Professor Ron Davis's response to Naviaux study, including Q and A with Dr Naviaux

[A.B.]

Something similar could be happening in ME/CFS if there is an excess of hydrogen sulphide producing pathogenic bacteria in the gut.

Does anyone else feel that minor gut upset can result in a systemic response with worsening of all symptoms? It seems to be able to trigger relapses that can, surprisingly, last a week or even longer.

 

[Gingergrrl]

@osisposis Is it possible to of all of these mast cell links into another thread since this one is supposed to be questions for the researchers on the article, Metabolomics testing, etc?

No one is more interested in MCAS than me but I wish they could be in another thread so easier to find etc. I apologize if this is out of line.

 

[eljefe19]

haven't read these yet but look interesting, full text available too.


Inflammatory-induced hibernation in the fetus: priming of fetal sheep metabolism correlates with developmental brain injury.

http://www.ncbi.nlm.nih.gov/pubmed/22242129

Microglia toxicity in preterm brain injury.
http://www.ncbi.nlm.nih.gov/pubmed/24768662
full
8. Combination of systemic inflammation and hypoxia–ischemia
There is considerable evidence that LPS-induced systemic inflammation can exacerbate the neuroinflammatory response and brain injury to cerebral hypoxia–ischemia [64] and excitotoxicity [65]. The LPS effects are dependent on the innate immune receptor TLR-4 [66] and the adaptor protein myeloid differentiation factor 88 (MyD88) [67]. Stimulation of other innate immune receptors also has the capacity to exacerbate hypoxic–ischemic injury. We showed that giving the viral mimic, poly inosinicoly cytidylic acid (Poly I:C), a synthetic ligand for TLR-3, increased infarct volume and reduced white matter in neonatal mice [68]. Interestingly, enhanced injury was associated with a decrease in reparative M2-like CD11b+ microglia, while there was no change in M1-polarized cells. Thus, experimental data propose that triggering innate immune responses systemically may affect both the intensity and characteristics of neuroinflammation. Although the precise underlying mechanisms remain unclear, inhibition of TNF-α [69] and IL-1β [70], the use of anti-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) peptides [71] and immune regulatory peptides [72] alleviate LPS-sensitization of hypoxic–ischemic brain injury, suggesting that inflammatory pathways are important.

12.2. Microglia and neurons
Neurons have been shown to activate microglia in co-culture [119]. Oxygen glucose deprivation (OGD) stressed cortical neurons activated microglia, which was mediated through extracellular glutamate binding to mGluRII and NF-κB [120], these activated microglia then further elicited neurotoxic effects on neurons, which involved mGluRII, NMDAR, NF-κB and TNF-α [103,120]. Lai and Todd [121] also found that culture media from mildly injured neurons induced microglial production of IL-1β, TNF-α and NO, this was due to neuronal production of glutamate and ATP. Exposing neuronal cultures to conditioned media from LPS activated microglia induced severe synapse loss, activated caspase-3 activity, DNA fragmentation and neuronal cell death, which was mediated by the MyD88 pathway [87,122,123]. Increased neuronal cell death was also seen when neurons were exposed to conditioned media from NMDA treated and mGlu2 stimulated microglia [103,104]. Studies utilizing microglia-neuron co-cultures have further highlighted the contribution of microglia to neuronotoxicity. Activating microglia with IFN-γ or LPS in co-culture with neurons results in increased neuronal cell death, suggested to be mediated through NO production [124]. ATP stimulated microglia also elicit neurotoxic effects on hypoxic neurons [81].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155935/


Innate immune regulation by toll-like receptors in the brain.
http://www.ncbi.nlm.nih.gov/pubmed/23097717

Antibodies as Mediators of Brain Pathology.
http://www.ncbi.nlm.nih.gov/pubmed/26494046

The brain fog is thick right now, can somebody explain if this has any current treatment applications?

 

[eafw]

Don't worry about asking questions.

First thank you Rose for all your work here and also to Ron, Dr Naviaux and the research team involved with this latest study - it's so nice to see good scientists doing good science on this disease.

Couple of quick thoughts and questions:

Would we expect to see different metabolic profiles in children/teens (who as a demographic seem have the best chance of recovery) ? Considering that their immune system is not fully developed - what clues does this give us as to how the "dauer state" is occurring - what mechanisms are/are not at play so they do not get as stuck so easily ? And possibly at the other end of the scale how about people who are old enough for their immune system to be considered "geriatric" ?

Would be interesting to see the metabolic studies matched over to the cytokine profiles, again especially in terms of population groups, teens vs early stage adults vs long term adults. Any plans for this and/or are there any other labs or research groups wanting to do follow-up or replication studies ? It seems like such an interesting area of research - they should be banging down your door !

Late edit as forgot another Q: the anecdotal reports where people say that they have a transient "remission" when fighing certain infections and then get ill again afterwards, "it's like my body stopped fighting itself for a moment and decided to have a go at the germs instead" - I wonder what is going on here and is there a way to leverage this effect in our favour at all ?

 

[Sushi]

I'd given him some of my high dose sodium diclofenac 75mg SRone a day upped to two a day after about 10 days. It had a remarkable effect. He went from being housebound to mowing my lawn. Then at about a month/6 weeks he began getting terrible breathlessness part after having a shower.

This is an interesting one. Diclofenac (I've taken it) is in a category of NSAIDs that have some significant risks, including breathing problems. So his response could be the type of cyclical response that we often see with things working, then not working, then working again. Or, it could possibly be related to a risk factor from the drug itself. I hope it keeps working this time.

 

[Gingergrrl]

This is an interesting one. Diclofenac (I've taken it) is in a category of NSAIDs that have some significant risks, including breathing problems.

That is interesting and I'd never heard of Diclofenac but this is probably b/c I am allergic to NSAIDS. It is good to know for future reference that it can cause breathing problems, thanks Sushi!

I hope it keeps working this time.

Me, too, and crossing my fingers that this continues to work for him.

 

[alex3619]

Ron says it will probably be done by mass spectrometry so there won't be kits. They will do extensive analysis of the metabolites of whomever they are testing.

I was unaware mass spec was widely used outside of research labs. If this is possible, even if there are only a few labs per country that do this, then rolling out a diagnostic test will be relative fast and easy. That is a very important consideration considering how long most of us have been waiting. I think there will be a major bottleneck in testing if this test is done by very few commercial labs globally. I might do a bit of investigating and find out how many labs do mass spec in my area.

 

[alex3619]

I just sent this site message to a local pathology service, QML:


Hi, I am interested in finding out how many labs can do simultaneous mass spectrometry for 20 or more substances in plasma samples.

Recent research points to a possible blood test for Chronic Fatigue Syndrome (strictly defined) with up to twenty metabolites implicated. http://www.pnas.org/content/early/2016/08/24/1607571113.full

Wide testing is currently being investigated as a commercial option in the USA, based at Stanford University. Shipping requirements to the US will include a lot of dry ice, which means high weight on an airmail delivery.

If the research is validated as diagnostically useful (Its already been replicated though the other two studies are not published yet), with sufficient sensitivity and specificity, how feasible would it be to roll out testing here in Australia?

Even if this testing is not disease diagnostic it will still be a very useful ancillary test to inform on treatment options and outcomes.

PS I just sent this to another path lab chain. Its also looking like most hospitals have the technology to do mass spec testing, but that option is likely to have major restrictions on how it is used based on my current understanding of the health care system here.

 

[Gingergrrl]

simultaneous mass spectrometry

Alex, Is this the same as the "Metabolon" test or something totally different? Sorry for my confusion!

 

[alex3619]

Alex, Is this the same as the "Metabolon" test or something totally different? Sorry for my confusion!

I am unsure of the specifics of the metabolon test. In any case, I am not looking for a specific test, but the capacity to do such testing. I doubt many places in the world can do such specific testing right now ... but that will change.

 

[CFS_for_19_years]

I was unaware mass spec was widely used outside of research labs. If this is possible, even if there are only a few labs per country that do this, then rolling out a diagnostic test will be relative fast and easy. That is a very important consideration considering how long most of us have been waiting. I think there will be a major bottleneck in testing if this test is done by very few commercial labs globally. I might do a bit of investigating and find out how many labs do mass spec in my area.

Mass spectrometry, in combination with gas chromatography (GC-MS) has been around since at least the 1970s when I first began my career as a medical technologist. It was used for drug screening in clinical specimens such as blood, urine and stomach contents. It was used routinely, not on a research basis. Only a few hospitals had them, and they would take in specimens from other hospitals.

I did some Google searching, and came across some links that might be of interest:
Future of Mass Spectrometry in
Clinical Research and Forensic
Toxicology
https://www.aacc.org/~/media/files/...8/future_of-mass_slides_sep_18_2013.pdf?la=en

Current and Future Applications of Mass Spectrometry to the Clinical Laboratory
http://www.medscape.com/viewarticle/753445_8

 

[alex3619]

Mass spectrometry, in combination with gas chromatography (GC-MS) has been around since at least the 1970s when I first began my career as a medical technologist.

Yes, but I have only seen it used in research labs, or hospitals. Here, due to the issues with funding and bureaucracy, we need private labs to do it. I am unsure how many do. Hence my enquiries.

 

[alex3619]

From QML, one of our two leading path services in this state:

Hi Alex,
QML Pathology does not offer this form of testing.

 

[eljefe19]

From QML, one of our two leading path services in this state:

Dude thank you so much for using your valuable finite energy on furthering our cause. We need more like this. What can I do to help ?

 

[alex3619]

Dude thank you so much for using your valuable finite energy on furthering our cause. We need more like this. What can I do to help ?

Its too soon to be talking about what to do. We need more info, like the service being up and running in the US for a start, plus some validating studies. The issue is that in much of the world access to such a test, even if we pay, might be restricted. So facilitating the bureaucratic process might be required on a country by country basis. Ask me in a year or two and I might have a better idea.

Meanwhile those in California will have such services soon, and work is underway to make that international. We need to wait and see, and be aware that even with a test there will be a need for advocacy.

 

[eljefe19]

Its too soon to be talking about what to do. We need more info, like the service being up and running in the US for a start, plus some validating studies. The issue is that in much of the world access to such a test, even if we pay, might be restricted. So facilitating the bureaucratic process might be required on a country by country basis. Ask me in a year or two and I might have a better idea.

Meanwhile those in California will have such services soon, and work is underway to make that international. We need to wait and see, and be aware that even with a test there will be a need for advocacy.

Ok well CA is one of the best places I call home so that's great to know.

 

[Sasha]

On Cort's forum, someone posted this info:

From: http://www.medicalnewstoday.com/articles/311572.php

In uncovering a compound's potential anti-aging properties, researchers reveal a fascinating result of the co-evolution of plants, bacteria, and animals over millions of years. They show the compound enables muscle cells in animals to protect themselves against one of the major causes of aging. The compound - called urolithin A - is naturally produced in the gut when a molecule that is present in pomegranates is digested by intestinal bacteria.

The researchers found that a compound produced when pomegranates are digested by gut bacteria prolonged lifespan in worms and improved exercise capacity in older mice. They are currently testing the compound's anti-aging effects in human trials.

Tests of urolithin A's effect in humans are not yet complete, say researchers from the École Polytechnique Fédérale in Lausanne (EPFL), Switzerland, who report promising results from studies using nematodes and rodents in the journal Nature Medicine. [...]

In the new study, the EPFL team establishes that urolithin A can restore mitophagy in cells where the process has become sluggish. Co-author Patrick Aebischer, a professor in neuroscience and president of EPFL, says urolithin A is unique in this respect:

"It's the only known molecule that can relaunch the mitochondrial clean-up process, otherwise known as mitophagy. It's a completely natural substance, and its effect is powerful and measurable."

He and his colleagues first tested the effect of urolithin A in the nematode worm Caenorhabditis elegans, a very useful model for studying human biology at the cell level for several reasons: it is multicellular, its cells have many features in common with human cells, and it develops from a fertilized egg.

For these reasons, and the fact that at 8-10 days of age, C. elegans is considered elderly, scientists also find the worm very useful for studying the process and effects of aging.

The researchers found that when they exposed C. elegans to urolithin A, the worms lived on average more than 45 percent longer.

The team also observed that urolithin A prevented the accumulation of dysfunctional mitochondria as the worms aged.

The rest is here: http://www.healthrising.org/forums/threads/pomegranate-substance-may-relaunch-mitochondria.4631/

They raise the question on that thread of whether mitophagy is something that could help in our situation.

Interesting question.

 

[TiredSam]

On Cort's forum, someone posted this info:



The rest is here: http://www.healthrising.org/forums/threads/pomegranate-substance-may-relaunch-mitochondria.4631/

They raise the question on that thread of whether mitophagy is something that could help in our situation.

Interesting question.

Just asked my wife to get me some pomegranates.

 

[AndyPR]

Just asked my wife to get me some pomegranates.

Just asked my broker to buy shares in pomegranates

 

[Neunistiva]

Does taking medication and supplements interfere with matabolic tests?

A lot of ME/CFS patients are trying out different medication (personally, I am taking beta-blockers and acetyl-l-carnitine) so if we were to get tested some day should we stop taking them before, and how much before the test?