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Ciguatera Toxin in CFS

Discussion in 'Other Health News and Research' started by Hip, Jun 8, 2010.

  1. Hip

    Hip Senior Member

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  2. richvank

    richvank Senior Member

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    Hi, Hip.

    Later work by Hokama et al. found that the positive results of PWCs on the ciguatoxin test resulted from cardiolipin, which is found almost exclusively in the mitochondrial membrane in humans. I believe this is additional evidence for damage to these membranes in CFS. There has been electron microscopy examination of these membranes, showing extensive damage. There is a great deal of evidence for oxidative stress in CFS, and the most vulnerable molecules are those in the phospholipid membranes of the mitochondria. So I think all of this fits together. It doesn't have anything to do with toxins. It's just that part of the ciguatoxin molecule is sufficiently similar to part of the cardiolipin molecule that this antibody test responds to both.

    Best regards,

    Rich
     
  3. dannybex

    dannybex Senior Member

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    Wow Rich, thanks for the update...I had no idea.
     
  4. kolowesi

    kolowesi Senior Member

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    richvank dannybex

    Thanks Danny & Rich!

    I was positive (2005?) at the level of a person with actual ciguatera poisoning; a level lower than the average CFS patient, just high enough to be diagnostic for CFS.

    I never got the RNase-L test and wonder whether it corresponds.

    Around the same time, I had some oxidative stress tests, one of which was off the scale, the other very high. I also had a high ESR (50) for about a year, in spite of the fact that I have blood clotting abnormalities (prothrombin and antithrombin antibodies, not cardiolipin tho) and high fibrinogen. Thick blood usually causes the ESR to be lower, so that might mean that I would have had an even higher sed rate than showed up.

    I do wonder if this is going to turn out to be related to XMRV. I am negative by culture, but hope to get the other test someday. Early on, I had very low B & T cell counts, which seems like it could be related to XMRV. Speculation.

    Do you know whether people are still getting this test? I might re-do it and I think it would be lower as I have less inflammation since taking valcyte 2007-08.

    Kelly
     
  5. Hip

    Hip Senior Member

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    Thanks Rich.

    So in fact, what is being observed by the ciguatoxin test in CFS patients is bits of cardiolipin floating around. Presumably cardiolipin itself is not toxic, but its presence indicates that the mitochondrial membranes are being damaged.
     
  6. kolowesi

    kolowesi Senior Member

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    I meant to thank you, too, Hip. I think this is a big clue.
     
  7. MNC

    MNC Senior Member

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    The National CFIDS Foundation has worked much on the ciguatera thing in the past years:

    http://www.ncf-net.org/

    http://www.ncf-net.org/library.htm#Toxicology

    Ask Gail, the President, and she will tell you a lot about it.

    EDIT: Sorry, I hadn't noticed that all the articles cited in that page of CFS-Ireland are from the National CFIDS Foundation. So, it is the same information.
     
  8. richvank

    richvank Senior Member

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    Hi, Hip.

    Yes, that's the way I understand it.

    Best regards,

    Rich
     
  9. richvank

    richvank Senior Member

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    Hi, Kelly.

    You're welcome.

    The Winter 2009/2010 issue of the NCF Forum reported that this test has been made available again. It costs $100. I suggest that you write to Dr. Hokama at yoshitsu at hawaii dot edu for details.

    Best regards,

    Rich
     
  10. BEG

    BEG Senior Member

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    "It is concluded that certain disease conditions and environmental exposures to deleterious factors (toxin, chemicals, microorganisms) trigger the release of lipids (probably by the liver) with similar epitopes to ciguatoxin, and that they react with MAbCTX. We designate these lipids as chronic phase lipids comparable to acute phase protein in inflammatory and traumatic diseases."


    Am I correct to interpret that other toxins, chemicals and microorganisms can do the same thing to the body as the ciguatera toxin?
     
  11. Hip

    Hip Senior Member

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    I would have thought that, in the light of Rich's comments, the ciguatera toxin test non longer has meaning, at least in the CFS context?

    If this ciguatera toxin test only measures cardiolipin levels, then in reality having high ciguatera toxin test results does not mean that you are intoxicated with ciguatera; rather it means that you have a lot of cardiolipin floating around in your system. And high cardiolipin, in turn, presumably means that your mitochondria are being damaged by high levels of oxidative stress.

    So in summary, as far as I understand it, the ciguatera toxin test actually measures, in an approximate way, your mitochondrial damage levels.
     
  12. Hip

    Hip Senior Member

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    From what Rich explained above, it seems that there in fact is no ciguatera toxin at all in CFS, even thought it was originally thought that there was.

    However, bacteria and viruses make all sorts of toxins and virulence factors, and these very likely contribute, if not cause, the condition of CFS.

    A virulence factor, by the way, is a chemical that is generated a released by a bacterium, virus, fungus, etc, which helps that microbe survive in the body. Many virulence factors are chemicals that significantly disrupt the operation of the immune system, which helps the microbe to avoid be destroyed by the immune system. Virulence factors may explain why there is so much immune malfunction in CFS.
     
  13. slayadragon

    slayadragon Senior Member

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    twitpic.com/photos/SlayaDragon
    Ciguatera

    Here are some quotes from two articles on this topic. (Thanks much to Rich for the cites.)


    Hokama et al 2008

    http://www.ncf-net.org/pdf/HokamaCardiolipinCFS2008.pdf


    During a recent examination of the clinical history of CFS and chronic Ciguatera fish poisoning (CCFP), it was shown that the clinical symptoms found in both diseases were remarkably similar, including recurrent fatigue, impaired memory and concentration, tender lymph nodes, muscle and joint pain, headaches and other neurological impairment.

    We have found that the “acute phase lipid” in the CFS lipid fraction appears to be associated with phospholipids of mitochondria found in many serum samples of disease including viral infections (Epstein-Barr, hepatitis viruses, and HIV), parasitic diseases, marine toxins (CTX, okadaic acid, palytoxin, polyether lipids) and other microbial infectious diseases. It was recently reported in a National CFIDS Foundation press release that CFS/ME, MS and idipathic epilepsy were caused by a Cryptovirus (Zoonotic virus), similar to the parainfluenza virus-5, originally found in swine. These disease processes, particularly CTX, most likely affect the major organ, the liver.

    Since phospholipid release is suspected, it is the mitochondria of these cells in the liver that is thought to be affected during the detoxification or destruction of the toxic entity. We hypothesize that damage or stimulation of the mitochondria results in the release of phospholipids, which in turn induce production of an autoimmune antibody (antiphospholipids). Many of the disease states aove have been found to involve antiphospholipids, including autoantibodies to cardiolipin (CL) of the immunoglobin G (IgG), IgM, and IgA isotypes.

    Thus, this work presents immunological data to show that these phospholipids are associated with the mitochondria and part of the CL, especially in CFS, CCFP, Gulf War veterans (GWV) and prostate cancer (PC) sera.

    The “acute phase lipids” found in the sera of CFS, CCFP, GWP and PC in this stud are part of the phospholipids of the mitochondrial membrane associated with CL, which appears in man or all disease, notably viral infections... Data show, in this study, a strong reaction with the “acute phase lipids” found in CFS, GWV and CCFP.

    The blocking or inhibition studies demonstrated that CTX, CL and CFS lipids and phosphlipids had an antigenic epitope with a structural configuation that reacted with the MAb-CTX and CFS serum aCL antibodies, thus immunologically indistinguishable.

    In Ciguatera studies by Terao et al, it was demonstrated that purifier CTX injected into inbred mice produced structural changes in the tissue of the mitochondria. Swelling and destruction of the inner membrane in the mitochondria of heart and liver tissue was demonstrated.

    It is suggested that the increase in phospholipids associated with CL and all may be associated with defective mitochondrial metabolism and thus apoptosis in regulation of program cell death, especially involved in the immune system, hence immune dysfunction status in CFS disease.

    *

    Hokama et al 2009:

    http://www.ncf-net.org/pdf/AnticardiolipinAntibodies.pdf

    A survey of the literature reports ACSs as common serological markers in many different types of diseases, including viral disease such as illnesses resulting from chemical and marine toxin exposure, HIV and Epstein-Barr virus, hematological cancers including CLL and acute myelocytic leukemias, exposure to fungal organisms, malaria, and staphylococcus infections, and autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, autoimmune hepatitis and more.

    This study demonstrates that a large percentage of patients clinically diagnosed with CFS have elevated levels of the IgM isotype to CL (95%), suggesting that CFS may be an autoimmune condition.

    As a possible autoimmune disease, CFS patients may be treated by suppression of the ACA or by diminishing the antigen CL in serum.

    Experiments are underway to further elucidate why ACSs are produced in individuals afflicted with CFS. Such studies include investigating the effects of specific chemical agents, marine toxins, and ACSs on mitochondrial metabolic pathways that are indicative of reduced or blocked energy production that may lead to the fatigued state in CFS. Such studies may lead to the development of potential therapeutic agents to block or reduce such interactions.


    *

    The last paragraph seems to suggest that the authors of the study suspect that some sort of chemical or toxin might be causing the structural changes in the mitochondria. The authors promise to try to figure out which one(s) it might be.

    There also are hints in this paper that viruses may be connected with the phenomenon. This is especially interesting in light of their observation that this phenomenon has been found in prostate cancer patients, since this group is also thought to be infected disproportionately with XMRV.

    This study points out that “marine toxins” (e.g. ciguatera) often cause this problem. Lyme toxins and fungal toxins are in the same family (ionophores). Insofar as CFSers are being affected by any of these toxins, it seems to me reasonable to suspect that they might be leading to the findings in the study.

    Unfortunately, it seems that all of these toxins are damaging to CFSers (or at least to me) in such small quantities that it’s hard to get any evidence that they actually are having an effect. That doesn’t mean that they’re not there though.

    It occurs to me in reading about ciguatera that this stuff is even more nasty than mold toxins. If I am as reactive to tiny amounts of this ionophore as I am to tiny amounts of mold toxins, God help me if I ever get exposed to even a smidge of it. Best to stay out of the water and never eat any big fish, perhaps.

    Thoughts would be appreciated, please.

    Best, Lisa
     
  14. Andrew

    Andrew Senior Member

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    I tested positive, and then I wondered what the heck to do about it.
     
  15. slayadragon

    slayadragon Senior Member

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    twitpic.com/photos/SlayaDragon

    To the anticardiolipin antibodies, or to the actual presence of ciguatera toxin?

    Lisa
     
  16. Andrew

    Andrew Senior Member

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    I don't know. It was a recent study and my blood got mailed to a study in Hawaii. The study was announced on this web site. That's all I remember now.
     
  17. citybug

    citybug Senior Member

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    I see the cardiolipin is from mitochondrial membranes. Basic question, aren't cell membranes also phospholipids? So does oxidative stress damage the outer membrane, and then inner mitochondrial membrane? Would the mitochondria pull in toxins? Could XMRV like to use the mitochondrial membrane?

    Are any therapies shown to repair this membrane like Kane protocol? Or any particular oils to repair it? Any fit with Cheney's statement that olive oil was better than fish oil for CFS energy?
     
  18. richvank

    richvank Senior Member

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    Hi, kdp.

    Yes, cell membranes are also made of phospholipids. There are several types of phospholipids. Cardiolipin is one of them, and it is found almost exclusively in the mitochondrial membranes, and mainly in the innner mitochondrial membrane. Its role or roles are the subject of ongoing research, and at least one of them seems to be involved with the process of apoptosis, i.e. the organized type of cell death.

    Most of the oxidizing free radicals in the cell are produced in the mitochondria, so when there is oxidative stress (i.e. an excess of oxidizing free radicals, in my hypothesis due to glutathione depletion), the mitochondrial membranes sustain the most damage.

    Yes, there are toxins in the mitochondria in CFS, as has been shown by the testing done by Dr. John McLaren Howard of Acumen Lab in the UK. Some of them may be able to diffuse through the mitochondrial membranes in response to a concentration gradient. Others may be actively imported by transporter proteins into the mitochondria. In my hypothesis, they remain there because glutathione is depleted, so that the normal detox processes that would take them out are not operating properly.

    I haven't heard of any research results suggesting an interaction between XMRV and the mitochondria. As I understand it, XMRV produces its complementary DNA from its RNA, and this DNA then becomes part of human nuclear DNA molecules.

    I'm aware of research conducted by Garth Nicolson and Rita Elliethorpe showing that NT Factor repairs mitochondrial membranes, causing the electrical potential across the membrane to move toward normal. As far as I know, other treatments that supply phopholipids or unsaturated fatty acids (omega-3 and omega-6) would be beneficial for these membranes, also. NT Factor is a nested liposomal treatment, and nested liposomes are more likely to be able to deliver phospholipids to the mitochondria, because they are able to penetrate other membranes in order to get to the mitochondria.

    One concern I have about supplying additional phospholipids or unsaturated fatty acids in CFS is that the oxidative stress may damage them. In lipid oxidation, there is a chain reaction process that can produce lipid peroxides in large quantities if oxidative stress is present. I think it is wise to counter the oxidative stress either simultaneously while supplying the lipids, or prior to doing so. In the Simplified Treatment Approach that I've suggested, phospholipids are supplied at the same time that supplements are given to lift the partial methylation cycle block, which allows glutathione to come up, thus countering the oxidative stress. I believe that in Dr. Kane's protocol, glutathione is given intravenously as part of the protocol, while phosphatidylcholine is also given in separate IVs.

    Dr. Cheney's views about which supplements are beneficial and which are not in CFS are based on his short-time measurements (of the order of a minute or a few minutes) of changes in the IVRT parameter in echocardiography, in response to applying a small amount of each supplement transdermally. In my view, this approach is not an accurate way to judge the benefit of supplements, because many biochemical changes take longer than a few minutes. I think this approach interrogates only the first step or steps in the metabolism of a substance applied in this way, and the overall effect of a substance will depend on its more complete metabolism and the effects of that on the cells. I have expressed this view to Dr. Cheney several times, but I don't think he has changed his mind about this. I'm not aware of anyone else who is using this approach to judge the merits of supplements. Dr. Cheney has not submitted this method to any formal peer review, as far as I know.

    Best regards,

    Rich
     
  19. citybug

    citybug Senior Member

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    I thought Cheney's point was that fish oil was more likely to oxidize. Have you heard of patients that improve with NT Factor (any particular brand)? It's expensive. (and I'm supposed to avoid soy which most of these products use. I do have the mito blockage, with hair dye maybe used once and benzene.)

    I think they say viruses can also destroy the mitochondria (apoptosis?) as well as oxidative stress.

    I brought up xmrv because of using lipid cell envelopes so I went back to trying to understand Gerwyn's hypothesis again. Do these CREB processes regulate mitochondria? Does it make any sense to you?

    Would vegetable and fish oils not have the cholesterol that viruses might use? (assuming virus and methylation problems)

    XMRV inserts into CREB gene, transcription start sites (Silverman 2007), can create insertional mutations (Silverman 2010).
    Creb master gene regulator including sterols (lipodystrophy 2002)
    On other threads generally say Viruses can cause mitochondrial disease. Herpes viruses can eliminate mitochondrial DNA (saffran 2007).
    XMRV may travel with lipid rafts cell to cell like HIV
    other gammaretroviruses like FLV cell envelopes create neurotoxins, and MULV?
    use the cells envelope to create new virus envelope

    Refs
    An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumor
    Proc Natl Acad Sci U S A (2007) 0: .
    Expression in hamster cells of the xenotropic and polytropic retrovirus receptor 1 allowed these cells to be infected by
    XMRV. XMRV provirus integration sites were mapped in DNA isolated from human prostate tumor tissue to genes for two
    transcription factors (NFATc3 and CREB5) and to a gene encoding a suppressor of androgen receptor transactivation
    (APPBP2/PAT1/ARA67). Our studies demonstrate that XMRV is a virus that has infected humans and is susceptible to inhibition
    by IFN and its downstream effector, RNase L. and Integration of the cDNA copy of the viral RNA genome is essential for retroviruses to establish a productive infection (for reviews, see reference [12]). However, because of its nonspecific nature, retroviral DNA integration is inherently a
    mutagenic event. Many retroviruses, especially members of the gammaretrovirus genus, can induce tumors as a consequence of
    integrating their viral genome into the host cell chromosome and activating proto-oncogenes via promoter or enhancer
    insertion, a mechanism referred to as proviral insertional mutagenesis [13]. XMRV is a member of the gammaretrovirus family,
    and does not encode host-derived oncogenes [1]. Genome-wide analyses of XMRV integration sites in a human prostate cell line,
    DU145, and prostate cancer tissues showed that XMRV integration favors gene-dense regions and genomic features frequently
    associated with structurally open, transcriptional regulatory regions of a chromosome, such as transcription start sites, CpG
    islands, and DNase hypersensitive sites [14]. The XMRV integration sites in prostate cancer tissues are further associated
    with cancer breakpoints, common fragile sites, and microRNA genes.

    FIDELITY OF TARGET SITE INTEGRATION, Silverman et al, 2010.
    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010255
    Gerwyn said : I have the hypothesis that XMRV does irs dirty work by causing the creb gene to malfunction.Untill this paper
    there was no actual evidence that XMRV could affect the CREB gene in this way.Insertional mutagenesis is such a
    mechanism.Xmrv can act as a duplication mutation or a deletion. Either way the proteins formed from CREB would be abnormal
    and affect their regulatory function.

    Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. 2002
    CBP enhances transcriptional activities via histone acetylation and the recruitment of additional co-activators such as SRC
    (steroid coactivator)-1 (r The CBP protein (cAMP response element binding protein (CREB) binding protein) is a co-activator
    for several transcription factors with a wide range of important biological functions, such as sterol regulatory element
    binding proteins This study demonstrates that CBP may function as a 'master-switch' between energy storage and expenditure.


    Herpes simplex virus eliminates host mitochondrial DNA, Holly A Saffran et al, 2007
    http://www.nature.com/embor/journal/v8/n2/full/7400878.html

    The Scientist: NewsBlog:
    New non-drug fix for HIV?

    Researchers are slowly establishing a connection between an extremely rare genetic disease and HIV -- and homing in on a
    safe, non-prescription compound that could treat both.
    Recently, James Hildreth at the Meharry Medical College School of Medicine in Nashville, Tenn., and his colleagues found
    that cells affected by Niemann-Pick Type C (NPC), which disrupts cholesterol trafficking, were unable to release HIV,
    suggesting these cells would not spread the virus.
    These findings, published May 27 in the Journal of Virology, are rooted in a hypothesis Hildreth has explored for a long
    time: that "cholesterol is somehow essential" to HIV, he said. For instance, HIV-1 relies on specialized structures known as
    lipid rafts, which are rich in cholesterol, to infect new cells.
    That line of thinking has led him to investigate whether a compound widely employed by the food and chemical industries
    (and used as a drug solubilizer) which depletes cells of cholesterol could serve as a preventative agent -- or even a
    treatment -- for HIV. And his growing body of evidence is suggesting the compound, known as cyclodextrin, might do just that.
     
  20. acer2000

    acer2000 Senior Member

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    Sorry if this is my second post of this question, but it appears my first one didn't go through. Since this assay seems to indirectly test for ciguatoxin by looking at the downstream effect, it doesn't seem all that specific for testing for actual Ciguatera poisoning. Is there an assay that can actually directly test for Ciguatera toxin?
     

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