Machine Learning-assisted Research on CFS

[mariovitali]

A new post where the algorithms used suggest Liver Disease and an interesting patent that uses Vitamin K for Mitochondrial Diseases (with mentions about pyruvate metabolism) :

cc : @JaimeS



http://algogenomics.blogspot.com/2017/05/results-from-classification-analysis.html

 

[mariovitali]

Just wanted to post a quick update.


I recently went to a mountain hike during which i had to walk up for about 5 hours in full gear. 2 years ago this hike would have been simply impossible for me to do!

As soon as i stopped walking and after about 20 minutes several well known symptoms started again. The next day i realised that i had a large bruise on my left arm. I am certain that i haven't bumped my arm anywhere.

This is a well known symptom, as discussed in OMF website :

Other symptoms some patients experience include muscle pain, sore throats, swollen lymph nodes, sound and light sensitivity, cold or heat sensitivity, headaches, easy bruising, and vertigo. In all, about 60 different symptoms can occur with the disease, and each patient’s symptom profile may be different

https://www.omf.ngo/what-is-mecfs/


Interestingly, this is also a -yet one more common- symptom over on the post-accutane group, apparently the user searched at Phoenix Rising !

http://www.acne.org/messageboard/to...from-accutane/?do=findComment&comment=3563139


This incident has reminded that despite me being symptom-free, this condition is by no means cured.

 

[mariovitali]

@Sushi Not sure if you are the right person for this, apparently the search function on PR is not working properly. I searched last week for "Fibroscan" and my post was the only hit.

I did this search again today and there are much older hits :


http://forums.phoenixrising.me/inde...-dr-charles-shepherd.28065/page-3#post-432935

I tried to look if user @tatt is still active but he/she isn't. @tatt discusses extensively about having a Fibroscan test which showed problems.

@Valentijn do you know what happened with this user? What is your take in having a Fibroscan for possible Liver disease? I am expecting more results from people who will have the test and will report back.

This user is spot on in my opinion :


http://forums.phoenixrising.me/inde...-dr-charles-shepherd.28065/page-3#post-446065

 

[Valentijn]

@Valentijn do you know what happened with this user? What is your take in having a Fibroscan for possible Liver disease? I am expecting more results and will report back.

My thought is that the liver isn't of particular relevance to ME/CFS, and it's probably exceedingly uncommon to have liver dysfunction while lab tests remain normal.

I'm also not sure why you're tagging me to ask who people are. In fact, I'd prefer you not tag me unless you're responding to something I've said. You know my views regarding your various theories, and I don't appreciate your repeated attempts to drag me into things.

 

[Sushi]

@Sushi Not sure if you are the right person for this, apparently the search function on PR is not working properly. I searched last week for "Fibroscan" and my post was the only hit.

You'll have better results using Google Site Search which is linked in the Search box.

 

[mariovitali]

@Valentijn

I've tagged you regarding this user because i saw you liked his/her posts and thought that you may had more conversations with him/her as you are one of the most active users here. I will not be tagging you ever again for the same purpose (asking you about users) so i apologise about this.

Regarding the Liver and particularly this phrase :

and it's probably exceedingly uncommon to have liver dysfunction while lab tests remain normal

This is not the case. It's not about this being my opinion but that is a fact.

Some few examples :

These data indicate that more than half of nonalcoholic liver disease patients with normal ALT levels have a potentially progressive liver disease, they said.

http://www.medpagetoday.com/gastroenterology/generalhepatology/10846

The economic burden of end stage liver disease is set to increase due to the rising prevalence of cirrhosis secondary to alcohol, viral hepatitis and fatty liver disease. Screening for liver disease has been advocated, as most cases of cirrhosis are preventable with early interventions. Liver function tests (LFTs) are routinely used as a first line investigation to screen for liver diseases but can be normal despite significant underlying liver fibrosis, hepatitis, steatohepatitis or even cirrhosis. Their relationships are far from linear and with little predictive value in some cases. Newer non-invasive modalities are emerging but currently their roles are largely experimental. This review will discuss the role of serum biomarkers and imaging techniques as new modalities to screen for liver disease.

https://www.ncbi.nlm.nih.gov/pubmed/19355898

So i do not see how "probably exceedingly uncommon" fits here. Please provide References for this statement.


Our well-known differences have nothing to do with the possibility of you having liver disease and not knowing about it, especially after reading about the problems you had with Metformin.

@JaimeS

I received the Liver Elastography results of a 31 year old female having CFS symptoms for more than 15 years. The doctor dismissed her saying that she has "mild fibrosis" and that she should forget about it. I asked her to send me over her results which you may see below.

The kPa of 6.0 does not seem to suggest a significant Liver fibrosis problem but the doctor decided to hand out a test with IQR 123.3 when in fact this should have been <30%. This test should be performed again.

This link is from the same SAMSUNG device that was used for the test (mentions IQR < 30%).

http://im2.medias.no/wp-content/uploads/2017/03/49_CS-S-Shearwave_150528.pdf

 

[hinterland]

I was also taking accutane at the time of illness onset. I'm still ill 18 years later.

I'm another who took Roaccutane (UK branding) in the year before falling ill... I expect it could have been a causal factor, but not necessarily the only one, or main one. However, it is certainly an extremely nasty pharmaceutical. Probably everyone who takes Accutane has also, previously, been on long-term broad spectrum antibiotics. It would not be surprising if this combination caused leaky gut!...

 

[mariovitali]

Here is the new post on ER Stress, the Unfolded Protein response, Medications and Viruses.

http://algogenomics.blogspot.com/2017/08/dili-viruses-and-er-stress.html

Please make sure that you read the following paper :

http://www.journal-of-hepatology.eu/article/S0168-8278(15)00299-8/pdf

Needless to say, i liked the following part :

"On the other hand, introducing advanced bioinformatics methodologies, machine learning [112], topic modelling [113], network analysis [114] and deep learning techniques [115] to clinical analysis will unmask hidden patterns/associations"

Looking forward for your comments.

 

[mariovitali]

I wanted to add the following snapshot because i feel that it shows a lot of useful information.


Note the various topics that we have seen many times before : Mitochondria, ER Stress, Innate immune response, Inflammation, Mitochondrial Damage, Bile Acids :

Unfortunately there were no mentions on UPR and ER Stress at the Symposium. Note also that viruses generate ER Stress.

In this review, we present a comprehensive summary of recent research in this field, which revealed that about 36 viruses trigger ER stress and differentially activate ER stress-related signaling pathways. We also highlight the strategies evolved by viruses to modulate ER stress-related signaling networks including immune responses in order to ensure their survival and pathogenesis.

Much has been learned about the functions of the UPR beyond being simply a means to manage ER stress. The UPR has also now been recognized for its role in immune cell differentiation and function, and in regulating immune and inflammatory responses, including those associated with infections, tumours and autoimmune responses

Hopefully they will consider looking at UPR/ER Stress soon.

 

[Janice Hargreaves]

Thank you for posting this information. Very interesting but very complex so it's taking me a while to get my head around at least the bits I can vaguely understand. I do love a challenge.

 

[mariovitali]

@Janice Hargreaves

Understood, please allow me to explain what i think is going on.

What we have happening here is an example of a perfect storm :

In the hypothesis, CFS Patients (and other people having Post-Accutane Syndrome, Post-Finasteride Syndrome, Gulf war Syndrome, etc) fall into a vicious cycle of Oxidative Stress. Basically the cycle begins with any kind of Liver Stressor :

-Medications (some)
-Prolonged Psychological Stress
-Viruses

The main problem is the fact that susceptible individuals have impaired Autophagy/Phagocytosis functioning (because of TAM Receptor / GAS6 / VDBP / LXR mutations ) AND Impaired ER Stress / Unfolded Protein response Functioning.

This perfect storm generates :

a) Inflammation
b) Autoimmunity
c) Oxidative Stress

These three elements further damage (?) hepatocytyes and as a consequence you have an even less functioning autophagy/er stress system. Then the vicious cycle begins.


@JaimeS @Janet Dafoe (Rose49)

Here is one more connection of the TAM Receptors with something we've seen in the Symposium : Langerin (and as a consequence Langerhans cells):

https://www.ncbi.nlm.nih.gov/pubmed/23071254

Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasis.

Transforming growth factor-β1 (TGF-β1) is a fundamental regulator of immune cell development and function. In this study, we investigated the effects of TGF-β1 on the differentiation of human Langerhans cells (LCs) and identified Axl as a key TGF-β1 effector. Axl belongs to the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase family, whose members function as inhibitors of innate inflammatory responses in dendritic cells and are essential to the prevention of lupus-like autoimmunity. We found that Axl expression is induced by TGF-β1 during LC differentiation and that LC precursors acquire Axl early during differentiation. We also describe prominent steady-state expression as well as inflammation-induced activation of Axl in human epidermal keratinocytes and LCs. TGF-β1-induced Axl enhances apoptotic cell (AC) uptake and blocks proinflammatory cytokine production. The antiinflammatory role of Axl in the skin is reflected in a marked impairment of the LC network preceding spontaneous skin inflammation in mutant mice that lack all three TAM receptors. Our findings highlight the importance of constitutive Axl expression to tolerogenic barrier immunity in the epidermis and define a mechanism by which TGF-β1 enables silent homeostatic clearing of ACs to maintain long-term self-tolerance.

EDIT : I would like to make a confession : I had no idea about the importance of LXR (Liver X Receptor) to all of this. If i knew i wouldn't have had it exposed in the Network Diagram. To my amazement, all along the Network Analysis graph was showing me the way (...!)

 

[mariovitali]

March 11, 2014

http://phoenixrising.me/archives/24058

Oxidative Stress

“Oxidative stress is an emerging focus of research, in view of recent findings that it contributes to the pathology and clinical symptoms of CFS.”

As has been well-established, oxidative stress for a short duration can provide potential health benefits. However, when unregulated, such stress causes distinct pathological damage. The paper goes further in this discussion and also reveals that oxidative damage may be a major contributing factor for the muscular symptoms seen in ME/CFS.

ROS Accumulation

“Recently, Kennedy et al. (2005) published results obtained from a large number of CFS patients divided into two groups those previously identified with cardiovascular risk factors and those that were not.

Both groups displayed significantly increased levels of isoprostanes and oxidized low-density lipoproteins, indicative of lipid peroxidation induced by ROS accumulation"

Actin and Myosin

The process that takes place is the binding of the the aforementioned myosin heads to specific binding sites on the actin filaments. The head is then unbound from the actin binding site and binds to the next binding site. With numerous myosin heads doing this simultaneously, the result is that the myosin in fact drags the actin filaments on the left and right closer together, resulting in the contracted sarcomere as portrayed in the diagram above.

 

[adreno]

The anti-fibrotic effect of chromium was accompanied by reductions in alpha-smooth muscle actin-positive matrix-producing cells and Smad 2/3 activity critical to the fibrogenic potential of transforming growth factor beta 1 (TGF-beta1). In addition, chromium effectively attenuated BDL-induced hepatic oxidative stress. The data indicate that chromium attenuates BDL-induced cholestatic liver injury, bile duct proliferation, and fibrosis. The hepatoprotective effect of chromium is associated with antioxidative potential.

https://www.researchgate.net/public..._damage_in_a_rat_model_of_chronic_cholestasis

 

[adreno]

@mariovitali

What do you think about n-acetylcysteine? It should be helpful in terms of tgf-beta and liver fibrosis.

 

[mariovitali]

@mariovitali

What do you think about n-acetylcysteine? It should be helpful in terms of tgf-beta and liver fibrosis.

I think it is a double-edge sword if your body does not handle well Cysteine. When i tried it i was getting short breath and getting tired very easily. Same for my mother when she tried it.

The algorithms for some reason output Ferulic Acid and i wasnt paying attention as i didnt want to change anything at my regimen. I looked it up however along with the latest findings for autophagy and found this :

The enhancement of autophagic flux by ferulic acid was almost equivalent to that of rapamycin. Furthermore, ferulic acid significantly enhanced autophagic degradation of 14C-leucine-labeled long-lived proteins of cultured mouse hepatocytes under nutrient-rich conditions, but not nutrient-deprived conditions. These results indicate that ferulic acid is almost the equivalent of rapamycin in the ability to inhibit mTor (TORC1), which makes it a potent activator of basal autophagy.
Ferulic Acid Induces Mammalian Target of Rapamycin Inactivation in Cultured Mammalian Cells.

https://www.researchgate.net/public...ycin_Inactivation_in_Cultured_Mammalian_Cells

I will soon post about LXR, i will CC you @adreno . I just had my first Ferulic acid tablet, i will see how it goes and report back. I am also looking forward to news from anyone that had a Fibroscan, i had no replies yet.

Based on the latest findings : It appears that we need support on Autophagy *and* ER Stress / UPR pathway.

Also i believe that this is good to know :

Mechanistic studies have unraveled an intricate system of signal transduction pathways and upstream regulators that control autophagy, which are reviewed in great detail else- where (for example79, 80). (Macro-)Autophagy is mainly controlled by nutrient availability81. Amino acids in particular suppress autophagy82, with more pronounced effects of leucine, glutamine, tyrosine, phenylalanine, proline, methionine, histidine and tryptophan81. On the other hand, nutrient deprivation mediated through amino acid deprivation83, serum deprivation84, 85, and caloric restriction86-89 are potent stimulators of autophagy.

* Autophagy in Health and Disease by Gotlieb

Hey Jeff if you are reading this... for reminding me about Rapamycin : Thanks Man

 

[adreno]

Interesting, I had never heard of ferulic acid before. If it is as effective as rapamycin, while being readily available OTC, and without the nasty side effects, it would be something of a boon. Is this the one you are taking:

https://iherb.com/pr/Source-Naturals-Trans-Ferulic-Acid-250-mg-60-Tablets/42064

 

[Gondwanaland]

If it is as effective as rapamycin, while being readily available OTC, and without the nasty side effects, it would be something of a boon.

Carnosine May Mimic Rapamycin
… and provide some of the same benefits of the mTOR inhibitor

However many people feel nothing from Carnosine and Carcinine seems to be much more effective.

 

[mariovitali]

@adreno, @Gondwanaland

Yep, that's the one. However what i am trying to explain here and in my posts at Algogenomics is that there are many pathways that need support.

I believe that this is not a condition with a SPOF but there are many -unfortunate to say the least- problems that end up to a very problematic situation. I think that Network Analysis has given us most of the pieces of the puzzle (will post more very soon on this).

 

[mariovitali]

Two days ago i found this entry in Phoenix Rising, which i had no idea it existed :

Date : MARCH 4, 2012

A Layman’s Guide to Chapter Six of “Chronic Fatigue Syndrome A Biological Approach” (Edited by Patrick Englebienne Ph.D., Kenny DeMeirleir M.D, Ph.D., CRC Press. Washington D.C. 2002)

The text has several entries that are known to those of you who follow this Thread :


ER Stress and UPR :

Recent evidence indicates that stress in the endoplasmic reticulum (ER) can also induce apoptosis. ER stress may be induced by amyloids (abnormal aggregations of proteins) and the unfolded protein response (UPR). (What an interesting finding given the recent Baraniuk paper suggesting that an amyloidic state may exist in the brains of CFS patients).

G-Actins Fragmentation

This is precisely what is seen in CFS. Caspase 9 activity exhibited a directly opposite pattern to that evidenced by calpains. This suggests that calpains are the most immediate source of increased caspase activity in.CFS. So far tests indicate that calpain can fragment RNase L, G-actin, and may be responsible for STAT 1, p53 and RLI fragmentation (!).

Phagocytosis, T-Cell Activation

This suggests that actin, along with RNase L and the other proteins, is being fragmented in the cells of CFS patients. Given actins immune activities the authors believe that actin fragmentation ‘undoubtedly’ further contributes to the immune problems seen in CFS. G-actin fragmentation could, by taking away the supply of usable actin, negatively impact membrane integrity, phagocytosis, cell adhesion and T-cell activation.

However no mention about Myosin.


Does anyone know what happened with this research?

 

[mariovitali]

@adreno

After trying Ferulic acid i can tell that too much is not good for me. One pill or even better half pill daily is fine. The good thing is that i immediately can tell if something works. What does appear to help is spermidine and putrescine and there may be a reason for this. I recently added Peas which -as it seems- they have good levels of Putrescine and Spermidine

I am also expecting a new Supplement which acts as an FXR Agonist. I will report back.


I added some new concepts as input to the Machine Learning algorithms and here is what we get :

We can see several topics that have been discussed :

-G-Actin
-Myosin
-Immune Response
-Peroxisome
-Mitochondria
-Liver Disease
-Fatty acids
-Acetylcholine
- (Interestingly) suramin
- Muscarinic (Receptors)

I get some emails from people asking why the output of the algorithms changes all the time. Actually, this is what should be happening and the easiest way i can describe it is that we would like several people to share their POV regarding the problem we are trying to solve.

It was interesting to see that Suramin has been selected and also Muscarinic (receptors) .