B-12 Deficiency in ME/CFS and FM May Provide Clues & Relief (Footnoted Version)
By Dana Myatt, NMD, Mark Ziemann, RN* •
April 11, 2008
The “triggers” that initiate ME/CFS and other multi-system illnesses - Fibromyalgia (FM), Multiple Chemical Sensitivities (MCS), Lyme disease, Post Traumatic Stress Disorder (PTSD) and Gulf War Syndrome - are numerous and varied. However, because these diseases ultimately have consistent and often-overlapping symptoms, researchers believe there may be biochemical abnormalities common to all sufferers.
If a common biochemical abnormality can be identified, treatments directed toward this alteration might hasten resolution or at least provide significant improvement for those afflicted.
In the quest for a “unifying theory” of ME/CFS and related multi-system diseases, two models have emerged that have gained much scientific credibility. Research is revealing a connection between these complicated and misunderstood diseases and an equally complicated and misunderstood vitamin that may hold the key to improved health for many.
The Vitamin B-12 - ME/CFS/FM Connection
In searching for common biochemical threads among ME/CFS/FM victims, researchers have noted that symptoms of vitamin B-12 deficiency closely parallel those of ME/CFS and other multi-symptom diseases. In fact, symptoms overlap to such a great extent that many respected ME/CFS/FM researchers and physicians - including Drs. Paul Cheney, Charles Lapp, Kenny DeMeirleir, Jacob Teitelbaum, and Martin Pall - consider vitamin B-12 a mainstay of supportive treatment. (1-6)
One study found improved energy levels even in people who were not deficient in vitamin B-12 but were administered the vitamin anyway. (7) B-12 (2,500–5,000 mcg) administered every two to three days was associated with improvement in 50% to 80% of a group of people with ME/CFS. Most improvement was seen after several weeks of vitamin B-12 administration.(8)
The Curious Symptoms of Vitamin B-12 Deficiency
Best known for participating in the manufacture of red blood cells, B-12 is also needed for production and maintenance of the myelin sheath that surrounds nerve cells, and for manufacture and maintenance of DNA. (9-12) Participating in nearly every function of the body, vitamin B-12 deficiencies have widespread consequences.
- Energy. Even minor deficiencies of vitamin B-12 can cause anemia, fatigue, shortness of breath and weakness. (9,10,13)
- The Nervous System. Deficiencies of B-12 can cause neurological changes including numbness and tingling in the hands and feet, (13,14) balance problems, depression, confusion, poor memory and Alzheimer's-like symptoms. (15) Long-term deficiencies of B-12 can result in permanent impairment of the nervous system. (16,17,18,70,71)
- The Gastro-Intestinal System. B-12 deficiency can cause decreased appetite, constipation, diarrhea or alternating constipation/diarrhea (also called Irritable Bowel Syndrome), weight loss and abdominal pain. (9,10,13)
- The Immune System. Vitamin B-12 is necessary for normal functioning of white blood cells. (19) Studies show that B-12 helps regulate Natural-Killer T-cells (20) and prevents chromosome damage. (21)
- The Cardiovascular System. Vitamin B-12 participates in the conversion of homocysteine to methionine. Elevated homocysteine levels are a known independent risk factor for heart attack, stroke and thrombosis. Without adequate B-12 levels, homocysteine levels typically rise. (22-34)
- Special Senses. Degenerative changes in the central nervous system caused by B-12 deficiency can also affect the optic nerve, resulting in blue-yellow color blindness. (35)
- Other Symptoms of vitamin B-12 deficiency include sore mouth or tongue (36)
- In Infants and Children, signs of vitamin B-12 deficiency include failure to thrive, movement disorders, delayed development, and megaloblastic anemia. (37)
So Is ME/CFS a Simple Vitamin B-12 Deficiency?
Although B-12 deficiency symptoms share many commonalities with ME/CFS and other multi-system diseases, researchers do not suggest that these diseases are simply a vitamin B-12 deficiency.
Two emerging theories of biochemical abnormality are believed to be heavily involved in ME/CFS and other multi-system diseases. In fact, either or both of these models of biochemical abnormality might be a central cause of ME/CFS. Interestingly, both of these abnormalities are related to forms of vitamin B-12 deficiency.
The Nitric Oxide/Peroxynitrite (“No, Oh No!”) Model of ME/CFS
ME/CFS and other multi-system diseases appear to be “triggered” by a wide variety of factors. Sufferers often report an initial viral, bacterial or other infection, a physical or psychological trauma, chemical exposure or other stressor before onset of symptoms. (38-41,43,48,50) In this regard, ME/CFS shares similarities with Fibromyalgia (FM), (44,45,48,50) Lyme disease, (47) Multiple Chemical Sensitivities (MCS), (46,48) PTSD (48) and Gulf War Syndrome. (40-42,48,49)
According to the theory of noted researcher Dr. Martin Pall, PhD, detailed in his book Explaining ‘Unexplained Illnesses’, ME/CFS and other multi-system diseases overlap in symptoms and initial triggers because they share a common metabolic origin, a ‘vicious cycle’ related to nitric oxide (NO-) and peroxynitrite (ONOO-) over-production. (51)
Because of the chemical abbreviations for these two substances (NO- and ONOO-) Dr. Pall calls this vicious cycle the "No, Oh No" cycle, and he presents solid evidence to make a case for this cycle as an underlying cause of ME/CFS and other multi-system diseases.
Dr. Pall has observed that virtually every known initiator of ME/CFS and other multi-system diseases either increases nitric oxide (NO) (52-62) or the superoxide radical (O2-) (63-66) or both. (54,57,73) These two molecules quickly react to form peroxynitrite (ONOO-), (67-72,79,81,85,115,117,121) a potent oxidant that is capable of damaging a wide range of biological molecules. (54,68,69,74-92)
Peroxynitrite (ONOO-) then acts through multiple mechanisms to regenerate O2- and NO-, the very molecules that create it. In this way, the NO-/ONOO- cycle becomes self-perpetuating, and a vicious cycle is initiated. (93-96) Unless something intervenes to break the cycle, it is possible that this biochemical "endless loop" could self-perpetuate indefinitely.
There is increasing evidence to support this pathway as a primary underlying abnormality in ME/CFS and other multi-system diseases.
This runaway NO-/ONOO- cycle has also been associated with increased perception of pain. (53,59)
[See Figure 1: The NO-/ONOO- Cycle, and Figure 2: Independent Consequences of Increased Superoxide (O2- ), nitric oxide (NO- ) and peroxynitrite (ONOO-).]
Figure 1: The NO-/ONOO- Cycle (click on image to enlarge)
Key to Figure 1: The NO-/ONOO- Cycle "Players"
- Nitric oxide (NO-) is a naturally occurring "messenger molecule" in the body and also a pro-oxidant and free radical. Depending on the amount and where it is released, NO- can be either beneficial or toxic. (141-145,223) Nitric oxide is known to play a role in blood pressure regulation, blood clotting, immunity, digestion, the special senses (sight and smell), and possibly learning and memory. Abnormal levels of NO- may play a role in diseases such as atherosclerosis, diabetes, stroke, hypertension, impotence, septic shock, and long-term depression. (52,145) In ME/CSF/FM and related multi-system diseases, research suggests that excess NO- may be a primary contributor to long-term energy depletion and immune dysfunction. (101,141-142,223)
- Superoxide (O2-) is a potent free radical. Like nitric oxide (NO-), O2- has independent deleterious effects when expressed in excess. Superoxide reacts with NO- to form ONOO-.
- OONO- (peroxynitrite) is a potent oxidant that damages cells. It is formed when NO- and O2- react with each other. Peroxynitrite in turn acts through multiple mechanisms to regenerate its precursors, NO- and O2-. In this way, a “vicious cycle” of damage creating more damage begins.
Figure 2: Independent Consequences of Increased Superoxide (O2-), Nitric Oxide (NO-) and Peroxynitrite (ONOO-).
Consequences of Superoxide (O2-) Excess:
- Inflammation (130,137)
- Vaso-spasm (131)
- Endothelial dysfunction (132,134,135,138,139)
- Associated with retinal cell death, pulmonary hypertension, general hypertension, atherosclerosis, neurodegenerative disease, type II diabetes (73,132,134,136-140)
- Decreased cellular respiration (133)
- Cell death (133)
Consequences of Nitric Oxide (NO-) Excess:
- Cellular energy depletion (97, 120)
- DNA damage (98-100, 118,123)
- Neurotoxicity, neuronal cell death and brain injury (52, 57, 58, 84,100-104,111-113, 115,123)
- Hypersomnolence and sleep apnea (102, 105)
- Lung injury (61,62,128,129)
- Increased pain perception and lowered pain threshold (53, 59)
- Lowered blood pressure (224-225)
- Inhibition of the methylation cycle (106, 107)
- Formation of carcinogenic substances (99)
- Increased inflammation (61, 62, 110,120,121,125,126, 130)
- Cytotoxicity (68,114,115,120, 123)
- Modification of cellular proteins (100,123)
- No is associated with Alzheimer's, Arthritis, Parkinson's, stroke, hemorrhagic shock, cancer, viral infections (57, 58, 97,98,113,115, 120,121,122,123)
- Damaged mitochondria (108,109,111,112, 114,115,127)
- Suppressed immune system (122)
- Assisted viral replication and pathogenesis (122, 124, 126,127)
Consequences of Excess Peroxynitrite (ONOO-)
- Neurotoxic (72,74,76,85, 88,89)
- Cytotoxic (68,82-84,87,119)
- Increases lipid peroxidation (54,87,90,119,125)
- Retinal cell death (73,75,86)
- DNA damage (77,87,118,119,125)
- Decreased mitochondrial respiration (cellular oxygen) (69,77,78,90,92,119)
- Increase viral replication (80)
- ONOO- is associated with Alzheimer's disease, rheumatoid arthritis, atherosclerosis, lung injury, amyotrophic lateral sclerosis, HIV, multiple sclerosis, kidney damage, Parkinson's disease, Huntington's disease, Sjogren's syndrome, septic shock and other diseases. (57,72,74,78,80,81,84,87,88,89,91)
Dr. Bell, one of the first physicians to recognize ME/CFS as a discrete medical condition, proposes in his book Cellular Hypoxia and Neuro-Immune Fatigue that cellular hypoxia (decreased oxygen to the cell) may be the underlying factor in ME/CFS and related multi-system diseases.(146). This is consistent with the NO-/ONOO- theory, because injuries of many types result in decreased oxygen to the cell, thus potentially initiating such a destructive runaway cycle.
Hydroxocobalamin Breaks the NO- / ONOO- Cycle
Hydroxocobalamin (cobinamide), a unique form of vitamin B-12, is a potent nitric oxide (NO-) scavenger. It is the only form of vitamin B-12 that effectively neutralizes the NO- molecule. Hydroxocobalamin is the preferred form of vitamin B-12 required to break the NO-/ONOO- vicious cycle of cellular damage. (147-149)
The Methylation Cycle and ME/CFS
The methylation cycle is a biochemical pathway required for the manufacture of DNA, RNA, phospholipids (myelin sheath of nerves), neurotransmitters, adrenal hormones and more than 100 enzymes. A fully functional methylation cycle is also required for numerous detoxification reactions. (150-157)
A defect in the methylation pathway is a second proposed mechanism in the development of ME/CFS. The research of Dr. Rich van Konynenburg, PhD, has been instrumental in development of a theory involving an intricate interrelationship between the methylation cycle and ME/CFS.(158)
Methylation defects cause reduced detoxification ability, decreased production of serotonin, dopamine, melatonin and other neurotransmitters, decreased production of adrenal hormones, increased levels of toxic homocysteine, and decreased cellular energy production.(159-163)
This reduced production of vital neurotransmitters may explain the feelings of depression and despondency that frequently strike ME/CFS victims and would explain the positive effects often achieved with the use of SSRI and other mood-altering pharmaceuticals. Unfortunately, many clinicians interpret the improvement seen with antidepressant medications as “proof” that ME/CFS is a psychiatric illness when in fact an understanding of the methylation pathway defect offers solid evidence of a biochemical basis for depression and low energy in ME/CFS.
[See Figure 3: The Methylation Cycle]
Figure 3: The Methylation Cycle (Click on image to enlarge)
- The overlap between the NO-/ONOO- cycle and the methylation cycle where excess NO- blocks methionine synthase, a critical enzyme in the methylation cycle. (106, 164-167)
- The methylcobalamin form of vitamin B-12 is a required nutrient in the methylation cycle. If any one step in the methylation cycle fails, the entire cycle fails.
Vitamin B-12: Which Form is Best?
What we know as vitamin B-12 is actually a collection of four related but different cobalt-containing molecules. Each of these forms plays a distinct role in the body as follows:
Hydroxycobalamin is a unique form of B-12 that quenches excess nitric oxide (NO?), the precursor to peroxinitrite (ONOO-).(147-149,172-176) Hydroxocobalamin (and methylcobalamin) also play a more important role in addressing neurological disorders than cyanocobalamin.(168)
Hydroxocobalamin participates in detoxification, especially cyanide detoxification. Cyanide levels are typically elevated in smokers, people who eat cyanide-containing food (like cassava) and those with certain metabolic defects. Excess cyanide in the tissues blocks conversion of cyanocobalamin to methylcobalamin or adenosylcobalamin. In such instances, hydroxocobalamin is the vitamin B-12 of choice.(169-171) Hydroxycobalamin is FDA- approved as a treatment for cyanide poisoning.(214)
Methylcobalamin is considered by many researchers to be the most active form of vitamin B-12.(177-179) It is the requisite form of vitamin B-12 in the methylation cycle.(179-186). Methylcobalamin protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity.(187-188) and promotes nerve cell regeneration.(189) Methylcobalamin is the only form of vitamin B-12 that participates in regulating circadian rhythms (sleep/wake cycles). It has been shown to support improved sleep quality and refreshment from sleep, as well as increased feeling of well-being, concentration and alertness.(190)
Adenosylcobalamin (dibencozide), another highly active form of vitamin B-12, is essential for energy metabolism(191) and is required for normal myelin sheath formation and nucleoprotein synthesis. Deficiencies are associated with nerve and spinal cord degeneration.(192-193)
Cyanocobalamin, the most common form of B-12 found in nutritional supplements, is a synthetic form of B-12 not found in nature. It has the lowest biological activity and must be converted in the liver to more biologically active forms. This conversion is inefficient and some people who may not benefit from cyanocobalamin due to lack of assimilation or conversion.(194-195) However, the cyano form of B-12 is needed to balance hydroxycobalamin in performing its NO-quenching function and should therefore be included in hydroxocobalamin supplements.(176)
Who is Vitamin B-12 Deficient and Why?
Research shows that a much larger segment of the general population is vitamin B-12 deficient than previously thought. Recent studies indicate that up to 78% of seniors are deficient. (196-197)
Irritable bowel syndrome (IBS), seen in as many as 77% of CFS patients and 78% of FM patients,(198-199) is a major cause of vitamin B-12 deficiency.(200) This leads one to ponder the “which came first, the chicken or egg” nature of this: Are ME/CFS patients B-12 deficient because of IBS, or is IBS a result of cellular or neurological insult caused by B-12 deficiency?
Other high-risk groups for B-12 deficiency include:
- Those who use acid-blocking or neutralizing drugs (such as Prilosec, Prevacid, Nexium and others) (201-204);
- Those who use drugs which impair intestinal absorption (such as Metformin, Questron and Chloromycetin) (205);
- And people who have had gastric surgery. (206-207)
Bacterial overgrowth of the small intestine, which occurs frequently in people with ME/CFS and low stomach acid, is a predisposing factor for B-12 deficiency because the bacteria themselves use vitamin B-12. (208-209)
The most recent and disturbing studies suggest that vitamin B-12 deficiency is more prevalent in young adults than previously thought. (210-211). One study found that vitamin B-12 deficiency was similar in three age groups (26-49 years, 50-64 years, and 65 years and older), but that early symptoms were simply less apparent in the young. This study also found that those who did not take a vitamin B-12-containing supplement were twice as likely to be deficient as supplement users, regardless of age.(210)
Secondly, unlike other water-soluble vitamins, B-12 is stored in the liver, kidneys and other tissues. Deficiencies of B-12 often appear so slowly and subtly as to go unnoticed, and blood tests for vitamin B-12 levels miss early deficiency states at least 50% of the time.(212-213)
Why Many People Need to Obtain Vitamin B-12 From Supplements
Medical science once believed that few people were vitamin B-12 deficient. This false assumption may stem from the fact that vitamin B-12 is produced in the body by a normal, healthy population of bowel bacteria.
Foods are not a significant source of vitamin B-12 in most diets. Meat, milk, eggs, fish, and shellfish contain the highest amount of B-12, but only 50% of this is absorbable even in a healthy gut. (215) Vegetarian sources of vitamin B-12, such as algae, are not bio-available and do not make a significant contribution to dietary vitamin B-12 levels. (216)
Further, absorption is hampered by low stomach acid, IBS, and bacterial overgrowth of the small intestine - conditions which are common in ME/CFS sufferers. The US Institute of Medicine recommends that adults over 50 obtain vitamin B-12 from supplements. (14)
Oral vs. Injectable: Which is Best?
Although vitamin B-12 has previously been given by injection, it is now accepted in conventional medicine that oral & sublingual vitamin B-12 is equally as effective as injection in treating pernicious anemia and other B-12 deficient states. (214, 217-220)
According to The National Institutes of Health (NIH), oral vitamin B-12 supplementation is extremely safe(221-222). It is also as effective as injections,(14,219-220) and inexpensive and more convenient compared to injection.(220)
All Roads Lead To B-12: Conclusions and Recommendations
The suffering from ME/CFS and other multi-system diseases is widespread and devastating. This affliction is beginning to receive more attention, perhaps because of the activism of those affected and the dedication of ME/CFS researchers and clinicians. Current research is providing us with new insights into the underlying mechanisms of this complicated illness.
The Nitric Oxide/Peroxynitrite model (NO-/ONOO-) and The Methylation Cycle have emerged as two likely contributory mechanisms to ME/CFS and other multi-system diseases including Fibromyalgia, Lyme disease, Multiple Chemical Sensitivities, PTSD and Gulf War Syndrome. Deficiencies of either of two forms of vitamin B-12 - hydroxocobalamin and/or methylcobalamin - play a significant role in these biochemical processes.
Since vitamin B-12 (especially the hydroxocobalamin and methycobalamin forms) offer such potential benefits for ME/CFS and other multi-system disease sufferers - without known risks - it seems reasonable to suggest that anyone suffering with ME/CFS or other multi-system illness should consider taking a supplement containing these two important forms of vitamin B-12.
Furthermore, because of the balancing effect that cyanocobalamin has on hydroxycobalamin (176) and the protective and regenerative effect that adenosylcobalamin exerts on the myelin sheath of nerves (192-193), these forms should also be considered as an important part of any complete vitamin B-12 supplement.
* * * *
* Dr. Dana Myatt, NMD, is a practicing naturopathic family physician, educator, author, and speaker with a special interest in nutrition. She lectures widely to medical and lay audiences, and hosts a website http://www.drmyattswellnessclub.com . Mark Ziemann, RN, Dr. Myatt’s husband and collaborator, is also an educator, author, and speaker specializing in holistic nursing practice and patient education.
- Explaining 'Unexplained Illnesses': Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, and Gulf War Syndrome; Martin Pall: Harrington Park Press; 1 edition (May 15, 2007) Page 106.
- Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness.Br J Nutr 1973;30:277–83.
- Lapp CW, Cheney PR. The rationale for using high-dose cobalamin (vitamin B12). CFIDS Chronicle Physicians’ Forum, 1993;Fall:19–20.
- Herbert V. Vitamin B12 in Present Knowledge in Nutrition. 17th ed. Washington, D.C.: International Life Sciences Institute Press, 1996.
- Combs G. Vitamin B12 in The Vitamins. New York: Academic Press, Inc, 1992.
- Herbert V and Das K. Vitamin B12 in Modern Nutrition in health and disease. 8th ed. Baltimore: Williams & Wilkins, 1994.
- Zittoun J and Zittoun R. Modern clinical testing strategies in cobalamin and folate deficiency. Sem Hematol 1999;36:35-46.
- Healton EB, et al. Neurological aspects of cobalamin deficiency. Medicine 1991;70:229-244.
- Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press. Washington, DC, 1998.
- Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev 1996;54:382-90.
- Roze E, et al. Neuropsychiatric disturbances in presumed late-onset cobalamin C disease.Arch Neurol. 2003 Oct;60(10):1457-62.
- van Goor L, et al. Review: cobalamin deficiency and mental impairment in elderly people. Age Ageing. 1995 Nov;24(6):536-42.
- Martin DC, et al. Time dependency of cognitive recovery with cobalamin replacement: report of a pilot study. J Am Geriatr Soc. 1992 Feb;40(2):168-72.
- Robertson JS, Hsia YE, Scully KJ. Defective leukocyte metabolism in human cobalamin defieciency: impaired propionate oxidation and serine biosynthesis reversible by cyanocobalamin therapy.J Lab Clin Med. 1976 Jan;87(1):89-97.
- Tamura J, et al. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment. Clin Exp Immunol. 1999 Apr;116(1):28-32.
- Fenech MF, Dreosti IE, Rinaldi JR. Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men. Carcinogenesis. 1997 Jul;18(7):1329-36
- Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). National Cholesterol Education Program, NationalHeart, Lung, and Blood Institute, National Institues of Health, September 2002. NIH Publication No. 02-5215.
- Selhub J, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995;332:286-91.
- Rimm EB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. J Am Med Assoc 1998;279:359-64.
- Refsum H, et al. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31-62
- Boers GH. Hyperhomocysteinemia: A newly recognized risk factor for vascular disease. Neth J Med 1994;45:34-41.
- Selhub J, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J Am Med Assoc 1993;270:2693-8.
- Malinow MR. Plasma homocyst(e)ine and arterial occlusive diseases: A mini-review. Clin Chem 1995;41:173-6
- Flynn MA, et al. Atherogenesis and the homocysteine-folate-cobalamin triad: do we need standardized analyses? J Am Coll Nutr 1997;16:258-67.
- Fortin LJ, Genest J, Jr. Measurement of homocyst(e)ine in the prediction of arteriosclerosis. Clin Biochem 1995;28:155-62
- Siri PW, Verhoef P, Kok FJ. Vitamins B6, B12, and folate: Association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr 1998;17:435-41.
- Ubbink JB, et al. The effect of a subnormal vitamin B6 status on homocysteine metabolism. J Clin Invest 1996;98:177-84.
- Bronstrup A, et al. Effects of folic acid and combinations of folic acid and vitamin B12 on plasma homocysteine concentrations in healthy, young women. Am J Clin Nutr 1998;68:1104-10.
- Remacha AF, et al. Enhanced risk of thrombotic disease in patients with acquired vitamin B12 and/or folate deficiency: role of hyperhomocysteinemia.Ann Hematol. 2002 Nov;81(11):616-21. Epub 2002 Nov 9.
- Beers MH, Berkow R, et al. The Merck Manual of Diagnosis and Therapy, Seventeenth Edition, 1999 Merck and Co., Chapter 127 page 867.
- Monsen ALB and Ueland PM. Homocysteine and methylmalonic acid in diagnosis and risk assessment from infancy to adolescent. American Journal of Clinical Nutrition 2003; 78:7-21.
- Carmel R. Megaloblastic anemias. Curr Opin Hematol 1994;1:107-12.
- Soderlund A, Malterud K. Why did I get chronic fatigue syndrome? A qualitative interview study of causal attributions in women patients. Scand J Prim Health Care. 2005 Dec;23(4):242-7.
- Kerr JR, Tyrrell DA. Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome. Curr Pain Headache Rep. 2003 Oct;7(5):333-41.
- Ferguson E, Cassaday HJ. Theoretical accounts of Gulf War Syndrome: from environmental toxins to psychoneuroimmunology and neurodegeneration. Behav Neurol. 2001-2002;13(3-4):133-47.
- Peckerman A, et al. Cardiovascular stress responses and their relation to symptoms in Gulf War veterans with fatiguing illness. Psychosom Med. 2000 Jul-Aug;62(4):509-16.
- Skowera A, et al. Cellular immune activation in Gulf War veterans. J Clin Immunol. 2004 Jan;24(1):66-73.
- Patarca R. Cytokines and chronic fatigue syndrome. Ann N Y Acad Sci. 2001 Mar;933:185-200.
- Lucas HJ, et al. Fibromyalgia - new concepts of pathogenesis and treatment. Int J Immunopathol Pharmacol. 2006 Jan-Mar;19(1):5-10.
- Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. J Rheumatol Suppl. 2005 Aug;75:6-21.
- Fiedler N, et al. A controlled comparison of multiple chemical sensitivities and chronic fatigue syndrome. Psychosom Med. 1996 Jan-Feb;58(1):38-49.
- Gaudino EA, Coyle PK, Krupp LB. Post-Lyme syndrome and chronic fatigue syndrome. Neuropsychiatric similarities and differences. Arch Neurol. 1997 Nov;54(11):1372-6.
- Jason LA, Taylor RR, Kennedy CL. Chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities in a community-based sample of persons with chronic fatigue syndrome-like symptoms. Psychosom Med. 2000 Sep-Oct;62(5):655-63.
- Kang HK, et al. Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans. Am J Epidemiol. 2003 Jan 15;157(2):141-8.
- Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.Arch Intern Med. 2000 Jan 24;160(2):221-7.
- Pall M. Explaining 'Unexplained Illnesses': Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, and Gulf War Syndrome. http://astore.amazon.com/prohealth-20/detail/078902389X/104-0633642-5692763 The Hawthorne Press Inc., 2007.
- McCann SM, et al. The nitric oxide hypothesis of aging. Exp Gerontol. 1998 Nov-Dec;33(7-8):813-26.
- Jeong JH, et al. Extremely low frequency magnetic field induces hyperalgesia in mice modulated by nitric oxide synthesis. Life Sci. 2006 Feb 23;78(13):1407-12. Epub 2006 Feb 7.
- Ródenas J, Mitjavila MT, Carbonell T. Simultaneous generation of nitric oxide and superoxide by inflammatory cells in rats. Free Radic Biol Med. 1995 May;18(5):869-75
- Zingarelli B, et al. Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation. Shock. 2000 Feb;13(2):126-34.
- Daghigh F, et al. Human gingival fibroblasts produce nitric oxide in response to proinflammatory cytokines. J Periodontol. 2002 Apr;73(4):392-400.
- Guix FX, et al.The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol. 2005 Jun;76(2):126-52.
- Molina JA, et al. The role of nitric oxide in neurodegeneration. Potential for pharmacological intervention. Drugs Aging. 1998 Apr;12(4):251-9.
- Larson AA, et al. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain. 2000 Aug;87(2):201-11.
- Zhan G, et al. Inducible nitric oxide synthase in long-term intermittent hypoxia: hypersomnolence and brain injury. Am J Respir Crit Care Med. 2005 Jun 15;171(12):1414-20. Epub 2005 Mar 4.
- Hesse AK, et al. Proinflammatory role of inducible nitric oxide synthase in acute hyperoxic lung injury.Respir Res. 2004 Sep 15;5:11.
- Lehtonen H, et al. Increased alveolar nitric oxide concentration and high levels of leukotriene B(4) and 8-isoprostane in exhaled breath condensate in patients with asbestosis. Thorax. 2007 Jul;62(7):602-7. Epub 2007 Jan 24.
- Imam SZ, et al. Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage. Ann N Y Acad Sci. 2000 Sep;914:157-71.
- Sviriaeva IV, Ruuge EK, Shumaev KB. Formation of superoxide radicals in isolated cardiac mitochondria: effect of adriamycin. Biofizika. 2007 Nov-Dec;52(6):1054-9.[PubMed abstract; article in Russian].
- Doroshow JH. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 1983 Feb;43(2):460-72.
- Yurkov IS, et al. Mechanism of superoxide anion generation in intact mitochondria in the presence of lucigenin and cyanide. Biochemistry (Mosc). 2003 Dec;68(12):1349-59.
- Pacher P, et al.; “Nitric Oxide and Peroxynitrite: in Health and disease” Physiological Reviews 2007, volume 87(1), page 315-424.
- Radi R, et al. Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem. 1991 Mar 5;266(7):4244-50. 69.)
- Pryor WA, Squadrito GL.The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol. 1995 May;268(5 Pt 1):L699-722.
- Beckman, J.S., Koppenol, W.H. Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and the ugly. Am J Physiol 271 C1424-C1437 (1996).
- Koppenol, W.H., et al. Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem Res Toxicol 5 834-842 (1992).
- Squadrito GL, Pryor WA.Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med. 1998 Sep;25(4-5):392-403.
- Oku H, et al. Endothelin-1 (ET-1) causes death of retinal neurons through activation of nitric oxide synthase (NOS) and production of superoxide anion. Exp Eye Res. 2008 Jan;86(1):118-30. Epub 2007 Oct 9.
- Pérez-De La Cruz V, et al. Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III). Neuroscience. 2005;135(2):463-74.
- Shibuki H, et al. Lipid peroxidation and peroxynitrite in retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3607-14.
- Kawano T, et al. iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. J Cereb Blood Flow Metab. 2007 Aug;27(8):1453-62. Epub 2007 Feb 7.
- Zingarelli B, et al. Effects of nicaraven on nitric oxide-related pathways and in shock and inflammation. Shock. 2000 Feb;13(2):126-34.
- Zingarelli B, et al. The potential role of peroxynitrite in the vascular contractile and cellular energetic failure in endotoxic shock. Br J Pharmacol. 1997 Jan;120(2):259-67.
- Pryor, W.A., Squadrito, G.L. The chemistry of peroxynitrite: A product from the reaction of nitric oxide with superoxide. Am J Physiol 268 L699-L722 (1995).
- Aquaro S, et al. The contribution of peroxynitrite generation in HIV replication in human primary macrophages. Retrovirology. 2007 Oct 21;4:76.
- Mendoza MG, et al. Kidney damage after renal ablation is worsened in endothelial nitric oxide synthase -/- mice and improved by combined administration of L-arginine and antioxidants. Nephrology (Carlton). 2008 Jun;13(3):218-27.
- Piao XL, Cho EJ, Jang MH. Cytoprotective effect of baicalein against peroxynitrite-induced toxicity in LLC-PK(1) cells.Food Chem Toxicol. 2008 May;46(5):1576-81. Epub 2007 Dec 31.
- Kimoto K, Aoki T, Shibata Y, Kamisuki S, Sugawara F, Kuramochi K, Nakazaki A, Kobayashi S, Kuroiwa K, Watanabe N, Arai T. Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death. J Antibiot (Tokyo). 2007 Oct;60(10):614-21.
- Jack C, Antel J, Brück W, Kuhlmann T. Contrasting potential of nitric oxide and peroxynitrite to mediate oligodendrocyte injury in multiple sclerosis. Glia. 2007 Jul;55(9):926-34.
- Martinez-Palma L, Pehar M, Cassina P, Peluffo H, Castellanos R, Anesetti G, Beckman JS, Barbeito L. Involvement of nitric oxide on kainate-induced toxicity in oligodendrocyte precursors.Neurotox Res. 2003;5(6):399-406.
- Ali TK, Matragoon S, Pillai BA, Liou GI, El-Remessy AB. Peroxynitrite Mediates Retinal Neurodegeneration by Inhibiting NGF Survival Signal in Experimental and Human Diabetes. Diabetes. 2008 Feb 19 [Epub ahead of print].
- Ho SC, Tsai TH, Tsai PJ, Lin CC. Protective capacities of certain spices against peroxynitrite-mediated biomolecular damage. Food Chem Toxicol. 2008 Mar;46(3):920-8. Epub 2007 Oct 30.
- Pehar M, Vargas MR, Robinson KM, Cassina P, England P, Beckman JS, Alzari PM, Barbeito L. Peroxynitrite transforms nerve growth factor into an apoptotic factor for motor neurons. Free Radic Biol Med. 2006 Dec 1;41(11):1632-44. Epub 2006 Aug 15.
- Jonnala RR, Buccafusco JJ.Inhibition of nerve growth factor signaling by peroxynitrite. J Neurosci Res. 2001 Jan 1;63(1):27-34.
- Pessayre D. Role of mitochondria in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S20-7.
- Cejková J, Ardan T, Simonová Z, Cejka C, Malec J, Jirsová K, Filipec M, Dotrelová D, Brunová B. Nitric oxide synthase induction and cytotoxic nitrogen-related oxidant formation in conjunctival epithelium of dry eye (Sjögren's syndrome).Nitric Oxide. 2007 Aug;17(1):10-7. Epub 2007 May 22.
- Szabó C, Day BJ, Salzman AL. Evaluation of the relative contribution of nitric oxide and peroxynitrite to the suppression of mitochondrial respiration in immunostimulated macrophages using a manganese mesoporphyrin superoxide dismutase mimetic and peroxynitrite scavenger. FEBS Lett. 1996 Feb 26;381(1-2):82-6.
- Chen Y, Gibson SB. Is mitochondrial generation of reactive oxygen species a trigger for autophagy? Autophagy. 2008 Mar-Apr;4(2):246-8. Epub 2007 Dec 14.
- Szabó C, Zingarelli B, O'Connor M, Salzman AL.DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1753-8.
- Goldstein S, Merényi G.The chemistry of peroxynitrite: implications for biological activity. Methods Enzymol. 2008;436C:49-61...and...Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. 2002 Mar;109(6):817-26.]
- Szabó C, O'Connor M, Salzman AL.Endogenously produced peroxynitrite induces the oxidation of mitochondrial and nuclear proteins in immunostimulated macrophages. FEBS Lett. 1997 Jun 9;409(2):147-50.
- Cuzzocrea S. Role of nitric oxide and reactive oxygen species in arthritis. Curr Pharm Des. 2006;12(27):3551-70
- Davies CM, Guilak F, Weinberg JB, Fermor B. Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis. Osteoarthritis Cartilage. 2007 Oct 16 [Epub ahead of print]
- Rui Hai Liu and Joseph H. Hotchkiss. Potential genotoxicity of chronically elevated nitric oxide: A review. Mutation Research/Reviews in Genetic Toxicology Volume 339, Issue 2, June 1995, Pages 73-89.
- Zhang L, Dawson VL, Dawson TM.Role of nitric oxide in Parkinson's disease. Pharmacol Ther. 2006 Jan;109(1-2):33-41. Epub 2005 Jul 7.
- Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM.Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci. 2007 Oct;8(10):766-75.
- Zhan G, Fenik P, Pratico D, Veasey SC.Inducible nitric oxide synthase in long-term intermittent hypoxia: hypersomnolence and brain injury. Am J Respir Crit Care Med. 2005 Jun 15;171(12):1414-20. Epub 2005 Mar 4.
- Dawson VL, Dawson TM. Nitric oxide neurotoxicity.J Chem Neuroanat. 1996 Jun;10(3-4):179-90.
- McCann SM. The nitric oxide hypothesis of brain aging. Exp Gerontol. 1997 Jul-Oct;32(4-5):431-40.
- Petrosyan M, Perraki E, Simoes D, Koutsourelakis I, Vagiakis E, Roussos C, Gratziou C. Exhaled breath markers in patients with obstructive sleep apnoea. Sleep Breath. 2007 Dec 11 [Epub ahead of print].
- Danishpajooh IO, Gudi T, Chen Y, Kharitonov VG, Sharma VS, Boss GR. Nitric oxide inhibits methionine synthase activity in vivo and disrupts carbon flow through the folate pathway. J Biol Chem. 2001 Jul 20;276(29):27296-303. Epub 2001 May 22.
- Campos AC, Molognoni F, Melo FH, Galdieri LC, Carneiro CR, D'Almeida V, Correa M, Jasiulionis MG. Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation. Neoplasia. 2007 Dec;9(12):1111-21.
- Brown GC. Nitric oxide and mitochondria.Front Biosci. 2007 Jan 1;12:1024-33.
- Jacobson J, Duchen MR, Hothersall J, Clark JB, Heales SJ.Induction of mitochondrial oxidative stress in astrocytes by nitric oxide precedes disruption of energy metabolism.J Neurochem. 2005 Oct;95(2):388-95. Epub 2005 Aug 16.
- Borutaite V, Moncada S, Brown GC.Nitric oxide from inducible nitric oxide synthase sensitizes the inflamed aorta to hypoxic damage via respiratory inhibition. Shock. 2005 Apr;23(4):319-23.
- Bal-Price A, Brown GC.Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci. 2001 Sep 1;21(17):6480-91.
- Brown GC, Borutaite V. Nitric oxide, mitochondria, and cell death.IUBMB Life. 2001 Sep-Nov;52(3-5):189-95.
- Mander P, Borutaite V, Moncada S, Brown GC.Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death. J Neurosci Res. 2005 Jan 1-15;79(1-2):208-15.
- Brown GC, Bal-Price A.Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol. 2003 Jun;27(3):325-55.
- Packer MA, Murphy MP. Peroxynitrite formed by simultaneous nitric oxide and superoxide generation causes cyclosporin-A-sensitive mitochondrial calcium efflux and depolarisation. Eur J Biochem. 1995 Nov 15;234(1):231-9.
- Jekabsone A, Neher JJ, Borutaite V, Brown GC. Nitric oxide from neuronal nitric oxide synthase sensitises neurons to hypoxia-induced death via competitive inhibition of cytochrome oxidase.J Neurochem. 2007 Oct;103(1):346-56. Epub 2007 Jul 10.
- Packer MA, Porteous CM, Murphy MP.Superoxide production by mitochondria in the presence of nitric oxide forms peroxynitrite. Biochem Mol Biol Int. 1996 Oct;40(3):527-34.
- Inoue S, Kawanishi S. Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett. 1995 Aug 28;371(1):86-8.
- Szabó C.The pathophysiological role of peroxynitrite in shock, inflamma
- Szabó C, Billiar TR. Novel roles of nitric oxide in hemorrhagic shock.Shock. 1999 Jul;12(1):1-9.
- Maeda H, Akaike T.Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc). 1998 Jul;63(7):854-65.
- Akaike T.Role of free radicals in viral pathogenesis and mutation. Rev Med Virol. 2001 Mar-Apr;11(2):87-101.
- Ebadi M, Sharma SK. Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. Antioxid Redox Signal. 2003 Jun;5(3):319-35.
- Zaki MH, Akuta T, Akaike T.Nitric oxide-induced nitrative stress involved in microbial pathogenesis. J Pharmacol Sci. 2005 Jun;98(2):117-29. Epub 2005 Jun 4.125.
- Akaike T, Suga M, Maeda H. Free radicals in viral pathogenesis: molecular mechanisms involving superoxide and NO.Proc Soc Exp Biol Med. 1998 Jan;217(1):64-73.
- Akaike T, Maeda H.Nitric oxide and virus infection.Immunology. 2000 Nov;101(3):300-8.
- Akaike T, Fujii S, Kato A, Yoshitake J, Miyamoto Y, Sawa T, Okamoto S, Suga M, Asakawa M, Nagai Y, Maeda H.Viral mutation accelerated by nitric oxide production during infection in vivo. FASEB J. 2000 Jul;14(10):1447-54.
- Fakhrzadeh L, Laskin JD, Laskin DL.Deficiency in inducible nitric oxide synthase protects mice from ozone-induced lung inflammation and tissue injury.Am J Respir Cell Mol Biol. 2002 Apr;26(4):413-9.
- Weinberger B, Fakhrzadeh L, Heck DE, Laskin JD, Gardner CR, Laskin DL. Inhaled nitric oxide primes lung macrophages to produce reactive oxygen and nitrogen intermediates. Am J Respir Crit Care Med. 1998 Sep;158(3):931-8.
- Elsasser TH, Caperna TJ, Li CJ, Kahl S, Sartin JL. Critical control points in the impact of proinflammatory immune response on growth and metabolism. J Anim Sci. 2008 Mar 14 [Epub ahead of print].
- FR Laurindo, PL da Luz, L Uint, TF Rocha, RG Jaeger and EA Lopes. Evidence for superoxide radical-dependent coronary vasospasm after angioplasty in intact dogs. Circulation, Vol 83, 1705-1715, Copyright © 1991 by American Heart Association.
- Robert P. Jankov, Crystal Kantores, Jingyi Pan, Jaques Belik. Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am J Physiol Lung Cell Mol Physiol 294: L233-L245, 2008.
- Ricci C, et al. Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis.Am J Physiol Cell Physiol. 2008 Feb;294(2):C413-22. Epub 2007 Dec 12.O2
- Cuzzocrea S, et al. Superoxide: a key player in hypertension. FASEB J. 2004 Jan;18(1):94-101.
- Tomasz J Guzik, et al. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation, 105(14):1656-62.
- Senthil Kumar Venugopal, et al. alpha Tocopherol Decreases Superoxide Anion Release in Human Monocytes Under Hyperglycemic Conditions Via Inhibition of Protein Kinase C. Diabetes 51:3049-3054, 2002.
- Alejandro MS Mayer, et al. Differential modulation of microglia superoxide anion and thromboxane B2 generation by the marine manzamines. BMC Pharmacology 2005, 5:6doi:10.1186/1471-2210-5-6.
- Zalba G, et al. Is the balance between nitric oxide and superoxide altered in spontaneously hypertensive rats with endothelial dysfunction? Nephrol Dial Transplant. 2001;16 Suppl 1:2-5. O2 and hypertension, endothelial dysfunction.
- Sánchez M, et al. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J Hypertens. 2006 Jan;24(1):75-84.
- Stefanovic A, et al. The influence of obesity on the oxidative stress status and the concentration of leptin in type 2 diabetes mellitus patients. Diabetes Res Clin Pract. 2008 Jan;79(1):156-63. Epub 2007 Sep 11.
- Dawson VL, Dawson TM. Nitric oxide in neurodegeneration.Prog Brain Res. 1998;118:215-29.
- Wahl SM, et al. Nitric oxide in experimental joint inflammation. Benefit or detriment? Cells Tissues Organs. 2003;174(1-2):26-33.
- Bredt DS. Targeting nitric oxide to its targets. Proc Soc Exp Biol Med. 1996 Jan;211(1):41-8.
- Yun HY, et al. Nitric oxide in health and disease of the nervous system. Mol Psychiatry. 1997 Jul;2(4):300-10.
- Berdeaux A. Nitric oxide: an ubiquitous messenger.Fundam Clin Pharmacol. 1993;7(8):401-11.
- Bell D. Cellular Hypoxia & Neuro-Immune Fatigue. Wingspan Press, July 2007.
- Broderick KE, et al. The Cobalamin Precursor Cobinamide Detoxifies Nitroprusside-Generated Cyanide. Experimental Biology and Medicine 232:789-798 (2007).
- Broderick KE, et al. Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide. J. Biol. Chem., Vol. 280, Issue 10, 8678-8685, March 11, 2005.
- Broderick KE, et al. The nitric oxide scavenger cobinamide profoundly improves survival in a Drosophila melanogaster model of bacterial sepsis.FASEB J. 2006 Sep;20(11):1865-73.
- Lee ME, Wang H. Homocysteine and hypomethylation. A novel link to vascular disease.Trends Cardiovasc Med. 1999 Jan-Feb;9(1-2):49-54.
- Qin J, et al. Arsenic detoxification and evolution of trimethylarsine gas by a microbial arsenite S-adenosylmethionine methyltransferase.Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2075-80.
- Dunlevy LP, et al. Integrity of the methylation cycle is essential for mammalian neural tube closure. Birth Defects Res. Part A Clin. Mol. Teratol. (2006)
- Mason P. Folic acid - new roles for a well known vitamin. The Pharmaceutical Journal Vol 263 No 7068 p673-677 October 23, 1999.
- Stempak, J. M., et al. Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model. Carcinogenesis, 2005 (Vol. 26) (No. 5) 981-990.
- James SJ, et al Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism Am J Clin Nutr 2004;80:1611–7.
- Miller A. The methionine-homocysteine cycle and its effects on cognitive diseases. Alternative Medicine Review, Feb, 2003.
- Nijhout HF, Reed M, Ulrich C. Mathematical Models of Folate-mediated One-Carbon Metabolism, in Vitamins & Hormones, Vol. 79, Folic Acid, ed. by G. Litwack (Accepted, 2008), Academic Press.
- Van Konynenburg R. Glutathione Depletion - Methylation Cycle Block Hypothesis for the pathogenesis of CFS. Paper presented at the International Association for Chronic Fatigue Syndrome, Ft. Lauderdale, Florida, January 10-14, 2007.
- Yasko A. Genetic Bypass. Matrix Press. 2005.
- Yasko A. Nutrigenomic Testing and the Methylation Pathway. Townsend Newsletter. 270: 69. 2006.
- Ganong W. F. Review of Medical Physiology, 11th Edition. Lange Medical Publications, Los Altos California, 1983. p.235.
- Martin Jr. D.W., et al. Harper's Review of Biochemistry, 19th edition. Lange Medical Publications, Los Altos California, 1983. p.312.
- Murphy TM, et al. The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer.Endocr Relat Cancer. 2008 Mar;15(1):11-25.
- Christensen B, Ueland PM. Methionine synthase inactivation by nitrous oxide during methionine loading of normal human fibroblasts. Homocysteine remethylation as determinant of enzyme inactivation and homocysteine export. J Pharmacol Exp Ther. 1993 Dec;267(3):1298-303.
- Christensen B, et al. Preoperative methionine loading enhances restoration of the cobalamin-dependent enzyme methionine synthase after nitrous oxide anesthesia.Anesthesiology. 1994 May;80(5):1046-56.
- Banerjee RV, Matthews RG. Cobalamin-dependent methionine synthase. FASEB J. 1990 Mar;4(5):1450-9.
- Drummond JT, Matthews RG. Nitrous oxide degradation by cobalamin-dependent methionine synthase: characterization of the reactants and products in the inactivation reaction. Biochemistry. 1994 Mar 29;33(12):3732-41.
- Freeman AG. Hydroxocobalamin versus cyanocobalamin. J R Soc Med. 1996 Nov;89(11):659.
- Linnell JC, Matthews DM. Cobalamin metabolism and its clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21.
- Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.
- Kate E. Broderick, et al. Cyanide Detoxification by the Cobalamin Precursor Cobinamide. Experimental Biology and Medicine 231:641-649; 2006.
- Sharma VS, et al. Reactions of nitric oxide with vitamin B12 and its precursor, cobinamide. Biochemistry. 2003 Jul 29;42(29):8900-8.
- Rochelle LG, et al. Interactions between hydroxocobalamin and nitric oxide (NO): evidence for a redox reaction between NO and reduced cobalamin and reversible NO binding to oxidized cobalamin. J Pharmacol Exp Ther. 1995 Oct;275(1):48-52.
- Kruszyna H, et al. Spectroscopic studies of nitric oxide (NO) interactions with cobalamins: reaction of NO with superoxocobalamin(III) likely accounts for cobalamin reversal of the biological effects of NO. J Pharmacol Exp Ther. 1998 May;285(2):665-71.
- Brouwer M, et al. Nitric oxide interactions with cobalamins: biochemical and functional consequences. Blood. 1996 Sep 1;88(5):1857-64.
- Broderick KE, et al. Nitric oxide scavenging by the cobalamin precursor cobinamide. J Biol Chem. 2005 Mar 11;280(10):8678-85. Epub 2005 Jan 4.
- Murray, Michael. Encyclopedia of Nutritional Supplements. Prima Publishing, 1996. Chapter 15,pg.130.
- Methylcobalamin. [No authors listed]. Altern Med Rev. 1998 Dec;3(6):461-3.
- Jepson B. Changing the Course of Autism. Sentient Publications, 2007. Chapter 10.
- Kapadia CR. Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and transport. Gastroenterologist. 1995 Dec;3(4):329-44.
- Morel CF, et al. Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B12 metabolism and transport. Mol Genet Metab. 2005 Sep-Oct;86(1-2):160-71.
- Rosenblatt DS, et al. Altered vitamin B12 metabolism in fibroblasts from a patient with megaloblastic anemia and homocystinuria due to a new defect in methionine biosynthesis. J Clin Invest. 1984 Dec;74(6):2149-56.
- Linnell JC, Bhatt HR. Inherited errors of cobalamin metabolism and their management.Baillieres Clin Haematol. 1995 Sep;8(3):567-601.
- Watkins D, Rosenblatt DS. Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG. J Clin Invest. 1988 Jun;81(6):1690-4.
- Suormala T, et al. The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J Biol Chem. 2004 Oct 8;279(41):42742-9. Epub 2004 Aug 2.
- Lebionka Y., Melvidas V.I. The ability of bacterial DNA methyltransferases to use methylcobalamine as a cofactor in DNA methylation reactions. Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry. 1990-7508 Issue Volume 1, Number 3 / September, 2007.
- Akaike A, et al. Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons. Eur J Pharmacol. 1993 Sep 7;241(1):1-6.
- Kikuchi M, et al. Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthalmol Vis Sci. 1997 Apr;38(5):848-54.
- Watanabe T, et al. 1994. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurol Sci 122:140-43.
- Mayer G.,Kroger M., Meier-Ewert K. Effects of vitamin B12 on performance and circadian rhythm in normal subjects. Neuropsychopharmacology,1996, vol. 15, no5, pp. 456-464.
- Olle Selinus, B. J. Alloway. Essentials of Medical Geology. Academic Press, 2005,p.519.ISBN 0126363412.
- The Pharmacological Basis of Therapeutics, Goodman and Gillman, Tenth Edititon, Page-1503-1513.
- R.S.Satoskar & S.D. Bhanderkar. Pharmacology and Therapeutics, Revised 12th, Page No.424-425.
- Andrès E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004 Aug 3;171(3):251-9.
- Rajan S, et al. Response of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults.J Am Geriatr Soc. 2002 Nov;50(11):1789-95.
- Herrmann W, et al. Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Clin Chem Lab Med. 2003 Nov;41(11):1478-88.
- Kwok T, et al. Randomized trial of the effect of supplementation on the cognitive function of older people with subnormal cobalamin levels.Int J Geriatr Psychiatry. 1998 Sep;13(9):611-6.
- Pimentel M, et al. Small intestinal bacterial overgrowth: a possible association with fibromyalgia. J Musculoskelet Pain 2001;9:107-113.
- Pimentel M, et al. Eradication of small intestinal bacterial overgrowth decreases symptoms in chronic fatigue syndrome: a double blind, randomized study. Gastroenterology 2000;118:A414.
- Chandy J. Vitamin B12 Deficiency with Neuro-Psychiatric Symptoms Serum B12 Level Below <300ng/l with or without Anaemia or Macrocytosis: A Retrospective Study 1981- 2006 (ongoing). Upublished research from the Shinwell Medical Centre, Horden Peterlee County Durham, UK. Report available on website: http://www.b12d.org/
- Bradford GS and Taylor CT. Omeprazole and vitamin B12 deficiency. Annals of Pharmacotherapy 1999;33:641-3.
- Kasper H. Vitamin absorption in the elderly. International Journal of Vitamin and Nutrition Research 1999;69:169-72.
- Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol 2000;30:29-33.
- Termanini B, et al. Effect of Long-Term Gastric Acid Suppressive Therapy on Serum Vitamin B12 Levels in Patients with Zollinger-Ellison Syndrome.American Journal of Medicine 1998; 104: 422-30.
- Bauman WA, et al. Increased intake of calcium reverses the B12 malabsorption induced by metformin. Diabetes Care 2000;23:1227-31.
- Sumner AE, et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery. Ann Intern Med. 1996 Mar 1;124(5):469-76.
- Adachi S, et al. Enteral vitamin B12 supplements reverse postgastrectomy B12 deficiency.Ann Surg. 2000 Aug;232(2):199-201.
- Suter PM, et al. Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. Gastroenterology 1991; 101:1039-45.
- Súbtil JC, et al. Dementia caused by bacterial overgrowth in a patient with Billroth II gastrectomy]Rev Esp Enferm Dig. 1996 Jun;88(6):431-3.
- Tucker KL, et al. J. Plasma vitamin B12 concentrations relate to intake source in the Framingham Offspring Study. Am J Clin Nutr 2000;71:514-22.
- Louwman MW, et al. Signs of impaired cognitive function in adolescents with marginal cobalamin status. Am J Clin Nutr. 2000 Sep;72(3):762-9.
- Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003 Mar 1;67(5):979-86.
- Pennypacker LC, et al.High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc. 1992 Dec;40(12):1197-204.
- Watanabe F. Vitamin B12 sources and bioavailability. Exp Biol Med (Maywood). 2007 Nov;232(10):1266-74.
- Dagnelie PC, et al. Vitamin B-12 from algae appears nonot to be bioavailable. Am J Clin Nutr. 1991 Mar;53(3):695-7.
- Lederle FA. Oral cobalamin for pernicious anemia: back from the verge of extinction. J Am Geriatr Soc 1998;46:1125-7.
- Kuzminski AM, et al. Effective treatment of cobalamin deficiency with oral cobalamin.Blood 1998;92: 1191-8.
- Lederle FA. Oral cobalamin for pernicious anemia. Medicine's best kept secret? JAMA 1991;265:94-5.
- Bolaman Z, et al. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study.Clin Ther. 2003 Dec;25(12):3124-34.
- National Institutes of Health Fact Sheet on vitamin B12 htp://ods.od.nih.gov/factsheets/vitaminb12.asp.
- Nilsson-Ehle H. Age-related changes in cobalamin (vitamin B12) handling. Implications for therapy. Drugs Aging. 1998 Apr;12(4):277-92.
- Bishop A, Anderson JE. NO signaling in the CNS: from the physiological to the pathological. Toxicology. 2005 Mar 15;208(2):193-205.
- Bucci M, et al. Endothelial nitric oxide synthase activation is critical for vascular leakage during acute inflammation in vivo. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):904-8. Epub 2005 Jan 7.
- Kaminski A, et al. Up-regulation of endothelial nitric oxide synthase inhibits pulmonary leukocyte migration following lung ischemia-reperfusion in mice. Am J Pathol. 2004 Jun;164(6):2241-9.
Note: This information has not been evaluated by the FDA. It is generic and is not meant to prevent, diagnose, treat or cure any condition, illness, or disease. It is very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team.
| (2 existing comments)
|Posted by: bay33
Apr 16, 2008
Thanks for this article. It is a topic of great interest to me since I have two kids with POTS, a form of dysautonomia, which has many overlying symptoms with CFS. One of the two has received some tremendous benefit from B12 injections, and there is no B12 deficiency based on lab results. However, it is noticeably very helpful, and if we slip up and forget the weekly injection she is reminded of it shortly thereafter when her baseline energy level begins to noticeably lag.
A big thank you to Dr. Myatt and other health professionals who are taking the interest, time, and effort to attempt to unlock some of the mysteries of these types of medical conditions!
|Posted by: AK_Rose
Apr 16, 2008
This is very timely for me as I was just prescribed B12 injections. I asked about sublingual B12, as I had seen ads for it, but was told that the absorption is not as good. I do plan to take this article to my HCP. Very helpful info as I have had ulcerative colitis w/removal of my large colon. Later injury in hip has never "healed" and I now am on pain meds and limited in my activities; have rec'd a FM diagnosis from a rheumatologist... Many of the symptoms are similar to mine, but I am not ready to accept another "surprise" diagnosis. After starting B12 I have been feeling much better, but also rec'd a Vit D shot and started on some other supplements at the same time, so it's difficult to know if there is any one thing making the difference, or if it's all of them... Thanks for the info... Brenda, AK
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