OMF-funded RBC Deformability Paper Published!

[nandixon]

I'm so disheartened - literally every time something positive and encouraging comes on here, people immediately retort with 'evidence' that it's useless/flawed/false ect. It's seriously getting me down!

Try to buckle up. The researchers need to have all of the relevant information available to them in order to make the best decisions for where to spend the very limited amount of money and manpower that exists and to hopefully find a treatment as soon as possible. As a former scientist researcher who's made my own share of mistakes I can tell you that it's not possible for any one person or several persons for that matter to be aware of all of the scientific literature pertaining to most ideas. As much information as possible needs to get out in the open and considered to hopefully avoid another 20 years going by without a treatment, which is how long I've had ME/CFS for.

 

[Belbyr]

I'm so disheartened - literally every time something positive and encouraging comes on here, people immediately retort with 'evidence' that it's useless/flawed/false ect. It's seriously getting me down!

It's the fact of the matter, unfortunately.

Keep an eye on Alzheimers, MS, and other similar conditions. They are now being linked to infections just within the last few years. Reminds me of the AIDS epidemic.

 

[Janet Dafoe]

If it were the cause then all of the other diseases that I noted (and a lot more diseases and conditions as well) which appear to suffer equally from oxidative stress and lipid peroxidation - and therefore potentially reduced RBC deformability - should seemingly exhibit our same ME/CFS symptomatology, unless the impairment of RBC deformability is greater in ME/CFS or is somehow otherwise different.


There's an additional problem that I wasn't going to mention, and that is that oxidative stress is found in psychological conditions as well (which have physical underpinnings of course). In fact, a meta-analysis found lipid peroxidation in major depression (ref), so chances are that (severely) depressed patients may show abnormal RBC deformability as well. An additional study would have to be done to see if that can be excluded and I'm not sure it's worth the money, at least not at this time.

It just seems that this RBC deformability issue is likely to be too common to be of much help for us other than showing oxidative stress is present. And we already knew that, although Dr Davis's methodology looks to be a lot more convenient than measuring malondialdehyde (a lipid peroxidation marker), for instance.

It seems to me that, given thousands of patients go to doctors and have lots of tests that all come out normal so they are told it's psychological, it will be good to have a simple test that can provide solid evidence that something is wrong. No one is saying that this test will solve everything. It may explain some of the symptoms. But maybe we could just acknowledge that we might have a usable simple test that all docs and labs can use that shows you're NOT HEALTHY, in a way that docs will believe. Science goes step by step. This is a step. I'm celebrating the step.

Also, all these articles about other diseases and past research are being passed on to Ron and team and are actually very helpful. Many of them he's seen already, but quite often you guys send things that are helpful.

Ron and team had seen and analyzed the Australian study and had a section in this paper about it. They took it out under editor pressure to shorten the paper. Now that the patient population has sent this on twitter and PR, Ron has asked them to put the section back in, so that patients can know it was analyzed. I think there is an issue of not very sensitive methods in that paper, but I might be remembering wrong.

We thank everyone for their scrupulous knowledge of all the science and for their very useful contributions to the research! Science is all about looking at all the data and finding the best answers based on data. It's good you send things and tear it apart.

 

[wigglethemouse]

If this marker holds up in a larger study, or identifies a subset of patients, just think of the possibilities. Detailed quantification of red blood cell deformability could lead to
* Longitudinal studies tracking measurement vs symptoms (like Jared Younger does)
* Study the relationship with disease severity
* Effect of treatment studies, both supplements and meds.
* Use in the 2 day CPET study to help gather more data

I'm particularly excited of anything I can use in my home that I can use to see if a supplement or medication I try has benefit, or is harmful. Right now all I can use is a HR monitor and step counter, it's a bit hit and miss, but I do see trends. Imagine if this could be used in home with a supported iPhone as the camera/analyzer........ or at least in clinical trials such as Cortene & Nancy Klimas 2 drug combination........

@Janet Dafoe (Rose49) has Ron explored a collaboration with the Computer Science department at Stanford to develop software for iPhone testers? When iPhones first came out I watched the CS dept programming series and the projects the students came up with were mind blowing............ I read THIS very recent OMF announcement and saw that there was no programming professor roped in yet.....

 

[Advocate]

Was the word “by” left out of a phrase in the third sentence?

 

[halcyon]

It seems to me that, given thousands of patients go to doctors and have lots of tests that all come out normal so they are told it's psychological, it will be good to have a simple test that can provide solid evidence that something is wrong. No one is saying that this test will solve everything. It may explain some of the symptoms. But maybe we could just acknowledge that we might have a usable simple test that all docs and labs can use that shows you're NOT HEALTHY, in a way that docs will believe. Science goes step by step. This is a step. I'm celebrating the step.

The problem is that we can just throw this evidence on top of the pile of existing biomarkers and tests that already exist that nobody cares about: abnormal EMG, qEEG, SPECT, RNase L, nagalase, CPET, repeat muscle strength test, enterovirus VP1 antigen test, etc. Heck, this abnormal RBC evidence has existed since the late 80s, they didn’t care then, why will they care now?

The bar had been set impossibly high for this disease. My belief is that the medical establishment will not accept any of this evidence until the disease is curable, not just treatable, but curable. We’ve had a treatment for years (ampligen) that normalizes a biomarker (RNase L) and nobody even cares.

 

[Vassie]

I'm so disheartened - literally every time something positive and encouraging comes on here, people immediately retort with 'evidence' that it's useless/flawed/false ect. It's seriously getting me down!

Don’t be disheartened! Like Janet says this is a step forward. Let’s celebrate!

And yes, it’s only one step and many more will have to follow, but don’t lose hope that we will get there.

Yesterday I was visiting the hematologist and she was as uninterested as possible about my weird blood results and my whole situation. She gave the impression that she really couldn’t care less. By the end of the consultation I summoned up my courage and gave her the new paper from Stanford. All of a sudden she lighted up and became quite enthusiastic. She said: “Oh, ‘Blood’, that’s a good magazine! Then I’m sure I can trust this, you know. Thanks! I’m going to read it when I get home!”

That’s what I meant when I said, this paper can make a difference.

 

[kangaSue]

Hmmm, Viagra anyone?

https://www.frontiersin.org/articles/10.3389/fphys.2018.00656/full
(Under the heading 'Secondary changes of metabolism',
[Recently it was found that sildenafil, which is a PDE inhibitor and well-known for its function in the treatment of erectile dysfunction and pulmonary hypertension, has beneficial effects on RBC deformability in sickle cell disease at low concentrations in vitro.]

Another interesting paper;
https://content.iospress.com/articles/journal-of-cellular-biotechnology/jcb15007
[A slight decrease in RBC deformability causes a significant increase in microvascular flow resistance and blood viscosity, as shown in Fig. 1. If deformable RBCs are replaced by solid 6- μm-sized particles, then the viscosity value at 50% volume concentration may increase 10-fold and thereby prevent flow in the vascular network. Thus, reduced RBC deformability is frequently reported in microvascular diseases such as diabetic complications. Indeed, various pathophysiological environments such as hyperglycemia can alter the deformability of RBCs, and reduced RBC deformability may in turn affect pathophysiology.]

 

[Janet Dafoe]

https://www.frontiersin.org/articles/10.3389/fphys.2018.00656/full;
(Under the heading 'Secondary changes of metabolism',
[Recently it was found that sildenafil, which is a PDE inhibitor and well-known for its function in the treatment of erectile dysfunction and pulmonary hypertension, has beneficial effects on RBC deformability in sickle cell disease at low concentrations in vitro.]

I couldn't get that link to work. I sent the other one on to Ron and Mohsen. Thanks.

 

[FMMM1]

If it were the cause then all of the other diseases that I noted (and a lot more diseases and conditions as well) which appear to suffer equally from oxidative stress and lipid peroxidation - and therefore potentially reduced RBC deformability - should seemingly exhibit our same ME/CFS symptomatology, unless the impairment of RBC deformability is greater in ME/CFS or is somehow otherwise different.


There's an additional problem that I wasn't going to mention, and that is that oxidative stress is found in psychological conditions as well (which have physical underpinnings of course). In fact, a meta-analysis found lipid peroxidation in major depression (ref), so chances are that (severely) depressed patients may show abnormal RBC deformability as well. An additional study would have to be done to see if that can be excluded and I'm not sure it's worth the money, at least not at this time.

It just seems that this RBC deformability issue is likely to be too common to be of much help for us other than showing oxidative stress is present. And we already knew that, although Dr Davis's methodology looks to be a lot more convenient than measuring malondialdehyde (a lipid peroxidation marker), for instance.

There a new paper by the Dr. Scheibenbogen [The expression signature of very long non‑coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome] which found increased expression of these non-coding RNA genes in ME/CFS: NTT, MIAT and EMX2OS. Analysing just two of these genes was enough to separate those with ME/CFS from healthy control. However the authors caution that as @nandixon has pointed out there may be other diseases which also have increased expression of these genes. @babeng However, if you have increased expression of these genes, and reduced red cell deformability, and fatigue ---, then this may help doctors to at least diagnose you with increased accuracy. Lets face it, your doctor only has symptoms to arrive at a diagnoses at this point. @Janet Dafoe (Rose49) has explained the potential benefits of a simple diagnostic test very well on this blog (i.e. potential of the red blood cell deformity test).

Also, the fact that ME/CFS may share a common mechanism (oxidative stress/activation of non-coding RNA genes etc.) with other diseases may be good news since this may help to get the research we need funded.

@Vassie Dr. Scheibenbogen is a European scientist on the EUROMEME group. Scheibenbogen's RNA discovery may be a useful lobbying tool i.e. to try to get the European Union to fund ME/CFS research/development of a diagnostic test. @Ben H

Overall I think there are some positives here.


Consider writing to your elected representative i.e. to request funding for ME/CFS research including the development of a diagnostic test.
I've written to the European Union Committee on the Environment, Public Health and Food Safety (ENVI) requesting that they lobby for funding for research into ME/CFS including the development of a diagnostic test [https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1003111].
Currently the ENVI Committee is lobbying for increased funding for research into Lyme disease and the development of a diagnostic test.
In 2016 the European Commission [European Union civil service] said [regarding Lyme disease] that "Both basic research and the development of new diagnostics, treatments and vaccines for Lyme borreliosis are funded by EU research and innovation framework programmes. The total EU contribution to such projects since 2007 amounts to EUR 33.9 million [US dollars]" [http://www.europarl.europa.eu/doceo/document/E-8-2016-008631-ASW_EN.html].

ME/CFS received no funding from the European Union [http://www.europarl.europa.eu/doceo/document/E-8-2017-006901-ASW_EN.html].

 

[babeng]

It seems to me that, given thousands of patients go to doctors and have lots of tests that all come out normal so they are told it's psychological, it will be good to have a simple test that can provide solid evidence that something is wrong.

Thanks for keeping us updated on Ron's thoughts from time to time! It's highly appreciated.
With regard to this, I'm just worried that if the test eventually can't seperate between severely depressed and ME/CFS patients, these doctors will still say it's all in the head. But let's hope that depression does not cause the same deformability problems. This seems relatively easy to test for though!?

 

[wigglethemouse]

I couldn't get that link to work. I sent the other one on to Ron and Mohsen.

Here is the link (without the semi-colon). Looks an interesting paper
https://www.frontiersin.org/articles/10.3389/fphys.2018.00656/full

A currently well-established tool to probe RBC deformability is osmotic gradient ektacytometry, which is routinely used in the diagnosis of patients with hereditary hemolytic anemia. The technique is performed on a Laser-assisted Optical Rotational Cell Analyzer (Lorrca). It assesses RBC deformability, osmotic fragility and cellular hydration status

Lots of interesting disease mechanisms discussed.

 

[pattismith]

Hmmm, Viagra anyone?

https://www.frontiersin.org/articles/10.3389/fphys.2018.00656/full;
(Under the heading 'Secondary changes of metabolism',
[Recently it was found that sildenafil, which is a PDE inhibitor and well-known for its function in the treatment of erectile dysfunction and pulmonary hypertension, has beneficial effects on RBC deformability in sickle cell disease at low concentrations in vitro.]

[

DHA omega 3 was shown to greatly ameliorate deformability in this specific disease:

Dietary supplementation with docosahexanoic acid (DHA) increases red blood cell membrane flexibility in mice with sickle cell disease


Abstract
Humans and mice with sickle cell disease (SCD) have rigid red blood cells (RBCs). Omega-3 fatty acids, such as docosahexanoic acid (DHA), may influence RBC deformability via incorporation into the RBC membrane. In this study, sickle cell (SS) mice were fed natural ingredient rodent diets supplemented with 3% DHA (DHA diet) or a control diet matched in total fat (CTRL diet). After 8 weeks of feeding, we examined the RBCs for: 1) stiffness, as measured by atomic force microscopy; 2) deformability, as measured by ektacytometry; and 3) percent irreversibly sickled RBCs on peripheral blood smears. Using atomic force microscopy, it is found that stiffness is increased and deformability decreased in RBCs from SS mice fed CTRL diet compared to wild-type mice.
In contrast, RBCs from SS mice fed DHA diet had markedly decreased stiffness and increased deformability compared to RBCs from SS mice fed CTRL diet.
Furthermore, examination of peripheral blood smears revealed less irreversibly sickled RBCs in SS mice fed DHA diet as compared to CTRL diet. In summary, our findings indicate that DHA supplementation improves RBC flexibility and reduces irreversibly sickled cells by 40% in SS mice. These results point to potential therapeutic benefits of dietary omega-3 fatty acids in SCD.

it was shown that ME/CFS patients have low omega 3 in their blood;
It would be interesting to know if their is any correlation between DHA or EPA or Omega3 and RBC deformability in our blood,@Janet Dafoe (Rose49)

 

[kangaSue]

I couldn't get that link to work. I sent the other one on to Ron and Mohsen. Thanks.

Sorry about that. I didn't realize the semi colon had highlighted too in the web address, corrected it now.

 

[nandixon]

Thanks for keeping us updated on Ron's thoughts from time to time! It's highly appreciated.
With regard to this, I'm just worried that if the test eventually can't seperate between severely depressed and ME/CFS patients, these doctors will still say it's all in the head. But let's hope that depression does not cause the same deformability problems. This seems relatively easy to test for though!?

It would probably be pretty expensive to do a proper study. I haven't done a complete search of all the existing scientific literature so it's possible that reduced red blood cell deformability has already been found in major depression. Certainly the lipid peroxidation finding I mentioned earlier suggests it may be there.

This reduced RBC deformability finding appears quite ubiquitous in a gamut of different diseases. Unfortunately, it has been found in psychiatric conditions as well. For instance, multiple studies from at least as early as the mid-1990s have found reduced RBC deformability in schizophrenic patients. See, e.g.: Erythrocyte deformability in schizophrenic patients (p < 0.001).

 

[raghav]

Hi @raghav

If you're referring to the eventual handheld Drs equipment I am not sure, not soon I would think as there will be further research on this.

However, it is possible to examine your rbc's under a microscope, in a very primitive way. I have done this, along with one healthy control and one moderate mecfs patients (I am severe) and my serum looked like an absolute warzone, in general but regards to rbc's too. Again on a very primitive level. Controls were not age matched but only gender matched and a sample of 3

The equipment used in this study is far far superior to any home experiment

But it was interesting nonetheless.


B

@Ben H Can you explain what exactly you mean by "warzone" ? I would like to take it up with a haematologist near my place. Is it possible to tell the difference between a normal person and an ME CFS person's blood using an ordinary microscope ? Thanks in advance.

 

[pattismith]

I agree with @nandixon , we need more studies with diseases controls ( classified as psy and as neurologic ones).


But erythrocytes parameters are getting more interest as potential biomarkers for diseases that desperately need blood biomarkers, so I think this area of research is still promising.

For example, in ALS, deformability seems increased:


"RESULTS:
Erythrocyte deformability and AChE activity were increased in patients with ALS in comparison to healthy donors. NO efflux from RBCs and concentration of intraerythrocytic nitrite were lower in ALS patients. In patients, we found that for higher NO range of values the respiratory function is worse and that for higher AChE range of values the RBCs nitrite content increase.

CONCLUSION:
The results of the present study indicate that NO efflux from RBCs and RBCs AChE should be further explored as potential biomarkers for ALS."

On the other hand, deformability appears decreased in MS, but they also found other potential biomarkers in RBC, like increased miRNA in remitting/relapsing MS.

In this study about Glaucoma:

Decreased erythrocyte deformability (ED), increased activity of erythrocyte acetylcholinesterase (AChE), increased values of nitrosoglutathione (GSNO) and nitic oxide (NO) and decreased plasma levels of NO metabolites, were described in primary open angle glaucoma patients.

 

[JES]

This reduced RBC deformability finding appears quite ubiquitous in a gamut of different diseases. Unfortunately, it has been found in psychiatric conditions as well. For instance, multiple studies from at least as early as the mid-1990s have found reduced RBC deformability in schizophrenic patients. See, e.g.: Erythrocyte deformability in schizophrenic patients (p < 0.001).

It is only a problem if the goal is to contrast ME/CFS against psychiatric disorders, which I can see has some value in order to get rid of the past baggage of ME/CFS being seen as a mental disorder. But from a scientific viewpoint it's not a problem necessarily I think. It is becoming increasingly clear that several traditionally mentally classified disorders have a large "physical component" (the BPS proponents love the term "psychological component", but often ignore the physical one). It is also of great benefit if findings like RBC deformability advance research in mental disorders and the understanding that they are often not in any way self caused or at least not as much as doctors used to think.

 

[FMMM1]

It is only a problem if the goal is to contrast ME/CFS against psychiatric disorders, which I can see has some value in order to get rid of the past baggage of ME/CFS being seen as a mental disorder. But from a scientific viewpoint it's not a problem necessarily I think. It is becoming increasingly clear that several traditionally mentally classified disorders have a large "physical component" (the BPS proponents love the term "psychological component", but often ignore the physical one). It is also of great benefit if findings like RBC deformability advance research in mental disorders and the understanding that they are often not in any way self caused or at least not as much as doctors used to think.

Here's an example from Wikipedia:
"Anti-NMDA receptor encephalitis is a type of brain inflammation due to antibodies. Early symptoms may include fever, headache, and feeling tired. This is then typically followed by psychosis which presents with false beliefs (delusions) and seeing or hearing things that others do not see or hear (hallucinations).
Anti-NMDA receptor encephalitis - Wikipedia
https://en.wikipedia.org/wiki/Anti-NMDA_receptor_encephalitis"

I think Jarred Younger has found evidence of brain - inflammation/encephalitis in ME/CFS (based on MRI findings which demonstrated increased temperature in the brain - inflammation/encephalitis). Check our Jarred's presentation at the recent OMF Symposium.

There a new paper by the Dr. Scheibenbogen* which found increased expression of these non-coding RNA genes in ME/CFS: NTT, MIAT and EMX2OS. Analysing just two of these genes was enough to separate those with ME/CFS from healthy control. The study points that MIAT is linked to schizophrenia:
"As for MIAT, it is known to play roles in a variety of disease processes, including myocardial infarction, microvascular dysfunction, schizophrenia, and neurogenic commitment".
*The expression signature of very long non‑coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome - https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1600-x

These are some random links from memory; I'm sure there are a lot more.

 

[Janet Dafoe]

I'm sending all these links to Ron and Mohsen. Thanks!