Machine Learning-assisted Research on CFS

mariovitali

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Doing metabolomics testing to understand one's individual biochemistry is essential. Having an understanding of one's genes, environmental exposures, etc. is critical, too. Then, a clever doctor can personalize a plan that meets the individual's needs.

We are all unique individuals with unique genes and environmental factors. It is pretty impossible for scientists to come up with sports of identical patients to run experiments are. We are not identical widgets.

Yes, I have hemachromatosis, and it has been treated. I had some other things, like chlamydia pneumoniae and heavy metal toxicity stressing my liver.

You make a good point that genetic conditions should be identified in individuals. I also have a lot of other interesting genes that may be impacting my situation, as other patients do, too.

As for curcumin, I have benefited in multiple situations from it. It has different mechanisms of action, which I have found to be extremely effective, and which are based on sound science. It is a COX-2 inhibitor, is a broad spectrum Phase II detoxifier, and has cancer-fighting properties. I have seen it reverse cancers that have been resistant to multiple chemo regimens. In my case, it has helped with removing toxic arsenic metabolites stuck halfway through the detox process. It has also calmed down brain and intestinal inflammation caused by intravenous immunoglobulins.

I suspect your network needs a few more data points to take into account all of my issues before recommending whether treatments that will or won't work. Real life is more complex than most studies.

It was not my intention to recommend to you anything, what i was trying to say is that it may not be good to you or someone else given specific circumstances.

According to the following paper, Curcuminoids may inhibit SULTs, CYPs and UGTs which for some people may be problematic :

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574793/
 

mariovitali

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This is why my doctors and I are individualizing my treatment, using knowledge of my genes, environmental exposures, and extensive lab work.
I couldn't agree more. It's just that many details have still not been accounted for.

The easiest example i can give is a test called Total Bile Acids. It is a simple test, yet i haven't seen any Researcher testing for those (to the best of my Knowledge).

Interestingly, i found many ME/CFS Patients having elevated Total Bile Acids. Some of these test results were forwarded to @Janet Dafoe (Rose49) but i will be forwarding them to two more Researchers i have in mind.

It is possible that these Researchers have given other tests that somehow include TBAs. I don't know to be honest but better be safe than (very) sorry.
 
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Gondwanaland

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I don't want to gang up against curcumin, but in my personal experience the frequent use of Turmeric as a food spice makes me amine intolerant I think because it is a MAO-inhibitor.
 

Learner1

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You're right. For most people I've seen, its not a problem. But for you, it may be.

https://www.ncbi.nlm.nih.gov/m/pubmed/18766332/

Curcumin (10-80 mg/kg, i.p.) dose dependently inhibited the immobility period, increased serotonin (5-hydroxytryptamine, 5-HT) as well as dopamine levels (at higher doses), and inhibited the monoamine oxidase enzymes (both MAO-A and MAO-B, higher doses) in mice.

Conclusion:

The study provides evidences for mechanism-based antidepressant actions of curcumin. The coadministration of curcumin along with piperine may prove to be a useful and potent natural antidepressant approach in the management of depression
 

mariovitali

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I wanted to provide an update on the latest regarding this Research.

- I sent yesterday an E-Mail to Dr Nancy Klimas. To summarise, the following Researchers have received the relevant Research Notes :

-Dr Nancy Klimas
-Professor Ronald Davis
-Professor Maureen Hanson
-Professor Derya Unutmaz
-Professor Richard Deth
-Professor Warren Tate
-Dr Alan Light

A mistake i made was that i didn't circulate this 32-page document to all of them from the start in order to speed things up.


I move on to the latest algorithmic findings. We have :

-Confirmation of relevance of Extracellular Vesicles (Maureen Hanson)
-Confirmation of relevance of Th17

Here is a sample run. Note the selection of Sepsis, Extracellular vesicles, Milk Fat Globule membrane in this particular run :




algorun.png



Cholecystectomy was also added to the list of factors that may set the stage for ME/CFS (Hypothesis)
 

neweimear

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@mariovitali I don't understand or have the ability to try to comprehend all you have posted. But if a metabolic trap is found to be cause of our disease....will everyone need a different treatment, combination of supplements etc....what about those of us not living in the U.S who don't have access to doctors that can test for these traps....how are we supposed to access our unique therapy? Or is there a possibility that it could be one size fits all?
 

mariovitali

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@neweimear

First of all i do not believe that the Metabolic Trap will be applicable to everyone as i find it quite simplistic (=that a metabolic trap creates this mess). I am trying to have Researchers identify whether many ME/CFS Patients have Liver/Gallbladder issues or simply impaired function of the Enterohepatic system which sets the stage for ME/CFS after a liver stressor takes place (EBV, certain medications, even prolonged stress).

I actually emailed Dr Phair (who was a very helpful person by the way during the time we had some discussions through email) and explained to him the vicious cycle that i was experiencing when i had problems. I was lucky because i had good days and bad days. This was a great opportunity to write down my symptoms, what i was eating what supplements i was taking and then ask from a Computer algorithm to tell me what are the common characteristics of "Good" vs "Bad" Days.

Dr Phair is also interested to something referred by many ME/CFS Patients as "crash". For me the crash was having "tinnitus" to one of my ears (unilateral) for 2-5 seconds. So i could actually experience this vicious cycle that Dr Phair is referring to.

The personalised regimen aims in creating the necessary environment so that we break this vicious cycle. In order to do so we need a very precise regimen where food and supplements are given according to specific SNPs. It is very logical to assume that if a "one size fits all" regimen existed, we would know it by now. Another important element is complete abstinence from alcohol and certain P450 inhibitors such as Grapefruit (i bet my two cents that most of ME/CFS patients have very negative opinion/experience with Grapefruit). Also it is imperative to identify any "Liver Stressors" such as elevated Bile Acids, Hemochromatosis, NAFLD, elevated Copper levels, Porphyria and many many others. If these are not been taken care of there can be no amelioration of Symptoms (hence the simplicity of "Metabolic Trap". Will "Metabolic Trap" fix Hemochromatosis?)

Of course i am not trying to sell anything here. What i am trying is to convince as many people as possible that this Theory may be correct and to have it evaluated for its validity by Scientists.
 

neweimear

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@mariovitali thank you. But my question remains unanswered...how is a patient in scotland/U.K or anywhere else, a patient that is almost completely bedridden who crashes very easily going to find out what their unique regimen is? Who is going to test them? I know that in many countries gps run standard blood tests, that's it. We don't have access to the ME specialists in the U.S!!!
 

mariovitali

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@mariovitali thank you. But my question remains unanswered...how is a patient in scotland/U.K or anywhere else, a patient that is almost completely bedridden who crashes very easily going to find out what their unique regimen is? Who is going to test them? I know that in many countries gps run standard blood tests, that's it. We don't have access to the ME specialists in the U.S!!!
A software exists that reads raw data from 23andme / MyHeritage and identifies specific SNPs. This software shows if the patient has problems in specific pathways such as Bile Acid Metabolism, Cholesterol Metabolism, Phagocytosis, Inflammation and more.

However this personalised regimen must first be evaluated by Medical Researchers. As soon as it is approved then all we need really is having the raw DNA data of each patient so that these issues may be identified for each case.
 

perrier

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A software exists that reads raw data from 23andme / MyHeritage and identifies specific SNPs. This software shows if the patient has problems in specific pathways such as Bile Acid Metabolism, Cholesterol Metabolism, Phagocytosis, Inflammation and more.

However this personalised regimen must first be evaluated by Medical Researchers. As soon as it is approved then all we need really is having the raw DNA data of each patient so that these issues may be identified for each case.
Dear Mr. Vitali
I am most interested in your work. However, I just don't know where to start to help a very very severely ill family member, who is struggling to go on due to the extreme nature of the symptoms, which are unrelenting.
The 23and me was done. What do we now do with this? Who can help us with this?

Have you been able to sit down with the researchers and explain things further? Have you had any responses from the CFS researchers so far. What is Dr Phair saying?

We are in a desperate situation because of the severity, and I would say, increasing severity, of this illness. Any suggestions are welcome.
 

mariovitali

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@perrier

I understand your situation. I am doing anything possible to have this Research evaluated. Since 2015 i have sent numerous emails and spent so much time in trying to convince Researchers to evaluate this work and i will not stop until i get an answer from them.

Unfortunately it is up to them whether they will move forward or not.
 
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mariovitali

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@Janet Dafoe (Rose49) @JaimeS

Something of particular interest to the Theory of this Thread : Nutmeg may "stave off" Liver Disease.

It works -possibly- through PPARA Induction. The analytical techhniques i use have identified the importance of Peroxisome Proliferators quite some time ago (see "pparalpha" node and "peroxisomes") below :

https://forums.phoenixrising.me/index.php?threads/machine-learning-assisted-research-on-cfs.51283/

More specifically nutmeg (in rats) :

-Lowered Inflammatory markers
-Decreased Oxidative Stress
-Lowered Transaminase Levels.

Since i immediately can tell the difference on whether something works to me or not, i stopped my regimen so i can see the effectiveness of nutmeg. It works very-very well for me so it is an addition to my regimen. I use a heaped spoon of Nutmeg powder mixed in hot water, three times a day.

Disclaimer : The above does not imply that you should supplement with Nutmeg without a Doctor's Supervision / Consent.

Links :

https://www.scotsman.com/read-this/nutmeg-may-stave-off-liver-disease

and

https://www.ncbi.nlm.nih.gov/pubmed/29664296
 
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wastwater

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HSPA6 which is heat shock protein hsp 70
Interest to me,I have a probable 37 fold decrease
I revisited Dr Alan Lights talk on YouTube
The summary at the end is worth rewatching
12 percent having hspa6 problems
25 percent steroid, wonder if that's to do with vitamin D
28 percent markers for general autoimmunity

Mitochondria would be tied up disassembling these misfolded proteins

FOXO1 and liver is the match I find
 
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mariovitali

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Here is a short update :

I continue sending E-Mails to anyone i feel that may be of help in identifying the potential importance of Liver Status in ME/CFS patients.

I added "Lactate" to the Machine Learning Algorithms and as i expected it gets a very high ranking of importance.

A first question here of course is why Lactate is high. Needless to say that Liver is the primary route from which Lactate is excreted so we have yet one more potential signal that Liver function may be impaired to ME/CFS patients.

The second question has to do with the treatment itself. Will bringing Lactate levels down is a sufficient treatment in the long run (assuming that bringing Lactate levels down is the preferred course of action) ?


Here are some snapshots from different methods that i use : Notice how Lactate is selected as being very important. Of interest are the entries of 'Gut' and 'Norepinephrine' getting very high rankings. Throughout most of the runs Liver Disease remains the most selected Topic :

fs1.png


and also :

FS2.png
 

mariovitali

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@Hip @Murph

I think that this is quite interesting :


Pyruvate dehydrogenase complex and lactate dehydrogenase are targets for therapy of acute liver failure.

Abstract
BACKGROUND & AIMS:
Acute liver failure is a rapidly progressive deterioration of hepatic function resulting in high mortality and morbidity. Metabolic enzymes can translocate to the nucleus to regulate histone acetylation and gene expression.

METHODS:
Levels and activities of pyruvate dehydrogenase complex (PDHC) and lactate dehydrogenase (LDH) were evaluated in nuclear fractions of livers of mice exposed to various hepatotoxins including CD95-antibody, α-amanitin, and acetaminophen. Whole-genome gene expression profiling by RNA-seq was performed in livers of mice with acute liver failure and analyzed by gene ontology enrichment analysis. Cell viability was evaluated in cell lines knocked-down for PDHA1 or LDH-A and in cells incubated with the LDH inhibitor galloflavin after treatment with CD95-antibody. We evaluated whether the histone acetyltransferase inhibitor garcinol or galloflavin could reduce liver damage in mice with acute liver failure.

RESULTS:
Levels and activities of PDHC and LDH were increased in nuclear fractions of livers of mice with acute liver failure. The increase of nuclear PDHC and LDH was associated with increased concentrations of acetyl-CoA and lactate in nuclear fractions, and histone H3 hyper-acetylation. Gene expression in livers of mice with acute liver failure suggested that increased histone H3 acetylation induces the expression of genes related to damage response. Reduced histone acetylation by the histone acetyltransferase inhibitor garcinol decreased liver damage and improved survival in mice with acute liver failure. Knock-down of PDHC or LDH improved viability in cells exposed to a pro-apoptotic stimulus. Treatment with the LDH inhibitor galloflavin that was also found to inhibit PDHC, reduced hepatic necrosis, apoptosis, and expression of pro-inflammatory cytokines in mice with acute liver failure. Mice treated with galloflavin also showed a dose-response increase in survival.

CONCLUSION:
PDHC and LDH translocate to the nucleus, leading to increased nuclear concentrations of acetyl-CoA and lactate. This results in histone H3 hyper-acetylation and expression of damage response genes. Inhibition of PDHC and LDH reduces liver damage and improves survival in mice with acute liver failure. Thus, PDHC and LDH are targets for therapy of acute liver failure.
 

mariovitali

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Dear All,

I wanted to share with you the latest results as suggested by the algorithmic approach i've been using.

We have two new targets relevant to ME/CFS : PTPN11 and EGFR.

I believe that the most interesting of the two is PTPN11 because it affects Bile Acid metabolism and Gut Integrity.


You can read more here :


http://algogenomics.blogspot.com/2018/08/the-multiple-roles-of-ptpn11.html
 

xcell

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Hello @mariovitali
Can you look with your ML into immune system? There are low NK cells and other not working properly immune cells (Dr Klinghardt, Dr Klimas):
to low: CD56, CD57, IL-2, IL-13, Th-1, white blood cell count (<4500)
to high: Th-2 (IL-4), IL-10, IL-1, IL-6, IL-8 and TNF-alpha, TGF beta-1