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

[Solstice]

Isn't the problem always with the BPS approach that they have an answer for everything, in that they will agree that there are physical changes and signs, but then claim that they come AFTER the person becomes depressed (ie that the psychological aspect comes first)? So it's a chicken and egg thing.....

It is a problem. But if you have metabolites showing physical changes and you can base a very effective treatment on that you'd have to be a fool to still offer CBT, regardless of what caused those changes. Fool's a-plenty, I know. But in the long run it's not gonna prevail I reckon.

 

[adreno]

The very definition of what Sir Karl Popper called nonscience.

Right, the psychosomatic "theories" are unfalsifiable = non-science.

 

[valentinelynx]

Finally we might have some proof that psychological causation of depression is unfounded, that its physical.

Thank you. Exactly what I've been thinking - true pathological depression is likely to be as biological in pathophysiology as any non-psychiatric disorder. You can't "talk" yourself out of real depression. The medications currently in use for depression are not perfect, but they do save lives. Amazing how a disease with such a high fatality rate as depression can be so belittled by not only the public but by medical professionals (a large percentage of whom will suffer from it during their lives).

Psychiatric disorders are disorders of the brain, after all. Dementia is a psychiatric disorder. The new DSM 5 term is "Major Neurocognitive Disorder." Psychiatrists and neurologists take the same board certification exam, and are certified in Psychiatry and Neurology.

 

[Ben H]

@Rose49 and @Ben Howell - We are so grateful to both of you for your time and effort in answering the many questions here on this thread.

I had previously asked about how Dr. Davis would explain the fact that ME patients have ongoing symptoms of chronic inflammation in the body. This has been backed up with evidence of ongoing neuroinflammation and elevated viral titers. Many ME experts have treated these patients with some success with antivirals and Ampligen. (see this post http://forums.phoenixrising.me/inde...d-a-with-dr-naviaux.46520/page-15#post-758657)

In other words, there is evidence of an ongoing pathogen harming the patients. It is not merely tired patients who are stuck in a lowered metabolic state because of a past trigger (which now is gone).

In addition, I was surprised to see that the next step suggested was a comparison with depression and PTSD patients. Why were these groups selected? Why not compare with MS and RA patients?

Hi @Nielk

I have forwarded this to Dr Naviaux. There has been many questions regarding chronic inflammation so hopefully we can see it addressed.

Neilk says: 'In addition, I was surprised to see that the next step suggested was a comparison with depression and PTSD patients. Why were these groups selected? Why not compare with MS and RA patients?'

Sorry, forgotten how to insert quote.

As I understand it, Naviaux is not a specifically ME researcher. He can only research other conditions if he gets funding to do so, and I assume he has funding in place to investigate depression and PTSD.

I can't see a problem with comparing the findings on ME with these conditions. A lot can be learned from seeing whether there are distinguishable differences in metabolites between ME and any other condition.

Hi @trishrhymes

Dr Naviaux does work on other conditions (autism prior to ME/CFS) but I do not think the choice to cross reference depression and PTSD was due to funding. Perhaps @Rose49 can help here. I have sent this to Dr Naviaux anyway to have him expand if possible. Agree on your last statement.

@Ben Howell

will there be soon a release about their future research plans? This could be interesting what they plan in the near future. This could be also good for their marketing.

Hi @Tuha

The Open Medicine Foundation's website is a great place to keep up to date and informed.

http://www.openmedicinefoundation.org/the-end-mecfs-project/

They are funding a large proportion of the research going on. The samples for the Severely Ill BIG DATA study has already been collected and are being analysed now!

Please sign up here to stay informed, and consider donating if you can and believe in the mission and the research-its all publically funded at the moment:

http://www.openmedicinefoundation.org/newsletter-sign-up/

I do not assume this.

By virtue of the character of the disorders noted for comparison, I fear it is others who will make unwise and unfair and even harmful assumptions.

But perhaps your second point is accurate, and the authors intent was to demonstrate conclusively differences between ME/CFS and depression and PTSD. I just wonder if they are the best starting points - if only because of the nature and history of ME/CFS politics, and as much as we might like, we cannot so easily disentangle ourselves from those.

I say this with the utmost respect for the authors and their study.

Hi @duncan

Ive asked Dr Naviaux to expand on this.

Also @Ben Howell is a beast and props to him

The strangest compliment I have ever recieved but made me laugh-thanks!

That would be an elegant solution to the problem, though I don't know if some metabolites decay or can be stored well, if they could be that would be amazing.

If handled correctly and frozen soon after the draw, metabolomics can be stored well. Im not sure for how long, but it is a period of months-it may be many. I should be able to find this out for you.


I hope all of this makes sense. The thread has exploded and im trying to keep on top. Most of the questions need Dr Naviaux or Ron's input-I wouldn't do them justice, and some I quite frankly do not know!

I have sent Dr Naviaux a second list and hopefully, when he has time, he will get back to us.

Thanks for the questions and interest guys,


B

 

[Gingergrrl]

If handled correctly and frozen soon after the draw, metabolomics can be stored well. Im not sure for how long, but it is a period of months-it may be many. I should be able to find this out for you.

Thanks @Ben Howell and I am also very curious about this and would appreciate the info! It sounds like my sample from May 2015 that was bio banked but not tested probably is no longer valid for the metabolites after all?

Am curious to learn what Dr. Davis and Dr. Naviaux feel is the cut off period and I don't want to run the sample if it wouldn't be valid and would rather do a new test through OMI once it becomes available.

 

[Ben H]

Thanks @Ben Howell and I am also very curious about this and would appreciate the info! It sounds like my sample from May 2015 that was bio banked but not tested probably is no longer valid for the metabolites after all?

Am curious to learn what Dr. Davis and Dr. Naviaux feel is the cut off period and I don't want to run the sample if it wouldn't be valid and would rather do a new test through OMI once it becomes available.

Hi @Gingergrrl

It may be absolutely fine. I am not qualified to say exactly, but I know it is months. Those months may be year(s)-I will try to find out for you.

Your best bet for all of this is to talk to OMI and your physician directly-they should know.


B

 

[slysaint]

@Ben Howell
don't know if someone has already asked this; Has Dr Davis any plans to run the Naviaux tests using Whitney as a subject?

 

[Ben H]

@Ben Howell
don't know if someone has already asked this; Has Dr Davis any plans to run the Naviaux tests using Whitney as a subject?

Whitney has had his metabolomics done. It was not with Dr Naviaux however. @Rose49 may be able to expand if necessary.


B

 

[Gingergrrl]

Hi @Gingergrrl

It may be absolutely fine. I am not qualified to say exactly, but I know it is months. Those months may be year(s)-I will try to find out for you.

Your best bet for all of this is to talk to OMI and your physician directly-they should know.


B

Thanks and I did ask them and hoping to learn the answer soon. When you said months (vs. Years) I thought maybe it was not worth running it now b/c so expensive and was curious if Dr. Naviaux had an opinion re: how long the sample was good and am glad others were asking too so it will be added to your loooong list of questions! Thank you again for doing this for us all. I agree you are a beast (this is a good thing)!

 

[slysaint]

Whitney has had his metabolomics done. It was not with Dr Naviaux however. @Rose49 may be able to expand if necessary.


B

Just wondering if he found the same 'biomarkers' as those in Naviaux study.

 

[alex3619]

Questions:

1. Given that the Lipkin et. al. finding of high cytokines in short term patients, and low after about three years, how many patients studied so far have illness duration earlier or longer than three years, and are there differences?

2. Is it possible that ME or CFS are initially high cytokine states, and then become more a dauer state if this is sustained for too long? In other words, are the hypometabolic findings found in shorter duration patients?

 

[osisposis]

seems to me it would be almost impossible to not have a brain disease or TBI that doesn't involve mood disorders, exspecially when the same areas involved in mood dysregulation are involved in the brain injury itself!

https://www.ncbi.nlm.nih.gov/pubmed/22313617

http://www.ncbi.nlm.nih.gov/pubmed/26372769

https://www.ncbi.nlm.nih.gov/pubmed/26581959

https://www.ncbi.nlm.nih.gov/pubmed/25545969

http://www.semarthritisrheumatism.com/article/S0049-0172(16)30069-5/abstract

http://www.semarthritisrheumatism.com/article/S0049-0172(14)00226-1/fulltext


http://www.fibromyalgiatreating.com/the-connection-between-brain-damage-and-fibromyalgia/

http://www.fibromyalgiatreating.com/how-a-traumatic-brain-injury-can-lead-to-fibromyalgia/

http://www.dailymail.co.uk/health/a...rain-injury-30-000-cases-chronic-fatigue.html

 

[Gingergrrl]

seems to me it would be almost impossible to not have a brain disease or TBI that doesn't involve mood disorders, exspecially when the same areas involved in mood dysregulation are involved in the brain injury itself!

In some of your prior posts when you wrote TBI, I had thought you meant "tick borne infection" but now I see you mean "traumatic brain injury" which makes more sense!

I don't think though that everyone with this illness has a brain injury or a mood disorder (although of course some do). I still think there are many subgroups, partially b/c of different triggers, but more so b/c of different symptoms. Hope this makes sense.

 

[osisposis]

Inflammation and Immune System Activation After Traumatic Brain Injury
KEYWORDS:InflammationTraumatic brain injuryMicrogliaDamage-associated molecular patternsCytokinePattern recognition receptor
http://link.springer.com/article/10.1007/s11910-014-0484-2

New perspectives on central and peripheral immune responses to acute traumatic brain injury
http://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-9-236

 

[osisposis]

Therapeutic hypothermia for traumatic brain injury.
http://www.ncbi.nlm.nih.gov/pubmed/22836524

Neuroprotective adaptations in hibernation: therapeutic implications for ischemia-reperfusion, traumatic brain injury and neurodegenerative diseases
http://www.sciencedirect.com/science/article/pii/S0891584901006281

Cerebral Vascular Injury in Traumatic Brain Injury
http://www.sciencedirect.com/science/journal/00144886/275/supp/P3

Treatment of traumatic brain injury with anti-inflammatory drugs
Traumatic brain injury rapidly induces inflammation. This inflammation is produced both by endogenous brain cells and circulating inflammatory cells that enter from the brain. Together they drive the inflammatory response through a wide variety of bioactive lipids, cytokines and chemokines. A large number of drugs with anti-inflammatory action have been tested in both preclinical studies and in clinical trials. These drugs either have known anti-inflammatory action or inhibit the inflammatory response through unknown mechanisms. The results of these preclinical studies and clinical trials are reviewed. Recommendations are suggested on how to improve preclinical testing of drugs to make them more relevant to evaluate for clinical trials.
http://www.sciencedirect.com/science/article/pii/S001448861500179X

Microglia in the TBI brain: The good, the bad, and the dysregulated
http://www.sciencedirect.com/science/article/pii/S0014488615300790

Up-regulation of an extracellular superoxide dismutase-like activity in hibernating hamsters subjected to oxidative stress in mid- to late arousal from torpor
http://www.sciencedirect.com/science/article/pii/S1532045606001165

 

[osisposis]

Hyperbaric hope for fibromyalgia sufferers
http://news.rice.edu/2015/06/02/hyperbaric-hope-for-fibromyalgia-sufferers-2/#sthash.MG0L46Za.dpuf

 

[Janet Dafoe]

Whitney has had his metabolomics done. It was not with Dr Naviaux however. @Rose49 may be able to expand if necessary.


B

Whoops, Ben, not true. Whitney has had his metabolomics done at Metabolon, and also by Naviaux several times.

 

[Ben H]

Whoops, Ben, not true. Whitney has had his metabolomics done at Metabolon, and also by Naviaux several times.

Thanks Janet. Thought Naviaux stuff was planned-he works fast! Apologies!

B

 

[Ben H]

First update from Dr Naviaux and Prof. Ron Davis!

"Naviaux and Davis responses to Qs about Viruses and CFS"


Will update initial post. Big thanks to @Rose49, and ofcourse Prof. Ron Davis and Dr Naviaux.

Prof. Ron Davis response:

Viruses and CFS, Statement by Ron Davis, 9-7-16


There is a great deal of evidence that a variety of viruses can initiate ME/CFS, but it is less clear that a virus is involved in sustaining the disease. However, some patients may have a continuous problem with viruses, especially those viruses we always carry like EBV and HHV6. These viruses are usually kept in check by the immune system. Any suppression of the immune system can cause reactivation of these viruses (e.g., shingles). It is possible (we have new supporting data on this) that the immune system is somewhat impaired in ME/CFS, which will make it difficult to keep these viruses suppressed. If we can find the cause of this disease and cure it, this virus problem should go away. Also, there is a common misunderstanding about viral infection among some patients and even some doctors. Most viral assays used by doctors test for the presence of antibodies to viruses, not the viruses themselves. The presence of antibodies shows that the person had a viral infection in the past, but does not constitute evidence that it is still present. A direct assay for a virus is needed in order to find out if any virus is present. The current state-of-the-art assay is a PCR test for DNA or RNA from a virus. (Serology tests are tests for antibodies, not viruses.) We are conducting these direct PCR assays in the Severely Ill Patient Study, as well as extensive DNA sequencing for any as-yet-undiscovered viruses. We need to keep an open mind and have all ideas on the table and follow the data. Our goal is to find an accurate biomarker, find the cause, find a treatment for the cause, find a cure and then prevent the disease.

Dr Naviaux response:

Q11. Many ME/CFS experts have improved the symptoms in some patients by treating with antivirals and Ampligen (polyIC double stranded RNA). I think this proves that ongoing viral infections are causing our symptoms. It is not merely “tired patients” who are stuck in a lowered metabolic state because of a past trigger (which now is gone).

First of all, it is important that people actually read our paper first before drawing conclusions from news reports and blogs and criticizing something that we never said. I have seen a number of generalizations starting to appear in blogs and reports by journalists in even good newspapers and magazines that are starting to drift too far afield from the actual science in our paper. We devoted a section of the paper to this and related questions about infections. The section title was, “A Homogeneous Metabolic Response to Heterogeneous Triggers”. It concluded with the sentence, “Despite the heterogeneity of triggers, the cellular response to these environmental stressors in patients who developed CFS was homogeneous and statistically robust.” As background for this conclusion, I recommend reading our paper on this topic entitled, “Metabolic features of the cell danger response” (PMID 23981537).

Second, many people do not understand that the first response our body mounts against a viral, bacterial, or any kind of infection is metabolic. Yes, our chemistry is our first line of defense. Our chemistry reflects our instantaneous state of health. Innate immunity is coordinated by mitochondria and is an essential first step in developing adaptive immunity to any infectious agent. Without innate immunity there can be no antibodies and no NK cell activation, no mast cell activation, and no T cell mediated immunity.

In addition, all antivirals have metabolic effects that have nothing to do with inhibiting viral DNA or RNA synthesis directly. Many antiviral drugs inhibit the key metabolic enzyme S- Adenosylhomocysteine Hydrolase (SAHH). Inhibition of SAHH causes an increase in intracellular SAH levels. SAH is a potent inhibitor of DNA, RNA methylation. This affects both viral and host cell epigenetics, gene expression, and mRNA translation. The inhibition of methylation reactions in the cell also affects neurotransmitter (dopamine, norepinephrine, and serotonin) and phosphatidylcholine membrane lipid synthesis, and many other reactions. So by giving antivirals, doctors are not just inhibiting viruses, they are also inhibiting many host cell metabolic functions. Sometimes the inhibition of host cell functions can attenuate ME/CFS symptoms for a time, but in other cases, using potent antiviral drugs inhibits mitochondrial and methylation reactions and can delay a full recovery from ME/CFS.

You also asked about Ampligen. Ampligen is nothing more than a form of double stranded RNA called poly(IC) for poly inosinic:cytosinic acid. We have studied the action of polyIC extensively and have published this in our studies of autism and virology. It acts by binding to an innate immune receptor called TLR3, creating a simulated viral infection. If you expose a pregnant animal to a single dose of polyIC at the beginning of the second trimester, she develops a 24- hour flu-like illness then completely recovers. However, her pups have social and cognitive abnormalities similar to autism for life. If you look at their brains, you find that they have
activated microglia and brain inflammation for life. In adults, Ampligen also binds the TLR3 receptor, and activates an incomplete antiviral response characterized by a non-MyD88 dependent activation of interferon and other cytokines. Long-term use of polyIC carries a risk for toxicity because of chronic innate immune stimulation. In certain clinical situations like cancer or Ebola virus infection the toxicity is actually part of the therapeutic effect. Chronic interferon release causes flu-like symptoms, and the inhibition of mitochondrial protein translation. This can lead to secondary mitochondrial dysfunction. As I noted in an earlier Q&A response, sometimes the inhibition of mitochondrial function can make some people with ME/CFS feel better temporarily because some symptoms can come from unbalanced overactivity of some of the hundreds of functions mitochondria perform. However, in the long term, any pharmacologic inhibition of mitochondrial function will delay a full recovery.

Third, latent and reactivated viral and bacterial infections can occur, but in the case of ME/CFS that has lasted for more than 6 months, this may be the exception rather than the rule. Some doctors and scientists have not done a good job at educating patients and other scientists about the difference between serological evidence of infection in the form of antibodies like IgM and IgG, and physical evidence of viral replication like PCR amplification of viral RNA or DNA, or bacterial DNA. We have learned in our autism studies with Dr. Judy Van de Water that supertiters of antibodies do not mean new or reactivated viral replication. Supertiters of IgG antibodies mean that the balancing T-cell and NK cell mediated immune activity is decreased. This is like the famous figure-and-ground illusion that shows the silhouette of two faces that also create the form of a vase. Both things happen. But which is cause and which is effect? Increased IgG antibodies to CMV, EBV, HHV6, Coxsackie, etc. are not good evidence of a reactivated viral infection. This can be proven in most cases by trying to measure viral DNA or RNA by PCR in the blood or swollen lymph nodes. In most cases, supertiters of IgG are PCR- negative. There are exceptions to this generalization. However, chronic PCR surveillance studies in healthy humans are showing that little waves of viral replication happen periodically throughout our lives. We have been, and are regularly infected by hundreds of viruses over a lifetime. Sometimes this is obvious and causes a symptom like blisters or an ulcer around the mouth. However, most of the time these waves of viral replication are silent and produce no symptoms at all because they are handled in the background by the innate and cell-mediated immune system. Even the deadly poliovirus infected 150 to 1800 people producing only mild or unnoticed infections for every one person who developed paralytic disease. In most of the cases of ME/CFS that I have seen where IgG antibody titers have been measured before, during, and after antiviral therapy, the antibody titers remain high after treatment, even though the patient may report symptomatic improvement. I believe the symptomatic improvement after antiviral treatment may have more to do with the metabolic effects of antivirals in ME/CFS than their action on viral replication. The good news is that this hypothesis can be studied scientifically and put to the test easily using the tools of PCR and metabolomics.

Good science needs to remain open, ask the questions without bias, design good experiments, take careful measurements, then have the courage to follow the data wherever they may lead.

Enjoy!


B

 

[slysaint]

Whoops, Ben, not true. Whitney has had his metabolomics done at Metabolon, and also by Naviaux several times.

And? How did the results compare to Naviauxs overall findings?