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Co-Cure Weekly Digest of research and medical posts only - 16 Jul 2007 to 21 Jul 2007

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Date:    Tue, 17 Jul 2007 14:06:42 +0200
From:    Jan van Roijen <j.van.roijen CHELLO.NL>
Subject: not,med: Chronic fatigue no longer seen as 'yuppie flu'

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[NOTE: This article was carried by several other newspapers, including the New York Times.]

http://www.kansas.com/188/story/123834.html


Kansas.com
The Wichita Eagle

Tuesday, Jul 17, 2007

Alive & Well

Posted on Mon, Jul. 16, 2007



Chronic fatigue no longer seen as 'yuppie flu'
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

BY DAVID TULLER

Science Times


For decades, people suffering from chronic fatigue syndrome
have struggled to convince doctors, employers, friends and even
family members that they were not imagining their debilitating
symptoms. Skeptics called the illness "yuppie flu" and "shirker
syndrome."

But the syndrome is now finally gaining some official respect.
The Centers for Disease Control and Prevention, which in 1999
acknowledged that it had diverted millions of dollars allocated by
Congress for chronic fatigue syndrome research to other
programs, has released studies that linked the condition to
genetic mutations and abnormalities in gene expression
involved in key physiological processes. The centers have also
sponsored a $6 million public awareness campaign about the
illness. And last month, the CDC released survey data
suggesting that the prevalence of the syndrome is far higher than
previously thought, although these findings have stirred
controversy among patients and scientists. Some scientists and
many patients remain highly critical of the CDC's record on
chronic fatigue syndrome, or CFS. But nearly everyone now
agrees that the syndrome is real.

"People with CFS are as sick and as functionally impaired as
someone with AIDS, with breast cancer, with chronic obstructive
pulmonary disease," said William Reeves, the lead expert on the
illness at the CDC, who helped expose the centers' misuse of
chronic fatigue financing.
Chronic fatigue syndrome was first identified as a distinct entity
in the 1980s. (A virtually identical illness had been identified in
Britain three decades earlier and called myalgic
encephalomyelitis.) The illness causes overwhelming fatigue,
sleep disorders and other severe symptoms and afflicts more
women than men. No consistent biomarkers have been
identified and no treatments have been approved for addressing
the underlying causes, although some medications provide
symptomatic relief.

Patients say the word "fatigue" does not begin to describe their
condition. Donna Flowers of Los Gatos, Calif., a physical
therapist and former professional figure skater, said the
profound exhaustion was unlike anything she had ever
experienced.

"I slept for 12 to 14 hours a day but still felt sleep-deprived," said
Flowers, 51, who fell ill several years ago after a bout of
mononucleosis. "I had what we call `brain fog.' I couldn't think
straight, and I could barely read. I couldn't get the energy to go
out of the door. I thought I was doomed. I wanted to die."

Studies have shown that people with the syndrome experience
abnormalities in the central and autonomic nervous systems, the
immune system, cognitive functions, the stress response
pathways and other major biological functions. Researchers
believe the illness will ultimately prove to have multiple causes,
including genetic predisposition and exposure to microbial
agents, toxins and other physical and emotional traumas.
Studies have linked the onset of chronic fatigue syndrome with
an acute bout of Lyme disease, Q fever, Ross River virus,
parvovirus, mononucleosis and other infectious diseases.

"It's unlikely that this big cluster of people who fit the symptoms
all have the same triggers," said Kimberly McCleary, president
of the Chronic Fatigue and Immune Dysfunction Syndrome
Association of America, the advocacy group in charge of the
CDC-sponsored awareness campaign. "You're looking not just
at apples and oranges but pineapples, hot dogs and
skateboards, too."

Under the most widely used case definition, a diagnosis of
chronic fatigue syndrome requires six months of unexplained
fatigue as well as four of eight other persistent symptoms:
impaired memory and concentration, sore throat, tender lymph
nodes, muscle pain, joint pain, headaches, disturbed sleeping
patterns and post-exercise malaise.

The broadness of the definition has led to varying estimates of
the syndrome's prevalence. Based on previous surveys, the
CDC has estimated that more than a million Americans have the
illness.

Last month, however, the disease control centers reported that a
randomized telephone survey in Georgia, using a less restrictive
methodology to identify cases, found that about 1 in 40 adults
ages 18 to 59 met the diagnostic criteria -- an estimate 6 to 10
times higher than previously reported rates.

However, many patients and researchers fear that the expanded
prevalence rate could complicate the search for consistent
findings across patient cohorts. These critics say the new figures
are greatly inflated and include many people who are likely to be
suffering not from chronic fatigue syndrome but from psychiatric
illnesses.

"There are many, many conditions that are psychological in
nature that share symptoms with this illness but do not share
much of the underlying biology," said John Herd, 55, a former
medical illustrator and a CFS patient for two decades.

Researchers and patient advocates have faulted other aspects
of the CDC's research. Jonathan Kerr, a microbiologist and
chronic fatigue expert at St. George's University of London, said
the CDC's gene expression findings last year were "rather
meaningless" because they were not confirmed through more
advanced laboratory techniques. Kristin Loomis, executive
director of the HHV-6 Foundation, a research advocacy group
for a form of herpes virus that has been linked to CFS, said
studying subsets of patients with similar profiles was more likely
to generate useful findings than Reeves' population-based
approach.

In response, Reeves said understanding of the disease and of
some newer research technologies is still in its infancy, so
methodological disagreements were to be expected. He
defended the population-based approach as necessary for
obtaining a broad picture and replicable results. "To me, this is
the usual scientific dialogue," he said.

Joseph Montoya, a Stanford infectious disease specialist
pursuing the kind of research favored by Loomis, caused a buzz
last December when he reported remarkable improvement in 9
out of 12 patients given a powerful antiviral medication,
valganciclovir. Montoya has just begun a randomized controlled
trial of the drug, which is approved for other uses.

Montoya said some cases of the syndrome were caused when
an acute infection set off a recurrence of latent infections of
Epstein Barr virus and HHV-6, two pathogens that most people
are exposed to in childhood. Flowers, the former figure skater,
had high levels of antibodies to both viruses and was one of
Montoya's initial CFS patients.

Six months after starting treatment, Flowers said, she was able
to go snowboarding and take yoga and ballet classes. "Now I
pace myself, but I'm probably 75 percent of normal," she said.

Many patients point to another problem with chronic fatigue
syndrome: the name itself, which they say trivializes their
condition and has discouraged researchers, drug companies
and government agencies from taking it seriously. Many patients
prefer the older British term, myalgic encephalomyelitis, which
means "muscle pain with inflammation of the brain and spinal
chord," or a more generic term, myalgic encephalopathy.

"You can change people's attributions of the seriousness of the
illness if you have a more medical-sounding name," said
Leonard Jason, a professor of community psychology at DePaul
University in Chicago.

[Return to top]

------------------------------

Date:    Tue, 17 Jul 2007 20:53:57 +0200
From:    Jan van Roijen <j.van.roijen CHELLO.NL>
Subject: res: Immune system, circadian clock linked

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http://www.the-scientist.com/news/home/53380/



TheScientist
MAGAZINE OF THE LIFE SCIENCE


By Melissa Lee Phillips


  ``````````````````````````````````````
NEWS

Immune system, circadian clock linked

Infectious and autoimmune diseases may promote
sleep by down-regulating circadian gene expression
  ``````````````````````````````````````


[Published 17th July 2007 10:20 AM GMT]


The immune system alters mammalian circadian clock gene
expression, perhaps explaining why fatigue accompanies some
infections and autoimmune diseases, according to a study in
this week's Proceedings of the National Academy of Sciences.
The authors found that a protein involved in mammalian immunity
interferes with circadian clock gene expression and promotes
sleep in mice.

"The study certainly provides a framework within which to
address the question of how immunomodulators affect both the
timing and the quantity or quality of sleep," said Mark Opp of the
University of Michigan in Ann Arbor, who was not involved in the
study.

The immune response to microbial infection activates
pro-inflammatory molecules such as tumor necrosis factor alpha
(TNF-a). Previous work has suggested that TNF-a causes
lethargy and fatigue in people with cancer, rheumatoid arthritis,
and sleep apnea. Animal studies have also shown that TNF-a
enhances sleep, but the mechanism has remained unknown.

To see if TNF-a directly regulates circadian oscillations,
researchers led by Gionata Cavadini of University Hospital
Zurich in Switzerland analyzed TNF-a's effects on expression of
circadian clock genes.

"There's very little known about how [immune response] is
related to circadian rhythms," said James Krueger of
Washington State University in Pullman, who was not involved in
the work.

The central circadian oscillator in mammals lies in the
suprachiasmatic nucleus (SCN) of the hypothalamus, but other
body cells also contain peripheral oscillators that keep their own
rhythms. Interacting loops of gene transcription and translation
form a negative feedback system that generates the 24-hour
mammalian clock.

The researchers first found that, in culture, TNF-a suppresses
the expression of three circadian clock genes called Period, and
the expression of three transcription factors they controlled by
clock genes. TNF-a only affected the genes' expression levels; it
did not affect the times at which they were expressed.

Other work has shown that activation of Period genes as well as
the transcription factors depends on a specific DNA sequence -
called an E-box - lying upstream of these genes. Transcription
factors bind to the E-box sequence to initiate these genes'
transcription.

When Cavadini and her colleagues mutated the E-box
sequence, administering TNF-a did not suppress transcription.
Conversely, TNF-a did not activate circadian clock genes whose
expression does not depend on an E-box sequence.

Their results suggest that TNF-a affects only clock genes that
contain an E-box and that the reduced activity of these genes
affects sleep regulation, co-author Thomas Birchler, also of
University Hospital Zurich, told The Scientist in an Email.

When the researchers tested the effects of TNF-a in live mice,
they found that animals treated with the cytokine kept normal
cycles -- sleeping during the day and becoming active at night -
but they moved less and rested more during their active periods
than did untreated mice. These results paralleled in vitro findings
showing that TNF-a changes clock genes' expression levels but
not timing, the authors say. Also, as in the in vitro studies, TNF-a
down-regulated expression of Period and the three
clock-controlled transcription factors in the liver.

It's possible that compensating effects by other clock-related
genes is keeping the circadian period normal in mice treated
with TNF-a, senior author Adriano Fontana of University Hospital
Zurich told The Scientist in an Email. "This may explain why
TNF-a, which influences the expression of several clock genes,
does not result in a shift of the circadian clock."

Another possibility, however, is that TNF-a is affecting not the
central circadian pacemaker in the SCN, but only peripheral
oscillators in the liver or other tissues, according to Vincent
Cassone of Texas A&M University in College Station, who
wasn't involved in the study. If Period gene expression is
suppressed, "you should get a change in [circadian] period," he
said. Since the authors don't see that, Cassone suspects that
they've found "purely a direct effect on output and peripheral
oscillations, which I think is kind of interesting."

The authors believe that TNF-a is affecting SCN rhythms,
because they found a slight reduction of one of the
clock-controlled transcription factors in the SCN of
TNF-a-treated mice. However, they didn't look at expression of
the other clock genes.

According to Krueger, the study's findings fit in well with previous
findings about immune response effects on sleep. However, he
said, "I don't think TNF's effects on sleep are entirely dependent
on activating or deactivating the circadian rhythm genes." TNF-a
also controls expression of many other genes, Krueger said, and
some of these likely influence sleep in other ways.

 From an evolutionary point of view, increased sleep during
illness may help animals to fight off infections or may keep sick
animals from socializing and spreading an infection to others,
Fontana said. It's possible that increased sleep is merely a
byproduct of illness, Opp said, but many researchers believe
that "the way we sleep when we are sick facilitates recovery."


Melissa Lee Phillips

mail@the-scientist.com


``````````````````````````````````````


Links within this article

K.Y. Kreeger, "Collecting clues to the mammalian clock," The
Scientist, April 15, 2002.
http://www.the-scientist.com/article/display/12992/

G. Cavadini et al., "TNF-a suppresses the expression of clock
genes by interfering with E-box-mediated transcription," PNAS,
published online July 16, 2007.
http://www.pnas.org

J. Lucentini, "The body sleeps, but the genes do not," The
Scientist, February 16, 2004.
http://www.the-scientist.com/2004/2/16/24/1/

Mark Opp
http://www.med.umich.edu/anesresearch/opp.htm

S. Akira et al., "Pathogen recognition and innate immunity," Cell,
February 24, 2006.
http://www.the-scientist.com/pubmed/16497588

D.R. Spriggs et al., "Recombinant human tumor necrosis factor
administered as a 24-hour intravenous infusion. A phase I and
pharmacologic study," Journal of the National Cancer Institute,
September 7, 1988.
http://www.the-scientist.com/pubmed/3411618

L.C. Pollard et al., "Fatigue in rheumatoid arthritis reflects pain,
not disease activity," Rheumatology (Oxford), July 2006.
http://www.the-scientist.com/pubmed/16449363

A.N. Vgontzas et al., "Marked decrease in sleepiness in patients
with sleep apnea by etanercept, a tumor necrosis factor-alpha
antagonist," Journal of Clinical Endocrinology and Metabolism,
September 2004. Sep;89(9):4409-13.
http://www.the-scientist.com/pubmed/15356039

J.M. Krueger, J.A. Majde, "Humoral links between sleep and the
immune system: research issues," Annals of the New York
Academy of Sciences, May 2003.
http://www.the-scientist.com/pubmed/12794042

J.P. Roberts, "What sets the biological clock?" The Scientist,
June 10, 2002.
http://www.the-scientist.com/article/display/13096/

James Krueger
http://www.vetmed.wsu.edu/research_vcapp/krueger/krueger.asp

U. Schibler, P. Sassone-Corsi, "A web of circadian
pacemakers," Cell, December 27, 2002.
http://www.the-scientist.com/pubmed/2507418

N. Cermakian, P. Sassone-Corsi, "Multilevel regulation of the
circadian clock," Nature Reviews Molecular and Cell Biology,
October 2000.
http://www.the-scientist.com/pubmed/11413490

Adriano Fontana
http://www.neuroscience.unizh.ch/e/groups/fontan00.htm

Vincent Cassone
http://www.bio.tamu.edu/FACMENU/FACULTY/CassoneV.htm

[Return to top]

------------------------------

Date:    Wed, 18 Jul 2007 14:26:32 -0400
From:    "Bernice A. Melsky" <bernice.melsky1 VERIZON.NET>
Subject: RES: Biology and therapy of fibromyalgia. Stress, the stress  response system, and fibromyalgia

Biology and therapy of fibromyalgia. Stress, the stress response system,
and fibromyalgia.

Arthritis Res Ther. 2007 Jul 6;9(4):216 [Epub ahead of print]

Martinez-Lavin M.

National Institute of Cardiology, Juan Badiano 1, 14080 Mexico City,
Mexico. mmlavin infosel.net.mx

PMID: 17626613


ABSTRACT:
Stress is a state of disharmony, or threatened homeostasis. A stressor
could have a psychological origin or a biological origin. Societies have
become more intricate with industrialization, and modern individuals try to
adapt to the new defiance by forcing their stress response system.

The main component of the stress response network is the autonomic nervous
system.

The present article reviews current knowledge on autonomic dysfunction in
fibromyalgia. Sympathetic hyperactivity has been consistently described by
diverse groups of investigators.

Fibromyalgia is proposed to be a sympathetically maintained neuropathic
pain syndrome, and genomic data support this contention. Autonomic
dysfunction may also explain other fibromyalgia features not related to pain.


[Return to top]

------------------------------

Date:    Wed, 18 Jul 2007 17:32:06 -0700
From:    "Rich Van Konynenburg........................via Co-Cure moderators"
Subject: RES, MED: Simplified Treatment Approach Based on GD-MCB Hypothesis--Update

[Moderator's note to readers: This appears similar to a July 4, 2007 posting on
the same subject, but it contains much additional information on treatment
outcomes.]


                               July 18, 2007


Simplified Treatment Approach Based on the Glutathione
Depletion-Methylation Cycle Block Pathogenesis Hypothesis for Chronic
Fatigue Syndrome (CFS)


by
Rich Van Konynenburg, Ph.D.



I first want to note that I am a researcher, not a clinician, and that
what I have to say here should not be interpreted as medical advice.

In January, 2007, in an effort to shed light on the validity of the
Glutathione Depletion-Methylation Cycle Block (GD-MCB) Pathogenesis
Hypothesis for Chronic Fatigue Syndrome (CFS), and to help clinicians
to develop a practical treatment based on this Hypothesis, I suggested
a simplified treatment approach.  This approach is designed to lift the
hypothesized methylation cycle block and to restore glutathione levels
to normal.  It was derived from a complete treatment program developed
by Dr. Amy Yasko, N.D., Ph.D., for autism and other disorders that are
also thought to involve methylation cycle block and glutathione
depletion.

A fairly large number of people with chronic fatigue syndrome (PWCs)
have since voluntarily chosen to try this treatment approach, many with
the help of their physicians.  It now appears to be working well for
many of these PWCs, but some serious adverse effects have also been
reported in a few cases.  Controlled testing of this treatment approach
has not yet been done, but early results from these volunteers suggest
that this would not only be worthwhile in view of indications of the
efficacy of this approach, but also necessary to ensure its safe
application.

I would like to describe the history of the Glutathione
Depletion-Methylation Cycle Block (GD-MCB) Hypothesis and the
simplified treatment approach that is based upon it, and point out what
I think the early treatment results mean with regard to this
Hypothesis.  But before I do so, I want to emphasize the following
cautionary statements:

While in the past I have stated that PWCs should cooperate with their
physicians in trying the simplified treatment approach, as a result of
experiences with this treatment approach that have been reported to me
recently, I have concluded that it must be entered upon only under the
supervision of a licensed physician, to make sure that if there are
individual issues that arise, they can be taken care of immediately.
The treatment approach itself consists only of nonprescription
nutritional supplements that are normally found naturally in the body
and are necessary for normal biochemistry to take place.  It would thus
appear to be fairly benign on its surface. However, it is now clear to
me that restarting the methylation cycle after it has been blocked for
extended periods, particularly in those PWCs whose general health has
become quite debilitated, or those who have certain respiratory,
cardiac, endocrine or autoimmune conditions, can present some serious
challenges and hazards.  I suspect that there is still much more to be
learned about possible adverse effects of applying this treatment
approach among the very heterogeneous CFS population, and this work
properly lies in the province of clinicians.  I believe that I have now
carried this work as far as a nonclinical researcher can appropriately
carry it.  I am hopeful that clinicians will apply and test this
treatment approach in order to learn how it may be safely, effectively,
and practically utilized to treat PWCs, and it appears that this is now
beginning to occur.

As some readers will probably be aware, I presented a poster paper
describing the above-mentioned Hypothesis at the most recent IACFS
conference in Florida last January.  It can be found on the internet on
Cort Johnson's website:

http://phoenix-cfs.org/GSH%20Methylation%20Van%20Konynenburg.htm

This Hypothesis has not yet been published in the peer-reviewed
literature.  My emphasis up to now has instead been upon addressing
questions that remained to be answered before this Hypothesis could be
considered for clinical testing and application in the form of a
practical treatment approach.

The history of the development of this Hypothesis is as follows:

In 1999, I first learned from two public talks presented by Dr. Paul
Cheney that many PWCs are depleted in glutathione, and that taking
steps to build glutathione can be helpful to many.  Dr. Derek Enlander
has since reported to me that he began injecting glutathione as part of
a complex into CFS patients as early as 1991.  I also found that Dr.
Patricia Salvato had reported in early 1998 on her use of intramuscular
injection of glutathione in 276 patients.  Over the years, quite a few
CFS doctors have incorporated means of building glutathione into their
protocols, either by administration of glutathione itself by various
routes, or by oral supplementation with glutathione precursors, such as
whey protein products.


What is glutathione, and what does it do?

Glutathione is technically a tripeptide, which can be thought of as
being like a very small protein, as it is made up of only three amino
acids (while proteins are made up of many more).  It is present
naturally in every cell of the body, as well as in the blood, the bile
and the fluid lining the lungs.  The liver is normally the main
producer of glutathione in the body.  Glutathione plays many important
roles in the body.  Probably the best known are its protection against
oxidative stress produced by oxidizing free radicals and other reactive
oxygen species, its support for the immune system, and its role in
removing a variety of toxic substances from the body.


When glutathione becomes somewhat depleted, as it does in many cases of
CFS, its normal functions are simply not performed well.  Many of the
symptoms of CFS as well as observed abnormal results on specialized lab
tests can be traced directly to glutathione depletion, as I described
in an earlier AACFS poster paper in 2004.  It can be found on Cort
Johnson's website:

http://phoenix-cfs.org/GluAACFS04.htm

As I noted in that paper, while direct efforts to build glutathione are
helpful to many PWCs, for most they provide only temporary improvement
and do not result in permanent restoration of glutathione levels or a
cure for CFS.  I suspected that a vicious circle mechanism must be
involved in holding down the glutathione levels in CFS.

Then, later in 2004, an important paper was published involving
research into autism by S. Jill James and her coworkers:  "Metabolic
biomarkers of increased oxidative stress and impaired methylation
capacity in children with autism"
(Am J Clin Nutr. 2004 Dec;80(6):1611-7).  The study they reported
showed that glutathione is depleted also in autism, and that this
depletion is associated with a block in what is known as the
methylation cycle (or methionine cycle).


Before discussing this further, I want to address the question "What is
the methylation cycle, and what does it do?"

The methylation cycle is part of the basic biochemistry of the body,
and is believed to operate in every cell.  This cycle includes the
amino acid methionine as well as S-adenosylmethionine (SAMe, used as a
supplement by some PWCs), S-adenosylhomocysteine, and homocysteine.
Some homocysteine is converted back to methionine, thus completing the
cycle.  There are two parallel pathways from homocysteine to
methionine.  They are the methionine synthase pathway and the BHMT
(betaine homocysteine methionine transferase) pathway.  The methylation
cycle is directly linked to the folate metabolism and to the
transsulfuration pathway.

The methylation cycle performs many vital roles in the body.  First, by
means of SAMe, it supplies methyl (CH3) groups to many different
biochemical reactions.  Some of them produce substances such as
coenzyme Q-10 and carnitine, which have been found to be depleted in
many PWCs. Methylation also plays an important role in "silencing"
certain DNA to prevent its expression, and in producing myelin for the
brain and nervous system.

The methylation cycle also controls the body's response to oxidative
stress, by governing how much homocysteine is diverted into the
transsulfuration pathway, which contributes to determining the rate of
synthesis of glutathione.

A third important role of the methylation cycle is to control the
overall sulfur metabolism of the body.  In this role, besides
controlling glutathione synthesis, it exerts control over synthesis of
several other important substances, including cysteine, taurine and
sulfate.

When the methylation cycle is blocked at the enzyme methionine
synthase, these important roles are not carried out properly.  In
addition, a methylation cycle block necessarily causes a block in the
folate metabolism, to which it is intimately linked, and this
interferes with synthesis of new DNA and RNA, among other important
effects.

Two of the most significant effects of a methylation cycle block are
that neither the immune system nor the detox system can operate
properly.  If the methylation cycle remains blocked for an extended
period of time, infections and toxins can be expected to build up in
the body.


After I read the paper by S. Jill James and her coworkers (referred to
above), I began to suspect that the genetic factors and biochemical
mechanism they had found in autism are the same or similar to those
important in CFS.  A block earlier than glutathione in the sulfur
metabolism, at the methylation cycle, could explain the persistent
glutathione depletion in CFS.  It began to dawn on me that other
aspects of CFS that did not appear to be explained by glutathione
depletion per se could be explained by a methylation cycle block.

It was difficult for me initially to believe that there was a
connection between autism and CFS, given the profoundly different
symptoms and different affected population groups (primarily boys in
autism, compared to primarily adult women in CFS).  However, I knew of
others who had publicly suggested such a connection in the past (Dr.
Michael Goldberg in the U.S. and Prof. Malcolm Hooper in the UK), and
this new study seemed to provide more detailed evidence of this
connection at the genetic and biochemical levels.

I began to look into autism in more detail, and I attended the Long
Beach conference of the Defeat Autism Now! (DAN!) project in October of
2005.  The more I learned about autism, the more I became convinced
that are dealing in CFS with many of the same issues at the genetic and
biochemical levels.  The book by Drs. Jon Pangborn and Sidney Baker
entitled "Autism: Effective Biomedical Treatments" (Autism Research
Institute, September, 2005) provides excellent explanations of the
biochemistry of autism, and the parallels with CFS can be seen there.

I want to emphasize that I did not develop the Glutathione
Depletion--Methylation Cycle Block Hypothesis out of thin air.  The
autism researchers had already provided a convincing basis for this
model in that disorder.  S. Jill James and coworkers did much of the
clinical work that underlies it.  Richard Deth and his coworkers had
worked out much of the theory of the methylation cycle block and had
applied it to autism.  Professors James and Deth had been presenting
talks on their work at autism conferences.  The physicians in the DAN!
project (as well as Dr. Amy Yasko, though I had not yet learned of her
work when I began to understand the importance of the methylation cycle
block) had already been treating autism cases by measures intended to
lift the methylation cycle block.  What I did was to apply the results
of their work to CFS, and to present a detailed biochemical and
symptomological case to support the proposition that this model also
applies to CFS.


What is the essence of the Glutathione Depletion-Methylation Cycle
Block Hypothesis for the Pathogenesis of CFS?

This hypothesis proposes first that in order to develop CFS, a person
must have inherited genetic variations  (also called SNPs or
single-nucleotide polymorphisms) in a combination of certain genes that
code for enzymes and other proteins associated with the methylation
cycle and related pathways.

The hypothesis further proposes that the person must also be subjected
to some combination of a variety of long-term physical, chemical,
biological or psychological/emotional stressors that lowers glutathione
levels to the point that a block occurs in the enzyme methionine
synthase in the methylation cycle, in response to the oxidative stress
that is inherent in glutathione depletion. The formation of this block
is aided by the presence of the inherited genetic polymorphisms.  This
lowering of glutathione levels also simultaneously removes the normal
protection that glutathione provides to vitamin B12 and allows the
accumulation in the body of toxins that can interfere with the
utilization of vitamin B12, mercury perhaps being the dominant one.

This hypothesis further proposes that the result of the above is that
the level of methylcobalamin is held too low to support the methionine
synthase reaction, and it therefore becomes chronically blocked. This
produces a vicious circle mechanism that causes CFS to become a chronic
condition.

Finally, this hypothesis proposes that all the features of CFS can be
shown to originate from this root cause. While I have not yet
demonstrated this for every feature of CFS, the first paper cited in
this article explains a large number of them in detail on this basis.
Previous treatments for CFS have dealt with downstream issues in the
pathogenesis, but they have not completely addressed this root cause,
and, in my opinion, that is we have not seen many completely cured CFS
cases up to now.  Note that when I refer to cured cases, I do not mean
that the genetic predisposition has been removed, but that that the
PWCs are healthy from the symptomatic point of view.


As I became more convinced of the parallels between autism and CFS, I
began to point out this connection to some clinicians directly and to
others via the internet, as well as to PWCs in internet groups, and I
began encouraging them to consider the treatments that were being used
by the Defeat Autism Now! project to treat autism, focusing on
unblocking the methylation cycle.  A small number of PWCs tried this
approach, and while some initial benefits were observed from this, it
did not seem to be an effective approach over the long term, at least
in the way I was suggesting that it be applied.
I then learned of the work of Dr. Amy Yasko, N.D., Ph.D. in autism.  I
studied her materials, including the book written by her and Dr. Garry
Gordon entitled "The Puzzle of Autism," joined her discussion forum at
 http://www.ch3nutrigenomics.com
and eventually attended her teaching seminar in Boston in October of
2006.  After considering all of this, I concluded that it was likely
that her treatment approach could help many PWCs, so I decided to
emphasize it.  An important feature of her work is her effort to tie
the genetics of individuals to the biochemistry and to do tailored
treatment based on genetics, again directed toward correcting the
methylation cycle block, but also incorporating support for a variety
of body systems and organs.  I also learned that Dr. Yasko had had some
experience in using her approach in cases of CFS as well as a variety
of adult neurological disorders, but that she was currently focusing
primarily on autism.

I wrote a short article pointing out the connection I was seeing
between autism and CFS and pointing to these treatments, and it was
published in the October 2006 issue of the Townsend Letter.  This can
be found at the following url:

http://findarticles.com/p/articles/mi_m0ISW/is_279/ai_n16865315

Quite a few PWCs acted on my suggestion to try Dr. Yasko's full
treatment approach, and they are currently continuing with it.  Many of
them participate in the Yahoo cfs_yasko internet group, a group that
was specifically formed for them, which can be found at

http://health.groups.yahoo.com/group/CFS_Yasko/

Most of them are currently in the first step of this treatment
approach, and they are generally reporting that this treatment is
producing considerable detoxification of their bodies, as monitored by
urine testing.  The full Yasko treatment approach involves detailed
genetic and biochemical testing, and is rather expensive and complex.
While some PWCs are in a position to pursue this treatment and appear
to be doing so successfully, it seemed to me that there are many others
for whom this approach is beyond reach, either for economic or
cognitive reasons or both.  Practicing physicians have generally also
found this treatment to be somewhat cumbersome to incorporate into
their practices because of the complexity and the considerable time and
expense required to tailor the treatment to each individual patient.

In response to these issues and to requests from clinicians for a
written description of practical CFS treatment based on this
hypothesis, I wrote an article that outlined the full Yasko treatment
approach, but also described a simplified treatment approach that
incorporated nutritional supplements that form the core of Dr. Yasko's
so-called "step 2."   This is the step in her treatment program that
involves actually lifting the block in the methylation cycle.  This
article can be found on Cort Johnson's website:

http://phoenix-cfs.org/GSH%20Methylation%20Treatment%20Konynenburg.htm

When I proposed this approach, I did not know what fraction of the PWC
population would be able to tolerate the resulting die-off of pathogens
and mobilization of toxins that would result from the consequent
ramp-up of the immune system and the detox system after they had been
dysfunctional for such long times during the long illness duration of
many PWCs.  As can be seen in the above-cited article, I was not very
optimistic.  However, I still thought it was worth a try, since the
existing full Yasko approach did not seem to have the characteristics
necessary for wide use in the CFS community, and it appeared that
lifting the methylation cycle block was the key to recovery for many
PWCs.  With the help of a woman (name omitted to protect her privacy)
who is currently receiving the full Yasko treatment herself, I selected
a basic set of seven supplements from Dr. Yasko's step 2, as discussed
in the above-mentioned article.

After this article was presented on the internet, another woman (name
omitted to protect privacy) decided to try this simplified treatment
approach.  As a result of benefits that occurred almost immediately,
she reported her experience on the ImmuneSupport.com CFS discussion
board.  In response to her reports, others began to try this approach.
This began in February of 2007, and the number of people on this
treatment has continued to grow, the longest duration of treatment now
being somewhat more than four months, ranging down to some as short as
a few days.

As experience has been gained, I have shortened the initial list of
seven supplements in the suggested simplified treatment approach to
five, as described below.   The cost of the basic five supplements is
somewhat more that two dollars per day.

After suggesting this treatment approach, I initially attempted to
maintain a list of those who were trying it, based on reports I
received from physicians and individual PWCs.  However, when the number
of people I was aware of grew past 60, I no longer felt that I could
maintain a complete count.  Many have been reporting their progress
periodically to the ImmuneSupport board, and a new Yahoo group also has
been established recently for PWCs trying this approach, at the
following url:

http://health.groups.yahoo.com/group/simplified_protocol_support/


I will now describe the current version of the simplified treatment
approach based on the Glutathione Depletion--Methylation Cycle Block
Hypothesis.

All the supplements used in this approach can be obtained from the
http://www.holisticheal.com site, or all but the Complete Vitamin and
Neurological Health Formula can be obtained elsewhere.  Please note
that I have no financial interest in any of the supplements that I have
suggested in the simplified treatment approach.

As I mentioned above, these supplements and dosages have been selected
by Dr. Amy Yasko as part of her complete treatment approach, as
described in her book "The Puzzle of Autism." Substitutions or changes
in dosages may not have the same effect as the combination of
supplements and dosages suggested, although it is wise to start with
smaller dosages than those given below, and it is also wise to start
with one supplement at a time and work up to the total of five
supplements, to test carefully for adverse effects.  It will take
somewhat longer to reach the suggested combination and dosages by this
route, but early experience has shown that this is prudent.

As I also mentioned above, this treatment approach should be attempted
only under the supervision of a licensed physician, so that any
individual issues that arise can be properly dealt with.  It's
important to "listen to one's body" when doing this treatment. If the
detox becomes too intense to tolerate, or if significant adverse
effects appear, as described below, the supplements should be
discontinued, and the situation should be evaluated immediately by a
licensed physician.  This treatment will produce die-off and detox
symptoms as the immune system and detox system come back to normal
operation and begin ridding the body of accumulated infections and
toxins. This appears to be inevitable, if health is to be restored.  It
may require considerable judgment and clinical experience on the part
of the physician to distinguish between inevitable die-off and detox
symptoms and possible adverse effects.

While die-off and detox symptoms are occurring, there will also likely
be improvement in CFS symptoms over time. The intensity of the expected
die-off and detox symptoms can be decreased by lowering the dosages of
the supplements.  These symptoms probably result from the body's
limited rates of excretion of toxins.  If toxins are mobilized more
rapidly than they can be excreted, their levels will rise in the blood,
and it is likely that this will produce more severe die-off and detox
symptoms.  By lowering the dosages, and thus slowing the rate of
mobilization of toxins, their levels in the blood can be lowered, thus
ameliorating the symptoms.

The temptation to try to get better faster by increasing the dosages
suggested by Dr. Yasko must be resisted. In particular, the suggested
dosages for the FolaPro and the Intrinsi/B12/folate supplements should
not be exceeded. Some who have done this have experienced very
unpleasant levels of detox symptoms that had momentum and did not
decrease rapidly when the supplements were stopped.

As improvements in energy level and cognition occur, it is tempting for
PWCs to overdo activities, which, early in the treatment, can still
result in "crashing."  It is wise to resist this temptation as well,
because complete recovery will not occur overnight with this treatment
approach.

I am not aware of negative interactions between the five basic
supplements and prescription medications used by physicians in treating
CFS. However, this treatment approach should not be attempted without
considering together with a licensed physician possible interactions
between the supplements included in it and any prescription medications
that are being taken.  This is particularly important if addition of
SAMe to the basic five supplements is contemplated.

When this treatment approach is used together with prescription
medications, a licensed physician must be consulted before
discontinuing any prescription medications. Some of them can cause very
serious withdrawal symptoms if stopped too abruptly.

If this treatment approach is begun by a PWC who is taking a thyroid
hormone supplement for a hypothyroid condition, the PWC and the
supervising physician should be alert to the possibility that
HYPERthyroid symptoms, such as palpitations and sweats, can occur, even
very soon after starting this treatment.  The physician should be
consulted about possibly adjusting or eliminating the thyroid hormone
supplementation if this occurs.


Here are the five supplements, as found in Dr. Yasko's book "The Puzzle
of Autism," (p. 49) and as described in detail on her website
http://www.holisticheal.com :

1.  One-quarter tablet (200 micrograms) Folapro (Folapro is 5-methyl
tetrahydrofolate, an active form of folate, which is sold by Metagenics
with a license from Merck, which holds the patent on synthesis).

2.  One-quarter tablet Intrinsic B12/folate (This includes 200
micrograms of folate as a combination of folic acid, 5-methyl
tetrahydrofolate, and 5-formyl tetrahydrofolate, also known as folinic
acid or leucovorin (another active form of folate), 125 micrograms of
vitamin B12 as cyanocobalamin, 22.5 milligrams of calcium, 17.25
milligrams of phosphorus, and 5 milligrams of intrinsic factor)

3.  Up to two tablets (It's best to start with one-quarter tablet and
work up as tolerated) Complete Vitamin and Ultra-Antioxidant
Neurological Health Formula from Holistic Health Consultants (This is a
multivitamin, multimineral supplement with some additional ingredients.
It does not contain iron or copper, and it has a high ratio of
magnesium to calcium. It contains antioxidants, some trimethylglycine,
some nucleotides, and several supplements to support the sulfur
metabolism.)

4.  One softgel capsule Phosphatidyl Serine Complex (This includes the
phospholipids and some fatty acids)

5.  One sublingual lozenge Perque B12 (2,000 micrograms
hydroxocobalamin with some mannitol, sucanat, magnesium and cherry
extract)


The first two supplement tablets are difficult to break into quarters.
One of the PWCs who is following the simplified treatment approach has
suggested that an alternative approach is to crush them into powders,
mix the powders together, and divide the powders into quarters using a
knife or single-edged razor blade and a flat surface. The powders can
be taken orally with water, with or without food, and do not taste bad.

Some people have asked what time of the day to take the supplements. A
few have reported that the supplements make them sleepy, so they take
them at bedtime. If this is not an issue, they can be taken at any time
of the day, with or without food.

Since some questions have been asked about which components of this
treatment approach are essential, and since some PWCs appear to be
taking augmented versions of the simplified GD-MCB treatment approach
that I wrote about in my January treatment paper (cited above), I want
to offer some comments to help PWCs and their physicians to evaluate
which supplements to include in treatment.

FolaPro--This is included because many PWCs have a genetic polymorphism
in their MTHFR (methylene tetrahydrofolate reductase) enzyme that
affects the production of 5-methyltetrahydrofolate (which is identical
to the product FolaPro). This form of folate is the one used by the
methionine synthase enzyme, which is the enzyme that appears to be
blocked in many cases of CFS. If PWCs were to have their genetics
characterized, as in the full Yasko approach, they would know for sure
whether they needed this supplement, but in the simplified approach I
suggest simply giving it to everyone.  This should not present
problems, because the total folate dose, including the FolaPro and the
folates in the Intrinsi/B12/folate supplement, amounts to 400
micrograms per day, which is within the upper limit for folate
supplementation for adults and for children four years of age and
older, as recommended by the Institute for Medicine of the U.S.
National Academy of Sciences.

Intrinsi/B12/folate--This supplement contains three forms of
folate--FolaPro, folinic acid (identical to the drug leucovorin) and
folic acid (the most common commercial folate supplement). It also has
some cyanocobalamin (the most common commercial vitamin B12 supplement)
and some intrinsic factor (identical to that normally secreted by the
stomach to enable vitamin B12 absorption by the gut) as well as some
other things. The folinic acid is helpful because some people can't use
ordinary folic acid well, as a result of genetic issues. Also, this
helps to supply forms of folate that will make up for the low
tetrahydrofolate resulting from the block in methionine synthase, until
this is corrected. This enzyme normally converts
5-methytetrahydrofolate to tetrahydrofolate, which is needed in other
reactions. This supplement also has some intrinsic factor and some
cyano-B12 to help those who have a type of pernicious anemia that
results from low production of intrinsic factor in the stomach and
which prevents them from absorbing B12 in the gut. Vitamin B12 is
needed by the enzyme methionine synthase, in the form of
methylcobalamin, but this supplement has cyanocobalamin, which must be
converted in the body by glutathione and SAMe to form methylcobalamin.
As glutathione and SAMe come up, this should become more effective.

Complete Vitamin and Ultra-Antioxidant Neurological Health
Formula--This is Dr. Amy Yasko's basic high-potency general nutritional
supplement. This is a general foundation for the biochemistry of the
body.  I suspect that this supplement is better for PWCs trying the
simplified treatment approach than other high-potency general
nutritional supplements, because it has particular things needed for
dealing with a methylation cycle block, including some TMG and sulfur
metabolism supplements as well as nucleotides. It is also high in
magnesium and low in calcium, and has no iron or copper.  As far as I
know, there are no other supplements with all these characteristics. I
therefore believe that this supplement is important for use in the
treatment approach.  The TMG helps to stimulate the BHMT pathway in the
methylation cycle, and that helps to build SAMe, which is needed by the
parallel methionine synthase pathway. The nucleotides will help to
supply RNA and DNA for making new cells until the folate cycle is
operating normally again.

Phosphatidylserine complex-This contains various phosphatidyls and
fatty acids, which will help to repair damaged membranes, including
those in cells of the brain and nervous system. It should help with the
cortisol response. It also has some choline, which can be converted to
TMG (betaine) in the body, to help stimulate the BHMT pathway.

Perque B12--This is sublingual hydroxocobalamin.  The dosage is fairly
large, in order to overcome the blocking of B12 by toxins such as
mercury in CFS.  As I mentioned above, B12 is needed to stimulate the
activity of methionine synthase. Methylcobalamin is actually the form
needed, but some people cannot tolerate supplementing it for genetic
reasons, and I'm also concerned that people with high body burdens of
mercuric mercury could move mercury into the brain if they take too
much methylcobalamin. Methylcobalamin is the only substance in
biological systems that is known to be able to methylate mercury.
(Note that methylcobalamin is the substance used by bacteria to perform
methylation on environmental mercury, and the resulting methylmercury
is concentrated in the food chain up to the large predatory fish and
enters the human diet.)  Methylmercury can readily cross the
blood-brain barrier.  Methylation of mercury by methylcobalamin has
been reported in the literature to occur within the bodies of guinea
pigs in laboratory experiments. Perque B12 is sublingual to compensate
for poor B12 absorption in the gut of many people.

There are also two other supplements that were included in the earlier
version of the simplified approach:

SAMe--This is normally part of the methylation cycle. Depending on
genetic variations (SNPs or polymorphisms) some PWCs can't tolerate
much of this, and some need more.  If PWCs can't tolerate this, they
should leave it out, because stimulating the BHMT pathway, using TMG
and choline in the other supplements, will probably make enough SAMe
for them naturally.  For people who can tolerate SAMe, a dosage of 400
mg per day is suggested.

Methylation Support RNA Formula--This is a mixture of RNAs that is
designed to help the methylation cycle. It is somewhat expensive, and
is not essential, but is helpful if people can afford it.  Dr. Amy
Yasko has since advised me that if a PWC desires to take only one of
her RNA Products, she would suggest choosing either the Health
Foundation RNA Formula or the Stress Foundation RNA Formula, rather
than the Methylation Support RNA Formula, as being most helpful to take
the edge off the detox.

The above suggested list of supplements may not be optimum, and future
clinical studies may produce an improved protocol.  I think that the
forms of folate and B12 are probably essential, because they target
what I believe is the root issue in the abnormal biochemistry of CFS. I
think the Complete supplement is important to support the general
biochemistry and to correct deficiencies that might be present in
essential nutrients, as well as to support the methylation cycle and
the rest of the sulfur metabolism.  I think that some way of
stimulating the BHMT pathway is important, also, to bring up SAMe, and
the phosphatidyl serine complex provides this, as does the TMG included
in the Complete supplement.

With regard to possible interactions between the supplements in the
simplified treatment approach and other supplements that PWCs may be
taking, I am aware of two: (1) I would not recommend taking additional
folate beyond what is suggested above, since the various forms of
folate compete with each other for absorption, and it is important to
get enough of the active forms into the body. Also, it is important not
to take too much folate, as mentioned above, because this can cause the
detox to develop a momentum, so that it will take some time to slow it
down if you want to do that.  (2) I would also not recommend taking
additional trimethylglycine (TMG, also called betaine) or additional
forms of choline, such as phosphatidylcholine or lecithin, since that
may stimulate the BHMT pathway too much at the expense of the
methionine synthase pathway. The betaine-HCl used to augment stomach
acid is something that may have to be omitted while doing this
treatment, too, since it will contribute to this stimulation.

Adding glutathione support will help some people, as will adding
molybdenum.
As more things are added, though, one is moving toward the full Yasko
approach, which is more complicated and expensive.  If this is done, I
recommend that it be done with the guidance of Dr. Yasko and under the
supervision of a personal physician. The simplified treatment approach
appears to work well by itself for many PWCs, but others may find that
the die-off and detox (or even adverse effects) from this approach used
by itself are too severe.  In those cases, the PWCs could consult "The
Puzzle of Autism," sold on Amazon.com, to consider together with their
doctors what else discussed there might help them. If the simplified
approach seems to help to some degree, and it captures one's attention
for that reason, but it still either does not accomplish all that is
desired, or it is not tolerated, then perhaps the next step would be to
consider the full Yasko treatment.  At least then there would be
stronger motivation to look into it.  Otherwise, it can appear very
daunting to many PWCs.

The reported responses to this treatment approach have mainly involved
a combination of two categories of effects:  (1) improvements in some
of the common CFS symptoms (some of them quite rapid and profound), and
(2) intensification or initial appearance of a variety of symptoms that
appear to result from increased detoxification and immune system attack
on infections.  The former are most welcome, and they are what continue
to motivate the people on this treatment, in the face of the detox and
die-off symptoms, which are unpleasant but appear to be inevitable,
given the large body burdens of toxins and infections that many PWCs
have accumulated during their illness, lacking adequate detox
capability and cell-mediated immune response during that time.

In addition to these main responses, a few PWCs have reported adverse
effects, some of them quite serious.  These are discussed below.  A few
of those who have started the treatment have stopped it for various
reasons, including adverse effects.  Some have taken breaks from the
treatment and have then returned to it or are planning to do so.

While this informal testing of the simplified treatment approach
currently is not being carried out in a controlled fashion, and while
not all the PWCs trying it are using the complete suggested complement
of supplements, it is nevertheless possible to state that the treatment
appears to be working for quite a few PWCs, though not all.

The following symptoms of CFS have been reported to have been corrected
by various PWCs on this treatment.  Note that these are gathered from
reports from many PWCs, so that not all have been reported by a single
person.

1.  Improvement in sleep (though a few have reported increased
difficulty in sleeping initially).
2.  Ending of the need for and intolerance of continued thyroid hormone
supplementation.
3.  Termination of excessive urination and night-time urination.
4.  Restoration of normal body temperature from lower values.
5.  Restoration of normal blood pressure from lower values.
6.  Initiation of attack by immune system on longstanding infections.
7.  Increased energy and ability to carry on higher levels of activity
without post-exertional fatigue or malaise.  Termination of "crashing."
8.  Lifting of brain fog, increase in cognitive ability, return of
memory.
9.  Relief from hypoglycemia symptoms
10. Improvement in alcohol tolerance
11. Decrease in pain (though some have experienced increases in pain
temporarily, as well as increased headaches, presumably as a result of
detoxing).
12. Notice of and remarking by friends and therapists on improvements
in the PWC's condition.
13. Necessity to adjust relationship with spouse, because not as much
caregiving is needed.  Need to work out more balanced responsibilities
in relationship in view of improved health and improved desire and
ability to be assertive.
14. Return of ability to read and retain what has been read.
15. Return of ability to take a shower standing up.
16. Return of ability to sit up for long times.
17. Return of ability to drive for long distances.
18. Improved tolerance for heat.
18. Feeling unusually calm.
19. Feeling "more normal and part of the world."
20. Ability to stop steroid hormone support without experiencing
problems from doing it.
21. Lowered sensation of being under stress.
22. Loss of excess weight.


The following reported symptoms, also gathered from various PWCs trying
this simplified treatment approach, are those that I suspect result
from die-off and detox:

1.  Headaches, "heavy head," "heavy-feeling headaches"
2.  Alternated periods of mental "fuzziness" and greater mental clarity
3.  Feeling "muggy-headed" or "blah" or sick in the morning
4.  Transient malaise, flu-like symptoms
5.  Transiently increased fatigue, waxing and waning fatigue, feeling
more tired and sluggish, weakness
6.  Dizziness
7.  Irritability
8.  Sensation of "brain firing: bing, bong, bing, bong," "brain moving
very fast"
9.  Depression, feeling overwhelmed, strong emotions
10. Greater need for "healing naps."
11. Swollen or painful lymph nodes
12. Mild fevers
13. Runny nose, low grade "sniffles," sneezing, coughing
14. Sore throat
15. Rashes
16. Itching
17. Increased perspiration, unusual smelling perspiration
18. "Metallic" taste in mouth
19. Transient nausea, "sick to stomach"
20. Abdominal cramping/pain
21. Increased bowel movements
22. Diarrhea, loose stools, urgency
23. Unusual color of stools, e.g. green
24. Temporarily increased urination
25. Transiently increased thirst
26. Clear urine
27. Unusual smelling urine
28. Transient increased muscle pain


Finally, the responses reported below are more serious, and I would
classify them as adverse effects of the treatment.  This list includes
all the adverse effects of which I am aware at the time of writing this
article, but I suspect that as more PWCs try this treatment with the
assistance of their physicians, this list will grow.  I am describing
these as they have been reported on the ImmuneSupport CFS discussion
board by the PWCs who experienced them.  Though this information may be
incomplete, and cause-effect relationships are difficult to determine
exactly from the available information, I'm hopeful that it will be
helpful to clinicians and other PWCs:

1.  One person had had a history of severe pesticide exposure and also
autonomous multi-nodular goiter, which she described as follows:
"Gradually the right lobe grew to over 4 cm x 4cm, and [I] had to have
right lobe out. . . This same surgeon made the decision to leave the
left lobe in, as I had always had trouble with thyroid med back then
too. So, they restarted my Synthroid and I  stayed on that for [a] few
more years. I ALWAYS had shortness of breath and became VERY
tachycardic upon ANY activity. . ."   This person started the
simplified treatment approach on March 21, 2007 (actually using higher
dosages than suggested for FolaPro and Intrinsi/B12/folate).  On May
19, she went to an emergency room with tachycardia, chest pain, trouble
breathing, trouble sleeping, elevated blood pressure and fever of 100.7
F.  She was admitted to the hospital and released the next day.   No
evidence was found for heart attack.  This person later reported the
following:  "I followed up with my PCP and had CT scan of neck and
chest and my goiter is causing tracheal compression, again, and
breathing is VERY hard. . .  My area hospitals can't do this surgery
because my goiter grows substernal, deep in my chest."  This person has
expressed a desire to continue the simplified treatment approach, but
is currently exploring the possibility of first having additional
surgery on the multinodular goiter.

2.  A second person had a history of lung problems due to both carbon
monoxide exposure and exposure to molds, as well as heart-related
symptoms.  She started part of the simplified treatment approach on May
27, 2007.  After having been nearly homebound for ten years, she was
able to begin riding a bicycle.  However, in early July, 2007, she went
to an emergency room twice with severe breathing problems (shortness of
breath), a fever of 99.8 to 100.1 F. that eventually lasted for sixteen
days, and severe chest and left arm pain.  No evidence was found for
heart attack.  She was diagnosed with an enlarged left atrium and
diastolic dysfunction.  She has currently discontinued the simplified
treatment approach and is under the care of cardiologists.

3.  A third person had a history of autoimmune disease, including
Sjogren's syndrome. After her fourth dosage of combined FolaPro and
Intrinsi/B12/folate, she experienced "a moderately severe autoimmune
flare, with numerous joint and soft tissue issues, fatigue, pain, etc."
  She also experienced a severe flare of Sjogren's syndrome, with "very
dry mouth, dry eyes, and severe eye pain."  Six days after
discontinuing the supplements, she had a thorough ophthalmology workup
and was diagnosed with autoimmune scleritis.  She has been given
topical steroids and has reported that her eyes are greatly improved.

4.  At least two persons experienced a temporary termination of
peristalsis of the gut and consequent constipation after beginning the
simplified treatment approach.  In these two cases, induction of
diarrhea cleared material from the gut, but did not restore the
peristalsis.  In both cases, peristalsis restarted twelve days after
terminating the folate-containing supplements.  One of these persons
had a history of treatment with psychotropic drugs, including Klonopin.
  About 18 hours after starting to get relief from the constipation, she
became very sick, with "vomiting, vise-like headache, and shaking."
She had many bowel movements over a ten-hour period, and then began to
feel better.  The other had a history of autoimmune diseases, including
Sjogren's syndrome and Autoimmune Ovaritis, as well as diastolic
dysfunction.


There are many questions remaining to be answered about this treatment
approach, including the following:

1. For which PWCs would this be an appropriate treatment approach?
2. For what fraction of the entire PWC population will this treatment
approach be beneficial?
3. How can PWCs who are likely to experience adverse effects from this
treatment approach be identified beforehand, so that these effects can
be avoided?
4. Are there PWCs who are too debilitated to be able to tolerate the
detoxing and die-off processes that result from this treatment
approach, and if so, will the full Yasko treatment approach be suitable
for them?
5. Will the simplified treatment approach actually lead to continuing
improvements over longer times for those who find it beneficial, all
the way to cured cases?
6. Will the simplified treatment approach be effective in cases of
"pure fibromyalgia" as it appears to be in many cases of CFS?
7. How can this treatment approach be further improved?

And many more.

However, the results to date seem encouraging. I suspect that many PWCs
can be helped by this treatment approach or something similar to it.  I
also believe that the appearance of improvement in such a wide range of
CFS symptoms when this treatment approach is used provides evidence
that a block in the methylation cycle does in fact lie at the root of
the biochemical and physiological derangements found in many PWCs, or
very near to it.  The wide range of symptoms that appear to be
associated with die-off and detox appear to give evidence that this
treatment is in fact stimulating more normal operation of the immune
and detox systems.

I want to reiterate what I wrote near the beginning of this article:
This treatment approach must be entered upon only under the supervision
of a licensed physician, to make sure that if there are individual
issues that arise, they can be taken care of immediately.  The
treatment approach itself consists only of nonprescription supplements
that are normally found naturally in the body and are necessary for
normal biochemistry to take place.  It would thus appear to be fairly
benign on its surface. However, it must be pointed out that restarting
the methylation cycle after it has been blocked for extended periods,
particularly in those PWCs whose general health has become quite
debilitated, or those who have certain respiratory, cardiac, endocrine
or autoimmune conditions, can present some serious challenges.  I
believe that there is still much more to be learned about the possible
hazards of applying this treatment approach to the very heterogeneous
CFS population, and this work properly lies in the province of
clinicians.  I am not a licensed physician, but a researcher.  I
believe that I have carried this work as far as a researcher can
appropriately carry it.  I am hopeful that clinicians will further test
this treatment approach in order to learn how it may be safely,
effectively, and practically utilized to treat PWCs, and it appears
that this is now beginning to occur.

I also hope that physicians or their patients who decide to try this
treatment approach will let me know how it works for them, though I may
not be able to answer all the emails I receive, as their volume is
growing.


Rich Van Konynenburg, Ph.D.
Independent Researcher and Consultant
richvank aol.com

[Return to top]

------------------------------

Date:    Thu, 19 Jul 2007 14:07:17 -0400
From:    "Bernice A. Melsky" <bernice.melsky1 VERIZON.NET>
Subject: RES: Effectiveness of muscle stretching exercises with and  without laser therapy at tender points for patients with fibromyalgia

Effectiveness of muscle stretching exercises with and without laser therapy
at tender points for patients with fibromyalgia.

Clin Exp Rheumatol. 2007 May-Jun;25(3):410-5.

Matsutani LA, Marques AP, Ferreira EA, Assumpção A, Lage LV, Casarotto RA,
Pereira CA.

Department of Health and Biological Sciences, FIEO University, Osasco, Brazil.

PMID: 17631737


OBJECTIVE: To assess the efficiency of a treatment composed of muscle
stretching exercises, associated or not to laser therapy at tender points,
for patients with fibromyalgia (FM), in view of bettering their quality of
life.

METHODS: Twenty FM patients were randomly assigned to two groups: one
submitted to laser therapy and stretching (LSG, n = 10), and the other only
to stretching exercises (SG, n = 10). The visual analog scale of pain (VAS)
and dolorimetry at tender points were used to assess pain; life quality was
evaluated by means of the Fibromyalgia Impact Questionnaire (FIQ) and the
36-item Short-Form Health Survey (SF-36).

RESULTS: After the treatment program, both in LSG and SG were detected pain
reduction, higher pain threshold at tender points (all p < 0.01), lower
mean FIQ scores, and higher SF-36 mean scores (all p < 0.05). No
significant differences were found between both groups.

CONCLUSION: The stretching exercises program proposed is efficient to
reduce pain and painful sensibility at tender points, thus enhancing
patients' quality of life. Laser therapy has not shown advantages when
added to muscle stretching exercises.


[Return to top]

------------------------------

Date:    Thu, 19 Jul 2007 19:03:08 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES,NOT: CFS and TNA-alpha

Source: The Economist
Date:   July 19, 2007
URL:                                        http://www.economist.com/science/displaystory.cfm?story_id=9507462

[Science & Technology]


Fatigue - Killing time
----------------------
Chronic fatigue may be a by-product of an anti-infection mechanism

Tumour necrosis factor alpha sounds a pretty intimidating molecule. And,
indeed, it is. One of its jobs is to kill cancer cells - or, rather, to
persuade them to commit suicide. But its name is a bit misleading. For
TNF-alpha, as it is known in the trade, does more than just shrink tumours.
It is one of a group of proteins called cytokines that are used by the immune
system to boss other body cells around. They do so by feeding the cells in
question signals that cause them to switch particular genes on or off in
response to infection.

Over the past few years, there have been hints that one of these responses
is fatigue. Moreover, TNF-alpha has been implicated in fatigue that is not
associated with infection. To look into this idea further, Thomas Birchler
of Zurich University Hospital and his colleagues decided to study the effect
of TNF-alpha on the biochemical clock that keeps bodies running in sync with
the sun. Their results, just published in the Proceedings of the National
Academy of Sciences, show that this effect is profound and may help to
explain the phenomenon of chronic fatigue.

The genes that control the body clock are most active in parts of the brain
called the suprachiasmatic nuclei. However, they are - like all other
genes - found in almost all cells and are frequently studied in specially
cultured fibroblast cells that are easy to work with. It was on these that
Dr Birchler began his investigation.

Adding TNF-alpha to the fibroblast system did indeed throw a spanner in the
works. Six of the clock genes were suppressed by the cytokine in ways that
would, in an actual animal, be expected to promote sleep. So, having proved
the point in a Petri dish, Dr Birchler and his colleagues went on to see
whether that expectation would be realised. It was. The same biochemical
changes took place in the brains of mice, and the mice in question were far
less active than untreated mice.

As a response to infection, such inactivity makes sense. Just as fever
(which is also controlled by cytokines) creates an environment hostile to
the reproduction of bacteria and viruses, so lethargy conserves energy that
can be directed to building up the immune system - an extremely demanding
task. In both cases what look at first sight to be damaging symptoms caused
by an infection are actually adaptive (though unpleasant) responses to it.
However, even well-evolved systems can go wrong and, just as the immune
system occasionally attacks the body it is supposed to be defending, causing
a so-called autoimmune disease, so it looks as though the TNF-alpha fatigue
response may sometimes appear at the wrong time.

One example of an autoimmune disease is rheumatoid arthritis. This is often
associated with fatigue, and an experiment carried out last year by Louise
Pollard of King's College, London, suggested TNF-alpha might be involved.
Dr Pollard injected fatigue-ridden arthritis patients with a protein that binds
specifically to TNF-alpha, and thus reduces its concentration in the body.
Those who underwent this treatment felt less fatigued as a result.

It is also possible that TNF-alpha is the explanation for the scourge called
chronic-fatigue syndrome. No one knows what this actually is, nor how it is
triggered. Some researchers, though, think viral infection is involved. That
would certainly activate the immune system, encouraging TNF-alpha production
- and enhanced levels of TNF-alpha have, indeed, been reported in people with
chronic fatigue syndrome. This has generally been thought of as a symptom -
and as support for the infection theory of the syndrome. But perhaps it is the
cause. If so, reducing the cytokine's level in sufferers might bring them some
relief.

--------
(c) 2007 The Economist


[Return to top]

------------------------------

Date:    Fri, 20 Jul 2007 14:14:55 -0400
From:    Fred Springfield <fredspringfield1 VERIZON.NET>
Subject: RES: Lymphatic drainage of the neuraxis in chronic fatigue syndrome: a hypothetical model for the cranial rhythmic impulse

Lymphatic drainage of the neuraxis in chronic fatigue syndrome: a
hypothetical model for the cranial rhythmic impulse.

Journal: J Am Osteopath Assoc. 2007 Jun;107(6):218-24.

Author: Perrin RN.

Affiliation: The Perrin Clinic, 11 St John St, Manchester, Greater
Manchester, M3 4DW, UK. rayperrin btconnect.com

NLM Citation: PMID: 17635902



The cranial rhythmic impulse is a palpable, rhythmic fluctuation believed
to be synchronous with the primary respiratory mechanism. The precise
physiologic mechanism of the cranial rhythmic impulse is not fully understood.

Based on traditional and current views of the cranial rhythmic impulse,
animal studies, and clinical findings in patients with chronic fatigue
syndrome, the author argues that the cranial rhythmic impulse is the rhythm
produced by a combination of cerebrospinal fluid drainage from the neuraxis
(brain and spinal cord) and pulsations of central lymphatic drainage
induced by the sympathetic nervous system.

In addition, evidence is provided to demonstrate that a disturbed,
palpable, and visible neurolymphatic process leads to chronic fatigue
syndrome. This process may also explain the pathophysiologic mechanisms
leading to other disease states.

Finally, the author's proposed manual treatment protocol for patients with
chronic fatigue syndrome is described.
[The full text of this article is available at

http://www.jaoa.org/cgi/content/full/107/6/218 ]

[Return to top]

------------------------------

Date:    Fri, 20 Jul 2007 07:10:59 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES: CFS/ME & FM papers, published since June 2007

Source: NCBI PubMed
Date:   July 20, 2007
URL:    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
        Topic=((chronic fatigue) OR (myalgic encephalomyelitis)) OR fibromyalgia
Ref:    In the update, you will only find journals that are indexed by
        Medline (PubMed).
          
        All scientific papers 1938-today,
        http://www.me-net.combidom.com/library/literature.htm#publications
          
        Search scientific papers,
        http://www.me-net.combidom.com/library/literature.htm#catalogue
          
        Figures computer analysis scientific papers,
        http://www.me-net.combidom.com/library/literature.htm#figure
          
        All popular papers 1900-today,
        http://www.me-net.combidom.com/library/literature.htm#popular


CFS/ME & FM papers, published since June 2007
---------------------------------------------

___ Matsutani LA, Marques AP, Ferreira EA, Assumpcao A, Lage LV, Casarotto
       RA, Pereira CA.
       Effectiveness of muscle stretching exercises with and without laser
       therapy at tender points for patients with fibromyalgia.
       Clin Exp Rheumatol. 2007 May-Jun;25(3):410-5.
___ Martinez-Lavin M.
       Biology and therapy of fibromyalgia. Stress, the stress response
       system, and fibromyalgia.
       Arthritis Res Ther. 2007 Jul 6;9(4):216.
___ Eisinger J.
       Dysautonomia, fibromyalgia and reflex dystrophy.
       Arthritis Res Ther. 2007 Jul 6;9(4):105.
___ Altindag O, Gur A, Calgan N, Soran N, Celik H, Selek S.
       Paraoxonase and arylesterase activities in fibromyalgia.
       Redox Rep. 2007;12(3):134-8.
___ Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE.
       Symptoms of autonomic dysfunction in chronic fatigue syndrome.
       QJM. 2007 Jul 7.
___ Sarchielli P, Mancini ML, Floridi A, Coppola F, Rossi C, Nardi K,
       Acciarresi M, Alberto Pini L, Calabresi P.
       Increased Levels of Neurotrophins Are Not Specific for Chronic
       Migraine: Evidence from Primary Fibromyalgia Syndrome.
       J Pain. 2007 Jul 3.
___ Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA,
       Bushnell MC, Chizh BA.
       Fibromyalgia patients show an abnormal dopamine response to pain.
       Eur J Neurosci. 2007 Jun;25(12):3576-82.
___ Wyller VB, Godang K, Morkrid L, Saul JP, Thaulow E, Walloe L.
       Abnormal thermoregulatory responses in adolescents with chronic
       fatigue syndrome: relation to clinical symptoms.
       Pediatrics. 2007 Jul;120(1):e129-37.
___ Gilula MF.
       Cranial electrotherapy stimulation and fibromyalgia.
       Expert Rev Med Devices. 2007 Jul;4(4):489-95.
___ Claypoole KH, Noonan C, Mahurin RK, Goldberg J, Erickson T, Buchwald D.
       A twin study of cognitive function in chronic fatigue syndrome: The
       effects of sudden illness onset.
       Neuropsychology. 2007 Jul;21(4):507-13.
___ Staud R.
       Future perspectives: pathogenesis of chronic muscle pain.
       Best Pract Res Clin Rheumatol. 2007 Jun;21(3):581-96.
___ Buskila D.
       Genetics of chronic pain states.
       Best Pract Res Clin Rheumatol. 2007 Jun;21(3):535-47.
___ Mannerkorpi K, Henriksson C.
       Non-pharmacological treatment of chronic widespread musculoskeletal
       pain.
       Best Pract Res Clin Rheumatol. 2007 Jun;21(3):513-34.
___ Goldenberg DL.
       Pharmacological treatment of fibromyalgia and other chronic
       musculoskeletal pain.
       Best Pract Res Clin Rheumatol. 2007 Jun;21(3):499-511.
___ Yunus MB.
       Role of central sensitization in symptoms beyond muscle pain, and
       the evaluation of a patient with widespread pain.
       Best Pract Res Clin Rheumatol. 2007 Jun;21(3):481-97.
___ Nielsen LA, Henriksson KG.
       Pathophysiological mechanisms in chronic musculoskeletal pain
       (fibromyalgia): the role of central and peripheral sensitization and
       pain disinhibition.
       Best Pract Res Clin Rheumatol. 2007 Jun;21(3):465-80.
___ Bliddal H, Danneskiold-Samsoe B.
       Chronic widespread pain in the spectrum of rheumatological diseases.
       Best Pract Res Clin Rheumatol. 2007 Jun;21(3):391-402.
___ Macedo JA, Hesse J, Turner JD, Ammerlaan W, Gierens A, Hellhammer DH,
       Muller CP.
       Adhesion molecules and cytokine expression in fibromyalgia patients:
       Increased L-selectin on monocytes and neutrophils.
       J Neuroimmunol. 2007 Jun 27.
___ Kratz AL, Davis MC, Zautra AJ.
       Pain acceptance moderates the relation between pain and negative
       affect in female osteoarthritis and fibromyalgia patients.
       Ann Behav Med. 2007 Jun;33(3):291-301.
___ Salemi S, Aeschlimann A, Wollina U, Gay RE, Michel BA, Gay S, Sprott H.
       Up-regulation of delta-opioid receptors and kappa-opioid receptors
       in the skin of fibromyalgia patients.
       Arthritis Rheum. 2007 Jun 28;56(7):2464-2466.
___ Ledina D, Bradaric N, Milas I, Ivic I, Brncic N, Kuzmicic N.
       Chronic fatigue syndrome after q Fever.
       Med Sci Monit. 2007 Jul;13(7):CS88-92.
___ Boutet G.
       Fibromyalgia [French].
       Gynecol Obstet Fertil. 2007 Jun 25.
___ Tomas-Carus P, Hakkinen A, Gusi N, Leal A, Hakkinen K, Ortega-Alonso A.
       Aquatic Training and Detraining on Fitness and Quality of Life in
       Fibromyalgia.
       Med Sci Sports Exerc. 2007 Jul;39(7):1044-1050.
___ Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ.
       Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue
       Syndrome.
       Neuropsychobiology. 2007 Jun 27;55(2):112-120.
___ Crofford LJ.
       Violence, stress, and somatic syndromes.
       Trauma Violence Abuse. 2007 Jul;8(3):299-313.
___ Sepici V, Tosun A, Kokturk O.
       Obstructive sleep apnea syndrome as an uncommon cause of
       fibromyalgia: a case report.
       Rheumatol Int. 2007 Jun 23.
___ Schmidt-Wilcke T, Luerding R, Weigand T, Jurgens T, Schuierer G,
       Leinisch E, Bogdahn U.
       Striatal grey matter increase in patients suffering from fibromyalgia
       - A voxel-based morphometry study.
       Pain. 2007 Jun 21.
___ Auwaerter PG.
       Point: antibiotic therapy is not the answer for patients with
       persisting symptoms attributable to lyme disease.
       Clin Infect Dis. 2007 Jul 15;45(2):143-8.
___ Orrego F, Quintana C.
       Darwin's illness: a final diagnosis.
       Notes Rec R Soc Lond. 2007 Jan 22;61(1):23-9.

--------
(c) 2007 NCBI PubMed

[Return to top]

------------------------------

Date:    Fri, 20 Jul 2007 07:25:44 +0200
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES,NOT: Darwin suffered from Crohn's disease, not CFS

Source: Notes and Records of the Royal Society of London
        Vol. 61, #1, pp 23-29
Date:   January 22, 2007
URL:    http://www.journals.royalsoc.ac.uk/content/110825/
       
        http://www.journals.royalsoc.ac.uk/content/d76541m888t15054/


Darwin's illness: a final diagnosis
-----------------------------------
Fernando Orrego(1), Carlos Quintana(2,3)
1 Origin of Living Beings, Faculty of Medicine, Universidad de los Andes,
  Santiago 6782468, Chile, forrego@uandes.cl
2 Department of Internal Medicine, Faculty of Medicine, Universidad de los
  Andes, Santiago 6782468, Chile
3 Department of Gastroenterology, School of Medicine, Catholic University
  of Chile, Santiago 6510260, Chile


Abstract

We have re-examined many of the abundant publications on the illness that
afflicted Charles Darwin during most of his life, including some of the 416
health-related letters in his correspondence, as well as his autobiographical
writings. We have concluded that he suffered from Crohn's disease, located
mainly in his upper small intestine. This explains his upper abdominal pain,
his flatulence and vomiting, as well as his articular and neurological
symptoms, his 'extreme fatigue', low fever and especially the chronic,
relapsing course of his illness that evolved in bouts, did not affect his
life expectancy and decreased with old age, and also the time of life at
which it started. It apparently does not explain, however, many of his
cutaneous symptoms. We do not support other diagnoses such as Chagas'
disease, lactose intolerance or the many psychiatric conditions that have
been postulated.


Keywords

Darwin, illness, Crohn's disease, Chagas, lactose intolerance

--------
(c) 2007 Royal Society Publishing

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------------------------------

Date:    Fri, 20 Jul 2007 17:45:07 +0100
From:    Stephen Ralph <stephen.e.ralph MEACTIONUK.ORG.UK>
Subject: RES, ACT:  Defiance of Science - Malcolm Hooper and Margaret Williams - 12th July 2007 (now online)

Defiance of Science

A comparison of quotations about ME/CFS from the MERUK International
Research Conference held on 25.05.07 in Edinburgh with quotations from the
Wessely School (who call it "CFS/ME")

Malcolm  Hooper         Margaret Williams      12th July 2007

http://www.meactionuk.org.uk/Defiance_of_Science.htm

[Return to top]

------------------------------

Date:    Sat, 21 Jul 2007 19:24:47 -0400
From:    "Bernice A. Melsky" <bernice.melsky1 VERIZON.NET>
Subject: RES: Is there a predisposition for the development of  autoimmune diseases in patients with fibromyalgia? Retrospective  analysis with long term follow-up

Is there a predisposition for the development of autoimmune diseases in
patients with fibromyalgia? Retrospective analysis with long term follow-up.

Rheumatol Int. 2007 Jul 20; [Epub ahead of print]

Kötter I, Neuscheler D, Günaydin I, Wernet D, Klein R.

Department of Internal Medicine II (Haematology, Oncology, Immunology and
Rheumatology), University Hospital, Otfried-Mueller-Str. 10, Tübingen,
Germany, ina.koetter@med.uni-tuebingen.de.

PMID: 17634900


The objectives of the study were to evaluate the prevalence of antinuclear
antibodies (ANA) in patients with fibromyalgia (FM) and the probability of
the development of clinically overt connective tissue diseases.

Four hundred and fifty FM patients were compared to 129 healthy matched
blood donors. ANA testing was performed by immunofluorescence on rat tissue
sections; in case of highly positive results, ANA were specified further by
ELISA and immunodiffusion. All ANA positive FM patients were invited for a
control examination. The ANA negative patients received a questionnaire,
which was designed to identify those patients with possible connective
tissue diseases (CTD).

There was no significant difference in the frequency of ANA or thyroid
antibodies between patients and controls (11.6% vs. 7%). Two patients had
developed SLE: one was already ANA/anti-dsDNA positive at time of first
diagnosis of FM; in the other, specific antibodies and SLE-related symptoms
developed after 4.5 years.

The probability for FM patients to develop CTD (SLE) within one year is
0.0027%, which is comparable to the incidence of SLE in the general
population (0.005%). The risk of CTD is not increased in FM. The detection
of ANA does not predict the development of CTD. However, in individual
cases, FM may be an early sign of an autoimmune disease.

[Return to top]

------------------------------

Date:    Sat, 21 Jul 2007 19:36:50 -0400
From:    "Bernice A. Melsky" <bernice.melsky1 VERIZON.NET>
Subject: RES: The effects of multidisciplinary therapy on positron emission tomography of the brain in fibromyalgia: a pilot study

The effects of multidisciplinary therapy on positron emission tomography of
the brain in fibromyalgia: a pilot study.

Rheumatol Int. 2007 Jul 20; [Epub ahead of print]

Walitt B, Roebuck-Spencer T, Esposito G, Atkins F, Bleiberg J, Foster G,
Weinstein A.

Washington Hospital Center, 110 Irving Street, Washington, DC, 20010, USA,
Brian.t.walitt@medstar.net.

PMID: 17634904


Aberrant central neurological functioning is believed to contribute to the
abnormal sensations of fibromyalgia (FM). This pilot study sought to
determine if alterations in regional brain metabolism from baseline occur
in FM after undergoing a multidisciplinary therapeutic regimen.

Regional brain metabolic activity was estimated using
(18)F-fluorodeoxyglucose positron emission tomography ((18)FDG PET). Nine
participants with FM received an 8-week comprehensive treatment program.
Serial testing with (18)FDG PET and the Fibromyalgia Impact Questionnaire
were performed. Statistical analysis was performed using repeated Wilcoxon
signed rank tests.

A clinical improvement (FIQ median change 20.68, P = 0.005) was noted with
treatment. With treatment, increases in brain metabolism were noted in
various components of the limbic system (P = 0.004-0.1).

An increase in limbic metabolism was noted with concomitant symptomatic
improvement, suggesting that the limbic system attenuates FM symptoms.

[Return to top]

------------------------------

Date:    Sat, 21 Jul 2007 19:31:30 -0400
From:    "Bernice A. Melsky" <bernice.melsky1 VERIZON.NET>
Subject: RES: 5-HT3 receptor antagonists regulate autonomic cardiac dysfunction in primary fibromyalgia syndrome

5-HT3 receptor antagonists regulate autonomic cardiac dysfunction in
primary fibromyalgia syndrome.

Rheumatol Int. 2007 Jul 19; [Epub ahead of print]

Seidel MF, Weinreich GF, Stratz T, Müller W.

Department of Rheumatology, Medizinische Universitäts-Poliklink,
Wilhelmstraße 35-37, 53111, Bonn, Germany, Matthias.Seidel ukb.uni-bonn.de

PMID: 17634903


Fibromyalgia syndrome (FMS) frequently presents with autonomic and/or
functional symptoms. Tropisetron, a selective serotonin-3 antagonist, is
widely used for the treatment of this disease. However, its effects on
autonomic function are not well known.

In the present study, we evaluated whether tropisetron improved cardiac
autonomic symptoms in FMS. Thirty-six patients were treated with
physiotherapy and 5 mg tropisetron intravenously for 5 days. An additional
36 patients were treated with physiotherapy alone. Thirty-six volunteers
served as healthy controls. The ISAX apparatus was used for spectral
analyses of cardiac R-R intervals. High frequencies and mid frequencies
were analysed to assess sympathetic and parasympathetic activity. The
findings were correlated with pain intensity.

ISAX findings were significantly different in FMS patients compared to
healthy controls and did not correlate with pain perception. Ten of 12
pathological parameters disappeared during treatment in the tropisetron group.

Our results indicate that tropisetron reduced not only pain perception but
also had a favourable effect on cardiac dysfunction during treatment.

[Return to top]

------------------------------

Date:    Sat, 21 Jul 2007 18:55:52 -0400
From:    "Dr. Marc-Alexander Fluks" <fluks dds.nl> (via Co Cure Moderators)
Subject: RES,NOT: American Family Physician: FM paper

The American Family Physician just published a paper on FM.

Surf to
 
 
 
  http://www.aafp.org/afp/20070715/247.html
 
 
 
  http://www.aafp.org/afp/20070715/afp20070715p247-of1.pdf

[Return to top]

------------------------------

Date:    Sat, 21 Jul 2007 21:23:05 -0400
From:    Co-Cure Moderators <auntiem6 PTD.NET>
Subject: MED:Patient Information on Valcyte Treatment for Chronic Fatigue Syndrome, by Richard Podell, M.D.

Moderators's note:
Chronic Fatigue Syndrome experts have long suspected a viral cause
for many cases of CFS. Recently Stanford Medical School researchers
reported dramatic improvement using Valcyte, a powerful anti-viral
drug that treats both Epstein Barr virus and Herpes Virus 6.

Richard Podell, M.D., a professor at New Jersey's Robert Wood Johnson
Medical School, has graciously given us a copy of the handout he has
prepared to inform his CFS patients.  He believes that Valcyte may
be a wonderful breakthrough, but it is also a potentially
toxic drug. Persons with severe CFS will have to carefully weigh
the potential risks and benefits.
-------------------------------



PATIENT INFORMATION ON VALCYTE TREATMENT
FOR CHRONIC FATIGUE SYNDROME—
Richard Podell, M..D. May 30, 2007
(www.DrPodell.org)

In December, 2006 Dr. Jose Montoya of Stanford Medical School reported
treating a series of twelve Chronic Fatigue Syndrome patients with
Valcyte, a potent anti-viral drug. For the large majority, symptoms and
functional activity improved dramatically during a six month treatment
period. Reportedly nearly all have continued to do well. If confirmed,
this could be an extraordinary treatment breakthrough.

Dr. Montoya selected patients who 1) had long standing CFS,
neurocognitive symptoms, 2) and also high blood antibody levels against
both Epstein Barr virus (EBV) and against Herpes Virus-6 (HHV-6). For
ten subjects their CFS had begun with a “flu-like” illness. Two did not
have a “flu-like” onset.

Nine of the ten “flu-like” onset patients improved dramatically with
Valcyte. One did not. Neither of the two non-flu-like onset patients
improved. A January 2007 press release from Stanford Medical School
reported that Dr. Montoya had, by then, treated 25 patients. Of these 21
had gained major improvement. Again, improvement was confined to the
patients whose illness had begun with “flu-like” symptoms. The press
indicates that one of the successful patients has remained well, so far,
for more than three years.

Caution—This was an “open” not a double blind study. However,
spontaneous remissions and long-lasting placebo effects are not common
with CFS, Therefore, I believe that Valcyte treatment is the probable
reason for the dramatic improvement.

Valcyte is an oral medicine that is approved by the FDA for treating
Cytomegalovirus (CMV) infection. CMV is a frequent problem among persons
with AIDS or certain organ transplants. Valcyte is also active against
HHV-6 and against EBV. HHV-6 and/or EBV are believed to cause a
substantial proportion of chronic fatigue syndrome cases. The body
converts Valcyte into a related molecule, another anti-viral drug,
Ganciclovir.

Unfortunately Valcyte/Ganciclovir has potential for severe toxic side
effects. These can be life-threatening.

Therefore, the decision of whether an individual with CFS should or
should not treat with Valcyte requires balancing the (probable but not
fully proved) potential gains against the potential risks.

Dr. Montoya’s patients had no dangerous toxicity during their treatment.
That may be because Dr. Montoya monitored his patients very closely,
obtaining blood tests twice weekly for the first three weeks and then
weekly over the six months of treatment. Medical visits were frequent.

In contrast studies of AIDS and organ transplant patients using Valcyte
find that more than a quarter of those treated have to lower or
discontinue their dose due to problems affecting the red blood cell,
white blood cell or platelet counts. Stopping Valcyte or reducing the
dose usually reverses the problems; but the potential for serious or
even fatal complications is real. Valcyte/ganciclovir can cause cancer
in animals. It is not known whether it causes cancer in humans.

In Dr. Montoya’s study all the patients who eventually improved first
had a period of worsening during the first month that lasted up to
several weeks. In contrast, patients who did not later improve, did not
have this flare-up. Probably the flare up was a “die off” reaction due
to the breakdown of viral particles-- also known as a Herxheimer
reaction. As such, an early flare-up with treatment may be a favorable
sign, that improvement is likely.

Roche Pharmaceuticals has given Dr. Montoya $1.3 to do a double blind
study using Valcyte to treat CFS. Realistically, it might be two years
or more before that study is completed and published. (That study is
accepting patients, but only if they live in the San Francisco area.)

For the new study Dr. Montoya has added an important diagnostic test, a
blood culture/antigen test to detect HHV-6 virus. (Commercially HHV-6
antibody tests are not highly reliable.) This new and better test is
available from only one source at present, the Wisconsin Viral Research
Group. Our office orders this test for patient whose commercial HHV-6
antibody tests are negative. (Unfortunately, the Wisconsin test costs
$495 and is considered “experimental” by some insurance plans, so might
not be reimbursed.)

Our Policy on Valcyte Treatment for CFS:

We offer Valcyte treatment for selected patients who 1) are severely ill
with CFS so that CFS greatly hinders their function and well-being 2)
had a “flu like” onset of their CFS 3) fully understand the potential
risks 4) promise, in writing, that they will faithfully adhere to the
rigorous schedule for blood tests and medical visits and 5) have someone
to care for them for several weeks if their symptoms flare during the
initial part of the treatment.

We require blood tests twice weekly during the first three weeks These
labs should be done at our Springfield office, since we receive these
reports back by computer within 24 hours. After this blood tests are
done weekly. These can be done at a laboratory near you. Patients will
be seen in our office weekly for the first three weeks and then every
two weeks. After improvement, some of these “visits” might be by
telephone or with a cooperating physician near you.

We are considering how we can help persons who live far away. One option
would be for our office to do the initial evaluation, to help decide
whether you are a good candidate for Valcyte treatment. We might then
consult with a physician near you, who you would select and who would
actually prescribe and closely monitor the treatment. Collaborating
physicians would have to agree in writing to the strict monitoring
protocol. In theory this could work; in practice, it might not be easy
to find a collaborating physician.

Our website (DrPodell.org) offers further information.

To read the abstract of Dr. Montoya’s December 2006 paper Go to the
National Library of Medicine: www. PubMed.gov. Enter in the search space
the wor99ds Montoya Valcyte HHV-6. This should bring up the abstract.

To read the January 2007 Stanford Medical School press release go to:
http://med.stanford.edu/news_releases/2007/january/montoya.html

Also see these two useful sites The HHV-6 Foundation (link to
www.hhv-6foundation.org) and The Wisconsin Viral Research Group (link to
www.wisconsinlab.com)

To read Roche Pharmaceutical’s FDA approved package insert on Valcyte go
to: http://www.rocheusa.com/products/valcyte/. Then click on “complete
product information” to read the formal package insert. Also click on
“patient information” for a much simpler version.

[Return to top]

------------------------------

Date:    Sat, 21 Jul 2007 22:01:53 -0400
From:    Co-Cure Moderators <auntiem6 PTD.NET>
Subject: NOT,MED:Refutation of the use of Functional Capacity Evaluation in testing disability in FMS/CFS patients

Moderator's Note:
This presentation by Richard Podell, M.D., provides a solidly referenced scientific and medical basis for refuting the common use of Functional Capacity Evaluation (FCE) exercises, a technique in which the insurance company tests a patients ability to do activities over several hours, and from this, draws a conclusion about their ability to work eight hours a day, week after week. Dr. Podell explains why this  technique is not valid and should not be used.  The information may be of use to both patients and attorneys involved with disability litigation.

--------------------------------------

Fibromyalgia (FMS) & Chronic Fatigue Syndrome (CFS).
Disability Insurance Litigation for Attorneys and Patients.
Why The Clinical Pattern of CFS and FMS requires new methods of testing.
Why the Functional Capacity Evaluation (FCE), as now used, is
scientifically not valid

Richard Podell, MD, MPH Clinical Professor, UMDNJ-Robert Wood Johnson
Medical School (105 Morris Avenue, Springfield, NJ, tel. 973 218-9191;
Web address: DrPodell.Org). This essay adapts Dr. Podell’s lecture to
the American Conference Institute’s 10th National Advanced Forum on
Resolving Disability Insurance Claims and Litigation, June 2007. The
American Conference Institute provides education for the legal
profession. Its seminars are balanced to provide equal participation
from attorneys for both plaintiffs and defense.


Introduction
9999999I will focus on these three pivotal questions:
1. What Is Fibromyalgia and What Is Chronic Fatigue Syndrome. What
"Objective" evidence of Illness do You Expect to Find on Physical
Examination or Laboratory Tests?
2. What is the Scientific Evidence That the Pain of Fibromyalgia and the
Fatigue of Chronic Fatigue Syndrome are in fact real?
3. How the clinical pattern of FMS and CFS is different from that of
many other conditions that disability insurance carriers see. Why that
causes misunderstanding
4. How this difference in clinical pattern requires different tools for
evaluating disability. Why the often used tool of Functional Capacity
Evaluation (FCE) should not be used for Fibromyalgia or Chronic Fatigue
Disability.



What Is Fibromyalgia?
What Is Chronic Fatigue Syndrome?

Definition of Fibromyalgia: The American College of Rheumatology
Criteria For Fibromyalgia Requires:

1) History of widespread chronic pain in 4 quadrants of the body and
2) Abnormal tenderness at 11 or more of 18 designated anatomic sites,
called tender points.
3) Appropriate Rule/outs

Clarification: Tender points are areas of muscle/tendon insertion. These
"points" are normally more sensitive to painful stimuli than other
sites. To be abnormal the patient must report pain, not just tenderness.
Examine pressing with the thumb using a force that just makes thumbnail
blanch.

Tender point counts can vary from day to day. Psychological distress
makes tender points more painful. A person who has chronic widespread
pain but < l1 of 18 tender points meets the definition for chronic pain
syndrome. Technically, fibromyalgia is a sub-class of chronic pain syndrome

Please note: The formal definition of fibromyalgia provides no guide to
assessing disease severity or disability. One can be disabled from
fibromyalgia despite having only 11 positive tender points on a given
day. Or one might be able to work despite having 18 out of 18 positive
tender points. In principle, one can be disabled due to chronic pain
syndrome, even when it does not meet the definition of fibromyalgia e.g.
if there is severe, widespread pain but with only a few positive tender
points.

Other than tender points there are no objective finding to be looked for
on physical examination or standard laboratory tests that measures the
severity of fibromyalgia (or of chronic fatigue syndrome). However
certain findings, when present, do provide evidence that illness is
major. For example, abnormal results on formal neurocognitive testing;
low blood pressure, increased heart rate and/or fall in blood pressure
with prolonged standing.

The same holds true for Chronic Fatigue Syndrome:
No specific physical exam or lab findings are required to make the
diagnosis.
There are no specific findings on physical exam or lab that reliably
measures disease dseverity.
There are no specific findings on physical exam or lab that distinguish
between one person with fibromyalgia or chronic fatigue syndrome who is
able to work from another person with fibromyalgia or chronic fatigue
syndrome who is, in fact, disabled.
So far as the physical exam and standard lab tests are concerned, both
persons can appear exactly the same. Yet despite the same appearance,
one person has the stamina to sustain a regular level of function for
five days a week. The other person cannot.


Definition of Chronic Fatigue Syndrome.
This section reprints sections from the Center for Disease Control’s
Webpage as last modified May 6, 2006:
http://www.cdc.gov/cfs/cfsdiagnosis.htm. I have omitted or adapted
non-essential parts for editorial clarity.

Diagnostic Challenges
Diagnosing chronic fatigue syndrome (CFS) can be complicated by a number
of factors: 1) there's no diagnostic laboratory test or biomarker for
CFS, 2) fatigue and other symptoms of CFS are common to many illnesses,
3) CFS is an invisible illness and many patients don't look sick, 4) the
illness has a pattern of remission and relapse, 5) symptoms vary from
person to person in type, number and severity, and 6) no two CFS
patients have exactly the same symptom set.

These factors have contributed to an alarmingly low diagnosis rate. Of
the four million Americans who have CFS, less than 20% have been diagnosed.


Clinical Evaluation
Because there is no blood test, brain scan or other lab test to diagnose
CFS, it's a diagnosis of exclusion. Your health care professional will
first take a detailed patient history, including a review of medications
that could be causing your fatigue. A thorough physical and mental
status examination will also be performed. Next, a battery of laboratory
screening tests will be ordered to help identify or rule out other
possible causes of your symptoms. Your professional may also order
additional tests to follow up on results of the initial screening tests.


Diagnostic Criteria
Your clinician should consider a diagnosis of CFS if these two criteria
are met:

1. Unexplained, persistent fatigue that's not due to ongoing exertion,
isn't substantially relieved by rest, is of new onset (not lifelong) and
results in a significant reduction in previous levels of activity.
2. Four or more of the following symptoms are present for six months or
more:
Impaired memory or concentration
Postexertional malaise (extreme, prolonged exhaustion and sickness
following physical or mental activity)
Unrefreshing sleep
Muscle pain
Multijoint pain without swelling or redness
Headaches of a new type or severity
Sore throat that's frequent or recurring
Tender cervical or axillary lymph nodes


Exclusionary Conditions
Chronic fatigue syndrome can resemble many other illnesses, including
mononucleosis, chronic Lyme disease, lupus, multiple sclerosis,
fibromyalgia, primary sleep disorders, severe obesity and major
depressive disorders. Medications can also cause side effects that mimic
the symptoms of CFS.

Because CFS can resemble many other disorders, it's important not to
self-diagnose CFS. It's not uncommon for people to mistakenly assume
they have chronic fatigue syndrome when they have another illness that
needs to be treated. If you have CFS symptoms, consult a health care
professional to determine if any other conditions are responsible for
your symptoms. A CFS diagnosis can be made only after other conditions
have been excluded.
It's also important not to delay seeking a diagnosis and medical care.
CDC research suggests that early diagnosis and treatment of CFS can
increase the likelihood of improvement.


What is the "Objective" Evidence (besides the patient’s self-report)
that the Pain of Fibromyalgia and the Fatigue of Chronc Fatigue are In
Fact "Objectively" Real?

In principle, an individual patient could fake or exaggerate his or her
report of pain on the tender point exam. However, many research studies
now show that, as a group, fibromyalgia patients do accurately report
the pain that they feel. Objective research studies confirm that
fibromyalgia patients
1) feel pain when exposed to much lower levels of minor trauma/adverse
stimuli compared to normals.
2) Experience a more rapid increase in pain levels when traumatic or
noxious stimuli are repeated
3) Have a slower decay/decline of pain levels after the experimental
stimulus is removed
4) Have a halt or reversal of the decline of pay after experimental
stimulus stops, if even a very small adverse stimulus is reintroduced.
In contrast, among normals, adding such small adverse stimuli do not
prevent the pain’s decline and resolution.


These research articles are relevant to establishing that
-- Fibromyalgia is real.
-- Fibromyalgia is mediated through physical mechanisms. Psychological
factors can trigger and/or exacerbate or result from fibromyalgia; but
the primary nature of this disease is physical.
-- The main "end organ damage" of fibromyalgia affects the pain
signaling pathways within the central nervous system (spinal cord and
brain).
-- Fibromyalgia patients, for the most part, accurately report on their
symptoms.


The following research articles that support these conclusions. I offer
representative quotations from their abstracts.

Cook D, Lange G Ciccone D et. Al., Functional imaging of pain in
patients with primary fibromyalgia, J Rheumatol 2004;31:364-78
"Subjects underwent fMRI scanning while receiving painful and nonpainful
heat stimuli… fMRI data indicated that the FM group exhibited greater
activity than controls over multiple brain regions in response to both
nonpainful and painful stimuli (p < 0.01). ... Data from the practice
session indicated brain activity in pain-relevant areas for the FM group
but not for controls. CONCLUSION: Our results provide further evidence
for a physiological explanation for FM pain.

Staud R and Rodriguez M, Mechanisms of Disease: pain in fibromyalgia
syndrome, Nature Clinical Practice Rheumatology, 2005; 3: 90-98

"Persistent or intense nociception (noxious stimuli) can lead to
transcriptional and translational changes in the spinal cord and brain
resulting in central sensitization and pain. This mechanism represents a
hall mark of fibromyalgia and many other chronic pain syndromes…"

Harris R and Clauw D, How Do We Know That the Pain in Fibromyalgia is
"Real"? , Current Pain and Headache Reports 2006; 10:403-7
" …neurobiological studies indicate that fibromyalgia patients have
abnormalities within central brain structures that normally encode pain
sensations in healthy pain-free controls…There are now multiple,
converging lines of evidence confirming that the pain of fibromyalgia is
"real" and that there are strong neurobiological underpinnings to this
condition."

Gracely R, Petzke F, Wolfe M, Clauw D Functional magnetic resonance
imaging evidence of augmented Pain Processing in Fibromyalgia, Arthritis
& Rheumatism 2002:46: 1333-43

"In FM patients, application of mild pressure produced subjective pain
reports and cerebral responses that were qualitatively and
quantitatively similar to many of the effects produced by application of
at least twice the pressure in control subjects."


In summary: Fibromyalgia was first recognized by rheumatology/arthritis
specialists. It was first thought to involve mainly the muscles and
joints. However, as research has developed, we now know that a major
part of this illness affects the pain signaling pathways of the central
nervous system–the brain and the spine. This is the main site of the
"end-organ damage". This distortion of neural pain pathways has been
given the name "neural sensitization". A useful way of thinking about
neural sensitization is to imagine a radio with the volume dial turned
up very high, and the station selection knob being slightly off
frequency. Hence, the amplification and distortion of pain signaling to
the brain.


What About Chronic Fatigue Syndrome (CFS) patients? Do they accurately
Report Their Symptoms?

There is an analogous research literature on chronic fatigue syndrome,
although this is less extensive than in fibromyalgia. However,
functional MRI studies also tend to confirm that brain activity during
effort is abnormal in CFS.

Lange G, Steffner, J, Cook, D et. Al. Objective evidence of cognitive
complaints in Chronic Fatigue Syndrome: A BOLD fMRI study of verbal
working memory, NeuroImage 2005; 26: 513-524

Using functional MRI, Lange compared a group of "mentally healthy"
patients with CFS to healthy controls. "Thus, CFS patients have more
anatomical changes in the brain than do healthy controls–independent of
whether or not they also have psychological illness."

Using changes in regional blood flow in the brain as a measure, Lange
also showed that CFS patients when challenged with a mental task, had to
recruit many more areas of the brain to fulfill the mental task than did
controls. This abnormality was present even among those whose formal
standard neuropsychological test results were normal.

"This confirms that there is something wrong with brain function among
chronic fatigue syndrome patients, that current standard
neuropsychological tests may be unable to detect. In these patients,
they are able to fulfill the initial challenge adequately in the short
term, but have to exert substantially greater mental effort to do so.
This is consistent with the clinical observation that many CFS patients
can think clearly for short periods, but pay the price of increased
symptoms and decreased function after prolonged effort...

Summary: "Individuals with CFS appear to have to exert greater effort to
process auditory information as effectively as demographically similar
healthy adults. Our findings provide objective evidence for the
subjective experience of cognitive difficulties in individuals with CFS."


How Medical Experts (should) Evaluate Chronic Fatigue Syndrome
Disability and Fibromyalgia Disability

The Moral: There are no standardly available laboratory tests or
physical examination findings that reliably distinguish between one
persons with CFS who is disabled and another person with CFS who is
still able to work. Given two individuals with CFS–one unable to work
and one able to work despite the obstacle of the illness–these two
individuals could have exactly the same findings on physical examination
and exactly the same values on most standard lab tests.

Therefore, to the extent that the patient’s self-reported symptoms and
limitations are credible, the judgment of disease severity must usually
be based, first and foremost, on the patient’s self-report of symptoms
and abilities. The credibility of these self-reports in turn should be
based on "objective" factors including, most importantly, the documented
medical records, consistency of the self-reports with the known patterns
of disease, the medical opinion of treating physicians, the medical
opinion of "expert" physicians, personal diaries, surveillance and other
information about how the patient in fact lives and functions.


The Delayed Post-exertional Flare-up Phenomenon–A Critical Difference
Between CFS/FMS and Other Conditions that Insurance Carriers are More
Used To

The most crucial difference between the clinical patterns of
Fibromyalgia and Chronic Fatigue Syndrome and those of many other
conditions is the timing of the Flare-Up of Symptoms that typically
occurs because of physical effort.

For example, when a person with angina, a lumbar disc or emphysema
pushes past their limits, the increase in symptoms typically occurs
during the period of exertion. We call this an immediate or acute
exertional flare-up. Symptoms increase during the exertion and decrease
rapidly once the activity is stopped. In an observed setting such as a
Functional Capacity Evaluation subjects report increased symptoms in
real time. The observer may observe signs of distress and/or objective
changes on vital signs, ability to bend over, strength, EKG, oxygen
saturation, etc.

In CFS and fibromyalgia the typical clinical pattern is very different.
The patient might or might not have increased symptoms during the
exertion, but whether they do or do not, their symptoms of fatigue,
pain, poor concentration, etc. typically flare some hours or even a day
or two later. We call this the Delayed Post-Exertional Flare-up Phenomenon.

The flare up of pain and/or fatigue typically lasts 24 hours or more.
The longer or more often the patient tries to push through, the worse
and the longer the flare-up.
In an FCE setting, the subject might appear to be okay at the end of the
session, but might then "crash" hours later or the next day. They might
then remain more symptomatic for 24 hours or more. Unless, the
Post-Exertional Flare-up Phenomenon is sought out by the observer, the
observer will necessarily be unaware of the negative consequences of the
activity session.

This fact alone negates the validity of current FCE protocols. Current
protocols do not seek out or attempt to recognize the delayed
post-exertional flare-up. Yet a key issue in deciding whether or not a
patient is disabled is whether they are, in fact, telling the truth—that
modest activity increases symptoms not necessarily during the exertion
but hours or a day later. In principle the truth or falsity of these
claims could be objectively determined e.g. by testimony of persons who
are familiar with the patient’s usual patterns of activity; by prolonged
(and fairly interpreted) video surveillance; by a patient’s wearing a
simple device that measures activity (e.g. a pedometer).
The post-exertional flare-up phenomenon is well known to physicians who
specialize in treating chronic fatigue syndrome and/or fibromyalgia
patients and has been measured in research studies. Reference: Kaufman K
and Goodnick P, Depression, Chronic Fatigue Syndrome, and Fibromyalgia:
An Update, Journal of Chronic Fatigue Syndrome, 2006; 13:77-106.
(This phenomenon is analogous to the delayed post-exertional pain and
fatigue that can often be seen among healthy persons who do "eccentric
contraction" muscle exercises at levels higher than usual. However, most
likely, the mechanisms are different.)

A second aspect of the Post Exertional Flare-up Phenomenon is that it’s
severity and duration both tend to increase with repeated attempts to
exceed the patient’s limits.

Thus a fibromyalgia or chronic fatigue syndrome patient who pushes
beyond their limits for 4 or 6 hours on one single day may have some
degree of flare-up the next day. But if that same individual repeats the
same activity for two days in a row, the symptom flare-up would
typically be more severe and the duration of flare-up would typically be
longer. All the more so if that activity were to continue to be pushed
through e.g. for five days in a row—as in a work week.

The take home lesson here is that an individual who can perform at a
relatively high level for just a few hours might or might not have the
reserve and stamina to maintain that level of performance on a regular
basis day after day and week after week. One subject can; another
cannot. But, limited short term observations cannot tell us which is
which. However, there is objective basis for judging the credibility of
the patient’s self-report and how, in fact, they live their lives. What
is objective is the paper trail of medical records, the medical opinion
of physicians, appropriate surveillance records and other information
that increases or decreases confidence that the self-reports are
accurate. This requires interpreting the data as it applies for each
specific claimant.


Current Functional Capacity Evaluation (FCE) protocols lack validity in
the context of chronic fatigue syndrome and fibromyalgia. Unless,
radically revised, FCE should not be used for CFS or FMS. Current
protocols lack empirical and also theoretical rationale. Conclusions
formed in this context are inherently flawed and misleading.
The FCE, as now used is not a reliable or valid measure for evaluating
the ability of persons with severe Chronic Fatigue Syndrome or
Fibromyalgia to work on an ongoing basis--week after week and month
after month. The research literature and common sense both make this clear.

The FCE asks subjects to repeatedly perform light to moderately intense
physical activities for a short period of time. Typical tasks might
include stooping, crawling, squeezing, balancing. This usually takes
place over two to four hours. In somecase testing is repeated on the
next day. The examiner then uses the findings over short periods of time
to extrapolate out to a judgment about much longer periods. The examiner
observes for just 4 ours over one or two days, but then extrapolates
from this to predict how that person could do over a 40 hours week—week
after week-- on a continuing basis in the context of a job.

This extrapolation is not valid, for two critical reasons 1. It lacks
face validity, because the FCE fails to evaluate precisely the main
reason that persons with CFS/FMS claims prevent them from working (the
prolonged but delayed and cumulative worsening after unaccustomed
exertion) and 2) there is no scientific, empirical research that support
the validity of extrapolating from short term observations to long term
ability to work.

Whatever applicability the FCE might or might not have for other
conditions such as angina, low back pain or emphysema, there has been no
medical research that provides a reasonable basis for applying current
FCE methods to fibromyalgia or chronic fatigue.


There are two main arguments against the use of current FCE protocols to
assess disability for persons with CFS or FMS:

1. The FCE self-consciously avoids evaluating directly assessing the
specific limitations that most CFS/FMS patients give as the reasons that
they are unable to work
2. There is no empirical medical research on chronic fatigue syndrome or
fibromyalgia that in any way justifies or supports any extrapolation
from a person’s ability to perform over a few hours to any conclusion at
all about that person’s ability to perform for 40 hours every week.


First, let’s list the main reasons that persons with CFS and/or FMS
claim they cannot sustain themselves at a job.

The most prominent are:

1) The person is too fatigued and limited in stamina to be able to
function for more than a few hours a day without their symptoms getting
worse.
Comment: The FCE does not attempt to verify whether or not this
historical claim is accurate or whether the person actually lives his or
her life within these limitations. There is no medical scientific basis
for extrapolating from the short term testing to a prediction about the
ability to perform for 40 hours every week.

2) The person is in too much pain and too limited in stamina to function
for more than a few hours a day without their symptoms getting worse.
Comment: The FCE does not attempt to verify whether this is true or
whether the person actually lives his or her life within these
limitations. There is no medical scientific basis for extrapolating from
the short term testing to a prediction about the ability to perform for
40 hours every week.

3) The person has too limited an ability to concentrate, think rapidly,
and/or multi-task to sustain effective concentration on an ongoing
basis. Attempting to do so further reduces cognitive abilities and
increases symptoms of "brain fog" and/or pain and/or fatigue.
Comment: The FCE does not attempt to measure cognitive stamina. Nor
would it be sufficient to measure cognitive ability over just one
session. Since the issue is cognitive stamina, one has to measure
whether,with repeated effort and compared to controls, cognitive test
scores would increase, remain stable or deteriorate over time.

4) The person suffers a prolonged increase in symptoms some hours or a
day after they attempt to push past their physical activity limits.
Comment: This phenomenon, the post-exertional flare-up, is
characteristic of FCE and CFS. It is not as prominent for other common
forms of illness. This is a crucial difference between CFS/FMS and those
health conditions that FCE testers and disability insurance physicians
often encounter. Current FCE protocols make no attempt to learn how the
patient fared in the hours or days after the testing. A similar flare-up
phenomenon can occur if patients push past their cognitive limits. By
ignoring this central question, current protocols forfeit their face
validity.

5) Patients often report that their worsening with exertion tends to be
cumulative. That is, five days of trying to push through causes much
more severe and longer flare-ups than does just one day of over-doing.
CFS and FMS patients also report that, unpredictably, they have days
where they are even much worse than usual. Many report that on such
"bad" days they can barely get out of bed. These unpredictable flare-ups
are in addition to those that can be expected due to over-activity on
prior days. Many report such especially "bad" days as occurring once or
twice a week. If these reports are accurate, persons with frequent "bad"
days would be unable to work regularly at a job just for that reason alone.
Comment: The FCE does not attempt to confirm or deny the "bad" day
phenomenon.


Current FCE protocols simply ignore these issues. They make no attempt
to assess them. But, one cannot reasonably ignore the very issues that
the claimant offers as the reason he or she can’t work. That is
scientifically incorrect. This limitation forfeits the FCE’s claim to
face validity. That is the method is invalid on its face, even before
one gets to empirical testing. Simply put, the FCE as now used, is
looking in the wrong place.

In practical terms, imagine an employer hiring someone with chronic
fatigue syndrome or fibromyalgia. Having interviewed on a "good day" the
employer used a current FCE protocol and that it "predicted" that this
person could sustain effective sedentary work function for 40 hours
every week. Next, imagine that after three or four 8 hour workdays this
employee had to call in sick as their stamina declined due to continuing
effort. Would it be fair for such an employer to feel misled over the
FCE results? Clearly the answer is Yes.


What empirical evidence underlies the FCE’s claim that measuring hand
strength, squatting, balancing etc for a few minutes is relevant to an
opinion about whether a person can work for 40 hours a week, week after
week? Particularly, does any research support such extrapolations for
the specific conditions, chronic fatigue syndrome or fibromyalgia?

The short answer is no. The rationale for this testing, when applied to
CFS/FMS, is entirely speculative, and unsupported by evidence. To
formally test this crucial question I ran a computer-assisted search of
the National Library of Medicine medical literature data base,
EntrezPubMed. PubMed contains more than fifteen million health journal
articles. It contains essentially all English Language medical
publications since 1966, and also a large number of foreign language
publications.

Based on the National Library of Medicine’s data base there are no
published controlled studies at all that support the validity of any
currently standard FCE protocol as applied to chronic fatigue syndrome
or fibromyalgia. By "no publications", this means literally zero–not one
or two publications, but literally zero.

On March 23, 2007 I submitted the keywords: functional capacity
evaluation, FCE, fibromyalgia and chronic fatigue syndrome.

The keywords fibromyalgia and functional capacity evaluation or FCE
identified two single references. However, based on the abstracts of
these articles–which are available on line--neither article assessed the
clinical relevance or validity of the FCE as a tool for evaluating FMS
disability.

A search using the keywords chronic fatigue syndrome and functional
capacity evaluation or FCE disclosed five articles. None of these
articles provided evidence to support the validity of the FCE for
patients with CFS. Indeed, their conclusions tended toward the contrary.


For example, consider: Ross SD, Estok RP, Frame D, Stone LR, Ludensky V,
Levine CB. Disability and chronic fatigue syndrome: a focus on function
Arch Intern Med. 2004 May 24;164(10):1098-107. Their conclusion states:
For questions of disability and employment in CFS, the limitations
inherent in the current literature are extensive. Methodologically
rigorous, longitudinal, and interventional studies are needed to
determine baseline characteristics that are associated with the
inability to work… Simple and consistent evaluations of functional
capacity in patients with CFS are needed.


For example, consider: Nijs J De Meirleir K Wolfs S, Duquet W Disability
Evaluation in chronic fatigue syndrome: association between exercise
capacity and activity limitations/participation restrictions Clin
Rehabil. 2004 Mar; 18(2):139-48.
CONCLUSIONS: These results suggest a moderate association between
exercise capacity and activity limitations/participation restrictions in
patients with CFS. The observed correlations lack strength to predict
activity limitations/participation restriction based on exercise
capacity parameters…

For example, consider: Barrows, D, Functional capacity evaluations of
persons with chronic fatigue immune dysfunction system (Am J Occup Ther.
1995 Apr; 49(4):327-37.
Abstract: Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) is
estimated to affect 2 to 5 million people in the United States. Despite
its high incidence, persons with CFIDS have been neglected by the
medical community mainly because there is no singular confirming
diagnostic test or proven effective treatment. The CFIDS population is
incorrectly stereotyped as upper-middle-class, white, female
hypochondriacs; consequently, symptoms often are belittled or ignored.
In reality, CFIDS is a severe medical condition that affects women, men,
and children of any race and often causes long-term or total disability.
The results of a modified functional capacity evaluation developed by
the author and completed on 86 persons with CFIDS between 1988 and 1990
confirm that this population has severe physical and cognitive
disabilities that affect their professional, familial, and social lives.

Please note, this study used the authors’ own unique and newly
formulated FCE protocol. They did not assess or attempt protocols that
are currently in use. Nor did they attempt validate their own protocol
against a "gold standard" of actual work-place performance.

For example, consider: Morriss, R et. al. Exploring the validity of the
Chalder Fatigue scale in chronic fatigue syndrome Psychosom Res. 1998
Nov; 45(5):411-7.)
The Chalder fatigue scale is widely used to measure physical and mental
fatigue… We examined the constructs of the 14-item fatigue scale in a
sample of 136 chronic fatigue syndrome patients… There were four factors
of fatigue explaining 67% of the total variance. Factor 1 was correlated
with subjective everyday cognitive difficulties, concentration
difficulties, and a deficit in paired associate learning. Factor 2 was
correlated with difficulties in maintaining sleep. Factor 3 was
inversely correlated with grip strength, peak VO2, peak heart rate, and
peak functional work capacity. Factor 4 was correlated with interview
and self-rated measures of depression. The results support the validity
of mental and physical fatigue subscales and the dropping of the "loss
of interest" item in the 11-item version of the fatigue scale

This study did not address standard FCE protocols or attempt to validate
their use.

The fifth study in the National Library of Medicine data base was a
clinical trial for treating chronic fatigue syndrome with an antiviral
medicine. It was not relevant to any current FCE protocols.


Therefore, so far as can be determined from the published medical
literature, there are no published studies that even attempt to validate
any of the currently used FCE protocols with regard to their validity
for predicting disability among persons with FMS or CFS.


There are other problems as well, for example, the relevance of the
tests given to the actual demands of the jobs for which the claimant
might qualify. Often, the tasks used in the FCE are only distantly
related to those actually required for the job. For example, if a job
requires sustained mental concentration and high level executive
decision making, the ability to do that effectively over an 8 hour day
and a 40 hour week is what needs to be tested. The ability to squat
repeatedly over several minutes or the ability to sit upright for
several hours misses the point.

Because the FCE as currently used does not attempt to evaluate the
specific limitations that CFS and FMS patients claims makes them unable
to work and because it lacks empirical medical research supporting its
methods for extrapolating from short to long term—for these sufficient
reasons FCE protocols should not be used for CFS or FMS.

Judging the validity of FCE for other disease conditions is beyond the
scope of this review. However, it is pertinent to this discussion that,
even aside from CFS and FMS, the FCE has been the subject of major
criticism.

For example, see Innes and Stroker’s internet essay on the more general
validity of work-related assessments (not focused on CFS or
fibromyalgia). They concluded:
"As with reliability, most work-related assessments have limited
evidence of validity. A number had insufficient evidence on which to
base an assessment of the level of validity. Of those that had adequate
evidence, validity ranged from poor to good....
There was, however, no instrument that demonstrated moderate to good
validity in all areas. Very few work-related assessments were able to
demonstrate adequate validity in more than one area…This highlights the
need for further research to be conducted in this area...
The acceptance of work-related assessments on the basis of their
longevity in the marketplace and clinic should not be assumed to equate
with adequate validity..."

Or consider this study conducted by Liberty Mutual Research Institute
for Safety Center for Disability Research. (Liberty Mutual Research is
sponsored by Liberty Mutual, the insurance company): Pranksy G and
Dempsey P Practical Aspects of Functional Disability Evaluation J Occup
Rehabil. 2004 Sep; 14(3):217-29.
Abstract: Physicians, employers, insurers, and benefits adjudicators
often rely upon functional capacity evaluations (FCEs) to determine
musculoskeletal capacity to perform physical work, often with legal or
occupational consequences. Despite their widespread application for
several decades, a number of scientific, legal, and practical concerns
persist. FCEs are based upon a theoretical model of comparing job
demands to worker capabilities. Validity of FCE results is optimal with
accurate job simulation and detailed, intensive assessments of specific
work activities. When test criteria are unrelated to job performance, or
subjective evaluation criteria are employed, the validity of results is
questionable… Evaluation of sincerity of effort, ability to perform
complex or variable jobs, and prediction of injury based upon FCE data
is problematic. More research, especially studies linking FCE results to
occupational outcomes, is needed to better define the appropriate role
for these evaluations in clinical and administrative settings.


Should we design an FCE protocol that actually observes patients over a
simulated 40 hour work-week? In some ways that might make sense, if such
a protocol were then evaluated objectively against a "gold standard" of
actual work performance on a job over the course of many months.
However, based on our knowledge of FMS and CFS, this degree of vigorous
testing would be expected to seriously exacerbate illness in a
substantial subset of patients. This would create a medical hazard.

Conclusion: Current FCE protocols should not be used for assessing
disability due to CFS or FMS. These protocols lack face validity, and
have absolutely no supportive evidence in terms of peer reviewed
articles published in the medical literature.

If the FCE is to be used at all for chronic fatigue syndrome or
fibromyalgia, it must first be redesigned and then validated by proper
testing to repair its deficiencies.

Based on the merits of the medical science involved, it seems highly
unlikely that current FCE protocols could survive a Daubert challenge.

Both insurance carriers and the public would benefit from a decision to
abandon the current FCE and to develop better tools for evaluating
disability for fibromyalgia and chronic fatigue syndrome. For insurance
carriers to rely on a provably invalid method such as the FCE, this
undermines public confidence in the insurance industry as a whole. In
the long run, public confidence is requires to sustain a friendly
environment of law and regulation so that insurance company’s can
function and so that disability insurance policies will remain available
to the public.


Since the FCE is Not Valid, What Tools Can We Use to Confirm or Deny a
Patient’s Self Report that their stamina is so Limited That They Cannot
Sustain the Activity Any Job Would Required for Forty Hours in a Work-Week?

As discussed above, the diagnosis of CFS and FMS requires evaluation of
the credibility of the patient’s self-reports. While self-reports are,
by definition, subjective—in that you can not look at a person and
automatically measure the truth of his or her statements—objective
evidence can and should be used to assess the self report’s credibility.
Most often the most important method is a careful review of the medical
records to see whether or not
a) complaints are documented over a long period of time are
b) consistent with the patient’s self-reports and
c) characteristic of the known pattern for CFS and FMS and
d) consistent with other independent evidence such as surveillance tapes
or testimony.
In reviewing disability litigation cases, the defense sometimes asserts
that a claimant is not disabled because the evidence that the physician
documents in the chart is "not objective". This uses the term objective
to mean that there should be an objective finding on physical exam or
lab testing that demonstrates disease severity. As discussed above the
criteria for CFS and FMS are such that normally we should not expect
physical findings or lab tests to assess disease severity or to
distinguish the patient who is disabled from the patient who can still work.
TFhis objective vs. subjective debate distracts from the valid
question—Are the patient’s self reports of symptoms and limitations
credible in view of the objective evidence available such as medical
records, opinion of treating and expert physicians, independent
testimony regarding actual life style, appropriate independent
surveillance.
As discussed in prior sections we face a paradox. The patient’s report
is in one sense subjective i.e. based on the patient’s self-report. But,
it is also objective in the sense that these reports can be verified or
denied objectively using medical records, testimony and independent
observations to confirm or deny the credibility of the self-reports?

One reason for doubt an individual patient’s credibility might be if the
patient’s report is not consistent with the typical pattern of their
disease. For example, it would be very atypical for a patient with FMS
or CFS to feel typically 100% well and be highly active for weeks at a
time, only to plunge back into severe illness for weeks at a time
thereafter. Some variation in symptoms from day to day or month to month
is typical but most often variation is modest. (Some CFS/FMS patients
will refer to periods of being "almost normal". However, they usually
see this in comparison to a very low baseline. Close questioning will
usually reveal that their energy reserves are still limited.)

Another reason for doubt might be information from the patient spouse,
or other observer claiming that the patient habitually engages in
activities that are inconsistent with their self-reports. For example,
persons with disabling fatigue and pain due to FMS/ CFS cannot typically
play vigorous singles tennis three times a week on a consistent or
regular basis. (Such activity might be tolerated once in a while, but
would typically flare-up their symptoms later that day or the next.)

Another factor is the medical judgments of physicians who know the
patient well. Physicians who have developed a relationship with a
patient will gain confidence in their medical opinion about the
patient’s reliability. By and large we should prefer the long-term
treating physician’s judgment about the patient’s credibility to that of
a physician who has seen the patient only once, or, if an opinion is
based just on a review of the file.

In some charts one can often sense from the physician’s note whether or
not the physician has substantial reservations about the accuracy or
truthfulness of the patient’s self-reports. However, in other charts, we
cannot tell.

One practical problem is that many physicians’ notes are not very
detailed. As important, the physician's main focus is most often on
issues other than quantifying the severity of symptoms or functional
impairment. Treating physicians tend to be much more interested in
diagnosing and treating, than in asking about or writing down how long a
person can sit in a chair or type on a keyboard.

Thus, a typical physician’s visit note might read something like:
"Still tired and achy. Ultram helped, but had to stop due to nausea.
Will send to PT and perhaps try Cymbalta."

This person’s illness could be mild, moderate or severe. One cannot tell
from this note. If specifically asked to, the physician might have
chosen to direct questions toward assessing severity and function.
However, in real world practice, other priorities take precedence. In an
ideal world, physicians might directly quote the language of all their
patients’ complaints. In practice, our notes are highly selective and
condensed.

If there is little or no mention of functional limitations in the chart,
one cannot necessarily conclude that function was normal or that no
limitations were reported. Physicians may regard complaints about
reduced function as more a vocational than medical concern. We’re
normally more concerned about a host of other issues.

Another practical problem is that many physicians don’t know enough
about the normal pattern of fibromyalgia or chronic fatigue syndrome--
such as the post-exertional flare phenomenon. Clinical records are often
silent, on what, in litigation, may turn out to be very important points.

We also face problems due to the patient’s limitations as a
communicator—e.g. limitations imposed by the duration of time allowed
for a visit, the patient’s purpose for certain visits being unrelated to
her FMS/CFS complaints.

Despite these limitations, the medical records remain the most important
tool we have.

Beyond this, we could in theory consider other objective measures. For
example, insurance industry attorneys can ask to review a claimant’s
credit card charges to construct a picture of the claimant’s activity
levels. They might obtain records from the local golf course to see how
often a claimant played. This is fair, since the insurance company does
have a right to do all they can to learn whether or not a claimant is in
fact living within the limits that they claim that they have.

Hidden video-surveillance is often used. This feels like an invasion of
privacy. Of course, in a sense it is. But, this is still a tool—if
properly used—that can provide objective evidence of a claimant’s
activity. Unfortunately, video surveillance can also be misused and
misinterpreted.

Videotaping a person shopping for two or three hours on one day with
stooping down to take things off shelves, reaching up to put things
back, of lifting packages in and out of a shopping cart—this should not
be viewed as evidence that a patient can work a 40 hours week. A
videotape of this kind is simply a less formal and planned version of
the FCE. It provides no scientific basis for extrapolating out from a
few hours of activity to any judgment at all about a 40 hours week. On
the other hand, a video tape that shows vigorous activity 4 hours every
day, five days a week, might reasonably be used to question a claimant’s
claim. (But, this works both ways. If there are four or five days of
surveillance and all that is observed in that time are one or two trips
to the store for shopping, this tends to support not deny the patient’s
report of limitations.



Summary of Dr. Podell’s Background Related to Chronic Fatigue Syndrome
and Fibromyalgia

Dr. Podell serves as clinical professor in the department of family
medicine, UMDNJ-Robert Wood Johnson Medical School. He is Board
Certified in both Internal Medicine and in Family Practice.

Chronic Fatigue Syndrome:

During 1998-2003 Dr Podell served as Principal Investigator for an FDA
approved phase III double blind trial of the drug, Ampligen, as
treatment for chronic fatigue syndrome. Dr. Podell also served as
Principal Investigator of an FDA approved open label study of Ampligen
for chronic fatigue syndrome.

Dr. Podell was an editorial advisor for a monograph on the diagnosis and
treatment of chronic fatigue syndrome that was published in 2002 by the
New Jersey Academy of Medicine and the New Jersey State Department of
Health.

Dr. Podell participated in National Institutes of Health’s working group
on Chronic Fatigue Syndrome, 1993.

Dr. Podell is author of a book for patients about chronic fatigue
titled, Doctor Why Am I So Tired?, Fawcett, 1987. This was a Book-of-the
Month Club Selection.

Dr. Podell has lectured on chronic fatigue syndrome to the Division of
Family Medicine, UMDNJ- Robert Wood Johnson Medical School, and other
professional and lay organizations.

Dr. Podell received the Achievement Award for 2002 from the New Jersey
Chronic Fatigue Syndrome Association

Dr. Podell is a member of the Chronic Fatigue Syndrome Association, the
primary organization of health professional specialists in Chronic
Fatigue Syndrome.

Fibromyalgia:

Dr. Podell is the author of two review articles for physicians on
Fibromyalgia--

Podell, R , Fibromyalgia: A Practical Guide for Diagnosis and Treatment,
accepted for publication in the Journal of Musculoskeletal Pain, 2007

Podell, R, Fibromyalgia: Practical Treatments for the Family Physician,
Perspectives, The Journal of the New Jersey Academy of Family Physicians
pages 8-13, 4Q, 2005

Dr. Podell has lectured on Fibromyalgia before the Division of
Rheumatology at UMDNJ-Robert Wood Johnson Medical School and other lay
and professional audiences.

Dr. Podell participated in the National Institutes of Health Workshop on
Fibromyalgia Research, National Institutes of Health, November, 2004

Dr. Podell is a member of the International Myopain Society, the leading
international professional organization of physicians and scientists
specializing in Fibromyalgia. Dr. Podell participated in the three most
recent Scientific Assemblies of the International Myopain Society.

Disability And Chronic Fatigue Syndrome or Fibromyalgia:

Dr. Podell served as invited medical expert consultant on Chronic
Fatigue Syndrome and Fibromyalgia for both the Seventh, Eighth and Ninth
National Advanced Forum on Litigating Disability Insurance Claims
presented by the American Conference Institute in 2005, 2006 and 2007.


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