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

Leopardtail

Senior Member
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1,151
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England
Another interesting quote from the paper:

.....Flavin Adenine Dinucleotide (FAD) Was Decreased. Plasma FAD was decreased in both males and females with CFS (Tables 2 and 3). FAD is synthesized from riboflavin (vitamin B2) and ATP. The gastrointestinal absorption, distribution, and transporter-medi-ated uptake of FAD are carefully regulated during health and disease (19). FAD is mobilized from tissues, increased in the plasma, and renal secretion is increased under conditions of stress or infection (20). FAD is an important cofactor for fatty acid oxidation and sterol synthesis and is required for activation and oxidation of vitamin B6 (pyridoxine); lipoic acid metabolism (E3 subunit) needed for pyruvate, alpha-ketoglutarate, and branched chain amino acid oxidation; vitamin A activation; 5-methyltetrahydrofolic acid synthesis; niacin and NAD synthe-sis; and glutathione reduction.....
Yes looking at the overall paper they stated that the disrupted pathways were FAD dependent and that in turn was disease dependent. This could simply indicate their subjects had either chronic infection, or chronic immune activation.

I wonder how this compares with simple B2 deficiency? I also noticed the subjects showed low Uric Acid - could that be downstream of most of us taking Vitamin C?
 

Leopardtail

Senior Member
Messages
1,151
Location
England
not quite. it rules out an acute CDR. Leave CDR on and you might see the opposite, perhaps. Not saying I believe that is the case, just that the study doesn't rule out CDR being the problem.
I agree the body changes response when a situation goes from acute to chronic. E.g. Thyroid output raises in acute illness but lowers in chronic illness.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
We need this confirmed in candidate patients, very early in the disease process; intermediate patients, who are typically post-diagnosis, and long term patients.
My first thought too Alex both on reading the cholesterol and Uric Acid data. Also way too many patients from one clinic.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
This is something Rich noticed--low FAD. He and Cheney used to collaborate and somewhere in his posts there is also something about a "hibernation" model.
Funny, I described the unconscious state I go into in PEM as nearer hibernation than sleep when my Endo was getting cocky some time ago.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
Um, got a reference for that? The paper gives 4 or 5 Dauer refs, all on worms. A quick google also brought up a ton of worm stuff. It would be very helpufl to see any evidence that this applies directly to humans, or even mammals.
One obvious example would be diversion of Tryptophan from Serotonin production to the kynurenine pathway thus promoting rest and isolation.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
I haven't been able yet to read through all the comments, so forgive me if this has already been discussed, but could the "dauer effect" be an explanation to why we don't always observe the expected muscular atrophy in ME-patients bed bound for long periods?
I vaguely remember that lactic acid produced during exercise plays a part in strengthening muscle. Given that Myhill unearthed two groups of M.E. patients with poor ATP production and one group utilised anaerobic energy production that produced excess lactic acid - that might also explain it. Guess we have two possibilities?
 
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FMMM1

Senior Member
Messages
513
Yes looking at the overall paper they stated that the disrupted pathways were FAD dependent and that in turn was disease dependent. This could simply indicate their subjects had either chronic infection, or chronic immune activation.

I wonder how this compares with simple B2 deficiency? I also noticed the subjects showed low Uric Acid - could that be downstream of most of us taking Vitamin C?


Check out Chris Armstrong's webinar, response below is based on same.

Re chronic infection, or chronic immune activation - Chris Armstrong (and Maureen Hanson) are suggesting low grade sepsis i.e. bacterial translocation from gut to blood (leaky gut). The cause of the leaky gut is that the gut is not sufficiently acidic i.e. the acidity of the gut and the blood are too close which allows bacteria to move from the gut into the bloodstream. The cause of the lower acidity in the gut is the effect of the change in metabolism caused by the sepsis (leaky gut) i.e. less acid is produced by the altered metabolism (shift from burning glucose to protein). I think Chris describes this as a negative feedback loop. Also, I think Chris points out that this is consistent with Hornig/Lipkin paper showing low grate infection response (cytokine paper).

Re low Uric Acid - Uric Acid is an antioxidant i.e. free radical scavenger which is converted to Alanine. Therefore, lower levels of Uric Acid and higher levels of Alanine (in urine or plasma) are indicative of oxidative stress. Chris has proposed that the increase in Alanine in urine may be used as a diagnostic test but they need to find something to correct for the dilution in urine (creatinine can't be used).

Separately, re references to "Tryptophan from Serotonin" - I'm interested in understanding how this would affect the day/night cycle i.e. being awake at night and asleep during the day and any suggestions re reversing same.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
Sorry for the confusion on this but wouldn't it be the opposite? Meaning someone is really a 40 or 50 if they were not getting help but b/c they do have help (from a spouse, parent, caregiver, etc) then it appears that they are a 60 but they really are not? This Karnofsky scale confuses me a bit as it relates to the people in the study!
We did start producing a rating scale in a thread, and evaluating the existing scales some time ago. I took the view we needed something that rated separate functions very explicitly and calculated an end result.

With ME we should always answer based upon what we NEED and what's typical without crashing.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
Check out Chris Armstrong's webinar, response below is based on same.

Re chronic infection, or chronic immune activation - Chris Armstrong (and Maureen Hanson) are suggesting low grade sepsis i.e. bacterial translocation from gut to blood (leaky gut). The cause of the leaky gut is that the gut is not sufficiently acidic i.e. the acidity of the gut and the blood are too close which allows bacteria to move from the gut into the bloodstream. The cause of the lower acidity in the gut is the effect of the change in metabolism caused by the sepsis (leaky gut) i.e. less acid is produced by the altered metabolism (shift from burning glucose to protein). I think Chris describes this as a negative feedback loop. Also, I think Chris points out that this is consistent with Hornig/Lipkin paper showing low grate infection response (cytokine paper).

Re low Uric Acid - Uric Acid is an antioxidant i.e. free radical scavenger which is converted to Alanine. Therefore, lower levels of Uric Acid and higher levels of Alanine (in urine or plasma) are indicative of oxidative stress. Chris has proposed that the increase in Alanine in urine may be used as a diagnostic test but they need to find something to correct for the dilution in urine (creatinine can't be used).

Separately, re references to "Tryptophan from Serotonin" - I'm interested in understanding how this would affect the day/night cycle i.e. being awake at night and asleep during the day and any suggestions re reversing same.
I had a related issue in mind. If you take ample Vitamin C, you body makes less Uric Acid because oxidative stress is lower and it's unnecessary.

The effect I might expect with severe depression depletion would be poor Melatonin levels and poor quality or too little sleep.

When I developed that issue I found forcing myself to stay wake by day and combining Melatonin tablets with sleep formula herbal teas can help. A lot depends upon what is causing the sleep disturbances.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
It's possible that this isn't directly related to how we metabolize pills, but that our bodies have gotten used to very low levels of different metabolites. Our receptors have shot up in sensitivity over time, which is what happens to anyone who has 'low' anything over time. Now, one little particle of adrenaline settling into a receptor shoots us into the stratosphere.

When we take a normal amount of a drug, to our hypersensitive cells, the effect is amplified many times over.

If you'll allow me a metaphor: a plant hasn't been watered in weeks. You pour a gallon of water over it, it doesn't perk up, it dies. Too much, too soon.



:thumbsup:



Re: HIV. The more I learn about HIV, the more similarities I see between the two. (Important differences as well.) I'm beginning to see why researchers like Klimas study both, and why clinically, both me and my mother were frequently told, "okay, this is going to be hard to hear, but I think you might have HIV." :rolleyes:

My mother must've been tested six or seven times, because anytime she saw a new doctor they just assumed she was in the early phases, and that's why she hadn't tested positive previously.
I find that side effects build up over time. When I came off fluoxetine it took six weeks for its effect to dissipate. I'm inclined to think we are slow to metabolise and eliminate drugs hence the side effects at higher doses.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
This raises a question: is the hypometabolic state not about fighting infection, but preventing excessive inflammatory responses?

QUESTION: What is the duration of illness for any outliers in the Naviaux et. al. study? This might be important for shorter and longer duration patients.
from an evolutionary perspective sick cave men can collect less food, a lower metabolic rate would spare energy.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
I'm not sure about that Simon. I'm pretty sure that a p value of 0.15 does mean that there's a 15% likelihood that it's due to chance.

I wasn't familiar with q values but it looks like they're used to correct the p value for multiple comparisons and result in a marginally less stringent level of confidence than the p value :

http://www.science.smith.edu/cmbs/wp-content/uploads/sites/36/2015/09/P-and-q-values-in-RNA-Seq.pdf

So - thanks - I've learned something :)
put simply the p value is the probability that a conclusion may be wrong. Ideally we want numbers more like p<0.005
 

FMMM1

Senior Member
Messages
513
Thank you for your reply Leopardtail. I need to check out the Melatonin tablets etc.

Oops, uric acid is oxidised to allantoin not Alanine as I stated in my previous post.

I think the interest in allantoin as a possible diagnostic test is interesting. It may simply be cheaper and easier to measure allantoin in urine using NMR and if the results indicate oxidative stress (e.g. from ME/CFS) then a follow test using Mass Spectrometry could be used to confirm same. The current word on the web is that a mass spectrometry test from folks linked to OMF will be roughly $1500 US dollars - pretty steep.

The effect of supplementation with vitamin C (or other antioxidants) on allantoin levels is interesting; hopefully something Chris Armstrong or others will look into.

It would be good to see a diagnostic test delivered; is it really that expensive to run a large study measuring allantoin in urine using NMR? Chris mentioned that the sample analysis costs for the studies conducted in his laboratory were less than $100,000 (not sure if this was USA or Australian dollars).
 

Leopardtail

Senior Member
Messages
1,151
Location
England
That made me laugh - they were from all over California. If you live in Britain, that's not such a small area.
The vast majority were Northern California and appear to be patients of one clinic! That could mean similar dietary interventions etc. I have driven two hundred miles in the USA and found the same houses, same crops grown, same accent, same food in restaurants. In. Britain you would see vast differences. The distances are not comparable.
 

Leopardtail

Senior Member
Messages
1,151
Location
England
I would like to see that bear's reaction if told to get on a treadmill.

Or to stop catastrophising.

(The nematode worm's reaction might be pretty good too, if subtle by comparison.)

Joking aside, I think this is the absolutely crucial implication of this study's finding that ME/CFS/SEID is a hypometabolic disease. If people are in a hypometabolic state, doing normal activities will damage them. Doing activities that are challenging for those who are normal metabolically, such as exercise, will be dangerous. Right? Otherwise wouldn't animals have evolved to get more active during times of environmental challenge? Oh look, says the toad, drought and famine are coming: time for some aerobic exercise to help me adapt.

I'm so enthused by this research. Makes such a lot of intuitive sense. I particularly like that it explains (not explicitly) how generally we with ME don't die (with extremely sad exceptions) although we can teeter on the brink for a long time, and how some improve and even recover, even after long periods of illness. I can completely understand that someone's body might just un-dauer itself, either spontaneously or in response to some change in the biochemistry caused by a treatment.

The switch idea also appeals - that mitochondria are turned off rather than broken. I made an initial complete-except-full-on-exercise recovery initially, and it felt like a dimmer switch gradually being turned up. I didn't have to do anything, just wait it out and function just returned gradually. Then I relapsed (due to full-on-exercise) and it felt like an on-off switch went firmly to the off position. It hasn't budged in 6 years.

Huge thanks to all the researchers and to all the bloggers for communicating these important findings to patients.
Fancy taking the blood sample from a hibernating bear KME?
 

ash0787

Senior Member
Messages
308
Hopefully the control group on the replication study will contain people with other debilitating illness,
one of the main concerns I see is that since metabolomics is relatively new the researchers might be looking at something thats actually common under certain circumstances and not unique to CFS.
 

Janet Dafoe

Board Member
Messages
867
Hopefully the control group on the replication study will contain people with other debilitating illness,
one of the main concerns I see is that since metabolomics is relatively new the researchers might be looking at something thats actually common under certain circumstances and not unique to CFS.
A lot needs to be done and it takes funding. I believe this next study has ME/CFS patients from all over N America with age and gender and region matched healthy controls. Of course we also need to differentiate between different diseases as soon as we can.