal cord injury following physical activity-based treatments. Overall, the data advocates the incorporation of increased physical activity as a component of the multidimensional treatment of spinal cord injury and underscores the critical need to employ research-based mechanistic approaches for developing future advances in the rehabilitation of neurological injury and disorders.
Regenerative Medicine 12/2006; 1(6):763-76. · 3.72 Impact Factor
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ABSTRACT: Spinal cord injury (SCI) results in muscle weakness but the degree of impairment at the level of single fibers is not known. The purpose of this study was to examine the effects of T9-level SCI on single muscle fibers from the tibialis anterior of rats. Significant decreases in cross-sectional area (CSA), maximal force (Po), and specific force (SF = Po/CSA) were noted at 2 weeks. Atrophy and force-generating capacity were reversed at 4 weeks, but SF remained impaired. Maximum shortening velocity (Vo) did not change after injury. SCI thus appears to affect various contractile properties of single muscle fibers differently. Normal cage activity may partially restore function but new interventions are needed to restore muscle fiber quality.
Muscle & Nerve 08/2006; 34(1):101-4. · 2.37 Impact Factor
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ABSTRACT: To evaluate selected laboratory components of a comprehensive periodic health evaluation program for patients with spinal cord injury and disorders (SCI/D).
A retrospective study.
A Department of Veterans Affairs spinal cord injury center.
Community-dwelling male veterans with SCI/D (N=350).
Not applicable.
Proportion of laboratory tests that resulted in new diagnoses (diagnostic yield) and proportion of laboratory tests that resulted in changes in management (therapeutic yield).
Although abnormality rates for many routine laboratory tests were high (up to 31.5%), diagnostic and therapeutic yields were low (<1.5%), with the exception of glucose (therapeutic yield, 3.4%) and lipid tests (up to a 4.1% diagnostic and 15.2% therapeutic yield).
Our data revealed that diagnostic and therapeutic yields for many laboratory components of the annual PHE program for veterans with SCI/D were low, consistent with findings in the general ambulatory population. Further data collection, particularly prospective longitudinal data, may help optimize the selection and frequency of laboratory tests performed as part of this program.
Archives of Physical Medicine and Rehabilitation 05/2006; 87(5):603-10. · 2.28 Impact Factor
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Howard Choi,
Wei-Lee Liao,
Kimberly M Newton,
Renna C Onario,
Allyson M King,
Federico C Desilets,
Eric J Woodard,
Marc E Eichler,
Walter R Frontera,
Sunil Sabharwal,
Yang D Teng
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ABSTRACT: Respiratory dysfunction after cervical spinal cord injury (SCI) has not been examined experimentally using conscious animals, although clinical SCI most frequently occurs in midcervical segments. Here, we report a C5 hemicontusion SCI model in rats with abnormalities that emulate human post-SCI pathophysiology, including spontaneous recovery processes. Post-C5 SCI rats demonstrated deficits in minute ventilation (Ve) responses to a 7% CO2 challenge that correlated significantly with lesion severities (no injury or 12.5, 25, or 50 mm x 10 g weight drop; New York University impactor; p < 0.001) and ipsilateral motor neuron loss (p = 0.016). Importantly, C5 SCI resulted in at least 4 weeks of respiratory abnormalities that ultimately recovered afterward. Because serotonin is involved in respiration-related neuroplasticity, we investigated the impact of activating 5-HT1A receptors on post-C5 SCI respiratory dysfunction. Treatment with the 5-HT1A agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH DPAT) (250 microg/kg, i.p.) restored hypercapnic Ve at 2 and 4 weeks after injury (i.e., approximately 39.2% increase vs post-SCI baseline; p < or = 0.033). Improvements in hypercapnic Ve response after single administration of 8-OH DPAT were dose dependent and lasted for approximately 4 h(p < or = 0.038 and p < or = 0.024, respectively). Treatment with another 5-HT1A receptor agonist, buspirone (1.5 mg/kg, i.p.), replicated the results, whereas pretreatment with a 5-HT1A-specific antagonist, 4-iodo-N-[2-[4(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.) given 20 min before 8-OH DPAT negated the effect of 8-OH DPAT. These results imply a potential clinical use of 5-HT1A agonists for post-SCI respiratory disorders.
Journal of Neuroscience 05/2005; 25(18):4550-9. · 7.11 Impact Factor
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ABSTRACT: We investigated whether permeability transition-mediated release of mitochondrial cytochrome c is a potential therapeutic target for treating acute spinal cord injury (SCI). Based on previous reports, minocycline, a second-generation tetracycline, exerts neuroprotection partially by inhibiting mitochondrial cytochrome c release and reactive microgliosis. We first evaluated cytochrome c release at the injury epicenter after a T10 contusive SCI in rats. Cytochrome c release peaked at approximately 4-8 h postinjury. A dose-response study generated a safe pharmacological regimen that enabled i.p. minocycline to significantly lower cytosolic cytochrome c at the epicenter 4 h after SCI. In the long-term study, i.p. minocycline (90 mg/kg administered 1 h after SCI followed by 45 mg/kg administered every 12 h for 5 days) markedly enhanced long-term hind limb locomotion relative to that of controls. Coordinated motor function and hind limb reflex recoveries also were improved significantly. Histopathology suggested that minocycline treatment alleviated later-phase tissue loss, with significant sparing of white matter and ventral horn motoneurons at levels adjacent to the epicenter. Furthermore, glial fibrillary acidic protein and 2',3' cyclic nucleotide 3' phosphodiesterase immunocytochemistry showed an evident reduction in astrogliosis and enhanced survival of oligodendrocytes. Therefore, release of mitochondrial cytochrome c is an important secondary injury mechanism in SCI. Drugs with multifaceted effects in antagonizing this process and microgliosis may protect a proportion of spinal cord tissue that is clinically significant for functional recovery. Minocycline, with its proven clinical safety, capability to cross the blood-brain barrier, and demonstrated efficacy during a clinically relevant therapeutic window, may become an effective therapy for acute SCI.
Proceedings of the National Academy of Sciences 04/2004; 101(9):3071-6. · 9.68 Impact Factor
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ABSTRACT: To determine if standardized testing results and other factors correlate with success on the 2001 American Board of Physical Medicine and Rehabilitation part 1 board certification examination (POE).
An anonymous two-part survey was distributed to 302 senior resident physicians in the American College of Graduate Medicine Education-accredited physical medicine and rehabilitation training programs in the United States deemed eligible for the 2001 POE.
A total of 94 of 302 distributed surveys (31.1%) were returned; 86 met the inclusion criteria (81 passes and five failures). A significant correlation was found between both quartile ranking on the Self Assessment Examination and United States Medical Licensing Examination (USMLE) passage on the first attempt with POE quartile rank (P < 0.01). Other factors, such as number of hours of faculty-led didactics per week, textbook use, and participation in formal board review courses did not correlate with POE quartile ranking.
Residents who were successful on previous standardized tests scored well on the POE. Quartile ranking on Self Assessment Examination and USMLE or National Board of Osteopathic Medical Examiners success was found to correlate significantly with POE quartile rank. This information may be helpful for future POE preparation and prospective candidate selection for physical medicine and rehabilitation.
American Journal of Physical Medicine & Rehabilitation 10/2003; 82(9):686-91. · 1.58 Impact Factor
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ABSTRACT: We investigated the effects of clenbuterol, a beta2-adrenoceptor agonist with known anabolic and neuroprotective properties, on G93A-SOD1 mice, a transgenic murine model of familial amyotrophic lateral sclerosis (ALS). Relative to saline-treated vehicle controls (0.2 ml/kg/day; i.p.), early pathologic G93A-SOD1 mice treated with clenbuterol (1.5 mg/kg/day; i.p.) demonstrated a delayed onset of hindlimb signs as measured by rotarod performance, slowed disease progression, as well as trends toward mitigated losses of lumbar motoneurons and body weight. Responses in female G93A-SOD1 mice were favorable to those of males, suggesting synergistic effects between clenbuterol and sex-specific factors. Overall, our data suggest that clenbuterol offers therapeutic effects on ALS-related neuromuscular degeneration.
Neuroscience Letters 397(1-2):155-8. · 2.11 Impact Factor
