Diagnosing Hypoxemia - Any doctors actually think about a problem - first principles?

[Violeta]

Is the problem that the adenosine builds up because it isn't being metabolized. Is the problem a lack of adenosine deaminase activity?

A lack of adenosine deaminase activity might also be the cause of caffeine sensitivity?

Adenosine deaminase stability is affected by zinc.
" Real-time 19F-NMR spectroscopy measuring the loss of Zn2+ showed that structural changes correlated with the loss of enzymatic activity."

The Role of Zn2+ on the Structure and Stability of Murine Adenosine Deaminase
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3005954/


Evidence of functional zinc deficiency in Parkinson's disease
https://pubmed.ncbi.nlm.nih.gov/10100031/#:~:text=Patients with PD showed a,loss (p < 0.05).

The single most consistent finding and the strongest environmental risk factor associated with RLS is iron insufficiency. Professor Nordlander first recognized the association between iron deficiency and RLS, and reported that treatment of the iron deficiency markedly improved, if not eliminated, the RLS symptoms.

I suggest that zinc deficiency is related to the iron insufficiency of RLS.

"We have demonstrated that zinc induces iron uptake and transcellular transport in intestinal cells via induction of DMT1 and FPN1 expression [16,17,19,20]. Therefore, zinc appears to be a key modulator of intestinal iron absorption and tissue iron distribution possibly mediated via regulating the DMT1 and FPN1 levels."

 

[Violeta]

Adenosine: Risks and 4+ ways to lower it.

"Zinc is the most important natural substance that increases the activity of ADA, the main enzyme that breaks down adenosine and reduces its levels. Zinc acts as a cofactor that this enzyme needs in sufficient levels to work well [88]."

Note: Caffeine is not advised.

https://selfhacked.com/blog/adenosine-risks/

 

[pgrovetom]

Adenosine deaminase stability is affected by zinc.
" Real-time 19F-NMR spectroscopy measuring the loss of Zn2+ showed that structural changes correlated with the loss of enzymatic activity."

The Role of Zn2+ on the Structure and Stability of Murine Adenosine Deaminase
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3005954/


Evidence of functional zinc deficiency in Parkinson's disease
https://pubmed.ncbi.nlm.nih.gov/10100031/#:~:text=Patients with PD showed a,loss (p < 0.05).

The single most consistent finding and the strongest environmental risk factor associated with RLS is iron insufficiency. Professor Nordlander first recognized the association between iron deficiency and RLS, and reported that treatment of the iron deficiency markedly improved, if not eliminated, the RLS symptoms.

I suggest that zinc deficiency is related to the iron insufficiency of RLS.

"We have demonstrated that zinc induces iron uptake and transcellular transport in intestinal cells via induction of DMT1 and FPN1 expression [16,17,19,20]. Therefore, zinc appears to be a key modulator of intestinal iron absorption and tissue iron distribution possibly mediated via regulating the DMT1 and FPN1 levels."

Please review some key recent research:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766678/
https://pubmed.ncbi.nlm.nih.gov/29358902/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444903/

I'm being a bit glib saying adenosine causes RLS but recent research shows adenosine and its cycles daily are deeply involved in RLS and iron deficiency is a common trigger and dopamine agonists interfere with the adenosine pathway in such a way to ease the symptoms.

 

[pgrovetom]

Adenosine deaminase stability is affected by zinc.
" Real-time 19F-NMR spectroscopy measuring the loss of Zn2+ showed that structural changes correlated with the loss of enzymatic activity."

The Role of Zn2+ on the Structure and Stability of Murine Adenosine Deaminase
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3005954/


Evidence of functional zinc deficiency in Parkinson's disease
https://pubmed.ncbi.nlm.nih.gov/10100031/#:~:text=Patients with PD showed a,loss (p < 0.05).

The single most consistent finding and the strongest environmental risk factor associated with RLS is iron insufficiency. Professor Nordlander first recognized the association between iron deficiency and RLS, and reported that treatment of the iron deficiency markedly improved, if not eliminated, the RLS symptoms.

I suggest that zinc deficiency is related to the iron insufficiency of RLS.

"We have demonstrated that zinc induces iron uptake and transcellular transport in intestinal cells via induction of DMT1 and FPN1 expression [16,17,19,20]. Therefore, zinc appears to be a key modulator of intestinal iron absorption and tissue iron distribution possibly mediated via regulating the DMT1 and FPN1 levels."

I do not believe there is a "pat" answer but adenosine metabolism and the pathways play key roles in many conditions including cancer, cardiac function, stomach acidity, RLS etc.... Its very complicated but using caffeine is just asking for trouble.

 

[Violeta]

--- I've taken iron supplements to see if I can increase red blood cell count or hemoglobin O2 carrying capacity with no real effect. My CBCs show normal hemoglobin and red blood cells

Do you know why iron supplementation didn't help you?

Did you try any dopamine agonists?

Other ways of dealing with adenosine are being investigated because they know that:
At the same time, dopamine agonists have risks and side effects associated with prolonged use or high doses. Dopamine agonists can be a useful treatment that enhances the quality of life, but they require careful administration and monitoring of symptoms to ensure safe use.

I am just wondering why some people have such problems with adenosine. There must be some root cause.

 

[pgrovetom]

No, I tried a variety of carefully chosen iron supplements with no change. I have used the dopamine agonist with success. It has only minor effects when the RLS begins to move up my body. In retrospect I may have taken 200 MG caffeine pills on the days of bodywide RLS. For bodywide RLS, just imagine the same building up feeling not just beginning in the feet moving up, imagine the exact feeling in torso and reaching as high as my chest.

I have a 600kb MEDIA (mitochondrial) deletion in my skeletal muscles and it 100% disables the electron transport chain and therefore no ATP can be produced. The main source of ongoing adenosine is the breakdown of ATP, ADP, AMP and CCAMP it is eliminated via enzymatic conversion to inositol. Failure to produce these essential intermitites by broken mitochondria can cause excess and circadian tried innspropriate levels.

Adenosine is in the top 10 metabolites in importance on a circadian basis in the entire body. It's dysregulation on a circadian basis ( levels as the daily cycle proceeds) has been linked to a variety of neurogenerative condtions, cancers, immune problems. Gi issues RLS and more.

 

[t27r]

@pgrovetom, where are you now with this situation?

Because it is SO similar to mine that it gave me chills when I read your post. My symptoms seem to be a bit less severe, yet at the same time the insomnia component alone has wrecked my life.

…

Could we/I be low in nitric oxide? Supporting NO has helped my RHR in the past: arginine, citrulline, beets. I want to experiment further.

In my case, I suspect I have NO issues related to urea cycle / ammonia issues. One of my personal tests is soda, which induces fatigue and cognitive impairment / brain fog, which I think is ammonia. I’ll be doing a urine amino acid test after drinking soda to confirm. This possibly-ammonia symptom set began for me in Jan 2017 alongside molybdenum deficiency (since resolved) and would explain so much of my situation, since NAC helps brain fog and RHR sometimes, and the urea cycle uses arginine/citrulline/ornithine as much as NO production.

…

I just randomly came across this old post of mine and wanted to update, even though OP's situation seems to have diverged from mine:

My issues were due to alkalosis, secondary to hyperammonemia. I had Arterial Blood Gas labs done while in this state, with high pH and low CO2.

High protein meals would trigger it the worst. Currently I take 2g ornithine + 2g arginine at each meal and this has solved it. Also 500mg yucca in the morning for good measure.

Some of my original nitric oxide experiments likely contributed to clearing ammonia. Recent experiments have shown me that citrulline is not as effective as ornithine/arginine. (I may further experiment and see if only ornithine helps.) I suspect I have OTC mutations, thus why ornithine/arginine helps.

Even though I mentioned ammonia 2 years ago, I didn't really understand what I was dealing with or how deleterious it could be. It wasn't until I began tracking my major breathing issues occurring after meat (and maybe coffee, which I avoid) that I came to appreciate how severe this situation was for me.

High ammonia then explained TONS of my other symptoms: brain fog, exercise intolerance, insomnia after 4 hours with rapid breathing, hypocalcemia episodes (it pushes calcium into urine), hypokalemia episodes (ammonium ions displace potassium ions), urgent bowel movements after eating, some sort of negative effect on methylation (irritability), effects on GABA/glutamine which is part of ammonia metabolism (agitation, tension, rumination, anxiety), low BH4 (so low serotonin/dopamine), and neuropathy/sizzling in eyes and tongue. All due to high ammonia causing high pH, and also messing with my precarious methylation.

 

[Violeta]

I just randomly came across this old post of mine and wanted to update, even though OP's situation seems to have diverged from mine:

My issues were due to alkalosis, secondary to hyperammonemia. I had Arterial Blood Gas labs done while in this state, with high pH and low CO2.

High protein meals would trigger it the worst. Currently I take 2g ornithine + 2g arginine at each meal and this has solved it. Also 500mg yucca in the morning for good measure.

Some of my original nitric oxide experiments likely contributed to clearing ammonia. Recent experiments have shown me that citrulline is not as effective as ornithine/arginine. (I may further experiment and see if only ornithine helps.) I suspect I have OTC mutations, thus why ornithine/arginine helps.

Even though I mentioned ammonia 2 years ago, I didn't really understand what I was dealing with or how deleterious it could be. It wasn't until I began tracking my major breathing issues occurring after meat (and maybe coffee, which I avoid) that I came to appreciate how severe this situation was for me.

High ammonia then explained TONS of my other symptoms: brain fog, exercise intolerance, insomnia after 4 hours with rapid breathing, hypocalcemia episodes (it pushes calcium into urine), hypokalemia episodes (ammonium ions displace potassium ions), urgent bowel movements after eating, some sort of negative effect on methylation (irritability), effects on GABA/glutamine which is part of ammonia metabolism (agitation, tension, rumination, anxiety), low BH4 (so low serotonin/dopamine), and neuropathy/sizzling in eyes and tongue. All due to high ammonia causing high pH, and also messing with my precarious methylation.

I read that post of yours, and I have to get back to that, too. I have several questions for you about it, but I have to get my dogs out and get something for lunch. Very interesting, and that's so great that you figured out your problem

I see lots of people on twitter having me/cfs and Long c who are waiting for the medical and drug associations to figure things out and find a cure. They are fortunate there are more studies being done because of the C virus, but geez, you really have to be able to look into stuff yourself, don't you?

 

[pgrovetom]

Well I found the answer. Turns out it was hiding in front of my face - and stupid doctors faces also. My blood pressure was low. So low barely any oxygenated blood was passing through my capillaries perfusioning my tissues. It appears my sympathetic nervous system was not innervating my SA node ( heart rate) or myocardium ( heart contractility) sufficiently while sleeping. Everyone's BP dips during sleep ( almost everyone) to give the heart a rest. But this averages around 10-15% for most people. But some people dip far more and if >25% are called extreme dippers. This doesn't cause too many problems when you are young but as one ages, the overall delivery of O2 declines for many reasons and it becomes more and more an issue. Turns out I'm about 30% which is not good. I can now measure this on an overnight Omron BP monitor which records 3 recordings each night. So after many nights, its easy to see both deep sleep and awake and sometimes near on another in time. I can have my BP in the 89/55 range while asleep and 20 minutes later when awake its 140/91.

So that's the answer to my CFS/ME problem. Very basic physiology. Because its blood pressure, my O2 saturation looks just fine. Even places like Stanford don't monitor BP during sleep studies which explains why they didn't catch it. DUH! The FDA has not seen fit to approve an overnight BP monitor so there is no easy way to check yourself. Doctors can order an ambulatory monitor for one night but they need to think of it plus its a hassle and one night's readings are not very thorough if one also has insomnia. The whole thing shows how the medical doctors are not that creative, rather lazy and most are downright stupid. They just happen to have gone to medical school rather than welding or car repair. Make sure your doctor is smart and creative. Dumb doctor's are half the problem. What kind of doctor doesn't think of blood pressure when presented with my facts. A dumb one.

 

[Violeta]

Well I found the answer. Turns out it was hiding in front of my face - and stupid doctors faces also. My blood pressure was low. So low barely any oxygenated blood was passing through my capillaries perfusioning my tissues. It appears my sympathetic nervous system was not innervating my SA node ( heart rate) or myocardium ( heart contractility) sufficiently while sleeping. Everyone's BP dips during sleep ( almost everyone) to give the heart a rest. But this averages around 10-15% for most people. But some people dip far more and if >25% are called extreme dippers. This doesn't cause too many problems when you are young but as one ages, the overall delivery of O2 declines for many reasons and it becomes more and more an issue. Turns out I'm about 30% which is not good. I can now measure this on an overnight Omron BP monitor which records 3 recordings each night. So after many nights, its easy to see both deep sleep and awake and sometimes near on another in time. I can have my BP in the 89/55 range while asleep and 20 minutes later when awake its 140/91.

So that's the answer to my CFS/ME problem. Very basic physiology. Because its blood pressure, my O2 saturation looks just fine. Even places like Stanford don't monitor BP during sleep studies which explains why they didn't catch it. DUH! The FDA has not seen fit to approve an overnight BP monitor so there is no easy way to check yourself. Doctors can order an ambulatory monitor for one night but they need to think of it plus its a hassle and one night's readings are not very thorough if one also has insomnia. The whole thing shows how the medical doctors are not that creative, rather lazy and most are downright stupid. They just happen to have gone to medical school rather than welding or car repair. Make sure your doctor is smart and creative. Dumb doctor's are half the problem. What kind of doctor doesn't think of blood pressure when presented with my facts. A dumb one.

That's so great that you figured that out, and had the endurance to stay on top of pushing for the testing.

That's a really big BP range!

Is the sympathetic nervous system not doing what it's supposed to be doing because of a problem with the HPA axis?

Have you ever had restless leg syndrome?

Have you seen any of the people who research ME/CFS talk about dropped BP while sleeping? For many years I woke up feeling like I had a hangover. It hasn't been so bad lately, but I still get it sometimes. There's a thread here of people talking about that.

 

[Violeta]

@pgrovetom, is it an adrenal insufficiency issue? I don't understand it very well, yet, and may be asking a stupid question, but am wondering.

 

[Violeta]

I have to look through your messages, but I'm going to put this here right now because I will lose it and forget about it, and if it's not important for you, just ignore it.



Adenosine, a purine nucleoside, decreases heart contractilityin a number of ways:

Slows heart rate: Adenosine slows the heart rate and the speed of impulses between heart muscles.

Reduces atrial contractility: Adenosine reduces atrial contractility.

Slows AV conduction: Adenosine slows the conduction between the atria and ventricles

Glutamate:

We conclude that L-glutamate stimulation of the LHAt lowers the cardiac output and heart rate by both parasympathetic and beta-adrenergic mechanisms and elicits hypotension by lowering cardiac output in the naive and electrically paced model

Calcium/endoplasmic reticulum:
The calcium that enters the heart cell through the calcium ion channel activates the ryanodine receptor to release enough calcium from the sarcoplasmic reticulum to initiate heart muscle contraction. This is done by binding to another structure, named troponin, inside the heart muscle cell.


The heart has several types of receptors that control contractility, including beta-adrenergic receptors and alpha-1-adrenergic receptors:

• Beta-adrenergic receptors
  These receptors increase the heart's rate and contractility. The human heart has three subtypes of beta-adrenergic receptors: beta-1, beta-2, and beta-3. The beta-1 subtype is the most common, and both the beta-1 and beta-2 subtypes are activated by the stress hormones epinephrine and norepinephrine. In heart failure, the number of beta-adrenergic receptors decreases, and the remaining receptors become uncoupled from Gs.
  
  
  
• Alpha-1-adrenergic receptors
  These receptors can mediate cardioprotection by inhibiting the death of cardiac myocytes, increasing protein synthesis, and increasing glucose metabolism. Alpha-1-adrenergic receptors can also increase myofilament Ca2+ sensitivity, which prolongs the duration of contraction.
  
  
  Butcher's broom:

• Ruscus aculeatus (butcher's broom) as a potential treatment for orthostatic hypotension, with a case report​

• https://pubmed.ncbi.nlm.nih.gov/11152059/

Chronic orthostatic hypotension (OH) is frequently a severely debilitating disease that affects large groups of the population with autonomic insufficiency--the elderly; patients with diabetes, Parkinson's disease, and chronic fatigue syndrome; and anyone on drugs that affect the autonomic nervous system.

Although it has never been suggested as a treatment for OH, it already has a long, proven record of use in Europe for treating a variety of circulatory disorders.

 

[pgrovetom]

That's so great that you figured that out, and had the endurance to stay on top of pushing for the testing.

That's a really big BP range!

Is the sympathetic nervous system not doing what it's supposed to be doing because of a problem with the HPA axis?

Have you ever had restless leg syndrome?

Have you seen any of the people who research ME/CFS talk about dropped BP while sleeping? For many years I woke up feeling like I had a hangover. It hasn't been so bad lately, but I still get it sometimes. There's a thread here of people talking about that.

That range is with Fludrocortisone. My HPA axis appears normal. Yes I have RLS. No I haven't seen any doctors that research ME/CFS. And I'm not claiming I found the deep molecular cause but rather the intermediate low BP which causes symptoms. There are many things at a molecular level that could cause the sympathetic nervous system to not regulate low BP while sleeping. That being said, extreme dipping is a known mechanism that has been tied to a lowering of the Baroreceptors threshold in the brainstem and hypothalamus regulatory functions. Why one person is 10% and another is 30% is not understood.

 

[Violeta]

I had restless leg/whole body while trying to sleep last night, and realized it was from eating too many grapes, some even after dinner.

So I will be more careful to not eat too much food high in potassium, especially in the evening, and also drink the salt water in the evening and then again some time during the night.

I do tend towards low blood pressure, but then I guess eating too much food high in potassium makes it dip too low at night. Now I'm thinking that may be why potatoes give me insomnia. They definitely make it more difficult to stand.

I had read that fruit it not helpful for flailing adrenals, I wonder if it's the potassium.

Anything that is a diuretic would be unhelpful. I realize someone said that earlier, and that everyone else knows that, but I'm just saying it for myself because understanding it on a deeper level.

 

[pgrovetom]

What do you mean by flailing adrenals. The HPA axis primary function is to regulate Cortisol via the hypothalamus CRH-> pituitary ACTH -> Adrenal Cortex Cortisol with negative feedback of Cortisol to both the hypothalamus and pituitary. The regulation is tied to the circadian rhythm such that Cortisol is minimal at night and increases to maximum in the early morning and drops through the day. Then the cycle repeats.

The adrenals also produce aldosterone which is used by the Kidneys to help regulate sodium. The adrenal medulla also produces hormonal catecholamines - adrenaline type hormones such as epinephrine and norepinephrine in response to the Sympathetic neural outflow which is increased by the fight-or-flight response, fear, emotional stress, upright posture, pain, cold, hypotension, hypoglycemia and other stressors. This regulates the background adrenaline in the blood which is additive to the Sympathetic NS targeted adrenaline.

 

[Violeta]

I am not saying adrenal fatigue is the cause of restless leg or low blood pressure or even blood pressure dips during the night for everyone, but I am pretty sure it is the cause for me.

That might be why Butcher's Broom and l-tyrosine help me, too, it helps conditions caused by low norepinephrine.

RLS and adrenal fatigue are closely associated

Dr Lam has some good information.

https://www.drlamcoaching.com/adrenal-fatigue/#what-is-adrenal-fatigue

https://www.drlamcoaching.com/diet/adrenal-fatigue-diet/adrenal-fatigue-diet-tips/

Maybe this info doesn't belong in this thread. I will read through the thread again in the morning.

 

[Florida Guy]

My theory is that oxygen is involved in the process that produces pem in the muscles. But its not because of a lack of oxygen, people have tried taking supplement 02 and even many sessions in a pressure chamber. While some got improvement in certain things or felt better, oxygen so far has not cured anyone with mecfs or prevented crashes. However, the symptoms of pain in the muscles is much the same as when people exercise too much and have stiffness and soreness later

When healthy people exercise they use oxygen to burn carbs etc for energy. Depending on fitness, at some point they are not able to use oxygen to create energy so they go into an ANaerobic phase rather than the usual aerobic phase. This evolved over millions of years to give animals a little extra energy to get away from the predator. The after effect is painful stiffness similar to some symptoms of pem.

What seems to be happening to us is instead of being able to walk, run or do some activity for a few hours or maybe 6 to 8 hours before getting tired, we run into our limits of the 'energy envelope' or whatever you want to call it, much sooner and start anaerobic metabolism. Healthy people don't do that unless they push themselves super hard but for us, it happens if we did even a little too much. We switch over to anaerobic instead of using oxygen as its supposed to work.

So even though we have plenty of oxygen in our bodies and in the bloodstream and even in the cells, we aren't able to use it properly. After a short time our body tries to switch over and there is less energy available for the cells. We get brain fog because the brain isn't using energy properly, other organs aren't working as well when we go into a crash and get various symptoms. It will take research to find the cause, it may be the lack of some enzyme or something else