Friday, 1 December 2017

Comments, Questions and Answers-December

If you have a question unrelated to the Posts this is the place for you. 

In the past we have done an advent calendar in December, to advertise the Research Day.

However, we do not know about the planning of this, 

So the mice are off on tour.

131 comments:

  1. Top 12 lessons learned (one for each month of 2017)

    ReplyDelete
    Replies
    1. Jan HSCT is the best thing since sliced bread
      Feb HSCT is the second best thing since sliced bread
      March is the third best thing since sliced bread
      April HSCT works by killing memory B cells...
      Is this what you want me to say :-)

      Maybe profG will do this as a new year round up...

      Best lessons learned depends on what you want to learn and each person will be different.

      Delete
    2. We want new year's resolutions now that Ocrevus and Cladribine are out! Hope it wont be only to try Ocrevus and Cladribine to SPMS :)

      Delete
    3. I meant more as 'the industry' or MS research zeitgeist.

      Delete
    4. I was hoping more the ms research domain, and treatment zeitgeist.

      Delete
    5. Researchers in the main, still have their head in the sand regarding B cells and MS but this is changing, slowly but surely.

      Delete
  2. Should a patient going on Ocrevus be tested to JCV prior to initiating? How common in PML with Ocrevus? Even though it will never be done, how do you think rituximab would fare in a head to head trial against Ocrevus?

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  3. Hemoglobin 10.2
    Platelet 38
    Abs Lymphocyte 0.1
    Absolute neutrophil 0
    Rbc 3.38

    I am day +5 Ahsct for ms ,and want to thanks All of Barts team

    being an excelent source of knowledge for every person living with ms

    Even when i dont agreed with some of the views i allways learn

    something

    Keep up the good work

    Obrigado
    Luis

    ReplyDelete
    Replies
    1. Well done Luis. Hopefully a bright future and free of DMDs. Hope recovery goes well.

      Delete
    2. Wow. "Absolute lymphocyte 0.1".

      Mine lymphocyte was 0 after day 5 of Alemtuzumab. And 0.2 at 1 month after.

      Or do the stem cells repopulate so quickly?

      Delete
    3. Hey Luis good luck with everything :)
      Always appreciate your comments even if you do leave me with yet more stuff to try to understand ;)
      Reckon we can get by without too many lymphocytes but hope those neutrophils recover quick... take care of yourself and let us all know how you're doing :)

      Ps are you in Sweden?

      Delete
    4. Abs Lymphocytes was 0 for 4 days they are coming ...A bit

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    5. Is there a rating list of HSCT clinics abroad? Does barts recommend any of these clinics based on safety and results?

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    6. We do not recommend places, as this is not our purpose.

      Please do not attempt to suggest any places as we will not post them.

      Delete
    7. Good luck Luis! Will you be following (posting?) your various B- & T-cell panel results? Should be interesting.

      Delete
    8. Just got tested for Cmv and Ebv

      Result: both negative :)

      So no "black swan" for me...loll :)

      Obrigado

      Luis

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    9. just as well otherwise you will end up with a lot of B cells

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    10. :)
      Thanks Md

      "B cells are not a single subpoulation"

      Gonna keep a close eye on those cd27+memory B cell coming back

      Obrigado
      Luis

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    11. ;-) Call it an experiment.

      Best wishes

      Delete
  4. My question to the neuros is, have you come across vit D tablets causing bladder stones? Pain when urinating, increased urgency and small blobs of blood in urine. thanks

    ReplyDelete
    Replies
    1. I found the following out:
      Getting too much vitamin D can cause kidney stones. The stones aren't made of vitamin D itself, though. Excess vitamin D can make you absorb too much calcium -- and if you have too much calcium in the urine, it can crystallize into stones.

      A kidney stone can cause symptoms when the small mass travels from the kidney through a narrow tube called the ureter toward the bladder. The stone can block or irritate the tube, causing intense pain.

      I know it is not usually advised to take both vit D and calcium supplements, unless advised by a doctor.

      Delete
    2. This site wont answer .

      Delete
    3. Wrong, yes we have come across this...

      ProfG knows about kidney stones

      Delete
    4. It's not the vitamin d that gives you kidney stones, it's the large amount of calcium they tell you to eat as well. People tend to be prescribed vitamin d for bone problems so they prescribe high calcium levels as well. Up to 4000iu a day of vitamin d has no effect on calcium the urine, assuming you are not eating calcium supplements. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241241/

      Delete
    5. I was on 2,500IU vit D daily, no calcium supplements and got kidney stones. I stopped the 2,500 IU vitamin D daily and the kidney stones stopped. Now I just take only 400IU vit D daily. My vitamin D levels were always Very good and that's why I only took 2,500IU.
      I think some people are more vulnerable to kidney stones.

      Delete
  5. This is the worst site have ever found in uk for ms .

    ReplyDelete
    Replies
    1. Anon, 9.27.
      Ok, it is the worst site for you and your needs but it does not make it the worst site. It happens to be the best site for me but that doesn't make it the best site.

      Delete
  6. Given HSCT and Alemtuzumab work in similar ways. Why not combine the two Treatments? After course of alemtuzumab. Give low dose radiation to kill the remaining b cells in marrow? That will derisk both treatments and reduce chance of 2nd autoimmunity. In addition the combined treatment will cheaper as no 2nd course of alemtzumab will be required or long stay in hospital with HSCT!

    ReplyDelete
    Replies
    1. There are plenty of examples where alemtuzumab was used in the HSCT procedure. But what does alemtuzumab do that HSCT does not?

      Interesting idea about bone marrow purging approach. I haven't heard of irradiation for some time.

      Delete
  7. Combined therapy of Alemtuzumab + Low dose of HSCT, plus spinal tap to inject antibody into CNS to kill long lived plasma cells = CURE. All this fuss over MS! MD1...MDN start clearing your desks. Problem solved!

    ReplyDelete
    Replies
    1. Distribution of antibodies into brain isn't easy. Lumbar puncture dose doesn't really flow up into brain, just kind of stays pooled. I suppose we could install a tap into the top of the skull........

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    2. Some of the long live B cells may reside in the bone marrow, Some people use cyclophosphamide to get at cells in the brain, can CLAD do this?

      Delete
    3. Thanks me, md. "Tap into the top of the skull". Hey If we're imaging why not create little nanobots that propel themselves to the brain?

      "Some of the long live b cells may reside in the bone marrow". Isn't that the reason why hstc works better than lemtrada? Chemo kills those cells?

      Delete
    4. As we're thinking outside the box. Why not re-engineer hiv virus to target immune cells and add a off switch using CRISP tech to add a flaw to the DNA of virus? hiv Is a efficient purger of the immune system.

      Delete
    5. Your idea reminded me this:

      Scientists Have Engineered Viruses To Deliver Genes Into The Brain

      “We have now developed a new collection of viruses and tools to study the central and peripheral nervous systems,” says Gradinaru. “We are now able to get highly efficient brain-wide delivery with just a low-dose systemic injection, access neurons in difficult-to-reach regions, and precisely label cells with multiple fluorescent colors to study their shapes and connections.”

      Gradinaru and her team modified the external surface of an AAV developed in 2016, engineering the virus’s shell, or capsid, to allow it to more efficiently deliver genes to cells in the brain and spinal cord following intravenous injection. They named the new virus AAV-PHP.eB.

      https://dailyaccord.com/scientists-have-engineered-viruses-to-deliver-genes-into-the-brain/

      Delete
    6. Would you be willing to get a virus that you couldn't get rid of if it went wrong?

      Delete
    7. One word / name: Pender.
      No need for a mutant virus.

      Delete
  8. https://www.researchgate.net/profile/Jamie_Cherup/publication/292707528_Insufficient_disease_inhibition_by_intrathecal_rituximab_in_progressive_multiple_sclerosis/links/56d993c708aee1aa5f82895d/Insufficient-disease-inhibition-by-intrathecal-rituximab-in-progressive-multiple-sclerosis.pdf
    Intrathecal ab anti cd 20 failed in progressive ms.

    ReplyDelete
    Replies
    1. Not really surprising as CD20 is not thought to be expressed on plasma cells and if they are one of the culprits in progession then rituximab which targets CD2o won't be effective. CD20 is on B memory cells which is why we think it is effective on RRMS.
      https://en.wikipedia.org/wiki/CD20.

      Delete
    2. In fact putting any immunoglobulin directly into the brain may not be a good idea if you already have a population of activated microglia which may be further stimulated to release toxic factors via their Fc receptors.

      Delete
    3. Trial didn't fail in preventing progression, but was stopped early b/c depletion of CD-20 cells in csf was only 10%, not the 50% they were hoping for.

      Delete
    4. intrathecal is at the bottom of the CSF drainpipe it was washed out into the blood and depleted the B cells there. However as MD2 says why use an anti-CD20 to try and target plasma cells, which does no express CD20.

      I bet someone will try intra-ventricular but again it is false logic.

      There was more than one trial ProfG was involved in one set Tpooing et al. 2016.

      Delete
  9. Laquinimod Fails to Slow Brain Atrophy and PPMS Progression

    Sweden’s Active Biotech said its experimental therapy Laquinimod failed to meet the primary and secondary objectives of Phase 2 clinical trial evaluating the drug’s potential to treat primary progressive multiple sclerosis (PPMS).

    http://www.activebiotech.com/press-releases?pressid=2153402

    ReplyDelete
  10. Insight into the neuroprotective effect of therapeutic hypothermia

    Brains of mice subjected to hypothermia showed an increase in RBM3 and consequently RTN3 while a global decrease of protein synthesis (40%) was observed.

    Moreover, therapeutic hypothermia improved neuronal survival and increased the lifespan of a mouse with prion disease by increasing RBM3 and RTN3.

    Even in the absence of cooling, overexpression of RTN3 in the brain of the prion mice provided neuroprotective effects. Altogether this work provides insight into the cellular mechanisms involved in the neuroprotective effect of therapeutic hypothermia but more importantly it provides a new pathway to explore in the search for therapies against neurodegeneration.

    https://www.technologynetworks.com/neuroscience/articles/how-keeping-it-cool-can-protect-your-brain-insight-into-the-neuroprotective-effect-of-therapeutic-285836

    ReplyDelete
  11. Study shows vagus nerve stimulation significantly reduces rheumatoid arthritis symptoms

    Clinical Immunology & Rheumatology of the Academic Medical Center/University of Amsterdam. "We have previously shown that targeting the inflammatory reflex may reduce inflammation in animal models and in vitro models of RA. The direct correlation between vagus nerve stimulation and the suppression of several key cytokines like TNF as well as reduced RA signs and symptoms demonstrates proof of mechanism, which might be relevant for other immune-mediated inflammatory diseases as well."

    "Our findings suggest a new approach to fighting diseases with bioelectronic medicines, which use electrical pulses to treat diseases currently treated with potent and relatively expensive drugs," said Anthony Arnold, Chief Executive Officer of SetPoint Medical. "These results support our ongoing development of bioelectronic medicines designed to improve the lives of people suffering from chronic inflammatory diseases and give healthcare providers new and potentially safer treatment alternatives at a much lower total cost for the healthcare system."

    https://www.technologynetworks.com/neuroscience/news/study-shows-vagus-nerve-stimulation-significantly-reduces-rheumatoid-arthritis-284383

    ReplyDelete
    Replies
    1. It will be tried in MS but once you say it blocks TNF, surely alarm bells will ring as this has been bad news for ms.

      Delete
    2. Well, the BCG vaccine too is supposed to block TNF but works great on MS. Could be that you can have different results when you initiate the body to react to an intervention than to guide it to specific targets with drugs. Just saying.

      Delete
    3. An accompanying editorial by neurologists Dennis Bourdette, M.D., of the Oregon Health & Science University and Multiple Sclerosis Centers of Excellence-West, Veterans Affairs Medical Center in Portland, and Robert T. Naismith, M.D., of the Department of Neurology at Washington University in St. Louis, Missouri, expressed reservations about BCG. “Despite the apparent long-term effects suggested by the present study, it seems unlikely that a single injection of BCG would be highly effective in a disease that lasts decades,” they wrote. “The safety of repeated administration of BCG is unclear, and in the case of repeated bladder injections for cancer treatment, serious side effects can include a systemic BCG immune reaction and localized or systemic BCG infection.”

      Delete
    4. Many new information has emerged since 2013 on the subject. There is a trial phIII going to start in Italy for BCG and MS (RIS cases). It true, the trial for diabetes I requests repeated vaccinations (2 to begin with). Its the same strain that is used for bladder cancer, -not all BCG vaccines seem to work- and this treatment is still the best there is for bladder cancer (Sanofi discontinued the vaccine and brought chaos to cancer patients). This trial already has positive results. It is supposed to have passed safety tests. I don't know how it will be used for MS now.
      In the first trial, 30% of CIS never developed MS. This is huge. If the new trial comes positive, it could totally change the way possible MS patients are treated.
      Also, these are not pharma funded trials, but the fact that some researchers insist (4 autoimmune areas at the moment, more to come) shows promise.
      A reminder: All efficient MS drugs are dangerous.

      Delete
    5. Until we get more data I think we can reserve judgement. We've been here before.

      Delete
    6. True. What is interesting about this though, is that is a different approach to autoimmunity. Because it seems that no matter how much you deplete, there is always going to be more. Depletion can't be the answer.

      Delete
  12. Missing profG's ***Speak posts. Are they permanently gone?

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  13. Health Canada has approved Mavenclad as a therapy to reduce the frequency of MS exacerbations and delay disease progression.
    The treatment is generally recommended for patients who failed to respond adequately, or are unable to tolerate, one or more MS therapies.
    *not highly active MS

    ReplyDelete
    Replies
    1. Thanks for the info

      Maybe there should be a re-evaluation of what should be first or second or third line.

      Is it based on safety ...now the answer is no. It was based on costs but now if makes no sense. If the new s1p1 got a first line licence and fingolimod has a second line licence it will be a nonsense.

      Delete
    2. That thing with Mavenclad and highly active was a HUGE bummer. It's like, thanks for nothing. Hope they will reconsider...

      Delete
    3. Australia approved Mavenclad
      "Mavenclad will be a welcomed treatment option for patients with the relapsing-remitting form of MS. As an oral therapy taken in two short courses over a 2-year period, Mavenclad will be convenient for all eligible patients in Australia, including those who may not live close to their treating healthcare professional."

      Delete
    4. Yet another win for the white knights ;-)

      Delete
  14. I found that lipoic acid causes hair thinning on my scalp.
    Also I found that this could be the symptom of biotin deficiency.
    Then I found that biotin shares the same transport system that lipoic acid utilizes.
    We know that biotin can probably be beneficial in MS.
    We also know that lipoic acid can probably be beneficial in MS.
    Coincidence? What do you think, Prof Mouse?
    Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells
    https://www.ncbi.nlm.nih.gov/pubmed/25809983

    Interaction of α-Lipoic Acid with the Human Na+/Multivitamin Transporter (hSMVT)*
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481234/

    ReplyDelete
    Replies
    1. this also
      Lipoic Acid Reduces the Activities of Biotin-Dependent Carboxylases in Rat Liver1,2
      http://jn.nutrition.org/content/127/9/1776.full

      Delete
    2. Sorry, this is all a bit heavy going for a layperson like me - are these saying that ALA may be a good substitute for biotin, that you shouldn't take ALA AND biotin (or just not simultaneously), or that you CAN (and maybe should) take ALA and biotin, simultaneously or otherwise?

      Delete
    3. I'm not a biologist neither a medical professional, but as far as I can understand from those papers ALA outcompetes biotin in the body, so when you take both ALA and biotin, only ALA will be "absorbed", and biotin will be wasted. So you can only take one or the other at a time.
      But it is not a substitute.
      The funny thing is is that they both shown some good effects in MS.
      Hope Mouse Doc can comment on this.

      Delete
    4. Great, thanks for clarifying. I don't take both, but do take ALA (as biotin and I didn't get on last time I tried it, so tried ALA instead).

      I'd be really interested in your thoughts too, Mouse Doc

      Delete
    5. There are supplements that combine ALA and Biotin because there is a hypothesis (I dont think it is confirmed though) that ALA can decrease Biotin. The biotin dosage for MS is tremendously higher than a regular intake, so I don't think there is a reason to worry about Biotin levels.

      Delete
    6. I'm taking high dose ALA rather than high dose biotin.

      Delete
    7. Do you have any issues with hair eg thinning?

      I'm thinking about cycling ALA/biotin but not sure if short cycles will make any sense.

      Delete
    8. Are you taking just ALA for MS? Because most MS drugs are causing hair thinning...

      Delete
    9. I had alemz some years ago, and, yes, noticed hair loss after. But ALA makes this even worse in my experience. I don’t take any other MS drugs.

      Delete
    10. I don't have any problems with hair thinning, and I was also contemplating cycling ALA and biotin. But getting on so well with ALA rather than biotin, I'm wondering whether to stay with ALA....

      Delete
    11. High doses of Biotin might not be a good idea for RRMS, as it can increase relapses. A small dose to maintain hair health I guess would be fine though.

      Delete
    12. That's really interesting. So something that exacerbates RRMS helps with SP/PPMS.....

      (I have PPMS, btw, no relapses for me)

      Delete
  15. The following article claims taurine can help with remylination. My question is can taurine cause any contradiction with licenced ms medicines. Also can taurine worsen ms? If not it's safe punt to try. I remember i use to take taurine As supplement when strength training and was not aware had ms. As soon as i stopped training and same time stopped drinking my ms started to rear it's ugly head.

    https://www.sciencedaily.com/releases/2017/12/171208143024.htm

    ReplyDelete
    Replies
    1. I dont know much about taurine...watch those Red Bulls and Monster.

      Many years ago we showed that there were increases in taurine in the spinal cord during mouse EAE

      Preece NE, Amor S, Baker D, Gadian DG, O'Neill JK, Urenjak J.
      Magn Reson Med. 1994;32:692-7.

      However the Taurine influence was not seen in Guinea pig EAE, so makes one think that Taurine may exhibit effects that are species specific EAE.

      Delete
    2. The new analysis and follow-up tests in cells showed that while the endogenous metabolite taurine cannot induce oligodendrocyte precursor cell maturation on its own, it can lend a helping hand when combined with the drugs benztropine or miconazole. The researchers described taurine as a "feedstock."

      "Combining taurine with drugs that induce differentiation significantly enhances the process," says Lairson. "You get more myelin."
      https://medicalxpress.com/news/2017-12-taurine-cells-multiple-sclerosis.html

      Delete
  16. Huntington's big breakthrough. Any beating on MS? Given there's no flow in CNS how can this drug work? Why not for MS by injecting antibodies to kill plasma cells?

    ReplyDelete
  17. http://www.bbc.co.uk/news/health-42308341

    The news regarding Huntington's - might this have a bearing on progressive MS?

    ReplyDelete
    Replies
    1. This was a gene silencing project and may have utility, but as there is no single gene effect in MS and so it is not going to be earth shattering influence

      However this story of the Allen Family brought back memories. Sandy (SJ Allen) worked with us on MS in the mid nineties before we started her family.

      The last time I saw Sandy was when I bumped into her and her hubby at Queen Square. This was the day she got a diagnosis, with not only the realization that she had the gene, but so did her mum and grandmum and possibly half her kids.

      Whilst this is amazing science, given that this is a single gene heterozygous problem, it strikes me that with genetic testing and IVF we could get rid of Huntingtons within a generation and not rely on a technology which I doubt is yet the answer, because as we have said many times an intrathecal injection is putting stuff at the bottom of the drainpipe so the uptake in the brain is not going to be optimal

      Allen SJ, Baker D, O'Neill JK, Davison AN, Turk JL. Isolation and characterization of cells infiltrating the spinal cord during the course of chronic relapsing experimental allergic encephalomyelitis in the Biozzi AB/H mouse. Allen SJ, Baker D, O'Neill JK, Davison AN, Turk JL. Cell Immunol. 1993;146(2):335-50.

      Delete
    2. But it seems to work, so their is a mechanism for delivery. I guess being able to deal with something more straightforward like Huntington does give hope that down the road this might be relevant for MS.

      Delete
    3. Maybe but they did say it was not a cure.

      Delete
    4. we started her family...I meant she not we. Ooops

      Delete
  18. In the new study, Professor Kingston Mills and Dr Caroline Sutton of Trinity College Dublin, and Dr Annie Curtis of RCSI (Royal College of Surgeons Ireland), and colleagues show that immune responses and regulation of autoimmunity are affected by the time of the day when the immune response is activated.

    Using mice as a model organism, they show that a master circadian gene, BMAL1, is responsible for sensing and acting on time-of-the-day cues to suppress inflammation. Loss of BMAL1, or induction of autoimmunity at midday instead of midnight, causes more severe experimental autoimmune encephalomyelitis, which is essentially an analogue of multiple sclerosis in mice.

    Professor of Experimental Immunology at Trinity, Kingston Mills, said: "In the year that the Nobel Prize in Medicine was awarded for discoveries on the molecular mechanisms controlling the circadian rhythm, our exciting findings suggest that our immune system is programmed to respond better to infection and insults encountered at different times in the 24-hour clock. This has significant implications for the treatment of immune-mediated diseases and suggests there may be important differences in time of day response to drugs used to treat autoimmune diseases such as multiple sclerosis."

    https://medicalxpress.com/news/2017-12-day-affects-severity-autoimmune-disease.html

    ReplyDelete
    Replies
    1. "autoimmune diseases such as multiple sclerosis."

      Hummm ....i know bart blog dont like this expression...:)

      Obrigado

      Delete
    2. You're right Luis, we prefer something a little more nuanced round these parts ;-)

      Delete
    3. It's Christmas so I,LL pass on this for the moment, too much to do.

      Delete
  19. Professor Robin Franklin has won the 2017 Barancik Prize for Innovation for his research into multiple sclerosis, which could offer a means of halting the progression of the disease.

    Franklin, a Professor of Stem Cell Medicine at the Wellcome Trust-MRC Cambridge Stem Cell Institute, was recognised for his research into how the coating of nerve fibres, called the myelin sheath, regenerates. It is hoped that his research could lead to the development of techniques to protect and even repair the nervous system of people suffering nerve damage as a result of multiple sclerosis, halting the progression of the disease.

    ReplyDelete
    Replies
    1. Well done Dr Franklinstein ;-)

      Be nice if there was a Dr.F link right about here:
      X
      https://multiplesclerosisnewstoday.com/2017/12/15/cambridge-scientist-wins-2017-barancik-prize-for-multiple-sclerosis-research-myelin-repair/

      "While myelin repair therapies are not yet a reality, several strategies to enhance re-myelination are currently under investigation, including small molecules, small interfering ribonucleic acids (RNAs), and monoclonal antibodies targeting specific components of the signaling pathways that underlie the myelination process.

      Specifically, Franklin works with oligodendrocytes, which are the myelin-producing cells in the brain that are damaged in MS. With his team at Cambridge, he identified a key factor that stimulates myelin repair, called “retinoid X receptors.” These finding were used to study Targretin (bexarotene), a drug that targets the retinoid X receptor gamma molecule.

      In mice studies, the team also uncovered clues to overcoming restrictions to myelin repair that come with aging.'

      Delete
    2. I saw ProfF in ECTRIMS and there is an exciting twist to the RXR story watch this space....

      Delete
    3. Why do you call him Franklinstein?

      Delete
    4. Anon 2:25

      Think it's an affectionate play on words, or rather names.

      Mary Shelley's Frankenstein was the famous fictional scientist who reanimated corpses using electricity. Franklin seems to be looking at a form of reanimation through regenerating non-functional nerves. Though thankfully not by plugging patients into the mains.

      Delete
    5. Actually, it's to do with parabiosis (stitching old and young mice together so they have a shared blood supply. A bit too grisly for my taste.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714794/

      Delete
  20. Α method for quickly detecting signs of multiple sclerosis has been developed by a University of Huddersfield research team.

    The discovery, using advanced mass spectrometry techniques, offers a diagnostic tool that enables the detection of multiple sclerosis (MS) to be made simply using blood samples. The current procedure for detection requires the invasive, often painful, process of collecting fluid from the brain and spine.

    The research has identified two natural biomarker compounds, which have been linked to multiple sclerosis.

    The compounds, sphingosine and dihydrosphingosine, were found to be at significantly lower concentrations in blood samples from multiple sclerosis patients.

    As well as offering a diagnostic tool to identify MS, the discovery will aid the investigation of the role of the compounds in the disease and assist potential new drug development, according to a new research article co-authored by Sean Ward, who is an analytical chemist and PhD student based at the University of Huddersfield’s IPOS unit.

    https://www.technologynetworks.com/neuroscience/news/blood-sample-detection-method-for-multiple-sclerosis-discovered-295148

    ReplyDelete
  21. Mavenclad/ cladribine is ABN category 1.2 on the MS Trust Decisions aid website. I am a little disappointed by this as it's the same category (More effective) like Tecfidera and Gilenya.

    ReplyDelete
    Replies
    1. I believe a lack of insight from the EMA but I believe this is the label they were asked to go for to get chance of going to market. It is probably safer than Alemtuzumab which has the most liberal licence. Therefore there is absolutely no logic to the staging of the different drugs based on their licencing.

      Delete
  22. What happens if a person with MS develops a secondary autoimmune disease after the first year of alemtuzumab (say it's Graves' disease). New round of alemtuzumab in the second year? Ocrevus? Mavenclad? Let's assume MS is in remission after the first alemtuzumab.

    ReplyDelete
    Replies
    1. I believe people typically get the next dose. Autoimmunity occurs in about 5percent after cycle 1. Maybe neuro will comment but they simply try treat the secondary autoimmunity.

      Delete
  23. Dear MouseDoctor, is there any rational explanation for giving another round of alemtuzumab in the second year ( other than : "it is the way it was done in the original studies"). I mean, look at the clinical practice with, for example, rituximab... half the dose seems to work just as well for RA.(even though original studies were not done that way)

    ReplyDelete
    Replies
    1. For alemtuzumab we know that about 50% of people receiving two cycles have disease break through. Therefore about 50% of people will need a third course. The third course gives about 85% NEDA so a real logic to be able to get at least three courses and stupid not to be offered that. This data is published by Cambridge group Tuohy et al and also supported by MS CARE extension.

      Next question Rituximab and dosing. Thes issue is that people have targeted to keep CD19 B cells at zero. But if we are righht and it is the CD19,CD27+ subset that is important then in some conditions and MS and RA are two of them where we can be over dosing.

      However many doctors will treat as per label and so unless a trial is done to show a lower dose is as effective then they wont change.
      Regulators like to see a dose-response in trials and pharma do this so you get idea of minimal ewffective dose. When academics do trials they pick one dose as they can't afford to do multiple doses.

      A good example is statin trial. They have picked high dose (80mg), which we know causes side effects in some people. What is the evidence that a standard 20mg dose with reduced side effects would not work similarly. Pharma would not get away with this one dose approach, why should academics?

      Delete
  24. Despite being approved for use as MS medications by Australian Therapeutic Goods Administration, there is bad news for some Aussie PwMS who were hoping to try Ocrelizumab or Cladribine at a subsidised cost:
    https://msra.org.au/news/two-ms-medications-knocked-back-pbac/

    Re Ocrelizumab - the Australian Pharmaceutical Benefits Scheme has not approved any subsidy for patients with PPMS - see page 11
    http://www.pbs.gov.au/industry/listing/elements/pbac-meetings/pbac-outcomes/2017-11/first-time-decisions-not-to-recommend-11-2017.pdf

    Cladribine has not been approved for subsidy either - see page 1
    http://www.pbs.gov.au/industry/listing/elements/pbac-meetings/pbac-outcomes/2017-11/subsequent-decisions-not-to-recommend-11-2017.pdf

    So - for any RRMS Aussies who were hanging out for Cladribine to be subsidised, their ship is sunk for the time being and they will have to reconsider the other options. For those of us Aussies with PPMS it means there are still no conventional medication options unless we happen to be made of money................

    ReplyDelete
    Replies
    1. Here at the London, it's given subcutaneously.
      http://onlinelibrary.wiley.com/doi/10.1002/acn3.410/abstract

      Delete
  25. Is there any cause for concern for a pwms who is in close contact with a person who has glandular fever?

    ReplyDelete
    Replies
    1. Not really, if you're an adult, you've probably already been infected with the EBV virus already and the number of pwMS who are EBV negative is vanishingly small.

      Delete
  26. "Today the National Institute for Health and Care Excellence (NICE) recommended five Disease Modifying Therapies (DMTs) for MS should no longer be available for new patients in England and Wales.

    The draft decision would mean Extavia (interferon beta-1b) will continue to be available on the NHS for new patients.

    All other beta interferons, and glatiramer acetate, will only be provided for people who are already taking them.

    NICE are proposing to make the following treatments unavailable to people who are newly diagnosed or want to change treatment:

    Avonex (interferon beta-1a)
    Betaferon (interferon beta-1b)
    Copaxone (glatiramer acetate)
    Plegridy (peginterferon beta-1a)
    Rebif (interferon beta-1a)

    They’ve made this recommendation because they believe all these treatments have a similar clinical effect, but only Extavia is cost-effective."

    Wish RTX would replace them but...

    ReplyDelete
  27. It doesn't mention MS but it fits the description

    Scientists Develop Biodegradable Nanoparticles That Could Treat Spinal Cord Injury

    A biodegradable nanoparticle injected after a spinal cord trauma prevented the inflammation and internal scarring that inhibits the repair process, reports a new Northwestern Medicine study, which was published in Neurobiology of Disease.

    The nanoparticles work by binding to the cells that cause the inflammation — inflammatory monocytes — and diverting them to the spleen. The particles are made of poly(lactic-co-glycolic) acid, a biocompatible substance already approved by the Food and Drug Administration (FDA) for use in re-absorbable sutures.

    Developed in the lab of Northwestern scientist Stephen Miller, the particles also are FDA approved as an investigational drug for a new clinical trial in celiac disease.

    https://dailyaccord.com/scientists-develop-biodegradable-nanoparticles-that-can-treat-spinal-cord-injury/

    ReplyDelete
    Replies
    1. Ah Steve Miller.........................the butterfly of neuroimmunology.

      Delete
  28. Interesting

    The Un. of Zurich discovered that when mice’s myelin coating became damaged, the animals’ cells digested it for recycling. An autophagy protein called ATG5 then showed parts of the myelin to T-cells. This action instructed the cells to start an immune attack against the myelin.

    The bottom line is that autophagy promotes the progression of MS, Christian Keller, lead author of the study, said in a press release.

    When the team blocked the ATG5 protein, mice did not develop an MS-like condition. And when researchers injected the animals with myelin-attacking T-cells, their disease was milder than normal, demonstrating that ATG5 plays a key role in driving MS.

    “This reactivation process is thought to play a decisive role in the development of autoimmune neuroinflammation,” Keller said.

    http://www.pnas.org/content/early/2017/12/11/1713664114.abstract

    ReplyDelete
    Replies
    1. And what we now know is that mouse EAE as it is usually performed immunologically bears little resemblance to MS. T cell disease in mice, B cell disease in humans.

      Delete
  29. Using Gene Therapy to Treat Type 1 Diabetes

    There are several kinds of T cells, and while regulatory T cells play a role in immune regulation, effector T cells are defensive responders to stimuli. In previous work by this group, gene editing successfully created T cells that could regulate other, dangerous effector T cells; those cells worked both in cells in culture and animal models. For this work, they are seeking to identify the deleterious effector T cells, and turn them into regulatory T cells.

    "These engineered regulatory T cells, when returned to a diabetic's body, would have the potential to stop effector T cells from destroying the insulin-producing cells," explained Rawlings. "We believe these cells could be used to treat type 1 diabetes as it begins, possibly leading to a long-term cure."

    https://www.labroots.com/trending/genetics-and-genomics/7587/using-gene-therapy-treat-type-1-diabetes?utm_content=buffer4c9f2&utm_medium=social&utm_source=facebook.com&utm_campaign=buffer

    ReplyDelete
    Replies
    1. For the study, researchers removed the participants' own T cells and stimulated them to boost their ability to recognize and destroy cells infected with Epstein-Barr virus. They then injected participants with infusions of escalating doses of T cells every two weeks for six weeks. They followed the patients through 26 weeks to look for evidence of side effects and possible improvement of symptoms.

      Three of the 6 participants showed improvement, starting two to eight weeks after the first infusion.

      "One person with secondary progressive MS showed striking improvement," Pender said. "This participant had a significant increase in ambulation from 100 yards with a walker at the start of the study, and over the previous five years, to three quarters of a mile, and was now also able to walk shorter distances with only one sided assistance. Lower leg spasms that had persisted for 20 years resolved."

      Pender said another participant with primary progressive MS showed improved color vision and visual acuity.

      All three responding participants had improvements in fatigue and ability to perform daily activities.

      "The best responses were seen in the two people who received T cells with the highest amount of reactivity to the Epstein-Barr virus," Pender said.

      https://medicalxpress.com/news/2017-04-preliminary-treatment-ms.html

      Delete
  30. Yep, I'm with this paper on clomipramine
    Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic
    https://www.nature.com/articles/s41467-017-02119-6

    They say its a wonder drug, can target MS in three ways, even affecting b-cells follicles, but animals don’t think they feel better on the drug…
    I wonder why did they seek for neuroprotection against FeSO4?

    ReplyDelete
    Replies
    1. "In a subsequent test, they treated mice with a disease that resembles progressive MS in humans. Here, too, the therapy proved effective, provided the researchers applied it immediately after the first clinical symptoms became apparent. Symptoms such as paralysis were thus reduced – unlike in control animals that were treated with placebo drugs."
      https://www.sciencedaily.com/releases/2017/12/171220121839.htm

      I thought too iron-mediated neurotoxicity was old :/

      Delete
  31. Wishing everyone at Barts Blog

    Merry Christmas and happy new year :)

    Obrigado

    Bom Natal

    ReplyDelete
  32. Sorry for the lame link but its interesting:

    (For EBV related cancers)
    Normally, EBV stays inside B cells, where it expresses proteins that can cause cells to replicate and expand, and the immune system keeps that replication in check. But under certain circumstances, such as when the immune system is compromised for one reason or another, the pathway to halting rampant proliferation is lost, which means the cells will keep growing and dividing, and the EBV will get transferred from B cell to B cell and the proliferative state can lead to cancer. "The more a cell proliferates the greater the chance of a mutation occurring and the more mutations that occur, the greater the chance of it turning into cancer," explains Ezra Cohen, a professor of medicine at the Moores Cancer Center, UC San Diego.

    In a 2013 study in Greece, researchers examined the effects of rituximab-based immunochemotherapy on 44 patients with low-grade B-cell lymphoma and found that after three monthly cycles of the drug, only one out of 17 patients who were EBV-positive before the study still tested positive for EBV after the treatment.

    ----What is happening to MS patients under RTX??----

    The hope is that some day EBV-related cancers could be prevented with a vaccine that prevents infection with the virus, much like the HPV vaccine has been found to help prevent cancers such as cervical cancer.

    The holy grail would be to develop a therapeutic vaccine that would stimulate the immune system in someone who already has an EBV-induced cancer to recognize these latent EBV-expressed proteins and kill them to fight the cancer, Moore adds. The problem is, right now, funding for research on virus-induced cancers including Epstein-Barr is fairly scarce, Moore says. "This is an underappreciated but easily treatable problem in the scientific world. Until people recognize this connection, not a lot of progress can be made."

    https://tonic.vice.com/en_us/article/mvbnxp/nearly-all-of-us-have-a-virus-that-causes-cancer

    ReplyDelete
  33. Researchers find potential path to repair multiple sclerosis-damaged nerves

    Gene expression in specific cells and in specific regions can provide a more precise, neuroprotective approach than traditional treatments for neurological diseases. For multiple sclerosis, specifically, increasing cholesterol synthesis gene expression in astrocytes of the spinal cord can be a pathway to repair nerves that affect walking.

    In the spinal cord - an area that's critical for walking—they found a decrease in the expression of cholesterol synthesis genes. Cholesterol does not leave the blood and enter the brain, instead it is made in astrocytes and plays a role in making myelin, the nerve coating, and synapses, the nerve connections. They hypothesized that while inflammation causes loss of myelin and synapses, it is the decrease in cholesterol synthesis gene expression in astrocytes that explains why lesions do not repair in MS. They treated MS mice with a drug that increased expression in cholesterol synthesis genes - and this resulted in improved walking ability.

    http://www.pnas.org/content/early/2017/12/20/1716032115

    ReplyDelete
  34. However,
    Lifetime Cancer Risk Lower in MS Patients Than General Public, Study Reports

    The immune system is known to play a large role in both MS and cancer, leading some scientists to suggest that a disease like MS would modify the risk of cancer.

    This lower risk, the team wrote, might be due to the physiological nature of MS itself. The disease is a product of autoimmunity — referring to the hyper-sensitivity of the immune system to self-antigens — and this could lead to increased immune vigilance against cancer cells.

    It might also be linked to the very use of DMTs. In fact, the researchers noted that several DMTs are currently being investigated for potential anti-tumor activity, including dimethyl fumarate (an approved MS treatment, under the brand name Tecfidera) in colon cancers, fingolimod (brand name, Gilenya) in various cancers, and teriflunomide (brand name, Aubagio) in triple-negative breast cancers.

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188120

    ReplyDelete
  35. Is there a way to predict a relapse through B cell blood levels? (I am not referring to monitor the response to anti cd20 therapies)

    ReplyDelete
  36. Old Russian anti-depressant repurposing for MS neuroprotection

    Based on in silico and animal model experiments, we sought to test our hypothesis that Pirlindole would reduce neuronal dysfunction in MS. In in vivo experiments using the MOG (Myelin Oligodendrocyte Glycoprotein)-induced Experimental Autoimmune Encephalomyelitis (EAE) murine model of progressive MS, pirlindole (BVA-201), at 30mg/kg (a pharmaceutically relevant dose) induced a sizeable improvement in disease progression, as represented by EAE severity clinical scores (Figure 1). Moreover, histological data showed that the drug’s MoA is not anti-inflammatory, but rather, pirlindole protects neuronal cells and myelin in a direct manner (Figure 2). The above data is supported by previous observations that Pirlindole acts not only as a MAO-A inhibitor, but is also involved in the reduction of oxidative stress and inhibition of lipid peroxidation.

    https://figshare.com/articles/Drug_repurposing_of_Pirlindole_for_Multiple_Sclerosis/4658932

    ReplyDelete
  37. The following article on the BBC today is a reminder that MS can advance fairly rapidly and severely in women.
    http://www.bbc.co.uk/news/uk-england-nottinghamshire-42043882
    Young MS sufferer was in home for elderly people

    ReplyDelete
    Replies
    1. Hopefully there wont be such hopeless cases of MS any more with HSCT around -if only doctors act more responsibly and send their patiens for treatment.

      Delete
  38. Zinbryta (daclizumab) may not be the best follow-up therapy for relapsing–remitting multiple sclerosis patients who stop taking Tysabri (natalizumab) for safety reasons, a case study suggests.

    Two months into Zimbryta, he had a debilitating relapse that included walking and eye problems.

    The patient had shown no signs that his disease was progressing under Tysabri, but after he started Zinbryta, an MRI scan spotted several new lesions in his brain.

    https://link.springer.com/article/10.1007%2Fs00415-017-8622-9

    ReplyDelete
  39. Mapranosis: New term for role of microbiota in neurodegeneration proposed

    Research in the past two decades has revealed that microbial organisms in the gut influence health and disease in many ways, particularly related to immune function, metabolism and resistance to infection. Recent studies have shown that gut microbes also may cause or worsen Parkinson's disease, Alzheimer's disease and other neurodegenerative conditions.


    The microbiota modulates (enhances) immune processes throughout the body, including the central nervous system.
    The microbiota may induce oxidative toxicity (free radicals) and related inflammation that contributes to neurodegeneration.
    Metabolites produced by the microbiota may be either beneficial (health sustaining) or damaging (pathogenic).
    Host genetics influence microbiota populations, illustrating that the gut-brain axis is bidirectional.

    https://www.sciencedaily.com/releases/2017/12/171222090323.htm

    (Its funny that there are more researches on the role of gut in other neurodegenerative disorders (Alz-Park.) than MS that is a totally immune-related disease.

    ReplyDelete

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