Naviaux et. al.: Metabolic features of chronic fatigue syndrome

[adreno]

Do we really believe that these 13000 dont try all the time all sort of things, paleo, low carb, high choline, whatsoever? If it worked, people would habe found it!

I never said any of these things would bring us out of ME. I said I believe taking choline is quite safe.

I was however unable to find any research sources that the hypometabolic state would be really maladaptive! Do you have any? Anyone?

There is no evidence on this. It's an entire new field of research. If you believe the hypo-metabolic state is protective, then obviously you should stop messing around with choline or other supplements.

 

[alex3619]

There is no evidence on this. It's an entire new field of research. If you believe the hypo-metabolic state is protective, then obviously you should stop messing around with choline or other supplements.

Calling ME or CFS adaptive for a given individual (as opposed to the species) requires that it protects us from damage or consequences that could result in severe results, such as death or permanent disability. Just look at how severe ME can be.

For now the best advice would seem to be that a balanced diet with slightly higher protein and avoiding things that you react to, with avoidance of as much processed food as possible, is the best advice. However individual variation, comorbidities etc. will likely play an important role.

So the short answer is eat as healthy as you can but don't expect a cure, while the long answer is we need lots of testing and good medical advice. Mass spec testing for metabolites is going to be very interesting. This research could change the picture entirely. However it appears unlikely that just dietary changes will correct the underling problem. That does not mean they cannot help. We often have deficiencies of vitamin E, and CoEnzyme Q10, for example, and its often advisable to treat deficiencies even if they will not result in cure. However if there are feedback loops then any treatment may trigger changes that decrease the impact of that treatment.

 

[CFS_for_19_years]

It might also be interesting to see if the plasma cytokines and spinal fluid cytokines measured by Hornig, et al., increase subsequent to exercise. Maybe they don't - but, if they did, it might create an increased sense that one's immune system has "revved up" - as if you were fighting an bad infection. I could see that causing the symptoms similar to those you describe ("heart pounding, ears ringing, increased insomnia, and above all, fever-like cerebral malaise that knocks me out").

Like this?

From http://static.www.bmj.com/sites/def...tachments/2015/01/Light A, et al 2009 (1).jpg

 

[BruceInOz]

Like this?
View attachment 17268
From http://static.www.bmj.com/sites/default/files/response_attachments/2015/01/Light A, et al 2009 (1).jpg

Yes I do! [sarcasm mode] Isn't amazing what those false illness beliefs can do to our neuroimmune system

 

[Forbin]

Like this?

Yes. I just thought it would be interesting to see if the Hornig panel of 51 cytokines would show a similar effect in response to exercise as the Light panel of 3 cytokines and 10 receptors. Those three cytokines - IL6, IL10 and TNFa - are shared by both studies,

 

[Cyndia]

try a vasso constriction tea next time see if it helps (not coffee).

Any suggestions on what kind of tea?

 

[Seven7]

Any suggestions on what kind of tea?

remine me again high BP or Low? If is low, you can try butchers broom. I think the people w high BP uses a car sickness drug instead (I dont remember the name since I am a low BP person)

 

[Cyndia]

remine me again high BP or Low? If is low, you can try butchers broom. I think the people w high BP uses a car sickness drug instead (I dont remember the name since I am a low BP person)

Its low. Thank you, I'll check out butchers broom.

 

[Groggy Doggy]

Absolutely @Kati -- the philosophy of etiology isn't something I'd thought of directly like that. Now we've identified at least three reasons why this must be done utilizing patients from multiple centres / diagnosing physicians!

Did we already discuss this reason? Gordon Medical has an online pharmacy that sells nutritional supplements, vitamins, herbs, & homeopathy. I can't recall, was this disclosed in the Naviaux study?

http://www.npscript.com/gordonmedical​

 

[Research 1st]

There is currently no way to speed up metabolism of fats. If there was, we would know about it. It would cute obesity, heart disease and probably other diseases as well.

Unless we are talking disease, where fat metabolism is slowed?

One example is if the ME CFS sufferer has developed adult Growth Hormone deficiency, which requires a special test practically no patient has had (GH Stimulation test) on here, as most doctors mislead the patient and tell them if their IGF-1 is normal, they can't have adult GH deficiency.

Post diagnosis, If you take injections of GH, the fat falls off your boobs (both sexes) hips and tummy and you feel less anxious, have a stronger heart, less anxiety, basically it makes you way better than trying to exist with a blow pituitary gland.

And it's funny in a way, that a major sign of the 2nd paragraph huge benefits, are being 'skinny fat', or looking like a rotund apple shape which of course we would all miss and put down to genetics or poor diet, as we as patients, tend to believe all the things we have wrong with us is 'ME CFS'.

 

[Research 1st]

This tells you the problem in very broad terms. To address it you would need specifics, and a doctor who understands the metabolic paths and associated paths, including regulation. A typical metabolic path involves multiple steps, multiple enzymes, multiple cofactors and at least one regulated step, which means a regulatory mechanism, though there can be more than one.

There are also effectively two paths by which fats are oxidized from what I recall. Which is affected? Both? You would need to know the specifics, as I said, in order to be clear about what might be attempted.

Hello. As unofficial forum test nerd I can help you out maybe with types of commercial tests regarding fatty acids:

Short Chain Fatty Acids Assay
Omega 3 Omega 6 Assay
Very Long Chain Fatty Acids Assay .

2 of 3 I tested for me, are exceptionally low, my short chain being practically zero.

Cause or effect? That's the million dollar question.

 

[cman89]

Much appreciated. That is actually, what I hope too, but I have seen also very credible voices against it. And I can support the voices against it by studies that some bacteria actually feed well on choline. Let me know if you wanna know more I dig it out. Most of all: if it was so easy then all people would simply resolve their probls by taking more choline, more B12, more cholesterin rich food, etc etc to supply exactly those things low as per Naviaux. There must be some hidden issue why it does not work for all or why it will work only short time, whatsoever... What is this issue? I worked out myself of ME by eating more B12, more cholesterin, etc etc by my high meat, high fat, low carb diet. But if it was so simple for all, then all would be healthy. Same for choline - If anyone is interested, here are all the details on my choline supplementation. My failures and my finally successful version. I am happy as a bird it works so well for me!
Just think of the 13000 members of PR! Why are there no masses leaving PR because their ME resolved? Do we really believe that these 13000 dont try all the time all sort of things, paleo, low carb, high choline, whatsoever? If it worked, people would have found it!

I was however unable to find any research sources that the hypometabolic state would be really maladaptive! Do you have any? Anyone?

It likely worked well for you because you were low in choline, just as B12 did amazing things for me when I first started it, and now, I dont notice much change when taking it. It keeps me stable, but setbacks occur due to other causes.

 

[A.B.]

@Jonathan Edwards I think I'm not the only one who is interested in your opinion on this study (I'm writing in the belief that you have not yet commented on it).

Do you agree with Ron Davis that it's ground breaking?

Is the hypometabolism something that could be caused by B cell mediated autoimmunity? Is there any indication of something similar happening in established autoimmune diseases?

What do you think about the idea proposed here that the effect of Rituximab could be due to it specifically killing off the cells that keep sending out the alarm signals that are maintaining the abnormal hypometabolic state? (at least that's how I understand this idea, personally I don't see how Rituximab relates to lipid rafts)

 

[Jonathan Edwards]

@Jonathan Edwards I think I'm not the only one who is interested in your opinion on this study (I'm writing in the belief that you have not yet commented on it).

Do you agree with Ron Davis that it's ground breaking?

Is the hypometabolism something that could be caused by B cell mediated autoimmunity? Is there any indication of something similar happening in established autoimmune diseases?

What do you think about the idea proposed here that the effect of Rituximab could be due to it specifically killing off the cells that keep sending out the alarm signals that are maintaining the abnormal hypometabolic state? (at least that's how I understand this idea, personally I don't see how Rituximab relates to lipid rafts)

I am uncertain abut this study. If it has identified a particular metabolic profile shift for ME/CFS then it may well be groundbreaking. However, despite the claim that they found a consistent signature they also say that most of the out of line findings were individual or idiosyncratic. I cannot quite follow that. What also worrisome is that if there is a consistent pattern you do not need multiple regression analysis - you just look at the scatter plots. In the past disease mechanisms have not been found this way. You may need to look at three variables, like calcium,phosphate and alkaline phosphatase to identify hyperparathyroidism, but three is about the most and there are obvious reasons for the triad. I am inherently cautious about big data fishing trips. The other issue is whether this is just a reflection of inactivity - as several people have said.

There are various aspects of context like confident statements about ME/CFS being treatable with supplements that look out of line for a rigorous scientific approach when so far we have no hint of mechanism for the metabolic profile.

Autoimmune disease can set in motion just about any mechanism or sequence of events you like because the autoantibody can bind to any of 40,000 proteins, each responsible for a different function. So yes, an autoimmune process could lead to a shifted metabolic state just as in Addison's disease or Hashimoto's disease.

So Rituximab could be working by removing B cells that generate antibodies that drive the hypo metabolic state although these would seem not to be alarm signals in the usual sense. But the proposal about rituximab working via lipid rafts is a misunderstanding of the biology. The killing mechanism is quite irrelevant to the effect of having no B cells, whether in autoimmunity or cancer. It has nothing to do with any relation of ME to cancer if there is one. I think that can be disregarded.

 

[JaimeS]

It's based on a 'misunderstanding' to state that Rituximab affects lipid rafts and that this is part of its mechanism of action? That appears to be a common 'misunderstanding of the biology'.

Effects of rituximab on lipids and rafts
Lipid components seem to play an important role in rituximab signaling through CD20. Binding of rituximab results in redistribution of CD20 to lipid microdomains or “rafts” in the membranes of cells from a Burkitt lymphoma cell line (11). In addition, deletion analyses have identified a membrane-proximal sequence in the cytoplasmic carboxyl tail of CD20 as being responsible for CD20 relocalization into rafts (12). This redistribution modifies raft stability and organization, and it modulates the associated signaling pathways (11). The clustering of CD20 into raft microdomains results in an apoptotic response mediated through an src kinase-dependent pathway (13). The integrity of lipid rafts and their association with CD20 and consequent activation of src kinases are all dependent on cholesterol, with cholesterol depletion inhibiting rituximab-induced apoptosis (14). In follicular lymphoma (FL) cell lines, we found that rituximab inhibits B-cell–receptor signaling by preventing B-cell–receptor relocalization into rafts and decreasing raft-associated cholesterol content (15).

CD20 translocation into rafts seems to be necessary for calcium mobilization and for rituximab-induced apoptosis in Burkitt lymphoma cell lines (16). However, it has also been shown that anti-CD20 antibodies induce cell death through a caspase- and raft-independent mechanism (17), and a recent study showed that, at supersaturating doses, calcium release induced by rituximab (without crosslinking) is independent of both rafts and src kinases (18).

In the absence of crosslinking, rituximab binding to CD20 can also induce a rapid, transient increase in acid-sphingomyelinase activity and ceramide generation in raft microdomains in Burkitt lymphoma and FL cell lines (19). The consequent increase in intracellular ceramide concentration can result, through protein kinase C ζ (PKCζ)-mTOR module inhibition, in a decrease in growth and survival (20).

From: http://mcr.aacrjournals.org/content/9/11/1435.long

 

[Lolinda]

However, despite the claim that they found a consistent signature they also say that most of the out of line findings were individual or idiosyncratic. I cannot quite follow that. What also worrisome is that

Indeed, the whole study is statistically worrysome. To put it simply: take a big bunch of variables; if the number is big enough, then
- there surely will be a few commonalities among patients
- there will be a combination of variables that set patients and controls apart

in fact, one could do the same with any variables such as shoe size, ...., colour of their underpants. If the number of variables is big enough, something would be found. Say the patients wear more of colour x and less of y. And one would also get some male-femal differences and some similarities , and all this would be statistically significant... And surprisingly soon some elaborate theory would pop up why cfs/me patents have an affinity to colour x....

But there is one thing that is difficult to produce this way: that Naviaux found 1 variable that has in itself already a decent statistical power to distinguish patients and controls. What I mean is his finding regarding sphingolipids. This I consider statistically a believable thing. A real find, that cannot be just produced by "big data fishing". If only this finding should be replicable, then the study is already awesome!

The other issue is whether this is just a reflection of inactivity - as several people have said.

I am curious, can low sphingolipids be a reflection of inactivity?

(and if anyone has an idea where one can get a sphingolipids test, let me know!!)

 

[JaimeS]

The article cited linking cancer to lipid raft dysregulation is here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255102/

It was linked in the article as well.

But as I said at the time, that link is very speculative. Cancer's increased incidence in ME could be due to any number of factors, including lowered NK cell function.

-J

 

[Jonathan Edwards]

It's based on a 'misunderstanding' to state that Rituximab affects lipid rafts and that this is part of its mechanism of action? That appears to be a common 'misunderstanding of the biology'.



From: http://mcr.aacrjournals.org/content/9/11/1435.long

That is the misunderstanding Jaime. Rituximab's mode of killing involves lips rafts but that has nothing to with how the drug improves B cell diseases - it does that by taking away the B cells. There is a confusion between two unrelated steps in the process. Rituximab only enters lipid rafts of cells that will be dead within minutes. After two days it ceases to have any action on anything. So whether or not the disease being treated involves lipid rafts in cells still present is irrelevant.

 

[Cheesus]

The other issue is whether this is just a reflection of inactivity - as several people have said.

Is it likely the results would be more homogenous if they arouse as a result of inactivity? One of the reasons I am excited about this study is that metabolic heterogeneity could explain symptom heterogeneity, so it fits well with that. Admittedly, however, there is nothing to explain the metabolic heterogeneity.

What kind of evidence would be required to affirm a direction of causality?

 

[Jonathan Edwards]

Is it likely the results would be more homogenous if they arouse as a result of inactivity? One of the reasons I am excited about this study is that metabolic heterogeneity could explain symptom heterogeneity, so it fits well with that. Admittedly, however, there is nothing to explain the metabolic heterogeneity.

What kind of evidence would be required to affirm a direction of causality?

You could do a post exercise analysis - obviously with potential problems but you might get useful information from rather inactive healthy people starting an exercise programme. Otherwise other control groups with low activity would be an obvious thing to look at.