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    Glad to see you posting again Dr. Davies.

    Comment


      Originally posted by antiquity
      Glad to see you posting again Dr. Davies.
      Aside, is this a contusion or hemispheric SCI model. "Neither not valid" -What you think antiquity.
      Last edited by Leif; 24 Oct 2007, 7:14 PM.

      Comment


        Leif,

        A really nasty scissor cut, in many ways, worse than a contusion. As I understand it, this type of injury is precisely reproducable, therefore any returns, or lack thereof, will be consistent.

        Comment


          Originally posted by Schmeky
          Leif,

          A really nasty scissor cut, in many ways, worse than a contusion. As I understand it, this type of injury is precisely reproducable, therefore any returns, or lack thereof, will be consistent.
          Sorry but some say contusion models all the time. Some also say bruses and sting to the cord. My question though, are; will it be possible to replace dead neurons and interneurons lost in the cord for future replacements to gain some functions back -in our lifetime? What one think. I think it is possible if we want it.

          Comment


            Then fibres having to find it's way say -find the muscles say in the lower leg. Then if one single nerve fibre outside the cord only grows a 1 mm a day this will take some 190 days at the best for a 6’4 – right. And this is outside of the cord. Inside the cord there is only good research like you reporting. Asking here though.

            ETA; Like if nerve fibres (axons) die off up to the connection point. Research will have to establish connections from cerebellum down to a muscle.
            Last edited by Leif; 24 Oct 2007, 8:40 PM.

            Comment


              I hope I'm not changing the thread too much, but I just wanted to get an answer about if decorin would have to be used in all types of chronic injuries or just say injuries that have had a severance of the cord. The reason I ask this is because I remember that Dr.Young stated that contused cords do not show thick deposits of collagen inside the cord at the injury site, rather only showing some on the surface of the cord. Further, I remember a study done by Tuszynski where he found that axons grew through the 'glial scar' when given bone marrow cells and growth factors in the rat contused spinal cord. Because of these factors is the 'glial scar' a factor at all in the contused spinal cord? I apologise if my facts are wrong, I'm just going from the top of my head.

              Comment


                Schmecky,

                I also want to thank you for making the trip to visit with Dr. Davies and to report back to us with what have learned to date. I will start sending a monthly donation as well. I liked Wise's earlier thought about donating a dollar a day to a research project when we were trying to figure out a few months ago what project we wanted to choose to donate and how to make it happen - unsuccessful as it was. Since a dollar a day wasn't really feasible for me, I started giving $30/mo. to Wise's research. I will do the same for Dr. Davie's project. For all of you on the fence about donating - think about it, a dollar a day. Most of us don't miss a dollar a day! When I logged on today, there were 450 members and guests on line. That is $13,500 a month. Dr. Davie's wrote me he estimates he needs $500,000 to conduct the remaining preclinical decorin experiments. Why don't we help him tackle this by donating a dollar a day monthly. Then we can focus on the $3,000,000 he needs. Dr. Davies's also wrote, " We are also developing the human form of our GDA cells as an equally important and complementary therapy to decorin. At present I am trying to raise $3 million to develop the human GDA cells to GMP standard so that they can be FDA approved. " Lets' assist him in his efforts. One dollar at a time, one dollar at a time HELPS.

                Claire

                Comment


                  Originally posted by zokarkan
                  I hope I'm not changing the thread too much, but I just wanted to get an answer about if decorin would have to be used in all types of chronic injuries or just say injuries that have had a severance of the cord. The reason I ask this is because I remember that Dr.Young stated that contused cords do not show thick deposits of collagen inside the cord at the injury site, rather only showing some on the surface of the cord. Further, I remember a study done by Tuszynski where he found that axons grew through the 'glial scar' when given bone marrow cells and growth factors in the rat contused spinal cord. Because of these factors is the 'glial scar' a factor at all in the contused spinal cord? I apologise if my facts are wrong, I'm just going from the top of my head.

                  Okay here is a long answer to a relatively short question.

                  Axon Sprouting in Chronic Scar
                  It has long been known (100 years) that scar tissue is not a 100% impenetrable barrier to axon growth at the acute stage post injury, and that axons are better able to penetrate chronic scar tissue at later time points post injury. My lab is the only lab that has conducted quantitative Western blot analysis (measuring the density of molecular bands on gels like you see on the TV show CSI) of how the levels of individual isoforms of multiple inhibitory proteoglycans (the CSPG inhibitors) change from acute to 6 months chronic in rat SCI. What we found was that indeed the levels of the CSPGs dropped in the chronic scar and therefore correlated with the increased sprouting of axons into chronic scar shown by many other labs over the years. However tha scar is still a problem in that it is still presenting a barrier to robust axon growth. So nothing much new on this point from Tuszynski in my opinion.

                  Using the right rats in SCI studies
                  There is also a big question mark over the Fisher strain of rats that were used in many Tuzsynski studies. These rats are highly inbred and because of this they do not form a proper scar after SCI. My lab knows this first hand. We have conducted a direct comparison of SCI in the Fisher rats with the outbred Sprague Dawley strain of rats that we and many other labs use. We found that the inbred Fishers formed larger, irregular shaped cavities at sites of injury that correlated with the poor ability to form a protective scar that would normally limit cavitation (one of the main reasons the scar forms in the first place). So, axons can sprout that much more easily across the margins and into injuries in Fisher rats than in the Srague Dawley rats, who had smaller cavities with much denser scarring for tha same sized intial injury (i.e. they're scarring is more like that seen in transection injuries in humans). We published this data last year in the Journal of Biology.

                  So, if a scientist wants to show better axon growth into or around the margins of an SCI in rats, be it a transection injury or a contusion injury, then they will show a lot more axon growth in an inbred Fisher rat. We don't use Fisher rats in my lab as we want to develop therapies that can be used on people that are hopefully not inbred!!

                  Note that Fisher rats are so inbred that they often develop leukemias, which current thinking suggests is due to problems with their immune system. Note that inflammation is thought to promote scar formation.

                  Transection versus contusion injury and scientific analysis.
                  Because there is also greater variability in the size of contusion injuries even in Sprague Dawley rats (when the central canal of the cord is ruptured in a contusion injury this can lead to greater variability from animal to animal in the eventual size of the cavity that can form), you will see that no lab has attempted to actually quantify changes in the levels of inhibitors that are found in contusion scar tissue (proper quatitative Western blot analysis of proteins). Whan a scientist says that the contusion injury does not form as bad a scar, this is therefore based on a qualitative assessment i.e. it is their opinion of what they see and not an actual scientific measurement. They also have to now state what rat strain they were looking at too.

                  Preserving tissue so you can see scar molecules
                  Another problem is that the tissue being studied, whether it be rat or particularly human cord, has to have been preserved in the right way to be able to stain and visualize the components of the scar. It took my lab 6 months to work out how to preserve the rat spinal cord so we could effectively stain for the CSPG inhibitors after SCI. If you use too much "fix" (paraformaldehyde is commonly used) then you can damage the molecules in the scar and the staining system (monoclonal and polyclonal antibodies) cannot bind to the scar molecules to allow us to visualize them. This leads labs who do not have our expertise to state that they do not see scar associated molecules. This becomes an even bigger problem when studying human tissue which is more often than not very poorly preserved (we have special techniques for preserving rat tissue that cannot be used on humans for technical reasons I will not go into in here.) These problems of variable tissue preservation have created a lot of confusion amongst scientists, let alone the SCI community.

                  As it is generally thought therefore that transection injuries form the worst kind of scar tissue, and as we have shown that decorin and GDA cells can promote axon growth across transection injuries (acute so far, we are working on the chronic), then we predict that these potential therapies will be that much more effective when used to treat contusion injuries.

                  Do the basic science in a transection injury where you can actually measure how effciently you have changed levels of inhibitors or other aspects of scar formation and then, apply what you have learned to contusion injuries where the only outcome measures are usually; whether there was functional recovery and / or sparing of neuron cell bodies and myelin / support cells, and it is therefore difficult to work out mechanisms.

                  We are now appying what we have learned with transection injuries and working on contusion injuries with several collaborating labs.
                  Last edited by Stephen Davies; 25 Oct 2007, 4:01 PM.

                  Comment


                    Originally posted by Stephen Davies
                    Okay here is a long answer to a relatively short question.
                    Dr.Davies,

                    Thank you so very much for answering my question in such detail. What are the differences between the results achived with decorin, as compared to chondroitinase? Also, would it be possible for hyperbaric oxygen to slightly minimise any collagen that is present where the scar is? I know from all my scars from my accident hyperbaric greatly helped reduced visible scar tissue so was just wondering if it would be possible to do the same in the cord?

                    Comment


                      Thanks for that explanation Dr. Davies. That probably explains why the successes achieved in rodent models haven't translated to humans. There was a different physiological response to injury and treatment. I'll be sure to give more credence to research carried out on Sprague Dawley rats in the future.

                      Comment


                        Decorin v Chondroitnase

                        Originally posted by zokarkan
                        Dr.Davies,

                        Thank you so very much for answering my question in such detail. What are the differences between the results achived with decorin, as compared to chondroitinase? Also, would it be possible for hyperbaric oxygen to slightly minimise any collagen that is present where the scar is? I know from all my scars from my accident hyperbaric greatly helped reduced visible scar tissue so was just wondering if it would be possible to do the same in the cord?
                        Decorin v Chondroitinase (Chase)

                        Safety:
                        Chase: It is my understanding that Chase has a very narrow window of dosage over which it has any benefical effects before there are toxicity problems.

                        Decorin: Has been administered at v.high concentrations directly into rat spinal cord and brain by my lab and there have been no signs of toxic side effects at the infusion site or in the animals in general. Infact it has been shown reduce cavitaion in acute CNS injuries. It has also been tested for toxicity at concentrations many tens of times above what is known to be effective, in two large animal models (not SCI models) and once again there were no signs of toxicity. This is because it is a molecule that is normally made by neurons and astrocytes in the CNS and other cells types in other tissues and therefore the body is used to using it to remodel tissue and then break it down.

                        Mechanisms of action
                        Effects on axon growth
                        Chase cleaves off the chondroitin sulfate glycosaminoglycan sugar side chains (GAGs) on the core proteins of the CSPG inhibitory molecules. Think of the CSPGs as looking like a bottle brush where the core protein is the handle and shaft of the brush and the GAGs are the bristles. Chase releases the GAGs to expose the core protein. Some labs are pushing hard that it is just the GAG side chains of the CSPGs that are responsible for the CSPG inhibitory effects however there are many publications that show that the core proteins of several CSPGs can directly signal to axons (nerve fibres) and shut down their growth. For example it has been shown that CHase treatment of the scar associated CSPG Phosphacan can actually make it more inhibitory to axon growth because the core protein is now exposed to axons. Even so, several labs have reported increased sprouting of axons in various SCI models in rats, though this effect may be specific to certain type of axon only (see papers from Liz Bradbury).

                        Note that CSPGs are not the only inhibitory molecules in the scar and that theoretically Chase is very specific for just the GAGs of CSPGs.

                        Although my lab has shown that CSPG levels are down in chronic scar, other labs have shown that molecules such as Collagen IV that can form a very effective misaligned physical barrier to axon growth (chronic scar is really dense when you poke it with forceps) are now at high levels. Theoretically Chase will have zero effect breaking down molecules like Collagen IV in chronic scar.

                        Anti inflammatory effects
                        However here is a crucial experiment in my opinion about the most important effect of Chase in promoting functional recovery. Dr. Caggiano at ACORDA has shown that there is indeed some recovery in function (BBB scoring which is now not accepted as being a sufficient test of locomotor recovery without additional tests ) with Chase treatment of severe contusion injuries in rats. Notably however there was no recovery in Chase treated rats with moderate contusion injuries.

                        These results are somewhat strange if the main mode of Chase activity is to promote recovery through axon regeneration / plasticity as you would expect even better recovery in the moderately contused cord which should have more spared axons and less scar that the severe contusion injury. However the results can be explained if you consider data from Michal Schwartz (of Proneuron fame) which shows that the GAGs can have an anti-inflammatory action. In effect, the GAGs released by Chase treatment can suppress neurotoxic inflammation in acute injuries, an effect that would be far more important for promoting recovery in a severe injury where a relatively small increase in numbers of surving axons could have a big effect on recovery.


                        Decorin:
                        Suppresses levels of both the CSPG GAGS and the CSPG core proteins by up to 90% (my labs data). Note we showed this effect on multiple types of inhibitory CSPGs in decorin treated rat cords.

                        We are investigating whether decorin has any effects on reducing levels of the other known scar associated inhibitors.

                        Decorin has been shown by several labs to a highly effective anti-inflammatory molecule and also be able to suppress programmed cells death (apoptosis).

                        We have shown that decorin can promote a major increase (17 times) in spinal cord production of an important enzyme called plasmin which can degrade the core proteins of CSPGs, and is known to have the ability to breakdown collagen IV. Plasmin in turn is known to have the ability to not only directly degrade scar associated molecules but has been shown to activate other enzymes (MMPs) that can also degrade scar tissue. Plasmin is also known to play a crucial role in the activation of neurotrophins. These are some (but not all) of the reasons we are investigating the effects of decorin on chronic scar tissue.

                        All the above effects of decorin are focused on it's ability to alter the environment of the injured spinal cord to make it more supportive of axon regeneration and / or plasticity of surviving axons. However, we are currently testing whether decorin can have a direct effect on the ability of axons to grow, as theoretically it should (more on this another time).

                        What I have tried to to is give a fair and balanced comparison of the potential of decorin and Chase to promote SCI repair.

                        As to whether hyperbaric oxygen can reduced chronic scar tissue and how this might work, I honestly do not know. Great if it does.

                        Comment


                          Donation Idea

                          Hi all,
                          (As we all know, this is one of the most promising researches and with an acceptable timeframe) Of course I will do my part to donate, and even try to get a few friends to donate to Dr. Stephen Davies Lab. as well, but that money can never come up to the amount of Ricky James's offer, so I thought I'll throw this idea in there, hopefully it works.

                          It was about 3 months ago, back in July when Ricky James offered to donate to Hans Keirstead laboratory $200,000, and that donation did not go through.
                          I was wondering if that offer is still available? If so, maybe instead of Dr. Keirstead's Lab, that money can be donated to Dr. Stephen Davies's Lab.

                          /forum/showthread.php?p=696228#post696228

                          Comment


                            Originally posted by vito
                            It was about 3 months ago, back in July when Ricky James offered to donate to Hans Keirstead laboratory $200,000, and that donation did not go through.
                            I was wondering if that offer is still available? If so, maybe instead of Dr. Keirstead's Lab, that money can be donated to Dr. Stephen Davies's Lab.
                            Can't hurt to ask.....

                            Stephen,

                            I understand that your rat models show that there is robust growth of axons through the injury site following treatment. Do you "see" these axons making effective connections that improve function or are they just growing willy-nilly. It would be nice to hear that there is some kind of signaling that directs the sprouting axons to legitimate targets. Have you/others looked at this issue?

                            Comment


                              Originally posted by redbandit
                              Can't hurt to ask.....

                              Stephen,

                              I understand that your rat models show that there is robust growth of axons through the injury site following treatment. Do you "see" these axons making effective connections that improve function or are they just growing willy-nilly. It would be nice to hear that there is some kind of signaling that directs the sprouting axons to legitimate targets. Have you/others looked at this issue?
                              redbandit, while you're waiting for a response, have you seen these videos?

                              bruce took them last april when dr davies presented his findings in dc.

                              /forum/showpost.php?p=648127&postcount=1

                              Comment


                                Redbandit,

                                Apologies for asking another question before yours has been answered. I remember reading that cord blood contains decorin and that lithium regulates the decorin gene. Is it possible the that these two combinations that will be used in the ChinaSCINet trials to be able to alone degrade the glial 'scar' by themselves because of the fact that they contain decorin?

                                Comment

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