A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

[Texas83]

This is HUGE. A huge step for the ME/CFS community and for all of the patients suffering. I am so impressed with Dr. Davis and what he has been able to accomplish so far. When you think of the funds that they are working with compared to other diseases that get billons- he has already discovered so much in a short time and made such an impact.
This definitely made my day/week and I am watching their research with lots of interest and HOPE.

 

[percyval577]

Between several differing labs, countries and research facilities they keep finding: measurable differences between the ME/CFS severe cohorts and healthy people.

We have a growing list of: these differences (see: heart rate, grey matter, non-deforming red blood cells, plasma weird, bad mix in the intestines, lactic acid pink brain, HPLA axis messed up, the immune cells, etc..) Then add the spinal/cervical/POTS-swarm. Measurable differences in this: I will call them subgroup. I think we most likely clearly have subgroups. In that regard, I believe ME is a syndrome with various versions.

And so: they report on a SINGLE test being published. Use the worn out old catch-all name Chronic Fatigue

I often wondered, why is there nothing conclusive (so far)?
There are tendencies (and in a true human world this would count).

But as I like to guess that the most findings are indeed not a fake, I wonder, how is it possible that with this strange disease so many different findings appear? but so far nothing holds the line in different circumstances (or recruitments). Does it tell anything? (I don´t mean a psycho-thing.) What would it tell about the body?

True, it might be sometimes due the lack of good guesses, and the technical investigations are sometimes difficult.
So all in all, giving credit to the finding by Davis et al, why would a cell reject to rechange the salts? What is it in the plasma, why would it cause this behaviour? Could there be any purpose?

 

[Rufous McKinney]

So, in that spirit of the triumph of hope over experience then, here's the article:

Our Triumph is then: RAINED UPON by Wessely and supposed Journalism.

This is another entirely LAME REPORT.

There is a serious problem in journalism. They are taught to: go find the exact opposite opinion and report on: controversy.

A major example of the horror of this type of journalism is: like Climate Change denial. Any report on climate change, go find the Denier.

It can be seriously damaging because they literally go find whomever is fighting a war with you. So they report on wars instead of on the Accomplishment and its implications.

I was managing a nature preserve. The local paper wants to report on our new preserve. But then they notice that the Off Road Vehicle people want to drive all over our wildlife. So it becomes an article on off road vehicles denied their fun time.

I say its time to: do a major campaign called: this is not Journalism, this is perpetuation of Crimes which have direct Adverse Effects on real lives.

We ARE BEING HARMED BY THESE REPORTS.

 

[Rufous McKinney]

I think you might be thinking of a different test Ron did that showed the plasma in CFS patients caused cellular dysfunction in healthy cells? . If I remember right and there's no guarantee for that!

Your probably right....my brain is Mudge. Most of the time, I manage to laugh about it. Good Grief.

I think I need to pull a Jennifer Brea...I take over this whole living room wall with notes, stickups, strings connecting dots, and come up with some way to track: Our Ditty.

 

[Rufous McKinney]

why would a cell reject to rechange the salts? What is it in the plasma, why would it cause this behaviour? Could there be any purpose

Seems to me: many diverse things could lead to: mitochondrial problems. So these salt-stressed cells can't garner the energy to: pump out that excess sodium.

The heart muscles: don't have the energy to pump up that blood ..one of the studies talked about muscle sending signals to the heart. But the heart is ALSO a muscle.

The brain cells: oxygen not getting there. If we could fix non-deforming red blood cells, perhaps that would increase oxygen to the brain. Reduce that lactate and heat.

To produce a molecule of anything, you need energy. The lack: feels profound. Affects everything.

 

[Moof]

But as I like to guess that the most findings are indeed not a fake, I wonder, how is it possible that with this strange disease so many different findings appear? but so far nothing holds the line in different circumstances (or recruitments). Does it tell anything? (I don´t mean a psycho-thing.) What would it tell about the body?

Throughout my 40-odd years of living with it, I've felt that ME is some kind of natural defence mechanism. I don't know what the perceived 'threat' is (or was), but so many of us are familiar with the phenomenon of treatment resistance. We find something that helps mitigate some of our symptoms; then it stops working. We find something else...ditto. Over and over.

It feels as if our bodies are trying to sabotage any effort to increase our activity levels, and I think this is partly why we've got stuck with the psychosomatic label. If you report this experience to a doctor who's trying to treat your symptoms, it can easily sound as if you've just come up with another excuse for avoiding activity.

I think it's a protective response; what worries me slightly is that we don't really understand whether or not it's an appropriate protective response. So for instance, if we found a drug that boosted our flailing metabolism but still didn't understand the reason for the under-powered performance, would it help or just make us more ill?

 

[Countrygirl]

If this is true then a quotation of that transcript might be a relevant finding for newspapers at this time?

I read it some years ago. and Ihave been trying to remember where. I suspect it may have been in one of Margaret William's and Prof Hooper's papers.

 

[Rufous McKinney]

I think it's a protective response; what worries me slightly is that we don't really understand whether or not it's an appropriate protective response.

I see what your suggesting and we should continue to keep these things in mind, so to speak.

so I did a personal forced GETS test. Maybe I am just lazy. Maybe I just need to push myself, like they say. So for three days in a row, I do this really modest little extra: walk around one block.

PEM for- at least 14 days. So in this case, I ignored psychogical messages, did the thing anyway and result was appalling. I was starting to even fall over and POTS myself.

But yes the message is so strong- Your Sick. Don't go Out There. Its NOT SAFE. Its too hard. Avoid that. Its such a powerful message. And I"m happy to fix it, if I could figure out how.

 

[PracticingAcceptance]

@lior

Is this British paper the Telegraph considered a credible news paper or is this a sensationalistic newspaper?

Credible. It's a broadsheet rather than tabloid. It's right leaning (I think that's the equivalent of Republican in US-speak).

 

[Mary]

It feels as if our bodies are trying to sabotage any effort to increase our activity levels, and I think this is partly why we've got stuck with the psychosomatic label. If you report this experience to a doctor who's trying to treat your symptoms, it can easily sound as if you've just come up with another excuse for avoiding activity.

I think it's a protective response; what worries me slightly is that we don't really understand whether or not it's an appropriate protective response. So for instance, if we found a drug that boosted our flailing metabolism but still didn't understand the reason for the under-powered performance, would it help or just make us more ill?

Paul Cheney talks about this issue in this Seminar, under the section Energy Conundrum:
https://paradigmchange.me/wp/cheney...Ieg9aZM2j6goro3ChWzK1LE_52m3nudQFVmmgn_cUnneY

if you continue to generate energy and you cannot cool the system, then you have to bring down energy to save your life. And we think this is exactly what is going on.

In other words, the energy downregulation is not the problem.

The energy downregulation is the solution to prevent a deeper problem.

And the problem is that something’s wrong with this redox cooling system.

Studies on some of these elements – SOD and GPx and catalase and the NADPH which reduces glutathione made in the liver – there’s something wrong with this system. And you can see it and prove it and measure it in every single patient.

It’s there if you just look for it.

If you have a defect in redox cooling, then there will be increased oxidative stress, and if you’re lucky, that will feedback loop inhibit mitochondria from producing energy. And then you will equilibrate at a lower energy state to save your life.

That doesn’t mean that the low-energy state is pleasant. It doesn’t mean that there aren’t complications from that. But your life is preserved.

I think if we found a drug to boost our flailing metabolism, we would just crash more. I recently underwent a treatment (I can't describe it here in a few words) that was supposed to increase energy or energy production, and I think it did do something, only my body's response was to crash more and have longer crashes. So I stopped it. A few things have increased my energy between crashes (BCAAs, B1, B6, d-ribose, a few others) but none of these have stopped my crashing or increased my energy/activity window. Though the BCAAs have cut my PEM recovery time in half.

 

[Rufous McKinney]

I think if we found a drug to boost our flailing metabolism, we would just crash more

Hence: my doctor recommended I try Modafinil 100 mg. It has helped his one OTHER ME patient (and she crashes afterwards, said, but she feels it helps her).

So my insurance denied. I finally: just paid $80 for 10 pills myself. I will likely try: taking 1/4 to see what happens.

I dont think I got any responses on a thread I started, asking about other's experiences with that.

So in my view, I'm nervous to try it.

But if it can help me get thru the airport......

 

[Rufous McKinney]

A few things have increased my energy between crashes (BCAAs, B1, B6, d-ribose, a few others) but none of these have stopped my crashing or increased my energy/activity window. Though the BCAAs have cut my PEM recovery time in half.

All that is encouraging, Mary. i've yet to the BCAAs but keep seeing that so .......

But yeah, its seems like it not worth it to get fake energy. We need the real deal.

 

[Murph]

Here's the full paper as an attachment for anyone who would like to download it.

The fact it is not specific to mecfs patients is not a reason to get downhearted. We go through this every time a lab releases a "pilot study." Pilot studies are small versions of the study they'd like to do. The pilot study acts as "bait" to attract funding, which will permit them to do a more comprehensive study.

This **is** a major breakthrough because it demonstrates a problem is visible at a cellular level in a lab, not just a systemic level in the person. That allows a lot of other experimental steps to be taken: Comparing this result to other disease groups; changing the conditions under which this test is run to see what happens (e.g. is it just salt that gets the result); filtering the plasma to see if they can change the result; adding drugs to the plasma to see if they can change the result. etc.

Best case scenario is some other lab has their own impedance device they can use and they find something similar.

 

[ljimbo423]

One question I have is, is this "something" in the blood that Ron found in an earlier experiment, that's probably causing the cellular dysfunction that they can measure with the nanoneedle.

Also be the something that is causing the microglia activation and low grade brain inflammation that Jarred Younger has found?

 

[Rufous McKinney]

Paul Cheney talks about this issue in this Seminar, under the section Energy Conundrum

I

I had never seen this before, Thank you!!! I read the text and found it remarkable for capturing what we're dealing with.

Dr. Cheney is insightful and much of what he says makes sense.

Something has changed here, over the last year. Its changed alot. Its that last phase he is describing.

I feel the disease trajectory needs much more exposure and discusson.

 

[nandixon]

we know that it is copaxone, right? see here: https://forums.phoenixrising.me/thr...s-at-stanford-discussion-thread.61590/page-18
They also found two drugs not in common use work : suramin and compound 31

They also found that pyruvate and (I think) lorazepam (Ativan) normalize the nanoneedle experiment as well. All of these drugs/substances share in common an ability to improve mitochondrial membrane potential (MMP), and I think that is what the nanoneedle is measuring. That possibility isn't mentioned in the latest study but I'm pretty sure Ron Davis himself suggested this a few months ago.

In 2014, a different research group fabricated a very similar microfluidic device to Ron's and used it to measure impedance resulting from decreases in MMP in isolated mitochondria that were subjected to a drug(s) that causes "uncoupling":

Mitochondrial Membrane Studies Using Impedance Spectroscopy with Parallel pH Monitoring
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101793

Ron's device uses a microfluidic channel that's about 20 times smaller than the 2014 device. One implication of this may be that the cells within the channel of Ron's device are brought into closer contact with the sensors thus making it unnecessary to actually isolate the mitochondria in order to measure their membrane potential/impedance (although this may also depend on the frequency window used).

If it's true that the nanoneedle is measuring MMP then virtually any disease of any significance - multiple sclerosis, Alzheimers, cancer, diabetes, etc. - I think would be likely to show an impedance signal similar to what was found in the ME/CFS patients in the present study. So the nanoneedle would possibly not be diagnostic for ME/CFS but could still be useful to show something is wrong.

Here are some references for a couple of the drugs that have normalized the nanoneedle and their effect on MMP:

Effect of Suramin on Mitochondrial Membrane Potential
https://journalbio.eenu.edu.ua/index.php/bio/article/view/143

Metabolic response to glatiramer acetate [Copaxone] therapy in multiple sclerosis patients
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079236/

[Note that lorazepam (Ativan) should affect MMP since it is a potent ligand for the TSPO receptor in the outer mitochondrial membrane.]

 

[Murph]

In 2014, a different research group fabricated a very similar microfluidic device to Ron's and used it to measure impedance resulting from decreases in MMP in isolated mitochondria that were subjected to a drug(s) that causes "uncoupling":

Mitochondrial Membrane Studies Using Impedance Spectroscopy with Parallel pH Monitoring
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101793

Ron's device uses a microfluidic channel that's about 20 times smaller than the 2014 device. One implication of this may be that the cells within the channel of Ron's device are brought into closer contact with the sensors thus making it unnecessary to actually isolate the mitochondria in order to measure their membrane potential/impedance (although this may also depend on the frequency window used).

Here's a simple question. The mitochondrial membranes are inside the cell. How come the impedance of the whole cell changes when the surface of one of its interior components changes?

 

[percyval577]

Throughout my 40-odd years of living with it, I've felt that ME is some kind of natural defence mechanism. I don't know what the perceived 'threat' is (or was), but so many of us are familiar with the phenomenon of treatment resistance. We find something that helps mitigate some of our symptoms; then it stops working. We find something else...ditto. Over and over.

It feels as if our bodies are trying to sabotage any effort to increase our activity levels, and I think this is partly why we've got stuck with the psychosomatic label. If you report this experience to a doctor who's trying to treat your symptoms, it can easily sound as if you've just come up with another excuse for avoiding activity.

I think it's a protective response; what worries me slightly is that we don't really understand whether or not it's an appropriate protective response. So for instance, if we found a drug that boosted our flailing metabolism but still didn't understand the reason for the under-powered performance, would it help or just make us more ill?

I too think that the body wants this state. But I don´t think that there is anything serious to fight against. So the influences work for a while and then the body says: "No, something has changed the state I want to be in. This needs to be eliminated."
It might be, I think, that the body is in a state of fighting or repairing process. Some pathways might be upregulated and interferre with other ones, and the body behaves not healthy here or there.
Especially I like to think that we feel ill without any serious illness. And there must be a mechanism which makes this feeling, eg, you can take ecstasy and strangly you will not feel tired for days .. tell this a doctor (especially an intelligent psychologist)...

Seems to me: many diverse things could lead to: mitochondrial problems. So these salt-stressed cells can't garner the energy to: pump out that excess sodium.

The heart muscles: don't have the energy to pump up that blood ..one of the studies talked about muscle sending signals to the heart. But the heart is ALSO a muscle.

The brain cells: oxygen not getting there. If we could fix non-deforming red blood cells, perhaps that would increase oxygen to the brain. Reduce that lactate and heat.

To produce a molecule of anything, you need energy. The lack: feels profound. Affects everything.

There might be a switch here or there. I don´t think though that it´s an unwanted failure, because influences should last in this case. So, It would be part of an organisation by pathways.
In my experience, sometimes (very occasionally) only slight things make me feel good, but then I feel/felt so bad again like being deeply ill. Sometimes my very cold limbs have been suddenly warm for a minute or an hour, this does not look like a failure in the machinery, it looks like a mistake in organisation. Also that we differ in symptoms (but all get the lack of refreshment and the profound worsening from doing) hints to an dysregulation, I think. And the question is: Is there a common core?

 

[Murph]

So the change in impedance could be due to mitochondrial dysfunction. That appears to leave a lot of symptoms unexplained. Like why is standing or lifting your hands above your head so hard? We need an answer that ties mitochondiral dysfunction to the vascular symptoms.

I went looking for one and found a beauty.

This study not only shows a link between mitochondrial dysfunction and imparied vasodilation, it implicates extracellular vesicles (e.g. exosomes) as the link between those two! And it also talks about ceramides and sphingolipids, which Naviaux found were at unusual levels in ME/CFS.

Am J Physiol Heart Circ Physiol. 2017 May 1; 312(5): H1096–H1104.
Published online 2017 Feb 17. doi: 10.1152/ajpheart.00680.2016

Vascular Biology and Microcirculation
Mitochondria-regulated formation of endothelium-derived extracellular vesicles shifts the mediator of flow-induced vasodilation
Julie K. Freed,

1,7 Matthew J. Durand,2,7 Brian R. Hoffmann,3,4,7 John C. Densmore,5 Andrew S. Greene,4,6,7 and David D. Gutterman3,7


Abstract
To examine the effect of endothelium-derived extracellular vesicles (eEVs) on the mediator of flow-induced dilation (FID), composition, formation, and functional effects on the mediator of FID were examined from two different eEV subtypes, one produced from ceramide, while the other was produced from plasminogen-activator inhibitor 1 (PAI-1). Using video microscopy, we measured internal-diameter changes in response to increases in flow in human adipose resistance arteries acutely exposed (30 min) to eEVs derived from cultured endothelial cells exposed to ceramide or PAI-1. FID was significantly impaired following exposure to 500K/ml (K = 1,000) of ceramide-induced eEVs (Cer-eEVs) but unaffected by 250K/ml. FID was reduced in the presence of PEG-catalase following administration of 250K/ml of Cer-eEVs and PAI-1 eEVs, whereas Nω-nitro-l-arginine methyl ester (l-NAME) had no effect.

Pathway analysis following protein composition examination using liquid chromatography tandem mass spectrometry (LC-MS/MS) demonstrated that both subtypes were strongly linked to similar biological functions, primarily, mitochondrial dysfunction. Flow cytometry was used to quantify eEVs in the presence or absence of l-phenylalanine-4′-boronic acid (PBA) and mitochondria-targeted [93-boronophenyl)methyl]triphenyl-phosphonium (mito-PBA), cytosolic and mitochondrial-targeted antioxidants, respectively. eEV formation was significantly and dramatically reduced with mito-PBA treatment. In conclusion, eEVs have a biphasic effect, with higher doses impairing and lower doses shifting the mediator of FID from nitric oxide (NO) to hydrogen peroxide (H2O2). Despite differences in protein content, eEVs may alter vascular function in similar directions, regardless of the stimulus used for their formation. Furthermore, mitochondrial ROS production is required for the generation of these vesicles.

FULL TEXT ON PMC HERE

I'm unsure of just how this fits in but it seemed too good not to share.

 

[nandixon]

Here's a simple question. The mitochondrial membranes are inside the cell. How come the impedance of the whole cell changes when the surface of one of its interior components changes?

That's a good point. Technically I guess they would be measuring the cell's plasma membrane potential rather than the mitochondrial membrane potential (MMP) directly. The mitochondria occupy a large percentage of the intracellular volume and it is known that when the MMP changes that the plasma membrane potential can correspondingly change. This can happen during apoptosis (programmed cell death), for example, where the mitochondria control both potentials (mitochondrial and plasma). I'm not sure what the exact mechanism would be.