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NO/ONOO- A New Paradigm of Human Disease: Martin Pall website

ahmo

Senior Member
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4,805
Location
Northcoast NSW, Australia
These last weeks my quest has been to understand NO and ammonia. I searched for a website for Martin Pall several times, but found nothing. Now @Gondwanaland linked me to an article about NO/ONOO- on the Inspire website. (This site puts a dark shield over the content unless you've joined. But I was able to copy the content and paste into a document, got the whole page fine....Having joined and then unjoined, I'm no longer able to access the page.:meh:
https://www.inspire.com/martiz/journal/first-steps-phases-to-correct-methylation-including-diet/ )

From that site I followed a link to a Yahoo NO/ONOO- forum, to which Pall, at least historically, responds. And from there I found his website.
I found the Yahoo group to be pretty inactive, with most of the posts of the past year concerning MCS and EMFs. However, it exists as a forum for asking questions. And in the File section there are a number of files and links. The forum and website are named The Tenth Paradigm.

I've also gotten much closer to understanding Pall's work from his 2 hour video from March 2014. The last 20" lists his suggested supplements, which are also covered on his site. I've gotten good symptom relief following his suggestions to add ALCAR, AdB12, reseveratrol, watermelon, switch my E succinate to Gamma E.

https://www.youtube.com/watch?feature=player_detailpage&v=6A7r1gemjto


https://groups.yahoo.com/neo/groups/TenthParadigmSociety/info
Group Description
"Every TRUTH passes through three stages before it is recognized. In the first, it is ridiculed. In the second, it is opposed. In the third, it is regarded as self-evident." ~~ Arthur Schopenhauer

The Tenth Paradigm Society mailing list is for the dissemination and discussion of information concerning the NO/ONOO- cycle mechanism, a new paradigm of human disease, proposed by Martin L. Pall, Ph.D.

Dr. Pall adopted the term "Multisystem Illness" to describe those diseases that fall under the tenth paradigm. They include: Chronic Fatigue Syndrome (CFS/CFIDS/M.E.), Multiple Chemical Sensitivity (MCS), Fibromyalgia (FM/FMS), Post-Traumatic Stress Disorder (PTSD), and Gulf War Syndrome (GWS).

There are fourteen other illnesses which are suspected of falling under this new disease paradigm. They are: Irritable Bowel Syndrome, Asthma, Tinnitus, Post-Radiation Syndrome (experienced by clean-up workers at Chernobyl), Multiple Sclerosis (MS), Autism, Overtraining Syndrome, Silicone Implant Associated Syndrome, Sudeck's Atrophy (a.k.a. Reflex Sympathetic Dystrophy), Post-Herpetic Pain, Chronic Whiplash-Associated Disorder, Amyotrophic Lateral Sclerosis (a.k.a. ALS or Lou Gehrig's Disease), Parkinson's Disease, and Alzheimer's Disease.

We will also discuss the research indications for treatment of these illnesses pointed to by the NO/ONOO- cycle and the implications for lifestyle, the environment and disability.

DISCLAIMER: Information provided here is intended for your general knowledge only and is not a substitute for professional medical advice or treatment for specific medical conditions. It is not intended to diagnose, treat, cure or prevent any disease.

More information about the Tenth Paradigm can be found at: http://www.thetenthparadigm.org/index.html

Dr. Pall's new book "Explaining Unexplained Illnesses" can be ordered from Amazon.com and other booksellers.
 

picante

Senior Member
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829
Location
Helena, MT USA
I think it's thought that the most common pattern in ME/CFS, assuming there is one, is that NO production from iNOS (NOS2) is likely to be increased more than it should be, while NO from eNOS (NOS3) may be lower than desirable. (The researcher Maes, I think, has looked at iNOS in ME/CFS.)

Also, I think that most researchers think that Pall's theory is more likely to only be a contributing problem in ME/CFS and not the fundamental issue.

After Nan posted this yesterday on the Alternatives to Arginine thread, I went looking for Maes, whose first name is Michael, and found this:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964747/

which I've tabbed to read later today, :rolleyes:.
 

Gondwanaland

Senior Member
Messages
5,092
I found I link of it with thiols:
Untitled-1.jpg

Source
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
The Tenth Paradigm and "no, oh no" (that is the "preferred" pronunciation) have been discussed on Phoenix Rising many times. I wrote a commentary for Marty on his book back when it came out. I used to debate with Marty online, along with Rich van Konyenburg. I have a lot of time for his models. It was Marty who encouraged me to go back to uni to finish my biochem degree.

His explanation of electromagnetic sensitivity is very very interesting, which is why I think it has been the main focus for debate recently. The response to this is due to interference, if I recall correctly, with voltage gated calcium channels.
 

Gondwanaland

Senior Member
Messages
5,092
His explanation of electromagnetic sensitivity is very very interesting, which is why I think it has been the main focus for debate recently. The response to this is due to interference, if I recall correctly, with voltage gated calcium channels.
mB12 and magnesium helped me a lot with that, but I am still intolerant to wi-fi
 

picante

Senior Member
Messages
829
Location
Helena, MT USA
Good heavens, izzy, I don't know how you can understand this stuff. :wide-eyed: That seems to be an article on nitric oxide sensors!

So the ONOO reacts with CO2 and thiols. I wonder what that reaction produces. Presumably that's eNOS in the image, since it's in contact with the endothelium.

Nice image! Can anyone comment on the implications? I'm a linguist, not a biologist.
 
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ahmo

Senior Member
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4,805
Location
Northcoast NSW, Australia
@alex3619 Maybe you can clear up something for me. Until I watched Marty Pall's 2 hr vid, I thought I'd been dealing with ammonia problems. I have a fairly discreet set of symptoms that respond favorably to ammonia-reducing supps. I'm now wondering if all along I've been actually coping with peroxy symptoms. I've not been too successful in understanding the relationship between ammonia and peroxynitrite, though someone did post an answer a few days ago. (Didn't write it down, so it's gone now) Does ammonia reduce to peroxy? Do the two essentially become indistinguishable?

During the past 2 months I've had 3 distinct episodes. One was quite clearly physical stress, PEM. By resting and implementing some of Pall's suggested supps, I avoided a crash. The other 2 episodes involve B vitamins. First B2, which I added to my otherwise very low dose B complex, hoping this would let me eat green veggies.100mg for 1-2 days, then 50mg for another day. It was great to eat some lettuce, but 2 days later I felt like I was drowning in "ammonia" and it took many days to eliminate.

Most recently I was needing a lot of ammonia-reducing supps, antioxidants. It occurred to me that maybe my P5P was contributing. I quit my 33mg dose for 2 days, then reduced it to 1/2, and now, again, I've stopped having the symptoms, and am no longer in high need for all the supps.

My diet is low thiol, only small amounts of meat. When I used sulfate strips I always tested next to lowest, regardless of how I was feeling. Maybe that supports the idea that it's actually a peroxynitrite problem, rather than an ammonia problem???

My current question is whether it's possible that since I've been using malic acid as my 'ammonia' fix, something has shifted so that now I need less P5P?? When I began P5P a couple years ago I went up to 3 caps for awhile, and didn't have any problem as best as I can recall. I've also followed someone's advice and upped my molybdenum, 3 weeks ago going from 300 to 1200mcg. so maybe this is playing a role.

I'm very happy using a range of Pall's suggestions. When I was in an acute state, I self-tested + for and used more...like ADB12. Now that my system has calmed down, I need less: no extra resveratrol, ubiquinol, butyrate; only very small amounts of ALCAR, little malic acid, much fewer carrots. Also my mast cell symptoms have quietened.

Can you offer a complete theory of everything for me??:nerd:;) thx.
 
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alex3619

Senior Member
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13,810
Location
Logan, Queensland, Australia
I don't have a complete theory of everything ... wish I did. I have also not been following Marty's recent work closely. Sorry. I was into this about ten years ago.

I would do a little digging to find answers but I am still struggling with my laptop, as my main computer is still away getting repaired. I might get it back tomorrow, or not. I am hoping I will. I have had almost two months of computer problems now, and its meant I cannot investigate all the things I want to.

Even if Marty is wrong about the Tenth Paradigm, something that advancing science will tell us, he is still right about the peroxynitrite being a big issue. Its very likely he is either right or partly right though. That is the big thing that models are prey to - a model is only as right as the things it takes into account, and I am fairly sure that ME and related disorders have a few surprises we have not uncovered yet.
 

picante

Senior Member
Messages
829
Location
Helena, MT USA
Until I watched Marty Pall's 2 hr vid, I thought I'd been dealing with ammonia problems. I have a fairly discreet set of symptoms that respond favorably to ammonia-reducing supps. I'm now wondering if all along I've been actually coping with peroxy symptoms.
Ditto ditto for me!

I actually swing between 3 different beliefs when my brain winds up in Dorothy's poppy field: 1) it's ammonia, 2) it's sulfites not converting to sulfates, 3) it's peroxynitrite.

A unified field theory of these three processes might help me, too, if I can understand it. My brain worked much better before I started methylation. And I could eat two eggs a day.
 

Gondwanaland

Senior Member
Messages
5,092
I know we need to lower ONOO-, but what about NO?
This finally is starting to make sense to me. Look at peroxynitrite in the bottom left, lowering ammonia you consequently lower ONOO- as well
idea.gif

Methylation-cycle.jpg
 

ahmo

Senior Member
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4,805
Location
Northcoast NSW, Australia
@alex3619 I just thought you might be familiar with the relationship of ammonia and peroxy. I'm very taken with Pall's theory, it makes more sense than most things I've seen as a broad explanation for the mechanism. At least what's keeping us stuck. Really, I jumped at the chance to ask you. I'm very impressed with your close relationship with him and the theoretical. ;)

@picante :):hug:
@drob31 Doesn't Ammonnia convert to NO which converts to peroxynitrite?
High ammonia levels caused by either poor methylation (forget the SNP's involved), or even liver issues.
I know people with cirrhosis have high ammonia levels.
So this could mean that when my liver's overloaded, I'm producing ammonia. which is why I'm doing coffee enemas.
As for sulfites to sulfates, I' don't know where I'd be getting sulfites. And my current decrease in symptoms reinforces that it's not sulfites for me, unless...something about those B vitamins produced sulfites???

@Gondwanaland
lowering ammonia you consequently lower ONOO- as well
idea.gif
:thumbsup::nerd:
So does that mean raising ONOO raises ammonia? I don't know about whether my NO is hi or low, only that I'm trying to reduce peroxy. I believe what Pall is saying is that if peroxy is lowered, NO becomes normalized...:confused:

Now I see ammonia on the chart, I think maybe I can stare at this long enough to make some sense of it. I think I'm at the point where the answer to my original question no longer matters. I have strategies that are working. Last night I didn't need any footbath, which means my body didn't need K+, glycine, malic acid, Lithium, vit C...something stopped the ammonia/peroxy overload. Maybe further days away from the P5P? Today's the 3rd day in a row I've been feeling great, even after having initiated anti-fungals. :)
 
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ahmo

Senior Member
Messages
4,805
Location
Northcoast NSW, Australia
OK, a few quotes from Pall's website:
http://www.thetenthparadigm.org/therapy.htm
We have, here, 17 diverse stressors implicated in initiating these illnesses, leading one to ask, how they may do so? What I have argued, in my book (1) and elsewhere (2-10), is that each of these can act to increase nitric oxide levels. Each is reported to increase the levels of nitric oxide, or in three cases where that has not been studied, to stimulate a process which is itself known to increase nitric oxide. This is a striking common response and leads to the question about how nitric oxide increases might lead to chronic illness? My answer to that question is that nitric oxide, acting primarily through its oxidant product peroxynitrite, initiates a biochemical vicious cycle that is responsible, in turn, for the chronic illness. We have, then, an initial cause of illness (short-term stressor or stressors) acting to start this vicious cycle, with the cycle responsible for causing the chronic phase of illness. We are now calling the cycle the NO/ONOO- cycle after the structures of nitric oxide (NO) and peroxynitrite (ONOO-) but pronounced no, oh no!


[re diagram] It can be seen that these arrows form a series of loops that can potentially continue to stimulate each other. An example of this would be that nitric oxide can increase peroxynitrite which can stimulate oxidative stress which can stimulate NF-kappaB which can increase the production of iNOS which can, in turn increase nitric oxide. This loop alone constitutes a potential vicious cycle and there are a number of other loops, diagrammed in the figure that can collectively make up a much larger vicious cycle. The challenge, according to this view, in these illnesses is to lower this whole pattern of elevations to get back into a normal range.

There are five principles underlying the NO/ONOO- cycle as an explanatory model:

  1. Short-term stressors that initiate cases of multisystem illnesses act by raising nitric oxide synthesis and consequent levels of nitric oxide and/or other cycle elements.

  1. Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of nitric oxide and peroxynitrite and other cycle elements is produced and maintained. This principle predicts that the various elements of the NO/ONOO- cycle will be elevated in the chronic phase of illness.

  1. Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity.

  1. Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because the mechanisms involved in the cycle act at the level of individual cells, the fundamental mechanisms are local. The consequences of this primarily local mechanism show up in the multisystem illnesses through the stunning variations one sees in symptoms and signs from one patient to another. Different tissue impact of the NO/ONOO- cycle mechanism is predicted to lead to exactly such variations in symptoms and signs. One also sees evidence for this fourth principle in published brain scan studies where one can directly visualize the variable tissue distribution in the brains of patients suffering from one of these illnesses.

Therapy should focus on down-regulating the NO/ONOO- cycle biochemistry. In other words, we should be treating the cause, not just the symptoms.

A second important part of the cycle involves the depletion of a compound called tetrahydrobiopterin (often abbreviated BH4), a compound that it oxidized by peroxynitrite (1,11). BH4 is what is known as a cofactor in the nitric oxide synthases (NOSs), and tetrahydrobiopterin depletion produces what has been called partial uncoupling of the NOSs. When a NOS enzyme is missing BH4, it produces superoxide in place of nitric oxide. The consequence of this is that in cells and tissues that have high NOS activity and partial uncoupling, one has many adjacent enzyme molecules, some producing nitric oxide and others producing superoxide and these will react rapidly with each other to form more peroxynitrite. This will, in turn oxidize more BH4, producing more partial uncoupling. This reciprocal relationship between peroxynitrite and BH4 depletion is, then a potential vicious cycle within the larger NO/ONOO- cycle and may constitute the essential core of the cycle. Lowering of this central couplet will be expected to produce a clinical improvement in these diseases, but will produce an increase in nitric oxide. So while I think that the net effect of nitric oxide in these diseases is negative one, agents that increase nitric oxide by lowering this central couplet should be helpful.
 

picante

Senior Member
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829
Location
Helena, MT USA
Today's the 3rd day in a row I've been feeling great, even after having initiated anti-fungals.
:balloons:
Still staring at the diagram: If you can increase conversion of homocysteine to methionine, it will decrease ammonia. So are you taking something that helps with the conversion? That's what I wonder.
 

Gondwanaland

Senior Member
Messages
5,092
:balloons:
Still staring at the diagram: If you can increase conversion of homocysteine to methionine, it will decrease ammonia. So are you taking something that helps with the conversion? That's what I wonder.
My Hcy is at its best right now (6.8), therefore I haven't had ammonia issues lately :thumbsup:
I attribute it to stopping the B vits and balancing minerals. Just wonder what is going to happen when I start vitamins again :nervous:
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
@alex3619 I just thought you might be familiar with the relationship of ammonia and peroxy.
I hope to comment after I get my real computer back. There is no way ammonia can directly give rise to ONOO, but there are so many potential interacting pathways where it might contribute to a rise that I didn't want to comment without investigating. You can see hints of that on the above diagram, but I wanted to see more detail before commenting.

For what its worth, a couple of years back it looked like the NO/ONOO model and methylation might merge. I don't know what is happening in that direction at the moment.