Can anyone explain in English what possibilities my doctor is hypothesizing?

[Starry]

 

[andyguitar]

Sounds like he does'nt know what is wrong so wants to do some tests. Also in point 8 it sounds like he thinks a sleeping problem maybe a significant factor in causing symptoms.

 

[Starry]

View attachment 34071

Yes he is listing possibilities.
In particular I am keen to understand what is meant by
1. Nitric Oxide peroxynite pathway disorders?
2. Underlying methylation pathway?
3. Polymorphism of COMT?
4. What is a cortisol profile?
I'm a bit worried he is focusing on my historic episode...

 

[wabi-sabi]

This looks like a problem list.

#5 Trying to figure out which of the metabolic pathways has gone haywire. (I have no idea which metabolic pathway the nitric oxide/peroxynitrite is, but I guess it's the one your doc thinks is messed up.) Thinks this is the pathway that's related to PEM and MCS. Wants to do some genetic testing to try to figure it out.

#6 Because your symptoms get worse with your cycle, there may be a hormone related piece. Doc is testing some "imbalance", but doesn't say which one or what tests. Also wants to do genetic testing for this.

#7 Make sure you don't have a virus. Doesn't say how this will happen...

#8 You're really stressed and having trouble sleeping. These two make each other worse. Doc is ordering cortisol (as a measure of stress response), blood sugar to make sure this is not going crazy when you're sleeping because this will stress your body and make sleeping worse. (And maybe you're having some tummy trouble that isn't helping your blood sugar.) Doc is trying melatonin (sleep hormone) to see if this will help, but you need to work on light exposure because melatonin is triggered by darkness and turned off by light to get your body to align with natural circadian rhythms (as much as possible ). So starting at a screen at night before bed (what do I do all night, right?) will just make the melatonin not work.

 

[wabi-sabi]

So I found a nice article on NO (nitric oxide) and peroxynitrite I think would be helpful.

Pacher, P., Beckman, J. S., & Liaudet, L. (2007). Nitric oxide and peroxynitrite in health and disease. Physiological reviews, 87(1), 315–424. doi:10.1152/physrev.00029.2006

I gather this is some pretty basic med school biochemistry. Here's what I can figure out...

1) NO is a very common cell signalling molecule, meaning it's one of the chemicals a cell squirts out when it wants to talk to other cells. I don't know exactly what message nitric oxide is sending, but it's used for both normal cellular functions and when cells are damaged, like in chronic disease. Maybe our chronic disease too, or at least this is what your doc is thinking and wanting to test.

2) When a cell squirts out a signalling molecule, something has to happen to that molecule after it finished its job. It can't just hang around because then the message gets messed up, like a phone that just won't stop ringing. So it either gets stuffed back into the cell for re-use later or it gets broken down and digested into something else.

3) NO gets broken down into peroxynitrite after its job is done. Peroxynitrite is an oxidant (meaning it's potentially harmful in large quantities and in the wrong place).

4) When a person is healthy, there's not much NO or peroxynitrite around. When a person is ill, there's loads of NO and peroxynitrite around. This can do lots of bad things in the body. When people talk about oxidative stress, this is one of the chemical reactions they are talking about. Your doc is trying to test this somehow or other, and it doing it through testing the methylation pathway. I guess you need that pathway running right to make the NO/peroxynitrite pathway run.

 

[gbells]

Paragraph 5 says that the doc is speculating that your disease could be due to a genetic defect that is disabling the nitric oxide (NO) system which is important in the regulation of blood flow. Not enough NO would keep the vessels constricted and make exercise difficult.

P6 says he wants to run tests to see if your esterogen and progesterone hormones are working properly.

P7. He wants to run tests to exclude any viral infections.

P8. He says your sleep habits are bad and speculates that correcting this could give you more energy. He prescribed melatonin supplement to help you sleep and is checking your stress hormone cortisol to see if you may have adrenal fatigue.

 

[Wishful]

3) NO gets broken down into peroxynitrite after its job is done. Peroxynitrite is an oxidant (meaning it's potentially harmful in large quantities and in the wrong place).

No, NO mostly breaks down into nitrates. If there's superoxide around, some of it may react with NO to produce peroxynitrite.

 

[wabi-sabi]

Sure, but when we're specifically looking at the NO/peroxynitrite pathway...

 

[wabi-sabi]

Quote from the article

"The formation of reactive nitrogen species is not an inescapable consequence of synthesizing NO. NO is efficiently removed by reacting with oxyhemoglobin to form nitrate, which prevents even the highest rates of NO synthesis from directly reacting with oxygen to form significant amounts of nitrogen dioxide. However, the simultaneous activation of superoxide synthesis along with NO will completely transform the biological actions of NO by forming peroxynitrite."

They say it so much better than I.

 

[percyval577]

NO is strongly guessed to be one key mediator for learning and memory. NO has been shown to have actions on the most types of nerves. Also microglia cells produce NO.

(Ever since I was a pupil I was convinced that too much learning is illness, /2)

 

[Wishful]

NO gets broken down into peroxynitrite after its job is done.

I was objecting to the misleading aspects of your statement. For one thing, NO doesn't really have a job; it is produced as a side effect by some reactions, and some other systems evolved to make use of the presence of NO, but a molecule of NO isn't produced with a specific task it is supposed to do. Secondly, the conversion to ONOO- isn't done after the NO reacts with something else; it occurs before it can do any other reaction. If you really want to think of the NO molecule being produced to signal a certain cell, it gets mugged along the way.

 

[percyval577]

... NO doesn't really have a job; it is produced as a side effect by some reactions, and some other systems evolved to make use of the presence of NO, but a molecule of NO isn't produced with a specific task it is supposed to do.

I like tot say here:

1. That tasks of molecules had evolved from side effects is not a surprise (though it cannot be proven, maybe shown by a computer simulation).

2. That NO wouldn´t have really a job is not true. There are three NOS enzymes known, two constitutive ones (sometimes also referred to as cNOS) and one inducible iNOS which releases NO when certain fragments from bacteria hit some cells (microglia, macrophages). The iNOS in microglia has been shown three times by two authors to depend on manganese blood levels, in its gene expression. The other two NOS enzymes depend on calcium influx and subsequently calmodulin change (I think it was).

3. The molecule NO has a lifetime of about two seconds or something like that (in organisms). It crosses very well cell membranes and acts with DNA or DNA mechanisms (I have forgotten right now),

a) This is obviously the reason why some immune cells use it, to slow down gene mechanisms in pathogens.

b) The osmosis (membrane crossing) is probably also the reason why it is used for nerves: it stimulates the surrounding nerves when released by a nerve cell (produced from nNOS upon opening of NMDAR and influx of Ca, a positive feedback mechanism, b/c NMDR´s will be elevated from NO effects on AMPAR´s). The very details of NO reception though are still not known, as far as I have looked. Agmatine has been guessed once to endongenously diminish the number of NMDR´s (probabaly when having learned enough).

c) For the discovery of the eNOS (endothedial Nitric Oxide Synthase) a Nobelprice has been given. Here also, I think, NO is used b/c it rapidly messages all the surrounding cells, possibly without a specific receptor (?!).

 

[percyval577]

If I remember rightly, ONNO- is prone to slow down mitochondrial complex I, which has quite a number of iron sulfur centers - I think it was seven or eight - lined up in a row, I would think to occasionally be "destroyed" by ONOO-.

Another Enzyme (GSH, I think) is able to "repair" the centers quickly, and only if there has been done too much "damage" (a three times hit, I think) the center is inevitable lost and a quick restart of the very electron tunnel will not be possible. (Hope I remember it rightly).

 

[Starry]

All very interesting but doesn't explain what type of disorders of NO path he is contemplating.
From this NO is apparently a pulmonary vasodilator. Given he is writing to my cardiologist who is treating me for OI /POTS I wonder if that is what he is thinking of. He's an Endocrine/diabetes guy as well as fatigue specialist and obsessed with my glucose even though I've never shown as at risk for diabetes and have a low bmi eat clean and dislike sugary food. What's the odds he tries to get me to go keto. Sigh.
https://www.ncbi.nlm.nih.gov/m/pubmed/15320480/

 

[nyanko_the_sane]

He's an Endocrine/diabetes guy as well as fatigue specialist and obsessed with my glucose even though I've never shown as at risk for diabetes and have a low bmi ear clean and dislike sugary food. What's the odds he tries to get me to go keto. Sigh.
https://www.ncbi.nlm.nih.gov/m/pubmed/15320480/

Seems like this doctors thinking is on par with what I have seen before. Whether they can actually help you depends if you respond to whatever treatment they comes up with. Since you avoid sugar, you are already on the right track. You just never know what might help, we are all so different. ME throws us for a loop, so it really does become a balancing act to try to put things right again.

 

[CFS_for_19_years]

P8. Reactive hyperglycaemia is elevated blood sugar levels that are controlled by insulin, which is affected by cortisol levels. I'm fuzzier on this aspect, but I think it means if you have proper cortisol levels glucose will enter your cells more readily, making you feel better. (Help me out here, folks.)

P8. He says your sleep habits are bad and speculates that correcting this could give you more energy. He prescribed melatonin supplement to help you sleep and is checking your stress hormone cortisol to see if you may have adrenal fatigue.

"Adrenal fatigue" is a reflection of low cortisol output throughout the day. Since the practitioner is concerned about problems with sleep, he's more likely to be concerned with elevated levels of cortisol in the evening and night which would interfere with sleep.

I've had both profiles - low cortisol output throughout the day, i.e. "flatlined" so badly that a doctor gave me hydrocortisone which I didn't tolerate- and more recently I've had the profile of having cortisol on the high side in the morning and evening, most likely due to intake of spironolactone and ever present stress from being sick. I also had my morning serum cortisol checked at my local clinic and it agreed with the saliva results. When I stopped taking spironolactone my thyroid medication started working much better.

Here are some good explanation of what you might see:
https://www.zrtlab.com/landing-pages/diurnal-cortisol-curves/
https://www.zrtlab.com/how-diurnal-curves-affect-sleep/

I've attached my cortisol profile and interpretation from when I was taking spironolactone a few years ago.

 

[Foxglove]

Yes he is listing possibilities.
In particular I am keen to understand what is meant by
1. Nitric Oxide peroxynite pathway disorders?
2. Underlying methylation pathway?
3. Polymorphism of COMT?
4. What is a cortisol profile?
I'm a bit worried he is focusing on my historic episode...

1) That sounds like the doctor has read Martin Pall.
https://me-pedia.org/wiki/Martin_Pall
Short and easy-to-read link on NO here.
How it relates to ME/CFS here or here. (same article, I think)

They talk about peroxynitrate causing oxidative stress, which is thought to be implicated in many kinds of diseases (more than Pall lists, but he's talking about a potential way to create oxidative stress).

The doctor mentions "the energy currency," which is ATP, and also the doctor mentions mitochondria.

Cellular metabolism occurs in a category of chemical reactions known as "redox," or reduction and oxidation reactions ( reducing or adding electrons or covalent bonds, which we follow by watching + or - charges, or addition or removal of hydrogen [H+], or changing to a lower-energy bond; in aerobic metabolism, oxygen is the final molecule which accepts electrons). APT production.

During these redox reactions, we produce reactive oxygen species (ROS), known as "free radicals", or oxidative stress. These are molecules with an unpaired electron. Normally that's not a problem because everything is kept in enzymes and progesses from one reaction to the next.

When the next component isn't ready, though, there could be an issue. Well, more than one issue. Both there might be oxidative stress, and you could have an assembly line problem, if there are also not enough backup molecules or fixing molecules.

Both problems in cellular metabolism could cause oxidative stress, and oxidative stress can break various things in the cell including stuff that makes up the mitochondrion itself.

Here's a journal accepting papers on oxidative stress and human disease (until January 2020).



2) Methylation is a way of putting labels on genes, to indicate what they are or when or how often to use them. It is closely related to epigenetics and genetic expression.
https://www.whatisepigenetics.com/dna-methylation/
http://www.ks.uiuc.edu/Research/methylation/

3) polymorphism is a way of saying genetic variant. (some people say "mutation")

You can read about COMT gene here or here. Also here.

 

[wabi-sabi]

Reactive hyperglycemia means that your blood sugar has tanked sometime during the night while you were asleep. In response, the liver produces tons of glucose to compensate (gluconeogenesis) and overshoots. The reactive part is the reacting to the blood sugar crash and the hyperglycemia part is the overshoot. This typically happens in diabetics if they take too much insulin before bed or don't have a large enough or right sort of bedtime snack.

There was a presentation about this recently on Healthrising and Cort explains well here: www.healthrising.org/blog/2019/06/15/emerging-insights-mcgregor-metabolism-chronic-fatigue-glycolysis/

The upshot is that people with ME/CFS often have trouble maintaining a proper blood sugar level. Maybe even when we do eat "clean"? If your doc can figure out if you're having reactive hyperglycemia, maybe s/he can figure out a dietary way to deal with it. I don't know about the keto thing. I tried it very briefly and it made me ever so much worse, but I hear it's great for DM2.

 

[wabi-sabi]

All very interesting but doesn't explain what type of disorders of NO path he is contemplating.

https://www.ncbi.nlm.nih.gov/m/pubmed/15320480/

I'm not honestly sure the NO pathway functions are well enough known to figure this out. All of the reading I've done suggest this pathway is ubiquitous in health and illness, as the article you attach states, If it's everywhere it must be doing something important, but not necessarily the same thing in every cell. This honestly sounds like a bit of a fishing expedition to me- Here's a pathway that's broken in lot's of chronic illness and is involved in most physiologic processes in the body so let's see if it's broken here. I'm curious about the role of the NO pathway in hypoxia and heart failure given Dr. Systrom's findings. That's what seems relevant to me for ME/CFS.