http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall

Dec 9 2002 [ Notes by Rich Murray are in square brackets. Pall has 45
items in PubMed since 1969.

The theory is quite complex. Most readers will not be familiar with the
biochemistry. I will focus on the many diseases that may be involved,
more and less, on MSG and on formaldehyde (an inevitable product of
methanol, the 11% component of aspartame), and the prospect for new
diagnostic tests and for treatments for aspartame disease. ]

http://www.wsunews.wsu.edu/detail.asp?StoryID=3281
News Bureau Washington State University wsunews@...

Pullman, WA 99164-1040 509/335-3581 FAX: 509/335-2220
See a complete list of news releases on the Web at:
http://wsunews.wsu.edu
Online Experts Directory: http://experts.wsu.edu

9/16/2002
Contact: Sharon Hatch, 509/335-4262, hatch@...
Martin L. Pall, 509/335-1246, martin_pall@...

WSU Biochemist Suggests Vicious Chemical Cycle May Cause
Multiple Chemical Sensitivity

PULLMAN, Wash. -- In the United States about 10 million people are
afflicted by severe multiple chemical sensitivity. Many MCS sufferers
give up air travel, some must find new work places or move out of their
homes to avoid exposure to certain chemicals. For them, grocery
shopping in the detergent aisle or attending events where someone may
wear perfume is risky. MCS symptoms, which may last for hours or days,
include pain–severe headaches and pain in joints and muscles–fatigue,
dizziness and an impaired ability to think clearly.

The onset of this chronic condition can usually be traced back to an
exposure to certain chemicals. But why the initial exposure results in
an often life-long, incurable condition has been a mystery. In an
article published in the September 2002 issue of the prestigious
publication of the Federation of American Societies of Experimental
Biology, “The FASEB Journal,” Washington State University biochemist
Martin Pall suggests that a vicious chemical cycle may be to blame.

Pall’s new theory is a fusion of two previous theories about MCS. One
of these, proposed by Pall earlier, states that MCS is produced by
excessive levels of two chemicals in the body–nitric oxide and its
oxidant product - peroxynitrite. He suggested certain mechanisms act to
keep levels of the two compounds elevated, thus producing chronic
changes. The second theory was proposed by Iris Bell, M.D, Ph.D. of the
University of Arizona. She proposed that the central mechanism in MCS
is neural sensitization in the brain.

“What my article reports,” said Pall, “is that if you assume both
previous theories are correct, you come up with a fusion that explains
all the most puzzling features of MCS. It explains why MCS is induced
by a previous chemical exposure and why MCS sufferers show such a high
level of sensitivity to a wide range of organic chemicals.”

Pall cites many studies that suggest that the initial chemical exposure
creates a hypersensitivity in the neurons in the brain, which react by
creating the two chemicals that cause further hypersensitivity.
“Ordinarily, these activities are highly regulated, acting only on
specific synapses in the brain where they are involved in learning and
memory. The MCS response is produced,” said Pall, “when chemical
exposure produces excessive responses over large regions of the brain.
In this way, normal and important mechanisms may act to generate this
chronic illness. Thus, not only is the brain constantly inundated by
chemicals to which it is normally somewhat sensitive, but the brain of
a person suffering from MCS becomes abnormally sensitive to the
chemicals–- from 100 to 1,000 times more sensitive than in an unaffected
person.” Two other mechanisms contribute to the sensitivity to by
allowing the offending chemicals to accumulate to higher levels in the
brains of MCS people.

MCS has overlaps with other medical conditions of uncertain mechanism
including chronic fatigue syndrome, fibromyalgia, posttraumatic stress
disorder, and Gulf War syndrome. Pall has proposed similar mechanisms
for all of these conditions. “The notion that a biochemical vicious
cycle may underlie all four is very exciting and, if correct, suggests
that this is a major new paradigm of human disease.”

Interrupting this cycle may be the key to effective MCS treatment, said
Pall.

Pall’s article is available on the Web at
http://www.fasebj.org/cgi/content-nw/full/16/11/1407/T1.
Access to this site is free to members of the Federation of American
Societies of Experimental Biology, others must pay a $7 access fee.

Comments: Dr. Gunnar Heuser, neurotoxicologist and clinical professor
at UCLA, who has published on brain changes in Chronic Fatigue
Syndrome, stated "I consider Dr. Pall's research a significant
contribution to the science of clinical toxicology and multiple
chemical sensitivity."
Brain Imaging Center, University of California, Irvine, USA.
gheuser@...

Dr. Grace Ziem, Maryland physician who practices occupational and
environmental medicine and specializes in chemically-induced illness,
said "I feel that Dr. Pall has done the most important biochemical
research and documentation toward understanding the mechanism of neural
sensitization underlying toxic injury to the brain and this research
has important implications for treatment."
http://www.mcsrr.org/resources/articles/S3.html
DR. GRACE ZIEM'S ENVIRONMENTAL CONTROL PLAN
FOR CHEMICALLY SENSITIVE PATIENTS
16926 Eyler's Valley Road, Emmitsburg MD 21727, 301-241-4346
Albert Donnay <donnay@...>
************************************************************************

http://molecular.biosciences.wsu.edu/Faculty/pall.html [photo]

http://molecular.biosciences.wsu.edu/Faculty/pall/pall_cfs.htm
Novel chronic fatigue syndrome (CFS) theory finally
produces detailed explanations for many CFS observations:
[ This is a detailed summary review, with diagrams, references, and some
hyperlinks. ]

http://molecular.biosciences.wsu.edu/Faculty/pall/pall_fibro.htm
Fibromyalgia, excessive nitric oxide/peroxynitrite and excessive NMDA
activity [ detailed summary review, with 14 references, including
2. Smith J. D., Terpening C. M., Schmidt S. O. F., Gums J. G. Relief of
fibromyalgia symptoms following discontinuation of dietary excitotoxins.
Ann Pharmacotherapy 2001; 35: 702-706.

http://groups.yahoo.com/group/aspartameNM/message/782
RTM: Smith, Terpening, Schmidt, Gums:
full text: aspartame, MSG, fibromyalgia 1.17.2 rmforall ]
************************************************************************

FASEB J 2002 Sep; 16(11): 1407-17
NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and
organic solvents as the mechanism of chemical sensitivity in multiple
chemical sensitivity.
Pall ML. [ 162 references, received 1.3.2 ]
School of Molecular Biosciences, Washington State University,
Pullman, Washington 99164-4660, USA. martin_pall@...

http://www.fasebj.org/cgi/content-nw/full/16/11/1407/T1. full text
Access to this site is free to members of the Federation of American
Societies of Experimental Biology, others must pay a $7 access fee.

Multiple chemical sensitivity (MCS) is a condition where previous
exposure to hydrophobic organic solvents or pesticides appears to
render people hypersensitive to a wide range of chemicals, including
organic solvents. The hypersensitivity is often exquisite, with MCS
individuals showing sensitivity that appears to be at least two orders
of magnitude greater than that of normal individuals. This paper
presents a plausible set of interacting mechanisms to explain such
heightened sensitivity.

It is based on two earlier theories of MCS: the elevated nitric
oxide/peroxynitrite theory and the neural sensitization theory. It is
also based on evidence implicating excessive NMDA activity in MCS. Four
sensitization mechanisms are proposed to act synergistically, each
based on known physiological mechanisms:
Nitric oxide-mediated stimulation of neurotransmitter (glutamate)
release;
peroxynitrite-mediated ATP depletion and consequent hypersensitivity of
NMDA receptors;
peroxynitrite-mediated increased permeability of theblood-brain barrier,
producing increased accessibility of organic
chemicals to the central nervous system;
and nitric oxide inhibition of cytochrome P450 metabolism.

Evidence for each of these mechanisms, which may also be involved in
Parkinson's disease, is reviewed. These interacting mechanisms provide
explanations for diverse aspects of MCS and a framework for
hypothesis-driven MCS research. PMID: 12205032

"...exposure to organophosphates or carbamates (1-7)...
hypersensitive... hydrophobic, volatile organic solvents... not to be
centered on an IgE-based allergic mechanism (1)... severe MCS in the
U.S. is ~4% with greatly reduced quality of life for the patient (2)...
less severe problems have been reported in ~15-30% of the population...
chemical sensitivity two or more orders of magnitude greater than do
normal individuals... no known mechanism whereby low levels of chemical
or chemicals of widely varied chemical structure can interact adversely
with numerous organ systems... Chronic fatigue syndrome (CFS),
fibromyalgia (FM), and post-traumatic stress disorder (PTSD)...
overlapping symptoms... preceded by short-term stress, only to be
followed by a chronic condition that typically lasts for years or
decades. Gulf War syndrome... may share a common etiologic mechanism
(16,23-29)... elevated nitric oxide/peroxynitrite mechanism (28-33)...
short-term stress... increases in nitric oxide (29-32)... reacts with
superoxide to form the potent oxidant peroxynitrite... six different
positive feedback loop mechanisms to increase the levels of nitric oxide
and its other precursor, superoxide, which in turn react to form more
peroxynitrite (30)... biochemical vicious cycle is initiated and
maintained that produces the chronic nature of these four conditions...
10 types of supportive evidence are summarized in Table 1...

The second precursor theory to this paper is the neural sensitization
theory origianlly proposed by Bell and co-workers (34)...
[ 34. Iris R. Bell, Miller CS, Schwartz GE.(1992).
An olfactory-limbic model of multiple chemical sensitivity syndrome:
possible relationships to kindling and affective spectrum disorders.
Biol. Psychiatry 1992; 32: 218-242.

35. Bell IR, Baldwin CM, Fernandez M, Schwartz GE.
Neural sensitization model for multiple chemical sensitivity: overview
of theory and empirical evidence.
Toxicol Ind. Health 1999; 15: 295-304. ]

... especially the limbic system... increased long-term synaptic
sensitivity induced by previous electrical and chemical
stimulation...long-term potentiation (LTP)... nitric oxide and the NMDA
[ N-methyl-D-aspartame ] excitatory neurotransmission system are
implicated in LTP, the presumed mechanism of neural sensitization...
increased Ca2+ influx into the cell... Excessive NMDA activity leading
to excessive levels of nitric oxide and peroxynitrite has been
implicated in several neurodegenerative diseases including
amyotrophic lateral sclerosis [ALS], Parkinson's disease, AIDS-related
dementia, stroke, epilepsy, Huntington's disease, and Alzheimer's
disease (67-72)... nitric oxide and peroxynitrite may act through known
mechanisms to increase both the stimulation of and the sensitivity of
NMDA receptors.

...volative organic solvents act in MCS by increasing NMDA activity.
The evidence for this (discussed below) is suggestive but not
conclusive... leading to ATP [ adenosine triphosphate, a primary energy
store and source in cells ] depletion as well... when neurons containing
NMDA receptors have lowered ATP pools, their NMDA receptors become
hypersensitive to stimulation... MCS individuals are often reported to
have low Mg2+ pools (7), and Mg2+ is known to lower NMDA sensitivity
(91).

...Acetylcholline will activate the muscarinic receptors, which are
known to produce increases in nitric oxide... people in buildings that
had been remodeled ("sick building syndrome"), thus exposing the
individuals to outgassing of organic solvents from the building
materials... (infection, physical trauma, and stress) may act to
increase nitric oxide levels (29,30,32)... carbon monoxide... chronic
sequelae (29), with symptoms similar to those in CFS, and carbon
monoxide is reported to induce excessive production of the two
percursors of peroxynitrite: superoxide and nitric oxide (29).

Peroxynitrite... to increase the permeability of the blood-brain barrier
in MCS... to increase chemical access to the CNS and thus increase
chemical sensitivity generated in the CNS...

Miller and Mitzel (6) reported that many MCS patients appear to be
hypersensitive to monosodium glutamate, a potential excitotoxin that can
act to stimulate NMDA receptors (64, 66, 91)...

One organic chemical often implicated in MCS-- formaldehyde... NMDA
stimulation... pain responses... by excessive NMDA activity and
consequent elevated nitric oxide levels...

...Donald Dudley... clinical observations on his MCS patients
(131)... known NMDA antagonist, dextromethorphan, appeared to block the
effects of organic solvents on his MCS patients... on an episodic
basis... stop the reaction before it gets started... Two other
physicians in Washington state,Gordon Baker and David Buscher,...
dextromethorphan for their MCS patients in a similar fashion, with
apparently similar results...

Part of the goal here is to suggest potentially important foci for
hypothesis-driven research, and clearly the many uncertainties in this
part of the hypothesis suggest many such topics of future study.

In her MCS review, [B.A.] Sorg (ref 2, Table 1) lists 18 neurological
symptoms as being found in MCS but lists other symptoms of
cardiovascular (two), respiratory (seven), gastrointestinal (three),
genitourinary (four), musculoskeletal (five), and dermatologic (one)
origin... various other organs appear to be affected in many
cases... inflammatory cytokines... will circulate to a variety of
tissues and have been reported to be induced by organic solvents
(28)... Furthermore,... nitric oxide transport... spreading to other
tissues... [ These many symptoms fit the profile of aspartame disease. ]

2. Sorg BA.
Multiple chemical sensitivity: potential role for neural sensitization.
Crit. Rev. Neurobiol. 1999; 13: 283-316.

...organic solvent exposure is an important risk factor in Parkinson's
disease (148-153)... Excessive NMDA activity is associated with
Parkinson's disease...

...funding for MCS disease is less than a thousandth of that available
for diabetes research... critical need for clear and compelling
hypotheses, consistent with the many reported properties of MCS, to
provide a basis for future research... four proposed consequent
mechanisms... are all expected to act synergistically, producing the
kind of exquisite sensitivity reported in MCS...

I thank Drs. James Satterlee, 'Jay" Wright and Joseph Harding for
helpful discussions."
************************************************************************

28. Pall ML, Satterlee JD.
Elevated nitric oxide/peroxynitrite mechanism for the common etiology
of multiple chemical sensitivity, chronic fatigue syndrome, and
posttraumatic stress disorder.
Ann N Y Acad Sci. 2001 Mar; 933: 323-9. Review. [ 45 references ]

Various types of evidence implicate nitric oxide and an oxidant,
possibly peroxynitrite, in MCS and chemical intolerance (CI). The
positive feedback loops proposed earlier for CFS may explain the chronic
nature of MCS (CI) as well as several of its other reported properties.
These observations raise the possibility that this proposed elevated
nitric oxide/peroxynitrite mechanism may be the mechanism of a new
disease paradigm, answering the question raised by Miller earlier:
"Are we on the threshold of a new theory of disease?"
Publication Types: Review Review, Tutorial PMID: 12000033

"MCS incitants...volatile organics, such as hydrocarbons, chlorinated
hydrocarbons, other organics, and pesticides...benzene (4-6), carbon
tetrachloride (7-9), formaldehyde (10-13), and chlorinated hydrocarbon
pesticides (14). Organophosphate pesticides...Such muscarinic receptor
stimulation is known to produce increases in nitric oxide levels.
(15-18)

...elevated neopterin levels...a biochemical marker...

In one study, several antioxidants were used to treat patients with MCS,
with some apparent success, (23), suggesting that oxidative damage may
have a role in MCS...blood of MCS patients...elevated levels of oxidants
...the serum to have lowers levels of antioxidants, as compared to
controls, (24)...

...stimulation of the limbic system...spontaneous seizures (kindling).
(25-29) ... inhibitor of nitric oxide synthase activity blocked the
characteristic sensitization response. (30-36)...arginine,...stimulated
the response. (32)...nitric oxide has an essential role in producing
neural sensitization and kindling...MCS."
***********************************************************************

29. Pall ML.
Common etiology of posttraumatic stress disorder, fibromyalgia, chronic
fatigue syndrome and multiple chemical sensitivity via elevated nitric
oxide/peroxynitrite. [ 93 references, received 10.19.0 ]
Med Hypotheses. 2001 Aug; 57(2): 139-45.

Three types of overlap occur among the disease states chronic fatigue
syndrome (CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS)
and posttraumatic stress disorder (PTSD). They share common symptoms.

Many patients meet the criteria for diagnosis for two or more of these
disorders and each disorder appears to be often induced by a relatively
short-term stress which is followed by a chronic pathology, suggesting
that the stress may act by inducing a self-perpetuating vicious cycle.

Such a vicious cycle mechanism has been proposed to explain the
etiology of CFS and MCS, based on elevated levels of nitric oxide and
its potent oxidant product, peroxynitrite. Six positive feedback loops
were proposed to act such that when peroxynitrite levels are elevated,
they may remain elevated. The biochemistry involved is not highly
tissue-specific, so that variation in symptoms may be explained by a
variation in nitric oxide/peroxynitrite tissue distribution.

The evidence for the same biochemical mechanism in the etiology of PTSD
and FM is discussed here, and while less extensive than in the case of
CFS and MCS, it is nevertheless suggestive. Evidence supporting the role
of elevated nitric oxide/peroxynitrite in these four disease states is
summarized, including induction of nitric oxide by common apparent
inducers of these disease states, markers of elevated nitric
oxide/peroxynitrite in patients and evidence for an inductive role of
elevated nitric oxide in animal models.

This theory appears to be the first to provide a mechanistic explanation
for the multiple overlaps of these disease states and it also explains
the origin of many of their common symptoms and similarity to both Gulf
War syndrome and chronic sequelae of carbon monoxide toxicity. This
theory suggests multiple studies that should be performed to further
test this proposed mechanism. If this mechanism proves central to the
etiology of these four conditions, it may also be involved in other
conditions of currently obscure etiology and criteria are suggested for
identifying such conditions. PMID: 11461161

"...The NMDA receptors are receptors for the amino acid glutamate and
the toxicity of excessive glutamate is mediated through these receptors
and specifically through their action in increasing the synthesis of
both nitric acid and peroxynitrite (20-26). In animal models of PTSD,
severe stress induces considerable oxidative damage, probably through
the action of peroxynitrite-induced oxidative chain reactions. Reported
oxidative changes include glutathione depletion, increases in lipid
peroxide levels and changes in the levels of antioxidant enzymes
(27-29)...

...The most characteristic symptoms in FM are muscle and joint pain and
tender points. It is well documented that nitric oxide stimulates many
but not all nociceptors (see, for example, refs 55-59) and I propose
that, as in the case of migraine headaches (58-59), much of the pain in
FM may be generated by elevated nitric oxide...

...Tissue hypoxia generated by excessive exercise...through increased
synthesis of superoxide, the other precusor of peroxynitrite (12 and see
below.)...

...symtoms of carbon monoxide (CO) toxicity include essentially all of
the overlapping symptoms typical of CFS, MCS, PTSD and FM, including
fatigue, headache, dizziness, memory impairmant, cognitive dysfunction,
weakness, vertigo and sleep deprivation (66-76). Many victims of CO
show chronic symptoms, lasting from many months to years after both CO
exposure has terminated and CO levels in the blood have returned to
normal (66, 67, 69-73)... [ These same symptom patterns are also
characteristic of aspartame reactors. ]

I suggest nine such criteria:
1. A pattern of possible induction by a short-term stress preceding a
chronic pathology.
2. Uncertain etiology.
3. Association with CFS, MCS, FM and/or PTSD.
4. Elevated tissue levels of nitric oxide/peroxynitrite.
5. Elevated levels of inflammatory cytokines.
6. Elevated levels of oxidants and lowered levels of antioxidants.
7. Chronic inflammation.
8. Chemical hypersensitivity.
9. Effective treatment wtih local glucocorticoid exposure.

...Glucocorticoids are used to treat such diseases as asthma and
psoriasis and are known to repress the synthesis of the inductible
nitric oxide synthase (92, 93). [ This gives many suggestions for
biochemical assays and treatments for aspartame reactors. ]

...grant from the Air Force Office for Scientific Research."
***********************************************************************

30. Pall ML.
Elevated, sustained peroxynitrite levels as the cause of chronic
fatigue syndrome. [ 125 references, received 7.29.98 ]
Med Hypotheses. 2000 Jan; 54(1): 115-25.

The etiology of chronic fatigue syndrome (CFS) has been both obscure and
highly contentious, leading to substantial barriers to both clear
diagnosis and effective treatment. I propose here a novel hypothesis of
CFS in which either viral or bacterial infection induces one or more
cytokines, IL-1beta IL-6, TNF-alpha and IFN-gamma.

These induce nitric oxide synthase(iNOS), leading to increased nitric
oxide levels. Nitric oxide, in turn, reacts with superoxide radical to
generate the potent oxidant peroxynitrite.

Multiple amplification and positive feedback mechanisms are proposed by
which once peroxynitrite levels are elevated, they tend to be
sustained at a high level. This proposed mechanism may lower the HPA
axis activity and be maintained by consequent lowered glucocorticoid
levels. Similarities are discussed among CFS and autoimmune and other
diseases previously shown to be associated with elevated peroxynitrite.
Multiple pharmacological approaches to the treatment of CFS are
suggested by this hypothesis. PMID: 10790736

"...widely discussed notion that post-viral fatigue syndrome (2) is a
form of chronic fatigue syndrome... overall notion of post-infectious
fatigue syndrome (4)....

"Peroxynitrite, OONO-, is a powerful oxidant formed from the reaction of
two relatively nonreactive free radicals, nitric oxide (*NO) and
superoxide (*OO-)... (10-12)... Nitric oxide is synthesized by three
different isozymes of nitric oxide synthase, two of which are
constitutive, eNOS and nNOS and one of which is highly inducible, iNOS.
It is the inducible iNOS isozyme which has the most central role in this
hypothesis. iNOS is higly induced in many cell types in response to four
different inflammatory cytokines... which are, in turn, induced by viral
infection or the presence of bacterial antigens... infections can lead
to the induction of high levels of iNOS, greatly increasing the levels
of nitric oxide and leading to a great increase in the levels of
peroxynitrite... this occurs in sepsis... mitochondrial and energy
metabolism dysfunction is one of the most important consequences of
elevated peroxynitrite (10, 11, 21-23).

...increasing Ca2+ levels will increase nitric oxide synthesis...

...such disease states as atherosclerosis, myocarditis, nephritis, and a
wide variety of automimmune diseases.

...uveoretinitis... rheumatoid arthritis, type I diabetes, multiple
sclerosis, systemic lupus erythrematosis... each show their own
characteristic distribution of peroxynitrite elevation as shown by such
measures as nitrotyrosine distribution in proteins or iNOS expression
pattern... A number of reports suggest that the
hypothalamic-pituitary-adrenal (HPA) axis may have lowered activity in
CFS patients and that this lowered activity may be responsible for many
of the characteristic symptoms of CFS (5, 47-55). These reports suggest
that lowered responsiveness of the hypothalalmus may be an important
cause of CFS and that the resulting lowered levels of glucocorticoids
may be responsible for many of the symptoms of CFS... What is
intriguing, however is that the low levels of glucocorticoids, produced
by low HPA axis activity in CFS patients, may have a substantial role in
the proposed sustained elevation of both inflammatory cytokine levels
and nitric oxide/peroxynitrite levels. Glucorticoids have long been
known to suppress both immune and inflammatory responses... to inhibit
induction of both the inducible nitric oxide synthase (iNOS) in multiple
tissues and also the induction of the inflammatory cytokines...

...one of the primary targets of peroxynitrite is the mitochodrion...
This predicts that energy metabolism disfunction should be
characteristic of CFS... measurements of phosphorylation
activity... mitochondrial structural changes as seen in the electron
microscope (78-84)... urine of CFS patients... two TCA cycle
intermediates, succinate and cis-aconitate, were both found to be
elevated in CFS patients (85, 86)... succinic dehydrogenase activity...
has been reported to be low (78, 80)... [ Unrelenting fatigue is often
part of aspartame disease. ] ...a CFS patient who had accumulated
unusual deletions in his mitochondrial DNA (82).... [ Formaldehyde from
the 11% methanol component of aspartame forms DNA adducts. ]

...polyunsaturated essential fatty acids are low in CFS patients (87)
may also be explained because the lipid peroxidation induced by
elevated peroxynitrite (10-12, 22) preferentially oxidizes such
polyunsaturated fatty acids...

...CFS patients have been reported to suffer from low NK syndrome,
characterized by low serum levels of cystine and glutamine (88). Low NK
syndrome is also found in several diseases characterized by elevated
peroxynitrite levels, including sepsis, Crohn's disease, ulcerative
colitis, AIDS dementia patients and some forms of cancer (89)...

...possible pharmacological intervention...
1. ...ubiquinone (coenzyme Q10) and carnitine may improve mitochondrial
function in CFS....
2. Nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin and
ibuprofen, have been reported to inhibit iNOS induction (91,92)...
3. Cell permeable superoxide dismutase mimetic agents...such as MnTBAP
to lower superoxide levels (93, 94)...
4. ...lower the induction of iNOS... vitamin D derivatives (95),
epigallocatechin-3-gallate and genistein... protein tyrosine kinase
inhibitors... linomide, a drug used to treat autoimmune disease (101),
and terpenoids (102).
5. ...antioxidants...
a. ...gamma-tocopherol...
b. N-acetyl cysteine...
c. Flavonoids... epigallocatechin gallate (107)... and genistein...
These two are found in high amounts in green tea and soy products,
respectively....
d. Ascorbic acid acts as a peroxynitrite scavenger, in addition to its
general activity as an antioxidant (108, 109)....
e. Many antioxidants have been shown to inhibit NF-kB activity...
6. Arginine... inhibit... nitric oxide synthrase enzymes... (19,20)...
7. ...Some inhibitors of NF-kB activity, such as TLCK or PDTC, act
indirectly as protease inhibitors or by other mechanisms... (113, 114).
...genistein...
8. Allopurinol is a well-documented inhibitor of xanthine
oxidase/xanthine dehydrogenase activity and has been widely used to
treat gout and other diseases... numerous flavonoids...
9. ...inhibitors of this enzyme... poly(ADP-ribose) synthase... have
been shown to improve cellular survival when challenged by peroxynitrite
(36-38).

This paper is dedicated to the memory of Stephanie Pall.

...neopterin levels are elevated to the urine or serum of CFS patients
(66, 119, 120)... closely linked to the induction of the inducible
nitric oxide synthase (123-125)... important, if indirect, evidence for
nitric oxide elevation in CFS patients..."
************************************************************************

31. Pall, ML.
Levels of nitric oxide synthase product citrulline are elevated in sera
of chronic fatigue syndrome patients.
J. Chronic Fatigue Syndr. 2002; 10(3/4): 37-41. [ 7 references ]

www.cfs.inform.dk/
http://www.cfs.inform.dk/Hypoteser/pall02.pdf free full text

Serum levels of citrulline, a product of nitric oxide synthase activity,
were measured in 36 CFS patients.

Serum citrulline levels were found to be significantly eleveated in CFS
patients and, in addition, there was a trend towards higher levels in
CFS patients with stronger symptoms.

These results provide support for the view that nitric oxide synthesis
activity tends to be elevated in CFS patients, thus supporting a
prediction of the elevated nitric oxide/peroxynitrite theory of CRS
etiology.

"INTRODUCTION
Chronic fatigue syndrome (CFS) is reported to impact a large number of
different biochemical, physiological and immunological properties in
patients, ranging from mitochondrial/energy metabolism to circulatory
function to neuroendocrine function to natural killer cell function
(discussed in 1,2). Similarly a wide range of symptoms are commonly
reported (3). One of the central questions facing CFS researchers is how
these diverse characteristics may be impacted by a single etiologic
mechanism.

A wide-ranging theory of CFS is the elevated nitric
oxide/peroxynitrite theory, which is supported by 12 different
biochemical/physiological observations about CFS (1,2,4) and explains
many of the diverse symptoms in this condition through known biochemical
and physiological mechanisms (2).

The same basic etiology may also explain the properties of three
conditions that overlap with CFS: multiple chemical
sensitivity, fibromyalgia and posttraumatic stress disorder (5,6).

According to this theory, CFS is initiated by stresses such as infection
that lead to elevated levels of nitric oxide and its oxidant product,
peroxynitrite. Peroxynitrite acts through several positive feedback
loops to elevate the levels of both of its precursors, nitric oxide and
superoxide, which will then react with each other to form more
peroxynitrite. In this way, a biochemical vicious cycle is initiated and
maintained with that vicious cycle being responsible for the chronic
nature of CFS.

According to this view, infection acts by inducing inflammatory
cytokines which induce, in turn, the inducible nitric oxide synthase
(iNOS). However, the chronic phase of CFS may be maintained through the
action of both iNOS and the other nitric oxide synthase isozymes, nNOS
and eNOS (1). A number of studies have reported that during the chronic
phase of CFS, both inflammatory cytokines that induce the iNOS gene are
elevated and that the marker for iNOS activity, neopterin levels, are
also elevated in CFS (references in 1,2,4). However, because both iNOS
and the other NOS isozymes are proposed to be involved in the chronic
phase of CFS, it is important to measure a marker of overall nitric
oxide synthesis, not just iNOS activity.

Because nitric oxide is unstable in vivo, nitric oxide synthase activity
in vivo is usually measured by either of two different markers. Either
nitrate/nitrite levels are measured because these are produced through
the degradation of nitric oxide and its oxidant product, peroxynitrite,
or L-citrulline levels are measured.

Because nitrate/nitrite levels are
elevated by diets including such foods as green vegetables and sausages
and other preserved meat and fish products, it is essential to closely
control the diet of people for whom nitrate/nitrite measurements are to
reflect NOS activity.

Citrulline, the coproduct of nitric oxide synthase activity, is stable
and its levels are much less likely to be perturbed by diet, as compared
with nitrate/nitrite, and may therefore be a preferred measurement
for this reason. In a recent study by Larson et al. (7), the citrulline
levels in the cerebrospinal fluid of fibromyalgia patients were reported
to be elevated, allowing them to infer that nitric oxide synthesis was
elevated in the central nervous systems of fibromyalgia patients as
compared with controls. In the current study, the serum levels of
citrulline of CFS patients are compared with those of controls and also
found to be elevated."

"7. Larson AA, Glovengo SL, Russell U, et al. Changes in the
concentration of amino acids in the cerebrospinal fluid that correlate
with pain in patients with fibromyalgia. Pain 2000; 87: 201-211."
************************************************************************

33. Pall ML.
Cobalamin [vitamin B12] used in chronic fatigue syndrome therapy is a
nitric oxide scavenger.
J. Chronic Fatigue Syndr. 2001; 8(2): 39-44. [ 38 references ]

Cobalamin (vitamin B12) in the form of hydrooxocobalamin or
cyanocobalamin injections has been widely used to treat chronic fatigue
syndrome (CFS).

Hydroxocobalamin is a nitric oxide scavenger and is proposed here to act
as such a scavenger in CFS treatment. Its possible efficacy in CFS
treatment, if further substantiated, may provide confirmation of a
prediction of the elevated nitric oxide/peroxynitrite theory of CFS
etiology. This interpreation of the possible role of cobalamin in CFS
treatment suggests a useful perspective for confirming and optimizing
this treatment.
***********************************************************************

http://www.immunesupport.com/library/showarticle.cfm?ID=2976
http://www.imunologie.cz/kveten01_6.htm
New Theory on Explanations for Chronic Fatigue Syndrome
by Dr. Martin L. Pall http://www.ImmuneSupport.com

02-13-2001 Editor's Note: Dr. Martin L. Pall, Ph.D., received
his Ph.D. in Biochemistry and genetics from Caltech after
receiving his B.A. degree at Johns Hopkins University. He is
a professor of biochemistry and Basic Medical Sciences at
Washington State University. He teaches medical students
and is the chief instructor at Washington State University in
the medical biochemistry course for first year medical students.

Dr. Pall writes that he came down with CFS in June/July
1997 after a severe bout of Varicella zoster infection. "My
CFS was diagnosed by my primary care physician and my
case did meet the 1994 CDC criteria. So this was, in many
ways, a typical case of post-viral fatigue syndrome, sudden
onset. However, I have had an excellent recovery, over about
a year and a half (possibly due to self-medication?), and
consider myself cured. So, I don't view myself as a CFS
patient. It was only after recovery from the severe cognitive
dysfunction that I was able to dedicate myself to
understanding the basis of CFS."

I asked Dr. Pall about his comment that he considers
himself cured. Is he not afraid of a relapse in the future?
Also, to what does he attribute the 'cure' and how does he
stay healthy? This is his response:

I became ill with CFS in June/July 1997 and spent most of
July and August in bed trying to recuperate. The following
semester, I was able to perform at a minimal level in my
teaching, taking lot's of sick leave, living from day to day, as
most of us do. I self medicated on several things (more
about that later) but had little apparent improvement.
However, the following winter, I did improve substantially and
by May was doing very well, not completely recovered but
maybe 80% recovered. A year later, I considered myself
completely recovered although I am still self-medicating, not
wanting to take any chances of having a relapse.
Specifically, over the past two summers, I have been able to
go on a series of fairly taxing Sierra Club hikes with no
post-exertional malaise. That is quite distinct from my earlier
condition where I could only walk (slowly) circa 50 yards
before having to sit down for a long rest.

My self medication was primarily with antioxidants (natural
mixed tocopherols, vitamin C, selenium, some carotenoids,
calcium/magnesium supplement, Ginkgo extract and
coenzyme Q10). I also tried some black currant seed oil and
some choline/inositol supplements - I did not think these
helped but maybe I was wrong? I am very careful with my
diet, eating nutritionally rich foods and antioxidant-rich foods
(it would take a book to tell you all about the food issue). I
did not have any GI tract problems so was able to tolerate
both the supplements and a wide variety of foods.

The most dramatic effects that I saw, appeared to be from
the Ginkgo extract (this over a period of two or more months,
however) and, following that, from the Co Q10 , the latter of
which was a dramatic, within 24 hours, recovery of cognitive
function. I have never had a problem with cognitive
dysfunction since that time and am still taking the Co Q10. I
am aware that most others who have tried Co Q10 have not
had as favorable a response, and I can only think that my
body was primed, possibly by the other supplements and
foods, to be ready to respond to it.

I have been running a clinical trial/pilot study with a
physician (Dr. Albert G. Corrado) using a series of
supplements based on my theory, and the results have been
both encouraging and discouraging -- encouraging because
essentially everyone who was on the trial and was able to
tolerate most of the supplements reported an improvement
but all reported a modest improvement, over a 150 day
period. So no one was cured over that time. I met yesterday
with a group of PWCS [Persons With Chemical Sensitivity],
a few of whom were on the trial, and
we are seeing some continued improvement (most people
opted to continue on the supplements after the trial was
officially completed, suggesting that they felt that the
supplements were helpful). One person even reported that
she was "almost normal" now about 13 months after starting
on the supplements. So, maybe there is hope.

With regard to your question about a possible relapse, that
is, of course, the nightmare of all us who have largely or
partially recovered from CFS. All I can say is that over the
past two years, I have functioned on a completely normal
level -- but then, I am still self-medicating and plan to
continue doing so indefinitely. Some of the hikes I have been
on have been quite taxing -- 8 1/2 to 9 mile fairly tough hikes,
with substantial elevation gains -- and the results have been
some fatigue afterwards, but normal fatigue, just requiring
normal resting. So I am hopeful that this functional recovery
is permanent.

Novel chronic fatigue syndrome (CFS) theory finally
produces detailed explanations for many CFS observations

A novel theory of the cause of CFS has been published
which is supported by diverse biochemical and physiological
observations of CFS, while providing explanations for five of
most difficult puzzles about this medical condition. The
theory has been published by Dr. Martin L. Pall (Professor of
Biochemistry and Basic Medical Sciences, Washington
State University) in several publications (1-4,9).

The theory starts with the observation that infections that
precede and may therefore induce CFS and related
conditions act to induce excessive production of
inflammatory cytokines that induce, in turn, the inducible
nitric oxide synthase (iNOS). This enzyme, in turn,
synthesizes excessive amounts of nitric oxide which reacts
with another compound (superoxide) to produce the potent
oxidant peroxynitrite. Peroxynitrite acts via six known
biochemical mechanisms to increase the levels of both nitric
oxide and superoxide which react to produce more
peroxynitrite. In this way, once peroxynitrite levels are
elevated, they may act to continue the elevation, thus
producing a self-sustaining vicious cycle. It is this cycle,
according to the theory, that maintains the chronic
symptoms of CFS and it is this cycle, therefore, that must
be interrupted to effectively treat this condition.
************************************************************************

http://www.ImmuneSupport.com/library/showarticle.cfm/id/4072
The Poisoning of America: The Rise of 'Mystery' Illnesses Including
Chronic Fatigue Syndrome, Fibromyalgia, and Gulf War Syndrome
ImmuneSupport.com 11-13-2002 By Jason Alexander Uttley
"Gulf War Syndrome... Fibromyalgia... Chronic Fatigue Syndrome... At the
heart of this horrific story lies a group of antibiotics called the
fluoroquinolones. Among the more common of these medications are:
ciprofloxacin (Cipro), levofloxacin (Levaquin), norfloxacin
(Noroxin), ofloxacin (Floxin), and trovafloxacin (Trovan).... Such
conditions include Irritable Bowel Syndrome, Multiple Chemical
Sensitivity Syndrome, Chronic Myofascial Pain Syndrome, and
Peripheral Neuropathy.... Just like all the other conditions mentioned
previously their symptoms often include: joint pain, muscle
stiffness/aches, tendon pain, dizziness, disorientation, burning and
tingling sensations, numbness, diarrhea, sensory sensitivities, and
brain fog." [ All these symptoms are common in aspartame disease. This
suggests that Pall may be on the right track with a theory that many CFS
type diseases share a common etiology. ]
***********************************************************************

http://groups.yahoo.com/group/aspartameNM/message/912
aspartame: methanol, formaldehyde, formic acid toxicity:
brief review: Murray 12.10.2 rmforall

Rich Murray, MA Room For All rmforall@...
1943 Otowi Road, Santa Fe NM 87505 USA 505-986-9103

http://groups.yahoo.com/group/aspartameNM/messages
for 912 posts in a public searchable archive

http://groups.yahoo.com/group/aspartameNM/message/862 long review

Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall

http://groups.yahoo.com/group/aspartameNM/message/910
formaldehyde & formic acid from methanol in aspartame:
Murray: 12.9.2 rmforall

It is certain that high levels of aspartame use, above 2 liters daily
for months and years, must lead to chronic formaldehyde-formic acid
toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month.
If 10% of the methanol is retained as formaldehyde, that would give 12
mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
from 10% retention of the 2 mg EPA limit for formaldehyde in drinking
water.

Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.

http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall

This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms, starting with
headache, fatigue, joint pain, irritability, memory loss, and leading to
vision and eye problems and even seizures. In many cases there is
addiction. Probably there are immune system disorders, with a
hypersensitivity to these toxins and other chemicals.

http://groups.yahoo.com/group/aspartameNM/message/860
RTM: FDA: objections to neotame approval 8.3.2 rmforall 38 pages

http://groups.yahoo.com/group/aspartameNM/message/868
Murray: submit complaints and papers to FDA Docket 02P-0317
by Jan 12 2003: Recall Aspartame as a Neurotoxic Drug 9.20.2 rmforall

http://www.dorway.com/tldaddic.html 5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRobertsMD@...
http://www.sunsentpress.com/ sunsentpress@...
Sunshine Sentinel Press P.O.Box 17799 West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax

http://groups.yahoo.com/group/aspartameNM/message/669
1038-page medical text "Aspartame Disease: An Ignored Epidemic"
published May 30 2001 $ 85.00 postpaid data from 1200 cases
available at http://www.amazon.com
over 600 references from standard medical research
http://www.aspartameispoison.com/contents.html 34 chapters

http://groups.yahoo.com/group/aspartameNM/message/859
RTM: Roberts: the life work of a brilliant clinician:
aspartame toxicity 8.2.2 rmforall

http://groups.yahoo.com/group/aspartameNM/message/790
RTM: Moseley:
review Roberts "Aspartame Disease: An Ignored Epidemic" 2.7.2 rmforall
************************************************************************