TGI Friday! ‘Lipkin Study’ results coming out next week and other research information | 14 September 2012

The return of TGI Friday! Recently published research study news and abstracts which sometimes make the news, sometimes don't. Here every Friday!

THE RESULTS OF THE LONG-AWAITED ‘LIPKIN XMRV/MLV STUDY' WILL BE ANNOUNCED NEXT TUESDAY (SEPTEMBER 18).

A press conference has been called for 10.30am (EDT) by the Center for Infection and Immunity attached to Columbia University, New York City.

Details here:

CII Press Conference
September 18th, 2012
10:30 AM (EDT)

“Multicenter Study on Chronic Fatigue Syndrome/Myalgic Encephalomyelitis”

The causes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) have long eluded scientists. In 2009/2010, two high-profile papers linked the syndrome to infection with a mouse retrovirus called XMRV (xenotropic murine leukemia virus (MLV)-related virus) and murine retrovirus-like sequences (designated pMLV: polytropic MLV). Given that affected patients often have symptoms consistent with a chronic infection, this viral connection was deemed plausible, and the findings were celebrated as a major achievement for a complex disease that afflicts nearly 1 million in the U.S.

However, follow-up investigations by several laboratories were unable to detect XMRV or pMLV in CFS patients.
To definitively resolve this issue, the National Institute of Allergy and Infectious Diseases commissioned a large-scale, multicenter study under the auspices of the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health, in partnership with the Centers for Disease Control and Prevention, the Food and Drug Administration, the NIH’s National Cancer Institute and Warren G. Magnuson Clinical Center, and others (see full list below).

Investigators from the multicenter study on CFS/ME and XMRV/pMLV will discuss their findings and future directions.
A live video will be posted below.

For attendance at the event, members of the media should RSVP by 9:00AM on Monday, Sept. 17th to Nsikan Akpan (212-342-9051 | nea2107@columbia.edu) or Stephanie Berger, Mailman School of Public Health (212-305-4372 | sb2247@columbia.edu).

When: Tuesday, September 18, 2012
Press Conference begins at 10:30 AM (EDT)

Who: W. Ian Lipkin, MD (Moderator)
Center for Infection and Immunity (CII), Mailman School of Public Health, Columbia University
Principal Investigator and Director of Center for Infection and Immunity
John Snow Professor of Epidemiology
Professor of Neurology and Pathology

Harvey Alter, MD
National Institutes of Health, Department of Transfusion Medicine
Distinguished NIH Investigator
Chief, Clinical Studies
Associate Director of Research

Mady Hornig, MD
Center for Infection and Immunity, Mailman School of Public Health, Columbia University
Director of Translational Research at CII
Associate Professor of Epidemiology

Judy Mikovits, PhD
Mikovits Consulting

Francis Ruscetti, PhD
National Cancer Institute, Frederick National Laboratory for Cancer Research
Head, Leukocyte Biology Section
Senior Investigator

Collaborating Research Groups:

Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD.
Mikovits Consulting, Oxnard, CA.
Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA.
Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, Frederick, MD.
Tissue Safety Laboratory, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD.
Nova Southeastern University, Fort Lauderdale FL.
Miami Veterans Affairs Medical Center, Miami, FL.
Brigham and Women’s Hospital, Boston, MA.
Infectious Disease Clinic, Stanford University, Palo Alto, CA.
Fatigue Consultation Clinic, Salt Lake City, UT.
Levine Clinic, New York, NY.
Simmaron Research Institute, Incline Village, NV.
Department of Biostatistics, Columbia University, New York, NY.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY.
Center for Infection and Immunity, Columbia University, New York, NY.
Department of Molecular Biology and Microbiology, Tufts University, Boston, MA.

From Medical Hypotheses. 2012 Aug 27. [Epub ahead of print]

Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Morris G, Maes M.

Maes Clinics @ TRIA, Bangkok, Thailand
Corresponding author. Address: Piyavate Hospital, 998 Rimklongsamsen Road, Bangkok 10310, Thailand. Tel.: +66 26602728.

Abstract

Fukuda's criteria are adequate to make a distinction between Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and chronic fatigue (CF), but ME/CFS patients should be subdivided into those with (termed ME) and without (termed CFS) post exertional malaise [Maes et al. 2012].

ME/CFS is considered to be a neuro-immune disease. ME/CFS is characterized by activated immuno-inflammatory pathways, including increased levels of pro-inflammatory cytokines, nuclear factor κB (NF-κB) and aberrations in mitochondrial functions, including lowered ATP.

These processes may explain typical symptoms of ME/CFS, e.g. fatigue,malaise, hyperalgesia, and neurologic and autonomic symptoms.

Here we hypothesize that increased NF-κB together with a loss of p53 are key phenomena in ME/CFS that further explain ME/CFS symptoms, such as fatigue and neurocognitive dysfunction, and explain ME symptoms, such as post-exertional malaise following mental and physical activities.

Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise. Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions.

All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of
increased activity cannot be met. In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function.

Future research should examine p53 signaling in ME/CFS.

From Antioxidants and Redox Signaling. 2012 Sep 3. [Epub ahead of print]

Is inflammation a mitochondrial dysfunction-dependent event in Fibromyalgia?

Cordero MD, Díaz-Parrado E, Carrión AM, Alfonsi S, Sánchez-Alcázar JA, Bullon P, Battino M, de Miguel M.
Dpto. Citología e Histología Normal y Patológica, Facultad de
Medicina. Universidad de Sevilla, 41009

Abstract

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Both mitochondrial dysfunction and inflammation have been implicated in the pathophysiology of FM.

We have investigated the possible relationship between mitochondrial dysfunction, oxidative stress and inflammation in FM.

We studied thirty women diagnosed with FM and twenty healthy women. Blood mononuclear cells (BMCs) from FM patients showed reduced level of CoQ10, mtDNA contents, and high level of mitochondrial ROS, serum TNF-alpha and transcript levels.

A significant negative correlation between CoQ10 and TNF-alpha levels (r = -0.588; P<0.01), and a positive correlation between ROS and TNF-alpha levels (r = 0.791; P<0.001) were observed accompanied by a significant correlation of VAS with serum TNF-alpha and transcript levels (r = 0.4507; P<0.05 and r = 0.7089; P<0.001, respectively).TNF-alpha release was observed in an in vitro (BMCs) and in vivo (mice) CoQ10 deficiency model. Oral CoQ10 supplementation restored biochemical parameters and induced a significant improvement in clinical symptoms (P0.001).These results lead to the hypothesis that inflammation could be a mitochondrial dysfunction-dependent event implicated in the pathophysiology of FM in several patients indicating at mitochondria as a possible new therapeutic target.

From the European Journal of Clinical Investigation, 7 September 2012

Second response by Nijs et al. to comments on their recent paper ‘How to exercise people with chronic fatigue syndrome: evidence-based practice guidelines'.

Time-contingent pacing and exercise therapy accounting for post-exertional malaise and central sensitization in chronic fatigue (central sensitivity) syndrome

Jo Nijs 1,2,3, Deborah Van Cauwenbergh 1,2, Margot De Kooning 1,2,3,
Kelly Ickmans 1,2,3

1 Chronic Pain and Chronic Fatigue Research Group (CHROPIVER), Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Belgium
2 Chronic Pain and Chronic Fatigue Research Group (CHROPIVER), Division of Musculoskeletal Physiotherapy, Department of Health Care Sciences, Artesis University College Antwerp, Belgium
3 Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Belgium

Address of correspondence and reprints requests to Jo Nijs, Vrije Universiteit Brussel, Building L-Mfys, Pleinlaan 2, BE-1050 Brussels, Belgium (phone +3226291154; fax +3226292876; e-mail: Jo.Nijs@vub.ac.be; website: www.chropiver.be)

We would like to thank the Editor for giving us the opportunity to respond to the letters to the Editor that further discuss our practice guidelines for clinicians applying exercise therapy for patients with myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) [1].

Both letters address the recommendation of using time-contingent rather than symptom-contingent exercise therapy for ME/CFS. However, this issue has been addressed in the discussion section of the guidelines paper [1]. Still, we welcome this opportunity to further explain our recommendation for using time-contingent activity self-management (including pacing) and exercise therapy for ME/CFS.

We agree with Kindlon and Chu et al. that it is clinically not so straightforward to provide time-contingent exercise therapy, and that we should take into account post-exertional malaise associated with ME/CFS. A time-contingent approach does not imply ignoring postexertional malaise, on the contrary. Likewise, a time-contingent approach does take the tolerance level of the patient into account. A time contingent approach to pacing and exercise interventions implies that exercise and activity levels are tailored in line with the load tolerance of the individual patients, that exercises/activities are followed by rest periods to account for the delayed recovery following physical activity etc. Moreover, using activity self-management in preparation of / prior to graded activity or graded exercise therapy makes sure that the load tolerance, post-exertional malaise, and delayed recovery following exercise in each individual ME/CFS patient is properly addressed.

Activity self-management for people with ME/CFS involves encouraging the patients to pace their activities and respect their physical and mental limitations, but not to stay or become dependent of nonspecific symptoms like pain, fatigue and brain fog. This pacing strategy involves encouraging the patient to achieve an appropriate balance between activity and rest in order to avoid exacerbations, but in a time-contingent way.

Why should clinicians prefer a time-contingent approach over a symptom-contingent approach? There are scientific and experienced-based arguments. Science learned us that both symptom-contingent and time-contingent approaches to exercise therapy are effective for patients with ME/CFS [1]. We agree with Tom Kindlon that such evidence is based on selfreport rather than on objective measures, but in the end of the day patients prefer treatments that make them feel better (subjectively) over treatments that improve objective blood results (but at the same time leave them feeling sick). In addition, science has learned us that ME/CFS is characterized by hypersensitivity of the central nervous system (i.e. central sensitization) [2]. Indeed, studies showed generalized hypersensitivity in ME/CFS for a variety of sensory stimuli and in various tissues, including the skin, muscle tissue, and the lungs (reviewed in [2]). Central sensitization in ME/CFS is in line with our current understanding of ME/CFS: it corroborates with psychological influences on the illness, the presence of infectious agents and immune dysfunctions, and the dysfunctional hypothalamus pituitary adrenal-axis as seen in these severely debilitated patients. The finding of dysfunctional endogenous analgesia in response to exercise in ME/CFS is one feature of central sensitization, one which accounts in part for post-exertional malaise [3,4]. The recent international consensus criteria for ME stress the importance of hyperexcitability of the central nervous system for this illness [5].

Central sensitization implies that the brain produces pain, fatigue and other ‘warning signs’ even when there is no real tissue damage. It implies that ME/CFS is not a disease of the mind, but rather a disease of the brain. Hence, the brain should become an important treatment target. A symptom-contingent approach may facilitate the brain in its production of nonspecific warning signs, while a time-contingent approach might deactivate brainorchestrated descending facilitatory pathways. This view is supported by findings of reduced central nervous system hyperexcitability following time-contingent treatment in patients with fibromyalgia [6], and an increase in prefrontal cortical volume in response to time-contingent therapy in patients with ME/CFS [7]. Importantly, explaining such an approach to patients with evidence from modern neuroscience rather than from psychology, is generally welcomed very positively by ME/CFS patients [8].Neuroscience education enables patients with ME/CFS to understand the controversy surrounding the illness, the lack of objective biomarkers for the illness, and the need for a time-contingent approach to activity and exercise therapy.

Addressing the experience-based arguments, more than 10 years of clinical experience with these patients has learned us that a symptom-contingent approach leads to short-term improvements [9], but makes long-term improvement, grading and functional recovery very difficult to achieve [10]. Still, even with time-contingent therapy grading remains a delicate issue for patients with ME/CFS, and full recovery is rarely achieved. Hopefully neurotechnology and its
innovative brain treatments will provide a better solution for this disabling illness.

Finally, the issue of the numerous patient surveys from different countries suggesting that many patients feel that exercise therapy have worsened their health was mentioned in the letter by Chu et al. Such surveys have value, but from a scientific viewpoint it remains an unanswered question who filled out these surveys (nothing but ME/CFS patients diagnosed by a physician?), to what extend selection bias, suggestion and recall bias have contributed to the study findings, etc. One cannot exclude the possibility that the survey results reflect the difficulty of clinicians around the globe to apply exercise therapy for patients with ME/CFS. In fact, this was the reason for us preparing and publishing the clinical guidelines for exercise therapy in these patients.

To conclude, we are happy to see that our practice guidelines has fueled international discussion of practicing exercise therapy in ME/CFS. Time-contingent approaches to activity self-management and exercise therapy in the field of ME/CFS are often misunderstood as therapies that refute the fact that ME/CFS patients are seriously ill and have ‘real’ symptoms. This is incorrect and often leads to fruitless discussions. Therefore we have explained that rehabilitation for patients with ME/CFS has moved on, accounting for our current understanding of this underestimated illness. This implies that time-contingent exercise therapy should be preceded by patient education and time-contingent activity selfmanagement, including pacing to account for the decreased load tolerance, delayed recovery following exercise and related post-exertional malaise. Such an approach accounts for the mechanism of hyperexcitability of the central nervous system in patients with ME/CFS. The field of chronic pain has taken this step (including the field of fibromyalgia!); it is time for the ME/CFS community to move on as well.

References

1. Van Cauwenbergh D, De Kooning M, Ickmans K, Nijs J. How to exercise people with chronic fatigue syndrome: evidence based practice guidelines. Eur J Clin Invest. 2012 May 25. doi:
10.1111/j.1365-2362.2012.02701.x.
2. Nijs J, Kosek E, Van Oosterwijck J, Meeus M. Dysfunctional endogenous analgesia during exercise in patients with chronic pain: To exercise or not to exercise? Pain Physician 2012;15: ES205-213.
3. Nijs J, Meeus M, Van Oosterwijck J, Ickmans K, Moorkens G, Hans G, De Clerck LS. In the mind or in the brain? Scientific evidence for central sensitization in chronic fatigue syndrome. European Journal of Clinical Investigation 2012;42(2):203-212.
4. Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, Lambrecht L and Paul L. Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. J Intern Med 2010;268(3):265-278.
5. Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. 2011;270(4):327-38.
6. Ang DC, Chakr R, Mazzuca S, France CR, Steiner J, Stump T. Cognitive-behavioral therapy attenuates nociceptive responding in patients with fibromyalgia: a pilot study. Arthritis Care & Research 2010;62:618-623.
7. de Lange FP, Koers A, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Toni I. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain 2008;131(8):2172-80.
8. Meeus M, Nijs J, Van Oosterwijck J, Van Alsenoy V, Truijen S, De Meirleir K. Pain Physiology Education Improves Pain Beliefs in Patients with Chronic Fatigue Syndrome compared to Pacing and
Self-management Education: a Double-blind Randomized Controlled Trial. Archives of Physical Medicine and Rehabilitation 2010; 91:1153-1159.
9. Nijs J, van Eupen I, Vandecauter J, Augustinus E, Bleyen G, Moorkens G, Meeus M. Can pacing self-management alter physical behavior and symptom severity in chronic fatigue syndrome? A case
series. J Rehabil Res Dev. 2009;46(7):985-96.
10. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy,
cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011;377(9768):823-36.

This article has been accepted for publication and undergone full peer
review but has not been through the copyediting, typesetting,
pagination and proofreading process, which may
lead to differences between this version and the Version of Record.
Please cite this article as doi: 10.1111/j.1365-2362.2012.02722.x