Machine Learning-assisted Research on CFS

mariovitali

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@mariovitali, did you post some new information on Twitter?
If so, can you post it here?
Thank you
Here is a latest update with some results :

The latest runs suggest a central role for glutamate metabolism. Glutamate has been found to be elevated in ME patients from some ME/CFS researchers. Also, we have new entries for Nitric Oxide metabolism and signalling, L-Arginine and vasoconstriction.

Regarding L-Arginine, I was very happy to read that there is upcoming research on this area by Dr Mercedes Rincon,I will definitely be watching this one :

Dr Mercedes Rincon is a Professor of Medicine, Division of Immunobiology Medicine at the University of Vermont. Her project is called “Exploring an Anti-Citrullinated Antibody Signature in MECFS”. This project seeks to argue that ME/CFS is not only an inflammatory disease, but that a subpopulation of patients possess a ME/CFS-specific antibody to a protein which has an abnormal switch of one amino acid (arginine) with another (citrulline). This will be done by measuring antibodies specific to citrullinated proteins from blood serum samples provided by the UK ME/CFS Biobank.
https://cureme.lshtm.ac.uk/researchers/our-collaborative-researchers/

Regarding Glutamate metabolism, an email was sent to Professor Bergquist for possible existence of hypoxanthine,xanthine and uric acid in cerebrospinal fluid. More specifically :

Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases.
Abstract
Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals. Hypoxanthine and lactate depict energetic impairment, while xanthine and uric acid reflect activity of radical producing xanthine oxidase. Cerebrospinal fluid (CSF) glutamate, hypoxanthine, lactate, xanthine, and uric acid were investigated in neurological patients. In multiple sclerosis, myelopathy, stroke, epilepsy and viral meningitis glutamate, hypoxanthine, xanthine, and uric acid are increased 2-3-fold compared to controls. Lactate is only elevated in meningitis. Normal lactate dehydrogenase (LDH) levels and absent correlation between the albumin ratio and neurochemical parameters exclude an artificial increase due to cell lysis and barrier damage. Absent correlation between neurochemical parameters within each patient group is most likely related to preserved glial and neuronal uptake mechanisms. CSF hypoxanthine, xanthine, and uric acid levels appear superior to lactate in reflecting glutamate-mediated excitotoxicity in neurological patients.
Also, for some reason which i still do not understand, there seems to be some similarity of ME/CFS with chronic kidney disease (CKD). I am working on this one to see why this is being output by these methods.


Here are the latest results, depicting the features selected by certain feature selection methods. You will find many known entries :

pns = parasympathetic nervous system
crh = corticotropin-releasing hormone


feature_selection290819.png
 

Violeta

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That's just so interesting, @mariovitali, I don't even know where to start. I've had chronic fatigue/fibromyalgia for so long and recently am finding myself looking at it from a point of view that includes so many of the words in your recent lists.

I have had bad reactions to some substances, such as bone broth, and since it's high in glutamates, I have thought it was from the glutamates. It causes severe issues in my brain.

Also, I had shingles 2 1/2 years ago, and still have postherpetic neuralgia. I had found information that some people are given gabapentin for the pain, so I looked for info to see if the pain is related to glutamate, and did find some hits. I don't take medicine, but I did try GABA. GABA doesn't work for me, but yes, I have glutamate issues.

Abstract
Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals
. Hypoxanthine and lactate depict energetic impairment, while xanthine and uric acid reflect activity of radical producing xanthine oxidase.

The glutamate-mediated excitotoxicity related to xanthine and uric acid is an amazing find since xanthine and uric acid at times cause almost immediate neuralgia in my trigeminal nerve where the shingles had been. I don't understand the part about activity of radical producing xanthine oxidase, though, I will have to study that.
 
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Violeta

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Cerebrospinal fluid (CSF) glutamate, hypoxanthine, lactate, xanthine, and uric acid were investigated in neurological patients. In multiple sclerosis, myelopathy, stroke, epilepsy and viral meningitis glutamate, hypoxanthine, xanthine, and uric acid are increased 2-3-fold compared to controls.

This is very interesting as you probably have read that people with multiple sclerosis are found to be LOW in uric acid. I always wondered where the uric acid was, had to be somewhere. It's in the cerebrospinal fluid!

Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals.

I need to know what to do about this. I need to know how to deal with the symptom and also how to reverse whatever damage is causing this.

This study might have some clues. "massive Ca2+ influx induces" "chelation of external calcium"

Xanthine oxidase activation and superoxide (O2.-) production are completely inhibited by concomitant incubation of glutamate with MK-801, a specific NMDA receptor antagonist, or by chelation of external calcium with EGTA. Partial inhibition of both cell death and parallel production of reactive oxygen species is achieved with allopurinol, a xanthine oxidase inhibitor, leupeptin, a protease inhibitor, reducing agents such as glutathione or dithiothreitol, antioxidants such as vitamin E and vitamin C, and externally added superoxide dismutase. It is concluded that glutamate-triggered, NMDA-mediated, massive Ca2+ influx induces rapid conversion of xanthine dehydrogenase into xanthine oxidase with subsequent production of reactive oxygen species that most probably have a causal involvement in the initial steps of the series of intracellular events leading to neuronal degeneration and death.

Kind of sounds similar to mast cell activation.

And I am seeing that hypoxia plays a part in glutamate toxicity. But I won't post any links at this point because I am not sure if I am looking at a tangent or not.
 
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Violeta

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I saw this in a study about glutamate levels in MS: "The glutamate scavanging is achieved by lowering glutamate levels in the blood by intravenous injection of the blood enzyme glutamate oxaloacetate transaminase (GOT)."

So I looked up SGOT, to see if it is related and I have had above normal levels on more than one test, and actually raised levels seem to run in my family.

"The SGOT test is a blood test that's part of a liver profile. It measures one of two liver enzymes, called serum glutamic-oxaloacetic transaminase. This enzyme is now usually called AST, which stands for aspartate aminotransferase. An SGOTtest (or AST test) evaluates how much of the liver enzyme is in the blood."

So I have raised serum levels of GOT, but I don't know what that would infer.
 

Violeta

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Also, for some reason which i still do not understand, there seems to be some similarity of ME/CFS with chronic kidney disease (CKD). I am working on this one to see why this is being output by these methods.
Uric acid is the commonality, but I don't know if the upstream cause is the same. But you probably already know this.

It looks like glutamate plays a part in CKD, too.
"Monosodium glutamate (MSG) is a commonly-used additive in processed food and Asian cuisine to increase palatability. ... Published data indicate that renal fibrosis is associated with the chronic consumption of MSG [4] and oxidative stress is the main cause of kidney injury"

CKD involves mineral disorders.
"Points to Remember. Mineral and bone disorder in chronic kidney disease (CKD) occurs when damaged kidneys and abnormal hormone levels cause calcium and phosphorus levels in a person's blood to be out of balance. ... The kidneys stop activating calcitriol and do not remove the phosphorus in the blood properly."

Reactions to glutamate aren't universal, so I wonder what it is about ME/CFS or CKD that sets one up for the reactions?

NAFLD?
"Growing evidence suggests that nonalcoholic fatty liverdisease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKDinclude excessive fructose intake and vitamin D deficiency."

(The vitamin D deficiency is a result of NAFLD)
(What mineral levels does fatty liver mess up?)
 
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Violeta

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Compromised brain energy metabolism plays a critical role in the pathogenesis of neurological diseases, such as stroke and Alzheimer's disease. Neurons are excitable cells that require large amounts of energy to support their multiple ion-motive enzymes to maintain ion homeostasis, electrochemical membrane potential, and signaling functions.1 The energy demand of neurons in the brain is increased when brain neurons are stimulated by glutamate, an excitatory neurotransmitter critical for cognition, motor function, and other behaviors.2 Abnormally high concentrations of synaptic glutamate or prolonged stimulation of glutamate receptors, particularly N-methyl-d-aspartate (NMDA) receptors in pathological conditions, could result in perturbed ion homeostasis, energy depletion, and the degeneration and death of neurons in a process called excitotoxicity.3,4 Excitotoxicity is implicated in the degeneration of neurons that occurs in a range of neurological disorders, including epilepsy, stroke, and Alzheimer's disease.3,5,6

Cellular energy stores are depleted during excitotoxicity with decreases in levels of ATP and nicotinamide adenine dinucleotide (NAD+). NAD+ is an important energy substrate and cofactor involved in multiple metabolic reactions,7 including glycolysis, DNA repair processes, and the function of several NAD...

You can read more about it at the link below.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645538/
 

Violeta

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massive Ca2+ influx induces rapid conversion of xanthine dehydrogenase into xanthine oxidase
This step, the conversion of xanthine dehydrogenase (good) to xanthine oxidase (bad) might be able to be avoided with NAD. I don't know.

Xanthine oxidase (XO)
Xanthine oxidoreductase (XOR) exists in two isoforms: XO and xanthine dehydrogenase (XDH). XDH can be converted to XO irreversibly by limited proteolysis or reversibly by thiol oxidation or phosphorylation.61 Only XO produces ROS, catalyzing the oxidative hydroxylation of purine substrates with the formation of O2·− and H2O2; under hypoxia significantly more H2O2 is formed than O2·−.62,63

This is where the calcium comes from. I was thinking it came from diet, and that avoiding dairy was important, but now I'm thinking that's not so important, but I don't know.

"Cellular levels of ATP (i.e. the cell's “energy currency”) fall. Cells are no longer able to maintain proper ion gradients across their membranes, and this precipitates a redistribution of Ca2+ ions. The elevated cytosolic Ca2+ concentration activates a protease capable of catalysing the conversion of xanthine dehydrogenase to xanthine oxidase."

Why are levels of uric acid and xanthine raised? Perhaps BBB is compromised, but I read one study where levels actually varied in people with certain conditions depending on if they were in a flare or not.

"During the protein breakdown phase serum uric acid may rise markedly (Robin et al. 1998), and this is associated with increased locomotor activity, a decrease in water excretion, and a rise in cortisol levels."
 
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mariovitali

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@mariovitali , if you haven't added thioredoxin and selenium to your search, would you consider adding them. Thank you

Oh, I am searching thioredoxin and see it has already been discussed. Thank you

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751730/
Thank you for reminding me about selenium. Yes, there is a connection and the proposed mechanism is through upregulation of PGC-1a :


Furthermore, selenite increased protein levels of peroxisome proliferator-activated receptor-γ coactivator 1alpha (PGC-1α) and nuclear respiratory factor 1 (NRF1), two key nuclear factors that regulate mitochondrial biogenesis. Finally, selenite normalized the ischemia-induced activation of Beclin 1 and microtubule-associated protein 1 light chain 3-II (LC3-II), markers for autophagy.
https://www.ncbi.nlm.nih.gov/pubmed/22776356
 
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Violeta

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Thank you for reminding me about selenium. Yes, there is a connection and the proposed mechanism is through upregulation of PGC-1a :




https://www.ncbi.nlm.nih.gov/pubmed/22776356
Thank you, and your link brought up this associated link, help in the hippocampus.

https://www.ncbi.nlm.nih.gov/pubmed/23110128

Selenite stimulates mitochondrial biogenesis signaling and enhances mitochondrial functional performance in murine hippocampal neuronal cells.

I am seeing that they use sodium selenite. I have been taking selenomethionine, but I may get some selenite.
Do you have an opinion on this?
 

Gondwanaland

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Thank you, and your link brought up this associated link, help in the hippocampus.

https://www.ncbi.nlm.nih.gov/pubmed/23110128

Selenite stimulates mitochondrial biogenesis signaling and enhances mitochondrial functional performance in murine hippocampal neuronal cells.

I am seeing that they use sodium selenite. I have been taking selenomethionine, but I may get some selenite.
Do you have an opinion on this?
For those with uric acid issues I remind to stay away from extra sodim. In my personal experience selenium glycine is the best one - methionine gives me brain fog
 

bread.

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Cerebrospinal fluid (CSF) glutamate, hypoxanthine, lactate, xanthine, and uric acid were investigated in neurological patients. In multiple sclerosis, myelopathy, stroke, epilepsy and viral meningitis glutamate, hypoxanthine, xanthine, and uric acid are increased 2-3-fold compared to controls.

This is very interesting as you probably have read that people with multiple sclerosis are found to be LOW in uric acid. I always wondered where the uric acid was, had to be somewhere. It's in the cerebrospinal fluid!

Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals.

I need to know what to do about this. I need to know how to deal with the symptom and also how to reverse whatever damage is causing this.

This study might have some clues. "massive Ca2+ influx induces" "chelation of external calcium"

Xanthine oxidase activation and superoxide (O2.-) production are completely inhibited by concomitant incubation of glutamate with MK-801, a specific NMDA receptor antagonist, or by chelation of external calcium with EGTA. Partial inhibition of both cell death and parallel production of reactive oxygen species is achieved with allopurinol, a xanthine oxidase inhibitor, leupeptin, a protease inhibitor, reducing agents such as glutathione or dithiothreitol, antioxidants such as vitamin E and vitamin C, and externally added superoxide dismutase. It is concluded that glutamate-triggered, NMDA-mediated, massive Ca2+ influx induces rapid conversion of xanthine dehydrogenase into xanthine oxidase with subsequent production of reactive oxygen species that most probably have a causal involvement in the initial steps of the series of intracellular events leading to neuronal degeneration and death.

Kind of sounds similar to mast cell activation.

And I am seeing that hypoxia plays a part in glutamate toxicity. But I won't post any links at this point because I am not sure if I am looking at a tangent or not.

you are onto something here. do I understanf you correctly? Vit E and C and Calcium are a bad idea? I have 6th fold increased hypoxanthine in blood.
 

Violeta

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you are onto something here. do I understanf you correctly? Vit E and C and Calcium are a bad idea? I have 6th fold increased hypoxanthine in blood.
I think what that paragraph means is that Vitamin E and C are good because they are antioxidants, same for superoxide dismutase. I think they are good because they stop the influx of Ca2+ influx, which causes damage, at least under the described conditions.