L Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) latest paper from fluge and mella

Wishful

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observed remissions are rare events and who even has them?
I didn't mean officially observed (by researchers with labs); just that some of us have observed them. I've certainly had more than 6. I (vaguely) recall other people reporting them here. They seemed to be total remission of the symptoms for some number of hours. I'm not sure whether the major boost of energy was an actual effect, or if it was just relief from the constant grind of ME. They were absolutely wonderful when they occurred though. :)
 

Pyrrhus

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so I liked this diagram because it at least shows us how collagen fibers are a key component of this vasculature.

So this damage to our physical structure- seems to be potentially linked into this dysfunction.


And here is a simpler diagram, if it helps:

Blood vessels are enclosed by a layer of cells called endothelial cells, which are similar to a layer of skin surrounding a blood vessel. These endothelial cells are themselves surrounded by a layer of muscle tissue. The muscle tissue can squeeze the endothelial cells, constricting the blood vessel, or they can relax, allowing the blood vessel to dilate. This muscle tissue is generally controlled by autonomic nerves. Any dysfunction in the constriction or dilation of a blood vessel might be referred to as "endothelial dysfunction".
 

Hufsamor

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One thing I don’t understand….
Fluge and mellar have ‘healed’ a few, like a 100%.
And their papers suggest this is really possible for many patients if they find and target the correct immune response for each person.

BUT! If lack of collagen is an issue, how will targeting the immune response bring collagen back into the vasculature?
Or is there something I’ve missed?
 
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“As Rituximab targets CD20-positive cells, patients whose autoantibody production occurs in CD20-positive plasmablasts would be likely responders. In the majority of patients, however, autoantibodies may be produced in CD20-negative, long-lived plasma cells not targeted by Rituximab”
Haven’t read the whole paper but here’s one thing I don’t understand:
If autoantibodies would play a major roll in mecfs, why does plasmapheresis or immunadsorption have little to no success as a treatment?
 

Hufsamor

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Ok, I’m trying to work myself slowly through the papers as I have the greatest respect for the doctors behind it.

“There is growing evidence for endothelial dysfunction in ME/CFS, affecting large arteries, assessed by flow-mediated dilation (FMD), and small arteries, assessed by postocclusive reactive hyperemia (refs. 9, 10, and Figure 1).

The endothelial dysfunction was not associated with laboratory markers of endothelial dysfunction seen in cardiovascular disease, which argues for a different mechanism, possibly related to an abnormal immune response .”

So- a vascular problem seems to be almost established.
 
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Hufsamor

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But here are what caught my interest,
“one subgroup” , and “other patients”


If I get this right: (all?) me/ cfs patients have a vascular problem.
But different ones.


Meaning, maybe, that a lack of collagen might be the main problem, or one of the main problems for some, but not for others.
But nevertheless the end result will be the same, not enough oxygen..
Leading to all sort of trouble.
Any thoughts?
@Pyrrhus ?


“Head-up tilt testing using extracranial Doppler measurements of carotid and vertebral arteries has shown reduced cerebral blood flow (11), which may contribute to PEM and cognitive dysfunction. In a recent study assessing ME/CFS patients with upright cardiopulmonary exercise test (CPET) and invasive monitoring,

a subgroup of the patients had reduced right atrial pressure and venous return (preload failure), with reduced cardiac output and reduced peak oxygen uptake on exertion (12).

Other ME/CFS patients showed evidence of microcirculatory disturbances with impaired peripheral oxygen extraction, compatible with arteriovenous (AV) shunting and possibly related to neurovascular dysregulation and small fiber neuropathy (12).

Impaired oxygen extraction in muscles during exercise tests has also been demonstrated by noninvasive measurements (13). According to the CPET test results, the circulatory disturbances could not be explained by deconditioning in patients with orthostatic intolerance and reduced cerebral blood flow upon head-up tilt testing (14) nor in patients with exercise intolerance and low biventricular filling pressures or impaired AV oxygen extraction (12
 
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I don’t know what to think of it. Too severe to read it completely so I skimmed it. Can anybody explain:

How does that translate to PEM severe patients get from reading? How does it explain the sensitivities to sound/light etc? How does it explain the metabolic impairments?

I would love to see a research group conducting a meta study linking all the findings of the last years and exclude those who are unlikely correct…

Edit: I find this part particularly interesting:

“ If so, one would expect a greater benefit for patients with less ongoing immune activation and less vascular dysregulation, but with main symptom contributions from the secondary autonomic adaptations. Conversely, patients with active immune disturbance and ongoing vascular dysregulation as the main symptom generators would have less impact from cognitive intervention, although psychosocial support and coping strategies may still have a beneficial impact on their quality of life.”

So, a friend of mine who had severe ME for year's with POTS got out of bed solely with DNRS. If I understand them right, it's more due to controlling the parasympaticus than the limbic system (as these programs claims).

So: If s.o. for example doesn't respond to let's say Mestinon and is negative for the Scheibenbogen GPR AAb, then he*she might be a responder to these “cognitive technics”

Did I get that wrong?
 
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Hufsamor

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Endothelial dysfunction with inadequate flow regulation to meet the demands of tissues, reduced venous tone and return, and reduced cardiac output on exertion as well as AV shunting with reduced peripheral oxygen extraction would all result in tissue hypoxia, which we believe may be a common pathomechanistic denominator in ME/CFS .

Several two-day CPET studies have shown that ME/CFS patients have ventilatory anaerobic threshold at a lower workload compared with healthy subjects, especially on day two (15), which is a manifestation of PEM. PEM often occurs with a time lag after exertion and may be sustained for days and weeks. One may speculate that some symptom-generating factors are pathologically reinforced by exercise. Moreover, patient reports of transient symptom improvement from oxygen inhalation, from nitroglycerin-mediated vasodilation (briefly alleviating the “brain fog”), or from saline infusions (to increase volume and venous pressure) may correspond with poor vasoregulation.

Evidence of neuroinflammation in ME/CFS, associated with lactate accumulation and microglia activation , could also be related to impaired autoregulation of blood flow and brain tissue hypoxia caused by mental or physical exertion.
 

Pyrrhus

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“There is growing evidence for endothelial dysfunction in ME/CFS, affecting large arteries, assessed by flow-mediated dilation (FMD), and small arteries, assessed by postocclusive reactive hyperemia (refs. 9, 10, and Figure 1).

The endothelial dysfunction was not associated with laboratory markers of endothelial dysfunction seen in cardiovascular disease, which argues for a different mechanism, possibly related to an abnormal immune response .”

So- a vascular problem seems to be almost established.
Note that the main vascular problem appears to be dysautonomia of the autonomic nerves that control the dilation or constriction of blood vessels. Some say that this dysautonomia is caused by an immune response targeting the autonomic nerves.

But there are other possible vascular problems as well:

Endothelial Dysfunction in ME
https://forums.phoenixrising.me/threads/endothelial-dysfunction-in-me.83521/


Meaning, maybe, that a lack of collagen might be the main problem, or one of the main problems for some, but not for others.
But nevertheless the end result will be the same, not enough oxygen..
Insufficient collagen might worsen any existing dysautonomic problems with constriction or dilation of blood vessels as it means the walls of the blood vessels are weaker:

ME/CFS Patients with Joint Hypermobility Show Larger Cerebral Blood Flow Reductions during Orthostatic Stress Testing... (van Campen et al., 2021)
https://forums.phoenixrising.me/thr...c-stress-testing-van-campen-et-al-2021.84635/


In a recent study assessing ME/CFS patients with upright cardiopulmonary exercise test (CPET) and invasive monitoring,

a subgroup of the patients had reduced right atrial pressure and venous return (preload failure), with reduced cardiac output and reduced peak oxygen uptake on exertion (12).
Here is that excellent study:

Insights from Invasive Cardiopulmonary Exercise Testing of Patients with ME/CFS (Joseph et al., 2021)
https://forums.phoenixrising.me/thr...patients-with-me-cfs-joseph-et-al-2021.82907/
 

Hufsamor

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How does it explain the metabolic impairments?
Several studies have reported metabolic changes in ME/CFS patients, e.g., A. Germain et al. (19) and Ø. Fluge et al. (20). The results suggest altered utilization of substrates for energy metabolism, such as increased use of amino acids and fatty acids for tricarboxylic acid cycle (TCA) fueling, with reduced glucose and pyruvate oxidation. Impaired pyruvate dehydrogenase (PDH) function due to increased expression of PDH kinases (PDKs) (20) may indicate chronic activation of physiological metabolic programs that normally protect cellular energy (ATP) supply under demanding conditions, such as endurance exercise, hypoxia, or starvation. Metabolic adaptations, aiming to maintain and restore energy supply, may be caused by an underlying tissue hypoxia on exertion in ME/CFS. This restriction will compromise homeostasis and promote energy strain and corresponding metabolic responses.
 
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Several studies have reported metabolic changes in ME/CFS patients, e.g., A. Germain et al. (19) and Ø. Fluge et al. (20). The results suggest altered utilization of substrates for energy metabolism, such as increased use of amino acids and fatty acids for tricarboxylic acid cycle (TCA) fueling, with reduced glucose and pyruvate oxidation. Impaired pyruvate dehydrogenase (PDH) function due to increased expression of PDH kinases (PDKs) (20) may indicate chronic activation of physiological metabolic programs that normally protect cellular energy (ATP) supply under demanding conditions, such as endurance exercise, hypoxia, or starvation. Metabolic adaptations, aiming to maintain and restore energy supply, may be caused by an underlying tissue hypoxia on exertion in ME/CFS. This restriction will compromise homeostasis and promote energy strain and corresponding metabolic responses.
I've read that paragraph but what bothers me is that it is (I) reduced to exertion while there are metabolic impairments without exertion and (II) these thesis is reduced on tissue hypoxia. Why should for example Abilify help with with it?
 

Boba

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I've read that paragraph but what bothers me is that it is (I) reduced to exertion while there are metabolic impairments without exertion and (II) these thesis is reduced on tissue hypoxia. Why should for example Abilify help with with it?
Could be the case that there are antibodies to the dopamine receptors, as there are for other G protein coupled receptors… So Abilify could be reducing the effects of autoimmunity via the increase of dopamine.

Maybe it’s a big family of gpcr antibodies which is giving us a hard time. Some known others unknown. I hope they will find treatments for those antibodies soon. Really wonder whether bc007 would help…
 
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Could be the case that there are antibodies to the dopamine receptors, as there are for other G protein coupled receptors… So Abilify could be reducing the effects of autoimmunity via the increase of dopamine.

Maybe it’s a big family of gpcr antibodies which is giving us a hard time. Some known others unknown. I hope they will find treatments for those antibodies soon. Really wonder whether bc007 would help…
Then all dopamine agonists should work (which would be a good thing)
Maybe I'm too stupid, but my brain doesn't want to make a common sense of all the findings of the last years
 

Boba

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Could be the case that there are antibodies to the dopamine receptors, as there are for other G protein coupled receptors… So Abilify could be reducing the effects of autoimmunity via the increase of dopamine.

Maybe it’s a big family of gpcr antibodies which is giving us a hard time. Some known others unknown. I hope they will find treatments for those antibodies soon. Really wonder whether bc007 would help…
Obviously this is not an explanation why it would help with blood flow aso
 
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Boba

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Then all dopamine agonists should work (which would be a good thing)
Maybe I'm too stupid, but my brain doesn't want to make a common sense of all the findings of the last years
You‘re not too stupid… It‘s complex and there are still missing pieces of the puzzle (big ones).

Autoimmunity is a root worth to explore. I will get my antibodies checked this week.
 

Hufsamor

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Why should for example Abilify help with with it?
Maybe it’s a big family of gpcr antibodies which is giving us a hard time.
“The vascular system and possibly GPCRs are potential targets for autoantibodies, which may affect endothelium or neurovascular control and autonomic small nerve fibers.”

Maybe abilify targets this particular problem better than other dopamine agonists.
 
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Why should for example Abilify help with with it?
Then all dopamine agonists should work (which would be a good thing)
Just an idea after a quick google search: It seems the specific D2 receptors to which Abilify binds are also important for endothelial function everywhere in the body. In this study a D2R agonist "increased phosphorylation of endothelial nitric oxide synthase, leading to enhance NO production" which would improve endothelial function.

Influence of bradykinin B2 receptor and dopamine D2 receptor on the oxidative stress, inflammatory response, and apoptotic process in human endothelial cells - PubMed (nih.gov)