Sunday, June 21, 2015

Rewrite the textbooks

UPDATE: October 2017  
Confirmation of the Kipnis Lab and University of Helsinki finding in humans.  
Researchers at NIH see the actual lymphatic vessels in the human brain. 

“We literally watched people’s brains drain fluid into these vessels,” said Daniel S. Reich, M.D., Ph.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published online in eLife(link is external). “We hope that our results provide new insights to a variety of neurological disorders.”   link

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The Journal of Experimental Medicine said it best in their recent tweet:

"The CNS is considered an organ devoid of lymphatic vasculature." Ed. note: "NOT"

Not. Decades of medical theory which considered the brain as different from other organs of the body and without lymphatic drainage system were, well, simply wrong.

The University of Helsinki has independently published a paper in the Journal of Experimental Medicine which confirms the University of Virginia's paper on lymph vessels published just two weeks ago. Both universities have found:
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

How have researchers had it SO WRONG for SO LONG?
If you're like me, you figured that neuroscientists had looked long and hard for any signs of lymphatic drainage surrounding the brain, and had proven that it simply didn't exist, and that the brain was indeed immune privileged, and separate from the rest of the body's peripheral immune system.

“Any neuroscience textbook that has ever been written will say that the central nervous system is devoid of a lymphatic system and that is one of the reasons the brain is immune privileged,” Louveau said. “When we started our project, our question was if there are so many immune cells surrounding the brain, how do they traffic there? By addressing this question we found vessels that weren’t supposed to exist. They were very well hidden and we think that is why it took so long to discover them.”
link

In fact, the whole concept of immune privilege of the brain and lack of lymphatic drainage was created 70 years ago and hasn't changed much in ensuing years.   This was around the same time EAE was created as the animal model for MS.  Why hasn't there been more exploration until recently?   I believe one reason is because the old theories have made people very rich.

Let's learn the history:
The theory of  immune privilege was invented to explain why foreign tissue grafts placed on brain tissue didn't cause an immediate immune reaction, as similar grafts did in other parts of the body, like the skin.  It was believed that antigens in the brain were concealed from the immune system by the blood brain barrier.  That's why it was assumed that when immune cells showed up in the brain--if they weren't there fighting an infection or as an inflammatory reaction after a stroke---there could only be one explanation--it was some sort of "auto-immune"and destructive inflammatory reaction.  

This theory of immune privilege was developed in the 1940s and became the foundation of transplantation immunology---or the reason why we need to block the immune system when patients receive a donated organ or a skin graft.  The body's immune response needs to be turned off, so that it will not reject the foreign tissue.  This process was discovered by Sir Peter Medawar, who wanted to understand how to help skin grafts survive.


Sir Peter Medawar, whose experiments in the 1940s established the basic rules of transplantation immunology [2], placed skin and or other types of grafts in the anterior chamber of the eye and the brain [3]. Observing that many of these grafts, unexpectedly, survived for prolonged intervals of time, he invented the term ‘immune privilege‘ to refer to the unexpected and prolonged acceptance of solid tissue grafts at specialized sites in the body. At the time, it was believed that the brain and eye lacked lymphatic drainage pathways, and that both organs resided behind stringent blood-tissue barriers. In light of this knowledge, Medawar proposed that immune privilege results from ‘immunologic ignorance’ because, on the one hand, in the absence of lymph pathways antigens could not escape from the eye, and on the other hand, immune effectors in the blood could not pass the vascular barrier to enter the sites where antigen resides. He speculated that antigenic material placed in privileged sites is sequestered from the immune system, and that the system remains unaware of the existence of grafts in privileged sites. link

This speculation on immune privilege has continued on for seven decades, mostly due to the fact that no one could find any lymphatic drainage pathways or understand how or why immune cells might get through the blood brain barrier.  

Not coincidently, the EAE model for MS was developed around the same time as the theory of immune privilege, as an example of how t-cells could break through the blood brain barrier and attack the brain in an auto-immune reaction.  It has been a prevailing theory in MS treatment development, which has also never been proven.  Another 70 year old theory which has lead to disastrous assumptions about the brain.


The presence of mild scant lymphocytic infiltrates in the demyelinating lesions has been generally interpreted as the evidence of an inflammatory autoimmune process. Because specific T-cell mediated autoimmunity can be reproduced in animals after myelin protein sensitisation (Experimental Allergic Encephalo- myelitis (EAE)) it has been assumed (but never proven) that a similar T-cell driven immune mechanism is responsible for demyelination in MS. 

The acceptance of EAE as a model for MS is an unfortunate error that has its basis on faith rather than science. Whilst EAE is a good example of an experimental organ-specific autoimmune disorder in animals, it cannot be accepted as a model for MS for a wide variety of reasons. This is particularly important in relation to the development of MS pharmacotherapy. We have analysed the literature on immune-modifying therapy in MS and it is clear that none of these agents can qualify as a candidate therapy under scrutiny.
link


The brain's relationship to the peripheral immune system is obviously much more communicative and complex than previously imagined.  The discovery of lymphatic vessels by neuroimmunologists means we need a do-over in MS research, as this science writer comments:

This data suggests that brain immune surveillance communicates with the immune system and can generate adaptive immune responses. The authors infer that previously characterized glymphatic washing of the brain likely connects to the lymphatic system; a testable hypothesis. The authors further suggest that this system will change the way we think about neurological disorders such as multiple sclerosis and Alzheimer’s.

The fact that MS has no disease-specific immune target,  no specific antigen, and does not look like EAE in mice, should give us all pause.   There has never been any concrete, scientific proof that MS is an autoimmune disease.  Just a theory,  which has been used to create a 20 billon dollar a year industry.  And that theory has completely unravelled.  The question is, will MS researchers let go of pharma money, in order to pursue the true etiology of MS?

If the brain requires immune cells for neuroprotection, stem cell regeneration and plasticity, than what are we doing suppressing the immune system with MS drug therapies?  What if this immune reaction is, as Dr. Michal Schwartz's research has shown, "protective", and should be modified, not stopped?  (notice that this paper was co-authored by Dr. Kipnis, a PhD graduate of the Weizmann Institute of Science, who now heads up the Kipnis Lab at the Univeristy of Virginia where these lymphatic vessels were discovered.)

For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases.
link


Israel Steiner, a neurologist at the Hadassah University Hospital in Jerusalem, agrees that EAE has blocked "effective progress" for decades. He thinks alternative theories should be put to the test. "I definitely believe it's high time to reconsider the entire field. It has not led us into understanding the disease or to a better therapy for patients," he says. 
"Many people in the community who do not have a vested interest in the autoimmune hypothesis share my views, but I'm not sure they would like to step out."  
New Scientist vol 176 issue 2369 - 16 November 2002, page 12 

Dr. Steiner would later publish the paper:  Experimental allergic encephalomyelitis: A misleading model of multiple sclerosis  link


The MS neurologists with "vested interest in the autoimmune hypothesis" were the very same ones who shut down CCSVI research before it could even begin, or be done correctly.  They were the first to say that veins would have nothing to do with MS, that it was an autoimmune disease, that the brain's drainage system was unimportant.  They created the narrative that those of us pleading for collaboration with Dr. Paolo Zamboni and the International Society of Neurovascular Disease (www.isnvd.org) were wackos, a fringe element, a Facebook/YouTube phenomena that would pass.  

But they were wrong.  The brain's venous system is most certainly important for efficient drainage of CSF, blood and now, lymph.  And the brain's immune system appears to be intimately tied to venous flow of the brain via newly discovered lymph vessels.  link 

In fact, the two large lymph vessels which collect the lymph drainage from the brain, head and neck can enter the blood stream at the internal jugular vein, the subclavian vein, or the junction of these two veins, called the venous angle.  Lymph relies on the low pressure venous system for drainage. To say that this discovery has "nothing to do with CCSVI" is to blatantly ignore physiology.  For patients, or neurologists, who would like to learn more about lymphatics:  link

The writing is on the wall, in medical journals, blogs and even twitter.
And we are all watching, reading, and waiting.

Time to rewrite the textbooks and help people heal,

Joan












32 comments:

  1. Thank you always from UK from me

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    1. Kevin Campbell We must not forget CHARCOT DREW the engorged blood vessels at the lesion sitesProving the Aetiological connection way befire the othe guys....as did Carswell ... research must be ful, accurate and complete n'est pas and take into account DIFFERENTIAL DIAGNOsis and bear in iond there is a serious difference between HUMAN and ANIMAL based experiments.

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    2. absolutely, Kevin! Rindfleish saw it first, even before Charcot, using a microscope in 1863--engorged veins near the lesions. The venous connection has a robust, published history. The University of Virginia researchers have seen these lymphatic vessels in human autopsied meningeal tissue--so we know that this lymphatic drain system is in humans. The next studies will be to see how lymphatic drainage is impacted by venous issues in the jugular/dural sinus. But if Putnam's study in dogs is any indication, venous stenosis is impactful on lymphatics, as well as blood and CSF.

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    3. Have to say two wrongs do not make a right and these discoveries have nothing to do with CCSVI

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    5. Here is Dr. Paolo Zamboni's commentary on the discovery. He has just returned from Houston, where he has been working with NASA, studing how microgravity affects venous drainage in astronauts. http://www.pagepressjournals.org/index.php/vl/article/view/5360

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    6. Here is Dr. Jonathan Kipnis on the discovery, in the NIH research update June edition,

      "The discovery of a pathway for immune cells to exit the central nervous system raises the question of whether disruption of this route may be involved in neurological disorders that are associated with immune system dysfunction, such as multiple sclerosis, meningitis, and Alzheimer’s disease." Thankfully, the NIH is continuing to fund both the Kipnis and Nedergaard Lab. Independent research in the US is leading the way. Helsinki University has also found these vessels. http://www.nih.gov/researchmatters/june2015/06152015lymphatic.htm

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    7. And finally, from Helsinki University, a comment on how drainage of lymphatic fluid and immune cells (which rely on venous drainage) will impact research on all neurodegenerative brain diseases. "We were stunned to find such an extensive network in connection to the brain. This incredible finding completely changes our understanding of how to brain is cleared of excess fluid and gives a chance to look at brain diseases from a completely new angle, he continues." http://www.sciencedaily.com/releases/2015/06/150615094258.htm

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    8. Dear Mouse Doctor---(I've edited my comment from this morning for mis-spelling of Dr. Kipnis' name. )
      Actually, I have spoken with both of the lead scientists at the Nedergaard Lab and the Kipnis Lab here in the US, and they disagree with your assessment. They see how this newly discovered (g)lymphatic drainage system relies on the intra and extra cranial veins for drainage, and there will be future studies how stenosis and venous reflux may be impacting the brain's removal of CSF and lymph, and impacting ALL neurovascular disease. This discovery is bigger than MS, bigger than EAE in mice and I'll continue to blog about it. Two wrongs have injured people with MS for too many years, and I intend to make sure that doesn't continue.

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  2. Thank you Joan, so smart and clear explanation.

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    1. more than welcome, Johana--let's get real answers for people with MS! xo

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  3. Thank you for this blog, Joan--you've explained the issues well!

    I posted this on the MS Society of Canada's facebook page (where they're doing a stupid "pledge" fundraising campaign) with the question: When will the MS Society pledge to make sure the textbooks are rewritten and admit MS is vascular and stop promoting the UNPROVEN autoimmune theory? Doubt I'll get an answer!

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  4. Again, Lyme was here before the theory of CCSVI AND can get into the vascular system.

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    1. Patients should be tested for Lyme before accepting an MS diagnosis, as it is a differential diagnosis. My husband saw a Lyme literate doctor, was tested by Ignenex and had a negative result. Not every person with an MS diagnosis has Lyme disease, but some do. Here's the full list of differentials to go through. https://neurology.wisc.edu/publications/2007/Neuro_2.pdf

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  5. see the last comment and reply on this MS blog - they are happy to make the categoric statement that this has nothing to do with CCSVI - too scared, too ignorant of anatomy to understand the implications or just a naked attempt to protect their paymasters? pitiful that some of these bloggers sit on the grant review board of the UK MS Society... the real implications of the excellent research you present in your blog Joan are going to be covered up by the MS 'establishment' for a while yet I fear.. they don't usually allow my comments to appear on their blog so I haven't bothered trying to post yet

    http://multiple-sclerosis-research.blogspot.com/2015/06/the-brain-drainfrom-nervous-to-immune.html

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    1. wow. thanks for the link, Alison. Troubling that the mouse doctor does not have a better grasp on physiology. I've never even tried to comment on that blog. But I'm sorry they don't allow you access to comment! I'm not sure how much longer they'll be able to be so myopic--considering it is neurolimmunologists who have made this discovery and are saying that venous drainage matters.

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  6. I just ran across your blog -- thanks for these posts. I wonder whether you have insight on how CCSVI can account for the high efficacy of immunosuppressive treatments like Tysabri, alemtuzumab, and HSCT. All of these treatments substantially decrease the rate of disability accumulation, over the course of at least several years. For Tysabri, there exist two large controlled studies establishing this over the course of two years, two long-term (open-label) extension studies showing this for >5 years, and many smaller observational studies showing this over variable periods of time, usually 1-3 years. For alemtuzumab, there are two large controlled trials (which unfortunately weren't double-blind) showing a decrease in disability accumulation over two years, and several long-term open-label extensions, one of which continued to 7 years. For HSCT, there are several smaller open-label studies, at least one of which extended past 5 years. The alemtuzumab and HSCT trials had the advantage that patients were given irreversible treatments. As a result, any effect observed in long-term follow up couldn't be attributed to selection bias, i.e. selective drop-out of patients for whom the drug was ineffective. These drugs really do appear to be effective, at least over the time-scales that they were studied.

    The data obviously don't establish that one should use any of these treatments; one may still think that their side effects are worse than the condition they are being used to treat. But the data do seem to show that these treatments are effective, to a highly non-trivial degree, in decreasing the accumulation of disability, and decreasing the rate of pathological processes associated with the disease, however we have been able to measure them (e.g. lesions, brain/cortical atrophy, NFL, etc). Is this efficacy predicted by CCSVI? If so, through what mechanism? I've given this a lot of thought, but I can't figure it out.

    Thanks!

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    1. I am rather dubious of severe immune ablating and suppressing drugs, as I have followed the work of Dr. Michal Schwartz for many years. Her research shows that inhibiting immune cells causes loss of neurons. My concern is in rate of gray matter atrophy in progressive patients. The mechanism of action in CCSVI venoplasty is restoration of glucose and O2 delivery, clearance of metabolites and proteins via improved CSF and lymphatics clearance...just as it is in intracranial hypertension endovascular treatments. Much too much to get into in the comments section. I'd advise reading the last year's blog postings for links and more research.

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    2. Thanks for your response. To clarify, I'm not asking about the proposed mechanism by which CCSVI causes MS. I'm also not asking about the detrimental side effects of immunosuppressive treatments, or about whether one should use these treatments. I actually like Michal Schwartz's work a lot. I'm not an expert in this area, but it seems fairly convincing that the immune system helps, e.g., to recover from a traumatic CNS injury.

      I'm asking about a different set of empirical results, which show that immunosuppressive treatments decrease the accumulation of disability and the rate of brain atrophy (including gray matter atrophy) in RRMS. This has been shown for the first 5-10 years of treatment. Do you deny that this is true? If not, can you help me understand why this decrease in disability accumulation is predicted by CCSVI?

      Again, this question is independent of whatever other effects immunosuppression has on people. Whatever else these treatments are doing -- and whatever other short and long-term dangers they pose -- they have a non-trivial degree of efficacy during at least the first 5-10 years of treatment. You seem to be an expert on CCSVI, which is why I'm posing this question. If CCSVI does in fact predict the efficacy of immunosuppressive treatments over this time scale, then it should be possible to explain why, even to someone as slow as me!

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    3. I will post two links which explain the understanding of MS as a disease of primary hypoperfusion with reperfusion injury in the beginning stage of the disease. This is why any drug modality which addresses reperfusion injury in the early RRMS stage will decrease inflammation, decrease edema, decrease the widening of the third ventricle (which can be seen on MRI as pseudo maintaining of gray matter, but does not reflect thalamic atrophy. These benefits do not last once the disease becomes progressive--in fact, brain atrophy worsens. Again, it is progressive MS which is the real MS--as Dr. Peter Stys' research has discussed (link in my other comment below) And these drugs do not have the same results in progressive MS. There's not enough time in the world to explain the research to everyone, individually. I hope you understand!
      Please read:
      http://ccsvi.org/index.php/the-basics/ccsvi-in-other-neurological-diseases
      http://ccsviinms.blogspot.com/2013/09/multiple-sclerosis-hypoperfusionreperfu.html

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    4. That makes sense! I now see the relevance of the Stys paper, which is great, thanks for sharing. Using a bit less of the technical jargon, the idea is that inflammation is a response to the underlying disease process, and this inflammatory response can itself cause damage. If you suppress the inflammation, then you shut off this secondary damaging response, and will see some decrease in disease activity in the short-term.

      If inflammation is only a secondary response, shouldn't you see a steady increase in disability for people who are on immunosuppressive drugs? I understand why you'll see fewer relapses, but shouldn't those people start to steadily accumulate disability caused by the underlying disease (which has been unaffected by the drugs)? This clearly happens for people who have already reached the progressive stage (and have EDSS>4) by the time they start treatment, but I've never seen this documented anywhere for people in the relapsing stage. That is, I've never seen average increases in disability for people who start taking these drugs in the early stage of the disease. This account seems to make a distinctive prediction about the type of disability accumulation expected in patients receiving treatment: it should be slow and steady, since it shares the same mechanism as the secondary progressive disease. This is a great prediction! Is it true? Do you really see people with EDSS 2 who have transitioned to secondary progression?

      Is your claim that Tysabri doesn't decrease gray matter atrophy? The only studies that I've seen suggest that it does (e.g. [1]). Do you think that these results aren't solid? I only know a little about signal processing, so I have a hard time judging!

      I know that you're busy, but these issues are non-trivial, and they don't seem to be explicitly spelled out in any of the links that I've seen.

      [1] http://msj.sagepub.com/content/18/12/1760.full#T3

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    5. Tamping down inflammation due to reperfusion injury in the RRMS stage of MS has real benefits--not debating that these drugs help some people. They obviously do! But using Campath or Tysabri for inflammation is like swatting a fly with a sledge hammer. UV ray therapy, nutrition, exercise, Nrf2 activators like curcumin and other less harsh means all show similar benefits of decreased inflammation, disability and gray matter atrophy. without crippling side effects. (search this blog with those terms for studies) But they are never tested with double blind placebo controlled trials by neuros, since who would pay for that study? The drugs have data, because pharma has paid for gold standard trials. So that's what is given to pwMS. Dr. Swank had siimilar stunning results with his patients, which he published, which were discounted because his trials were not placebo controlled. Dr. Terry Wahls is showing similar benefits today, and publishing. Again, discounted. I hope that explains the underlying problem.

      Also, the brain has wonderful neuronal reserves and plasticity, which allow for rewiring during early stage of disease...why MS is relapsing and remitting for so long fo so many. Some simply have better neuronal reserve. Until the don't, and then progressive disbilities set in. Keep learning, look into "alternatives", keep following the new lymphatic studies, and I sincerely hope you'll read more of this blog. All the best.

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    6. Finally...here is the program I created for my husband, which he still follows, now 8 years past his MS diagnosis with a reversal of gray matter atrophy, no new lesions and no disease progression. He is still jogging, skiing, and composing music full time, traveling the world as a conductor/performer, at age 52. It is based on Nobel winning science into nitric oxide and the endothelium. These cells line all our blood and lymph vessels, and their health is essential. http://ccsvi.org/index.php/helping-myself/endothelial-health

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    7. Thanks for these responses. Again, to be clear, I'm not advocating the use of Tysabri, Alemtuzumab, or HSCT. They may be too dangerous, and there may exist safer alternatives, as you say. I'm also not asking about the optimal treatment regimen for MS. I'm asking about the scientific implications of CCSVI, since that's what this blog is all about.

      If the underlying disease process is unaffected by immunosuppressive treatments, and if this is the same disease process which causes secondary progression, then CCSVI will predict that people on these treatments will enter secondary progression at very low levels of disability, e.g. EDSS 1 or 2. That is, they won't see any more damage from inflammation -- which is being shut off by the treatments -- but they will acquire damage from the underlying progressive disease mechanism. This won't happen to everyone on these treatments, since as you say, some people stay RRMS for decades, but it should happen for the average patient.

      As I said above, this is a great prediction! It sharply distinguishes the autoimmune theory of MS from CCSVI. Is it true?

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    8. Dr. Zamboni is following his patients w/neurological evaluations and MRI and Dr. Dake is following his: including my husband who has had a reversal of gray matter atrophy on MRI, no more lesions, no more disability now 6 years past venoplasty treatment, 8 yrs. past MS diagnosis. He is at an EDSS of 1 at age 52. Yes, if venoplasty for CCSVI has corrected underlying insufficiencies in venous flow, than the primary disease of hypoperfusion and axonal loss should be halted. This research may one day distinguish the hypothesis of the autoimmune theory from that of CCSVI. The hope is that my husband and other treated patients will never have any more MS progression, God willing. Hard to call a reversal of gray matter atrophy "placebo." Only time will tell. But I'll keep blogging and following the research.

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    9. Thank you for your response. I'd like to delve deeper in Michal Schwartz's work, but my current understanding of it is fairly superficial -- I can understand the abstracts and what's going on at a high level, but without knowing about the methods in more detail, I don't trust my judgment of the work. Do you think that you could run some posts that really dig into the methods in her papers? I'd particularly like to understand the biochemistry better, since it's so important for interpreting her work.

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    10. You can read complete papers and delve further into methodology at the Weizmann Institute site---they offer key publications, in toto, online for free. http://www.weizmann.ac.il/neurobiology/labs/schwartz/publications

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    11. Thanks, that's what I've been trying to do actually. Let me give you an example of the sort of question I have. In one paper (https://www.weizmann.ac.il/molgen/members/Kimchi/PDFs/2002-2003/Schori,%20Schwartz%202002.pdf), they discuss results from a DAP-k knockout mouse, showing that it has greater resistance to glutamate toxicity than wild-type. But they don't discuss their targeting strategy for the knockout, and there don't even seem to be any western blots in the paper! My questions (as I would always have for this sort of work) are a) what was the efficiency of the knockout, b) whether there were any off-target effects of the gene targeting, and c) how this was evaluated. I'm sure that someone who's delved deeply into this could easily answer, which is why I'm asking you!

      There's nothing distinctive about this case, it just illustrates the sorts of questions that I, as an outsider, have when reading these papers.

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    12. ...just a simple "outsider" :-) Yup, I believe that! I'd suggest contacting Jony Kipnis directly. kipnis@virginia.edu He's very able to discuss the specifics of the work at the Weizmann Institute. All the best to you, "ccsvi-throwaway" I'm done playing stump the band.

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    13. Okay, thanks, I don't see anything about playing stump the band. I'm asking whether you can explain some of the details of these papers, since I think it would be helpful for your readers. I'm not asking for you to explain the particular paper that I cited -- just explaining the ones you're most interested in would be very valuable. You've been posting about Michal Schwartz's work, so it seems like something very relevant to the purpose of this blog. If Jony Kipnis ran a blog which discussed research in the field, I would ask him too. (I ask Scott Aaronson to explain things on his blog, and he's always been gracious, since running a blog is an invitation to ask questions.)

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  7. As far as "high efficacy" of these drugs---anything that calms CNS inflammation: be it steroids, UV rays, NrF2 activators, nutrition or ablating drugs (all have been shown to be effective in published research), will help alleviate MS symptoms, decrease disability and calm exacerbations. At the beginning of the process, MS is an inflammatory disease. Again, my concern is long-term disability and gray matter atrophy--until we understand why these drugs do not help people with progressive MS, we are no closer to decreasing long term disability. Read Dr. Peter Stys on this--- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673225/

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