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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #341
    Quote Originally Posted by crabbyshark View Post

    There are two papers now. Here is a third.

    Attached: "Synergistic Effects of Transplanted Adult Neural Stem/Progenitor Cells, Chondroitinase, and Growth Factors Promote Functional Repair and Plasticity of the Chronically Injured Spinal Cord"

    Why exactly did you cite this paper?

  2. #342
    Quote Originally Posted by crabbyshark View Post
    GRAMMY,

    I was able to find the full article from the 2011 abstract you shared. Thank you. In the article, there was nothing about a chronic contusive injury, animals breathing again after 1.5 years, or cutting into the spinal cord resulting in functional improvement. I'm looking for stuff released in peer reviewed journals about that (especially the bit about cutting into the spinal cord). If you have something, please send it my way. The videos are ok but if Jerry Silver has taught us anything, it's that we should be extremely skeptical of anything said in a video.
    You have no idea what you're talking about. A C-2 Hemisection was used so as to only paralyze one lung. (If he'd paralyzed both lungs the lab animal dies. Simple. There are no rat respirators). I don't think you grasp the concept of nerve grafting...

  3. #343
    Quote Originally Posted by NowhereMan View Post
    Why exactly did you cite this paper?
    Because it's animals with chronic spinal cord injury getting better without cutting into the spinal cord.

  4. #344
    Quote Originally Posted by crabbyshark View Post
    Because it's animals with chronic spinal cord injury getting better without cutting into the spinal cord.

    Dr. Silver was referring to: "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)"

    The paper does not show such regeneration.

  5. #345
    Dear Crabbyshark,

    There are two papers now. Here is a third.

    Attached: "Synergistic Effects of Transplanted Adult Neural Stem/Progenitor Cells, Chondroitinase, and Growth Factors Promote Functional Repair and Plasticity of the Chronically Injured Spinal Cord"


    Thanks for citing this one from the Fehlings lab because it demonstrates nicely the role of scar associated inhibitory molecules in curtailing stem cell migration especially at chronic stages after injury. You and Wise should actually read it. Just look at the title. The authors demonstrate yet again the need for a combinatorial strategy that breaks down CSPGs (via chondroitinase) and adds a cocktail of neurotrophins to keep stem cells alive in order to allow them to escape the lesion, migrate remarkable distances and remyelinate axons. Without chondroitinase at chronic stages the stem cells remained trapped within the scar. This is not a paper about axonal regeneration to restore function but likely remyelination of axons or possibly sprouting effects. None-the-less, it is a very nice paper giving hope that a proper combinatorial strategy employing stem cells can restore some useful function at chronic time points following SCI.

    PS. The research leading to the result of respiratory recovery following ch'ase injections into the cord 1.5 years after C2 hemisection is still ongoing in the lab. A post-doctoral student from the Fawcett lab has joined ours and this is going to be her project. We have more work to do to make this paper the best we possibly can. However, we did present the results in a public forum (Soc for Neuroscience Meetings) and, therefore, I feel that it is OK to discuss the results. An abstract of the presentation is published.
    Last edited by jsilver; 01-30-2013 at 10:41 AM.

  6. #346
    Quote Originally Posted by jsilver View Post
    It doesn't seem as if you are both on the same page to me....

    I thought we were headed in the right direction but, alas, we're as far apart as ever. The scar (or let's call it the lesion environment) is a potent barrier that needs strong measures to remove or over power it. It is absolutely not growing weaker and weaker just because Wise says so. Crabby person and Wise mention the Tuszynski paper as an example of axon regeneration past an established glial scar. Here's what they had to do to get a very small number of sensory axons past an established scar without physically removing it. (1) They fill the lesion with genetically altered neurotrophin expressing marrow stromal cells, then they (2) express the same powerful neurotrophin just beyond the scar using a virus and finally (3) they have to condition the sensory neurons with a prior crush lesion. At 6 weeks following injury using this approach they get several dozens of axons across the lesion and at 15 months post injury they get just a handful of sensory axons across a well established scar. Once past the scar the axons stop abruptly in the trophic oasis in the white matter on the other side of the lesion. No synapses, no functional recovery. I encourage you all to carefully read this paper ( it's downloadable from the Crabbyfish post above) and learn what it takes to get the smallest number of axons past an established scar. Does that sound weak to you? Just yesterday I saw a guardrail on the side of the road that had been smashed through by a fast moving vehicle. It was good example of the point I am trying to make. No barrier is absolute but would you suggest that steel guardrails are not potent barriers?
    Jerry,

    May I suggest that you press the button [Quote] on the lower right side of the post that you are answering. This includes the words and name of the person that you are answering. This reduces confusion of what you are saying versus the person that you are answering. You can put what you write either on top or below the quoted post, as well as edit what you want to quote. I also suggest that if you answer within the quotation that it is easier to read if you select your words and highlight them by changing the color of the text. All capitalized words indicate shouting on Internet and is considered poor manners. You also have be careful not to delete the {/quote} (curly brackets indicating square brackets) which is necessary to close the quotation. If you don't mind, I can edit your posts to clear up these display issues.

    I like your use of the term "lesion environment", instead of "glial scar". It accurately depicts the situation. Regarding the Lu, et al. (2012) paper that I had previously posted, the number of axons that are growing across the transection and transplantation site in the paper are quite numerous. Many thousands of axons are growing form the transplanted cells. But, as I have pointed out already, these axons come from the transplanted neural stem cells lines and may not behave like normal neurons.

    So, perhaps we should discuss another paper by Lu, et al. (2012) also from the Tuszynski lab. The reference and abstract of the paper is below. The study assesses the growth of reticulospinal axons across a transection site transplanted with mesenchymal stem cells and that has an area expressing BDNF on the other site. It is a beautiful study that shows that growing reticulospinal axons ignore the gliosis to grow into the injury site and can be enticed to grow out of the graft by expression of BDNF in the distal cord.

    Lu, P., Blesch, A., Graham, L., Wang, Y., Samara, R., Banos, K., et al. (2012). Motor axonal regeneration after partial and complete spinal cord transection. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 32(24), 8208–8218. doi:10.1523/JNEUROSCI.0308-12.2012
    1Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, 2Veterans Administration Medical Center, San Diego, California 92161, 3Spinal Cord Injury Center, Heidelberg University Hospital, D-69120 Heidelberg, Germany, 4Department of Anesthesiology, University of California, Irvine, Irvine, California 92697, and 5University of Alberta, Centre for Neuroscience, Edmonton, Alberta T6G 2E1, Canada
    We subjected rats to either partial midcervical or complete upper thoracic spinal cord transections and examined whether combinatorial treatments support motor axonal regeneration into and beyond the lesion. Subjects received cAMP injections into brainstem reticular motor neurons to stimulate their endogenous growth state, bone marrow stromal cell grafts in lesion sites to provide permissive matrices for axonal growth, and brain-derived neurotrophic factor gradients beyond the lesion to stimulate distal growth of motor axons. Findings were compared with several control groups. Combinatorial treatment generated motor axon regeneration beyond both C5 hemisection and T3 complete transection sites. Yet despite formation of synapses with neurons below the lesion, motor outcomes worsened after partial cervical lesions and spasticity worsened after complete transection. These findings highlight the complexity of spinal cord repair and the need for additional control and shaping of axonal regeneration.

    Lu, et al. dorsally hemisected the spinal cord, placed a bone marrow stromal cell graft into the hemisetion site, labeled reticulospinal axons by injecting biotinylated dextran amine (BDA) into the brainstem, stimulated the axons to grow by injecting cAMP, and then transfected cells in the distal spinal cord to express brain-derived neurotrophic factor (BDNF). For the purposes of discussion, I attach Figure 2 from that article.

    Just to orient people, the figure shows photomicrographs of C5 hemisected spinal cords after combinatorial treatment with cAMP, a cell graft into the lesion site, and transected cells that express BDNF beyond the lesion site. Reticulospinal neurons (from brainstem) are labelled with BDA (red), host astrocyte GFAP in blue (showing the gliosis), and BDNF (a neutrophin) is green.

    I know that the figure legends gives the explanation but let me point out the salient findings in each panel. Panel A shows a low powered view where the lesion site (Les) is situated on the left, there is blue (gliosis) around the lesion site, and a flame-like gout of green towards the right.

    Panel B is a higher power view of the left side of the lesion site. The lesion site is filled with many red fibers. The spinal cord to the left of the lesion site clearly has axons that are heading into and through the gliosis (blue) to the lesion site. The dotted white line indicates the border of the lesion site. There are no glial cells on the lesion side.

    Panel C is a higher power view of the right side of the lesion site. You can see that some of the red (BDA-labelled) reticulospinal axons are leaving the lesion site and growing into the green (BDNF) expressing cells.

    Panel D is the same as Panel C except that the green color was removed, so that you can the large number of red reticulospinal axons that are growing out of the lesion site.

    Panel E is the a higher power view of the right (caudal) cord where you can see many red (BDA-labelled) reticulospinal axons growing beyond the area of BDNF expressing cells.

    Panel F-I are from another spinal cord where the graft (g) can be seen on the left and they have stained the cells not with fluorescence but stained DAB for BDNF light microscopy (dark black cells). The axonal growth seems to be where BDNF is expressed.

    This study indicates that
    1. Many thousands of reticulospinal axons grow into a hemisection site that had been grafted with mesenchymal stem cells.
    2. The reticulospinal axons clearly cross the area of gliosis into the mesenchymal graft and out of the graft into the distal spinal cord.
    3. The axonal growth seem to be associated with BDNF expressing cells. This is of interest because it suggests that axons don't like to leave the graft but can be induced to do so by BDNF in the host spinal cord.
    4. The regenerated axons make synapses with neurons in the distal spinal cord but the animals do not walk (although it seems to have reduced their spasticity).
    5. Finally, despite robust regeneration of reticulospinal axons (probably other axons as well) and connections of these axons with neurons below the injury site, the authors did not see improved motor function.


    The last point is of course discouraging. The authors have regenerated many axons in the spinal cord, showed that the cells have connected, but motor outcomes worsened. One possible reason is that the rats did not receive intensive locomotor training.

    Wise.
    Attached Images Attached Images  
    Last edited by Wise Young; 01-30-2013 at 02:55 PM.

  7. #347
    Here is the full paper Lu, et al. 2012 that I referred to in my last post.

  8. #348
    You can fix my responses if you like. I haven't attempted to figure out the use of all the buttons. I didn't think there was much new info in the Lu paper you cite. Same techniques as before, except this time they added cAMP injections to the reticular formation rather than a conditioning type of lesion that they use to improve the intrinsic growth capacity of the DRGs. But now they were focusing on efferent projections with the hope of getting some crude locomotor recovery. Instead, they got a lot of spasticity and no improvements. Yes, again axons can cross a lesion if one simultaneously pushes them and pulls them forward. I don't know why you feel obligated to get dramatic and use the word "ignore" because clearly not all axons can bypass the lesion. Although clearly some do others are still stuck, and by the way where do you come up with "thousands" when the authors themselves report hundreds. Again this is an acute injury model. Why the animals develop spasticity is a matter of speculation but my guess is that directing several hundreds of axons to a single location might be causing a hyperinnervation of the cord.

  9. #349
    Jerry,

    Is the intermittent hypoxia you did with the rats the same as, or similar to, intermittent hypoxic training?

    Best,

    Steven
    ...it's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.

  10. #350
    Jerry,

    Is the intermittent hypoxia you did with the rats the same as, or similar to, intermittent hypoxic training?

    Best,

    Steven
    Yes , this is basically the procedure we used but we did this for much less time per day and only for 5 days. The ch'ase really helped us to lower the amount of IH that we needed to give the animals.
    Last edited by Sue Pendleton; 01-30-2013 at 10:20 PM. Reason: Quote fix.

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