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Neocortical tissue obtained from rat embryos was frozen and stored at - 70 degrees C for 6 h prior to transplantation into the cerebellum of neonatal rats. Growth, differentiation, and integration of this tissue within the host brain was... more
Neocortical tissue obtained from rat embryos was frozen and stored at - 70 degrees C for 6 h prior to transplantation into the cerebellum of neonatal rats. Growth, differentiation, and integration of this tissue within the host brain was comparable to that obtained from freshly dissected and transplanted tissue. It is suggested that freezing to low temperatures does not adversely effect the viability or transplantability of the neural tissue.
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Earlier, we showed that antibodies specific for human serum albumin are able to bind to erythrocyte-associated albumin and inhibit complement mediated hemolysis. In the present study we determine if inhibition is occurring at the membrane... more
Earlier, we showed that antibodies specific for human serum albumin are able to bind to erythrocyte-associated albumin and inhibit complement mediated hemolysis. In the present study we determine if inhibition is occurring at the membrane attack phase of complement activation or at an earlier step. We show that although cell-bound anti-albumin antibodies do not inhibit binding and activation of C3 or uptake of C9, they do appear to cause cells to become refractory to lysis by the membrane attack complex as they inhibit both the kinetics and the extent of hemolysis in a reactive lysis system which employs preformed C5b6 plus C7, C8, and C9. We believe that this is the first report of inhibition of the hemolytic activity of the membrane attack complex by antibodies bound to an erythrocyte surface antigen.
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Current dogma states that meaningful recovery of function after spinal cord injury (SCI) will likely require a combination of therapeutic interventions comprised of regenerative/neuroprotective transplants, addition of neurotrophic... more
Current dogma states that meaningful recovery of function after spinal cord injury (SCI) will likely require a combination of therapeutic interventions comprised of regenerative/neuroprotective transplants, addition of neurotrophic factors, elimination of inhibitory molecules, functional sensorimotor training, and/or stimulation of paralyzed muscles or spinal circuits. We routinely use (1) peripheral nerve grafts to support and direct axonal regeneration across an incomplete cervical or complete thoracic transection injury, (2) matrix modulation with chondroitinase (ChABC) to facilitate axonal extension beyond the distal graft-spinal cord interface, and (3) exercise, such as forced wheel walking, bicycling, or step training on a treadmill. We and others have demonstrated an increase in spinal cord levels of endogenous neurotrophic factors with exercise, which may be useful in facilitating elongation and/or synaptic activity of regenerating axons and plasticity of spinal neurons below the level of injury.
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In this study, the role of the calcineurin pathway in skeletal muscle atrophy and atrophy-reducing interventions was investigated in rat soleus muscles. Because calcineurin has been suggested to be involved in skeletal and cardiac muscle... more
In this study, the role of the calcineurin pathway in skeletal muscle atrophy and atrophy-reducing interventions was investigated in rat soleus muscles. Because calcineurin has been suggested to be involved in skeletal and cardiac muscle hypertrophy, we hypothesized that blocking calcineurin activity would eliminate beneficial effects of interventions that maintain muscle mass in the face of atrophy-inducing stimuli. Hindlimb suspension and spinal cord transection were used to induce atrophy, and intermittent reloading and exercise were used to reduce atrophy. Cyclosporin (CsA, 25 mg · kg−1 · day−1) was administered to block calcineurin activity. Soleus muscles were studied 14 days after the onset of atrophy. CsA administration did not inhibit the beneficial effects of the two muscle-maintaining interventions, nor did it change muscle mass in control or atrophied muscles, suggesting that calcineurin does not play a role in regulating muscle size during atrophy. However, calcineurin ...
Research Interests: Physiology, Transcription Factors, Exercise therapy, Signal Transduction, Female, and 15 moreAnimals, Spinal Cord, Male, American, Cyclosporine, Medical Physiology, Cell nucleus, Atrophy, Rats, Rat, Calcineurin, Calcineurin inhibitors, DNA binding proteins, Biochemistry and cell biology, and Axotomy
Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high... more
Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high therapeutic value. For successful ...
Research Interests: Neuroscience, Treatment Outcome, Cell and Tissue Transplantation, Chronic Disease, Female, and 13 moreAnimals, Spinal Cord, The, Cervical Vertebrae, Nerve Regeneration, Rats, Peripheral nerves, Peripheral Nerve, Spinal Cord Injuries, Recovery of Function, Psychology and Cognitive Sciences, Medical and Health Sciences, and axon regeneration
Mouse neural tube development in vitro was examined following the isolation and culturing of specific regions of the neural tube. Developmental characteristics of neuron formation and differentiation were assessed both quantitatively and... more
Mouse neural tube development in vitro was examined following the isolation and culturing of specific regions of the neural tube. Developmental characteristics of neuron formation and differentiation were assessed both quantitatively and qualitatively. A 1 mm length of embryonic day 10 mouse neural tube was cut into 32 microfragments of equal size and cultured on collagen coated cover-slips. Neuronal cells were observed to emerge after 3 days in culture and to migrate away from the fragment upon an immature astroglial precursor cell layer that had begun to form within the first 24 h of culturing. The extent of neuronal migration, the density and total number of neurons per outgrowth zone, and the size distribution of neurons was quantitated after 21 days in culture. Three distinct patterns of neuronal outgrowth (Types II, III and IV) could be observed with a fourth pattern (Type I) best described as being neuron free. Neuron free outgrowth zones (Type 1) were comprized totally of gl...
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Studies were carried out to determine if an intraspinal transplant (Trpl) of fetal spinal cord tissue or hind limb exercise (Ex) affected the changes in myosin heavy chain (MyHC) composition or myofiber size that occur following a... more
Studies were carried out to determine if an intraspinal transplant (Trpl) of fetal spinal cord tissue or hind limb exercise (Ex) affected the changes in myosin heavy chain (MyHC) composition or myofiber size that occur following a complete transection (Tx) of the lower thoracic spinal cord of the adult rat. In one group of animals, transplants were made acutely, whereas in a second group, daily cycling exercise was initiated 5 days after injury, with animals in both groups being sacrificed 90 days after injury. The soleus muscle is normally composed of myofibers expressing either type I (90%) or type IIa (10%) MyHC. Following a spinal transection, expression of type I MyHC isoform decreased (18% of myofibers), type IIa MyHC expression increased (65% of myofibers), and the majority of myofibers (80%) expressed type IIx MyHC. Most myofibers coexpressed multiple MyHC isoforms. Compared with Tx only, with Ex or with Trpl, there was a decrease in the number of myofibers expressing type I or IIa isoforms but little change in expression of IIx MyHC. Myofibers expressing the IIb isoform appeared in several transplant recipients but not after exercise. Transection resulted in atrophy of type I myofibers to approximately 50% of normal size, whereas myofibers were significantly larger after exercise (74% of control) and in Trpl recipients (77% of control). Type IIa myofibers also were significantly larger in Trpl recipients compared with the Tx only group. Overall, the mean myofiber size was significantly greater after exercise and in Trpl recipients compared with myofibers in Tx only animals. Thus, although neither strategy shifted the MyHC profile towards the control, both interventions influenced the extent of atrophy observed after spinalization. These data suggest that palliative strategies can be developed to modulate some of the changes in hind limb muscles that occur following a spinal cord injury.
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Embryonic neocortical and brainstem tissues were frozen, stored for variable periods, thawed and transplanted into the cerebellum of neonatal host rats. Various conditions related to freezing, media for freezing, DMSO as the... more
Embryonic neocortical and brainstem tissues were frozen, stored for variable periods, thawed and transplanted into the cerebellum of neonatal host rats. Various conditions related to freezing, media for freezing, DMSO as the cryoprotectant, and thawing were analyzed. The findings indicated that the following conditions yielded best results for neocortical transplantation: freezing at a rate of 1 degrees C/min, using rat amniotic fluid as the medium for freezing, using 10% DMSO as the cryoprotectant, storing the frozen tissues at -90 degrees C, thawing the tissues fast just prior to transplantation, and transplanting them in the host brain with little or no delay. Other conditions having adverse effects on the neural tissues were considered. Issues pertaining to transplantability and retainability of the neural tissues inside the host brain, and effects of freezing and thawing on the long-term viability of the neural tissues and their growth are discussed.
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Research Interests: Biology, Medicine, Axon, Chronic Disease, Female, and 15 moreAnimals, Neurons, Corticospinal Tract, Nerve Regeneration, Clinical Sciences, Genetically Modified, Experimental Neurology, Axons, Neurosciences, Motor activity, fibroblasts, Genetic Therapy, Medical and Health Sciences, axon growth, and axon regeneration
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Research Interests: Neuroscience, Spinal Cord Injury, Exercise therapy, Medicine, Spasticity, and 15 moreFemale, Animals, Spinal Cord, Rats, Homeostasis, Copper Acetates, Reflex, Spinal Cord Injuries, Gene Expression Regulation, Tibial nerve, Chlorides, Random Allocation, Psychology and Cognitive Sciences, Bumetanide, and Medical and Health Sciences
Research Interests: Psychology, Regeneration, Medicine, Extracellular Matrix, Cats, and 15 moreFemale, Animals, Spinal Cord, CAT, Animal Model, Nerve Regeneration, Clinical Sciences, Experimental, Peripheral nerves, Peripheral Nerve, Experimental Neurology, Growth Inhibition, Axons, Neurosciences, and axon regeneration
The relationship between astrocytes forming in the presence of dibutyryl cyclic AMP (dBcAMP) in culture and reactive astrocytes responding to a cerebral cortex stab wound was investigated using computerized image analysis (Zeiss IBAS 1)... more
The relationship between astrocytes forming in the presence of dibutyryl cyclic AMP (dBcAMP) in culture and reactive astrocytes responding to a cerebral cortex stab wound was investigated using computerized image analysis (Zeiss IBAS 1) and immunocytochemical staining. The diameters of the nuclei of astrocytes in primary cultures of newborn mouse neopallial cells were compared to those of the nuclei of normal and reactive astrocytes in histological sections of mouse cerebral cortex. We found that the nuclei of astrocytes that formed in the presence of dBcAMP in cultures are significantly larger than those of spontaneously occurring small stellate astrocytes in culture and of normal astrocytes of the cerebral cortex in vivo but corresponded more closely to the nuclei of reactive astrocytes in the area surrounding a stab wound in the cerebral cortex. Large stellate cells formed in the presence of dBcAMP had vimentin and an increase in GFP-containing intermediate filaments. Formation of reactive astrocytes in vivo is also associated with an increase in both vimentin and GFP-containing intermediate filaments. These observations indicate a closer relationship of astrocytes formed in the presence of dBcAMP in cultures to the reactive astrocytes in the cerebral cortex than to normal astrocytes. We propose, therefore, that the large stellate astrocytes that form in the presence of dBcAMP be referred to as reactive astrocytes in culture.
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Although initially argued to be a feature of immature neurons with incomplete polarization, there is clear evidence that neurons in the peripheral nervous system retain the capacity for intra-axonal protein synthesis well into adulthood.... more
Although initially argued to be a feature of immature neurons with incomplete polarization, there is clear evidence that neurons in the peripheral nervous system retain the capacity for intra-axonal protein synthesis well into adulthood. This localized protein synthesis has been shown to contribute to injury signaling and axon regeneration in peripheral nerves. Recent works point to potential for protein synthesis in axons of the vertebrate central nervous system. mRNAs and protein synthesis machinery have now been documented in lamprey, mouse, and rat spinal cord axons. Intra-axonal protein synthesis appears to be activated in adult vertebrate spinal cord axons when they are regeneration-competent. Rat spinal cord axons regenerating into a peripheral nerve graft contain mRNAs and markers of activated translational machinery. Indeed, levels of some growth-associated mRNAs in these spinal cord axons are comparable to the regenerating sciatic nerve. Markers of active translation tend ...
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The selective involvement of a subset of neurons in many psychiatric disorders, such as gamma-
Research Interests: Cognitive Science, Algorithms, Behavior, Fluorescence, Action observation, and 15 moreCell Culture, Brain, Female, Animals, Artifacts, Diagnostic Imaging, Action potential, Behavioral Research, Action Potentials, Culture Media, Equipment Design, Cell Survival, Data Acquisition System, Data Transmission, and Automatic data processing
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Intra-axonal localization of mRNAs and protein synthesis machinery (PSM) endows neurons with the capacity to generate proteins locally, allowing precise spatiotemporal regulation of the axonal response to extracellular stimuli. A number... more
Intra-axonal localization of mRNAs and protein synthesis machinery (PSM) endows neurons with the capacity to generate proteins locally, allowing precise spatiotemporal regulation of the axonal response to extracellular stimuli. A number of studies suggest that this local translation is a promising target to enhance the regenerative capacity of damaged axons. Using a model of central nervous system (CNS) axons regenerating into intraspinal peripheral nerve grafts (PNGs) we established that adult regenerating CNS axons contain several different mRNAs and protein synthetic machinery (PSM) components in vivo. After lower thoracic level spinal cord transection, ascending sensory axons regenerate into intraspinal PNGs but axon growth is stalled when they reach the distal end of the PNG (3 versus 7 weeks after grafting, resp.). By immunofluorescence with optical sectioning of axons by confocal microscopy, the total and phosphorylated forms of PSMs are significantly lower in stalled compare...
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Research Interests: Psychology, Regeneration, Humans, Chronic Disease, Animals, and 15 moreSpinal Cord, Central Nervous System, Life Expectancy, Neurons, Nerve Regeneration, Clinical Sciences, Disease Progression, Experimental Neurology, Environment, Neurosciences, Long Distance, Acute Disease, Recovery of Function, axon growth, and axon regeneration
Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that correlates with sensory fiber sprouting. Recent data indicate that exercise initiated early after SCI prevents the development of allodynia and modulated... more
Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that correlates with sensory fiber sprouting. Recent data indicate that exercise initiated early after SCI prevents the development of allodynia and modulated nociceptive afferent plasticity. This study determined if delaying exercise intervention until pain is detected would similarly ameliorate established SCI-induced pain. Adult, female Sprague-Dawley rats with a C5 unilateral contusion were separated into SCI allodynic and SCI non-allodynic cohorts at 14 or 28 days postinjury when half of each group began exercising on automated running wheels. Allodynia, assessed by von Frey testing, was not ameliorated by exercise. Furthermore, rats that began exercise with no allodynia developed paw hypersensitivity within 2 weeks. At the initiation of exercise, the SCI Allodynia group displayed marked overlap of peptidergic and non-peptidergic nociceptive afferents in the C7 and L5 dorsal horn, while the SCI No Allody...
Research Interests: Cognitive Science, Exercise therapy, Female, Animals, Neuronal Plasticity, and 13 moreLectins, Glycoproteins, Clinical Sciences, Rats, Cholera toxin-b, Spinal Cord Injuries, Neurosciences, Pain Measurement, Hyperalgesia, Calcitonin Gene-Related Peptide, Functional Laterality, Motor activity, and Neuralgia
Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine... more
Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex. We observed numerous tyrosine hydroxylase (TH)(+) neurons in the autonomic nuclei and superficial dorsal horn in L6-S3 spinal segments. These neurons are dopamine-β-hydroxylase (DBH)(-) and some contain detectable dopamine decarboxylase (DDC), suggesting their capacity to produce DA. Interestingly, following a complete thoracic spinal cord injury (SCI) to interrupt supraspinal projections, more TH(+) neurons emerged in the lumbosacral spinal cord, coincident with a sustained, low level of DA expression there and a partially recovered micturition reflex. Non-selective blockade of spinal DA receptors reduced bladder activity whereas activation...
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Although intra-axonal protein synthesis is well recognized in cultured neurons and during development in vivo, there have been few reports of mRNA localization and/or intra-axonal translation in mature CNS axons. Indeed, previous work... more
Although intra-axonal protein synthesis is well recognized in cultured neurons and during development in vivo, there have been few reports of mRNA localization and/or intra-axonal translation in mature CNS axons. Indeed, previous work indicated that mature CNS axons contain much lower quantities of translational machinery than PNS axons, leading to the conclusion that the capacity for intra-axonal protein synthesis is linked to the intrinsic capacity of a neuron for regeneration, with mature CNS neurons showing much less growth after injury than PNS neurons. However, when regeneration by CNS axons is facilitated, it is not known whether the intra-axonal content of translational machinery changes or whether mRNAs localize into these axons. Here, we have used a peripheral nerve segment grafted into the transected spinal cord of adult rats as a supportive environment for regeneration by ascending spinal axons. By quantitative fluorescent in situ hybridization combined with immunofluore...
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Large animal and primate models of spinal cord injury (SCI) are being increasingly utilized for the testing of novel therapies. While these represent intermediary animal species between rodents and humans and offer the opportunity to pose... more
Large animal and primate models of spinal cord injury (SCI) are being increasingly utilized for the testing of novel therapies. While these represent intermediary animal species between rodents and humans and offer the opportunity to pose unique research questions prior to clinical trials, the role that such large animal and primate models should play in the translational pipeline is unclear. In this initiative we engaged members of the SCI research community in a questionnaire and round-table focus group discussion around the use of such models. Forty-one SCI researchers from academia, industry, and granting agencies were asked to complete a questionnaire about their opinion regarding the use of large animal and primate models in the context of testing novel therapeutics. The questions centered around how large animal and primate models of SCI would be best utilized in the spectrum of preclinical testing, and how much testing in rodent models was warranted before employing these mo...
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Spinal cord injury (SCI) is a traumatic event from which there is limited recovery of function, despite the best efforts of many investigators to devise realistic therapeutic treatments. Partly this is due to the multifaceted nature of... more
Spinal cord injury (SCI) is a traumatic event from which there is limited recovery of function, despite the best efforts of many investigators to devise realistic therapeutic treatments. Partly this is due to the multifaceted nature of SCI, where there is considerable disarray and dysfunction secondary to the initial injury. Contributing to this secondary degeneration is neurotoxicity, vascular dysfunction, glial scarring, neuroinflammation, apoptosis and demyelination. It seems logical that addressing the need for neuroprotection, regeneration and rehabilitation will require different treatment strategies that may be applied at varied stages of the post-injury response. Here we focus on a single strategy, exercise/physical training, which appears to have multiple applications and benefits for an acute or chronic SCI. Exercise has been demonstrated to be advantageous at cellular and biochemical levels, as well as being of benefit for the whole animal or human subject. Data from our ...
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The cytotoxic effects of N-ethyl-N-nitrosourea (ENU) and the potential for recovery from this damage in the developing rat spinal cord was investigated. Emphasis was placed on determining the severity and location of initial cell necrosis... more
The cytotoxic effects of N-ethyl-N-nitrosourea (ENU) and the potential for recovery from this damage in the developing rat spinal cord was investigated. Emphasis was placed on determining the severity and location of initial cell necrosis and the subsequent reorganizational changes in the damaged tissues. Pregnant rats were injected i.v. with a single dose of ENU (60 mg/kg) on one of days 12-16 of gestation. At 6, 12, 24 and 48 h post-injection one pregnant rat from each gestational stage was anesthetized, the embryos were removed, fixed and processed for embedding in paraplast or epon-araldite. Transverse sections from embryos killed at 6 h revealed extensive necrosis throughout the neuroepithelium in accordance with the temporal-spatial patterns of neurogenesis. At this dose level the post-mitotic neuroblasts appeared unaffected. Regeneration of the damaged neural tissue as defined by the restoration of the neuroepithelial cell layer and removal of necrotic debris proceeded quickl...
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The high clinical relevance of models of incomplete cervical spinal cord injury (SCI) creates a need to address the spontaneous neuroplasticity that underlies changes in functional activity that occur over time after SCI. There is... more
The high clinical relevance of models of incomplete cervical spinal cord injury (SCI) creates a need to address the spontaneous neuroplasticity that underlies changes in functional activity that occur over time after SCI. There is accumulating evidence supporting long projecting propriospinal neurons as suitable targets for therapeutic intervention after SCI, but focus has remained primarily oriented toward study of descending pathways. Long ascending axons from propriospinal neurons at lower thoracic and lumbar levels that form inter-enlargement pathways are involved in forelimb-hindlimb coordination during locomotion and are capable of modulating cervical motor output. We used non-invasive magnetic stimulation to assess how a unilateral cervical (C5) spinal contusion might affect transmission in intact, long ascending propriospinal pathways, and influence spinal cord plasticity. Our results show that transmission is facilitated in this pathway on the ipsilesional side as early as ...
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To test whether known growth factors could promote the regenerative reponse of chronically injured neurons, we exposed the injured adult rat spinal cord to insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF) or... more
To test whether known growth factors could promote the regenerative reponse of chronically injured neurons, we exposed the injured adult rat spinal cord to insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF) or transforming growth factor beta 1 + 2 (TGFβs) 1 month after creation of a hemisection lesion. At 1 week later an autologous peripheral nerve graft was apposed to the rostral cavity wall and 1 month later Nuclear Yellow (NY) was used to retrogradely label neurons that had grown an axon into the graft. Neurons capable of axonal regeneration after a long term (5 weeks) injury were double labeled with True Blue (TB, provided at the time of hemisection lesion) and NY. Exposure to any of the three growth factors, compared to a PBS-treated control, resulted in a significant increase in the total number of regenerating supraspinal neurons, with the greatest increase after treatment with TGFβs. Treatment with TGFβs or bFGF led to a significant increase in the n...
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The potential of two interventions, alone or in combination, to restore chronic spinal cord transection-induced changes in skeletal muscles of adult Sprague-Dawley rats was studied. Hind limb skeletal muscles were examined in the... more
The potential of two interventions, alone or in combination, to restore chronic spinal cord transection-induced changes in skeletal muscles of adult Sprague-Dawley rats was studied. Hind limb skeletal muscles were examined in the following groups of animals: rats with a complete spinal cord transection (Tx) for 8 weeks; Tx with a 4-week delay before initiation of a 4-week motor-assisted cycling exercise (Ex) program; Tx with a 4-week delay before transplantation (Tp) of fetal spinal cord tissue into the lesion cavity; Tx with a 4-week delay before Tp and Ex; and uninjured control animals. Muscle mass, muscle to body mass ratios, and mean myofiber cross-sectional areas were significantly reduced 8 weeks after transection. Whereas transplantation of fetal spinal cord tissue did not reverse this atrophy and exercise alone had only a modest effect in restoring lost muscle mass, the combination of exercise and transplantation significantly increased muscle mass, muscle to body mass ratio...