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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #271
    Quote Originally Posted by crabbyshark View Post
    Axonal regeneration, in the absence of neuron regeneration, has shown to result in significant functional improvement.

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    SOURCE
    Look carefully at the data. This is an acute study, not chronic. Also, notice that the claimed regeneration is all WITHIN the lesion site. Stimulating regeneration INTO the lesion is easy. Stimulation of regeneration all the way through the lesion and beyond is the hard part. Notice also that the spontaneous regeneration in the Bradke paper is only about 150 um which is remarkably small and likely not beyond the distal end of the lesion. True axon regeneration (meaning significant regrowth of axons from the distal end of a cut axons well beyond the lesion) is incredibly limited after injury and comes to a halt over time with the development of dystrophic axon tips, stuck indefinitely in the proximal end of the scar. However, sprouting (which is collateral branching from cut or uncut axons as well as terminal arbor sprouting from surviving axons to invade denervated territory is an extremely slow process that can occur over an entire lifetime. Sprouting/plasticity can be enhanced by intense rehab training, epidural stimulation or chondroitinase.

  2. #272
    Quote Originally Posted by jsilver View Post
    Look carefully at the data. This is an acute study, not chronic. Also, notice that the claimed regeneration is all WITHIN the lesion site. Stimulating regeneration INTO the lesion is easy. Stimulation of regeneration all the way through the lesion and beyond is the hard part. Notice also that the spontaneous regeneration in the Bradke paper is only about 150 um which is remarkably small and likely not beyond the distal end of the lesion. True axon regeneration (meaning significant regrowth of axons from the distal end of a cut axons well beyond the lesion) is incredibly limited after injury and comes to a halt over time with the development of dystrophic axon tips, stuck indefinitely in the proximal end of the scar. However, sprouting (which is collateral branching from cut or uncut axons as well as terminal arbor sprouting from surviving axons to invade denervated territory is an extremely slow process that can occur over an entire lifetime. Sprouting/plasticity can be enhanced by intense rehab training, epidural stimulation or chondroitinase.
    Perhaps they took the picture before the axons crossed all the way through?

    The stem cells and axons in the picture are going into and across the injury site. The rats that got the stem cells showed significant functional improvement compared to the ones that did not.

    Let's say I get a stem cell injection and the stem cells and axons cross the injury site but for some reason mysteriously stop just before crossing into the other side and I still show significant improvement. I'm ok with that.

    Here's one titled "Axon regeneration through scars and into sites of chronic spinal cord injury"
    Last edited by crabbyshark; 01-23-2013 at 07:45 PM.

  3. #273
    Quote Originally Posted by crabbyshark View Post
    Perhaps they took the picture before the axons crossed all the way through?

    The stem cells and axons in the picture are going into and across the injury site. The rats that got the stem cells showed significant functional improvement compared to the ones that did not.

    Let's say I get a stem cell injection and the stem cells and axons cross the injury site but for some reason mysteriously stop just before crossing into the other side and I still show significant improvement. I'm ok with that.

    Here's one titled "Axon regeneration through scars and into sites of chronic spinal cord injury"
    It is absolutely clear that at acute stages following spinal cord injury, a variety of different types of stem cells can potently and therapeutically affect the inflammatory cascade that leads to secondary damage. Notice also in the paper you cite that the lesion volume was decreased which is a good indication that secondary injury had been ameliorated. This spares axons in the lesion penumbra and leads to better recovery. You do not need frank regeneration to occur at acute stages after injury to improve function. Sparing of axons at risk is also a very productive effect of stem cells when administered acutely. The evidence for frank regeneration into but also, and most importantly, beyond the lesion, is lacking in such studies.

    In the Lu et al paper that you cite, the authors used a virus to express a very powerful neurotrophin within and beyond the lesion. The intensity of such expression can, in part, overpower the scar that had formed and draw a relatively small number of sensory axons right through the scar. There is no doubt that the scar is not completely impenetrable. That is a good thing. The question that remains unanswered is whether at long chronic stages following SCI the use of lithium or any type of stem cell (including UMBC) can act potently enough to stimulate axon growth sufficiently strongly and provide a bridge potently growth supportive enough to provide a route across an established scar. There simply is no in vitro or in vivo evidence in any animal model to support this conclusion. If stem cell administration at chronic stages after injury does result in functional benefits (and I hope it does) then the reasons for functional improvement will be a matter of speculation. Functional improvements could result from rehab therapy, enhancements of sprouting in the vicinity of the lesion or possibly from re-myelination of axons. The possibility of recovery at chronic stages due to frank regeneration via stem cell transplantation has not been born out by the experimental literature.

  4. #274
    Quote Originally Posted by Wise Young View Post
    ........
    3. What clinical trials of "glial scar" therapies are you talking about? I know of no clinical trial being planned that will test any "glial scar" therapy. Are you referring to chondroitinase or the CSPG receptor blockers? If either of these therapies stimulate regeneration, it would confirm that gliosis does not pose a tight mechanical barrier to axon growth.

    ......

    Wise.
    Wise,

    I was referring to what you posted:

    Quote Originally Posted by Wise Young View Post

    .....
    I just returned from China and heard yet another researcher proposing to cut out 10 mm of “glial scar” from the spinal cord of people and replacing it with biomaterials. Carlos Lima and his colleagues cut out a piece of the spinal cord at the injury site to put in nasal mucosa, saying that it is only “glial scar”. A clinical trial is going on in New Zealand still doing this. As you know, there are companies that are proposing to cut out the “glial scar” from the spinal cord. It is not theory any more. It is being practiced.

    .......

    Wise.
    So I hope that these trials will prove that removing the fiborotic scar and/or the glial scar will be safe and maybe also effective in combiantion with some therapy.

    About Carlos Lima, correct me if I am wrong, but I believe his approach has been proven to be safe, but not effective.
    BTW I spoke to him few times before he died.. he said to me that in real life (which I think he had more experience than you as you posted a while ago that you are just starting to see human spinal cords with chronic SCI) very often there is a very visible fibrotic scar in the lesion site and mainly this is what he believed needed to be removed.

    Paolo
    Last edited by paolocipolla; 01-26-2013 at 07:02 PM.
    In God we trust; all others bring data. - Edwards Deming

  5. #275
    Quote Originally Posted by t8burst View Post
    Really? So when Silver builds a multi-country clinical trials network (when is this planned for by the way?) and start clinical trials on humans (remind me again when this is going to happen again?) he will prove... well we don't know do we. Because he is doing none of those things.
    It is easy to believe newer unproven research. By the time (if) Silver's research gets to where UMBC-Li is I am sure there will be other therapies in the pipe that may seem better. Science builds on its successes and failures and unfortunately for us takes a long time.
    Quote Originally Posted by t8burst View Post
    More my point was that I don't doubt Jerry Silver is good at what he does and Wise is very good at what he does. My point was they do very different things yet people are comparing them apples to apples.
    T8burst, I've already explained my position :
    Quote Originally Posted by kivi66 View Post
    Paolo, let him to do what he is doing. Without alchemists we wouldn't have the Chemistry.

  6. #276
    Quote Originally Posted by c473s View Post
    Scar or no scar Dr. Silver will not be taking his work into humans unless he changes heart from what he said at a recent conference. He said he didn't need any more money for research since he was not interested in being involved in translating his rat work to a larger animal or primate model or work to see the research reach human studies. He said that was for someone else to pick up and run with.
    This is where SCI orgs/people can and must help I believe.
    For example CDRF has supported and promoted the on going E-stim study.
    ISRT is working to hopefully move Ch'ase to trials with or without Acorda...

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  7. #277
    Quote Originally Posted by Wise Young View Post
    Paolo,

    1. Where is your evidence that such "fibrotic scars" exist inside injured human spinal cords? Do you have any evidence that removal of such scars helps any animal or human with spinal cord injury? You don't because there isn't any evidence. In fact, removal of glial scars have been shown to be damaging to the spinal cord.

    2. No, I would not remove "fibrotic scar" from inside the spinal cord because there is no credible evidence that physical removal of glial scar improves recovery and ample evidence suggesting axons will grow through such scars with several non-invasive therapies, e.g.
    • If axons are activated to grow with cAMP, PTEN deletion, mTOR activation.
    • Lithium and chondroitinase stimulate regeneration through such scars.

    3. What clinical trials of "glial scar" therapies are you talking about? I know of no clinical trial being planned that will test any "glial scar" therapy. Are you referring to chondroitinase or the CSPG receptor blockers? If either of these therapies stimulate regeneration, it would confirm that gliosis does not pose a tight mechanical barrier to axon growth.

    When confronted with evidence that you are wrong, you obfuscate with false claims and ad hominem attacks.

    Wise.
    Wise,

    please refer to the answer of Dr. Silver for point 1 and 2. I can't for sure give a better answer.

    In case I haven't been very clear, my question about the fibrotic scar was mainly directed to the case of a penetreting wound (by a bone fragment for example which is not uncommon) where the fibrotic scar is very visible. So even in that case you would leave it there and you believe axons can grow through it.
    Is there any study that show axons growing through fibrotic scar?

    Paolo
    Last edited by paolocipolla; 01-23-2013 at 09:55 PM.
    In God we trust; all others bring data. - Edwards Deming

  8. #278
    Quote Originally Posted by amole View Post
    Good point. No conspiracy, much less a "conspiracy theory", is needed for 3 or 4 people to spend most of their time attacking the beliefs of someone trying to prove something.

    It is puzzling why they don't just wait for the results the trials. It seems like they are afraid he might be right.
    I wish I am wrong, but I am afraid I am right. See the results below (they don't look positive to me).
    Problem is that as long as we put our hope and effort in the wrong direction a cure will just take longer to come.
    I just don't want to waste time as I have been waiting (wasting time) too many times. I know some people get that.. fortunatly.

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  9. #279
    Quote Originally Posted by jsilver View Post
    It is absolutely clear that at acute stages following spinal cord injury, a variety of different types of stem cells can potently and therapeutically affect the inflammatory cascade that leads to secondary damage. Notice also in the paper you cite that the lesion volume was decreased which is a good indication that secondary injury had been ameliorated. This spares axons in the lesion penumbra and leads to better recovery. You do not need frank regeneration to occur at acute stages after injury to improve function. Sparing of axons at risk is also a very productive effect of stem cells when administered acutely. The evidence for frank regeneration into but also, and most importantly, beyond the lesion, is lacking in such studies.
    It is very good for chronics that stem cells work so well at the acute stage.

    There is evidence to suggest that stem cells work better after the acute stage (Here, 1 week > 2 weeks > 12 hours):
    Our results suggest that transplanted cMSCs promote the formation of neuronal network through regulating the intracellular pathways of the actin cytoskeleton to overcome repulsive forces which result from scar formation and severance of axon.

    To further verify the role of cMSC transplantation in the regeneration of injured spinal cords, NT-3 was investigated as a neurotrophic factor. Exogenous cMSCs provided a supportive environment for neuronal repair and regeneration through trophic effects (4,29,31,32). Neurotrophic factors secreted by transplanted stem cells may have a more prominent therapeutic effect than differentiation of transplanted stem cells and establishment of functional connections (4). In the present study, levels of NT-3 and neuronal markers were increased in 1-week and 2-week TP groups. These results demonstrate that increases of GFAP or neuronal marker levels were consistent with NT-3 production, which was similar to that reported by a previous study (28).

    Our results indicate that cMSCs transplanted to the site of SCI improved clinical signs by anti-inflammatory effect, regulating signal molecules related to astrogliosis, neuronal extension, and NT-3. These collective effects have been more enhanced in 1 wk transplantation after SCI than in 2-week transplantation after SCI. The optimal time for cMSC transplantation as a therapeutic modality may not be immediately after SCI or once fibrosis has progressed.
    SOURCE

    Here, they are having trouble getting neural stem cells to work at all in the acute stage:
    We've done transplants, actually not all of which I've talked about today, but at four different times after injury in thoracic and now moving into cervical models. So immediately, 9 day delay, 30 day delay or 60 day delay to try to push into a more chronic setting.

    We see, we have seen recovery of function at anything that is a delayed transplant; nine, thirty, or sixty. It's the exact same transplantation protocol, same number of cells, same location, and so on.

    Where we don't see recovery, actually, is in immediate transplants and I didn't talk about that today. We see that the cells behave very differently in that microenvironment. We can get recovery, but we have to change the microenvironment by manipulating the inflammatory cascade. So we think it may be even possible to even extend transplant time further as things go on but there's a lot of basic science there that we have to understand yet and that's how basic and translational science really have to go hand in hand to move things on.
    SOURCE (6:10)

    Quote Originally Posted by jsilver View Post
    In the Lu et al paper that you cite, the authors used a virus to express a very powerful neurotrophin within and beyond the lesion. The intensity of such expression can, in part, overpower the scar that had formed and draw a relatively small number of sensory axons right through the scar.
    It doesn't say relatively small number. It says:
    Anatomical analysis 3 months post-injury revealed extensive astrocytosis surrounding the lesion site, together with dense deposition of the inhibitory extracellular matrix molecule NG2. Despite this inhibitory environment, axons penetrated the lesion site through the chronic scar. Robust axonal regeneration occurred into chronic lesion cavities expressing NT-3.
    Quote Originally Posted by jsilver View Post
    There is no doubt that the scar is not completely impenetrable. That is a good thing. The question that remains unanswered is whether at long chronic stages following SCI the use of lithium or any type of stem cell (including UMBC) can act potently enough to stimulate axon growth sufficiently strongly and provide a bridge potently growth supportive enough to provide a route across an established scar. There simply is no in vitro or in vivo evidence in any animal model to support this conclusion.
    The subjects that received stem cells without the neurotrophin still improved:
    Axons cross the host–graft interface and extend throughout GFP-MSC and NT3/GFP-MSC grafts in the non-resected, chronic lesion site. (A) Six weeks following delayed introduction of GFP-MSC grafts, modest numbers of neurofilament (NF)-labeled axons cross perilesioned scar tissue and the host–graft interface, distributing throughout the core of grafts in lesion site (shown). (B) NT3/GFP-MSC grafts are more densely penetrated by axons. Scale bar A, B = 44 μm. (C) Quantification of NF-labeled axon density in cellular grafts demonstrates a significant increase in NT3/GFP-MSC grafts (n = 8) compared to control GFP-MSC grafts (n=5).
    Much of your work focuses on incompletes. What if in an incomplete injury, that's all it takes to get significant improvement?

    Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord.
    Transplantation of neural progenitor cells (NPCs) holds great potential for the treatment of spinal cord injuries. The survival and differential fates of transplanted NPCs in the cord are key factors contributing to the success of the therapy. In this study, we investigate the effects of lithium, a widely used antidepressant drug, on the survival, proliferation and differentiation of spinal cord-derived NPCs in cultures and after transplantation into the spinal cord. Our results show that clinically relevant doses of lithium increase the proliferation of grafted NPCs at 2 weeks post-grafting and neuronal generation by grafted NPCs at 2 weeks and 4 weeks post-grafting. However, lithium does not cause preferential differentiation of NPCs into astrocytes or oligodendrocytes both in vitro and after transplantation. Our results also show that chronic treatment with lithium (up to 4 weeks) reduces microglia and macrophage activation, indicating that lithium treatment can affect the host immune response. The results of the present study provide evidence that lithium may have therapeutic potential in cell replacement strategies for CNS injury due to its ability to promote proliferation and neuronal generation of grafted NPCs and reduce the host immune reaction.
    SOURCE

    If lithium enhances stem cells, and if stem cells are already aiding axonal growth past the scar wall and across the injury site, it is more than reasonable to conclude that stem cells enhanced by lithium would greatly aid axonal growth past the scar wall and across the injury site.

    Quote Originally Posted by jsilver View Post
    If stem cell administration at chronic stages after injury does result in functional benefits (and I hope it does) then the reasons for functional improvement will be a matter of speculation
    From the first study:
    Taken together, the behavioral data demonstrate that USSC transplantation significantly improved the locomotor performance compared to spinal injured animals lacking the stem cell graft.
    Quote Originally Posted by jsilver View Post
    Functional improvements could result from rehab therapy,
    Do you know any chronic ASIA A's who have tried really hard to start walking again? I do. They go to physical therapy for a few weeks every couple years, as soon as their insurance allows, and try as hard as they can to walk again.

    It never happens.

    Quote Originally Posted by jsilver View Post
    Enhancements of sprouting in the vicinity of the lesion or possibly from re-myelination of axons. The possibility of recovery at chronic stages due to frank regeneration via stem cell transplantation has not been born out by the experimental literature.
    "Axon regeneration through scars and into sites of chronic spinal cord injury" suggests it's a very good possibility:
    Collectively, these findings indicate that inhibitory factors deposited at sites of chronic SCI do not create impenetrable boundaries and that inhibition can be balanced by local and diffusible signals to generate robust axonal growth even without resecting chronic scar tissue.
    Quote Originally Posted by jsilver View Post
    It is absolutely clear that at acute stages following spinal cord injury, a variety of different types of stem cells can potently and therapeutically affect the inflammatory cascade that leads to secondary damage.
    Do you think this is something that might be worth further investigating?? Could this maybe help chronics? Why doesn't every. single. thing. that you do involve stem cells somehow?

    Historically speaking, you are in the exact right field at the exact right time. It is wide open. For instance, what if a large group of stem cells that occurred regularly together in nature, emitting different neurotrophins, didn't cure Alzheimer's Disease, but two or three isolated from the group and mixed together, did?

    Quote Originally Posted by jsilver View Post
    If stem cell administration at chronic stages after injury does result in functional benefits (and I hope it does)
    Do you really? All of the evidence suggests otherwise.

    Why are you fighting this?

    It is so strange.

    I badly want big things to come out of Cleveland. The weather sucks. Our football team sucks, our baseball team sucks, our basketball team sucks. Our scientists definitely don't suck, but some of them are certainly barking up the wrong tree.
    Last edited by crabbyshark; 01-24-2013 at 06:11 AM.

  10. #280
    Originally Posted by jsilver
    There is no doubt that the scar is not completely impenetrable. That is a good thing. The question that remains unanswered is whether at long chronic stages following SCI the use of lithium or any type of stem cell (including UMBC) can act potently enough to stimulate axon growth sufficiently strongly and provide a bridge potently growth supportive enough to provide a route across an established scar. There simply is no in vitro or in vivo evidence in any animal model to support this conclusion.
    Jerry,

    I don't know if you are aware of the following studies on lithium treatment of spinal cord injury.

    The first one is by Wutian Wu and his group at Hong Kong University in 2004. In that J. Neurotrauma paper, they hemisected the spinal cord to cut the rubrospinal tract and used fluorogold retrograde labelling of that tract to label neurons in red nucleus. They compared lithium alone, chondroitinase, and the combination of lithium and chondrotinase. The combination therapy resulted in retrograde labeling of 42% of the neurons in the red nucleus and saw functional recovery associated with the regeneration. Wu, et al. also showed that lithium treatment of the animals stimulated proliferation of neural stem cells and BDNF release in the spinal cord.

    The second paper is by Dill, et al. in the J. Neuroscience who studied the effects of GSK3b blockers, including lithium, on a variety of spinal cord injury models as well as in vitro growth of axons in the presence of myelin. They found robust regeneration and recovery of function in the transection and contusion model in rats. I attach the reprints just in case.

    I have previously listed and reviewed nearly two dozen papers from independent laboratories reporting beneficial effects of umbilical cord blood mononuclear cell therapy of rat and dog spinal cord injury. So, I won't do it here again.

    Wise.

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