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High b12/folate but normal mma, normal homocysteine/MMA....please help

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by jj929, Apr 9, 2012.

  1. jj929

    jj929

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    I recently found out that I am heterozygous for MTHFR C677T. I also have been battling lyme disease for a long time..... perhaps due to methylation issues.

    Thanks to this great site I am learning a great deal about methylation block, as well as, practical strategies for dealing with it.

    My situation as it relates to methylation is rather strange as my serum b12 (1700 up from 1400 a couple of months ago... this without prior supplementation) and folate are high (>24).....I understand that I may not be converting the b12/folate to a usable form for my body and that perhaps I may be folate or b12 deficient.

    However, what I find strange about my situation is that that my homocysteine level is not elevated but in the low normal range. It has actually dropped in the past couple of months from 6.6 to 5.6. The MMA is also normal.

    Can someone please explain what I'm dealing with here?

    Thank you so much!

    JJ
  2. richvank

    richvank Senior Member

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    Hi, JJ.

    Welcome!

    The high serum B12 and folate are consistent with a functional B12 deficiency and folate draining from the cells. This suggests that the GD-MCB hypothesis might fit your case.

    Homocysteine has not been found to be a reliable marker of functional B12 deficiency in ME/CFS. The reasons seem to be that over time, methionine becomes depleted in many cases, so that the production of homocysteine is not being fed at as high a rate as normal. In addition there can be genetic polymorphisms, such as in the AHCY and CBS enzymes, which can lower the homocysteine level.

    MMA can also be an unreliable marker for functional B12 deficiency if either the amino acids levels drop too low or there are deficiencies in vitamin B6 or B2 or both, so that the amino acids are not fed into the MMA pathway at normal rates.

    To find out what is going on, it is necessary to run some lab tests. I would suggest running the methylation pathways panel from Health Diagnostics and Research Institute in New Jersey, which requires an order from a physician or a chiropractor. Contact information is below. If feasible, I would suggest also running a urine organic acids panel and a plasma amino acids panel. Testing for toxic and essential elements is also a good idea. Some people run the Metametrix ION profile or the Genova Diagnostics NutrEval panel, which contains a combination of tests. These are available without a doctor's order from www.directlabs.com

    Best regards,

    Rich


    Methylation Pathways Panel

    This panel will indicate whether a person has a partial methylation cycle block and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block. I am not associated with the lab that offers this panel.

    The panel requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on a clinicians letterhead.


    Available from:

    Health Diagnostics and Research Institute
    540 Bordentown Avenue, Suite 2300
    South Amboy, NJ 08879
    USA
    Phone: (732) 721-1234
    Fax: (732) 525-3288

    Email: lab@vitdiag.com

    Lab Director: Elizabeth Valentine, M.D.

    Dr. Tapan Audhya, Ph.D., is willing to help clinicians with interpretation of the panel by phone, or you can use the interpretive guide below:


    March 25, 2012


    Interpretation of Results of the Methylation Pathways Panel

    by
    Richard A. Van Konynenburg, Ph.D.
    Independent Researcher
    (richvank@aol.com)


    Disclaimer: The Methylation Pathways Panel is offered by the European Laboratory of Nutrients in the Netherlands and the Health Diagnostics and Research Institute in New Jersey, USA. I am not affiliated with these laboratories, but have been a user of this panel, and have written these suggestions at the request of Tapan Audhya, Ph.D., Director of Research for the Health Diagnostics lab, for the benefit of physicians who may not be familiar with this panel. My suggestions for the interpretation of results of the panel are based on my study of the biochemistry involved, on my own experience with interpreting panel results as part of the analysis of a fairly large number of cases of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) over the past four years, and on discussion of some of the issues with Dr. Audhya. I am a researcher, not a licensed physician. Treatment decisions based on the results of applying this panel and its interpretation to individual cases are the responsibility of the treating physician.

    Application: In addition to being useful in analyzing cases of ME/CFS, this panel can also be usefully applied to cases of autism and other disorders that involve abnormalities in glutathione, methylation and the folate metabolism.

    The panel includes measurement of two forms of glutathione (reduced and oxidized), S-adenosylmethionine (SAMe), S-adenosylhomocysteine (SAH), adenosine, and seven folate derivatives.

    According to Dr. Audhya (personal communication), the reference ranges shown on the lab reports for each of these metabolites were derived from measurements on at least 120 healthy male and female volunteer medical students from ages 20 to 40, non-smoking, and with no known chronic diseases. The reference ranges extend to plus and minus two standard deviations from the mean of these measurements.

    Glutathione (reduced): This is a measurement of the concentration of the
    chemically reduced (active) form of glutathione (abbreviated GSH) in the blood
    plasma. The reference range is 3.8 to 5.5 micromoles per liter.

    Glutathione plays many important roles in the biochemistry of the body, including serving as the basis of the antioxidant enzyme system, participating in the detoxication system, and supporting the cell-mediated immune response, all of which exhibit deficits in CFS. The level of GSH in the plasma is likely to be more reflective of tissue intracellular glutathione status than the more commonly and more easily measured red blood cell or (essentially equivalent) whole blood glutathione level, which is about three orders of magnitude greater, because red blood cells are normally net producers of glutathione. Also, knowledge of the level of the reduced form, as distinguished from total (reduced plus oxidized) glutathione, which is more commonly measured, is more diagnostic of the status of glutathione function.

    In order to be able to approximate the in vivo level of reduced glutathione when blood samples must be shipped to a lab, it is necessary to include special enzyme inhibitors in the sample vials, and these are included in the test kit supplied by these two laboratories.

    Most people with chronic fatigue syndrome (PWCs), but not all, are found to have values of GSH that are below the reference range*. This means that they are suffering from glutathione depletion. As they undergo treatment to lift the partial methylation cycle block, this value usually rises into the normal range over a period of a few months. I believe that this is very important, because
    glutathione normally participates in the intracellular metabolism of vitamin B12, and if it is low, a functional deficiency of vitamin B12 results, and insufficient methylcobalamin is produced to support methionine synthase in the methylation cycle. In my view, this is the mechanism that causes the onset of ME/CFS. This functional deficiency is not detected in a conventional serum B12 test, but will produce elevated methylmalonate in a urine organic acids test. In my opinion, many of the abnormalities and symptoms in ME/CFS can be traced directly to glutathione depletion.

    Anecdotal evidence suggests that PWCs who do not have glutathione depletion do have abnormalities in the function of one or more of the enzymes that make use of glutathione, i.e. the glutathione peroxidases and/or glutathione transferases. This may be due to genetic polymorphisms or DNA adducts on the genes that code for these enzymes, or in the case of some of the glutathione peroxidases, to a low selenium status.

    Glutathione (oxidized): This is a measurement of the concentration
    of the oxidized form of glutathione (abbreviated GSSG) in the blood
    plasma. The reference range is 0.16 to 0.50 micromoles per liter.

    Normally, oxidized glutathione in the cells is recycled back to reduced glutathione by glutathione reductase, an enzyme that requires vitamin B2 and NADPH. If this reaction is overwhelmed by oxidative stress, the cells export excess GSSG to the plasma. In some (but not all) PWCs, GSSG is elevated above the normal
    range, and this represents oxidative stress. It is more common in CFS to see this level in the high-normal range. This value may increase slightly under initial treatment of a partial methylation cycle block.*

    Ratio of Glutatione (reduced) to Glutathione (oxidized): This is not shown explicitly on the panel results, but can be calculated from them. It is a measure of the redox potential in the plasma, and reflects the state of the antioxidant system in the cells. The normal mean value is 14. PWCs often have a value slightly more than half this amount, indicating a state of glutathione depletion and oxidative stress. This ratio has been found to increase during treatment of a partial methylation cycle block, but other types of treatment may be necessary to bring it to normal.*

    S-adenosymethionine (RBC): This is a measure of the concentration of S-adenosylmethionine (SAMe) in the red blood cells. The reference range is 221 to 256 micromoles per deciliter.

    SAMe is produced in the methylation cycle and is the main supplier of methyl (CH3) groups for a large number of methylation reactions in the body, including the methylation of DNA and the biosynthesis of creatine, carnitine, phosphatidylcholine, coenzyme Q10, melatonin and epinephrine. This measurement is made in the red blood cells because the level there reflects an average over a longer time and is less vulnerable to fluctuations than is the plasma level of SAMe.

    Most PWCs have values below the reference range, and treatment raises the value.* A low value for SAMe represents a low methylation capacity, and
    in CFS, it usually appears to result from an inhibition or partial block of the enzyme methionine synthase in the methylation cycle. Many of the abnormalities in CFS can be tied to lack of sufficient methylation capacity.

    S-adenosylhomocysteine (RBC): This is a measure of the
    concentration of S-adenosylhomocysteine (SAH) in the red blood cells. The reference range is 38.0 to 49.0 micromoles per deciliter.

    SAH is the product of the many methyltransferase reactions that utilize SAMe as a source of methyl groups. In CFS, its value ranges from below the reference range to above the reference range. Values appear to converge toward the reference range with treatment.

    Sum of SAM and SAH: When the sum of SAM and SAH is below about 268
    micromoles per deciliter, it appears to suggest the presence of
    upregulating polymorphisms in the cystathionine beta synthase (CBS)
    enzyme, though this may not be true in every case. For those considering following the Yasko treatment program, this may be useful information.

    Ratio of SAM to SAH: A ratio less than about 4.5 represents low
    methylation capacity. Both the concentration of SAM and the ratio of
    concentrations of SAM to SAH are important in determining the
    methylation capacity, because they affect the rates of the methyltransferase reactions.

    Adenosine: This is a measure of the concentration of adenosine in the
    blood plasma. The reference range is 16.8 to 21.4 x 10(-8) molar.

    Adenosine is a product of the reaction that converts SAH to homocysteine. It is also exported to the plasma when mitochondria develop a low energy charge, so that ATP drops down to ADP, AMP, and eventually, adenosine. Adenosine in the plasma is normally broken down to inosine by the enzyme adenosine deaminase.

    In some PWCs adenosine is found to be high, in some it is low, and in some it is in the reference range. I don't yet understand what controls the adenosine level in these patients, and I suspect that there is more than one factor involved. In most PWCs who started with abnormal values, the adenosine level appears to be moving into the reference range with methylation cycle treatment, but more data are needed.

    5-CH3-THF: This is a measure of the concentration of 5L-methyl
    tetrahydrofolate in the blood plasma. The reference range is 8.4 to 72.6 nanomoles per liter.

    This form of folate is present in natural foods, and is normally the most abundant form of folate in the blood plasma. It is the form that serves as a reactant for the enzyme methionine synthase, and is thus the important form for the methylation cycle. It is also the only form of folate that normally can enter the brain. Its only known reactions are the methionine synthase reaction and reaction with the oxidant peroxynitrite.

    When there is a partial block in methionine synthase, the other forms of folate continue to be converted to 5L-CH3-THF by the so-called methyl trap mechanism. Some of the 5L-CH3-THF is broken down by reaction with peroxynitrite, which results from the condition of oxidative stress that is usually concomitant with glutathione depletion.

    Many PWCs have a low value of 5L-CH3-THF, consistent with a partial block in the methylation cycle. Most methylation treatment protocols include supplementation with 5L-CH3-THF, which is sold over-the-counter as Metafolin, FolaPro, or MethylMate B (trademarks), as well as the newer Quatrefolic (trademark) and in the prescription medical foods supplied by PamLab, including Deplin, CerefolinNAC and Metanx. There are some others on the market that include both racemic forms (5L and 5R) of this folate.

    When methylation treatment is used, the level of 5-CH3-THF rises in nearly every PWC. If the concentration of 5-CH3-THF is within the reference range, but either SAM or the ratio of SAM to SAH is below the reference values, it suggests that there is a partial methylation cycle block and that it is caused by inavailability of sufficient bioactive B12, rather than inavailability of sufficient folate. A urine organic acids panel will show elevated methylmalonate if there is a functional deficiency of B12. I have seen this combination frequently, and I think it demonstrates that the functional deficiency of B12 is the immediate root cause of most cases of partial methylation cycle block. Usually glutathione is low in these cases, which is consistent with such a functional deficiency. As the activity of the methylation cycle becomes more normal, the demand for 5-CH3-THF will likely increase, so including it in the treatment protocol, even if not initially low, will likely be beneficial.

    10-Formyl-THF: This is a measure of the concentration of 10-formyl
    tetrahydrofolate in the blood plasma. The reference range is 1.5 to 8.2 nanomoles per liter.

    This form of folate is involved in reactions to form purines, which form part of RNA and DNA as well as ATP. It is usually on the low side in PWCs, likely as a result of the methyl trap mechanism mentioned above. This deficiency is likely the reason for some elevation of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) often seen in PWCs. This deficit may also impact replacement of cells lining the gut, as well as white blood cells.

    Rarely, 10-formyl-THF is found to be much higher than the normal reference range. If this is found, the patient should be examined for cancer, since cancer cells upregulate this form of folate in order to make purines more rapidly to support their rapid cell division.

    5-Formyl-THF: This is a measure of the concentration of 5-formyl
    tetrahydrofolate (also called folinic acid) in the blood plasma. The reference range is 1.2 to 11.7 nanomoles per liter.

    This form is not used directly as a substrate in one-carbon transfer reactions, but it can be converted into other forms of folate, and may serve as a buffer form of folate. Most but not all PWCs have a value on the low side. It is one of the
    supplements in some methylation protocols. It can be converted to 5L-CH3-THF in the body by a series of three reactions, one of which requires NADPH, and it may also help to supply other forms of folate to the cells until the methionine synthase reaction comes up to more normal activity.

    THF: This is a measure of the concentration of tetrahydrofolate in
    the blood plasma. The reference range is 0.6 to 6.8 nanomoles per liter.

    This is the fundamental chemically reduced form of folate from which several other reduced folate forms are synthesized, and thus serves as the hub of the folate metabolism. THF is also a product of the methionine synthase reaction, and participates in the reaction that converts formiminoglutamate (figlu) into glutamate in the metabolism of histidine. If figlu is found to be elevated in a urine organic acids panel, it usually indicates that THF is low. In PWCs it is lower than the mean normal value of 3.7 nanomoles per liter in most but not all PWCs.

    Folic acid: This is a measure of the concentration of folic acid in
    the blood plasma. The reference range is 8.9 to 24.6 nanomoles per liter.

    Folic acid is a synthetic form of folate, not found in nature. It is added to food grains in the U.S. and some other countries in order to lower the incidence of neural tube birth defects, including spina bifida. It is the oxidized form of folate, and therefore has a long shelf life and is the most common commercial folate supplement. It is normally converted into THF by two sequential reactions catalyzed by dihydrofolate reductase (DHFR), using NADPH as the reductant. However, some people are not able to carry out this reaction well for genetic reasons, and PWCs may be depleted in NADPH, so folic acid is not the best supplemental form of folate for these people.

    Low values suggest folic acid deficiency in the current diet. High values, especially in the presence of low values for THF, may be associated with inability to convert folic acid into reduced folate readily, such as because of a genetic polymorphism in the DHFR enzyme. They may also be due to high supplementation of folic acid.

    Folinic acid (WB): This is a measure of the concentration of folinic acid in the whole blood. The reference range is 9.0 to 35.5 nanomoles per liter.

    See comments on 5-formyl-THF above. Whole blood folinic acid usually tracks with the plasma 5-formyl-THF concentration. They are the same substance.

    Folic acid (RBC): This is a measure of the concentration of folic acid in the red blood cells. The reference range is 400 to 1500 nanomoles per liter.

    The red blood cells import folic acid when they are initially being formed, but during most of their lifetime, they do not normally import, export, or use it. They simply serve as reservoirs for it, giving it up when they are broken down.

    Many PWCs have low values of this parameter. This can be caused by a low folic acid status in the diet over the previous few months, since the population of RBCs at any time has ages ranging from zero to about four months. However, in CFS it can also be caused by oxidative damage to the cell membranes, which allows folic acid to leak out of the cells. Dr. Audhya reports that treatment with omega-3 fatty acids has been found to raise this value over time in one cohort.

    If anyone finds errors in the above suggestions, I would appreciate being notified at richvank@aol.com.

    * Nathan, N., and Van Konynenburg, R.A., Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia, poster paper, 9th International IACFS/ME Conference, Reno, Nevada, March 12-15, 2009. (http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf)
  3. jj929

    jj929

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    High B12/folate but normal homocysteine and MMA......please help

  4. richvank

    richvank Senior Member

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    Hi, JJ.

    You're welcome. You can find out more about the GD-MCB hypothesis by viewing the video and/or slides at this website:

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

    Yes, it's O.K. to start the simplified protocol before running the methylation pathways panel. The panel will still be valid.

    I think that product looks O.K., except that I think you will need to take additional B12 sublingually, in order to get enough into the blood to overcome the functional deficiency of B12. The amount that can be absorbed into the blood by the normal oral route is limited. I would favor trying sublingual hydroxocobalamin at about 2,000 micrograms per day. The most recent version of the simplified methylation protocol that I have suggested is pasted below.

    Best regards,

    Rich


    March 30. 2011

    SIMPLIFIED TREATMENT APPROACH
    FOR LIFTING THE PARTIAL METHYLATION CYCLE BLOCK
    IN CHRONIC FATIGUE SYNDROMEMarch 30, 2011 Revision
    Rich Van Konynenburg. Ph.D.
    (Based on the full treatment program
    developed by Amy Yasko, Ph.D., N.D.
    which is used primarily in treating autism [1])

    SUPPLEMENTS

    1. General Vitamin Neurological Health Formula [2]: Start with tablet and increase dosage as tolerated to 2 tablets daily
    2. Hydroxy B12 Mega Drops [3]: 2 drops under the tongue daily
    3. MethylMate B [4]: 3 drops under the tongue daily
    4. Folinic acid [5]: capsule daily
    5. Phosphatidyl Serine Complex [6]: 1 softgel capsule daily (or lecithin, see below)

    All these supplements can be obtained from http://www.holisticheal.com.
    The fourth supplement comes in capsules that contain 800 mcg. It will be necessary to open the capsules, dump the powder onto a flat surface, and separate it into quarters using a knife to obtain the daily dose. The powder can be taken orally with water, with or without food.
    These supplements can make some patients sleepy, so in those cases they take them at bedtime. In general, they can be taken at any time of day, with or without food.
    Phosphatidyl serine can lower cortisol levels. Patients who already have low evening cortisol levels may wish to substitute lecithin [7] (at one softgel daily) for supplement number 5 above. Lecithin is also available from http://www.holisticheal.com.
    For those allergic to soy, lecithin from other sources is available.
    GO SLOWLY. As the methylation cycle block is lifted, toxins are mobilized and processed by the body, and this can lead to an exacerbation of symptoms. IF THIS HAPPENS, try smaller doses, every other day. SLOWLY work up to the full dosages.
    Although this treatment approach consists only of nonprescription nutritional supplements, a few patients have reported adverse effects while on it. Therefore, it is necessary that patients be supervised by physicians while receiving this treatment.

    [1] Yasko, Amy, Autism, Pathways to Recovery, Neurological Research Institute, 2009, available from http://www.holisticheal.com or Amazon.
    [2] General Vitamin Neurological Health Formula is formulated and supplied by Holistic Health Consultants LLC.
    [3] Hydroxy B12 Mega Drops is a liquid form of hydroxocobalamin (B12), supplied by Holistic Health Consultants. 2 drops is a dosage of 2,000 mcg.
    [4] MethylMate B is a liquid form of (6s)-methyltetrahydrofolate supplied by Holistic Health Consultants, based on Extrafolate S, a trademark of Gnosis S.P.A. 3 drops is a dosage of 210 mcg.
    [5] Folinic acid is 5-formyltetrahydrofolate. capsule is a dosage of 200 mcg.
    [5] Phosphatidyl Serine Complex is a product of Vitamin Discount Center. 1 softgel is a dosage of 500 mg.
    [7] Lecithin is a combination of phospholipids without phosphatidylserine. One softgel is a dosage of 1,200 mg.
  5. jj929

    jj929

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    high B12/folate but normal homocysteine and MMA......please help



    Thank you for your response, Rich,......this is extremely helpful!

    Just so I am clear, are you suggesting that I can take the xymogen product I mention above which contains 1000mcg of methyl b12 along with 2000mcg of hydroxycobalamin? Do you recommend that I start this gradually (i.e. open the capsule and divide the contents into smaller doses) in order to prevent adverse affects related to release of toxins?

    I have elevated lead levels which have not been addressed yet.....will correcting the methylation block enable the lead to be excreted naturally? I would appreciate any advice regarding this issue as it may relate to methylation protocol and/or detox process.



    Thanks again for your help!
  6. richvank

    richvank Senior Member

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    Hi, JJ.

    Yes, I think you can take them together, and yes, starting with a lower dosage at first would be a good idea, in my opinion.

    You won't absorb much of the methyl B12 from the oral product. They have set the dosage high enough that it would be adequate for a person who did not have ME/CFS. However, in ME/CFS, because of the glutathione depletion, there is a functional B12 deficiency rather than an absolute B12 deficiency, as in other people. This functional deficiency makes it necessary to use a much higher dosage of B12, and the only ways to get enough into the blood are sublingually, transdermally, liposomally, or by injection.

    If the lead levels are not too high, you should be able to get the methylation cycle and the rest of the sulfur metabolism working well enough that you will take out the lead normally. However, if it is too high, it may block enzymes too much, and in that case, you may have to chelate it first. Sodium calcium EDTA is a good chelator for lead. Make sure that you do not use disodium EDTA, because that can deplete calcium too much and can cause serious problems. I would encourage you to work with a physician on this type of treatment.

    Best regards,

    Rich
  7. jj929

    jj929

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    :confused:


    Rich, thank you for your response.

    I don't think I have ME/CFS, but as a lyme person I'm sure that I have some of the same issues as those with ME/CFS.

    As someone who is hetero C677T, would methyl b12 be easier for me to absorb than hydroxy b12? If so, would it be better for me to supplement the xymogen product with sublingual methyl b12?

    The last time I had a metals test done through Doctors Data I think my level was around 20 or 25. My lyme doctor wants me to chelate using DMSA and Detoxamin suppositories every 3rd night but have not started yet due to other health issues that have come up. Do you think that with this level of lead I should chelate first before attempting to lift the methylation block?

    I'm glad you mentioned not to use disodium EDTA, as I just realized that this what Detoxamin is......I will discuss this issue with my doctor.....thanks for bringing this to my attention. I have borderline osteopenia/osteoporosis and the last thing I need is to have calcium depletion.

    Thank you!
    JJ
  8. richvank

    richvank Senior Member

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    Hi, JJ.

    I would still suggest starting with hydroxo B12. Without some testing, there isn't enough information to decide which form would be best. If hydroxo B12 doesn't give you results, you could switch to methyl B12. Some people are not able to handle that, so I recommend starting with hydroxo B12 unless testing shows very low glutathione and SAMe.

    I don't know enough to say at what level on the Doctor's Data test lead needs to be chelated before trying to stimulate the methylation cycle. It also depends on whether the test was chelator-provoked or not, if so which chelator, and what the duration of the urine collection was. But even if I knew those things, I still don't know enough to answer your question. You may have to experiment.

    Best regards,

    Rich
  9. jj929

    jj929

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    Thank you, Rich, I will try what you suggest.

    JJ

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