Some of the giants of the ME world, including Professor Malcolm Hooper, Professor Basant Puri, Dr. Byron Hyde, Dr. Bruce Caruthers, Jane Colby and Dr. Ian Gibson MP, will be speaking. For more information and an application form for this conference please contact meconference2006@investinme.org or see

 http://www.investinme.org/IIME%20Campaigning-ME%20Awareness%20S

Several CFS researchers including Dr. Puri, Dr. Hooper and Dr. Kerr will be speakers. Dr. Kerr will do a talk on the Genetics of CFS. Dr. Hooper will give a talk on Multi-chemical sensitivity, Gulf War syndrome and chronic fatigue syndrome.

The need for Dr. Wessely or his cohorts to put him onto Wikipedia is not particularly noteworthy or even surprising; this doctor does after all love the spotlight. What is noteworthy is the beginnings of a retreat from the positions he’s held. In fact most of the article concerns the physical abnormalities he’s found in CFS, not his psychological interpretation of it. Check out this from at the end of the article. "Wessely counters that few deny a physical cause, and research conducted under his direction has detected markers of physical abnormalities in CFS." As evidence continues to build that CFS is real this man may slowly be starting to back away from his own past.

A – several difference making papers on CFS pathophysiology

D – 1 or no important papers on CFS pathophysiology but several on other aspects of CFS

F – no important papers on CFS

December Research Rating – B - For this month we have a stunning view of protein production in the brains of CFS patients, an interesting theory on enterovirus production in CFS and a study finding immune activation during exercise.

This paper is a breakthrough in CFS research in a number of ways. First it is the first paper to utilize proteomics, a sister technology to genomics that has much discussed but little used to date. While genomics research measures patterns of gene expression, proteomics measures patterns of protein expression. Since genes code for proteins and it is proteins that actually do the work of the cell, measuring the proteins present is a logical extension of the gene expression program. Since not all gene mRNA is actually translated into proteins one could argue that protein expression is a more primary and important measure than gene expression.

Secondly, instead of searching the blood the researchers explored the cerebrospinal fluid (CSF) – a much more difficult medium to access. Thirdly, the main finding of this study that a unique pattern of protein expression exists not just in CFS patients but in GWS and FMS patients as well suggests a similar pathophysiology exists in these closely related syndromes. This is big news; we know that their symptom presentation is quite similar but researchers have been mainly stymied in their efforts to explain how. The finding of a similar proteome in each suggests that the Baraniuk team has been able to find a central dysregulation common to each.

A Disease Process Proposed - One very positive aspect of these findings was their coherence. Unlike some gene expression studies the investigators were able to easily outline a pathological process involving the proteins found. The protein signature found in the CSF of CFS patients suggested that a brain injury (oromuscoid proteins) causing bleeding (heme scavenger proteins) possibly due to extracellular protein accumulations (gelsolins) in the blood vessels prompted the release of anti-hemorrhage factors (PDEF) and central nervous system repair proteins (Behabs). In short the authors suggested CFS was a cerebral amyloid-like condition with an angiopathy, i.e. a cerebral amyloid angiopathy.

A Biomarker for CFS? Probably the most significant outcome of this study was the development of a proteome ‘biosignature’[. A statistically produced model indicated that the presence of any one of five proteins (keratin 16, @-2-macroglobullin, orosomucoid-2, autotoxin, pigment epithelium-derived factor) differentiated ‘CFS’ patients from controls with a high degree of confidence. Since the protein expression of the GWS, FMS and CFS patients was so similar all their data was merged into a category called ‘CFS’. This is, of course, only initial evidence but this protein set and these protein findings are the first distinctive neurological evidence found in CFS; i.e. the first neurological findings that are distinct to CFS.

A Permeable Blood Brain Barrier (BBB) in CFS? - The authors also brought up the idea that a more permeable BBB could be allowing more proteins to enter the cerebral spinal fluid. Their theory that increased histamine activity could increase BBB permeability in CFS could explain why tricyclic antidepressants such as doxepin elixir and imipramine that are able to cross the blood brain barrier and block histamine receptor activity in the brain are effective in CFS while other histamine receptor blockers unable to pass through the BBB are not. Researchers have for years speculated whether increased permeability of the BBB in CFS patients might allow pathogens or other factors access to the brain. Spence and Khan found CFS patients exhibited a hypersensitive histamine response in the skin.

Bridging the Gap: Linking Protein and Gene Expression Studies – Although not mentioned by the authors some evidence supporting their theory can be found in some of the gene expression studies as well as other studies done in CFS. No CSF gene expression studies have yet been done (although one is planned) but several gene expression studies using peripheral blood mononuclear cells (PBMC’s) have found evidence of neuronal dysfunction in CFS.

More nervous system genes than immune genes were upregulated in the 2005 Kauschik/Kerr study. Remarkably, one of the genes found upregulated in the Kauschik/Kerr study involved gelsolin, a protein which was up regulated in the present study (see below). One of the early gene expression studies by the CDC found that a gene involved in Huntington’s disease, a devastating neurodegenerative disease involving amyloidosis, was also upregulated in CFS.

One of the proteinases upregulated, anti-chymotrypsin, is able to degrade elastase. Could anti-chymotrypsin activity suggest increased elastase activity as well? Increased elastase levels have been implicated in acute pancreatitis, an amyloidic condition as well as the RNase L fragmentation present in CFS patients.

Transforming Growth Factor Beta (TGF-B) and Amyloidosis in CFS? – The authors did not mention TGF-B but the increased levels of plasma TGF-B mostly seen in CFS studies are intriguing given TGF-B’s link to amyloidosis. Natelson, unfortunately, did not measure TGF-B in his cerebral spinal fluid study. Increased TGF-B production in transgenic mice is correlated with the degeneration of the brain blood vessels, amyloid deposition and chronic microglia activation. Baraniuk et. al. also suggested glial cell activation could account for many of t he proteins seen. Obstruction of the blood vessels in these mice eventually results in reduced cerebral blood flows, reduced metabolism and neuronal dysfunction. TGF-B production in the brain can be triggered by ischemia, trauma and or/oxidative stress. Low brain blood flows in CFS could contribute to ischemia and numerous studies now indicate increased oxidative stress in several parts of the bodies of CFS patients. Thus some of the factors triggering TGF-B production may be present in CFS.

Conclusion - The authors propose, however, that CFS is a "non-lethal, protein–misfolding, cerebrovascular amyloidosis-like syndrome". (Thank God they came up with a simple description). Most encouragingly they state that their

"proteomic model provides initial objective evidence for the legitimacy of CFS as a distinct neurological disease".

and in an interview Baraniuk stated

"This ushers in a whole new era for identifying [and] recognizing the legitimacy of these disorders,'

Lets hope he's right.

(For those interested in the ‘nuts and bolts’ of this issue a list of some of the proteins found in CFS patients is below).

Oxidation- related - Orosomucoid I and II- suggest a brain injury has occurred. Synthesized at sites of trauma or astroglial cell activation ORM I and II are antioxidants that sequester iron. Iron is a notable catalyst for free radical production. Since bacteria need iron? The body often attempts to sequester as much free iron as possible during bacterial infections.

Heme scavengers - Heme scavengers were present in both groups but were more frequently encountered in CFS patients. Since heme is a by-product of bleeding the authors posit sites of localized bleeding are present in brains of CFS.

Amyloidosis – A surprising number of the proteins found only in CFS patients had to do with amyloidosis, a process characterized by the extracellular accumulation of proteins in the brain (or elsewhere). Amyloidosis plays an important role in several central nervous system (CNS) diseases.

Gelsolin is a protein that caps actin, a key part of the cytoskeleton. Actin can be present as a monomer (G-actin) or as a polymer (F-actin) but only polymerized actin is incorporated into the structures that make up the cells cytoskeleton. Gelsolin is one of the two actin capping proteins that prepare actin for polymerization. Gelsolin also has numerous connections to ‘amyloidic’ diseases. Mutant gelsolin forms lead to protein misfolding and gelsolin cleavage can lead to the production of amyloid products.

Transthyretin is a thyroid transport protein whose misfolding can contribute to amyloidosis. Sternberg in the NIH sponsored 2003 Neuroimmume Mechanisms and CFS conference suggested that the hypothyroid-like fatigue seen in CFS could be due reduced transthyretin efficacy.

Prohormones – Chromogranin B, PEDF, autotoxin, Prohormones are precursors to hormones. Hormones and neuropeptides are released when proteases (protein cleaving enzymes) break them up. Increased amounts of prohormones in CFS patients suggests, then, that increased levels of proteolytic activity are present. A recent paper indicates increased proteolytic activity is present in the blood of CFS patients.

Protease Inhibitors – The counterpart to the increased proteolytic activity occurring is increased levels of protease inhibitors in CFS patients. Anti macroglobulin inhibits thrombin and other proteases. A mutant allele of @2-macroglublin promotes Alzheimer’s disease.

@-1-antichymotrypsin inhibits chymotrypsin, a serine protease involved in inflammation. Chymotrypsin is similar to elastase, the RNase L fragmenting enzyme, that appears to be increased in some CFS patients. While elastase is not its main target anti-chymotrypsin is able to inhibit elastase. Could increased anti-chymotrypsin activity suggests increased elastase activity as well?

Epithelial proteins – Six newly described keratin proteins were found in the CSF of CFS patients. The presence of keratin 16 suggests a dysfunction in the two portions of the brain fronting the BBB, choroids plexus and the leptomeningeal system. The authors suggest the presence of keratin 16 is due to immune system activation or to epithelial cell activation in the CNS of CFS patients. The epithelium is a layer of cells covering the surfaces of the skin, the mucous membranes and the glands. Could epithelial cell activation suggest trauma or injury?

Central Nervous System Repair – Greatly elevated levels Behab mRNA in gliomas and brain injury suggest Behab is involved in CNS repair. Gliomas are CNS tumors.

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In this paper Chia gives a review of the current state of science in CFS regarding enteroviruses. Chia, a physician in Southern California, begins his review by stating that his data suggests that CFS is a heterogeneous condition – this, in itself, is of course not a new assertion – but his suggestion that much of the heterogeneity seen in CFS is due to different kinds of infections, is not often heard.

The track record of enterovirus studies on CFS is similar to that other pathogens; the data is sometimes compelling and sometimes conflicting and problems with diagnosis (pathogen characterization) muddy the field considerably. Both PCR and antibody studies have had varying results, some suggest the rate of enterovirus infection is increased in CFS while others have not.

Since enteroviruses generally infect the muscles but muscle biopsies in CFS have shown little evidence of muscle cell necrosis (death) or inflammation, enteroviruses seem to be strange pathogen to build a case for in CFS. Chia, however, asserts that since exercise is a metabolic state that favors expression of the virus the low exercise levels of CFS patients are actually an avoidance mechanism to prevent activation of the virus. Their ability to do so keeps the viral populations at low enough levels to preclude the development of frank muscle damage. Thus it is possible that enteroviruses are present. The need for Immune activation to continually suppress the virus and its consequences such as sickness behavior (fatigue, fever, aching muscles, etc.) could account for many of the symptoms in CFS.

Even if CFS patients are able to eliminate the virus some evidence suggests this may not be the end of the story. Studies have indicated that enterovirus RNA can persist in muscle tissues long after the pathogen has been eliminated. Indeed the ability of the immune system to eliminate the virus but not viral RNA suggests different processes are used to clear the two from the system. Thus the immune systems of CFS patients could be effective at clearing the body of the virus but not of the RNA left behind by the virus. This could be a real problem given the ability of enterovirus RNA to spread throughout the organs of the body during an acute infection.

Chia believes that enteroviral RNA inside the cell can produce viral proteins (but not complete virions) that trigger the antibody response seen. Glaser has a similar theory regarding EBV. He points to a recent study of Sjogren's Syndrome, an autoimmune disease, that found increased rates of enterovirus proteins but not virions. In a study of 200 patients suffering from severe fatigue following a flu-like illness Chia found little evidence of HHV-6, EBV and CMV infection but frequent (@50%) elevation of neutralizing antibodies to enteroviruses (Coxsackie viruses and five echoviruses. Enteroviral RNA was found in the PBMC’s of 70% of these patients but only rarely in the blood. This presumably suggests it was not spreading from the PBMC’s to other sites through the blood? A large PCR study found enterovirus RNA was commonly found in CFS patients (n=236, 48%) but rarely in controls (n=118, 8%). Serial testing indicating that 38% of the CFS patients tested positive more than once suggested viral persistence occurred in a large subset of people with CFS.

Some evidence suggests that CFS patients have been able to only incompletely suppress the virus. One study that found a high proportion of ‘negative strain’ enteroviruses in CFS patients relative to controls (1:1 vs 100:1) suggested that defective control of enteroviral RNA synthesis could result in the persistence of a defective virus. This is a new twist altogether; Chia appears to suggest that incomplete immune interference with enteroviral syhthesis results in unusual forms of the pathogen in CFS.

A big question concerns why cells containing enteroviral RNA are not eliminated. Unfortunately Chia does not identify the immune processes responsible for eliminating aberrant RNA. He does suggest that enteroviruses could be hiding out long-lived ‘immunologically privileged’ cells such as macrophages, muscles, heart cells and neurons.

As with HHV-6 the success of treatment regimes designed to eliminate enteroviral infections probably provide the best evidence that these infections may play a major role in the pathology of a subset of the CFS patients. Chia reports that 8 of 14 severely ill CFS patients with enteroviral RNA in their leukocytes responded very positively to IFNa/b treatment. All relapsed, however, after the treatment was discontinued.

Although CFS patients have long reported their symptoms are greatly exacerbated by exercise. study findings during exercise have been inconsistent. While some studies have found reduced peak oxygen uptake, reduced peak heart rate and increased lactate levels others have not.

Few studies, however, have examined the immune functioning during exercise. As noted above Chia has posited that activation of enteroviral RNA in the muscles impedes exercise and causes fatigue in CFS. One study examining immune functioning during exercise found activation of a branch of the immune system called the complement system was activated in CFS. Another found that fragmentation of the antiviral enzyme, RNase L, was correlated with reduced peak oxygenation during exercise. This present study, which focused on the interferon (IFN) mediated immune response (RNase L, PKR) deepened the examination of immune functioning during exercise in CFS patients.

Viral production in a cell produces double-stranded RNA (dsRNA) and the activation of three components of the IFN response; the RNase L and PKR enzymes and Mx (click here). RNase L degrades viral mRNA and PKR activates various aspects of the immune system, that help to combat the infection. One of these is inducible nitric oxide synthase (iNOS), an enzyme which produces nitric oxide (NO) a compound that in the immune system plays a major role in macrophage cytotoxicity. Monocytes/macrophages, the main immune producers of NO, produce enormous amounts of NO when activated.

Nitric oxide up regulation has been proposed by several researchers (Pall, De Meirleir) to play a major role in CFS. De Meirleir et. al. have proposed that increased NO production in CFS contributes to exercise impairment by causing an inappropriate vasodilation of the blood vessels. Blood vessel dilation is usually accomplished through the activity of endothelial NOS, not iNOS. These researchers appear to suggest that monocytes/macrophages traveling through the blood vessels produce so much NO that they prompt the blood vessels to dilate.

De Meirlier et. al. have also proposed that a channelopathy caused by RNase L fragmentation (see A Channelopathy in CFS?) could impair muscle activity by causing outflows of magnesium from muscle cells. RNase L fragmentation has thus far been found only in two closely related immune cells; monocytes/macrophages. These researchers are, by suggesting that an RNase L induced channelopathy causes Mg outflows from muscles, appears to be proposing that RNase L fragmentation also occurs in muscle cells (?).

This study examined three facets of the IFN immune response; RNase L activity and fragmentation, PKR activity and NO production by monocytes/macrophages. Lastly intracellular levels of the protease, elastase, believed to fragment RNase L was measured. There was no control group.

Findings - The study indicated that the IFN immune response was activated during exercise. This in itself is a remarkable fact; why would the immune system be activated during exercise? Could Chia’s theory of enteroviral activation during exercise apply here? All the CFS patients displayed increased elastase activity and increased rates of RNase L fragmentation and 95% displayed increased RNase L activity. PKR activation was abnormally high in only about 30% of CFS patients and NO production by monocytes or macrophages in about 50%. Intracellular elastase is used by neutrophils to kill pathogens in its cell membranes.

A correlation analysis indicated that elastase and PKR activation were associated with reduced oxygen uptake, reduced workload and reduced peak heart rate and RNase L activity and fragmentation were associated with respiratory exchange ratio (RER) when it equaled I or at rest. RER is the ratio of the net output of carbon dioxide to the net uptake of oxygen. No link was found between NO production and any of the indices of exercise.

Analysis - The authors stated that the correlation between elastase and reduced oxygen uptake makes sense given elastase’s role in various respiratory diseases. Increased extracellular elastase levels contribute to the lung dysfunction in chronic obstructive pulmonary disease (COPD) and cystic fibrosis. This study, however, measured intracellular elastase production and the authors had some difficulties explaining how increased levels of intracellular elastase could contribute to impaired lung functioning. They did note that a former study finding bronchial hyperresponsiveness in CFS was associated with cytotoxic T-cell activation  (click here) and that Tc cells release elastase in order to ‘establish their cytotoxicity’. This appears to suggest that T-cell activation in the lungs could result in increased elastase levels and that could contribute to the reduced oxygen uptake seen.

This was the first time that I am aware of that elastase, the putative agent of RNase L fragmentation, has been measured in CFS. The high levels of elastase and their strong correlations with indices of exercise impairment suggest that immune activation by monocytes/macrophages plays a role in the exercise impairment found in CFS patients. PKR’s association with reduced workload and RNase L’s association with RER suggest that both components of the IFN response are also implicated in the exercise problems of CFS patients.

The problem is that without more information it is difficult to understand how and the authors gave us little help here. Increased levels of intracellular elastase could be linked to the RNase L fragmentation seen but association of RNase L fragmentation with RER was not addressed. The authors speculated that RNase L fragmentation could lead to depleted muscle magnesium levels but these were not measured.

This study was not as ‘full’ as one might have wished; the authors indicated that budgetary constraints resulted in a less than optimal sample size, there was no control group and some factors that might have shed some light on the studies findings (e.g. extracellular elastase levels) were not included. Budgetary constraints continue to handicap many innovated and committed CFS researchers.

by Cort Johnson

As part of an ongoing series of papers examining the pitfalls and promises of CFS research this paper examines the granting process involving the National Institutes of Health (NIH), the primary disburser of public medical research funds in the U.S.. In particular we examine the progress of a large ($4,000,000) stand alone (RFA) grant for CFS research. Request for Applications (RFA) are one-time events that seek research proposals on specific topics. This is the first RFA that I know of for CFS and it suggests the NIH has become a bit more serious about this disease.

There is no more critical problem for CFS patients than funding. The ‘1000’s’ of papers published on CFS over the past 20 years are frequently noted in discussions of the complexities and mysteries of this disorder. These reviewers rarely note, however, that scientific studies make up only a small fraction of these papers and that CFS, a multi-system disorder remains severely under funded relative to its needs. Any large grant devoted entirely to explicating the physiological mechanisms behind CFS is a cause for celebration.

Getting the grant, however, is only the first step. Using the money wisely to further our understanding of CFS is the next critical step. Both CFS advocates and NIH officials will chart the progress of the studies the grant funds closely. If the studies it funds are successful the NIH may be inclined to increase funding for CFS; if they are not, they may very well not. It is, therefore, very important that that the studies this grant funds have a good chance of explicating the biological processes underlying CFS.

In order to understand how the neuro-immune RFA came about and what we can expect from it we need to go back to the 2003 Conference on Neuroimmune mechanisms that inspired it. This conference was designed to foster new thinking on CFS and new, innovative, cross-disciplinary grant proposals for CFS research. Officials at the NIH have stated that one reason for the poor funding of CFS research have been the inadequate grant proposals offered them. Thus this conference, through its investigation of the dynamic interface between the central nervous and immune systems, was designed to jumpstart the field and open new ground.

This is important not only for CFS patients but also for CFS researchers. Grant proposal writing is a time-consuming and laborious process that researchers are not likely to engage in unless they have some expectation of success. By signaling or not signaling interest in their particular field of research conferences like these can turn on or turn off researchers.

It was surprising how few of the researchers speaking at this conference had done research on CFS. Ten of the fifteen speakers (Sternberg, Dhabhar, Lopez, Adler, Richardson, Toth, Opp, Park, Heitkemper, Arnold) had never published on CFS. One (Zubieta) published one paper 12 years ago and four speakers (White, Vernon, Jones and Klimas have published frequently on CFS. Of those a PubMed search revealed that none had published on neuroimmune issues in CFS. Klimas is an immunologist, Vernon has primarily done genetic research but has a strong background in immunology, Jones has done immune, genetic and epidemiological research and White has focused psychological studies on CFS. Gaab,

One cannot expect a conference designed to open up new avenues of research in CFS to consist solely of CFS researchers – that would be counter-productive. One does expect, however, that their talks address subjects germane to CFS and that a good mix of CFS researcher be present. This paper will address whether those needs were fulfilled.

Three emphases were present in the conference, stress and the HPA axis, the autonomic nervous system, sleep and cytokines, and ‘central mechanisms’.

Sleep and Cytokines - Some CFS patients do sleep poorly and many do not. Several studies indicate only minor sleep perturbations for CFS patients. The most recent CDC study on sleep found that ‘while (CFS subjects are) fatigued, CFS subjects are not sleepy". The recent NIH sponsored Buchwald twin sleep study found little difference in sleep quality between healthy twins and their CFS counterparts and stated "patients with CFS may mistake their chronic disabling fatigue for sleepiness". Indeed it is clear that poor sleep in itself cannot account for the magnitude of the fatigue seen in CFS; people with far worse sleep disorders than occur in CFS are not nearly disabled to the extent that many CFS patients are. Increased cytokine production can, however, contribute both to impaired sleep and to reduced wakefulness and fatigue. Results have been mixed but Klimas posits that poor laboratory techniques could account for some of the negative findings in CFS. Most of the presentations involved the role cytokines may play in disrupting sleep. None, unfortunately, attempted to  elucidate the role cytokine production can play in causing 'fatigue' a more central element in CFS. Evidence is accruing that cytokine production may play a major role in several fatigue disorders. 

Central Mechanisms - Remarkably, the session titled ‘Will Understanding Central Mechanisms Enhance the Search for the Causes, Consequences and Treatments of CFS’ contained two talks on Fibromyalgia, one on Irritable Bowel Syndrome and only one centered on CFS. That talk, which focused on gene expression studies, had little to do with the issues addressed by the conference. Several suggested factors in IBS (ANS dysregulation, increased serotonin activity) that may play a role in CFS as well were addressed. Zubieta's talk talk involving altered opioid neurotransmission and increased pain was engaging despite its emphasis on a symptom, pain, that is not particularly significant in CFS. Zubieta nevertheless painted an intriguing scenario that could have ramifications for CFS. 

CFS Researchers - Only three of the presenters (Klimas, Zubieta, White) were able to integrate findings from CFS research into their talks in a more than perfunctory fashion. Nancy Klimas’s talk on ‘Evaluating Immune Function in CFS’, is very important topic for those doing immune research in CFS, but did nothing to actually illuminate the neuroimmune interface. John Bar Zubieta’s talk involving opiate neurotransmission was engaging and was one of the few to present an explicit model for CFS. Peter White’s talk on ‘CNS and ANS Responses to Exercise in Patients with CFS’ was certainly germane to the subject matter of the conference but instead of suggesting topics for neuroimmune research in CFS, White’s conclusion that CFS was a ‘biopsychosocial’ phenomenon rather than a ‘biomedical’ one essentially foreclosed further exploration into this area. This could hardly have surprised the organizers of the conference who apparently went to some expense to ensure White spoke; he was the only presenter located outside the U.S.

Chronic Fatigue Syndrome (?) - Despite speaking at a conference on CFS there was actually little discussion of CFS in most of the talks. Researchers either did not (Adler, Opp) or hardly mentioned (Dhabhar, Kruger, Lopez, Sternberg) CFS in their talks. Remarkably, even the Chair of one session on the autonomic nervous system, another area of great interest in CFS, David Goldstein, was unable to relate any of his findings to those of CFS or to suggest fruitful avenues of research in his introduction to the field. His remarks on CFS were limited to one paragraph.

Indeed, if it were not for the conference title one might have had trouble discerning which disease this conference was on from the titles of the presentations. One wonders why the ORWH felt it important to include a talk on the ‘HPA Axis and Autonomic Nervous System Function in Fibromyalgia’, ‘Family Studies in Fibromyalgia’ and ‘The Cognitive Neuroscience of Fibromyalgia’ in a conference on CFS? There were as many talks reviewing FMS as CFS in the pathophysiology section of this conference. This does not mean these talks were not valuable but NIH sponsored conferences on CFS do not happen often and CFS patients and their advocates have the not unreasonable expectation that when one on CFS does take place that the focus will actually be on CFS.

Alternatives – While some of the talks were very informative there is an evolving field of research involving neuroimmune mechanisms and fatigue that was mostly ignored

Conclusions - This conference had a somewhat strange mix of presenters. While researchers with CFS experience were rare several researchers experienced in other CFS-like illnesses such as IBS and FMS were present. Several areas of potential interest were apparently ignored while the organizers focused on the HPA axis and sleep. The talks at the conference focused on the effects HPA axis alterations can have on the immune system; none, unfortunately, focused on the opposite situation  in which high cytokine levels can dysregulate the HPA axis. Little attempt, as well,  was made to specifically articulate neuroimmune models that could account for CFS. The presence of Peter White an advocate of a biopsychosocial interpretation of CFS was puzzling in a conference devoted not to psychological issues but to neuroimmune mechanisms.

Cleare AJ, Messa C, Rabiner EA, Grasby PM. 2005. Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635. Biol Psychiatry.;57:239-46.

Freeman R, Komaroff AL. 1997. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med. 102(4):357-64.

Gaab J, Huster D, Peisen R, Engert V, Schad T, Schurmeyer TH, Ehlert U. 2002. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med. 2002 64(2):311-8.

The GK, Prins J, Bleijenberg G, van der Meer JW.. 2003. The effect of granisetron, a 5-HT3 receptor antagonist, in the treatment of chronic fatigue syndrome patients--a pilot study. Neth J Med.;61(9):285-9.

Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. 2000. J Clin Endocrinol Metab. 85(2):692-6.

Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, Kuratsune H. 2003. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochem Biophys Res Commun.311(2):264-6.

Stewart JM. 2000 Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res. 48 :218-26.

Streeten DH, Thomas D, Bell DS. 2000. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci. 320(1):1-8.

Visser J, Graffelman W, Blauw B, Haspels I, Lentjes E, de Kloet ER, Nagelkerken L. 2001. LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. J Neuroimmunol. 119(2):343-9.

Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L. 2001. Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors.
J Investig Med. 49(2):195-204.

Visser J, Blauw B, Hinloopen B, Brommer E, de Kloet ER, Kluft C, Nagelkerken L. 1998.CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone. J Infect Dis.177(2):451-4.

Yamamoto S, Ouchi Y, Onoe H, Yoshikawa E, Tsukada H, Takahashi H, Iwase M, Yamaguti K, Kuratsune H, Watanabe Y.. 2004. Reduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport. (17):2571-4.