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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #191
    yeah, I am obviously a complete layman but I too was impressed with NowhereMan's posts

  2. #192
    Quote Originally Posted by jsilver View Post
    NowhereMan. What is your background? Are you are scientist? You're asking many excellent questions that suggests you have in depth knowledge of spinal cord injury research.
    Because the things are so obvious that continue ignoring them becoming just impossible.

  3. #193
    Quote Originally Posted by NowhereMan View Post
    I can't say with 100% certainty which would be harder because neither have been repaired yet. However, I think most neuroscientists would argue that acute injury is an easier puzzle to solve and fix than chronic injury is. Mammals don't regenerate their spinal cord.
    Wrong.
    When a peripheral nerve is cut, the axon segments distal to the injury (furthest away from the spinal cord) die off in a process called "Wallerian degeneration." When the nerve is repaired, the axons in the proximal segment (closest to the spinal cord) regrow into the distal, denervated segment. This growth occurs at a rate of about 1 mm per day. This translates roughly to 1 inch per month, or 1 foot per year. Once the axons regrow back into the denervated muscles, the muscles will begin to function again.
    Axonotemesis
    This injury is defined pathologically by loss of axonal continuity and subsequent Wallerian degeneration. The endoneurial sheath is preserved, however, and each regenerating axon is confined to its original sheath. This ensures faithful reinnervation of the appropriate end organ, and full functional recovery inevitably results. In clinical terms, the initial deficit involves complete motor, sensory, and sympathetic function. Nerve conduction distal to the injury site disappears within 24-72 hours after the injury, and fibrillation potentials are present within the denervated muscles. Recovery of motor function in this type of injury follows sequentially from proximal to distal muscles. The timing of recovery follows quite predictably the rate of axonal growth-approximately 1 mm per day or 1 inch per month, although the growth rate is more complex when carefully studied. The progression of regeneration can be followed along sensory fibers by tracing the progress of Tinel's sign. The delay in recovery of function exceeds that observed after neuropraxia, and is usually measured in months rather than days or weeks.
    Quote Originally Posted by NowhereMan View Post
    Also, I don't understand why you would think that. In all the links you provided showing that UCB cells helped recovery, they were all done in acute injury animals. None were in chronic. Why then would you argue acute SCI could be harder to repair than chronic? That makes no sense.
    Because of what's happening in the body during the acute phase of SCI. Without all that craziness perhaps the stem cell therapy could work even better?

    Quote Originally Posted by NowhereMan View Post
    Just because animals that received treatment during an acute injury recovered slightly more than control animals does not mean that axons regenerated across the injury site. It is most likely caused by preservation of more axons and/or remylination of preserved axons. I don't think you appreciate the magnitude of the challenge of getting axons to regenerate in a mammal spinal cord.
    They didn't get "slightly better" than the control groups. They got significantly better. I do appreciate the magnitude of the challenge. It's why I've stayed up til 5 AM writing these posts. It's also why Jerry Silver is back on the forum after he recently vowed never to come here again.

    You keep going on about how every single UCBMC study is acute.
    Quote Originally Posted by Wise Young View Post
    You should not be equating rat time with human time. This is one of the most common errors that are made by scientists. Rat time is the not the same as human time. I estimate that rat time is at least four times faster than human time. For example, rat heart rate is four time faster. Its metabolism is four times faster. Its drug clearance is four times faster. It reaches a plateau in its recovery curve by 6-8 weeks, whereas it takes a human 6-12 months (depending on the severity of injury). The more severe the injury, the faster one reaches the plateau. So, a 6-week period in a rat is similar to 6 months in human.
    In the study, they waited 7 DAYS before implanting the cells, which would be 28 days human time.

    Quote Originally Posted by NowhereMan View Post
    Which figure in this publication shows axons growing across the injury site?
    I misread the slide.
    Figure 4:
    Quantitative analysis of endogenous oligogenesis by hUCB-MSCs. At 2 weeks after cell transplantation, BrdU and cell-specific markers were observed up to the edge of the SCI region.
    Quote Originally Posted by Wise Young View Post
    We are currently testing the hypothesis that umbilical cord blood cells injected into the surrounding cord will migrate into the injury site and produce a bridge of cells.
    Perhaps the study shows UCB cells are migrating towards the injury site?

    This study (published here) shows, with pictures, axonal growth across lesion resulting from UCBMC therapy. (scroll to page 66).

    Evidence was provided revealing that CNS axons have the intrinsic capacity to regenerate (David and Aguayo, 1981, Benefey and Aguayo, 1982). Hence approaches are under investigation to improve axonal regeneration. To investigate whether USSC transplantation has beneficial effects on axonal regeneration, immunohistochemical stainings against the axonal marker neurofilament (NF) and anterograde tracing experiments were performed. Immunohistochemical stainings revealed that USSC survived for at least three weeks after transplantation. Surviving cells were mainly confined to the injury site (Fig. 4.7A). Beyond the lesion site, only a few cells could be identified between the injection site and the lesion center. A high number of NF-positive fibers was found in the lesion center after USSC grafting. In close proximity to the grafted cells, numerous elongated neurofilament-positive fibers were present (Fig. 4.7B). In contrast, in control rats lacking USSC grafts,
    neurofilament labeling was virtually absent in the lesion area (Fig. 4.7C).
    Quote Originally Posted by NowhereMan View Post
    I'd gladly take you up on that but there is no one authoritative figure who would have final say. I forsee different scientists having different opinions.
    It's in a published study. If you're willing to accept this as truth:
    Quote Originally Posted by NowhereMan View Post
    In the acute rat studies you provided, I saw no evidence of axon growth across the injury site. If you look at the PTEN study, you will see nice images of axons growing across the injury site. Show me just one UCB study that has photographic evidence of axon growth.
    http://www.ncbi.nlm.nih.gov/pubmed/20694004
    Then you ought to be willing to accept as true any images released when this study is published. If you are confident Dr. Wise is lying to the world or somehow gravely confused or mistaken about the DTIs, he's making up that people are starting to walk again, and the 26 studies he posted about UCBMC therapies are all simply axonal preservation, you have nothing to worry about.
    Last edited by crabbyshark; 01-12-2013 at 06:57 AM.

  4. #194
    Quote Originally Posted by crabbyshark View Post
    No I am not wrong. If mammal's spinal cords regenerate then we wouldn't be in wheelchairs. Your link is discussing Peripheral nerves. Those are nerves outside the central nervous system and they do have the ability to regenerate. The spinal cord is part of the Central Nervous System and does not regenerate, hence permanent paralysis.

    You've been injured for almost 8 years, if not more. You should know this already.

    Quote Originally Posted by crabbyshark View Post
    Because of what's happening in the body during the acute phase of SCI. Without all that craziness perhaps the stem cell therapy could work even better?
    I'm not going to repeat myself on this. You can re-read my earlier posts. 20+ references of UCB studies and all on acute. None showing efficacy in chronic. That should tell you something on which is harder to fix.


    Quote Originally Posted by crabbyshark View Post
    You keep going on about how every single UCBMC study is acute.


    In the study, they waited 7 DAYS before implanting the cells, which would be 28 days human time.
    That is one scientist's opinion. I don't know if that is true or not. That seems like it is an easy thing to abuse. Why not just do animal studies 2-3 months after injury to be sure it is a chronic model? Also, none of the studies I read mentioned the 4X recovery time nor considered their injury model to be chronic. So if the scientists actually performing the study first hand don't consider their own model to be a chronic injury, why should Dr. Wise?

    Quote Originally Posted by crabbyshark View Post
    I misread the slide.
    Figure 4:
    That figure is not showing axons, but Oligodendrocytes...i think.

    Quote Originally Posted by crabbyshark View Post

    This study (published here) shows, with pictures, axonal growth across lesion resulting from UCBMC therapy. (scroll to page 66).
    a) yes, at least this image actual shows axons in the injury site. This is a great thing to see in a publication claiming regrowth.

    b) I wouldn't consider the amounts of axons to be robust. Looking at figure 4.8 on pg. 67, I only see a few axons.

    c) I don't see them crossing all the way across the injury site, let alone going past it.

    d) This study says they used USSC cells from Umbilical Cord blood. It also says that this is the 1st time these cells were used in any pre-clinical animal study (pg. 22). The study says that all other UCB cell experiments in the past were using Mesenchymal cells from the cord blood, and that they had inconsistent and conflicting results. Is Wise's trial using USSC cells or Mesenchymal cells or both in his human trial?



    Quote Originally Posted by crabbyshark View Post
    It's in a published study. If you're willing to accept this as truth:
    Not all publication journals are created equal. Some have rigorous standards and are prestigious, others are not. A published study can be in a shi--y journal and becomes almost weightless.

    Quote Originally Posted by crabbyshark View Post
    Then you ought to be willing to accept as true any images released when this study is published. If you are confident Dr. Wise is lying to the world or somehow gravely confused or mistaken about the DTIs, he's making up that people are starting to walk again, and the 26 studies he posted about UCBMC therapies are all simply axonal preservation, you have nothing to worry about.
    I'm not a scientist. I do not know anything about DTI imaging, nor have I seen any from Dr. Young's trial. I will wait to hear opinions from other scientists in the field before I pass judgement on how much/ what they prove. I will be open-minded.


    I have only seen acute and incomplete injury animal studies that have shown slight recovery (bbb scores improving 1-3 points). I have yet to see any chronic and/or complete injury models that reflect the human population that are in the human trial. I'm not trying to cause an argument over justification of the trial. I'm just setting the record straight. Like I said before, I will be open-minded with Dr. Wise's published results and I ask that you be the same.
    Last edited by NowhereMan; 01-12-2013 at 07:53 PM.

  5. #195
    Quote Originally Posted by Wise Young View Post
    Paolo, you are wrong. Wise.
    Wise,

    it is possible that you are not very well informed, as it could be the case that someone is not telling you the truth not to hurt you, but I am afraid that no UCB cells trial will happen in Norway as you keep saying.
    Time will tell who is right here.

    I hope this post will not be removed. I'll save the screen.. just in case.

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

  6. #196
    Quote Originally Posted by Wise Young View Post
    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.


    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.
    Wise,

    did you see the second presentation of Jerry Silver at W2W 2012?

    Do you have any comment?

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

  7. #197
    Quote Originally Posted by Wise Young View Post
    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.
    Wise,

    if you test with electrophisiology a rat who has 25 mm drop SCI do you see any signal crossing the injury site?
    According to the MASCIS study (page 457) after a 25 mm drop the average BBB score is 10.6 which means that the rats can support their weight, which makes them ASIA D.

    Paolo
    Last edited by paolocipolla; 01-12-2013 at 08:55 PM.
    In God we trust; all others bring data. - Edwards Deming

  8. #198
    Quote Originally Posted by jsilver View Post
    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?
    Thanks Dr. Silver for the expalination and for the critical considerations.

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

  9. #199
    Quote Originally Posted by paolocipolla View Post
    Wise,

    if you test with electrophisiology a rat who has 25 mm drop SCI do you see any signal crossing the injury site?
    According to the MASCIS study (page 457) after a 25 mm drop the average BBB score is 10.6 which means that the rats can support their weight, which makes them ASIA D.

    Paolo
    This should be an average score. What MASCIS study are you referring to? Are you referring to the original BBB score paper? A 10.6 is not equivalent to an ASIA D. A lot of people can do weight-bearing and they are not ASIA D.

    A 25 mm weight drop eliminates somatosensory evoked potentials in 90% of rats.

    Wise.

  10. #200
    Quote 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
    That may suggest you that there is something wrong in SCI research, that is why it is necessary to learn and question as much as possible rather than having blind faith and just rise money for SCI research. Too much money going into SCI research are wasted. In some cases it is impossible to tell in advace which one are wasted (that's research), but sometimes there are elements to determine what worth founding and what it doesn't.

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

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