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  • Paolo,

    A transected spinal cord is extremely rare and not something that anybody can easily do a clinical trial of, except in very special centers. Why are you so concerned about transected spinal cords? Do you happen to know of somebody with a transected cord? Are you interested because of In Vivo Therapeutics? If they are planning a therapy that can only be done on people with transected spinal cords, that is not a very good business model. If they are planning to transect or remove part of the spinal cord of chronic patients to transplant some scaffolding, I have already indicated repeatedly that this would not be justifiable.

    Dr. Henreich Cheng in Taiwan is the only doctor that I know who has a treatment that he has applied to transected spinal cords of patients with spinal cord injury. As people here may recall, he published an important paper in 1995, reporting that peripheral nerve grafts between white and gray matter allows axons to grow across the gap of a transected cord. For perhaps 15 years, he has been doing searching for patients with transected spinal cords to do his bridging therapy on. I am not sure how many he has found but I think that he has found only several patients to date who have transected spinal cords.

    Please stop saying that we have selected less severely injured patients. It is not true. You don't know what you are talking about. All the patients that we studied have severe spinal cord injuries. They all had ASIA A complete injuries. The only patient that we excluded from the study is one patient who had a DTI scan showing more than 3 segment gap of his white matter. All the patients had a clear gap in their white matter at the injury site. None of the patients that were screened for the trial had a transected spinal cord.

    Have you read the paper by Liu, et al. (2011)? I attach it and suggest that you read it, if you have not. Yes, there is extensive sprouting in the rostral spinal cord but axonal growth continue for many weeks in hemisected mice. Why aren't the additional corticospinal axons blocked, not only from growing across the rostral but across the caudal side of the lesion? In animals where PTEN had not been deleted (they were injected with AAV-GFP rather than AAV-Cre), the growing axons stop right at the rostral lesion edge. Why do they stop? Jerry Silver and others have suggested that they stop because of the glial scar and the presence of chondroitin-6-sulfate-proteoglycan (CSPG). The deletion of PTEN from the cortex of these mice does not eliminate CSPG or gliosis at the lesion edge and yet the axons grow through the so-called glial scar.

    By the way, if you read the papers, note that axons don't like to grow where astrocytes are absent. For example, Liu, et al. wrote in their discussion that robustly axons failed to penetrate into GFAP-negative areas of the lesion site. Interesting that the axons don't stop where the glial cells are.
    Notably, despite robust regenerative growth of CST axons rostral to a spinal cord injury in Pten-deleted mice, many robustly growing axons failed to penetrate into the GFAP-negative area at the lesion site. This suggests that the lesion site, and particularly the GFAP-negative area, remains a formidable barrier to regenerating axons from PTEN-deleted corticospinal neurons. Thus, a combination of PTEN deletion and other strategies, such as neutralizing extracellular inhibitors at the lesion site42,43 and bridging the lesion site with permissive grafts44,45, may further promote maximal axon regeneration after spinal cord injury.
    Absence of astrocytes in fact deters growth of axons. Axons prefer to grow on glia. Incidentally, this is similar to what Michael Sofroniew also observed in his review of the role of reactive astrocytes in brain and spinal cord repair. Axons grow readily through thickets of reactive glia. He concluded that astrocytes protect tissue and preserve function rather than block regeneration and repair. Sofroniew pointed out that there are opposing views concerning whether reactive astrocytes are friend or foe.

    Our study of contused spinal cords show that a loose tissue matrix of mostly astrocytes accumulate at the contusion site. Many axons enter into this tissue matrix and some may even exit, accounting for why there may be delayed recovery in some animals after spinal cord injury. If there were a tight barrier that prevents axon growth at the contusion site, why are there many axons entering the injury site? There are many reasons why axons entering the injury site may not grow into the distal cord, including the presence of CSPG, Nogo, and other growth inhibitors at the caudal edge. Probably some axons do grow out of the contusion site. In any case, it doesn't matter. The fact that the axons are growing into the injury site is a strong argument against an important role of the glial scar preventing axonal growth into the injury site.

    Wise.



    Originally posted by Paolo Cipolla
    Originally Posted by Wise Young
    Paolo,

    Penetrating wounds of the spinal cord are relatively rare.
    Ok, but what would you do in this case?

    For example, we did not see any case of a penetrating or transecting wound of the spinal cord in 41 ASIA A patients that we transplanted cells into so far, 28 of which are chronic and 13 were subacute. All the spinal cord appear intact from the outside. We inject the cells into the spinal cord surrounding the injury site, into the dorsal root entry zones above and below the injury site.

    Yep! Unfortunatly the inclusion criteria of the trial exclude people with more devastating SCI.
    C'mon Wise let's be serious.


    Yes, Liu, et al. 2010 did assess regeneration in "acute" spinal cord injury, in the sense that the rats already had PTEN deleted before they were injured. On the other hand, the regeneration across the injury site took a long time. Kai Liu had to wait 6-8 weeks before he saw the axons grow across the injury site. In rat and mouse time, each week is equal to about a month. If a glial scar formed, it should have been there within 2-3 weeks.

    In fact the more robust grow happens in the first two weeks.

    It seems to me that the burden of proof should lie on those people claiming that there is a "scar" that obstructs axonal growth rather than on people who don't see any scar there and are finding axons that grow into the contusion site. If a scar is there and is truly blocking axonal growth in contused spinal cords, why are we seeing so many axons crossing the injury site in the chronically injured spinal cord?

    Then why these axons you are talking about don't grow out of the injury site and make functional connections?


    Wise.
    Last edited by Wise Young; 01-02-2013, 04:54 AM.

    Comment


    • Originally posted by paolocipolla View Post
      Thank you Wise for the publication.

      I see the rats were euthanized within 6 weeks as you say which is a bit too early to call it chronic especially if we are talking about the scar.

      Then I see that even with the 50 mm drop SCI model (which I think is rarely used if ever as a contusion model) rats recover a BBB score of 8 out of 21, which would be probably like an ASIA C human.

      So when you refer to this study to support your position about the scar you could be right if we were talking about the scar present in people ASIA C or D.

      Unfortunatly people with ASIA A likely have a much worse scar problem, which I wish had been studied more rather than just saying the scar is not an issue.

      Paolo
      Paolo, you don't know what the BBB score means. A BBB score of 8 is a non-walking score. Most of the movements that occur in BBB scores from 1-8 are probably reflexive. At a score of 10 or less, the rat is unable to stand or support its weight with its legs. The 25-mm weight drop contusions that we are studying in the rats is equivalent to ASIA A injury in human.

      Wise.
      Last edited by Wise Young; 01-02-2013, 04:35 AM.

      Comment


      • Originally posted by GRAMMY View Post
        Here's a link to 1,120 references to research studies you can review.

        http://www.ncbi.nlm.nih.gov/pubmed?term=glial%20scar
        Thank you! I feel like a kid in a candy store.

        Comment


        • Perhaps some discussion will help clear things up. There are few, if any, absolutes in biology. All cell-to-cell interactions involve balances between positive and negative influences. Astrocyte/axon interactions are no exception. Astrocytes are highly maleable cells. They respond to a variety of factors in their environment in different ways and they differ in their responses depending on their state of maturity and upon what they encounter. Astrocytes produce both growth promoting as well as inhibitory molecules that they deposit in various ratios upon their surfaces again depending upon what they interact with. When astrocytes encounter vigorously growing axons, even when the astrocytes are mature, they can provide support and guidance for axonal growth and they produce less inhibition. They also align themselves and wrap around the axons. Unfortunately, in the adult, just after SCI astrocytes do not encounter robustly growing axons, unless pTEN is deleted long before the injury. Instead, they encounter mostly inflammatory cells and dystrophic axons and myelin debris. Here their job is to build a wall around the injury which is both physically obstructive because the cells arrange themselves perpendicular to the lesion and they also hypertrophy and form lots of tight junctions between themselves. In addition, they produce far more inhibitory molecules. Everybody but Wise refers to this process as "scarring". In the mouse after a surgical or narrow crush lesion, and where pTEN is deleted, the lesion remains relatively small (compared to rat or human) and axons are in a robust growth state from the moment they are lesioned. Thus, the balance shifts, at least partially, to a growth supportive astrocyte rather than just a reactive scarring astrocyte. Actually, it is likely that there would be a mixture of both scarring and bridge building cells. Even in the pTEN deletion animals most axons still get hung up at the rostral end of the lesion. The majority of pTEN deleted axons that don't cross the injury site do so where they lack a bridge but they also likely see more inhibitory astrocytes and lakes of macrophages. Unfortunately, we have yet another cell in the lesion core that is very destructive to axon regeneration and that is the macrophage (who is a really bad guy especially at early stages after injury). Thus, things are far more complicated and fluid than the black and white picture that Wise likes to present. It helps to make his case that there is no scar because he is claiming to have promoted an unprecedented long distance regeneration in chronically injured humans, who would have well established scar, without doing anything especially potent to remove or overcome it. He has not deleted pTEN or made any attempt remove scar. I would love to see even in vitro evidence that UMBCs form highly growth growth supportive substrates that can overcome inhibitory molecules. Those of you who would believe as a matter of faith that whatever Wise tells you is absolutely true then that is your right. However, I have have a multitude of questions that need answering before I accept an unprecedented conclusion:

          Truly regenerating axons NEVER grow in tightly aligned bundles. Regeneration in the adult is not like the fasciculated axon growth that occurs in the embryo. Indeed, the presence of aligned bundles of axons passing in the vicinity of a cord lesion is always suggestive of spared axons.

          Axons can regenerate in relative alignment if they are given an aligned cellular environment such as that which could be induced by a biomatrix or tube. Given that there was no attempt to align the UMBCs it is very unlikely that axons could regenerate as a single straight bundle.

          The idea that a lengthy, truly regenerated bundle of axons could degenerate and then magically regenerate yet again in the chronically injured human cord is absurd. Just stop and think of the myriad of barriers that would be thrown up after that.

          Without specific axonal labels how does one conclude definitively using DTI only that a bundled structure is axonal?

          Without the use of multiple intermediate images to document a growing front of the bundle how does one conclude that it is growing but has not yet reached its target. It is incredibly premature to conclude this.

          How can adult human neurons grow so rapidly (1mm per day according to Wise) without any modification of their intrinsic growth potential?
          Last edited by jsilver; 01-03-2013, 02:41 PM.

          Comment


          • "They also align themselves and wrap around the axons."
            With nodes of Ranvier formation?

            Comment


            • From my reading of CareCure over the last 6 years, I tend to believe that both Jerry and Wise are correct in thier observations and statements relating to their observations. Both have convincing arguments and support for their statements.

              One main variable between the "chronic" mouse/rat model and the human chronic model seems to be time. A chronic mouse/rat is considered chronic after 20+ days or so. A human is considered chronic after several years. It is visually obvious that both the mouse/rat and humans loose sensory and motor function immediately after SCI injury. The spinal cords in both try to wall off the injury site. Inflamation and necrosis occurs in both. Above, Jerry described the damage done to the spinal cord in great detail.

              In Jerry's 20+ day chronic model, he has the advantage of seeing slices of mouse/rat spinal cords under powerful microsopes before and after treatments. Dr. Young does not have that opportunity as the humans are still living. Dr. Young does have the opportunity to view human spinal cords during surgery. However, portions of the treated human's spinal cords are not viewable under a microscope as the patients are still alive. So, Dr. Young has structured a battery of tests to observe patients and score changes observed in the body.

              Would it not be possible that a 10 year post chronic spinal cord may have made changes over time to breakdown a portion of the gilia scar barrier that was originally developed? That may partially explain Dr. Young's posts about the motor changes in Christopher Reeves at 3+ years post injury. That would also explain some of the positive changes observed with the UCB cell transplants in the China studies.

              Comment


              • Originally posted by 6 Shooter View Post
                A human is considered chronic after several years.
                Really? I thought it was much sooner than that.
                Roses are red. Tacos are enjoyable. Don't blame immigrants, because you're unemployable.

                T-11 Flaccid Paraplegic due to TM July 1985 @ age 12

                Comment


                • Originally posted by lynnifer View Post
                  Really? I thought it was much sooner than that.
                  i was under the understanding it was 18 months from date of injury?

                  Comment


                  • Dr. Young and Dr. Silver,

                    I ask this with the utmost respect and no intention of stirring stife, but speaking of the existence of this scar tissue, how can two scientists come away with different opinions on the existence of something that should be quite evident?

                    Todd

                    Comment


                    • Sooner than that I thought.
                      Roses are red. Tacos are enjoyable. Don't blame immigrants, because you're unemployable.

                      T-11 Flaccid Paraplegic due to TM July 1985 @ age 12

                      Comment


                      • Originally posted by lynnifer View Post
                        Really? I thought it was much sooner than that.
                        I think "a few weeks" is a good estimate. See:

                        http://www.google.com/url?sa=t&rct=j...55534169,d.eWU

                        Comment


                        • Would it not be possible that a 10 year post chronic spinal cord may have made changes over time to breakdown a portion of the gilia scar barrier that was originally developed?

                          Yes, indeed, the scar does change over time. It becomes thinner and its associated inhibitory proteoglycan extracellular matrices become more restricted to the cell surfaces. In some very severe contusive injuries, Schwann cells eventually invade through the dorsal portion of the scar and enter the core of the lesion. It is unknown how they do this. Schwann cells are extremely growth promoting and they provide a scaffold for axonal growth, mostly of sensory axons from the roots, that can pass through the scar wall and into the core of the lesion. This phenomenon demonstrates that the scar is not totally but only relatively impenetrable. However, the presence of axons in the lesion core does not mean that scar does not exist but, rather, that over time the scar changes and one of these changes is that Schwann cell invasion occurs. However, axons do not pass completely through the lesion as Wise suggests but only into the lesion core where they remain trapped and functionally useless.

                          Comment


                          • Originally posted by 6 Shooter View Post
                            From my reading of CareCure over the last 6 years, I tend to believe that both Jerry and Wise are correct in thier observations and statements relating to their observations. Both have convincing arguments and support for their statements.

                            One main variable between the "chronic" mouse/rat model and the human chronic model seems to be time. A chronic mouse/rat is considered chronic after 20+ days or so. A human is considered chronic after several years. It is visually obvious that both the mouse/rat and humans loose sensory and motor function immediately after SCI injury. The spinal cords in both try to wall off the injury site. Inflamation and necrosis occurs in both. Above, Jerry described the damage done to the spinal cord in great detail.

                            In Jerry's 20+ day chronic model, he has the advantage of seeing slices of mouse/rat spinal cords under powerful microsopes before and after treatments. Dr. Young does not have that opportunity as the humans are still living. Dr. Young does have the opportunity to view human spinal cords during surgery. However, portions of the treated human's spinal cords are not viewable under a microscope as the patients are still alive. So, Dr. Young has structured a battery of tests to observe patients and score changes observed in the body.

                            Would it not be possible that a 10 year post chronic spinal cord may have made changes over time to breakdown a portion of the gilia scar barrier that was originally developed? That may partially explain Dr. Young's posts about the motor changes in Christopher Reeves at 3+ years post injury. That would also explain some of the positive changes observed with the UCB cell transplants in the China studies.
                            6 Shooter, irrespective of the timeframe for chronics as it really is irrelevant in the context of what you're saying, I think that this is a really good point that you make and look forward to hearing what the specialists (i.e. Wise and Jerry, not Paolo) have to say. I hope this doesn't just get burried in a discussion about the definition of a chronic.

                            Clayton
                            "Wheelie Wanna Walk!"

                            Comment


                            • Originally posted by Le Type Fran├žais View Post
                              Dr. Young and Dr. Silver,

                              I ask this with the utmost respect and no intention of stirring stife, but speaking of the existence of this scar tissue, how can two scientists come away with different opinions on the existence of something that should be quite evident?

                              Todd
                              I have been studying this structure for most of my scientific career. I have had a long standing NIH grant entitled "Regeneration beyond the glial scar" for nearly 30 years. If one simply reads the literature , uses the proper techniques and does the right experiments there is no doubt that scar exists. Indeed, the scar is well known by neurosurgeons who attempt to aspirate away non-invasive brain tumors that are surrounded by scar. They, aspirate until they push up against a tough tissue border that is the surrounding scar. By the way, contrary to what Wise suggests, there is no need for fibroblasts to create the tough scar. If you'd like, read my 2004 Nature Reviews Neuroscience review. Regeneration beyond the glial scar : Article : Nature Reviews ...
                              http://www.nature.com/nrn/journal/v5...l/nrn1326.html - Similar
                              Review. Nature Reviews Neuroscience 5, 146-156 (February 2004) | doi : 10.1038/nrn1326 ... the glial scar. Jerry Silver1 & Jared H. Miller1 About the authors ...

                              Here is another reference:


                              Glial scar
                              From Wikipedia, the free encyclopedia
                              Glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the Central Nervous System. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system. In the context of neurodegeneration, formation of the glial scar has been shown to have both beneficial and detrimental effects. Particularly, many neuro-developmental inhibitor molecules are secreted by the cells within the scar that prevent complete physical and functional recovery of the central nervous system after injury or disease. On the other hand, absence of the glial scar has been associated with impairments in the repair of the blood brain barrier.[1]

                              Contents [hide]
                              1 Scar components
                              1.1 Reactive astrocytes
                              1.2 Microglia
                              1.3 Endothelial cells and fibroblasts
                              1.4 Basal membrane
                              2 Beneficial effects of the scar
                              3 Detrimental effects of the scar
                              4 Primary scar molecular inducers
                              4.1 Transforming growth factor β (TGF-β)
                              4.2 Interleukins
                              4.3 Cytokines
                              4.4 Ciliary neurotrophic factor (CNTF)
                              4.5 Upregulation of nestin intermediate filament protein
                              5 Suppression of glial scar formation
                              5.1 Olomoucine
                              5.2 Inhibition of Phosphodiesterase 4 (PDE4)
                              5.3 Ribavirin
                              5.4 Antisense GFAP retrovirus
                              5.5 Recombinant monoclonal antibody to transforming growth factor-β2
                              5.6 Recombinant monoclonal antibody to interleukin-6 Receptor
                              6 References
                              Last edited by jsilver; 01-03-2013, 09:27 PM.

                              Comment


                              • Dr. Silver,
                                Do you foresee any positive results in an Asia A complete injury ever regaining their bowel and blatter function back in the next decade? I would be happy to finish my life out with regaining these functions. I appreciate your comments.

                                Comment

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