Discussion in 'BioMedical ME/CFS Research' started by Andy, Feb 21, 2019.
Paywalled at https://www.cell.com/biophysj/fulltext/S0006-3495(18)31946-5
A lot of discussion about the research behind this paper is here, https://www.s4me.info/threads/eryth...ronic-fatigue-syndrome-davis-et-al-2018.6938/
One parasite and one bacterium leap to mind as potential culprits: Babesia and Bartonella, respectively.
This is all well above my meager understanding of biology, but this seems interesting:
From Wikipedia (quotes below are all from wiki, the paper is not yet available on sci-hub):
Higher levels is not at the same level as dramatic increase, so cell damage may not occur at slightly elevated concentrations but other consequences of oxidative stress may still play a role.
Egg, or chicken?
Could elevated levels but-not-quite-dramatically-increased of ROS explain hyperacusis? High levels seem capable of causing deafness, could slightly elevated levels cause inflammation that make them oversensitive?
ROSes play a role in pathogen response... hmmm:
Now I'm curious if it can be checked whether ME patients have faster cell renewal, the production of which would certainly be energy intensive and could explain telomere reduction?
Anyway, this is above my cognitive level but very interesting. It could potentially explain the mechanism of PEM, when increased oxygen demand can't be met because oxygen can't be transported efficiently, leading to a cascade of effect from oxygen-starved cells.
Can't wait to read the paper and not understand most of it, but it seems promising.
Technically that would comport with anemia, just not the PEM part. It's a curious tie-in, nonetheless. Babesia is notorious for hemolytic anemia. I satisfy diagnositcs for both. My RBC's are warped as evidenced by out-of -range small RBCs and abnormal MCV and mhcv etc.
All this reflected in the paper may not have anything to do with a downstream effect from infection, but fun to think about.
As I recall, the import of the paper was LESS deformability, though, or deformability instances, but perhaps I have that wrong.
Apparently this is just a short article. The paragraph you see in the link is all there is. There will be no further details in this article.
Didn’t one of the main figures in the paper show significant overlap between ME and HC? Everytime there’s a biomarker paper out it always turns out that there is just too much overlap to be useful and biomarker is more or less pointless beyond adding to the research knowledgebase on ME.
I think the only paper I’ve seen that didn’t have any overlap was MyHill’s mitochondrial energy score (MES)
Chronic fatigue syndrome and mitochondrial dysfunction
Look at Figure 4, that’s what we are looking for in a biomarker, composite or otherwise.
This result on deformability from the first Davis et al RBC paper shows no overlap. The number of patient was low in this initial study. There was a very clear difference. I've not seen an ME study with such a marked differnce
The second article that this thread is based on mentions a recovering patient looks much better. Les Simpson in his large studies noticed the same. In a longitudinal study RBC's looked more normal when patients were in a "better" phase.
Like you I've been impressed with this paper. However nobody over the years has been able to replicate this finding. Most recently Karl Morten from Oxford in his NZ lecture stated that both his team and Julia Newtons team had tried to replicate with funding from the ME association and they had not been able to. In fact he said handling of the blood plays a huge role in the results you get and testing 24hours later like the ATP profile test does bares no resemblance to testing on fresh blood. I recommend watching that presentation.
Had anyone other than Karl Morten tried? Norman Booth pestered MEA for years to get interest and replication.
Whilst disappointing that it could not be replicated, the recent research has found a number of interesting anomalies, and created interest.
Both Karl Mortens team and a Newcastle team failed to replicate. These teams are considered experts on Mitochondria in the UK. Other places have previously tried to replicate but were not successful. The recent ME Association write up of Karl Mortens talk mentions this replication work.
The late Norman Booth talked about some of the earlier failed replication work on PR
Link : https://forums.phoenixrising.me/threads/mitochondrial-and-energy-metabolism-dysfunction-in-me-cfs-—-myhill-booth-and-mclaren-howard-papers.47488/post-785000
Many people have also used the commercially available (and very expensive) Seahorse instrument from Agilent to test mitochondrial energy. Ron Davis talked about it at IMEC13 (Cara Tomas at Newcastle has also published on this).
Ron Davis also has the nanoneedle test he is working on and Karl Morten has reproduced issues with muscle cells. Both have included plasma swap experiments showing something in the blood is affecting energy.
Hopefully we will get more info on the biomarker bake-off at some point then we will see how reliable each test is.
EDIT : Here is Cara Tomas Seahorse paper. There is overlap between patients and controls.
@wigglethemouse have Davis and co said what other chronic inflammatory illnesses they will test for deformability? To test if this is specific to ME/CFS or simply a sign of many chronic inflammatory illnesses? I think others have also expressed concern about the test's potential lack of specificity.
Thank you for pointing this figure out.
I have not read anything about testing other illnesses at this stage. From what I've seen other people post, this test is unlikely to be disease specific, but can be useful to show something biologically is wrong.
Les Simpson tested his own RBC's during infection and noticed changes
Link to Post on PR - https://forums.phoenixrising.me/threads/research-update-from-prof-ron-davis-video.56737/post-959242
Les Simpson did a study on RBC comparing ME to MS
Link to Post on PR - https://forums.phoenixrising.me/thr...er-mohsen-nemat-gorgani-phd.61118/post-994417
Les Simpson wanted to establish a clinic to test red blood cells. If Davis et al can come up with a working test maybe his dream can become reality.
Link : http://www.cfidsreport.com/Articles/researchers/lessimpson.htm
There’s a major problem with this approach since many (or most) PwME have comorbidities or other diseases which are autoimmune and/or inflammatory. I also have psoriasis for example, which might significantly contribute to reduced erythrocyte deformability.
While they wouldn’t necessarily have to show that reduced deformability is specific to ME, they would possibly have to show that it isn’t significant in cohorts of patients without ME that have common ME comorbidities, as well as other major diseases (such as psoriasis which isn’t a common ME comorbidity).
So this test might not be helpful to show there is something biologically wrong that isn’t attributed to a comorbidity or other existing disease.
Could a negative test be developed for example most patients with ME are said to react badly to alcohol are there any other safer more common substances to try
Include unusual reactions as well
Alcohol tolerance is an interesting subject - Searching "erythrocyte alcohol" brings up lots of interesting papers e.g.
The Effect of Alcohols on Red Blood Cell Mechanical Properties and Membrane Fluidity Depends on Their Molecular Size
So if our RBC's are already impaired it makes sense that alcohol would worsen the situation.
Les Simpson hoped that if we have a good clinical test for RBC issues that correlates to "bad" and "better" days as his research seemed to indicate, then we can track treatments to see what effects they have on RBC's. Is the treatment the helping or hindering.
I think one of the reasons there is so little Big Pharma interest in our disease is the fact that there is no biomarker to track to biologically see if their drugs help. Even such simple things as does for example Ubiquinol help is really hard to decide (note : Nancy Klimas is testing this supplement in GWI phase II clinical trial). My dream is that maybe an RBC deformability test would help facilitate clinical trials of treatments in ME. Of course an awful lot of work is needed to prove this marker tracks with illness level, and it's probably going to take NIH level funding if not more to really quantify.
I enjoyed this talk from last years #CMRC2018 conference about research from the perspective of a father of two kids with ME/CFS and a Pharmaceutical company employee - it is given by Dr Mark Jones from UCB Pharma. He describes the importance of having biological markers that can be tracked during drug development and clinical trials. That's why finding those markers is so important for our research field.
It is also interesting to hear how research work has changed significantly in the last few years due to the abundance of big data and availability of computing power, and how patient involvement really helps.
The strong alcohol intolerance symptom isn’t consistently present over time.
I had very strong and sudden alcohol intolerance after getting ME, and it remained that way for about 2 years. Immediate vomiting, nausea, strong hangover after drinking just a fraction of a glass of wine.
But then it started to gradually reduce as the years went on, all the while I’ve continued to get worse. I still have some intolerance if I drink beyond two glasses of wine in one sitting, but the symptoms are different than long ago, it mostly just causes PEM.
I think people need to specify what they mean by alcohol intolerance. Thank you for sharing this @leokitten.
For me i never ever thought of drinking alcohol in the first few years of my illness. I already felt horrible, so why add further load to an already overburdened body?
These days (10 years later) I can tolerate a little bit of wine, like half a glass.
While the biochemistry of alcohol intolerance is interesting and could give insight into the disease, the real significance is easy to overlook.
ME and CFS are so often dismissed as a form of depression or a neurotic fear of exercise, yet in our society it is accepted to cliche level that someone like that uses alcohol to cope.
The fact that we do not self medicate with alcohol - managing to tolerate some wine hardly counts when you think about it, it is more of a confirmation of alcohol intolerance than otherwise.
I believe this is proof that something physiological is going on in our bodies and for that reason should be more prominent.
Brenu et al note no difference in deformability using a different methodology.
Saha et al note that some patients were taking various medications such as LDN, Rituxan, Vitamin D etc and this could well affect the results, especially given the small sample size. Secondly, no sensitivity of specificity of the association is discussed, presumably because the test of this association as a biomarker needs to be done as a replication.
Altered morphology has been noted before, but of uncertain specificity or signifiance. https://me-pedia.org/wiki/Red_blood_cell
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