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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #321
    So my understanding is that you both believe axonal growth, with the right cocktail, can grow across barriers in the lesion. However, you simply disagree that a sufficient number of axons can grow through the lesion after a certain stage in the lesion development? Wise thinks it is possible, while Jerry believes a bridge will be necessary to cross even a limited number of neurons necessary for some basic functions?
    Am I understanding this correctly?

    Yes, from what we are learning in our own lab with our latest strategy, in order for true axonal regeneration to occur beyond a CHRONIC (at least 2 months post-injury) large contusive injury in the rat spinal cord (which I am defining as re-growth of many hundreds, at least, of lengthy axons well beyond the lesion environment and into the distal spinal cord) we need to first gently remove the toughest part of the scar which lines the lesion cavity and build a proper bridge across the lesion combining certain growth factors and chondroitinase. We don't cut out a big chunk of cord but very carefully pick away the innermost wall of the scar. It is quite palpable. We are very excited that true regeneration can even happen at all so long after injury and as far as we know this is the very first demonstration that such regeneration can occur at a chronic stage. We are seeing nice return of bladder function, but so far no return in locomotion. I presented this new strategy at the very end of my 2012 W2W presentation. This is not to say that some totally new strategy might also work, but at least we are now quite hopeful that future improvements can build upon our initial success to bring about even more functional recovery.

    Regarding the phenomenon of sprouting/plasticity ( which is collateral growth of axons from remaining uncut axons, or back branching from cut axons) this process can occur throughout a lifetime, but the sprouting/plasticity needs help to overcome barriers in the so-called perineuronal net around synapses. The phenomenon of plasticity is especially relevant to people with any surviving function below the lesion. Again, many strategies can help to promote plasticity including intense physical rehab, FES, epidural stimulation, intra-spinal micro stimulation, increasing serotonin levels, chondroitinase, anti-NOGO therapy, increasing transmitter release, increasing receptor sensitivity or numbers,neurotrophin delivery and more. These additional therapies might also help regenerating axons find there proper targets and wire correctly. For instance we have seen strong return of diaphragm function 1.5 years following a C2 hemisection lesion using a single injection of chondroitinase. See the U2FP website for a description of this result. The functional recovery is further augmented if we give the animal intermittent hypoxia which is a form of respiratory therapy. The bottom line is that, in my mind, there is surely hope for return of significant function after chronic SCI.

  2. #322
    Quote Originally Posted by jsilver View Post
    So my understanding is that you both believe axonal growth, with the right cocktail, can grow across barriers in the lesion. However, you simply disagree that a sufficient number of axons can grow through the lesion after a certain stage in the lesion development? Wise thinks it is possible, while Jerry believes a bridge will be necessary to cross even a limited number of neurons necessary for some basic functions?
    Am I understanding this correctly?

    Yes, from what we are learning in our own lab with our latest strategy, in order for true axonal regeneration to occur beyond a CHRONIC (at least 2 months post-injury) large contusive injury in the rat spinal cord (which I am defining as re-growth of many hundreds, at least, of lengthy axons well beyond the lesion environment and into the distal spinal cord) we need to first gently remove the toughest part of the scar which lines the lesion cavity and build a proper bridge across the lesion combining certain growth factors and chondroitinase. We don't cut out a big chunk of cord but very carefully pick away the innermost wall of the scar. It is quite palpable. We are very excited that true regeneration can even happen at all so long after injury and as far as we know this is the very first demonstration that such regeneration can occur at a chronic stage. We are seeing nice return of bladder function, but so far no return in locomotion. I presented this new strategy at the very end of my 2012 W2W presentation. This is not to say that some totally new strategy might also work, but at least we are now quite hopeful that future improvements can build upon our initial success to bring about even more functional recovery.

    Regarding the phenomenon of sprouting/plasticity ( which is collateral growth of axons from remaining uncut axons, or back branching from cut axons) this process can occur throughout a lifetime, but the sprouting/plasticity needs help to overcome barriers in the so-called perineuronal net around synapses. The phenomenon of plasticity is especially relevant to people with any surviving function below the lesion. Again, many strategies can help to promote plasticity including intense physical rehab, FES, epidural stimulation, intra-spinal micro stimulation, increasing serotonin levels, chondroitinase, anti-NOGO therapy, increasing transmitter release, increasing receptor sensitivity or numbers,neurotrophin delivery and more. These additional therapies might also help regenerating axons find there proper targets and wire correctly. For instance we have seen strong return of diaphragm function 1.5 years following a C2 hemisection lesion using a single injection of chondroitinase. See the U2FP website for a description of this result. The functional recovery is further augmented if we give the animal intermittent hypoxia which is a form of respiratory therapy. The bottom line is that, in my mind, there is surely hope for return of significant function after chronic SCI.
    Jerry, thank you for further clarification.

    My point now is simply that the disagreement between you and Wise is, from a human testing standpoint, purely academic. If and when your current lab method can be tested on humans, AWESOME!!! I'll be the first to cheer because bladder functionality is my number 1 concern!! (seriously). But, until then, and I think most would agree with me, we might as well test whatever therapies are available for humans. If we see some functional return and it bears as being *caused* by the therapy then we simply have another piece of the puzzle ready to go when your therapies and ideas become testable for humans.

    Again, I thank BOTH of you, and all the guys in SCI over the world, who are so dedicated to helping me and my brothers and sisters. I recognize that you are both competitive individuals in a competitive field. But I would think that between the two of you there is a ground for win-win here.

    All of us are counting on you to find it.

  3. #323
    Quote Originally Posted by jsilver View Post
    Yes, from what we are learning in our own lab with our latest strategy, in order for true axonal regeneration to occur beyond a CHRONIC (at least 2 months post-injury) large contusive injury in the rat spinal cord (which I am defining as re-growth of many hundreds, at least, of lengthy axons well beyond the lesion environment and into the distal spinal cord) we need to first gently remove the toughest part of the scar which lines the lesion cavity and build a proper bridge across the lesion combining certain growth factors and chondroitinase.
    Perhaps unnecessary:
    Relesioning the spinal cord was not necessary to achieve axonal growth either into or beyond the chronic lesion site in this study, enhancing clinical relevance: relesioning the spinal cord risks further deterioration of function, particularly in cervically injured subjects that are critically dependent of neural systems spared immediately above the lesion site to support residual function.
    Source is attached.

    Quote Originally Posted by jsilver View Post
    This is not to say that some totally new strategy might also work
    Hopefully there are lots of strategies.

    Quote Originally Posted by jsilver View Post
    For instance we have seen strong return of diaphragm function 1.5 years following a C2 hemisection lesion using a single injection of chondroitinase. See the U2FP website for a description of this result. The functional recovery is further augmented if we give the animal intermittent hypoxia which is a form of respiratory therapy.
    When is this being published? Was this an isolated incident? Did the animal have poor diaphragm function or no diaphragm function? If it had no diaphragm function, how did you all keep the animal alive for 1.5 years with no diaphragm function? How much of the diaphragm function return is related to the intermittent hypoxia respiratory therapy?

    Quote Originally Posted by jsilver View Post
    We are seeing nice return of bladder function, but so far no return in locomotion. I presented this new strategy at the very end of my 2012 W2W presentation.
    Where is this published? Is it being submitted for publication? Is this the same study:
    What about those animals that didn’t recover in your lab? All of our work is double blind, and we’ve done the work 3 separate times, so I know it’s not a fluke. We try to do all the injuries exactly the same, then using the doses that worked well in tissue culture, and we saw the variability you heard about this morning. Some got a lot of walking back, some got none at all. Some got urination, some got none. Some got both, some got neither. Why? Maybe the injuries are not exactly the same.
    SOURCE

    Quote Originally Posted by jsilver View Post
    We are very excited that true regeneration can even happen at all so long after injury and as far as we know this is the very first demonstration that such regeneration can occur at a chronic stage.
    Attached: "Combined Intrinsic and Extrinsic Neuronal Mechanisms Facilitate Bridging Axonal Regeneration One Year after Spinal Cord Injury"
    Last edited by crabbyshark; 01-28-2013 at 08:25 PM.

  4. #324
    Crabbyshark, Jerry's work gets published in the top medical journals.

  5. #325
    Quote Originally Posted by Christopher Paddon View Post
    Crabbyshark, Jerry's work gets published in the top medical journals.
    Often times, the articles have clever titles.

  6. #326
    I don't know anything about the relevance of clever titles, but here's the factual information about the research on restoration of diaphragm for breathing for those not familiar with the work being done at Case Western Reserve University by Dr. Silver's Lab. It was published in Nature and presented at W2W 2011. It's been discussed here already many times for those following SCI research.
    __________________________________________________ ___________________________

    Functional regeneration of respiratory pathways after spinal cord injury
    http://www.nature.com/nature/journal...ture10199.html
    http://www.nature.com/nature/journal...re10199-s1.pdf
    http://www.bbc.co.uk/news/health-14139204
    http://www.cleveland.com/science/ind..._use_expe.html



    Last edited by GRAMMY; 01-29-2013 at 02:21 AM.

  7. #327
    The information on bladder studies and nerve grafting.




    The information about the new research on peptide therapy.


  8. #328
    Incidentally crabbyshark, Nature doesn't publish anything that isn't of the highest scientific standard. It has that reputation. But you probably know that.

  9. #329
    Quote Originally Posted by jsilver View Post
    Hey, I think we finally made it to the same page. Still, there is not much evidence out there yet that these strategies for intrinsic axon growth stimulation can get large numbers of axons across well established scar. Very recent evidence suggests that some axons can get across mature scar when neurons are strongly stimulated by neurotrophins or pTEN/SOCS3 manipulation but their numbers are dwindling. None-the-less, I remain extremely hopeful (and our newest results are bearing this out) that with the right cocktail to stimulate and guide axonal growth, coupled with a proper bridge across the lesion, certain types of axons can be regenerated and restore at least some primitive functions (eg, bladder, crude locomotion, breathing) even at clearly chronic stages after injury.
    I am glad that we are on the same page concerning glial scars. Glial scars do form when the spinal cord is transected or hemisected and the dura is not closed and particularly when a non-CNS material (such as fibrin or laminin) is placed at the cut site. I also agree that the combination of fibrosis and gliosis is a strong deterrent to axon growth.

    However, in contusion models, while there is gliosis, one usually doesn't have a wall of fibrosis preventing axonal growth. I think that it is wrong to apply the word "scar" to the gliosis that surrounds a contusion site. Such gliosis not only does not prevent axonal growth but removing the gliosis leads to further damage of the spinal cord without improved regeneration or recovery.

    In a minority of the contused rat spinal cords (20-30%), a cavity develops as necrotic tissues are removed but the cavity is not (yet) filled by astrocytes. Even in such cases, usually there are spaces for axons to grow into, for example in the pial rim that surrounds the cavity. In a large majority of cases, the contusion site is filled with a loose matrix of astrocytes that clearly support axonal growth.

    Over the past two decades, as more and more evidence show that axons can grow through both gliosis and fibrosis, the glial scar theory keeps retreating into weaker and weaker subterfuges. The first subterfuge was the concept of chemical barrier instead of a physical barrier. Now, the subterfurge is "mature" or "established" scar. This is weaker because it is not clear that such "scars" are present in most contused spinal cords.

    You keep saying that the injury site is complex. I agree with you. I believe that we should stop trying to fit it into the oversimplistic glial scar theory. Many factors influence the ability of axons to grow and out of the injury site, not just gliosis and fibrosis. Glia do not form an impenetrable barrier to axon growth. In fact, glia supports axonal growth, as you know. Also, if axons are strongly stimulated to grow, some will even grow through "established scars".

    Despite all our discussion here, the glial scar theory is still misleading many people. Despite the lack of evidence that it is helpful and evidence that such removal is harmful, people here still think that it is a good idea to cut the scar out physically. There are doctors who have convinced people that it is all right to cut a chunk out of their contused spinal cord, telling them that it is only glial scar. I worry about that.

    Thanks very much for all your comments.

    Wise.
    Last edited by Wise Young; 01-29-2013 at 05:02 AM.

  10. #330
    It doesn't seem as if you are both on the same page to me....

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