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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #311
    Quote Originally Posted by jsilver View Post
    Wise,
    Show me actual convincing evidence (not speculation or assumptions drawn from other papers) that your Li +UMBC strategy is sufficiently potent to stimulate regeneration clearly through ( not into) a well established glial scar and I will sing your praises.
    There in lies the problem. Wise cannot because his subjects are humans. He cannot put humans to death and/or cut out sections of their spinal cords to view under a microscope. Nor can he insert green florescent dye into their spinal cords to see where the axons and neurons hit the glial scar wall or veiw where and how far they pass through. So, it seems that Wise, as promised, will have to wait 12 months or so for all the patient followup data before he can begin to have a cursory amount of convincing evidence. His objective was to test UCBSC cells and lithium (both proven safe in humans over the last 10+ years) in chronic SCIs and wait to see first if it was safe and produced NO HARM. If an Asia A patient happened to also show some improvement in sensory or motor, then that would be a BONUS if also first determined safe.

    Thank you both for your herculean efforts to try to solve the SCI challenge. It is quite apparent that SCIs are still mostly paralyzed, even 50 years post injury. Something is obviously in place that prevents spinal cord self repair/regeneration.

    I firmly believe that it will take a few more years and more collaborative efforts in both rodent spinal cord research and human trials to find the best cure available. I see it like the letter "V" where Jerry is on the right side of the top of the V and Wise on the top of the left side. Both approaches are slowly coming together towards the bottom of the V and the SCIs persons will be the eventual winner.

  2. #312
    Quote Originally Posted by t8burst View Post
    It does, thanks. One last question. From your earlier (or later) comments it is clear that this study shows growth through scar tissue. I am interested in the Lu study which transects the cord and places a medium with growth inducers. Do you see this as something that would become a therapy for someone like me, who doesn't have a transected cord? In other words to regrow connections will we need to cut the cord and put this bridge between the section or will simply surrounding the damaged area of the cord with the same cocktail be sufficient to produce grow across a damaged but not transected cord?

    Thanks,
    Tom
    Tom,

    Let me re-iterate two things that you seem to have missed in the paper and in my comments.

    First, the axons that regenerated in the Lu study were not the rats' own axons. They were the axons of neurons produced by or differentiated from the transplanted neural stem cells! We don't know whether any of the rats' own axons are crossing the injury site. If not, the rats' brains must send axons to connect with the transplanted cells and those cells must then talk to neurons below the injury site in order to walk. On the other side, it is not clear whether any of the rats ascending sensory axons are crossing the injury site. If the rats' own sensory axons are not crossing the injury site and growing all the way to the brain, the rats have no sensation. By the way, rats with transected spinal cords can recover up to a BBB score of 4 but a score of 6 or 7 would be very rare.

    Second, while they showed an improvement of BBB scores from 2 to 6-7, this is from a minor twitches of the legs to non-functional movements of the legs. It is possible that some of the rats' axons grew into the injury site and connected with the transplanted neurons. Lu, et al. showed activation of neurophysiological responses in the lower spinal cord in response to electrical stimulation of the spinal cord. This could happen if some transplanted sent axons both rostrally (towards the head) and caudally (towards the tail), some of the rats' axons grew into the injury site and connected with the transplanted neurons. They also showed responses in the upper spinal cord C7 when they stimulated the lower spinal cord at T6 (figure 5). The lesion site was at T3. These responses declined when they applied kynurenic acid to block excitatory synapses. This suggests that ascending axons from the rat have entered the injury site and connected with neurons that have sent ascending axons to the C7.

    The study proved that transplanted neurons can send axons that grew across glial scars and reconnected with the rats neurons above and below the injury site. It suggests that some axons from the rat entered into the injury site and connected with the transplanted neurons that have sent axons into the rostral and caudal spinal cord. I don't think that this particular injury and treatment paradigm should be done in humans. On the other hand, we are trying to do something that this to replace neurons in the lumbosacral spinal cord. We want to transplant neural stem cells into the contused lumbosacral spinal cords, get the neural stem cells to produce neurons that replace damaged motoneurons, encourage these motoneurons to send axons out the ventral roots to reinnervate muscle. Then we want grow axons from the CPG and various descending tracts to connect with these new neurons.

    Wise.

  3. #313
    Cripwalk

    Obviously UBCMN cells + lithium are not going to cure spinal cord injuries. But the trial is into phase III. Whether the data is positive or negative, WHO CARES? It just helps us ALL figure out what might work, and what won't. The network to test human alone is a massive step forward, and hopefully the therapies in the future will build on each other. I will be the first one to cheer if and when there is a bridge built to overcome the scar which can be tested in humans. But until that happens, I find the discourse which although enlightening is not very open minded.

    I like you er thinking and straight Talking . I say enough about scar tissue Why not put the lot in the one syringe then both will be right
    AS I SIT HERE IN MY CHAIR . I LOOK OUT UPON THE GROUND .I WONDER WILL I EVER GET UP AND WALK A ROUND ??


    http://justadollarplease.org

  4. #314
    Quote Originally Posted by Wise Young View Post
    1. Deng XY, Zhou RP, Lu KW and Jin DD (2010). [Lithium chloride combined with human umbilical cord blood mesenchymal stem cell transplantation for treatment of spinal cord injury in rats]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 30: 2436-9. Department of Spinal Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China. dengxuyong@tom.com. OBJECTIVE: To observe the effects of lithium chloride combined with human umbilical cord blood mesenchymal stem cell (hUCB-SCs) transplantation in the treatment of spinal cord injury in rats. METHODS: Eighty female SD rats with complete T9 spinal cord transaction were randomized into 4 groups (n=20), namely the control group (group A), lithium chloride group (group B), hUCB-SCs group (group C) and hUCB-SCs(+) lithium chloride group (group D). On days 1 and 3 and the last days of the following weeks postoperatively, the motor function of the hindlimb of the rats were evaluated according to the BBB scores. At 8 weeks, all the rats were sacrificed and the spinal cords were taken for morphological observation. The spinal cord tissues at the injury site were observed with Brdu nuclear labeling to identify the survival and migration of the transplanted SCs. The regeneration and distribution of the spinal nerve fibers were observed with fluorescent-gold (FG) spinal cord retrograde tracing. RESULTS: Brdu labeling showed that the transplanted hUCB-SCs survived and migrated in the spinal cord 8 weeks postoperatively in groups C and D. FG retrograde tracing identified a small amount of pyramidal cells that migrated across the injury site in groups C and D. The BBB scores of the hindlimb motor function 8 weeks postoperatively were 4.11-/+0.14, 4.50-/+0.15, 8.31-/+0.11 and 11.15-/+0.18 in groups A, B, C and D, respectively. CONCLUSION: Lithium chloride can promote the survival and differentiation of hUCB-SCs into neural cells at the injury site. Lithium chloride combined with hUCB-SCs transplantation may accelerate functional recovery of the hindlimbs in rats with complete transection of the spinal cord.
    Full-text: http://www.j-smu.com/pdf2/201011/2010112436.pdf
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  5. #315
    Quote Originally Posted by ay2012 View Post
    I would have a similar question: much of this talk has surrounded the differences between a severely contused cord and a full transection. Is the latter a "harder" model to generate regeneration in? Would it then follow that the neural stem cells with the fibrin gel could perhaps result in even more robust regeneration and return of function in a severe contusion? Or are they simply not comparable models? Thanks!
    ay2012,

    Please see my answer to T8burst. In my opinion, there is no reason why the lesion site should be removed. There are many ways to modify the lesion site so that it is more hospitable to axons and to produce neurotrophins at the lesion site. In fact, umbilical cord blood and lithium seem to do this and we are testing this in clinical trial.

    Retarding the difference between transection and contusion, I personally think that contusion model is much more difficult to regenerate than a transection. The Liu and Lu studies were done respectively with hemisections and transection models. Liu is trying to get regeneration of contused rat spinal cords in the PTEN deleted mouse but it is difficult.

    Wise.

  6. #316
    cripwalk,

    I originally thought that Jerry and I were arguing over semantics. I objected to the word "scar" because it is misleading and is leading to undesirable clinical practices. After the last few exchanges, I am not sure that it is just semantics between us.

    I believe that fibrosis and inhibitory extracellular molecules such as CSPG will slow or stop axon growth. However, I am convinced from recent evidence that neurotrophins and other stimulants that increase neuronal cAMP and activate mTOR allow axons to grow through CSPG and even glial scars.

    Wise.

    Quote Originally Posted by cripwalk View Post
    Is it just me, or are you guys still arguing over semantics. If I understand correctly, wise agrees glial scars form a barrier, however, he claims that it is not, and you *seem* to agree, an impenetrable barrier.

    To him, that disproves the glial scar theory. To you, it does not. All that is really separating your view on glial scar theory is perspective.

    IMO it seems like Wise is saying that IF 'rocket fuel' neutrophons (sp?) can help axons grow through the lesion, then all we need is the correct rocket fuel.

    It seems to me Jerry that you are saying, regardless of which rocket fuel you use, the scar needs some sort of bridge for axons to cross.

    It is impossible for you both to be right, but it seems hard to believe either of you have enough evidence to have proven yourselves right. This might be the hill to die on for regenerating the cord, but you are both working towards the same goal. Can we get some fucking collaboration here?

    Obviously UBCMN cells + lithium are not going to cure spinal cord injuries. But the trial is into phase III. Whether the data is positive or negative, WHO CARES? It just helps us ALL figure out what might work, and what won't. The network to test human alone is a massive step forward, and hopefully the therapies in the future will build on each other. I will be the first one to cheer if and when there is a bridge built to overcome the scar which can be tested in humans. But until that happens, I find the discourse which although enlightening is not very open minded.

    Die on the hill of truth. The evidence will bare out the truth.

    I want to thank both Wise and Jerry for all their hard work and especially their passion for the truth. But this is far more personal than is necessary.

  7. #317
    Thank you for your comments and you are welcome. Wise.

    Quote Originally Posted by 6 Shooter View Post
    There in lies the problem. Wise cannot because his subjects are humans. He cannot put humans to death and/or cut out sections of their spinal cords to view under a microscope. Nor can he insert green florescent dye into their spinal cords to see where the axons and neurons hit the glial scar wall or veiw where and how far they pass through. So, it seems that Wise, as promised, will have to wait 12 months or so for all the patient followup data before he can begin to have a cursory amount of convincing evidence. His objective was to test UCBSC cells and lithium (both proven safe in humans over the last 10+ years) in chronic SCIs and wait to see first if it was safe and produced NO HARM. If an Asia A patient happened to also show some improvement in sensory or motor, then that would be a BONUS if also first determined safe.

    Thank you both for your herculean efforts to try to solve the SCI challenge. It is quite apparent that SCIs are still mostly paralyzed, even 50 years post injury. Something is obviously in place that prevents spinal cord self repair/regeneration.

    I firmly believe that it will take a few more years and more collaborative efforts in both rodent spinal cord research and human trials to find the best cure available. I see it like the letter "V" where Jerry is on the right side of the top of the V and Wise on the top of the left side. Both approaches are slowly coming together towards the bottom of the V and the SCIs persons will be the eventual winner.

  8. #318
    I originally thought that Jerry and I were arguing over semantics. I objected to the word "scar" because it is misleading and is leading to undesirable clinical practices. After the last few exchanges, I am not sure that it is just semantics between us.

    I believe that fibrosis and inhibitory extracellular molecules such as CSPG will slow or stop axon growth. However, I am convinced from recent evidence that neurotrophins and other stimulants that increase neuronal cAMP and activate mTOR allow axons to grow through CSPG and even glial scars.


    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.

  9. #319
    Dr. Silver ,
    Hi, is there any way you can work with Dr. Young to start your clinical trial in chinascinetwork , or usscinetwork ? Or if you rather , is there any pharm. co. that you can talk and convince them (medically and financially) to start the result of your lab work in chronic sci human clinical trial ? Even partial recovery (bladder and bowel function recovery ,etc. ) from your method would help us significantly. Has any company(S) showed any interest to take your chronic sci work to clinical trial lately (other than acorda ) ? Also ,do you know when your new paper on chronic sci will be published ? Thank you .
    Last edited by kz; 01-26-2013 at 09:45 PM.

  10. #320
    Quote Originally Posted by jsilver View Post
    I originally thought that Jerry and I were arguing over semantics. I objected to the word "scar" because it is misleading and is leading to undesirable clinical practices. After the last few exchanges, I am not sure that it is just semantics between us.

    I believe that fibrosis and inhibitory extracellular molecules such as CSPG will slow or stop axon growth. However, I am convinced from recent evidence that neurotrophins and other stimulants that increase neuronal cAMP and activate mTOR allow axons to grow through CSPG and even glial scars.


    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.
    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?

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