Talk:Chronic fatigue syndrome/Archive 4

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Archive 4

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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.^[1]^[2]^[3]

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. (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.

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 [6] (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)

POV?

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.

Making the article shorter

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

Toxic Agents

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 [7] (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)

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)

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

Categories: Talk archives

Talk:Chronic fatigue syndrome/Archive 4

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Contents

Alcohol Intolerance; a vital clue !

La Fourchette

Notable cases

Chocolate Cure

Jagra

More forking, splitting, disambiguating

NICE criticism sources

Removed stuff

Jagra: inflammation

Hyper-response and Immune Dysfunction in CFS

Substrate Depletion

Fatigue and Energy

Oxidative stress and Antioxidants

Effects of some essential fatty acid metabolites

Blood Brain Barrier in CFS

Hyde: new and simple definition

Myalgic Encephalomyelitis

POV?

Making the article shorter

Toxic Agents

POV?

Making the article shorter

Toxic Agents

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