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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #361
    My favorite part of the paper:

    "We recently reported that pain reliever ibuprofen improved axon
    growth and functional recovery in SCI rodents when applied at a
    dose of 60 mg/kg/d, which is a higher dose than that used clinically
    as a cyclooxygenase inhibitor (Fu et al., 2007)."

    Amazing isn't it that this ended up in a good journal. The BBB locomotor scoring system can't be used efficiently in a dorsal hemisection model nor in a very moderate contusion lesion because the control animals regain back so much locomotor ability. Once at or above the magic number of BBB 13 in the controls (frequent coordinated stepping) any changes in locomotion are very tiny and it is difficult to be totally objective. A couple of points of improvement at that end of the scale is a clear sign that the treatment is likely NOT to be therapeutic in vivo and NOT to be trusted as a sufficiently severe injury model to predict therapeutic value in the real world. This is the same major criticism of the Stephen Davies model for testing Decorin ( he uses a very small quadrantic lesion to start). How many of you out there have frequent coordinated walking to start? Nobody takes this paper seriously as strong evidence for a potentially robust effect of lithium in the real world setting of spinal cord injury. In vitro, notice the tiny changes in neurite length in all the treatment qroups. Again not very robust changes and the authors used very low concentrations of inhibitory molecules to start, likely so they could demonstrate any differences at all. Again not very strong evidence for a potentially potent effect in vivo. As Grammy points out they've already reported the most bogus observation of all suggesting that ibuprophen might be therapeutic; really. The take home message is that people tend to over hype meager results and sometimes politics or naive reviewers let such stuff end up in good journals. That is why we teach our students how to critically evaluate the published literature and why it is sooooo important for results such as this to be verified independently and in a more severe injury model.

  2. #362
    Quote Originally Posted by jsilver View Post
    The take home message is that people tend to over hype meager results and sometimes politics or naive reviewers let such stuff end up in good journals. That is why we teach our students how to critically evaluate the published literature and why it is sooooo important for results such as this to be verified independently and in a more severe injury model.
    This is a fair enough point Dr. Silver, as are your critiques of the paper, but perhaps then you and Grammy can do away with the argument that some experiment or another was published in a "low impact journal". Anybody in any academic field know there is some politics to publishing so for those of us equipped to talk about the science (you all) maybe we can just focus on the scientific arguments themselves. Thanks, as always, for your comments!
    Last edited by ay2012; 02-01-2013 at 01:46 PM.

  3. #363
    Quote Originally Posted by jsilver View Post
    My favorite part of the paper:

    "We recently reported that pain reliever ibuprofen improved axon
    growth and functional recovery in SCI rodents when applied at a
    dose of 60 mg/kg/d, which is a higher dose than that used clinically
    as a cyclooxygenase inhibitor (Fu et al., 2007)."

    The BBB locomotor scoring system can't be used efficiently in a dorsal hemisection model nor in a very moderate contusion lesion because the control animals regain back so much locomotor ability. Once at or above the magic number of BBB 13 in the controls (frequent coordinated stepping) any changes in locomotion are very tiny and it is difficult to be totally objective. A couple of points of improvement at that end of the scale is a clear sign that the treatment is likely NOT to be therapeutic in vivo and NOT to be trusted as a sufficiently severe injury model to predict therapeutic value in the real world. This is the same major criticism of the Stephen Davies model for testing Decorin ( he uses a very small quadrantic lesion to start). How many of you out there have frequent coordinated walking to start? Nobody takes this paper seriously as strong evidence for a potentially robust effect of lithium in the real world setting of spinal cord injury. In vitro, notice the tiny changes in neurite length in all the treatment qroups. Again not very robust changes and the authors used very low concentrations of inhibitory molecules to start, likely so they could demonstrate any differences at all. Again not very strong evidence for a potentially potent effect in vivo. As Grammy points out they've already reported the most bogus observation of all suggesting that ibuprophen might be therapeutic; really. The take home message is that people tend to over hype meager results and sometimes politics or naive reviewers let such stuff end up in good journals. That is why we teach our students how to critically evaluate the published literature and why it is sooooo important for results such as this to be verified independently and in a more severe injury model.
    I think it's important to replicate results independently and in an appropriate model for SCI. I know there's lots of talk about reconsituting uses for drugs already approved by the FDA. However, that doesn't automatically translate into an effective treatment to white matter injuries including spinal cord trauma given the wide use of a pharmacutical in humans. The authors pointing out the pain reliever (ibuprofen) was a perfect example of that. Thank you for pointing out the injury model problem when predicting therapeutic value.

  4. #364
    Quote Originally Posted by GRAMMY View Post
    My favorite part of the paper:

    "We recently reported that pain reliever ibuprofen improved axon
    growth and functional recovery in SCI rodents when applied at a
    dose of 60 mg/kg/d, which is a higher dose than that used clinically
    as a cyclooxygenase inhibitor (Fu et al., 2007)."
    Here is the article for that.

  5. #365
    .....
    Last edited by GRAMMY; 02-02-2013 at 02:39 PM. Reason: boring outdated acute research theory

  6. #366
    Quote Originally Posted by jsilver View Post
    As Grammy points out they've already reported the most bogus observation of all suggesting that ibuprophen might be therapeutic; really.
    Really.
    Subcutaneous injections of ibuprofen via minipumps to rats with a thoracic spinal cord transection or contusion injury result in substantial corticospinal and serotonergic axon sprouting in the caudal spinal cord and promote locomotor functional recovery, even delaying the treatment 1 week after trauma.

  7. #367
    Quote Originally Posted by jsilver View Post
    My favorite part of the paper:

    "We recently reported that pain reliever ibuprofen improved axon
    growth and functional recovery in SCI rodents when applied at a
    dose of 60 mg/kg/d, which is a higher dose than that used clinically
    as a cyclooxygenase inhibitor (Fu et al., 2007)."

    Amazing isn't it that this ended up in a good journal. The BBB locomotor scoring system can't be used efficiently in a dorsal hemisection model nor in a very moderate contusion lesion because the control animals regain back so much locomotor ability. Once at or above the magic number of BBB 13 in the controls (frequent coordinated stepping) any changes in locomotion are very tiny and it is difficult to be totally objective. A couple of points of improvement at that end of the scale is a clear sign that the treatment is likely NOT to be therapeutic in vivo and NOT to be trusted as a sufficiently severe injury model to predict therapeutic value in the real world. This is the same major criticism of the Stephen Davies model for testing Decorin ( he uses a very small quadrantic lesion to start). How many of you out there have frequent coordinated walking to start? Nobody takes this paper seriously as strong evidence for a potentially robust effect of lithium in the real world setting of spinal cord injury. In vitro, notice the tiny changes in neurite length in all the treatment qroups. Again not very robust changes and the authors used very low concentrations of inhibitory molecules to start, likely so they could demonstrate any differences at all. Again not very strong evidence for a potentially potent effect in vivo. As Grammy points out they've already reported the most bogus observation of all suggesting that ibuprophen might be therapeutic; really. The take home message is that people tend to over hype meager results and sometimes politics or naive reviewers let such stuff end up in good journals. That is why we teach our students how to critically evaluate the published literature and why it is sooooo important for results such as this to be verified independently and in a more severe injury model.
    I disagree with one of your statements here and some of the reasons that you stated for the your opinions concerning the BBB score.

    1. The BBB score can be used to assess mild and moderate contusions. We (MASCIS) showed that the score is linearly related to the remaining white matter at the contusion site in severe (50 mm), moderate (25 mm), and mild (12.5 mm) contusions. It is true that the BBB score is less reliable in the range of 0-6 and 13-20 range because the signs that you look for are less conspicuous and can be easily missed. A lot of people have never been trained to use the BBB score properly. When people are properly trained to use the BBB score, its entire range is usable. The BBB score was not designed for evaluation of hemisection models.

    2. The BBB score should not be used to assess dorsal hemisection models but not for the reasons that you stated ("inefficient" and "tiny changes above 13"). The BBB score was designed to assess contusion injuries and not hemisections, whether dorsal or lateral. The scale was developed from observation of rats after spinal cord contusion. The ordinal scale is ordered based on timing of recovery of locomotor behaviors after injury. Behaviors that recover later are assigned a higher value. This results in a smooth recovery curve. Given time (6-8 weeks), all rats should recover walking (BBB scores in the range of 18) after dorsal and lateral hemisection.

    3. Cutting the dorsal columns eliminates proprioception but proprioceptive loss is not readily evident on overground locomotion unless the rats are charging around, which they don't necessarily do in open field tests. To detect the proprioceptive deficits, one has to test the rats on grid walking. Lateral hemisections result in the equivalent of a Brown-Secquard syndrome in rats and they will be weak and have proprioceptive loss on cut side but pain and temperature loss on the other side. Since the BBB score is a force choice score representing both legs, it is not a reliable measure of locomotor recovery after lateral hemisections.

    With regard to the Fu, et al. paper, I thought that is interesting that Indomethacin and other NSAID's do block rho and increases neurite growth in the presence of CSPG and myelin. As figure 3 in the article shows (

  8. #368
    Quote Originally Posted by jsilver View Post
    My favorite part of the paper:

    "We recently reported that pain reliever ibuprofen improved axon
    growth and functional recovery in SCI rodents when applied at a
    dose of 60 mg/kg/d, which is a higher dose than that used clinically
    as a cyclooxygenase inhibitor (Fu et al., 2007)."

    Amazing isn't it that this ended up in a good journal. The BBB locomotor scoring system can't be used efficiently in a dorsal hemisection model nor in a very moderate contusion lesion because the control animals regain back so much locomotor ability. Once at or above the magic number of BBB 13 in the controls (frequent coordinated stepping) any changes in locomotion are very tiny and it is difficult to be totally objective. A couple of points of improvement at that end of the scale is a clear sign that the treatment is likely NOT to be therapeutic in vivo and NOT to be trusted as a sufficiently severe injury model to predict therapeutic value in the real world. This is the same major criticism of the Stephen Davies model for testing Decorin ( he uses a very small quadrantic lesion to start). How many of you out there have frequent coordinated walking to start? Nobody takes this paper seriously as strong evidence for a potentially robust effect of lithium in the real world setting of spinal cord injury. In vitro, notice the tiny changes in neurite length in all the treatment qroups. Again not very robust changes and the authors used very low concentrations of inhibitory molecules to start, likely so they could demonstrate any differences at all. Again not very strong evidence for a potentially potent effect in vivo. As Grammy points out they've already reported the most bogus observation of all suggesting that ibuprophen might be therapeutic; really. The take home message is that people tend to over hype meager results and sometimes politics or naive reviewers let such stuff end up in good journals. That is why we teach our students how to critically evaluate the published literature and why it is sooooo important for results such as this to be verified independently and in a more severe injury model.
    I disagree with one of your statements here and some of the reasons that you stated for the your opinions concerning the BBB score.

    1. The BBB score can be used to assess mild and moderate contusions. We (MASCIS) showed that the score is linearly related to the remaining white matter at the contusion site in severe (50 mm), moderate (25 mm), and mild (12.5 mm) contusions. It is true that the BBB score is less reliable in the range of 0-6 and 13-20 range because the signs that you look for are less conspicuous and can be easily missed. A lot of people have never been trained to use the BBB score properly. When people are properly trained to use the BBB score, its entire range is usable. The BBB score was not designed for evaluation of hemisection models.

    2. The BBB score should not be used to assess dorsal hemisection models but not for the reasons that you stated ("inefficient" and "tiny changes above 13"). The BBB score was designed to assess contusion injuries and not hemisections, whether dorsal or lateral. The scale was developed from observation of rats after spinal cord contusion. The ordinal scale is ordered based on timing of recovery of locomotor behaviors after injury. Behaviors that recover later are assigned a higher value. This results in a smooth recovery curve. Given time (6-8 weeks), all rats should recover walking (BBB scores in the range of 18) after dorsal and lateral hemisection.

    3. Cutting the dorsal columns eliminates proprioception but proprioceptive loss is not readily evident on overground locomotion unless the rats are charging around, which they don't necessarily do in open field tests. To detect the proprioceptive deficits, one has to test the rats on grid walking. Lateral hemisections result in the equivalent of a Brown-Secquard syndrome in rats and they will be weak and have proprioceptive loss on cut side but pain and temperature loss on the other side. Since the BBB score is a force choice score representing both legs, it is not a reliable measure of locomotor recovery after lateral hemisections.

    With regard to the Fu, et al. paper, I thought that is interesting that Indomethacin and other NSAID's do block rhoA and increases neurite growth in the presence of CSPG and myelin. As figure 3 suggests indomethacin and ibuprofen both increased mean neurite length to about 1.5 mm compared to less than 0.5 mm in culture on myelin and 1.0 on CSPG. This correlated with inhibition of RhoA.

    As pointed out above, I don't think that BBB scores should be used to assess locomotion after hemisections. However, there must be an error in the legend of figure 7, which states the locomotor behavior recovery occurred after transection or contusion injury. They must have been referring to overhemisection and not transection in panel A-D. I am surprised that this escaped peer review. Panel E and F show the data for the contusion injuries and the improvement in BBB score is more believable. A 3-point difference between control of 12 and Ibu-treated of 15 is a meaningful effect.

    On the other hand, Fu, et al. did use other measures, including grid-walking and stride length. However, The improvement in percentage grid walking is small and present only for Ibu. The differences in stride length and width are not impressive and I am surprised that they have such small standard errors of means. By selecting which stretches of footprints to analyze, the data can be easily manipulated. So, I am not impressed by these data.

    Nevertheless, the increased neurite growth due to Ibu and Ind and the BBB score improvement of the contused animals are of interest and credible. I am looking forward to other people replicating this work. Both Ibu and Ind are feasible treatments for clinical trial, particularly in combination with other therapies. I wonder if they actually have to be given for such long time (they showed data for 4-week treatments and did not show data for shorter treatment periods).

    Wise.

  9. #369
    I understand your points about proper use of the BBB rating scale. I've sent several of my students to the Ohio State summer course to learn spinal cord injury techniques where Phil Popovich and Dana McTigue and colleagues do a marvelous job of training students. We have been doing BBB analyses now for a couple of years in the lab so I am getting more familiar with its pros and cons. I'm never impressed anymore with around 2 point improvements in the BBB especially at the low or high end of the scale in terms of potential translational potential. In speaking personally to all of the 3 B's who invented this rating scale (Basso, Breshnahan and Beattie) they suggest a great place to start is at a BBB score of 9-10. This way if a treatment causes harm you can more easily characterize a decline in score and if the treatment is highly potent then you can observe scores that climb above 13. The BBB scale is not linear and this particular part of the scale between 9-13 is especially important because it is more exciting when changes occur in this portion of the range. In this area animals progress form minimal weight bearing steps to fully coordinated walking. I am quite familiar with in vitro assays of neurite elongation and again I caution you that such small changes using low concentrations of inhibitory molecules as substrates worries me. Finally , when I see such small error bars on a plot of BBB scores over time that really concerns me because they used the NYU impactor. We purchased one of these but had quite variable results in terms of our ability to apply highly reproducible impacts to the cord. We had far to much variability in our control animals for my taste in terms of where their BBB scores stabilized over time. One of my students actually did a very careful comparison of the force produced by the NYU impactor versus the computerized Infinite Horizons Device (that we had to purchase at much greater expense) using a mechanical force plate. The data is quite convincing. The Infinite Horizons Device produces far more consistent impacts than does the NYU impactor. So seeing such tiny error bars tells me something is suspicious.
    Last edited by jsilver; 02-02-2013 at 08:00 PM.

  10. #370
    Senior Member lynnifer's Avatar
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    Ibuprofen was tested on ... lab animals???

    2 Feb 2013The Windsor Star
    DR. JANICE HUNTINGFORD Pet Doctor
    Dr. Janice Huntingford practises integrative veterinary medicine in Essex. Contact her at Drjan@essexanimalhospital.ca
    Ibuprofen toxic to pets

    Ibuprofen and acetaminophen are a frequent source of toxicity in pets. . In dogs, acetaminophen has been used for pain relief at a very small dose but it is not recommended. It cannot be used in cats at any dose. Overdoses of acetaminophen lead to liver and kidney toxicity. Clinical signs include depression, weakness, difficulty breathing, vomiting, blood changes, hypothermia, facial or paw swelling, liver necrosis, and death. Ibuprofen is not used in dogs or cats due to toxicity. It tends to cause gastric ulceration and bleeding and kidney and liver failure. The most common signs of ibuprofen toxicity include anorexia, nausea, vomiting, lethargy, diarrhea, black stool, weakness and staggering, and excess drinking and urination. In addition, weakness, hypotension, seizures, heart and blood pressure problems can result.

    Treatment may involve administration of activated charcoal and intestinal protectants along with intravenous fluids. Medications to decrease acid in the stomach are also recommended. From a holistic standpoint, there are a few herbs that are helpful in treating these toxicities. Milk thistle is extremely beneficial for treating liver and kidney toxicities. Rehmannia is another herb that I frequently use.

    If your pet has ingested a human pain medication, it needs to be seen immediately. Prognosis depends on speed.
    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

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