1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
Part 2: Brain Cells Making us Sick? Messed up microglia could be driving symptoms
Simon McGrath looks at theories that microglia, the brain's immune cells, might be overactive and driving the symptoms of ME/CFS and fibromyalgia.
Discuss the article on the Forums.

Could it be folate?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by PhoenX, Nov 7, 2011.

  1. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    752
    Hi, GlobalPilot.

    I think you are on the right track here. Cells normally die by apoptosis, which is an orderly process in which the contents of the cells are contained in membrane-bound bodies and are engulfed and digested by phagocytes such as macrophages. However, under disease conditions, cells also die by necrosis, in which the cell membrane is ruptured and the contents are released. I think that this latter process is more likely to lead to development of autoantibodies, because substances that are normally not exposed to the immune cells would be exposed in this case.

    I don't know of studies of necrosis in ME/CFS. I do know that there have been two or three studies that have found elevated rates of apoptosis in ME/CFS. I also know that Dr. Howard at AcumenLab often finds elevated cell-free DNA in PWMEs/PWCs, which comes from cells that have died, and I also know that Howard Urnovitz and his company Chronix have reportedly found that cell-free DNA can be analyzed for complementary DNA sequences that are characteristic of retroviruses. Chronix has joined forces with the company that promotes Ampligen, and I understand that they are calling this "Next Generation Sequencing." Before the blow-up involving Judy Mikovits and the WPI, I think I heard that they were going to pursue this type of DNA sequencing to look for the retroviruses, but I don't know what the status of that is now.

    Anyway, a possible scenario is that viral or retroviral infection causes cells to die prematurely (whether by apoptosis or necrosis, I don't know), and that this causes release of fragments of DNA and perhaps other intracellular substances to the blood plasma, and that this provokes formation of autoantibodies. Perhaps this accounts for the (I think, mild) elevation of autoantibodies in ME/CFS. These autoantibodies may help to promote inflammation by other parts of the immune system.

    If this mechanism is valid, then perhaps the Rituximab treatment (in the cases in which it was successful) knocked out the B cells and thus the production of autoantibodies, and perhaps this then lowered the inflammation and the accompanying oxidative stress, allowing glutathione to recover and breaking the vicious circle involving the partial methylation cycle block, correcting the dysfunction in the sulfur metabolism and the Th2 immune shift, so that the people were able to recover.

    Well, there are a lot of "what if's" in this little fairy tale, but you asked for my thoughts! :D

    Best regards,

    Rich
  2. rydra_wong

    rydra_wong Guest

    Messages:
    514
    Likes:
    31
    Effect of 18x800mcg methylfolate on someone with the genes seen in my footer while exposed to an androgen receptor blocker (DHEA blocker) (a flea control product):

    Starting at 6 pills (but not 5) I began to experience improved neural perfusion. Going from 6 to 12 pills increased the perfusion somewhat but there were diminished returns going from 12 to 18 pills. (I think 6-7 pills at a time gains the maximal perfusion obtainable by this substance for me). The increased perfusion felt like an effervescence, as if Vicks Vaporub had been applied, and also soothed neural tension and knots, adding peace to areas of the brain. However it did not overcome what feels like radical oxygen species caused in some way by the flea control product. In other words, the headache and swelling moved around, was lessened and eased in places, but not dispersed. So the upper headache became earaches and a lower headache. The inflammation feels like someone taking a piece of sandpaper to the brain (but it is not a belt sander as with hyperthyroid, so its a low level abraided feeling).

    The effervescence indicates to me that this is part of the solution. But the methylfolate by itself didnt work. I remembered some comment about having to take a lot of mB12 with it (and certainly Freddd does since he gives himself injections) so I took two mB12 sublinguals (Jarrow).

    It made no difference. But I noticed a few things one that my back felt like it was going to break, my chest got tight, and my whole body was taken over by tension (a clear sign of deficient alkaline minerals something I often feel from hypoglycemia). I remembered Freddd saying it is important to take extra potassium with this so I too 500mg potassium, 300mg calcium itrate, and 300mg magnesium. It took away most of the tension, the worst of it, but not all. I could have taken a bit more. I also took 1 Thorne Basic B becauseI decided these nutrients cant work in a vacuum.

    I also noticed my wrist got REALLY weak and painful. This is something my cousin and I identified a few years ago as osteoarthritis and a sign of insufficient SAMe (according to Life Extension). I decided to heck with this experiment, this is about me feeling good, so I took 1g. TMG. That fixed the wrist promptly. Does this mean the only way I could get methylation is via the BHMT/TMG path? It seemed to me that the extra folate, while giving me brain perfusion, all the same acted like a vortex sucking down methyls instead of generating them (afterall, I did not have the wrist symptoms before I took the mfolate).

    I also notice I have tinnitus. I never had that before I went hyperthyroid last year. I associate it with radical oxygen species in the brain. I probably had tinnitus all day and was just tuning it out until I started this experiment. But not sure.

    I next noticed I started feeling slightly like I was catching a cold (sinus impairment) which indicates a zinc deficiency as zinc averts colds. I remember Freddd going on and on about zinc and how it is needed in this protocol and anyway I always take zinc for colds. So I took 30mg zinc. This averted the cold, but I woke up with a zit (which for me also indicates a zinc shortage) so I am thinking 30mg was not enough zinc. Something about this protocol may raise zinc requirements or it could have been coincidence.

    I no longer feel like I cant stand to be touched, but cannot say if that is due to the nutrients or just attenuation from flea product exposure.

    So, end result, it does not work for me while exposed to a flea control product but it is promising. It seemed to me that there is a balance between all these supplements that is not easy to find.
  3. rydra_wong

    rydra_wong Guest

    Messages:
    514
    Likes:
    31
    PhoeniX .

    I have no time to answer your post just now - evening class. But I want to say that I have taken 900mg P5P and 3g TMG and 1600mg mfolate and 2 mB12 sublinguals to try to avert flea control product exposure issues and it does work but only for 1-2 hours, which is not a workable solution for me.

    The literature all says that CBS mutations UPregulate the gene. I believe the supplements I take and the hormones and the chemicals I avoid all play a role in NORMO-regulating it. I have perfect homocysteine after I take my protocol. However certain chamicals may be screwing with that regulation. In other words, the effect of those genes may be what makes me prone to problems with chemicals and such.

    Regards,
    Rydra
  4. rydra_wong

    rydra_wong Guest

    Messages:
    514
    Likes:
    31
    Awesome! Thanks, Rich!

    (And also cool that one doesn't have to bake it oneself).
  5. rydra_wong

    rydra_wong Guest

    Messages:
    514
    Likes:
    31
    Actually I am touched that u r trying to help. I am usually beyond help you know as I have so many genes gone wrong that everyone throws up their hands including me. I do have a new class strating inj a few minutes though so just accept my thanks for now. Take care

    Rydra
  6. PhoenX

    PhoenX

    Messages:
    15
    Likes:
    0
    Austria
    Thanks for the information about CBS. I must have been tired and probably confused the C677T with the C699T polymorphism in the study.

    F1.large.jpg

    I'm not shure if we can infer from just two CBS polymorphisms that you have an overactive CBS enzyme, but let's assume this is the case. Does it make sense to further increase the CBS enzyme activity through P5P? Or do you need P5P for a different purpose(BHMT, SHMT)?

    Are you using 23andme?
    I wonder if they test more CBS polymorphisms than Yasko.
  7. rydra_wong

    rydra_wong Guest

    Messages:
    514
    Likes:
    31
    PhoenX, I am not concluding anything from my genetic map. My genes supposedly UPregulate CBS, however environmental factors obviously override that because I had high homocysteine. So I followed Fredd's protocol and that DOWNregulated it back to normal. What I am trying to say is that there are a bazillion supplements, hormones, oxidants, chemicals, and other environmental factors that UP/DOWN regulate your enzymes so nothing substitutes testing. I think a homocysteine test is worth its weight in gold. Should be 6.3. If it is higher you need to DOWN regulate (regardless of the state of your genes) and if it is lower you need to UPregulate.

    Don't worry, don't blow a fuse on this. I am just fine if I don't run afoul of something that dysregulates me. I just need to figure out the things that are going to do that and how to avoid them. If you run across anything that might be of help I'd be glad to hear it, but please do not burn brain cells on my account because there are a lot of people here way worse off than me. I do wonder if the real problem with genetic mutations is not whether they are UP or DOWN regulated but that they are excessively UP/DOWN regulatABLE.

    Regards,
    Rydra
  8. rydra_wong

    rydra_wong Guest

    Messages:
    514
    Likes:
    31
    Don't know if you already know this but I had never heard of autoimmune against folate before so I was looking it up and I found this:


    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715943/
    Dev Med Child Neurol. 2008 May; 50(5): 346352.

    A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome
    Vincent T Ramaekers, MD, Jeffrey M Sequeira, MS, Nenad Blau, PhD, and Edward V Quadros, PhD*

    In cerebral folate deficiency syndrome, the presence of autoantibodies against the folate receptor (FR) explains decreased folate transport to the central nervous system and the clinical response to folinic acid. Autoantibody crossreactivity with milk FR from different species prompted us to test the effect of a milk-free diet. Intervention with a milk-free diet in 12 children (nine males, three females; mean age 6y [SD 4y 11mo], range l19y), decreased autoantibody titer significantly from 2.08pmol of FR blocked per ml of serum (SD 2.1; range 0.248.35) to 0.35pmol (SD 0.49; range 01.32; p=0.012) over 3 to 13 months, whereas FR autoantibody titer increased significantly to 6.53 (SD 6.08; range 0.5414.07; p=0.013) in nine children who were reexposed to milk for 6 to 14 weeks. In 12 children on a normal diet (eight males, four females; mean age 5y 5mo [SD 4y 1mo], range 1y 6mo16y 4mo), the antibody titer increased significantly from 0.84pmol of FR blocked per ml (SD 0.39; range 0.241.44) to 3.04pmol (SD 1.42; range 0.846.01; p=0.001) over 10 to 24 months. Decreasing the autoantibody titer with a milk-free diet in conjunction with folinic acid therapy may be advocated for these patients.
    merylg likes this.
  9. merylg

    merylg Senior Member

    Messages:
    764
    Likes:
    494
    Sydney, NSW, Australia
    Hi rydra,
    Interesting paper re Milk-Free diet. Thanks.
    Just found this site re benefits of Folinic Acid (as Calcium Folinate) in Cerebral Folate Deficiency. I seem to tolerate Folinic Acid in this form quite well.

    http://www.psychiatrywithoutdrugs.co.uk/folinic.htm

    meryl
  10. globalpilot

    globalpilot Senior Member

    Messages:
    592
    Likes:
    209
    Ontario
    Hi Rich,

    Thank you. This all makes sense (except I still don't understand why knocking out B cells would reduce oxidative stress bc other immune factors such as macrophages produce it).
    I do have cell free DNA at elevated amounts so it appears I have another marker.

    BTW, I was wondering why so many were having reactions to GCMAF. Reading through this paper they said administation of 100ng to humans resulted in an 30 fold increase in superoxide production by macrophages. Thats' a lot of additional oxidative stress. Do you think that could be the problem ?
  11. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    752
    Hi, globalpilot.

    As has always been true over the past several years, you were immediately able to put your finger on the weak point in my story! :D:D
    I agree that the connection between the B cells and inflammation (and oxidative stress) is not as clear as I would like. I'm still working on that part!

    I like your hypothesis about superoxide and the activation of the macrophages by GcMAF. Makes sense to me.

    Thanks for the scrutiny, as always, and best regards,

    Rich
  12. globalpilot

    globalpilot Senior Member

    Messages:
    592
    Likes:
    209
    Ontario
    Hi Rich,
    I forgot to post the article:
    http://www.transonc.com/pdf/manuscript/v01i02/neo08106.pdf

    In it, it says that B and T lymphocytes are involved in activating macrophages. Maybe that is how knocking out B cells helps - it reduces macrophage activation and thus the oxidative stress.

    It's funny though b/c anything I've read about inflammation doesn't say B or T lymphocytes are involved.

    GP


  13. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    752
    Hi, globalpilot.

    Thanks for posting this paper. It does seem to me that you have found the explanation. I had been looking for something like this, but hadn't quite grasped it. Perhaps this is fairly new information that Yamamoto has figured out. Immunology is a very fast-moving discipline these days. It's hard for the textbooks to keep up with new developments. I had known that T cells were involved in activating macrophages via the Th1 mode, but people with ME/CFS are Th2-shifted, so that didn't seem to fit. But the news that both a T cell and a B cell have to "sign off" in order for Gc protein to become GcMAF looks to me as though it could be the key. Thanks much!

    Best regards,

    Rich
  14. globalpilot

    globalpilot Senior Member

    Messages:
    592
    Likes:
    209
    Ontario
    Hi Rich,
    If we are right that this is the explanation, it appears rituximab accomplishes the opposite of what GcMAF accomplishes - ie downregulates macrophage activation.

    Isn't that an interesting twist ?

    Globalpilot
  15. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    752
    Hi, globalpilot.

    Yes, it is! It would be interesting to know if one of them works on one subset, and the other works on another subset. What I mean is this: Perhaps GcMAF is beneficial in a subset that has types of infections that activated macrophages can knock out (such as intracellular bacteria), while Rituximab is helpful in those who have infections for which elevated glutathione is needed (such as herpes family viruses). This is just a shot in the dark.

    Rich
  16. rydra_wong

    rydra_wong Guest

    Messages:
    514
    Likes:
    31
    Thanks, Meryl,

    I was especially struck by this quote at your website: What's more Folinic acid raises tetrahydrobiopterin (BH4) levels which is a crucial cofactor for the manufacture of all mood-regulating neurotransmitters like dopamine, noradrenalin and of course serotonin itself.

    Since I have 3 genes lowering BH4. I only take the amall amount of folinic acid in my Thorne Basic B. I think I'll get a bottle of pure folinic acid so I can experiment. BTW, mfolate makes my brain very happy -- it just isn't enough to counteract flea medicine. I am sure w/o the flea medicine it's great. But what I am really looking for is supplements that help make me immune to disruptors. So I'll give folinic acid a try.

    Take care,
    Rydra
  17. Rosebud Dairy

    Rosebud Dairy Senior Member

    Messages:
    166
    Likes:
    4
    L-Methyl Folate, Methylcobalamin, MTHFR and immune dificiencies

    Patient with heterozygous C-677T mutation reports subjective improvement on:

    15 mg L-methylfolate (as generic prescription Deplin) split into two doses ALONG WITH

    10,000 mcg of methylcobalamin

    currently in addition to T-3 (25 mcg/day) and hydrocortisone (2.5 mg/day) and bioidentical progesterone therapy

    Improvements seen:
    reduction in brain fog
    increase in daily energy--being able to carry on a "normal" without the need for a 1 hour nap in the middle
    reduction in depressive-type moods
    increase in ability to form complete sentences that make sense to listener
    reduction in overall pain levels
    increase in ability to plan and complete tasks

    Patient may need to add potassium and/or magnesium

    Patient is also being screened for Common Variable Immune Deficiency, but has passed
    the Pneumovax and Tetanus challenges

    Previously Secretory IGA was low
    as were IGG total and IGG Subclass 2's
    (Numbers not currently available, but can be found)

    Immuno doc does not know of possible connection between MTHFR mutations and B-cell deficiencies

    Patient has been sick more than well since August with a two-month sinus infections, month-long stomach virus, and a weeklong respiratory febrile illness (flu swab and strep swabs were negative) (possibly mycoplasma) as family members have been passing around a fever since October.

    Patient has drug reactions (SJS with oxaprozin, distonic reaction to Compazine, and gut problems with many antibiotics)

    Patient avoids antibiotics generally but will take them if infection is found because of gut issues which seem to be controlled with dietary restrictions such as Specific Carbohydrate Diet or GAPS diet.
  18. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    752
    Hi, Rosebud.

    Thanks for posting this information.
    The B12 and the folate are the essence of the methylation protocols, and they are likely working to lift the partial methylation cycle block that PWMEs have. Progesterone can help to counter the excitotoxicity that this treatment often causes. Dr. Amy Yasko has included it in her list of treatments for this. I don't know if the patient of whom you speak has Hashimoto's hypothyroidism and HPA axis dysfunction, but these are common in M.E., and the T3 and hydrocortisone would be helping with those. Potassium and magnesium are indeed often helpful. Potassium, because it is the main positive ion inside cells, and the treatment with folate and B12 will help to make new DNA and RNA for the production of new cells. Magnesium because intracellular magnesium is low in M.E., probably stemming from the glutathione depletion, leading to an energy crisis for the membrane ion pumps. Potassium and magnesium are also the two most important minerals for maintaining a normal heartbeat.

    I suggest that there are several reasons for the immune dysfunction in M.E., including glutathione depletion. Folate is needed to make new B cells, which must undergo clonal proliferation in order to produce enough antibodies to counter infections. The MTHFR polymorphism hinders the folate metabolism and contributes to forming the partial methylation cycle block. When that occurs, and glutathione is also low, peroxynitrite rises and reacts with methylfolate. Over time, this lowers the folate levels in the cells, and that lowers the production of new B cells.

    The problems with infections are likely secondary to the immune dysfunction.

    Drug sensitivities are common in M.E., partly because of inherited polymorphisms in cytochrome P450 enzymes, and partly because the detoxication system in general is dysfunctional because of the partial methylation cycle block and glutathione depletion.

    Gut problems are also common in M.E. My current view is that they must be dealt with in parallel with lifting the partial methylation cycle block, because there are numerous interactions in both directions between the vicious circle involving the partial methylation cycle block and the function of the digestive system. Limiting carbohydrates is beneficial in M.E. to deny food to the yeasts and dysbiotic bacteria, to avoid producing swings in blood glucose levels, and to avoid weight gain that results from inability to burn carbs and fats in the Krebs cycle, owing to the depletion of glutathione.

    Anyway, I think that what you have reported makes a lot of sense. If you would like more information on the GD-MCB hypothesis and the methylation treatment based on it, I encourage you to view the video and/or slides that can be found here:

    http://iaomt.media.fnf.nu/2/skovde_2011_me_kroniskt_trotthetssyndrom/$%7Bweburl%7D

    Best regards,

    Rich
  19. Rosebud Dairy

    Rosebud Dairy Senior Member

    Messages:
    166
    Likes:
    4
    Thank you for the rapid response! Information will be passed on to interested parties quickly.

    Patient does not have Hashimoto's disease
    Patient did have low FT3 for some time
    HPA axis dysfunction - Yes.
    Gluten sensitivity Yes (borderline secretory AGA and positive ALCAT allergies for gluten)
    Heritable Celiac genetic analysis - negative
    Patient had water damage in home - kitchen sewage was leaking onto main trunk line of air handler for 2-3 years before the patient found a leak.

    Patient is ready to start orphan drug VIP - Vasoactive Intestinal Peptide, as this has been low/low-normal, but a recent settled-dust MSQPCR sample would be best before beginning if patient can manage this before the holidays. The hope is that VIP should help with drug and chemical sensitivities, and should help bring resolution in gut issues (diarrhea). Patient is ready to try magnesium again, but all oral forms aggravate diarrhea. Liquid salts as a transdermal may help this problem.

    Patient's father is living and in good health--reports ADHD-like symptoms for all of adult and learning lifetime.
    Patient's mother died from a heart attack at age 63 with multiple health issues throughout lifetime.
  20. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    752
    Hi, Rosebud.

    If this patient is suffering from biotoxin illness due to exposure to molds/bacteria in a water-damaged building,
    I just want to pass on the information that Dr. Ritchie Shoemaker, who pioneered the use of VIP for this
    disorder, strongly emphasized at his recent Biotoxin Illness seminar in Santa Rosa, CA, that VIP should be used
    only after other things are done, including removal from the exposure and a sequence of treatments directed at
    correcting a series of abnormalities. Scott Forsgren discussed this in his blog:

    http://betterhealthguy.com/joomla/blog/251-biotoxin-illness-conference-2011

    Best regards,

    Rich

See more popular forum discussions.

Share This Page