http://clinicaltrials.gov/ct/search?term=chronic+fatigue+syndrome

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

The 8th International IACFS Conference on Chronic Fatigue Syndrome, Fibromyalgia and Other Related Illnesses is just a year away and will take place from January 11-14, 2007 at Ft Lauderdale Fl.

"This four day scientific medical conference will focus on integrative themes such as fatigue, pain, sleep, cognition & brain function. Each session will ask what is the science of the area (e.g. fatigue, pain etc), and close on the practical applications in the art of clinical medicine. There will be a panel discussion on the new pediatric case definition, and lectures on latest research, newest clinical protocols, a session on what genes can teach us and other innovative recent advances." Is it not time for a yearly conference?

We all want our charitable dollars to go as far as possible. As CFS patients we in fact need to be able to maximize our contributions. Three CFS patients in the U.K. have just made it easier to do so. These three individuals will donate money every time someone sets up a ‘standing order’ (monthly contribution) to MERGE, the outstanding CFS research group in the U. K., from February through the end of May. MERGE, which receives no governmental funding, relies completely on charitable donations to continue its work. The way I see it – the more work MERGE does, the better I chance I have of getting well before I hit the grave. You can access their announcement by clicking on the below url , and download the standing order for MERGE by clicking on this URL http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0601B&L=CO-CURE&P=R1797&I=-3

 and access MERGE's standing order form by clicking on below

From the press release - "Invest in ME (IiME) is publishing on its web site the ITV Meridian programme which shows the devastating affects of ME on whole families. In a programme made by Meridian Television severely affected sufferers explained the devastating effect the illness has had on them and their families. Despite the vast number of sufferers…the Government has given no money for bio-medical research, choosing instead to squander £11.2 million by setting up ME/CFS centres to deliver programmes of Cognitive Behaviour Therapy (CBT) and Graded Exercise Therapy (GET). Doctor Jonathon Kerr of Imperial College, London has recently found that in people with M.E. there are 15 genes which are 4 times more active than in healthy people, which indicates that their immune system is working overtime. In the programme he says he is confident that he will have a cure within a year.

To see the programme on-line and for more detailed information on the condition and problems faced by Suzy and Lauren and thousands like them, visit www.investinme.org or go direct to the Meridian link at http://www.investinme.org/Mediatelevision.htm#Meridian_TV_–_ME_Expose

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

Every month the editor picks out what he, based on his admittedly limited understanding of CFS, believes to be the most important paper published that month for an in-depth examination. In this month’s paper we find that investigators are getting at the source of the natural killer cell dysfunction present in CFS patients.

While attempts to find a single pathogen responsible for CFS have failed, there is considerable evidence (increased markers of lymphocyte activation, and increased production of pro-inflammatory and Th2 cytokines) that the immune systems of CFS patients are reacting to something. Some indices of immune system functioning have been difficult to replicate but impaired Natural Killer Cell (NK) functioning (cytotoxicity - cell killing ability) has consistently been seen.

This study measured both NK cell numbers and cytoxicity and attempted to ascertain the cause of the reduced NK cell killing ability in CFS patients by assessing the levels of perforin, an important killing agent.

Natural killer cells are a white blood cell (lymphocyte) involved in the innate immune defense system. They troll the bloodstream looking for cells that display signs of cancer or infection. Unlike T and B cells which need time to mount a response NK cells are always on the alert and are ready to attack. They are amongst the first immune cells invaders typically encounter and they are responsible, among other things, for keeping the invaders in check before the adaptive immune response involving T and B cells kicks in. They are typically activated by cytokines produced either by infected cells (interferons) or by macrophages.

Patients deficient in NK cells prove to be highly susceptible to the early phases of herpes virus infection. Mice engineered to be perforin deficient are less able to clear viruses and tend to produce autoantibodies that attack the mouses tissues.

This study indicates that the perforin content and thus the killing ability of two major immune cells are reduced in CFS patients. The immune activation seen in conjunction with the reduced cytoxicity exhibited by both the NK and T-cells in this study suggested to these researchers that the NK and T cells had essentially suffered burnout! The authors proposed that the lymphocytes in CFS have been activated for so long – and have presumably killed so many infected or damaged cells – that they have basically begun to run out of ammunition.

Studies examining NK cell function in chronic hepatitis C and HIV found that just this process has occurred. HIV researchers have gone so far to as to examine perforin expression in different subsets of cytotoxic T-cells. Since HIV is a disease of immune suppression HIV patients often support different types of pathogens. Since cytotoxic T-cells are pathogen specific it is possible to segregate cytotoxic T-cells according to the type of pathogen they are primed to attack. In this case HIV researchers found that perforin expression in HIV patients was low only in cytotoxic T-cells that were primed to attack HIV, not those primed to attack a less virulent pathogen, cytomegalovirus (CMV). This demonstrated that reduced perforin expression in these patients was probably due to ‘overwork’. (Isn’t amazing what you can discover when you have sufficient funding?)

Other potential consequences of reduced perforin levels - Increased pathogen levels are not the only potential consequence of reduced perforin levels. Two disorders characterized by very low perforin levels, hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), result in increased T lymphocyte and macrophage levels and activation. Researchers speculate that increased pathogen levels due to poor NK cell functioning could result in an excessive antigen driven T-cell activation; simply put, the failure of NK cells to dampen down an infection results in an exaggerated T-cell attack when it occurs. T-cells produce a number of cytokines (IFN-y, granulocyte macrophage stimulating factor (GM-CFS)) that could result in high macrophage activation.

MAS is found to at least some degree in many rheumatic (joint and muscle) diseases, and, of course, CFS patients often are plagued by joint and muscle problems. In MAS, the destruction of red blood cell precursors due to high levels of activated macrophages in the bone marrow, results in low red blood cell levels, anemia and, at times, an aplastic crisis. CFS patients do not undergo aplastic crises but do sometimes exhibit reduced red blood cell mass. Could the reduced red blood cell mass in CFS be due to perforin dysfunction and chronically increased levels of activated macrophages in their bone marrow?

Ongoing Research – None known.

NK cell dysfunction has been of interest in CFS from the beginning. The first paper describing NK cell dysfunction in CFS was only the second paper ever published on CFS*. Since then reduced NK cell functioning has been one of the very few immune abnormalities consistently seen in CFS. There has been much huffing and hawing in the scientific community over the inconsistent study findings in CFS and how heterogeneous the patient population is, etc. and one could understand some reluctance to commit precious research funds to such a confusing disorder. But poor NK functioning has, with only a few exceptions, been consistently been found in CFS. One might expect that when researchers found something consistently abnormal in CFS, the public research institutions would take note of it and focus on it. One might think that twenty years later the cause of this distinctive dysfunction in CFS would have been well researched by now.

But this is not so at all. There has been no coterie of researchers chipping away at the question of NK cell dysfunction, no research group intensely focused on why this part of the immune system is impaired in CFS. Research into NK cell functioning has exhibited the same slogging, mediocre pace of most of the other research efforts into CFS. Instead of a concentrated widespread effort we have a small group of researchers that have been intermittently but innovatively chipping away at this problem. We are very lucky to have them - we depend on them and groups like them for so much! - but it has taken us far too long to get to where we are today. Only now, almost twenty years after we discovered NK cell functioning is a problem in CFS, are we beginning to get at the source of that problem, and we really are just at the beginning. Now that we know the NK cells in CFS patients are low in perforin we need to find out why and find ways to resolve it. In how many other diseases would this have taken so long? Twenty years is a long time to be ill. That’s a lot of water under the bridge – a lot of suffering by a lot of people.

Read the timeline below and weep. This is one reason why you and I are still ill today. Histories like this occur when public research institutions are not serious about resolving medical issues. They occur when too few research funds are spread among too many researchers. In CFS NK cell research must compete with a vast number of other research interests including genes, gene expression, protein expression, cortisol, DHEA, serotonin, HLA markers, acetylcholine, RNase L, orthostatic intolerance, corticomotor excitation, oxidative stress, cytokines, vascular abnormalities, red blood cell levels, low blood volume, cardiac abnormalities, etc., etc. not to mention the tremendous amount of money going to epidemiological research and cognitive behavior type studies and psychological research! The funding pie is simply too small and our research needs too large for any but the really hot topics to move on at an acceptable pace. This is why it can literally take decades to accomplish in CFS research what takes a few years in other well-funded diseases.

This is why we need to be as vocal and supportive as we can be with our time and our money in ensuring that public research institutions display the commitment and private research institutions such as the CAA, MERGE and the CFS Research Foundation have the money they need to uncover the cause of and treatment for this illness. Do we want to wait another twenty years for the next breakthrough in CFS to occur?

Two of the studies listed below (Tirelli et. al. in 1994, Ogawa et. al. in 1998) found abnormalities in other aspects of NK cells (NK cell subset abnormalities, L-arg enhanced NK cell activity). Normally one would expect that ‘successful’ studies, i.e. ones that in which their thesis was proved correct would receive a follow up, but this has not been true at all.

1987 –NK cell number and cell killing ability (cytoxicity) low in CFS (Caligiuri et. al.).

1990 – High NK cell number and low NK cell killing ability (Fletcher, Maher et. al.)

1991 – Reduced NK cell levels (Gupta and Vayuvegula)

1993 – NK cell number normal (Straus et .al.)

1994 – NK cell number normal, reduced NK cell activity (Barker et. al.)

1994 – Low NK cell activity correlated with symptom expression in CFS (Ojo-Maize et. al.)

1994 – NK cell number and activity reduced (Masuda et. al.)

1994 – NK cell activity normal (Rasmussen et. al.)

1994 – Reduced NK cell number, atypical expression of NK cell subsets, increased levels of adhesion markers (Tirelli et. al.)

1997 – NK cell number and function normal (Mawle et. al.)

1997 – NK number increased (Peakman et.al.)

1998 – Low NK cell activity in family with CFS (Levine et. al.)

1998 – NK cell number normal (Natelson et. al.)

1998 – The inability of L-arg to enhance NK cell activity in CFS patients relative to controls suggests a dysfunction in nitric oxide mediated activation of NK cells (Ogawa et. al.)

2001 – NK cell number low (Racciatti et. al.)

2002 – NK cell activity reduced (Masuda et. al.)

2002 – More sensitive test for measuring intracellular perforin developed (Maher, Klimas et. al.)

2005 – NK cell number normal (Robertson et. al. )

2005 – Nk cell number and killing ability reduced, proximate source of NK cell dysfunction identified (Maher, Klimas, et. al.)

NO ORTHOSTATIC INTOLERANCE IN CFS?

(but perhaps something else?)

Let’s not mince words here. This is one of the most disappointing papers to appear on CFS in quite some time. A great deal of work has suggested that orthostatic intolerance (OI) – the inability to stand without having symptoms – occurs in at least a significant subset of CFS patients. Past studies have suggested that between 20% and 90% of CFS patients have OI. Several studies, some of them quite large, are currently underway trying to figure out the cause of the OI in CFS¼ .and now the CDC steps in (at this rather late date) and says, Oh, OI? It’s no more commonly found in CFS than in the general population. This is the kind of study that makes you just want to throw up your hands and scream.

The CDC measured heart rate and blood pressure (BP) during standing and heart rate, BP, oxygen saturation, respiratory rate and ECG during the tilt table test as well as various laboratory measures (plasma renin, aldosterone, norepinephrine, serum osmolality, BUN, etc.) often correlated with OI.

None of the laboratory measures or indices of orthostatic intolerance were significantly increased in CFS patients. Nor was symptom expression; the control group actually exhibited a greater prevalence of symptoms of orthostatic intolerance than did CFS patients (!). In fact, even though it wasn’t significantly different, a far greater percentage of the healthy controls had some form of OI (NMH, POTS) than did CFS patients (58-30%). When the time to orthostatic intolerance was measured CFS patients did not more rapidly proceed to neurally mediated hypotension (NMH - low blood pressure) or postural tachycardia syndrome (POTS – rapid heartbeat) than did the healthy controls.

The study also indicated that the stand up tilt test often used by physicians to assess OI in lieu of doing a tilt table test was not a good predictor of tilt table performance.

There was one bit of intriguing news. A significant correlation of serum osmolality with the time to OI in both groups indicated that low blood volume is related to orthostatic intolerance. Serum osmolality is a measure of hydration. Reduced red blood cell mass has been positively correlated with low blood volume. Decreased blood volume could be due to a variety of factors including impaired vasoconstriction and blood pooling. Since these effects can take a while to kick in this suggests a mechanism whereby CFS patients could tolerate standing at first but eventually fade over time.

We weren’t done with disconcerting news about OI, however – a report on the prevalence of OI in Gulf War Syndrome also appeared last month¼

This study examined the prevalence of neurally mediated hypotension (NMH, low blood pressure upon standing) and postural tachycardia syndrome (POTS, increased heart beat upon standing) in GWS patients, Gulf War veterans without GWS and veterans who did not serve in the Gulf War. The GWS patients had to meet a criteria that was similar to CFS but not as strict; they had to have fatigue plus 2 of the following symptoms; impaired cognition, headaches, joint pains without swelling, unrefreshing sleep and post-exertional fatigue.

This study found that while there appeared to be a gradient in the prevalence of NMH with GWS patients displayed the highest and non Gulf War vets displayed lowest rate of it, the results were not statistically significant. The incidence of POTS was the same in both groups.

The GWS did display some altered physiological parameters, however. Palpitations occurred in 2/3rds of them compared to 6% of controls and they had a higher respiratory rate (breathing) and lowered tidal CO2 than the non-deployed vets. The number of symptoms evoked during the tilt testing was also much greater in the GWS patients. Thus, while the incidence of OI in these patients was not increased, they did react differently to the tilt tests than did the healthy controls.