New video from Australia with research summary, etc

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Here's what this video contains:
Screen Shot 2018-08-04 at 10.53.27 AM.png


I watched Don Staines at the 7 minute mark. He's from the Griffith University team that does the research on calcium channels etc.

They have a clear theory that ion channel deficiency is the key, including in the brain and spinal cord.

I find it plausible - and it has strong explanatory power. It's clear he is on a quite different track to other researchers. But I think that could be a good thing. It's good to dig in multiple places and there could be connections. It's not impossible these ion channel defects could play a part in an immune response, or in prolonging an immune response. Certainly calcium flux is a big part of purinergic signalling, which is Naviaux's theory.

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Around the 23 minute mark that GP explains how to do a standing test anyone could do at home (excluding Blood pressure measurements) to assess for Orthostatic Intolerance.

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The physio is an expert in the kind of cardio pulmonary exercise testing they use in research. Seems very good.

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The immunologist: talks about mast cells, irritants, etc. For mine, not a great speech.

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Dietitian : did not watch.

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Q and A. moderately interesting. Staines describes ME/CFS as unique and out on its own rather than being part of a family of autoimmune diseases. I'm a maybe on that. Some similarities to autoimmune diseases are apparent to me.
 

alex3619

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This is a moderately good video, though I am dubious about the proof of some claims, I do acknowledge that further research might get there.

The highlights for me were -

1. Mast cells are found in peripheral blood, they should not be there.
2. We often have non-allergic rhinitis. This is one of my major problems as it links into more severe breathing episodes.
3. Exercise metabolism testing shows carb use flatlining and fat use declining dramatically. This clearly shows a metabolic problem with exercise if it can be independently validated.
4. Be careful spending money on supplements that may not work or may make things worse, get a motorised wheelchair and good internet access. These help you connect with the world.

I hope NCNED can succeed in their aims, but I am cautious about whether or not the problems are consistent, and whether or not they are primary or secondary. Further research should help answer that, and I look forward to reading it.

PS I was amazed at the pictures of a patient's feet. Those are MY feet, all the time, and no doctor can explain it. This probably arises because of orthostatic intolerance.
 
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Gemini

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Mast cells are found in peripheral blood, they should not be there.
@alex3619, I've only watched half of the video, haven't gotten to mast cells, but have a quick question:

Ron Davis' is looking for something in patient's plasma (or missing from it) that can alter cell function? Any possibility it could be mast cell related?
 

alex3619

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@alex3619, I've only watched half of the video, haven't gotten to mast cells, but have a quick question:

Ron Davis' is looking for something in patient's plasma (or missing from it) that can alter cell function? Any possibility it could be mast cell related?
I would think it would be possible, but nothing more can be said than that. Mast cells themselves are too big. It would have to be a released product. The comment on mast cells was almost a one-liner, and I do not know how well its substantiated. I did find it very interesting though, its a line of investigation I have not thought about ... I am not used to thinking of mast cells as migratory or in general circulation.
 
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ljimbo423

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Ron Davis' is looking for something in patient's plasma (or missing from it) that can alter cell function? Any possibility it could be mast cell related?
This is the size of the filter Ron Davis used to filter out most of what was causing the cell dysfunction in the serum. This quote is from his wife Janet-

Yes you are.
Big = larger than 10,000 molecular weight. Proteins, protein groups or antibodies (including autoantibodies). Amino acids are smaller, around 300 molecular weight.
LINK post #115
 
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A little bit off topic, but if you haven't been tested for orthostatic intolerance, please do. It is highly correlated with ME/CFS.

Ron Davis' is looking for something in patient's plasma (or missing from it) that can alter cell function
I certainly can't speak for Dr. Davis, but my understanding is that his current metabolic trap hypothesis is a bit different than this theory.
 

alex3619

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I certainly can't speak for Dr. Davis, but my understanding is that his current metabolic trap hypothesis is a bit different than this theory.
My current understanding is four metabolic trap hypotheses are being looked at, and probably many more that we are not even aware of. When you don't have certainty in science it often pays to consider all the potentially valid possibilities. The high molecular weight substance is an empirical determination, and until we know what it is or might be not much more can be said.
 

ljimbo423

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very simple question: how should this approach explain the ME outbreaks? These are all more consequences of something infectious !? outbreaks can not be explained otherwise
This is the view of Derya Unutmaz, a leading ME/CFS researcher-

Putting the patient back together

Unutmaz hypothesizes that ME/CFS is caused by a change in a patient’s microbiome after an infection. Our microbiome consists of our microbes—trillions of bacteria, viruses, and fungi that are living in and on our bodies.

A misbalance in our microbes can change the makeup of our entire microbiome, which triggers an inflammatory response and causes the immune system to perceive that there is still a danger in our bodies – even when an infection is long gone.
LINK

Here is a study that also has the hypothesis that an infection could be a trigger for ME/CFS-

One current model of disease suggests that a trigger event (e.g. infection) results in a chronic inflammatory state characterized by increased proinflammatory cytokine production, increased reactive oxygen and nitrogen species,

altered intracellular signaling, increased intestinal permeability and systemic activation of innate immune receptors, altered glutaminergic and dopaminergic neurotransmission, mitochondrial dysfunction, and aberrant autoimmune responses
LINK
 

Gemini

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I would think it would be possible, but nothing more can be said than that. Mast cells themselves are too big. It would have to be a released product. The comment on mast cells was almost a one-liner, and I do not know how well its substantiated. I did find it very interesting though, its a line of investigation I have not thought about ... I am not used to thinking of mast cells as migratory or in general circulation.
@alex3619 I too haven't thought about that and like you find it very interesting!

I listened to Prof. Pete Smith make his comment [about 36.28 on the video] and checked PubMed for two mast cell papers he might have been referring to, but that wasn't too clear on the video:

https://www.ncbi.nlm.nih.gov/pubmed/27362406
https://www.ncbi.nlm.nih.gov/pubmed/29223146

Papers seem to say mast cells circulate in immature form in the circulation and ordinarily not in mature form. Their researchers found activated mast cells in patients and more mast cell progenitor cells circulating in the blood than in controls.

Interestingly, doing a quick internet search I see that large-scale mast cell degranulation-- cells burst and spill their contents-- can cause "hypovolemia" (low blood volume), hypotension, vascular permeability, and other symptoms. Also "exercise" can trigger mast cell activation. Astronauts get hypovolemia in space which resolves when they return to the gravity on earth; perhaps this is how it occurs in those of us earth-bound!

So now I'm wondering (1) as you point out Alex whether any mast cell contents might be in the plasma getting through the filter @ljimbo423 indicates Ron Davis used; and (2) whether cytokines Dr. Montoya measured after exercise might have come from mast cell activation due to the exercise.

Also be nice to know if Maureen Hanson's planned exercise research will include mast cells (she said at the London Conference she'd be looking at immune cells by type) and that Dr. Chia would be collaborating. Could that be to examine the tissue microenvironment where one might find viruses and mature mast cells?

So many questions and excellent research going on!
 
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This is the view of Derya Unutmaz, a leading ME/CFS researcher-


LINK

Here is a study that also has the hypothesis that an infection could be a trigger for ME/CFS-

LINK
Unfortunately that does not make sense. or why in an outbreak, by chance, should so many people have the same microbial response to a pathogen? how to turn it and turn it must be a pathogen that is the cause of ME. no gene and no microbiome...
 
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very simple question: how should this approach explain the ME outbreaks? These are all more consequences of something infectious !? outbreaks can not be explained otherwise
We recently learned a way that infection can screw with our genetics: Research showed EBV infection seemed to increase the risk of autoimmunity by binding to the genes at the exact locations where the autoimmunity problems crop up.

https://www.nih.gov/news-events/new...ein-can-switch-risk-genes-autoimmune-diseases

The insight here was that the infection can act as an epigenetic factor, something that switches genes on and off, or in some other way alters gene function.

So, hypothetically, the genetic problems associated with ion channels that Staines and Marshall-Gradisnik believe they have found could also be triggered by infections.

(This is pure speculation, but it provides a pathway to answer your question that does not require going via the microbiome, as I don't see a link from the microbiome to ion channel problems)
 
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@alex3619 I too haven't thought about that and like you find it very interesting!

I listened to Prof. Pete Smith make his comment [about 36.28 on the video] and checked PubMed for two mast cell papers he might have been referring to, but that wasn't too clear on the video:

https://www.ncbi.nlm.nih.gov/pubmed/27362406
https://www.ncbi.nlm.nih.gov/pubmed/29223146

Papers seem to say mast cells circulate in immature form in the circulation and ordinarily not in mature form. Their researchers found activated mast cells in patients and more mast cell progenitor cells circulating in the blood than in controls.

Interestingly, doing a quick internet search I see that large-scale mast cell degranulation-- cells burst and spill their contents-- can cause "hypovolemia" (low blood volume), hypotension, vascular permeability, and other symptoms. Also "exercise" can trigger mast cell activation. Astronauts get hypovolemia in space which resolves when they return to the gravity on earth; perhaps this is how it occurs in those of us earth-bound!

So now I'm wondering (1) as you point out Alex whether any mast cell contents might be in the plasma getting through the filter @ljimbo423 indicates Ron Davis used; and (2) whether cytokines Dr. Montoya measured after exercise might have come from mast cell activation due to the exercise.

Also be nice to know if Maureen Hanson's planned exercise research will include mast cells (she said at the London Conference she'd be looking at immune cells by type) and that Dr. Chia would be collaborating. Could that be to examine the tissue microenvironment where one might find viruses and mature mast cells?

So many questions and excellent research going on!
Great analysis! I just contacted @profepetesmith on twitter to see if he can tell us more about that finding of mast cells in circulation.
 
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My current understanding is four metabolic trap hypotheses are being looked at, and probably many more that we are not even aware of. When you don't have certainty in science it often pays to consider all the potentially valid possibilities. The high molecular weight substance is an empirical determination, and until we know what it is or might be not much more can be said.
Where did you hear four?
 

alex3619

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Where did you hear four?
I think it was in one of Ron's video talks, or a Q and A. The modelling showed four potential traps, and all need to be examined. Its all theoretical. I hope I am not misremembering, that happens sometimes.

Right now we have lots of data, a few theories, and very little that tells us with any certainty about causation.
 

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RE: MAST Cells detected in CFS patients peripheral blood. Also found in non CFS. My bold.

..
Mast cells may be cultured from human peripheral blood in the presence of recombinant human stem cell factor (rhSCF). The characteristics of the cells in peripheral blood that give rise to mast cells are unknown.
Source:
Mast Cells Cultured From the Peripheral Blood of Normal Donors and Patients With Mastocytosis Originate From a CD34+/Fc6RI- Cell Population
Menachem Rottem, Tadashi Okada, Julie P. Goff, and Dean D. Metcalfe
www.bloodjournal.org
August 5, 2018.
 
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Relevant to Don Staines talk above and maybe quite big news, his team just posted this on Facebook.

A turning point for CFS/ME Research
NCNED have announced that a pivotal research publication has been accepted: ‘Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients’. This article proves a significant impairment in TRPM3 function in NK cells and that TRPM3 function is significantly compromised in CFS/ME patients. NCNED used the ‘gold standard’ of patch-clamp electrophysiology to demonstrate this world-first discovery.
NCNED used NK cells as a model for all cells in the body expressing this essential calcium ion channel. TRPM3 calcium ion channels are widely distributed in numerous body systems such as the central nervous system, metabolic and endocrine systems (particularly regulating pancreas and insulin function), cardiovascular system, gastrointestinal system, skeletomuscular system and immune system.
NCNED are now pursuing additional TRPs they have previously identified in CFS/ME patients and are accelerating drug investigations for pharmaco-therapeutic applications in CFS/ME patients.

We particularly wish to acknowledge the support of Stafford Fox Medical Research Foundation, Mr Douglas Stutt, the Mason Foundation, the Alison Hunter Memorial Foundation, the Blake Beckett Foundation, McCusker Charitable Foundation, Buxton Foundation, Change for ME Charity, Qld ME/CFS/FM Support Association Qld Inc. and the ACT ME/Chronic Fatigue Syndrome Society.

Reference: Cabanas H, Muraki K, Eaton N, Balinas C, Staines D and Marshall-Gradisnik S: Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients, Molecular Medicine, Accepted 2018.

Best wishes
Sonya, Don and the NCNED team
 

Research 1st

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Relevant to Don Staines talk above and maybe quite big news, his team just posted this on Facebook.

A turning point for CFS/ME Research
Thanks, don't know if this helps us understand a bit more regarding your post?
Transient receptor potential (TRP) melastatin 3 (TRPM3) is a member of the TRP ion channel family. It is expressed in several different tissues, including the kidneys, eyes, sensory neurons of the dorsal root ganglia, and pancreatic β cells (Oberwinkler and Philipp, 2014). TRPM3 has been proposed to play roles in a variety of physiological and pathophysiological processes. It is activated by high temperatures and was shown to function as a noxious heat sensor in dorsal root ganglion neurons (Vriens et al., 2011). The neurosteroid pregnenolone sulfate (PregS) activates TRPM3 in pancreatic β cells (Wagner et al., 2008), and the channel has been proposed to play important signaling roles in those cells (Thiel et al., 2013). A missense mutation in TRPM3 was recently shown to underlie inherited cataract and high-tension glaucoma in humans (Bennett et al., 2014). In mice, genetic deletion of TRPM3 caused impaired pupillary light reflexes (Hughes et al., 2012).

TRP channels are activated by a wide range of stimuli and play roles in a variety of physiological and pathophysiological processes (Wu et al., 2010). Given their diversity, general principles in their regulation are difficult to establish. As the majority of TRP channels have been reported to be regulated by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), it is possible that phosphoinositides are general regulators of all TRP channels.
Probably clutching at straws here, but exercise increases core temperature, as does having a hot bath and both make me terrible. 'CFS' is also associated to abnormal heat shock protein production.

Source:
Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel
Doreen Badheka, Istvan Borbiro, and Tibor Rohacs
J Gen Physiol. 2015 Jul; 146(1): 65–77.
doi: 10.1085/jgp.201411336
PMCID: PMC4485020
PMID: 26123195
 

Research 1st

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Also if I recall correctly there are at least two cases in the non censored UK literature of Dorsal Root Ganglionitis in fatal ME cases. Which explained their sensory problems, such as pain.

I wonder if somehow the Immune system, via the NK Cells fighting a chronic infection could case a chronic low grade neuroinflammation state leading to this in some patient subsets.

The Australian researchers work could be very important regarding this matter.