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              ---------------------------------------------
                       This is a special digest of
                  Co-Cure Research & Medical posts only
               Problems? Write to mods@co-cure.org
              ---------------------------------------------

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


Date:    Tue, 3 Jul 2007 17:26:17 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Adhesion molecules and cytokine expression in fibromyalgia patients: Increased L-selectin on monocytes and neutrophils

Adhesion molecules and cytokine expression in fibromyalgia patients:
Increased L-selectin on monocytes and neutrophils.

J Neuroimmunol. 2007 Jun 27; [Epub ahead of print]

Macedo JA, Hesse J, Turner JD, Ammerlaan W, Gierens A, Hellhammer DH,
Muller CP.

Institute of Immunology, Laboratoire National de Santé, 20A rue Auguste
Lumière, L-1950, Luxembourg; Department of Immunology of the Graduate
School of Psychobiology, University of Trier, 54290 Trier, Germany.

PMID: 17602758


Several lines of evidence implicate the immune system in the
pathophysiology of fibromyalgia (FM). We investigated the role of cytokines
and adhesion molecules involved in immune cell trafficking and the
influence of 1.5 mg of dexamethasone (DEX) per os on their expression.

L-selectin was elevated on monocytes and neutrophils of FM patients.
Differences in group response to DEX were observed for CD11b on NK cells,
sICAM-1 and IL-2.

This study shows a slight disturbance in the innate immune system of FM
patients, and suggests an enhanced adhesion and recruitment of leukocytes
to inflammatory sites.

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Date:    Wed, 4 Jul 2007 13:16:01 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Chronic widespread pain in the spectrum of rheumatological diseases

Chronic widespread pain in the spectrum of rheumatological diseases.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):391-402.

Bliddal H, Danneskiold-Samsøe B.

The Parker Institute, Frederiksberg Hospital, Ndr Fasanvej 57, 2000
Frederiksberg, Denmark.

PMID: 17602990


Chronic pain is very common in all European countries, with musculoskeletal
problems predominating. About 1% of the adult population develops a
syndrome of chronic muscle pain, fibromyalgia (FMS), characterized by
multiple tender points, back or neck pain, and a number of associated
problems from other organs, including a high frequency of fatigue.

Evidence points to central sensitization as an important neurophysiological
aberration in the development of FMS. Importantly, these neurological
changes may result from inadequately treated chronic focal pain problems
such as osteoarthritis or myofascial pain. It is important for health
professionals to be aware of this syndrome and to diagnose the patients to
avoid a steady increase in diagnostic tests.

On the other hand, patients with chronic widespread pain have an increased
risk of developing malignancies, and new or changed symptoms should be
diagnosed even in FMS. In rheumatology practice it is especially important
to be aware of the existence of FMS in association with immune inflammatory
diseases, most commonly lupus and rheumatoid arthritis.

Differential diagnoses are other causes of chronic pain, e.g. thyroid
disease. The costs of this syndrome are substantial due to loss of working
capability and direct expenses of medication and health-system usage.

Fibromyalgia patients need recognition of their pain syndrome if they are
to comply with treatment. Lack of empathy and understanding by healthcare
professionals often leads to patient frustration and inappropriate illness
behavior, often associated with some exaggeration of symptoms in an effort
to gain some legitimacy for their problem.

FMS is multifaceted, and treatment consists of both medical interventions,
with emphasis on agents acting on the central nervous system, and physical
exercises.

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

Date:    Wed, 4 Jul 2007 13:20:02 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Epidemiology of chronic musculoskeletal pain

Epidemiology of chronic musculoskeletal pain.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):403-25.

McBeth J, Jones K.

ARC Epidemiology Unit, The Medical School, The University of Manchester,
Manchester, M13 9PT, UK.

PMID: 17602991


The rate of musculoskeletal pain in adolescent and adult populations is
examined, with a focus on three commonly reported pain disorders: shoulder
pain, low back pain and fibromyalgia/chronic widespread pain.

There is a paucity of data on musculoskeletal pain in adolescent
populations. Those studies available suggest that pain is common, although
the actual rates are unclear. This is probably due to differences in study
methodologies and populations.

Pain is commonly reported among adult populations, with almost one fifth
reporting widespread pain, one third shoulder pain, and up to one half
reporting low back pain in a 1-month period. The prevalence of pain varies
within specific population subgroups; group factors (including
socioeconomic status, ethnicity and race) and individual factors (smoking,
diet, and psychological status) are all associated with the reporting of
musculoskeletal pain.

However, the precise nature of these relationships, and particularly the
mechanisms of association, are unclear and require further investigation.

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Date:    Wed, 4 Jul 2007 13:24:01 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Myofascial pain syndromes and their evaluation

Myofascial pain syndromes and their evaluation.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):427-45.

Bennett R.

Oregon Health & Science University, SNORD-219, 3455 SW Veterans Road,
Portland, OR 97239-2941, USA.

PMID: 17602992


Myofascial pain refers to a specific form of soft-tissue rheumatism that
results from irritable foci (trigger points) within skeletal muscles and
their ligamentous junctions. It must be distinguished from bursitis,
tendonitis, hypermobility syndromes, fibromyalgia and fasciitis.

On the other hand it often exists as part of a clinical complex that
includes these other soft-tissue conditions, i.e., it is not a diagnosis of
exclusion. The clinical science of trigger points can be traced to the
pioneering work of Kellgren in the 1930s, with his mapping of myotomal
referral patterns of pain resulting from the injection of hypertonic saline
into muscle and ligaments.

Most muscles have characteristic myotomal patterns of referred pain; this
feature forms the basis of the clinical recognition of myofascial trigger
points in the form of a tender locus within a taut band of muscle which
restricts the full range of motion and refers pain centrifugally when
stimulated.

Although myofascial pain syndromes have been described in the medical
literature for about the last 100 years, it is only recently that
scientific studies have revealed objective abnormalities.

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

Date:    Thu, 5 Jul 2007 03:11:18 +0200
From:    Jan van Roijen 
Subject: res: Abnormal Thermoregulatory Responses in CFS Adolescents

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~


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From: Frank Twisk 


http://pediatrics.aappublications.org/cgi/content/abstract/120/1/e129?rss=1


PEDIATRICS Vol. 120 No. 1 July 2007, pp. e129-e137
(doi:10.1542/peds.2006-2759)


ARTICLE


Abnormal Thermoregulatory Responses in Adolescents
With Chronic Fatigue Syndrome: Relation to Clinical Symptoms
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Vegard Bruun Wyller, MDa,b, Kristin Godang, BScc, Lars
Mrrkrid, MD, PhDd, Jerome Philip Saul, MDe, Erik Thaulow,
MD, PhDa and Lars Wallre, MD, PhDb

a Departments of Pediatrics
c Endocrinology
d Medical Biochemistry, Rikshospitalet-Radiumhospitalet
Medical Center, Oslo, Norway
b Department of Physiology, University of Oslo, Oslo, Norway
e Department of Pediatrics, Medical University of South
Carolina, Charleston, South Carolina

OBJECTIVES.

Chronic fatigue syndrome is a common and disabling disease
of unknown etiology. Accumulating evidence indicates
dysfunction of the autonomic nervous system. To further explore
the pathophysiology of chronic fatigue syndrome, we
investigated thermoregulatory responses dependent on
catecholaminergic effector systems in adolescent patients with
chronic fatigue syndrome.

PATIENTS AND METHODS.

A consecutive sample of 15 patients with chronic fatigue
syndrome aged 12 to 18 years and a volunteer sample of 57
healthy control subjects of equal gender and age distribution
were included. Plasma catecholamines and metanephrines
were measured before and after strong cooling of 1 hand. Acral
skin blood flow, tympanic temperature, heart rate, and mean
blood pressure were measured during moderate cooling of 1
hand. In addition, clinical symptoms indicative of
thermoregulatory disturbances were recorded.

RESULTS.

Patients with chronic fatigue syndrome reported significantly
more shivering, sweating, sudden change of skin color, and
feeling unusually warm. At baseline, patients with chronic fatigue
syndrome had higher levels of norepinephrine, heart rate,
epinephrine, and tympanic temperature than control subjects.
During cooling of 1 hand, acral skin blood flow was less
reduced, vasoconstrictor events occurred at lower temperatures,
and tympanic temperature decreased more in patients with
chronic fatigue syndrome compared with control subjects.
Catecholamines increased and metanephrines decreased
similarly in the 2 groups.

CONCLUSIONS.

Adolescent patients with chronic fatigue syndrome have
abnormal catecholaminergic-dependent thermoregulatory
responses both at rest and during local skin cooling, supporting
a hypothesis of sympathetic dysfunction and possibly explaining
important clinical symptoms.
`

````````
Key Words: chronic fatigue • thermal regulation • adolescents •
pathogenesis

Abbreviations: CFS—chronic fatigue syndrome •
AVA—arteriovenous anastomosis • CDC—Centers for Disease
Control and Prevention • ASBF—acral skin blood flow •
TT—tympanic temperature • HR—heart rate • MBP—mean
blood pressure • CI—confidence interval

````````
Accepted Jan 25, 2007.



#############


Comment:

In the full text of this article is stated in the *subject*-section, that
the accompanying symptoms of the CDC definition (headache,
muscle pain, joint pain, sore throat, tender lymph nodes,
impaired memory/concentration, unrefreshing sleep, and
postexertional malaise) were not required in this study.

I will add the discussion section below.

The Full text can be found here:

pdf format::
http://pediatrics.aappublications.org/cgi/reprint/120/1/e129

html format:
http://pediatrics.aappublications.org/cgi/content/full/120/1/e129

~jvr


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

DISCUSSION


The most important findings of this study are that (1) patients
with CFS report several symptoms that might indicate
thermoregulatory disturbances; (2) at baseline, patients with
CFS have higher levels of norepinephrine and epinephrine and
higher TT than control subjects; and (3) during cooling of 1 hand,
the neuroendocrine responses are similar in the 2 groups, but
ASBF is less reduced among patients with CFS, whereas the
baseline differences in TT disappear. Furthermore, the
relevance of these findings is strengthened by the strikingly
homogeneous responses within the CFS group, creating
significant differences from control subjects despite the small
number of subjects studied.

Baseline Observations

The finding in this study of increased norepinephrine levels in
patients with CFS seems to be novel, whereas increased levels
of epinephrine have been reported sporadically.27,28 A higher
level of acute emotional stress among patients with CFS might
explain the epinephrine differences; however, plasma levels of
norepinephrine are less influenced by such mechanisms.7 Thus,
the findings seem to indicate a more substantial alteration of
physiology.

A high level of norepinephrine in the antecubital vein plasma
might suggest increased sympathetic nerve activity to forearm
skin and skeletal muscle.29 Likewise, a high plasma level of
epinephrine might be a result of increased sympathetic nerve
activity to the adrenals. However, there are several alternative
explanations. Generally, high levels of plasma catecholamines
could result from either increased spillover or reduced removal,
which, in turn, depends on both sympathetic nerve activity, the
capacity of different reuptake and breakdown pathways, and
local blood flow.7,29 Furthermore, a high norepinephrine
concentration in forearm venous blood might simply reflect
increased arterial levels, which, in turn, could be because of
enhanced spillover in other parts of the body.

The plasma levels of metanephrines are not good markers of
activity in either the adrenal medulla or the sympathetic neurons
and are only weakly correlated with the plasma levels of the
respective catecholamines.7,29 Thus, similar levels of
metanephrines among patients with CFS and control subjects
do not rule out a state of catecholamine excess in the former.

The finding of increased TT in patients with CFS is in agreement
with previous reports of increased skin temperature in this
population30 but contrasts with 2 other studies that did not find
any deviations in core body temperature.31,32 However, these
latter studies focused primarily on alterations in circadian
temperature rhythms. In this study, the increased TT might be
partially caused by high levels of epinephrine, which increase
basal metabolic rate and heat production.7 In addition, a
tendency toward shivering, as reported in our patients with CFS,
might contribute. Increased levels of thyroid hormone are an
alternative explanation that has not been specifically addressed
in this study; however, overt thyroid hyperfunction was ruled out
in the patient group during routine clinical investigations.

The high resting HR found in this study fits well with other
studies, documenting similar hemodynamic abnormalities both
at rest and during orthostatic stress.3,33 An abnormal
sympathetic predominance of cardiovascular regulation is one
possible interpretation of these results, which is consistent with
the reduced ASBF found in the CFS group, because skin AVAs
are strongly controlled by sympathetic neural activity.22,34

Taken together, our baseline observations might indicate a
general enhancement of sympathetic nerve activity to different
regions and organs, including the forearm, the adrenals, and the
heart. Patients' report of shivering, sweating, and paleness
further suggest enhanced sympathetic outflow to skeletal
muscles, sweat glands, and skin arterioles, respectively, a
possibility that should be the subject of further research.

Observations During and After Cooling

Strong, rapid cooling of 1 hand normally promotes a general
enhancement of sympathetic nerve activity, causing increased
plasma levels of both norepinephrine and epinephrine.7 The
stimuli for this response are not only reduced skin temperature in
the immersed hand but also painful sensations. The similar
increase in norepinephrine and epinephrine among control
subjects and patients with CFS, as documented in this study,
suggests that patients with CFS have preserved response
abilities toward local cooling within the sympathetic nervous
system. Thus, there are no indications of gross autonomic
neuropathy, as have been proposed by others.35 Although not
the focus of this report, the significant reduction of
normetanephrine and metanephrine on cooling observed in both
groups is an interesting finding, which seems to be unique to this
report.

Moderate, slow cooling of 1 hand normally causes a gradual
reduction of ASBF down to a certain temperature level, at which
ASBF suddenly ceases, presumably because of a coordinated
closure of all of the AVAs23 (Fig 1). Although the precise
mechanisms behind this phenomenon have not been fully
elucidated, one possible explanation is synthesis of local signal
substances that increase the postsynaptic sensitivity for
norepinephrine or antagonize neuronal reuptake.36,37 Still, the
closure is also dependent on central sympathetic outflow.23 We
have provided evidence of abnormally increased core body
temperature at baseline among patients with CFS. If the part of
the effector system that controls the AVAs functions normally, an
adequate response would be to elicit heat loss, that is, ensuring
preserved blood flow in the AVAs as the temperature in the
water bath falls. Consequently, our observation of prolonged
preservation of ASBF left in patients with CFS on cooling, which
has not been reported before, might be interpreted as a normal
regulatory response to abnormally increased core temperature
at baseline. Accordingly, TT did fall in the CFS group during the
experiment, indicating successful heat loss and normalization of
core temperature, whereas the normal ASBF responses in the
control subjects seemed to maintain TT constant in that group.

Alternatively, our results might indicate a defect in local
vasoconstrictor mechanisms. Interestingly, recent experimental
studies applying acetylcholine to small skin areas have found
stronger vasodilative responses among patients with CFS than
healthy control subjects, suggesting subtle alteration of the
endothelial microvascular regulatory system.38,39 Other studies
have documented a strong relation between CFS and the
postural orthostatic tachycardia syndrome,40 a condition that
seems to be characterized by reduced norepinephrine reuptake
in the sympathetic synapse.41 Altogether, the previous studies
and our own results underscore the need for research
specifically addressing the complicated interaction of
adrenergic, cholinergic, and other microvascular control
mechanism in patients with CFS.


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

Date:    Thu, 5 Jul 2007 16:27:23 +0200
From:    "Dr. Marc-Alexander Fluks" 
Subject: RES,NOT: CFS genes research in Australia

Source: Australian Associated Press
Date:   July 5, 2007
Author: Tamara McLean
URL:    http://www.news.com.au/adelaidenow/story/0,22606,22020918-5005962,00.html
Ref:    See also these reports,
        http://www.abc.net.au/news/stories/2007/07/05/1970542.htm
        http://english.people.com.cn/90001/90781/6208295.html
        http://www.bloomberg.com/apps/news?pid=20601102&sid=aFl3ZU6yc_qQ


Gene cluster linked to chronic fatigue
--------------------------------------

Australian researchers have identified a cluster of genes linked to chronic
fatigue syndrome which may help finally explain the mysterious condition.

The team from the University of NSW sifted through more than six million pieces
of DNA information in people who had glandular fever, including half who went on
to develop chronic fatigue.

Their goal was to identify which genes appeared to be more active in the people
who went on to get fatigue, to shed light on what triggers the unexplained
condition.

Professor Andrew Lloyd and his colleagues at the Centre for Infection and
Inflammation Research were able to find 35 genes linked to the symptoms of the
illness. 'These (35) genes might point to the nature of the disease process that
underlies chronic fatigue syndrome, which is currently unknown,' said Prof
Lloyd, whose findings are published in the latest Journal of Infectious
Diseases.

Chronic fatigue is most commonly triggered by an acute illness, like glandular
fever. It is characterised by extreme tiredness but recent studies have left
researchers puzzled as to what it actually is.

'We know it's not a psychiatric disorder, and doesn't appear to have anything to
do with immune responses or hormones or the severity of the virus,' Prof Lloyd
said. 'So that's left us thinking it's some kind of brain disorder.'

The team decided to analyse brain patterns by studying blood samples of 15
people with glandular fever, including some who also developed fatigue.
The work was part of a larger project tracking the long-term health of people
infected by three infections - the mosquito borne Ross River virus, Q fever
bacterial infection and Epstein-Barr virus, which causes glandular fever - in
the central NSW city of Dubbo.

Prof Lloyd said the findings were the tentative beginnings of better
understanding the disease. 'It's given us the starting point for some gene
expression pattern that might become a diagnostic test for the condition,' he
said. 'And it's given some clues of what the disease process might be that
underlies the disorder.'

--------
(c) 2007 AAP

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Date:    Thu, 5 Jul 2007 12:13:14 -0400
From:    "Dr. Charles Shepherd  (via Co-Cure Moderators)"
Subject: RES,MED:Gabapentin and autonomic dysfunction

MAY BE REPOSTED

Gabapentin is an interesting drug in that it was originally used in the
treatment of epilepsy but it has also been found to be an effective and
generally well tolerated drug for the management of pain, particularly
where this has a neuropathic quality (ie burning, shooting or searing)
but also for some types of musculoskeletal pain. In relation to pain in
ME/CFS, it is a drug that is worth considering when moderate to severe
pain has not responded to more usual forms of analgesic medication.

New research (1) just published from a group in Sydney, Australia
suggests that a further use for gabapentin could be in the area of
autonomic dysfunction.  This can be a very disabling problem that
affects blood vessels, bowel and bladder function in some people with
ME/CFS.

The Australian study involved six patients whose dysautonomia followed a
traumatic brain injury.  Gabapentin helped to control paroxysmal
autonomic changes and posturing in the early post-acute stage following
limited success with conventional medication regimes.  The results
cannot be adequately explained by gabapentin's effect on neuropathic
pain.

It is interesting to note that gabapentin has also been reported to help
'hot flashes' (ie feelings of warmth, redness, sweating) that occur in
women receiving systemic therapy for breast cancer (2) - possibly in
part being caused by a disturbance in hypothalamic function.

Whether or not gabapentin could be helpful in autonomic dysfunction
associated with ME/CFS remains a matter of speculation. But I would be
interested to hear from anyone using this drug as to whether it has had
any beneficial effect on ME/CFS symptoms apart from just pain.


References:

1  Baguley IJ, et al.  Gabapentin in the management of dysautonomia
following severe traumatic brain injury: a case series. Journal of
Neurology, Neurosurgery and Psychiatry 2007; 78: 539 - 541.

2  Pandya K, et al.  Gabapentin for hot flashes in 420 women with breast
cancer:  a randomised double-blind placebo-controlled trial.  Lancet
2005; 366: 818 - 824.


Dr Charles Shepherd
Medical Adviser, ME Association (UK)

http://www.meassociation.org.uk

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Date:    Thu, 5 Jul 2007 17:04:14 +0200
From:    "Dr. Marc-Alexander Fluks" 
Subject: RES,NOT: Paper: CFS genes research in Australia

Source: Journal of Infectious Diseases
        Vol. 196, #1, p 56 - 66
Date:   July 1, 2007
URL:    http://www.journals.uchicago.edu/JID/journal/available.html
        http://www.journals.uchicago.edu/JID/journal/issues/v196n1/37954/37954.html


Gene Expression Correlates of Postinfective Fatigue Syndrome after Infectious
Mononucleosis
-----------------------------------------------------------------------------
Barbara Cameron, Sally Galbraith, Yun Zhang, Tracey Davenport, Ute
Vollmer-Conna, Denis Wakefield, Ian Hickie, William Dunsmuir, Toni Whistler,
Suzanne Vernon, William C. Reeves, Andrew R. Lloyd, and Dubbo Infection Outcomes
Study


Abstract

Background.
Infectious mononucleosis (IM) commonly triggers a protracted postinfective
fatigue syndrome (PIFS) of unknown pathogenesis.

Methods.
Seven subjects with PIFS with 6 or more months of disabling symptoms and 8
matched control subjects who had recovered promptly from documented IM were
studied. The expression of 30,000 genes was examined in the peripheral blood by
microarray analysis in 65 longitudinally collected samples. Gene expression
patterns associated with PIFS were sought by correlation with symptom factor
scores.

Results.
Differential expression of 733 genes was identified when samples collected early
during the illness and at the late (recovered) time point were compared. Of
these genes, 234 were found to be significantly correlated with the reported
severity of the fatigue symptom factor, and 180 were found to be correlated with
the musculoskeletal pain symptom factor. Validation by analysis of the
longitudinal expression pattern revealed 35 genes for which changes in
expression were consistent with the illness course. These genes included several
that are involved in signal transduction pathways, metal ion binding, and ion
channel activity.

Conclusions.
Gene expression correlates of the cardinal symptoms of PIFS after IM have been
identified. Further studies of these gene products may help to elucidate the
pathogenesis of PIFS.

--------
(c) 2007 University of Chicago Press

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Date:    Thu, 5 Jul 2007 16:51:56 +0200
From:    "Dr. Marc-Alexander Fluks" 
Subject: RES,NOT: Press release: CFS genes research in Australia

Source: University of New South Wales
Date:   July 5, 2007
URL:    http://www.unsw.edu.au/news/pad/media/2007/jul/chronic_fatigue_syndrome.html


Chronic fatigue: clues in the blood
-----------------------------------

Researchers at UNSW believe that blood may hold vital insights into what is
happening in the brain of patients with chronic fatigue syndrome (CFS).

In a study unparalleled in its scope, a team led by UNSW Professor Andrew Lloyd
of the Centre for Infection and Inflammation Research, has studied the
differences in gene expression patterns in the blood of people who either
recover promptly after acute glandular fever or develop the prolonged illness
called post-infective syndrome.

The researchers examined six million pieces of gene expression information for
analysis in the project, known as the Dubbo Infection Outcomes Study. The study
is named after the NSW town in which the work was conducted. The team studied
the expression of 30,000 genes in the blood, testing each of the 15 individuals
between four and five times over a 12-month period.

The team was able to narrow its findings to the expression of just 35 genes
whose pattern of expression correlated closely with the key symptoms of the
illness when examined from onset through to recovery. Gene expression is
significant because it is the process by which a gene’s DNA sequence is
converted into the proteins which ultimately determine the manifestations of
disease.

The research paper has been published and selected for editorial comment in the
prestigious Journal of Infectious Diseases.

Since 1999, the team has been tracking the long-term health of individuals
infected with Ross River virus (RRV), Q fever infection and Epstein-Barr virus,
which causes glandular fever.

'These [35] genes might point to the nature of the disease process that
underlies CFS, which is currently unknown,' said Professor Lloyd, who is based
in the School of Medical Sciences at UNSW. 'None of them are ones that I would
have predicted, except for those relating to neurotransmitters,' he concedes.
'Some of them relate to transport of zinc and other metal ions within the
cell, which may suggest a fundamental disturbance in cellular function.'

The researchers now hope to narrow the focus of research onto the expression of
these 35 genes in the blood of a much larger group of subjects from the Dubbo
Infection Outcomes Study, with varied patterns of illness and recovery.

'There are very few complex diseases which have been comprehensively analysed,
with large scale and longitudinal studies, like this,' said Professor Lloyd.
'It sets a standard for highly sophisticated, comprehensive gene expression
studies in the blood of all sorts of human diseases from rheumatoid arthritis
and multiple sclerosis through to schizophrenia.'

Contact details: Professor Andrew Lloyd, 0413 112 701 or Susi Hamilton, UNSW
media unit, 9385 1583 or 0422 934 024.

--------
(c) 2007 University of New South Wales

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Date:    Thu, 5 Jul 2007 21:28:31 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition.ccc

Pathophysiological mechanisms in chronic musculoskeletal pain
(fibromyalgia): the role of central and peripheral sensitization and pain
disinhibition.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):465-80.

Nielsen LA, Henriksson KG.

Laboratory for Experimental Pain Research, Center for Sensory-Motor
Interactions (SMI), Department of Health Science and Technology, Aalborg
University, Frederik Bajers Vej 7, D3DK-9220 Aalborg, Denmark.

PMID: 17602994


Chronic musculoskeletal pain has biological, psychological and social
components. This review deals with the biological factors, with emphasis on
the fibromyalgia syndrome (FMS).

Studies on central sensitization of pain-transmitting neurons, changes in
endogenous pain modulation that give rise to pain disinhibition, referred
pain, pain-related decrease in muscle strength and endurance, and pain
generators in deep tissues are reviewed.

In FMS there is strong scientific support for the statement that the
biological part of the syndrome is a longstanding or permanent change in
the function of the nociceptive nervous system that can be equated with a
disease. Further research is necessary in order to determine which methods
are best for diagnosis of the pain hypersensitivity in clinical practice.

FMS may be the far end of a continuum that starts with chronic
localized/regional musculoskeletal pain and ends with widespread chronic
disabling pain.

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

Date:    Thu, 5 Jul 2007 21:35:51 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain

Role of central sensitization in symptoms beyond muscle pain, and the
evaluation of a patient with widespread pain.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):481-97

Yunus MB.

Section of Rheumatology, University of Illinois College of Medicine at
Peoria, One Illini Drive, Peoria, IL 61605, Illinois, USA.

PMID: 17602995


Patients with widespread pain or fibromyalgia syndrome have many symptoms
besides musculoskeletal pain: e.g. fatigue, sleep difficulties, a swollen
feeling in tissues, paresthesia, cognitive dysfunction, dizziness, and
symptoms of overlapping conditions such as irritable bowel syndrome,
headaches and restless legs syndrome.

There is evidence for central sensitization in these conditions, but
further studies are needed. Anxiety, stress and depression are also present
in 30-45% of patients. Other factors that may contribute to symptoms
include endocrine dysfunction, psychosocial distress, trauma, and disrupted
sleep.

Evaluation of a patient presenting with widespread pain includes history
and physical examination to diagnose both fibromyalgia and associated or
concomitant conditions. Fibromyalgia should be diagnosed by its own
characteristic features. Some patients with otherwise typical symptoms of
fibromyalgia may have as few as four to six tender points in clinical
practice.

Patients with rheumatoid arthritis and systemic lupus erythematosus should
be evaluated for fibromyalgia, since 20-30% of them have associated
fibromyalgia, requiring a different treatment approach.

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

Date:    Thu, 5 Jul 2007 21:42:38 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain

Pharmacological treatment of fibromyalgia and other chronic musculoskeletal
pain.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):499-511.

Goldenberg DL.

Newton-Wellesley Hospital, Division of Rheumatology, 2000 Washington
Street, Suite 304, Newton, MA 02468, USA.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):499-511.

PMID: 17602996


The pharmacologic management of fibromyalgia is based on the emerging
evidence that pain in this disorder is primarily related to central pain
sensitization.

There is strong evidence that tricyclic antidepressants are effective, and
moderate evidence for the effectiveness of serotonin reuptake inhibitors
and dual serotonin-norepinephrine reuptake inhibitors.

Recent work suggests that the anti-seizure medications pregabalin and
gabepentin are also effective.

The only analgesic demonstrated to be helpful is tramadol.

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[Return to top]

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

Date:    Fri, 6 Jul 2007 19:04:59 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Non-pharmacological treatment of chronic widespread musculoskeletal pain

Non-pharmacological treatment of chronic widespread musculoskeletal pain.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):513-34.

Mannerkorpi K, Henriksson C.

Department of Rheumatology and Inflammation Research, Sahlgrenska Academy,
Göteborg University, Guldhedsgatan 10, SE-413 46 Göteborg, Sweden.

PMID: 17602997


Non-pharmacological treatment for patients with chronic widespread pain
(CWP) and fibromyalgia (FM) aims to enhance overall health. This chapter
reviews studies of exercise, education, movement therapies and sensory
stimulation.

Based on a systematic review of randomized controlled trials (RCTs), we
suggest that aerobic exercise of low to moderate intensity, such as walking
and pool exercise, can improve symptoms and distress in patients with CWP
and FM, and it may improve physical capacity in sedentary patients. Aerobic
exercise of moderate to high intensity has been shown to improve aerobic
capacity and tender-point status.

Educational programmes have been shown to enhance self-efficacy and health
perception. There is no conclusive evidence about the type of educational
programme that works best, but a small-group format and interactive
discussions appear to be important components.

Exercise combined with education appears to produce synergies.

Studies of movement therapies (such as qigong) and sensory treatments (such
as acupuncture and massage) are few in number. There is today no conclusive
evidence about the effects of these treatments in CWP, although positive
effects have been reported in a few studies.

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

Date:    Fri, 6 Jul 2007 19:10:01 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Genetics of chronic pain states

Genetics of chronic pain states.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):535-47.

Buskila D.

Department of Medicine H, Soroka Medical Center and Faculty of Health
Sciences, Ben Gurion University, Beer Sheva, P.O.B 151, Israel 84101.

PMID: 17602998


Chronic pain states are common in the general population. Genetic factors
can explain a significant amount of the variability in the perception of
pain. Fibromyalgia syndrome (FMS) and related conditions are syndromes
characterized by generalized pain sensitivity as well as a constellation of
other symptoms. Family studies show a strong familial aggregation of FMS
and related conditions, suggesting the importance of genetic factors in the
development of these conditions.

Recent evidence suggests a role for polymorphisms of genes in the
serotoninergic, dopaminergic and catecholaminergic systems in the
pathogenesis of FMS and related conditions. Environmental factors may
trigger the development of these disorders in genetically predisposed
individuals.

Future large well-designed studies are needed to further clarify the role
of genetic factors in FMS and related conditions. The knowledge of these
gene polymorphisms may help with better subgrouping of FMS patients and in
designing a more specific pharmacologic treatment approach.

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

Date:    Fri, 6 Jul 2007 19:13:54 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Future perspectives: pathogenesis of chronic muscle pain

Future perspectives: pathogenesis of chronic muscle pain.

Best Pract Res Clin Rheumatol. 2007 Jun;21(3):581-96.

Staud R.

Department of Medicine, University of Florida College of Medicine,
Gainesville, FL 32610-0221, USA.

PMID: 17603001


Chronic painful muscle conditions include non-inflammatory and inflammatory
illnesses. This review is focused on chronic non-inflammatory pain
conditions such as myofascial pain syndrome (MPS) and fibromyalgia syndrome
(FM), and will not discuss metabolic, genetic or inflammatory muscle
diseases such as McArdle's disease, muscular dystrophy, polymyositis,
dermatomyositis, or inclusion body myositis.

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

Date:    Fri, 6 Jul 2007 19:31:42 -0400
From:    Fred Springfield 
Subject: RES: A twin study of cognitive function in chronic fatigue syndrome: The effects of sudden illness onsetc

A twin study of cognitive function in chronic fatigue syndrome: The effects
of sudden illness onset.

Journal: Neuropsychology. 2007 Jul;21(4):507-13.

Authors: Claypoole KH, Noonan C, Mahurin RK, Goldberg J, Erickson T,
Buchwald D.

Affiliations:
Claypoole, Keith H.: Department of Psychology, University of Hawaii,
Honolulu, HI, US
Noonan, Carolyn: Department of Medicine, University of Washington School of
Medicine, Seattle, WA, US
Mahurin, Roderick K.: Department of Neurology, University of Washington
School of Medicine, Seattle, WA, US
Goldberg, Jack: Department of Epidemiology, University of Washington School
of Medicine, Seattle, WA, US
Erickson, Tom: Regional Epilepsy Center, University of Washington School of
Medicine, Seattle, WA, US
Buchwald, Dedra: Department of Medicine, University of Washington School of
Medicine, Seattle, WA, US

NLM Citation: PMID: 17605583


Variable reports of neuropsychological deficits in individuals with chronic
fatigue syndrome (CFS) may, in part, be attributable to methodological
limitations. In this study, these limitations were addressed by controlling
for genetic and environmental influences and by assessing the effects of
comorbid depression and mode of illness onset.

Specifically, the researchers conducted a co-twin control study of 22 pairs
of monozygotic twins, in which 1 twin met strict criteria for CFS and the
co-twin was healthy. Twins underwent a structured psychiatric interview and
comprehensive neuropsychological assessment evaluating 6 cognitive domains.
Results indicated that twin groups had similar intellectual and visual
memory functioning, but fatigued twins exhibited decreases in motor
functions (p = .05), speed of information processing (p = .02), verbal
memory (p = .02), and executive functioning (p = .01). Major depression did
not affect neuropsychological functioning among fatigued twins, although
twins with sudden illness onset demonstrated slowed information processing
compared with those with gradual onset (p = .01).

Sudden onset CFS was associated with reduced speed of information
processing. If confirmed, these findings suggest the need to distinguish
illness onset in future CFS studies and may have implications for
treatment, cognitive rehabilitation, and disability determination.


((c) 2007 APA, all rights reserved).

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

Date:    Sat, 7 Jul 2007 16:55:16 +0200
From:    "Dr. Marc-Alexander Fluks" 
Subject: RES,NOT: CFS conference, 4/5 oktober 2007

Source: National Network for CFS/ME Therapists
Date:   July 2007
URL:    http://www.ppaonline.co.uk/download/Invitation_Booklet_NCCCFSME%202007.doc
Poster: http://www.ppaonline.co.uk/download/Conference_poster.pdf


Collaborative Conference on CFS/ME
----------------------------------
AYME and Action for ME in collaboration with the National Network for
CFS/ME Therapists and the National NHS Collaboration

Milton Keynes 4th - 5th October


Invitation and Registration Programme

You are invited to attend the first Collaborative Conference on CFS/ME,
which has been developed with a broad base of support and is intended to
interest a wide audience. Many of you will know that the National Network
of therapists has met in October for many years, and this conference
stands in the place of the meeting this year.

The National NHS Collaboration grew from the national meetings of the
Clinical Network and Coordinating Centres representatives, and continues
to coordinate the development of effective NHS services for people with
CFS/ME. There is of course an overlap in membership between the Network
and the Collaboration. The programme was developed in collaboration with
AYME and AfME, and we hope that the learning and networking opportunities
at the conference will be stronger as a result.


Programme Outline

The programme will be divided into three sections. The first, on Thursday
morning, involves a choice of meetings. The second, on Thursday afternoon,
involves a choice of workshops. Plenary sessions and the Keynote Speaker,
Professor Gijs Bleijenberg, will take place during the day on Friday. In
addition, there will be a poster presentation throughout the conference,
and a conference dinner on Thursday evening.


Registration and registration fees

You will find a registration form at the end of this document: please
complete this, and return it before the first of August for an "Early
Bird" discount.


Registration Fees are:

Early registration (until 1st August) 100 pounds for one day, 180 pounds
for both Late registration 125 pounds for one day, 200 pounds for both
days Paediatric Special Interest Group alone: 50 pounds Conference Dinner:
25 pounds plus wine

Accommodation is not included within these costs (see below for
accommodation details). CME approval is pending: attendance certificates
will be supplied.


Invitation To Submit Abstracts For Posters

The CFS Network is inviting delegates to submit posters about their work.
We would like particularly to attract work from health professionals at
the grassroots level of CFS (clinical and research) and encourage those
who may not have published previously in this field.

The conference programme will include an “interactive� poster session
when authors can give a 3-minute talk summarising their poster and answer
questions. Delegates will also have the opportunity to view posters before
the conference and during the breaks.

The subject matter for posters should fall into one or more of the
following categories:
1. Reports of evidence based practice with patients with CFS
2. Original research (which may be ongoing) which advances our theoretical
   understanding of CFS or its treatment
3. Issues affecting the provision of services for patients with CFS
4. CFS Service Audits

Members of the executive committee will review abstract submissions.
Successful submissions will be invited to display the poster at the
Conference, where invited judges will choose the best poster.

We are hoping to be able to offer a prize for the best poster and
presentation

Please submit your poster abstract in MS Word as an email attachment, by
Friday 3 August 2007 to:
Gabrielle.murphy@royalfree.nhs.uk
Your abstract should contain the following information:

Title
Authors
Affiliation
Email address of contact author
Body of abstract – no more than 200 words. Please structure this as
appropriate for the subject material, e.g. for research reports, use the
following headings: Background/objectives; design/methods; results;
discussion/conclusions/clinical implications. Case studies or reports of
qualitative work may vary from this format.

You will be informed by Friday 17th August whether your abstract has been
accepted for a poster at the conference. At this time you will be sent
more advice on formatting your poster. The maximum size for posters is
likely to be B1 (100cm x 70cm).


Conference Meetings: Thursday Morning

There will be three meetings held at the same time, which are:
1. Paediatric Special Interest Group Inaugural Meeting
   The Royal College of Paediatrics and Child Health Paediatric CFS/ME
   Special Interest Group will have its inaugural meeting at the conference,
   chaired by Dr Tim Chambers. This will include a mixture of research and
   clinical practice sessions. All are welcome to join.
2. National Network for CFS/ME Therapists AGM
   The network membership includes general practitioners, occupational
   therapists, physicians, physiotherapists, psychiatrists, nurses and
   psychologists. The Network functions across the Primary/Secondary Care
   boundary, and across the Paediatric/Adult boundary. The Network is also a
   stakeholder group in the development of the NICE guidelines for CFS/ME.
   The network has met once a year for an annual autumn multiprofessional
   study and information day for several years, and it’s meeting this
   year is combined with the Collaborative Conference. All are welcome.
3. CFS/ME Champions and Co-ordinators Meeting
   This is a closed meeting for the current clinical champions and network
   coordinators, scheduled following our last meeting in May 2007.


Workshops: Thursday Afternoon

Delegates can choose to attend two out of the following workshops:
- Vincent Deary: Using CBT with adults
- Dr Esther Crawley: collecting data to understand CFS/ME
- Facilitator tbc: implementation of the NICE Guidelines
- Dr Hugh Rickards: Depression, anxiety and the problems with differential
  diagnosis
- Chris Daniels/Rosanne Walton: Innovations in service delivery for severely
  affected users
- Professor Trudie Chalder and Dr Mary Burgess: Working with adolescents


Friday: Keynote Speaker and Plenary Sessions

- Keynote Speaker: Professor Gijs Bleijenberg
  Head of the Nijmegen Expert Centre for Chronic Fatigue, Netherlands
  Cognitive behavioural therapy for chronic fatigue syndrome: the role of
  pain and the effects of guided self-management.
- Dr Brian Marien
  The evidence supporting an integrated (mind/body) explanatory model for
  CFS/ME.
- Professor George Davey-Smith
  The future of genetic research and CFS/ME
- Dr Manny Bagary
  Sleep and CFS/ME research
- Dr Julia Newton
  Standing up for Fatigue: Autonomic Nervous System Dysfunction in CFS/ME


Speaker Information and Biographies

- Keynote speaker: Professor Gijs Bleijenberg
  Clinical psychologist and Head of the Nijmegen Expert Centre for Chronic
  Fatigue, Radboud University Nijmegen Medical Centre in the Netherlands.
  The Expert Centre for Chronic Fatigue is a multidisciplinary collaboration
  focussing on the study of chronic fatigue. Furthermore, the ECCF isalso
  a national referral centre for patients with chronic fatigue. Abo300
  patients a year can be seen for fatigue diagnostics, not only CFS patients
  but also patients with cancer related fatigue or with fatigue and a
  chronic disease. About 200 of them are treated with diverse forms of
  cognitive behavioural therapy.
- Professor George Davey-Smith
  Professor of Clinical Epidemiology and head of the new MRC centre for
  genetic research in Bristol University, Director of ALSPAC, and Honorary
  Consultant with North Bristol NHS Trust, from October 1994.  A world
  leader in epidemiology and genetic epidemiology, George Davey Smith has
  led the way in discovering which genes are important in traits such as
  obesity and height. He thinks we can do the same for fatigue and discover
  some of the important biological pathways for CFS/ME. Come and find out if
  this is true!
- Dr Julia Newton
  Senior Lecturer in the Institute for Cellular Medicine, Newcastle
  University. She is the academic lead of the internationally renowned
  Cardiovascular Investigation Unit (Falls and Syncope Unit), which is
  arguably the largest autonomic nervous system testing laboratory in
  Europe. She has a reputation in the investigation of autonomic function
  in the pathogenesis of fatigue with a research programme funded by the
  MRC, ME Research UK, and Liver North. She founded and chairs the local
  multidisciplinary Fatigue Interest Group.
  The talk will focus on the physiological changes that occur when humans
  stand, and how autonomic nervous system responses to assuming the upright
  position may be impaired in those with CFS/ME.
- Professor Trudie Chalder
  Professor of Cognitive Behavioural Psychotherapy in the Dept. of
  Psychological Medicine at King’s College London. She has worked as a
  clinician and a researcher in the area of chronic fatigue syndrome for
  about 18 years and has in the last decade turned her attention to the
  needs of adolescents.
- Dr Mary Burgess
  Works in the Chronic Fatigue Syndrome Research and Treatment Unit at
  King's. She is specifically interested in the needs of the severely
  affected and is currently piloting and evaluating a home based treatment
  for this group.
- Vincent Deary
  Is currently MRC Research Fellow at the University of Newcastle conducting
  research into medically unexplained dysphonia (hoarseness and voice the
  loss). He has been researching and treating (so called) medically
  unexplained symptoms for 12 years and, with Trudie Chalder, has pioneered
  the use of cognitive behavioural therapy to treat children and adolescents
  with chronic fatigue syndrome.
- Rosanne Walton
  Acting Head OT with the chronic pain and fatigue management team based at
  Rayners Hedge in Aylesbury. She was involved in setting up the fatigue
  component of the team in 1998 and has worked in it since. They run
  interdisciplinary chronic fatigue management programmes using a cognitive
  behavioural therapy approach with graded exercise therapy. They also offer
  a limited amount of individual outpatient fatigue management. She
  initially trained as a biologist, then did an OT degree and has since done
  a postgraduate diploma in psychology. Rosanna is currently trialling the
  use of Videophone with people at home. This means the client has a hands-free
  videophone at their house connected to one in the hospital.
- Chris Daniels
  A qualified counsellor and previously the Clinical service Manager for
  Action for ME, Chris now manages the NHS counselling and information
  telephone service for Avon Gloucester Wiltshire, and more recently Greater
  Manchester. This telephone service is targeted at the severely affected.
  Chris also works as a counsellor in the Bristol CFS/NHS Adult team.
- Dr Hugh Rickards
  Dr Rickards is a Consultant in Neuropsychiatry who is part of an
  interdisciplinary neuropsychiatry team based in Birmingham and in the West
  Midlands. He leads the CFS/ME Service in this region.


Accommodation

The link below (which you need to click on to open) will take you to a
Milton Keynes website which lists various hotels in Milton Keynes. Jurys
Hotel (the conference venue) is listed/flagged as 'B'.
   http://maps.google.co.uk/maps?hl=en&q=hotels&near=Milton+Keynes,+UK&ie=UTF8&z=13&ll=52.032746,-0.738659&spn=0.076883,0.159645&om=1

---------------------------------------------------------------------
Registration Form: Collaborative Conference on CFS/ME 2007
Jurys Hotel, Milton Keynes, Bucks
Thursday 4th and Friday 5th October 2007

Please print clearly in block capitals. Your name, place of work and
Profession/position held: these will be used for your name badge, the
attendance list and your certificate of attendance.

Full name and title      ............................................
Place of employment      ............................................
Profession/Position held ............................................
Postal address           ............................................
County                   ............................................
Postcode                 .................. Tel No...................
Email                    ............................................
Special dietary requirements or other special needs .................
                         ............................................

Please tick the boxes as appropriate.
(O) I have enclosed a cheque for: Until 1st August 07 100 pounds for one day,
    180 pounds for both days. After 1st August 07 (late registration) 125
    pounds for one day, 200 pounds for both days. This does not include your
    hotel accommodation which you need to book independently. Paediatric SIG
    only 50 (Please note that this is the only form of payment we are able to
    accept and cheques must be made payable to North Bristol NHS Trust budget
    code B09052)
(O) I would like attend the conference dinner at 25 pounds per head plus wine
(O) I would like to be sent directions and/or a map.

Please return your completed form to:
Sue Webb
9 Osterley Close
Newport Pagnell
Bucks
MK16 0EZ

Reservation is a contract. Cancellations must be made in writing and will be subject
to a 10% administration charge. No refunds will be made for cancellations notified
within fourteen days of the event, but substitute delegates will be accepted at any
time.

For further information please email:
mecfsnetwork@fsmail.net
---------------------------------------------------------------------

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

Date:    Sun, 8 Jul 2007 10:40:23 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Cranial electrotherapy stimulation and fibromyalgia

Cranial electrotherapy stimulation and fibromyalgia.

Expert Rev Med Devices. 2007 Jul;4(4):489-95.

Gilula MF.

President and Director, Life Energies Research Institute, 2510 Inagua
Avenue, Miami, FL 33133, USA. mgilula@mindspring.com.

PMID: 17605684


Cranial electrotherapy stimulation (CES) is a well-documented
neuroelectrical modality that has been proven effective in some good
studies of fibromyalgia (FM) patients. CES is no panacea but, for some FM
patients, the modality can be valuable.

This article discusses aspects of both CES and FM and how they relate to
the individual with the condition. FM frequently has many comorbidities
such as anxiety, depression, insomnia and a great variety of different
rheumatologic and neurological symptoms that often resemble multiple
sclerosis, dysautonomias, chronic fatigue syndrome and others. However,
despite long-standing criteria from the American College of Rheumatology
for FM, some physicians believe there is probably no single homogeneous
condition that can be labeled as FM.

Whether it is a disease, a syndrome or something else, sufferers feel like
they are living one disaster after another. Active self-involvement in care
usually enhances the therapeutic results of various treatments and also
improves the patient's sense of being in control of the condition. D-ribose
supplementation may prove to significantly enhance energy, sleep, mental
clarity, pain control and well-being in FM patients. A form of evoked
potential biofeedback, the EPFX [Electro-Physio-Feedback-Xrroid], is a
powerful stress reduction technique which assesses the chief stressors and
risk factors for illness that can impede the FM patient's built-in healing
abilities.

Future healthcare will likely expand the diagnostic criteria of FM and/or
illuminate a group of related conditions and the ways in which the
conditions relate to each other. Future medicine for FM and related
conditions may increasingly involve multimodality treatment that features
CES as one significant part of the therapeutic regimen. Future medicine may
also include CES as an invaluable, cost-effective add-on to many facets of
clinical pharmacology and medical therapeutics.

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

Date:    Sun, 8 Jul 2007 13:33:35 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Randomized controlled study of the antinociceptive effect of ultrasound on trigger point sensitivity: novel applications in myofascial therapy?

Randomized controlled study of the antinociceptive effect of ultrasound on
trigger point sensitivity: novel applications in myofascial therapy?

Clin Rehabil. 2007 May;21(5):411-7.

Srbely JZ, Dickey JP.

Department of Human Health and Nutritional Sciences, University of Guelph,
Guelph, Ontario, Canada. jsrbely@uoguelph.ca.

PMID: 17613561


OBJECTIVE: To investigate whether therapeutic ultrasound modulates the pain
sensitivity of myofascial trigger points.

DESIGN: Repeated measures, single-blinded randomized controlled trial of
ultrasound treatment of trigger points.

SETTING: Outpatient injury rehabilitation clinic. SUBJECTS : Forty-four
patients (22 males, 22 females) with trigger points identified within the
trapezius muscle.

INTERVENTIONS: Five-minute therapeutic intensity of ultrasound versus 5-min
low-intensity application of ultrasound to a trapezius myofascial trigger
point locus.

MAIN MEASURES: Pain pressure threshold readings were measured at the
trapezius trigger point site before and after exposure to the ultrasound
intervention.

RESULTS: Pain pressure threshold scores increased an average of 44.4
(14.2)% after therapeutic exposure to ultrasound (pre-ultrasound test 35.4
(8.5) N, post-ultrasound test 51.1 (12.8) N). No significant difference in
pain pressure threshold scores was observed with low-intensity ultrasound
exposures (pre-ultrasound 36.1 (6.1) N, post-ultrasound 36.6 (4.8) N).

CONCLUSIONS : Therapeutic exposures to ultrasound reduce short-term trigger
point sensitivity. Ultrasound may be a useful clinical tool for the
treatment and management of trigger points and myofascial pain syndromes.

[Return to top]

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

Date:    Sun, 8 Jul 2007 14:23:45 +0200
From:    "Dr. Marc-Alexander Fluks" 
Subject: RES,NOT: Paper: CFS genes research in Australia (Full text version)

Source: The Journal of Infectious Diseases
        Vol. 196, #1, p 56-66
Date:   July 1, 2007
URL:    http://www.journals.uchicago.edu/JID/journal/available.html
        http://www.journals.uchicago.edu/JID/journal/issues/v196n1/37954/37954.html


Gene Expression Correlates of Postinfective Fatigue Syndrome after Infectious
Mononucleosis
------------------------------------------------------------------

Barbara Cameron(1), Sally Galbraith(2), Yun Zhang(2) Tracey Davenport(4), Ute
Vollmer-Conna(3), Denis Wakefield(1), Ian Hickie(4), William Dunsmuir(2),
Toni Whistler(5), Suzanne Vernon(5), William C. Reeves(5), and Andrew R.
Lloyd(1) for the Dubbo Infection Outcomes Study

1 School of Medical Sciences,
2 School of Mathematics, and
3 School of Psychiatry, University of New South Wales, and
4 Brain and Mind Research Institute, Sydney University, Sydney, Australia;
5 Division of Viral and Rickettsial Diseases, Centers for Disease Control and
  Prevention, Atlanta, Georgia

Received 5 December 2006; accepted 12 January 2007; electronically published
  24 May 2007.
Potential conflicts of interest: none reported.
Financial support: National Health and Medical Research Council of Australia
  (project grants 157092 and 157062); US Centers for Disease Control and
  Prevention (cooperative research agreement U50/CCU019851-01).
Correspondence: Prof. Andrew Lloyd, Centre for Infection and Inflammation
  Research, School of Medical Sciences, University of New South Wales, Sydney
  2052, Australia (A.Lloyd@unsw.edu.au).
See the editorial commentary by White, on pages 4-5.


Background.

Infectious mononucleosis (IM) commonly triggers a protracted postinfective
fatigue syndrome (PIFS) of unknown pathogenesis.

Methods.
Seven subjects with PIFS with 6 or more months of disabling symptoms and 8
matched control subjects who had recovered promptly from documented IM were
studied. The expression of 30,000 genes was examined in the peripheral blood
by microarray analysis in 65 longitudinally collected samples. Gene
expression patterns associated with PIFS were sought by correlation with
symptom factor scores.

Results.
Differential expression of 733 genes was identified when samples collected
early during the illness and at the late (recovered) time point were
compared. Of these genes, 234 were found to be significantly correlated with
the reported severity of the fatigue symptom factor, and 180 were found to be
correlated with the muscu- loskeletal pain symptom factor. Validation by
analysis of the longitudinal expression pattern revealed 35 genes for which
changes in expression were consistent with the illness course. These genes
included several that are involved in signal transduction pathways, metal ion
binding, and ion channel activity.

Conclusions.
Gene expression correlates of the cardinal symptoms of PIFS after IM have
been identified. Further studies of these gene products may help to elucidate
the pathogenesis of PIFS.

In industrialized countries, 40%-65% of primary Epstein-Barr virus (EBV)
infections occur asymptomatically during early childhood [1, 2]. In contrast,
primary EBV infection in young adults often causes symptomatic infectious
mononucleosis (IM). Most cases of acute IM resolve within several weeks
without sequelae, but some individuals experience a prolonged and disabling
illness marked by fatigue extending over weeks or months. Prospective cohort
studies examining the kinetics of recovery from acute IM [3-5] have revealed
that almost 50% of subjects had ongoing symptoms at 2 months after onset and
that ~10% had disabling symptoms marked by fatigue lasting 6 months or more.
These subjects did not have clinical features of chronic, active EBV (CAEBV)
infection, which is attributable to congenital [6] or acquired [7, 8]
impairments of T cell immunity. Similarly, detailed medical and psychiatric
assessments conducted in the Dubbo Infection Outcomes Study (DIOS) [5] did
not reveal an alternative medical or psychiatric explanation for this
postinfective fatigue syndrome (PIFS), indicating that subjects with PIFS
represent a subset of the more heterogeneous and enigmatic clinical disorder
termed "chronic fatigue syndrome" (CFS) [9, 10].

We recently reported the outcomes of a detailed assessment of virological and
immunological correlates of PIFS in a case-control series of DIOS subjects
followed from the onset of acute IM [11]. There was no difference in cellular
EBV load at any time point between the case subjects, who developed PIFS, and
the control subjects, who recovered promptly. Although minor alterations in
the kinetics of both antibody and T cell responses to EBV were evident, these
did not correlate with the timing of recovery, arguing against the popular
immunological and virological hypotheses of the pathogenesis of PIFS [12,
13]. In combination with available evidence from other studies of patients
with CFS, these data point to the central nervous system (CNS) as the likely
site of the pathophysiological disturbance [13-16]. Thus, we predicted that
neurochemical and neuroinflammatory genes would be differen- tially expressed
in the peripheral blood of subjects with PIFS.

Accordingly, the present study adopted a gene discovery approach as a novel
strategy to elucidate the pathophysiology of PIFS. Peripheral blood was
chosen for study, first because it was readily available; second because the
utility of peripheral blood gene expression to explore the pathogenesis of
complex diseases of the CNS has recently been demonstrated in predicting
emergent posttraumatic stress disorder [17] and in distinguishing subjects
with schizophrenia or bipolar disorder from healthy control subjects [18];
and finally because preliminary studies examining samples collected from a
group of subjects during acute IM discovered novel gene expression correlates
of the symptoms of the acute sickness response [19]. Thus, the present study
used microarray technology to examine gene expression in a matched
case-control series of subjects followed from shortly after the onset of
acute IM that was of short duration or that persisted into PIFS.


SUBJECTS, MATERIALS, AND METHODS

Subjects.

Participants were enrolled in DIOS after presentation with symptoms of acute
IM and detection of IgM antibodies against EBV capsid antigen. Follow-up was
conducted at regular intervals for 12 months or more. Provisional serological
diagnoses were confirmed by testing longitudinally collected serum samples
[20].

At each visit, detailed self-report and interview assessments of physical and
psychological health were recorded. The severity and duration of symptoms
were monitored using a self-report questionnaire, the Somatic and
Psychological Health Report [21, 22]. A score of 3 or more (of a possible 12)
on a validated subscale (called "the SOMA") was used to designate clinically
significant fatigue states [23-25].

In those subjects with persistent symptoms beyond 3 months (designated as
having provisional PIFS cases), structured medical and psychiatric
assessments as well as laboratory investi- gations to exclude CAEBV infection
or unrelated causes of illness were undertaken in accordance with the
diagnostic criteria for CFS [9, 10]. Seven subjects with PIFS (i.e., those
who had unexplained illness persisting for 6 months or more after onset of
symptoms and met the diagnostic criteria for CFS) and 8 control subjects who
had recovered more promptly, matched as a group by age and sex, were selected
for the present study [5].

To allow investigation of the gene expression correlates of the symptom
complex, scores for each subject at each time point for the 6 symptom factors
(as described elsewhere [5]) - fatigue, musculoskeletal pain, mood
disturbance, neurocognitive disturbance, acute sickness, and irritability -
were calculated from their self-report data sets. The study protocol was
approved by the relevant institutional review boards. Written, informed
consent was provided by all subjects.


Specimens and laboratory methods.

Blood samples were collected in the morning and transported to the laboratory
within 6 h. Then, peripheral blood mononuclear cells (PBMCs) were separated
(Lymphoprep; AXIS-SHIELD) and cryopreserved with 10% DMSO (Sigma) and 50%
autologous plasma, and aliquots were stored in the vapor phase of liquid
nitrogen. Subsequently, the thawed PBMCs were lysed in Tri Reagent (Sigma).
RNA was extracted and quantified by spectrophotometry, and quality was
evaluated by denaturing gel electrophoresis.

Glass arrays (MWG Biotech) carrying 50mer oligonucleotides for 30,000 genes
(10,000 on each of the 3 arrays, designated A, B, and C) were used. The A
array bore 10,000 well-characterized genes; the B array carried a mix of
known genes and expressed sequence tags (ESTs); and the C array bore all ESTs.
Biotinylated cDNA probes were prepared from 1 mg of sample RNA as described
elsewhere [26] and were hybridized to the arrays on the Ventana instrument
(Ventana Medical Systems). Hybridization was for 8 h at 42 C with the ChipMap
kit, with three 10-min stringency washes at 42 C (NaCl-Na citrate buffer at
2x 1x, and 0.1x ). This was followed by a 30-min incubation in streptavidin-
labeled gold-particle solution (RLS system; Invitrogen [previously Genicon
Sciences]) before vigorous washing to remove the oil, application of a liquid
optical coating, and air drying.

A total of 65 samples were included, representing from 3 to 7 time points per
subject (table 1). RNA of sufficient yield and quality (a 28S:18S ratio of
1.8-2.0) was available to hybridize with all 3 arrays for 43 sampling points,
whereas only hybridization with the A and B arrays was conducted for 13
samples, and, for a further 9 samples, hybridization with the A array alone
was performed. All subjects had hybridizations preformed with all 3 arrays
for at least 2 sampling points. For each subject, probe synthesis and
hybridizations for all samples were performed in a single run. Arrays from a
case and a control subject were run together where possible, to control for
run-to-run effects.


Data handling and analysis.

Arrays were scanned (GSD-501; Invitrogen [previously Genicon Sciences]) with
settings chosen to saturate a minimum of 1 feature on each array. Array
images were analyzed (ArrayVision RLS; Imaging Research) to remove
unacceptable features (i.e., "flags" due to dust or other technical
artifacts) after manual confirmation as well as to quantify the relative
expression of each feature in comparison to background. The raw intensity
values ranged from 0 to 64,000. Flagged features as well as blanks and
Arabidopsis con- trols were removed from the analysis [27].


Normalization.

The data were normalized within each array by assuming that the intensity
values plus an array-specific constant, after log_2 transformation, followed
a normal distribution, with zero values representing left-censored observa-
tions. Parameters of the distribution were estimated by maximum likelihood
(S.G. and W.D., submitted manuscript). This approach transformed the data to
normality, removed artificial array-specific effects, and recognized left
censoring of intensity values at zero.


Filtering.

It was assumed that the majority of the genes would not be differentially
expressed and that including these noninformative genes might distort the
clustering and correlation analyses [28]. In addition, it was assumed that
the genes of interest in relation to PIFS would be differentially expressed
when comparing the early illness phase with recovery, consistent with our
recent evidence that all of the phenotypic characteristics of the PIFS
illness are present from onset but resolve slowly [5]. The filtering
procedure therefore compared expression levels in samples collected from
subjects with a SOMA score of 3 or more at baseline (T1; representing data
from samples collected during the early symptomatic phase of IM) with levels
in subjects with a SOMA score <3 by 9 months (T4) and also during the
preceding 3 months (representing data from samples collected well after
recovery from IM and PIFS) (table 1). A feature was deemed to be
differentially expressed if a 2-sample t test for equality of the means of
normalized expression levels between the 2 groups (not assuming equality of
variances) resulted in a P value of .01 or less. Outlying data points in the
second group (expression levels 11.5 times the interquartile range below the
first quartile or above the third quartile) were excluded before performing
the t test.


Overabundance analysis.

To assess the significance of the correlations between symptom scores and
expression data of the filtered set of features, overabundance analysis was
performed as described elsewhere [17]. This technique compared the number of
features designated as being differentially expressed with the number
expected by chance, which was ob- tained by randomly permuting the group
labels 1000 times for different P value cutoffs. The 2-sample t test was
performed for each permutation, and the number of P values less than each
cutoff, averaged over all permutations, represented the expected number of
features "differentially expressed" under the null hypothesis of no
difference in expression levels between the 2 groups.


Clustering.

Clustering was used to determine whether expression levels for the filtered
features at baseline (T1) were able to classify subjects correctly according
to case/control status. Clustering was performed using DoublePCluster
software (available in the public domain ScoreGenes package [version December
2002]; see http://www.compbio.cs.huji.ac.il/ scoregenes/), which implements
an unsupervised hierarchical biclustering approach [17]. For subjects with 11
array at T1, the first array was used.


Correlation analyses.

For each of the 6 symptom domains, Pearson correlations between symptom
factor scores and expression levels were calculated for each feature. All
subjects and time points were included in this analysis. To test the null
hypothesis of zero correlation, an upper 1-sided t test was performed.
Features with a P value <.05 were deemed to be significantly positively
correlated, and those with a P value >.95 were deemed to be significantly
negatively correlated. To assess the significance of the resulting sets of
features, overabundance analyses were again performed using 1000 random
permutations of the group labels.


Bioinformatics.

The National Center for Biotechnology Information UniGene cluster ID as well
as the RefSeq (reference sequence) and GenBank accession numbers were sought
for each feature on the arrays by use of the SOURCE automated-annotation Web
site (http://source.stanford.edu/). Of the original 30,000 features, 13,956
with gene annotations were identified. WebGestalt (WEB-based GEne SeT
AnaLysis Toolkit) software (http://bioinfo.vanderbilt.edu/webgestalt/) [29],
which includes GOTree Machine software, was used for comparative functional
analysis. Gene ontology (GO) terms were sought for each annotated feature.
For each GO term, the total number of features on the array belonging to that
category was determined, before comparisons were made with the lists of
symptom factor-correlated features identified in the analyses described
above. Statistical analysis of the enrichment by GO category was completed
using the hypergeometric test, which accounts for the problem of sampling
without replacement associated with comparison of the filtered and symptom
factor-correlated genes from the remaining features on the arrays. A GO
category was considered to be differentially regulated if the significance
level was <.01.

Finally, to validate the biological relevance of the symptom
factor­correlated genes, the subject group was divided into 3 subgroups on
the basis of the course of illness: those who remained symptomatic throughout
the 9 months or more of follow-up (n=4; subjects PIFS1­3 and PIFS7 in table
1); those who were symptomatic on enrollment but subsequently recovered (n=8;
subjects PIFS4-6 and C1-5); and those who had already recovered from IM
shortly before enrollment in the cohort and remained symptom free over the
period of prolonged follow-up (n=3; subjects C6-8). For each gene, the mean
normalized expression values and mean symptom factor scores for these 3
subject subgroups were plotted. Candidate genes were retained if (1) the
pattern of change in expression over time was consistent with that predicted
from the categorization of the subjects--that is, the mean intensity was
highest in those who were symptomatic and lowest in those were not (or the
converse for negatively correlated genes) - and (2) the pattern of recovery
from illness over time was reflected by a 1.5-fold or greater (>=log_2 0.59)
change in mean expression levels between the extremes of the data set. A
single outlying data point in the mean trend lines was ignored, but the
presence of 2 or more outlying data points led to the exclusion of that gene
from further interest.

Functional and pathway information for the finalized list of genes was
obtained from the BioCarta (http://www.biocarta.com/) and Kyoto Encyclopedia
of Genes and Genomes (http://www.genome.ad.jp/kegg/kegg4.html) databases.
Figure 1 provides a schematic summary of the complete data analysis process.


RESULTS

The subjects with PIFS included 2 males and 5 females with a mean age of 24
years (table 1). At enrollment, these subjects reported a mean of 22 days out
of role and 14 days in bed since the onset of IM, whereas the control group,
which included 5 males and 3 females with a mean age of 24 years, reported a
mean of 17 days out of role and 9 days in bed. With the exception of 1
Hispanic individual, all subjects were white. All subjects had a clinical
illness consistent with IM, featuring fever and pharyngitis. Generalized
lymphadenopathy was evident in 10 subjects, splenomegaly in 1, and rash in 1.
None of the group had preexisting medical illnesses that might have
contributed to the symptom complex or influenced gene expression, with the
possible exception of 1 case subject who had idiopathic epilepsy well
controlled by sodium valproate therapy. Five subjects reported recent use of
prescribed antibiotics (1 case and 4 control subjects) at baseline. Two
females (1 case and 1 control subject) were taking the oral contraceptive
pill. All subjects reported occasional use of simple analgesics, typically
paracetamol, during the illness.

The cluster analysis sought a gene expression signature to distinguish case
from control subjects during early illness (T1), to allow prediction of the
subsequent development of PIFS. The solution dendrogram (figure 2)
categorized the subjects into 2 broad groups, with 6 of the 7 case subjects
in one arm and the remaining case subject (PIFS1) in the other arm. This
subject was significantly older (49 years) than the other case subjects and
was 1 of the 2 who had sustained illness over 12 months or more of follow-up.
The 6 clustered PIFS cases were associated with 3 control subjects (C1, C3,
and C5), who had no apparent distinguishing features. Cluster analysis of the
T3 data set, which included the case subjects with 6 months or more of
illness and the recovered control subjects, did not provide a coherent gene
expression signature for PIFS.

Gene expression correlates of the 6 symptom domains were sought by analysis
of the filtered gene list and the symptom factor scores for all subjects at
all time points (figure 3). The fatigue factor was correlated, positively or
negatively, with 197 genes, and the musculoskeletal pain factor was
correlated with 138 genes. Overabundance analyses revealed that these 2, but
not the other 4, symptom factors were associated significantly more commonly
than by chance alone (P<.0001 for fatigue and P=.007 for musculoskeletal
pain). Of these genes, 83 were associated with both factors, giving a
combined list of 252 genes.

Of the 252 fatigue- and/or pain-associated genes, 35 were validated by
analysis of the temporal course of the illness in relation to the gene
expression pattern (figure 4). Analysis of the enrichment of these 35 genes
by GO category did not identify recognized biological processes, molecular
functions, or cellular components in which 11 gene from the diseaseassociated
list was implicated, indicating significant enrichment in comparison to the
GO categories associated with all annotated features on the arrays.
Nevertheless, it is apparent that several members of the gene list are
involved in similar biological themes, including signal transduction
pathways, metal ion binding, and ion channel activity (table 2).


DISCUSSION

The present study provides the first comprehensive and longitudinal
examination of the peripheral blood transcriptome in patients with
well-characterized PIFS. Although peripheral blood is a complex tissue, a
previous study revealed relatively restricted interindividual and
within-individual variability in gene expression when studied by microarray
analysis and also showed that this variance was markedly less than that
observed in disease states [30]. In addition, recent data from the Microarray
Quality Control project indicates good intraplatform consistency across test
sites as well as a high level of interplatform concordance in terms of genes
identified as being differentially expressed [31]. Several of the recognized
confounding influences on peripheral blood gene expression were controlled
for in the present study [30], including age (by matching in the case-control
series), medication use (generally none), and time of day at which blood
sampling was conducted (standardized). In addition, we previously reported no
significant differences in leukocyte subpopulations between these subject
groups [11].

In the DIOS cohort, we have already established that PIFS is a stereotyped
illness complex, consistent with the diagnostic criteria for CFS, with a case
rate of 11% of subjects at 6 months after the onset of infection [5]. The
prospective, population-based research design in the present study can be
contrasted with traditional CFS research, which has focused almost
exclusively on cross-sectional studies of subjects recruited from tertiary
referral clinics. Such subjects feature clinical heterogeneity and
chronicity, which are likely to reflect diversity in risk factors, illness
course, and pathophysiology [9, 32, 33]. This heterogeneity is likely to be
a major reason why the pathogenesis of CFS remains largely unknown, despite
several de- cades of hypothesis-driven research [13, 14]. The PIFS model used
here therefore provides a unique opportunity to critically examine the
popular hypotheses on the pathogenesis of CFS.

The findings of the present study provide preliminary evidence for the
potential of studies of peripheral blood gene expression to identify
biomarkers for the major symptoms of the PIFS illness and to open new
investigative pathways for studies of pathogenesis. The gene expression
signature identified by cluster analysis on the baseline samples generally
predicted subsequent PIFS status. However, this signature should be regarded
as exploratory only, because it was not unique to the subjects who went on to
a PIFS illness. In addition, a cross0sectional analysis of the gene
expression data set at 6-9 months after the onset of infection could not
reliably distinguish subjects with PIFS from those who had recovered
uneventfully from IM.

The genes of interest associated with the major symptoms of PIFS included
several with functional roles in metal ion binding within the cell (CBFA2T2,
NDUFS2, CHEK2, ZNF596, MT1X, ZBTB41, and ZDHHC3); immune response pathways
(PRDX1, SCARB1, SH2D1B, RAE1, ASAH2, and IL11RA); hormonal responses (IGF2AS
and ACBD3); and neuronal pathways (SORCS3 and KCND3). The association between
each of these genes and PIFS was validated by demonstrating first that the
expression in subjects who had recovered from IM differed from those with
ongoing symptoms and second that the pattern of change in gene expression
over time was associated in a consistent fashion with the longitudinal course
of illness (either with ongoing PIFS or with recovery).

It may be noteworthy that none of these candidate genes are shared with those
identified in previous studies of patients with CFS, although similar
biological processes have been implicated [34-38]. However, these previous
studies were cross-sectional and were based on comparison of patients with
long-standing CFS, with the likely heterogeneity inherent in that patient
group [9, 32]. For instance, a recent analysis of the clinical phenotypes
within the diagnosis of CFS in a population-based sample and the associated
peripheral blood gene expression pattern revealed at least 5 patient
subgroups, each associated with relatively distinct gene expression
signatures [39]. Nevertheless, the common biological process identified in
these various studies is the transport of iron, zinc, and copper ions, and,
in terms of functional pathway, it appears that immune response genes and
neuronal genes are commonly expressed. Because these processes and pathways
constitute a large proportion of all well-characterized genes in the
transcriptome, the fundamental premise of this study - that peripheral blood
gene expression will inform a better understanding of the pathogenesis of CFS
- remains speculative.

Additional factors beyond alterations in the pattern of peripheral blood gene
expression reflecting the host response to the initial infection are likely
to contribute to the duration of illness after IM. These may include
behavioral response patterns such as alterations in sleep, exercise, and mood
as well as the modulating influences of sex [40], which in turn may also
influence peripheral blood gene expression [37, 41]. There were no genes
identified here that were shared with those previously identified as exercise
induced, either in control subjects or in patients with CFS [37].

Further studies of the genes of interest identified here in an expanded
case-control series of subjects followed from the onset of acute IM are
therefore needed to verify the association with the illness complex of PIFS
and to investigate the impact of behavioral changes on gene expression.
Confirmation of these gene expression correlates by real-time polymerase
chain reaction in the subjects reported here and in subjects who developed
PIFS after having other infections included in the DIOS cohort - as well as
in independent postinfective cohorts - may make possible novel investigative
approaches to elucidate the pathophysiology of PIFS and CFS.


Acknowledgments

The support of the general practitioners and the diagnostic pathology
services in the Dubbo region and the enduring cooperation of the subjects who
participated in this research are gratefully acknowledged.


Tables

Table 1. Subject groups, symptom scores, and sampling time points (T1­T4) for the
         microarray analysis.
---------------------------------------------------------------------------------------
                 Symptom scores^b by time after onset
                 ----------------------------------------------------------------------
                 T1              T2              T3              T4
                 --------------  --------------  --------------  ----------------------
Subjecta (sex,   0-3     3-6     6-9     9-12    3-6     6-9     9-12    >12     >12
age in years)    weeks   weeks   weeks   weeks   months  months  months  months  months
PIFS1 (F, 49)             8       7       8       8       8               4       5
PIFS2 (F, 17)             3       6               9      10      11      10       5
PIFS3 (F, 23)            11       8                              10       6
PIFS4 (F, 17)     6       9                       4               7       0
PIFS5 (M, 18)            11      NA       8       7               3       2       0
PIFS6 (M, 23)             4                       5                       0
PIFS7 (F, 19)             5               8       3
C1 (F, 34)                5       4                                       0
C2 (M, 17)                        8       0
C3 (M, 19)                9       2                       0               0
C4 (M, 48)                3              NA               0               1
C5 (M, 18)        3       1                       0                       0
C6 (M, 18)        0       2       0                                       1
C7 (F, 19)                2       2       1                               0
C8 (F, 18)        1       0       0                                       0
---------------------------------------------------------------------------------------
NOTE. Shaded and unshaded areas indicate the illness and the recovery period,
  respectively, for each subject. NA, not available.
a Case patients with postinfective fatigue syndrome are indicated by "PIFS"; matched
  control subjects who recovered within 6 weeks of onset are indicated by "C."
b Symptom score on the SOMA subscale of the Somatic and Psychological Health Report
  (possible range, 0­12; a score of 3 or more indicates a clinically significant fatigue
  state).


Table 2. Postinfective fatigue syndrome­associated genes: function, subcellular localization, tissue expression, and disease associations.
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
GenBank     Gene name                                       Gene symbol Gene function                                      Subcellular        Tissue expression                             Associated phenotype(s)
accession no.                                                                                                              localization
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
NM_003171   Suppressor of var 1, 3-like 1 (S. cerevisiae)   SUPV3L1     Cofactor of survivin in apoptosis suppression;     Mitochondrion      Ubiquitous
                                                                        ATP and RNA binding; helicase activity
NM_182961   Spectrin repeat containing, nuclear             SYNE1       Actin binding; laminin binding; Golgi and nuclear  Golgi apparatus;   Ubiquitous
            envelope 1                                                  organization and biogenesis; myocyte               cytoskeleton;
                                                                        differentiation                                    nuclear envelope
AC013478    Phospholipase C-like 1                          PLCL1       Calcium ion binding; hydrolase activity;                              Ubiquitous
                                                                        phospholipase C activity
AL034421    Core-binding factor; runt domain,               CBFA2T2     Metal ion binding; regulation of transcription;    Nucleus            Ubiquitous                                    Translocation in acute myeloid leukemia produces
            alpha subunit 2                                             cell proliferation                                                                                                  a chimeric gene product associated with nuclear
                                                                                                                                                                                            corepressor/histone deacetylase complex to
                                                                                                                                                                                            block hematopoietic differentiation
AF013160    NADH dehydrogenase (ubiquinone) Fe-S            NDUFS2      Metal ion binding; mitochondrial electron          Mitochondrial      Ubiquitous                                    Mitochondrial complex I deficiency
            protein 2, 49 kDa (NADH-coenzyme                            transport; NADH dehydrogenase                      inner membrane
            Q reductase)                                                (ubiquinone) activity; oxidative
                                                                        phosphorylation
NM_002574   Peroxiredoxin 1                                 PRDX1       Antioxidant enzyme activity; antiviral activity    Cytoplasm          Ubiquitous                                    Increased expression in Alzheimer disease, Down
                                                                        in CD8 T cells; cell proliferation; skeletal                                                                        syndrome, and lung injury
                                                                        development
AL117330    CHK2 checkpoint homolog (S. pombe)              CHEK2 (also ATP, Mg, nucleotide, and protein binding;          Nucleus            Ubiquitous                                    Associated with cancer susceptibility, including breast,
                                                            CDS1)       serine/threonine kinase activity;                                                                                   colorectal, and prostate cancer
                                                                        response to DNA damage; cell cycle
                                                                        regulation
NM_005938   Myeloid/lymphoid or mixed-lineage               MLLT7       Transcription factor; cell cycle arrest; cell      Nucleus;           Ubiquitous
            leukemia                                                    differentiation; negative regulation of            cytoplasm
                                                                        angiogenesis, cell proliferation, and
                                                                        muscle cell differentiation; AKT and Ras
                                                                        signaling pathways
AC004908    Zinc finger protein 596                         ZNF596      DNA and metal ion binding; DNA-dependent           Nucleus            Ubiquitous
                                                                        regulation of transcription
AF351784    DnaJ (Hsp40) homolog, subfamily C,              DNAJC14     Heat shock protein and unfolded protein            Membranes of the   Ubiquitous
            member 14                                                   binding; interacts with angiotensin receptor­1     endoplasmic
                                                                        (AGTR1), dopamine receptor­1 (DRD1), and           reticulum
                                                                        lysosomal trafficking regulator (LYTR)
NM_016412   Insulin-like growth factor 2 antisense          IGF2AS      Growth factor inhibition                                              Brain; liver; placenta; plasma; pancreas
NM_005505   Scavenger receptor class B, member 1            SCARB1      Apoptosis; cell adhesion; cholesterol              Plasma membrane    Ubiquitous                                    HCV entry cofactor; amyloid B protein interaction
                                                                        metabolism
AL365449    Sortilin-related VPS10 domain                   SORCS3      Neuropeptide signaling pathway                     Membranes of the   Brain; testis; cranial nerve; blood; liver;
            containing receptor 3                                                                                          endosomes,         stomach; colon; muscle; larynx;
                                                                                                                           Golgi, lysosomes   tonsil; mammary gland
                                                                                                                           and nucleus
NM_053282   SH2 domain containing 1B                        SH2D1B      Intracellular signaling; NK cell­mediated                             Blood; spleen; thymus; kidney;
                                                                        cytotoxicity; interacts with NK cells;                                stomach; skin; lung; muscle; testis
                                                                        lymphocyte adhesion
NM_024882   Chromosome 6 open reading frame 155             C6orf155
AK026814    Sorting nexin 25                                SNX25       Signal transduction; phosphoinositide                                 Ubiquitous
AF255647    Transmembrane protein 163                       TMEM163                                                                           Ubiquitous
NM_003610   RAE1 RNA export 1 homolog (S. pombe)            RAE1        Interacts with NK cell lectins, nucleoporin; RNA   Cytoskeleton;      Ubiquitous
                                                                        binding and export; microtubule binding;           nuclear
                                                                        mitotic spindle assembly                           membrane
NM_005952   Metallothionein 1X                              MT1X        Iron, zinc, copper, and cadmium ion binding;                          Ubiquitous
                                                                        electron transport
AC010974    LY6/PLAUR domain containing 1                   LYPD1       GPI-anchored protein binding                       Plasma membrane    Ubiquitous
AC063956    Casein alpha s2-like A                          CSN1S2A     Transporter activity                               Extracellular      Muscle
AK002014    Chromosome 6 open reading frame 70              C6orf70                                                        region             Ubiquitous
NM_014319   LEM domain containing 3                         LEMD3       Nuclear endoplasmic reticulum­associated           Nuclear inner      Ubiquitous                                    Buschke-Ollendorff syndrome; melorheostosis
                                                                        degradation pathway; glycosylation of              membrane                                                         with osteopoikilosis
                                                                        mammalian N-linked oligosaccharides;
                                                                        nucleotide binding
NM_019893   N-acylsphingosine amidohydrolase                ASAH2       Ceramide, lipid, and sphingolipid metabolism       Mitochondria;      Skin; bladder
            (non-lysosomal ceramidase) 2                                signal transduction; apoptosis                     plasma membrane
AF020762    Acyl-Coenzyme A binding domain                  ACBD3       Maintenance of Golgi structure and function;       Golgi membrane;    Ubiquitous
            containing 3                                                hormonal regulation of steroid formation           cytoplasm;
                                                                                                                           mitochondrion
BC029816    Ovostatin 2                                     OVOS2       Endopeptidase inhibitor activity                   Secreted protein   Testis; lung; eye; brain; lymph node;
                                                                                                                                              mammary gland; pituitary gland;
                                                                                                                                              bone; kidney; cranial nerve
AL356315    Zinc finger and BTB domain containing 41        ZBTB41      Nucleic acid, protein, and zinc ion binding        Nucleus            Ubiquitous
NM_014473   Dimethyladenosine transferase                   HSA9761     rRNA modification and processing; transferase      Nucleus            Ubiquitous
                                                                        activity
AF004813    Solute carrier family 4, sodium bicarbonate     SLC4A4      Intracellular pH regulation; sodium ion binding    Cell membrane      Ubiquitous                                    Proximal renal tubular acidosis with ocular
            cotransporter, member 4                                     and transport; anion exchange activity
NM_004512   Interleukin 11 receptor, alpha                  IL11RA      Hematopoietin/interferon-class (D200-domain)       Plasma membrane    Ubiquitous                                    High expression in Hodgkin lymphoma; possible
                                                                        cytokine receptor activity; Jak-STAT signaling                                                                      prostate cancer
                                                                        pathway
NM_004980   Potassium voltage-gated channel, Sha            KCND3       Regulation of neurotransmitter release, heart      Plasma membrane;   Brain; testis; prostate; lung; thyroid;
            l-related subfamily, member 3                               rate, insulin secretion, neuronal excitability,    voltage-gated      mammary gland; colon; heart;
                                                                        epithelial electrolyte transport, smooth           potassium          adrenal gland
                                                                        muscle contraction, and cell volume; metal         channel complex
                                                                        ion, potassium, and protein binding
NM_016598   Zinc finger, DHHC-type containing 3             ZDHHC3      Acyltransferase activity; metal ion binding        Vacuolar membrane  Ubiquitous
NM_017594   GIPC PDZ domain containing family,              GIPC1       Interacts with integrins, b-adrenergic receptor    Cytoplasm; plasma  Ubiquitous
            member 1                                                    signaling pathway; spliceosomal assembly           membrane;
                                                                                                                           nucleus
NM_017594   Small nuclear ribonucleoprotein                 SNRPG       RNA and protein binding; RNA splicing;             Nucleus            Ubiquitous
            polypeptide G                                               spliceosome assembly
NM_002922   Regulator of G-protein signaling 1              RGS1 (also  G-protein signaling; adenylate cyclase inhibition  Plasma membrane    Ubiquitous
                                                            BL34)       pathway; GTPase activator activity; calmodulin
                                                                        binding
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Figure captions

Figure 1.
Schematic outline of the data analysis process

Figure 2.
Cluster analysis of the filtered gene list including data from the baseline
time point (T1). The gene expression data from T1 for the 733 features
included in the filtered list were used in an unsupervised hierarchical
cluster analysis, to identify a gene expression signature early during the
course of infectious mononucleosis that predicted postinfective fatigue
syndrome (PIFS) or recovery. Individual genes are in rows, and subjects
("PIFS" indicates case subjects; "C" indicates control subjects) are in
columns.

Figure 3.
Symptom factor scores over time for case subjects with postinfective fatigue
syndrome (PIFS) and control subjects. Normalized symptom factor scores for
all data points for each subject at each categorized time point (T1­T4) were
calculated [5]. Subjects with PIFS are represented by black circles, and
control subjects are represented by white circles.

Figure 4.
Expression of postinfective fatigue syndrome­associated genes over time in
subjects with varied illness outcomes. Selected genes of interest of the 35
identified with temporal expression patterns consistent with the course of
illness, associated with either fatigue (A) or musculoskeletal pain (B), are
shown. The size of the symbols is proportional to the mean symptom factor
score for the subgroup of subjects.


References

 1. Callan M, Steven N, Krausa P, et al. Large clonal expansions of CD8
    T cells in acute infectious mononucleosis. Nat Med 1996; 2:906-11.
 2. Kieff E, Rickinson A. EBV and its replication. In: Knipe D, Howley P,
    eds. Fields virology. Vol. 2. 4th ed. Philadelphia: Lippincott Wilkins &
    Williams, 2001:2511-74.
 3. White P, Thomas J, Kangro H, et al. Predictions and associations of
    fatigue syndromes and mood disorders that occur after infectious
    mononucleosis. Lancet 2001; 358:1946-54.
 4. Buchwald D, Rea T, Katon W, Russo J, Ashley R. Acute infectious
    mononucleosis: characteristics of patients who report failure to recover.
    Am J Med 2000; 109:531-7.
 5. Hickie I, Davenport TA, Wakefield D, et al. Viral and non-viral path-
    ogens precipitate post-infective and chronic fatigue syndromes: a pro-
    spective cohort study. BMJ 2006; 333:575-8.
 6. Sullivan J, Woda B. X-linked lymphoproliferative syndrome. Immu-
    nodefic Rev 1989; 1:325-47.
 7. Aoukaty A, Lee I-F, Wu J, Tan R. CAEBV infection associated with
    low expression of lair-1 on NK cells. J Clin Immunol 2003; 23:141-5.
 8. Kimura H, Hoshino Y, Kanegane H, et al. Clinical and virological
    characteristics of chronic active EBV infection. Blood 2001; 98:280-6.
 9. Wilson A, Hickie I, Hadzi-Pavlovic D, et al. What is chronic fatigue
    syndrome? Heterogeneity within an international multicentre study.
    Aust N Z J Psychiatry 2001; 35:520-7.
10. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A.
    The chronic fatigue syndrome: a comprehensive approach to its defi-
    nition and study. International Chronic Fatigue Syndrome Study
    Group. Ann Intern Med 1994; 121:953-9.
11. Cameron B, Bharadwaj M, Burrows J, et al. Prolonged illness after
    infectious mononucleosis is associated with altered immunity but not
    with increased viral load. J Infect Dis 2006; 193:664-71.
12. Wakefield D, Lloyd A. Pathophysiology of myalgic encephalitis. Lancet
    1987; 2:918-9.
13. Prins JB, van der Meer JWM, Bleijenberg G. Chronic fatigue syndrome.
    Lancet 2006; 367:346-55.
14. Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psy-
    chiatry 2003; 160:221-36.
15. de Lange F, Kalkman J, Bleijenberg G, et al. Neural correlates of the
    chronic fatigue syndrome - an fMRI study. Brain 2004; 127:1948-57.
16. Georgiades E, Behan W, Kilduff L, et al. Chronic fatigue syndrome:
    new evidence for a central fatigue disorder. Clin Sci 2003; 105:213-8.
17. Segman RH, Shefi N, Goltser-Dubner T, Friedman N, Kaminski N,
    Shalev AY. Peripheral blood mononuclear cell gene expression profiles
    identify emergent post-traumatic stress disorder among trauma sur-
    vivors. Mol Psychiatry 2005; 10:500-13.
18. Tsuang M, Nossova N, Yager T, et al. Assessing the validity of blood-
    based gene expression profiles for the classification of schizophrenia
    and bipolar disorder: a preliminary report. Am J Med Genet B Neu-
    ropsychiatr Genet 2005; 133:1-5.
19. Vernon S, Nicholson A, Rajeevan M, et al. Correlation of psych-neu-
    roendocrine-immune (PNI) gene expression with symptoms of acute
    infectious mononucleosis. Brain Res 2006; 1068:1-6.
20. Robertson P, Beynon S, Whybin R, et al. Measurement of EBV-IgG
    anti-VCA avidity aids the early and reliable diagnosis of primary EBV
    infection. J Med Virol 2003; 70:617-23.
21. Hadzi-Pavlovic D, Hickie I, Hooker A, Ricci C. The IFI: some neu-
    rasthenia related scales. Sydney: Academic Department of Psychiatry,
    St. George Hospital, 1997.
22. Hickie I, Davenport T, Hadzi-Pavlovic D, et al. Development of a
    simple screening tool for common mental disorders in general practice.
    Med J Aust 2001; 175:S10-7.
23. Hadzi-Pavlovic D, Hickie I, Wilson A, Davenport T, Lloyd A, Wakefield
    D. Screening for prolonged fatigue syndromes: statistical and longi-
    tudinal validation of the SOFA scale. Soc Psychiatry Psychiatr Epide-
    miol 2000; 35:471-9.
24. Koschera A, Hickie I, Hadzi-Pavlovic D, Wilson A, Lloyd A. Prolonged
    fatigue, anxiety and depression: exploring relationships in a primary
    care sample. Aust N Z J Psychiatry 1999; 33:545-52.
25. von Korff M, Ustun T, Ormel J, Kaplan I, Simon G. Self-report dis-
    ability in an international primary care study of psychological illness.
    J Clin Epidemiol 1996; 49:297-303.
26. Ojaniemi H, Evengard B, Lee D, Unger E, Vernon S. Impact of RNA
    extraction from limited samples on microarray results. Biotechniques
    2003; 35:968-73.
27. Whistler T, Unger E, Nisenbaum R, Vernon S. Integration of gene
    expression, clinical, and epidemiologic data to characterize chronic
    fatigue syndrome. J Transl Med 2003; 1:10.
28. Garrett-Mayer E. Overview of standard clustering approaches for gene
    microarray data analysis. In: Allison D, Page G, Beasley T, Edwards J,
    eds. DNA microarrays and related genomics techniques. Boca Raton,
    FL: Chapman & Hall CRC, 2006:131-58.
29. Zhang B, Kirov S, Snoddy J. Webgestalt: an integrated system for ex-
    ploring gene sets in various biological contexts. Nucleic Acids Res 2005;
    33:W741-8.
30. Whitney A, Diehn M, Popper SJ, et al. Individuality and variation in
    gene expression patterns in human blood. Proc Natl Acad Sci USA
    2003; 100:1896-901.
31. MAQC Consortium. The Microarray Quality Control (MAQC) project
    shows inter- and intraplatform reproducibility of gene expression mea-
    surements. Nat Biotechnol 2006; 24:1151-61.
32. Hickie I, Lloyd A, Hadzi-Pavlovic D, Parker G, Bird K, Wakefield D.
    Can the chronic fatigue syndrome be defined by distinct clinical fea-
    tures? Psychol Med 1995; 25:925-35.
33. Lloyd AR. Chronic fatigue and chronic fatigue syndrome: shifting
    boundaries and attributions. Am J Med 1998; 105:7S-10S.
34. Powell R, Ren J, Lewith G, Barclay W, Holgate S, Almond J. Identi-
    fication of novel expressed sequences, up-regulated in the leucocytes
    of chronic fatigue syndrome patients. Clin Exp Allergy 2003; 33:1450-6.
35. Vernon SD, Unger ER, Dimulescu IM, Rajeevan M, Reeves WC. Utility
    of the blood for gene expression profiling and biomarker discovery in
    chronic fatigue syndrome. Dis Markers 2002; 18:193-9.
36. Steinau M, Unger ER, Vernon SD, Jones JF, Rajeevan MS. Differential-
    display PCR of peripheral blood for biomarker discovery in chronic
    fatigue syndrome. J Mol Med 2004; 82:750-5.
37. Whistler T, Jones JF, Unger ER, Vernon SD. Exercise responsive genes
    measured in peripheral blood of women with chronic fatigue syndrome
    and matched control subjects. BMC Physiol 2005; 5:5.
38. Kaushik N, Fear D, Richards SCM, et al. Gene expression in peripheral
    blood mononuclear cells from patients with chronic fatigue syndrome.
    J Clin Pathol 2005; 58:826-32.
39. Carmel L, Efroni S, White PD, Aslakson E, Vollmer-Conna U, Rajeevan
    MS. Gene expression profile of empirically delineated classes of un-
    explained chronic fatigue. Pharmacogenomics 2006; 7:375-86.
40. White PD. What causes chronic fatigue syndrome? BMJ 2004; 329:
    928-9.
41. Rossi EL. Psychosocial genomics: gene expression, neurogenesis, and
    human experience in mind-body medicine. Adv Mind Body Med 2002;
    18:22-30.

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(c) 2007 Infectious Diseases Society of America.

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Date:    Mon, 9 Jul 2007 12:59:57 -0400
From:    "Bernice A. Melsky" 
Subject: RES: Fibromyalgia patients show an abnormal dopamine response to pain

Fibromyalgia patients show an abnormal dopamine response to pain.

Eur J Neurosci. 2007 Jun;25(12):3576-82.

Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA,
Bushnell MC, Chizh BA.

McGill University Centre for Research on Pain, Faculty of Dentistry, 3640
University Street, Strathcona Building, Montreal, QC, Canada, H3A 2B2.

PMID: 17610577


Fibromyalgia is characterized by chronic widespread pain and bodily
tenderness and is often accompanied by affective disturbances. Accumulating
evidence indicates that fibromyalgia may involve a dysfunction of
modulatory systems in the brain.

While brain dopamine is best known for its role in pleasure, motivation and
motor control, recent evidence suggests that it is also involved in pain
modulation. Because dopamine is implicated in both pain modulation and
affective processing, we hypothesized that fibromyalgia may involve a
disturbance of dopaminergic neurotransmission.

Fibromyalgia patients and matched healthy control subjects were subjected
to deep muscle pain produced by injection of hypertonic saline into the
anterior tibialis muscle. In order to determine the endogenous release of
dopamine in response to painful stimulation, we used positron emission
tomography to examine binding of [(11)C]-raclopride (D2/D3 ligand) in the
brain during injection of painful hypertonic saline and nonpainful normal
saline.

Fibromyalgia patients experienced the hypertonic saline as more painful
than healthy control subjects. Control subjects released dopamine in the
basal ganglia during the painful stimulation, whereas fibromyalgia patients
did not. In control subjects, the amount of dopamine release correlated
with the amount of perceived pain but in fibromyalgia patients no such
correlation was observed.

These findings provide the first direct evidence that fibromyalgia patients
have an abnormal dopamine response to pain. The disrupted dopaminergic
reactivity in fibromyalgia patients could be a critical factor underlying
the widespread


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End of Co-Cure Weekly Digest of research and medical posts only - 2 Jul 2007 to 9 Jul 2007

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