Talk:Myalgic encephalomyelitis/chronic fatigue syndrome

Alcohol Intolerance; a vital clue !

Have researchers missed a vital clue in CFS? “The Cause of Chronic Fatigue Syndrome; Light at the End of the Tunnel” Author David Eather. ISBN 0646389025 David is a CFS sufferer who ‘discovered’ a treatment for his form of CFS. He interested academics and they worked out the biochemical processes involved. He then self published the book himself in 2000 but is now out of print? As several have expressed a passing interest I have prepared this summary only.

Essentially the book is an hypothesis, that blames CFS symptoms on build up of acetylaldehyde in tissues. He begins by comparing the symptoms of CFS in the book by Dr Anne McIntyre “ME Post-Viral Syndrome and how to live with it” ISBN: 0044403186; Paperback; 1989-04) with the symptoms of an ‘aldehyde reaction’ had by people born without the enzyme to break down aldehyde (after consuming alcohol) and points out the remarkable similarities, with CFS. Ref for Reaction is a Pharmaceutical Product Guide for product Antabuse First some biochemistry, in the mitochondria alcohol is broken down to acetyl-aldehyde by the enzyme ‘alcohol dehydrogenase’ then into acetic acid (vinegar) by “aldehyde dehydrogenase” 90% of alcohol is converted in liver mitochondria but in muscles also. Now during aerobic glycolysis also in the mitochondria, during pyruvate conversion to Acetyl CoA, amounts of acetyl alderhyde escape from the ‘pyruvate dehydrogenase’ enzyme. In the healthy the ‘alderhyde dehydrogenase’ enzyme cleans this up. But his hypothesis for CFS is that the mitochondrial ‘alderhyde dehydrogenase’ enzyme is faulty.

The book goes on to explain how acetylaldehyde a very toxic substance damages cellular membranes and causes various symptoms of CFS. Muscles, brain, liver, crosses the blood / brain barrier, affects neurotransmitters and causes tinnitus. Explains why patients have chemical sensitivity to substances that give off acetelalderhyde or formalderhyde. Explains how acetylaldehyde combines with NAD and reduces anaerobic energy, thus compromising two energy processes. When NAD is tied up alternative pathway cytochrome P 450 is activated to clear chemicals and this produces more toxic by-products in much the same way as seen in chronic alcoholics. L-Methionine is supposedly a standard treatment for acetylalderhyde poisoning, and for alcohol liver damage. Nicotinamide replaces tied up NAD and eases some symptoms, but he suggests should be used with caution, lest exuberance produces more acetylalderhyde. I think it may be the same subset who benefit from NADH treatment. PMID 10071523 PMID 15377055 if so this hypothesis provides an explanation for these trial results. Reference for alcohol intolerance in CFS is Dr Clive Sheperd “Living With M.E.” ISBN 0091816793; Paperback; 1999-02-01) Who apparently says ‘if there is no alcohol intolerance there is not CFS”. Note this theory also explains vinegar sensitivity/intolerance in CFS. Jagra 11:11, 1 October 2007 (UTC)

A request for accuracy, please. It is Dr Anne Macintyre; it is Dr Charles Shepherd - not Dr Clive Sheperd! MEagenda 16:44, 9 October 2007 (UTC)

So those two trials (26 and 31 patients) show some benefit for NADH, but were they conducted to test Dr Sheperd's hypothesis? "Have researchers missed a vital clue in CFS?" - if the hypothesis has not been adequately tested then they may have. Is this mirrored by increased incidence of CFS in populations with known reduced acetaldehyde dehydrogenase levels, such as the Japanese? And your comment on vinegar makes no sense at all - vinegar is acetic acid, which is what acetaldehyde is converted to by ALDH! Are you suggesting the enzyme works backwards (which is not in itself impossible). Online Mendelian Inheritance in Man (OMIM): 100640 is a useful read. JFW | T@lk 12:09, 1 October 2007 (UTC)

JFW, the OMIM data you linked says the mitochondrial form is ALDH 2 and that has high affinity for NAD, and is deficient in 50% of Orientals, I agree it would be interesting to compare. Do we have statistics for incidence of CFS in Japan? By coincidence it seems the first NADH trial was published about the same time as Dr Sheperd’s book, but predated David Eather’s hypothesis by about a year, so I doubt the hypothesis has been fully tested, certainly they did not include all elements such as the L-methionine in either trial. Indeed the biochemical pathways show the aldehyde dehydrogenase enzyme as two way, but in addition David explains the sequesting of NAD partly shuts down the KREB cycle so any dietary vinegar has no where else to go? The supplementary NADH replacing that produced normally by the KREB cycle. Where as David's approach was to increase NAD and kick start the KREB cycle to produce NADH. Testing both approaches on the same responders would further test the hypothesis? Jagra 11:38, 2 October 2007 (UTC)

I don't think this is the forum to set up trials, but I wish you luck in getting this looked at. JFW | T@lk 22:28, 6 October 2007 (UTC)

La Fourchette

Ronline (talk · contribs) unilaterally split off the "treatment" section into a new article. I have reverted on several grounds; futher explanation is here on Ronline's talkpage. JFW | T@lk 12:09, 1 October 2007 (UTC)

I think the article could be slimmed down some, before any talk of splitting. Although I'm sure even that will not be an easy task. Certainly discussion is needed before any significant action is taken. (This is the only article I have ever come across in Wikipedia which doesn't like to load properly on any browser I've tried.) Cheers. --- Taroaldo 19:58, 1 October 2007 (UTC)

I'm not so sure to be honest. I think its a very, very complex subject, surely it needs a very long article? Just a thought Thedreamdied 20:15, 1 October 2007 (UTC)

Agree with Taroaldo that the article should be slimmed down, not forked to bits. As I told Ronline, the "treatment" section depends on other parts of the article for clarification (e.g. immune boosting for immune deficiencies, fludrocortisone for orthostatic intolerance).

There are large swathes of the article that haven't been reviewed properly by anyone for months. I'm referring to the bit where the references have no PMID/DOI codes. Perhaps that is the content that should be examined closely for redundancies. JFW | T@lk 20:40, 1 October 2007 (UTC)

How about two pages....page one.....summary of article sections for those casual searchers....page two....detailed article like we have now. Page one can be protected ......page two unprotected....that would serve both purposes....page one quick read...page two for what is thought/known and for changes....have fun....sno —Preceding unsigned comment added by Sno2 (talk • contribs) 20:52, 1 October 2007 (UTC)

The bulk of the article is contained within two sections ("proposed causes and pathophysiology" and "treatment") and these sections are related (as JFW pointed out). Much of the treatment is also "proposed" as well and not universally accepted. Considering that these two sections take up a lot of space and are related, perhaps they can be forked together onto a page titled "proposed pathology of and treatments for CFS". Some areas could use a trim, but other areas could be expanded on. A single page would be ideal, but is this practical or likely to become much better any time soon? Other medical articles have separate pages for different aspects of the illness (e.g. diabetes and schizophrenia). I've never had trouble loading this article, but several other editors have expressed issues with it, which could mean that many other people who visit here also have trouble with it. - Tekaphor 03:12, 2 October 2007 (UTC)

I think the problem is editing the article. I have never had problems loading the article, but sometimes if I edit the whole article (rather than individual sections) it takes a very long time or hangs when submitting changes. I think we should seriously trim the "proposed" bits and only have summaries of things that are speculative. --Sciencewatcher 21:44, 5 October 2007 (UTC)

I firmly support the removal of outlandish theories, but I don't think it will happen without a fight. JFW | T@lk 22:29, 6 October 2007 (UTC)

Notable cases

A new name was added to the names list so I checked it out; the reference doesn't describe any illness, and a search on the person (news articles, her own blog and biography) mentions nothing about CFS, it only mentions anorexia and even mild stroke. Therefore I removed it. The name list has gone wild and unchecked. Due to the "internet copy and paste effect" many other websites have been citing Wikipedia for these names, and people are assuming in good faith that it is accurate. Going through this list requires checking out related Wikipedia entries for references or finding new references; but I'm sure we all have more important things to do than solely dedicating ourselves to this one task, so perhaps we all need to help out with a few names each. - Tekaphor 04:11, 2 October 2007 (UTC)

Chocolate Cure

Just thought i'd bring up something i found on the bbc website that i think is relevant: [1] —Preceding unsigned comment added by 84.68.64.84 (talk) 18:40, 2 October 2007 (UTC)

Well, we know chocolate is addictive and gives a mood lift especially it seems to the ladies!, this is done thru increased Serotonin. Now it may be that there is a subgroup of CFS patients with high cortisol, but these have not been isolated in studies to date! Increased serotonin a neurotransmitter, means further reduced cortisol. After all that is how Tricyclic antidepressants work (increase serotonin reduce cortisol). 'Can't hurt', I would not be too sure about that! Jagra 11:00, 4 October 2007 (UTC)

Dark chocolate contains flavonoids that are good for the bloodstream and work slightly anti-inflammatory. Combined with sugar, however, the total effect of chocolate quickly turns bad. Guido den Broeder 11:10, 4 October 2007 (UTC)

Interesting. So are we saying that the above link has at least some merit? I am interested in this as i myself suffer from CFS, and would be glad to make the switch to dark chocolate if there is a good chance it would help at all, even in the slightest bit.

Being a full time student really puts a strain on my energy levels, and any help or additional info would be welcome! - original link submitter

Jagra

At first glance, an excellent new section i think! although could you explain what this "Beta-endorphin a natural pain killer is considered low" means for me please? Thedreamdied 12:19, 3 October 2007 (UTC)

Beta-endorphin is a natural opioid, the reason morphine acts in humans is because it targets cell receptors in the peripheral and central nervous system, meant for our own opioid. CFS is considered a pro-inflammatory condition, cortisol suppresses inflammation, in CFS cortisol is low. Certain immune system changes such as cytokines are pro-inflammatory, essential fatty acid metabolite ratio changes in CFS such as increased LTB4 are pro-inflammatory and so on. With increased inflammation goes increased pain, lower circulating opioid means the pain is felt more, whether this translates to more central sensitization I cannot say. Beta-endorphin also has immune system and neurotransmitter function, the authors of the paper cited say “This finding may reflect the condition of chronic immune activation in CFS” and “Therefore, we would postulate that the fatigue and weakness typical of CFS could be related to low beta-endorphin concentrations at the central nervous system level.” It is found in neurons of the hypothalamus, as well as the pituatary gland, in this regard the latest findings of the CDC in classes of unexplained chronic fatigue, found alterations in gene expression of POMC a precursor polypeptide synthesised in the hypothalamus and pituatary glands that can be cleaved to form products including beta endorphin a natural opiod and pain killer, as well as ACTH which stimulates the adrenal glands to produce cortisol and other hormones. PMID 16610949. So I think it is a consequence rather than the cause! Jagra 10:43, 4 October 2007 (UTC)

Pain in CFS is, however, primarily caused by the build-up of lactic acid, not by inflammation. Guido den Broeder 10:53, 4 October 2007 (UTC)

Yes it seems lactic acid increase is normally associated with increased beta-endorphin PMID 7836218 presumably to reduce pain, so less b-endorphin in CFS also goes to more exercise induced muscle pain as well as more inflammatory pain, viz. in joint pain and probably spasm induced pain, trigger points etc. The beta-endorhin findings in CFS and Fibromyalgia also differentiate from findings in Depression PMID 12131069 I probably should add this ref to the article as well.Jagra 11:52, 4 October 2007 (UTC)

IIRC there is research that shows that abnormal pain perception in CFS only occurs if there is comorbid Fibromyalgia. Regards, Guido den Broeder 12:56, 4 October 2007 (UTC)

b-endorphin is released along with acth in the pituitary as part of the hpa axis, so this again could be related to the hpa axis. Also, there is research showing that fibromyalgia patients tend to have hpa axis overactivation (which could explain the pain) and cfs tend to have underactivation. However I don't know if this research has been replicated or applies to all patients, and it confuses things when you consider that there is a large overlap between cfs and fibromyalgia anyway. The dysfunction is likely to be in the brain, so I don't think we're going to get any real answers until we can look at individual neurons inside the brain in patients to see what is happening. Possibly the hpa axis is normal most of the time, but goes out of whack only during (or after) periods of physical or mental stress. So the only way you're ever going to see what is going on is to somehow look inside the brains of patients 24 hours a day and see what is going on and how it corresponds with symptoms. And I don't see this happening any time soon. --Sciencewatcher 21:40, 5 October 2007 (UTC)

Sciencewatcher, I am unable to find any studies showing high circadian cortisol, acth, or high beta-endorphin in fibromyalgia, can you provide ref? Jagra 09:48, 9 October 2007 (UTC)

This particular dysfunction is situated in and at the mitochondria, although lactic acid will build up in the brain as well. Guido den Broeder 00:36, 6 October 2007 (UTC)

At the 8th International Association for CFS/ME conference, Dr Nestadt discussed his findings of ventricular lactate levels: about 3 times higher in ME/CFS patients than in generalized anxiety disorder patients and about 3.5 times higher than healthy controls, plus this increase correlated with self reported levels of fatigue. Nestadt believes there is a shift to anaerobic metabolism, mitochondrial compromise and increased oxidative stress. The study is now in a larger more comprehensive second phase. - Tekaphor 02:20, 6 October 2007 (UTC)

Tekaphor, that fits with David Eather's acetaldehyde hypothesis, mitochondrial compromise and less aerobic puts more reliance on anaerobic energy. Do you have any ref's for Nestadt's work other than conference? Jagra 09:48, 9 October 2007 (UTC)

Jagra, unfortunately I was unable to locate a proper citation, perhaps it hasn't been published. If they publish the larger more comprehensive study, it will be a good reference for the neurological section. - Tekaphor 02:54, 10 October 2007 (UTC)

More forking, splitting, disambiguating

Jklsc (talk · contribs) is an infrequent contributor who has on numerous occasions made rather sweeping moves. I just noticed that on 1 September he changed the page myalgic encephalomyelitis into a redirect to the improperly (capitals) named page, and on the same day turned Myalgic Encephalomyelitis into a separate page that had previously redirected here. Angus Lepper (talk · contribs) subsequently removed large swathes of information directly lifted from certain websites.

I find it really unhelpful to have multiple articles. I am completely aware of certain voices that insist that ME is a distinct entity from CFS, but these voices happen to be in the minority even in the CFS/ME research community. I am fully supportive of mentioning these voices here, but I think having a separate article very much clouds the issue and just adds to fragmentation. Can we please settle the matter once and for all? JFW | T@lk 06:42, 7 October 2007 (UTC)

On a separate note, thanks to Guido for boldly removing several kibibytes of unsourced cruft. JFW | T@lk 06:42, 7 October 2007 (UTC)

My pleasure. ;-)

No matter can be settled 'once and for all' on Wikipedia. But I still prefer a separate article on Myalgic encephalomyelitis. CFS, is after all, only a working diagnosis. The CFS article could then focus on criteria, symptoms and management, while the ME article could focus on causes, risks and treatment. Guido den Broeder 09:18, 7 October 2007 (UTC)

Are you suggesting ME is not a working diagnosis? Surely, unless MRI or EEG/EMG show changes suggestive of an inflammatory process, or a biopsy is performed (quod non), it is sheer conjencture to suggest an ME patient has -itis of his encephalon and his myelum?

The problem with a separate ME page is that it will immediately become a POV fork, free from the constraints of our present carefully-established editors' panel? A large majority of scientists seems to regard itself as "lumpers" (putting CFS/ME/PVFS in one melting pot) as opposed to a handful of "splitters". Why otherwise would the journal have been called Journal of Chronic Fatigue Syndrome (as opposed to J Myalg Encephalomyelitis)? And I think we can count large names like Leonard Jason, who uses the term without apology in an Arch Intern Med article of which he is the first author. JFW | T@lk 20:30, 7 October 2007 (UTC)

That is correct. ME is not a working diagnosis but a disease entity. Guido den Broeder 21:48, 7 October 2007 (UTC)

So how am I expected to differentiate ME from CFS? Do a brain biopsy looking for an inflammatory process? JFW | T@lk 16:54, 8 October 2007 (UTC)

You can't. It's the same patient (unless you're counting GWS as CFS, too), just a different type of diagnosis. The ones without ME will, once found out, lose the CFS label. Guido den Broeder 18:30, 8 October 2007 (UTC)

You have not answered my question. If encephalitis or myelitis cannot be demonstrated during the patient's lifetime, how can we possibly label them with such a diagnostic label? Encephalitis and myelitis both have characteristic findings (on MRI/EEG and EMG/MRI/NCS, respectively), which to the best of my knowledge are usually absent in people who have received the diagnosis "ME". I have great difficulty with this. Please clarify. JFW | T@lk 19:37, 9 October 2007 (UTC)

It can be done with a scan from inside the skull, I suppose, but I wouldn't recommend it today. What we need is a nano-scanner. However, ME causes certain measurable characteristics other than the CNS inflammation itself. Guido den Broeder 20:11, 9 October 2007 (UTC)

You're being very coy, Guido. Perhaps you could tell us these characteristics? Thedreamdied 20:16, 9 October 2007 (UTC)

"C.F.S." vs "M.E."

Regardless of the issue of central inflammation, or whether they are the essentially same illness, or about the accuracy of ME-itis; the last 20 years has been vastly dominated by CFS research that didn't require several key ME symptoms in the study participants. By comparison there isn't much ME research in existence and most of that is decades old, so while people can point out that evidence for many claims about ME/CFS is lacking, we are faced with the fact that a lot of needed research simply hasn't been done. Unless such research is conducted that uses strict criteria and looks for all currently known possible signs of CNS inflammation, merely saying "the evidence is lacking" is unlikely to discourage ME proponents from referring to the older research and the CNS inflammation found more recently in some patients who died. Perhaps there could also be a larger "CFS vs ME" subsection in the article (as well as a subsection for "CFS vs chronic fatigue").

Leonard Jason may be a "lumper" as JFW implies, but his work and comments highlight the existence of subtypes, problems with the name, and the weaknesses of currently used criteria. We can't expect all ME/CFS patients to have the same pathology or response to treatments, in a similar way this isn't done for all tumour or all depression or all cerebral palsy. He also found the Canadian 2003 definition distinguishes patients with less psychiatric comorbidity and more physical impairment with more neurological symptoms, which questions previous assumptions from other researchers that increasing the requirement of somatic symptoms in CFS criteria necessarily increases the association with psychiatric disorders. Most of all this is essentially already mentioned in a section of the article but could be better reflected through the rest of the article as Bricker previously stated.

Tekaphor 03:43, 9 October 2007 (UTC)

Could you give us a citation for the Jason study that uses the Canadian guidelines to differentiate the patients with psychiatric comorbidity? That could actually be very useful in clinical practice! JFW | T@lk 19:37, 9 October 2007 (UTC)

I don't think the Jason et al study 'differentiates the patients with psychiatric comorbidity' as such. But this is the reference: Jason L.A. Torres-Harding S.R. Jurgens, A. Helgerson, J. "Comparing the Fukuda et al. Criteria and the Canadian Case Definition for chronic Fatigue Syndrome". Journal of Chronic Fatigue Syndrome 12(1):37-52, 2004.

A shorter article for the patient community by Jason: Jason, L. Comparing the Canadian Clinical Definition and the Fukuda Criteria For Chronic Fatigue Syndrome , "Quest", National ME/FM Action Network #67, 2004. Available on: http://www.mefmaction.net/default.aspx?page=consensusjasonstudy Also available on the One Click Website, Archive number 614.

The Jason et al study and the usefulness of the Canadian Guidelines in identifying patients with more severe physiological impairment has not been utilised by NICE: now 'fatigue' and one other symptom is all that is needed to get a diagnosis of 'CFS/ME' according to them. Angela Kennedy 22:06, 9 October 2007 (UTC)

JFW, 10.1300/J092v12n01_03 is in the "Issues with the definitions/criteria" section under "Improving accuracy". There are several reasons why some patient groups prefer these guidelines, with this study being an example. - Tekaphor 03:04, 10 October 2007 (UTC)

NICE criticism sources

Sources offered for consideration:

• Shepherd C (2007), "ME guideline is unworkable", British Medical Journal 335 (7619): 528-528
• Den Broeder G (2007), "NICE guideline", Lees ME #3, ME/CVS Vereniging, 32-35 (in Dutch)

Guido den Broeder 22:01, 7 October 2007 (UTC)

Hmm. WP:COI applies to the second source, which is in Dutch, for a public not affected by the Guideline in any form or description. Nice. And really suitable for the article, Guido.

Dr Sheperd's reaction in the BMJ (PMID 17855294 ) is predictable. Does he honestly suggest that the trials with GET and CBT were falsified by the trialists? Then why would patients' organisations get such radically different results from the groups that performed the trials?

The letter does not indicate whether Dr Shepherd has written this latter on behalf of the ME Association or a titre personnel. If it was the official response from this large ME charity then perhaps it would be a useful source. JFW | T@lk 16:54, 8 October 2007 (UTC)

Not sure if I'm allowed to put the Dutch reference in. On nl:Wikipedia, I am presently hanging from the highest tree for being so bold with another publication, even though relevance had been established.

The ME Association's position seems equal to Shepherd's, from their press release[2]. Guido den Broeder 18:26, 8 October 2007 (UTC)

But you haven't quoted the ME Association website, you have quoted Suzy Chapman's blog. No attempts have been made in that blog post to provide a URL to the ME Association's statement. Blogs are not generally regarded as WP:RS. JFW | T@lk 21:53, 8 October 2007 (UTC)

At the time at which the ME Association's statement was posted on ME agenda blog the MEA's webmaster had not updated the MEA's website, although the MEA's press release on NICE had been published on various sites, elsewhere. The MEA's press release can be read on the MEA's site here. I have now added a rider to the ME agenda blog entry, redirecting readers to the MEA's site. The MEA's press release is supported by two additional national ME registered charities/patient organisations: The 25% Group for severe ME sufferers and The Young ME Sufferers Trust. MEagenda 14:41, 9 October 2007 (UTC)

The response of Dr Charles Shepherd, Medical Adviser to the MEA, via eBMJ Rapid Responses to the NICE guideline Editorial and Review was also published a week or two later, in the print edition of the BMJ. MEagenda 14:53, 9 October 2007 (UTC)

Guido, I won't have you "hanging from the highest tree" but I really don't think you should have used your own publication (not in English, by and for people not affected by the NICE guideline) as a cite. I've changed it for the URL helpfully provided by Suzy. JFW | T@lk 20:38, 9 October 2007 (UTC)

The fact that it is independent criticism could also be seen as an advantage, and it's a published article, peer-reviewed even. You could choose both references. I'll leave it up to you, and others. Guido den Broeder 21:54, 9 October 2007 (UTC)

Do you have a URL? I'll review it and offer my opinion. Which peer reviewed it? The Countess of Mar, or Lord Turnberg? JFW | T@lk 13:35, 10 October 2007 (UTC)

You can find it here: [3]. Guido den Broeder 18:53, 11 October 2007 (UTC)

Peer was a fellow scientist / experience expert with extensive guideline experience. Guido den Broeder 21:49, 11 October 2007 (UTC)

Removed stuff

From the "treatment" section I removed a piece that belongs in the "crystal ball-gazing" category. It seems to have only indirect bearing on CFS/ME and is quite POV:

Due to the multi-systemic nature of the illness, and others like it, an emerging branch of medical science called psychoneuroimmunology is exploring how all the various theories fit together.

It's here for consideration, and because I've managed to trace the references. JFW | T@lk 21:53, 8 October 2007 (UTC)

Jagra: inflammation

Why do you need to include "inflammation" when the sentence already includes "the immune system" (which itself includes inflammation). You are just adding duplication which we really need to be removing. --Sciencewatcher 15:00, 10 October 2007 (UTC)

I agree with Jagra. Include inflammation to make it clear what is meant. Thedreamdied 16:29, 10 October 2007 (UTC)

But that isn't what was meant. It was meant to include the entire function of the immune system, not just inflammation. Why don't we just list all of the facets of the immune system and have an extra 100 lines in the article? Come on guys, we're trying to cut down the crud here, not add more! --Sciencewatcher 18:46, 10 October 2007 (UTC)

The concept of inflammation is extremely broad, and in recent years has complete exceeded the classical criteria of calor, rubor, color and tumor (or even functio laesa). Researchers (in any field of medicine) refer routinely to "inflammation" when they are only referring to increased systemic inflammatory mediators. Atherosclerosis is now regarded as an inflammatory condition, as there is substantial evidence that monocytic infiltrates in atherosclerotic plaque secrete inflammatory mediators, as well as responding to generalised inflammatory states.

At the moment, the article is extremely vague about the exact nature of the immune dysfunction in CFS. It claims that patients have both increased infections (as a result of immune failure) and autoimmune phenomena (as a result of immune hyperactivity). Obviously there are states in which these phenomena coexist (e.g. IgA deficiency, CVID, Wiskott-Aldrich syndrome), but the article does make it clear what immunological phenomena might lie at the root of this "imbalance". If there is no clear explanation, perhaps we should state this directly, because the studies are small, the inclusion criteria vague and imprecise, the methodology doubtful etc etc.

Another phenomenon well recognised in these "immune imbalance" diseases (such as CVID and Wiskott-Aldrich), is the increased risk of neoplasms, particularly lymphomata. Has this ever been documented in CFS/ME? JFW | T@lk 19:26, 10 October 2007 (UTC)

What we are discussing here is whether the HPA axis influences inflammation outside of the immune system. Jagra? --Sciencewatcher 15:58, 11 October 2007 (UTC)

There is the theoretical possibility that the HPA axis influences the reaction of tissues to the inflammatory process (e.g. attentuation of endothelial dysfunction), but I am not sure if that is adequately addressed by the wording change. JFW | T@lk 18:51, 11 October 2007 (UTC)

Sciencewatcher, Having access problems at present, think provider not wiki. I agree inflammation not dealt with adequately in article, and I could not find under immune dysfunction. Certainly immune system viz cytokines involved but also outside of this are essential fatty acid metabolites such as LTB4 and LTB4 /PGE2 ratio, and these are normally controlled by cortisol through lipocortin, yes vasoconstriction also implicated in this, I think this deserves separate mention, if not expansion. Hear your plea regards space saving but these two words are on an existing line, no extra article length involved.Jagra 02:08, 12 October 2007 (UTC)

JFW, Immune system up and down regulation do occur in CFS even if no fixed pattern is discernable (yet) in fact one can beget the other making it more difficult to interpret. There is an explanation for this in the literature, I can post more on this if you like? Jagra 02:29, 12 October 2007 (UTC)

Jagra: LTB4 is a Leukotriene which is produced inside white blood cells, so it is part of the immune system. --Sciencewatcher 15:09, 12 October 2007 (UTC)

Sciencewatcher, LTB4 and PGE2 are essential fatty acid metabolites created from cell membrane constituents called phospholipids cleaved by phospholipases controlled by lipocortin controlled by cortisol, they are intracellular messengers and autocoids involved as extracellular signal messenger and modulators in a host of functions in the body systems not just involving the immune response. The essential fatty acids and their derivatives have physiological function in their own right as well as modulating other systems such as immune responses.Jagra 23:39, 12 October 2007 (UTC)

Please post a link with further info. I only found the info from wikipedia (above) which says they are produced by white blood cells. Are we even talking about the same things? --Sciencewatcher 00:00, 13 October 2007 (UTC)

Not sure what you are after but many cells not just white blood cells can express LTB4 including this one on lung epithelial cells PMID 17517102 , this one in brain cells PMID 16708542, some skin cells PMID 9435249 have a look at other refs recently posted You may be confusing the role of LTB4 with the cysteinyl LT,s? Leukotrienes are very important agents in the inflammatory response. Some such as LTB4 have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary immune cells to the tissue, it also opens up the tissue (inflammation) for immune cell entry. Immune cells then either add cysteinyl leukotrienes or amplify the whole process. This is one of the roles ie modulating the immune response, but is not the response. Cortisol is necessary in controlling inflammation via the essential fatty acid metabolites and the immune response seperately.Jagra 02:06, 13 October 2007 (UTC)

Jagra: I think one of us is getting confused here. The articles you mention talk about 5-lipoxygenase expression, not LBT4. 5-lipoxygenase does not have anything to do with inflammation. The Leukotrienes do have a function in inflammation, but they are produced in white blood cells. --Sciencewatcher 15:53, 13 October 2007 (UTC)

Sciencewatcher, lipoxygenase is the biological process that produces Leukotrienes and cyclooxygenase the process to produce Prostaglandins. If tissues have 5-lipoxygenase expression they produce LTB4 and therefore everything to do with inflammation. The tissues as indicated in the above ref's can produce both types of LT's without immune cells others produce LTB4 and that has a chemotactic effect as mentioned above that attracts immune cells to produce the cysteinyl LT's, in an immune response. One more time, LTB4 modulates the immune response but has other roles as well. You are also ignoring the effects of other essential fatty acid metabolites on inflammatiuon viz PGE2 (PMID 17878511) that also is proinflammatory and has other roles, and as you can see produced by tissue and also reduced by cortisol. Both LTB4 and PGE2 are found disordered with inflammation/pain in fibromyalgia. PMID 11831483 and symptoms reduced with glucocorticoids PMID 11902610. Thus cortisol reduces inflammation not only from an immune response. Jagra 11:16, 15 October 2007 (UTC)

"If tissues have 5-lipoxygenase expression they produce LTB4": do you have any reference for this? --Sciencewatcher 15:30, 15 October 2007 (UTC)

Try this one, "We hypothesized that human bronchial epithelial cells (HBECs) express a complete and active 5-LO pathway for the synthesis of LTB4 and LTC4, either constitutively or after stimulation."RESULTS: Constitutive mRNA and protein expression for 5-LO, 5-LO-activating protein (FLAP), LTA4 hydrolase and LTC4 synthase were demonstrated in primary HBECs and in the 16-HBE 14o- cell line. Human bronchial epithelial cells were shown to generate bioactive LTs, with primary HBECs generating 11-fold more LTC4 and five-fold more LTB4 than 16-HBE 14o- cells". PMID 17517102 and these PMID 15661803 "5-LOX was also expressed in all the eight esophageal cancer cell lines." "Our data also showed that both LTB4, a product of 5-LOX---" PMID 10877525 "LTB4 production is initiated by the enzyme 5-lipoxygenase" (5-LOX).Jagra 10:15, 16 October 2007 (UTC)and expression of 5-lipoxygenase (5LO) in pulmonary artery endothelial cells PMID 11772398 Jagra 11:15, 18 October 2007 (UTC)

Okay, sounds good. Feel free to add the inflammation again if you wish. It might be useful to say that cortisol can affect inflammation outside the immune system to clear up any confusion about why inflammation and the immune system are both there. --Sciencewatcher 16:51, 16 October 2007 (UTC)

Hyper-response and Immune Dysfunction in CFS

The role of essential fatty acid metabolites in the pathogenesis of CFS is poorly understood even by immunologists, here is the likely scenario. Reduced cortisol reduces lipocortin, increases PLA2, increases lipid peroxidation hence oxidative stress, increases essential fatty acid metabolites, reduces anti oxidants including GSH. Reduced GSH increases LTB4 and reduces PGE2, increases nitric oxide, increase cytokines, reduces CRH. A vicious circle, what stops it, reduced cellular substrates, as found in CFS, PMID 14744043 Many immune responses are intended for relatively short term effect but sustained extracellular signalling and intracellular amplification leads to exhaustion of substrate and inactivated enzymes (including the D6D). Other feedback loops exist but can become disordered as hyper response causes increased down regulation of receptors leading to chronic hypo responsiveness. As EFAM’s are potent immuno-modulators we see chronic stimulation leading to both hyper responses and paradoxically hypo responsiveness of the immune system, varying depending upon individual diathesis. Once established the chronic state is maintained by minor stressors. PMID 7968718

For the Article I propose as a rider to the immune dysfunction section a statement that; ‘Sustained hyper responses of the immune system can variably lead to substrate depletion, down regulation of receptors and enzymes leading to hypo responsiveness, that may account for variable immune system findings in CFS. Some of the more common findings include;' (reduce some of the current leading para). Jagra 08:04, 17 October 2007 (UTC)

Substrate Depletion

I think the substrate depletion is WP:NOR. If immunologists don't understand this, how can we possibly claim that they do, especially in an inherently un-understood disease like CFS? JFW | T@lk 11:06, 19 October 2007 (UTC)

Unless I am mistaken, and precedence would not seem to indicate otherwise, NOR does not apply to this talk page unless pretence is involved. As to what we can include in the Article I think you will find I have not suggested other than what is already in the literature. Jagra 08:45, 22 October 2007 (UTC)

Substrate depletion of cell membrane essential fatty acids in CFS was first discovered and reported by the Behan’s (university of Glascow) in two studies, supported by Prof D Horrobin an authority on the subject of EFA’s and subsequent findings have largely supported that: ISBN 0-471-56693-4, cite book |author=Behan PO, Behan WMH, editor=Horrobin, D F. |title=Omega-6 essential fatty acids: pathophysiology and roles in clinical medicine |publisher=Wiley-Liss |location=New York |year=1990 |pages=275-282. Also reported in ISBN 0-9695662-0-4, cite book The Nightingale Research Foundation Review of The Clinical and Scientific Basis of ME / CFS, Chpt. 70, pp 628-633. Also; PMID 2270749, PMID 14744043, PMID 16380690, PMID 1337561, PMID 12784262 showed increases in chronic phase lipids. Some more definitive work was presented in the Conference Proceedings, The Clinical and Scientific Basis of CFS, Sydney 1998, including;

-p38 ‘Alterations in Plasma Lipid Composition In Patients with CFS’ (university of Newcastle NSW) which concluded “The alterations in the plasma lipid concentrations in the CFS patients was associated with dysregulation of D6-desturase activity and then n-6 poly- fatty acids which were consistent with an inflammatory event in CFS patients “

-p39 ‘Assessment of Lipid Homeostasis in Sudden and Gradual Onset CFS Patients’( university of Sydney) which found “Both sudden onset and gradual onset patients therefore had the same fatty acid anomoly differentiating them from controls” and “ the primary lipid changes in CFS patients were related to other potentially non-viral induced lipid changes”

-p40 ‘Classification of CFS Patients by Assessing Plasma Lipid Homeostasis’ (university of Newcastle NSW) “these data indicated that the CFS patients had significantly different plasma lipid profiles to the controls” and “The characteristics assessed in the CFS profiles were suggestive of anomolies in cholesterol, saturated fatty acid and n-6 fatty acid homeostasis as well as B-oxidation of fatty acids.”

-p41 ‘Assessment of Plasma Lipid Homeostasis in Relationship to EBV Antibody Titres in Patients Reporting Sudden Onset CFS’ (university of Newcastle NSW) “ lipid changes associated with EBNA and EBVIgG were not associated with the lipid alterations differentiating CFS patients from controls previously reported”

This is supported by findings in CFS of increased lipid peroxidation, and associated lowered antioxidant status, PMID 11388705, PMID 17159817, PMID 12745627, PMID 12870659,

As to what we include in the Article; only what is published. Which includes; “This relationship among membrane lipids, lipid peroxides, and eicosanoids can lead to amplification of the intercellular signals mediated by cytokines and immune globulins in ways that create hyper-responsive states and lead to pathophysiology”. and how “Sustained extracellular signalling and intracellular amplification soon lead to exhaustion of substrate and inactivated enzymes and to pathophysiology” and “ The feedback loops controlling EFAM’s (essential fatty acid metabolites) may become disordered as production rates escalate out of order in hyper-response with increased down regulation of receptors leading to chronic hypo-responsiveness” finally “As EFAM’s are potent immuno-modulators we see that chronic stimulation and or hyper-response of EFAM’s can lead to hyper and hypo-responsiveness of the immune system” PMID 3111318 PMID 7968718 These cover the statement proposed above, showing it is not OR and I know of no other published explanation for the immune findings in CFS. Jagra 08:45, 22 October 2007 (UTC)

When cells have substrate depletions of essential fatty acids they substitute other fatty acids in their lipid membranes. Which means saturated and mono-unsaturated fatty acids, as in EFA deficiency, and as found in CFS (see above ref's). This compromises immune function which becomes hypo-responsive and decreases the fluidity of the cell membrane bilayer. As normal tissue function requires normal supplies of oxygen and metabolic substrates, the changes to red blood cell shape found in CFS and ME that affect deformability in capillaries are considered to contribute to symptoms in CFS. in ISBN 0-9695662-0-4, cite book The Nightingale Research Foundation Review of The Clinical and Scientific Basis of ME / CFS, Chpt. 65, pp 597-605. PMID 2927808 PMID 2046589 PMID 8474717 As such changes are associated with free radical generation and oxidative stress and symptoms PMID 17174731 PMID 10905542 PMID 10939298 this work further supports the likelihood of a hyper-response with substrate depletion in CFS.Jagra 07:26, 25 October 2007 (UTC)

Fatigue and Energy

Essential fatty acid deficiency, ( quite apart from oxidative changes to RBC deformability, the likely result of hyper-response in CFS, depriving muscle and tissue of oxygen and energy (see above)), causes a reduction of about one third in how soon fatigue occurs, PMID 8929585 As Bricker has pointed out this ref PMID 11508520 shows why substrate depletion may not be the direct cause of (normal) fatigue, but instead it is the need to prevent substrate depletion further, that triggers the CNS to produce a fatigue state and slow or stop the patient's level of activity. The often extreme fatigue state CFS patients experience could well be protective, although highly distressing, but not inherently pathological. The possibilities tie in with the CDC comments Guido reported below in the (ME section). Main factors; “Cognition loss/sleep loss, Musculoskeletal problems, Inflammation and infection. As a result of these findings, investigators are beginning to consider fatigue as an end product rather than a causal factor of CFS.” EFAD certainly contributes to cognition, pain sensitivity, body temperature irregularity, altered inflammatory responses and less slow wave sleep. PMID 9566599 PMID 2512606 PMID 12757109 Jagra 03:00, 29 October 2007 (UTC)

Note that fatty acids need to be transported. This is where carnitine deficiency amplifies the problem, since carnitine is, among other things, responsible for the transportation. Disrupted responsiveness, meanwhile, is a more general issue in ME, as it also pertains to hormones. The key to this all seems to be a distorted protein folding as reported by Baraniuk. Guido den Broeder 16:55, 29 October 2007 (UTC)

Guido, my understanding is that carnitine is needed to transport long chain fatty acids into the mitochondria where B-oxidation produces energy and shortens fatty acid chain length. Specific enzymes are needed in the lipid membranes to enable this, whilst carnitne shortage (produced only in the liver) is found in CFS and said to be the cause of excessive ammonia given off (in sweat) by CFS patients. PMID 10540873 There are contradictory reports, meaning it may only apply to subgroups. PMID 15967423 Down regulation of these transport enzymes does not seem to be involved? PMID 14970749 Although you will note from above references that B-oxidation is affected in (some) CFS. The immune dysgegulation arises from substrate depletion in lipid membranes and presumably these changes could effect other membrane functions, such as the carnitine transport. Do you have any references showing why this may be occuring? Certainly mitochondrial energy disruption would add to other fatigue, although it has been suggested that resulting low acetyl-carnitine, a neuro-transmitter in the brain may be responsible for fatigue sensation PMID 12414265 so may be we come full circle for substrate depletion and fatigue sensation?? and it seems also to immune system dysfunction. PMID 15591010 What is the distorted protein folding attributed to? Jagra 05:46, 30 October 2007 (UTC)

I think not. The fatigue in ME/CFS is not a matter of erroneous sensation; it is real, caused by rapid ATP depletion (where carnitine is also involved), i.e. the neurotransmitters do this job right. Guido den Broeder 10:21, 30 October 2007 (UTC)

Guido, care to back up those statements with evidence? Surely, if this ATP depletion in ME is unequivocal, all is revealed? And how does it explain the benefits of graded exercise and CBT in methodologically sound trials? (Yes, I know that some patients get worse, but how does one explain the many patients who do?) JFW | T@lk 21:19, 30 October 2007 (UTC)

JFW, I know you are aware of the fact that the selection criteria used in the majority of trials with thumbs up for CBT/GET are a source of controversy themselves. So as for the patients who get better: Who guarantees they had the same disease as those who got worse? The Oxford research definition perhaps, being one of the least restrictive?JayEffage 22:31, 30 October 2007 (UTC)

I could level exactly the same accusations at the studies on which these pronouncements are based ("ATP depletion", "carnitine is involved"). What are their inclusion criteria? Is their methology transparent? Have the results been duplicated? JFW | T@lk 16:41, 31 October 2007 (UTC)

By all means yes, you could do that, and correctly so. Finally there is some common ground(Playing Griegs "Morning Mood"). I personally think that - given the background of sky high prevalence figures we have been hearing lately - these anmbiguities could ultimately explain a large part of the controversy. 82.135.91.194 02:26, 1 November 2007 (UTC) JayEffage 02:27, 1 November 2007 (UTC) (forgot to sign...)

By itself, the term CGT is not very informative. What matters is which cognitions are learned or unlearned. If CGT aims to teach the patient to rest in time, i.e. before the ATP cycle fails, and to vary which muscles are used, he will experience significantly less fatigue. This type of CGT combines well with pacing and envelope techniques. If, on the other hand, the therapist thinks he can cure the patient and tries to teach the patient to ignore all signals of fatigue, and exercise is graded up, then there is the risk that not only ATP, but even ADP runs out, and the muscles are damaged. This is why so many patients get worse after this kind of therapy and have to stop halfway through. Guido den Broeder 23:36, 30 October 2007 (UTC)

In the Alcohol Intolerance section above it was explained how a shortage of mitochondrial aldehyde dehydrogenase may effect energy production in CFS principally aerobic glycolysis but also compromises anaerobic and KREB cycle production of ATP. The reason for that shortage was not postulated in the book cited, however aldehyde dehydrogenase is required to breakdown the essential fatty acid metabolites most likely produced in a hyper-response of the immune system, namely Leukotriene B4 (LTB4) and Prostaglandin PGE2. This study PMID 9536005 found that ”The addition of low concentrations of ethanol dramatically changes the relative amounts of these metabolite products by inhibiting the alcohol dehydrogenase-mediated (Beta) oxidation” and that “Ethanol, at physiologically relevant concentrations, could alter eicosanoid metabolism in the liver by inhibiting LTB4 (breakdown) metabolism and altering that of PGE2.” Alterations in LTB4 and PGE2 were indicated in CFS immune system responses in CFS. PMID 7968718 So in CFS, hyper-responsiveness ties up aldehyde dehydrogenase in breaking down excess essential fatty acid metabolites and alcohol ingestion effectively increases the affects of the hyper-response and worsens symptoms and energy availability. This may explain why in CFS alcohol produces a ‘hangover’ effect lasting for days where as in Orientals a shortage of the enzyme only causes more rapid intoxication. Also alcohol intolerance in CFS is another indication of immune system hyper-responsiveness. Jagra 02:32, 31 October 2007 (UTC)

Aldehyde dehydrogenase shortage postulated in CFS due to hyper-responsiveness of the immune system and requirements for this enzyme in breakdown of excessive essential fatty acid metabolites (see above) also has another affect on energy production and fatigue in CFS. The production of Carnitine in the liver, but also in the kidney and brain, PMID 6770910 also requires availability of aldehyde dehydrogenase. PMID 6813145 This may explain the reason for reduced Carnitine and the neurotransmitter acetyl-carnitine in CFS groups as due to the consequences of immune hyper-response. Carnitine is considered to regulate immune responses and inflammation, PMID 15591010 treatment of CFS subgroup patients having low acetyl-carnitine, using an immunomodulator saw improvement of symptoms which the authors said ”could be explained by the modulating effect on a chronic primed state of the immune cells of the brain, or the activated peripheral immune system”. PMID 16911783 Jagra 03:24, 1 November 2007 (UTC)

Oxidative stress and Antioxidants

There is gold standard evidence of oxidative stress in CFS indicative of a free radical attack on lipids PMID 16085177 Cell membrane fluidity and fatty acid composition is altered in CFS associated with oxidative stress PMID 11118815 There is evidence of reduced levels of anti-oxidants, including ubiquinone (CoQ10), glutathione (GSH), and free-radical scavenging enzymes, PMID 12745627, low levels of GSH is found associated with low magnesium levels in CFS. PMID 10872900

Glutathione (GSH) an antioxidant is essential for proper lymphocyte responses. Impaired lymphocyte responses to mitogens are one of the more common immune findings in CFS, and may arise as a consequence of sustained hyper-response of the immune system. GSH is also essential for aerobic muscular contraction. An undesirable competition for GSH precursors between the immune and muscular systems may develop. PMID 10608272 Thus immune hyper-responsiveness may explain several symptoms and findings in CFS. Zinc (an anti-oxidant) levels are found low in CFS, and the low findings are found related to low mitogen T-cell responses PMID 16338007 Among the altered lipids in CFS are findings of low n-3 essential fatty acids, related to low zinc findings and lowered mitogen stimulated responses. PMID 16380690 PMID 16264414 This can be explained as zinc activates the production of glutathione (GSH) PMID 17847717 PMID 16723490

Zinc is also involved in the regulation of aldehyde dehydrogenase. Low levels of zinc inhibit the enzyme, but increased levels of zinc rapidly disinhibit and increase production of acetaldehyde dehydrogenase, likely via increased GSH. Zinc inhibits some enzymes that are not necessarily zinc enzymes, e.g. glyceraldehyde and glycerol phosphate dehydrogenases, and aldehyde dehydrogenase. PMID 11306104 (GSH) glutathione mediates zinc transfer from enzymes to thionein PMID 9520393 Thionine removes the metal from an inhibitory zinc-specific enzymatic site with a resultant marked increase of enzyme activity PMID 10051573 This increase in aldehyde dehydrogenase has effects on cellular energy and also since glycerol phosphate dehydrogenase is a key enzyme in energy metabolism, the effect of zinc is expected to elicit significant physiological responses, including immune responses. In CFS plasma transferrin (lipid protective) levels are found lowered PMID 11388705 and MDA levels (a sign of oxidative stress and lipid peroxidation) are found raised. PMID 17174731 PMID 17159817 Metallothionein synthesis can be stimulated in many organs by various metals such as dietary zinc. When zinc-metallothionein was given experimentally in animal studies, it raised transferrin and lowered MDA and reduced lipid peroxidation PMID 9035732 Showing the potential for GSH increase via zinc in treatment of hyper-responsive immune systems. Large scale trials that involved injected glutathione in CFIDS/CFS have shown high incidence of improvements. Also suggested was use of selenium supplementation to increase GSH PMID 11365019 In mammals, a major function of selenium (Se) and Se-dependent GSH-Peroxidase is to protect cells from oxidative stress. Zinc supplements are recommended for CFS PMID 16338007 PMID 10767667

Alpha lipoic acid supplementation has also been suggested for CFS PMID 11703165 It has recently been found that mitochondrial oxidative stress may inactivate aldehyde dehydrogenase and that the mitochondrial reduced form of A-lipois acid, restores mitochondrial aldehyde dehydrogenase activity by a different means than zinc PMID 17102135 Alpha lipoic acid also blocks cytokine formation of one of the likely products of a hyper-response, the essential fatty acid metabolite PGE2 PMID 16365401 and assists the benefit of n-3 fatty acids in reducing lipid peroxidation. PMID 11146327 Cysteine levels have been found low in CFS PMID 9367343 N-acetyl cysteine (NAC)and Alpha-lipoic acid can increase GSH concentration indirectly. NAC provides cysteine for GSH synthesis, and alpha lipoic acid is believed to increase intracellular GSH levels by reducing extracellular cystine to cysteine, bypassing the cystine transporter PMID 11703165.

CoQ10 has been found low in CFS. PMID 12745627 It is considered valuable as an anti-oxidant and an aid to energy production in neurological and neuromuscular conditions, and is used in association with alpha lipoic acid. PMID 14519086 PMID 17080429, Alpha-lipoic acid maintains CoQ10 in its anti-oxidant form and experiments demonstrate a superadditive effect with such combination of ubiquinone (CoQ10) in preventing peroxidation of biomembranes. PMID 10049509 CoQ10 supplementation was reported of benefit in CFS PMID 15889950 PMID 8241699 In CFS increased ascorbic acid (vitamin C) demand is found PMID 15715687 and low vitamin E PMID 10872900 PMID 12531455 Vitamin C and vitamin E help maintain glutathione in its reduced form GSH PMID 12614841. Magnesium supplementation increased serum Vitamin E and reduced lipid peroxidation in CFS PMID 10872900

In view of the many findings of lipid peroxidation and high level evidence for associated oxidative stress in CFS, I propose that the Oxidative stress section of the Article should include the lipid peroxidation findings and that the Treatment section should contain an item on anti-oxidants, where evidence is available and/or where deficiency is found in CFS. Jagra 03:01, 5 November 2007 (UTC)

Effects of some essential fatty acid metabolites

LTB4 this essential fatty acid metabolite and its derivatives LTC4, D4, E4, are considered proinflammatory and involved in a number of CFS symptoms and associated conditions including IBS, broncho hypertension, leaky gut syndrome, food intolerance, allergies, also implicated in other conditions such as asthma, atherogenesis, peripheral vascular disease, arteriosclerosis, coeliac disease, and IBD. There is little doubt that this family of metabolites are pro-inflammatory in their own right. LTB4 is also vasoconstrictive and is produced in the brain, does this explain reduced cerebral and arterial blood perfusion findings in CFS? PMID 17420968 PGE2 a prostaglandin is basically vasodilative and down regulation of PGE2 adds to up regulation effects of LTB4. Both PGE2 and PGD2 are produced in the brain by astrocytes due to numerous stimuli including cytokines. In the hypothalamus they control sleep / wake and hot / cold regulation and disordered essential fatty acid metabolites can explain numerous symptoms in CFS both neurological and in other body systems. Also of relevance is that circulating EFAM’s such as PGE2 can cross the blood brain barrier and LTB4 weakens the BBB. PMID 7976633 PMID 2996417 as can arachodonic acid excess PMID 10696506 due to hyper response and increased phospholipase ie reduced cortisol. Jagra 23:39, 12 October 2007 (UTC)

Blood Brain Barrier in CFS

Whilst some have proposed a virus for increasing the permeability of the BBB in CFS. It does not need a virus for a weakened BBB to be implicated, for instance others have shown PMID 11461179 PMID 12000033 that the weakening can occur from; increased serotonin, depleted glutathione (GSH), essential fatty acid deficiency, cytokines, nitric oxide, and peroxynitrite, and stress, all implicated in CFS symptoms. A weakened BBB can allow a virus access to the CNS as a perpetuating factor! I propose adding to the neurological section the consequences of increased serotonin; reduced HPA axis function including reduced cortisol and beta-endorphin also weakening of the blood brain barrier. Jagra 23:39, 12 October 2007 (UTC)

It seems a bit speculative, unless you have research showing weakened BBB in CFS patients and evidence of CNS infection in patients. --Sciencewatcher 00:03, 13 October 2007 (UTC)

No, under Neurological Abnormalities, at this time I am interested in the serotonin findings in CFS and the known affect on BBB permiability. but for discussion I will add later some thing on virus and CNS Jagra 10:02, 13 October 2007 (UTC)

Hyde: new and simple definition

@Sciencewatcher, you claim that the publication

Hyde B. "A New and Simple Definition of Myalgic Encephalomyelitis and a New Simple Definition of Chronic Fatigue Syndrome & A Brief History of Myalgic Encephalomyelitis & An Irreverent History of Chronic Fatigue Syndrome"

does not exist. Why would you say that, in view of [4]? Guido den Broeder 20:27, 11 October 2007 (UTC)

I had a look on the nightingale site and I couldn't find it anywhere. --Sciencewatcher 21:18, 11 October 2007 (UTC)

So? There is no list of publications on that site, so it's hard to tell if one is missing. Guido den Broeder 21:39, 11 October 2007 (UTC)

Guido, it's simple. You keep Byron Hyde, I keep the Wessely letter. JFW | T@lk 22:07, 11 October 2007 (UTC)

That is a very strange proposition. Are we here to improve an article or to play a game? There is nothing wrong with mentioning a controversy or with the reference to Wessely, but your text does not cover the tale. And if it appears that Hyde's booklet indeed does not exist, it should not be in.Guido den Broeder 08:59, 12 October 2007 (UTC)

The Wessely letter had a second author (David), so it was not just one person. Also, I don't have the actual letter and it is not available free so I can't tell what Wessely actually discussed in it. But since Wessely is an established expert on the subject it would seem to be appropriate to mention it. --Sciencewatcher 16:58, 12 October 2007 (UTC)

The letter can be found here: [5]. Regards, Guido den Broeder 17:52, 12 October 2007 (UTC)

Myalgic Encephalomyelitis

It is ridiculous, confusing and unncessary that there is a seperate page for ME. Even though are some small differences between the conditions according to some definitions, it is often referred to as CFS/ME, and there is potential for contradictory information in the two articles, as well as simply making more work for everyone. JFW, is it possible to redirect here and protect? Thedreamdied 17:03, 14 October 2007 (UTC)

I have reverted again to a redirect. I have warned Jklsc (talk · contribs) that the page will get locked if he continues. I don't think I should lock it myself, given that I may now have a conflict of interest, but in an obvious case other admins will respond when asked formally. What I have now done is moved the edit history of Myalgic Encephalomyelitis to myalgic encephalomyelitis. Whether it gets forked or not, the former name is in violation of the naming criteria. JFW | T@lk 21:33, 16 October 2007 (UTC)

NOTE: Kmclellan (talk · contribs) has started a vote on Talk:Myalgic encephalomyelitis to the effect that the page should be forked. Please place your votes on that page. I strongly recommend, as I have above, that the pages should remain merged because most authorities use CFS and ME interchangeably (e.g. Leonard Jason), and because the supposed differences between these conditions can only be explained in the standing article. JFW | T@lk 19:51, 17 October 2007 (UTC)

To clarify: the notation A/B in medical nomenclature does not imply that the two are the same. Guido den Broeder 09:43, 22 October 2007 (UTC)

Oh really ? Seems OR, as I always understood that at very least it does imply that both being considered together (eg COPD/COAD are discussing the same thing, although one is a depreciated term). I would read "A/B" as merely a copyediting style against, as an alternative, "A(B)". PubMed gives both "CFS/ME" and "CFS (ME)" in various papers. I think your line of discussion falls within WP:NOR, as based upon WP:Cite, WP:RS and WP:UNDUE. As example where same particular discussion is being held and yet a variety of editorial styling used, consider:

• "Chronic fatigue syndrome / Myalgic encephalomyelitis". National Institute for Clinical Excellence (NICE). August 2007. - The UK guideline uses "A/B"
• Baker R, Shaw EJ (2007). "Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): summary of NICE guidance". BMJ. 335 (7617): 446–8. doi:10.1136/bmj.39302.509005.AE. PMID 17762037. - a BMJ article summarising the NICE guidelines for UK doctors, uses "A or B"
• White P, Murphy M, Moss J, Armstrong G, Spencer P (2007). "Chronic fatigue syndrome or myalgic encephalomyelitis". BMJ. 335 (7617): 411–2. doi:10.1136/bmj.39316.472361.80. PMID 17762005.{{cite journal}}: CS1 maint: multiple names: authors list (link) (abstract) - an editorial on the above paper which begins with "The uncertainty inherent in making a diagnosis of chronic fatigue syndrome (CFS) is reflected by the variety of names (such as myalgic encephalomyelitis; ME) it has been given". Uses "A or B" in its title (the editorial is of course commentating on the paper in that edition of the BMJ), yet within the editorial it is using "A(B)" format in mentioning the two.

Clearly considered within the majority opinion (and that is the medical community), rightly or wrongly (NB wikipedia follows WP:NPOV not some "truth" of WP:SPOV), the same syndrome. Now I grant that there may be different causes for CFS/ME, but when and if these are identified, then there will be a whole host of specific names for the various conditions (or perhaps one name qualified in a classification system, eg X Type 1 and X Type 2, just as there is for Diabetes mellitus type 1 and Diabetes mellitus type 2) David Ruben ^Talk 13:36, 22 October 2007 (UTC)

Sigh. You are simply repeating the same faulty rethorics that JFW is displaying. Guido den Broeder 14:39, 22 October 2007 (UTC)

Fortunately, we have a good article on the meaning of a slash. I quote: "The most common use is to replace the hyphen or en dash to make clear a strong joint between words or phrases, such as "the Hemingway/Faulkner generation". I don't think that Hemingway and Faulkner are the same person, or that Hemingway should be a redirect to Faulkner. Guido den Broeder 16:31, 22 October 2007 (UTC)

Sorry if i'm boring you, your continued skirting around WP:AGF risks formal action being taken. In your example clearly there is a choice of terms. Whilst obviously Hemingway was not the same as Faulkner, the slash does mean that "Hemingway-generation" is being signalled as equivalent to the "Faulkner-generation". Likewise in "Victorian/latter 19th centuary", a Queen and a centuary are different conceps, but in the conjunction, the same time frame is being considered. Your seem to be arguing for your own minority opinion against the established medical majority view (again remember WP reports vs decides, is not a soap-box, gives less weight to the minority viewpoint even if the majority is wrong). Please note WP:COI re your edits to ME/CVS Vereniging. It is time for some other editors to comment as this needs be a consensus, not endless debate between just a few of editors. David Ruben ^Talk 17:14, 22 October 2007 (UTC)

Sorry - but this is nonsense. There is no COI at all in Guido's edits to the Verenging page, as he is the only one with any knowledge of the subject whatsoever. Also, there is no need at all for threatening "formal action" against Guido just because he happens to have a different viewpoint to yourself - this isn't about "assuming good faith" in this case, Guido is neither assuming nor not assuming good faith, hes just trying to provide his viewpoint, which you seem very much determined to stifle! Even though i tend to disagree with him. Thedreamdied 17:19, 22 October 2007 (UTC)

If Martians were triangular, then "triangular/Martian people" would denote these aliens, and an article title could be "On the mating habits of the triangular (Martian) people", and there could be thousands of such titles, and if Martianhood were hard to detect most would focus on triangularity and perhaps not even mention Martianhood, and still triangular and Martian would not be synonymous, nor would triangularity be the single term of preference. Guido den Broeder 19:29, 22 October 2007 (UTC)

I have watched this debate without commenting to date as I have no real view on the matter, and find it a distraction as in my neck of the woods the CFS definition is used for diagnosis. However JFD and Guido both obviously hold passionate veiws (as they are entitled to) and Idon't think that is grounds for formal action or apologies. My understanding is that the diagnostic criteria for ME is stricter but fits within the broader CFS reseach definition. If this is the case then I feel it should included on the same Article. However if my assumption is incorrect and ME merely overlaps to some degree with CFS, then I consider it should be treated the same as other overlap conditions such as Fibromyalgia with its own article. It is likely that FMS fits within an even broader definition and CFS and FMS are sometimes included as seperate catergories in the same research. Although I have not seen CFS and ME seperately catergorised in this way. If you folk decide on one Article and it can be shown that ME research produces different outcomes then editors should be entitled to add such clarifications throughout (having regard to undue weight. Whilst on the subject of diagnosis, how do you catergorize a patient that follows a management stratergy that improves them to the point where they no longer have fatigue, but clearly are neither cured or in 'remission', but would now no longer fit any definition / criteria (as long as they maintain that strategy)? Jagra 10:06, 23 October 2007 (UTC)

Hi Jagra, in general it can be said that a patient with ME also has CFS. The reverse is not true. If the Fukuda criteria are followed, about half of the patients diagnosed with CFS will (if continued diagnostics are applied) later be proven to have a cardiac condition, Lyme, Hashimoto, Fibromyalgia, a mitochondrial or other metabolic disorder, a form of depression, anorexia, poisoning, diabetes, etc. However, your last question raises an interesting point. Except for the severely ill, it is quite possible for ME patients to adjust their behaviour such that fatigue is no longer continuously present. At that time they would not satisfy most CFS criteria, but they have not recovered one bit, they are just coping. They still have ME, and will get fatigued as soon as they increase their activity to more than a bare minimum. Regards, Guido den Broeder 12:51, 23 October 2007 (UTC)

Hi Guido - I am having difficulty in understanding your position on this. Can you differentiate (sympton/disease/whatever-wise) between CFS and ME for me? Thedreamdied 12:59, 23 October 2007 (UTC)

“Ramsay AM, Dowsett EG, "Myalgic Encephalomyelitis -- Then and Now: An Epidemiological Introduction", pp. 81-84 in Hyde (1992) describe ME as follows:

“A syndrome initiated by a viral infection commonly described as a respiratory/gastro intestinal illness but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognized.

1. Generalized or localised muscle fatigue after minimal exertion with prolonged recovery time.
2. Neurological disturbance, especially of cognitive, autonomic and sensory functions, often accompanied by marked emotional lability and sleep reversal.
3. Variable involvement of cardiac and other bodily systems.
4. An extended relapsing course with a tendency to chronicity.
5. Marked variability of symptoms both within and between episodes.”

These are symptoms. Of course, the name further implies inflammation of the central nervous system, which makes it a disease entity, and which is not a condition for any CFS diagnosis. The third symptom is central in the Nightingale definition of ME. Guido den Broeder 15:06, 23 October 2007 (UTC)

I think it is obvious that most researchers and doctors use "ME" and "CFS" interchangeably. I am somewhat surprised that Guido is arguing the point so strongly that this doesn't commonly occur, although I agree with many of his other points. As far as I know the CDC intended CFS to be a catch-all replacement definition; partially in response to the growing number of people presenting with severe chronic fatigue, but also inclusive of people who would have otherwise been diagnosed with older ME criteria prior to 1988; so researchers and doctors began using this new definition instead. Therefore it's no surprise that CDC-CFS appears to be some sort of middle-ground between "idiopathic chronic fatigue" and the older criteria of "myalgic encephalomyelitis". CFS revolves around fatigue with some optional accompanying "minor" symptoms; whereas ME revolves around inappropriate fatigability with prolonged recovery time, among other major key symptoms which are just as important.[6] The older ME criteria and literature doesn't have the same supposed authority or unified recognition of the newer CFS literature, so it's given less weight in the article; but I can see why patient groups are disgruntled with the swallowing of stricter ME into the slacker CFS without any subtyping. I'm not sure where I stand on the naming issue yet, but I think the criteria issue is extremely important. L Jason has pointed out the inappropriateness of using the research results from different criteria interchangeably; to a lesser degree I think this also applies to the naming issue when the different names used different criteria at different times, so I don't think it is totally appropriate to use these terms interchangeably without highlighted caveats. - Tekaphor 16:56, 23 October 2007 (UTC)

PS - Saraceno's statement about the WHO classification implies that if there wasn't a viral onset then it isn't myalgic encephalomyelitis. If CFS is supposed to be synonymous with ME then it must be a form of post-viral syndrome according to the WHO classification. The CDC-CFS symptom profile can be very similar to that of neurasthenia so it's no surprise that CFS is being courted by psychiatry, or that many CFS patients could also be diagnosed with neurasthenia. If ME is an "artefact of the past", neurasthenia is more so. I suspect that part of the attraction towards the more organic-sounding literature is simply that it often does a much better job at detailing descriptions about the specific symptoms as well as mentioning the research that was conducted before 1988 using stricter ME criteria. I was impressed with the Canadian definition when first reading it earlier in the year and have since become a supporter of it. I think that different criteria should be used simultaneously in the larger studies. - Tekaphor 16:56, 23 October 2007 (UTC)

Thanks Guido. But my understanding was that inflammation in the CNS has not been proved conclusively at this time. Personally, I feel that the overwhelming confusion that this topic has generated is a good example of why they should be combined. It would be impossible to decide what to put in what article on the basis of disagreements between WHO, NICE, patients, patients groups etc. Thedreamdied 17:01, 23 October 2007 (UTC)

Hmmm, my feeling is that a split could quickly resolve the confusion. This is what we presently know to support the encephalomyelitis:

• The immune system acts like there is ongoing inflammation.
• Human autopsies show CNS inflammation; however, there have only been a few.
• Monkey autopsies show CNS inflammation; however, this was just one study.
• Brain scans show signs of demyelination.
• Brain scans show significant brain damage.
• Stomach biopsies show mild inflammation.
• ME is related to MS and polio which both have CNS inflammation. Guido den Broeder 17:23, 23 October 2007 (UTC)

Not sure what to make of this (draft, 2003):

"The CDC is currently conducting population studies to develop an empiric definition of CFS that is based on statistical modeling. These studies show that people with CFS have an illness with three closely correlated factors:

• Cognition loss/sleep loss
• Musculoskeletal problems
• Inflammation and infection

As a result of these findings, investigators are beginning to consider fatigue as an end product rather than a causal factor of CFS" Guido den Broeder 21:47, 23 October 2007 (UTC)

Guido, do we have any indication of what inflammation CDC might be looking to, there seems to be little on this in the Article ? If CDC do move to less emphasis on fatigue and more to the three correlated factors above, would that not indicate that the CFS definition is likely to evolve more towards an ME criteria, which provides oppurtunity to contrast findings within one article? Jagra 11:09, 24 October 2007 (UTC)

Ah. This was the preparation for [7] which may therefore be seen in another light (Jason was very negative re an empirical definition). Guido den Broeder 11:37, 24 October 2007 (UTC)

Guido, where do the authors comment negatively on an empirically derived definition? Or did you mean that the implications of (PMID 16356178) are negative for the accuracy of CFS research in general? These comments from that study are rather sobering:

• "There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF (insufficient symptoms or fatigue), who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm."
• "To some extent, the inconsistent and often conflicting results from studies of CFS reflect referral bias. Most published studies concerning CFS recruited patients from tertiary referral clinics. Patients receiving care for CFS are neither similar across clinics nor necessarily representative of the population of people who suffer from CFS."
• "In addition, the lack of consistent findings concerning the etiology, pathophysiology and risk factors for CFS reflects lack of standardized reproducible diagnostic criteria for CFS."
• "In contrast, most studies of CFS merely note that they used the 1994 case definition and they do not generally specify how disability, fatigue and symptom occurrence were elucidated. Thus, it is difficult to assess the validity of their diagnostic criteria and essentially impossible to compare results between studies critically."

Tekaphor 16:59, 24 October 2007 (UTC)

Guido, you are giving misinformation again. There is no evidence of brain damage in CFS, and CNS inflammation is not a feature of the illness. A few patients have been found to have inflammation but it was due to herpes virus. And it is ridiculous to say that "ME is related to MS and polio" because it is simply not true.

I think the problem is that different patients have different symptoms. No patients fit exactly into any definition of CFS or ME, and most doctors believe that it is a single illness which has different symptoms in different patients. Some patients have muscle pain, others don't. Some have fatigue, others don't. Some have depression, others don't. But it is the same illness. Neither definition is correct, and I personally believe it would be better to have some kind of heristic points-based diagnosis.

Anyway, the fact is that most doctors and researchers believe that CFS and ME are the same illness, so we should not have two separate articles. Guido's argument that "A/B" can mean "A" and "B" are different things is just ridiculous. "A/B" can mean either "A and B are synonymous" or "we are talking about A and B". In the case of CFS/ME it is clearly indicating that CFS and ME are synonomous. --Sciencewatcher 18:24, 24 October 2007 (UTC)

I agree with Tekaphor, The comments from that study are rather sobering and negative for the accuracy of previous CFS research. However that cannot be said for the CDC work as it seems that empirical classification was the basis for the 2006 CDC studies where different gene expression profiles were found for CFS and unexplained chronic fatigue (IFS). PMID 16610957 PMID 16610949 In commenting on the publication of 14 papers it is said by the CDC that the altered gene expression can differentiate sudden and gradual onset CFS and between CFS and chronic unexplained fatigue conditions. So Guido, it seems the definition is evolving and differentiating. Gene studies may further that process so has any gene expresion work been done on ME criteria and can it differentiate ME from these other catergories, or is it too early to say? Jagra 05:28, 25 October 2007 (UTC)

Hi Jagra, the value of gene expression studies should not be overstated. It is a new form of symptom analysis. These specific results, however, are not new; ME researchers already noticed differences between sudden and gradual onset cases decades ago, as did Lyme researchers, MS researchers, etc. Guido den Broeder 14:36, 28 October 2007 (UTC)

@Sciencewatcher: all the information I gave is correct. Guido den Broeder 14:38, 28 October 2007 (UTC)

Brain Scans

Guido: you said "Brain scans show significant brain damage." which is simply not true. No brain damage has been shown in brain scans. I think you are confused here into thinking that the SPECT scans show brain damage (they don't). SPECT scans show functional blood flow, which may or may not be due to brain damage. Patients with depression have abnormal SPECT scans, but no brain damage. Autopsies on CFS patients have not shown any brain damage, so what you are saying is simply untrue. --Sciencewatcher 20:32, 2 November 2007 (UTC)

Which autopsies are you refering to? JayEffage 21:00, 2 November 2007 (UTC)

None. As I said there haven't been any autopsies showing brain damage. --Sciencewatcher 16:07, 3 November 2007 (UTC)

First of all: Even if what you stated were true (which it isn't, see Sophia Mirza) you are implying that (your feeling of) absence of evidence is tantamount to the evidence of absence. That, of course, is wrong from a scientific perspective. JayEffage 14:03, 4 November 2007 (UTC)

Sohpia Mirza had no evidence of brain damage. And it isn't up to me to prove that no brain damage has even been found (which is impossible). It is up to Guido to provide some references showing that it has been found, as it was him who stated that brain damage has been found in CFS patients. So far he hasn't come up with anything. --Sciencewatcher 21:21, 4 November 2007 (UTC)

Sciencewatcher, please cite your references on this page, as you demand of other contributors. Which patients with 'depression' have abnormal Spect scans, show that they are not co-morbid CFS, FMS or other hypocortisol patients. Show which areas of the brain are involved, are they the same?. Without references we cannot tell. You also neglect the MRI findings in CFS, do 'depressed' patients have the same? provide references. How do you explain the MRI UBO's, others consider sites of congregation of lymphocytes in the perivascular spaces, and as such potential inflammatory focii (see Nightingale book page 428/9)? Jagra 10:09, 5 November 2007 (UTC)

ME patients have a significant loss of gray matter, especially in the cognitive and and autonomous centers of the brain (Okada e.a., 2004). There is also hypoperfusion a.o. around the brainstem (Costa e.a., 1992), while depression shows hyperfusion in the prefrontal cortex (Ito e.a., 1996). Hypoperfusion in other parts of the brain is present in a.o. Alzheimer and epilepsy. Guido den Broeder 10:24, 5 November 2007 (UTC)

Guido, could you get into the habit of adding PMID numbers?

Jagra: how can you see lymphocytes on an MRI scan? And who says that all CFS & FMS patients are hypocortisolaemic? And are you expecting us to regard Nightingale publications as representative? JFW | T@lk 13:29, 5 November 2007 (UTC)

Regarding the reductions in gray-matter volume, Guido is talking about PMID 15461817 (and PMID 15955487). According to the related article and its references, Sophia Mirza had "unequivocal inflammatory changes" that were "abnormal and showed disease"; but inflammation in general may or may not result in tissue damage so I don't know if she had "brain damage" in the traditional sense. Apparently the changes were very similar to that caused by herpes, reactivation of which has been implicated in CFS. However, we don't know how representative Sophia was of the general CFS population. As far as I know, no autopsies relating to CFS have been published in appropriate journals and all we have is a few websites describing the inflammation found in a few patients after their death. Perhaps it is interesting that out of those few notable autopsies done, inflammation was found; but the needed research simply isn't being done and the development of an autopsy protocol [8] would be extremely valuable. - Tekaphor 15:15, 5 November 2007 (UTC)

The SPECT studies cited in the CFS article itself talk about the SPECT abnormalities present in patients with major depression. But that is common knowledge. It is not common knowledge that CFS patients have brain damage, hence it is up to you to give references. As you haven't done so, we can assume that CFS patients do not have brain damage. Having statistically less grey matter than controls is not "brain damage". There have been lots of autopsies on CFS patients, and we certainly would have heard by now if brain damage was a factor. --Sciencewatcher 15:39, 5 November 2007 (UTC)

For the second time sciencewatcher: "Absence of evidence" is not equal to "evidence of absence". You cannot assume that CFS patients do not have brain damage from the fact that Guido cannot give you a reference, or there is no reference at present. That is a classical non sequitur. You can assume though, that nothing unreferenced will go into the article.

Also for the second time, what autopsies are you talking about? JayEffage 16:30, 5 November 2007 (UTC)

BTW: Here is a study about yet different MRI findings: PMID 10567042 JayEffage 16:46, 5 November 2007 (UTC)

Brain damage, i.e. reduced gray matter volume, was shown by Okada e.a., 2004, and confirmed by De Lange e.a., 2005. The effect is the same as gray matter reduction from aging, except that the cognitive and autonomous centra are strongly affected areas (Okada). Hence the loss of information processing and mult-tasking skills, and a general homeostatis failure. Guido den Broeder 16:39, 5 November 2007 (UTC)

@Tekaphor: the reactivation of latent viruses such as Herpes is an inherent part of the disease entity. Guido den Broeder 16:53, 5 November 2007 (UTC)

Reduced grey matter is not brain damage. And anyway we do not know what causes this reduction or if it happens in all patients. It may simply be due to inactivity. That would not be "brain damage".

Jay: you don't seem to understand what we are talking about here. Guido said "Brain scans show significant brain damage", so it isn't up to me to prove that patients do not have brain damage. It is up to him to give details of those brain scans. And it isn't up to me to give details of autopsies that show no brain damage. As you yourself said that would never prove anything. But you can take Sophia Mirza as one example. No brain damage was found. If you want to say that "CFS patients have brain damage" you need to have some evidence. Otherwise lets just say that CFS patients have a wandering womb that causes their illness. Can you prove that they don't? What autopsies have you got that show their wombs are normal? --Sciencewatcher 19:55, 5 November 2007 (UTC)

I consider the womb excurse as attempt to be humorous. Whether what was found in Mirzas Brain is brain damage is a least worth a question mark. But you claimed there were lot's of autopsies. For the third time: What are you talking about?JayEffage 10:54, 6 November 2007 (UTC)

Loss of gray matter is generally considered damage. ME is not the only disease with such damage; for instance, sleep apnea has gray matter loss in areas that regulate speech and breathing [9]. One does not need an autopsy to determine this damage. Guido den Broeder 20:17, 5 November 2007 (UTC)

If the grey matter loss is a normal reaction by the brain to lack of activity, and if the grey matter comes back to normal after the patient recovers then it could not be called "damage". We also don't know if the grey matter loss even causes any symptoms. Just because it is correlated with fatigue does not mean it causes it. As usual you are clutching at straws in an attempt to validate your theory of the illness. People with real brain damage do not get CFS, even when they have lost more than half of their grey matter. --Sciencewatcher 21:22, 5 November 2007 (UTC)

You know best. After all, you are so active on this talk page that you must easily have tripled your gray matter by now, leaving precious little to the rest of us. Sleep tight, Sciencewatcher. Guido den Broeder 23:40, 5 November 2007 (UTC)

I didn't know there were "lots of autopsies" of CFS patients; I'd be interested in reading about them. Keep in mind that Sophia's findings had to be specifically sought out, suggesting a standard autopsy may not be good enough, why else would a special protocol be in development? Afterall, they are looking for the cause of death, not doing a detailed investigation of the patients' health. One US death [10] supposedly involved heart inflammation, which wasn't found in Sophia. As for the gray-matter studies, the controls were matched for activity, so I doubt the "inactivity" explanation unless it is otherwise demonstrated, although it may be more difficult to precisely match CFS patients in terms of cognitive activity. The 2005 study mentions that the reduction correlated with the severity of "CFS symptoms" and physical activity, which implies more than just "fatigue" was measured, although I can't be certain since I don't have access to the full article. I think half the problem here has been individual interpretations of the word "damage". - Tekaphor 02:37, 6 November 2007 (UTC)

Good point about the individual interpretations. Do you know about any classification that could be used? (I am not married to the brain damage concept, I just think there should be one question mark rather than two exclamation marks...) JayEffage 11:09, 6 November 2007 (UTC)

A correlation is to be expected, but the causality is that the brain damage causes exercise intolerance, not the other way around. Note that the incubation time of ME can be as short as 4 days, and the disease hits previously active persons just as easily as previously inactive persons. Guido den Broeder 10:21, 6 November 2007 (UTC)

Interesting point Sciencewatcher. I do remember reading a story on bbc news about a man whos skull was virtually totally full of water, and small bits of his brain at the edges had taken over all the functions perfectly fine. Not really relevant, but there we go. [11] Thedreamdied 11:05, 6 November 2007 (UTC)

Yep, that's the guy I was thinking about. And he didn't have any CFS symptoms. That lays Guido's theory to rest ("the causality is that the brain damage causes exercise intolerance"). Guido you should stick to stating the proven facts rather than dressing up your half-baked theories as fact. --Sciencewatcher 16:25, 6 November 2007 (UTC)

No, that does not lay a possible causality in the direction brain abnormality/damage --> CFS symptoms to rest, which is - by the way - not necessarily Guidos theory. If you want to actually put that theory to rest you will have to come up with actual references to CFS other than your half-baked "original research" involving a conclusion drawn from above case. For the time being you will in all likelyhood not be able to put anything around CFS to rest and I suggest you tone down your rethoric on this page. JayEffage 16:56, 6 November 2007 (UTC)

Sciencewatcher, I'd apreciate it if you would stop suggesting that my being ill is my own fault (not active enough, ahem, I played football and tennis at the time I went ill) and that anything that might indicate otherwise are just my personal half-baked theories or my clutching at straws. I get enough of that from the local tabibu juha, I don't need it from you. Guido den Broeder 16:38, 6 November 2007 (UTC)

Ok ok, lets think about this people - no-one is ever going to agree on this, and theres no point just descending into argument. Lets just agree to disagree and let someone else adjudicate on whether or not the articles should be combined. Or whatever it is we're arguing about at the moment. Thedreamdied 17:03, 6 November 2007 (UTC)

JFW, I have been unable to access/edit the site for last 48 hrs, so a bit behind discussion. Are you suggesting that the Nightingale book ISBN 0969566204 that I cited and paraphrased above is not WP:RS? Frankly I prefer to leave aside matters of medico-political innuendo when considering science, however (although I have no POV on the matter) if you provide your references of RS evidence that any of the scientists in those papers are less than reputable, I will consider it.

Sciencewatcher, of those two Spect/depression studies in the Article only one appears to be on Primary depression and does find different results compared to CFS, Primary depression of course is characterised by hypercortisol. Cleare and Demitrac's CFS patients from tertiary referral centres were found hypocortisol, and to my knowledge there are no studies in CFS that find hypercortisol! Given Guido's clarification on hyperperfusion in depression Spect scams and hypoperfusion in CFS scans, (given cortisol is anti-inflammatory, it might just be vasodilative!) These refs finds only hypoperfusion in CFS Spect scans PMID 1491843 PMID 8542261 PMID 1491843 PMID 8141022 and confirmed in PET study PMID 9790483 the two mentioned Article abstracts then are not representative and PMID 10974961 is the odd one out, and I think this should be clarified in the Article or removed. But perhaps you have other references you can cite that show differently? Jagra 21:33, 6 November 2007 (UTC)

According to the wikipedia article on brain damage, it is "the destruction or degeneration of brain cells", while damage itself is defined by dictionary.com as "injury or harm that reduces value or usefulness". Sciencewatcher's rhetorical argument "if the grey matter loss is a normal reaction by the brain to lack of activity, and if the grey matter comes back to normal after the patient recovers then it could not be called damage" cannot be appropriately inferred from the related studies, because there was no association between inactivity and atrophy (i.e. controls were matched for activity) and volume normalisation with illness recovery wasn't part of the research. Even if the volume normalised with the patients' recovery, damage doesn't have to be functionally permanent to be classified as damage. Perhaps with CFS we are dealing with a grey area between damage and functional impairment (pun intended). Sciencewatcher suggests that because other people with reduced grey matter volume don't also have CFS then it doesn't have any causal significance, but I think that is a major oversimplification. We don't know why the CFS participants' global volume or specific areas had atrophied, so it is inappropriate to make conclusions; and as I pointed out before, the controls were supposedly matched for activity so "inactivity" shouldn't be the repetitive default assumption. A few radical cases of hydrocephalus, assuming they are literally true, don't automatically render grey-matter studies inapplicable either. Following that logic, it could also be said that the existence of a single CFS patient who doesn't experience chronic stress (and there are plenty of them) would "lay Sciencewatcher's theory to rest" (that CFS is perpetuated by chronic stress) and this would be similarly ridiculous. Even in extreme primary sources, such as John Lorber's work (Is your brain really necessary? | R Lewin, et al | Science 210, 1232 (1980) | DOI: 10.1126/science.7434023), there may be some individuals who seem relatively functional when considering their supposed brain size but there is still a general correlation between reduced brain size and intellectual retardation. Something similar could be said for the grey-matter CFS studies (and probably most other CFS studies) where some individual participants may appear relatively normal in their test result but overall the group demonstrated a correlation between abnormal findings and symptom severity. PS: just to be a smart-arse and share in JayEffage's entertainment, the wondering womb example is amusing because many people with CFS are male. - Tekaphor 07:00, 7 November 2007 (UTC)

Grey matter does not regenerate spontaneously. What is gone, stays gone, until we find a way to induce regeneration. Meanwhile, the brain adapts. fMRI studies show that ME patients use both sides of the brain for certain tasks, where healthy people use one side. That works, but it is suboptimal. Therefore we appear clumsy, IQ scores drop significantly, multi-tasking is not possible, information processing is impaired, we miss nuances and can't easily switch (and therefore may sometimes come across, e.g. on Wikipedia, as irritating with one-track minds, while we really aren't, we're just slower to defocus and more literal than we used to be), etc. Guido den Broeder 08:31, 7 November 2007 (UTC)

I think what you're saying is fascinating Guido, but it just seems to me, if it was as definite as you say it is, then it would be wider knowledge. Thedreamdied 15:05, 7 November 2007 (UTC)

Well, it seems that it is, see white matter: "Changes in white matter known as amyloid plaques are associated with Alzheimer's disease and other neurodegenerative diseases. White matter injuries ("axonal shearing") may be reversible, while gray matter regeneration is less likely." :-) Guido den Broeder 16:37, 7 November 2007 (UTC)

As people have said, we don't know enough to know whether or not there is actual "brain damage" in CFS, and if it is reversed after recovery. The loss of brain tissue in the hippocampus in PTSD is reversed after recovery (but that is not "grey matter" as far as I know). And it is well known that the brain adapts by growing and killing off cells (PTSD is just one example of this). People with brain damage have recovered the ability to move/speak when other parts of their brain have taken over the functions. And I never suggested that Guido's (or anyone else's) CFS was due to inactivity. I was suggesting that the loss of grey matter might be due to the mental or physical inactivity caused by having CFS (not the other way around) - it is generally OVER activity that causes CFS, not the other way around! --Sciencewatcher 21:42, 7 November 2007 (UTC)

No, overactivity does not cause CFS either. People with brain damage can and do indeed regain certain functions that way, but always with some level of impairment remaining. Guido den Broeder 22:50, 7 November 2007 (UTC)

Overactivity alone does not cause CFS, but it is certainly one of the factors that is known to cause CFS. And many CFS patients have recovered fully (with no impairment), which is another argument against brain damage in CFS. --Sciencewatcher 17:36, 8 November 2007 (UTC)

No, it's not (overactivity). Personally, I do not know a single CFS patient who has fully recovered. Partially, yes, even significantly, but never back to their old level of functioning. With age, however, the difference usually gets smaller, since healthy people lose grey matter, too. Guido den Broeder 19:35, 8 November 2007 (UTC)

Well if you want I can give you details of lots of people who have recovered. And yes, overactivity definitely is a factor. As we have discussed before, stress has always been shown to be a significant factor in triggering CFS. The types of stress tend to be excess responsibilities, excess workload, physical overtraining, and interpersonal emotional problems at home or work. So overactivity is definitely a major factor. --Sciencewatcher 20:48, 8 November 2007 (UTC)

Who says that overactivity is a factor, sciencewatcher? You? Could you please stop making weasel claims like "it has always been shown" and give us references to back up your statements? JayEffage 09:52, 9 November 2007 (UTC)

Look at the stress and trauma section of the article. And for more info do some research on overtraining syndrome. --Sciencewatcher 15:30, 9 November 2007 (UTC)

Look at the CFS definition, where it says "is not due to ongoing exertion". You can't get CFS through over exertion. Overtraining syndrome is a differential diagnosis with a different classification and biological findings. MEspringal 06:57, 14 November 2007 (UTC)

Show me a patient who has fully recovered, and I show you a patient who never had it. ME/CFS patients who are formally recovered will typically say that the illness has changed their lives, that they are more careful now, rest more, etc.

Stress can weaken the defenses, and overactivity can be a factor in creating stress, but so can any other grade of activity or passivity. Research shows no correlation. Guido den Broeder 21:08, 8 November 2007 (UTC)

I think you have just described why you have never met anyone who has recovered - you automatically assume they didn't have CFS in the first place. How convenient! That's certainly one way to maintain your illusion of the nature of the illness. --Sciencewatcher 15:30, 9 November 2007 (UTC)

Goodbye, Sciencewatcher. Guido den Broeder 15:54, 9 November 2007 (UTC)

The extent of which the volume reduction can be reversed depends on the nature of the atrophy. Obviously neurodegeneration or serious cellular damage is more difficult to correct, but some of the "volume" consists of non-neuron support structure that responds to activity (i.e. blood vessels, glial cells, branching connections between neurons). I'm not convinced that the "average CFS patient" has brain damage that is comparable to that found in CP, MS, PD etc (so if it exists, it must be rather subtle). However, Guido's other recent statements are rather interesting because much of the objective evidence (neuroimaging) for the subjective experience of cognitive difficulties in CFS seems to suggest (to me anyway) that compensation is occurring via the increased activity needed to achieve the same cognitive result as people without CFS (PMID 17092441)(PMID 15907308)(PMID 17408973)(PMID 17079703)(PMID 15240435). Personally I suspect that both the atrophy and the need for increased cognitive effort is largely caused by some underlying biochemical interference to cellular function, and to a lesser extent could also be related to the deconditioning that would occur from pathologically enforced inactivity. This makes regaining function even more difficult than usual or even impractical in some cases as long as the underlying CFS mechanism remains, because it seemingly prevents both efficient utilisation and proper maintenance of the tissue even when it is stimulated adequately. - Tekaphor 05:52, 9 November 2007 (UTC)

The full recovery rate seems low, even after "successful" CGT where improvements were observed; so considering the heterogeneous nature of the case definitions and the current lack of understanding, I wouldn't view these full recoveries as a clear reason to totally dismiss any "damage" in non-recovering patients. Note that rehab-programs can even assist people recovering from currently recognised brain damage, however in more severe damage and/or cases where the cause of the damage is ongoing (e.g. MS and PD) rehabilitation attempts are unlikely to reverse the damage or restore much function. We don't yet if there is brain damage specific to CFS, and if there is, whether it was caused by initial injury (i.e. acute infection) or ongoing processes (e.g. immune activity). Furthermore, association with "stress" doesn't necessarily rule out tissue damage either; because viruses, oxidative stress, altered immunity etc, could have a greater impact than usual. But getting back on track, how do we resolve this argument about brain damage? Unless we better define it and use evidence from solid sources, the term "brain damage" probably shouldn't be used in the article. - Tekaphor 05:52, 9 November 2007 (UTC)

CFS was termed ‘Yuppie Flu’ because at one time it was seen to afflict mainly ’young upward mobile professional persons’ usually totally time committed at work and play. So overactivity does have an historical relationship to induction. Of course not all such individuals contract CFS. So other factors are as relevant, maybe genetic, may be different ways of internalising load, infections and maybe the sum of all these factors, we really do not know yet? Once triggered it is clear then stress / overactivity does play a more significant part in perpetuating the condition, making management and ‘recovery’ if there is such a thing, more difficult. Even with the current state of research, no individual can any longer be “blamed” for their CFS. What we need to do here is to try and make sense of the findings without pushing POV, to do this an ‘ideal scientific neutral observer’ position is required. Understanding other editor’s perspectives can unmask biases, and that is what we see on this talk page, hopefully it will be constructive, although some of it of late seems to be taking on a more personal edge. Keeping medico-political issues separate from the science is also needed, particularly as consensus (or lack there of) should relate to the topic of discussion and not whether one agrees with another’s politics. Jagra 01:47, 10 November 2007 (UTC)

It was termed "yuppie flu" because (so the story goes) these were the people who either fought to be seen by doctors. It is not the case that only the young, affluent actually got CFS, as has since been verified. We know from the history of the disease that it can affect everyone from schoolkids to housewives to nurses to sheep farmers. MEspringal 06:57, 14 November 2007 (UTC)

Overtraining and CFS

Sciencewatcher, Overtraining unlike CFS is associated with high cortisol and therefore not directly comparable to CFS. PMID 12696983 There are some similarities in the cytokine profiles but that does not equate with similar induction, unless you can explain the differences? PMID 14738459 It seems chronic inflammation has been associated with long term brain damage, but more likely to occur with Primary depression because high cortisol in that condition (unlike CFS) restricts regeneration of neuronal networks. PMID 17705097 If there is brain damage / injuries then supplementation with n-3 fatty acids is advisable. PMID 15129302 and have shown benefit in such injury PMID 12640327 This paper links ACTH vasodilation of the adrenal glands with n-3 fatty acid (EPA) release and increased cortisol. PMID 17446179 n-3 fatty acids (EPA) are vasodilative in the brain and reduce inflammatory PGE2 PMID 2141767 PMID 1590442 Fish oil supplementation reduces exercise induced prostaglandin PGE2 and increased cortisol PMID 17923401 and improves blood flow in other exercise intolerant conditions PMID 16770472

Thus n-3 fatty acid has potential benefit in CFS, indeed n-3 fatty acids are found deficient in CFS (likely due to hyper-response) Supplementation with (EPA) has been demonstrated by MRI to improve brain structure in CFS and reduce symptoms PMID 15117099 PMID 16935966 I propose these recent findings be included in the article.Jagra 01:08, 11 November 2007 (UTC)

No, overtraining is associated with high cortisol during the initial stages, follewed by low cortisol during the chronic phase, which is likely similar to CFS. See for example http://www.rrca.org/resources/articles/sum99ots.htm. The CFS fish oil study was done on one patient with no controls, so we don't know if it was actually the fish oil that helped. The MRI doesn't prove that the fish oil caused the changes in the brain - the placebo effect could have caused the change (or else just natural recovery). Basant Puri has been proposing fish oil for years as a treatment for CFS, but so far he has not come up with any controlled studies that actually show it has a benefit, as far as I am aware. And there has been speculation for even longer that fish oils might help schizophrenia and bipolar disorder, but again the evidence isn't very strong. --Sciencewatcher 19:03, 12 November 2007 (UTC)

Interesting but not WP:RS unlike references above, note also different sympathetic function to CFS, so not the same! Do you have any evidence of high cortisol in CFS, at any stage, I'm not aware of it? Fish oil trials, lack of sufficient evidence, is not evidence of lack? prelimunary trials include PMID 15041033, lack of commercial sponsor for a natural product just as likely a reason. A search of pubmed will reveal 139 papers by Puri B, his expertise appears to be in MRI brain studies in conditions with known fatty acid changes, the reason he advocates fish oil is because he has observed and reported many such improvements including ( only recently) with new techniques/tecnology in CFS PMID 16777669 PMID 16777668. I would not shoot the messenger just yet! Have to disagree, there is nothing natural about recovery in CFS. Jagra 02:04, 13 November 2007 (UTC)

Would agree I've never heard of high cortisol in CFS, which isn't say it may be an acute phase phenomenon. But finding similarities between CFS and in this case, overtraining simply on the basis of cortisol and cytokines (whch are quite non specific) is superficial as there are far too many other findings to take into account. Anyway most sources agree that CFS is likely discrete even if it's heteregenous, so attempts to redefine it as effectively misdiagnosed overtraining etc are flimsy (even if, to complicate matters, CFS is as Hyde says, often a misdiagnosis). MEspringal 06:57, 14 November 2007 (UTC)

As stress is a common trigger for CFS (and stress is associated with high cortisol), you could say that CFS patients have high cortisol before they develop CFS. At the moment the research into the HPA axis in CFS patients is confusing, probably because it changes a lot depending on what stage of the illness the patient is in. Overtraining and CFS are similar in that both are triggered by stress. You could say that overtraining is being misdiagnosed as CFS, but then you are making an assumption that CFS is not a stress-related illness. --Sciencewatcher 23:49, 15 November 2007 (UTC)

Sciencewatcher, Even where stress is involved in CFS induction, the evidence indicates it is just as likely due to allostatic load PMID 16610956 PMID 16610958 CFS is considered a Type 4 load which suggests it is a protective adaptive response of the body, become chronic. Where low HPA responsiveness may result in increased activity of other systems including the immune responses and have health implications. See FIG.1 and discussion following in the full text ot this one PMID 10649824. Which means it is already hypocortisol maybe even chronic in some before CFS induction not just starting afterwards as you claim above.Jagra 08:00, 16 November 2007 (UTC)

I'm only aware of one study where CFS patients were more likely than healthy controls to have exercised regularly before illness onset (67% vs 40%) [PMID 8644768]. However, terms like "over-training" and "over-activity" are relative and dependent on individual capacity or circumstance. No one here is proposing that CFS is the same as overtraining syndrome, but even the similarities between them have been overstated; as far as I know, there is no solid evidence that high cortisol is actually involved in either condition's acute phase. Furthermore, overtraining is not merely "triggered by stress" as implied above but is specifically caused by ongoing physical over-exertion, something which is exclusionary for a CFS diagnosis. Of course, someone who assumes that all stress has the same biological effect could argue that chronic psychological stress could be a form of over-activity. Perhaps the studies about the HPA axis in CFS are confusing because the HPA axis simply isn't as fundamentally involved as assumed. There is so much more to exertion than the blood concentration of cortisol. I'm sure we can all concede that over-activity at least could be one of many co-factors for some people's CFS. I agree with Jagra that over-exertion seems to become much more of a problem once CFS has developed, and with Guido that over-exertion prior to CFS could increase susceptibility by lowering defences (or whatever). As for essential fatty acid trials, don't forget about [PMID 2270749]. - Tekaphor 08:08, 16 November 2007 (UTC)

Yes, it is either physical or mental over-exertion that seems to trigger CFS. In the case of overtraining it is physical, and in the case of CFS it is generally mental/emotional, and sometimes illness as well (although it is difficult to tell if the illness is an actual trigger or just another symptom). The common factor in both is excessive stress, which acts on the body in the same way whether it is physical, mental or emotional, or due to illness. In both overtraining and CFS, the symptoms and physiological abnormalities are consistent with stress/burnout.---- Sciencewatcher (talk) 18:19, 16 November 2007 (UTC)

Which specific "physiological consistencies" are you referring to? - Tekaphor (talk) 02:21, 21 November 2007 (UTC)

Abnormalities in the HPA axis and autonomic nervous system...typically a reduced HPA axis drive. --Sciencewatcher (talk) 21:47, 21 November 2007 (UTC)

Sciencewatcher, This study found HPA-axis in burnout normal, hyper-cortisol in primary depression and hypo-cortisol in CFS PMID 16150550 Burnout is characterized by low serotonin or low dopamine, PMID 17641533 Some studies indeed show high cortisol in burnout as might be expected. PMID 12782748 Burnout then would seem to have more in common with Overtraining than CFS. CFS has high serotonin, low cortisol, and there are no studies linking CFS onset with high cortisol. Cortisol levels in infectious mononucleosis have not been found predictive of CFS, PMID 12877399 but there is some evidence that high cortisol levels can cause reactivation of latent Epstein Barr virus PMID 12191645 PMID 11719627 In which case hypo-cortisol might even be seen as a protective strategy! So whilst there may be some overlap in symptoms with other conditions of hypo-cortisol more directly linked to stress, it is still a long bow to draw to conclude that CFS is therefore the same, and "consistent with stress/burnout ". Jagra (talk) 01:12, 25 November 2007 (UTC)

Stress generally causes high cortisol, but after burnout it changes to low cortisol. However as you point out, not all studies show low cortisol in burnout - some show normal cortisol. And the same is true for stress and overtraining. So it is not possible to correlate cortisol with stress or burnout. However what we can say is that abnormal (high or low) cortisol is a pointer that indicates an abnormality in the HPA axis, and in the absence of any organic pathology is due to stress or burnout. You also have to look at the causes, which are the same for burnout, cfs and overtraining. --Sciencewatcher (talk) 16:02, 7 December 2007 (UTC)

POV?

First off, I'd like to apologize for placing the POV tag without prior discussion. After reading the article through a few times late last night, I had some vague concerns about the tone of the article, though didn't know how to fix them. I see that alternate (negative) viewpoints on the classification and impact of CFS are mentioned in the article, I just believe that they are first stated, and then argued against extensively. An example of this would be the entire "Social Issues" section, where it begins with:

Many patients find that a chronic fatigue syndrome diagnosis carries a considerable stigma, and has frequently been viewed as malingering, hypochondriac, phobic, "wanting attention" or "yuppie flu".

And follows this statement with many others that seem to argue as to why this is not the case. Other statements just seem to have an odd tone, for example:

Many CFS sufferers are confined to their house and/or bed. They are unable to take part in normal social activity. They are also excluded from workplace and school socialising.

It's entirely possible that I am incorrect, but these type of phrases seem unencyclopedic to me, as they seem more "personal" and situational rather than objectively factual - even if true. I have intermittent internet access and may not be able to fully participate in a discussion, but I wanted to explain my placing of the tag. I fully support that it has been removed; if regular or more knowledgeable editors deem that there are no tone issues with the article, I have no issues with it whatsoever. I also apologize for having trouble expressing my thoughts on the subject, though hopefully someone knows what I'm getting at. *Vendetta* _{(whois talk edits)} 17:29, 18 November 2007 (UTC)

Thanks for explaining, Vendettax. First of all, both statements that you quote are in accordance with the facts as I know them. That said, this is a difficult topic with many emotions involved, and it is quite possible and even likely that some sections carry an undertone that regular contributors do not notice. Feel free to suggest any textual improvements! Regards, Guido den Broeder (talk) 17:42, 18 November 2007 (UTC)

I agree that some of the tone could be improved or better referenced, although the basis of the content is usually warranted. Some of this wording is probably remanents from much earlier versions of the article. - Tekaphor (talk) 02:40, 21 November 2007 (UTC)

What if any significance are the brain right sided asymmetry findings in CFS. In Spect scans PMID 9121617 PMID 10974961, with MRI finding more right sided activation, PMID 17079703 and in ME an association with right hemispheric biochemical dominance PMID 12745627. Is this connected with the symptom of emotional lability in ME/CFS? PMID 8588009 that might go to the emotiveness? Jagra (talk) 08:16, 21 November 2007 (UTC)

Making the article shorter

I'm thinking perhaps underneath "Course", it could be changed just list the names of symptoms, rather than detailed descriptions? —Preceding unsigned comment added by Jobers (talk • contribs) 12:08, 22 November 2007 (UTC)

I agree that symptom information without sources should be slashed. JFW | T@lk 23:52, 22 November 2007 (UTC)

Would you intend to list all symptoms? which criteria will be reference base? At last count i was aware of over 100, do you intend an exhaustive listing, at present it is rather arbitrary ? If we use just symptom names (medical) then some plain english explanation will also be neededJagra (talk) 08:24, 23 November 2007 (UTC)

Toxic Agents

Orangemartin, regarding your edit war on this item, sorry to disappoint you but actually this little piece is not mine but I do think it is supportable, by references, it is time you explained your asinine revision comments, or with your wording change is it semantics you are really interested in?

At present the Article reads; Toxic agents, (ditto, ditto) “have a possible effect on the course of CFS” This ref PMID 7565234 studies CFS patients to CDC criteria, and CFS patients with history of prior exposure to unspecified toxic chemicals. It finds the CFS group has a significantly higher level of toxin than the controls and the 'CONCLUSION: The results suggest that recalcitrant organochlorines may have an aetiological role in CFS'. All courses have a start, and my understanding of English is that ‘may have an aetiological role in CFS” supports the article words of “have a possible effect on the course of CFS”. It is further supported by PMID 8604201 in CFS and PMID 8809349 (with DDE in CFS with a history of exposure) Jagra (talk) 11:23, 30 November 2007 (UTC)

You're citing two studies (and one letter to the editor) from 12 years ago. Is there more recent evidence or reliably sourced opinion that toxic exposures play a role in CFS? I mean, I could pull a number of papers by respected authors, from respected medical journals, from the early 1980's which state that we don't know the cause of AIDS, and say: "Look, reliable sources say we don't know what causes AIDS." Citing "preliminary" studies from 12 years ago without reference to current understanding of CFS is potentially undue weight and original synthesis. Does the current understanding of CFS include toxic exposure (according to reliable sources)? MastCell ^Talk 17:53, 30 November 2007 (UTC)

Toxic chemicals like pesticides are a burden on the immune system which is compromised in ME/CFS, and may therefore build up faster. However, exposure to pesticides does not cause ME/CFS. It does (as is to be expected) increase chronic fatigue, according to more recent research [12] (organophosphates, but chlorines will be similar, is my guess), but that is not the same. A condition from toxic exposure can be mistaken for ME/CFS, and should be excluded in areas where pesticides are still used. Regards, Guido den Broeder 18:25, 30 November 2007 (UTC)

OK - so then we're not saying that toxic chemicals have a role in CFS itself, but that they may possibly be associated with fatigue that should be differentiated from CFS? (Just making sure I have this right). MastCell ^Talk 18:50, 30 November 2007 (UTC)

Typical fringe theory pushers. Pull out a quote from an unreliable source and attempt to make a point. I get so tired of this. OrangeMarlin ^{Talk• Contributions} 19:56, 30 November 2007 (UTC)

@MastCell: yes, toxic poisoning by chemicals is a differential diagnosis. Guido den Broeder 21:21, 30 November 2007 (UTC)

What a load of horse manure. It's good to know that this article is being run by a POV-warriors. OrangeMarlin ^{Talk• Contributions} 22:25, 30 November 2007 (UTC)

Mastcell, It is because toxic poisoning is an exclusion from the research definition for CFS that the studies i cited also differentiate the patient groups in the study. Note that the CFS patients that do not have a history of toxic exposure actually had the highest accumulations of toxic chemicals, and this was significantly higher than the control group. I happen to have a copy of the paper and in discussion it goes on to say, "The significantly higher incidence of HCB contamination and the significantly higher concentration of DDE in the CFS patients than in the control group suggests links between the development of chronic fatigue symptoms and an age dependent bioaccumulation of organochlorine hydrocarbons' "There was a very strong correlation of age with HCB in the CFS group which was not observed in either the control or toxic exposure group" It is the research scientists that concluded therefore that accumulation of such chemicals 'may have an aetiological role in CFS'. If you have any research to the contrary, post that date, then bring it forward, it is RS information that counts not your or Orangemartin's opinions, or colourful turns of phrase. Guido is correct, Toxic chemicals like pesticides are a burden on the immune system which is compromised in ME/CFS, and any such burden will have "a possible effect on the course of CFS" therefore the citation meets the current wording.

Orangemartin also seems to have overlooked the fact that the heading Toxic Agents is actually a subheading under the Main heading of "PROPOSED CAUSES and PATHOPHYSIOLOGY" therefore the study conclusion 'may have an aetiological role in CFS' meets that requirement and either way is a valid citation.Jagra 03:43, 1 December 2007 (UTC)

Mastcell, other papers I origonally posted included this also PMID 8766847 which Orangemartin seemed to have difficulty understanding so let me interpret what it says. That although proof of a causal relationship was not possible 93 out of 320 patients with a probable or possible connection (the two highest categories) between neurological health impairment and neurotoxic agents had all symptoms of CFS. Such toxic agents included; Pentachlorophenol and Lindane 63%, organic solvents 25%, formaldehyde 15%, dental materials 15%, pyrethroides 13%, other biocides 19% This paper certainly went to the text of the Article at that time, before changed, which said “various organic solvents, herbicides, and several other chemical compounds are often named.” If for no other reason this supports dental materials (not just amalgam).Jagra 04:28, 1 December 2007 (UTC)

I understand what the papers say, and I looked at the full text. What I didn't get, and still don't totally get, is why they're being presented as evidence that toxic exposure is involved in CFS when I don't see any current sources making that claim. My sense was that Guido was on the same page with me, in that toxic exposure may cause fatigue, but does not cause the entity of CFS. Am I missing something? MastCell ^Talk 05:16, 1 December 2007 (UTC)

Guido, it seems that the sheep farmer organochloride study is a reliable source despite Orangemartins protestations as it is also here PMID 12765866

Mastcell, try some of these as recent literature also seems to more widely accept insecticides and pesticides, toxins and chemicals as involved in the pathogenesis of CFS PMID 17873115 PMID 15018881 PMID 11513068 PMID 10794403 PMID 8921568 remember also we are dealing with Toxic agents as "PROPOSED CAUSES and PATHOPHYSIOLOGY" there are no proven aetiologies only proposed theories. You may also be expecting to find which straw broke the camels back' given allostatic load findings in CFS, accumulated chemicals and toxins might well contribute to aetiology and/or pathogenesis. Either way the findings in the cited reference are still relevant today Jagra 10:10, 1 December 2007 (UTC)

As already detailed above this study found dental materials in CFS associated with neurological health impairment. PMID 8766847 Whilst this references PMID 16648791 found in CFS sensitization to a variety of dental metals including metals in amalgam, nickel and gold. This controlled study found hyper-sensitivity to nickel and mercury. PMID 11462117 So what is this nonsense about “In other words, doesn't support the statement.” Am I to understand that the authors findings of “metal-driven inflammation” and their conclusion that this “may affect the hypothalamic-pituitary-adrenal axis (HPA axis)” does not support the Article wording of "a possible effect on the course of CFS"?

Perhaps the wording in this one PMID 11460087 Which is a larger study with similar findings to the above references regarding dental metal in CFS “Nickel was the most common sensitizer, followed by inorganic mercury, gold, phenylmercury, cadmium and palladium. As compared to lymphocyte responses in healthy subjects.” And the conclusion is similar “We propose that an inflammatory process induced by metals may modulate the hypothalamic-pituitary-adrenal axis (HPA axis) and trigger multiple non-specific symptoms characterizing CFS and other chronic conditions like myalgic encephalitis (ME) and multiple chemical sensitivity (MCS).” As such the present Article wording of amalgam is inadequate and should be replaced with ‘Dental metals including amalgam’ Jagra 01:11, 2 December 2007 (UTC)

With regard to inorganic poisons the same holds as for organic poisons: they are not ME/CFS, and do not cause ME/CFS, but (a) some of them can cause similar complaints and (b) if you have ME/CFS you are likely to accumulate more of these toxic agents (which does, by the way, not imply that every patient should replace there amalgam fillings). Furthermore some metals, nickel in particular, can cause an allergic reaction, and pre-existing allergies tend to be more severe with ME/CFS. Guido den Broeder 09:28, 2 December 2007 (UTC)

Alternative medicine

Guido, the Hong Kong paper has a PMID number and therefore is peer reviewed, a likely reliable source, it could be tested on the Reliable source noticeboard. Acupuncture certainly is no longer Fringe Theory (discussed by the mainstream) These Refs you might consider also discuss Alternative medicine and CFS. PMID 17459162 PMID 15889950 PMID 16444659 PMID 10882883 Jagra 05:14, 1 December 2007 (UTC)

Jagra, could you expand on those three PMID numbers, rather than expecting us to parse them ourselves?

The Hong Kong paper is a case report. I think case reports usually fall below the notability horizon. The orthomolecular thing needs more discussion, as the J Orthomol Med is obviously the organ of the orthomolecular movement. JFW | T@lk 23:00, 1 December 2007 (UTC)

JFW, The current Article wording says in effect, that CFS patients use alternative medicine partly because conventional treatments are poorly tolerated or ineffective. This study found certain non-prescribed supplements more effective than prescribed medicines and psychological support. Treatments at 6 months that predicted significant subsequent fatigue improvement were vitamins, exercise and Yoga. PMID 15889950 This study on CFS discordant twins found individuals with CFS frequently used alternative medical treatments and a large proportion found alternative therapies helpful; and more of those with CFS than those without CFS discussed their use of alternative medicine with a physician. PMID 10882883 Whilst the third study found people with CFS-like illness were significantly more likely to use body-based therapy (chiropractic and massage) and compared to non-fatigued persons, those with CFS-like illness or chronic fatigue were most likely to use body-based and mind-body therapies. All categories of CAM use were associated with significantly poorer physical health scores, but use of alternative medicine systems was not associated with significantly poorer mental health scores. PMID 17459162

So these 3 references support the general line of the wording. As to modalities I agree that needs further consideration. Unless I am wrong this Hong Kong study on acupuncture in CFS is a blinded controlled trial of 100 that supports the wording? PMID 17997936 It is further supported by these for acupuncture alone PMID 16318125 PMID 16248250 and by these refs of large study on combined treatments including acupuncture? PMID 17710799 PMID 17078435

The effective use of vitamins by patients is of interest as there have been calls for the use of anti-oxidants in CFS by researchers PMID 17693979 PMID 11703165 PMID 10767667 PMID 12531455 PMID 9367343 PMID 17239370 PMID 13677625 PMID 12639396 and by support groups. Trials have been carried out with injected GSH, PMID 11365019. Many of these substances could be classified as alternative medicine, so I will look further into specific references to cite.Jagra 04:54, 2 December 2007 (UTC)

Jagra, you are blinding me with science. You know what: let's do WP:BRD. You write something that is not WP:NOR or WP:SYNTH on the uses of alternative medicine in CFS. Also see my next comment on in vitro studies. JFW | T@lk 09:39, 2 December 2007 (UTC)

The "orthomolecular medicine" reference is poor science: it is fringe theory, and there were no controls. The acupuncture reference is almost as bad. If you look at the actual results, there was not a very significant difference between the controls and active group. The controls symptoms were reduced just slightly less than the active group. Also, they did not ask patients to guess which treatment group they were in, so there is no way of determining whether the patients were actually blinded. Most likely they were not, because the sham treatment did not penetrate the skin. --Sciencewatcher 05:39, 4 December 2007 (UTC)

I agree that one single reference with a poor-quality study may not be suitable for inclusion. I am already opposed to the single case report on acupuncture. Sciencewatcher, you must agree that several studies have shown that patients cannot tell the difference between sham and real acupuncture needles; sham acupuncture is the only way to perform randomised double-blinded controlled trials with real acupuncture.

I am still waiting for Jagra's next move in the BRD cycle. JFW | T@lk 05:52, 4 December 2007 (UTC)

Thanks. The text should indicate that such treatments are offered, not that they are effective. I have changed the wording, hopefully it is more clear now. Guido den Broeder 10:48, 4 December 2007 (UTC)

But apart from a single case report, do you have any other evidence that acupuncture is "offered"? One single case in a Chinese journal (and therefore not easily verifiable) is absolutely insufficient to serve as a basis for such a generalisation. JFW | T@lk 11:34, 4 December 2007 (UTC)

JFW: the problem is that as far as I am aware, there is no acupuncture sham which actually works (i.e. where the patients do not know whether or not they had the real treatment). For the study to have any value, they need to test the blinding by asking patients to guess which treatment they had. This acupuncture trial did not do that. Currently the only sham procedure for acupuncture that has been shown to work is to actually puncture the skin, but to do it at a non-acupuncture point. When this is done there is no difference between acupuncture and the sham procedure, meaning that acupuncture is either completely placebo effect, or that it is the needles puncturing the skin that causes the effect (but it doesn't matter where you stick them). Overall, acupuncture research (and in fact most CAM research) is riddled with shoddy trials which do not have effective sham procedures. --Sciencewatcher 16:23, 4 December 2007 (UTC)

I have added a second article on acupuncture. The fact that an article is in Chinese does not make it less verifiable. That's your shortcoming; not the article's. Guido den Broeder 16:31, 4 December 2007 (UTC)

The article you added had no controls, so I removed it along with the others you also added. Please stop adding worthless studies to support your position. --Sciencewatcher 16:35, 4 December 2007 (UTC)

Please refrain from editwarring and insults. The text is, by the way, unrelated to 'my position', I merely improved and sourced an older text. Guido den Broeder 16:50, 4 December 2007 (UTC)

All the alternative medicine section is saying is that there are modalities being researched. Really, only acupuncture is being researched. The orthomolecular medicine reference is to a single case study, of a single patient, nearly eight years ago. That means that orthomolecular medicine was reported once, to work for a single person. That's not a program of research, that's a single case report. I think given the statement in the article, it's best to call that section 'acupuncture' and leave out alternative medicine barring other sources. WLU 21:09, 4 December 2007 (UTC)

Agreed, for the moment. If we find other research, we can always expand. Thanks, Guido den Broeder (talk) 22:30, 4 December 2007 (UTC)

There are lots of speculative treatments being researched, but they should not be listed in an encyclopedia article unless they have been shown to work. The references given for acupunture do not show that it helps cfs at all. --Sciencewatcher (talk) 21:56, 4 December 2007 (UTC)

Given the continuous back-and-forth reversion, I have now requested protection (diff) so we can actually work out a consensus rather than be silly. Jagra has posted a large number of studies, but I have no access to most of them and would much prefer if any contributor (preferably Jagra himself) could propose a non-controversial paragraph here that summarises alternative medical approaches being studied for CFS. Keeping in mind my comment below, the studies need to be clinical studies with clearly set clinical endpoints, rather than looking at CD56+/CD16- lymphocyte subsets or other surrogate markers. JFW | T@lk 02:32, 5 December 2007 (UTC)

I haven't been on-line much the past three days, so I haven't seen it. Right now the page reads Acupuncture is being researched as an alternative treatment for chronic fatigue syndrome, with some evidence suggesting that acupuncture may reduce symptoms.[259][260] Other alternative treatments are sometimes proposed for CFS, especially when conventional treatments are poorly tolerated or fail to relieve symptoms. Seeing as the two articles referenced are pubmed articles, I think that's a reasonable summary of the two articles. The other sentence doesn't have references, but they do seem reasonable if no-one else objects. That's my two cents, I'm happy to see this version protected and I don't think much else could be said given the references. WLU (talk) 02:35, 5 December 2007 (UTC)

I'm with WLU on this one. It goes against Wikipedia to assume that only English sources are verifiable. And constantly deleting a section while others are working to improve it does not strike me as constructive. Guido den Broeder (talk) 09:17, 5 December 2007 (UTC)

Despite Guido's insinuations, I have my doubts about the verifiability of non-English references. The first one of the Chinese studies has a control group, which used sham acupuncture. Contrary to Sciencewatcher, I believe that sham acupunture methods have been adequately validated (example). If it would be possible to find an English reference supporting claims about acupuncture research, that would be much to be preferred.

Obviously many more alternative modalities "are being investigated" for CFS. Tiredness is a very common presentation where conventional medicine has little to offer, and where complimentary/alternative medicine may offer detoxification, healing, meditation, crystals, dolphins and other things more. I cannot believe that nobody has documented efforts to apply these to "case definition positive" CFS (or even ME). JFW | T@lk 03:02, 5 December 2007 (UTC)

JFW: I had a look at the article about sham procedures you posted, and it does seem to be valid. But what procedure did this Chinese study use? Unless someone can answer that simple question, the study has to go... --Sciencewatcher (talk) 03:13, 5 December 2007 (UTC)

Also: have a look at Table 1 (inside the full text article). It seems pretty clear that the results are NOT significant (even though the authors claim they are). Example: the difference between the "before" scores of the control and active groups is twice as high as the difference between the "after" scores! Also the control group's reduction in symptoms is about 80% of the active group, meaning that the placebo effect is accounting for at least 80% of the improvement. And the difference in scores between active and controls is about 25% of the standard deviation. Any way you look at it, it is an incredibly poor study and it certainly doesn't give any credence whatsoever to the idea that acupuncture helps CFS. --Sciencewatcher (talk) 03:30, 5 December 2007 (UTC)

The full text of this article can be found here. Reduction of fatigue symptoms in the control group is 53% (mental) and 65% (physical) of that of the trial group, not 80% as Sciencewatcher claims. Improvement in SF-12 score was 54% of that of the trial group. There is no reason to assume that these differences are wrongly reported as significant, Sciencewatcher is comparing apples (standard deviations within a group) with pears (standard deviations of changes). Guido den Broeder (talk) 10:05, 5 December 2007 (UTC)

The reduction in symptoms is meaningless when the baseline score was so different between the control and active groups. If you take 30 as the baseline for the physical fatigue before score, then the reduction of the control vs active group is 81.7%, as I said. And how can a difference of 1.17 in the mental fatigue after scores be "P<0.01" when the difference in baseline scores between the two groups was 2.1 before treatment! Please explain to us all how you think the figures were fudged to calculate the P<0.01 so we can all have a good laugh. --Sciencewatcher (talk) 16:32, 5 December 2007 (UTC)

As for your 81,7% - the baseline wasn't 30 in both groups, was it? JayEffage (talk) 19:21, 5 December 2007 (UTC)

It was different in both groups, and that is my point. Obviously the group with the higher symptoms before the study is going to improve more. It is just as valid (or invalid) to compare the final outcome against a common baseline than to compare against two different baselines. --Sciencewatcher (talk) 20:42, 5 December 2007 (UTC)

"Obviously the group with the higher symptoms before the study is going to improve more". Could you explain that statement a bit please?

Explain please why the improvment here is not only bigger in relative but also in absolute terms (After treatment value for mental fatigue in sicker group better than after treatment value in sham-treatment group)JayEffage (talk) 21:26, 5 December 2007 (UTC)

I can think of a number of possible reasons. If the treatment cures the patient, then the original baseline is irrelevant. If a patient is sicker at the start then he will obviously have a greater improvement when cured. But more to the point: how can the result be significant if the original groups differed by more at the start than at the end? The study is assuming that the difference at baseline is non-significant. Therefore, logically, the (smaller) difference between the groups after treatment must also be non-significant. --Sciencewatcher (talk) 22:24, 5 December 2007 (UTC)

You missed my point. You are explaining a general, hypothetical scenario in which patients are cured (not the case in this study) and the relative gain in health by the group which was sicker before it was cured is trivially bigger than the gain in health by the group which was less sick before it was cured. In this study, the patients are still sick. But the group with the sicker patients before treatment is now the group with the less sick group in ABSOLUTE terms. (Or in other words: The sicker group is cured beyong the point of cure of the less sick group.) The algebraic signs of the two differences are not equal, they are opposite. So the study must not necessarily assume that the difference at baseline is non-significant. JayEffage (talk) 22:56, 5 December 2007 (UTC)

I think you missed my point. The whole point of a control group is that it is the same population as the treatment group. If you have to assume that the control group is statistically significantly different from the treatment group at baseline then the study is meaningless. Error and bias works in both directions, and that is more likely to explain the results than the treatment. --Sciencewatcher (talk) 01:14, 6 December 2007 (UTC)

I think it is the original authors who were comparing apples and pears. If you use their logic then the control and active groups also fit the P<0.01 significance for being different, rendering the entire trial useless. Can someone shed some light on the exact calculation that is used to determine these probabilities? --Sciencewatcher (talk) 16:38, 5 December 2007 (UTC)

You might gain some insight if you first try and formulate what these probabilities stand for (these are probabilities of what?). Hint: they have nothing to do with what you have said so far. Guido den Broeder (talk) 17:09, 5 December 2007 (UTC)

Your smugness is unbecoming and though not uncivil, isn't helping with the acrimony on the page; if you've a problem with SW's conclusions, state them. We're not children, and there is some merit in my mind to SW's objections. Sciencewatcher, my problem with this edit is that it is verifiable that acupuncture has been investigated and as reported in a reliable source, there's some evidence it might work. Non-english sources are acceptable, and with a pubmed number I'm inclined to say it's a reliable source. It's phrased as a suggestion of symptom reduction, not a definitive treatment. I agree that the stats don't look great, and their conclusions are wildly inappropriate, but the articles exist and do add information to the page pending better sources. Perhaps we could agree on a watered down version of the current page, even just 'acupuncture is being investigated as a symptomatic treatment for CFS'? WLU (talk) 18:49, 5 December 2007 (UTC)

Hey Guido, I know exactly what the probabilities mean. I just don't know off the top of my head how to calculate them. But it is clear that the numbers they have calculated have no basis in fact - they have either misunderstood or <deleted>, and you are doing the same. And you haven't answered any of my criticisms. I am not going to waste my time figuring out how to correctly calculate the probabilities for an obviously poor study. If you really want to defend the study, perhaps you can post an analysis showing how they might have arrived at those probabilities, so that we can critique it.

WLU: Having a pubmed number is definitely not a guarantee of being a reliable source. --Sciencewatcher (talk) 20:36, 5 December 2007 (UTC) deleted insult Guido den Broeder (talk) 23:27, 5 December 2007 (UTC)

@everybody: If you run the paper through babelfish, you can see that they used "variance analysis". That's the only mehtod name I found in the gibberish. if you run the numbers (active and control for mental fatigue) through a Forumula for "F" and compare to a fisher's table for 0.01 you will find that it it holds.JayEffage (talk) 21:26, 5 December 2007 (UTC)

Hardly worth the trouble though, nobody in their right senses - be them western or eastern - will try to cheat you in statistics by rigging anything in a traceable (e.g. numerical) way. The devil is mostly in the things that conveniently don't get a mention.

I think we should settle for WLU's suggestion and leave fisk and counterfisk to the friendly folks at the accupuncture page. JayEffage (talk) 22:10, 5 December 2007 (UTC)

If you do a 2-tailed student's t test on the baseline scores for mental fatigue for the 2 groups, you get a probability of 0.0424, which is statistically significant. And if you do the test on the "after" scores, the probability is 0.22, which is not statistically significant. Therefore the control and treatment groups are statistically different BEFORE the treatment, but not after. I think the problem is that the study is using meaningless statistics. --Sciencewatcher (talk) 23:25, 5 December 2007 (UTC)

These are irrelevant comparisons. The hypothesis is that the trial group improves more than the control group. That, and only that, is what is the p-values reflect. Guido den Broeder (talk) 23:36, 5 December 2007 (UTC)

But that statistic is meaningless if the trial and control groups are statistically significantly different at baseline (which they are). The populations are more different at baseline than after the treatment. The whole point of a "control" group is that it comes from the same population as the treatment group, and the study variables should be similar in both groups at baseline, otherwise the entire study is completely meaningless. The same errors and bias that result in differences at baseline will result in differences after treatment. --Sciencewatcher (talk) 01:14, 6 December 2007 (UTC)

Although the match could have been better, the two groups do not seem to be significantly different from each other before treatment. Guido den Broeder (talk) 01:35, 6 December 2007 (UTC)

See my comment above regarding the Student t test, which confirms they are significantly different before treatment. That is the reason why the study is invalid (along with not validating the blinding). You can confirm the t-test yourself here--Sciencewatcher (talk) 03:36, 6 December 2007 (UTC)

You cannot interpret your outcome that way. The groups have four characteristics. Odds are, that such a test will show a difference in one of them purely by chance. Taken together, the four differences are within normal range. Guido den Broeder (talk) 11:20, 6 December 2007 (UTC)

Well, this discussion has nothing to do with WLU's suggestion anymore. For what it's worth, I did the t-test as sciencewatcher suggested - and it turned out as he claimed(= not significant). If, however, you do a variance analysis as the authors of the paper did, you do indeed get a significant result. That is odd, one good explanation is that I did it wrong - but then the authors would have done it wrong as well, which I doubt. In addition, it raises the question why they used that method.

I personally disagree with sciencewatchers conclusion that the ex-ante difference in active and controll group renders the study invalid, because the direction of the difference changes before and after the study - that is an extra piece of information which cannot be discounted on a purely rethorical basis like "there was a difference - therefore invalid". Although it gives the entire paper a strange taste.

If we want a definitive answer, we have to contact the authors (email is in the pdf...) and as them about their methodology, if the control/active differences are accident or purpose etc..

Alltogether, it's probably not worth the effort. I still think we should go for WLU's suggestion.JayEffage (talk) 11:50, 6 December 2007 (UTC) (sorry, forgot to sign)11:48, 6 December 2007 (UTC)

I'm sorry, but SW's t-test is invalid, so yes, you did it wrong, too, but the authors didn't. You cannot look at the outcomes and then say: "Hey, this difference seems big, let's test it separately." The proper test is the probability of the largest of four differences being that big or bigger. Another one is to test the pattern as a whole. These are tests that we cannot perform, because we don't have the covariances, but rest assured that they will come out OK. A rough estimate for the second test would be to take the geometric mean of all four p-values. Guido den Broeder (talk) 12:49, 6 December 2007 (UTC)

Perhaps you will understand it this way: the p-value for a separate test on the second largest difference, physical fatigue, is 0.1647. This means, that SW is investigating a p-value of 0.0424, for something that he picked to be less than 0.1647 for certain. The t-test, however, knows nothing about SW's deliberate choice to select the largest of four differences, and merely assumes that it is less than 1, i.e. it assumes a full t-distribution, while in reality it is truncated: a large portion of all the probabilities is unavailable. Therefore, the true p-value for SW's test is 0.0424/0.1647=0.2574, which is not significant. Regards, Guido den Broeder (talk) 13:52, 6 December 2007 (UTC)

But Guido, why should SW's test be invalid?

And if I did it wrong, then why did I reach at the same conclusion as the Authors, namely the difference after treatment for mental fatigue having p < 0,01? Please note that the authors used a little symbol (two delta signs/triangles) to denote the p < 0,01 signigicance specifically for the outcome of mental fatigue. Or am I reading that wrong?

You might still have a point, because the text talks about some sort of repeat analysis (and that's where variance analysis is commonly used). As I said, if you want a comprehensive answer, you will have to contact the authors, we can just guess what they did or didn't do.

If you think that's worth it...I am perfectly happy with WLU's statement.JayEffage (talk) 14:09, 6 December 2007 (UTC)

You have a test with 19 white balls and one red ball. Then you remove 16 of the white balls from the test without telling anyone, and still claim that if the red ball comes out something must be terribly wrong. Guido den Broeder (talk) 16:20, 6 December 2007 (UTC)

Been off-line for 4 days for technical reasons, unable to respond to JFW invitation, seems things have moved on, so I will add to discussion whilst protected. Support WLU comment and think the sentence "Other alternative treatments are sometimes proposed for CFS, especially when conventional treatments are poorly tolerated or fail to relieve symptoms" is supported by the three references commented on at the top ie. PMID 17459162 PMID 15889950 PMID 10882883. Except that I would phrase it as "CFS patients use alternative medicine, at times in consultation with their practitioner, partly because conventional treatments are poorly tolerated or ineffective".When it comes to modalities there is some evidence also for anti-oxidant use in CFS, and I will add this further.Jagra (talk) 05:09, 6 December 2007 (UTC)

Guido: you don't seem to have understood what I'm talking about. You mentioned "differences" but that is not what I was testing (and I didn't have the information to do that anyway). The Student t test is for comparing two groups to see if they came from the same population. That is what I was testing. The control and treatment groups at baseline are significantly different according to the t test. We have all the information that is needed to do that test.

Jay: surely it doesn't matter that the signs are different. Think of it this simpler way: there is a large error/bias/noise/whatever in the "before" scores. The difference in the "after" scores is actually less than this noise, and is therefore irrelevant. Of course you can come up with statistics that will give a "significant" result, but statistics must be based on some kind of foundation to be meaningful and valid. --Sciencewatcher (talk) 15:51, 6 December 2007 (UTC)

If you want to test whether the groups are different you must test on all four variables simultaneously. This t-test is only for the simple case where there is just one variable.

The hypothesis is not that the treatment creates a difference between the two groups, but that the improvement of the trial group is larger than of the controls. Guido den Broeder (talk) 16:29, 6 December 2007 (UTC)

As I said, for the study to be valid the variables at baseline have to be similar between the two groups. You can do all the statistics you like, but the study is still invalid. You can use the t test to test each individual variable at baseline and you'll see that they are significantly different. That is what the t test is designed for, and that is how you use it. You certainly do not need to "test all 4 variables simultaneously". --Sciencewatcher (talk) 16:39, 6 December 2007 (UTC)

Yes, you do. If the rules of statistical inference were as you claim them to be, you could render any two groups different by simply adding more variables until one pops out that fails your t-test. Say, 8 patients in the first group were born on a Monday, and only 6 in the second group. Then, according to you, the study would become invalid when we added these data. Guido den Broeder (talk) 16:48, 6 December 2007 (UTC)

All that this t-test does is estimate the probability that a single-variable difference is a random occurrence. It is not a proof; the cut-off point is arbitrary. We simply agree that if the probablity is less than e.g. 5%, it's too unlikely. But we could be wrong, it could still be a coincidence. Now, if we have more variables, the odds of finding one such difference purely by chance increase dramatically, to {1 - 95%x95%x...} if they are uncorrelated. Therefore, we won't use the same cut-off point. Get it now? Guido den Broeder (talk) 17:12, 6 December 2007 (UTC)

But the study results are each calculated on single variables (mental fatigue, physical fatigue, etc.) so if it's valid for the study to base its results in individual variables, then it is equally valid to do the same for the baseline scores. --Sciencewatcher (talk) 20:49, 6 December 2007 (UTC)

No, it's not. Furthermore, that's not what you set out to do, not what you did, not what you claimed to do. Guido den Broeder (talk) 21:37, 6 December 2007 (UTC)

So, ignoring Guido's last incomprehensible comment, can we assume that nobody has any objections to deleting this acupuncture reference due to the severe methodological problems? I suggest we revert either to my last revision, or to OrangeMarlin's revision on 30 November (where the alternative medicine section is simply deleted). While there is evidence that alternative medicine helps CFS, there is no evidence that it is any better than placebo. As for acupuncture, there is good evidence that poking needles into the skin reduces pain over and above the placebo effect, but it doesn't seem to matter whether you poke them into acupuncture points or non-acupuncture points. So it might in theory reduce pain in CFS, but I can't see it helping with much else. --Sciencewatcher (talk) 16:55, 8 December 2007 (UTC)

I object as well. Guido's last statement is neither less nor more valueable as your above non-backed-up drivel about your personal feelings regarding alternative medicine and what you feel about the placebo effect. The statistical question is not settled - and while the discussion was sure interessting and partly revealing - this page is not the place to pick the contents of a study appart.

Again, I would go for WLU's suggestion, that accupuncture is researched in CFS. JayEffage (talk) 11:15, 10 December 2007 (UTC)

Well I for one would object and add a further modality for discussion.

Alternative medicine and Anti-oxidants

A hyper-responsive immune system with resulting lipid peroxidation is associated with oxidative stress in CFS. Although there are several enzyme systems within the body that scavenge free radicals, the principle antioxidants are vitamin E, vitamin C, n-acetylcysteine and a-lipoic acid. The vitamins C and E are thought to protect the body against the destructive effects of free radicals. Oral administration with selected antioxidants, a-tocopherol (vit E), and ubiquinone (CoQ10) potentiate antioxidant defence systems. Additionally, selenium, a trace metal that is required for proper function of one of the body's antioxidant enzyme systems, glutathione (GSH). PMID 17535753 Zinc and L-carnitine are both anti-oxidant and increase glutathione. PMID 16338007 PMID 17826175 (see discussion item 10.3 above for more inter relationships) Researchers are calling for the use of anti-oxidants including these substances and others in CFS (see references above)

Research has found low levels of anti-oxidants indicative of high demand in CFS, including; ubiquinone (CoQ10), glutathione, and free-radical scavenging enzymes, (SOD and catalase) PMID 12745627 PMID 10872900 low vitamin E PMID 10872900 PMID 12531455 low serum Zinc PMID 16338007 lower serum total carnitine, free carnitine and acylcarnitine levels, PMID 12414265 PMID 9854142 PMID 8544970 Increased ascorbic acid (vitamin C) demand PMID 15715687

The following is proposed for addition to the Alternative medicine section of the Article; Supplementation/treatment with anti-oxidants, glutathione, ubiquinone (CoQ10), oral L-carnitine, acetylcarnitine, and propionylcarnitine, and vitamin C infusion, has shown benefit in CFS PMID 11365019 PMID 8241699 PMID 9018019 PMID 15039515 PMID 8986468 Serum vitamin E improved after magnesium supplementation PMID 10872900 Jagra (talk) 03:41, 10 December 2007 (UTC)

This article is about people

At the moment, we quote a lot of research that is primarily in vitro work. PMID 16648791, which is the only reference supporting a role for "dental amalgam", is primarily a laboratory study on lymphocytes, with clinical improvement added as some sort of afterthought. There is an enormous loss to follow-up (less then half of the original cohort), very much indicating that the study is open to recall bias - perhaps those who didn't improve couldn't be bothered to have their veins stabbed again and declined to respond. The abstract also doesn't indicate how improvement was measured - subjectively or through well-validated tools.

Ideally we should have some sort of standard on the quality of studies we base this article on. JFW | T@lk 09:39, 2 December 2007 (UTC)

I think that's why we're here as editors. One or two people can throw in a reference, without actually reading it, and claim it proves one point or another. A neutral point of view requires reliable sources, avoidance giving undue weight to fringe theories, and not creating a conclusion when one isn't there. I read these references put in by alternative supporters--the strongly positive ones usually come from non-peer-reviewed sources and are biased, or they actually don't support the statement. Either way, we should delete. OrangeMarlin ^{Talk• Contributions} 02:39, 5 December 2007 (UTC)

Seems to me the Melisa test is merely pathology and is used as such,in this study, test- diagnose- treat- test again- observe (people). Tell me why it should be considered otherwise? There are many reasons testing is done 'invitro' and not 'in-vivo' including for ethical reasons. Still a large study on 248 people!Jagra (talk) 04:45, 6 December 2007 (UTC)

There are many problems with this study. What is the mechanism for these metals causing CFS when they aren't known to do that? Where is the control group? Where is the randomised placebo control (and how do you do that?) Bear in mind that the placebo effect can result in significant changes to the immune system which could cause the Melisa results, and dental amalgam removal will obviously generate a huge placebo effect. As Orangemarlin says, this study simply doesn't support the author's conclusions. It is poor, fringe science. --Sciencewatcher (talk) 16:46, 6 December 2007 (UTC)

Sciencewatcher, you too are missing the point, Toxic agents comes under "PROPOSED CAUSES and PATHOPHYSIOLOGY" and the Article wording says '(may) have a possible effect on the cause and/or course of CFS'. The authors propose an improvement on the course, no one has said it is the cause! We do not know how long the follow up period was, but the reason for such longer follow up is because placebo effects wear off quickly, if as Bricker points out below there were any at all, 'a huge placebo effect' is your POV? Given I have already posted 3 RS papers by seperate authors with similar results and Pubmed shows 18 studies in a range of journals, I think it easy to demonstrate it is discussed by the mainstream and not likely 'fringe'. What is the basis for your assertation, show me something RS that says is fringe. For your edification Orangemartin did not make any such comment in relation to the paper under discussion, but to this one PMID 11462117 a smaller study. Jagra (talk) 05:59, 7 December 2007 (UTC)

The kind of placebo effect that would be in effect here would be the same as for depression, which gradually takes effect over a period of months. I suggest you do some more research. I wasn't giving a POV, just a possible explanation. The placebo effect will be huge if the circumstances are right, as they are in this experiment, whether or not there is a clinical effect. It doesn't matter how many papers you have if they all have the same methodological problems. There are hundreds of papers "proving" that homeopathy works. --Sciencewatcher (talk) 15:41, 7 December 2007 (UTC)

How can you have a "huge" placebo effect, but no clinical effect? Bricker (talk) 04:31, 8 December 2007 (UTC)

I meant no effect from the treatment. Why don't you do something useful instead of always insulting and picking hairs, like actually contribute to the article? --Sciencewatcher (talk) 16:25, 8 December 2007 (UTC)

While of course, the extensive statistical analysis you just took part in on this talk page, wasn't picking hairs. Give us a break, sciencewatcher...JayEffage (talk) 16:47, 8 December 2007 (UTC)

So we agree it is not 'fringe', but you do not think the treatment might have a 'possible effect on the course of CFS' because of a supposed placebo effect the authors had not considered. How about you do your research and post some references to prove your point of the 'huge placebo effect'Jagra (talk) 03:51, 10 December 2007 (UTC)

Unexplained and persistent fatigue

Without wanting to add to controversies, I think it might be wise to clarify at this time, for all concerned, whether or not this Article encompasses ’unexplained and persistent fatigue’. For those not familiar with the term and its historical synonyms, such as ‘CFS like’ or ‘resembling Chronic Fatigue Syndrome‘ this is code by researchers for “CFS that does not meet the 1994 CDC research criteria” But today may well meet the NICE guidelines for CFS diagnosis, and is not to be confused with ‘chronic fatigue’ per se. Serious CFS researchers (such as the CDC) are now carrying out parallel studies on this category and finding some distinct features (such as different gene expression), it may well end up being called CFS type 3 or the like. There is a body of evidence already out there and so it needs some consensus as to how it should be referenced in the Article, rather than ignored, as if it belonged in a different Article! My suggestion for what it is worth, is to distinguish such in the text (as we sometimes do for ME) For instance “this is found in CFS and/whilst in UPF that ---etc” Jagra (talk) 09:55, 6 December 2007 (UTC)

Jagra, there should be a "CFS vs fatigue" section that explains the differences. We have previously discussed the unreliable and arbitrary nature of CFS definitions, but discussion also faces the problem of interpreting the nature of the symptoms; physical and emotional symptoms can be misinterpreted on questionnaires, which is made more difficult when considering possible overlap and interaction. You may also be interesting in or already know that at the 8th International Association for CFS-ME conference, Dr Porter discussed the need to have different ways to describe "fatigue". Her study (with 200 controls and 120 with CFS) used factor analysis to differentiate various types of fatigue and found 5 terms based on subject reports: wired fatigue, brain fog fatigue, molasses fatigue (extreme heaviness), flu fatigue and post-exertional fatigue. Only flu fatigue was found in the normal controls. I think something similar exists for pain too, but "general aches and pains" is about as specific as health professionals usually get with CFS in practice. Perhaps more comparison needs to be done with fatigue and pain in CFS vs other illnesses. - Tekaphor (talk) 05:15, 7 December 2007 (UTC)

Tekaphor, interesting about different types of fatigue, and I agree with your suggestion for a 'CFS vs chronic fatigue' section and concerning practitioner diagnosis. But same cannot be said for experienced CFS researchers who are familiar with CFS fatigue, but if a patient has say only three not four additional symptoms from the list then it is not CDC research definition CFS but now is 'undefined and persistent fatigue' or 'CFS like' Could even meet NICE criteria, so also a double edged sword if labelled chronic fatigue, as no longer could it be claimed CFS is not chronic fatigue. Which side of the fence does it then fall, as far as the Article is concerned? Jagra (talk) 10:54, 7 December 2007 (UTC)

Keep in mind that England is only a tiny part of the world, and even there nobody has accepted the NICE criteria. Guido den Broeder (talk) 14:01, 7 December 2007 (UTC)

If the patient has chronic fatigue but doesn't meet the criteria for CFS then the illness is generally called "chronic fatigue" (or sometimes "idiopathic chronic fatigue"). This is already mentioned in the introduction and in "CDC 1994 criteria" section. —Preceding unsigned comment added by Sciencewatcher (talk • contribs) 16:52, 7 December 2007 (UTC)

The point being these are different to ’unexplained and persistent fatigue’. For those not familiar with the term and its historical synonyms, such as ‘CFS like’ or ‘resembling Chronic Fatigue Syndrome‘ this is code by researchers for “CFS that does not meet the 1994 CDC research criteria” But today may well meet the NICE (or other CFS) guidelines for CFS diagnosis, and is not to be confused with ‘chronic fatigue’ per se. Something the article does not yet distinguish. Jagra (talk) 03:57, 10 December 2007 (UTC)

Placebo, what placebo?

http://www.slate.com/id/2176465/

Those who freely invoke the notion of placebo to explain away results might want to take note of the following studies on placebo and related methodological issues:

PMID: 8839653

PMID: 11372012

PMID: 11816328 ("CONCLUSION: We found no reliable evidence that placebo treatments in general had effects of clinical importance.")

PMID: 12007544

PMID: 12535498

PMID: 15161896 ("CONCLUSIONS: The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocols. Published articles, as well as reviews that incorporate them, may therefore be unreliable and overestimate the benefits of an intervention.")

PMID: 15257721 ("CONCLUSION: We found no evidence of a generally large effect of placebo interventions. A possible small effect on patient-reported continuous outcomes, especially pain, could not be clearly distinguished from bias.")

PMID: 15266510 ("CONCLUSIONS: There was no evidence that placebo interventions in general have clinically important effects. A possible small effect on continuous patient-reported outcomes, especially pain, could not be clearly distinguished from bias.")

PMID: 15817527 ("CONCLUSIONS: Most randomised clinical trials have unclear allocation concealment on the basis of the trial publication alone. Most of these trials also have unclear allocation concealment according to their protocol.")

PMID: 16117920 ("DISCUSSION: Outcomes in randomised trials are often reported selectively.")

PMID: 17060210 ("CONCLUSIONS: The blinding status of key trial persons was incompletely reported in most randomized clinical trials. Unreported blinding may be frequent, but one of five 'double blind' trials did not blind either patients, treatment providers or data collectors. Authors, referees, and journal editors could improve the completeness of reporting of blinding, eg, by adhering to the CONSORT statement. It is inappropriate to presume blinding of key trial persons based only on the ambiguous term 'double blind'.")

PMID: 17076559 ("CONCLUSIONS: This review classifies blinding methods and provides a detailed description of methods that could help trialists overcome some barriers to blinding in clinical trials and readers interpret the quality of pharmacologic trials.")

PMID: 17311468 ("CONCLUSIONS: This study classifies blinding methods and provides a detailed description of methods that could overcome some barriers of blinding in clinical trials assessing nonpharmacological treatment, and provides information for readers assessing the quality of results of such trials.")

PMID: 17440024 ("CONCLUSIONS: Blinding is rarely tested. Test methods vary, and the reporting of tests, and test results, is incomplete. There is a considerable methodological uncertainty how best to assess blinding, and an urgent need for improved methodology and improved reporting.")

PMID: 17517809 ("CONCLUSION: Two-thirds of conclusions in favour of one of the interventions were no longer supported if only trials with adequate allocation concealment were included.")

PMID: 17652297 ("CONCLUSIONS: The high proportion of meta-analyses based on SMDs that show errors indicates that although the statistical process is ostensibly simple, data extraction is particularly liable to errors that can negate or even reverse the findings of the study. This has implications for researchers and implies that all readers, including journal reviewers and policy makers, should approach such meta-analyses with caution.")

Bricker (talk) 23:42, 6 December 2007 (UTC)

There are just as many well-designed studies showing that the placebo effect does have a significant clinical effect over and above no treatment. Perhaps they just chose the studies that fit their pre-conceived conclusions? Or perhaps they chose studies where the placebo effect is likely to have little effect (such as cancer) instead of studies where it is likely to have a large effect (headache and depression). --Sciencewatcher (talk) 23:47, 6 December 2007 (UTC)

Some more thoughts on this: take the example of stress. Stress alters the immune system, causes headaches, increases blood pressure, and causes various other symptoms. It's pretty easy to see that a psychological factor (i.e. a placebo) that reduces the stress will also reduce all of these symptoms. So the question is: how could there possibly not be a placebo effect? --Sciencewatcher (talk) 23:58, 6 December 2007 (UTC)

I too used to believe the placebo effect was at least significant, and possibly powerful. But given the above evidence I have changed my mind. That's evidenced based reasoning for you. Did you even read those studies I quoted? A whole 5 minutes passed between my posting and your first response, and 16 minutes until your second response. No way you read through, understood, and carefully considered and responded to them in that very short time. That was a purely reflexive and ideologically driven response.

Other editors here will notice that SW's criticisms were not backed with even a single reference, a common tactic from SW.

For example, we are still waiting on the evidence for SW's claim about the "lots of autopsies" that show no brain damage; and some solid evidence about SW's overtraining claim, because the one reference SW gave us for that was laughable, and frankly more than a little hypocritical given SW's endless criticisms of his/her opponent's evidence, and demands they meet the highest scientific standard possible, and accusations of bias, etc. No, what we get from SW is just some slippery rhetoric about "Perhaps they just chose the studies that fit their pre-conceived conclusions?", and "how could there possibly not be a placebo effect?", and so on. Pathetic.

Bricker (talk) 01:14, 7 December 2007 (UTC)

Interesting article and studies Bricker! I also believed in the potential of the placebo effect, but it was actually CFS which challenged my pre-conceived notions that said illness would be resolved through stress management and cognitive changes and exercise. I am still somewhat reluctant to dismiss the placebo effect, but I get the impression that even when observed, it usually seems to have a temporary impact which eventually declines back to baseline. From many of the studies presented above, there seems to be a rather mild placebo effect on subjective measurements (especially pain), but these effects couldn't be clearly distinguished from bias, which itself is mentioned as a problem in so-called "randomised trials". As the Slate article implies, while there are subjective psychological effects in placebo studies, the objective improvements are lacking. We see something similar in CBT research for CFS; where some people say they feel subjectively better, but they lack the expected equivalent of objective improvements in performance. While I agree that Sciencewatcher's rapid response and accusation against the placebo researchers are suspicious, some of SW's other statements about the types of illness involved in the placebo studies warrant further consideration. - Tekaphor (talk) 04:56, 7 December 2007 (UTC)

Well Bricker, you are right, I did just spend 5 minutes reading the article regarding the 130 trials investigated. Perhaps that is because there is only the abstract to read! Assuming you have purchased the full article (which you would have to in order to see exactly what they were looking at), you would be so good as to give more details so we can discuss it properly.

It is very convenient that all the references you posted are by the same researcher! As I said, the placebo effect has very good science behind it, so you would need to have very good evidence to debunk it. Do you have that evidence? Or do you just have something against the placebo effect? --Sciencewatcher (talk) 15:54, 7 December 2007 (UTC)

You have missed the point, SW. It is not possible to determine the degree of placebo effect (if any) in trials that only have an active treatment, and a placebo arm. It is also necessary to have a no treatment/no placebo arm to compare against placebo, and when you look at all the studies that do have that form the result is no significant difference between placebo and no treatment. That is the evidence. Any other form of placebo controlled study doesn't count in determining the role of placebo. In light of the above work I cited, it is no good simply asserting placebo exists and there is lots of good science behind it, and accusing me of bias against the placebo (as I already stated, I used to believe it was real and significant). You have to show us the evidence. Or do you have something against the possibility that the placebo effect is not true, or at least far less significant than previously believed?

And we are still waiting for the evidence on autopsies, and overtraining, amongst other claims you have made. If you can't provide such evidence, then you should withdraw your claims.

Bricker (talk) 00:42, 8 December 2007 (UTC)

Bricker, as I already said above, there are lots of well designed studies that compare NO TREATMENT (just in case you miss it again) with placebo and show a significant effect. Did your researcher miss all of those? That is basic science, and I'm not going to waste my time pointing out the obvious, especially to someone who tells me to "sod off" and that my references are "laughable". I find it interesting that you told me to "sod off" when I simply mentioned the word psychosomatic in the same sentence as CFS! Clearly you have a problem, and no amount of evidence is going to sway you from your beliefs. --Sciencewatcher (talk) 16:23, 8 December 2007 (UTC)

"Clearly you have a problem, and not amount of evidence is going to sway you from your beliefs". Well, I guess I takes one to know one, sciencewatcher.

Additionally, we all have a problem with a repeat pattern in your rehtoric, namely making exaggerated claims ("lot's of autopsies", "CFS = Burnout") or airy claims ("NICE should say it's psychosomatic") and failing to come up with anything other than more rethoric when probed in depth.JayEffage (talk) 16:45, 8 December 2007 (UTC)

Exactly.

"Bricker, as I already said above, there are lots of well designed studies that compare NO TREATMENT (just in case you miss it again) with placebo and show a significant effect."

So where are they? Once again you make a claim and fail to back it. The studies I quoted about placebo did precisely what you claimed they didn't do, looked at ALL the eligible studies of that form, and found NO significant difference between placebo and no treatment/no placebo arms.

And we are still waiting on the evidence for the autopsies, over training/burnout, and also an explanation of how stress is a major precipitator of CFS without any objectively measurable changes to the stress system occurring until well after onset, amongst other problems with your various claims.

Bricker (talk) 23:27, 8 December 2007 (UTC)

Wilson's temperature syndrome

Please add some link to Wilson's syndrome (Wilson's Thyroid Syndrome or Wilson's Temperature Syndrome) from which I quote:

In March of 2006 an article for Wilson’s Temperature Syndrome was published on PubMed. Friedman M, Miranda-Massari JR, Gonzalez MJ (2006). "Supraphysiological cyclic dosing of sustained release T3 in order to reset low basal body temperature.". P R Health Sci J. 25 (1): 23-9. PMID 16883675. —Preceding unsigned comment added by Sohale (talk • contribs) 14:18, 8 December 2007 (UTC)