Wednesday, May 26, 2010

Lyndonville News from David Bell

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Negative Papers on XMRV

On January 6, 2010, the first paper to refute the Lombardi et al.(1) paper in Science was published in the journal PLoS ONE: Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue syndrome.(2) It was bound to happen. Then came papers two and three, again polymerase chain reaction studies on stored blood(3, 4). Nothing in ME/CFS is easy, but this is the way it works in science. There are two possible scenarios:

Scenario one is that several quick papers can't find it. The first paper was two months from idea to lab tests to writing to review to publication - that's quick. The Science paper was two years in the making and the review process itself took six months! So, we may have a rush to judgement here. In this scenario the scientists will get discouraged and accept the inevitable - this is just another of many, many dead ends. The Science study will be quickly buried and forgotten. It has happened before.

Scenario two is how science should work. Someone publishes a paper showing a virus called XMRV is found in persons with ME/CFS. Somebody else says it cannot be detected. And reading the fine print it turns out that one study uses heparinized tubes, the other ACD tubes. Then they collaborate and share data and work out some of the differences. And there are many, many differences. I remember that in 1990 I asked the Fedex driver to hold the samples in his lap because the back of the truck was frozen with Upstate New York January air. At that time I didn't know if freezing was going to alter the results.

With each study we should learn something. A study may show different numbers and a slightly different sequence. We learn something. A scientist pokes holes in a colleagues paper. That colleague goes home, thinks about it and learns something. He or she comes back into the lab and does another experiment. It is a marvelous process. And I remain confident that we will arrive at the truth, whatever that is.

And the papers published so far have not "failed to replicate," as none of them have tried to replicate. And, as Hilary Johnson has pointed out, there was an enormous rush to pin AIDS on HIV when it had been found in a couple of people. XMRV has been isolated from seventy five individuals.

Dr. Nancy Klimas said in her lecture, "And if you see some negative papers coming out, don't be discouraged. It's going to happen. There are going to be some negative papers. People really jump to do this. And the method is not that easy, and getting the right bits and pieces you need together, it's not: read the paper and then go do it."

Quote of the Day

"and I would like to be around when all those snarks have to swallow their vastly irritating lumps of hubris." I am not quite sure what it means but it was referring to the negative papers.

Advocacy and Funding

I have heard third hand that someone at the CFSAC meeting did not like the letter I wrote asking persons to contribute $10 each to the WPI. I agree, it is not the way science works. It is absurd to think that a few $10 bills will change anything. It is also a little embarrassing. Oh well.

There have been over 5,000 scientific papers written on ME/CFS. Huge amounts of money have been spent on psychological studies, behavioral therapy studies. Even trying to define the illness has been impossible, but the money goes there as well. It may be time to put some research effort into good virology. But here is the letter I wrote. And I have sent in my $10 check.

To my friends with ME/CFS,

I would like to put out a personal appeal for funds to be sent to the Whittemore-Peterson Institute (WPI) in order to speed up the progress of the current research. Here is my reading of a very complex situation.

Medical authorities, educational institutions, governmental agencies, and most practicing physicians have disrespected and minimized CFS in just about every way possible, from creating an insulting name for the illness to advising extreme caution in treatment, except cognitive behavioral treatments.

It is easy to dismiss my remarks to follow by saying that I am biased. And it is true, I am very biased and for twenty five years I have quietly sat on the sidelines believing that science will win out and true progress will be made. I am beginning to think this has been a great mistake. The profession I love has failed miserably.

In 1985 an outbreak of CFS hit Lyndonville NY and affected 210 persons, 60 of whom were children. The official response from the CDC and the New York Health Department was that this was mass hysteria. No one talked with a single patient. In 1990 I worked with Dr. Elaine DeFreitas and Dr. Paul Cheney and a retrovirus was found and the material published (DeFreitas E, Hilliard B, Cheney P, Bell D, Kiggundu E, Sankey D, et al. Retroviral sequences related to T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci. 1991;88:2922-6). A second paper had been accepted by PNAS and contained a photograph of C-type retroviral particles from a tissue culture of spinal fluid of one of the children in the Lyndonville outbreak. This paper was suddenly pulled and not published after a couple of flawed negative papers. A complete description of these troubled times is in Osler's Web by Hilary Johnson. The funding for our studies was pulled and all work on this abruptly stopped.

I think the same tactics are being employed to hamper the current work on XMRV by the WPI. The WPI is a private organization and, as I understand it, no federal grants or funding has been forthcoming. There have been three negative PCR-only studies which have established only that CFS can not to be superficially studied. At this time no study that has attempted to replicate the WPI study has been heard from. Many CFS research organizations have declared publically that "XMRV is a dead issue."

Nothing is farther from the truth. I cannot predict the future, but my fear is that the current political and scientific organizations who do not want to see retroviral involvement will attempt to stifle studies on XMRV in CFS. Huge amounts of money are spent on studies on cognitive therapy, and studies proving that CFS is heterogeneous (you can argue that polio is heterogenous).

We have not heard from the CDC, other than the inappropriate comment that this was not likely to turn out to be anything, made right after the Science paper publication in October 2009. We are now eight months later and not a peep. Maybe they are finding XMRV and want to be very careful. Maybe they haven't looked and are assuming that this heretical idea will blow away. Eight months? And the Band Played On.

It is possible that thirty other labs are finding XMRV in CFS or that no one else in the world is even looking for it. Science requires that labs do not disclose their findings prior to publication and I agree with this rule. But is the WPI going to be isolated by the scientific community and wither away because of lack of funding? Is XMRV going to become more of the compost of CFS research?

But there is an alternative. We cannot wait ten years for science to grind out its conclusions. Every person in the world who believes that CFS is important should send $10 to the WPI. I plan to send $10 today. It may not be much, but it is a start. There may be 10 million persons in the world with CFS. Lets see, that's…I need a calculator. May 12 is our day. Let's do this.

After 25 years of work in this field I do not have much. But I have my integrity. I feel that WPI has made an important discovery and I feel they are an ethical organization, they are not padding their pockets. But I also have my fears. And the greatest fear of all is that their discovery may not be appropriately followed up.

For the 9,999,999 other people out there who think CFS is both real and important, send $10 to: Whittemore Peterson Institute, 6600 N. Wingfield Parkway, Sparks, NV 89436. Thank you.

ME/CFS Essay: Fatigue with and without Orthostatic Intolerance 

Over the past twenty five years I have had the opportunity to see lots of things through CFS colored glasses. For example there are all these case definitions and diagnostic criteria. Yet as the years pass I see patients who go from one set of criteria to another. Presently I am writing the twenty-five year follow-up paper. And some remarkable things have emerged. They are so remarkable, non-clinicians will not believe them. Here is an example.

Mary got sick in 1985 with a typical mono-like illness and missed two years of school. She experienced the usual discrimination and physician abuse, except (I hope) in my office. She was for real. Strong, gutsy kid who kept up her studies despite not going to class. Her SAT scores were good and she went to college, part time at first, then almost full time and graduated. Fell in love, got married, had kids, had a job. She did great.

In 1995 we published a "Thirteen year follow-up" and she was one of the recovered patients. 80% of the kids followed up at 13 years were doing well, and it is one of the reasons there has been the general perception that kids are more likely to recover. I had made a mistake and did not realize what I know now. So we do the 25 year follow up questionnaire.

The first question on the SF-36 is "how do you rate your health?" excellent/very good/good/fair/poor are the response choices. Mary put down Very good. Then we look at her daily symptoms. Severe headaches. Moderate muscle and joint pain, doctors don't know what it is. Irritable bowel syndrome. Sleep is terrible. Memory and concentration is poor. Severe fatigue. When you look at all the questionnaire scores she is as bad as she was twenty five years ago. Except for one questionnaire.

Her activity is 16 hours a day. She can function a whole day, so she can work and raise a family. At the beginning of her illness her activity was only three hours a day - that was why she could not attend school. The only thing that has improved is the orthostatic intolerance - the ability to function in the upright position. And that is why she feels that she has recovered. The daily somatic symptoms are an annoyance which she copes with very well; ignores in fact. It is ironic that her fatigue is severe, but without orthostatic intolerance, so she considers herself to be "recovered."

But she has not recovered. She is still ill with all the symptoms of CFS except orthostatic intolerance. So when people say whether or not they are better, usually they refer only to that one central symptom that determines if you can function like a normal person. The degree of recovery is, in fact, merely the improvement of this one central symptom.

As we are testing some persons for XMRV, it turns out that people who say they are well, may not be fully recovered. One person, a regular blood donor, considered herself pretty well after "recovering" from CFS. She was positive for XMRV. Do you call them a positive control or a positive XANDer who is doing pretty well? The studies to take place in the next few years are not for the faint of heart.

Question and Answer


In the Dubbo study, a percentage of persons developed CFS after Epstein-Barr virus, Ross River virus or Q fever. They must have saved blood from those who came down with CFS and those who did not. Test the blood for XMRV. If this virus is present in the subjects who came down with CFS, but not present in the blood of those people who had regular illnesses and quickly recovered, we would have the answer as to whether XMRV "causes" CFS.


Excellent question. I would hope that the CDC and the Australian government are doing exactly this.

1. Lombardi V, Ruscetti F, Gupta J, Pfost M, Hagen K, Peterson D, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. . Science. 2009;326(5952):595-89.
2. Erlwein O, Kaye S, McClure M, Weber J, Wills G, Collier D, et al. Failure to detect the novel XMRV in chronic fatigue syndrome. PLoS ONE. 2010;5: e8519. doi:10.1371/journal.pone.0008519.
3. Groom H, Boucherit V, Makinson K, Randal E, Baptista S, Hagen S, et al. Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology. 2010;7(10 [Epub ahead of print]).
4. Kuppeveld F, de Jong A, Lanke K, Verhaegh G, Melchers W, Swanink C, et al. Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ 2010;340(doi:10.1136/bmj.c1018).
5. DeFreitas E, Hilliard B, Cheney P, Bell D, Kiggundu E, Sankey D, et al. Retroviral sequences related to T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci. 1991;88:2922-6.


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Disclaimer Any medical advice that is presented in the Lyndonville News is generic and for general informational purposes only. ME/CFS/FM is an extremely complex illness and specific advice may not be appropriate for an individual with this illness. Therefore, should you be interested or wish to pursue any of the ideas presented here, please discuss them with your personal physician.


© 2010 David S. Bell


Overview from CFS Patient Advocate on the recent Invest in ME Conference

Below is an overview from CFS Patient Advocate on the recent Invest in
ME Conference which took place in London, UK.


Tuesday, May 25, 2010
London Conference May 24, 2010

Here is my report from the Invest in ME conference in London that took
place on May 24, 2010. This report is my attempt to communicate to
others - to those patients who could not attend (including my
daughter) - what I saw and heard. I am aware that this report reflects
my own bias.

This is the fourth year that I have attended the Invest in ME
conference in London. The guiding lights of this effort are Richard
and Pia Simpson. These dedicated individuals work tirelessly to make
this conference happen. Their hospitable and generous presence is felt
everywhere, and I cannot imagine a CFS/ME speaker having a better
platform from which to make a presentation.

The one-day conference takes place in a beautiful lecture hall at the
very edge of St. James Park. During breaks you can go out and sit in
the sun on a park bench and see the world go by. The hall seats 230
people. Each year this conference grows in number, and this year the
hall was packed – mostly with patients and patient advocates. Soon the
sponsors will have to find a bigger venue. Each year the appropriate
government and public health officials are invited to attend and to
make a contribution - and each year no one shows up. At least they
show a great consistency. (In the UK one is startled by what the NHS
does not provide for the citizens of this country. The health care for
CFS/ME is Kafkaesque and anyone interested in government run health
care should take a good look at this situation and disabuse themselves
of their utopian dreams. The situation is pathetic and very sad for
the patients, who are desperate.)

Invest in ME invites the top medical or research practitioners to
present at this conference. Surprisingly (or not surprisingly) the
participants are increasingly American researchers and doctors. The
all-day conference delivers a disciplined and hard-hitting set of
lectures, one after another. It is an exhausting but rewarding day and
the audience member has a front row seat to the most current issues in
CFS/ME, warts and all. In the past I have seen Garth Nicholson, Sarah
Myhill, John Chia, Kenny de Meirleir, A. Martin Lerner, Basant Puri
and Jonathan Kerr. The lectures are usually 45 minutes long and the
day is broken into several sections with two tea breaks and a lunch
break. A fine lunch is served. During the breaks conversation is
encouraged and it is possible to buttonhole the speakers.

The concept behind this conference is healthier and more focused than
the semi-annual meetings in the US. These US conferences, of which I
have attended two, are four days long and have a great amount of
"filler" or academic cannon fodder. The sponsors try to please
everyone and in the process please no one. The viewer gets none of
this feeling at the Invest in ME conference.

Mondays lectures started early with Dr. Leonard Jason. He is a good
choice to get the day going. I have heard Dr. Jason speak a number of
times and each time he is better. He has been previously well received
at his conference and for good reason. He presents precise and
well-organized statistical information attempting to define the
parameters of CFS/ME in a legible and understandable fashion. Given
the history of CFS/ME and its various confusions, this is not an easy
task. Along the way, he delves into subject matter that is quite
surrealistic, often bizarre and funny. Dr. Leonard works is a
disciplined way, mostly on his own, out of DePaul University in
Chicago. He strives towards clarity regarding the language and
definitions of CFS, and he is appreciated and respected by a growing
number of people.

Dr. Jason's inclinations and work can be gleaned from the internet.
This is true of all the speakers. My intention in writing this report
is less to detail the contents of the lectures and more to give a
feeling about the conference from my perspective. Things are changing
with rapid dissemination of information worldwide and personally, I
did not expect to learn a whole bunch of useful items that I did not
already know. There were a few tidbits that I will include in this

The second presentation was a solid academic talk by Nora Chapman from
the University of Nebraska. I imagine that the science of this talk
passed over the head of most of the audience, including mine. Chapman
and her associates have demonstrated that selection of defective
enterovirus in heart and other tissues leads to persistent infections
despite active antiviral immune responses. Paired with this lecture
was Dr. John Chia, who also works with enteroviruses. Dr. Chia was
back for the third straight year and he gave updated research
information, including case studies, enumerating his belief that
enteroviruses are a major causes in CFS/ME. Dr. Chia strikes a nice
balance with his research ideas and his treatment possibilities. In
this case, he spoke at length about Equilibrant (Oxymatrine) and its
effectiveness in about half of his CFS patients. As he likes to point
out, this is a quite a high percentage of success for any CFS
protocol. Dr. Chia lectures can be seen online or on DVDs. Cort
Johnson has several good interviews of and discussions with Dr. Chia
on his site. Dr. Chia collaborates with his son Andrew on research.
This year Andrew had to attend classes at the U of Southern California
where he is in pharmaceutical school. Among other things he wants to
learn and lobby for the development of anti-enteroviral drugs. I was
hoping that Andrew could meet my son Peter, who is about his age.
Peter was attending the conference and doing a little filming. Maybe
next year, the two can meet.

After the morning break, Cheney gave a lecture on oxygen toxicity and
diastolic dysfunction. Cheney's big problem was squeezing his usual
three-hour lecture into 45 minutes - and I can say that he did not do
a good job of this. Twenty minutes into the lecture I turned to my son
Peter and said that Dr. Cheney was proceeding as if he had three hours
- and that he had better speed it up. He didn't and the consequence
was that Dr. Cheney had to just stopped in the middle of his lecture.
However, it was not a big problem as any 45-minute slice of Dr. Cheney
is worth its weight in gold, and this day was no exception. Dr. Cheney
is a quite fantastic fellow. This was his first appearance at this UK
conference. Most of what he presented can be culled from his research
website or from his recent DVD from April 2009. Dr. Cheney gives
credence to the new discovery of a retrovirus. After all, Dr. Cheney
has long believed that a retrovirus could be at the center of this
disorder. In his lecture, Dr. Cheney indicated that 38 of 47
consecutive patients in his practice were XMRV positive by culture
testing at VIP lab.

Jonathan Kerr gave one of his exquisite low-key barely audible
presentations. He plows along in his genetic work, this time speaking
on his continuing work to subtype CFS by SNPs. In a nice bit of
symmetry his slides matched his inaudibility - and they were
completely washed out and unviewable. What was with this? I guess
under current circumstances he was embarrassed to be at this
conference and wished he were somewhere else. Dr. Kerr used to do very
important work. Each year he seems to have less funding. In the past,
at the end of his lecture, he would show his band of researchers,
shrinking magnificently each year. This time I noticed that he didn't
show the usual picture of his colleagues - so I guess he doesn't have
any. This sophisticated research is fueled by cash and it seems to be
drying up. Certainly the UK government gives him nothing. One gets the
feeling that the research of this lonely aspirant languishes. He was
going to fetch up with the WPI but I wonder what happened to that?
Long ago it was my suggestion that Dr. Kerr move to the US where he
could make a real contribution to CFS/ME research instead of stalling
out. Surely he knows that there are a lot of Brits living in the US
and if he moved to Minneapolis I would take him to Brit's Tavern for a
Speckled Hen.

Nancy Klimas spoke on various immune markers. I prefer Kerr's
quietness or Peterson's dour seriousness to Klimas' happy optimism.
She seems to be a " real professional" – full of self-importance, weak
research and false promises. I would like to see something substantial
come from her lab but I don't think I will ever see it and now she has
put her emphasis in running her own clinic. I think the CFS/ME
patients need more hard science research, not necessarily more
clinics. All this makes one suspicious of this person's intention.

Towards the end of the day, things heated up a bit. Brigitte Huber
gave a talk on her HERV-K18 research and then added a coda on XMRV.
She did an unexpected and gratuitous job of sandbagging Judy Mikovits,
who was the next speaker. Huber methodically went through her recent
XMRV "study", explaining in her officious voice that her PCR test was
the "assay of choice" and "very sensitive". She tested 228 samples,
112 from Susan Levine, 105 from Taylor in Chicago, and 11 from the
HHV6 foundation. Then she put up a slide with red letters that said,
"All samples were negative for XMRV integrase".

Huber said, "We cannot see in our patients XMRV like in the Science
article". In a further confounding maneuver she hinted or charged that
the WPI study was "contaminated". This charge needs to be challenged,
as it is a lie. As she was leaving the lectern Huber said in a
wonderfully disingenuous voice (to no one special, but I suppose it
was directed towards Judy Mikovits), "Sorry". It was a revealing and
weasily moment.

To me it is becoming obvious that certain people, especially doctors
who have been treating patients unsuccessfully for years with
half-baked treatments, or researchers who are connected to the
academic research money tit, are trying to sink Mikovits and the WPI.
This is not science; this is venality. This negative reaction has
little to do with whether XMRV has any validity or not. That is a
separate issue and there are two sides to the argument; and it needs
to be fought out according to established scientific methods. I think
that certain critics sense, perhaps correctly, that soon they might be
out of a job.

The day before the conference, there was a brain storming session with
the various participants at this conference – Cheney, Chia, Huber,
Jason, Whittemore, Chapman. It is a great idea and
discussion/disagreement (sometimes fierce) is often a necessary and
useful result of such exchanges. In this afternoon session, Huber
launched an attack on Mikovits. Mikovits did her usual job of
defending herself. Huber left the group early (maybe to go shopping?).
As she left Huber promised that she would not create a controversy by
revealing her study results the next day.

Overnight Huber changed her mind, honest soul that she is, and made
her awkward revelation. It was all quite unseemly, and did not fit the
tone and tenor of this conference - which is heavily ladened with sick
patients, hanging on by a thread. They make a great sacrifice to get
to this conference, but not to hear this kind of shit. After all this
is really not a scientific conference, and this nice bit of spite was
entirely out of place.

When was the last time that Huber gave one iota of thought about CFS
patients? I can tell you exactly – it was… Never!

I watched this with fascination, realizing that Huber in her
righteousness had put her head on a block and asked to have her face
kicked in. It was a great setup, a "once in a lifetime situation", and
Mikovits came through big-time, doing what she needed to do. She
remained calm (inside she must have been boiling) and delivered a
splendid lecture (the best that I have seen her do) and demolishing
Huber. The effect was that Huber shrank down to the size of a pea. I
had talked to Mikovits the day before about Huber and advised her in
general to disregard her critics and just roll over this woman (not
that Mikovits spends one moment listening to me). Some critics need to
be rolled and this was just what happened. At the end of her lecture,
Mikovits got a loud and sustained applause showing deeply felt

The moderator of the conference once again was Malcolm Hooper, who
represents the best of the UK ME doctors and researchers. Dr. Hooper
is known for the Hooper files, which are included on the conference
DVD to be released in several weeks. Dr. Hooper has an easygoing
manner, moves things long nicely, keeps the conversation focused and
gives helpful commentary when necessary. This man obviously has
multiple gifts.

Invest in ME's primary idea (I believe) in creating this conference
was to bring the most recent research and treatment information to the
UK, a tidal backwater in regards to recognition of the seriousness of
this disease (not that the US is much better). Beyond this they want
to facilitate these personalities to sit down and talk together and to
share their ideas. In general CFS doctors and researchers are a lonely
band of folks, comfortable and happy with their isolation. In other
words their social skills are limited, especially in relating to each
other. In the last few years, things have gotten much better in this
regard, mainly due to this conference and a few other "retreats" of
CFS/ME notables, supported by private donors.

The high-mindedness of these talks always disintegrates at the end of
the day with a plenary session where patients and patient advocates
plead for treatment advice – treatment readily available in the US and
denied the patients in the UK. (Whether these treatments work or not
is another conversation.)

The question is why, with so much of this information readily
available, one would bother to attend this conference. It is a good
question. My answer is that this conference allows me to get a sense
of the direction of things, the "zeitgeist" of this field - and also
to talk directly to the participants in the more informal parts of the
conference. Unexpected things happen and one picks up bit of
information or has other items reinforced. For instance, I got to hear
Dr. Chia talk for a few hours at dinner. What a pleasure this was! I
got to watch him "interrogate" a patient advocate about their patient.
Dr. Chia seeks out particular symptoms and circumstances that occur at
the onset of the illness. It is a bit like 19th century medicine - but
CFS/Me is a 19th century disease. And this form of questioning yields
answers for Dr. Chia.

I have been inclined towards Dr. Chia since I first heard him speak.
He has a forthright, unadorned quality that is makes you pay
attention. Dr. Chia has worked in the trenches for twenty or more
years, learning about this illness the hard way, and developing his
own resources to maintain and increase his research. Dr. Chia is
definitely onto something "specific" - in a field where so much is
elusive and speculative. If I were going to give a newcomer to this
field a bit of advice (and I do not have a whole lot to give) I would
recommend learning about Dr. Chia, his testing and his treatment. It
is a good bet, and perhaps you will get lucky.

At another point, I got to hear Dr. Cheney give an informal
mini-lecture on parts of his protocol: artusenate, minocycline,
wormwood, and cell signaling factors. In regards to this last item Dr.
Cheney related his enthusiasm about a new gel that he has made from
afterbirth material. Citing studies on hamsters, Cheney described a
process where non-stem cell material is extracted from stem cells and
injected back into the hamsters, curing them as if it were stem cells.
Dr. Cheney has made a similar gel from human afterbirth that gets a
very strong reaction on his Echo machine, much stronger than any
existing CSF. He is very excited about this.

I observed several individuals from the WPI doing their presentations
and establishing connections. I can assure you that the announcement
of the demise of the WPI is premature. They are moving faster than
ever. The WPI is on a trajectory that will leave its critics in the
dust. While others quibble over this and that, and lay traps to
distract them, the WPI are putting all that aside and focusing on the
task at hand. More specific and accurate testing is close at hand, as
is means to track improvement in patient's immune status, as well as
clinical trials using various existing anti-retroviral drugs. Peptide
T is still in the picture. (Another non-WPI source indicates that
GCMAF might be a player.) (Time will tell in all this and the
nay-sayers have put great effort into trying to cut off the funding
and grants for the WPI. In this they have been somewhat successful,
leaving it to the rest of us to do what we can to increase funding for
this important scientific research.)

The WPI is in the process of projecting and clarifying their mission
and of making collaborative connections with the international
community in a manner that has never been seen before in this disease.

Needless to say, this was a great conference.

Christopher Cairns

Tuesday, May 25, 2010

Biomarkers in Chronic Fatigue Syndrome: Evaluation of Natural Killer Cells

'Biomarkers in Chronic Fatigue Syndrome: Evaluation of Natural Killer
Cell Function and Dipeptidyl Peptidase IV/CD26'
Mary A. Fletcher1,2,3#*, Xiao R. Zeng1,2, Kevin Maher1, Silvina
Levis1,2, Barry Hurwitz3, Michael Antoni3, Gordon Broderick4, Nancy G.
1 Department of Medicine, University of Miami Miller School of
Medicine, Miami, Florida, United States of America, 2 Miami Veterans
Health Care Center, Miami, Florida, United States of America, 3
Department of Psychology, University of Miami, Coral Gables, Florida,
United States of America, 4 Department of Medicine, University of
Alberta, Edmonton, Alberta, Canada

Chronic Fatigue Syndrome (CFS) studies from our laboratory and others
described decreased natural killer cell cytotoxicity (NKCC) and
elevated proportion of lymphocytes expressing the activation marker,
dipeptidyl peptidase IV (DPPIV) also known as CD26. However, neither
these assays nor other laboratory tests are widely accepted for the
diagnosis or prognosis of CFS. This study sought to determine if NKCC
or DPPIV/CD26 have diagnostic accuracy for CFS.

Subjects included female and male CFS cases and healthy controls. NK
cell function was measured with a bioassay, using K562 cells and 51Cr
release. Lymphocyte associated DPPIV/CD26 was assayed by qualitative
and quantitative flow cytometry. Serum DPPIV/CD26 was measured by
ELISA. Analysis by receiver operating characteristic (ROC) curve
assessed biomarker potential. Cytotoxic function of NK cells for 176
CFS subjects was significantly lower than in the 230 controls.
According to ROC analysis, NKCC was a good predictor of CFS status.
There was no significant difference in NK cell counts between cases
and controls. Percent CD2+ lymphocytes (T cells and NK cells) positive
for DPPIV/C26 was elevated in CFS cases, but there was a decrease in
the number of molecules (rMol) of DPPIV/C26 expressed on T cells and
NK cells and a decrease in the soluble form of the enzyme in serum.
Analyses by ROC curves indicated that all three measurements of
DPPIV/CD26 demonstrated potential as biomarkers for CFS. None of the
DPPIV/C26 assays were significantly correlated with NKCC.

By ROC analysis, NKCC and three methods of measuring DPPIV/C26
examined in this study had potential as biomarkers for CFS. Of these,
NKCC, %CD2+CD26+ lymphocytes and rMol CD26/CD2+ lymphocyte, required
flow cytometry, fresh blood and access to a high complexity
laboratory. Soluble DPPIV/C26 in serum is done with a standard ELISA
assay, or with other soluble factors in a multiplex type of ELISA.
Dipeptidyl peptidase IV on lymphocytes or in serum was not predictive
of NKCC suggesting that these should be considered as non-redundant
biomarkers. Abnormalities in DPPIV/CD26 and in NK cell function have
particular relevance to the possible role of infection in the
initiation and/or the persistence of CFS.

Citation: Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, et al.
(2010) Biomarkers in Chronic Fatigue Syndrome: Evaluation of Natural
Killer Cell Function and Dipeptidyl Peptidase IV/CD26. PLoS ONE 5(5):
e10817. doi:10.1371/journal.pone.0010817

Editor: Derya Unutmaz, New York University, United States of America

Received: April 9, 2010; Accepted: May 2, 2010; Published: May 25, 2010

Copyright: © 2010 Fletcher et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source
are credited.

Funding: This work was supported by grants from the NIAAA: R21AA016635
(PI MA Fletcher); NIAID: R01AI065723 (PI MA Fletcher); CFIDS Assoc. of
America: (PI N Klimas); NIAID: UO1 AI459940 (PI N Klimas), NHLBI: RO1
HL65668 (PI B Hurwitz); NIAMD: R01 AR48932-01A1 (PI S Levis). The
funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing
interests exist.

* E-mail:

# These authors contributed equally to this work.

Monday, May 24, 2010

More on Lerner's Antiviral Research

Its rare to get good news on the treatment end but Dr. Lerner's latest
paper is full of it. The paper analyzes the progress of his patients
over the past 10 years who have undergone long-term antiviral
treatments for herpesviruses. The results were surprising; Dr. Lerner
reported that about  30% of his patients had near or full recoveries,
many others returned to normal functioning (ie they were able to work
in a sedentary job full time) and about 25% did not respond. Treatment
effectiveness was a function of illness duration (yes, it does matter,
at least somewhat, how long you been ill) and treatment duration (when
he says longterm he does mean longterm - probably at least a year for
many patients). The paper also suggested that a significant number CFS
patients also have another infection such as Lyme disease that need to
be treated for that infection as well.

It's an exciting paper - we don't know what percent of
patients these therapies apply to - and a rigorously controlled
treatment trial is needed to fully assess their effectiveness -  but
this paper is very good news for CFS patients in a treatment arena that
is often dominated by CBT/GET etc. It should spur more research and,
hopefully, federally funded treatment trials. 

Check out Learning CFS: the Lerner Longterm Antiviral Study Succeeds  -

Dr. Lerner's Antiviral Research

'Subset-directed antiviral treatment of 142 herpesvirus patients with
chronic fatigue syndrome'
A Martin Lerner1, Safedin Beqaj2, James T Fitzgerald3, Ken Gill4,
Carol Gill4, James Edington4
Published Date May 2010 , Volume 2010:2

1Department of Medicine, William Beaumont Hospital, Royal Oak; 2Wayne
State University School of Medicine, Detroit; 3Department of Medical
Education, University of Michigan Medical School, Ann Arbor, Michigan;
4The Dr A Martin Lerner Chronic Fatigue Syndrome Foundation, Beverly
Hills, Michigan, USA

Purpose: We hypothesized that chronic fatigue syndrome (CFS) may be
caused by single or multiple Epstein–Barr virus (EBV), cytomegalovirus
(HCMV), or human herpesvirus 6 (HHV6) infection. To determine if CFS
life-altering fatigue and associated findings including muscle aches,
tachycardia at rest, chest aches, left ventricular dysfunction,
syncope, and elevated herpesvirus serum antibody titers are reversed
by long-term subset-directed valacyclovir and/or valganciclovir.

Patients and methods: Data were collected at physician visits every
4–6 weeks from 142 CFS patients at one clinic from 2001 to 2007. To be
included in this study, patients had to be followed for at least six
months. The data captured included over 7000 patient visits and over
35,000 fields of information. Severity of fatigue was monitored by a
validated Energy Index Point Score® (EIPS®). Baseline and follow-up
serum antibody titers to EBV, HCMV, and HHV6, as well as coinfections
with Borrelia burgdorferi, Anaplasma phagocytophila, Babesia microti,
and antistreptolysin O, 24-hour ECG Holter monitors, 2D
echocardiograms, cardiac dynamic studies, symptoms, and toxicity were
captured and monitored. International criteria for CFS plus a
specifically designed CFS diagnostic panel were used.

Results and conclusions: The Group A herpesvirus CFS patients (no
coinfections) returned to a near-normal to normal life
(P = 0.0001).
The long-term EIPS value increased (primary endpoint, P < 0.0001) with
subset-directed long-term valacyclovir and/or valganciclovir therapy.
Secondary endpoints (cardiac, immunologic, and neurocognitive
abnormalities) improved or disappeared. Group B CFS patients
(herpesvirus plus coinfections) continued to have CFS.

Sunday, May 23, 2010

New Fibro Site

Dear Friends:
I am pleased to let you know that the website, which was built in
support of the Fibromyalgia: Reconnecting to What Matters patient
information sessions, is now LIVE! Please visit  where you'll find the active
site.  Please also note the link to the National ME/FM Action Network
on the left hand side. You will note that our logo is missing at the
moment but we hope to have that amended shortly.

Although these patient sessions are presently scheduled for Ontario
only, that will be amended in the future so be sure to check in to
see new information as the site develops.

Lydia E. Neilson, M.S.M.
Chief Executive Officer
National ME/FM Action Network
512 - 33 Banner Road
Nepean, ON K2H 8V7 Canada
Tel. (613) 829-6667     Fax (613) 829-8518