Machine Learning-assisted Research on CFS

mariovitali

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Dear All,

cc : @sb4, @Murph , @Gondwanaland ,@Learner1 , @Jesse2233 , @Janet Dafoe (Rose49), @JaimeS


After a long time i am giving an update here on the latest developments since last year :

1) I am delighted to announce that i started a collaboration with CureME team at the London School of Hygiene and Tropical Medicine. We used specific analytical techniques to enrich patient records with medications and supplements taken by PwME. We are writing up the paper but most importantly, our work has been selected to be presented in one of the biggest conferences in the world, American Public Health Association (APHA) :

APHAconf.png

We now have the technology to analyse hundreds of thousands of patient records and understand better if some supplement combinations do work.

2) The machine learning approach continues to outperform other findings. The latest examples are from the webinar presented by SolveCFS. Findings by Birch et. al regarding Glycogen storage disease and iron metabolism have been identified by Machine Learning in 2017 and 2018 respectively (i have references available to any researcher or Organisation wishing to confirm)

3) We have a confirmation of findings by the highly prestigious Karolinska Institutet, Dr Petter Brodin. Since 2018 , Machine Learning has identified the vagus nerve as a potential target but i did not know why. What happened with Jen Brea after her CCI operation gave us -i hypothesise- the importance of cholinergic signalling and most importantly the Cholinergic Anti-Inflammatory Pathway (CAP). Please also note that the Liver has a Cholinergic Nerve with which it communicates with the brain. Snapshots are shown below :

Karolinska.png


and Jen Brea discusses her problems with Bile Acids Metabolism - Identified with Machine Learning since 2015

JenB Tweet.png

and


JenB2-bileacids.png


If Acetylcholine is indeed central to ME/CFS, Machine Learning has identified this since 2015 in a post here on Phoenix Rising.


4) I continue working, trying to put more pieces of the puzzle together. I am currently looking at how the kynurenine pathway fits into the picture and it does. I hypothesise that the vicious cycle discussed by Dr Phair has to do with excitotoxicity and the NMDA Receptor via Quinolinic Acid. If we keep excitotoxicity in check we may stop the vicious cycle :


quinolinic-nmda.png




Unfortunately, since 2015 i had no help from anyone in the sense that these techniques should be used by Medical Professionals and not myself. I sincerely hope this changes soon.
 

Learner1

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Nice work @mario...:)

We used specific analytical techniques to enrich patient records with medications and supplements taken by PwME.
We now have the technology to analyse hundreds of thousands of patient records and understand better if some supplement combinations do work.
Not wanting to be rude, but I've been wondering how, exactly anyone would ever be able to collect my health records out of the 20 EHR systems they are in and the drugs and supplements which are always wrong in them and make any sense out of them.

There have been numerous recent articles here in the US about the rampant inaccuracies in such systems, even causing medication mistakes with serious consequences.

My typical experience is that I hand a 2 column, single spaced page to a nurse, who runs out of time after spending 5 minutes valiantly trying to type it all in. Some scan it, but I have never yet seen it anywhere close to right. And I use 5 pharmacies and buy from 17 different supplement sources, with things prescribed by 6 doctors.

How can you collect accurate info to make a system that is based on valid data? And how.do you account for the subsets of patients or the varying levels of expertise of prescribes? And varying outcomes of patients?
 

mariovitali

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@Learner1

No problem, i will try to answer as much as i can, given the fact that there are some things that i cannot disclose at the moment.

1) We cannot account for the fact that a patient was given Drug A and instead it was written as Drug B

2) We do account for typos. To achieve this we use an algorithm called Edit Distance. This means that if someone will enter the word Magnesium as Mangesium or Magnesum, this will be identified as Magnesium.

3) The extraction system was applied to questionnaire data. In other words there was a text field where patients would enter their medications and supplements. Therefore, If we have electronic records where a text field contains this information,we are able to capture it.

4) The system does not identify dosages. It identifies supplements and medications. There is more pre-processing involved which i will not discuss at present.

5)We have to start thinking outside of the box. This technology enables us to identify further hypotheses. Yes, there are limitations but that doesn't mean that we shouldn't try, keeping in mind the limitations.
 

mariovitali

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According to De Goldstein NMDA excitotoxicity was the primary mechanism in me/CFS pathogenesis.

Most of his work is focused on modulating the NMDA receptor, and his favourite treatment, IV ketamine, is a strong NMDA antagonist
This is great to know, Thanks.

Just to add that the cholinergic system needs to be investigated as well and more specifically the cholinergic anti-inflammatory pathway. So it is not about just giving an NMDA inhibitor. Moreover, there may exist patients that have liver issues. These have to be identified and corrected (hypothesis)
 
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mariovitali

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Just found this. Microglia Activation (=Jarred Younger, VanElzakker) and the LXR Receptor :

cc @Learner1


Liver X receptor-dependent inhibition of microglial nitric oxide synthase 2.
Secor McVoy JR1, Oughli HA2, Oh U3.
Author information

Abstract
BACKGROUND:
The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis.

<SNIP>

CONCLUSIONS:
LXR can be targeted to modulate microglial activation.
LXR-dependent repression of inflammatory genes may be stimulus-dependent and impaired by HDAC inhibition. Endogenous LXR activity does not appear to modulate CNS inflammation, but LXR activity can be partially restored in the CNS by administration of exogenous LXR agonist with an impact on clinical disease severity at early, but not late, time points in EAE.

We go back to May 8, 2017 , first page of this thread :


https://forums.phoenixrising.me/threads/machine-learning-assisted-research-on-cfs.51283/#post-846815


You can see LXR Receptor being identified in the Network Analysis. Of course this may be a false signal but we cannot afford not to look at it.
 
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Violeta

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@mariovitali, I am glad you have found people to work with that appreciate your work. What good news.

Quickly looking through this most recent page of comments makes me think that your findings may be used to help people with Alzheimer's, or maybe even help people avoid Alzheimer's.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791143/

Excitatory glutamatergic neurotransmission via N-methyl-d-aspartate receptor (NMDAR) is critical for synaptic plasticity and survival of neurons. However, excessive NMDAR activity causes excitotoxicity and promotes cell death, underlying a potential mechanism of neurodegeneration occurred in Alzheimer’s disease (AD).
 

mariovitali

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More on LXR Receptor. It protects cholinergic neurons (in mice) :

Liver X receptor activation attenuates inflammatory response and protects cholinergic neurons in APP/PS1 transgenic mice.
Cui W1, Sun Y, Wang Z, Xu C, Peng Y, Li R.
Author information

Abstract
Alzheimer's disease (AD) is associated with beta-amyloid deposition, glial activation, and increased levels of the cytokines, as well as cholinergic dysfunction. Liver X receptor (LXR) has been found to inhibit the expression of pro-inflammatory genes. However, the effects of LXR activation on inflammatory response and on cholinergic system in AD are not yet clear. The present results revealed that LXR activation markedly attenuated several inflammatory markers and decreased microglial activation and reactive astrocytes in amyloid precursor protein (APP)/PS1 transgenic mice. Additionally, LXR activation significantly increased the number of cholinergic neurons in the medial septal regions and the basal nucleus of Meynert (NBM), and attenuated cognitive impairment. Furthermore, we observed that LXR activation inhibited the production of COX-2 and iNOS from Aβ(25-35)-induced microglia. LXR activation and nuclear factor kappa B (NF-κB) inhibitor PDTC both attenuated Aβ(25-35) induction of NF-κB activation. These results suggest that LXR agonists suppress the production of pro-inflammatory molecules, at least in part, by modulating NF-κB-signaling pathway. Collectively, these studies suggest that LXR agonists may have therapeutic significance in AD.
Network-LXR.png
 

Violeta

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4) I continue working, trying to put more pieces of the puzzle together. I am currently looking at how the kynurenine pathway fits into the picture and it does. I hypothesise that the vicious cycle discussed by Dr Phair has to do with excitotoxicity and the NMDA Receptor via Quinolinic Acid. If we keep excitotoxicity in check we may stop the vicious cycle :
This article has some information about B6 being a remedy for this part of the problem. I realize there already is lots about this at Phoenix Rising, but if anyone is interested in what to do about it, they might find this helpful.

I understand that you are looking to find how this relates to the liver; I am following to see if you find the answer.

http://www.hormonesmatter.com/reduc...zby0pOwjmUgVMZ70NYXFiYws2pMFNnincQiPeVawVe8E4

https://www.ncbi.nlm.nih.gov/pubmed/23046794
 
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mariovitali

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This article has some information about B6 being a remedy for this part of the problem. I realize there already is lots about this at Phoenix Rising, but if anyone is interested in what to do about it, they might find this helpful.

I understand that you are looking to find how this relates to the liver; I am following to see if you find the answer.

http://www.hormonesmatter.com/reduc...zby0pOwjmUgVMZ70NYXFiYws2pMFNnincQiPeVawVe8E4
I actually found a combination of supplements (from a research paper) that appears to be working synergistically but yes, P5P is one of them
 

mariovitali

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When you have time, I would be interested in the combination.
Here is the paper. Please note that we do not know whether this is applicable / holds for ME patients :

The degradation of tryptophan in severe liver disease.
Rossouw JE, Labadarios D, Davis M, Williams R.
Abstract
Patients with severe acute or chronic liver disease were found to have a high mean plasma free tryptophan, an abnormal urinary excretion pattern of tryptophan-kynurenine metabolites and low circulating levels of the vitamins required for tryptophan degradation, i.e. pyridoxine, thiamine and ascorbic acid. In patients with decompensated chronic liver disease (DCLD), ineffective vitamin B6(pyridoxine hydrochloride) supplementation with effective thiamine and ascorbic acid supplementation increased urinary 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid excretion. Effective B6(pyridoxal phosphate) supplementation did not cause a similar change. It is postulated that the combination of increased input into the pathway together with vitamin B6 deficiency may explain the abnormal tryptophan-kynurenine pathway in severe liver disease. Imbalanced or ineffective vitamin supplementation may aggravate the disturbance of tryptophan degradation.
What requires further investigation :

a) Do we see high mean plasma free tryptophan / abnormal urinary excretion of tryptophan/kynurenine metabolites in ME Patients ?

b) Are B6 + Thiamine + Vitamin C indeed required for tryptophan degradation?

Vitamin C increases iron absorption. If you have haemochromatosis, this could be a problem for this condition.
 

NotThisGuy

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Here is the paper. Please note that we do not know whether this is applicable / holds for ME patients :



What requires further investigation :

a) Do we see high mean plasma free tryptophan / abnormal urinary excretion of tryptophan/kynurenine metabolites in ME Patients ?

b) Are B6 + Thiamine + Vitamin C indeed required for tryptophan degradation?

Vitamin C increases iron absorption. If you have haemochromatosis, this could be a problem for this condition.
Some people here did this genova metabolic thing test. tryptophan and kynurenine is measured there in urine. Maybe you can find those people via search and PM them if they havent uploaded it on here. But some uploaded their results here on this Forum. Only problem is that some people chose to check aminoacids in blood and not in urine with the genova test, but I know there were people on here who did the urine test for amino acids.So sometimes you will find tryptophan in blood or urine but kynurenine always is urine in those reports.

I can only say for myself that when I frist started B1 supplementation I felt like I was almost cured the first 2 days. I was still pretty well the following 4-8 weeks but then crashed hard.
Today I still take B6 (P5P) and Vit. C but cant tolerate any B1 anymore.

Also yes, P5P is indeed required for tryptophan degradation.
https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.1961.tb46120.x?sid=nlm:pubmed
This study claims Vit.C is needed for tryptophan-5-hydroxylase.
Only thing I can find about B1 is that a deficiency is causing higher tryptophan to NAD degradation.
But I haven't fully read any of the studies (just the outline) so dont quote me.

PS: I have done a amino acid blood test and my tryptophan was normal.
1561893424898.png
 

Violeta

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Some people here did this genova metabolic thing test. tryptophan and kynurenine is measured there in urine. Maybe you can find those people via search and PM them if they havent uploaded it on here. But some uploaded their results here on this Forum. Only problem is that some people chose to check aminoacids in blood and not in urine with the genova test, but I know there were people on here who did the urine test for amino acids.So sometimes you will find tryptophan in blood or urine but kynurenine always is urine in those reports.

I can only say for myself that when I frist started B1 supplementation I felt like I was almost cured the first 2 days. I was still pretty well the following 4-8 weeks but then crashed hard.
Today I still take B6 (P5P) and Vit. C but cant tolerate any B1 anymore.

Also yes, P5P is indeed required for tryptophan degradation.
https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.1961.tb46120.x?sid=nlm:pubmed
This study claims Vit.C is needed for tryptophan-5-hydroxylase.
Only thing I can find about B1 is that a deficiency is causing higher tryptophan to NAD degradation.
But I haven't fully read any of the studies (just the outline) so dont quote me.

PS: I have done a amino acid blood test and my tryptophan was normal.
View attachment 33440 [/QUO
These two most recent posts made me wonder if tryptophan is involved in the neuropathy that people attribute to B6 toxicity.

The B6 toxicity actually being that it's not being used correctly by the body due to error caused by some other deficiency, or I suppose oversupplementing.

I found this study that could indicate it is actually the tryptophan causing the neuropathy. But maybe others already know this.

https://www.ncbi.nlm.nih.gov/pubmed/2162498
 

Violeta

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Here is the paper. Please note that we do not know whether this is applicable / holds for ME patients :



What requires further investigation :

a) Do we see high mean plasma free tryptophan / abnormal urinary excretion of tryptophan/kynurenine metabolites in ME Patients ?

b) Are B6 + Thiamine + Vitamin C indeed required for tryptophan degradation?

Vitamin C increases iron absorption. If you have haemochromatosis, this could be a problem for this condition.
I think a missing ingredient is zinc, but I'm not sure. Please take a look at this study and let me know what you think.
This would, of course, necessitate that one is not deficient in B2 so that the B6 is actually available.

https://www.ncbi.nlm.nih.gov/pubmed/3804611
 
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Violeta

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Some people here did this genova metabolic thing test. tryptophan and kynurenine is measured there in urine. Maybe you can find those people via search and PM them if they havent uploaded it on here. But some uploaded their results here on this Forum. Only problem is that some people chose to check aminoacids in blood and not in urine with the genova test, but I know there were people on here who did the urine test for amino acids.So sometimes you will find tryptophan in blood or urine but kynurenine always is urine in those reports.

I can only say for myself that when I frist started B1 supplementation I felt like I was almost cured the first 2 days. I was still pretty well the following 4-8 weeks but then crashed hard.
Today I still take B6 (P5P) and Vit. C but cant tolerate any B1 anymore.

Also yes, P5P is indeed required for tryptophan degradation.
https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.1961.tb46120.x?sid=nlm:pubmed
This study claims Vit.C is needed for tryptophan-5-hydroxylase.
Only thing I can find about B1 is that a deficiency is causing higher tryptophan to NAD degradation.
But I haven't fully read any of the studies (just the outline) so dont quote me.

PS: I have done a amino acid blood test and my tryptophan was normal.
View attachment 33440
Have you ever taken zinc? Or do you seem to have any symptoms related to zinc deficiency? I am wondering if you had good results from thiamine but then crashed because the thiamine burned off any zinc that was available. I looked up thiamine and zinc and did see some stuff that would back this up, but nothing worth linking yet.
 

Violeta

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Here is the paper. Please note that we do not know whether this is applicable / holds for ME patients :



What requires further investigation :

a) Do we see high mean plasma free tryptophan / abnormal urinary excretion of tryptophan/kynurenine metabolites in ME Patients ?

b) Are B6 + Thiamine + Vitamin C indeed required for tryptophan degradation?

Vitamin C increases iron absorption. If you have haemochromatosis, this could be a problem for this condition.

Iron plus quinolinic acid is not a good thing.


https://www.ncbi.nlm.nih.gov/pubmed/11378528
 

NotThisGuy

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Have you ever taken zinc? Or do you seem to have any symptoms related to zinc deficiency? I am wondering if you had good results from thiamine but then crashed because the thiamine burned off any zinc that was available. I looked up thiamine and zinc and did see some stuff that would back this up, but nothing worth linking yet.
yes i take zinc.