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Thread: Report on SCI Conference - Toronto Sep 27, 2002

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    Senior Member mk99's Avatar
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    Report on SCI Conference - Toronto Sep 27, 2002

    I attended the Charles Tator - Barbara Turnbull Lectureship Series in Spinal Cord Injury and wanted to share some info.

    First of all I must say I was pretty impressed. The conference was well run, Rick Hansen was a key speaker and he was quite inspirational.

    Brief Summary:

    1. The underlying theme was: There is Hope
    2. Most of the injury models were the clip compression variety (ie: contusion)
    3. They mentioned the human clinical trials going on overseas (ie: Cheng, Brunelli, etc). However, there was no mention of OEGs at all... kind of strange. I wanted to ask about this but questions were limited to 1 per speaker. Too bad
    4. No mention of combination therapies being worked on

    Below is a summary of each speaker and their work:

    John Steeves, PhD
    Departments of Neurosurgery, Anatomy and Zoology
    University of British Columbia & Vancouver Hospital, Vancouver, BC
    Recent Advances in the Repair of the Injured Spinal Cord

    Over the past decade, there have been numerous reports of axonal regeneration after spinal cord injury (SCI) in animal models. The degree of regeneration is sometimes modest, but the nature and variety of experimental therapies that facilitate axonal outgrowth is continually expanding. Although the term regeneration implies a recapitulation of development, the complex molecular and cellular differences between the injured adult and fetal CNS suggests a strategy that relies on more than just a reactivation of neural development.
    Fortunately, there is ample evidence that severing the axonal projections of descending or ascending pathways does not trigger the death of their parent neurons. Furthermore, even chronically injured neurons appear capable of mounting a regenerative response when they are stimulated in an appropriate positive manner.
    Our understanding of the functional morphology of CNS glial cells and extracellular matrix has also increased dramatically, as have our insights about immune responses after CNS injury. We are learning there are a large number of molecules expressed or secreted by adult glial cells that inhibit, or at least, are less than supportive of axonal regeneration. We have also been able to expand the list of "growth" factors that directly or indirectly promote regrowth by damaged axons. Not surprisingly, an individual molecule that is inhibitory to one population of neurons may conversely promote the regeneration of another neuronal pathway, and vice versa.
    The formation of fluid-filled cyst cavities surrounding a chronic CNS injury site may require the transplantation of a substitute substrate for axons to navigate across the damaged region. Novel sources for cellular growth substrates have been identified including peripheral Schwann cells, fetal neural tissue, olfactory ensheathing glia, biocompatible polymers gels, and progenitor stem cells.
    Once axons have regenerated to target tissue, the next step in re-establishing useful functional circuitry is the formation of synaptic connections at correct locations. Developmental studies have again provided the jumping board to elucidating the molecular cues after adult CNS injury. Since the CNS is wired as a series of maps, such findings will have implications for the integration of sensory input with appropriate motor output after SCI.
    Finally, after axons have been guided to their approximately correct locations, activity-dependent mechanisms must be invoked to strengthen and consolidate appropriate connections and remove misplaced ones. Intense, active physical rehabilitation of each individual with SCI will be required for the best functional outcome.
    In conclusion, it is widely acknowledged that functional recovery after human SCI will involve the application of a combination of therapeutic interventions in the appropriate sequence. It might appear as an insurmountable task, but recent progress has been impressive in defining the spatial and temporal criteria and mechanisms to: 1) limit the extent of the initial SCI damage, 2) establish an environment that stimulates and supports axonal regeneration, and 3) provide the necessary guidance to and functional consolidation with an appropriate functional target.


    Charles H. Tator, CM, MD, MA, PhD, FRCSC, FACS
    Department of Surgery-Division of Neurosurgery, Toronto Western Hospital and the University of Toronto
    Regenerative Strategies For Spinal Cord Repair

    Neuroprotection with agents such as methylprednisolone and surgical strategies such as spinal cord decompression are more effective for incomplete spinal cord injuries. In contrast, complete injuries of the spinal cord will require actual regeneration of central nervous system tissue for effective restoration of function. Recent research shows that there is considerable potential for regeneration in the adult mammalian spinal cord. One of the most exciting discoveries has been the finding that the adult mammalian central nervous system is capable of regeneration through the presence of stem and progenitor cells in the brain and spinal cord. A large number of regeneration strategies have shown promising results in experimental settings including transplantation, neurotrophic factors, and gene therapy. Neurotrophic factors produce a remarkable proliferation of nervous tissue in vitro and in vivo and have produced improvement of function in several experimental models of neurotrauma. Indeed, specific types of neural and glial regeneration can be induced by specific neurotrophic agents. For example, the neurotrophic factor BDNF produces a dramatic proliferation of schwann cells, axonal regeneration and myelination in the injured spinal cord. Indeed, rehabilitation with methods such as physiotherapy has been placed on a much firmer basis with the discovery that the brain produces increased levels of neurotrophic factors during exercise. Systemic or intrathecal neurotrophic factors have not yet been successful in patients with non-traumatic neurological disorders, although there have been no reported trials in patients with brain or spinal cord injury. Transplants have included activated macrophages, stem cells, olfactory ensheathing glia, peripheral nerves, and whole segments of fetal or adult spinal cord. Many transplants attach to injured cord tissue and support axonal regeneration. Indeed, fetal cord tissue has been transplanted into patients with posttraumatic syringomyelia, and porcine stem cells are being injected into the spinal cords of patients with cord injuries. Recently, patients with spinal cord injury have shown limited functional improvement after peripheral nerve grafts were inserted into the spinal cord rostral to the injury site to create a bridge from the spinal cord to successfully reinnervate previously non-functioning muscles.


    Molly S. Shoichet, PhD
    Department of Chemical Engineering and Applied Chemistry Department of Chemistry
    Institute of Biomaterials and Biomedical Engineering University of Toronto
    Tissue Engineering Strategies for Spinal Cord Injury Repair

    The spinal cord is injured by either compression or transection. We are designing two methodologies to overcome injury, taking the injury modality into consideration. For compression injuries, we have developed a minimally invasive drug delivery strategy that allows local delivery of therapeutic agents at the site of injury. We have demonstrated safety of the technique and have begun to observe signs of efficacy in rat animal models. For transected injuries, we have developed an entubulation strategy that serves as a bridge through which damaged axons can regenerate. This multi-component tubular device provides both haptotactic (i.e. contact-mediated) and chemotactic (i.e. diffusible) cues of regeneration. We invented a new process to synthesize hollow fiber membranes (i.e. tubes) and have observed regenerated, myelinated axons within rat animal models. To further enhance regeneration, we are designing scaffolds with longitudinal pores that incorporate both haptotactic (i.e. peptides) and chemotactic (i.e. growth factors) cues of regeneration. I will describe our latest research to create cell-adhesive chemical channels using advanced 3-D patterning technology and exciting results to immobilize concentration gradients of growth factors that can be used to stimulate axonal guidance. This lays the framework for additional studies where we can test our fundamental hypotheses in vivo.


    Lynne C. Weaver, DVM, PhD
    Spinal Cord Injury Laboratory, BioTherapeutics Research Group John P. Robarts Research Institute University of Western Ontario, London, ON
    Dealing With The First 48 Hours Of The Inflammatory Response To Spinal Cord Injury

    A significant degree of the post-traumatic tissue damage and subsequent neurological deficits that occur after spinal cord injury (SCI) are due to a self-perpetuating feedback loop of secondary reactive processes. These include the release of chemokines, cytokines, free radicals and proteases, the peroxidation of lipids and the influx of neutrophils and macrophages. An early anti-inflammatory treatment may diminish this destructive cycle and limit secondary injury. Accordingly, we have correlated improved autonomic, sensory and locomotor function with white matter sparing after an early anti-inflammatory treatment (2, 24 and 48 h post-SCI) with an antibody to the ocD subunit of a2 integrin. This antibody treatment attenuates hematogenous neutrophil/macrophage infiltration into the injured cord by blocking the interaction between vascular adhesion molecules and cell surface oc2 integrins. Two weeks post-SCI, myelin content in cryostat sections from a 4 mm cord segment containing the lesion was assessed by luxol fast blue staining. Cord lesions from anti-ocD antibody-treated rats demonstrated significantly more myelin 1.5 mm rostral and caudal to the lesion epicentre compared to saline-treated rats. Myelin was barely detectable at the lesion epicentre after saline treatment, but white matter sparing was always observed after anti-ocD antibody-treatment.
    In addition to white matter sparing, the effect of anti-oD antibody-treatment on neuroprotection was also assessed. Immunohistochemical staining of the lesion with a neuron-specific antibody (anti-NeuN) was used to assess the number of neurons and the dorsal horn area containing neurons. Compared to spinal cord from saline-treated rats, the dorsal horn contained 64% more neurons in a 90% larger area after the anti-ocD antibody treatment. Consistent with this neural sparing, immunoreactivity for activated caspase-3 was decreased by 30-70% within 2 mm of the lesion epicentre. After SCI, cytokines and growth factors activate astrocytes, microglia and O2A oligodendrocyte precursors and stimulate production of glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycans (CSPG). CSPGs such as neurocan are secreted into an extracellular matrix that forms the axon growth-inhibiting glial scar, hi uninjured CNS, intact neurocan (270 kDa) is uncommon but cleavage products, Neurocan-C (150 kDa) and Neurocan-N (130 kDa), are detectable. Western blot analysis of SCI lesion homogenates demonstrated that intact neurocan, neurocan-C and GFAP protein content was increased 7 and 14 days post-SCI. Preliminary results suggest that anti-ocD antibody treatment decreased GFAP and intact neurocan protein content (n=5). In summary, anti-inflammatory treatment with the anti-ocD antibody promotes white matter sparing and neuroprotection near the SCI lesion. These beneficial effects also are accompanied by altered astrocyte and CSPG composition of the glial scar. Early anti-inflammatory strategies clearly have the potential for clinical benefits after spinal cord injury. Support: ICOS Corporation, Canadian Institutes of Health Research and Ontario Neurotrauma Foundation. Acknowledgements: Daniel R. Marsh, Denis Gris, Yuhua Chen and Gregory A. Dekaban


    Andrei Krassioukov, MD, PhD
    Department of Surgery-Division of Neurosurgery, Toronto Western Hospital and the University of Toronto Department of Physical Medicine and Rehabilitation, University of Western Ontario, London, ON
    Autonomic Cardiovascular Pathways In Injured Human Spinal Cord: Clinical And Histopathological Correlations

    Cardiovascular dysfunctions are common after spinal cord injury (SCI). Individuals with SCI face two major opposing hemodynamic changes that complicate their management: (a) hypotension in both the acute and chronic stages of SCI; and (b) extreme hypertensive episodes known as autonomic dysreflexia (AD), which may lead to myocardial infarction and cerebral hemorrhage. At least three important elements related to abnormal cardiovascular control after SCI have been identified within the spinal cord circuits: descending vasomotor pathways (DVPs), sympathetic neurons, and dorsal afferents.
    The purpose of this study was first to examine the association of cardiovascular abnormalities in individuals with traumatic cervical SCI and the severity of demyelination as well as axonal preservation within the DVPs. We focused on two areas of DVP in animals and humans, which have been described in dorsolateral aspect of the lateral horn (Area I), and dorsal portion of the lateral funiculus (Area II). Five individuals (2M, 3F; mean age 51.4 y) with well-documented cardiovascular abnormalities and neurological outcomes of SCI were analyzed. The mean survival in the post-injury period was 11.6 mos. Severe hypotension immediately after SCI was observed in 3 individuals. Two of these subjects also developed AD. The histopathological findings from these individuals were compared to findings from 2 individuals with no cardiovascular abnormalities. There were no significant differences in the severity of demyelination between two groups. However, the number of axons within areas I & II of DVP in individuals with cardiovascular dysfunctions was significant lower than subjects without cardiovascular abnormalities (P<0.001). These data suggest that severity of destruction of DVP could contribute to cardiovascular abnormalities after SCI. (Christopher Reeve Paralysis Foundation; Heart & Stroke Foundation of Ontario; Cervical Spine Research Society)


    Peter K. Stys, MD, FRCP(C)
    Ottawa Health Research Institute University of Ottawa
    Molecular Mechanisms of Acute Spinal Cord Injury

    Central nervous system axons play the critical role of transmitting electrical impulses within the CNS with high fidelity and reliability. Spinal cord injury commonly disrupts axonal tracts resulting in serious morbidity and mortality. Cellular Ca overload is a key event leading to irreversible injury of CNS white matter tracts, with extracellular Ca entering axons and glia through reverse Na-Ca exchange, voltage-gated Ca channels and AMPA-kainate receptors. In turn, non-inactivating voltage-gated Na channels contribute to this deleterious Ca entry by causing axonal Na overload and depolarization, which promotes reverse Na-Ca exchange and glutamate release via reverse Na-dependent glutamate transport. Recent evidence suggests that while a significant portion of Ca overload originates from outside the axon, the substantial quantity of stored Ca within cells and fibers may play a key role in the initiation of white matter injury. Release of Ca from intracellular stores in white matter is controlled by depolarization, gating L-type voltage-sensitive Ca channels which then activate ryanodine receptors, analogous to "excitation-contraction coupling" in muscle cells. If confirmed, such a mode of Ca release may have profound implications for the development of therapeutic strategies; for instance, interventions aimed at the reduction of transmembrane Ca influx (eg. NMDA receptor antagonists, Ca channel blockers) will be doomed to failure if control over internal Ca sources is not achieved during the hyperacute phase of spinal cord injury. Successful protection of spinal cord tissue early in the injury will undoubtedly increase the chance of success of any regenerative strategies designed to promote regrowth of damages fibers: it is argued that only a coordinated neuroprotective/regenerative strategy will lead to optimal clinical outcome.


    P. Ken Rose, PhD
    Department of Physiology Queen's University, Kingston, ON
    A 'Plan B' For The Formation Of New Axons? - Lessons Learned From The Study Of Motoneurons Following Permanent Axotomy

    Most neurons in the mammalian nervous system have two morphologically, molecularly, and functionally distinct compartments. One compartment consists of multiple tree-like structures that arise from the cell body and, together, form a dendritic tree. The other compartment, the axon, also originates from the soma, but unlike the dendritic tree, this compartment has only one first-order branch and often projects for long distances before forming right-angled branches and pre-synaptic specializations called boutons. This polarity is a fundamental feature of cellular neuroscience. In the present study we have examined the consequences of axotomy on the polarity of motoneurons. Our results suggest that the polarity of motoneurons is not fixed. Instead, over a protracted period of time, 20 to 35 weeks, permanently axotomized motoneurons develop new axons that arise from the ends of distal dendrites. These axons have many of the morphological and molecular features of functional axons, including myelin and bouton-like swellings. This rearrangement of neuronal polarity may represent an alternative strategy for the growth of new axons following neurotruama. (Supported by the Ontario Neurotrauma Fund and the Canadian Institutes for Health Research).
    Acknowledgements: V. MacDermid, M. Neuber-Hess, CIHR Group in Sensory-Motor Neuroscience


    Molly C. Verrier, Dip. P & OT, MHSc
    Departments of Physical Therapy, Physiology and Rehabilitation Science University of Toronto
    Reorganization Of Motor Cortex And Functional Recovery Post Cervical Spinal Cord Injury

    Reorganization within human primary motor cortex (Ml) following cervical spinal cord injury (SCI) has been demonstrated using functional magnetic resonance imaging (fMRI; Mikulis et al, 2001). However, the relationships between motor cortical reorganization and motor and functional recovery remain unclear. We have used fMRI to compare cortical activation maps in 9 patients with chronic SCI and 14 controls. Paradigms consisted of tongue and right wrist movements. Patients were assessed using the ASIA scale to determine motor function. Mean distance between tongue and wrist areas within Ml was smaller (p < 0.05) in patients (30.3 ± 13.8 mm; controls = 43.3 ± 6.7 mm). This distance in patients was related to motor function of the right upper limb (r = 0.89, p < 0.02). Two additional patients were each studied at three points (< 6 months) following SCI. A progressive increase in distance was associated with improved function; a progressive decrease was associated with no improvement. This study raises the question as to whether decreased distance between the tongue and wrist areas within Ml over time reflect poor recovery from cervical SCI and whether fMRI analysis can enhance our understanding of recovery following spinal cord injury Supported by the Ontario Neurotrauma Foundation and NSERC. Acknowledgements: M.T. Jurkiewicz, W.E. Mcllroy, D.J. Mikulis, M.G. Fehlings.


    Michael G. Fehlings, MD, PhD, FRCSC
    Department of Surgery-Division of Neurosurgery, Toronto Western Hospital and the University of Toronto
    Neuroprotection of the Injured Spinal Cord

    The pathophysiology of spinal cord injury is characterized by a primary mechanical injury which is followed by a series of molecular and cellular events, including glutamatergic excitotoxicity,perturbatioins in ionic homeostasis, free radical mediated cell injury, ischemia and apoptosis, which work in concert to create a secondary injury. This talk will focus on recent work from our laboratory which has identified a number of clinically relevant neuroprotective targets including a) sodium-mediated cell injury; b) AMPA-kainate receptor mediated white matter degeneration and c) FAS and p75 death receptor mediated cell death. Opportunities for clinical translation of these therapeutic strategies will be briefly discussed.

  2. #2
    Senior Member X-racer...'s Avatar
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    thankx for the update M99, its nice to hear researchers mentioning trials outside the normal trials frame work,maybe their starting to feel a little outside competition.



    LIVE IT UP AND LIVE IT LARGE!!!!

  3. #3
    Thanks Mike, this is good news! Nice letter in CPA's Total Access too BTW!

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    Senior Member Tara's Avatar
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    Thanks Mike,
    Yeah CANADA!....I just wanted to add that I hear there are plans in the works to open a new research centre in Vancouver, B.C. The facility would be headed by Dr. John Steeves of UBC (mentioned above) and would be focused on Spinal Cord Research. The Name of the institute is ICORD and is supposed to be one of the largest in Canada. So that sounds promising....

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    Senior Member Jeremy's Avatar
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    Tara - ICORD has a website http://cord.ubc.ca/ I didn't know if you knew or not.

    "If the wind could blow my troubles away. I'd stand in front of a hurricane."

    [This message was edited by Jeremy on Sep 28, 2002 at 05:48 PM.]

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    Senior Member mk99's Avatar
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    Hi Tara. Dr. John Steeves was supposed to be at the conference and making closing remarks but for some reason he wasn't there so they closed off with Rick Hanson instead.

    Rick was talking about setting up a large institution including 17 SCI centres of excellence throughout Canada. Obviously ICORD would be involved too.

    Emi, I didn't get last months' Total Access but I more or less remember what I wrote... I will be writing a regular "Research Update" column in upcoming issues in Total Access. So long as I promise not to irritate or offend the "anti-cure" crowd too much, the magazine feels it may be time to start something like this. Increased awareness & education can only help!

  7. #7
    Nice work MK. I have never heard of the magazine, is it produced in Canada?

  8. #8

    Super Mike

    Thanks for filling us all in.

    "Life is about how you
    respond to not only the
    challenges you're dealt but
    the challenges you seek...If
    you have no goals, no
    mountains to climb, your
    soul dies".~Liz Fordred

  9. #9
    Thanks for sharing this Mike.

    ...the brain produces increased levels of neurotrophic factors during exercise.
    Interesting.

  10. #10
    Senior Member mk99's Avatar
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    CarlR:

    Yes, Total Access is a Canadian Magazine. I know there is some relationship between the CPA (Canadian Paraplegic Association) and the magazine but I am not 100% clear on the relationship.

    I believe all CPA members receive the magazine though... maybe we can slowly start to open some people's eyes to what is going on and why there is real reason for hope.

    thanks for the kind words to everyone

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