Hot Story
The media reports have been sizzling! Griffith University, the home of the NCNED group in Australia that produced the study, called it “groundbreaking”. IFL Science lead off with a piece called “People With Chronic Fatigue Have A Defective Channel In Immune System Cells” which stated,
“The finding confirms earlier research that CFS is a biological condition, not a psychological one, and opens lines of inquiry for potential treatment options.”
Even a government official got involved telling the Tech Times
“This discovery is great news for all people living with Chronic Fatigue Syndrome (CFS) and the related Myalgic Encephalomyelitis (ME), as it confirms what people with these conditions have long known – that it is a ‘real’ illness – not a psychological issue,” Leeanne Enoch, the Science Minister of Queensland.
Donald Staines, one of the researchers associated with the study, went so far as to say
“This is huge because for the first time we have documented the pathology in this illness. Up until now people have not really understood the illness,” Staines
Natural Killer (NK) Cell Study
The study was putatively on natural killer cells but if the NCNED group in Australia is right NK cells are just the beginning of the story.NK cells are a good place to start, though. Reduced NK cell cytotoxicity is the most consistently found immune aberration found in chronic fatigue syndrome (ME/CFS). Despite several attempts to identify the cause of the NK cell problems in ME/CFS- they haven’t been nailed down yet.
The NCNED group at Griffith University in Queensland, Australia has been digging more deeply into the cause of the NK cell problems in ME/CFS than any other group.
They appear to have had TRP (transient receptor potential) ion channels in their cross-hairs for at least a couple of years. These ion channels allow calcium and magnesium into our cells. Calcium does much more than build strong bones. Inside the cell it plays an essential role in cellular signaling and homeostasis. Changes in calcium concentration also allow our muscles to contract during exercise.Calcium also modulates the activity of many enzymes including mitochondrial enzymes. It affects neurotransmitter release from our nerves. It’s an essential intracellular element; mess with calcium levels and our cells won’t work so well.
But is low calcium the cause of the natural killer cell problems in ME/CFS? In March 2016 the NCNED group looked for and found significantly increased numbers of polymorphisms or mutations in the genes expressing transient receptor potential (TRP) and acetylcholine receptors (AChRs) in people with ME/CFS. That suggested that problems with these ion channels could be limited calcium inflows into our cells.
Crystalline structure of a calcium ion channel
Then May 2016, the NCNED team proved that these ion channels exist on natural killer and B-cells(nobody had shown that before), and then showed that fewer than normal of them were present on the NK cells of people with chronic fatigue syndrome (ME/CFS).
The big finding, though, was finding reduced cytoplasmic calcium levels in those cells. That suggested that reduced numbers of ion channels on the NK cells of ME/CFS patients were indeed depriving them of an essential element – and possibly impacting their ability to function
The Study
In the present study NCNED researchers determined if the reduced numbers of TRPM3 receptors on the NK cells were causing (a) reduced calcium levels in NK cells and more importantly (b) responsible for the reduced NK cell cytotoxicity (killing capacity),
These papers are very difficult to understand. Hopefully most of this is correct.
The natural killer cells from 15 ME/CFS (Fukuda definition) and 25 healthy controls were labeled with fluorescent antibodies to determine the levels of TRPM3 receptors/ion channels and two other receptors (CD107a, CD69) associated with NK cell activation.
They looked at two kinds of NK cells: the cytotoxic NK cells and NK cells involved in immune surveillance and cytokine production.
They stimulated the cells with various substances (pregnenolone sulphate (PregS), 2-aminoethoxydiphenyl borate (2APB), ionomycin, and thapsigargin (TG)) known to increase intracellular calcium.
The Results
The Gist
- First the NCNED team found that several mutations trhat were increased in ME/CFS patients affect the ion channels that allow calcium into NK cells
- Next they determined that the dysfunctional NK cells found in ME/CFS patients were indeed low in calcium – an essential element in cellular functioning
- Using a series of tests they demonstrated that problems with calcium ion channel functioning exist in two kinds of NK cells in ME/CFS patients
- Increasing calcium levels returned the NK cells to normal functioning
- Because the dysfunctional ion channels are found in tissues across the body they could conceivably impact many areas of the body
- Large studies are needed but the NCNED appears to be confident they’ve uncovered a core pathology in ME/CFS.
- The next steps are developing a diagnostic test, testing their finding out in larger groups, and looking for pharmaceutical treatments.
- The NCNED team recently received $4 million to do just that.
NK Cells Involved in Cytokine Production
At baseline both the number of TRPM3 receptors and the intra-cellular calcium levels were significantly reduced in ME/CFS patients compared to the controls. Given the reduced calcium stores found, the TRPM3 finding was strange. The number of TRPM3 ion channels on the cell should increase when calcium stores are reduced; i.e. ME/CFS patients should have had more ion channel receptors on their NK cells- yet they had less.
Stimulating these cells with a TRPM3 booster to increase cellular calcium levels resulted in increased calcium levels in both groups but reduced calcium levels in the ME/CFS patients relative to the healthy controls; i.e. their calcium levels were up but were still low.
The number of TRPM3 ion channels on the NK cells increased equally in both groups but as noted healthy control NK cells accumulated more calcium. Something was clearly still keeping the calcium levels down in the ME/CFS group.
Cytotoxic NK Cells
The cytotoxic NK cells were different. Stimulating the TRPM3 receptors resulted in increased receptor expression in the healthy controls but not in the ME/CFS patients.
Ionomycin increased TRPM3 expression on the ME/CFS patients’ NK cells compared to the controls, but not enough to increase cytotoxic T-cell activity. That may be because another enzyme (extracellular-regulated kinase (ERK)) needed for that process is depleted in ME/CFS.
The only way the researchers were able to increase cytotoxic T-cell activity in the ME/CFS patients was by whacking their NK cells with a calcium depleter first and then activating them with a ion channel (TRPM3) enhancer. It appears that the first part of that process – the calcium depleting process – stimulates the enzyme ME/CFS patients are low in. Once that enzyme is present calcium levels could be increased.
Putting those substances together had no effect on healthy controls who presumably have functioning NK cells.
It’s clearly a complex situation but the takeaway message I got was that both types of NK cells had problems with ion channel (TPRM3) expression and calcium levels.
The TRPM3 Ion Channels
Is an essential intracellular element – calcium – low in many ME/CFS patients cells?
Because these ion channels allow calcium into the cell, a deficit of these channels could result in reduced intracellular levels of calcium – an essential element. (TRPM3 also controls levels of magnesium in the cell.) As we’ve seen, deficits in these ion channels were found in both types of NK cells.
The NCNED’s earlier research suggests that ME/CFS patients may have increased levels of mutations in the genes that produce these ion channels. They’ve also found low intracellular calcium levels in ME/CFS patients NK cell Increasing those levels may help with the NK cell killing problems. The studies are small but the evidence seems to be adding up.
The Big Picture
The big news, though, is not the NK cells but the possibility that the same gene mutations have impaired the activity of these ion channels in cells across the body.
A review of these ion channels suggests they may in particular affect the sensory neurons – an intriguing finding given the many weird sensations ME/CFS patients experience. These ion channels, interestingly enough, given the feelings of heat or burning experienced by some patients, appear to play a role in the sensation of heat and could induce a hypersensitivity to heat. They are also found in the brain, spinal cord, sensory neurons, pituitary, kidney, eye, testis and fatty tissue, plus they’re also expressed in sperm cells, ovaries, pancreas, heart, blood vessels and bladder. That could make them a perfect fit for a disease that affects so many areas.
Donald Staines of the NCNED explained ME/CFS like this:
“This dysfunction affects the brain, the spinal cord, the pancreas, which is why there are so many different manifestations of the illness – sometimes patients will suffer from cardiac symptoms, sometimes it will be symptoms in the gut.”
Has a key to chronic fatigue syndrome been found? Bigger studies await.
Other kinds of stress have not yet been associated with these still poorly researched ion channels, but Staines noted that similar ion channels are known as “threat receptors”. That fits in with the increased sense of threat or wiredness that seems almost ubiquitous in this disease.
Sonya Marshall-Gradisnuk – the leader of the group – told IFL Science that these receptors are so primitive virtually any stressor – from an infection to a toxin to perfume – could set them off. According to Science Alert Staines suggested that these stressors cause calcium receptors to ramp up – exposing the genetic problems present – and causing chaotic calcium conditions in the cells.
Regarding treatments, Staines was optimistic stating that potential treatments for malfunctioning ion channels “are already being used for other conditions.” Because we already have “good safety data” on them and know how well they are tolerated, etc. “if they are found to work in the lab, clinical trials should be smoother sailing.”
Staines wasn’t willing to talk about a cure, but hey, a normal life would be a huge step up: “We don’t know that we can necessarily cure the illness but we can help people lead a normal life.”
Dr, Gradisnuk-Marshall was willing to answer the following questions:
Can you say what the putative biomarker would consist of? All the polymorphisms associated with TRPM3 or some of them or the polymorphisms plus other factors?
We are exploring a number of potential biomarkers. We are not limiting ourselves here because of the extraordinary complexity of this illness.
Have you been able to check out other cells yet to see if the TRPM3 problems are present in them?
Our investigation of other cell types is ongoing.
Are you satisfied that the TRPM3 problems are causing the NK cell killing problems?
Still a long way to go as these ion channels behave in complex ways with many additional interactions which may have a role in the pathology.
Will you be examining the polymorphism in other disease groups?
We are totally focused on CFS/ME at this stage.
Take care and best wishes
Sonya and Don
Conclusions
The studies have been quite small but the NCNED is clearly confident that they’re onto something important. A diagnostic test is a top priority and has been for a year or so. Last year a news report stated the team was searching for partners to produce an ME/CFS diagnostic test involving these genetic polymorphisms. Last December they scored $4 million (@ $3 million U.S.) in funding to develop this diagnostic test and explore drug treatments. That’s on top of the $2.5 million (@ $1.9 million U.S.) they received earlier to do likewise.
It’ll be fascinating to find out what percentage of patients have these SNP’s or mutations.The NCNED identified a range of TPMR3 polymorphisms (as well as other polymorphisms) in an earlier study. Does the potential biomarker consist of all of those polymorphisms (in combination with others?) or?
If the group is correct that the TRPM3 problem is body-wide in ME/CFS, it could help explain the huge range of symptoms found in ME/CFS. No study evidence indicates that these problems exist in other cells, but the NCNED group’s willingness to assert that that’s probably the case suggests they may already have evidence of that in their lab. Bigger studies involving other disease groups as well as studies that establish symptom relevance are needed and it appears are coming.
This is exciting. Hope to hear more soon.
Wonderful, wonderful news. Now if these things that need to be done could be done quickly (as well as accurately)!
The nice thing is that they got a nice grant; i.e. they have some money….Hopefully this will proceed quickly 🙂
What about guaifenesin protocol?
Could this be why gabapentin is effective for many people with CFS? Doesn’t it affect ion channels somehow? Or could it be making CFS worse based on its mechanism of action? I’m curious what the drugs are that they mention that are already in use for other conditions.
I don’t know…This a really complex field. For instance there are at least five different kinds of calcium channels. The ones the NCNED team dug up belong to the T-type which are primarily found on neurons. Gabapentin does bind to calcium channels but I couldn’t tell if it affects these particular ones.
I’m trying to find out what drugs they are interested in.
I’m looking too. I’ll let you know if I find anything. I’m really interested.
GABA is an over the counter supplement and I found out that is affecting trafficking of voltage dependent calcium channels in the central nervous system. Due to my serotonin syndrome it is contraindicative for me. For others worth trying.
MOST INFERESTING. THEY ARE ACTUALLY ON TO SOMETHING. WE ARE ALWAYS HOPFUL…..HIPJAVEN@gmail.com
Where is any mention of the “dauer” theory? It’s like Naviaux’s groundbreaking theory is just like every other days’ blog-post – yesterday’s news and NOT groundbreaking at all – when in reality it is literally the ONLY thing any medical professional in the real world will look at. My GP got tired of me urging him to read information like this about 50 blog-posts ago. If new information is to be used to help ordinary ME sufferers as we helplessly struggle to obtain medical care and be taken seriously, then the new information has to stop being random bottomless rabbit holes and bridges to nowhere, and must contain references and ties to legitimate theories.
Of course time will tell with the Aussie finding. The good news is that they have some money to explore further so hopefully this is one “breakthrough” that further study will determine how much a breakthrough it is.
The same is true, of course, for the Naviaux and metabolomics findings. Time will tell…At least there appears to be enough interest in both for us to get somewhere with them.
Your GP will probably start getting interested when we have some nice BIG, rigorously done studies that he feels he can count on. We haven’t had many of those to date.
I wonder why there is never much mention of neuroendocrine function in current research directions. The focus on metabolites, especially calcium regulation, seems to be an end-of-the-line (symptomatic) investigation…?
I agree that there hasn’t been. I did hear that a really good study is underway at Stanford, though. It does pop up in Brodericks modeling studies as well but in general not so much.
When will there be help for us
Heartening to hear there’s a study happening at Stanford, Cort. Eager to hear more about this…
Thanks as always for your light.
He was happy with the one LITTLE Naviaux study. With that study my whole world got better: he stopped urging me to go to a psych, and/or sighing sympathetically, and prescribed real honest-to-goodness medication that has changed my everyday existence from horrific to tolerable. But he’s getting anxious – no one ever mentions follow up on it, and no one ever cites to it in other studies; it’s just one new rabbit hole after the next with all new theories. If even one important study – or scientist, like Lipkin – would cite to Naviaux my doctor could at least be refueled and refreshed to continue caring about me and my disease. Without it he’s losing interest.
A really nice response! Naviaux should have a paper out soon on Autism I believe. Aside from that it’s going to take some time to get that ME/CFS study done. I’m sure that we’ll see other metabolomics papers, though, and I would be surprised if they didn’t cite him…
Keep an eye open for those metabolomics studies; so far they’re showing much the same thing.
Dauer could fit as an alternative immune function when NK cells fail: the oxidative stress involved in Dauer acts strongly against bacteria, yiests and parasites and the hardening of the cell wall caused by Dauer makes access of all of the mentioned pathogens plus virusses to the cell a lot harder. So it does not have to be completely unrelated.
Great news hopefully get some treatment soon. Had this horrible illness for nearly 40yrs. Would love to feel good and no pain, and have a bit of a good life before its to late.
That is exactly how I feel?
Couldn’t you just get your intracellular calcium level checked and if it’s ok you could assume this isn’t your particular issue?
I have no idea….
Wonder whats in the Low Dose Naltrexone that helps many
No one is really sure but I think the idea is that it is damping down the inflammation caused by the microglial cells in the brain. That inflammation may be setting the pain pathways off – causing increased pain sensitization. When the inflammation is removed the pain subsides.
LDN put me in the worst possible mood. My anxiety was through the roof and I was so angry it was insane. It’s unfortunate because I did start to notice improvement in my physical endurance.
It once helped me then all of a sudden I had a bad reaction to it. Bazarr
I posted the following information on LDN on my Facebook page a while back.
LOW DOSE NALTREXONE
Low-dose naltrexone (LDN) describes the off-label use of the medication naltrexone at low doses for diseases such as multiple sclerosis (MS) and fibromyalgia. Low-dose naltrexone has been demonstrated to reduce symptom severity in diseases such as MS, fibromyalgia, CFS, complex regional pain syndrome, Crohn’s disease, and more.
HOW DOES LDN WORK TO TREAT THESE DISEASES?
If these diseases originate with a lack of the enzymes that digest dietary proteins – protease and DNase 1 – then the effectiveness of LDN must be attributed to it addressing some part of the underlying disease pathway that results from these missing enzymes. So, the question is, what part of the underlying disease pathway caused by a lack of protease and DNase 1 does LDN address?
LDN AND MICROGLIA (IMMUNE CELLS OF THE BRAIN AND SPINAL CORD)
LDN is considered a glial cell modulator. As the following study (link follows) from Stanford University on LDN and fibromyalgia states, naltrexone is a glial cell modulator that has been demonstrated to suppress the release of proinflammatory factors from microglia …read more at: http://www.painmed.org/2012posters/abstract-251/
So, LDN works via its action on microglia. Activated microglia play a central role in the autoimmune, CFS, and fibromyalgia disease process. For instance, in the following study the researchers stated that “microglial activation” in MS is thought to contribute directly to central nervous system damage. In addition, the researchers concluded, “A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune disease.”
Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis.
Benveniste EN. 1997. J Mol Med (Berl). 75(3):165-73.
“One of the characteristic features of microglia is their rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. This review focuses on the role of the microglia in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), and in the animal model of MS, experimental allergic encephalomyelitis (EAE). Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms…A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune disease.”
http://www.ncbi.nlm.nih.gov/pubmed/9106073
WHAT IS ACTIVATING THE MICROGLIA IN PATIENTS WITH AUTOIMMUNE DISEASE, CFS, AND FIBROMYALGIA?
One answer is, elevated levels of the amino acid homocysteine. Homocysteine is elevated in patients with CFS, fibromyalgia, and autoimmune disease due to a lack of the enzymes that digest dietary proteins – protease and DNase 1.
In the following study the researchers found that homocysteine promoted “proliferation and activation” of microglia. The researchers concluded: “Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.”
Homocysteine promotes proliferation and activation of microglia.
Zou CG, et. al. 2010. Neurobiol Aging. 31(12):2069-79.
“In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation)…Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. …Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.” http://www.ncbi.nlm.nih.gov/pubmed/19131143
ELEVATED HOMOCYSTEINE IN AUTOIMMUNE DISEASE, CFS, AND FIBROMYALGIA
Research confirms elevated levels of homocysteine in patients with autoimmune disease, CFS, and fibromyalgia. For instance, in the following study the researchers found that homocysteine (Hcy) levels were “significantly increased” in MS patients.
Increased plasma homocysteine levels in patients with multiple sclerosis and depression.
Triantafyllou N, Evangelopoulos ME, et al. 2008. Ann Gen Psychiatry 7: 17.
“…Hcy levels were significantly increased in MS patients compared to controls…”
http://www.ncbi.nlm.nih.gov/pubmed/18782433
TAKE HOME MESSAGE:
LDN works via its action on activated microglia. Microglia are activated in patients with autoimmune disease, fibromyalgia, and CFS due,in part,to elevated levels of the amino acid homocysteine. Homocysteine is elevated in autoimmune disease, fibromyalgia, and CFS due to a lack of the enzymes that digest dietary proteins – protease and DNase 1.
Thanks!
Thank you very much for this info. It’s very interesting.
I have a MTHFR compound heterzygous gene mutation. (https://www.dietvsdisease.org/mthfr-c677t-a1298c-mutation/)
These mutations elevate your homocysteine levels as well. Having testing done this week to check my level. I will talk to my Rhuemy about LDN. Thanks again!
I don’t know about the low low doses being used, but a few studies found that somewhere between 125-500 ug/kg of Naltrexone reduced hypothalamic down regulation of the HPA axis by temporarily blocking opiate receptors. Patients had a rise in ACTH and cortisol levels after taking the Naltrexone.
As one of the components of CFS seems to be a blunted HPA response to stress, maybe Naltrexone is making it less blunted in addition to stabilizing microglia?
I was taking 4.5mg LDN for months with minimal effect, so I upped it to 9mg two days ago to match the 125ug/kg from the study. If I don’t notice an effect in 2-3 weeks, will try increasing it again.
I’m not sure a cohort of 15 people can ever be described as ground breaking. I wonder how this would correlate with Naviaux’s findings?
Good question. The studies have been small (the polymorphism study had about 70 people; those studies tend to be larger) but the NCNED group seems very confident. That makes me think they may have unpublished supportive data.
They have an ongoing study in Norway, they have recently figured out that our cells doesn’t process glukose in to energy like a normal person, so that can maybe be a piece in the puzzle. If our cells can’t process calsium, and this affects other functions Of the cells. That might be why the cells can’t process glucose properly either.
Just a thought from the top Of my head.
It’s an appropriate sample size, if the difference between the patients and the healthy controls is significant. There are guidelines for sample size requirements. It’s also only economically viable to run an exploratory study at this size. If it shows clear trends, then it can be repeated with a larger group. No point testing 400 subjects for an uncertain hypothesis, clinical trials are expensive! The scarce funds need to be spent effectively.
How does this theory fit with having anti calcium channel autoantibodies? I’ve seen similar articles to this one recently, and am certain this is very relevant to my case, if only I knew how to piece it all together?!
That’s an interesting idea. That sure sounds like another way to cause the low calcium levels. I wonder how many patients have the genetic polymorphisms that effect those calcium ion channels. Generally I think its rare for an entire disease group to have something like that (????) but autoantibodies would seem to be another way to cause the problem.
Great job Cort!!! How you can muster enough brain power to tackle to decipher studies as complex as these having CFS is a testament to the tenacity humanity is endowed with.
If healthy people realized the tremendous effort and determination that takes to stay to task given our load, they would see how great our daily fight is.
I too work from home in a complex field pushing my mind constantly to support my family. It is a huge struggle, and yet a blessing to be able scrape enough energy to produce a bit so that we can bring some money in. A shadow of what we are truly capable of if healthy. But I am so grateful for whatever I can do. Yes we all know it is not a product of only determination, since it can put us in bed, but the careful dance we must play with what energy we have. But most importantly the state of our health.
Whey protein (immunocal), vit d2 (not d3) and meditation have helped me so much.
Anyway, the study makes one wonder if the channels are another way to enforce a liwer energy state.
Looking hopeful! I trust science and good solid research to pave the way. I have a fear. I moved and cannot find a doctor that knows anything about it. If a drug is developed that could relieve some of our symptoms, how do we convince a doctor to prescribe it? This is great research but the AMA still has to do their homework on the subject. The way that I feel and I’m living with my 80 year old parents because of it right now, I get frightened and upset just thinking that I might have to convince a doctor to prescribe what research could hand out to us. I’m reading the science but are they?
Thank you for posting this and giving a nice layman’s summary. This is a very hopeful development and, like you said, it is well funded- so that in itself is amazing! If new research proves promising, reproducible and effective, I think the likelihood of other researchers/pharmaceuticals jumping on board would be quick if there was the potential to market a treatment to millions of folks who have not been able to be previously treated.
I.e. if doctors had a diagnostic test and concrete treatment options and if the pharmaceutical industry could profit, both ME/CFS patients and research would suddenly be interesting and valid.
What is disheartening is that even after they figure out the “whys” and “how comes” of this horrible disease, and all of the pharma companies dive onboard to get their share of the ME/CFS pie, which will be huge, anyone in my situation will never see more than a doctor’s office sample of these breakthrough, life-changing meds. Sad, but true.
Being too sick to work, I can’t afford them, and being on Medicare also means I can’t afford them.
Well they would need to be covered by Medicare. I know that seems a long way away but it has, of course, happened for many disease. “All” that is needed is for the FDA to approve a drug.
More exciting news … it’s a real race to the finish now. Who will win, the Aussies, the Norwegians, or the Americans? Someone is going to be very famous for solving this puzzle and it’s gonna happen sooner rather than later.
Having battled this dreadful disease for 32 years, for me it cannot happen soon enough.
Or the Japanese…they are doing some clever stuff in CFS too!
One might hope that the USA could do more given its huge population and wealth (no pressure my dear American friends!). Maybe divert some of that crazy military spending to much more medical research?
(sorry to get political)
No apologies needed about getting political on money for medical research. It’s been cut back for a long time. One boondoggle bomber could have cured….who knows what. We have plenty of smart folks and good labs; need more will to do it. Would help to have some high-up Congress person’s kid to have CFS/ME.
Cort, I really appreciate the work that you do. I tried reading the studies and the effort fried my brain. Your report is so much easier to understand. Thank you.
I keep wondering what is happening with the dna database that Nancy Klimas and her group are assembling? Are they sharing the dna data they are gathering from many of us with some of these studies that are looking at genes?
Any reaction yet
from other experts such as Klimas, Light, Bateman, Montoya, et al?
We have the concern in this house that the Aussies are using too weak a clinical definition – Fukuda is nowhere near the rigourous standard of the Canadian or International Consensus. This could readily result in a weak and unreliable signal in larger population studies.
This is, nonetheless, hopeful news, especially in light of funding for ongoing biomedical work.
Do you know if the SNP’s related to this condition can be found on our 23andme tests? If so, which ones should we look for?
Hi Susan. Please see my reply to Cory below.
Having had ME since the 1980s, several years ago I was put on APO-AMLOPIDINE which is a calcium channel blocker or calcium ion antagonist. After taking approximately 4-5 days extremely painful spasms of cramp at night distorted left leg and foot, similar to tetany. Also my skin became hard and flakey on arms and legs. Stopped Amlopidine 8-12-2008, the cramping ceased, the skin condition took longer to resolve. It is interesting to wonder if the Amlopidine significantly agravated an ME condition that we knew nothing about?
One severe reaction when this calcium channel blocker SHOULD BE STOPPED IMMEDIATELY is described as ‘muscle stiffness, uncontrolled body movement’ the apparent tetany reaction fits this description only too well.
Just looking up Apo-Amlopidine, I see it lowers (high) blood pressure. I am now wondering if there is a connection between the blocking of the calcium channel, or reduction in functioning of the calcium channel, that these Australian researchers found in ME/CFS and the low blood pressure problems which also commonly occur with us? If these findings bear out, it sounds like what those of us with ME/CFS might need is a treatment which caused the opposite of Apo-Amlopidine.
I also felt amused by Stan’s post above when I thought of the idea of a boat race. It reminded me of the America’s Cup Challenge when he spoke of this race to the finish among the Aussies, the Norwegians and the Americans–all big competitors in sailing. If only we would get the Brits competing more, and some of the others….
Tetany can be the result of an electrolyte imbalance. Most often, it’s a dramatically low calcium level, known as hypocalcemia. But, it can also be caused by magnesium deficiency or too little potassium. Having too much acid (acidosis) or too much alkali (alkalosis) in the body can also result in tetany.
Interesting correlation in this description of Tetany. I certainly used to have acidosis too. The low calcium level findings look very promising.
I will never forget that downwind leg when Australia won the America’s Cup!
How does this theory fit in with what Fluge and Mella found to be a deficiency in Pyruvate Dehydrogenase that inhibits the Krebs cycle? Somebody correct me if I’m not remembering this correctly. Thanks again Cort for helping decipher this stuff.
Studies in Bristol in the 1960s and 1970s, led to the recognition that four mitochondrial dehydrogenases are activated by calcium ions. These are FAD-glycerol phosphate dehydrogenase, pyruvate dehydrogenase, NAD-isocitrate dehydrogenase and oxoglutarate dehydrogenase.
https://www.ncbi.nlm.nih.gov/pubmed/19413950
Thanks Jason. It would be really beautiful to have these different research findings fit together and make sense. Hopefully the researchers themselves stay on top of what the others are doing and are able to come up with the information that really matters – that which helps people.
The only thing I can think of is that intracellular calcium can effect mitochondria enzymes. I don’t know how; I don’t know if it pertains at all – but it does do that.
Thanks for the article Cort. I’m a bit more cautious about this research now having read this article, but it still sounds to be of some promsie
They develop a commercial test. All the alarm bells go off. Is this’ breakthrough ‘ the next hype? Yes, i think so.
Great article. I have CFS and Fibromyalgia. Ever since I been sick, my serum calcium levels have been mildly elevated (10-10.5) that’s without taking any calcium supplements. It did go to (11) when I was taking one calcium pill. Parathyroid tumor and cancer ruled out. My question is…Is serum calcium only extracellular? And if so, how do you test for intracellular? Does anybody know?
Some people have already done 23andme genetic testing. Does anyone know if that test includes the TRPM3 SNPs?
Good question!
Cory, I use Livewello to interpret 23andme results and there is a TRPM3 health report. However, 6 out of 9 SNPs have not been genotyped. Of the three that were genotyped, 2 of mine were heterozygous and one was normal. At this point, Livewello isn’t super helpful.
I have 2 homozygous, 2 heterozygous mutations and 1 normal out of 5 SNP that are available in Livewello in the TRPM3 report. Wish there were all 13 genes available in our data to verify the hypothesis.
This appears to be Cort’s 2015 forum post on the NCNED SNP study:
https://www.healthrising.org/forums/threads/ion-channel-problems-found-in-me-cfs.2449/
(The paper is available for free from the link in the post).
The following are the 13 SNPs were significantly associated with CFS patients compared with the controls (I have put a * next to the ones present in my 23&Me Data – 5 out of the 13. I can’t remember which version of the test my data was derived from; if anyone knows how to find the version, I will do so and add it here):
TRPM3 [rs12682832; rs11142508; rs1160742*; rs4454352; rs1328153*; rs3763619*; rs7865858; rs1504401; rs10115622]
TRPA1 [rs2383844; rs4738202*]
TRPC4 [rs6650469; rs655207*]
https://www.healthrising.org/forums/threads/23andme-trpm3-snps-for-cfs-griffiths-research.5396/
Yes, 23&me has some snps to identify. Some of us have them.
I reread your blog @Cort, and noticed they first had to deplete the calcium and then work on upping the TRPM4 receptors. That would fit with what works for me. GastroCrom and Tramadol are both mild calcium channel blockers (this keeps calcium from going into the cells properly and causes a vasodilation affect) – I use those at night. Then in the a.m. use Pregnenolone which can up this action of TRPM3. This seems like this is a fine balancing act and may be something to do with receptors or autoimmune dysfunction. If we could tweak and create an epigenetic response to over ride these mutations (which is probably what I’m doing) things get better. In addition to working on MTHFR mutations and upping acetylcholine, I’m much improved. Also thinning my blood with herbs (due to APS) is helping alot.
Issie
Here’s an interesting article on choline and it helping POTS and CFS.
http://www.wellnessresources.com/health/articles/choline_helps_pots_chronic_fatigue_autoimmune_disorders/
Also, another thread line we have going on it. It may tie in to this.
https://www.healthrising.org/forums/threads/who-doesnt-benefit-from-acetylcholine-supplements.5216/page-2#post-28694
Issie
Aussie! Aussie! Aussie! Oi, oi, oi!
n=15, and no sick controls? Nothing to see here yet.
I look forward to this groups bigger and more robust studies developing this work, and wish they’d hold back the breakthrough announcements until the findings are more robust.
He says somewhat grumpily.
I couldn’t agree more! After 27 years of this illness and having been led down this garden path once too many times…we will await a larger cohort before we begin to celebrate.
Well said, Simon. Couldn’t agree more. They’re far too quick to announce major breakthroughs, and are terrific at whipping up a media frenzy, but the results to date don’t warrant the excitement. I’m reserving judgement until we see this replicated in a larger cohort, a cohort which has been confirmed to have PEM (they used Fukuda, and havent indicated how many of the 15 pwME/CFS experience PEM, so it’s possible that none do) and, crucially, see a comparison with other illnesses. A long way to go yet… they’re far from having a test ready for commercialisation, which I’ve seen some claim.
I’m grumpy too!
I wonder if pathogens such as nanobacter would have an effect on calcium ion channels and cellular calcium. This pathogen utilises calcium to form its calcium shell and has been implicated in multiple illnesses. Blood serum calcium may also be raised with this pathogen.
I’m wondering if anyone else has problems taking calcium supplements? I stopped taking them about two years ago because they started causing severe muscle twitches and spasms. Experimentation has found no correlation to increasing or decreasing magnesium or potassium supplements. I’m barely getting any calcium now, since I stopped consuming any dairy over one year ago because of what I’ve assumed is inflammation. GP, nurses, nutritionist have been neither helpful nor very concerned about either the symptoms or my lack of calcium. I’m curious if this study somehow explains my apparent calcium intolerance.
Some symptom difficulties might be due to issues with one or all of the following: 1. using incompatible ratios of cal mag pot and other macro minerals so the absorption is nil, and the calcium ends up in inappropriate places like the heart valves and joints, causing osteoporosis. gout, kidney stones, oxalate crystals causing pain, and eventual tooth loss; 2. the minerals are not bioavailable because they are in non-chelated or other cellularly absorbable forms; 3. essential trace minerals are lacking that could help to assimilate macro minerals; 4. the fillers and binders and other non-organic stuff might be clogging the gears; 5. food-sourced minerals are not being obtained from non-GMO foods or food-based multivitamins such as the Paradise or other other high-end organic brands; 6. polluted water with heavy metals and chemicals, fluoride, etc. are mopping up calcium and competing for limited receptor surfaces needed for intracellular absorption; 7. your individual genetics might be involving any of the above factors. One domino falls, all dominoes fall. Western medicine has failed too many for the last hundred or more years because it evaluates teeny tiny compartmentalized factors, and most lifetimes are not that long. Leaf molecules are studied rather than the whole tree ecosystem, for one metaphor. The best researchers are now starting to connect the dots and see the patterns that have been there all along. The better biomarker research and protocols have come from integrative approaches available from the Klimas and other like-minded supportive teams.
Kat, sorry to gear that. This is just something that worked for me when that happened: I took potassium and it went away. I thought it might be causing some kind of imbalance when I took the calcium, exacerbating my already low potassium? It happened a number of times but maybe it was just a coincidence. I take a lot of minerals. Good luck.
Cort, Thank you for your tremendous work! You have created such a great resource.
I was wondering, if hair analysis shows high levels of calcium, which means your absorbing it, could one assume that they don’t have these channel receptor issues?
This stuff is so complex that I have no idea…
You need to take the active form of Vitamin D(calcitriol) to absorb calcium.
I can’t take calcium either. More studies are coming out pointing to issues with calcium channels both issues with receptors and antibodies.
Magnesium is a more natural type calcium channel blocker/modifier.
And if there are protoza/Lyme issues most LD docs feel calcium contributes to formation of biofilm. There are other doctors who think it’s are issue with magnesium. I tried doing without both and I seem to need the magnesium but don’t tolerate the calcium.
If you eat a lot if veggies you get calcium in a usable form. Concentrated minerals and vitamins are not a natural form. They are missing assistors that assist in their breakdown and assimilation. I don’t take any of my mineral supplements daily. I do find a magnesium oil to be beneficial.
Issie
Great work, but a couple questions arise. If the killer cells are impaired, then how to explain the up-regulation of the immune system found in so many ME/CFS sufferers? The impairment must be very selective for a certain pathogen and not general, but that contradicts the finding of widespread calcium deficiency.
Also, if some drug could correct the cellular calcium deficiency and revive the killer cells’ potency, then perhaps the underlying pathogen, if there is one, would be quickly clobbered, and the disease cured.
This is actually nothing new as a concept, it’s just a more detailed look inside the body.
Vitamin D has been shown for years to affect the functioning of calcium in the body. I was greatly helped by this regimen:
10,000 IU Vitamin D3 (liquid, AOR brand for greater absorption)
200mg Vitamin K (we lose vitamin K from 12yrs on, it helps calcium form in bones, not tissue)
400-700mg magnesium glycinate (Glycinate is more absorbable)
What was missing in this chronic fatigue Vitamin D study was K2 and magnesium. K2 has just recently been understood as to its effects on Vitamin D and calcium.
https://iacfsme.org/PDFS/Attachment-E-Annedore-Hoeck,-Vitamin-D.aspx (cholicaciferol is Vitamin D3)
It’s possible the Australian researchers knew what they’d find and their interest is in gaining a pharma backer for their lab which will try to mimic the effects of Vitamin D.
I too was wondering about vitamin K2, as that is meant to help get the calcium to where it needs to go. But if those receptors have gone missing, would that still work? And can we get these back, or have CFS sufferers always had fewer of these without realising? And a person with the right amount would have been able to overcome the factors that made us break down?
Nimodipine is a calcium channel blocker. According to an article on the site, “Dr. Jay Goldstein found Nimodipine to be one of his most effective CFS/ME medications”
https://www.healthrising.org/treating-chronic-fatigue-syndrome-mecfs/drugs-for-chronic-fatigue-syndrome-mecfs-treatment/nimodipine-chronic-fatigue-syndrome-fibromyalgia/
So does another Dr. whose name escapes me…Very important part of her treatment.
Cort – how big of a deal do you think this study is? We’ve all been on for a ride of someone claiming a major breakthrough in CFS. For some reason, though, it seems like they are getting close.
I think its a possibility. They seem like really good researchers and they seem excited. That said the body is a mysterious thing and it has a way of throwing “boomerangs”. I feel cautiously optimistic. Time will tell but until then it’s good to see that they think they’re onto something.
I have found that lorazepam helps with my pain levels. I don’t know why. I know it acts as
a GABA agonist, and I have long felt there must be a connection there? Does that make any sense as relates to this finding? I have no biological knowledge…any input would be greatly appreciated.
I’m on a few medications. However, if I could only pick one medication, it would be clonazepam (benzodiazepine like lorazepam). It seems to help with a lot of symptoms, which a doctor would then say, well, it means it’s all anxiety. Sorry Doc, but anxiety doesn’t cause small-fiber neuropathy, POTS, and psoriatic arthritis. I doubt it could be the cause of post-exertional malaise, and maybe possibly brain fog. No it’s not just anxiety
Lorazepam is very effective in shutting down mast cells. Did you test for Mast Cell Activation Disorder
I have paramyotonia as it runs in my family (had a genetc test to verify). It is a disorder related the sodium channels in skeletal muscle cells. I had dealt with the stiffness nd periodic weakness, easily being able to exercise through my eatly 20s. However, about 15 years ago I started developing symproms of CFS – autonomic dysfunction, brain fog, post-exertional fatigue, etc… at first, I thought it was related to my PMC, but I was getrig dry eyes, psoriasis and am finally being treated for psoriatic arthritis. Therefore, my neuromuscular specialist said, I have two things going on – paramyotonia and a small fiber neuropathy. Now I’m wondering if it’s all itsnterconnected since what are the chancestors of having all of that stuff.
My understanding is that balanced calcium/magnesium levels in the muscles are essential for contraction/expansion. Whilst the report initially states looking at both the remainder would appear to focus only on calcium. Whilst most of us undergoing a regular blood test would show normal magnesium levels we actually have low levels held in the muscles, this would only be shown via a RHBC test.
If we try to pump too much calcium into our bodies without looking at magnesium levels at the same time won’t that make things worse not better?
The link for the diagnostic test might have moved or something. I ended up on the general news page. Here is the one I found by searching:
https://app.secure.griffith.edu.au/news/2016/12/01/4m-grant-to-aid-chronic-fatigue-syndrome-diagnosis/
Great news 🙂
Glutamate also affects calcium channels. GastroCrom and Tramadol both mild calcium channel blockers. Tramadol works on all neurotransmitters including NMDA (glutamate/GABA channels). Both vasodilate. Tramadol seems to slow down over sympathetic respose for many. I think we have subsets here. What works for one set, won’t work for another. Also may be of interest – muscarinic receptor antibodies. 1 & 2 in POTS – 3 in Sojourn.
Issie
Hi great article. The concepts are really confusing and you’ve summarised them in clear concise terms.
Thanks Francis!
I can say that tramodol has greatly relieved pain throughout my body. It’s like a waive of relief, especially the legs where it is worse. But unfortunately I can’t really take it as it makes me sick to my stomach, and cause intestinal spasms.
One thing I noticed after onset of severe and chronic CFS and Fibro 4 yrs ago was that I stopped taking the medication Spironolactone. I was taking it for about 5 yrs to treat symptoms of PCOS, until my insurance ended and I couldn’t afford any medications. Does anyone here understand how this drug might be involved in relation to this article? A pubmed article gave this information: “Calcium channel antagonist effects of spironolactone, an aldosterone antagonist.
Mironneau J1.
Abstract
The effect of spironolactone on the contractility of vascular smooth muscle cells and on calcium channel currents of isolated cells was investigated using the patch-clamp method. Concentrations of 10 and 60 microM of spironolactone resulted in 50 and 100% inhibition, respectively, of isometric contractions. Whereas fast calcium channel current was essentially unaffected by spironolactone, slow calcium channel current was inhibited 50% by 5 to 7 microM concentrations of the drug. These results suggest that spironolactone acts on slow calcium channels in a manner similar to that of calcium blockers.”
Hi there. Has everyone forgotten about HMRV and Judy Mikovits? I read her book recently and it is compelling. I trust her and the story and believe it fits perfectly for many many people. Especially as she had a five year gag order put on her,was banned from facebook for life and that subsequent to her research, millions have been invested in cleaning up the blood supply. They cant admit it, but they have revealed the truth by their very actions and the subsequent death of one of one scientist who backed up Judy`s research.That was no accident.
It has been found an excess of metabolic phosphates buildup in the cells, at kidney level not releasing this excess.Causing calcium and magnesium recycling issues. Many people with CFS and Fibro have sylicylate issues and oxalate issues clogging up their energy metabolism. The more herbs and aspirin one takes they clog up receptor sites in kidney so metabolic excesses don’t get released. Pure guaifenesin opens the kidney tubules up to release the excess of metabolic wastes. Many will release tons of crystals from eyes and urine from different parts of body; joints and muscles. Helps with gout. Can not block kidneys, that means all hygiene products with herbs and sylicylates are to be avoided. Gardening must be done with gloves to avoid salicylates from plants. See Dr. Paul St. Amand online. Need special diet as well to reduce this buildup of crystals. Avoiding sugary and bad carbs in diet that cause blood sugar issues in insulin that only induces kidney reabsorption of phosphates that intensifies symptoms. CFS and Fibro run in families showing possible gene mutation expressions.
i am a 57 year old male in north dakota with cfs and fibro on guaifenisen for 20 months some better all happened after 2 surgeries my fibro is getting better but still can not work or function very well hope this works or something else is missing am taking famvir for viral load to see if it helps been to mayo clinic no help
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Cycling Valtex completely eliminated symptoms of my chronic fatigue syndrome.
I take 1g of valtrex twice a day(every 12 hours) for 4 consecutive days, once a month. I am a male and weigh about 180lb. ATTN, recovery mechnism is delayed, for the first 6-8 weeks I saw no improvement, and then I had full recovery. Also, I tried 500mg – it does not work for me.
Here is my story in greater detail:
My condition started with a flue and then continued with all the standard horrific symptoms. After two years of research and a couple of molecular cell biology courses, I narrowed my hypothesis down to Epstein-barr virus and HHV1 – high antibody titters kept on showing up in my bloodwork. Based on the information I could find, it seemed that EBV is suppressed by Valtres only at high concentrations while HHV1 is suppressed at both high and low concentrations. So, I started taking Valtrex – 1g ever 8 hours. After a couple of weeks i clearly felt that my body was suffering side effects from Valtrex. My stool turned white and I started loosing weight. I stopped after a month. And then, about 6-8(approximate) weeks since I first started (and so 2-4 weeks after I stopped taking Valtrex) I had a full recovery. Energy, comfort of being in my own body and sleep all returned. That was so odd! Recovery lasted about 6 weeks, and then I relapsed back into CFS. So, I started experimenting, and
to keep the long story short, I discovered that the minimum dose was 7 1g pills of valtrex taken consecutively at 12 hour intervals ( I take 8 just in case). Recovery is delayed by 6-8 weeks, and then lasts another 6 weeks. So, to keep myself from relapsing I started taking it every month as described. And I have been feeling well since.
I know Valtrex does not work for everybody, and I know that it works for some. I never tried Valcyte, I don’t know if cycling that in a similar way helps with other types of hhv
Wow. Congrats for finding something that works Andrei and thanks for sharing it. I request that you put your story into Health Rising’s Recovery stories section – https://www.healthrising.org/forums/recovery-stories/…
Hi Cort, heads up that the in-website Print Friendly service is having some issues. At least it looks like Print Friendly is the service you use. When I tried to download a PDF or print this or this post “A Biomarker for Chronic Fatigue Syndrome (ME/CFS)? Immunosignature Provides Another Possibility” and the images say “full size,” they are missing and just the text that goes w/ the pic is there, but it’s overlapping the article text. When I select “small images,” they show up but overlapping text and the text is compressed vertically of to the right or left. However, when I go to PrintFriendly’s website and plug in the web address for Health Rising’s article, it shows up just perfect and I can print it. But I can’t use the print function on Health Rising b/c of above issues. Maybe there is an update needed for the print plug-in on Health Rising? Formatting issue? Idk, I’m not a web page expert. It may affect many or all other articles/posts, these are just the first 2 I’ve tried printing in a couple months or so. Thanks for all you do to keep us informed!
Hi,hopefully u guys come with a 100% cure we are all tired of cfs and we really want to live a normal life,thanks a lot
Im glad for this, but it still seems like they are working around the fringes. And that is, perhaps, as good as it gets at the moment. Still, its good news that they are picking up some clues and that someone is allocating finances for further study. Wouldn’t it be grand if several of the leading research groups were to formally collaborate, share their findings, and brainstorm directions for further research? One can dream.
Great idea. Ron Davis and the Solve ME/CFS Initiative are doing collaborative workshops. We definitely need more of this.
Cort, regarding biomarkers check this out:
A new approach to find biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) by single-cell Raman micro-spectroscopy [SCRS]
Jiabao Xu,a Michelle Potter,b Cara Tomas,c Joanna L. Elson,c Karl J. Morten,b Joanna Poulton,b Ning Wang,d Hanqing Jin,d Zhaoxu Houd and Wei E. Huang*a
“A machine learning classification model achieved an accuracy rate of 98% correctly assigning Raman spectra to either the CFS group or the control group. SCRM combined with a machine learning algorithm therefore has the potential to become a diagnostic tool for CFS”
With COVID-19 long-haulers and many emerging cases of CFS on the horizon this work is now more important than ever. Please keep up the momentum and find us a cure!
Love to all who are suffering and to those who are helping us.
I wish you all the best of success.
@Cort
has there been much progression on the test Don Staines from Griffith University was working on?