Saturday, June 26, 2010

Justice John Paul Stevens -- Practice of Medicine and Rule of Law

 

A little Off-Topic Humor

 

Pain Characteristics of People with CFS

The scientific report entitled "Pain Characteristics of People with Chronic Fatigue Syndrome" has now been published in Journal of Musculoskeletal Pain http://informahealthcare.com/toc/mup/18/2  and a summary of the findings can be read below.

This study was part of a programme of work funded jointly by ME Research UK and Glasgow Caledonian University. Details of other research projects funded by ME Research UK and its partners, including a list of scientific papers enamating from projects, can be found here http://www.meresearch.org.uk/research/projects/completed.html  

Pain Characteristics of People with Chronic Fatigue Syndrome

Journal of Musculoskeletal Pain 2010; 18(2): 127-137

Rebecca Marshall, Dr Lorna Paul, Dr Angus K. McFadyen, Danny Rafferty, Dr Leslie Wood. Division of Nursing & Health Care, Faculty of Medicine, Glasgow University, UK, and School of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK

ABSTRACT

Objectives: Until now, there has been a lack of fundamental research into the pain experienced in chronic fatigue syndrome [CFS]. The aims of this study were to (1) investigate the pain experiences of people with CFS with a range of disability, and (2) identify specific pain characteristics of people with CFS.

Methods: Fifty people were recruited, including 10 people who were severely disabled by CFS [25% Group]. Participants completed a structured interview and a series of pain assessments about their current pain, which included the McGill Pain Questionnaire [MPQ], the Pain Anxiety Symptoms Scale [PASS], and visual analog scales.

Results: Muscle pain was the most reported painful symptom [68 percent]. The current pain intensity was 43.2 mm ± 20.8 mm measured on a visual analog scale. The MPQ pain rating index was 23.6 ± 10.8. The PASS total score was 37.9 ± 17.6. Thirty percent [N = 15] of participants reported the cervical spine the location of "most severe" pain, followed by the left and right scapular and right lumbar spine [N = 10 each, 20 percent each]. Further analysis indicated that those people, who were severely disabled by CFS, also experienced significantly more pain [P<0.05].

Conclusion: The results of this study provide objective data to support anecdotal and clinical reports of pain in people with CFS. Pain in people with CFS should be accepted and treated as seriously as other conditions where pain is a significant symptom. Management strategies need to  be tailored to the individual requirements of patients presenting with symptoms of both fatigue and pain.

ACKNOWLEDGEMENTS
This study was jointly funded by Glasgow Caledonian University and ME Research UK


Dr Neil Abbot
Operations Director
ME Research UK
The Gateway
North Methven St
Perth PH1 5PP, UK
Help us by shopping with Amazon http://www.meresearch.org.uk/support/shopping.html
 

Seunghee Hong Dissertation on XMRV

This is a PhD dissertation by Seunghee Hong on XMRV in prostate
cancer, with Ms. Hong's advisor being Robert Silverman, co-discoverer
of XMRV. As you can see by looking at the table of contents, the whole
thing is a hundred and sixty-something pages long and is basically a
book on XMRV, complete with overviews of the IFN-2-5A/RNase L
pathways, XPR1 cellular receptors, XMRV gene expression, etc. For
anyone up to the challenge, it looks to be a pretty good resource for
some good old fashioned book learnin'.

http://etd.ohiolink.edu/send-pdf.cgi/Hong%20Seunghee.pdf?case1251739728

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


IMPLICATIONS FOR XMRV INFECTIONS IN PROSTATE CANCER
by SEUNGHEE HONG
Submitted in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
Thesis Advisor: Dr. Robert H. Silverman
Department of Molecular Biology and Microbiology- Molecular Virology Program
CASE WESTERN RESERVE UNIVERSITY
January, 2010

http://etd.ohiolink.edu/send-pdf.cgi/Hong%20Seunghee.pdf?case1251739728


TABLE OF CONTENTS

LIST OF TABLES ......................................................................................................4
LIST OF FIGURES
....................................................................................................5
ACKNOWLEDGEMENTS
..........................................................................................7
LIST OF ABBREVIATIONS
........................................................................................9
ABSTRACT ............................................................................................................
12

CHAPTER 1. INTRODUCTION...................................................................................
14
IFN system in innate immunity
.................................................................................
14
2-5A/RNase L pathway in the interferon anti-viral system
............................................ 15
Role of RNase L in the biology of prostate cancer
...................................................... 18
Identification of xenotropic gammaretrovirus in prostate tumor tissues
.......................... 19
Replication-competent XMRV genome has been constructed
...................................... 30
XPR1 as a receptor for xenotropic and polytropic murine leukemia
viruses .................... 31
SEVI dramtically boosts HIV-1 infection
....................................................................
34
Retrovirus Restriction Factors
...................................................................................
35
Summary of Introduction
..........................................................................................
39

CHAPTER 2. MATERIALS AND METHODS
.............................................................. 41
Cell Culture ............................................................................................................
41
XPR1 Expression and XMRV Infection of MEFs and CHO Cells
................................... 41
Nested RT-PCR Assays for XPR1
............................................................................
42
XMRV preparations and infectivity assays
................................................................. 43
Effect of SEVI on viral infectivity
...............................................................................
43
Immunofluorescence assay
.....................................................................................
44
Effects of semen on viral infectivity
...........................................................................
44
Preparation of PSA, PSMA, PAP
............................................................................
45
Plasmids and experiments with recombinant viruses
................................................. 45
Isolation of RNA in EPS
..........................................................................................
46
Depletion of XPR1 mRNA using siRNA
.....................................................................
47
Quantitive RT-PCR
.................................................................................................
47
Nested RT-PCR .....................................................................................................
49
Illumina cDNA microarray for gene expression profiles
............................................... 50
Preparation of in vitro co-cultures
.............................................................................
51

CHAPTER 3. XPR1 as a host cellular receptor for XMRV
........................................... 52
Summary ..............................................................................................................
52
Introduction ...........................................................................................................
52
Results .................................................................................................................
55
TCID50 of infectious XMRV supernatant was determined.
........................................... 55
Expression of human XPR1 in mouse cell does not render susceptible to
XMRV infection.
...............................................................................................................
56
XPR1 expression renders hamster cells susceptible to XMRV Infection.
...................... 57
Downregulation of XPR1 in prostate human cells reduces XMRV
infectivity. ................. 62
Discussion.............................................................................................................
68

CHAPTER 4. SEVI boosts infections by XMRV, a Human Retrovirus
Associated with Prostate Cancer
..................................................................................................................
71
Summary ..............................................................................................................
71
Introduction ...........................................................................................................
71
Results .................................................................................................................
73
SEVI promotes XMRV infection of human prostatic and non-prostatic cell
types. ......... 73
SEVI potently increases the infectious titer of XMRV.
............................................... 80
SEVI and semen enhance infectivity at the level of virion attachment
and fusion. ......... 80
XMRV RNA isolated and sequenced from expressed prostatic secretions.
.................. 88
Discussion.............................................................................................................
98
Potent enhancement of XMRV infectivity mediated by SEVI or semen.
........................ 98
Host restriction of XMRV replication by RNase L.
...................................................... 99
The SEVI effect and presence of XMRV in
EPS........................................................ 100

CHAPTER 5. Gene expression profiles regulated by XMRV infection in
human primary prostate cell cultures
...............................................................................................................
102
Summary .............................................................................................................
102
Introduction ..........................................................................................................
103
Results ................................................................................................................
105
Discussion............................................................................................................
139

CHAPTER 6. Stromal-epithelial cell interaction and apoptosis affected
by XMRV infection in prostate cancer progression
..........................................................................................................
144
Summary .............................................................................................................
144
Introduction ..........................................................................................................
144
Results ................................................................................................................
146
Discussion............................................................................................................
157

CHAPTER 7. DISCUSSION AND PERSPECTIVE
.................................................... 160
Summary .............................................................................................................
160
XPR1 as an XMRV receptor
...................................................................................
160
Host restriction factors
..........................................................................................
161
XMRV and prostate carcinogenesis
........................................................................
163
XMRV as a sexually transmitted infection
............................................................... 164
Possible involvement of IL-8 in IFN systems
............................................................ 166
Apoptosis induced by Camptothecin upon XMRV
infection........................................ 168
Antiviral effects of camptothecin
.............................................................................
168
BIBLIOGRAPHY ...................................................................................................
169

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

Implications for XMRV Infections in Prostate Cancer
Abstract
By SEUNGHEE HONG

The xenotropic murine leukemia virus - related virus (XMRV) has
recently been identified in prostate cancer tissues and may contribute
to prostate tumorigenesis. XMRV is the first murine leukemia virus
(MLV) -related virus found in humans and a full-length,
replication-competent XMRV genome was recently constructed from
prostate tissue RNA. Currently, little is known about how this virus
infects and/or is transmitted in the human population or how this
virus promotes prostate tumorigenesis.

To determine how XMRV recognizes the host and initiates infection, we
sought to identify the XMRV receptor. (Chapter 3) Expression of human
xenotropic and polytropic retrovirus receptor 1 (XPR1) in resistant
hamster cells rendered them susceptible to infection by XMRV.
Moreover, down-regulation of XPR1 in susceptible human cell lines
reduced XMRV infectivity, thus implicating XPR1 as a cognate receptor
for XMRV. (Chapter 4) In addition, amyloidogenic fibrils known as
semen-derived enhancer of virus infection (SEVI) derived from prostate
acid phosphatase dramatically enhanced XMRV infections of various
human cells including prostate epithelial and stromal cells. The
enhancing effect of SEVI occurred at the level of viral attachment and
entry but did not bypass the requirement for XPR1. Furthermore, XMRV
RNA was detected in prostate secretions of some prostate cancer
patients, implying that XMRV infection is found in an environment that
secrets a natural enhancer of viral infection, SEVI. (Chapter 5) To
discover global effects of XMRV infection in primary prostate cells,
gene expression profiles upon XMRV infection were determined. Our
results revealed that XMRV induced changes in expression of a
relatively small number of genes. Among those, IL-8, a chemokine
previously shown to be involved in prostate carcinogenesis and
metastasis, was induced by XMRV infection. (Chapter 6) To study
dynamic interactions between prostate stromal and epithelial cells
upon XMRV infection, co-culture experiments were performed but were
inconclusive. However, XMRV was observed to inhibit the ability of the
camptothecin, an inhibitor of topoisomerase I, to induce apoptosis in
primary prostate stromal cells. (Chapter 7) These investigations
provide insight into how XMRV infects and spreads in the human
population with implications for prostate carcinogenesis.
 

CBT & GET are dangerous for ME/CFS Patients

 
<karlkrysko@yahoo.co.uk>


Greg Crowhurst's recent posting of reasons Why It Is Wrong To Prescribe GET
And CBT To Anyone With Severe ME is wholly correct, but misses a crucial
point that shows it is dangerous for less compromised or partly recovered
patients as well.

We have gleaned for quite some years now from the early super work of people
like Suzanne Vernon that exercise challenge elevates the abnormal expression
of already up regulated genes in ME patients. We also have plenty of
evidence that mitochondrial compromise is involved in these patterns of
metabolic dis regulation, and can result in such outcomes as oxidative
stress, which is potentially very damaging. For every extra molecule of
vital ATP energy mitochondria are required to produce with activity demands,
in ME these damaged cell organelles also release one extra unit of super
oxide. These is a direct one to one correlation between both cell products,
and acts just like smoking 5 cigarettes a day that will also produce a given
level of cell damage.

Graded Exercise or Graded Activity Therapy in any patient suffering from ME
whatever the severity will thus increase the demand for ATP energy and hence
increase super oxide leakage longitudinally as well. GET and GAT is
therefore like telling our 5 a day smoker that going to 30 or 40 a day will
not harm them, and then reporting that doing so does not appear to make
patients worse. Such irresponsible and dangerous statements have even been
made by ME supporters in regard to CBT and GET here in Wales, for example,
where we unfortunately still have several such therapy clinics.

A protracted long term GET induced oxidative stress complication is only one
of very many other molecular consequences where systems can similarly be
over driven causing potential damage to DNA, the vascular system, cell
membranes and channels, other cell organelles, and so on almost endlessly,
just as with additional graded nicotine use. And, of course, GET and GAT
clinics do not check up on their clients some years down the line to see how
they are doing health wise, any more than does the tobacco industry.

With CBT, also, patients are not generally encouraged at all to investigate
medical and research findings, or attend national or local ME support group
meetings since such warnings  about oxidative stress, and the like, will
only re enforce the patient's 'faulty' health belief
that they are still
organically ill following some long since passed viral or traumatic
incident, and that has merely left them physically de conditioned (or so the
the story goes).
Because of the latter state, any current additional activity only induces a
fatigue or pain responce accordingly (unfortunately confirming the patient's
misinformed suspicion that they are still medically sick).

So, the CBT aim is to discourage talk about ME symptoms, discourage the use
of quite unnecessary health props such as wheelchairs or walking sticks, and
restore the original level of fitness gradually by incremented exercise and
activity that should eventually return the patient to symptom free
normality, and even work.

With this CBT approach, ME patients will never be given medically helpful
advice showing, for example, that CoQ 10 could block the action of super
oxide in oxidative stress, protecting patients from its effects.

Keeping patients deliberately in the dark medically in this way, and from
informed understanding and choices about what damage GET and GAT itself can
potentially do according to current informed thinking has got to be immoral
and a scandal, and will deserve its place in medical history one day, with
its promoters.

Not, therefore, to diminish any of the important comments of Greg Crowhurst,
in one way the long term effects of both CBT and GET are more deviant,
covert and eventually health compromising to the less severely effected ME
patient attending these UK NHS Clinics because, mercifully, the severely
effected individual simply cannot sustain the damaging upward trend to extra
effort required in graded exercise and activity that the approach demands
over time. But the stronger ME patients might go on damaging themselves,
like chain smokers, for many months, years or indefinitely, looking well
enough - until something gives.

Abnormal gene up regulation responses observed with increased exertion in ME
patients, with knock on consequences for oxidative stress and other serious
long term molecular damage, refutes and medically counter indicates the
psychological behavioural school of Graded Exercise and Graded Activity for
so called de conditioning in ME, along with its immoral attempt to
cognitively obviate the patient's 'misconstrued' health instincts,
experience and deeper medical understanding.

Karl Krysko BA. BSc.

CAN BE RE POSTED

Komaroff says....

During the question-and-answer period of his recent lecture given to
the Massachusetts CFIDS/ME & FM Association, Dr. Anthony Komaroff was
asked whether he would consider CFS to be a neurological
illness.  This was his answer:

"I would certainly say … that there is now abundant evidence of
measurable abnormalities in the central nervous system and the
autonomic nervous system in people with this illness.

"That makes it neurological.
  That's why I think it makes sense, as
Dr. Gurwitz said, to call it Myalgic Ecephalomyelitis or
Encephalopathy, because I think those two words adequately classify
or describe an underlying biology that tests have shown to be the case."

Dr. Komaroff is Simcox/Clifford/Higby Professor of Medicine at
Harvard Medical School, Senior Physician at Brigham and Women's
Hospital in Boston, and Editor-in-Chief of Harvard Health
Publications.  He was a co-author on both the Holmes (1988) and the
Fukuda (1994) definitions of CFS.

For more from a fascinating lecture and question-answer session, go
to the Massachusetts CFIDS/ME & FM Association website:

http://www.masscfids.org/news-a-events/2/221 

Mary Schweitzer

U Miami CFS Awareness Day Videos

Thanks to Dan Moricoli of the CFSKnowledge Center, the three videos of
the University of Miami CFS Awareness Day presentation by Dr. Nancy
Klimas, Dr. Irma Rey, and Dr. William K. Scott (Genomics Research) are
now available for viewing on line at
http://cfsknowledgecenter.com/expert-assistance.php .
 

Most Effective Treatments

http://mcs-america.org/june2010.pdf



The Most Effective Rated
Treatments for Chronic
Fatigue Syndrome




Norwegian scientists surveyed 828 chronic fatigue
syndrome patients to find out what treatments were
most and least helpful.

Rest was rated the most helpful by 97% of
participants, followed by pacing at 96%.

Pacing is a method of managing energy expenditure
by limiting activities to the most essential that can
be handled at a comfortable pace.
The easiest way to understand pacing is to imagine
starting the day out with a handful of cards and each
time energy is expended, a card is lost.

When the cards are low, the day is over and sleep is
required.

Each activity of the day requires a card, including
getting dressed, bathing, cooking, and visiting with
someone.

If too many activities exhaust the supply of cards, a
deficit ensues and one nights sleep is not enough to
recuperate.

Most of us start the day with unlimited cards.
Certainly we have enough to get through until
bedtime.

For people with chronic fatigue syndrome, they have
few cards to begin with and must pick and choose
how they expend their energy so that they don't run
out of cards and collapse.

This forces them to prioritize, establish routines,
schedule extra rest, and keep activities short. This is
known as pacing.


People with chronic fatigue syndrome also engage in
shielding, which was rated as highly helpful by 96%
of study participants.

Shielding involves surrounding oneself in quiet and,
in some cases, darkness. People with chronic fatigue
syndrome are often sensitive to light and sound,
which expends their limited supply of energy by
stimulating the central nervous system.




       ````````````````````````
       *Graded training may cause
         deterioration of the condition
         in many patients.*

       ````````````````````````



One of the most misconceived treatments
recommended by the medical profession is graded
exercise therapy, yet 79% of the participants
experience deterioration as a result.

It stands to reason that with such limited energy to
expend, using too much on exercise leaves woefully
little, if any, energy for tasks of survival such as
fixing meals, eating, paying bills, and bathing.


Patients' experience is important in this context,"
says Bjorkum and colleagues, Graded training may
cause deterioration of the condition in many
patients."


Another failed treatment was cognitive behavior
therapy, yet this is also widely recommended despite
the scientific knowledge that chronic fatigue
syndrome is a serious neurological disorder which can
not simply be thought" away.


More than 4 million Americans suffer from chronic
fatigue syndrome and over 2.5% of the population
aged 18-59 years meet the diagnostic criteria. Only
20% have been properly diagnosed. Though more
frequent in women aged 40-59 years, people of all
ages, ethnicities, economic statuses, and both sexes
may be affected.


The exact cause is uncertain and likely multifactorial.
Conditions that have been proposed to trigger the
development of chronic fatigue syndrome include
viral infection, immune disorders,
hypothalamic-pituitary adrenal (HPA) axis
dysfunction, and toxic exposure.



Reference


Bjrrkum T, Wang CE, Waterloo K. [Patients'
experience with treatment of chronic fatigue
syndrome] Tidsskr Nor Laegeforen. 2009 Jun
11;129(12):1214-6. [Article in Norwegian]


~~~~~~

Notes from Dr. De Meirleir on Madrid Conference

http://bit.ly/bkFCV9

Referat fra Prof. De Meirleir og Dr Petersons XMRV-foredrag

*Yesterday we have gone to Madrid to hear Dr. Dan Peterson's lecture.


It was an all morning session about XMRV, and the
first to talk was Dr. Dan Peterson. He shared with
everybody some of the findings in XMRV (nothing
new) with many references to Dr. Judy Mikovits and
the WPI, and his slides were the same that Dr.
Mikovits uses in her lectures. The reasons for leaving
the WPI were more a personal decision in order to
have more time for himself after 25 years of service
in WPI. He seems to be having a nice rest and is
very happy to have the time to go sailing again.

At some point It was mentioned by Daniel Peterson,
that so far the best biomarker for CFS is the Low
NKCell function test, and that if your budget was
restricted, this would be the test to do, I guess He
was referring to the same direction than Dr. Klimas
is always talking about as well. http://bit.ly/cJ7YVc

The second lecture was from Dr. Kenny De Meirleir,
very interesting, focused on the fact that the most
important thing now is to have a simple and good
XMRV Test for all the researchers. He assured that
they already have the test and it works, and it is a
matter of days that they will make it available, 3 to
4 weeks probably.

De Meirleir also talked about all the work that is
being done and possible treatments, but curiously
never mentioned the Ampligen. Dr. Marc Fremont's
lecture was very technical about this test, and
finally, Dr. Chris Roelant talked about the urine test
they already have, which indicates intestinal
dysbiosis is present in these patients.

Some of the questions posted in the Conference
were regarding the recent German study, and the
fact that XMRV is 3 times more present in immune
compromised patients already tells you that there is
an immune problem on CFS patients where most of
them have the retrovirus.

There are three pathways affected on CFS which
affect muscles and CNS:

25-A
PKR
NO

There are also 3 pats of the immune system
affected:

Th1 Linked to viral reactivation and intracellular
infection due to an excessive hypersensitivity
Th2 Linked to pathogens, allergies and inflammation
and blood brain barrier dysfunction
Th17 Linked to autoimmunity and inflammation and
blood brain barrier dysfunction

De Meirleir elaborated later on that Th2 imbalance
that causes diseases such as CFS, Autism, HIV, MCS,
Mercury exposure, Allergies, Parasites.
Th1 relates to cell-based immunity Th2 relates to
Humoral immunity

You can see a bit on the conference in this link:

http://www.youtube.com/watch?v=ywLnptBQLeg

When we asked Daniel Peterson to comment on Dr.
Hubert lecture of last Monday in London, his answer
was that Huber had positives 17 of the 19 samples
that were sent to her, but She only spoke of the
samples of other doctors who have tested negative.
Daniel Peterson has said that once again we face the
uncertainty of correctness in the samples tested, but
also added that if She would have done a good job,
She could not have all negatives, at least 3% would
be positive, as we see is happening with the recent
German study.

When we asked about the fact that HIV patients that
are XMRV positive and have CFS, are not reacting to
their current antiretroviral treatment, and that could
lead to the possibility that XMRV is just a passenger
virus in a depressed immune system, his answer was
that actually that would be one possibility, and the
other one is that they are taking the wrong drug,
because XMRV is a different retrovirus, and they are
being treated for HIV.

When we asked about the German study, and the
fact that XMRV has been found now in the respiratory
tract, and that could lead to new ways to detect
XMRV different from the ones used in WPI, He said
that is a big possibility. As we know blood is not the
reservoir of XMRV, maybe the brain or the liver…

There were some other questions regarding the
prevalence of CFS in children, banning blood
donations, etc…


I will try to add the whole Conference next week if I
have the time to do so, but basically these would be
the headlines of the Conference.*

Two articles re: possible XMRV treatments- 'HIV drugs could have second life'

Two articles re: possible XMRV treatments- 'HIV drugs could have
second life as treatment for retrovirus correlated with prostate
cancer' and 'HIV Drugs Might Combat Two Other Diseases'

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

'HIV drugs could have second life as treatment for retrovirus
correlated with prostate cancer'- Scientific American
Apr 1, 2010 05:01 PM in Health & Medicine
By Katherine Harmon
http://www.scientificamerican.com/blog/post.cfm?id=hiv-drugs-could-have-second-life-as-2010-04-01


Some medications already being used to treat HIV appear to inhibit a
retrovirus that has been linked to prostate cancer and chronic fatigue
syndrome, reports a new study published online April 1 in PLoS ONE.

Like HIV (human immunodeficiency virus), XMRV (xenotropic murine
leukemia virus-related virus) is a retrovirus that infects host cells
with its RNA through reverse transcriptase enzymes, using protease
enzymes to process proteins for viral assembly and integrase enzymes
to help infect the host cell's DNA. Many of the drugs approved to
treat HIV target one of these processes to slow or prevent host cells
from becoming infected.

After testing 28 approved drugs on XMRV cultures, researchers found
that four of the medications (raltegravir, L-000870812, Zidovudine
(AZT) and tenofovir disoproxil fumarate) were able to stop XMRV from
replicating. Two of the drugs are reverse transcriptase inhibitors,
and the others (including raltegravir, which worked the best) are
integrase enzyme inhibitors.

In addition to the similar success of the drugs' compounds, the
researchers found that the use of the antiretrovirals might do well to
follow HIV treatment protocol, in which multiple treatments are often
used together. "These drugs inhibited XMRV at lower concentrations
when two of them were used together, suggesting that highly potent
'cocktail' therapies might inhibit the virus from replicating and
spreading," Raymond Schinazi, a professor of pediatrics and chemistry
at Emory University's Center for AIDS Research, said in a prepared
statement. "This combination of therapies might also have the added
benefit of delaying or even preventing the virus from mutating into
forms that are drug-resistant."

XMRV is one of only a few retroviruses known in humans and was found
in 2006. Since then, some studies have found a correlation between it
and some forms of prostate cancer (which is the second most common
cancer among men) as well as chronic fatigue syndrome (estimated to
affect four to 10 people per thousand). Other studies have had mixed
results, so the implications of the results hinge largely on future
findings about this retrovirus's role in human disease. "It is not yet
clear if any illnesses are directly caused by XMRV," the researchers
wrote in their study. But "our data indicates that XMRV infections
might be prevented or treated with specific antiviral agents."

And if the retrovirus does prove to play a role in causing illnesses,
the findings could help in designing clinical trials to test the
treatments in vivo.

In the meantime, Ila Singh, an associate professor of pathology at the
University of Utah School of Medicine and lead author on the new
study, concluded in a prepared statement that, "These results offer
hope to infected persons."


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


'HIV Drugs Might Combat Two Other Diseases'
Prostate cancer, chronic fatique are new research targets
-- Robert Preidt
http://health.msn.com/medications/articlepage.aspx?cp-documentid=100256517


THURSDAY, April 1 (HealthDay News) -- Four anti-HIV drugs inhibit a
retrovirus recently linked to prostate cancer and chronic fatigue
syndrome (CFS), say U.S. researchers.

If further investigation proves that the retrovirus xenotropic murine
leukemia virus-related virus (XMRV) causes prostate cancer or CFS,
these HIV drugs may be an effective treatment for the two conditions.

In this study, researchers from the University of Utah and Emory
University/Veterans Affair Medical Center tested how effectively 45
compounds used to treat HIV and other viral infections worked against
XMRV. Raltegravir was the most effective, and three other drugs --
L-00870812, zidovudine (ZDV or AZT), and tenofovir disoproxil fumarate
(TDF) -- also prevented XMRV replication.

"Our study showed that these drugs inhibited XMRV at lower
concentrations when two of them were used together, suggesting that
possible highly potent 'cocktail' therapies might inhibit the virus
from replicating and spreading," Raymond F. Schinazi, a professor of
pediatrics and chemistry and an investigator with the Center for AIDS
Research at the Emory University School of Medicine and the Atlanta
VA, said in a news release.

"This combination of therapies might also have the added benefit of
delaying or even preventing the virus from mutating into forms that
are drug-resistant," Schinazi added.

"These results offer hope to infected persons, but we are still at the
early stages of our understanding of the potential link between XMRV
and these diseases," Dr. Ila R. Singh, an associate professor of
pathology at the University of Utah Medical School, said in the news
release.

The study was published April 1 in the journal PLoS One.

More information

The U.S. Centers for Disease Control and Prevention outlines the
possible causes of chronic fatigue syndrome-
http://www.cdc.gov/cfs/cfscauses.htm

SOURCE: University of Utah Health Sciences, news release, April 1, 2010
Copyright @2010 HealthDay. All Rights Reserved.

'Raltegravir Is a Potent Inhibitor of XMRV

'Raltegravir Is a Potent Inhibitor of XMRV, a Virus Implicated in
Prostate Cancer and Chronic Fatigue Syndrome'
Ila R. Singh1*, John E. Gorzynski1, Daria Drobysheva1, Leda Bassit2,
Raymond F. Schinazi2

1 Department of Pathology, University of Utah, Salt Lake City, Utah,
United States of America, 2 Center for AIDS Research, Laboratory of
Biochemical Pharmacology, Department of Pediatrics, Emory University
School of Medicine and Veterans Affairs Medical Center, Decatur,
Georgia, United States of America

Citation: Singh IR, Gorzynski JE, Drobysheva D, Bassit L, Schinazi RF
(2010) Raltegravir Is a Potent Inhibitor of XMRV, a Virus Implicated
in Prostate Cancer and Chronic Fatigue Syndrome. PLoS ONE 5(4): e9948.
doi:10.1371/journal.pone.0009948

Full text- http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009948


Abstract

Background
Xenotropic murine leukemia-related retrovirus (XMRV) is a recently
discovered retrovirus that has been linked to human prostate cancer
and chronic fatigue syndrome (CFS). Both diseases affect a large
fraction of the world population, with prostate cancer affecting one
in six men, and CFS affecting an estimated 0.4 to 1% of the
population.

Principal Findings
Forty-five compounds, including twenty-eight drugs approved for use in
humans, were evaluated against XMRV replication in vitro. We found
that the retroviral integrase inhibitor, raltegravir, was potent and
selective against XMRV at submicromolar concentrations, in MCF-7 and
LNCaP cells, a breast cancer and prostate cancer cell line,
respectively. Another integrase inhibitor, L-000870812, and two
nucleoside reverse transcriptase inhibitors, zidovudine (ZDV), and
tenofovir disoproxil fumarate (TDF) also inhibited XMRV replication.
When combined, these drugs displayed mostly synergistic effects
against this virus, suggesting that combination therapy may delay or
prevent the selection of resistant viruses.

Conclusions
If XMRV proves to be a causal factor in prostate cancer or CFS, these
discoveries may allow for rational design of clinical trials.




Editor: Peter Sommer, Institut Pasteur Korea, Republic of Korea


Received: February 18, 2010; Accepted: March 11, 2010; Published: April 1, 2010

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

Funding: This work is supported in part by NIH grant 2P30-AI-50409
(CFAR to RFS), and by the Department of Veterans Affairs (RFS). The
funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.

Competing interests: RFS is a founder and major shareholder of RFS
Pharma, LLC that is developing Amdoxovir clinically and he receives
royalties from the sales of 3TC. This does not alter the authors'
adherence to all the PLoS ONE policies on sharing data and materials.

* E-mail: ila.singh@path.utah.edu



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Introduction Top
Xenotropic murine leukemia-related retrovirus (XMRV) is a recently
discovered infectious agent [1] that has been linked to human prostate
cancer [2] and chronic fatigue syndrome (CFS) [3]. Both diseases
affect a large fraction of the world population, with prostate cancer
affecting one in six men, and CFS affecting an estimated 0.4 to 1% of
the population [4], [5]. XMRV nucleic acid or proteins are found in
27% of prostate cancers and in 68% of chronic fatigue syndrome
patients, and in less than 4–6% of normal controls, suggesting an
association between the virus and human disease [2], [3].

CFS, a disease characterized by severe debilitating fatigue, has had
an uncertain etiology since its recognition. While a series of viral
agents and environmental toxins have been proposed to be associated
with CFS, no clear evidence for these has ever been presented
(reviewed in [6]). The recent association of XMRV with CFS from the
Whittemore Peterson Institute in Reno, Nevada, while far from being
proven causal, is the strongest viral association to be made yet.
Three recent reports, using plasmid DNA as positive controls, did not
find XMRV in CFS patients in Europe [7] [8] [9]. The prevalence of
XMRV in prostate cancer in Europe is uncertain, with one German group
reporting the presence of XMRV in human prostates [10], and the other
not detecting any [11]. However, the notion that a retrovirus might be
involved in both cancer and a neuroimmune illness in humans is not
without precedence. Human T-cell lymphotrophic virus, type 1 (HTLV-1),
another retrovirus, causes both T-cell lymphoma/leukemia as well as
tropical spastic paraparesis, a myelopathy due to immune defects
resulting from the viral infection.

Infectious XMRV has been isolated from sera of CFS patients [3]. The
presence of circulating infectious retrovirus particles in the blood
invokes a scenario not unlike infection with another retrovirus, human
immunodeficiency virus type 1 (HIV-1). Since there is no effective
treatment for this profoundly debilitating illness, the use of
antiretroviral agents that have proven to be reasonably safe for human
use, might be of benefit. The discovery of effective antiretroviral
agents against XMRV would allow for rational design of clinical trials
to prevent progression of prostate cancer or to treat CFS.

In this study, we report the effect of 45 compounds on XMRV
replication in MCF-7 and LNCaP cells, cell lines generated from human
breast and prostate cancers, respectively. We studied drugs used in
the treatment of HIV-1 infections, as well as compounds used to treat
other viral infections in humans. XMRV is a gammaretrovirus, closely
related to the murine leukemia viruses (MLV) [1]. At the amino acid
level, it shares considerable identity with sequences of Moloney
murine leukemia virus (MoMLV), a prototype MLV. The maximum similarity
between XMRV and MoMLV proteins is found in the sequences for viral
protease (96% identity), and the least similarity is between the two
envelope proteins (66% identity) [1]. Unfortunately, not many
actively-used antiretroviral agents have been tested for activity
against MLV, with the exception of ZDV, which effectively suppresses
MLV [12], and was recently demonstrated to be effective against XMRV
as well [13]. In contrast, while there is a lot of information on
antiviral activity against essential HIV-1 proteins, there is very
little similarity between HIV-1 and XMRV proteins, with the proteases
(PR) of the two viruses sharing 28% identity at the amino acid level,
the reverse transcriptase proteins (RT) sharing 17% and the integrase
(IN) proteins sharing just 14% identity. This low sequence similarity
makes it difficult to predict which, if any, of the antiretroviral
agents that are effective against HIV-1 would be effective against
XMRV. We chose several drugs from each major class of antiretroviral
agents: nucleoside and non-nucleoside RT inhibitors (NRTIs and
NNRTIs), IN inhibitors, and PR inhibitors (PI). The envelope proteins
of the XMRV and HIV-1 are widely divergent in size (70 kD and 160 kD
respectively), utilize different receptors for viral entry and do not
share any significant similarity. Therefore, peptidomimetics that act
on the HIV-1 envelope protein to prevent viral entry were not included
in our study. A few inhibitors that are known to inhibit replication
of viruses other than retroviruses were also evaluated. A significant
number of compounds tested in our study, viz. 28 out of a total of 45,
are already FDA-approved for the treatment of infection with HIV-1 or
other viruses. We report here for the first time that the integrase
inhibitor, raltegravir (RAL), is extremely potent and selective
against XMRV, when used at low submicromolar concentrations in both
cell culture systems. Another IN inhibitor, L-000870812, and two
NRTIs, ZDV and tenofovir disoproxil fumarate (TDF), also inhibit XMRV
replication, but at higher concentrations. When combined, these
compounds display synergistic effects, suggesting combined modalities
to treat XMRV infection, thus delaying or preventing the selection of
resistant viruses.

Results Top
We tested a total of 45 compounds belonging to different classes of
HIV-1 inhibitors, and a few inhibitors of viruses other than
retroviruses, for their ability to inhibit XMRV replication in
cultured cells. LNCaP and MCF-7 cells were chosen for their ability to
support robust in vitro replication of XMRV. MCF-7 cells, because of
their better growth properties in culture were initially used to test
all 45 compounds (Figure 1). Compounds with anti-XMRV activity were
subsequently tested in both LNCaP and MCF-7 cells (Table S1). To
determine if a reduction in viral release might be due to toxicity of
the compound and not due to specific antiretroviral activity, cellular
morphology was monitored every 24 h by microscopic examination, and an
MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphen​yltetrazolium bromide]
colorimetric assay was used to measure potential cytotoxicity produced
by the compounds. Supernatants were collected every 24 h and assayed
for viral release by measuring RT activity. Inhibition of RT activity
(see Figure 2) was averaged over 3–6 experiments, each performed in
duplicate, and used to calculate the median (EC50) and 90% effective
concentrations (EC90) for each compound (Figure 1). For comparison
purposes, all compounds evaluated in these studies were also tested
against HIV-1LAI in primary human lymphocytes.

Figure 1. EC50, EC90 and CC50 values of compounds tested in
XMRV-infected MCF-7 cells, and in HIV-1 infected peripheral blood
mononuclear cells.

All compounds were evaluated in duplicate at least three times. Values
shown are average of replicate assays.
*(4S)-8-Chloro-4-methyl-5-(3-methylbut-2-eny​l)-3,4,5,6-tetrahydro-1H-
[1], [3]diazepino[4,5,6-cd]indole-2(2aH)-thione.

doi:10.1371/journal.pone.0009948.g001
Inhibitors of HIV-1 reverse transcriptase
The following NRTI inhibitors of HIV-1 RT were tested in our XMRV
replication assays: ZDV, 3′-azido-3′-deoxyadenosine (AZA),
3′-azido-3′-deoxyguanosine (AZG), 3′-azido-3′-deoxy-5-methyl-cytidine
(CS-92), lamivudine (3TC), emtricitabine [(-)-FTC], tenofovir (TNV)
and its prodrug form TDF, 9-(β-D-1,3-dioxolan-4-yl)guanine (DXG) and
its prodrug form, amdoxovir (DAPD, AMDX), (-)-carbovir (CBV),
stavudine (D4T) and its corresponding cytosine analog (D4C), videx
(ddI), zalcitabine (ddC), and 3′-fluoro-3′-deoxythymidine (FLT). We
also tested the NNRTIs efavirenz, and a TIBO derivative that was shown
to be effective in a murine system [14]. Among these, the most potent
XMRV inhibitors were ZDV and TDF (Figure 2, A, B). The EC50 and EC90
in MCF-7 cells were 0.11 µM and 7.3 µM for ZDV, and 0.24 µM and 15.3
µM for TDF respectively (see Figure 1). The EC50 and EC90 values were
also determined in LNCaP cells, a prostate cancer cell line, and there
was a consistent difference of up to 5 fold between the two cell
lines, which may be related to their differing rates of nucleoside
uptake and bioconversion to the active nucleoside triphosphate analog.
The EC50 and EC90 in LNCaP cells were 0.14 µM and 1.1 µM for ZDV, and
0.9 µM and 4.2 µM for TDF, respectively. CBV, AZA, FLT and D4T all
showed greater than 70% inhibition of XMRV replication (see Table S1),
but at the much higher concentration of 100 µM. AZG, CS-92, (-)-FTC,
3TC, ddI, DAPD and DXG were essentially inactive at 100 µM (Figure 1).
TFV was also ineffective against XMRV, probably due to its polar
nature, which may not allow sufficient drug to penetrate into the
cells. The NNRTIs efavirenz (EFV) and the TIBO derivative, did not
demonstrate any major activity against XMRV.

Figure 2. Inhibition of XMRV replication in LNCaP cells in the
presence of increasing concentrations of antiviral agents.

Viral release from XMRV-infected LNCaP cells in the presence of
increasing concentrations of (A) ZDV (B) TDF (C) RAL and (D)
L-000870812, was determined by measuring RT activity in the
supernatants. Percent inhibition was calculated based on infected
cells exposed to DMSO alone being set to 0% inhibition, and naïve
cells in the absence of any compounds set at 100% inhibition. Cell
viability was checked by microscopy, quantified by the MTT assay, and
represented by shaded bars. Data for each compound were derived from
an average of at least three independent experiments, each performed
in duplicate.

doi:10.1371/journal.pone.0009948.g002
Inhibitors of HIV-1 Integrase
IN inhibitors raltegravir (RAL or MK-0518) and L-000870812 [15] were
also evaluated for their ability to inhibit XMRV in the two cell
systems (Figure 1, Figure 2 C and D). Of all the compounds tested, RAL
was the most potent, with an EC50 of 0.005 µM and an EC90 of 3.5 µM in
MCF-7 cells, and an EC50 of 0.03 µM and an EC90 of 0.46 µM in LNCaP
cells (Table S1). L-000870812, showed activity against XMRV
replication at considerably higher concentrations, with an EC50 and
EC90 of 0.16 µM and 26.9 µM in MCF-7 cells, and 0.7 µM and 4.5 µM in
LNCaP cells, respectively.

Inhibitors of HIV-1 Protease
Nine known HIV-1 PIs were evaluated for activity against XMRV (Figure
1). The most effective was nelfinavir, albeit with an EC50 of 34.3 µM.
The following PIs had very modest anti-XMRV activities: atazanavir
(EC50 of 64.8 µM), amprenavir (EC50 of 68.0 µM), lopinavir (EC50 of
72.2 µM), and ritonavir (EC50 of 76.4 µM). Darunavir, indinavir,
saquinavir and tipranavir were essentially ineffective against XMRV in
vitro, when tested up to 100 µM.

Inhibitors of viruses other than HIV-1
A select number of antiviral agents known to inhibit viruses other
than retroviruses were also evaluated. These included the
anti-herpetic drugs acyclovir (ACV), ganciclovir (GCV), vidarabine
(ara-A), 5-Iodo-2′-deoxyuridine (IdUrd), penciclovir (PCV), foscarnet
(PFA), vistide (HPMPC); the anti-hepatitis drugs entecavir (ETV),
telbivudine (LdT), and ribavirin (RBV). ETV was also selected because
it was recently reported to inhibit HIV-1 replication, both in vitro
and in humans [16]. Other compounds claimed to be effective against
XMRV, MLV, HIV-1 and other viruses, such as chloroquine [17],
dehydroepiandrosterone (DHEA) [18], methylene blue and aspirin were
also evaluated for anti-XMRV activity in vitro. Methylene blue is
known to have antiherpetic activity and also can inactivate HIV-1
[19]. Unfortunately, most of the compounds listed above, except IdUrd
were ineffective against XMRV, or were effective at toxic
concentrations (Figure 1). IdUrd demonstrated a low therapeutic index
(TI, the ratio of CC50/EC50) and cannot be considered as a specific
antiviral agent against XMRV.

Combination effects of active compounds on XMRV replication
Binary combinations of the most potent compounds, viz. RAL,
L-000870812, TDF and ZDV were tested for activity against XMRV in
LNCaP cells. Compounds were tested at increasing concentrations, in
three different sets, with the ratio of the two compounds kept
constant. The data were analyzed using the CalcuSyn method originally
described by Chou and Talalay [20]. A summary of results for all
combinations evaluated in LNCaP cells is presented in Figure 3.

Figure 3. Evaluation of drug-drug interactions against XMRV at 50%,
75%, 90%, and 95% inhibition.

Combination Index (CI) values were determined for a mutually exclusive
interaction using CalcuSyn program, where CI <1 indicates synergism,
CI = 1 indicates additive effect, and CI >1 indicates antagonism.
Weighted average CI value (CIwt) was assigned as [CI50 + 2CI75 + 3CI90
+ 4CI95]/10. RAL, raltegravir; TDF, tenofovir disoproxil fumarate;
ZDV, zidovudine.

doi:10.1371/journal.pone.0009948.g003
For the combinations tested (RAL with TDF or ZDV or L-000870812; TDF
with ZDV or L-000870812; L-000870812 with ZDV), an additive or mostly
synergistic interaction was noted at all effect levels without
apparent cytotoxicity at the highest concentrations used. In the
computational analysis for either one of the four drugs (RAL, TDF,
L-000870812, or ZDV), the linear correlation coefficient (r values) of
the median-effect plot or for their constant ratio combinations ranged
from 0.92 to 0.99 (data not shown), matching the law of mass-action.
The in vitro effect of the combination of RAL with either TDF or ZDV,
showed a favorable dose reduction at all ratios. In addition, all
Combination Index (CI) values (see Materials and Methods) were less
than 1, suggesting synergy when the combination ratios of either TDF
or ZDV and RAL were analyzed (Figure 3). In addition, dual
combinations of either ZDV and L-000870812 or TDF were also tested.
The weighted CI (CIwt) values of 0.1 to 0.5 for TDF + ZDV, indicated
synergistic effects at all ratios tested (Figure 3). Moreover, the
dual combination of L-000870812 and ZDV at ratio 1:2 indicated a
nearly additive effect (CIwt of 1.0); however at ratio of 1:0.4, the
CI value was 0.3, indicating synergism (Figure 3). Of significance was
that all dual combinations containing RAL, the most potent antiviral
agent against XMRV, demonstrated marked synergy at all effect levels
without any apparent cytotoxicity. Interestingly, the combination of
the two IN inhibitors was not antagonistic or additive, but was found
to be synergistic, suggesting that these two compounds may have
different antiviral mechanisms (see discussion).

Discussion Top
In the absence of a clear etiology, the treatment of CFS has been both
empirical and unconventional. Therapies have included immunostimulant
therapy through injections of staphylococcus toxoid [21], intravenous
immunoglobulin therapy [22] [23],[24], and hydrocortisone [25] each
with uneven results. Interferon-β and TNF-α inhibitors have been tried
in very small numbers of patients. Anti-depressants, NSAIDs,
anxiolytic drugs, stimulants, anti-allergy drugs and anti-hypotensive
drugs have all been used, but are not universally beneficial [26]. The
lack of effective therapy has led to use of plant extracts [27],
homeopathy [28], [29], hypnosis [30], acupuncture [31], and whole body
periodic acceleration stress [32], none with sustained benefits. 1The
only modalities of treatment that have any proven benefits are
cognitive behavioral therapy and graded exercise programs, both of
which appear to aid by improving coping skills rather than reduce
symptoms [33]. If, XMRV proves to have a causal association with human
disease, then the knowledge that certain antiretroviral agents inhibit
XMRV at submicromolar concentrations in vitro, and have synergistic
effects when combined, as shown in this study, might lead to clinical
trials. We found that RAL, L-000870812, ZDV, and TDF strongly inhibit
XMRV in cell culture, with RAL being the most potent, at an EC50 of
0.005 µM, and others such as L-000870812 (EC50 = 0.16 µM), ZDV (EC50 =
0.11 µM) and TDF (EC50 = 0.24 µM) being quite effective as well. In
addition, these compounds had high therapeutic indices, with values
for ZDV = 591; TDF = 218; RAL = 18,460 and L-000870812 = 378,
indicating that it should be possible to achieve therapeutic antiviral
levels with minimal toxicity.

Several compounds that we evaluated had a limited effect on XMRV
replication in vitro. Some of these effects can be explained by
currently understood mechanisms. For example, both 3TC and (-)-FTC
need a functional YMDD motif in RT to be active. The M184V mutation in
HIV-1 RT makes the virus resistant to 3TC and (-)-FTC [34]. These
drugs are ineffective against MoMLV, because in MoMLV RT, V is the
natural residue in this motif in place of M. Similarly, V is also the
natural residue at this location in XMRV RT, making 3TC and (-)-FTC
ineffective. Why none of the HIV-1 PIs were effective against XMRV (a
finding that has been reported for selected PIs before [13]) remains
unclear at this time, but could be related to the size of the PI
pocket as well as other biochemical and structural factors.

There was a difference in activities of compounds when tested in
different cell types, which may be related to drug uptake by cells,
the different levels of natural dNTP in the cells, as well as
different intracellular phosphorylation capacity [35]. In general, the
EC50 for the active compounds listed above were lower in MCF-7 than
LNCaP cells suggesting greater potency. Relative to HIV-1, the
compounds were generally less potent against XMRV than HIV-1,
especially at the EC90 level.

The use of monotherapy for treating HIV infections has lead to the
appearance of drug resistant virus [36], [37]. The finding that RAL,
L-000870812, TDF and ZDV have strong synergistic effects when combined
in dual combination bodes well for combination therapy in case of XMRV
infection. If XMRV infection parallels other retroviral infections,
then the use of combination antiretroviral therapy might maintain XMRV
suppression, prevent the emergence of resistance to antiretroviral
agents and possibly also cause amelioration of disease. For HIV-1,
combination therapy works especially well when the combined drugs have
different viral protein targets, or in the case of nucleosides,
utilize different kinases for their activation to NTP analogs [31].
We, therefore, judiciously selected drug combinations that inhibit
XMRV, such as RAL with ZDV or TDF or L-000870812. When the data were
analyzed using the robust method of Chou and Talalay, additive or
synergistic interactions were found at all effect levels when these
agents were tested in LNCaP cells. Of significance was that no
antagonism was noted for any of the combinations evaluated in these
cells. To our surprise, even the two IN inhibitors displayed a
synergistic effect. Both IN inhibitors act by inhibiting the strand
transfer reaction, but if their mechanism of action were to be
identical, they would display an additive effect in combination. A
synergistic effect suggests that there might be subtle mechanistic
differences in the actions of these two IN inhibitors, a finding that
is corroborated by unpublished biochemical experiments (personal
communication, Dr. Daria Hazuda, Merck Research Laboratories, West
Point, PA). It is important to note here, that XMRV differs from HIV-1
in one aspect that is significant for these studies: XMRV isolates
show very limited sequence diversity compared to HIV-1 or MLV. Of all
the sequenced XMRV isolates that currently exist, both from cases with
prostate cancer as well as CFS, obtained from geographically distant
parts of the United States, the two least related genomes differ from
each other in only 27 out of a total of over 8,100 nucleotides. A
similar degree of limited genetic diversity has been found for HTLV-1
[38], another retrovirus implicated in both cancer and neuroimmune
illness. It has been suggested that this lack of diversity in XMRV
sequences implies that the number of replication cycles within one
infected individual is limited [39]. This would suggest that XMRV has
a considerably lower potential for developing drug-resistant
mutations, as compared to HIV-1. Furthermore, it is likely that a
combination of just two drugs might be sufficient for preventing the
emergence of drug-resistant mutant virus, though this would need to be
tested before any therapeutic recommendations can be made. We have
attempted to select for RAL resistant viruses in culture for several
months now, and have not yet been successful at isolating drug
resistant viruses.

When an assay to measure XMRV viral loads becomes available, virus
levels in the blood might become an objective surrogate marker for an
effective response to antiviral drugs, in addition to clinical
outcomes. While it is not yet clear if any illnesses are directly
caused by XMRV, our data indicates that XMRV infections might be
prevented or treated with specific antiviral agents. In the presence
of any evidence of causality of human disease, our findings should
provide the basis for designing clinical trials to treat them.

Materials and Methods Top
XMRV, Cells and Infection with XMRV
293T cells (ATCC, CRL-11268) were transfected with pXMRV1, an
infectious clone of XMRV [2]. Virus released in the supernatant was
harvested and titrated by inoculating MCF-7 cells, a breast cancer
cell line (ATCC, HTB-22) at 70% confluence, with a series of ten-fold
dilutions of XMRV in serum-free medium, followed 36–48 hrs later by
fixation of cells in paraformaldehyde and processing for
immunofluorescence using a rabbit antiserum developed against
inactivated XMRV [2]. Typical virus preparations gave titers of
approximately 2–5×106 infectious units/ml. Virus was diluted in
serum-free medium and used to inoculate cells at a multiplicity of
infection (MOI) of approximately 3, in the presence of various
antiviral compounds as described below. LNCaP, a prostate cancer cell
line (ATCC, CRL-1740) and MCF-7 cells were grown to about 50%
confluence in DMEM containing 10% heat inactivated fetal bovine serum,
100 µg/ml penicillin, and 100 IU/ml streptomycin. Cells were washed
twice with Dulbecco's phosphate buffered saline (DPBS, Gibco), and
incubated with the viral inoculum for 90 min at 37°C in the presence
of 95% air and 5% CO2, cells were washed twice with DPBS, detached
with Trypsin-EDTA (0.25% Trypsin; Cellgro), and counted. One thousand
cells were added to each well of a 96-well plate, along with an equal
volume of medium containing the retroviral inhibitor at 2-fold the
desired concentration. Inhibitors were dissolved in DMSO or water,
depending on their solubility, and were all tested at 0.01 to 100 µM
in 10-fold increments. Where the drug was found to be active at 0.01
µM, further dilutions from 1 nM to 0.01 nM were tested. Each inhibitor
was tested in duplicate a minimum of three separate times in MCF-7
cells in a completely blind fashion using coded compounds, and the
results averaged. Active compounds were also evaluated for antiviral
activity in LNCaP cells to confirm activity in a secondary cell line
known to support XMRV replication. For controls, wells containing
water or DMSO at appropriate concentrations were used.

Assays for cytotoxicity and XMRV replication
Each well was carefully monitored for signs of cellular toxicity due
to the inhibitors by microscopic observation every 24 h. In addition,
cell viability was measured using the CellTiter 96 AQueous One
Solution cell proliferation assay according to the manufacturer
(Promega, Madison, Wis). Viral release from the cells was assayed by
measuring RT activity in the supernatant. For this, supernatant from
each well was collected every 24 h and frozen at −20°C until it was
analyzed by RT assay for viral release as described previously [40].
In brief, oligo(dT)·poly(rA) primer-template assays were performed in
the presence of radiolabeled [α-32P]dTTP and Mn2+. After incubating
the viral supernatants with the RT reaction mix for 1 h at 37°C,
samples were spotted onto DE81 DEAE cellulose paper (Whatman) and
unincorporated label washed away with 2× SSC (1× SSC = 0.15 M NaCl and
0.015 M sodium citrate). Virion-associated RT was analyzed using a
Typhoon 9410 PhosphorImager (GE Healthcare) and quantified with the
Image J software (http://rsbweb.nih.gov/ij/). Inhibition of viral
release as measured on day 6 after inoculation was averaged over 3–5
experiments and plotted. The antiviral EC50 and cytotoxic
concentrations (CC50,) was determined from the concentration–response
curve using the median effect method [20]. HIV-1 replication assays
were performed as described previously using peripheral blood
mononuclear cells (PBMC) obtained from the American Red Cross,
Atlanta, GA, that were stimulated with phytohemagglutinin (PHA) for 72
hr [41].

Combination studies
To evaluate whether the antiviral effects of dual drug combinations
of: RAL with TDF or ZDV or L-000870812; TDF with ZDV or L-000870812;
L-000870812 with ZDV were synergistic, additive or antagonistic, drug
combinations at several constant ratios were evaluated. RAL,
L-000870812, ZDV and TDF were first tested alone to determine the EC50
and EC90 values, at least three times, each in duplicate. For the
median-effect analysis, the compounds were combined at several ratios
based on multiples of their EC50 or EC90 values. For each drug (alone
or in combination), three to four independent experiments were
performed and all samples were processed in duplicate. Analysis was
performed using the software CalcuSyn (Biosoft, Ferguson, MO, USA)
(see Figure 3 for CI values), which allows automated simulation of
synergism and antagonism at all dose and effect levels and displays
the methods of Chou and Talalay [20], including median effect plot and
CI values. Because the high degree effects are more therapeutically
relevant than the low degree of effects, the additional weighted
average CI (CIwt) was calculated, which uses the formula: CIwt = [CI50
+ 2CI75 + 3CI90 + 4CI95]/10, where CI50, CI75, CI90, CI95 are the CI
values at 50%, 75%, 90% and 95% inhibition, respectively. [20], [42].

Supporting Information Top
Table S1.

EC50, EC90 and CC50 values of compounds active against XMRV in MCF-7
cells, as tested in XMRV-infected LNCaP cells. Compounds found to have
significant activity in MCF-7 cells were tested in LNCaP cells for
activity. All compounds were evaluated in duplicate at least three
times. Values shown are average of replicate assays. Corresponding
values in MCF-7 cells are shown for comparison.

(0.11 MB TIF)

Acknowledgments Top
We thank Mervi Detorio and Melissa Johns for their excellent technical
assistance, and Daniel Choe and Robert Schlaberg for their help with
preliminary experiments.

Author Contributions Top
Conceived and designed the experiments: IRS RFS. Performed the
experiments: JEG DD. Analyzed the data: IRS JEG LB RFS. Contributed
reagents/materials/analysis tools: IRS RFS. Wrote the paper: IRS RFS.

References Top
Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, et al. (2006)
Identification of a novel Gammaretrovirus in prostate tumors of
patients homozygous for R462Q RNASEL variant. PLoS Pathog 2: e25. Find
this article online
Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR (2009) XMRV is
present in malignant prostatic epithelium and is associated with
prostate cancer, especially high-grade tumors. Proc Natl Acad Sci U S
A 106: 16351–16356. Find this article online
Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, et al.
(2009) Detection of an infectious retrovirus, XMRV, in blood cells of
patients with chronic fatigue syndrome. Science 326: 585–589. Find
this article online
Hayat MJ, Howlader N, Reichman ME, Edwards BK (2007) Cancer
statistics, trends, and multiple primary cancer analyses from the
Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist
12: 20–37. Find this article online
Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, et al.
(1999) A community-based study of chronic fatigue syndrome. Arch
Intern Med 159: 2129–2137. Find this article online
Devanur LD, Kerr JR (2006) Chronic fatigue syndrome. J Clin Virol 37:
139–150. Find this article online
Erlwein O, Kaye S, McClure MO, Weber J, Wills G, et al. (2010) Failure
to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS
One 5: e8519. Find this article online
Groom HCT, Boucherit VC, Makinson K, Randal E, Baptista S, et al.
(2010) Absence of xenotropic murine leukaemia virus-related virus in
UK patients with chronic fatigue syndrome. Retrovirology 7:
10.1186/1742-4690-1187-1110. Find this article online
van Kuppeveld FJ, Jong AS, Lanke KH, Verhaegh GW, Melchers WJ, et al.
(2010) Prevalence of xenotropic murine leukaemia virus-related virus
in patients with chronic fatigue syndrome in the Netherlands:
retrospective analysis of samples from an established cohort. BMJ 340:
c1018. Find this article online
Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H, et al. (2008)
Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer.
J Clin Virol 43: 277–283. Find this article online
Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N, et al.
(2009) Lack of evidence for xenotropic murine leukemia virus-related
virus(XMRV) in German prostate cancer patients. Retrovirology 6: 92.
Find this article online
Ruprecht RM, O'Brien LG, Rossoni LD, Nusinoff-Lehrman S (1986)
Suppression of mouse viraemia and retroviral disease by
3′-azido-3′-deoxythymidine. Nature 323: 467–469. Find this article
online
Sakuma R, Sakuma T, Ohmine S, Silverman RH, Ikeda Y (2009) Xenotropic
murine leukemia virus-related virus is susceptible to AZT. Virology.
Ho W, Kukla MJ, Breslin HJ, Ludovici DW, Grous PP, et al. (1995)
Synthesis and anti-HIV-1 activity of
4,5,6,7-tetrahydro-5-methylimidazo-[4,5,​1-jk][1,4]benzodiazepin-
2(1H)-one (TlBO) derivatives. 4. J Med Chem 38: 794–802. Find this
article online
Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT,
et al. (2006) Antiretroviral activity, pharmacokinetics, and
tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed
as monotherapy for 10 days in treatment-naive HIV-1-infected
individuals. J Acquir Immune Defic Syndr 43: 509–515. Find this
article online
Yamada A, Sako A, Nishimura S, Nakashima R, Ogami T, et al. (2009) [A
case of HIV coinfected with hepatitis B virus treated by entecavir].
Nippon Shokakibyo Gakkai Zasshi 106: 1758–1763. Find this article
online
Naarding MA, Baan E, Pollakis G, Paxton WA (2007) Effect of
chloroquine on reducing HIV-1 replication in vitro and the DC-SIGN
mediated transfer of virus to CD4+ T-lymphocytes. Retrovirology 4: 6.
Find this article online
Schinazi RF (1990) Antiviral activity of dehydroepiandrosterone. In:
MKaW Regelson, editor. The Biological Role of Dehydroepiandrosterone
(DHEA). Berlin New York: Walter de Gruyter & Co. pp. 157–177.
Floyd RA, Schinazi RF (1998) Thiazine dyes used to inactivate HIV in
biological fluids. In: USPaT Office, editor. USPTO Patent Full-Text
and Image Database. USA: Oklahoma Medical Research Foundation.
Chou TC, Talalay P (1984) Quantitative analysis of dose-effect
relationships: the combined effects of multiple drugs or enzyme
inhibitors. Adv Enzyme Regul 22: 27–55. Find this article online
Zachrisson O, Regland B, Jahreskog M, Jonsson M, Kron M, et al. (2002)
Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue
syndrome–a randomised controlled trial. Eur J Pain 6: 455–466. Find
this article online
Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J (1990) A
double-blind, placebo-controlled trial of intravenous immunoglobulin
therapy in patients with chronic fatigue syndrome. Am J Med 89:
561–568. Find this article online
Peterson PK, Shepard J, Macres M, Schenck C, Crosson J, et al. (1990)
A controlled trial of intravenous immunoglobulin G in chronic fatigue
syndrome. Am J Med 89: 554–560. Find this article online
Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, Tymms K, Wakefield D, et
al. (1997) Intravenous immunoglobulin is ineffective in the treatment
of patients with chronic fatigue syndrome. Am J Med 103: 38–43. Find
this article online
Cleare AJ (2003) The neuroendocrinology of chronic fatigue syndrome.
Endocr Rev 24: 236–252. Find this article online
Afari N, Buchwald D (2003) Chronic fatigue syndrome: a review. Am J
Psychiatry 160: 221–236. Find this article online
Tharakan B, Manyam BV (2006) Botanical therapies in chronic fatigue.
Phytother Res 20: 91–95. Find this article online
Weatherley-Jones E, Nicholl JP, Thomas KJ, Parry GJ, McKendrick MW, et
al. (2004) A randomised, controlled, triple-blind trial of the
efficacy of homeopathic treatment for chronic fatigue syndrome. J
Psychosom Res 56: 189–197. Find this article online
Ernst E (2004) A randomised, controlled, triple-blind trial of the
efficacy of homeopathic treatment for chronic fatigue syndrome. J
Psychosom Res :: 57–503; author reply 504. Find this article online
Gregg VH (1997) Hypnosis in chronic fatigue syndrome. J R Soc Med 90:
682–683. Find this article online
Mears T (2005) Acupuncture in the treatment of post viral fatigue
syndrome–a case report. Acupunct Med 23: 141–145. Find this article
online
Sackner MA, Gummels EM, Adams JA (2004) Say NO to fibromyalgia and
chronic fatigue syndrome: an alternative and complementary therapy to
aerobic exercise. Med Hypotheses 63: 118–123. Find this article online
Reid S, Chalder T, Cleare A, Hotopf M, Wessely S (2000) Chronic
fatigue syndrome. BMJ 320: 292–296. Find this article online
Schinazi RF, Lloyd RM Jr, Nguyen MH, Cannon DL, McMillan A, et al.
(1993) Characterization of human immunodeficiency viruses resistant to
oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother 37:
875–881. Find this article online
Schinazi RF, Hernandez-Santiago BI, Hurwitz SJ (2006) Pharmacology of
current and promising nucleosides for the treatment of human
immunodeficiency viruses. Antiviral Res 71: 322–334. Find this article
online
Volberding PA, Lagakos SW, Grimes JM, Stein DS, Balfour HH Jr, et al.
(1994) The duration of zidovudine benefit in persons with asymptomatic
HIV infection. Prolonged evaluation of protocol 019 of the AIDS
Clinical Trials Group. JAMA 272: 437–442. Find this article online
Land S, McGavin C, Lucas R, Birch C (1992) Incidence of
zidovudine-resistant human immunodeficiency virus isolated from
patients before, during, and after therapy. J Infect Dis 166:
1139–1142. Find this article online
Van Dooren S, Pybus OG, Salemi M, Liu HF, Goubau P, et al. (2004) The
low evolutionary rate of human T-cell lymphotropic virus type-1
confirmed by analysis of vertical transmission chains. Mol Biol Evol
21: 603–611. Find this article online
Coffin JM, Stoye JP (2009) Virology. A new virus for old diseases?
Science 326: 530–531. Find this article online
Telesnitsky A, Blain S, Goff SP (1995) Assays for retroviral reverse
transcriptase. Methods Enzymol 262: 347–362. Find this article online
Schinazi RF, Sommadossi JP, Saalmann V, Cannon DL, Xie MY, et al.
(1990) Activities of 3′-azido-3′-deoxythymidine nucleotide dimers in
primary lymphocytes infected with human immunodeficiency virus type 1.
Antimicrob Agents Chemother 34: 1061–1067. Find this article online
Bassit L, Grier J, Bennett M, Schinazi RF (2008) Combinations of
2′-C-methylcytidine analogues with interferon-alpha2b and triple
combination with ribavirin in the hepatitis C virus replicon system.
Antivir Chem Chemother 19: 25–31.

SSDI and Fibromyalgia/CFS

Source: 24-7
Date:   June 26, 2010
URL:    
http://www.24-7pressrelease.com/press-release/social-security-disability-and-fibromyalgia-158003.php


Social Security Disability and Fibromyalgia
-------------------------------------------
Social Security disability benefits are often the ultimate safety net
for persons suffering from medical impairments that make it impossible
for them to work.

Social Security disability benefits are often the ultimate safety net
for persons suffering from medical impairments that make it impossible
for them to work. For many people, however, struggling through the
Social Security Administration's bureaucracy is frustrating, confusing
and slow. For people suffering from conditions such as Fibromyalgia and
Chronic Fatigue Syndrome, the requirements of the Social Security Act
can become overwhelming. This article will explain and simplify in
general terms the requirements of the Social Security disability program
and describe the application and appeals process.


Two Different Programs - SSDI and SSI

There are two programs under the Social Security Act providing benefits
for persons who are unable to work. The first is the Social Security
Disability Insurance (SSDI) program found in Title II of the Social
Security Act. The second is the Supplemental Security Income program
contained in Title XVI of the Social Security Act. The medical test
for both programs is identical. The differences are in the non-medical
eligibility requirements.


Non-Medical Requirements

SSDI benefits are paid to totally disabled individuals who have worked
and paid into the Social Security system with the FICA taxes that are
deducted from paychecks. These FICA taxes are analogous to insurance
premiums paid for automobile, homeowners or other private insurance.
The FICA payments, which are matched by employers, buy coverage under
the Social Security Retirement, Disability and Medicare programs. For
SSDI, there are two requirements: a worker must have worked and paid
FICA taxes for at least 40 quarters lifetime (10 years) and, also 20
quarters had to have been paid in during the ten years prior to the
date of becoming totally disabled. For example, a 40 year-old Claimant
who became disabled in 2003 would have had to have worked and paid
FICA taxes for at least 10 years during his lifetime, and for at least
5 years between 1992 and 2002.

If approved for SSDI the Social Security Administration pays a monthly
benefit based upon how much was earned and paid into the Social
Security system. Benefits are also paid to dependent children who are
under 16 years old, or who are under 18 years old and still in high
school. Medicare eligibility begins twenty-nine months after the onset
date of total disability.

The SSI program requires that an individual be totally disabled and
"indigent." "Indigent" basically means that a single Claimant has
little or no income and less than $2,000.00 in non-exempt assets. A
home and furniture are not counted. One car is exempt. Bank accounts,
IRAs, profit sharing plans, cash value life insurance and similar
assets are all included in determining assets, even if penalties and
taxes would be incurred if the asset were converted to cash. In
addition, a spouse's assets and income are "deemed" to the disabled
Claimant - this deeming rule wreaks havoc on many disabled persons,
particularly the stay-at-home parent.

In 2004 SSI will pay a basic monthly benefit of $564.00 which may be
supplemented by some states. A disabled person receiving SSI will
also be eligible for food stamps and a Medicaid card from the state.

The Social Security disability program is designed to pay benefits to
claimants suffering from medical problems causing symptoms so severe
that it becomes impossible to sustain function at any type of work.
Issues of employability, job existence, insurability and location or
desirability of alternative work will not be considered, although age
and education are often important factors. The fact that a person can
not do the work performed in the past is usually not determinative.
This is a medical program that focuses upon medically proven symptoms
and their impact on the ability to perform work activities.

Therefore, the focus in on function, not on diagnosis; SSA often
admits that Claimants have medical problems and are "impaired," but
denies that they are "totally disabled." The debate is over what the
Claimant can "do" despite the medical problems.

The Social Security Administration's Regulations require determination
of disability be based upon on "objective proof" of both the medical
problem and of the severity of the symptoms. "Objective proof" means
the findings contained in medical tests that are not dependent on the
patient's subjective responses. A MRI, a cardiac treadmill test, an
x-ray and a pulmonary function test are all "objective" tests. Asking
a patient if she is in pain is "subjective." In Fibromyalgia and CFS
claims, it is often difficult to objectively prove either the existence
of the disease, or the severity of the symptoms. This has caused many
claims based upon these conditions to be denied - especially at the
first two levels of review.

The focus in all disability claims is upon the medical evidence, i.e.
the treating physicians' clinical findings, office notes, reports, and
medical test results. This evidence is primary and is often more
important than the testimony of the Claimant. While a Claimant's
description of the impact on daily activities, social functioning and
concentration must be considered by SSA, the content of the medical
documentation is the most important source of evidence in deciding the
claim.

In Fibromyalgia claims the clinical notes and a report of the treating
rheumatologist are most important. A 1996 decision by the Seventh
Circuit Court of Appeals established that a rheumatologist is the
primary source for proof of this disease. Office notes from the
rheumatologist should consistently document the positive findings for
the tender points which are diagnostic for this disease. In addition,
the patient should be complaining at each office visit of the fatigue
and pain that are consistent with this condition. A report that
establishes that all other causes for the symptoms have been ruled
out helps establish the existence of the disease.

Since the extent of fatigue and pain can not be measured, consistency
of complaints in the various medical records will be important. The use
of pain medications, even if just for trial periods is an important
consideration in evaluating the severity of pain. Use of mild analgesics
indicates less severe symptoms; prescription of stronger narcotics
indicates that the treating specialist felt the pain problems more
severe. Also, documentation by the physicians of concentration
impairments, and the inability to perform routine daily activities such
as housework, shopping, and social functioning, are also factors
considered by Social Security Administration decision makers.

Chronic Fatigue Syndrome claims have been made clearer by the adoption
of Social Security Ruling 99-2p. This Ruling finally acknowledges that
CFS is a medically determinable impairment and describes the various
findings that can establish the diagnosis. This Ruling is quite useful
and can be found at the SSA's website, http://www.ssa.gov. Generally,
the focus is on a longitudinal view of the medical evidence and the
extent and nature of the treatment provided by the various physicians.
The clinical findings and summaries of the patient's complaints in the
office notes are critical in terms of establishing the existence of a
medical impairment. As to whether the symptoms are totally disabling,
SSA will consider the medical opinions, as well as the statements of
the Claimant and third parties, as in any other disability claim.

Claimants who suffer from depression should also seek treatment from
a mental health professional. Whether the depression is a symptom of
the disease, or results from the significant impact on a Claimant's
lifestyle, or is a separate disabling medical condition, the treatment
notes and histories often lend credibility to the claim. However, SSA
will generally not give significant weight to depression treated by a
family doctor or social worker - emphasis will always be given to the
records and reports of an M.D. psychiatrist or Ph.D. psychologist.
Depression does not usually negate the existence of other underlying
impairments but instead confirms the severity of their impact. On
occasion, this diagnosis provides an alternative theory for an
Administrative Law Judge who wishes to award benefits but will not
approve a claim based on CFS or Fibromyalgia.


The Application Process

There are multiple levels of review of an application filed under the
Social Security Act. In an effort to increase productivity, and
decrease processing time, the Social Security Administration is testing
different review models across the country. This article will describe
the basic system which is still in place throughout most of the United
States.

A claim is initiated by filing an application. This can be done over
the telephone, on SSA's web site at www.ssa.gov (for SSDI claims only)
or, preferably, in person at the local Social Security Administration
District Office. The application will require a list of all of the jobs
performed during the last 15 years, a list of all medical providers, a
list of current medications, names and dates of all prior marriages and
divorces, and a copy of the Claimant's birth certificate. Generally our
practice is to recommend as much be done with Social Security face to
face at the District Offices - this decreases the chance for errors. At
the time of this writing, only SSDI claims can be filed over SSA's web
site.

After the application is filed, the Social Security Administration will
send the file to a Disability Determination Service (DDS) administered
by that State. Each state has a contract with SSA to perform the first
two levels of review. At the DDS the file will be assigned to an
adjudicator who will be responsible for gathering medical documentation,
getting any additional information from the Claimant, arranging for
consultative examinations and obtaining medical and vocational opinions
from the DDS's internal experts. A written decision is issued in about
90 days on average, although the time frame can vary widely. Historically
only about 36% of claims are paid at this level.

If denied, the second step is the filing of a Request for Reconsideration
at the SSA District Office. A Claimant is allowed 60 days from the date
of the initial denial to file this appeal, although there is usually
little to gain by waiting. The Request for Reconsideration is also
processed by the state DDS. Historically only about 17% of claims are
approved at this level and SSA is testing elimination of this step.

The third level of review, for those claims denied at Reconsideration, is
the hearing before the Administrative Law Judge (ALJ). These are informal
administrative hearings held before independent judges who hear
testimony, review the medical records and issue written decisions. While
progress had been made in reducing the backlog in setting hearing dates,
the delays have been increasing once more. Time frames vary widely across
the nation, many hearing offices now take at least twelve months from the
date the Request for Hearing is filed to set a hearing date.

The hearing is critical to the review process because it is the only time
that a Claimant has the opportunity to see, and talk to, the decision
maker. Up until this time all decisions are based upon paper, i.e. medical
reports and written questionnaires. This is the only time in the process
where the decision maker gets to see and question the Claimant. That face
to face observation is critical and in this author's experience is one of
the factors causing ALJs to reverse many reconsideration denials.

While all Social Security cases first focus on medical proof, the testimony
at an administrative law judge hearing may tip the scale in favor of a
sympathetic and credible Claimant. It is important that a Claimant fully
explain the limitations and the effects of the disease on their daily
activities. Testimony, which is consistent with the medical evidence and
credible, can persuade a Social Security judge to award benefits in a
claim based upon Fibromyalgia or CFS.

The final two steps in the review process are the Appeals Council, and if
unsuccessful, the United States District Court. These reviews are
primarily based upon the medical evidence and testimony from the ALJ
hearing. Since there is no additional testimony, and very little additional
medical evidence can be supplied, these two levels of review are helpful in
only a small percentage of claims. The backlog at the Appeals Council is
now almost two years.

NOTE: SSA has begun testing different application processes in different
parts of the nation. Some Claimants will not have a reconsideration stage;
some will not have Appeals Council review. All Claimants will have an
opportunity for an Administrative Law Judge hearing.


Representation

This Social Security disability application and appeals process was
designed so that Claimants are not required to obtain representation.
However, people with representation have much higher success rates.
Familiarity with SSA's Regulations, Rulings, the federal caselaw
interpreting the Act, and with SSA's internal guidelines called the POMS
and HALLEX, help guide preparation of a claim. Representatives do not
have to be licensed attorneys and there are paralegals and other non-
attorneys who do provide representation.

This author's strong preference is to become involved in a claim as
early in the process as possible. The earlier a Claimant understands
the issues in her particular situation, and the earlier the review of
the existing available medical proof, the greater the chance the
assistance will be granted at some point in the process. In addition,
care needs to be exercised in the completion of many of the early
questionnaires sent by the DDS adjudicators - many answers on these
forms end up being twisted and serving as the basis for denials by
adjudicators and ALJs.

Almost all attorneys who focus in this area of the law will agree to
representation on a contingency fee basis - that means that fees are
only awarded in the event of a favorable outcome. In addition, the
Social Security Administration always retains the right to review
attorney fees.


Conclusion

Many claims for SSDI and SSI benefits are approved for persons with
Fibromyalgia and Chronic Fatigue Syndrome. Claimants must have the
support of their treating specialists - especially the rheumatologist
and/or pain specialist and must maintain good communication regarding
their symptoms and limitations. If depression has become an issue then
treatment with either a Ph.D. psychologist or M.D. psychiatrist is
important. The earlier a Claimant obtains experienced representation
the greater the chance for success, and the less stressful the battle
through the various levels of appeal and review. Perseverance will
prevail and disabled persons can obtain this much needed assistance.

Nothing in this article is intended to be specific legal advice or to
create an actual or implied attorney-client relationship. This article
has been a brief summary of the basic law and persons seeking benefits
should contact experienced representatives for advice upon which they
can rely. Hopefully, however, this brief analysis will provide some
insight into the disability system.


Article provided by Jeffrey A. Rabin & Assoc
Visit us at http://www.rabinsslaw.com

--------
(c) 2010 24-7 Press Release.com
 

Friday, June 25, 2010

Where to Buy "Invisible" -- a MUST SEE film for family and friends!

 
The NOVA CFS/ME Support Group is very large in membership.  Let's hope you get many, many orders for your fine documentary film from Elly's annct.  She works hard to keep the Support Group going.  I had to laugh at the line in the film that quoted someone else who said he/she was too tired to attend support group meetings.  That's me, as well.   Elly is very good to keep in touch with so many of us by e-mail.
 
Carol
----- Original Message -----
From: Elly
Subject: [CFSupport] New Film: "Invisible" - How to Buy it, See it at our Next Meeting

 

Meeting Alert: At our July 17, 2010,  2-4 pm NOVA meeting in Chantilly, VA, we will be watching a DVD called "Invisible" about people with CFS, ME, FMS, CFIDS.

Thanks to CFSupport member Carol O for writing the producers and getting us a copy. 
From the letter to me from Rik Carlson and Michael Thurston of the VT CFIDS Association (www.vtcfids.org)

"Elly: It is our great pleasure to present with your complimentary copy of  INVISIBLE. We ask that you show and share INVISIBLE with those to whom it will make a difference. INVISIBLE addresses the misunderstanding that Chronic Fatigue Syndrome is the product of an overworked imagination or even a deliberate act of behavior. We are forever amazed that such a misunderstanding even exists. 

INVISIBLE examines how this hideous illness is denied legitimacy, causing the properties of CFS to become exacerbated and prolonged. INVISIBLE informs how social environmets and family structures are destroyed as a result. In many cases, lack of legitimacy becomes far worse and more damaging than simply being terribly sick.

A physician loaned a pre-release version of INVISIBLE to a patient and she in turn showed it to her family as a group. Her report back says it all. 'Not only do they now get it, but they treat me differently."

That's the power of INVISIBLE. It's a film that works.
INVISIBLE provides us that rare opportunity to improve lives, one at a time.
Thank you, Elly, for helping us do that."



Here are more details, where to buy it for yourself ($19.95), reviews.


http://invisiblethemovie.com/invisible_home.html


ABOUT THE MOVIE (From the back of the DVD cover:)

"The film is powerful, very powerful."
Imagine what it's like to be so sick you cannot function.
Imagine there is no known pathology for your illness, only symptoms.
Imagine you are too weak to find your own voice...and because you are silent and confused, your physician says "it's all in your head".
Imagine.
Because your illness is invisible, you disappear.
INVISIBLE gives voice to a select group of Vermonters who are gravely ill, and until now, have been out of sight. You will hear first person accounts from your Vermont neighbors as they talk about living with Chronic Fatigue Syndrome, CFIDS, Fibromyalgia, or Myalgic Encephalomyelitis, the disease with a thousand names and no known cause or cure.
You will hear the devastating impact this illness wields, not only for those who suffer the symptoms, but for those who are left trying to understand what their loved ones are experiencing. This is a film for millions of people around the globe from your Vermont neighbors around the corner...tenacious Vermont neighbors who struggle against unimaginable odds to make their voices heard.
They are just like us...except they got sick...
and they are tired of being INVISIBLE.

REACTION, What people are saying:

 

INVISIBLE, in an early draft form, made its debut at the 9th International Association for Chronic Fatigue Syndrome and ME Conference in Reno, Nevada during the Patient's Session on March 12, 2009. It was widely reviewed as the first film of its kind to tell the Chronic Fatigue story from the patient's point of view, and was lauded for its ability to lend credibility to those suffering Chronic Fatigue.

 

A doctor in Vermont placed a draft copy of INVISIBLE in a lending library she maintains in her office. One patient borrowed the film, and upon bringing it back told the doctor: "I made my family sit down and watch INVISIBLE with me. They treat me differently, now."


P.A.N.D.O.R.A., headquartered in Florida, screened a draft version of INVISIBLE in Fort Lauderdale on International CFIDS awareness day, May 12, 2009. Again, the response was enthusiastic and uniform: INVISIBLE tells it the way it should be told.


My congratulations are way over due! INVISIBLE is well organized, complete, germane, sensitive, and professional!! I hope someday I will actually be well enough to offer good, sensitive medical care to some of our own. (Terry Nauman, MD, CFIDS sufferer)


WOW!  The film is powerful, very powerful. It is beautifully photographed. The 'cast' does a terrific job...a very difficult topic in a well informed and wonderfully executed manner. (Ruth Friedman)


I'm here in Reno at the International Association for Chronic Fatigue Syndrome with a whole bunch of people watching this great movie called "Invisible."
"Invisible" ... And the reality that patients do not have doctors, and that doctors need testing and treatment blueprints. Patients saying over and over again "nobody has any idea what to do with this disease." One of our group suggested that this needs to be required viewing at every medical school in the country.
When I saw "Invisible" it was clear that my Bob is like Rik's Barbara. It really makes a difference coping with the disease to have support in the family. The response from a room of about 500 people in Reno was a lot of laughter and recognition - and then long applause. (Mary Schweitzer)


Perhaps a couple members of a local support group could offer to bring the DVD [to the local medical school] and answer questions, to show with these stories that we are not lazy people looking for an excuse to lounge on the couch, but "I was a marathoner", "I was a rising political star"; we had everything to lose and nothing to gain by taking to our beds, and let them see that by the end of the session, this woman who looked normal at the start is now ready to curl up and nap on the floor before she can make it back to her car. (Karen M. Campbell, Founder www.CFSFacts.org)

 

Rik, you always just amaze me. You have done so much for the CFIDS etc. community, not just in Vermont but everywhere. Your book and your Pandora winning film, all the work you have done toward informing MDs and on and on. I want to compliment you on all the work you do for all of us who are so isolated. And I also wanted to put myself on the list to be alerted when Invisible is released. I am very anxious to see it and probably donate a copy to my local library and the library I once worked for as well. Again, thank you Rik. (Taffy Todd, passed away on April 28, 2009)

Superbly made. Great advocacy. Not shrill. Quite an accomplishment. (Phil Carlson)