Is Science On The Verge of an ME/CFS Breakthrough?

Dana Myatt, N.M.D., Mark Ziemann, R.N.

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 sufferers.

The Vitamin B12 – ME/CFS Connection

In searching for common biochemical threads among ME/CFS victims, researchers have noted that symptoms of vitamin B12 deficiency closely parallel those of ME/CFS and other multi-symptom diseases. In fact, symptoms overlap to such a great extent that many respected CFS researchers and physicians --- including Drs. Paul Cheney, Charles Lapp, Kenny De Meirleir, Jacob Teitelbaum, and Martin Pall --- consider vitamin B12 a mainstay of treatment. (1-6)

One study found improved energy levels even in people who were not deficient in vitamin B12 but were administered the vitamin anyway. (7) B12 (2,500–5,000 mcg) administered every two to three days resulted in improvement in 50–80% of a group of people with ME/CSF. Most improvement was seen after several weeks of vitamin B12 administration. (8)

The Curious Symptoms of Vitamin B12 Deficiency

Best known for participating in the manufacture of red blood cells, B12 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 B12 deficiencies have widespread consequences.

  • Energy. Even minor deficiencies of vitamin B12 can cause anemia, fatigue, shortness of breath and weakness. (9,10,13)
  • The Nervous System. Deficiencies of B12 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 B12 can result in permanent impairment of the nervous system. (16,17,18,70,71)
  • The Gastro-Intestinal System. B12 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 B12 is necessary for normal functioning of white blood cells. (19) Studies show that B12 helps regulate Natural-Killer T-cells (20) and prevents chromosome damage. (21)
  • The Cardiovascular System. Vitamin B12 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 B12 levels, homocysteine levels typically rise. (22-34)
  • Special Senses. Degenerative changes in the central nervous system caused by B12 deficiency can also affect the optic nerve, resulting in blue-yellow color blindness. (35)
  • Other symptoms of vitamin B12 deficiency include sore mouth or tongue (36)
  • In Infants and Children, signs of vitamin B12 deficiency include failure to thrive, movement disorders, delayed development, and megaloblastic anemia. (37)

So Is ME/CFS A Simple Vitamin B12 Deficiency?

Although B12 deficiency symptoms share many commonalities with ME/CFS and other multi-system diseases, researchers do not suggest that these diseases are simply a vitamin B12 deficiency.

Two biochemical abnormalities have been uncovered, each heavily involved in ME/CFS and other multi-system diseases. In fact, either or both of these biochemical abnormalities might be a central cause of ME/CFS. Interestingly, both of these abnormalities are related to forms of vitamin B12 deficiency.

The Nitric Oxide / Peroxynitrite (“No, Oh No!”) Model of ME/CFS

ME/CFS and other multi-system diseases can 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 noted researcher Dr. Martin Pall 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‾ --- 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)

Figure 1: The NO‾/ONOO‾Cycle

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.


Consequences of Superoxide (O2‾) Excess:

1.) Inflammation (130,137)
2.) Vaso-spasm (131)
3.) Endothelial dysfunction (132,134,135,138,139)
4.) Associated with retinal cell death, pulmonary hypertension, general hypertension, atherosclerosis, neurodegenerative disease, type II diabetes (73,132,134,136-140)
5.) Decreased cellular respiration (133)
6.) Cell death (133)
+ Consequences of Nitric Oxide (NO‾) Excess:

1.) Cellular energy depletion (97, 120)
2.) DNA damage (98-100, 118,123)
3.) Neurotoxicity, neuronal cell death and brain injury (52, 57, 58, 84,100-104,111-113, 115,123)
4.) Hypersomnolence and sleep apnea (102, 105)
5.) Lung injury (61,62,128,129)
6.) Increased pain perception and lowered pain threshold (53, 59)
7.) Lowered blood pressure (224-225)
8.) Inhibition of the methylation cycle (106, 107)
9.) Formation of carcinogenic substances (99)
10.) Increased inflammation (61, 62, 110,120,121,125,126, 130)
11.) Cytotoxicity (68,114,115,120, 123)
12.) Modification of cellular proteins (100,123)
13.) 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)
14.) Damaged mitochondria (108,109,111,112, 114,115,127)
15.) Suppressed immune system (122)
16.) Assisted viral replication and pathogenesis (122, 124, 126,127)
Consequences of Excess Peroxynitrite (ONOO‾)

1.) Neurotoxic (72,74,76,85, 88,89)
2.) Cytotoxic (68,82-84,87,119)
3.) Increases lipid peroxidation (54,87,90,119,125)
4.) Retinal cell death (73,75,86)
5.) DNA damage (77,87,118,119,125)
6.) Decreased mitochondrial respiration (cellular oxygen)
7.) Increase viral replication (80)
8.) 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, Sjögren's syndrome, septic shock and other diseases. (57,72,74,78,80,81,84,87,88,89,91)

Fig. 2: Independent Consequences of Increased Superoxide (O2‾ ), nitric oxide (NO‾ ) and peroxynitrite (ONOO‾ ).

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 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 (hypoxia) to the cell, thus initiating this 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 B12 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 has been instrumental in demonstrating the 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.

Figure 3: The Methylation Cycle

Note 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 B12: 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 B12 that quenches excess nitric oxide (NO‾), the precursor to peroxinitrite (ONOO‾).(147-149,172-176) Hydroxocobalamine (and methylcobalamine) are also more effective at treating neurological disorders than cyanocobalamine. (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 B12. (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) Methylcobalamine is the only form of vitamin B-12 that participates in regulating circadian rhythms (sleep/wake cycles). It has been shown to improve 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 B12, 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 B12 found in nutritional supplements, is a synthetic form of B12 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 cyanocobalamine due to lack of assimilation or conversion. (194-195) However, the cyano form of B12 is needed to balance hydroxycobalamin in performing its NO-quenching function and should therefore be included in hydroxocobalamine supplements. (176)

Who is Vitamin B12 Deficient and Why?

Research shows that a much larger segment of the general population is vitamin B12 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 B12 deficiency. (200) This leads one to ponder the “which came first, the chicken or egg” nature of this: are ME/CFS patients B12 deficient because of IBS, or is IBS a result of cellular or neurological insult caused by B12 deficiency?

Other high-risk groups for B12 deficiency include those who use acid-blocking or neutralizing drugs (such as Prilosec, Prevacid, Nexium and others) (201-204), 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 B12 deficiency because the bacteria themselves use vitamin B12. (208-209)

The most recent and disturbing studies suggest that vitamin B12 deficiency is more prevalent in young adults than previously thought. (210-211). One study found that vitamin B12 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 B12-containing supplement were twice as likely to be deficient as supplement users, regardless of age. (210)

Secondly, unlike other water-soluble vitamins, B12 is stored in the liver, kidneys and other tissues. Deficiencies of B12 often appear so slowly and subtly as to go unnoticed, and blood tests for vitamin B12 levels miss early deficiency states at least 50% of the time. (212-213)

Why Vitamin B12 MUST Be Obtained From Supplements

Medical science once believed that few people were vitamin B12 deficient. This false assumption may stem from the fact that vitamin B12 is produced in the body by a normal, healthy population of bowel bacteria.

Foods are not a significant source of vitamin B12. Meat, milk, eggs, fish, and shellfish contain the highest amount of B12 but only 50% of this is absorbable even in a healthy gut. (215) Vegetarian sources of vitamin B12, such as algae, are not bio-available and do not make significant contribution to dietary vitamin B12 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 their vitamin B12 from supplements. (14)

Oral vs. Injectable: Which is Best?

Although vitamin B12 has previously been given by injection, it is now accepted in conventional medicine that oral vitamin B12 is equally as effective as injection in treating pernicious anemia and other B12 deficient states. (214, 217-220).

According to The National Institutes of Health (NIH), oral vitamin B12 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 B12: 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 (FM), Lyme Disease, Multiple Chemical Sensitivities (MCS), PTSD and Gulf War Syndrome. Deficiencies of either of two forms of vitamin B12 --- hydroxocobalamin and/or methylcobalamin --- play a significant role in these biochemical processes.

Since Vitamin B12 (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 B12.

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 B12 supplement.


 4.) -
 6.)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.
 7.Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment
 of tiredness.Br J Nutr 1973;30:277–83.
 8.Lapp CW, Cheney PR. The rationale for using high-dose cobalamin
 (vitamin B12). CFIDS Chronicle
 Physicians’ Forum, 1993;Fall:19–20.
 9.) Herbert V. Vitamin B12 in Present Knowledge in Nutrition. 17th
 ed. Washington, D.C.:
 International Life Sciences Institute Press, 1996.
 10.) Combs G. Vitamin B12 in The Vitamins. New York: Academic
 Press, Inc, 1992.
 11.) Herbert V and Das K. Vitamin B12 in Modern Nutrition in
 health and disease. 8th ed. Baltimore: Williams & Wilkins, 1994.
 12.) Zittoun J and Zittoun R. Modern clinical testing strategies
 in cobalamin and folate deficiency. Sem Hematol 1999;36:35-46.
 13.) Healton EB, Savage DG, Brust JC, Garrett TF, Lindenbaum J.
 Neurological aspects of cobalamin deficiency. Medicine
 14.) 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.
 15.) Bottiglieri T. Folate, vitamin B12, and neuropsychiatric
 disorders. Nutr Rev 1996;54:382-90.
 16.) Roze E, Gervais D, Demeret S, Ogier de Baulny H, Zittoun J,
 Benoist JF, Said G, Pierrot-Deseilligny C, Bolgert
 F.Neuropsychiatric disturbances in presumed late-onset cobalamin C
 disease.Arch Neurol. 2003 Oct;60(10):1457-62.
 17.) van Goor L, Woiski MD, Lagaay AM, Meinders AE, Tak PP.Review:
 cobalamin deficiency and mental impairment in elderly people. Age
 Ageing. 1995 Nov;24(6):536-42.
 18.) Martin DC, Francis J, Protetch J, Huff FJ. Time dependency of
 cognitive recovery with cobalamin replacement: report of a pilot
 study. J Am Geriatr Soc. 1992 Feb;40(2):168-72.
 19) 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.
 20) Tamura J, Kubota K, Murakami H, Sawamura M, Matsushima T,
 Tamura T, Saitoh T, Kurabayshi H, Naruse T. 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.
 21) 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
 22.) 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.
 23) Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW,
 Belanger AJ, O'Leary DH, Wolf PA, Scaefer EJ, Rosenberg IH.
 Association between plasma homocysteine concentrations and
 extracranial carotid-artery stenosis. N Engl J Med
 24) Rimm EB, Willett WC, Hu FB, Sampson L, Colditz G A, Manson J
 E, Hennekens C, Stampfer M J. 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.
 25) Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and
 cardiovascular disease. Annu Rev Med 1998;49:31-62
 26) Boers GH. Hyperhomocysteinemia: A newly recognized risk factor
 for vascular disease. Neth J Med 1994;45:34-41.
 27) Selhub J, Jacques PF, Wilson PF, Rush D, Rosenberg IH. Vitamin
 status and intake as primary determinants of homocysteinemia in an
 elderly population. J Am Med Assoc 1993;270:2693-8.
 28) Malinow MR. Plasma homocyst(e)ine and arterial occlusive
 diseases: A mini-review. Clin Chem 1995;41:173-6
 29) Flynn MA, Herbert V, Nolph GB, Krause G. Atherogenesis and the
 homocysteine-folate-cobalamin triad: do we need standardized
 analyses? J Am Coll Nutr 1997;16:258-67.
 30) Fortin LJ, Genest J, Jr. Measurement of homocyst(e)ine in the
 prediction of arteriosclerosis. Clin Biochem 1995;28:155-62
 31.) 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.
 32.) Ubbink JB, van der Merwe A, Delport R, Allen R H, Stabler S
 P, Riezler R, Vermaak WJ. The effect of a subnormal vitamin B6
 status on homocysteine metabolism. J Clin Invest 1996;98:177-84.
 33) Bronstrup A, Hages M, Prinz-Langenohl R, Pietrzik K. 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.
 34) Remacha AF, Souto JC, Rámila E, Perea G, Sarda MP, Fontcuberta
 J.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.
 35.) Beers, M.H., Berkow, R. et al. The Merck Manual of Diagnosis
 and Therapy, Seventeenth Edition, 1999 Merck and Co., Chapter 127
 page 867.
 36.) 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.
 37.) Carmel R. Megaloblastic anemias. Curr Opin Hematol
 38.) 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.
 39.) 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.
 40.) 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.
 41.) Peckerman A, LaManca JJ, Smith SL, Taylor A, Tiersky L, Pollet
 C, Korn LR, Hurwitz BE, Ottenweller JE, Natelson BH. Cardiovascular
 stress responses and their relation to symptoms in Gulf War
 veterans with fatiguing illness. Psychosom Med. 2000
 42.) Skowera A, Hotopf M, Sawicka E, Varela-Calvino R, Unwin C,
 Nikolaou V, Hull L, Ismail K, David AS, Wessely SC, Peakman
 M.Cellular immune activation in Gulf War veterans. J Clin Immunol.
 2004 Jan;24(1):66-73.
 43.) Patarca R. Cytokines and chronic fatigue syndrome. Ann N Y
 Acad Sci. 2001 Mar;933:185-200.
 44.) Lucas HJ, Brauch CM, Settas L, Theoharides TC.
 Fibromyalgia--new concepts of pathogenesis and treatment. Int J
 Immunopathol Pharmacol. 2006 Jan-Mar;19(1):5-10.
 45.) Mease P. Fibromyalgia syndrome: review of clinical
 presentation, pathogenesis, outcome measures, and treatment. J
 Rheumatol Suppl. 2005 Aug;75:6-21.
 46.) Fiedler N, Kipen HM, DeLuca J, Kelly-McNeil K, Natelson B. A
 controlled comparison of multiple chemical sensitivities and
 chronic fatigue syndrome. Psychosom Med. 1996 Jan-Feb;58(1):38-49.
 47.) 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.
 48.) 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.
 49.) Kang HK, Natelson BH, Mahan CM, Lee KY, Murphy FM.
 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.
 50.) Aaron LA, Burke MM, Buchwald D. Overlapping conditions among
 patients with chronic fatigue syndrome, fibromyalgia, and
 temporomandibular disorder.Arch Intern Med. 2000 Jan
 51.) Paul M. Explaining 'Unexplained Illnesses': Disease Paradigm
 for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity,
 Fibromyalgia, Post-Traumatic Stress Disorder, and Gulf War
 Syndrome. The Hawthorne Press Inc., 2007.
 52.) McCann SM, Licinio J, Wong ML, Yu WH, Karanth S, Rettorri V.
 The nitric oxide hypothesis of aging. Exp Gerontol. 1998
 53.) Jeong JH, Kum C, Choi HJ, Park ES, Sohn UD. 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.
 54.) 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.
 55.) Zingarelli B, Scott GS, Hake P, Salzman AL, Szabo C. Effects
 of nicaraven on nitric oxide-related pathways and in shock and
 inflammation. Shock. 2000 Feb;13(2):126-34.
 56.) Daghigh F, Borghaei RC, Thornton RD, Bee JH. Human gingival
 fibroblasts produce nitric oxide in response to proinflammatory
 cytokines. J Periodontol. 2002 Apr;73(4):392-400.
 57.) Guix FX, Uribesalgo I, Coma M, Muñoz FJ.The physiology and
 pathophysiology of nitric oxide in the brain. Prog Neurobiol. 2005
 58.) Molina JA, Jiménez-Jiménez FJ, Ortí-Pareja M, Navarro JA.The
 role of nitric oxide in neurodegeneration. Potential for
 pharmacological intervention. Drugs Aging. 1998 Apr;12(4):251-9.
 59.) Larson AA, Giovengo SL, Russell IJ, Michalek JE. 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.
 60.) 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.
 61.) Hesse AK, Dörger M, Kupatt C, Krombach F.Proinflammatory role
 of inducible nitric oxide synthase in acute hyperoxic lung
 injury.Respir Res. 2004 Sep 15;5:11.
 62.) Lehtonen H, Oksa P, Lehtimäki L, Sepponen A, Nieminen R,
 Kankaanranta H, Saarelainen S, Järvenpää R, Uitti J, Moilanen
 EIncreased 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.
 63.) Imam SZ, Islam F, Itzhak Y, Slikker W Jr, Ali SF. 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
 64.) 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
 65.) Doroshow JH. Effect of anthracycline antibiotics on oxygen
 radical formation in rat heart. Cancer Res. 1983 Feb;43(2):460-72.
 66.) Yurkov IS, Kruglov AG, Evtodienko YV, Yaguzhinsky LS.
 Mechanism of superoxide anion generation in intact mitochondria in
 the presence of lucigenin and cyanide. Biochemistry (Mosc). 2003
 67.) Pacher, P.; Beckman, J. S.; Liaudet, L.; “Nitric Oxide and
 Peroxynitrite: in Health and disease” Physiological Reviews 2007,
 volume 87(1), page 315-424.
 68.) Radi R, Beckman JS, Bush KM, Freeman BA. 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.
 70.) 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).
 71.) Koppenol, W.H., Moreno, J.J., Pryor, W.A., et al.
 Peroxynitrite, a cloaked oxidant formed by nitric oxide and
 superoxide. Chem Res Toxicol 5 834-842 (1992).
 72.) 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.
 73.) Oku H, Fukuhara M, Komori A, Okuno T, Sugiyama T, Ikeda
 T.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
 74.) Pérez-De La Cruz V, González-Cortés C, Galván-Arzate S,
 Medina-Campos ON, Pérez-Severiano F, Ali SF, Pedraza-Chaverrí J,
 Santamaría A. 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.
 75.) Shibuki H, Katai N, Yodoi J, Uchida K, Yoshimura N. Lipid
 peroxidation and peroxynitrite in retinal ischemia-reperfusion
 injury. Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3607-14. 76.)
 Kawano T, Kunz A, Abe T, Girouard H, Anrather J, Zhou P, Iadecola
 C. 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. 77.) Zingarelli B,
 Scott GS, Hake P, Salzman AL, Szabo C. Effects of nicaraven on
 nitric oxide-related pathways and in shock and inflammation. Shock.
 2000 Feb;13(2):126-34.
 78.) Zingarelli B, Day BJ, Crapo JD, Salzman AL, Szabó C. The
 potential role of peroxynitrite in the vascular contractile and
 cellular energetic failure in endotoxic shock. Br J Pharmacol. 1997
 79.) 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).
 80.) Aquaro S, Muscoli C, Ranazzi A, Pollicita M, Granato T,
 Masuelli L, Modesti A, Perno CF, Mollace V. The contribution of
 peroxynitrite generation in HIV replication in human primary
 macrophages. Retrovirology. 2007 Oct 21;4:76.
 81.) Mendoza MG, Castillo-Henkel C, Medina-Santillan R, Jarillo
 Luna RA, Robles HV, Romo E, Rios A, Escalante B. 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
 82.) 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.
 83.) 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.
 84.) 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.
 85.) 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.
 86.) 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].
 87.) 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.
 88.) 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.
 89.) Jonnala RR, Buccafusco JJ.Inhibition of nerve growth factor
 signaling by peroxynitrite. J Neurosci Res. 2001 Jan
 90.) Pessayre D. Role of mitochondria in non-alcoholic fatty liver
 disease. J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S20-7.
 91.) 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.
 92.) 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.
 93.) 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.
 94.) 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.
 94.) Goldstein S, Merényi G.The chemistry of peroxynitrite:
 implications for biological activity. Methods Enzymol.
 95.) 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.]
 96.) 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
 97.) Cuzzocrea S. Role of nitric oxide and reactive oxygen species
 in arthritis. Curr Pharm Des. 2006;12(27):3551-70. 98.) 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]
 99.) 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.
 100.) 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. n
 101.) 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
 102.) 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.
 103.) Dawson VL, Dawson TM. Nitric oxide neurotoxicity.J Chem
 Neuroanat. 1996 Jun;10(3-4):179-90.
 104.) McCann SM. The nitric oxide hypothesis of brain aging. Exp
 Gerontol. 1997 Jul-Oct;32(4-5):431-40.
 105.) 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]. S
 106.) 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.
 107.) 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.
 108.) Brown GC. Nitric oxide and mitochondria.Front Biosci. 2007
 Jan 1;12:1024-33.
 109.) 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.
 110.) 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.
 111.) 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.
 112.) Brown GC, Borutaite V. Nitric oxide, mitochondria, and cell
 death.IUBMB Life. 2001 Sep-Nov;52(3-5):189-95.
 113.) 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.
 114.) Brown GC, Bal-Price A.Inflammatory neurodegeneration mediated
 by nitric oxide, glutamate, and mitochondria. Mol Neurobiol. 2003
 115.) 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.
 116.) 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.
 117.) 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.
 118.) 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.
 119.) Szabó C.The pathophysiological role of peroxynitrite in
 shock, inflamma
 120.) Szabó C, Billiar TR. Novel roles of nitric oxide in
 hemorrhagic shock.Shock. 1999 Jul;12(1):1-9.
 121.) Maeda H, Akaike T.Nitric oxide and oxygen radicals in
 infection, inflammation, and cancer. Biochemistry (Mosc). 1998
 122.) Akaike T.Role of free radicals in viral pathogenesis and
 mutation. Rev Med Virol. 2001 Mar-Apr;11(2):87-101.
 123.) Ebadi M, Sharma SK. Peroxynitrite and mitochondrial
 dysfunction in the pathogenesis of Parkinson's disease. Antioxid
 Redox Signal. 2003 Jun;5(3):319-35.
 124.) 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.
 126.) Akaike T, Maeda H.Nitric oxide and virus
 infection.Immunology. 2000 Nov;101(3):300-8.
 127.) 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.
 128.) 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
 129.) 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.
 130.) 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
 131.) 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.
 132.) 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.
 133.) Ricci C, Pastukh V, Leonard J, Turrens J, Wilson G, Schaffer
 D, Schaffer SW. 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 134.)
 Cuzzocrea S, Mazzon E, Dugo L, Di Paola R, Caputi AP, Salvemini
 D.Superoxide: a key player in hypertension. FASEB J. 2004
 135.) Tomasz J Guzik, Shafi Mussa, Daniela Gastaldi, Jerzy
 Sadowski, Chandi Ratnatunga, Ravi Pillai, and Keith M Channon.
 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.
 136.) Senthil Kumar Venugopal, Sridevi Devaraj, Teddy Yang, and
 Ishwarlal Jialal. alpha Tocopherol Decreases Superoxide Anion
 Release in Human Monocytes Under Hyperglycemic Conditions Via
 Inhibition of Protein Kinase C. Diabetes 51:3049-3054, 2002.
 137.) Alejandro MS Mayer, Mary L Hall, Sean M Lynch, Sarath P
 Gunasekera, Susan H Sennett, Shirley A Pomponi. Differential
 modulation of microglia superoxide anion and thromboxane B2
 generation by the marine manzamines. BMC Pharmacology 2005,
 138.) Zalba G, Beaumont FJ, San José G, Fortuño A, Fortuño MA, Díez
 J.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.
 139.) Sánchez M, Galisteo M, Vera R, Villar IC, Zarzuelo A, Tamargo
 J, Pérez-Vizcaíno F, Duarte J. Quercetin downregulates NADPH
 oxidase, increases eNOS activity and prevents endothelial
 dysfunction in spontaneously hypertensive rats. J Hypertens. 2006
 140.) Stefanovic A, Kotur-Stevuljevic J, Spasic S,
 Bogavac-Stanojevic N, Bujisic N. 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.
 141.) Dawson VL, Dawson TM.Nitric oxide in neurodegeneration.Prog
 Brain Res. 1998;118:215-29.
 142.) Wahl SM, McCartney-Francis N, Chan J, Dionne R, Ta L,
 Orenstein JM. Nitric oxide in experimental joint inflammation.
 Benefit or detriment? Cells Tissues Organs.
 2003;174(1-2):26-33.143.) Bredt DS. Targeting nitric oxide to its
 targets. Proc Soc Exp Biol Med. 1996 Jan;211(1):41-8.
 144.) Yun HY, Dawson VL, Dawson TM. Nitric oxide in health and
 disease of the nervous system. Mol Psychiatry. 1997
 145.) Berdeaux A. Nitric oxide: an ubiquitous messenger.Fundam Clin
 Pharmacol. 1993;7(8):401-11.
 146.) Bell D. Cellular Hypoxia & Neuro-Immune Fatigue. Wingspan
 Press, July 2007.
 147.) Broderick KE, Balasubramanian M, Chan A, Potluri P, Feala J,
 Belke DD, McCulloch A, Sharma VS, Pilz RB, Bigby TD, Boss GR. The
 Cobalamin Precursor Cobinamide Detoxifies Nitroprusside-Generated
 Cyanide. Experimental Biology and Medicine 232:789-798 (2007).
 148.) Broderick KE, Singh V, Zhuang S, Kambo A, Chen JC, Sharma VS,
 Pilz RB, Boss GR. Nitric Oxide Scavenging by the Cobalamin
 Precursor Cobinamide. J. Biol. Chem., Vol. 280, Issue 10,
 8678-8685, March 11, 2005.
 149.) Broderick KE, Feala J, McCulloch A, Paternostro G, Sharma VS,
 Pilz RB, Boss GR. The nitric oxide scavenger cobinamide profoundly
 improves survival in a Drosophila melanogaster model of bacterial
 sepsis.FASEB J. 2006 Sep;20(11):1865-73.
 150.) Lee ME, Wang H. Homocysteine and hypomethylation. A novel
 link to vascular disease.Trends Cardiovasc Med. 1999
 151.) Qin J, Rosen BP, Zhang Y, Wang G, Franke S, Rensing C.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.
 152.) Dunlevy LP, Burren KA, Mills K, Chitty LS, Copp AJ, Greene
 ND.Integrity of the methylation cycle is essential for mammalian
 neural tube closure. Birth Defects Res. Part A Clin. Mol. Teratol.
 153.) Mason P. Folic acid - new roles for a well known vitamin. The
 Pharmaceutical Journal Vol 263 No 7068 p673-677
 October 23, 1999.
 154.) Stempak, J. M., Sohn KyoungJin, Chiang EnPei, Shane, B., Kim
 YoungIn.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.
 155.) 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.
 156.) Miller A. The methionine-homocysteine cycle and its effects
 on cognitive diseases. Alternative Medicine Review, Feb, 2003.
 157.) Nijhout HF, Reed M, Ulrich C, Mathematical Models of
 Folate-mediated One-Carbon Metabolism, in Vitamins & Hormones, Vol.
 79, Folic Acid, edited by G. Litwack (Accepted, 2008), Academic
 158.) 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.
 159.) Yasko A. Genetic Bypass. Matrix Press. 2005.
 160.) Yasko A. Nutrigenomic Testing and the Methylation Pathway.
 Townsend Newsletter. 270: 69. 2006.
 161.) Ganong W. F. Review of Medical Physiology, 11th Edition.
 Lange Medical Publications, Los Altos California, 1983. p.235.
 162.) Martin Jr. D.W., Mayes P.A., Rodwell, V.W. Harper's Review of
 Biochemistry, 19th edition. Lange Medical Publications, Los Altos
 California, 1983. p.312.
 163.) Murphy TM, Perry AS, Lawler M.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. 164.) 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.
 165.) Christensen B, Guttormsen AB, Schneede J, Riedel B, Refsum H,
 Svardal A, Ueland PM. Preoperative methionine loading enhances
 restoration of the cobalamin-dependent enzyme methionine synthase
 after nitrous oxide anesthesia.Anesthesiology. 1994
 166.) Banerjee RV, Matthews RG.Cobalamin-dependent methionine
 synthase. FASEB J. 1990 Mar;4(5):1450-9.
 167.) 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.
 168.) Freeman AG. Hydroxocobalamin versus cyanocobalamin. J R Soc
 Med. 1996 Nov;89(11):659.
 169.) Linnell JC, Matthews DM. Cobalamin metabolism and its
 clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21.
 170.) 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.
 171.) Kate E. Broderick, Prasanth Potluri, Shunhui Zhuang, Immo E.
 Scheffler, Vijay S. Sharma, Renate B. Pilz, and Gerry R. Boss.
 Cyanide Detoxification by the Cobalamin Precursor Cobinamide.
 Experimental Biology and Medicine 231:641-649; 2006.
 172.) Sharma VS, Pilz RB, Boss GR, Magde D. Reactions of nitric
 oxide with vitamin B12 and its precursor, cobinamide. Biochemistry.
 2003 Jul 29;42(29):8900-8.
 173.) Rochelle LG, Morana SJ, Kruszyna H, Russell MA, Wilcox DE,
 Smith RP. 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.
 174.) Kruszyna H, Magyar JS, Rochelle LG, Russell MA, Smith RP,
 Wilcox DE. 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.
 175.) Brouwer M, Chamulitrat W, Ferruzzi G, Sauls DL, Weinberg JB.
 Nitric oxide interactions with cobalamins: biochemical and
 functional consequences. Blood. 1996 Sep 1;88(5):1857-64.
 176.) Broderick KE, Singh V, Zhuang S, Kambo A, Chen JC, Sharma VS,
 Pilz RB, Boss GR. Nitric oxide scavenging by the cobalamin
 precursor cobinamide. J Biol Chem. 2005 Mar 11;280(10):8678-85.
 Epub 2005 Jan 4.
 177.) Murray, Michael. Encyclopedia of Nutritional Supplements.
 Prima Publishing, 1996. Chapter 15,pg.130.
 178.) Methylcobalamin. [No authors listed]. Altern Med Rev. 1998
 179.) Jepson B. Changing the Course of Autism. Sentient
 Publications, 2007. Chapter 10.
 180.) Kapadia CR. Vitamin B12 in health and disease: part
 I--inherited disorders of function, absorption, and transport.
 Gastroenterologist. 1995 Dec;3(4):329-44.
 181.) Morel CF, Watkins D, Scott P, Rinaldo P, Rosenblatt DS.
 Prenatal diagnosis for methylmalonic acidemia and inborn errors of
 vitamin B12 metabolism and transport. Mol Genet Metab. 2005
 182.) Rosenblatt DS, Cooper BA, Pottier A, Lue-Shing H, Matiaszuk
 N, Grauer K. 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
 183.) Linnell JC, Bhatt HR.Inherited errors of cobalamin metabolism
 and their management.Baillieres Clin Haematol. 1995
 184.) Watkins D, Rosenblatt DS. Genetic heterogeneity among
 patients with methylcobalamin deficiency. Definition of two
 complementation groups, cblE and cblG. J Clin Invest. 1988
 185.) Suormala T, Baumgartner MR, Coelho D, Zavadakova P, Kozich V,
 Koch HG, Berghaüser M, Wraith JE, Burlina A, Sewell A, Herwig J,
 Fowler B. 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.
 186.) 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.
 187). Akaike A, Tamura Y, Sato Y, Yokota T. Protective effects of a
 vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity
 in cultured cortical neurons. Eur J Pharmacol. 1993 Sep
 188.) Kikuchi M, Kashii S, Honda Y, Tamura Y, Kaneda K, Akaike
 A.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.
 189.) Watanabe T, et al. 1994. Ultra-high dose methylcobalamin
 promotes nerve regeneration in experimental acrylamide neuropathy.
 J Neurol Sci 122:140-43.
 190.) 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.
 191.) Olle Selinus, B. J. Alloway. Essentials of Medical Geology.
 Academic Press, 2005,p.519.ISBN 0126363412.
 59.) The Pharmacological Basis of Therapeutics, Goodman and
 Gillman, Tenth Edititon, Page-1503-1513.
 192.) The Pharmacological Basis of Therapeutics, Goodman and
 Gillman, Tenth Edititon, Page-1503-1513.
 193.) R.S.Satoskar & S.D. Bhanderkar. Pharmacology and
 Therapeutics, Revised 12th, Page No.424-425.
 194.) Andrès E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB,
 Perrin AE, Noblet-Dick M, Maloisel F, Schlienger JL, Blicklé JF.
 Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004
 Aug 3;171(3):251-9.
 195.) Rajan S, Wallace JI, Brodkin KI, Beresford SA, Allen RH,
 Stabler SP. Response of elevated methylmalonic acid to three dose
 levels of oral cobalamin in older adults.J Am Geriatr Soc. 2002
 196.) Herrmann W, Obeid R, Schorr H, Geisel J.Functional vitamin
 B12 deficiency and determination of holotranscobalamin in
 populations at risk. Clin Chem Lab Med. 2003 Nov;41(11):1478-88.
 197.) Kwok T, Tang C, Woo J, Lai WK, Law LK, Pang CP. 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.
 198.) Pimentel M, Chow EJ, Hallegua D, et al. Small intestinal
 bacterial overgrowth: a possible association with fibromyalgia. J
 Musculoskelet Pain 2001;9:107-113.
 199.) Pimentel M, Hallegua D, Chow EJ, et al. Eradication of small
 intestinal bacterial overgrowth decreases symptoms in chronic
 fatigue syndrome: a double blind, randomized study.
 Gastroenterology 2000;118:A414.
 200.) 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).
 Unpublished research from the Shinwell Medical Centre, Horden
 Peterlee County Durham, UK. Report available on website:
 201.) Bradford GS and Taylor CT. Omeprazole and vitamin B12
 deficiency. Annals of Pharmacotherapy 1999;33:641-3.
 202.) Kasper H. Vitamin absorption in the elderly. International
 Journal of Vitamin and Nutrition Research 1999;69:169-72.
 203.) Howden CW. Vitamin B12 levels during prolonged treatment with
 proton pump inhibitors. J Clin Gastroenterol 2000;30:29-33.
 204.) Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Jensen
 RT. 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.
 205.) Bauman WA, Shaw S, Jayatilleke K, Spungen AM, Herbert V.
 Increased intake of calcium reverses the B12 malabsorption induced
 by metformin. Diabetes Care 2000;23:1227-31.
 206.) Sumner AE, Chin MM, Abrahm JL, Berry GT, Gracely EJ, Allen
 RH, Stabler SP. 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.
 207.) Adachi S, Kawamoto T, Otsuka M, Todoroki T, Fukao K. Enteral
 vitamin B12 supplements reverse postgastrectomy B12 deficiency.Ann
 Surg. 2000 Aug;232(2):199-201.
 208.) Suter PM, Golner BB, Goldin BR, Morrow FD, Russel RM.
 Reversal of protein-bound vitamin B12 malabsorption with
 antibiotics in atrophic gastritis. Gastroenterology 1991;
 209.) Súbtil JC, Betés M, Corella C, Iriarte J, Muñoz-Navas
 MA.Dementia caused by bacterial overgrowth in a patient with
 Billroth II gastrectomy]Rev Esp Enferm Dig. 1996 Jun;88(6):431-3.
 210.) Tucker KL, Rich S, Rosenberg I, Jacques P, Dallal G, Wilson
 WF, Selhub. J. Plasma vitamin B12 concentrations relate to intake
 source in the Framingham Offspring Study. Am J Clin Nutr
 211.) Louwman MW, van Dusseldorp M, van de Vijver FJ, Thomas CM,
 Schneede J, Ueland PM, Refsum H, van Staveren WA. Signs of impaired
 cognitive function in adolescents with marginal cobalamin status.
 Am J Clin Nutr. 2000 Sep;72(3):762-9.
 212.) Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician.
 2003 Mar 1;67(5):979-86.
 213.) Pennypacker LC, Allen RH, Kelly JP, Matthews LM, Grigsby J,
 Kaye K, Lindenbaum J, Stabler SP.High prevalence of cobalamin
 deficiency in elderly outpatients.J Am Geriatr Soc. 1992
 215.) Watanabe F. Vitamin B12 sources and bioavailability. Exp Biol
 Med (Maywood). 2007 Nov;232(10):1266-74.
 216.) Dagnelie PC, van Staveren WA, van den Berg H. Vitamin B-12
 from algae appears not to be bioavailable. Am J Clin Nutr. 1991
 217.) Lederle FA. Oral cobalamin for pernicious anemia: back from
 the verge of extinction. J Am Geriatr Soc 1998;46:1125-7.
 218.) Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum
 J. Effective treatment of cobalamin deficiency with oral
 cobalamin.Blood 1998;92: 1191-8.
 219.) Lederle FA. Oral cobalamin for pernicious anemia. Medicine's
 best kept secret? JAMA 1991;265:94-5.
 220.) Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca
 S,Senturk T. Oral versus intramuscular cobalamin treatment in
 megaloblastic anemia: a single-center, prospective, randomized,
 open-label study.Clin Ther. 2003 Dec;25(12):3124-34.
 221.) National Institutes of Health Fact Sheet on vitamin B12
 222.) Nilsson-Ehle H. Age-related changes in cobalamin (vitamin
 B12) handling. Implications for therapy. Drugs Aging. 1998
 223.) Bishop A, Anderson JE. NO signaling in the CNS: from the
 physiological to the pathological. Toxicology. 2005 Mar
 224.) Bucci M, Roviezzo F, Posadas I, Yu J, Parente L, Sessa WC,
 Ignarro LJ, Cirino G. 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
 225.) Kaminski A, Pohl CB, Sponholz C, Ma N, Stamm C, Vollmar B,
 Steinhoff G. 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.