New video from Australia with research summary, etc

Research 1st

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Thanks.

So the conclusion of the researchers is this:

This investigation may inform the pathomechanism of reduced NK cell cytotoxicity in CFS/ME patients.
And for those that don't understand the lingo, this means the 'CFS' patients had reduced ability to kill stuff like viruses, and thus also kill cancer cells. If repeated and proven, it would thus be a form of immune suppression but worse as it would affect your CNS not just fighting off a common cold. Then it would get more interesting as not only could you compare Severe to Mild, but 30 years sick vs 3 years sick and measure if the reduced NK function worsens over time and if it does, how long it takes.

Would be interesting to get a comment from Dr Nancy Klimas on this, as she is the 'CFS' NK function queen.
 

Research 1st

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RE: Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels - also known as.....TRPM3... (my bold).

So lastly before I fall off the bed, regarding what might effect TRPM3 in us patients?
Doesn't the hormone Progesterone stick out below like a sore thumb or am I mistaken?
Probably not, but worth a post I thought for the smart people here to look at.

Endogenous and exogenous ligands of TRP channels

TRPM3 Endogenous agonists:
Pregnenolone sulphate Wagner et al. (2008)
D-erythro-sphingosine Grimm et al. (2005)

TRPM3 Endogenous antagonist:
Progesterone Majeed et al. (2012)

TRPM3 Exogenous antagonist:
Rosiglitazone Majeed et al. (2011a)
Mefenamic acid Klose et al. (2011)
Naringenin, hesperetin, ononetin, eriodictyol Straub et al. (2013)
TM3E3 (polyclonal antibody) Naylor et al. (2008)
Source:
Transient receptor potential (TRP) channels: a clinical perspective
Yosuke Kaneko1 and Arpad Szallasi
Br J Pharmacol. 2014 May; 171(10): 2474–2507.
Published online 2014 Apr 28. doi: 10.1111/bph.12414
PMCID: PMC4008995
PMID: 24102319
 
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They've been chasing this abnormality for ages now and by the phrasing what seems to be new in the latest paper is they've established more definitive proof than the "is associated with" used in the paper above.

I hope there's some extra tidbits in the paper than just the same finding but with more certainty.

I'm most interested to hear if they have any proof of the channel being dodgy in cells other than NK cells. This phrasing in their facebook post stands out: "...and that TRPM3 function is significantly compromised in CFS/ME patients."

Is body-wide ion channel deficiency plausible? Maybe? The good news is there are compounds shown to stimuate TRPM3. Whether they'd work as treatments idk but it's better than discovering a problem in a pathway with no known agonists.



@Research 1st it would be neat and almost laughably simple if the issue was reacting badly to heat. (I bet the solution would not be neat, nor laughable nor simple). I certainly struggle in the heat.
 
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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)
but that makes only limited sense again. should it be a coincidence then that so many people are out of this pile of so many outbreaks that this genetic change occurs after an infection and then all get ME at the same time?

Unfortunately, I miss the logic, sorry. in addition, the pathogen must still be present because there are clusters. Even spouses get stuck with each other after years! As stated above, considering the folding outbreaks and clusters of ME, one can only conclude that ME must be an infectious disease and that all other findings are only secondary consequences of this infection (this infection must persist!)

I absolutely do not understand why science does not take this into account anymore. is it fear to end like Mikovits? is it because you do not get any research funding? Lot of questions ... but also the unpleasant questions must be asked.
 

alex3619

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The problem might be with particular isoforms of the receptor, which will localise to specific but potentially broad types of tissue. It wont be universal, but those tissues might be almost everywhere, so its close to universal. On the other hand if its some pervasive tissue type, like vascular connective tissue, it will affect every organ in the body.

Presuming this is right, and independently validated and tested, it still does not show causation. It might be a primary issue, or secondary to something else, or a piece of a mechanism but still not complete. What it might show, with the right studies, is that this can drive some, many, most or all of our symptoms.
 

alex3619

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I found this interesting -

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844244/

TRPM3 in temperature sensing and beyond

TRPM3, also known as melastatin 2 (MLSN2), LTRPC3 (long TRPC3) and KIAA1616, is a member of the TRPM subfamily of transient receptor potential (TRP) ion channels. The channel was originally identified as a volume-regulated ion channel that can be activated upon reduction of the extracellular osmolality. Later, the channel was proposed to be involved in the modulation of insulin release in pancreatic islets. However, new evidence has uncovered a role of TRPM3 as a thermosensitive nociceptor channel implicated in the detection of noxious heat. The channel is functionally expressed in a subset of neurons of the somatosensory system and can be activated by heat. The purpose of the present review is to summarize existing knowledge of the expression, biophysics and pharmacology of TRPM3 and to serve as a guide for future studies aimed at improving the understanding of the mechanism of thermosensation and proposed physiological functions of TRPM3.
(my bolding)

Temperature sensitivity, and particularly heat sensitivity, might be explained by this to some extent, though I still like the small fiber ideas as well.
 

Gemini

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Presuming this is right, and independently validated and tested, it still does not show causation. It might be a primary issue, or secondary to something else, or a piece of a mechanism but still not complete. What it might show, with the right studies, is that this can drive some, many, most or all of our symptoms.
I agree with you @alex3619, your points are very well taken.

Went back and re-listened to Staines [about 15:00 on the video] where he describes his 2-hit theory--one, patients experience an initial infectious trigger, then two,"some other catastrophic event happens" impacting on ion channel receptors The test they're developing will involve the genetics of the receptors and should be quite interesting.

@Murph mentioned how Naviaux's theory's a bit different and it's good to have different perspectives. He and Ron Davis' team are examining why the immune system is chronically activated be it infection, autoimmune, or some other problem blocking it from "resetting." The first step of Naviaux's 3-step treatment strategy is to eliminate triggers if still there which may address causation.

@Research 1st mentioned Nancy Klimas' NK cell research and Prof. Smith N-of-1 studies at the end of his talk. Hopefully with today's advanced technologies researchers will start to put the parts together and test for Klimas' NK cell abnormalities; Mark Davis' T-cell clonal expansion; Ian Lipkin's polyclonal hypergammaglobulinemia; Smith's mast cell activation; autoantibodies; cytokine signatures, and genetic immune abnormalities in the "same patient" and raise our understanding of immune system dysfunction up a notch...
 
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but that makes only limited sense again. should it be a coincidence then that so many people are out of this pile of so many outbreaks that this genetic change occurs after an infection and then all get ME at the same time?

Unfortunately, I miss the logic, sorry. in addition, the pathogen must still be present because there are clusters. Even spouses get stuck with each other after years! As stated above, considering the folding outbreaks and clusters of ME, one can only conclude that ME must be an infectious disease and that all other findings are only secondary consequences of this infection (this infection must persist!)

I absolutely do not understand why science does not take this into account anymore. is it fear to end like Mikovits? is it because you do not get any research funding? Lot of questions ... but also the unpleasant questions must be asked.
Those outbreaks are very well documented, [leaving this for posterity but it's wrong: [but there's only been three, each about 30 years apart. (Royal Free Hospital, Incline Village on Lake Tahoe, the other one)]]. 99.9% of patients aren't part of an outbreak. Furthermore, huge amounts of work have gone into hunting for persistent pathogens. That work is ongoing. For example, Michael van Elzakker is looking into whether a virus is infecting the vagus nerve.

But so far the great pathogen hunt has yielded nada. They have found lower levels of virus particles in blood than in normal people.

So for now the preferred model for understanding the disease is like this: some patients have a predisposition (because of their genetics or microbiome or other reason) such that when they get hit by an infection they develop a problem in their (immune/metabolic/microbiome) systems, that doesn't go away and causes ME/CFS symptoms.

The problem in the ion channels described by the Australian researchers here could be one of these types of susceptibility. They are now looking for more ion channel problems.

If you want to explain outbreaks, perhaps you can imagine that everyone has levels of susceptibility, and certain viruses harm people with even low susceptibility and turn them into MECFS sufferers, while other viruses only harm the highly susceptible. The outbreaks must represent those more powerful viruses.This is just a theory. In any case the disease is perpetuated by the body not the virus.

I think it's important to remain open-minded about the possibility of pathogens, but be guided by evidence.
 
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alex3619

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There have been many more than three outbreaks, and depending on how people count them it can be from over fifty to over a hundred - I am not clear on exactly how many any more. Take Lake Tahoe for example, at about the same time there were several other outbreaks in the US, just not so well documented. Three outbreaks with even a token effort to investigate might be a bit more accurate. The first outbreak is I think the 1934 Californian outbreak, Australia has had a few of them, as has New Zealand, though the only one here that was really examined to any extent was the dual outbreak in Adelaide, South Australia, one in 1948, the other in 1949. From that study they infected monkeys and on autopsy they had spinal lesions. That was published in 1955.

The 1934 outbreak was interesting though. The first two cases were actually from 1932, then a break, then the big outbreak.
 

wigglethemouse

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Those outbreaks are very well documented, but there's only been three, each about 30 years apart. (Royal Free Hospital, Incline Village on Lake Tahoe, the other one). 99.9% of patients aren't part of an outbreak.
There are a large number of documented outbreaks. The thing is, after about 1990 they stopped documenting them.
https://me-pedia.org/wiki/List_of_myalgic_encephalomyelitis_and_chronic_fatigue_syndrome_outbreaks

I was really surprised when I saw this list. I lived 20 miles from one of the outbreaks in the 1980's and I didn't even know about it!
 

heapsreal

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Research 1st

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I found this regarding TRPM3 again, from some of the main researchers in the NK finding, from around 3 months ago.

Decreased Expression of TRPM3 and mAChRM3 in the Small Intestine in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
IJCM> Vol.9 No.5, May 2018

Results: There was significantly decreased expression of TRPM3 in the CFS/ME patient (35% ± 9%) and a significant decrease in mAChRM3 in the CFS/ME patient (54% ± 9%). There was no difference in IL-1α between CFS/ME patient and NFC, however; there was an increase in IFNy (13% ± 6%) in the CFS/ME patient compared to NFC. There was a difference observed in TNFα in CFS/ME compared to NFC.

Conclusion: Differences were noted in the expression of specific TRP ion channels and cholinergic receptors in CFS/ME compared with NFC, with CFS/ME demonstrating decreased TRPM3 and mAChRM3. Further, IFNy was increased, and TNFα decreased, in the small intestine of the CFS/ME patient with reported gastrointestinal disturbance.
So from what I can see, although statistically insignificant at the moment, they did find an TRPM3 related issue in tissue (ONE ME CFS patient with gut symptoms Vs a non fatigued control -NFC) as well as NK Cells later on in more patients.

Still, it's interesting if it can be repeated though in maybe 50-100 patients and see what it comes out like. I can't imagine there are many ME CFS patients out there who would volunteer for stomach biopsies though!
 
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Is it a coincidence then that so many people are in a pile where this genetic change occurs after an infection and then all get ME at the same time? Unfortunately, I miss the logic, sorry. in addition, the pathogen must still be present because there are clusters. Even spouses get stuck with each other after years! As stated above, considering the folding outbreaks and clusters of ME, one can only conclude that ME must be an infectious disease and that all other findings are only secondary consequences of this infection (this infection must persist!) , I absolutely do not understand why science does not take this into account anymore. is it scary how to end Mikovits? is it because you do not get any research funding? ask questions ... but also the unpleasant questions must be asked.
Those outbreaks are very well documented, [leaving this for posterity but it's wrong: [but there's only been three, each about 30 years apart. (Royal Free Hospital, Incline Village on Lake Tahoe, the other one)]]. 99.9% of patients aren't part of an outbreak. Furthermore, huge amounts of work have gone into hunting for persistent pathogens. That work is ongoing. For example, Michael van Elzakker is looking into whether a virus is infecting the vagus nerve.

But so far the great pathogen hunt has yielded nada. They have found lower levels of virus particles in blood than in normal people.

So for now the preferred model for understanding the disease is like this: some patients have a predisposition (because of their genetics or microbiome or other reason) such that when they get hit by an infection they develop a problem in their (immune/metabolic/microbiome) systems, that doesn't go away and causes ME/CFS symptoms.

The problem in the ion channels described by the Australian researchers here could be one of these types of susceptibility. They are now looking for more ion channel problems.

If you want to explain outbreaks, perhaps you can imagine that everyone has levels of susceptibility, and certain viruses harm people with even low susceptibility and turn them into MECFS sufferers, while other viruses only harm the highly susceptible. The outbreaks must represent those more powerful viruses.This is just a theory. In any case the disease is perpetuated by the body not the virus.

I think it's important to remain open-minded about the possibility of pathogens, but be guided by evidence.
In short, you could be more concerned with the outbreaks and the course of diseases that started as epidemics and then became a pandemic. as an example HIV (oh..a retrovirus..just coincidence?). HIV first appeared in epidemics. And today? Could one say that "99.9% do not occur in epidemics";) why is that? Because a retrovirus weakens over time as it passes through several vertebrates and epidemics become pandemics. the cause has long since been found and all known treatments which have remission have antiretroviral activity. Especially, of course, the HIV medications such as tenofovir and lamivudine, which have even brought patients with Bell 0 in remission. coincidence? decide for yourself.
 

Gemini

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I think it's important to remain open-minded about the possibility of pathogens, but be guided by evidence.
@Murph, excellent point.

In June at the London Conference Ron Davis said he's working on techniques to detect RNA viruses (they've pretty much ruled out DNA viruses after extensive testing). RNA viruses include enteroviruses long associated in the literature, and in some outbreaks, with ME/CFS.

Guided by evidence he said he's also going to test for all known strains of trypanosomes, associated with African Sleeping Sickness, as well as other parasites. So the research on pathogens is very active and on-going.

A real breakthrough in this line of inquiry would come if Mark Davis were to identify a pathogen, or not, as the cause of the clonal expansion of those interesting T-cells he's been looking at. Really looking forward to his next update.