Friday, July 19, 2013

English transcripts of ME/CVS Vereniging's Prof. Dr Kenny De Meirleir

English transcripts of ME/CVS Vereniging's Prof. Dr Kenny De Meirleir's
ME/CFS videos, numbers 1-13

http://bit.ly/1aYga4T i.e.
http://www.mediafire.com/download/syufbda0dpnuadj/wvp-Web_seminar_1-13_KDM.pdf

(407KB, smallish file in today's terms)

... ---------
It is permitted to disseminate all transcripts within the project
Wetenschap voor Patiënten (Science to Patients), under the explicit
condition that the source ME/cvs Vereniging,
http://www.me-cvsvereniging.nl/ is clearly mentioned.

ME/CFS and Polio -- similarities that should not be ignored

 
 
"Among the first signs of polio are fatigue, vomiting and back pain." 
 
Hmm, same first symptoms I had.  But because most US doctors haven't seen a case of polio since the vaccine came out in the late 1950s, it wouldn't have rung a bell with any of the ones I saw, all of whom had been to medical school after polio was considered eradicated in the US..
 
It intrigued me when I first heard the proper name, Myalgic Encephalomyelitis, that it shares a root word with poliomyelitis.  I have a friend with polio, and learned by experimenting that what her doctors were telling her (to rest and not overdo) worked better for me than the usual exhortation "no pain, no gain."
 
The more I read about polio, the more I saw commonalities with what I experienced myself. 
 
I have a distinct recollection of lining up to receive my polio vaccine on a sugar cube as a child.  But the vaccine only protects against the three most potent variants of the disease, leaving several dozen varieties you're not protected against.  No one ever tested me for polio; not only it wouldn't have crossed their minds in the 1980s, but I wasn't paralyzed. 
 
If it was a strain of polio, the aftereffects were seemingly mild. 
 
Until a dozen years of pushing my body to work full-time and do all the housework myself caught up with me; in 2000 I did start experiencing paralytic muscle weakness until I learned to stay within my limits.  Half an hour of typing -- no pushing through, "I'm almost done", finishing what I was writing had to wait until I'd rested my hands for a couple hours.  Walking short distances -- no pushing through, "I'm almost home" -- when I reached my limit, I found the nearest place to sit down.  If I was lucky, I was near a cafe where I could sit in air conditioning for an hour; if not, I sat on the sidewalk in as much shade as I could find. 
 
Fortunately, I do have that friend with polio, so I steadfastly defended my decision to rest muscles before they reached paralytic muscle weakness against ignorant doctors and laypeople who insisted that I had to exercise my way back to health.  Been there, done that, saw that it made the paralytic muscle weakness last longer.

Meanwhile, those who had never seen that happen insisted that they were right, I was wrong, and that my refusal to exercise my way back to health was pure laziness ... unwilling to accept that I would have liked nothing more than to go out for a long walk or dancing the night away, but my body rebelled -- not only my legs became too weak to hold me up, but my other symptoms increased.  Not for a few hours, but for weeks afterward.  The more I toughed it out, the sicker I got.
 
"Then there's polio: Only 223 cases were reported last year, down from 350,000 in 1988. Islamist extremists in Nigeria and Pakistan have murdered vaccination workers, but the disease is still inching toward eradication."
 
 
 

Monday, July 15, 2013

CFS and IBS

Source: Clinical and Experimental Gastroenterology
Vol. 6, Pages 101-107
Date: July 3, 2013
URL: http://www.dovepress.com/getfile.php?fileID=16639
http://www.dovepress.com/chronic-fatigue-in-patients-with-unexplained-self-reported-food-hypers-peer-reviewed-article-CEG


Chronic fatigue in patients with unexplained self-reported food
hypersensitivity and irritable bowel syndrome: validation of a
Norwegian translation of the Fatigue Impact Scale
---------------------------------------------------------------
Ragna Lind(1,*), Arnold Berstad(2), Jan Hatlebakk(1,3), Jorgen
Valeur(2)
1 Department of Medicine, Haukeland University Hospital, Bergen,
2 Unger-Vetlesen Institute, Department of Medicine, Lovisenberg
Diakonale Hospital, Oslo,
3 Department of Clinical Medicine, University of Bergen, Bergen,
Norway
* Correspondence: Ragna Lind
Department of Medicine, Haukeland University Hospital, N-5021
Bergen, Norway. Tel +47 5597 6103. Email ragna.lind@med.uib.no

Received: 26 March 2013
Accepted: 28 May 2013
Published: 04 July 2013


Abstract

Background
Patients with unexplained self-reported food hypersensitivity and
irritable bowel syndrome (IBS) suffer from several health complaints,
including fatigue. The aim of the present study was to validate a
Norwegian translation of the Fatigue Impact Scale (FIS), and to assess
the impact of fatigue in patients with self-reported food
hypersensitivity and IBS, as compared with healthy controls.

Methods
Thirty-eight patients with unexplained self-reported food
hypersensitivity and IBS, who participated in the validation of the
FIS completed the following additional questionnaires: the Short Form
of Nepean Dyspepsia Index for assessment of quality of life, the
Subjective Health Complaint Inventory, and questionnaires for
diagnosis and severity of IBS. Impact of fatigue was studied in 43
patients with unexplained self-reported food hypersensitivity, 70%
diagnosed with IBS, and 42 healthy controls.

Results
Cronbach's alpha for the FIS was 0.98, indicating excellent agreement
between individual items. Scores on the FIS correlated with scores on
the Short Form of Nepean Dyspepsia Index (r=0.50, P=0.001),
indicating good convergent validity, and were higher in patients
(median 85.0, interquartile range 36.8-105.3) than in controls (median
14.0, interquartile range 3.0-29.0, P=<0.0001).

Conclusion
The Norwegian translation of the FIS performed excellently
in patients with unexplained self-reported food hypersensitivity and
IBS, with patients reporting significantly more impact of chronic
fatigue than healthy controls.

Keywords: irritable bowel syndrome, fatigue, food hypersensitivity,
quality of life

--------
(c) 2013 Dove Press

Clinical Misdiagnosis project update

Permission to Repost



Hello there,



Some months ago I embarked on trying to find out about issues of clinical
misdiagnosis surrounding Chronic Fatigue Syndrome in the NHS since the late
1980's when Dr Simon Wessely took on CFS and rigorously promoted CFS and
then CFS/ME in the NHS and in the media.



Here are my present findings….




There is no doubt that patients with rare diseases with a remarkably similar
symptom set as that suffered by people with ME have been wrongly diagnosed
as having CFS or CFS/ME since 1988.



The majority of those being wrongly diagnosed are being misdiagnosed by GP's
and general specialists.



Patients are in some instances living for decades with a clinical
misdiagnosis because their case was never escalated upwards to
super-specialists at regional research centres.



Putting it bluntly – nobody knows just how many patients currently labelled
as having CFS or ME or CFS/ME or even Fibromyalgia have been and are now
living with a clinical misdiagnosis.



I have been collecting statements from patients on a Behçet's forum and
those who have contributed so far are all angered that they had to go
through what they went through before they finally got a re-diagnosis….



All had been touched by the misdiagnosis of CFS or "Chronic Fatigue" or ME.



It is a simple and unchallengeable fact that GP's and general specialists
are not experts in identifying rare auto-immune diseases such as Behçet's
disease or Ehlers Danlos Syndrome or Familial Mediterranean Fever amongst
other complex and relatively rare conditions.



However, all of these conditions are amenable in some way to specialist and
super-specialist level treatment that is denied to anyone who has been
misdiagnosed with "CFS/ME" or Fibromyalgia.



Below I have reproduced the statements I have received so far.



I have removed the contributors names but should anyone wish to investigate
individual cases further I can supply contact details or liaise with the
contributor privately.



I am still collecting statements so this is very much the start of something
that will grow.



My recent cease and desist e.mail



As some of you here will remember, I recently sent out a "cease and desist"
e.mail to all the relevant liaison psychiatrists – lead by Professor Sir
Simon Wessely and including Professor Peter White, Professor Michael Sharpe
and Professor Trudy Chalder along with Dr Esther Crawley and Dr Vincent
Deary.



They may have scoffed at that e.mail and had a laugh about my intent or they
may all have just ignored it and carried on regardless.



I would be grateful for anyone reading this to contact me either via
MEActionUK or privately should they see any further claims in any future
research studies from UK liaison psychiatry making claims that the list of
symptoms they perpetually set out are perpetually "medically unexplained."



As I pointed out to them all, the symptoms they quote in study after study
are fully medically explainable when related to Behçet's disease and other
rare diseases.



As I pointed out to them all, Behçet's disease and other rare diseases can
and do present themselves with few or even no obvious visible signs that a
GP or a general specialist could observe at an out-patient clinic.



This is precisely how a patient becomes a victim of clinical misdiagnosis.



Should anyone reading this spot any future claims that the many symptoms of
ME or indeed CFS or indeed Fibromyalgia are "medically unexplained physical
symptoms" I would like to see such references be they future research papers
or media articles.



I have support on this list and back channel within and without the ME
community to lodge formal complaints to the relevant professional bodies
about any doctor who makes any further claims with full knowledge that the
"invisible" symptom set relating to Myalgic Encephalomyelitis or "CFS/ME"
can be medically explained when applied to the almost identical "invisible"
symptom set shared by rare auto-immune inflammatory diseases.



We can all take a stand on this issue and I have no doubt that we can stop
these doctors seriously misleading , misrepresenting and misinforming the
medical profession as a whole as well as the public at large.



For over 25 years the use of the diagnosis of CFS and "CFS/ME" has acted
like a massive dragnet scooping up all manner of patients into a truly
heterogeneous patient group.



As with any indiscriminate dragnet, patients who were never originally
intended to caught up have been caught up because nothing was put in place
to facilitate an accurate differential diagnostic process.



Any doctor with a medical degree and 12 months clinical practice has been
able to diagnose a case of "CFS/ME" yet the majority of those diagnosing
doctors are not sufficiently qualified or experienced to spot cases of rare
diseases.



Because of the diagnosis of "CFS/ME" the dragnet of patients are not being
referred on to super specialists and instead patients are all being shunted
into a cul-de-sac where CBT and Graded Exercise Therapy are persisting as
best practice treatments that will be of no use or possibly harmful to
patients carrying a clinical misdiagnosis – especially misdiagnosed patients
who are being denied pharmacological treatments.



In this respect I am now of the view that the NHS and Liaison Psychiatry has
been seen to be negligent in protecting an unknown number of vulnerable and
seriously ill patients from being clinically misdiagnosed since 1988.



Should anyone reading this know of any other forums such as Facebook where
misdiagnosed patients could be put in touch with me then by all means do
pass this e.mail on and let anyone interested have my e.mail address (
stephen . e. ralph @ btinternet . com )



I will post a further update when I have made further progress.



Sincerely,



Stephen Ralph DCR(D) Retired.



Statements from patients subjected to a clinical misdiagnosis



24th May 2009



Dear Stephen,



I hope you do not mind me contacting you; I was very interested to read your
comment on the New Scientist website in reply to the interview with Prof.
Wessely and then found your email address from the ME Action UK website.



I have been seriously ill since 1997 and for most of that time have had a
diagnosis of CFS or somatisation disorder (depending on which doctor I was
seeing). My health continued to deteriorate and about two years ago I
finally managed to get some doctors to take me seriously after my health
problems became severe enough to require hospitalisation.



I then went through a long journey of medical investigations which concluded
with the fact that I have Behcet's Disease and Ehlers-Danlos Syndrome.



For a long time I have been of the opinion that many people diagnosed with
CFS or ME probably actually have other illnesses (either currently known
about or not). Whilst going through my diagnosis for Behcet's it became very
clear to me quite how many serious, but often treatable, physical illnesses
there are with the same groups of symptoms. Many of these are complicated to
diagnose and most patients given a diagnosis of CFS are not thoroughly
investigated for other possible conditions.



I can accept that somatisation disorder and Wessely's form of CFS exist, but
I think relatively few patients have these disorders. I strongly feel, that
for the majority of patients with serious physical conditions causing a
multitude of symptoms, the psychological treatment approach is nothing less
than psychological torture.



Reading your comment made me wonder how many other people with Behcet's
disease have been put through this.



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



30th April 2013



Hi everyone,


Just to let everyone know that myself, my son aged 21 and my daughter aged
12 have been diagnosed with Ehlers Danlos Syndrome type 3 at UCH by
Professor Graham and my daughter with hypermobility at Gt Ormond St.



My son and myself have also been diagnosed with P.O.T.S. by Professor
Mathias at St Mary's Paddington and I have the added pleasure of
dysaunotomia.



My daughter is awaiting a referral for P.O.T.S symptoms backed up by Prof
Graham after I relayed my feeling that Gt Ormond St had not taken me or her
seriously.

I was diagnosed with M.E. by William Weir in 1990 and my children have a
history of migraine, febrile temperature, severe growing pains, fatigue,
nausea and dizziness.



None of us have ever dislocated joints, have overly stretchy skin or can do
the splits!



Am I angry?



I'm angry about the kids.



I have been accused of projection of symptoms and both my kids were referred
and assessed by the child and adolescent mental health service, with no
action required!



For my 12 yr old who has the most severe symptoms of the two it's hugely
important as she will not be treated in the same way I have endured for the
last 20 odd years, but of course for a mother it's a hollow victory.



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



6 May 2013



Hi Steve



Good on you (for working on your misdiagnosis project)



1) what was the misdiagnosis?



Coeliac Disease (this was before the new blood tests were available). I had
a spike in my coeliac enzymes and was told I had coeliac disease for about 2
years before that was discarded.



Also because of the punched out lesions etc a few dermatologists labelled me
as doing 'self mutilation' but as the specialists now are saying I was
presenting with oral and genital ulcers at the same time and as one doctor
said that should have been a 'red rag to a bull'.



Years ago I was told I had chronic fatigue but one doctor said that was a
symptom not a diagnosis which makes sense as a lot of diseases cause chronic
fatigue.



2) how long did you have to struggle with that misdiagnosis? - 10 years



Hope your project helps others.

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



7 May 2013



It took 20yrs to diagnose my behcets. Kept being told that joints were down
to arthritis and general wear and tear, Fatigue was down to too many late
nights and ulcers down to bad oral hygiene and genital ulcers were herpes.



I ended up in hospital with another problem, where after talking to drs
(different hospital) they realised , with all other problems, it all added
up to behcets. Since receiving the right treatment I have improved and for
most of the time it stays under control although still have flares of
differing degrees.



In a way I was lucky to be in the right place at the right time when I got
diagnosed, as I do really think that if I had continued to see someone at
the first hospital I would still be undiagnosed and not on the correct
medication.



With regards to my bones, I was found to have very little wear and tear and
a higher than average bone density (which helps while being on long term
steroids)

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



13 May 2013



Hello Stephen,



My medical history has spanned a continuous period of disability and ill
health since approximately 1989. However it is possible that I have in fact
been ill since birth.



My first diagnosis and recognition of muscle weakness and other debilitating
symptoms was also one of Chronic Fatigue Syndrome. I was basicly left to get
on and find my own solutions to my condition which progressed to my being
virtually bedridden all the time.



By 2000 I was retired from work in the Local Authority as I was given no
assistance to be able to return. I was forced to accept retirement under a
psychiatric cause because the Local Authority at that time refused to accept
that Chronic Fatigue Syndrome existed and could be a permenant condition.



However I was then rediagnosed with Behcets Disease but still not given
treatment as the Doctors I saw didn't connect the muscle weakness and other
neurological Symptoms to the behcets. This still went under the diagnosis of
Chronic Fatigue Syndrome and thus was ignored. I then had an EMG test on my
right eye due to facial drooping which was then diagnosed with Myasthenia
Gravis but the further tests to confirm Generalised Myasthenia were negative
and so the diagnoses of Myasthenia Occuar was given.



The diagnosis of Behects was withdrawn in favour of it being Chronic Fatigue
Syndrome and Myasthenia Occular.



I was not given any medication for the myasthenia and by this time I had
lost my balance with vision, speech difficulties, incontinence, urine
retention, extreme pain and spasm and spasticity, numbness, tingling and a
whole realm of under skin lumps, pustules etc. I was also suffering weak
breathing muscles and had also been diagnosed with Sleep Apnea.



By fluke around 2007 I attended my local hospital eye department who
diagnosed me with a stroke but this couldn't be proved on MRI. I was
referred to a new Neurologist who diagnosed me with Neurobehects and ataxia.



The eye department further diagnosed and undiagnosed 5 other vision problems
including macular, optic neuritis, myasthenia. But then decided it wasn't
any of these so have left me with my vision deteriating at a fast rate.



I was referred back to my rheumatologist in another hospital and taken into
hospital. A different Neurologist [who I had never met and didn't even
examine me] said there was nothing wrong with me at all and it was "all in
my mind". I was referred to a psychiatrist for sommertisation but fought
this referral and lack of diagnosis through the hospital complaints
procedure. It was then changed back again to Behcets Disease,



Myasthenia Occular, Chronic Fatigue Syndrome, sleep apnea and a whole realm
of other symptons. The list took up the first page of the doctors reports
which naturally caused problems when attending new Dr's or hospitals.



My illness was so bad at one time that I was confined to bed, unable to
speak with memory loss and cognative problems. I couldn't eat and drink and
thought I would die. I errupted in lumps under the skin and was rushed into
hospital where I obtained the first treatment/medication I'd ever been
given. Prednisolone was given at extremely high doses and I picked up enough
to be sent home.



The Doctors I had been seeing continued on with the prednisolone and added
Immune Suppressants which have had there own set of problems.



Since then I still have numerous problems with my health some of which is
attributed to behects and some which is either just ignored or passed over.
This is still the same today even though now it is accepted I do have a
medical problem there is nearly always an argument between doctors with me
in the middle. Each time I have another symptom I am referred to yet another
specialist who looks into my problems but cannot diagnose me and never talks
to my other doctors to get a consensous. I must have seen around 12
different consultants in the last year alone. There are mistakes and
incorrect information all over my medcial file which has now made it
impossible.



This in my opinion has made me more ill and I still am not really convinced
they have it right.



You may or may not be surprised that it was at Guy's and St THomas's
Hospital neurology department I was

re-diagnosed with Chronic fatigue Syndrome. Around 2008 The psychiatrist I
saw to confirm this was attached to the CFS clinic at Kings. At the time all
the other symptoms I was experiencing [i.e balance, speech, drooping facial
muscles, incontinence etc etc] were written in my psychological report as
"Unexplained Medical Symptoms" and brushed aside.



I was meant to attend Kings CFS clinic but my PCT refused funding as there
was a clinic at my local hospital. I attended my local clinic and saw a
clinical psychologist who was appalled at my story and wrote a 5 page report
stating that I did indeed have the symptoms of CFS but that she had never
seen the additional symptoms that had been written off as "Unexplained
Medical Symptoms" within their clinic and she hoped they would continue to
be investigated.



She copied this to my Neurologists at Guy's and had 10 sessions at a CFS
course at my local hospital for learning how to pace myself, no other
assistance or treatment was given. All the other people at these sessions
were newly diagnosed and completely shocked at seeing me in such a state. It
didn't help them to know I had been diagnosed with CFS since 1989/90 and it
didn't help me because this was targeted at people newly diagnosed, most of
whom were still able to work and predominantly had the fatigue element of
CFS.



At my next appointment at Guy's when I saw the neurologist again she stated
I'd had a miraculous recovery and signed me off her books. Of course I
hadn't had a miraculous recovery at all. But moreso I thought it was
punishment for the clinical psychologist challenging her diagnosis....I was
a trouble maker in otherwords.



I was therefore left to get on with it once again and by then I was so ill I
couldn't get out of bed and was moved in to the back room of my house and
stayed there for around 2 years trying to fight my own way out. It was by
fluke at my local hospital again that the eye department did a field test on
my eyesight and found out I had gone blind down 1 side of my vision. They
thought i'd had a stroke and at the time I was relieved to hear this [sounds
strange but at least it was some explanation]. I told them of all these
other symptoms and was referred to a neurologist again who diagnosed me with
Neurobehcets. He referred me back to Guy's and St Thomas's Rheumatologist
who had previously diagnosed me with behcets.



This Consultant took me into St Thomas's for 5 days and it was during this
stay that a consultant from the Guy's Neurology Department [again] came to
see me for 5 minutes and refused to examine me stating that I had a mental
health problem and not a medical one. He wrote to all my Dr's telling them
this and stated that he would not agree with my having any medication at
all. Further unbeknown to me he wrote a referral to a Psychiatrist attached
to guy's stating that he thought I had sommertisation. Luckily one of the
Rheumatology Student Dr's was so appalled that he secretly copied me in on
the letter's....otherwise I wouldn't have known until the psychiatrists
appointment had come through.



Once again I was left with no treatment and became stuck between 3
consultants basicly arguing amongst themselves. I was having to take photo's
of my private areas to show the blisters and ulcers and take them with me to
put on file. I was terrified for my life that I would be written off with a
label of "sommertisation". Another twist of fate was found as the PCT
refused the funding for the psychiatrist. I had written to them explaining
that I'd had no previous knowledge of the referral and was in the process of
complaining about the Neurologist who had referred me. This was enough to
put the PCT off from funding it.



The rheumatologist at St Thomas's stuck with me and agreed that I didn't
need to see a psychiatrist and I am still with him and the neurologist at my
local hospital.



As I said before, my problems still exist within the medical system but can
you imagine what might of happened to me if the Neurology Department at
Guy's had got their own way and I got the label of "Sommertisation".....it's
bad enough now, but I dread to think what it could have been.



sorry if I have gone on....but this example is still just a short version of
what has happened to me in the medical system.....I have thought of getting
a Doctor to look through all my medical files and try to piece together my
medical history because the files are in such a mess with lots of
unaccuracy's, mistakes and things......but who could I trust to do that ????



I had the drive to fight before but I am so unwell now that tackling these
things makes me more ill.



Sorry if I went on but you know what it's like once you get going.....this
is only a short version.



I admire someone like you and hope you gain headway in this......if there is
anything you think may help...let me know.



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

13 May 2013



Hello Stephen,



I was told that l perhaps had ME and was treated like a time waster for
years until l became so ill that l could barely walk and lost a huge amount
of weight. l was unable to eat as my joints in my body were so painfull that
even my jaws were so sore l couldn't chew food.



When l developed genital ulcers my doctor told me to go to the VD clinic in
the Royal Voctoria Hospital in Belfast and it was there that an imunoligist
diagnosed Behcets. l had to fight for benefits and was told by a board
doctor that if l could eat bread and drink water l would be fine.



l wrote to the chief medical officer of Northern Ireland and he replied that
the doctors comments were perfectly correct. lt wasn't until the diagnoses
of Behcets that l was given a low rate of DLA.



l am now being told by ATOS that l am fit for work despite being almost bed
ridden most days and l am actually seeing my doctor today to get a letter to
say l am unable to attend a work activity club. For some reason Behcets
suffers are not understood. lt isn't a visual illness and is not outwardly
evident so most individuals feel it doesn't exist.



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

13 May 2013



Wow you guys have had it tuff and still smiling .



Well hear is my little boring story.



i think it all started with me when i was about 5 that is when i had my fist
tooth taken out .by 8 i had all my front teeth out and had false teeth pit
in from then to now all ways had bad teeth and i am just about to have an op
to have the last 4 ( all i have ) out and fixed . i never smiled as a kid
well not even now .



then when i was about 8 or 9 i suffered tummy pain all the time my mother
was told my body was changing i was growing up it was nothing just some
tummy ulcers given some med's and told i would grow out of them . then the
bad headaches started and over my teen years they just grow and grow i did
not think pain could be so bad . the Dr put me on the pill to see if that
would help but no .



at 19 i was married headaches pain still growing had fist baby at 23 next 24
from then on my headaches went to migraines i think i was given every
treatment and drug known to man eg: cryogenics, morphine,pethidine,lidocaine
infusions ,opium ,marcaine injections,(in to head face eye ) grass ( that
made me sick ) and there were a few more things . i have just trend 50 and
can;t think of a day i have not had a headache .



in my late 30th's i was told my joint pain was arthritis and you will just
have to live with it . 7 days ago it has been 7 years i was told i had BD
now all the pain and funny things that have happen to my in my life and i am
would think there is a lot more to come i can deal with most things but it
is the pain I have that i can't handle 24/7 you can only cry so much .



but i will not let this bet me . i hope this helps in some little way if you
wont to know more just ask .



thank you



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

15 May 2013



Hello Stephen,



I had numerous bouts of 'tonsillitis' from a very young child but this and
repeated mouth ulcers were the only problems I had until aged 24, when I had
a complete physical collapse.



It was diagnosed by a hospital consultant as ME (very fashionable 25 years
ago.) Looking back I can see that it was, of course, Behcets - joint pains,
exhaustion, headaches, muscle weakness, ulcers, stomach problems,
memory/concentration problems etc.



After complete bed rest for nearly a year I recovered to a reasonably good
extent, though never back to the energetic person I had formally been. I
changed my lifestyle accordingly and things were okay until a couple of
years after the birth of my 2nd child. Then everything started up again,
with the joint pains and ulcers (now genital as well) becoming severe.



My GP was very sympathetic and sent me for lots of tests, including for STIs
(which I knew wasn't the case!) Eventually a biopsy was done on one of the
genital ulcers by a consultant gynaecologist - a grim procedure but the
biopsy result came back as "entirely consistent with



Behcets Disease", so that - along with the other associated symptoms - meant
I was given the diagnosis of Behcets with a lot of certainty on the
consultant's part. What a relief, after more than a decade of knowing that
ME was just not correct.



However, my GP refused to accept the consultant's diagnosis. To say I was
upset is an understatement! I wanted to understand what I actually had, and
how it could be treated so I could try to get my life back on track.



The GP was keen for me to 'accept' that I had Chronic Fatigue Syndrome, as
he termed it. He then decided I might have Lupus. Or a stomach ulcer.
Basically, he said, he wanted us to keep an open mind in case the consultant
was wrong - he said that he had other patients whose diagnosis changed and
they had found this very difficult. He felt it did not matter what the
disease was called anyway...I tried to explain that it mattered very much to
me, the patient - but could not get through to him.



I think this GP was well meaning, but for me it was a disaster. I felt like
I was hitting my head against a brick wall, and using up so much energy I
didn't have...it was a very upsetting time.



Anyway, I changed GPs and have had no problems since then - with GPs or
consultants. Some may not know much about Behcets but they accept the
diagnosis and I am treated accordingly :-)



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

16 May 2013



I also experienced a similar thing a couple of years ago, prior to my
Behcet's diagnosis. I was told by a rheumatologist that it did not matter
what the name of the disease was. She told me that what counts and is
important is for me to feel better... but what these doctors seem to forget
is that without knowing exactly what disease it is, then how can you get
better without the proper treatment?



For people who are supposed to be very intelligent professionals, they
sometimes act clueless. I could kind of see her point in a small way; but
its not only important because of the need for proper, disease-specific
treatments, but also for our own peace of mind.



Without knowing exactly what it was that I had that was making me so sick
and causing so much pain, I was so scared and full of so much anxiety.
Sometimes I was so afraid to go to sleep at night because I had no clue if
my mysterious illness was life-threatening or not.



Also, without having a positive diagnosis to label my mysterious illness, I
often doubted its true existence and would go through weaker moments when I
believed I was just imagining it all or was going crazy.



The doctors in the emergency room would very quickly treat me as a "drug
seeker" especially because at that time, I ended up in the ER with severe
pain attacks, but had no known reason for the ongoing pain. I even had a
"pain specialist" who dealt with weaning people off painkillers come see me
during one of my bad Behcet's attacks-- she actually stood there at my
bedside telling me that I needed to stop demanding pain meds before I become
fully dependant on them-- the dumb thing was that I wasn't even on around
the clock pain management at home during this time and that's why I ended up
in the ER when it would get bad enough.



She couldn't grasp the understanding that I was truly experiencing as severe
of pain as I was, mainly just because I didn't have a diagnosis of a
disease. So I very much agree that getting a proper diagnosis is vital to a
person's well-being, both physically and emotionally.



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

Statement from the author



Last year I received an e.mail from a subscriber to Co Cure www.co-cure.org
who had read one of my articles about medical misdiagnosis.

The writer told me she knew of a 19 year old woman in Australia who had died
from untreated Behçet's disease because the patient had been wrongly
diagnosed with Chronic Fatigue Syndrome.



Several years ago whilst I was fighting my re-diagnosis battle I had a
lengthy conversation with a woman in London who was volunteering on the
Behçet's Syndrome Society helpline.



This woman told me that she went for a little over 10 years with the wrong
diagnosis of Chronic Fatigue Syndrome (CFS).



Having made prior attempts to have her CFS diagnosis overturned, her
diagnosis was only changed to Behçet's syndrome when she suddenly lost the
total sight in her left eye and the partial sight in her right eye.



It was only when this woman became almost totally blind did the medical
profession start taking her "invisible" symptoms seriously in the context of
an autoimmune vasculitic disease.



At that time I was told by the Behçet's Syndrome Society on many occasions
that Chronic Fatigue Syndrome was the most common misdiagnosis for cases of
Behçet's disease amongst their membership.



In January 2013 during an e.mail exchange with Professor Sir Simon Wessely,
he revealed to me that he could not say whether or not he had ever seen a
case of Behçet's disease pass through his out-patient clinic.



Recently I joined a forum for people like me who have Behçet's disease and I
asked a question about clinical misdiagnosis.



The replies I received are all printed below however I have removed anyone's
name to protect their privacy.



All those who have contributed knew that I was working on a misdiagnosis
project.



My project started off purely dealing with Chronic Fatigue Syndrome being
wrongly diagnosed in patients who suffer Behçet's disease.



However, I now know that there are other rare conditions that are also being
wrongly diagnosed as Chronic Fatigue Syndrome including Familial
Mediterranean Fever (FMF) and Ehlers Danlos Syndrome (EDS).



Any single clinical misdiagnosis can be devastating for the patient and
their families due to the fact that the correct treatment, medication and
therapies are denied those who are medically misdiagnosed.



In my own case, my parents had to become my full time carers for 8 years
when I became 75% bedbound and 95% housebound from the severity of my
symptoms.



My illness forced my Mum and Dad to move house to a different region so we
could afford a property large enough for me to have my own bedroom as I had
been living in their lounge that had been turned into a bedsit with blacked
out windows.



Patients die due to misdiagnoses yet the doctors involved do not take it
seriously unless such cases end up with the patient dying and the case being
taken to Court.



By and large, doctors get away with making misdiagnoses and are rarely ever
held accountable for their medical mistakes that can condemn a patient for
decades of unneeded suffering.



The patient has absolutely no protection as you will see from reading the
statements I have printed below.



Something needs to be done and a line needs to be drawn in the sand.



This situation – an open wound in the NHS - needs to be brought to an end.



Today, patients are now being routinely misdiagnosed by doctors
insufficiently qualified or experienced to recognise complex biomedical
autoimmune and neuroimmune diseases.



These doctors are empowered with the benign psychosocial diagnosis of
Chronic Fatigue Syndrome to enable them to make those misdiagnoses.



Back in 1988, Chronic Fatigue Syndrome (pioneered by the then Dr Simon
Wessely) was introduced to the NHS in a totally uncontrolled fashion.



Any doctor - be they a GP or a general specialists - became able to diagnose
a case of Chronic Fatigue Syndrome yet only a handful of super-specialists
here in the UK are fully competent to recognise and diagnose relatively rare
diseases such as Behçet's disease, EDS or FMF.

Instead of patients being referred upwards to regional super-specialist
centres; patients who need this sort of referral are instead being told they
have CFS and are being shunted sideways into a dead end cul-de-sac.



As a retired diagnostic radiographer it is my view that those in charge of
vigorously proliferating CFS and then ME/CFS across our National

Health Service should have firstly checked to ensure that their definition
of Chronic Fatigue Syndrome relating to the symptoms they claim to be
"medically unexplained physical symptoms" did not partially or wholly
overlap the identical set of symptoms relating to diseases that GP's and
general specialists would be unqualified to recognise and correctly diagnose
themselves.



Those in charge of CFS should have given the rest of the medical profession
from GP level upwards a sort of "watch list" so that doctors who may not
know much about BD, EDS or FMF amongst other rare diseases were aware of all
the alternative diagnostic possibilities.



I have established from Professor Sir Simon Wessely that he and his
colleagues never did take a look to see if their "medically unexplained
physical symptoms" effectively smothered patients presenting with diseases
that manifest the same set of "invisible" symptoms whilst presenting with
few or even no visible signs.



In this respect, twenty five years ago when Chronic Fatigue Syndrome came to
the NHS, this diagnosis alone "broke" the well established and respected
process of accurate differential diagnosis and the accompanying process of
upward referral to regional super-specialist centres.

After 25 years of clinicians medically misdiagnosing patients because of the
availability of CFS, nobody knows how many patients have become innocent
victims of those who still vigorously promote Chronic Fatigue Syndrome as a
functional psychosomatic disorder in the present day NHS.



As an indicator to just how widespread this situation has become; the
ability to correctly diagnose and treat cases of Behçet's disease was so bad
that only last year the Behçet's Syndrome Society succeeded in setting up 3
specialist centres across NHS England.



These super-specialist centres rely upon GP's and general specialists being
able to recognise cases of Behçet's disease when such cases may not present
with the stereotypical visible signs of mouth and or genital ulcers.



As Behçet's disease can present with no visible signs on examination, it is
still be the case that GP's and general specialists will unwittingly
misdiagnose patients with CFS until there is a fundamental change to the
present differential diagnostic process that puts Chronic Fatigue Syndrome
front and centre as a benign diagnostic option for "complex" cases that
appear to a GP or a general specialist to have no apparent cause.



Yours sincerely,



Stephen Ralph DCR(D) Retired.



(Clinically misdiagnosed with CFS from 1996 to 2008)



27th June 2013.



stephen . e . ralph @ btinternet . com
<mailto:stephen.e.ralph@btinternet.com>



Proven Treatments for CFS and Fibromyalgia

http://bipolarnews.org/?p=1929

Proven Treatments for Fibromyalgia and Chronic Fatigue Syndrome
July 12, 2013


At the 2012 meeting of the Collegium Internationale
Neuro-Psychopharmacologicum (CINP), a symposium was held to discuss
fibromyalgia and chronic fatigue syndrome, two illnesses that remain
mysterious.

Fibromyalgia

Fibromyalgia is more common in women than in men and is characterized
by aching all over, decreased sleep, stiffness upon waking, and most
prominently, being tired all day, as well as a host of other symptoms
including headache, dizziness, and gastrointestinal upset. Researcher
Siegried Kasper suggested that treating fibromyalgia requires more
than just medication. His approach is known as MESS, which stands for
medication, exercise, sleep management, and stress management.

Medications to treat the illness include milnacipran (not available in
the US), duloxetine (Cymbalta, a serotonin-norepinephrine reuptake
inhibitor or SNRI), or pregabalin (Lyrica), and if tolerated, low
doses of the tricyclic amitriptyline (Elavil).

According to Kasper, SSRIs and anti-inflammatory drugs don't work, and
benzodiazepines decrease the deepest phase of sleep (stage 4) and can
exacerbate the syndrome.

Recommended exercise is moderate, graded (to a pulse of about 120, or
at a level where the patient can still talk, but can't sing), and
should be done in the early morning rather than the late afternoon
where it might interfere with sleep.

Good sleep hygiene is recommended, such as keeping the same sleep
schedule every day and abstaining from caffeine (even in the morning).

Working on developing active coping strategies for stressors that are
likely to occur is a good idea. Mindfulness and other meditative
techniques may also be helpful. Joining a support group (that
encourages exercise rather than discouraging it) was also recommended.

Chronic Fatigue Syndrome

At the CINP meeting researcher Simon Wessely discussed chronic fatigue
syndrome (CFS), which has many overlaps with fibromyalgia. He reported
that careful controlled study of more than 15,000 individuals has
indicated that the illness is not associated with a viral infection.
Just as many people with and without chronic fatigue syndrome were
found to be infected with a virus.

However, like the myth that vaccines cause autism, the myth that
chronic fatigue is associated with a virus remains popular despite the
lack of evidence. A large randomized study validated Wessely's
treatment techniques, but he has continued to be vilified for the
position that the illness is not virally based. The study showed that
patients who participated in cognitive behavior therapy and graded
exercise improved more than those who received conventional medical
management.

Wessely thought the most important cognitive change to make was
accepting that exercise is not harmful for patients with chronic
fatigue syndrome, and is in fact helpful and therapeutic. Many older
treatment approaches had advocated rest, rest, and more rest, or even
"intensive rest." However, Wessely indicated that this would be
counter-productive, as the patient would lose muscle mass and
cardiovascular conditioning, and would become even more tired and
chronically fatigued.

---

Although the editors of BipolarNews.org have made every effort to
report accurate information, much of the work referenced here is in
abstract or pre-publication form, and may not have received proper
review by the scientific community at this time. Patients should
consult with their physicians about any treatment decisions.
Physicians should consult the peer-reviewed literature.
 

Time for a Patient Revolution

Simon McGrath has written an interesting and informative article on
this issue. It mixes calls for increased patient involvement in
medicine with some examples of what happens in ME/CFS

http://phoenixrising.me/archives/17658

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

It's a bit long so, for anyone who doesn't make it, here's an extract
-------------------------------
"... Unfortunately, such an enlightened approach has yet to reach
ME/CFS, as was shown by the world's largest CFS clinical trial, the £5
million PACE study, which defined success and failure without
consulting patients.
...
Not everyone wants to collaborate with patients...

The PACE Trial's recent paper
http://www.qmul.ac.uk/media/news/items/smd/89978.html claimed that 22%
of patients 'recovered' with CBT or Graded Exercise (compared with 7%
without). However, they had abandoned their original protocol
definition of recovery and created a new version with much looser
criteria. To give an idea of how far-fetched some of the new
'recovery' criteria are, 11% of patients met the fatigue or function
'recovery' criteria at the start of the trial - while simultaneously
meeting criteria for 'severe and disabling fatigue'. And a quarter of
patients seen in wider clinical practice
http://qjmed.oxfordjournals.org/content/106/6/555 had physical
function scores that met PACE recovery criteria. Surely the prime
arbiters of what counts as recovery should be patients, who live the
real-world consequences of the illness, not researchers who might be
more concerned with making their study look good.

When it came to measuring treatment 'Harms', the PACE trial did go
further in collecting data than any previous study of CBT and graded
exercise. But they revised the original protocol definition of 'Harms'
http://bit.ly/16L3IQV i.e.
http://iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx
, making it harder to for problems to count as 'harm', and made it
technically impossible for anyone to deteriorate seriously in the
second 6 months of the trial. They also published the proportion of
patients improving by a 'clinically useful difference' in their 2011
paper but failed to provide the corresponding proportion of patients
deteriorating by the same amount. Following a Freedom of Information
request http://bit.ly/11FOSfy i.e.
http://forums.phoenixrising.me/index.php?posts%2F360415%2F it appears
they will now be publishing the data - more than 2 years later.

As well as 'no decision about me without me', perhaps we also need a
firm commitment from the Government there should be 'no research about
me, without me'.

It's also worth noting that ME/CFS patient surveys - based on patients
receiving normal clinical services rather than the highly controlled
therapy of research trials - consistently find high levels of adverse
reactions with CBT and graded exercise. This information hasn't always
been taken very seriously by researchers and clinicians.
-------------------------------

Two is better than one

Jennifer Spotila summarises, in layman's terms, a recent paper on two
day repeat exercise testing in CFS (i.e. do two exercise tests, 24
hours or so apart):
------
Snell CR, Stevens SR, Davenport TE, Van Ness JM. Discriminative
Validity of Metabolic and Workload Measurements to Identify
Individuals With Chronic Fatigue Syndrome. Phys Ther. 2013 Jun 27.
[Epub ahead of print]
------

Extract from Jennifer's blogpost:
"In Test 1, the CFS patients did not perform as ...well as controls.
Multiple measurements were lower in the CFS group, including VO2max,
peak workload, and workload at the anaerobic threshold. However, only
the peak workload difference was statistically significant. In Test 2,
the differences were quite dramatic. The controls performed the same
or even better on the second test. But the CFS patients demonstrated a
drop in VO2max, oxygen consumption at the anaerobic threshold, peak
workload, and workload at the anaerobic threshold. The mean for the
last value – workload at the anaerobic threshold – dropped by more
than 50%. Respiratory measurements prove that all subjects gave a
maximal effort in both tests, so the reduction is not due to lack of
effort."

--

Here's an extract from the full text she has access to:
"This functional deficit may provide an objective indication of PEM.
Despite considerable patient heterogeneity with respect to illness
duration and type of onset, analysis of data from the second test was
able to correctly classify 49 out of 51 individuals with CFS and 9 out
of 10 controls."

http://bit.ly/175kgm0 i.e.
http://www.occupycfs.com/2013/07/03/two-is-better-than-one/

Differentiating Diagnoses with Post-Exertional Fatigue

http://ptjournal.apta.org/content/early/2013/06/26/ptj.20110368.abstract

Discriminative Validity of Metabolic and Workload Measurements to
Identify Individuals With Chronic Fatigue Syndrome
Christopher R. Snell, Staci R. Stevens, Todd E. Davenport
(tdavenport@pacific.edu) and J. Mark Van Ness

Author Affiliations

C.R. Snell, Department of Sport Sciences, University of the Pacific,
Stockton, California.
S.R. Stevens, Workwell Foundation, Ripon, California.
T.E. Davenport, Department of Physical Therapy, University of the
Pacific, 3601 Pacific Ave, Stockton, CA 95211 (USA).
J.M. Van Ness, Department of Sport Sciences, University of the Pacific.

Abstract

Objectives Reduced functional capacity and post-exertional fatigue
following physical activity are hallmark symptoms of chronic fatigue
syndrome (CFS) and may even qualify for biomarker status. That these
symptoms are often delayed may explain the equivocal results for
clinical cardiopulmonary exercise testing among individuals with CFS.
Test reproducibility in healthy subjects is well documented. This may
not be the case with CFS due to delayed recovery symptoms. The
objectives for this study was to determine the discriminative validity
of objective measurements obtained during CPET to distinguish
individuals with CFS from non-disabled sedentary individuals.

Methods Gas exchange data, workloads and related physiological
parameters were compared between 51 individuals with CFS and 10
control subjects, all females, for two maximal exercise tests
separated by 24 hours.

Results Multivariate analysis showed no significant differences
between controls and CFS for Test 1. However, for Test 2 the
individuals with CFS achieved significantly lower values for oxygen
consumption and workload at peak exercise and at the
ventilatory/anaerobic threshold. Follow-up classification analysis
differentiated between groups with an overall accuracy of 95.1%.

Conclusions The lack of any significant differences between groups for
the first exercise test would appear to support a deconditioning
hypothesis for CFS symptoms. However, results from the second test
indicate the presence of a CFS related post-exertional fatigue. It
might be concluded that a single exercise test is insufficient to
reliably demonstrate functional impairment in individuals with CFS. A
second test may be necessary to document the atypical recovery
response and protracted fatigue possibly unique to CFS, which can
severely limit productivity in the home and workplace.

Received October 27, 2011.
Accepted June 23, 2013.

© 2013 American Physical Therapy Association

Broken Brain

Too tired to think straight? A recent study suggests a key energy producing
process that provides the fuel for complex thought may not only be broken
in people with GWS/ME/CFS but, get this, may be at its worst after exercise.

Check out the study that may explain the post-exertional brain drain in

- *Your Brain Without Energy: Broken Brain Energy Loop Wipes Out
Cognitive Functioning in GWS Patients with ME/CFS*

http://www.cortjohnson.org/blog/2013/07/01/your-brain-without-energy-broken-brain-energy-loop-wipes-out-cognitive-functioning-gws-me-cfs/

De Meirleir offers hope for the future

Dr. De Meirleir has learned a few things in his 20 year odyssey of treating
ME/CFS patients and he laid out some of those things in his "Treatment'
video from the ME/CFS Association. Find out what Dr. De Meirleir said about
Rituximab, fecal transplants, antibiotics and more as well as the next big
discovery that might just be around the corner in

*Treatment and Hope: Dr. De Meirleir on 20 years of the Treatment Chronic
Fatigue Syndrome and Hope for the Future*

http://www.cortjohnson.org/blog/2013/06/28/treatment-and-hope-dr-de-meirleir-on-20-years-oftreating-chronic-fatigue-syndrome-and-the-hope-for-the-future/

What De Meirleir has been working on....

Source: European Patent Office
Date: February 27, 2013
URL: http://www.freepatentsonline.com/EP2561879.html
https://data.epo.org/publication-server/rest/v1.0/publication-dates/20130227/patents/EP2561879NWA1/document.pdf


European Patent Application EP2561879
-------------------------------------

Abstract

The present invention relates to Macrophage Activating Factors such as
GcMAF and compositions thereof, for use in the treatment of a patient
suffering from CFS/ME and/or XMRV infection.


Inventors:

Roelant, Christiaan ('s Hertogenlaan 115, B-3000 Leuven, BE)
De Meirleir, Kenny (Stuivenberglaan 89, B-2800 Mechelen, BE)


Application Number:

EP20110178511


Publication Date:

02/27/2013


Filing Date:

08/23/2011

(...)


Assignee:

Protea Biopharma N.V. (De Tyraslaan 111, 1120 Neder-Over-Heembeek, BE)


International Classes:

A61K35/407; A61K31/714; A61K38/19; A61K38/20; A61K38/21; A61P31/12; A61P43/00


View Patent Images:

http://www.freepatentsonline.com/EP2561879.pdf


Attorney, Agent or Firm:

Paemen, Liesbet R. J. (De Clercq & Partners Edgard Gevaertdreef 10 a,
9830 Sint-Martens-Latem, BE)



Claims:

1. A composition comprising a Macrophage Activating Factor for use in
the treatment of a patient suffering from chronic fatigue
syndrome/myalgic encephalomyelitis (CFS/ME) and/or an infection by
xenotropic murine leukemia virus-related virus (XMRV).

2. The composition according to claim 1, wherein said patient is
characterized by reduced NK cell activity and increased inflammatory
mediators.

3. The composition according to claim 1 or 2, for reducing at least
one symptom chosen from the group consisting of substantial impairment
in short-term memory or concentration, sore throat, tender lymph
nodes, muscle pain, multi-joint pain without swelling or redness,
headaches of a new type, pattern, or severity; unrefreshing sleep,
post-exertional malaise lasting more than 24 hours, widespread pain,
fatigue, feeling run down, sluggish muscle cramps and pains,
unexplained or excessive weight gain, inability to lose weight,
gastrointestinal problems, irritable bowel syndrome, poor sleeping,
headaches and migraines, constipation, orthostatism and exhaustion.

4. The composition according to any one of claims 1 to 3, wherein said
patient is diagnosed with aberrant and/or increased metabolite
production.

5. The composition according to claims 1 to 4, wherein said Macrophage
Activating Factor is GcMAF.

6. The composition according to any one of claims 1 to 5, in which
said Macrophage Activating Factor is the only active ingredient.

7. The composition according to any one of claims 1 to 5, further
comprising one or more other active ingredients.

8. The composition according to claim 7, where one of said one or more
other active ingredients is Vitamin B12.

9. The composition according to claim 7 or 8, where at least one of
said one or more other active ingredients is selected from the group
consisting of interferon alpha, interferon beta, interferon gamma and
interleukin-7.

10. The composition according to any one of claims 7, 8 or 9, wherein
at least one of said one or more other active ingredients is selected
from a viral inhibitor and/or an ecto-nox-modifying agent.

11. The composition according to any one of claims 7 to 10, further
comprising a mammalian liver extract.

12. The composition according to any one of claims 1 to 11, wherein
said composition is an enteral composition.

13. The composition according to any one of claims 1 to 12, wherein
said patient is diagnosed with CFS/ME and with XMRV infection.




Description:

FIELD OF THE INVENTION

The present invention relates to the therapeutic and/or prophylactic
use of Macrophage Activating Factors.


BACKGROUND OF THE INVENTION

Macrophage Activating Factors (MAFs) are lymphokines that prime
macrophages to become cytotoxic to tumors. These factors also control
the expression of la antigens on the macrophage cell surface. There
are indications that the use of MAFs, particularly the GcMAF protein,
is effective in the treatment of certain cancers and HIV (EP0837932,
Yamamoto).

Chronic fatigue syndrome (CFS) is a difficult to diagnose, ubiquitous
disorder characterized by extreme fatigue, lymph gland enlargement and
constitutional symptoms such as weight loss, loss of appetite, memory
deterioration and loss of intelligence in some patients. Some CFS
patients manifest neuropsychiatric changes such as depression, loss of
memory and similar derangements. Thus, chronic fatigue syndrome is
sometimes difficult to distinguish from entirely neurological
disorders, particularly situational depression. An accumulating body
of evidence suggests that CFS is associated with disregulation of both
humoral and cellular immunity, including mitogen response,
reactivation of viruses, abnormal cytokine production, diminished
natural killer cell function and changes in intermediary metabolites.
CFS is also referred to by some as CFS/ME (myalgic encephalomyelitis).
The term myalgic encephalomyelitis refers to muscle aches or pains and
inflammation of the brain and spinal cord. While inflammation of the
brain is not observed in all CFS patients, the group of patients
referred to under CFS/ME typically suffer from the same symptoms and
lack a clear etiology

A number of further diseases have been associated with CFS/ME because
of the similarity of the symptoms observed with CFS/ME patients and
patients suffering from such CFS/ME-related diseases. For instance,
fibromyalgia, autoimmune thyroid disease, xenotropic murine leukemia
virus-related virus (XMRV) and several other diseases have been
suggested as being related to CFS/ME and present similar symptoms of
widespread pain, fatigue, feeling run down, sluggish muscle cramps and
pains, unexplained or excessive weight gain, inability to lose weight,
gastrointestinal problems, irritable bowel syndrome, poor sleeping,
headaches and migraines, constipation and exhaustion.

For many CFS/ME patients, cognitive behavioural therapy and graded
exercise therapy have shown only moderate effectiveness (Whiting et
al. JAMA 286: 1360-1368, 2001). Many patients do not fully recover
from CFS/ME even with treatment (Rimes et al. Occupational Medicine
55: 32-39, 2005). Other treatments of CFS/ME have been proposed but
their effectiveness has not been confirmed (Prins et al. Lancet 367:
346-355, 2006).

XMRV is an infectious human gamma-retrovirus, which has been linked to
both CFS/ME and human prostate cancer (Kearney et al. JID 202:
1463-1466, 2011). Although in vitro studies have indicated that
raltegravir (Trade name Isentress(r)) can act as an inhibitor for XMRV
replication (Singh et al., PLoS ONE 5: e9948, 2010), its effect on the
in vivo XMRV replication is not yet documented.

There remains a need for compounds for use in the treatment and/or
prevention of CFS/ME and CFS/ME-related diseases, such as XMRV
infection. More particularly, there is a need for novel and improved
compounds that are capable of reducing, inhibiting or decreasing the
particular symptoms that are observed in patients suffering from
CFS/ME and/or CFS/ME-related diseases and disorders, such as for
example XMRV infection.


SUMMARY OF THE INVENTION

The present invention relates to a Macrophage Activating Factor (MAF)
for use in the treatment of a patient suffering from chronic fatigue
syndrome/myalgic encephalomyelitis (CFS/ME) and/or one or more
CFS/ME-related diseases and/or disorders, such as infection by
xenotropic murine leukemia virus-related virus (XMRV). In particular
embodiments, the present invention provides a composition comprising a
MAF for use in the treatment of a patient suffering from CFS/ME and/or
an infection by XMRV. In a further aspect the present invention
provides use of a MAF for the manufacture of a medicament for the
treatment of CFS/ME and/or CFS/ME related diseases and disorders, such
as infection by XMRV in a mammal.

Indeed, the inventors found that the administration of a MAF leads to
a significant decrease of the manifestation of the symptoms of CFS/ME
and CFS/ME-related diseases, more particularly of XMRV. For instance,
the inventors have found that administration with a MAF, more
particularly GcMAF, is capable of suppressing or reducing at least one
of the biological parameters associated with CFS/ME and CFS/ME-related
diseases. More particularly, it has been established that indicators
of Natural Killer (NK) cell activity and inflammation, are affected
when patients suffering from such diseases are treated with MAF. Thus,
in particular embodiments, the patient is characterized by reduced NK
cell activity and increased inflammatory mediators. In certain
embodiments, the patient is diagnosed with CFS/ME and with XMRV
infection.

It is further considered that treatment with MAF ensures important
clinical improvement, for example as measured on the Karnofsky scale
or the Bell disability scale (D.S. Bell, The Doctor's Guide to Chronic
Fatigue Syndrome, Reading, MA: Addison-Wesley, 1994). Specifically,
the MAF or compositions according to the present invention are useful
for reducing at least one symptom chosen from the group consisting of
substantial impairment in short-term memory or concentration, sore
throat, tender lymph nodes, muscle pain, multi-joint pain without
swelling or redness, headaches of a new type, pattern, or severity;
unrefreshing sleep, post-exertional malaise lasting more than 24
hours, widespread pain, fatigue, feeling run down, sluggish muscle
cramps and pains, unexplained or excessive weight gain, inability to
lose weight, gastrointestinal problems, irritable bowel syndrome, poor
sleeping, headaches and migraines, constipation, orthostatism and
exhaustion.

In particular embodiments, the present invention provides a MAF as
described above provided in a conjugate or in a pharmaceutical
composition comprising a pharmaceutically acceptable excipient and a
therapeutically effective amount of said MAF.

In certain embodiments, the MAF as described herein is the only active
ingredient of the composition as described herein. In further
embodiments, the present invention provides a MAF as described above
provided in a conjugate or in a pharmaceutical composition consisting
of a pharmaceutically acceptable excipient and a therapeutically
effective amount of said MAF.

In particular embodiments, the present invention relates to methods
for treating a patient having been diagnosed with CFS/ME and/or one or
more CFS/ME-related disease(s) based on aberrant ecto-nox functioning
as described herein. In particular embodiments, the patient described
above is diagnosed with aberrant and/or increased metabolite production.

In particular embodiments, the MAF in the present invention is GcMAF protein.

A further aspect of the present invention relates to the compositions
as described above, wherein said MAF according to the invention is
provided in combination with one or more other pharmacologically
active compounds or ingredients. In particular embodiments, one of the
one or more other active ingredients is Vitamin B12. In certain
embodiments, at least one of the one or more other active ingredients
is selected from the group consisting of interferon alpha, interferon
beta, interferon gamma and interleukin-7. In certain embodiments, at
least one of the one or more other active ingredients is selected from
a viral inhibitor and/or an ecto-nox-modifying agent. In certain
embodiments, the compositions according to the present invention
further comprise a mammalian liver extract.

In particular embodiments, the present invention relates to
compositions as described above, for enteral administration. In
another embodiment, the present invention relates to compositions as
described above, for parenteral administration.


DETAILED DESCRIPTION OF THE INVENTION

In the following passages, different aspects of the invention are
described in more detail. Each aspect so described may be combined
with any other aspect or aspects unless clearly indicated to the
contrary. In particular, any feature indicated as being preferred or
advantageous may be combined with any other feature or features
indicated as being preferred or advantageous.

In the context of the present invention, the terms used are to be
construed in accordance with the following definitions, unless a
context dictates otherwise.

As used herein, the singular forms 'a', 'an', and 'the' include both
singular and plural referents unless the context clearly dictates
otherwise.

The terms 'comprising', 'comprises' and 'comprised of' as used herein
are synonymous with 'including', 'includes' or 'containing',
'contains', and are inclusive or open-ended and do not exclude
additional, non-recited members, elements or method steps.

The recitation of numerical ranges by endpoints includes all numbers
and fractions subsumed within the respective ranges, as well as the
recited endpoints.

The term 'about' as used herein when referring to a measurable value
such as a parameter, an amount, a temporal duration, and the like, is
meant to encompass variations of +/-10% or less, preferably +/-5% or
less, more preferably +/-1% or less, and still more preferably +/-0.1%
or less of and from the specified value, insofar such variations are
appropriate to perform in the disclosed invention. It is to be
understood that the value to which the modifier 'about' refers is
itself also specifically, and preferably, disclosed.

This invention relates to the use of Macrophage Activating Factors
('MAFs') in the treatment of CFS/ME and/or in the treatment of
infection by xenotropic murine leukemia virus-related virus (XMRV) in
a mammal.

The term 'Macrophage activating factor' or 'MAF' as referred to herein
designates a lymphokine protein that stimulates monocytes and/or
macrophages (designated as macrophages hereafter). This stimulation
results in the macrophages to become cytotoxic to tumors, and/or
primes the phagocytosis of pathogens by macrophages.

In particular, the present invention relates to a GcMAF protein for
use in the treatment of a mammal suffering from CFS/ME and/or one or
more CFS/ME-related diseases, such as for example infection by XMRV.

The term 'GcMAF' as referred to herein designates a Gc (group specific
component) protein derived macrophage activating protein, or a domain
III (natural or cloned) derived macrophage activating protein (e.g.

US patent 6410269, Yamamoto, which is included herein by reference).
The term 'domain III' as referred to herein designates the domain III
region of the Gc protein. The term 'Gc protein' as referred to herein
designates a Vitamin D binding protein (DBP); DBP is also known as
gc-globulin.

A first aspect of the invention relates to a composition comprising a
Macrophage Activating Factor (MAF) for use in the treatment of
patients diagnosed with chronic fatigue syndrome/myalgic
encephalomyelitis (CFS/ME) and/or CFS/ME-related diseases and
disorders. Accordingly, the present invention provides for a treatment
that reduces, inhibits or decreases the symptoms of CFS/ME and
CFS/ME-related diseases, such as XMRV infection.

It is known that CFS/ME and CFS/ME related diseases seriously
interfere with the immune system, causing a dysfunctioning thereof.
The present inventors have found that by using a composition
comprising a MAF, the activity of natural killer cells (or NK cells),
i.e. cytotoxic lymphocytes that play a major role in the regulation of
the innate immune system, is increased. Thus, use of MAF in patients
suffering from CFS/ME or CFS/ME-related diseases causes a positive
stimulation of the immune system. Furthermore, the inventors have
found that by using a MAF in the treatment of patients suffering from
CFS/ME and/or CFS/ME-related diseases, inflammation is reduced.

The term 'chronic fatigue syndrome' or 'CFS' as referred to herein
designates a condition which is diagnosed based on the following
criteria (as developed by the U.S. Centers for Disease Control and
Prevention in 1994):
1. Clinically evaluated, unexplained persistent or relapsing chronic
fatigue that is of new or definite onset (i.e., not lifelong), is not
the result of ongoing exertion, is not substantially alleviated by
rest, and results in substantial reduction in previous levels of
occupational, educational, social, or personal activities.
2. The concurrent occurrence of four or more of the following
symptoms: substantial impairment in short-term memory or
concentration; sore throat; tender lymph nodes; muscle pain;
multi-joint pain without swelling or redness; headaches of a new type,
pattern, or severity; unrefreshing sleep; and post-exertional malaise
lasting more than 24 hours. These symptoms must have persisted or
recurred during 6 or more consecutive months of illness and must not
have predated the fatigue.

The term 'CFS/ME and CFS/ME-related diseases and disorders' refers to
diseases and/or disorders with having an underlying biological
mechanism of action and/or signaling pathways that are the same or
similar to those known to underlie CFS and/or presenting the same or
similar symptoms as observed with patients suffering from CFS.

Several standardized tests exist to follow up patients suffering from
CFS/ME, such as the Activities of Daily Living Questionnaire (ADL)(see
e.g. Collin et al. Int. Disabil. Stud. 10:61-63, 1988), the (Cognitive
Deficit Subset of the) Symptom Checklist Questionnaire (SCL-90-R) (see
e.g. Diaz-Mitoma et al. Journal of Chronic Fatigue Syndrome 11:71-95,
2003) and the Karnofsky Performance Score (KPS) (Karnofsky D and
Burchenal JH. Clinical evaluation of chemotherapeutic agents in
cancer. In Macleod CM. (ed) Evaluation of chemotherapeutic agents.
Columbia University Press, New York 1949; 199-205). An alternative
performance score specifically developed for CFS/ME patients is the
Bell disability scale (D.S. Bell, The Doctor's Guide to Chronic
Fatigue Syndrome, Reading, MA: Addison-Wesley, 1994).

Thus, in particular embodiments, the present invention provides for
compositions comprising a MAF, for use in the treatment of CFS/ME and
CFS/ME related diseases, which are capable of reducing the clinical
symptoms of CFS/ME and/or CFS/ME related diseases as determined by one
or more of the above-described evaluation methods. More particularly
the compositions of the invention ensure a 10% improvement, more
particularly a 20%, 30%, 40%, 50%, 60%, 70% or 80% or more improvement
of clinical symptoms compared to prior to administration of the
composition of the invention.

On a physiological level, CFS/ME has been associated with a variety of
immune abnormalities. For instance, it has been reported that CFS/ME
patients suffer from a suppression of NK cell activity (Whiteside et
al. Am. J. Med. 105: 27S-34S, 1998). Published results also
demonstrate an association between clinical improvement of patients
suffering from CFS/ME and enhanced NK cell activity (Diaz-Mitoma et
al. Journal of Chronic Fatigue Syndrome 11:71-95, 2003). It is also
reported that CFS/ME is associated with diminished intracellular
perforin, a protein found in the granules of NK cells (Maher et al.,
Clin. Exp. Immunol. 2002, 142, 505). Therefore, NK activity and/or
intracellular perforin levels are suitable indicators for monitoring
the disease state in patients suffering from CFS/ME.

Additionally, CFS/ME is associated with indications of inflammation.
For example, CFS/ME patients often exhibit elevated levels of
pro-inflammatory cytokines such as Interleukin-8 (IL-8). Patients
suffering from CFS/ME also frequently have elevated C4a serum levels
(Sorensen et al. J. Allergy Clin. Immunol. 112: 397-403, 2003). C4a is
an anaphylatoxin generated by cleavage of complement component 4 (C4),
upon activation of the complement system. Anaphylatoxins are able to
trigger degranulation of endothelial cells, mast cells or phagocytes,
which produce a local inflammatory response. Thus, indications of
inflammation such as IL-8 and/or C4a levels are additional parameters
which can be monitored in order to follow up patients suffering from
CFS/ME.

In particular embodiments, the present invention provides for
compositions comprising a MAF, for use in the treatment of CFS/ME and
CFS/ME related diseases, which are capable of reducing the
physiological symptoms of CFS/ME and/or CFS/ME related diseases such
as but not limited to reduced NK cell activity and elevated
inflammatory response. Most particularly, the invention provides
compositions capable of ensuring a 10% improvement, more particularly
a 20%, 30%, 40%, 50%, 60%, 70% or 80% or more improvement of the
physiological symptoms of CFS/ME compared to prior to administration
of the composition of the invention. More particularly, the
compositions of the invention can be used to normalize the NK activity
and/or inflammatory response in a patient suffering from CFS/ME or a
CFS/ME related disorder.

It will be understood that in view of the nature of the disease and
the diagnostic criteria, not all patients suffering from CFS/ME are
characterized by reduced NK cell activity and/or increased
inflammatory responses. Thus, in particular embodiments, the present
invention provides compositions for use in the treatment of patients
suffering from CFS/ME, wherein the patient is diagnosed with increased
C4a serum level, increased IL-8 serum level and/or decreased NK cell
activity. In particular embodiments, the patient is diagnosed with at
least one element selected from the group consisting of increased C4a
serum level, increased IL-8 serum level and decreased NK cell
activity. 'Increased C4a serum level' as used herein refers to a C4a
serum level above 1500 ng/mL, preferably above 2500 ng/mL. 'Increased
IL-8 serum level' as used herein refers to an IL-8 serum level above
15 pg/mL, preferably above 25 pg/mL. 'Decreased NK cell activity' as
used herein refers to a perforin mRNA expression in peripheral blood
mononuclear cells (PBMCs) below.

It has been described that further indicators of CFS/ME include an
aberrant functioning of constitutive ecto-nox proteins.

WO2010109009, which is hereby incorporated by reference, provides
methods for determining the presence of aberrant ecto-nox functioning
in the sample of a patient.

The term 'ecto-nox protein' or 'membrane NADH oxidase' as used herein
refers to a cell-surface protein with both hydroquinone oxidase and
protein-disulfide-thiol interchange activity. Constitutive ecto-nox
proteins or prions are constitutively present in cellular membranes.
They differ in this respect from mutated ecto-nox proteins present
e.g. in cancer cells, such as t-nox.

More particularly the method described in WO2010109009 can be used to
determine whether a patient is suffering from CFS/ME, more
particularly whether the patient is susceptible to treatment with a
compound capable of reducing aberrant ecto-nox functioning.

It is noted in this regard that the term 'normal' when used in the
context of ecto-nox protein or membrane NADH oxidase as used herein
refers to the membrane NADH oxidase identifiable on normal,
non-diseased cells and is characterized by the fact that it is heat
sensitive (loss of activity when subjected to 70 degrees Celsius for
10 min.) and preferentially activated under hypotonic conditions. The
term 'aberrant' when used in the context of ecto-nox protein or
membrane NADH oxidase herein refers to an ecto-nox protein which does
not function properly. In particular embodiments, the ecto-nox protein
is in a permanently activated state and characterized by the fact that
it is heat insensitive (retains activity when subjected to 70 degrees
Celsius for 10 min.) and shows highest activity under isotonic
conditions.

In particular embodiments, the present invention provides for
compositions comprising a MAF, for use in the treatment of CFS/ME and
CFS/ME related diseases, which are capable of reducing aberrant
ecto-nox functioning in patients suffering from CFS/ME and/or CFS/ME
related diseases. Most particularly, the invention provides
compositions capable of ensuring a 10% reduction, more particularly a
20%, 30%, 40%, 50%, 60%, 70% or 80% or more reduction of the aberrant
ecto-nox functioning in patients with CFS/ME compared to prior to
administration of the composition of the invention, more particularly
as determined by the methods disclosed in WO2010109009. More
particularly, the compositions of the invention can be used to
normalize the ecto-nox functioning in a patient suffering from CFS/ME
or a CFS/ME related disorder.

In particular embodiments, the present invention provides compositions
for use in the treatment of patients suffering from CFS/ME, wherein
the patient is diagnosed to have aberrant ecto-nox functioning, more
particularly as determined by the methods disclosed in WO2010109009.

Further indications of CFS/ME also include an increased amount of
metabolites in physiological fluids such as urine. The metabolite
concentration in physiological fluids can be detected and monitored
using reducible dyes, which allows monitoring of the disease
(WO2010142322, which is hereby incorporated by reference).

In particular embodiments, the present invention provides for
compositions comprising a MAF, for use in the treatment of CFS/ME
and/or CFS/ME related diseases, which are capable of reducing aberrant
metabolite production in patients suffering from CFS/ME and/or CFS/ME
related diseases. Most particularly, the invention provides
compositions capable of ensuring a 10% reduction, more particularly a
20%, 30%, 40%, 50%, 60%, 70% or 80% or more reduction of the aberrant
metabolite production in patients with CFS/ME compared to prior to
administration of the composition of the invention, more particularly
as determined by the methods disclosed in

WO2010142322. More particularly, the compositions of the invention can
be used to normalize the ecto-nox functioning in a patient suffering
from CFS/ME or a CFS/ME related disorder.

In particular embodiments, the present invention provides compositions
for use in the treatment of patients suffering from CFS/ME, wherein
the patient is diagnosed with increased metabolite production, more
particularly as determined by the methods disclosed in WO2010142322.

While the link between both conditions remains controversial, there is
increasing evidence that a significant number of patients suffering
from CFS/ME is infected with xenotropic murine leukemia virus-related
virus.

The term 'xenotropic murine leukemia virus-related virus' or 'XMRV' as
referred to herein designates an infectious gamma-retrovirus as found
in prostate tumors, particularly in prostate tumors of patients
homozygous for RNASEL variant, R462Q (e.g., Urisman et al., PLoS
Pathog. 2(3): e25, 2006; Dong et al., Proc. Natl. Acad. ScL USA
104(5): 655, 2007 and

WO 2006/110589; all of which are incorporated herein by reference in
their entirety). The term 'xenotropic murine leukemia virus-related
virus' or 'XMRV' includes any strain of the virus including XMRV VP35
(GenBank Accession No. DQ241301), XMRV VP42 (GenBank Accession No.
DQ241302) and XMRV VP62 (GenBank Accession No. DQ399707).

In addition, a number of diseases have been associated with CFS/ME
because of the similarity of the symptoms observed with CFS/ME
patients and patients suffering from such CFS/ME-related diseases. For
instance, fibromyalgia, autoimmune thyroid disease, xenotropic murine
leukemia virus-related virus (XMRV) and several other diseases have
been suggested as being related to CFS/ME and presenting similar
symptoms of widespread pain, fatigue, feeling run down, sluggish
muscle cramps and pains, unexplained or excessive weight gain,
inability to lose weight, gastrointestinal problems, irritable bowel
syndrome, poor sleeping, headaches and migraines, constipation,
orthostatism and exhaustion.

Although such CFS/ME-related diseases may contribute in the
pathogenesis of CFS/ME, often a causative link between CFS/ME and such
diseases has not been unequivocally established.
Accordingly, it is envisaged herein that while a subgroup of
patients with CFS/ME may additionally have one or more CFS/ME-related
diseases, such as an infection with XMRV not all patients with CFS/ME
are necessarily suffering from an additional CFS/ME related disease,
such as an infection with XMRV. In addition, not all patients with for
example diagnosed to be infected with XMRV, are additionally diagnosed
with CFS/ME, despite that fact that they may show at least some
symptoms of CFS/ME.

The compositions of the present invention are envisaged to be of use
in the treatment of both CFS/ME and CFS/ME related diseases. In
particular embodiments however, the present invention relates to the
treatment of patients with CFS/ME in which an infection with XMRV has
been identified.

The present invention relates to a MAF for use in the treatment of
CFS/ME and/or CFS/ME related diseases or disorders, such as an
infection by XMRV in a mammal. In particular embodiments, the present
invention relates to use of a MAF for the manufacture of a medicament
for the treatment of CFS/ME and/or infection by XMRV in a mammal. In
particular embodiments, the present invention relates to the a MAF for
use in the treatment of CFS/ME and/or infection by XMRV in a mammal.

In particular embodiments, the present invention relates to the use of
a MAF in the manufacture of a medicament for the treatment of, CFS/ME
and/or infection by XMRV in a mammal.

In particular embodiments, the present invention relates to
compositions comprising a MAF for use in the treatment of a patient
suffering from CFS/ME and/or one ore more CFS/ME-related diseases,
such as an infection by XMRV. In particular embodiments, the patient
is also characterized as having aberrant ecto-nox functioning, e.g. by
the method disclosed in WO2010109009. In particular embodiments, the
patient is also diagnosed with aberrant and/or increased metabolite
production, e.g. by the method disclosed in WO2010142322.

In further particular embodiments, the present invention provides in
compositions as described above, comprising a pharmaceutically
acceptable excipient and a therapeutically effective amount of said
MAF. In particular embodiments, the MAF as described herein, is GcMAF.

In particular embodiments, the compositions of the present invention
comprises MAF as the sole active ingredient or consists of a MAF.
However, treatment regimes are also envisaged wherein the MAF is
administered in combination with one or more other therapeutic
compounds. The present invention further envisages treatment regimes
wherein a patient suffering from CFS/ME or a CFS/ME related disorder
is treated with (Gc)MAF in combination with one or more compounds
selected from a viral inhibitor and/or an ecto-nox modifying agent,

More particularly, the present invention relates to the therapeutic
use of a MAF as described above used in combination with at least one
specific inhibitor of a virus wherein said virus is associated with
CFS/ME, more particularly wherein said virus is XMRV. In particular
embodiments, (one of) said viral inhibitor(s) is Raltegravir(r).

In particular embodiments, the present invention relates to the
therapeutic use of a MAF as described above used in combination with
an ecto-nox modifying agent. The term 'ecto-nox protein modifying
agent' as used herein refers to any compound capable of converting a
normal ecto-nox protein (or membrane NADH oxidase) into an aberrant
ecto-nox protein (or membrane NADH oxidase) or capable of inducing
aberrant NADH oxidase activity in a sample. In particular embodiments,
the ecto-nox protein modifying agent is a molecule having NADH oxidase
activity capable of competing with the ecto-nox protein, or a molecule
capable of inhibiting the association of an ecto-nox protein with the
plasma membrane, or an NADH oxidase inhibitor. In particular
embodiments, the ecto-nox modifying agent is selected from the group
consisting of a prion molecule (such as NADH oxidase) and a solvent
(such as dimethyl sulfoxide, i.e. DMSO).

In further particular embodiments, the present invention relates to
the therapeutic use of a MAF as described above used in combination
with at least one mammalian liver extract. Mammalian liver extract has
shown NADH oxidase activity and an antiviral activity against certain
viruses. Mammalian liver extract has been commercialized under the
names of Kutapressin(r) and Nexavir(r).

US5,055,296 describes the use of a mammalian liver extract for the
treatment of viral infections and chronic fatigue syndrome. The
extract is described to be thermostable, acetone-insoluble and soluble
in water. Chemical analysis of the liver extract revealed at least
five polypeptides of which one was found to have
bradykinin-potentiating activity. In US5,334,395, which relates to the
use of a mammalian liver extract in the treatment of Epstein Barr
Virus (EBV) infection, 9 peptides are identified in the Kutapressin
extract as having angiotensin converting enzyme inhibitory activity.
One of these peptides is demonstrated to be capable of inhibiting EBV
infection in vitro.

The inventors further discovered positive synergistic effects when the
MAF of the present invention was used in combination with Vitamin B12.
In particular embodiments, the present invention thus relates to the
therapeutic use of a MAF as described above used in combination with
Vitamin B12. In particular embodiments, the MAF of the present
invention and Vitamin B12 are administered to the patient separately.

The inventors also discovered positive synergistic effects when the
MAF of the present invention was used in combination with one or more
compounds selected from interferon alpha, interferon beta, interferon
gamma and/or interleukin-7. In particular embodiments, the present
invention relates to the therapeutic use of a MAF according to the
present invention used in combination with one or more compounds
selected from interferon alpha, interferon beta, interferon gamma
and/or interleukin-7. In particular embodiments, the MAF of the
present invention and interferon alpha, interferon beta, interferon
gamma and/or interleukin-7 are administered to the patient separately.

As described hereabove, in the treatment regimens envisaged in the
context of the present invention the MAF can be administered
separately or simultaneously with another compound of interest. When
administered simultaneously, the compounds may be comprised in the
same or separate formulations. However, in particular embodiments, the
invention provides compositions for combined treatment regimens. Thus,
in particular embodiments, the present invention relates to a MAF or
composition as described above, and/or to the use thereof,wherein said
MAF is provided in combination with at least one other
pharmacologically active compound, for example, a viral inhibitor, an
ecto-nox protein modifying agent, a mammalian liver extract, vitamin
B12, interferon alpha, interferon beta, interferon gamma and/or
interleukin-7.

In particular embodiments, at least one other pharmacologically active
compound is selected from a viral inhibitor, and an ecto-nox protein
modifying agent. In particular embodiments the composition comprises,
or further comprises a mammalian liver extract, preferably Nexavir(r).
In particular embodiments the composition comprises, or further
comprises Vitamin B12. In particular embodiments, the composition
comprises, or further comprises one or more compounds selected from
interferon alpha, interferon beta, interferon gamma and/or
interleukin-7.

The present invention provides a use of a MAF or composition as
described above in the manufacture of a medicament for the treatment
of CFS/ME and/or for inhibiting infection by XMRV in a mammal, wherein
said MAF is provided in a conjugate or in a pharmaceutical composition
further comprising a pharmaceutically acceptable excipient and a
therapeutically effective amount of said MAF.

The term 'therapeutically effective amount' as used herein means that
amount of MAF, compound, conjugate or pharmaceutical agent that
elicits the biological or medicinal response in a tissue, system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of the
symptoms of the disease being treated.

The pharmaceutical composition can be prepared in a manner known per
se to one of skill in the art. For this purpose, at least one MAF, one
or more solid or liquid pharmaceutical excipients and, if desired, in
combination with at least one other pharmaceutical active compound,
are brought into a suitable administration form or dosage form which
can then be used as a pharmaceutical in human medicine or veterinary
medicine.

Particular forms of the pharmaceutical composition may be, for
example, solutions, suspensions, emulsions, creams, tablets, pills,
capsules, nasal sprays, liposomes or micro-reservoirs, especially
compositions in orally ingestible or sterile injectable form, for
example, as sterile injectable aqueous or oleaginous suspensions or
suppositories and sterile packaged powders (which are usually
reconstituted prior to use) for administration as a bolus and/or for
continuous administration. The solid carrier may comprise one or more
excipients, e.g. lactose, dextrose, sucrose, sorbitol, mannitol,
starches, gum acacia, calcium phosphate, alginates, tragacanth,
gelatin, calcium silicate, microcrystalline cellulose,
polyvinylpyrrolidone, polyethylene glycol, fillers, disintegrating
agents, binders, e.g. cellulose, carboxymethylcellulose or starch or
anti-stick agents, e.g. magnesium stearate, to prevent tablets from
adhering to tabletting equipment, (sterile) water, methylcellulose,
methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible
oils, vegetable oils and mineral oils or suitable mixtures thereof.
Tablets, pills and boluses may be formed so as to disintegrate rapidly
or to provide slow release of the active ingredient. The formulations
can optionally contain other pharmaceutically active substances (which
may or may not lead to a synergistic effect with the MAF of the
invention) and other substances that are commonly used in
pharmaceutical formulations, such as lubricating agents, wetting
agents, emulsifying, and suspending agents, dispersing agents,
desintegrants, bulking agents, fillers, preserving agents, sweetening
agents, flavoring agents, flow regulators, release agents, etc. The
compositions may also be formulated so as to provide rapid, sustained,
or delayed release of the active compound(s) contained therein, for
example using liposomes or hydrophilic polymeric matrices based on
natural gels or synthetic polymers.

For the purposes of the present invention, the MAF or compounds or the
pharmaceutical composition of the present invention may be
administered by any of several routes including but not limited to
oral administration, buccal (e.g. sub-lingual) administration, topical
administration and parenterally injection, i.e. including intravenous,
intraperitoneal, intramuscular, intrasternal or subcutaneous
injection. The MAF or compound of the present invention will generally
be administered in an 'effective amount', by which is meant any amount
of a MAF that, upon suitable administration, is sufficient to achieve
the desired therapeutic or prophylactic effect in the individual to
which it is administered.

Usually, depending on the condition to be prevented or treated and the
route of administration, such an effective amount will usually be
between 0.01 to 100 ng, preferably between 0.1 and 50 ng and even more
preferably between 0.1 and 10 ng of the MAF per kilogram body weight,
which may be administered as a single daily dose, divided over one or
more daily doses, or essentially continuously, e.g. using a drip
infusion.

In particular embodiments, the effective amount is between 25 and 200
ng MAF/dose. In further particular embodiments, the effective amount
is between 25-500ng, more particularly about 10 ng MAF per week.

In particular embodiments, the MAF or pharmaceutical composition of
the present invention are administered once per week, during 2 to 50
weeks, preferably during 5 to 40 weeks, such as during 15 weeks.

The amount(s) to be administered, the route of administration and the
further treatment regimen may be determined by the treating clinician,
depending on factors such as the age, gender and general condition of
the patient and the nature and severity of the disease/symptoms to be
treated.

In accordance with the method of the present invention, said
pharmaceutical composition can be administered separately at different
times during the course of therapy or concurrently in divided or
single combination forms. The present invention is therefore to be
understood as embracing all such regimes of simultaneous or
alternating treatment and the term 'administering' is to be
interpreted accordingly.

For an oral administration form, the compositions of the present
invention can be mixed with suitable additives, such as excipients,
stabilizers or inert diluents, and brought by means of the customary
methods into the suitable administration forms, such as tablets,
coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
Examples of suitable inert carriers are gum arabic, magnesia,
magnesium carbonate, potassium phosphate, lactose, glucose or starch,
in particular, corn starch. In this case, the preparation can be
carried out both as dry and as moist granules. Suitable oily
excipients or solvents are vegetable or animal oils, such as sunflower
oil or cod liver oil. Suitable solvents for aqueous or alcolholic
solutions are water, glycerol and sugar solutions. Polyethylene
glycols and polypropylene glycols are also useful as further
auxiliaries for other administration forms. As immediate release
tablets, these compositions may contain microcrystalline cellulose,
dicalcium phosphate, starch, magnesium stearate and lactose and/or
other excipients, binders, extenders, disintegrants, diluents and
lubricants known in the art.

The oral administration of a pharmaceutical composition comprising the
MAF according to the invention, is suitably accomplished by uniformly
and intimately blending together a suitable amount of said MAF in the
form of a powder, optionally also including a finely divided solid
carrier, and encapsulating the blend in, for example, a hard gelatin
capsule. The solid carrier can include one or more substances, which
act as binders, lubricants, disintegrating agents, coloring agents,
and the like. Suitable solid carriers include, for example, calcium
phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,
gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion
exchange resins.

Oral administration of a pharmaceutical composition comprising the MAF
according to the present invention can also be accomplished by
preparing capsules or tablets containing the desired amount of said
MAF, optionally blended with a solid carrier as described above.
Compressed tablets containing the pharmaceutical composition of the
invention can be prepared by uniformly and intimately mixing the
active ingredient with a solid carrier such as described above to
provide a mixture having the necessary compression properties, and
then compressing the mixture in a suitable machine to the shape and
size desired. Molded tablets maybe made by molding in a suitable
machine, a mixture of powdered compound or MAF according to the
invention moistened with an inert liquid diluent.

For parenterally administration such as subcutaneous or intravenous
administration, the MAF or compounds of the present invention, if
desired with the substances customary therefore such as solubilizers,
emulsifiers or further auxiliaries, are brought into solution,
suspension, or emulsion. The MAF or compounds of the invention can
also be lyophilized and the lyophilizates obtained used, for example,
for the production of injection or infusion preparations. Suitable
solvents are, for example, water, physiological saline solution or
alcohols, e.g. glycerol, in addition also sugar solutions such as
glucose or mannitol solutions, or alternatively mixtures of the
various solvents mentioned. The injectable solutions or suspensions
may be formulated according to known art, using suitable nontoxic,
parenterally-acceptable diluents or solvents, such as mannitol,
1,3-butanediol, water, Ringer's solution or isotonic sodium chloride
solution, or suitable dispersing or wetting and suspending agents,
such as sterile, bland, fixed oils, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.

For topical administration, which includes the application of
medicinal substances to the skin or various body orifices, the MAF or
compounds of the present invention may be applied in a variety of
forms such as liquid, semisolid or solid. Some of the possible
components of topical, transdermal and transmucosal formulations and
delivery devices include solubilizing agents, suspending agents,
dispersing agents, preservatives, animal and vegetable fats, oils, or
waxes, emollients, stabilizing agents, thickening or gelling agents,
buffering agents, adhesive agents, adjuvants and additives,
emulsifiers and penetration enhancing agents as known to the person
skilled in the art.

For sub-lingual administration, the MAF or compounds of the present
invention may be formulated in admixture with with at least a proper
excipient typical of sublingual formulations. As non limiting example
for the artisan skilled in the art, said excipients are selected from
the group including: water-soluble inert excipients (such as, for
example, mannitol, sorbitol, lactose); water-insoluble excipients
which help the delivery of the active substance at the sublingual
mucosa level (such as, for example, microcrystalline cellulose);
sweeteners (such as, for example, aspartame, sodium saccharate);
flavourings (such as, for example, peach, apricot, banana, strawberry,
orange, mandarin flavours); lubricants (such as, for example,
magnesium stearate, PEG 6000); taste correctors (such as, for example,
sodium citrate); other excipients, additives, carriers commonly used
in the formulation pharmaceutical art.

In addition to administration with conventional carriers, the MAF or
compounds of the present invention may be administered by a variety of
specialized oligonucleotide or nucleic acid delivery techniques such
as by encapsulation in various encapsulating materials, such as in
unilamellar liposomes (Bayard et al., Eur. J. Biochem. 151: 319, 1985)
or by conjugation to carrier molecules such as poly(L-lysine).
Reconstituted Sendai virus envelopes have been successfully used to
deliver RNA and DNA to cells (Arad et al., Biochem. Biophys. Acta. 85:
88, 1986). Moreover, the virus envelope is not limited to Sendai
virus, but could include encapsulation in any retroviral amphotrophic
particle. These techniques may be utilized for introduction of the
present Macrophage Activation Factors into cells.

The pharmaceutical compositions of this invention can be administered
to humans in dosage ranges specific for each MAF or compound comprised
in said compositions. The MAF or compounds comprised in said
composition can be administered together or separately.

It will be understood, however, that specific dose level and frequency
of dosage for any particular patient may be varied and will depend
upon a variety of factors including the activity of the specific MAF
or compound of the invention employed, the metabolic stability and
length of action of that MAF or compound, the age, body weight,
general health, sex, diet, mode and time of administration, rate of
excretion, drug combination, the severity of the particular condition,
and the host undergoing therapy.


EXAMPLES

1. Effect of GcMAF on a patient suffering from CFS/ME.

The patient, a 29 year old female, has suffered from CFS/ME ever since
an acute Epstein-Barr virus infection at the age of 17. The patient
also tested positive for XMRV in three laboratories with different
diagnostic techniques. The patient was treated with intravenous
injections of GcMAF, once a week during 10 weeks. Upon each injection,
200 ng of GcMAF was administered to the patient.

The patient showed significant clinical improvement after the
treatment with GcMAF. In addition, indicators of NK cell activity and
inflammation were positively affected. The results are summarized in
Table 1.

The GcMAF treatment resulted in a decrease of Interleukin-8 (IL8)
concentration in the serum. IL8 is a protein produced by macrophages
and other cell types such as epithelial cells, and is associated with
inflammation. Thus, the decrease of IL8 concentration indicates
reduced inflammation.

Moreover, also a significant decrease of the patient's C4a serum level
was measured after treatment with GcMAF. The C4a measurement was
performed using a Becton Dickinson OptEIA human C4a elisa kit.

Additionally, an increase of intracellular perforin in PBMCs was
observed. The Perforin mRNA level was measured by real-time PCR, using
gene expression assay reagents from Applied Biosystems.

As a conclusion, the results in Table 1 show that the treatment with
GcMAF on a patient suffering from CFS/ME resulted in increased NK cell
activity and reduced inflammation. As reduced NK cell activity and
inflammation are associated with CFS/ME, this indicates that GcMAF
treatment is effective in the treatment of patients suffering from
CFS/ME.


Table 1: Laboratory results before and after GcMAF treatment.
-------------------------------------------------------------
Before After
-------------------------------------------------------------
IL8 serum (pg/mL) 29 12.6
Perforin PBMC 552 1184
C4a serum level (ng/mL) 4519 2292
-------------------------------------------------------------

2. Clinical study on 108 patients suffering from CFS/ME.

A clinical test fo the effects of GcMAF was run on 108 CFS/ME
patients, aged between 18 and 65. The patients tested positive on
Murine Leukemia Virus infection (34 patients), XMRVc (XMRV detection
in co-culture - 54 patients) or serology (20 patients). The patients
were treated with intravenous injections of GcMAF, once a week. Upon
each injection, 25-100 ng GcMAF in 1 mL physiological serum was
administered. 75% of the patients were treated with 100 ng GcMAF per
week.

Already after fifteen weeks, 68 of the 108 patients showed clear
improvements, as listed in Table 2. These results clearly show that
the administration of GcMAF results in clinical improvements of
patients suffering from CFS/ME.


Table 2: Clinical improvements in 68 after 15 weeks of GcMAF treatment.
-----------------------------------------------------------------------
Clinical improvement Fraction of patients
-----------------------------------------------------------------------
Fatigue reduced or disappeared 44/68
Improvement of sleep quality 39/68
Pain reduced or disappeared 35/68
Memory/concentration improved 27/68
Faster or normalized recovery 42/68
Orthostatism reduced or disappeared 22/68*
Digestive problems reduced or disappeared 22/68
-----------------------------------------------------------------------
* Not all patients suffered from orthostatism prior to GcMAF treatment.

--------
(c) 2013 EPO