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    Originally posted by paolocipolla

    Paolo
    I like everyone cannot wait to hear the true results if this trial and truly feel we would know more info and seen more about it if certain people would just go away.

    Comment


      I know that I am likely to get a fall from this but as things seem to be progressing I cannot help but have a positive outlook the way developments have occurred during the last few years, in regards to potential cures and therapy’s etc.

      Dr Wise I know your going to start phase 3 soon. Could I ask as to when and for how long until the final phase (I assume) being four, will begin and end?. And how long will it take before the rest off us can participate in the treatment? If possible.

      Do you think that your therapy and others will be applicable to most of us by 2020? Or later like 2030.

      Thank-you for all your help

      Comment


        Originally posted by Barrington314mx View Post
        Sorry if I over looked it, but how long after injury did she have the untethering surgery? Is there a point in which its "been too long" to have a successful untethering?
        Barrington,

        I was just explaining to the audience in the Open House that we have made a decision to include surgical decompression and untethering as the control rather than use a non-surgical control. The case has not been published and I believe that the Kunming group is planning to publish the case. I presented the case only to point out that decompression and untethering may restore function even in a very severe case of spinal cord injury. The Kunming group is now collecting all the data that they have from untethering surgery over the years and I am encouraging them to publish the data.

        Many surgeons have reported anecdotal cases of improved function after delayed decompression and untethering surgery. I have described such cases in the past. For example, Hank Bohlman at Case Western Reserve in Cleveland published series of surgical cases where he decompressed and untethered the spinal cord up to several years after injury. He suggested that it needed to be done within 3 years and that he did not see as much recovery at longer times. Note that these were all decompression cases, where the spinal cord was still being compressed. I have posted abstracts of these papers in past on the forum before.

        So, the concept that decompression and untethering surgery may be beneficial is not new. We decided to propose to the principal investigators of the ChinaSCINet to make the control group of the phase III trial into an untethering surgery as opposed to a no-surgery control. Please note that it is possible that our investigators may decide that this would not be an acceptable option, i.e. they may say that untethering on its own is unlikely to be beneficial and they do not want to subject their patients to the surgical risk. Or, they may think that it is a good idea. We shall see. We are holding the principal investigator meeting on March 2-3.

        Wise.

        Comment


          wise, based what you see concerning efficacy in these trials, are you guys still motivated to move this therapy to higher level chronics? And if so: whats the proposed timeframe? Has it changed or been altered?

          Because I would think that if this shows efficacy in the lower level injuries, the trial for higher injuries might be accelerated...

          And also when will you be able to comment surely on b/b/b?
          "That's not smog! It's SMUG!! " - randy marsh, southpark

          "what???? , you don't 'all' wear a poop sac?.... DAMNIT BONNIE, YOU LIED TO ME ABOUT THE POOP SAC!!!! "


          2010 SCINet Clinical Trial Support Squad Member
          Please join me and donate a dollar a day at http://justadollarplease.org and copy and paste this message to the bottom of your signature

          Comment


            ay2012,

            At the risk of repeating myself, the fact that there is no change in motor and sensory scores does not mean that there has been no improvement in motor or sensory function. There have also been some changes in motor and sensory scores of some patients but this particular patient did not have any change in his scores. There is no contradiction between these statements.

            Let me try again. Motor and sensory scores represent specific voluntary function. The examination is done with the subject lying down and the examiner asks the subject to move specific muscles, such as the knee extensors (quadriceps) or ankle extensors (gastrocnemius) against resistance, etc. The strength of each muscle is scored. The examiners also pokes a pin or touch each dermatome and asks the subjects whether or not he can feel the pin, whether it is sharp or not, etc.

            As I have said repeatedly, we are finding that subjects can walk like the video shown without showing improvements in voluntary movement of individual muscles or feeling pinprick or touch in their legs. I have already explained that I think that the recovery of function is a result of the subjects being able to activate their central pattern generator (CPG). The fact that they can activate their CPG does not mean that they are able to activate the individual muscles directly or that they are able to feel the parts of their legs.

            I have not looked at this particular subject's neurological scores in detail. I only know that this subject did not show big changes in his scores. When we publish the data, we will do the detailed correlation. I don't mind being asked questions and I answer them to the best of my ability but I hope that people will be patient. I cannot and will not present detailed scores of individual subjects.

            Finally, I want to emphasize that I am hoping that these individuals will eventually recover motor and sensory scores in their legs. As the MRI/DTI suggests, the growth across in injury site is very slow. At 6 months, they are barely reaching across the injury site and they may not have reached far enough to the distal spinal cord or brainstem to result in voluntary activation of muscles or ability to feel pinprick or touch.

            Wise.



            Originally posted by ay2012 View Post
            I'm a little confused that there aren't any motor or sensory improvements at six months (and maybe it will be shown that indeed there were some when the data is fully analyzed and released) and mostly because this thread contains MANY times where someone associated with the trial or carecure (either Dr. Young or Jim relaying information from him) states that some patients seemed to be getting increased sensation, "more and better improvement in sensory and motor scores", etc. Some of these claims go back to shortly after the first patients were given the treatment, some are as recent as a couple months ago. So I don't really understand what is going on here... Did those things never happen? Were they reported by patients but then failed to show through in more rigorous neurological analysis? I fully realize Dr. Young has repeatedly said time and again that its too early to say the treatment is effective, even things that happen (the truly amazing locomotor improvement) have not been shown to be due to the treatment, etc. but either these things happened or not. Or is this standard, that for example changes in sensation could occur and leave before the time to analyze the patients?
            I'd also appreciate if noone responded saying that I am being impatient, demanding too much, want the trial to fail, wasting Dr. Young's time or something like this. I am wholly invested in this trial succeeding and hope it will bring good things for all of us. I just think this discrepancy is something that warrants a question. Thanks as always!
            Last edited by Wise Young; 8 Feb 2013, 8:47 PM.

            Comment


              Originally posted by lunasicc42 View Post
              wise, based what you see concerning efficacy in these trials, are you guys still motivated to move this therapy to higher level chronics? And if so: whats the proposed timeframe? Has it changed or been altered?

              Because I would think that if this shows efficacy in the lower level injuries, the trial for higher injuries might be accelerated...

              And also when will you be able to comment surely on b/b/b?
              Lunasicc42,

              Yes, I am still motivated to move this therapy to higher levels. I don't know the specific time frame but it will depend on our ability to get permission to do the trials, to convince investigators to do so, and successfully raising the funds for the trials. Regarding the B/B/B, I don't know. We haven't analyzed all the data yet and I am not going to comment on the details of the data until it is published.

              Wise.
              Last edited by Wise Young; 8 Feb 2013, 8:48 PM.

              Comment


                Originally posted by CAS View Post
                I know that I am likely to get a fall from this but as things seem to be progressing I cannot help but have a positive outlook the way developments have occurred during the last few years, in regards to potential cures and therapy’s etc.

                Dr Wise I know your going to start phase 3 soon. Could I ask as to when and for how long until the final phase (I assume) being four, will begin and end?. And how long will it take before the rest off us can participate in the treatment? If possible.

                Do you think that your therapy and others will be applicable to most of us by 2020? Or later like 2030.

                Thank-you for all your help
                CAS,

                Phase III trials lead to regulatory approval. Phase IV trials are post-approval, to look for long-term complications, etc. We are working as hard as we can to get the phase III started and completed before 2020. Barring any complications (such as lack of funding), we should know the whether the treatment is effective and safe in 2015.

                That phase II trials have yielded several surprising findings. The first is that MRI/DTI images are showing evidence fiber bundles growing across the injury site, suggesting of regeneration and that this grown is occurring a 6-12 months after transplantation of the cells. The second is that a majority of the transplanted subjects are showing improvements in locomotor scores without improvement in motor and sensory scores, at least at 6 months and in some cases at 12 months.

                We would like to confirm these findings as soon as possible in formal phase III randomized and controlled clinical trials. It is important to find out whether or not we see fiber bundles growing in the spinal cord when we do not transplant cells. Likewise, we need to find out whether the subjects do not show this kind of walking improvement without cell transplantation. Finally, of course, we are hoping that the subjects will show motor and sensory score improvements eventually.

                Wise.

                Comment


                  thanks for the response... and regarding my questioning regarding b/b/s is I know repetative but it's REALLY important
                  "That's not smog! It's SMUG!! " - randy marsh, southpark

                  "what???? , you don't 'all' wear a poop sac?.... DAMNIT BONNIE, YOU LIED TO ME ABOUT THE POOP SAC!!!! "


                  2010 SCINet Clinical Trial Support Squad Member
                  Please join me and donate a dollar a day at http://justadollarplease.org and copy and paste this message to the bottom of your signature

                  Comment


                    Originally posted by Christopher Paddon

                    "At the risk of repeating myself, the fact that there is no change in motor and sensory scores does not mean that there has been no improvement in motor or sensory function."
                    Especially the sensory part.
                    I can kind of understand the motor improvement because of CPG. But how does this happen in sensory?

                    Comment


                      Originally posted by Christopher Paddon

                      I too am confused by the news that comes out of the ChinaSCINet. Here is a classic quote:

                      "At the risk of repeating myself, the fact that there is no change in motor and sensory scores does not mean that there has been no improvement in motor or sensory function."
                      What is so confusing with this quote? The Asia motor scores don't include all the muscles in the body. It only includes about 5 in the legs. Here is an example:
                      if you can wiggle your big toe it will show on your motor scores.
                      If you can wiggle your little toe it will not show on your motor scores, but you will have motor function.

                      The quote makes perfect sense to me.
                      Originally posted by paolocipolla
                      Moe,

                      I... don't care about what I think ... you should just ignore my posts.

                      I don't understand ... words.

                      Paolo

                      Comment


                        Originally posted by Solan View Post
                        What is so confusing with this quote? The Asia motor scores don't include all the muscles in the body. It only includes about 5 in the legs. Here is an example:
                        if you can wiggle your big toe it will show on your motor scores.
                        If you can wiggle your little toe it will not show on your motor scores, but you will have motor function.

                        The quote makes perfect sense to me.
                        Solan,

                        Thanks for trying.

                        Motor strength is graded on a scale of 0-5. When people cannot move a specified muscle on command at all, that is a score of 0. If they can move the muscle slightly against no resistance, so that it can be felt but not necessarily seen, that is a score of 1. If the movement can be seen, the score is 2. If the movement can oppose gravity, the score is 3. By the way, for the legs, that is quite a lot of strength, since the leg is heavy. If the movement can oppose manual resistance in addition to gravity, the score is 4. If the strength of the muscle is normal, the score is 5.

                        In the case of the person in the video, that person is able to move his legs when walking but cannot move individual muscles when lying down. I have not checked for this specific subject but many of the subjects that are able to walk at KLS IV have 0 motor scores in their major leg muscles. For example, if the subject is lying on his back in a bed and we ask him to lift his leg from the hip, he cannot. If we push him to the left side, bend his right leg, and ask him to straighten his right leg, he is not able to do so. Or, if we ask him to flex his ankles up and down, he cannot. Or, if we ask him to wiggle his toes, he cannot. By the way, those are the five muscle groups that we test for the motor scores in the legs.

                        We were surprised to find this. Of course, some subjects are able to move some muscles in their legs if they wiggle around and get spasms going. However, if we ask them to move specific muscles without any sensory activation, they cannot. We think that this is because they are activating the central pattern generator when they are walking. The central pattern generator is located in the lower spinal cord and contains programs for walking, trotting, running, etc. In order for the program to run, it must get sensory feedback from the legs. Note that sensory feedback is going to the CPG but not necessarily to the brain. Once the walking motion is started, the person can take step after step after step, each step activating the next step. They have to get it going and sensory feedback is needed.

                        The concept that people with spinal cord injury walk with their CPG is not new. Many people who recover walking after spinal cord injury do not have strong voluntary control of their muscles. Nevertheless, they are able to walk and often for long distances with minimal help. Many people who are able walk do not have feelings in their feet or lower legs. By the way, I am presenting our observations and learning from them. I was not expecting this finding. Incidentally, the doctors at Kunming have been documenting the walking with electromyography as well. The subjects do show electromyographical activation of muscles when they are walking, so it is not just a trick that they are employing.

                        I can understand that some people are confused but I am also puzzled by why the concept of activating CPG is so difficult for people to understand. After all, most people with spinal cord injury know what a spasm is. Spasms can be very strong. For example, leg spasms or multi-point movements that can be activated when people are being pushed in a wheelchair over cobblestone. Their legs often go rigid. Stepping motions can be activated by simply stimulating the L2 spinal cord. This has been shown many times now. I think that this is the beginning of walking. People are able to activate walking of their legs voluntarily even though they cannot move individual muscles.

                        We want to document this unexpected phenomenon. We hypothesize that this occurs more frequently in subjects that we have transplanted umbilical cord blood mononuclear cells into but this hypothesis now needs to be confirmed in a phase III trial where we can compare transplanted subjects with non-transplanted subjects. We are also hopeful that we will eventually find some recovery of motor and sensory scores in the patients. We have not even collected 12 month followup data on many of the subjects. If the fiber bundles that we saw in the Hong Kong trial represent axonal growth, most of the subjects did not have growth across the injury side until 12 months. It is simply to early to conclude that the people will not get motor and sensory function. That is why we have asked the subjects whether or not we can follow them for another year.

                        This is what doing Phase II trials are all about. We keep your eyes open and learn from what the subjects are doing.

                        Wise.
                        Last edited by Wise Young; 10 Feb 2013, 9:27 AM.

                        Comment


                          Wise,

                          I have a few questions for you.....

                          1) When testing for voluntary motor scores in lying or sitting are you using the EMG? ie are we testing for the grade 1 scores? Or is the EMG only being used when stepping?

                          2) Are you testing motor scores in the trunk at all? And if not, why?

                          3) Will the goal of Phase III be to confirm the hypothesis that UBCB+Lithium+666 results in increased CPG-activated stepping if you observe no motor/sensory recovery by 12-18 month time points?

                          4) If your observations are correct that bundles of axons have crossed the injury site but no motor/sensory recovery is observed (at say 18 months time points) would you consider returning to a chronic animal study to investigate why synapses are not being formed?

                          Cheers
                          Fly Pelican Fly

                          Comment


                            Originally posted by Fly_Pelican_Fly View Post
                            Wise,

                            I have a few questions for you.....

                            1) When testing for voluntary motor scores in lying or sitting are you using the EMG? ie are we testing for the grade 1 scores? Or is the EMG only being used when stepping?

                            2) Are you testing motor scores in the trunk at all? And if not, why?

                            3) Will the goal of Phase III be to confirm the hypothesis that UBCB+Lithium+666 results in increased CPG-activated stepping if you observe no motor/sensory recovery by 12-18 month time points?

                            4) If your observations are correct that bundles of axons have crossed the injury site but no motor/sensory recovery is observed (at say 18 months time points) would you consider returning to a chronic animal study to investigate why synapses are not being formed?

                            Cheers
                            Fly Pelican Fly
                            1. In the trial, we are collecting the ASIA scores in the standard and recommended method. The patient is lying down and each muscle is tested in the prescribed position. The Kunming group has done EMG in walking patients but it is not routinely done. It is not part of our protocol.

                            2. We are not testing trunk motor scores although we collect sensory scores. There is no validated clinical examination for trunk motor scores. There have been several efforts to develop an EMG form of such scores but these types of specialized tests would be expensive and difficult to implement in China.

                            3. Good question. We are considering making the KLS and WISCI scores our primary outcome measure in the Phase III study. That will be discussed in our upcoming principal investigator meeting in Xi'an. I am not satisfied with either of these scoring approaches.

                            4. Yes, of course, we are considering doing animal studies. Several laboratories have shown substantial regeneration and even reconnection of regenerating axons without locomotor recovery in animals. I am trying to put together a travelling clinical group to study these patients in the Phase III study, to study the mechanisms of walking in subjects who are walking without motor or sensory score improvements. I also want to emphasize that it is premature to speculate that these patients will not recover motor and sensory scores. We have not yet even collected all the 12-month data.

                            Wise.
                            Last edited by Wise Young; 10 Feb 2013, 11:05 AM.

                            Comment


                              Originally posted by Wise Young View Post
                              1. In the trial, we are collecting the ASIA scores in the standard and recommended method. The patient is lying down and each muscle is tested in the prescribed position. The Kunming group has done EMG in walking patients but it is not routinely done. It is not part of our protocol.

                              2. We are not testing trunk motor scores although we collect sensory scores. There is no validated clinical examination for trunk motor scores. There have been several efforts to develop an EMG form of such scores but these types of specialized tests would be expensive and difficult to implement in China.

                              3. Good question. We are considering making the KLS and WISCI scores our primary outcome measure in the Phase III study. That will be discussed in our upcoming principal investigator meeting in Xi'an. I am not satisfied with either of these scoring approaches.

                              4. Yes, of course, we are considering doing animal studies. Several laboratories have shown substantial regeneration and even reconnection of regenerating axons without locomotor recovery in animals. I am trying to put together a travelling clinical group to study these patients in the Phase III study, to study the mechanisms of walking in subjects who are walking without motor or sensory score improvements. I also want to emphasize that it is premature to speculate that these patients will not recover motor and sensory scores. We have not yet even collected all the 12-month data.

                              Wise.
                              Thanks Wise.

                              Comment


                                Dr.Young ,
                                Hi, Did any of china sci network centers use FES after their umbilical cord blood cells transplants on subjects? If not, do you think using FES on some specific muscles after transplants (in addition to walking program) could have some effect on motor scores etc. ? just a thought .

                                Comment

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