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First Direct Evidence of Neuroinflammation - 'Encephalitis' - in ME/CFS
A small study with just nine patients has captured the attention of patients and researchers alike after reporting direct evidence of inflammation in the brain of ME/CFS patients. The finding was one of the highlights picked out by Professor Anthony Komaroff in his IACFS/ME...
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new article Multi-System Breakdown in CFS: Central Nervous System

Discussion in 'Neurological/Neuro-sensory' started by Jody, Sep 8, 2009.

  1. Jody

    Jody Senior Member

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  2. Freddd

    Freddd Senior Member

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  3. ramakentesh

    ramakentesh Senior Member

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    It also points to a MYRIAD of other mechanisms - perhaps ones that are readily demonstrated but its funny how people always jump to the more complicated and iffy mechanisms as their conclusion.

    The cognitive deficits in CFS could all be and according to a number of studies appear to cause by reductions in cerebral blood perfusion - either due to cerebral vasoconstriction (vasospasm) from inappropriate vasoconstriction or venous pooling.

    In most CFS patients there is also demonstratable sympathetic system activity - sympo-excitation which appears unopposed by parasympathetic responses.

    http://www.nymc.edu/fhp/centers/syncope/cfs.htm
    http://www.nymc.edu/fhp/centers/syncope/Vascular Dysfunction in CFS.htm

    Through a variety of mechanisms, the ultimate result is increased norepinephrine, reduced cerebral or thoratic volume and sympo-excitation.

    The immune system may be involved either by the aberrant release of vaso-active peptides such as substance-P or calcitonin gene related peptide. If this occurs in the stomach it would result in excessive endothelial nitric oxide release and excessive blood pooling in the stomach = reduced blood flow to the brain and cognitive deficits.

    Another mechanism could be occuring. Chronic inflammation from an auto-immune response to either to a chronic infection or some other mechanism results in the chronic increase in inflammatory markers like TNF alpha, the interleukins and c-reactive protein. C-reactive protein interfered with the catabolism of angiotensin II. Increased angiotensin II levels result in increased endothelial oxidisive stress and more importantly, reduces neuronal nitric oxide. This potentiates the effects of norepinephrine at the inter cynaptic cleft and you have chronic sympo-excitation.

    Chronic sympo-excitation, chronic inflammation and chronic reductions in cerebral blood flow account for the disfunctions found in the chronic fatigue syndrome and also accounts for the large number of patients that test positive for more obvious forms of orthostatic intolerance.
    taniaaust1 likes this.
  4. Freddd

    Freddd Senior Member

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    Hi ramakentesh,

    The simplest hypothesis is lack of active b12s and active folate. Their lack can afflict everything you mention. It does't have to get any more complicated than that. Methylb12 and methylfolate bring C-reactive protein down to the bottom of the scale as tissue heeling occurs. A lack of these causes chronic inflammation in endothelial and epithelial tissues. It also causes over-reactivity in the nervous system as well as under reactivity at other times and places. It massively affects the funtioning of the entire cnetral and preipheral nervous system of all varieties. They are invloved in regulating nitric oxide. You may describing in techincal terms some of the 600 or so things that go wrong with methylb12 and folate deficiencies. The study of cyanocobalamin, hydroxycobalamin and folic acid can entirely miss the boat on this as they don't cause the tissue healing and reduction of C-RP.
    taniaaust1 likes this.
  5. ramakentesh

    ramakentesh Senior Member

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    Yeah but my problem with it is that its all speculative. Most CFS patients arent found to have specific and obvious deficiencies in either. There could be other, yet to understood reasons for the improvement found from b12 injections in CFS.
  6. Freddd

    Freddd Senior Member

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    Hi Ramakentesh,

    Yeah but my problem with it is that its all speculative.

    That's not even intellectually true. Studies have found depressed CNS/CSF cobalamin levels in CFS/FMS patients. However, there is no understanding of that and standard blood draws don't detect that. How many folks do you know with this that get a spinal draw?


    Most CFS patients arent found to have specific and obvious deficiencies in either

    Every symptom of FMS and CFS are symptoms of active b12 and/or active folate deficiencies or of critical cofactors whose lack can prevent these from working. You are blinded by decades of lousy definitions based on inactive b12s like cyanob12 and hydroxyb12 and of folic acid. The standards set for "low" serum levels of low cobalamins are laughable. They are completely nonpredicitive of responses to active b12s which are documented to produce healing responses despite serum levels over 1500pg/ml, above the top end of usual cobalamin range, prior to treatment. Is it a shock to you that inactive psuedo vitamins are inactive and ineffective compared to the real thing?


    There could be other, yet to understood reasons for the improvement found from b12 injections in CFS

    There could be, but I think that is stretching to avoid the obvious. Don't forget quality sublinguals of active b12s also produce the same improvments and healing. So you want to invent a whole new explanation besides the obvious of why people, almost 100% of this group, respond to active b12s and active folate outside of a deficiency definition supported by hundreds of deficiency symptoms. I would say that you are working very hard to defend a laboratory mistake being awarded a mistaken Nobel prize. Why do you not want this class of people to have the benefit of the real vitamins? Why do you want to keep them sick?
  7. Freddd

    Freddd Senior Member

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    SYMPTOMS, SIGNS AND CO-CORRELATES OF METHYLB12, ADENOSYLB12,
    METHYFOLATE AND SELECTED COFACTOR DEFICIENCIES
    LAST UPDATE -
    Version 1.01, 12/01/09

    mouth sensitive to hot and cold
    sore burning tongue
    beef-red tongue, possibly smoother than normal
    sore mouth, no infection or apparant reason
    teeth sensitive to hot and cold
    canker sores
    burning bladder (no UTI)
    painful urgency (no UTI)
    burning urethra (no UTI)
    burning muscle pain
    accumulating muscle pains following exertion
    sore muscles
    lack of muscle recovery after exercise
    exercise does not build muscle
    extremely sore neck muscles reversing normal curvature of neck
    exercise deblitates for up to a week, making things much worse
    painfully tight muscles, especially legs and/or arms
    frequent muscle spasms anywhere in body
    muscle pain especially around attachment points to bones
    Eighteen severely tender muscle spots of FMS
    Bursitis
    dyspepsia - sick stomach, nausea, regurgitation, vomiting, bloating, not emptying
    flatulence
    altered bowel habits
    abdominal pain
    loss of appetite for meat, fish, eggs, dairy, the only b12 contining foods, nutrient specific anorexia
    intermittent constipation
    intermittant diarrhea
    irritable bowel syndrome
    Crohns disease (direction of causality if any not established)
    Celiac disease (direction of causality if any not established) - gluten sensitivity
    Dairy sensitivity
    sores, ulcers and lesions along entire GI tract or any part
    anorexia
    Bullimia
    reduced libido - loss of sexual desire
    loss of orgasmic intensity
    unsatisfying orgasms
    inability to orgasm
    loss and/or change of genital sensations - "gloved" loss of sensation
    burning genital skin sensation
    unable to become aroused
    reduced testosterone
    MEN
    erectile disfunction
    low sperm count
    poor sperm motility
    Poor sperm quality
    Zero sperm count
    WOMEN
    post partum depression
    post partum psychosis
    False positive pap smears, noncancerous cellular changes
    menstrual symptoms
    Frequent miscarriage
    child with neuro tube defects
    PMS
    paleness
    rapid heart rate
    heart arythymias
    shortness of breath
    heart palpitations
    weak pulse
    congestive heart failure
    arteriosclerosis
    Widespread pain throughout body
    Hypothyroid (direction of causality if any not established)
    High homocysteine
    High urinary MMA

    dizziness - even unable to walk
    vertigo

    irritable
    depression
    SAD - Seasonal Affective Disorder
    mental slowing
    personality changes
    chronic malaise
    poor concentration
    moodiness
    tiredness
    mood swings
    memory loss
    listlessness
    impaired connection to others
    mentally fuzzy, foggy, brainfog
    psychosis, including many of the most florid psychosis seen in literature, megoblastic madness
    Alzheimer's
    delirium
    dementia
    paranoia
    delusions
    hallucinations
    strange "smells" that are not present like linen being ironed, burnt odors or tidal flats etc
    strange "sounds" that are not present, rustlings, mummurings, detonations etc
    deja vu experiences
    anxiety or tension
    nervousness
    mania
    impaired executive function
    cognitive impairment
    memory impairment
    Hypersensitivity to touch
    Hypersensitivity to odors
    Hypersensitivity to tastes
    Hypersensitivity to clothing texture
    Hypersensitivity to chemicals
    Hypersensitivity to body malfunctions, symtoms
    Hypersensitivity to sounds and noises
    Hypersensitivity to light and visual stimuli
    Hypersensitivity to blood sugar changes
    Hypersensitivity to internal metabolic changes
    Hypersensitivity to temperature changes
    Hypersensitivity to foods
    mild to extremely severe fatigue
    continuous extremely severe fatigue
    easy fatiguability
    severe abnormal fatigue up to and including apparent paralysis leading to death
    spastic paralysis
    weakness

    sleep disorders
    non restorative sleep
    lack of dreaming
    Night terrors
    Prolonged hypnogogic state transitioning to sleep
    Sleep paralysis
    alteration of touch all over body, normal touch can be unpleasant and painful
    alterations and loss of taste
    alterations and loss of smell
    loss of smell and taste of strawberries specifically
    loss or alteration of smell and taste of potato chips specifically
    roughening and increased raspiness of voice, mb12 can smooth it outin mid word
    blurring of vision - can be sudden onset and sudden return
    dimmed vision - usually not noticed going into it because change can be very slow or present for life
    Visual impairment can be seen; ophthalmological exam may show bilateral visual loss
    optic atrophy
    optic neuritis
    optic neuropathy
    centrocecal scotomata
    intolerance to bright light
    diminished hearing - gradual onset or present for life, sudden return possible
    unclear hearing, garbled
    tinnitus - ringing in ears
    always feeling cold
    intolerance to loud sounds
    intolerance to multiple sounds
    inability to pick pick out one voice amongst many
    Brainstem or cerebellar signs or even reversible (with mb12) coma may occur
    neural tube defect not caused by folate deficiency or child with it
    demyelinated areas on nerves
    subacute combined degeneration
    axonial degeneration of spinal cord
    unsteadiness of gait
    ataxic gait, particularly in dark
    positive Romberg
    positive Lhermittes
    neuropathies, many types
    progressive bilateral neuropathies
    demyelination of nerves - white spots on nerves on MRIs
    loss of detail and sensual aspects of touch all over body
    paresthesias in both feet - burning, tingling,cobwebs, wet, hairs, pain, numbness, etc
    paresthesias in both legs - burning, tingling, cobwebs, wet, hair, pain, numbness, etc
    paresthesias in both hands - burning, tingling, cobwebs, wet, hairs, pain, numbness, etc
    paresthesias in both arms - burning, tingling, cobwebs, wet, hairs, pain, numbness, etc
    Loss of position sense is the most common abnormality (or vibration sense)
    Loss of vibration sense is the most common abnormality (or position sense)
    Loss of sense of joint position
    hands feel gloved with loss of sensitivity
    feet feel socked by loss of sensitivity
    trembling
    neuropathic bladder
    unable to release bladder, mild to severe
    urinary incontenance - occasionally to frequently
    fecal incontinance - occasionally to frequently
    sudden electric like shocks/pains shooting down arms, body, legs shooting down from neck movement
    standing with eyes closed, a slight nudge or bump causes loss of balance
    most patients have signs of both spinal cord and peripheral nerve involvement
    The effect on reflexes is quite variable
    Motor impairment may range from only mild clumsiness to a spastic paraplegia
    clumsiness
    slowed nerve impulses
    decreased reflexes
    difficulty swallowing
    brisk reflexes
    decreased deep tendon reflex
    toes turn up instead of down in reflex to sole stimulation
    Positive bilateral Babinski reflex
    Foot Drop
    impaired white blood cell response
    poor resistance to infections
    easy bruising
    pronounced anemia
    macrocytic anemia
    megablastic anemia
    pernicious anemia
    decreased blood clotting
    low hematocrit
    MCV > 92-94 first warning, MCV > 97-100 alert
    elevated MCH (Mean Corpuscular Hemoglobin)
    elevated LDH
    big fat red cells (when said this way usually with happy or healthy modifying it completely misinterpreting results of MCV
    platelet dysfunction, low count
    white cell changes, low count
    hypersegmented neutrophils
    migraine headache cycles
    headaches
    inflamed epithelial tissues - mucous membranes, skin, GI, vaginal, lungs, bladder
    inflamed endothelial tissues - lining of veins and arteries, etc
    high CRP without infection
    mucous becomes thick, jellied and sticky
    dermatitis herpetiformis, chronic intensely burning itching rash
    frequent infected follicles
    Seborrheic dermatitis
    dandruff
    eczema
    dermatitis
    skin on face, hands, feet, turns brown or yellow if anemia occurs
    poor hair condition
    thin nails
    transverse ridges on nails, can happen as healing starts
    splits/sores at corners of mouth
    Hyperhidrosis - excessive sweating
    Bariatric surgery
    glutathione, glutathione producing supplements such as NAC/glutamine
    Dilantin,
    tegretol and some other medications
    Relatives, grandparant, parent, sibling, child, grandchild ever needing b12 shots or supplement
    coma
    seizures
    brain atrophy with ileal tuberculosis preventing b12 absorbtion

    STARTING AS INFANT OR CHILD
    delayed myelination
    failure to thrive
    autism
    delayed speech
    depression
    frequent or continuous toncilitis
    frequent strep
    frequent pneumonia
    frequent longlasting supposed viral illnesses that linger and linger and linger
    everything goes to the lungs for extended periods
    headaches
    growing pains
    skin problems
    dandruff
    allergies
    asthma
    continuous swolen glands in neck
    low grade fever for years
    Night terrors
    Prolonged hypnogogic state transitioning to sleep and/or prolonged hypnopompia transitioning from sleep
    Sleep paralysis
    seizures
    coma
  8. Freddd

    Freddd Senior Member

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    Hi Ramakentesh,

    Here is a much more complete list of active b12 and active folate deficiency symptoms.

    This list was assembeled from USA based lists that are based largely on cyanocobalamin, UK, Australian, New Zealand lists based largely on hydroxycobalamin, India based lists based on a largely vegetarian population and Canadian with a mix of hydroxycobalamin and cyanocobalamin.

    The subset of symptoms based on cyanocobalamin has some overlap with the subset of symptoms based on hydroxycobalamin. As both of those non-active cobalamins are totally ineffective on approximately 1/3 of the population and are at best effective on about 1/3 of the total set of symptoms when they are effective, the lists based on either one is far from complete. Further they cover different subsets of symptoms so combining them produces a much larger view of deficiency. Further the list has had some one line descriptions expanded so the person who is asked if they have paesthesias and answer "no" will say "yes" to tingling, numbness, electrical shooting pains etc. Those who don't know Llermites from a hole in the ground recognize shooting electrical type pain.

    The list also includes widespread symptoms that diminish or go away with active b12s and methylfolate. Healing unfortutnately is rarely 100% of everything. People have damage that doesn't heal. 95% healing and restoration to normal life may be as good as it gets for many. They also have comorbid conditions that are uncovered when the majority of symptoms recede. Most of the symptoms can have more than one cause. However, a person that has 200 symtpoms is much more likely to have one or two conditions that can cause all of these than 20 different conditions that can't be healed. After being sick all my life with these multitude of apparantly untreatable unrelated conditions I am now healthy and have only a tiny fraction of the symptoms I had 6.5 years ago. And most of those are attributable to long term deficiency CNS and peripheral nerve damage or a car wreck.

    Further the list includes co-correlates, things like hypothyroid, that are associated with low b12 but don't necessarily heal with it. As many have the idea that low b12 only shows up with macrocytic anememia, this includes the widespread and much more common neurological and neuropsychiatric symptoms, which can often show up with "normal" blood cobalamin because these central symptoms depend upon the cerebral spinal fluid levels of BOTH active b12s. There are actually 4 distinct b12 deficiency patterns.
    1. Body methylb12
    2. Body adenosylb12
    3. CNS methylb12
    4. CNS adenosylb12
    Thes 4 patterns are further complicated by lack of active methylfolate. 20% of the population can't convert folic acid AT ALL to methylfolate. 50% can't convert it to the biological limit of about 800mcg/day. For many, the 800mcg per day is not adequate. A "normal" folate level is not indicative of lack of responsive symptoms to methylfolate. A "normal" cobalamin level does not indicate a lack of responsive symptoms to methylb12 or adenosylb12. A "normal" MMA does not predict adequate adenosylb12 or a lack of response to adb12. A "normal" HCY does not predict adequate methylb12, methylfolate or p-5-p or a lack of responsive symptoms. "Normal" MCV and MCH do not predict adequate mb12, methylfolate and p-5-p or lack of responsive symptoms.

    This is further complicated by missing critical cofactors which can almost completely prevent response to active b12s and methylfolate including; zinc, D3, magnesium, l-carnitine fumarate, SAM-e, B-complex TWICE a day and probabvly some others.

    Lack of adb12, mb12 and methylfolate cause breakdowns in over 600 processes in the body. There are tests for three of those breakdowns.

    Following the locgic you do I was condemned to a lifetime of ill health and misery and an early death. Making a more complete definition of "b12 deficiency" allowed me to be healed. There should be no surprises on the composite list as virtually all items show up on other lists. In fact I am going to be revising it shortly as I have found another reputable list that includes items not included on this list.
  9. aquariusgirl

    aquariusgirl Senior Member

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    This is utter tripe.

    Paul Cheney has been saying for years that PWCs have no b12 in the brain & I although I intellectually understood this, it wasn't until recently that I proved it to myself.

    I've been taking b12 ...mostly high dose hydroxocobalamin ..for years without any real noticeable effects.

    I finally found I could tolerate methyl b12 in significant quantities if I took it with Valtrex.. which presumably reduced my oxidative stress levels.

    It is helping significantly with brain function. The b12 that is. (i've taken the valtrex on its own..so I can tell the difference.)

    I am so pissed. We know that lack of B12 causes brain shrinkage....so just imagine the damage to my brain from the long term deficiency I have suffered.

    The problem with this whole issue.. is testing. Serum B12 tests are misleading and serum folate tests can be too under certain circumstances.

    Richvank has explained this very well.

    But pls, PLEASE, do not mislead people by saying these deficiencies are speculative. They are the root of our illness.
  10. Freddd

    Freddd Senior Member

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    Hi Aquariusgirl,

    I have been dealing with family situations for some while and decided to stop in when I saw your reply. I'm glad to hear that you are having good results. I do wonder what the Valtrex connection is; very curious. I suspect that the entire B12/folate deficiency problem is largely definitional. As the definitions of "deficiency" symptoms is based on the very limited activity of the two faux b12s, cyancbl and hydroxycbl and folic acid, when the actual active mb12, adb12 and methylfolate are looked at they produce more results, more complete results, on a lot more symptoms for a lot more people. Also the balance between these three things does appear to make potentially substantial differences. I am finding that larger doses of Metafolin produce more beneficial results with the larger mb12 doses. Also doses of adb12 that are too large relative to mb12 appear to produce certain central mb12 deficiency changes, especially in mood and personality.

    The recent research pointing at long term mitochondrial malfunction leading to neuron damage producing Parkinson's, thought to be detectable perhaps 20 years in advance by early symptoms, the depressed CSF cobalamin (not distinguishing types) in other recent research in Parkinson's (and CFS/FMS and Alzheimer's) and that the 20 year previous to diagnosis symptoms of Parkinson's appear to line right up with the CNS symptoms of adb12 deficiency look very suggestive.

    An MS diagnosis is supposed to rule out b12 deficiency first. How in blazes can they actually do that with tests based entirely on expectations based on cyanocbl and hycbl? So if they don't find homocysteine, MMA and have serum levels over 200pg/ml they rule out b12 deficiency? And yet many many people with MS have profound results when they try the mb12, adb12, l-carnitine fumarate etc.

    At this point, rapidly approaching plus 8 years after starting mb12, the vast majority of symptoms are just plain gone and never came back even with my most severe damage (subacute combined degeneration) suffering some setbacks for various reasons. The list a few posts up is still quite accurate in predicting what will respond to these things. I am refining it to distinguish as well as I can at this point the 4 categories of b12 deficiencies.

    I'm not happy either about all the CNS damage I suffered from the lack of the active b12s in doses that penetrate the CSF/CNS. Good luck and good health.
  11. alex3619

    alex3619 Senior Member

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    Hi aquariusgirl, I have no doubt that methylation cycle problems are part of the symptomology of ME/CFS. I also have not doubt that select folate and B12 preparations are beneficial in ME/CFS. I am one who fits both cases, and I take activated folate.

    It is extremely premature to call any of this the root of our illness. Its a part, certainly, but we have yet to prove exactly where it fits. Its like claiming XMRV is entirely the cause of our illness. I'm a big fan of XMRV research, but its not proven causal till its proven causal. It the same for the methylation cycle hypothesis - we still need more research to know where it fits.

    Bye
    Alex
    taniaaust1 likes this.
  12. Freddd

    Freddd Senior Member

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    Hi Alex,

    "Proof" may be 50-100 years away. In the meantime the best we likely can get is demonstrations of pronounced healing. While something CAUSES these deficiencies, it's hard to get more fundamental/root than vitamins.

    If people follow the procedure outlined many can demonstrate to themselves that they can have healing to the point of being able to gradually start exercising and rehabilitation in 6-12 months. Cofactors are very important in this.

    The problem with XMRV or any other virus, bacteria, protozoan (ie Giardia) or traumatic injury being "proven" as THE cause is that they all may be causes. Many of us got triggered by a very definite obviously infective illness with many others around us also being ill with the same illness. The difference is that some people are triggered into an aftermath that lasts possibly the rest of their life. Perhaps these people are on the border and are pushed over the edge by any of many possible triggers from which they can't recover without additional input of the active b12s and folate. Then there are a variety of complicating genetic factors, aging factors and so forth. Another problem is that despite looking intensively for any actual research evidence of the re-establishment of the entero-hepatic b12 recirculation loop nobody was able to find any. Conventional treatment aqssumes that the body is "recharged" with a few mgs of inactive cobalamins (or active for that matter) and that then monthly or quaterly injections do the trick. The only problem is that it doesn't actually work for most things. It can be easily demonstrated that it takes months of daily doses of active b12s to recharge the depleted body and that symptoms start reappearing about 3 days after the last mb12 dose regardless of size of how given. Adb12 may last a few days to a few weeks before reappearance of those specific symptoms. This can be easily demonstrated as many have done for themselves. It takes a really determined person to decide to remain ill to support some researchers theoretical stances that can be demonstrated to not correspond to how the active b12s actually perform in many people while those same researchers may be absolutely correct about the effects of hydroxcbl and cyanocbl. I don't believe that people should sacrifice their life or health to support a theoretical stance, but it is their choice of course.

    I'll tell you what. If you want to sponsor a team of those with suitable CFS/FMS without comorbidities or injuries and I will sponsor a matched pair team of the same and we have 2 years from the start of treatment for healing and rehabilitation and they prepare for 5k races 3 days in a row, how much would you bet on the active b12/folate etc team versus the inactive cobalamin team? I pick 5k 3 days in a row as an absolutely impossible task for those CFS/FMS and quite doable for those who have healed. However, as many of us have conditions of old injuries, as do I, that might make actual running impractical, it could be 40 minutes of aerobic swimming or treadmill or whatever to specified aerobic levels. No person with CFS/FMS could do that as far as I know and it is a reasonable thing for even us late middle aged folks who are no longer ill with CFS/FMS. I personally experienced a number of such triggers in my life recovering in a year or two from mono, unknown viruses and the like until the ones I didn't have any recovery from for 17 years. Then we could discuss meaningfully what is fundamental.
  13. Glynis Steele

    Glynis Steele Senior Member

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    Hi all,

    Hope no-one minds me putting this here, it's a paper on d-lactate and b12 deficiency, and thought it might be of interest.

    Abnormal Fecal Lactobacillus Flora and Vitamin B12 Deficiency in a Patient With Short Bowel Syndrome
    Hojo, Kenichi*; Bando, Yuki†; Itoh, Yoko†; Taketomo, Naoki*; Ishii, Masahiro†

    Free AccessArticle Outline
    Author Information*Food Science Institute, Meiji Dairies Corporation, Odawara, Japan

    †Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Japan

    Received October 10, 2006; accepted May 23, 2007.

    Address correspondence and reprint requests to Kenichi Hojo, Food Science Institute, Meiji Dairies Corp, 540 Naruda, Odawara, Kanagawa 250-0862, Japan (e-mail: kenichi_houjou@meiji-milk.com).

    The authors report no conflicts of interest.
    Lactobacillus overgrowth has been reported in patients with short bowel syndrome (SBS) (1-4). We previously reported D-lactic acidosis that Lactobacillus overgrowth caused in a male SBS patient (5). He had severe anemia related to vitamin B12 deficiency 9 years later. It has been generally accepted that B12 deficiency in SBS patients results from the inadequate absorption of B12 and/or the bacteria-host competition for uptake of B12 (6). In the present study, we suspected the recurrence of Lactobacillus overgrowth as a possible cause, because some lactobacilli require B12 for growth. Therefore, we analyzed the fecal flora and the B12 auxotrophy of Lactobacillus isolates.
    Back to Top | Article Outline
    CASE REPORT
    A 14-year-old boy presented in June 2005 with severe anemia and complaints of general fatigue. His medical history included an extensive small-bowel resection to treat obstructive ileus in September 1995. Subsequent malabsorption was treated with intravenous hyperalimentation and elemental diet for 2 months. The first attack of D-lactic acidosis was observed in this patient in early 1996. Similar attacks were observed 6 times in 5 months. Bacterial analyses revealed an increase of D-lactate producers, namely Lactobacillus delbrueckii subsp. lactis. We concluded that this increase was responsible for the D-lactic acidosis attack (5). Before the June 2005 presentation, he had been free from D-lactic acidosis for 9 years.
    The laboratory findings on admission suggested megaloblastic anemia with pancytopemia. The serum B12 level was <50 pg/mL (reference range 180-914 pg/mL), unsaturated B12-binding capacity 2351 pg/mL (650-1340 pg/mL), serum folate 6.5 ng/mL (>3.1 ng/mL), serum iron 83 μg/dL (48-154 μg/dL), hemoglobin 4.2 g/dL (14-18 g/dL), and red blood cells 149 104 cells/mm3 (410 104-530 104 cells/mm3). The levels of other vitamins such as B1, B6, A, and E were normal. Bone marrow aspirates showed megaloblastic erythropoiesis; therefore, megaloblastic anemia due to B12 deficiency was diagnosed. He was treated with physiological doses (1000 μg/day) of B12 (Methycobal, Eisai, Tokyo, Japan) by intramuscular injection. Given 5 days of treatment, serum B12 level recovered within 2 weeks and the other hematological parameters normalized within 1 month. Subsequently, he was treated with B12 by mouth for 6 months without any other complication.
    Back to Top | Article Outline
    MICROBIOLOGICAL STUDIES
    Fecal samples were obtained in September 2001 at a periodical medical checkup (during normal conditions) and in July 2005, when the patient was hospitalized (during B12 deficiency). Bacteriological analyses were carried out using methods described in a previous study (5,7). As shown in Table 1, the number of lactobacilli and the percentage of lactobacilli in the total bacteria count during B12 deficiency (9.45 log10 CFU/g and 45.2%) were higher than during the normal conditions (9.16 log10 CFU/g and 8.6%). During B12 deficiency, the number of bacteroidaceae, eubacteria, clostridia, and anaerobic cocci was <107/g in the fecal sample (Table 1).
    Table 1
    Image ToolsWe obtained 35 Lactobacillus isolates from the feces sampled during normal conditions, and 45 isolates from the B12-deficient sample. Lactobacillus isolates were identified by 16S rDNA sequence similarity (>98%) and a species-specific polymerase chain reaction method described by Torriani et al (8). The 16S rDNA sequence analysis could not discriminate clearly between L pentosus and L plantarum, or between L gasseri and L johnsonii. Table 2 shows that L fermentum was the predominant species, followed by L pentosus/plantarum and L gasseri/johnsonii, during the normal conditions. During B12 deficiency, L gasseri/johnsonii was predominant, followed by L mucosae and L delbrueckii subsp. lactis. We explored whether L delbrueckii subsp. lactis isolates in this study were the same strains that caused D-lactic acidosis in our previous study (5). Randomly amplified polymorphic DNA analysis (9) revealed that the isolates obtained in the present study were different from the previous isolates.
    Table 2
    Image ToolsTo determine the B12 auxotrophy of Lactobacillus isolates, each isolate was anaerobically inoculated in a chemically defined medium (10) with or without B12 (40 μg/L) for 24 hours at 37C. As shown in Table 2, all of the isolates of L gasseri/johnsonii and L delbrueckii subsp. lactis required B12. During the normal conditions, the ratio of these B12 auxotrophs to the total bacteria was only 1% in the feces (Table 2). Surprisingly, the population of B12 auxotrophs was one fourth (25.8%) of the total fecal flora during B12 deficiency.
    Short-chain fatty acids in feces, urine, and serum samples were identified using a high-pressure liquid chromatography system (Shimadzu, Kyoto, Japan) (11). D- and L-lactate concentrations in the samples were identified by an enzymatic method (Boehringer, Mannheim, Germany). The serum lactate levels during B12 deficiency (D-lactate, 0.93 mmol/L; L-lactate, 2.82 mmol/L) were excessively higher than those during the normal condition (D-lactate, 0.04 mmol/L; L-lactate, 1.51 mmol/L) (Table 3). Moreover, the fecal D- and L-lactate levels during B12 deficiency were 23.82 mmol/kg and 37.13 mmol/kg, respectively; these levels were higher than those during the normal conditions (1.13 and 2.18 mmol/kg, respectively). The pH of fecal samples during the normal conditions and B12 deficiency was 5.6 and 4.5, respectively.
    Table 3
    Image ToolsBack to Top | Article Outline
    DISCUSSION
    Valman and Roberts (12) measured B12 absorption in SBS patients who underwent ileal resections in childhood. They found normal B12 absorption in infants in whom the residual terminal ileum was ≥15 cm in length. In our patient, the residual terminal ileum with an intact ileocecal valve was about 52 cm in length when he was operated on for intestinal volvulus. In light of the previous article (12), the length and segment of the residual terminal ileum are sufficient for normal B12 absorption. In the present study, therefore, we examined whether intestinal bacteria were associated with B12 deficiency in our patient. Bacteriological analyses in feces revealed that the ratio of fecal lactobacilli to total bacteria during B12 deficiency (45.2%) was higher than that during normal conditions (8.6%) (Table 1). The number of bacteroidaceae, eubacteria, and clostridia, which are usually predominant in human feces (7), was <107/g. This may be related to the lactobacilli overgrowth because the overproduced lactate would suppress the other bacteria. In fact, the fecal pH during B12 deficiency was extremely low, and total lactate concentration in the feces during B12 deficiency was extremely high. From these results, we presume that Lactobacillus overgrowth recurred in this patient.
    In humans, the relation between the microorganisms that constitute the intestinal microflora and B12 metabolism has been discussed. From this viewpoint, the ratio of B12 producer/consumer may be crucial for B12 uptake. In this report, L gasseri/johnsonii and L delbrueckii subsp. lactis required B12. Surprisingly, the ratio of these B12 auxotrophs during B12 deficiency (25.8%) was much higher than that during normal conditions (1.0%) (Table 2). It is known that patients with SBS have a predisposition to B12 malabsorption because of ileal resection and bacterial overgrowth (6). In the present study, we cannot rule out possible causes other than bacterial competition for uptake of B12, especially the inadequate absorption of B12, because we did not carry out a Schilling test for the determination of B12 absorption ability. Moreover, because our patient went through pubertal growth at about 11 years of age, it is not evident whether B12 deficiency was under the influence of pubertal growth. However, the possibility that lactobacilli may compete with the host for the uptake of B12 was implied by the finding that predominant Lactobacillus species required B12. The B12 auxotrophic lactobacilli apparently competed for uptake of B12 with our patient. To our knowledge, this is the first case indicating that B12 deficiency may be attributable to the overgrowth of the Lactobacillus strains.
    Here, we would like to address a question: Why did our patient evade D-lactic acidosis despite the recurrence of Lactobacillus overgrowth? The serum D-lactate level during B12 deficiency (0.93 mmol/L) was higher than that during normal conditions (0.04 mmol/L) (Table 3); however, it was lower than that observed at 1 day after the attack of D-lactic acidosis in our previous study (2.32 mmol/L) (5). Before and during the episode of anemia, our patient had no typical D-lactic acidosis symptoms such as confusion, speech disturbance, and unusual behavior. We can suggest at least 2 possible explanations. One is dietary management, including carbohydrates, with related changes in the bacterial cell counts of D-lactate producers. Mayne et al (13) suggested that manipulation of carbohydrate intake may be used to treat severe, recurrent D-lactic acidosis in a patient with SBS. We had instructed our patient to avoid large amounts of simple carbohydrates after the onset of D-lactic acidosis (5). Therefore, restricted sugar administration probably contributed to the prevention of D-lactic acidosis. The second possible explanation is the difference in the bacterial cell counts of D-lactate producers. The number of lactobacilli that produced D-lactate was 9.0 log10 CFU/g in our previous study (5), whereas the number of D-lactate producers, namely, the isolates of L delbrueckii subsp. lactis, was 8.3 log10 CFU/g in the present study (Table 2).
    In conclusion, it is evident that lactobacilli overgrowth recurred in our patient. Moreover, B12 auxotrophic Lactobacillus species increased during B12 deficiency. We believe that the overgrowth of these B12 auxotrophs may be implicated in B12 deficiency, although other causes were not excluded, such as the inadequate absorption of B12. From the results presented in this study, our patient seems to be predisposed to lactobacilli overgrowth; therefore, the lifelong control of intestinal flora would be required for the patient with SBS. Restricted intake of simple carbohydrates seems promising to improve and/or prevent abnormal intestinal Lactobacillus flora. In addition, routine hematological analyses, including minerals and vitamins, are needed for the detection of nutritional deficiencies before clinical symptoms occur.

    Glynis
  14. aquariusgirl

    aquariusgirl Senior Member

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    Very interesting Glynis.
    So if one had d lactic acidosis & a methylation block.. it would be a double whammy if I understand correctly.
    Do you know if d lactic acidosis is often seen with gastroparesis?
  15. aquariusgirl

    aquariusgirl Senior Member

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  16. Freddd

    Freddd Senior Member

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    Hi Aquariusgirl,

    Bacterial overgrowth is a moderately common known cause of b12 deficiency. A very recent study indicated that certain antibiotics were effective in clearlng up the overgrowth thereby relieving the IBS which itself is a common symptom of b12 deficiency (and FMS). Howver, the relief only lasted for about 3 months before bacterial overgrowth occurred again. Three months is not long enough to restore b12 status to normal. Sublingual b12 avoids the entire set of problems around intestinal absorption. and improves the immune system.
  17. richvank

    richvank Senior Member

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    Hi, Freddd.

    It's good to see you back posting here again. I've missed you, and was wondering if you were O.K. I've tried to represent your views to people asking about your protocol, while you were gone, and hope I have done so accurately.

    Best regards, and welcome back!

    Rich
  18. Freddd

    Freddd Senior Member

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    Hi Rich,

    Thankyou. It's been a rough period in so many ways. My daughter in law is having problems and nobody knows why and is currently seeing one specialist after another. I have a few questions I want to ask you specifically about software. I've been doing some reading and have a lot of catching up to do. I have been prototyping some software in Excel and now comes taking what I learned in that and coming up with some algorithms that work, fast enough, somewhere between brute force and elegance. The latest research on Parkinson's appears to point at damage from a long term neurological mitochondrial malfunction which combined with the previously found low csf cobalamin level, and I'm currently collecting data on Parkinson's symptoms 20 years before diagnosis and that points right at the same mitochondrial neurological symptoms of adb12 deficiency of the CSF/CNS that so many demonstrate. It is exactly what my prototype software model demonstrates. It's kind of spooky it lines up so well. I need a lot more data and that is the software I am designing now.

    In looking things over I see you have been holding the fort and want to thank you for doing so.
  19. richvank

    richvank Senior Member

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    Hi, Freddd.

    I'm sorry to hear about your DIL's situation, and hope someone will be able to sort it out and help her soon.

    I'm glad to hear that you are working on Parkinson's. I just want to note that Dr. Amy Yasko has reported that prior to shifting her focus mainly to autism, she had a private practice in which she treated several cases of adult neurological diseases, including Parkinson's. She found that treating the methylation cycle was also helpful in these disorders.
    Of course, B12 and folate would have been part of the treatments she used.

    I'm somewhat puzzled by your suggestion of the involvement of adenosyl B12 in Parkinson's though. As you probably know, the brain normally operates primarily on glucose as a fuel. Adenosyl B12 is used to feed some of the amino acids as well as odd-chain fatty acids and propionate into the Krebs cycle in general, via the methylmalonyl CoA pathway. But I'm not aware that the neurons use these much for fuel. So I would suspect that methyl B12 may be the important one, because of its role in controlling oxidative stress, which can impact the mitochondria.

    Another thing that might be relevant is the recent discovery of the benefit of coconut oil in Alzheimer's disease. The mechanism is that coconut oil is high in medium chain fatty acids. When they get to the liver, much of them is converted to ketones, some of which make it to the brain via the blood. As you are probably aware, the brain is able to use ketones as an energy source, though glucose is normally its main energy source. Ketones are fed into the Krebs cycle, and don't go through glycolysis and the pyruvate dehydrogenase complex, as does glucose. Apparently there is a partial block at the pyruvate dehydrogenase complex in Alzheimer's, so glucose is not able to feed the Krebs cycle and thus the mitochondria. But the ketones can, and that apparently fuels the neurons that are having problems in Alzheimer's.

    Again, welcome back!

    Rich
  20. Freddd

    Freddd Senior Member

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    Hi Rich,


    I started advising HMO clients back in 1981-83 to design their data systems to include the information needed for effective “data mining” despite the term not being invented at that date. However, the limited data-set size at that time precluded having all the information needed included in medical records. Data-sets were saved on tape, often by company or group and even year and reloaded as needed for batch processing. In using any active monitoring for alerts, backtracking has to be possible and insufficient data was preserved to allow backtracking of diagnoses, etc. That is no longer the case with t-byte drives being available even a desktop or portable PC can do an immense amount of review and processing. Give me a million person database with all the right info included and there is a huge amount to be learned that could improve the health of large numbers of people.



    I'm somewhat puzzled by your suggestion of the involvement of adenosyl B12 in Parkinson's though. As you probably know, the brain normally operates primarily on glucose as a fuel. Adenosyl B12 is used to feed some of the amino acids as well as odd-chain fatty acids and propionate into the Krebs cycle in general, via the methylmalonyl CoA pathway. But I'm not aware that the neurons use these much for fuel.


    “I'm somewhat puzzled” – Actually so was I until I went looking for it because I too believed the glucose description. Even so I don’t know how much of the metabolism is based on adb12/mitochondria activity but it is very clear that some is. I don’t have the money to read all the latest things or any that require payment. But the quote below indicates it was known at least back to 1998. With the recent publication, (in the news recently but I don’t have a reference) that it appears that Parkinson’s has CNS neuronal mitochondria malfunction dating back 20 years with non-specific symptoms long before diagnosable symptoms appear and prior to that, there being low CSF levels of cobalamin, that elevated MMA is found in the CSF of Parkinson’s patients along with elevated Hcy whereas MS patients just have elevated Hcy and low CSF cobalamin levels. As MMA is an indicator of a specific mitochondrial malfunction, this is quite interesting. There are many articles now indicating elevation of CSF MMA and/or Hcy in many neurological disorders.


    http://msj.sagepub.com/content/9/3/239.abstract
    [FONT=&quot]Cerebrospinal fluid methylmalonic acid concentrations in neurological patients with low and normal serum cobalamin concentrations[/FONT]


    Objective – To determine whether cerebrospinal fluid (CSF) methylmalonic acid (MMA) is increased in neurological patients with low serum cobalamin (Cbl, vitamin B12) concentrations as opposed to neurological patients with normal serum Cbl concentrations. Material and methods – We measured MMA concentrations in serum and CSF of neurological patients with low serum cobalamin concentrations, but without overt cobalamin related manifestations such as anemia or combined disease of the cord, and neurological patients with normal serum cobalamin concentrations (controls). Results – Serum and CSF MMA concentrations were significantly higher in patients than in controls. Serum MMA was elevated in 4 patients of whom 3 had clearly elevated CSF MMA concentrations. Conclusion – Strong indications for cobalamin deficiency can be found not only in serum but also in CSF of patients with seemingly asymptomatic low serum cobalamin concentrations.

    I dispute the seemingly asymptomatic statement. The symptoms are quite clearly there if one knows what to look for. They are of course contained in that set of symptoms called "non-specific" and ignored by all docs for decades until somebody's body starts having serious breakdowns of functioning such as CFS, FMS, Alzheimer's, Parkinson's ALS MS, subacute combined degeneration, possibly heart attacks and strokes and who know what else. MMA and HCY as well as all those bood changes don't happen in actually healthy people, the are NOT the beginning of breakdown but the markers that damage is already well under way for possibly 20 years.

    So now we take the research evidence of CSF MMA and/or CSF Hcy and we start to have a matrix of characteristics. We have evidence of “low csf cobalamin” in Parkinson’s, MS, CSF, FMS, Alzheimer’s, ALS and probably some additional ones. We have specific evidence of elevated CSF MMA AND Hcy in Parkinson’s and ALS but of Hcy only in MS. So it is pretty clear that brain neurons do indeed have some degree of mitochondrial adb12 energy production and it makes a difference in how the neurological disease manifests and develops.

    As you point out I appear to have certain genetic characteristics. I appear unable to interconvert most forms of cobalamin to sufficiency. If demonstrated pragmatically, so do a sizable percentage of those posting on Phoenix. I appear to have problems getting adequate active folate from folic acid which includes at least half the population generally and probably more than that of those posting here which can be demonstrated pragmatically. Further I appear to have difficulty with transport of cobalamins into the CSF and probably with the retention of cobalamins in the CSF (from research it appears to be 2 separate problems and may very well be genetic), as is likely with most everybody with CSF and/or FMS. FMS, CSF, ALS, MS, Alzheimer’s all appear to have various combinations of these 5 specific deficiencies already described plus probably some additional ones including most specific certain fatty acids as you point out which are used in myelin generation plus probably other uses.


    Then let’s take that one more step. I have been able to document in myself and others both on the Phoenix forums, and specific b12 deficiency forums that there are 4 specific differential symptoms sets of mb12 and adb12. There is the body-adb12, body-msb12, CSF-adb12 and CSF—mb12. A further complicating factor is methylfolate deficiency. I don’t have any information indicating whether there is or is not a CSF deficiency separate from a body methylfolate deficiency. There are a further set of potential critical factors that complicate the matrix of symptoms sets.

    So when we look back to the “non-specific” and earliest symptoms of people who later develop Parkinson’s in my spreadsheet and already identified as CSF-adb12 deficiency symptoms, we find most all of those earliest of “pre- Parkinson’s” symptoms.

    As regards MS symptoms, most of them can be put into substantial long term remission with large enough SC mb12 injections with critical cofactors, to penetrate the CSF by diffusion of the correct neurologically active mb12. However, this requires 1-3 10mg SC injections per day to maintain the remission and most injectable mb12 is near worthless due to light exposure and/or variety of mb12 crystal. Because of my damage and genetic characteristics I can distinguish the most neurologically active mb12 from that which apparently works well for everything else except the neurons in anywhere from 2 hours after injection to 1 week, depending upon how superior or inferior the specific mb12 happens to be. For the worst of the injectable mb12 a single sublingual Enzymatic Therapy or Jarrow sublingual mb12 will be noticeably superior after 3 days to 1 week. There is just as much variation amongst injectable mb12 as there is amongst brands of sublingual mb12. This of course confounds all sorts of studies and causes poor results in some studies when they ought to produce excellent results.

    I am currently engaged in getting in depth lifetime symptoms and medical history from a few persons with Parkinson’s. This isn’t a mass data gathering but rather for prototyping. .I’ll let the software do the mass gathering. So far there are no surprises at all. The symptoms do indeed show up 20-40 years earlier and are essentially identical with those found in the b12 deficiency symptoms, CSF-adb12 subset with some of the less obvious mb12 specific symptoms. As basically NONE of them are hydroxycbl or cyanocbl correctable symptoms they generally are not recognized as b12 deficiency symptoms officially. And since CSF Hcy and MMA don’t generally show up as serum or urine increased levels no clue there and can occur with much of the “normal” range of serum cobalamin. The entire problem of early diagnosis might come down to failure to generally recognize the CSF-adb12 and/or CSF-mb12 symptoms because of the 60 year legacy of a lab mistake and the added weight of decades of research on the lab mistake and it’s inactive successor.

    While I might say “95% recovery or so across the board with most symptoms 100% gone and some remaining, almost nothing unchanged” what does that actually mean in indirect measures. I am rehabilitated. I can work up to and maintain whatever level of aerobic fitness I am willing to give the time to. I can walk 5 miles and do that each day. I can work in the garden with pick and shovel for hours at a time. I can go hiking. I would even consider going skiing again if I had the money and medical insurance as I can’t afford to get injured. I’m not in a wheel chair. I’m not falling down. I can balance on one foot. I haven’t had an “accident” of incontinence in 8 years. I don’t have acid rising into my throat each night, I don’t vomit daily, I haven’t had a cold in 7 years. I haven’t been sick in 7 years except for H1N1 flu last year and it was mild. I haven’t had a pneumonia or two. I don’t have multiple chemical sensitivity any more. I don’t have daily chronic headaches, muscle spasms all over uncontrollably, no more IBS, CFS, FMS etc. I have a life again. Now for the quantifiable.

    As my 8th anniversary my 5 star mb12 startup approaches I have reached the 7th anniversary of the beginning of large savings on my medical and pharmacy costs. My pharmacy costs went down about $1000/month of previous to that next year and stayed down. Over the next year or so my physician visits fell off more than 50% to the minimum needed to maintain my remaining prescriptions and my tests fell off about 90%. In the past 7 years I have saved approximately $100,000 which is the difference between being homeless and having a place to live. I feel decent at least instead of in continual misery.


    Applying a little game theory would appear to indicate that we as a country can’t afford to ignore the possibility that what I am saying is essentially correct. For instance b12 deficiency has to be “ruled out” for a diagnosis of MS, and the test is applied to serum but not CSF despite the KNOWN deficiency in the CSF of those with MS, there is probably not a single case of MS in which CNS/CSF b12 deficiency has actually been ruled out.. People with MS tend to have HUGE responses to 10mg SC injections of neurologically active mb12. The Japanese research into large doses of mb12 indicates recovery of function occurs in MS and ALS as long as the sizable doses continue. The stakes we are playing for here amount to perhaps 100,000,000 people in the USA alone at a lifetime cost $100,000 to $1,000,000 per person not including loss of wages. That comes out to an estimated value of $100,000,000,000 to $100,000,000,000,000. If I am even 1% correct we are still talking a 1 billion to 1 trillion dollars for the people presently alive. If I am completely correct we are speaking 100 trillion dollars in today’s dollars, the difference between bankrupting health care in the USA and making it affordable.

    Of course methylation failure is a major player here as half or so of all the mb12 symptoms are a result of methylation failure. Methylfolate appears to improve both mb12 and adb12 response in a good 50% of people

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