Theoretical Immunology

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notasperfectasyou
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Therapeutic Advances and Future Prospects in Progressive MS

Post by notasperfectasyou »

Here is an review paper I found that may be of interest:

Shirani, Afsaneh et al. 2016 Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis. Click here for Full Text

This paper discusses:

Adrenocorticotropic Hormone (ACTH)
Biotin (Vitamin B-7)
Amiloride, Fluxetine and Riluzole
LINGO-1
Domperidone
Erythropoietin
Hematopoetic Stem Cell Therapy (HSCT)
Ibudilast
Idebenone
Lipoic Acid
Lithium
Masitinib
MIS416
Natalizumab
NeuroVax
Phenytoin and Oxcarbazpine
Rituximab and Ocrelizumab
Simvastatin
Siponimod
Sunphenon Epigallocatechin-3-Gallate
Tcelna
It would be really nice to be able to put links in here

If I have included a bad link, google the word "Scholar", click link for "Google Scholar". Search for the name of the paper and author in Google Scholar.
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Leonard
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Re: A new concept and treatment options for MS

Post by Leonard »

Hi Scott,

Thank you for your reaction and for the reference to the Groningen study. http://www.mstranslate.com.au/ms-epstei ... te-part-2/

Disease patterns show activation of all sorts of cellular mechanisms, e.g. the alfa B-crystalline anti-oxidant is one, enzymatic arginine modifications like methylation and citrullination is another sort.

Citrullination and methylation control the expression of genes. Citrullination and methylation appear antagonists and mutually exclusive. Methylation is associated with silencing foreign segments; citrullination seems more related to turning the cell in a crisis mode with chemo and cytokines release. Where the immune system starts to attack citrullinated proteins leading to autoimmune diseases such as MS and Rheuma Arthritis (RA).

In fact, pathological protein citrullination has been associated with a range of diseases including MS, RA, Alzheimers, and psoriasis. Where tests for the presence of anti-citrullinateds protein anti-bodies are highly specific 88-96% for RA.

The introduction of these papers provide a very useful background reading on epigenetic regulation.

Protein Arginine Methylation and Citrullination in Epigenetic Regulation, 2016
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802296/

Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation, 2015
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463550/

Chemical and biological methods to detect post-translational modifications of arginine, 2014
https://www.ncbi.nlm.nih.gov/pubmed/23576281

Interestingly, the citrulline arginine is related to the uric acid cycle and the biochemical reaction for ATP production. Where it would seem that impairment is - besides the superoxide/NO/peroxonitrite biochemistry - a second mechanism that may result in distorted ATP production and ion pump failure.

The cellular state and chromatin function is very complex with very many interactions. Eukaryotic cells co-evolved with the gut micro biota for over 1.5 Billion years. While cells may be for as much as half of foreign origin, most pathogenicity is lost, but some coding capacity may still remain. Normally, this is silenced by epigenetic regulation with a central role for the gut micro biome. But in the case of autoimmune diseases, there is dysregulation with a distorted micro biome. To note the gut problems often seen in MS patients.
https://multiplesclerosisnewstoday.com/ ... -sclerosis
http://www.cnbc.com/2016/12/01/parkinso ... teria.html

Epigenetic regulation of gene expression is essential to eukaryotic life, and its dysregulation is involved in numerous human diseases. Currently, there are four types of enzymatic arginine modifications. The best characterized modifications are methylation and citrullination. Lots of work is done on epigenetics and the micro biome, the outcome so far unclear.

The Groningen study hypotised a changed T-cell target being displayed by B- cells [is this the reason they are not removed?] and autoreactivity T-cells that attack myeline. This one point of view.

But many people have high concentration of EBV B-cells, and they are not sick! Only some get MS, some get RA, some get lupus or another autoimmune disease. So, it is not only the immune cells. There must be something more to it and it must be tissue specific (e.g. CNS or joints or ..).

To get sick one needs the endothelial expression of specific tissue to get the cross-reaction with the immune cells. That is what gives MS, or RA, or … I think that citrullination is here one of the mechanisms to signal cellular crisis and activate the cytoskeleton.

The articles below note that citrullination results in novel epitopes. But the cascade of events may not be as straightforward as that. I think that due to gut dysfunction there is first of all HERV expression. There may be a contribution by older viral content or SNPs e.g. in or near HERV loci in the X-chromosome which would immediately explain the gender bias in autoimmunity. And then there may be more recent viral content like 10-40 million year old EBV that also shows up.
https://www.biomol.de/dateien/Cytoskele ... nation.pdf
http://www.cytoskeleton.com/blog/citrul ... -detailed/

While microbiome to cell signaling may be a hugely complex cascade, citrullination may be just one signalling mechanism inside the cell governing the activity of a cell’s intra cellular events that activates the cytoskeleton to present epitopes. And this is including EBV epitopes if there has been prior EBV infection of cells. To note that the viral tolerance is breached at this point!

And it is precisely the EBV epitopes that then cause the cross-reaction of EBV B cells. Where for MS patients, the EBV anchored itself in the CNS after a long cascade that started with ccsvi.

The academic world and researchers in general tend to see most things in isolation. They forget about the viral dimension, about the almost ubiquitous nature of herpes virinae and EBV in men, about the HERV expression, about the all important role of the gut in epigenetic regulation and immunity. And they don’t see or they don’t want to see the bigger picture. It occurs to me that much academic research is motivated by the money, to find “access points” for medication, to open up new revenue streams, and not necessarily to unravel and understand the broader picture of specific disease patterns.
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Re: Therapeutic Advances and Future Prospects in Progressive

Post by Leonard »

notasperfectasyou wrote:Here is an review paper I found that may be of interest:

Shirani, Afsaneh et al. 2016 Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis. Click here for Full Text
Hi,

Thanks for reference to the article. Unlike what is in its title, these are not advances.

As said in the article several times, they haven't understood what is MS, in fact they ain't got a clue.
They just try the crappy medication and see if it works, perhaps how it modulates the disease a bit.

Before considering therapeutic options, they should first learn what is MS, and understand the mechanisms behind the disease.
Perhaps they find inspiration in the assessment below and the deliberations on the previous page 53 of this thread.


When Zamboni found a connection between vascular narrowings in the neck (CCSVI) and MS, there was still a long way to go. CCSVI is on top of a long chain.

Hypoperfusion weakens the immunity of the nasopharynx. Herpes virinae go from latent to lithic cycle and spread through the meninges. The CNS has a meningual layer; possibly the Virchow Robin space contributes to the viral spread. Where it is of interest to note that our immune system has never been able to get rid off the herpes virus completely, at best to keep it down.

VZV, a viral strain of the herpes, causes microbleeds and breaches the Blood Brain Barrier (BBB). The EBV (another herpes strain) can anchor and infects brain cells, particularly fast dividing cells such as OPC’s. As there is viral tolerance (cells are still seen as “self” and the immune system stays quiet), people remain healthy but are predisposed.

Herpes virinae also affect the immune system. VZV infects T-cells for its own benefit, slowing down T-cell response to VZV leading to inflammatory MS when the vitamin D receptor gets blocked, the ATP fuel runs down and the ion pump slows down. After a bit of time the immune system reacts with force. This is RR-MS.

EBV also infects B-cells. The T-cell target protein on the B-cell changes and the normal process of B-cell depletion stops. A high concentration of immortalized B-cells develops. Still, many people have a high concentration but they are healthy.

The progression comes when endothelial cells express EBV epitopes. And a cross-reaction starts with the immune cells. That happens when the gut micro biota gets distorted resulting in a dysregulation of the epigenetics. DNA segments that are normally silenced though methylation are replaced by citrullinated arginine proteins. Cells change phenotype from “self” to “foreign” and turn into a crisis mode.

EBV working on Peyer’s Patches adds to the problem. This results in an IgA deficiency and leaky gut and a distorted gut function. The immunity of the meninges thoughout the whole body will be weakened because of an IgA deficiency giving more room to the viral spread into the CNS. Toxins (60kDa) and micro-organisms leak into the circulation and provide material for genetic rearrangement of transgenic cells (e.g. Epsilon toxin in transgenic OPC’s leading to white matter lesions).

EBV B-cells shed superoxide. This reacts with the NO in cell membranes and forms peroxynitrite, the worst oxidant. Citrullination impairs uric acid and the Krebs cycle. Mitochondria successively fail, the ATP production runs down, the ion pump lacks the energy to pump and one has progressive MS. Where high vitamin D during the main phases of cellular growth (fetus, adolescence) will result in more mitochondria per cell and thus more resistance.


My MS has been progressing for the last 15 years. Several years ago, I could still walk 3-4 miles. And then on holidays, when the legs were completely empty, I would rest a bit and eat some grapes that I found in an adjacent wineyard. Literally five minutes later, I would walk again as a well-oiled machine.

Progressive MS has nothing to do with demyelination, the time constants simply don’t match. Demyelination is a slow process that takes years, but recovery happens in a matter of minutes. MS progression has everything to do with a failure to charge the ion pump because the pump lacks the ATP fuel. Where a short pause and fast glucose will replenish the cell with new energy.

The undue emphasis of MS as a demyelinating disease is one of the biggest catastrophies.
Last edited by Leonard on Tue Jan 24, 2017 1:27 am, edited 6 times in total.
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Re: A new concept and treatment options for MS

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Hi Leonard,

The something else might be ADMA. If there is a mechanism that leads to excessive production of that rather than the symmetrical form then you will be inhibiting all isoforms of nitric oxide synthase. https://www.semanticscholar.org/paper/O ... 5d94d9dd20

The end result will be a preponderance of iNOS over nNOS and, importantly, eNOS. The Superoxide from EBV B-cells can react with the nitric oxide formed by iNOS leading to excessive peroxynitrite production. It's possible that the PH of the cell is affected by this making it more acidic. Vasodilation will be impaired. This will lead to a disaster for the mitochondria and ATP production.
An alternative,overlapping, path would be ischemic insult. This is common in heart disease but can happen anywhere that oxygenated blood flow is reduced. If it occurs at the periformis you will be struggling to walk.
When the neurotransmitter, aceytlcholine, triggers sodium to flood into the cell to drive calcium to be released from the sacoplasmic reticulum that calcium passes through the ryanodine receptor (an ion channel) to the muscle protein strands so they bind for contraction. The ATP is needed to break those bonds. If the ATP is unable to meet that energy demand then the bonds remain and your muscle is spastic. When ischemia occurs the pool of ATP breaks down into purines which are slow to reform into ATP and start washing out of the cell. That shows up in a measure of the uric acid level. A good book on this is ATP and the heart by Prof Joanne Ingwall.
I agree with your sentiment that MS research has been hijacked too much focus on demylination. There's a lot more going on.

Regards,
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Re: A new concept and treatment options for MS

Post by Leonard »

Hi Scott,

You are right, muscular spasticity is a big issue in progressive MS. And not only of the muscles that we need for walking, but also of other muscles such as the muscles that control our bladder. Caused by the neurological damage and mitochondrial failure, the problem with stretching is clearly an issue. As you rightly say, the lack of ATP and the failure to break the bonds may be a key component of the spasticity, this besides an insufficient inhibition of the reflex via the tendon strain sensors into a muscle due to neurological damage in the spinal cord.
https://en.wikipedia.org/wiki/Spasticity

As the disease progresses, I am sure it is no longer a localized problem in the CNS or spinal column but becomes a systemic problem that gets a substantial role and may affect the whole body. Elevated oxidative stress and anti-oxidant depletion will occur whenever there is substantial oxidative stress in a substantial volume of tissue where the anti-oxidant depletion will cause tissues to be more susceptible to oxidant damage.

In his book Explaining Unexplained Illnesses, Martin Pall suggests how the cycle biochemistry develops and spreads as well as of a number of mechanisms that may contribute including iNOS and low levels of ATP in the muscles. But while Pall in his book misses out on the point of super-oxygen generation by EBV B-cells, I am sure the high concentration of EBV B-cells and the rather ubiquitous nature of EBV in men are close to the etiology of the oxidative stress mechanism .

The wiki page below expands on the cell damage reactive oxygen and nitrogen species cause on cells. All of these reactions affect protein structure and function and thus have the potential to cause changes in the catalytic activity of enzymes, altered cytoskeleton organization and intra-cell signal transduction.
https://en.wikipedia.org/wiki/Reactive_oxygen_species

The reaction and signaling cascades of the cell to stressors is complex and subject to a lot of research. As the article https://www.semanticscholar.org/paper/O ... 5d94d9dd20 in your above posting suggest, arginine modifications by histone modifying enzymes affecting arginine residues is central. ADMA is part of it, as is a changed balance ADMA/SDMA.

If you take the articles on the chemical biology of protein arginine modifications in epigenetic regulation in my above posting of 4 Jan 7:12am, we learn about histone arginine modifying enzymes as a hallmark of epigenetic regulation. I think enzymatic changes such as those responsible for ADMA/SDMA are incited by the gut micro biome and imply a loss of epigenetic control of gene expression. Here, asymmetric dimethylation of histones (ADMA) has been associated with transcriptional activation. On influences of diet and the gut microbiome on epigenetic modulation, see e.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609101/

As you say, the steps that follow will be a preponderance of iNOS over eNOS and nNOS which with the superoxide leads to the excessive production of ROS and oxidative stress, affected cell PH and vasolidation, and ultimately mitochondrial failure, lower ATP and muscle spasm. And with the slow diffusion of the process as described in Martin Pall’s book, there is the potential to propagate strengthening the cycle mechanism.

I was diagnosed with MS 12 years ago, it has been progressing since. My brother was diagnosed with a mitochondrial energy failure some 7 years ago, but it is not MS. As time goes by, we are seen to converge more and more to the same ‘end-state’. Apart from perhaps some early lesions, I think progressive MS in its final stage is not very different from mitochondrial energy failure. From the family history, that may be expected as we will both have a high EBV load and thus oxidative stress. What's more, a very extensive analysis of my blood with over 100 parameters tested revealed a perfectly normal situation except two things: herpes immune complexes and muscle titres.

In the papers on the epigenetic regulation, I find some further links to the enzymatic modification of arginine, namely the link to citrullination (arginine deimination). As said, NETosis which is necessary for citrullination of the cell is dependent on both ROS and on PAD4/2. Where it is interesting to note that four SNPs in PAD4 have been associated with an increased risk of developing RA. What’s more, it is said the altered histone citrullination seen in RA, MS, lupus does not only cause cellular expression and cytokine behaviour but also a citrullination of the myelin basic protein ultimately leading to demyelination. Of course, the latter with prior anchoring of EBV in OPCs (permissible cells that divide fast).
[post-script 15May17: Molecules affecting myelin stability: A novel hypothesis regarding the pathogenesis of multiple sclerosis
on http://www.thisisms.com/forum/general-d ... ic900.html
https://www.ncbi.nlm.nih.gov/pubmed/157 ... t=Abstract ]

So from this analysis, the link between dysregulated PAD4 activity (SNPs) with a resulting modification in arginine residues (from SDMA to ADMA and citrullination, gut micro biota will be involved) and disease onset is extremely strong while it would seem that demyelination is likely a terminal point in a long cascade.

I would welcome any views and or comments.

Regards,
Last edited by Leonard on Mon May 15, 2017 12:03 am, edited 3 times in total.
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Re: A new concept and treatment options for MS

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The immunity of our cells is called the innate immunity. It is the first line of defense that protects our cells from viral invasion. This cellular defense mechanism should protect the cells against herpes viruses such as VZV and EBV.

But in MS patients, the cell defense mechanism is not fit and therefore cells are more susceptible and run higher risk of infection. Where in healthy persons the cellular interferon mechanism is promoted against the virus, it is believed that in MS patients the intra-cellular signaling after viral infection is distorted, blocking interferon induction.

If interferon induction fails, viruses escape from an appropriate viral response, there is increased susceptibility to infection e.g. by double-stranded RNA (dsRNA) herpes virinae.

I believe the viral escape is the very mechanism that underlies RR-MS where the mitochondrial antiviral signaling protein (MAVS) is degraded. As a direct consequence, mitochondrial working may be impaired, ATP production runs down, the ion pump lacks the energy to pump, and motor functions fail.

There is assumed an association of MAVS single nucleotide polymorphisms (SNPs) with infectious diseases and indeed with RR-MS. This article is of great tutorial value and a must-read for anyone reading here. http://journals.plos.org/plosone/articl ... ne.0151173

When I was 14 years old, I lost control of my left hand for weeks. Now they would probably say this was a Clinically Isolated Syndrome (CIS). What really happened is that in a period of immune deficiency, the herpes virus VZV distorted mitochondrial working.

My gut was probably O.K. at the time, gut problems only started in my early 40’s. Therefore, it is likely to assume that the HERV was not expressed at 14 and that the SNP related MAVS failure is a distinct mechanism from the HERV expression. Of course, when the HERV comes to expression later on in life, which then induces the progressive phase, it can not be excluded that certain SNPs in or near HERV loci are no longer silenced and therefore that cellular anti-viral signaling gets further distorted, introducing a new or additional viral susceptibility and risk.

As regards therapeutic options, I see a cure for MS should be some sort of amalgamation of the following main lines:

1. anti-viral: (val)acyclovir; interferon; Vit D; MAVS SNPs tells risk, susceptibility and severity
2. silence HERV: metformin; micro biome supplementation; green diet; Low Molecular Weight (LMW) substances such as butyrate are influences
3. depletion of EBV B-cells: cyclophposphamide; mabs such as Rituximab; rATG; above 60 years of age B cell production stops; with the note that EBV-related growth of B cells raises immunization against the HERV protein and might inhibit EBV lymphomagenesis [lower cancer risk seen in MS]
4. anti-oxidant: diet to supply anti-oxidants (phytonutritients induce antioxidants); measures anti-spasticity and anti-oxidant depletion.

The need arises to rewrite my thesis to take account of the learnings of the last several pages. If there are professionals reading here who would like to help, please send me a pm.
Last edited by Leonard on Fri Mar 03, 2017 8:06 am, edited 3 times in total.
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Re: A new concept and treatment options for MS

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Hi Leonard,

Read ATP and the Heart by Prof Joanne Ingwall. She is looking at the technical aspects of ATPs role in energy production for heart cells but the rules will be the same in other cells as well.

Whilst I agree with the validity of your therapeutic options, I found a different way around points 3 and 4.

Valacyclovir, in my case, works very effectively to control EBV B-cell influence but it doesn't work on other pathogens such as mycoplasmas etc. So they still need to be dealt with.
The thing that I feel may have triggered my 2014 attack was too much N-aceytl-glucosomine which I was trying as a supplement. 50% of a peptidoglycan (bacterial mesh-like cell wall) is made of NAG and there is a role in inflammation (http://www.jbc.org/content/280/21/20177.full). These underlying infections can produce inflammatory responses as a result. I remember you once mentioned that this sort of response could be exacerbated by cells with prior EBV priming. So they still need to be looked for and cleared up.
The antioxidant idea is very important but a lot of oxidants start in the mitochondria so we get back to how competently mitochondria are working. To make ATP we need fatty acids crossing the mitochondrial membrane as well as a viable electron transport chain to pass the electrons down the chain to undertake oxidative phosphorylation . To help me drive that I take 1000 mg twice daily of acetyl-l-carnitine to create the shuttle for the fatty acids across the membrane and 750mg of CoQ10 to populate the electron transport chain. I got this idea from Stephen Sinatra's book, The Sinatra solution: Metabolic Cardiology. It really does help as long as the Q10 you use is a viable product.
If spasticity is an issue then I find Dantrium is the most effective option as it blocks calcium from leaving the cell to form rigor bonds in muscle. It is almost terrifyingly effective as it exposes how weak you have become and the answer is to rebuild strength by eccentric muscle movement which is what you get in Pilates and Yoga.
What you have discussed above looks right to me but it won't undo muscle tightness so that requires intervention for a specific purpose.
Regards,
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Re: A new concept and treatment options for MS

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Hi Scott, all,

As Joanne Ingwall says: ATP is the fundamental currency for movement: contraction, ion movement and synthesis. The requirement for ATP is absolute; regulation and integration of a myriad of metabolic pathways to supply the ATP is crucial. In disease, there is a molecular reprogramming where fuels available for ATP synthesis change. https://www.amazon.com/ATP-Heart-Basic- ... 1402070934

The ATP biochemistry is the central theme in both inflammatory and progressive MS. But although SNPs and HERV segments in the epigenetic make-up of our cells play a major role in the mitochondrial failure and the impairment of ATP production, the mechanisms underlying the failure are a bit different. A synopsis on the problem could then flow a bit as follows:

[Title: MS Etiology and Pathogenesis; Arresting Decline, Boosting Recovery

Preface: my own story as an MS patient in crisis; diagnosis IBS, diagnosis MS, diagnosis ccsvi/family lived for generations in the shadow of the heavy metal industry, EBV trail in my family NPC/coronary artery aneurism/mitochondrial energy failure/Hodgkin, MRI results/NMES response spasticity; extensive blood analysis shows only two values out of range: herpes immune complexes, smooth muscle titres; and how it all fits together]

0. Intro, vit D (= cholesterol under the skin + sun exposure) and number of mitochondria per cell [lifestyle relation: low fat diet - low cholesterol, indoor life- low sun exposure, washing vit D under the skin away, migration - darker skin types at more northern lattitudes], identical twins that get separated before adolescence, double peak in graph age of onset two mechanisms, gender bias inflammatory disease, MS patients have an overall reduced cancer risk, MS in primates, low fat [Swank] butyrate and other LMW substances, oxygen tank, air pressure, temperature effects, ccsvi, walk-stop-walk ATP-ion pump, eye nerve degradation no myelin, mitochondrial disorder and (cellular) atrophy, atrophy and acyclovir LDL and Simvastatin [The Lancet March 2014], cortisol cellular feeding metabolic processes and pregnancy http://www.thisisms.com/forum/general-d ... ml#p247214 , fish consumption and anti-sense RNA,

1. double-stranded DNA herpes virus and immunity, SNPs and double stranded DNA viral recognition, immune sysem never got rid off herpes completely, herpes even in fish, EBV more recent, herpes surpressed under secondary immunity but bad diet/lifestyle weakens immunity
2. nasopharynx, ccsvi, hypoperfusion, low immunity, CNS meningal layer, viral spread, viral tolerance, microbleeds breach BBB, EBV spread
3. VZV T-cells immune evasion, immune deficiency, MAVS deficiency, mitochondrial failure, ATP depletion, acute relapse, SNPs in X-chromosome and gender bias
4. methylation, citrullination, myeline basic protein, death of the brain cells that produce myelin, triggering a subsequent immune system mop-up operation to clean up the cells and the myelin, demyelination https://www.sciencedaily.com/releases/2 ... 075914.htm

5a. interaction between various immune T/B cells including regulatory cells, EBV and other herpes virinae and the fat metabolism; EBV B cells not cleaned up; immortalised EBV B cells; transition from the inflammatory to the progressive phase
5b. EBV B-cells, interaction with Peyer's Patches, IgA Deficiency; leaky gut; LMW substances; HERV expression; autoimmunity
5c. micro-biome, SNPs shown association with microbiome configuration and susceptibility to several diseases including MS and other auto inflammatory disorders, LMW substances such as butyrate, LDL, HERV expression, SNPs in HERV loci,
6. EBV B-cells, superoxide, ADMA, iNOS, peroxynitrite, ischemic conditions, biochemistry, mitochondria slow down, ATP production down, slow progression, 6a. above age 60 B-cells production down, PP start to work better, gut microbiota improves, HERV expression down + B cell oxidate stress down, stabilisation
7. ion pump lacks ATP, nerve connectivity down, inhibited tendon reflex, anti-oxidant depletion, lacks ATP to break bonds muscle cells, ATP muscle spasticity

8. therapeutic options: anti-HIV HAART experiences; Borody's experience with gut microbiota transplantation, experiences with ccsvi liberation, experiences with chemo cyclophosphamide, cyclophosphamide, mitoxantrone, HSCT, others
8a. arresting decline; anti viral; anti-HERV; probiotics for micro-biome; anti EBV B-cells;
8b. boosting recovery; detoxification, anti-oxidant supplementation

9. next steps, action plan

I am sure that once we have got this high-level assessment right, the detail could and would be filled in by an army of professionals rather quickly. The challenge is to get the big picture right.

We are close but I need the reflection power of a group of professionals. I wish medical professionals would jump on this train and help me out with the preparation.

Regards,
Last edited by Leonard on Mon Oct 23, 2017 12:38 am, edited 24 times in total.
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Re: A new concept and treatment options for MS

Post by Leonard »

Hi Scott, I amended the previous posting a bit to stress the all important role of ATP production, and the biochemical failure in the epigenetics that underlies MS. Reg, Leo
Last edited by Leonard on Tue Feb 21, 2017 4:49 am, edited 1 time in total.
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Re: A new concept and treatment options for MS

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Hi Leo,

When you get to point 6 after ATP depletion (or availability), I think it would then go on to Loss of Ionic Homeostasis and then split into two paths;1) Loss of intracellular potassium and raised extracellular potassium and 2) Gain in Tissue Calcium (as Sodium pours into the cell) leading to mitochondrial Ca2+ overload and reduced ATP synthesis (ie a loop). The other part of the loss of ionic homeostasis would be the higher intracellular sodium would push fluids into the interstitial space leading to Oedema (something our wheelchair bound friends often have to put up with). If there is contraction of blood vessels at the same time from vasodilation issues then it could be extreme. Probably a series of loops going on from here. Cardiologists should be all over this stuff.

Regards,
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Re: A new concept and treatment options for MS

Post by Leonard »

The net is closing.

Mitochondrial dysfunction ....whereby reduced ATP production [in demyelinated segments of upper motor neuron axons] impacts ion homeostasis, .... and contributes to progressive neurological disability in MS patients.

https://www.ncbi.nlm.nih.gov/pubmed/16392116
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Re: A new concept and treatment options for MS

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Hi Leo,

Obviously it is a series of steps to get this far. The loss of proper calcium regulation because ATP supply cant keep pace with demand explains many of the problems, explains why many treatments have partial success and makes you scratch your head about many of the treatments that the visitors to these pages are subjected to.

A lot of problems just go away when ATP is adequate. The surgeons who do organ transplant are all over this issue. Their greatest fear is ischemia. Under ischemic conditions ATP breaks down into purines and rebuilding them back into ATP takes a very long time. Muscle spasms become inevitable when muscle becomes ischemic.

Reperfusion becomes an issue. Whatever the reason for a reduction in the supply of oxygenated blood ( inflammation, oxidative damage, microvascular injury) the redox signalling can have disastrous consequences and perpetuate a cycle of more and more damage. The process of oxidative phosphorylation is dependent on passing electrons down the electron transport chain. That all happens in the mitochondria. When the mitochondria is flooded with Calcium problems feed on themselves and these steps are affected..
If your muscles are tight or you have oedema blame it on the lack of adequate ATP leading to Calcium disregulation as a first step.
I deal with it using 750mg of CoQ10 and 2000 mg of aceytl-l-carnitine daily. I don't have fatigue and I am getting over muscle tightness but need Dantrium and magnesium to help that as I assume, some proteins now fold the wrong way.

Regards,
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Re: A new concept and treatment options for MS

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This ACTRIMS 2017 Forum has a wonderful programme:
https://www.actrims.org/forum2017/
http://forum2017.actrims.org/forum2017/ ... t-a-glance

The programme was summarised as follows:
Quote from https://multiplesclerosisnewstoday.com/ ... o-florida/

The focus ... will be environmental factors, genetics, and epigenetics in MS susceptibility and clinical course. Presenters will disclose recent advances on the relationship between MS susceptibility and diet; the effects of sex chromosomes, hormones, and puberty on the risk of MS and the clinical course of the disease; reveal emerging data on the role of the microbiome in MS development; review controversies regarding the role of viruses in MS; convey state-of-the-art data on genetic and epigenetic factors as risk factors and disease modulators in MS; and other MS-related topics of interest. unquote


The programme breaks with anything we have seen in the past and sets a whole new agenda.
It is the most hopeful development in MS research in recent years.
Congratulations ACTRIMS!

There must be a big vision behind the programme.
In fact, I think that vision is the same as the big picture that underlies my concept/posting of Feb 1, 2017 here above.
It is the best possible confirmation that the thrust behind the last few pages of this thread is right!

I wonder how the MS community will now respond.
The main ingredients are there but if they continue to be considered in isolation or from within a narrow/specific medical field, the big picture will remain hidden or obscure.
One will need to think across boundaries, look beyond individual facets, disconnect from old mindsets, and look with a pair of fresh eyes at the problem .
And then, the main challenge will be to CONNECT all sort of 'agents' in the MS field to the big picture that emerges.
And please don't wait too long, there are hundreds of thousands of patients desperately waiting for the good news every day again!

Good luck ACTRIMS.
You have made a very important contribution to solving the MS mystery and set an important first step in the right direction.
I trust that you will now launch an appropriate action programme expeditiously.
Last edited by Leonard on Thu Jan 17, 2019 6:51 am, edited 3 times in total.
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Leonard
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Re: A new concept and treatment options for MS

Post by Leonard »

Hi Scott,

Muscle ischemia and related spasticity is definitely a big issue, in particular in progressive MS.

The MRI of my CNS has been stable for the last 8 years or so (is my liberation from ccsvi related in some way?). But muscle spasticity has been increasing. An extensive blood analysis revealed only two things: (1) high muscle titres and (2) high herpes and EBV immune complexes (on this last point more below). The doctor literally said "I was eating my own muscles" and in fact you can see I loose muscle volume. Lately, spasticity accelerated which might be related to the start late Nov of intense MS specific physiotherapy (faster ATP depletion in 'muscles at rest' with resulting failure to break the bonds and thus increased spasticity?). Incidently, the NMES response of my bad right leg is considerably lower than that of my good left leg which I think is also an indication of muscle spasticity.

The ischemic condition causes mitochondrial failure. My brother was diagnosed with a mitochondrial energy failure but it was confirmed that it is not MS. Conversely, my MS diagnosis was confirmed. (what's in the name?). He is evolving towards the same end-state than me. If I eat a lot of carb and start physical exercise, I have to pee four times in an hour, like water in big volumes. I think it is the liver that pushes because there is energy demand but the cells don't open (fast) enough or don't take the glucose/energy. And then the kidney filters out the high glucose. When I discussed this with a local endocrinologist - already now several years ago - he basically suggested that view. N.B a fasting serum insuline test was perfectly normal.

I am sure the EBV trail that I see in my family underlies the problem. Incidently, the extensive analysis of my blood revealed (2) high EBV immune complexes. Where EBV immortalised B cells are causing the superoxide release, oxidative stress and ischemic conditions. At around 60 years of age the situation may stabilise because the EBV production goes down. And that is indeed what we see in the MS progression charts - which in my view - confirms the (declining) role of the B cells.

I think that herpes vininae affect T cells [which may cause immune evasion], and that in particular the EBV strain infects B cells. The interaction between T cells, B cells and regulatory cells is very complicated. But clearly, the T cells fail to remove the EBV infected B cells. In an above posting, we have seen that possibly a protein change in the B cells makes that they are no longer recognised by the T cells. Or it could be the T cells or even a combination. And a very high concentration of immortalised EBV infected B cells then develops, like in my own blood. With as a consequence a huge oxidative stress.

Chemo (cyclophosphamide, mitoxantrone?) will correct the immune system, including T, B and regulatory cells (very complex interaction). Bad B cells may be washed away, either by the chemo or by the new T cells that start working again. A weak indication on the important role of T cells is that recent research demonstrates that long chain fatty acids produce bad T cells and precisely here you can see a soft/gradual transition to (secondary) progressive when B cells will go out of control. This would seem to confirm Swank. https://multiplesclerosisnewstoday.com/ ... ne-system/

And of course you are right Scott, failed mitochondria are flooded with Calcium. Cells shrink in seize which, when failure is concentrated in the brains, explains the brain atrophy.

Together with the above postings, I think we are there. The story now needs to be tidied up and written down.

Thanks a whole lot for your input and let's stay in touch.

Regards,
Last edited by Leonard on Thu Mar 09, 2017 12:09 pm, edited 7 times in total.
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Scott1
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Re: A new concept and treatment options for MS

Post by Scott1 »

Hi Leo,

We seem to be on the same page.

I wrote a piece on this for MStranslate and tried to keep it simple. It was broken into parts but the links to all of it are in the last bit - http://www.mstranslate.com.au/ms-many-s ... y-muscles/ .

I think you can get out of those muscle issues but it will take quite a while.

The EBV immortalised B cell issue is well understood by you. Managing it is why I take Valacyclovir. I don't expect to ablate the infection but just interrupting the cycle works for me. It's part of the inflammatory processes.

The muscles I treat as though they are a separate issue. The depletion of ATP in striated muscle (cardiac and skeletal) will cause spasticity as ion homeostasis breaks down. Trauma to the spine, particularly the cervical spine, will impact the autonomic (sympathetic and parasympathetic) immune system because the signalling between the brain and that system is not perfect.

If you leave the skeletal muscles wrapping around your spine locked up then you are not going to be able influence the quality of smooth muscle action. Making your spine flexible is a huge part of recovery. You are going to have to start to move it. The form of movement that works is eccentric rather than concentric muscle movement. Building muscle strength in an elongated state which is what you are doing with Pilates or Yoga will help build the strength.

Of course, you have to create a way of breaking the rigor bonds formed as a result of the calcium overload. If you don't then exercise will have a fairly limited benefit and may prove to be close to impossible to do.

I think it's safe to assume our bodies are not perfect. We have had years of lipid peroxidation and inflammation so some proteins are bound to fold the wrong way and signalling is not always helpful. We do need some medication.

For spasticity, I found Dantium to be the best. It's used in high doses in transplant surgery to stop the organ host body from going into spasm during surgery but we only need 25mg twice daily. Its role is to block ryanodine receptors which are the ion channels that calcium passes through to reach the muscle fibres. As it is so effective you definitely need to do eccentric muscle strengthening otherwise you will fall down and stairs become dangerous places.

As the rigor bonds break and you strengthen the elongated muscle you will still find some things don't just magically recover. The process can be sped up by really good massage (it will hurt) and dry needling. The needling creates micro tears in the muscles so the stretching then becomes more effective. I found massage works best if heat packs are applied to the area for 10 minutes before the massage starts. Hot rocks work well also.

The problems you have with your legs may not come from where you feel it. The role of the different muscles is important to understand. For the issues you describe it would be the Psoas ( ) which is a massive muscle in your trunk and Periformis ( ) which controls external hip rotation. The Periformis can irritate the sciatic nerve and cause cramps all the way down the leg. If you wake up in the middle of the night with a leg cramp down into the calf that will be the periformis crushing the sciatic nerve. The muscle spasmed because you were lying on it or it hadn't been moved as it would when you are awake.
When these muscles are in spasm then you have to overuse your hip flexors and adductors and they fatigue and become very sore. All those altered movements can also mean you switched off the glutes and, significantly, the multifidus which is the muscle group that connects directly to the spine. If the multifidus is switched off then you become round shouldered and stoop. Any of these things can cause your hips to tilt from neutral and other muscles pull and become tight.

I needed cortisone injected into the fascia over the periformis to release mine and it still takes time.

I would definitely look at Dantrium but if you don't exercise then don't bother. The Dantrium will show you how weak your muscles have become and the answer is eccentric muscle strengthening.

I think you have got the picture pretty right now but recovery is different to decline and the strategies to get better are a topic on their own. Arresting decline does not imply any recovery so its a different game.

Regards,
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