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Co-Cure Weekly Digest of research and medical posts only - 19 Feb 2007 to 26 Feb 2007

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Date:    Tue, 20 Feb 2007 08:06:38 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES: CFS/ME & FM papers, published since January 2007

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

        Search scientific papers,
        http://www.me-net.combidom.com/library/literature.htm#catalogue

        Figures computer analysis scientific papers,
        http://www.me-net.combidom.com/library/literature.htm#figure

        All popular papers 1900-today,
        http://www.me-net.combidom.com/library/literature.htm#popular


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

___ Winfield JB.
       Fibromyalgia and Related Central Sensitivity Syndromes: Twenty-five
       years of Progress.
       Semin Arthritis Rheum. 2007 Feb 12.
___ Watanabe Y.
       Molecular imaging for drug development [Japanese].
       Nippon Rinsho. 2007 Feb;65(2):357-62.
___ Van Hoof E, De Becker P, Lapp C, Cluydts R, De Meirleir K.
       Defining the occurrence and influence of alpha-delta sleep in chronic
       fatigue syndrome.
       Am J Med Sci. 2007 Feb;333(2):78-84.
___ Gupta S, Aslakson E, Gurbaxani BM, Vernon SD.
       Inclusion of the glucocorticoid receptor in a hypothalamic pituitary
       adrenal axis model reveals bistability.
       Theor Biol Med Model. 2007 Feb 14;4(1):8.
___ Gansky SA, Plesh O.
       Widespread Pain and Fibromyalgia in a Biracial Cohort of Young Women.
       J Rheumatol. 2007 Feb 1.
___ Ferrari RR, Russell AS.
       Fibromyalgia: 30 years of drug-seeking behavior.
       Nat Clin Pract Rheumatol. 2007 Feb;3(2):62-3.
___ Varni JW, Burwinkle TM, Limbers CA, Szer IS.
       The PedsQL as a patient-reported outcome in children and adolescents
       with fibromyalgia: An analysis of OMERACT domains.
       Health Qual Life Outcomes. 2007 Feb 12;5(1):9.
___ Boiko AN, Batysheva TT, Matvievskaya OV, Manevich TM, Gusev EI.
       Characteristics of the formation of chronic fatigue syndrome and
       approaches to its treatment in young patients with focal brain damage.
       Neurosci Behav Physiol. 2007 Mar;37(3):221-8.
___ Kasatkin DS, Spirin NN.
       Possible mechanisms of the formation of chronic fatigue syndrome in
       the clinical picture of multiple sclerosis.
       Neurosci Behav Physiol. 2007 Mar;37(3):215-9.
___ Van de Glind G, de Vries M, Rodenburg R, Hol F, Smeitink J, Morava E.
       Resting muscle pain as the first clinical symptom in children
       carrying the MTTK A8344G mutation.
       Eur J Paediatr Neurol. 2007 Feb 9.
___ Cohen ML, Quintner JL.
       Comment on Vierck CJ Jr: Mechanisms underlying development of
       spatially distributed chronic pain (fibromyalgia). Pain 2006;124:
       242-62.
       Pain. 2007 Feb 8.
___ Yuen KC, Bennett RM, Hryciw CA, Cook MB, Rhoads SA, Cook DM.
       Is further evaluation for growth hormone (GH) deficiency necessary
       in fibromyalgia patients with low serum insulin-like growth factor
       (IGF)-I levels?
       Growth Horm IGF Res. 2007 Feb 5.
___ Ter Wolbeek M, van Doornen LJ, Coffeng LE, Kavelaars A, Heijnen CJ.
       Cortisol and severe fatigue: A longitudinal study in adolescent
       girls.
       Psychoneuroendocrinology. 2007 Feb 5.
___ Young JL, Redmond JC.
       Fibromylagia, Chronic fatigue, and adult attention deficit
       hyperactivity disorder in the adult: a case study.
       Psychopharmacol Bull. 2007 Winter;40(1):118-26.
___ Edwards CR, Thompson AR, Blair A.
       An 'Overwhelming Illness': Women's Experiences of Learning to Live
       with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.
       J Health Psychol. 2007 Mar;12(2):203-14.
___ Schwartz TL, Rayancha S, Rashid A, Chlebowksi S, Chilton M, Morell M.
       Modafinil treatment for fatigue associated with fibromyalgia.
       J Clin Rheumatol. 2007 Feb;13(1):52.
___ Gowans SE, Dehueck A.
       Pool exercise for individuals with fibromyalgia.
       Curr Opin Rheumatol. 2007 Mar;19(2):168-73.
___ Rooks DS.
       Fibromyalgia treatment update.
       Curr Opin Rheumatol. 2007 Mar;19(2):111-7.
___ Roizenblatt S.
       Respiratory sleep disorders and fibromyalgia.
       J Bras Pneumol. 2006 Jul-Aug;32(4):xviii-xix.
___ Brockow T, Wagner A, Franke A, Offenbacher M, Resch KL.
       A randomized controlled trial on the effectiveness of mild water-
       filtered near infrared whole-body hyperthermia as an adjunct to a
       standard multimodal rehabilitation in the treatment of fibromyalgia.
       Clin J Pain. 2007 Jan;23(1):67-75.
___ Jerjes WK, Taylor NF, Wood PJ, Cleare AJ.
       Enhanced feedback sensitivity to prednisolone in chronic fatigue
       syndrome. Psychoneuroendocrinology. 2007 Feb 2.
___ Chapenko S, Krumina A, Kozireva S, Nora Z, Sultanova A, Viksna L,
       Murovska M.
       Activation of human herpesviruses 6 and 7 in patients with chronic
       fatigue syndrome.
       J Clin Virol. 2006 Dec;37 Suppl 1:S47-51.
___ Komaroff AL.
       Is human herpesvirus-6 a trigger for chronic fatigue syndrome?
       J Clin Virol. 2006 Dec;37 Suppl 1:S39-46.
___ Kogelnik AM, Loomis K, Hoegh-Petersen M, Rosso F, Hischier C, Montoya JG.
       Use of valganciclovir in patients with elevated antibody titers
       against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who
       were experiencing central nervous system dysfunction including long-
       standing fatigue.
       J Clin Virol. 2006 Dec;37 Suppl 1:S33-8.
___ Dell DD.
       Getting the point about: fibromyalgia.
       Nursing. 2007 Feb;37(2):61-4.
___ Donnelly D, Rockland RH, Reisman S, Quigley KS.
       Continuous measurement of BRSI in chronic fatigue syndrome.
       Conf Proc IEEE Eng Med Biol Soc. 2004;2:906-8.
___ Theadom A, Cropley M, Humphrey KL.
       Exploring the role of sleep and coping in quality of life in
       fibromyalgia.
       J Psychosom Res. 2007 Feb;62(2):145-51.
___ Germanowicz D, Lumertz MS, Martinez D, Margarites AF.
       Sleep disordered breathing concomitant with fibromyalgia syndrome.
       J Bras Pneumol. 2006 Jul-Aug;32(4):333-8.
___ Sephton SE, Salmon P, Weissbecker I, Ulmer C, Floyd A, Hoover K,
       Studts JL.
       Mindfulness meditation alleviates depressive symptoms in women with
       fibromyalgia: Results of a randomized clinical trial.
       Arthritis Rheum. 2007 Jan 31;57(1):77-85.
___ Lind BK, Lafferty WE, Tyree PT, Diehr PK, Grembowski DE.
       Use of complementary and alternative medicine providers by
       fibromyalgia patients under insurance coverage.
       Arthritis Rheum. 2007 Jan 31;57(1):71-76.
___ Natelson BH, Intriligator R, Cherniack NS, Chandler HK, Stewart JM.
       Hypocapnia is a biological marker for orthostatic intolerance in
       some patients with chronic fatigue syndrome.
       Dyn Med. 2007 Jan 30;6:2.
___ Stejskal VD, Hudecek R, Stejskal J, Sterzl I.
       Diagnosis and treatment of metal-induced side-effects.
       Neuro Endocrinol Lett. 2006 Dec 29;27(Suppl1).
___ Valentine-Thon E, Muller KE, Guzzi G, Kreisel S, Ohnsorge P, Sandkamp M.
       LTT-MELISA(R) is clinically relevant for detecting and monitoring
       metal sensitivity.
       Neuro Endocrinol Lett. 2006 Dec 29;27(Suppl1)
___ Jespersen A, Dreyer L, Kendall S, Graven-Nielsen T, Arendt-Nielsen L,
       Bliddal H, Danneskiold-Samsoe B.
       Computerized cuff pressure algometry: A new method to assess deep-
       tissue hypersensitivity in fibromyalgia.
       Pain. 2007 Jan 24.
___ Ifergane G, Shelef I, Buskila D.
       Migraine and fibromyalgia developing after a pontine haemorrhage.
       Cephalalgia. 2007 Feb;27(2):191.
___ Williams DA, Gracely RH.
       Biology and therapy of fibromyalgia. Functional magnetic resonance
       imaging findings in fibromyalgia.
       Arthritis Res Ther. 2007 Jan 17;8(6):224.
___ Arshad A, Kong KO.
       Awareness and perceptions of fibromyalgia syndrome: a survey of
       Malaysian and Singaporean rheumatologists.
       Singapore Med J. 2007 Jan;48(1):25-30.
___ Friedberg F, Quick J.
       Alexithymia in chronic fatigue syndrome: associations with momentary,
       recall, and retrospective measures of somatic complaints and emotions.
       Psychosom Med. 2007 Jan-Feb;69(1):54-60.
___ Hooten WM, Townsend CO, Sletten CD, Bruce BK, Rome JD.
       Treatment outcomes after multidisciplinary pain rehabilitation
       with analgesic medication withdrawal for patients with fibromyalgia.
       Pain Med. 2007 Jan-Feb;8(1):8-16.
___ Nicolson GL.
       Metabolic syndrome and mitochondrial function: Molecular replacement
       and antioxidant supplements to prevent membrane peroxidation and
       restore mitochondrial function.
       J Cell Biochem. 2007 Jan 22.
___ Gulec H, Sayar K.
       Reliability and validity of the Turkish form of the Somatosensory
       Amplification Scale.
       Psychiatry Clin Neurosci. 2007 Feb;61(1):25-30.
___ Carpenter J, Hutchings A, Raine R, Sanderson C.
       An experimental study of the influence of individual participant
       characteristics on formal consensus development.
       Int J Technol Assess Health Care. 2007 Winter;23(1):108-15.

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

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Date:    Tue, 20 Feb 2007 12:42:10 -0500
From:    "Bernice A. Melsky" <bernicemelsky@VERIZON.NET>
Subject: RES: A Critical Analysis of the Tender Points in Fibromyalgia

A Critical Analysis of the Tender Points in Fibromyalgia.

Pain Med. 2007 Mar;8(2):147-156.

Harden RN, Revivo G, Song S, Nampiaparampil D, Golden G, Kirincic M, Houle TT.

Center for Pain Studies, Rehabilitation Institute of Chicago, Northwestern
University Feinberg School of Medicine, Chicago, Illinois, USA.

PMID: 17305686


Objective. To pilot methodologies designed to critically assess the
American College of Rheumatology's (ACR) diagnostic criteria for fibromyalgia.

Design. Prospective, psychophysical testing.

Setting. An urban teaching hospital.

Subjects. Twenty-five patients with fibromyalgia and 31 healthy controls
(convenience sample). Interventions. Pressure pain threshold was determined
at the 18 ACR tender points and five sham points using an algometer
(dolorimeter).

Outcome Measures. The patients "algometric total scores" (sums of the
patients' average pain thresholds at the 18 tender points) were derived, as
well as pain thresholds across sham points.

Results. The "algometric total score" could differentiate patients with
fibromyalgia from normals with an accuracy of 85.7% (P < 0.001). Even a
single tender point had a diagnostic accuracy between 75% and 89%. Although
fibromyalgics had less pain across sham points than across ACR tender
points, sham points also could be used for diagnosis (85.7%; Ps < 0.001).
Hierarchical cluster analysis showed that three points could be used for a
classification accuracy equivalent to the use of all 18 points.

Conclusions. There was a significant difference in the "algometric total
score" between patients with fibromyalgia and controls, and we suggest this
quantified (although subjective) approach may represent a significant
improvement over the current diagnostic scheme, but this must be tested vs
other painful conditions. The points specified by the ACR were only
modestly superior to sham points in making the diagnosis. Most importantly,
this pilot suggests single points, smaller groups of points, or sham points
may be as effective in diagnosing fibromyalgia as the use of all 18 points,
and suggests methodologies to definitively test that hypothesis.

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Date:    Tue, 20 Feb 2007 12:38:10 -0500
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Assessment of vulvodynia symptoms in a sample of US  women: a prevalence survey with a nested case control study

Assessment of vulvodynia symptoms in a sample of US women: a prevalence
survey with a nested case control study.

Am J Obstet Gynecol. 2007 Feb;196(2):128.e1-128.e6.

Arnold LD, Bachmann GA, Rosen R, Rhoads GG.

Department of Epidemiology, School of Public Health, University of Medicine
and Dentistry of New Jersey, Piscataway, NJ; Women's Health Institute, Robert
Wood Johnson Medical School, University of Medicine and Dentistry of New
Jersey, New Brunswick, NJ.

PMID: 17306651


OBJECTIVE: Vulvodynia is a chronic pain syndrome of unknown origin with
scant data on frequency. This study assessed the prevalence of vulvodynia
symptoms in a sample of US women and compared health characteristics of
symptomatic and asymptomatic women.

STUDY DESIGN: A phone survey contacted 2127 US households to identify 100
symptomatic women, who were matched on age and time zone to 325
asymptomatic controls. Odds ratios (ORs) and logistic regression were used
to model associations between pain, medical conditions, and health care
utilization variables.

RESULTS: Current vulvar pain of at least 6 months duration was reported by
3.8% of respondents, with a 9.9% lifetime prevalence. Forty-five percent of
women with pain reported an adverse effect on their sexual life and 27% an
adverse effect on their lifestyle. Cases more frequently reported repeated
urinary tract infections (OR, 6.15; 95% CI, 3.51-10.77) and yeast
infections (OR, 4.24; 95% CI, 2.47-7.28). Associations existed with chronic
fatigue syndrome (OR, 2.78; 95% CI, 1.33-6.19), fibromyalgia (OR, 2.15; 95%
CI, 1.06-4.36), depression (OR, 2.99; 95% CI, 1.87-4.80), and irritable
bowel syndrome (OR, 1.86; 95% CI, 1.07-3.23).

CONCLUSION: Lifetime chronic vulvar pain was less prevalent in this
national sample of women than previous data suggest and was correlated with
several comorbid chronic medical conditions and substantial reduction in
self-reported quality of life.

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Date:    Wed, 21 Feb 2007 11:59:39 -0000
From:    Stephen Ralph <stephen.e.ralph MEACTIONUK.ORG.UK>
Subject: NOT,RES: Facts from Florida - Corrections

Permission to Repost

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

Margaret Williams thanks those who have queried her reference in her article
"Facts from Florida" to Dr P Chaney being at the Mayo Clinic.

She wondered about this herself but accepted in good faith the notes of Dr
Lesley Ann Fein which clearly stated that Dr Cheney was at the Mayo Clinic.

http://www.cfidsreport.com/News/07-IACFS_Conference_2007_Research_Summary.htm

Margaret also apologises for the numerous typing errors including "peforin"
which should of course be perforin and "disarry" which should of course be
disarray.


[Return to top]

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Date:    Wed, 21 Feb 2007 14:37:24 -0500
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Decreased pain and improved quality of life in  fibromyalgia patients treated with olanzapine, an atypical neuroleptic

Decreased pain and improved quality of life in fibromyalgia patients
treated with olanzapine, an atypical neuroleptic.

Pain Pract. 2006 Jun;6(2):112-8.

Freedenfeld RN, Murray M, Fuchs PN, Kiser RS.

KRK Medical Research, Richardson, Texas, USA.

PMID: 17309719


Fibromyalgia is a significant clinical problem associated with generalized
pain and significant interference with daily activities. Although a variety
of treatment modalities have been utilized, clinicians have struggled to
find an effective means of treatment. Therefore, this study assessed the
efficacy of the atypical neuroleptic olanzapine for the treatment of
fibromyalgia symptoms.

To examine the efficacy of olanzapine for the treatment of fibromyalgia
symptoms, the charts of 51 patients treated with olanzapine were evaluated
for improvements in pain and daily life functioning. At the time of initial
assessment, patients had been diagnosed with a variety of medical and
psychiatric disorders and a history of neuroleptic treatment. Pain was
widespread and characteristic of pain associated with fibromyalgia.

Pretreatment ratings on pain and the interference scales averaged 6.54-8.69
on a 0-10 scale. Post-treatment ratings on the same scales revealed
significant improvement on virtually all scales. The benefits of olanzapine
to improve fibromyalgia symptoms must, however, be carefully considered
because there were a variety of side effects (i.e., weight gain,
somnolence/sedation) that were of sufficient strength to cause a number of
patients to discontinue treatment.

In general, the data provide strong support that olanzapine can, in certain
patients, improve symptoms associated with fibromyalgia in patients who
have had limited success with other treatment modalities.

[Return to top]

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Date:    Thu, 22 Feb 2007 13:04:48 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES,NOT: HPA-axis models in CFS

Source: Theoretical Biology and Medical Modelling
        Vol 4, #1, p 8
Date:   February 14, 2007
URL:    http://www.tbiomed.com/content/pdf/1742-4682-4-8.pdf

        http://www.tbiomed.com/content/4/1/8


Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal
axis model reveals bistability
----------------------------------------------------------------------------
Shakti Gupta, Eric Aslakson*, Brian M. Gurbaxani, Suzanne D. Vernon
Division of Viral and Rickettsial Diseases, National Center for Zoonotic,
Vector- Borne, and Enteric Diseases, Centers for Disease Control and
Prevention, 600 Clifton Rd, MS-A15, Atlanta, Georgia USA 30333
* Corresponding author
Email addresses: Shakti Gupta: shaktig@gmail.com, Eric Aslakson: btl0@cdc.gov,
Brian M. Gurbaxani: buw8@cdc.gov, Suzanne D. Vernon: svernon@cdc.gov


Abstract

Background
The body's primary stress management system is the hypothalamic pituitary
adrenal (HPA) axis. The HPA axis responds to physical and mental challenge
to maintain homeostasis in part by controlling the body's cortisol level.
Dysregulation of the HPA axis is implicated in numerous stress-related
diseases.

Results
We developed a structured model of the HPA axis that includes the
glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of
pituitary GR synthesis. The nonlinear effect arises from the fact that GR
homodimerizes after cortisol activation and induces its own synthesis in the
pituitary. This homodimerization makes possible two stable steady states
(low and high) and one unstable state of cortisol production resulting in
bistability of the HPA axis. In this model, low GR concentration represents
the normal steady state, and high GR concentration represents a dysregulated
steady state. A short stress in the normal steady state produces a small
perturbation in the GR concentration that quickly returns to normal levels.
Long, repeated stress produces persistent and high GR concentration that
does not return to baseline forcing the HPA axis to an alternate steady
state. One consequence of increased steady state GR is reduced steady state
cortisol, which has been observed in some stress related disorders such as
Chronic Fatigue Syndrome (CFS).

Conclusions
Inclusion of pituitary GR expression resulted in a biologically plausible
model of HPA axis bistability and hypocortisolism. High GR concentration
enhanced cortisol negative feedback on the hypothalamus and forced the HPA
axis into an alternative, low cortisol state. This model can be used to
explore mechanisms underlying disorders of the HPA axis.


Background

The hypothalamic pituitary adrenal (HPA) axis represents a self-regulated
dynamic feedback neuroendocrine system that is essential for maintaining
body homeostasis in response to various stresses. Stress can be physical
(e.g. infection, thermal exposure, dehydration) and psychological (e.g.
fear, anticipation). Both physical and psychological stressors activate the
hypothalamus to release corticotropin releasing hormone (CRH). The CRH is
released into the closed hypophyseal portal circulation, stimulating the
pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH is released
into the blood where it travels to the adrenals, inducing the synthesis and
secretion of cortisol from the adrenal cortex. Cortisol has a negative
feedback effect on the hypothalamus and pituitary that further dampens

Cortisol affects a number of cellular and physiological functions to
maintain body homeostasis and health. Cortisol suppresses inflammation and
certain immune reactions, inhibits the secretion of several hormones and
neuropeptides and induces lymphocyte apoptosis [1,2]. These widespread and
potent effects of cortisol demand that the feed forward and feedback loops
of the HPA axis are tightly regulated. Disruption of HPA axis regulation is
known to contribute to a number of stress-related disorders. For example,
increased cortisol (hypercortisolism) has been shown in patients with major
depressive disorder (MDD) [3, 4], and decreased cortisol (hypocortisolism)
has been observed in people with post-traumatic stress disorder (PTSD), Gulf
War illness, post infection fatigue and chronic fatigue syndrome (CFS)[5-9].
While it is not clear if dysregulation of the HPA axis is a primary or
secondary effect of these disorders, there is evidence that stress-related
disorders are influenced by early life adverse experiences that affect the
neural architecture and gene expression in the brain [10]. Childhood events
such as severe infection, malnutrition, physical, sexual and emotional abuse
are associated with many chronic illnesses later in life [11].

Definitive research on HPA axis function in chronic diseases has been
hampered by the complexity of the numerous systems affected by the HPA axis,
such as the immune and neuroendocrine systems, the lack of known or
accessible brain lesions and the correlative nature of much of the existing
data. Since the organization of the HPA axis has been characterized to
detail the feedback and feed forward signalling that regulates HPA axis
function [12], it is a system that is amenable to modelling. Models of the
HPA axis have been constructed using deterministic coupled ordinary
differential equations [13-17]. These models were successful in capturing
features such as negative feedback control and diurnal cycling of the HPA
axis. Our goal was to understand the dynamic effects of CRH, ACTH and
cortisol with a mathematically parsimonious model to gain insight into HPA
axis regulation. This model is novel in that it incorporates expression of
the glucocorticoid receptor (GR) in the pituitary and demonstrates that
repeated stress and GR expression reveals the bistability inherent in the
HPA axis given the enhanced model.


Model

The HPA axis has three compartments representing the hypothalamus, pituitary
and adrenals regulated by simple, linear mass action kinetics for the
production and degradation of the primary chemical product of each
compartment. In this model, stress to the HPA axis (F) stimulates the
hypothalamus to secrete CRH (C). CRH (C) signals the induction of ACTH
synthesis (A) in the pituitary. ACTH (A) signals to the adrenal gland and
activates the synthesis and release of cortisol (O). Cortisol (O) regulates
its own synthesis via inhibiting the synthesis of CRH (C) in the
hypothalamus, and ACTH (A) in the pituitary. The equation for the
hypothalamus can be written as:

dC                      O
--  = (K_c + F ) * (1 - -- ) - K_cd C                    (1)
dT                      K_i1

In this equation, - K_cd C models a constant degradation rate of CRH in the
blood of the portal vein.  O
The term  (K_c + F) * (1 - -- ) models a circadian production term K_c and a
                           K_i1
stress term  F , both reduced by a linear inhibition term represented by
     O               O                                   O       K_c + F
(1 - -- ). For small --  , we may write (K_c + F) * (1 - -- ) ~~ -------  .
     K_i1            K_i1                                K_i1    1 + O/K_i1
                 K_c + F
The latter form, -------    corresponds to standard linear inhibition of
                 1 + O/K_i1
(K_+F) with inhibition constant K_i1. This form also guarantees positive
ACTH concentrations. We write for the hypothalamus:

dC   K_c + F
-- = ------- - K_cd C                                    (2)
dT   1 + O/K_i1

For the pituitary:

dA   K_a C
-- = -------------- - K_ad A                             (3)
dT   1 + O/K_i2

Equation 3 models a constant degradation rate of ACTH by the term - K_ad A
and an ACTH production term,  K_a C  , with a cortisol inhibition factor
similar to (2).               -----
                              1 + O/K_i2
For the adrenal:

dO
-- = K_o A - K_od O                                      (4)
dT

Equation 4 models a constant degradation rate of cortisol - K_ad O and a
cortisol production rate K_o A linearly dependent on ACTH.

We have augmented this model by including synthesis and regulation of the
glucocorticoid receptor (R) in the pituitary [18, 19]. In the pituitary,
cortisol enters the cell and binds the glucocorticoid receptor in the
cytoplasm, causing the receptor to dimerize. This dimerization causes the
complex to translocate to the nucleus (dimerization, translocation, and
transcription factor binding are not modelled, but assumed to be fast),
where it up regulates glucocorticoid receptor (R) synthesis and down
regulates production of ACTH (A).

The following are the differential equations written for the HPA axis model
that includes glucocorticoid receptor synthesis and regulation in the
pituitary (Figure 1).

For the hypothalamus:

dC   K_c + F
-- = -------   - K_cd C                                  (5)
dT   1 + O/K_i1

For the pituitary:

dA   K_a C
-- = ------- - K_ad A                                    (6)
dT   1 + OR/K_i2

dR   K_r (OR)2
-- = ----------- + K_cr - K_rd R                         (7)
dT   K + (OR)2

For the adrenal:

dO
-- = K_o A - K_od O                                      (8)
dT

Equation (7) describes the production of GR in the pituitary. The term
K_r (OR)2
---------- in equation 7 is in Michaelis-Menten form since we assume the
K + (OR)2

bound glucocorticoid receptor (OR) dimerizes with fast kinetics, so that the
amount of dimer is in constant quasi-equilibrium, depending on the abundance
of OR and the equilibrium binding affinity (K). The model further assumes
that cortisol (O) and the glucocorticoid receptor (R) bind to each other
with very fast kinetics compared to the rate of change of the 4 state
variables (A, C, O, and R), so that OR stays in quasi- equilibrium as well.
These are reasonable assumptions, given that high affinity receptor-ligand
kinetics are often much faster than enzyme kinetics (as is assumed in the
standard Michaelis-Menten equation) or than steps requiring transcription
and/or translation for protein synthesis. Equation (7) also models a linear
production term K_cr and a degradation term - K_rd R for pituitary GR
production. Equation (6) reflects the inhibition dependence of
glucocorticoid receptor (R) and cortisol (O) with an inhibition constant
K_i2.

Scaling of the equations (5)-(8) has been done to reduce the parameters used
in simulations. The scaled variables are defined as;
                 K_od C        K2_od A       K3_od O
t = K_od T , c = ------- , a = -------- , o = -----------
                 K_c           K_c K_a        K_c K_a K_o

    K_od R          K_cd          K_ad           K_rd
r = ------ , k_cd = ---- , k_ad = ----  , k_rd = ----
    K_r             K_c           K_od           K_ad

The scaled equations thereby obtained are;

dc    1 + f
-- = -----   - k_cd c                                    (9)
dt   1 + o/ki1

da      c
-- = ------- - k_ad a                                    (10)
dt   1 + or/ki2

dr    (or)2
-- = ---------- + k_cr - k_rd r                          (11)
dt   k + (or)2

do
-- = a - o                                               (12)
dt

These scaled equations were used in the simulations. The advantage of
scaling is that it obviates the need for knowledge of unknown parameter
values such as the synthesis rate of CRH in the hypothalamus and ACTH and GR
in the pituitary. The parameter values that can be measured are the
degradation rates of CRH, ACTH, and cortisol. The scaled parameter values
used in simulation were, k_cd=1, k_ad=10, k_rd=0.9, k_cr=0.05, k=0.001,
k_i1=0.1 and k_i2=0,1. Further, these simulated results for CRH, ACTH and
cortisol are converted back to their commonly used dimensions and values
obtained in experiments. The simulated time course plots ignore the
circadian input to the hypothalamus.

Models were programmed in Matlab (The Mathworks, Natick, MA). The meta-
modeling of bi-stability used the CONTENT freeware package. All Matlab
serum cortisol data [9].


Results

To determine if these equations could predict the general features of
cortisol production, the experimental data was compared to a cortisol curve
generated using equation 4. As shown in Figure 2, equation 4 predicts a fit
that is very similar to the actual cortisol production in this healthy human
subject. Experimental fitting of ACTH is not possible since hypothalamic
derived CRH cannot be measured.


Steady States

Equations (9)-(12) permit one or three positive steady states depending upon
the parameter values. The three positive steady states exist because of
homodimerization of the GR with cortisol. Figure 3 shows the variation of
GR and cortisol steady state with respect to parameter k_rd. Variations in
k_rd from person to person may be expected due to genetic differences in the
details of GR production and degradation. For a high value of k_rd, there
exists only a low GR concentration steady state. As the value of k_rd
decreases, these equations produce two more steady states, one stable and
another unstable in GR concentration. As k_rd decreases further, a low GR
concentration state disappears and only a high GR concentration state exists
(Figure 3a). In this model, we postulate that the low GR concentration
represents the normal steady state, and high GR concentration denotes a
dysregulated HPA axis steady state as it results in persistent low cortisol
levels (hypocortisolism) (Figure 3b). Hypocortisolism results from the
negative feedback between GR (i.e. the symbol "R" in Figure 1) and ACTH
(A), and hence cortisol (O) produced downstream of it, as shown in Figure 1
and reflected by the inverse relationship between cortisol and GR in Figure
3. Thus individuals with very large values of k_rd would be constitutively
healthy in this model, i.e. impervious to a dysregulated HPA-axis no matter
how much they are stressed, and those with very low values of k_rd would be
constitutively unhealthy.


Normal stress response

The response of the normal HPA axis to small perturbations is essential to
the survival of an organism. Stress activates the HPA axis to regulate
various body functions; first by increasing ACTH synthesis followed by
increased cortisol production and then returning to the original state.
Figure 4 shows a simulation of the response of the HPA axis to a short
stress. The initial condition of the HPA axis was set to a normal steady
state and at T=0, a stress was given for 0<T<1. The HPA axis responded to
this disturbance by secreting CRH. The synthesis of CRH induced the
synthesis of ACTH and cortisol (Figures 4a and 4b). The synthesis of CRH
stopped once the stress ended, and the concentration of CRH quickly
decreased due to CRH degradation (Figure 4c). CRH returned to steady state
meanwhile stimulating the release of ACTH that also peaked shortly after the
short stress ended (Figure 4b). Synthesis of cortisol followed the peak
ACTH secretion (Figure 4a). The concentration of GR was only slightly
elevated following the short stress and then returned to baseline (Figure
4d).


Adaptation of HPA axis

The robustness of the system was illustrated by the fact that short stress
produced small transients that returned to the original, normal steady
state. To simulate adaptation of the HPA axis to repeated stress, recursive
stress was applied at T=0, 8 and 16 hours for 2 hour periods. The
simulation results showed the continuous decrease in maximum ACTH and
cortisol concentration after every stress (Figure 5a and b) while CRH is
relatively unaffected (Figure 5c). The decrease in secretion of ACTH and
cortisol occurred because of an increase in pituitary GR concentration and
the fact that the system was pulsed with the stresses before it had time to
fully recover (Figure 5d).


Chronic stress response

To simulate the response to chronic stress, a long stress was given for
0<T<10 hours to perturb the normal steady state of the HPA axis.
Simulation results show the bistability in the HPA axis; a long stress
forces the HPA axis to an alternate steady state (Figure 6). The HPA axis
secreted cortisol in response to stress. The increased concentration of
cortisol induced the synthesis of GR and the inhibition of pituitary ACTH.
When stress was applied for long periods, GR synthesis continued and crossed
the threshold middle unstable steady state of GR (Figure 3a). At this
point, the HPA axis reached the basin of attraction of the second stable
steady state and remained there even after the removal of stress. The higher
concentration of GR triggered further pituitary ACTH inhibition, resulting
in a lower basal level ACTH and cortisol production (Figures 6a and b).


HPA axis challenge

Psychologic stress, CRH and dexamethasone (DEX) tests are used to assess HPA
axis function. The model was used to simulate these various HPA axis
function tests. To simulate a psychologic stress experiment, the same
stress was given with two different initial conditions: normal steady state
(low GR concentration) that would occur in a control group, and low cortisol
state (high GR concentration) that would occur in a hypocortisolemic patient
group. Because the high concentration GR inhibited ACTH synthesis, the
patient group exhibited continued low cortisol and ACTH responses compared
to the control (Figures 7a and b). To simulate the CRH test, e.g., one that
requires exogenous CRH administration, CRH concentration was increased by a
constant amount. This resulted in increased pituitary and adrenal gland
synthesis of ACTH and cortisol respectively. The high concentration of
pituitary GR in the patient group blunted both responses compared to the
control (Figures 8a and b). Both Figures 7 and 8 demonstrate that the
model behaves in a qualitatively similar fashion to observed experimental
results.


Discussion

Previous models of the HPA axis have not demonstrated bistability in steady
state cortisol or ACTH. We believe this is because none of the previous
models have explicitly accounted for nonlinear kinetics, such as the
homodimerization of GR after cortisol activation [18, 19]. This is
essential for the negative feedback control of the HPA axis. This
homodimerization engenders the existence of two stable steady states and one
unstable steady state in GR expression in the pituitary. While increased
cortisol following a short period of stress produces a small perturbation in
GR concentration, long and repeated periods of stress resulting in elevated
cortisol levels produce a large perturbation in GR concentration that force
the HPA axis into an alternate steady state. Because of the existence of
two stable steady states in this model, a small increase GR concentration
can be regulated, but a large perturbation in GR concentration is sustained
even after the removal of the long duration stress. A higher concentration
of GR increases the concentration of cortisol-GR complexes that in turn
enhance the inhibition of ACTH synthesis in the pituitary. Since ACTH
stimulates the production of cortisol, less ACTH results in lower cortisol
secretion and a decrease HPA axis activity.

GR is found in cells throughout the human brain and body. However, GR
synthesis and regulation is tissue and organ specific. For example, while
corticosterone injection in rats inhibits the synthesis of GR-mRNA in
lymphocyte, hypothalamic and hippocampal cells [20, 21], it induces the
synthesis of GR-mRNA and increases the sensitivity in the anterior pituitary
[22, 23]. Our model incorporates the increased synthesis of GR in the
anterior pituitary. Increased GR makes anterior pituitary cells more
sensitive to cortisol and enhances the negative feedback effect of cortisol
on ACTH production. Enhanced negative feedback control of ACTH production
in the anterior pituitary may produce a hypocortisol state.

We were also able to demonstrate that these simulation results are
qualitatively similar to cortisol levels measured in a human subject (Figure
2). A large number of studies have investigated alterations of the HPA axis
in CFS, including both studies of basal HPA axis activity as well as studies
of HPA axis responsiveness to challenge (for review see [24]). A
hypocortisol steady state, such as was demonstrated in this modelling and
simulation study, is in keeping with many of these studies

There may be other physiologically plausible mechanisms that produce bi-
stability other than the anterior pituitary GR homodimerization mechanism
investigated here. The point of this investigation is not to conclusively
prove that pituitary GR dimerization is the cause of hypocortisolism, but
rather to demonstrate that there are physiologically plausible mechanisms
for producing bistability in the HPA-axis that are stress modulated.
Further mining of the experimental literature together with mathematical
modelling will reveal additional plausible mechanisms.


Conclusions

Moderate, short-lived stress responses that result in transient increases in
cortisol are important and necessary for maintaining body homeostasis and
health. Strong and prolonged stress can force the HPA axis into an altered
steady state. We demonstrate bistability in the HPA axis due to pituitary
GR synthesis. This altered steady state, characterized by hypocortisolism,
is observed in a number of stress- related illnesses. The elucidation of
bistability in this model of the HPA axis through the action of pituitary GR
effects may lead to targeted treatments of stress-related illness where
hypocortisolism is the primary clinical manifestation.


Authors' contributions

SG was responsible for programming the differential equation models,
producing the mathematics for the meta-analysis on stress response and
bistability, and writing of the manuscript. EA and SDV were responsible for
the concept, the design of this study and preparation, validation, writing,
and critical review of the manuscript. BMG provided assistance on the
mathematical analysis and was responsible for critical review and editing of
the manuscript.


Acknowledgements

The funding for this project was made possible by funding from DARPA MIPR
number 05-U357. We would also like to acknowledge the Dr. Leslie Crofford
and the University of Michigan (GCRC M01-RR00042 and R01-AR43148) for
providing experimental data.


Disclaimer

The findings and conclusions in this report are those of the author(s) and
do not necessarily represent the views of the funding agency.


Declaration of competing interests

The authors declare that they have no competing interests.


Figure captions

Figure 1
F is an external stress that triggers the hypothalamus to release CRH (C)
that signals to the pituitary to release ACTH (A) stimulating the synthesis
and release of cortisol (O) from the adrenals. Release of cortisol
negatively regulates CRH and ACTH after binding to the glucocorticoid
receptor (R) in the pituitary. Here, GR and cortisol regulate further GR
synthesis. The left panel shows the existing model, the right panel shows
the additional added pituitary sub compartment in the new model.

Figure 2
Experimental ACTH and cortisol from a human subject shown in blue and red in
top and bottom panels respectively. Modelled cortisol using equation 4
displayed with solid black line in lower panel.

Figure 3
Variations of steady state (a) GR and (b) cortisol with k_rd. Solid and
dashed lines denote the stable and unstable steady states, respectively.
If k_rd for a given patient is in the region where GR and cortisol are
multivalued, then the given patient can be pushed from one value of steady
state GR or cortisol to equally valid altered steady state levels by the
application of an extreme stress.

Figure 4
The response of the HPA axis following a short stress. Short time stress as
indicated by the shaded larea was given for 0<T<1 hr.

Figure 5
Transient responses of HPA axis to recursive stresses. Initially HPA axis
was at a lower GR steady state and stress was given at T=0, 8 and 16 for 2
hours. Repeated stresses are shown by shaded areas.

Figure 6
Transient responses of HPA axis to chronic stress. Extended length stress
was given for 0<T<10. Stress is indicated with shading.

Figure 7
Transient responses of HPA axis a simulated stress experiment. The same
stress was given with two different initial conditions; normal steady state
(low GR concentration) that would occur in a control group, and low cortisol
state (high GR concentration) that would occur in a patient group. Stress
was given for 0<Time<1 hr. Dash and solid lines indicate the normal and
dysregulated HPA axis responses respectively and stress is indicated with
shading.

Figure 8
Transient responses of HPA axis to CRH test. The exogenous CRH was injected
at T=0. Dashed and solid lines indicate the normal and dysregulated HPA axis
responses respectively.


References

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    Trends Endocrinol Metab 2004, 15: 55-9

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

Date:    Thu, 22 Feb 2007 13:42:29 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES,NOT: Hypocapnia, orthostatic intolerance, and CFS

Source: Dynamic Medicine
        Volume 6, #1, p 2
Date:   January 30, 2007
URL:   http://www.dynamic-med.com/content/6/1/2

       http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17263876

       http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1796865&blobtype=pdf


Hypocapnia is a biological marker for orthostatic intolerance in some patients
with chronic fatigue syndrome
------------------------------------------------------------------------------
Benjamin H Natelson(1,*), Roxann Intriligator(1), Neil S Cherniack(2),
Helena K Chandler(1) and Julian M Stewart(3)
1 Department of Neurosciences, UMDNJ-New Jersey Medical School, Newark NJ, USA
2 Department of Medicine, UMDNJ-New Jersey Medical School, Newark NJ, USA
3 Department of Pediatrics, New York Medical College, Valhalla, NY, USA
* Corresponding author
Email: Benjamin H Natelson - natelson@njneuromed.org; Roxann Intriligator -
rgator5@aol.com;  Neil S Cherniack - cherniack@njneuromed.org; Helena K
Chandler - chandler@njneuromed.orgt; Julian M Stewart - stewart@nymc.edu

Received  19 June 2006
Accepted  30 January 2007
Published 30 January 2007


Abstract

Context
Patients with chronic fatigue syndrome and those with orthostatic
intolerance share many symptoms, yet questions exist as to whether CFS
patients have physiological evidence of orthostatic intolerance.

Objective
To determine if some CFS patients have increased rates of orthostatic
hypotension, hypertension, tachycardia, or hypocapnia relative to
age-matched controls.

Design
Assess blood pressure, heart rate, respiratory rate, end tidal CO2 and
visual analog scales for orthostatic symptoms when supine and when standing
for 8 minutes without moving legs.

Setting
Referral practice and research center.

Participants
60 women and 15 men with CFS and 36 women and 4 men serving as age matched
controls with analyses confined to 62 patients and 35 controls showing
either normal orthostatic testing or a physiological abnormal test.

Main outcome measures
Orthostatic tachycardia; orthostatic hypotension; orthostatic hypertension;
orthostatic hypocapnia or combinations thereof.

Results
CFS patients had higher rates of abnormal tests than controls (53% vs 20%,
p<.002), but rates of orthostatic tachycardia, orthostatic hypotension, and
orthostatic hypertension did not differ significantly between patients and
controls (11.3% vs 5.7%, 6.5% vs 2.9%, 19.4% vs 11.4%, respectively). In
contrast, rates of orthostatic hypocapnia were significantly higher in CFS
than in controls (20.6% vs 2.9%, p<.02). This CFS group reported
significantly more feelings of illness and shortness of breath than either
controls or CFS patients with normal physiological tests.

Conclusion
A substantial number of CFS patients have orthostatic intolerance in the
form of orthostatic hypocapnia. This allows subgrouping of patients with CFS
and thus reduces patient pool heterogeneity engendered by use of a clinical
case definition.


Background

Chronic fatigue syndrome (CFS) is an ailment characterized by medically
unexplained fatigue, severe enough to produce a substantial decrease in
activity plus infectious, rheumatological and neuro-psychiatric symptoms.
Orthostatic intolerance (OI) is defined by medically unexplained symptoms of
lightheadedness, fatigue, neurocognitive deficits, nausea, abdominal pain,
and shortness of breath when upright and improved by recumbency; patients
with OI often have a chronic problem with fatigue even when not standing
[1]. CFS patients commonly complain of symptom worsening during standing
[2], and one early study reported that 22 of 23 CFS patients reported
symptom worsening during orthostatic challenge. [3]. This association led to
the hypothesis that some CFS patients had orthostatic intolerance which
could be identified, quantified, and specifically treated.

Evaluation for OI in CFS has usually focused on abnormalities of heart rate
and blood pressure control. An early report noted a high rate of delayed,
neurally mediated hypotension (NMH) during upright tilt table testing of CFS
patients. [3]. Although there is evidence in support of more NMH in CFS
patients than healthy controls [4,5], two carefully controlled studies
matching patients to controls found no difference in prevalence of this
orthostatic syndrome [6,7]. A second symptomatic physiological abnormality
occurring in CFS patients was reported to be orthostatic tachycardia.
However, some groups reported increased rates of this physiological marker
of orthostatic intolerance in CFS [8,9] while others did not [10]. One
recent population-based study found no evidence for OI in CFS [11]. Thus,
the existence of OI in CFS remains controversial.

A recent report noted that cardiovascular measures of OI in patients with
CFS were often accompanied by hypocapnia, a pulmonary manifestation of OI
where blood carbon dioxide is at lower levels than normal [9]. Since
respiratory indices had not previously been assessed during orthostatic
challenge, this report led us to hypothesize that the primary manifestation
of OI in CFS might be orthostatic hypocapnia. To investigate this
hypothesis, we performed standing tests in CFS patients and in age- and
sex-matched healthy volunteers.


Methods

The subjects were 75 patients (60 women and 15 men) fulfilling the 1994 case
definition for CFS. [12]. Thus all these patients reported having new onset
of fatigue that was severe enough to produce a substantial decrease in
activity as well as having problems with at least four of eight infectious,
rheumatological or neuropsychiatric symptoms. No medical explanation for the
fatigue could be found with a set of rule-out blood tests including thyroid
and liver panels, CBC, Lyme titer, ANA, and rheumatoid factor. The patients
came either from a tertiary care practice devoted to medically unexplained
illnesses or as volunteers responding to media reports on our research; they
were evaluated regardless of medication regimen. Because earlier work had
suggested an association between CFS illness severity and cardiac function.
[13], patients were stratified into "severe" and "not severe" groups (30 and
45, respectively). "Severe CFS" was defined as those patients also
fulfilling the more demanding 1988 case definition for CFS [14] and
endorsing at least seven of the minor symptoms as producing substantial,
severe or very severe problems for the patient in the month prior to intake
(i.e., >= 3 on zero to five Likert scales). Subjects also included 40 age
matched controls reporting themselves to be in excellent or good health and
not taking any medications other than birth control pills (36 women and 4
men). The controls came from a data base of individuals interested in
participating in research or via recruitment by research staff.

After giving informed consent, subjects filled out a questionnaire to assess
current mood (Centers for Epidemiological Study-Depression. [15]) and were
instrumented with a blood pressure cuff (OMRON HEM-711AC IntelliSense
Automatic Blood Pressure Monitor) to allow automatic determination of blood
pressure and heart rate and a nasal cannula to allow automatic determination
of respiratory rate and end tidal CO2 (Oridion Microstream). Subjects were
instructed in the use of visual analog scales to indicate their levels of
dizziness, anxiety, shortness of breath, and of feeling ill (10 cm
horizontal lines ranging from "not at all" to "as ____ as I can imagine."
They were allowed to lie undisturbed for 10 minutes and then each of the
above variables were recorded twice - one minute apart - with the
subject in the supine position. Then, subjects were asked to stand with
their feet about 8 inches from a wall; they were then told to lean back,
touching only their upper back to the wall and not allowing movement of
their legs for 8 minutes. This is a variant of a test used by NASA
researchers to test for OI [16]; it reduces muscular influences on venous
return, a major cause of variability in orthostatic testing. Heart rate,
respiratory rate, blood pressure and eTCO2 as well as self report data of
symptom severity were collected every minute while leaning upright.

Orthostatic tachycardia was defined as (a) more than one standing reading
showing an increase from baseline of >= 30 beats per minute or an absolute
rate of 120 beats per minute or (b) one such reading prior to subjects'
being unable to tolerate further standing. Orthostatic hypertension was
defined as (a) more than one standing systolic reading of >= 140 mmHg or
diastolic reading of >= 90 mmHg or (b) one such systolic or diastolic
reading prior to subjects' being unable to tolerate further standing.
Orthostatic hypotension was defined as (a) more than one standing reading
showing a drop of blood pressure of >= 20 mmHg systolic or 10 mmHg diastolic
or (b) one such reading prior to subjects' being unable to tolerate further
standing. Orthostatic hypocapnia was defined as (a) more than one standing
reading of =< 30 mmHg eTCO2 or (b) one such reading prior to subjects' being
unable to tolerate further standing. The presence of orthostatic tachycardia,
orthostatic hypotension, orthostatic hypertension, or orthostatic hypocapnia
defined an abnormal standing test.


Data analysis and statistics

Statistical analysis to determine differences of "count" data between CFS
and controls used Fisher's tests, and differences of continuous data used
one-way ANOVAs with subsequent Bonferroni tests; when p values are given for
individual post-hoc comparisons, the overall F value was significant to <.05.
For data with repeated measures, hierarchical linear modeling (SPSS,
Mixed) was done to assess differences from mean supine to standing values
among groups. While we had a complete data set for physiological measures,
we did not have self report data from 25 patients and 5 controls as we only
began collecting these data after we realized they would be needed to
evaluate the possibility that anxiety or depressed mood might explain our
findings. Results are presented as means p/m s.e.m. unless otherwise
specified.


Results

Because of the possibility that one abnormal reading while standing might
have been an erroneous reading, we dropped data from subjects with only one
abnormal blood pressure or one eTCO2 value in the absence of orthostatic
symptoms (4 controls and 5 CFS and 1 control and 3 CFS respectively). In
addition, we excluded from further analysis data from 3 CFS patients with
baseline end tidal C02 values >= 30 mmHg because they appeared to be
chronic hyperventilators [17]. Including the data from all these subjects
would not have changed the overall results of this study. Finally two CFS
patients on treatment for hypertension developed orthostatic hypotension,
and so their data were also dropped. Following these exclusions, we analyzed
the data from 62 CFS patients and 35 controls.

There was no significant difference in age between patients and controls
(43.3 p/m 10.5 [sd] years and 40.4 p/m 7.9). Significantly more CFS patients
than controls fulfilled our criteria for abnormal standing tests (53% vs
20%, p<.002). For both groups, abnormalities were mostly confined to one
parameter - heart rate, blood pressure or end tidal CO2 (see Table 1).
Rates of orthostatic tachycardia, orthostatic hypotension, and orthostatic
hypertension did not differ significantly between patients and controls
(11.3% vs 5.7%, 6.5% vs 2.9%, 19.4% vs 11.4%, respectively; note that some
subjects had more than one form of OI). However rates of orthostatic
hypocapnia were significantly higher in CFS than in controls (20.6% vs 2.9%,
p<.02). The first occurrence of a hypocapnic value occurred in the first 3
minutes of standing for 8 of the 13 subjects. However, the magnitude of
hypocapnia increased over time (see Figure 1).

In an effort to evaluate possible variables producing orthostatic
hypocapnia, we did a post-hoc analysis confined to CFS patients with
orthostatic hypocapnia (n=13) with two comparison groups - CFS patients
with normal physiological responses to orthostatic challenge (n=30) and
healthy subjects with normal physiological responses to orthostatic
challenge (n=28).

There was no difference in rates of "severe CFS" between patients with
orthostatic hypocapnia and patients with no orthostatic intolerance (38% vs
30%). There was no difference in the change in respiratory rates from supine
to standing among groups; however both CFS groups tended to breath slower
while supine than controls (orthostatic hypocapnia: 15.4 p/m 1.4; no
intolerance: 16.1 p/m 0.6; controls: 18.5 p/m 0.6; p=.052 and .06 for each
comparison). There were no differences among the 3 groups for supine
systolic/diastolic blood pressure or for heart rate while supine or for the
magnitude of change when standing. During orthostatic challenge, end tidal
CO2 values showed a small decline over time for the CFS group without
orthostatic intolerance and the controls (F7,185.5=2.89, p<.001); this
effect of orthostatic challenge on normals has been previously reported
[18].

Anxiety and illness ratings in the supine position were higher in both CFS
groups than in the controls (p<.04 for comparisons on anxiety and < .001
on illness). Ratings of shortness of breath and dizziness in the supine
position did not differ among groups.

Magnitude of change in anxiety did not differ among groups going from supine
to standing. Magnitude of change in feeling ill ratings going from supine to
standing increased for the CFS group with orthostatic hypocapnia but not for
the other CFS group or the controls (F [Int]7,60.5=4.14; p<.001).
Magnitude of change in shortness of breath going from supine to standing was
significantly greater for the CFS group with orthostatic hypocapnia than the
CFS group without orthostatic intolerance (F1,30.4 = 4.44, p<.05). Both
CFS groups reported a greater increase in shortness of breath while standing
compared to controls (p<.005 for both comparisons). In terms of increases
in dizziness ratings going from supine to standing, it was the CFS group
without orthostatic abnormalities that was higher than controls (F1,47.3=
14.2, p<.001) with the CFS group with hypocapnia being intermediary.

There was no significant difference in depressed mood between the 2 CFS
groups as assessed by the CES-D, but both were significantly higher than
controls (p < .001; medians for those with orthostatic hypocapnia, no
orthostatic intolerance and controls, respectively were 20.5, 19.5, 6.0).


Discussion

We used a simple, real-life orthostatic challenge to determine rates of the
different physiological manifestations of orthostatic intolerance in CFS.
Previous studies of orthostatic intolerance in CFS have focused on changes
in blood pressure and heart rate with approximately 25% of patients having
these abnormalities. [19]. However, orthostatic changes in heart rate and
blood pressure are not uncommon in healthy people too [4,11]. In our
studies, CFS patients did show higher rates of orthostatic tachycardia,
hypertension, and hypotension than healthy controls. However, the
differences were not significant, and substantially larger sample sizes
would have been necessary for significance to have emerged.

In contrast, 21% of CFS patients studied here compared to only 3% of
controls had orthostatic hypocapnia, usually occurring without
cardiovascular indices of OI. These patients reported more problems with
shortness of breath and feeling ill during the orthostatic challenge than
patients without physiological evidence of OI or controls. An earlier study
using a longer duration orthostatic challenge - 30 min of head up tilt -
noted hypocapnia to occur in the presence of other cardiovascular indices of
OI [9]. That report as well as this one suggests that alterations in
respiration are the primary manifestation of OI in patients with CFS. The
identification of a subset of CFS patients with this physiological
manifestation of orthostatic intolerance is important in that its existence
can be used as a stratification strategy to reduce the patient pool
heterogeneity inherent in using a clinical case definition to diagnose CFS.

We thought we might find a relation between CFS illness severity and
orthostatic intolerance, but we did not. We found the same rates of "severe
CFS" in patients with orthostatic hypocapnia as in patients without
orthostatic intolerance. In addition, we found no difference in rates of
clinically meaningful depression in the two CFS groups as assessed by the
CES-D. Whether some other illness-related variable is predictive of
orthostatic intolerance remains to be determined.

One limitation in our study was that we evaluated successive patients in
either a private practice or a research setting regardless of whether or not
they were taking medicine. While we did drop data from two patients who
developed orthostatic hypotension due to their being on anti-hypertensive
medication, use of other medications did not explain the tendency of
patients to show more orthostatic hypotension or tachycardia than controls.
It is not apparent why medications would produce orthostatic hypocapnia in
the absence of other syndromes of orthostatic intolerance; however, this
remains a possibility which will require further study of unmedicated CFS
patients.

There are at least two explanations to account for orthostatic hypocapnia
– hyperventilation or reduced delivery of CO2 to the lung secondary to
reduced venous return to the right side of the heart. If it were the latter,
one would expect transient hypocapnia occurring early during standing.
Instead, we found that hypocapnia was sustained and progressive, and the
hypocapnia usually occurred without other cardiovascular manifestations of
orthostatic intolerance. This analysis supports the idea that the hypocapnia
was due to hyperventilation; although we did not assess ventilation in this
study, we did in another study and found hyperventilation in adolescents who
became hypocapnic during tilt testing [20]. But why orthostatic hypocapnia
develops as the primary mechanism for developing symptoms of OI in CFS
patients is an important research question. Our data indicate that emotional
factors related to anxiety or depression are not important. Our working
hypothesis is that this phenomenon comes from a complex interaction among
the baroreflex, chemoreceptors, and thoracic blood volume. Nonetheless, the
occurrence of isolated orthostatic hypocapnia in CFS suggests that it is an
important marker for orthostatic intolerance in some patients with medically
unexplained fatigue, which may eventually be susceptible to treatment.
Finding such a marker in a subgroup of CFS patients is the first step in
moving this illness from a clinical syndrome to one diagnosable by
laboratory testing.


Conclusion

The occurrence of isolated orthostatic hypocapnia in CFS suggests that it is
an important marker for orthostatic intolerance in some patients with
medically unexplained fatigue, which may eventually be susceptible to
treatment. Finding such a marker in a subgroup of CFS patients is the first
step in reducing the patient pool heterogeneity implicit in using a clinical
case definition for diagnosis.


Acknowledgements

Supported in part by NIH grants AI-54478 and HL-66007.


Figure caption

Figure 1
End tidal CO2 (mmHg) and time (min) before and after upright leaning


Table

Table 1. Rates of Normal and Different Abnormal Standing Tests
--------------------------------------------------------------
                                          CFS      Controls
--------------------------------------------------------------
Normal                                    30       28
Orthostatic tachycardia (OT) alone         5        1
Orthostatic hypertension (HT) alone        9        4
Orthostatic hypertension (HT) plus OT      1        0
Orthostatic hypotension (ht) alone         4        1
Orthostatic hypocapnia alone              11        0
Orthostatic hypocapnia plus OT             0        1
Orthostatic hypocapnia plus HT             1        0
Orthostatic hypocapnia plus HT plus OT     1        0
--------------------------------------------------------------
Total Normal/Abnormal                     30/32    28/7
--------------------------------------------------------------


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 2. Low PA, Opfer-Gehrking TL, McPhee BR, Fealey RD, Benarroch EE, Willner
    CL, Suarez GA, Proper CJ, Felten JA, Huck CA, .: Prospective evaluation
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 3. Bou-Holaigah I, Rowe PC, Kan J, Calkins H: The relationship between
    neurally mediated hypotension and the chronic fatigue syndrome.
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 4. Schondorf R, Benoit J, Wein T, Phaneuf D: Orthostatic intolerance in
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    J Autonom Nerv Sys 1999, 75:192-201.
 5. Freeman R, Komaroff AL: Does the chronic fatigue syndrome involve the
    autonomic nervous system?
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 6. LaManca JJ, Peckerman A, Walker J, Kesil W, Cook S, Taylor A, Natelson
    BH: Cardiovascular response during head-up tilt in chronic fatigue
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    Clin Physiol 1999, 19:111-120.
 7. Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D: Results of
    isoproterenol tilt table testing in monozygotic twinds discordant for
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    Arch Intern Med 2000, 160:3461-3468.
 8. Yamamoto Y, LaManca JJ, Natelson BH: A measure of heart rate variability
    is sensitive to orthostatic challenge in women with chronic fatigue
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 9. Naschitz JE, Rosner I, Rozenbaum M, Gaitini L, Bistritzki I, Zuckerman
    E, Sabo E, Yeshurun D: The capnography head-up tilt test for evaluation
    of chronic fatigue syndrome.
    Semin Arthritis Rheum 2000, 30:79-86.
10. Winkler AS, Blair D, Marsden JT, Peters TJ, Wessely S, Cleare AJ:
    Autonomic function and serum erythropoietin levels in chronic fatigue
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    J Psychosom Res 2004, 56:179-183.
11. Jones JF, Nicholson A, Nisenbaum R, Papanicolaou DA, Solomon L, Boneva
    R, Heim C, Reeves WC: Orthostatic instability in a population-based
    study of chronic fatigue syndrome.
    Am J Med 2005, 118:1415.e19-1415.e28.
12. Fukuda K, Straus SE, Hickie I, Sharpe MC, Komaroff A, Schluederberg A,
    Jones JF, Lloyd AR, Wessely S, Gantz NG, Holmes GP, Steele L, Reyes M,
    Abbey  S, Rest J, Jolson H, Peterson DL, Vercoulen JHMM, Tirelli U,
    Evengard B, Natelson BH, Reeves WC: The chronic fatigue syndrome: A
    comprehensive approach to its definition and study.
    Ann Intern Med 1994, 121:953-959.
13. Peckerman A, LaManca JJ, Dahl K, Qureishi B, Natelson BH: Abnormal
    impedance cardiography predicts symptom severity in chronic fatigue
    syndrome.
    Am J Med Sci 2003, 326:55-60.
14. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus
    SE, al. : Chronic fatigue syndrome: a working case definition.
    Ann Intern Med 1988, 108:387-389.
15. Radloff LS: The CES-D scale: A self-report depression scale for
    research in the general population.
    Appl Psychol Measurement 1977, 1:385-401.
16. Shvartz E, Meroz A, Magazanik A, Shoenfeld Y, Shapiro Y: Exercise and
    heat orthostatism and the effect of heat acclimation and physical
    fitness.
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17. Jack S, Rossiter HB, Pearson MG, Ward SA, Warburton CJ, Whipp BJ:
    Ventilatory responses to inhaled carbon dioxide, hypoxia, and exercise
    in idiopathic hyperventilation.
    Am J Respir Crit Care Med 2004, 170:118-125.
18. LeLorier P, Klein GC, Krahn A, Yee R, Skanes A, Shoemaker JK: Combined
    head-up tilt and lower body negative pressure as an experimental model
    of orthostatic syncope.
    J Cardiovasc Electrophysiol 1993, 14:920-924.
19. Schondorf R, Freeman R: The importance of orthostatic intolerance in
    the chronic fatigue syndrome.
    Am J Med Sci 1999, 317:117-123.
20. Stewart JM, Cherniack NS, Natelson BH: Postural hypocapnic
    hyperventilation is associated with enhanced peripheral vasoconstriction
    in postural tachycardia syndrome with normal supine blood flow.
    Am J Physiol Heart Circ Physiol 2006, 291:H904-H913.

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(c) 2007 BioMed Central Ltd

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Date:    Thu, 22 Feb 2007 12:18:10 -0500
From:    "Bernice A. Melsky" <bernicemelsky@VERIZON.NET>
Subject: RES: Exercise-based motivational interviewing for female patients with fibromyalgia: a case series

Exercise-based motivational interviewing for female patients with
fibromyalgia: a case series.

Clin Rheumatol. 2007 Feb 20; [Epub ahead of print]

Ang D, Kesavalu R, Lydon JR, Lane KA, Bigatti S.

Division of Rheumatology, Department of Medicine, Indiana University School
of Medicine, 1110 West Michigan St. Room 545, Indianapolis, IN, 46202, USA,
dang iupui.edu.

PMID: 17310268


The objective of the study is to determine the effects of motivational
interviewing (MI), a novel technique of behavioral counseling to promote
exercise, on pain and physical function in patients with fibromyalgia (FMS).

Patients who met the American College of Rheumatology criteria for FMS and
had a visual analog pain score of >/=6 were enrolled in a single group
intervention pilot study. Participants received two supervised exercise
sessions and an exercise prescription. Thereafter, six exercise-based MI
phone calls were made over a 10-week period. Assessments were done at
baseline, week 12 (immediate postintervention) and week 30 (follow-up). The
primary endpoints were changes from baseline in the fibromyalgia impact
questionnaire (FIQ)-pain and physical impairment at week 30. Secondary
measures were brief pain inventory (BPI)-pain severity and BPI-pain
interference, the number of exercise minutes (NEM) per week, and the
arthritis impact measurement scale (AIMS)-depression.

The 19 enrolled female participants had a mean age of 52.2  9.1 years,
mean disease duration of 7.5  5.0 years, and a mean FIQ-pain score of
7.7  1.4. By week 30, there was significant improvement in both FIQ-pain
(-2.6  2.6, p < 0.001) and FIQ-physical impairment (-1.3  2.1, p =
0.01). Likewise, BPI-pain severity and pain interference were reduced by
-2.4  2.1 (p < 0.001) and -2.4  2.0 (p < 0.001), respectively. While
the median NEM per week increased from 0 to 32 min (p = 0.001) at week 30,
AIMS-depression score was unchanged.

In this pilot study, we conclude that telephone-delivered MI to promote
exercise was associated with an improvement in patient's level of pain and
physical impairment.

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Date:    Fri, 23 Feb 2007 13:33:37 -0500
From:    Fred Springfield <fredspringfield VERIZON.NET>
Subject: RES: Munchausen Syndrome by Proxy/Fabricated and Induced  Illness: Does the diagnosis serve economic vested interests, rather  than the interests of children?

[This may be of interest, given that Munchausen Syndrome by Proxy
is often an issue raised in the pediatric ME/CFS community.]


Munchausen Syndrome by Proxy/Fabricated and Induced Illness: Does the
diagnosis serve economic vested interests, rather than the interests of
children?

Journal:  Medical Hypotheses, Volume 68, Issue 5, 2007, Pages 960-966

Author: Lynne Wrennall [E-mail: L.Wrennall@ljmu.ac.uk ]

Affiliation: Public Health Research Group, Criminology Programme, School of
Social Science, Liverpool John Moores University, Clarence Street,
Liverpool L3 5UG, United Kingdom

Received 16 June 2006;
accepted 3 October 2006.
Available online 1 December 2006.



Summary
The discourse of Munchausen Syndrome by Proxy/Fabricated and Induced
Illness posits the widespread incidence of a highly dangerous form of child
abuse in which illness and developmental delay in children, is caused by
their parents or carers. The discourse has been linked to false allegations
of child abuse, hostile adoptions and miscarriages of justice. It has also
stimulated concerns that the children's real medical and developmental
needs are neglected when their conditions are misdiagnosed as child abuse.

This study examines the critical claims that have been levelled against the
Munchausen discourse. They provide explanations of the children's problems
that compete with the discourse. The claim of the discourse to scientific
validity is thereby shown to be questionable. The explanations have been
distilled into specific hypotheses, to stimulate further research.

The literature from which the hypotheses were derived, identifies problems
in the MSbP/FII discourse in five broad areas of science, regarding: the
test validity of techniques; construct validity; statistical methods;
evidentiary standards and adverse impacts.

The main conclusion is that the detailed critical hypotheses, cohere around
the central claim that the discourse of Munchausen Syndrome by
Proxy/Fabricated and Induced Illness serves economic vested interests,
rather than the interests of children. The hypotheses predict adverse
health and social outcomes, as a result of the discourse. Consequently, the
continued deployment of the discourse would probably be "unsafe and
therefore unwise".
_________________________
Sources of Support in the form of Grants. I have received funding for my
research in this area from the University Research Fund and the School of
Social Science Research Fund at Liverpool John Moores University.

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Date:    Sat, 24 Feb 2007 14:22:30 -0500
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: The neuronal 5-HT(3) receptor network after 20 years of  research - Evolving concepts in management of pain and inflammation

The neuronal 5-HT(3) receptor network after 20 years of research - Evolving
concepts in management of pain and inflammation.

Eur J Pharmacol. 2007 Jan 30; [Epub ahead of print]

Faerber L, Drechsler S, Ladenburger S, Gschaidmeier H, Fischer W.

Department of Pharmacology, Regensburg Medical School, Universitaetsstr.
31, 93053 Regensburg, Germany.

PMID: 17316606


The 5-HT(3) receptor is a pentameric ligand-gated cation channel which is
found in the central and peripheral nervous system and on extraneuronal
locations like lymphocytes, monocytes and fetal tissue. Five monomer
subtypes, the 5-HT(3A-E) subunits, have been identified which show
differences in the amino-terminal and the transmembrane region. The
functional relevance of different receptor compositions is not yet clarified.

5-HT(3) receptors are located predominantly in CNS regions that are
involved in the integration of the vomiting reflex, pain processing, the
reward system and anxiety control. The preferential localization on nerve
endings is consistent with a physiological role of 5-HT(3) receptors in the
control of neurotransmitter release such as dopamine, cholecystokinin,
glutamate, acetylcholine, GABA, substance P, or serotonin itself.

5-HT(3)-receptor agonists cause unpleasant effects like nausea and anxiety,
and no clinical use has been considered. In contrast, the introduction of
5-HT(3)-receptor antagonists for chemotherapy-induced vomiting was
extremely successful. After development of other gastrointestinal
indications like postoperative vomiting and diarrhea-predominant irritable
bowel syndrome recent research focuses on rheumatological indications such
as fibromyalgia, rheumatoid arthritis and tendinopathies.

Positive effects have also been observed for pain syndromes such as chronic
neuropathic pain and migraine. These effects seem to be related to
substance P-mediated inflammation and hyperalgesia. Furthermore,
antiinflammatory and immunomodulatory properties have been observed for
5-HT(3)-receptor antagonists which might explain promising findings in
systemic sclerosis and other immunological conditions.

For all of these innovative indications the optimal dosing schedule is a
crucial issue, since a bell-shaped dose-response curve has been observed
repeatedly for 5-HT(3)-receptor antagonists, particularly in CNS effects.

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Date:    Sun, 25 Feb 2007 09:31:22 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks COMBIDOM.COM>
Subject: RES,NOT: NIH awarded a $1.4 million grant for FMS tissue bank

Source: Arizona Republic
Date:   February 23, 2007
Author: Charles Kelly
URL:                                                       http://www.azcentral.com/community/westvalley/articles/0223gl-fibro23Z20.html


1st fibromyalgia tissue bank set up at Sun Health Institute
-----------------------------------------------------------

A new tissue bank and new research at the Sun Health Research Institute could
offer hope to millions of people in this country suffering from fibromyalgia,
a chronic syndrome whose many symptoms include fatigue and muscle, joint and
bone pain.

The National Institutes of Health has awarded a $1.4 million grant to Dr.
Dianne Lorton, head of the institute's Robert J. Hoover Center for Arthritis
Research, to establish the world's first fibromyalgia tissue bank.

"Tissue collected from fibromyalgia patients will be an incredible resource
for finding answers to the questions of what causes fibromyalgia and how we
can successfully treat it," Lorton said.

The bank will lay the groundwork for the institute to do innovative research
on glial cells - activated brain and spinal cord cells - which are the focus
of the latest theory on what causes fibromyalgia pain.

The expanded arthritis research project is made possible not only by the NIH
grant but also by a $100,000 grant from the American Fibromyalgia Syndrome
Association and a pilot project grant from the NIH.

The institute needs fibromyalgia patients to donate tissue, Lorton said.
"Pain in fibromyalgia is poorly understood and managed," she said. "It is
expected this innovative new research will lead to a potentially revolutionary
treatment for the millions of people suffering with severe chronic pain."

Lorton is collaborating with Dr. Linda Watkins at the University of Colorado-
Boulder, in doing this research, which may help sufferers of long-term pain
associated not only with fibromyalgia, but also with shingles, diabetes,
arthritis, cancer and AIDS.

Tissue donation will not occur until the donor's death. However, fibromyalgia-
tissue donors will be asked to visit the institute each year to have their
malady checked and to complete a pain-assessment questionnaire.

For information on becoming a tissue donor, call (623) 875-6528.

--------
(c) 2007 Arizona Republic

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Date:    Mon, 26 Feb 2007 13:22:45 -0500
From:    "Bernice A. Melsky" <bernicemelsky VERIZON.NET>
Subject: RES: Fear of movement and (re)injury in chronic musculoskeletal pain: Evidence for an invariant two-factor model of  the Tampa Scale for Kinesiophobia across pain diagnoses and Dutch,  Swedish, and Canadian samples

Fear of movement and (re)injury in chronic musculoskeletal pain: Evidence
for an invariant two-factor model of the Tampa Scale for Kinesiophobia
across pain diagnoses and Dutch, Swedish, and Canadian samples.

Pain. 2007 Feb 19; [Epub ahead of print]

Roelofs J, Sluiter JK, Frings-Dresen MH, Goossens M, Thibault P, Boersma K,
Vlaeyen JW.

Department of Medical, Clinical, and Experimental Psychology, Maastricht
University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.

PMID: 17317011


The aims of the current study were twofold. First, the factor structure,
reliability (i.e., internal consistency), and validity (i.e., concurrent
criterion validity) of the Tampa Scale for Kinesiophobia (TSK), a measure
of fear of movement and (re)injury, were investigated in a Dutch sample of
patients with work-related upper extremity disorders (study 1). More
specifically, examination of the factor structure involved a test of three
competitive models: the one-factor model of all 17 TSK items, a one-factor
model of the TSK (Woby SR, Roach NK, Urmston M, Watson P. Psychometric
properties of the TSK-11: a shortened version of the Tampa Scale for
Kinesiophobia. Pain 2005;117:137-44.), and a two-factor model of the
TSK-11. Second, invariance of the aforementioned TSK models was examined in
patients with chronic musculoskeletal pain conditions (i.e., work-related
upper extremity disorders, chronic low back pain, fibromyalgia,
osteoarthritis) from The Netherlands, Sweden, and Canada was assessed
(study 2).

Results from study 1 showed that the two-factor model of the TSK-11
consisting of 'somatic focus' (TSK-SF) and 'activity avoidance' (TSK-AA)
had the best fit. The TSK factors showed reasonable internal consistency,
and were modestly but significantly related to disability, supporting the
concurrent criterion validity of the TSK scales.

Results from study 2 showed that the two-factor model of the TSK-11 was
invariant across pain diagnoses and Dutch, Swedish, and Canadian samples.

Altogether, we consider the TSK-11 and its two subscales a psychometrically
sound instrument of fear of movement and (re)injury and recommend to use
this measure in future research as well as in clinical settings.


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