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Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

Sing

Senior Member
Messages
1,782
Location
New England
@nandixon That is interesting. Well then I will adjust down a bit some other things I take at night to see if there is a linkage and synergy going on resulting in that dry mouth. I'll do some gentle tinkering.

For you, are the beneficial effects of cimetidine a noticeable improvement in overall energy and a reduction in the time it takes you to get through PEM? That is what I remember your saying.

I think that Jarred Younger might be very interested in cimetidine or something like it, in order to improve our metabolic processes. I noticed that some of the studies linked to via this thread connect the mTorc1 pathway to leptin. Maybe this is why Younger got that mysterious result a few years ago relating ME/CFS with leptin levels. Hunger signalling or the lack of it didn't seem directly pertinant--not to me--yet why was a persistant low energy, hypo condition so linked to leptin? Why are there metabolic similarities with sepsis and starvation for that matter? The links aren't immediately obvious but there must be similarities in the metabolic pathways employed by these disparate conditions. Sorry I am not better educated scientifically so I can really be in the conversation, but if you want to comment, I will try to understand what you write.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
@nandixon @MeSci I have been trying Cimetidine 50 mg twice a day over the past several days. It causes so much dryness of mouth when I am sleeping that it interferes with maintaining sleep, so I will back off to just taking it once a day an hour or so after breakfast. This must be its anti-histamine aspect which is causing the excessive dryness. Otherwise it didn't cause any problems. On the positve side I had a feeling of more pressure. Can't say for sure if blood pressure improved--went up but it seemed I could walk better. I will continue in a longer trial. From the post #675 above, it seems that improved mTorc1 signalling might be linked to improved sympathetic nerve activity and blood pressure? The science here is above my level, but @nandixon do you think that cimetidine could improve, raise, low blood pressure? Thanks!
I can't remember what I found - I did quite a lot of searches online before starting it to make sure there wouldn't be any predicted adverse results, and I recall a slowing of metabolism of something I take (nebivolol?) but nothing drastic, and there don't seem to be any adverse effects with 50 mg.

Nebivolol is to combat my HIGH blood pressure!

There may be slightly increased slowing. Hope I'm making sense.
 

Sing

Senior Member
Messages
1,782
Location
New England
@MeSci Yes, you are making sense. I recall gabapentin as being one of the medications that is cleared a little more slowly but I would be happy about that. It seems as though, metaphorically speaking, cimetidine can reach the general gas pedal and the brake, not for drastic effects, but just the fact that it is even in contact with the gas and the brakes is interesting. It seems indicative that it is affecting a main metabolic pathway--would that be correct?
 

nandixon

Senior Member
Messages
1,092
@nandixonFor you, are the beneficial effects of cimetidine a noticeable improvement in overall energy and a reduction in the time it takes you to get through PEM? That is what I remember your saying.
Yes, more energy and a higher threshold for development of PEM. But the ME/CFS has continued to progress in the two years since starting it. Early on the cimetidine basically took me from entering into a bedridden state to about half a level up from that to more middle-moderate.

I think that Jarred Younger might be very interested in cimetidine or something like it, in order to improve our metabolic processes. I noticed that some of the studies linked to via this thread connect the mTorc1 pathway to leptin. Maybe this is why Younger got that mysterious result a few years ago relating ME/CFS with leptin levels. Hunger signalling or the lack of it didn't seem directly pertinant--not to me--yet why was a persistant low energy, hypo condition so linked to leptin?
We'll need a more effective treatment than cimetidine for ME/CFS. But on the subject of Younger's 2013 leptin study, one guess is that leptin may be going high in order to try to activate mTORC1 - but without success.

Why are there metabolic similarities with sepsis and starvation for that matter?
They both have an under-activated mTORC1 pathway. In the former case it seems aberrant while in the latter it's in response to a lack of nutrients.
 
Messages
23
@Sing
Dry mouth is usually a sign of anticholinergic effects. That's really why antihistamines cause dry mouth, they have anticholinergic properties independent of their antihistamine effects (which is why they can worsen cognition & cause dementia with long term use). Cimetidine itself has anticholinergic side effects.

Here's an article listing anticholinergic meds that contains links to the source papers if you want more detailed info:
www.peoplespharmacy.com/2015/02/01/where-can-i-find-a-list-of-anticholinergic-drugs/

To help with the side effects of cimetidine, you could reduce doses of cimetidine or other drugs you take that have anticholinergic effects...or you could try taking some procholinergic sups/meds to counteract the dry mouth, like PhosChol, etc.

P.s. Ordering Cimetidine & PhosChol today to try myself.
 

kangaSue

Senior Member
Messages
1,851
Location
Brisbane, Australia
I have been trying Cimetidine 50 mg twice a day over the past several days. It causes so much dryness of mouth when I am sleeping that it interferes with maintaining sleep, so I will back off to just taking it once a day an hour or so after breakfast. This must be its anti-histamine aspect which is causing the excessive dryness.
If you are also taking a calcium channel blocker, cimetidine can increase the effect of that so you may have too much calcium channel inhibition which can cause a dry mouth. Reducing the strength of the CCB is a work around if that's the case.
 

nandixon

Senior Member
Messages
1,092
Cimetidine itself has anticholinergic side effects.
Cimetidine only shows appreciable anticholinergic activity in large experimental in vitro doses. There shouldn't be any noticeable effect in humans taking therapeutic size doses, especially not 50 mg at a time.

I would definitely know it if cimetidine had any bothersome anticholinergic activity because I'm very sensitive to that due to having below normal RBC acetylcholinesterase activity.

However, cimetidine can definitely potentiate the effects of other anticholinergic medications. It actually used to be used that way in hospitals on purpose.

So a person who's been taking diphenhydramine, for example, may very well need to adjust that down.
 
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deleder2k

Senior Member
Messages
1,129
hi could uou tell me what you are respnding to here. i have not read the whole thread. ive always said i feelbetter when i dont eat

I am not sure what I responded to, but my point is that fasting seems to alleviate some of my symptoms.
 

nandixon

Senior Member
Messages
1,092
Not sure. If it turns out there is impaired S1P signaling, and it has an autoimmune basis, then I guess there might be a chance of it being helpful. [Edit: Although fingolimod initially acts as an agonist to the S1P receptor it ultimately behaves as a functional antagonist, so definitely not what we want.]
I've rethought about the possibility of fingolimod potentially working in ME/CFS. There's actually a way it just might work, as I'll explain below.

My original idea was (and still is) that the Fluge & Mella study is showing that the mTOR (mTORC1) pathway is under-activated in ME/CFS.

I thought a good candidate for causing this under-activation could be impaired sphingosine-1-phosphate (S1P) signaling. That's because Naviaux's last study showed that ceramides (from which S1P is made in two steps) were low in ME/CFS, and because there are S1P receptors (e.g., S1PR1 aka S1P1) just upstream of both Akt and Erk, two of several pathways that lead to mTORC1. Not to mention that additional pathways using S1P signaling seem to be impaired in many ME/CFS patients, especially those involving endothelial function and blood pressure/volume regulation.

The question then still remains as to what's causing the low ceramides. It may be that there's some impairment in the synthesis of ceramides, but an additional theoretical possibility might be that ceramides are being kept purposefully low in order to protect neural cells in the brain from higher levels of S1P potentially exacerbating some problem there. (S1P has both good and bad effects throughout the body.) Various S1P receptors are located on a variety of neural cell types, e.g. microglia, neurons, astrocytes, etc.

And this is where fingolimod might come in. If, for example, there are agonistic autoantibodies against S1P receptors in neural cells, or if there are neural cells that are somehow dysregulated and S1P is contributing to this, then an S1P "agonist" like fingolimod, which actually behaves as a functional antagonist against many S1P receptors, might be useful after all.

It looks like using fingolimod would be exactly the wrong thing from a peripheral point of view (for endothelial function, etc), but in the brain it might just have the correct effect and that might override everything else. Because when fingolimod acts on neural S1P receptors, it stimulates brain-derived neurotrophic factor (BDNF) which can then activate both Akt and Erk and thus mTORC1. (See, e.g., some of the studies in this Pubmed search string.)

BDNF was shown to be low in one ME/CFS study but normal in a subsequent one. Both of these studies may actually be wrong, though, because it's possible that neither plasma nor CSF levels may give an accurate read on local brain tissue levels.

In addition, fingolimod may have a general neuroprotective and neuro-regenerative/-restorative effect. (2016 study)

It would be nice to have a more selective drug than fingolimod to try, but since it's not clear exactly what effect one might want it may be worth trying. It's very difficult to predict how bad the side effects could be with this drug in ME/CFS. If it worked, though, it might be a good alternative to rituximab.
 

Snow Leopard

Hibernating
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5,902
Location
South Australia
"Sphingolipids in Psychiatric Disorders and Pain Syndromes" (book chapter)
http://link.springer.com/chapter/10.1007/978-3-7091-1511-4_22

Abstract

Despite the high prevalence and devastating impact of psychiatric disorders, little is known about their etiopathology. In this review, we provide an overview on the participation of sphingolipids and enzymes responsible for their metabolism in mechanisms underlying psychiatric disorders. We focus on the pathway from sphingomyelin to proapoptotic ceramide and the subsequent metabolism of ceramide to sphingosine, which is in turn phosphorylated to yield anti-apoptotic sphingosine-1-phosphate (S1P).

The sphingomyelinase/ceramide system has been linked to effects of reactive oxygen species and proinflammatory cytokines in the central nervous system as well as to synaptic transmission. Compared to ubiquitously expressed acid sphingomyelinase, acid and neutral ceramidase and neutral sphingomyelinase are highly active in brain regions. Depressed patients show elevated plasma ceramide levels and increased activities of acid sphingomyelinase which is functionally inhibited by many anti-depressive drugs. Exposure to alcohol is associated with an activation of acid and neutral sphingomyelinase observed in cell culture, mouse models and in alcohol-dependent patients and with increased concentrations of ceramide in various organs.
Levels of sphingomyelin and ceramide are altered in erythrocytes and post-mortem brain tissues of schizophrenic patients in addition to changes in expression patterns for serine palmitoyltransferase and acid ceramidase leading to impaired myelination. After induction of anxiety-like behavior in animal models, higher serum levels of S1P were reported to lead to neurodegeneration. Correspondingly, S1P infusion appeared to increase anxiety-like behavior. Significantly upregulated levels of the endogenous ceramide catabolite N,N-dimethylsphingosine were observed in rat models of allodynia. Conversely, rats injected intrathecally with N,N-dimethylsphingosine developed mechanical allodynia. Moreover, S1P has been implicated in spinal nociceptive processing.

May be of interest.

Sphingomyelinase is responsible for breaking sphingomyelin (SM) down into phosphocholine and ceramide. The activation of SMase has been suggested as a major route for the production of ceramide in response to cellular stresses. (from Wikipedia)

Also, type-2 diabetes is associated with elevated ceremides
https://www.ncbi.nlm.nih.gov/pubmed/23835113

Studies using cultured cells, animal models, and human subjects demonstrate that ceramide is a key player in the induction of β-cell apoptosis, insulin resistance, and reduction of insulin gene expression. Ceramide induces β-cell apoptosis by multiple mechanisms namely; activation of extrinsic apoptotic pathway, increasing cytochrome c release, free radical generation, induction of endoplasmic reticulum stress and inhibition of Akt. Ceramide also modulates many of the insulin signaling intermediates such as insulin receptor substrate, Akt, Glut-4, and it causes insulin resistance. Ceramide reduces the synthesis of insulin hormone by attenuation of insulin gene expression.
 
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TrixieStix

Senior Member
Messages
539
I'd really like to thank those who brought up primary biliary cirrhosis as a possibility. My symptoms match pretty well (especially my itchy skin!) I spent the evening reading about it and am going to test the theory that it's an extension of celiac disease/gluten enteropathy.

I wanted to try the keto diet, but I think that's going to have wait. I've switched to a higher protein paleo diet (grain and dairy free with low sugar). I also intend to use resistant starch and soluble fiber to improve gut health. The resistant starch has already helped lessen my Raynaud, so I'm hoping it will help with this possible PBC too. But the lack of bile flow in a PBC situation makes bacterial overgrowth much more likely, so this could be tricky.

I'm anxious to get to the point where I can tolerate vitamin A. I think it's extremely important for autoimmune conditions, but it taxes my already low protein reserves. (I already have ankylosing spondylitis, Raynaud and suspicion of Hashimoto, so the autoimmune etiology seems likely in my case.)
Did you end up getting tested for PBC?
 

kangaSue

Senior Member
Messages
1,851
Location
Brisbane, Australia
S1P is made from ceramides in two steps:

ceramides--> sphingosine--> S1P
http://pubmedcentralcanada.ca/pmcc/articles/PMC3661866/
1. Sphingolipid Metabolism
Over the past 20 years, sphingolipids have emerged on the scene as pleiotropic signaling molecules implicated in the regulation of various cellular functions [3]. The first necessary step in the de novo pathway of ceramide generation involves Palmitoyl Co-A and the amino acid serine condensation, via the action of the enzyme serine palmitoyl transferase (SPT), to form dihydrosphingosine (DHS) (Fig. 1). Recently shown, SPT can undergo a change in substrate preference, from serine to alanine or glycine, leading to the production of 1-deoxysphinganine and 1-deoxymethylsphinganine, respectively [4]. Following its synthesis, serine-derived DHS then becomes acylated via action of the ceramide synthases to become dihydroceramide (Fig. 1) [5]. Dihydroceramide is then desaturated to form ceramide. Members of the large family of CerS are responsible for the addition of varying lengths of acyl chains, resulting in numerous dihydroceramide and ceramide species (Fig.1). Ceramide may also be generated by the breakdown of membrane sphingomyelins or via degradation of complex glycosphingolipids by the action of sphingomyelinases (SMase) and glucosyl ceramidases (GCase) respectively, as seen in Fig 1. Degradation of ceramide is carried out by the ceramidases (CDase), whereby the acyl chain is removed from ceramide and the 18 carbon amino-alcohol compound sphingosine is formed. Sphingosine then serves as the substrate for the sphingosine kinases (SKs) which are responsible for phosphorylating sphingosine at the primary hydroxyl group, resulting in the production of sphingosine 1-phosphate (Fig.1) [6]. In lieu of being phosphorylated by SK to S1P, sphingosine can be recycled back to ceramide via CerS-mediated reacylation [7]; this mechanism of ceramide generation is referred to as the salvage pathway. Of particular interest to this review are the SK enzymes as well as their product, the bioactive sphingolipid molecule sphingosine 1-phosphate (S1P)

http://pubmedcentralcanada.ca/pmcc/articles/PMC3661866/figure/F1/ (Sphingolipid metabolic pathway diagram)
 

kangaSue

Senior Member
Messages
1,851
Location
Brisbane, Australia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529762/
Lysosomes coordinate mTORC1 signalling.
While the signaling functions of mTORC1 have long been appreciated, lysosomes have more recently been identified as the major intracellular site where growth factor and nutrient signals converge to activate mTORC1

Taking a cue from the above, I've seen it mentioned in a number of quarters that abnormal levels of lipids have been detected in skeletal muscle in ME/CFS. A similar occurrence can happen in some Lysosomal Storage Disorders too, has anyone had a Lysosomal Enzyme Storage Panel done to see if they have any irregularities there?

Neuropathy and chronic gut problems tend to go hand in hand with this.

GM1 Gangliosidosis is one such thing that comes under the Lysosomal Storage Disorders umbrella that I have seen found in both the people who had ME/CFS in one small study;
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896049/
[This study provides strong support for the long-standing observation by Pestronk and colleagues that a one-to-one complex of GM1:GalC constitutes a very sensitive antigen for screening MMN sera(Pestronk et al., 1997). Indeed, in this cohort of 33 MMN cases, all sera were reactive against the GM1:GalC complex in glycoarray screening, including those that were not reactive to either GM1 or GalC alone. In addition, 4 cases whose sera were negative for antibodies to the GM1:GalC complex by ELISA, were positive by glycoarray. These findings need to be viewed cautiously until the overall conclusions can be validated in other cohorts of MMN cases and appropriate controls. Although the 33 cases from our national area were randomly selected for inclusion in this survey, referral bias to both our diagnostic neuroimmunology laboratory and clinical service may have been a factor in increasing the proportion of antibody positive cases. The principle clinical point emerging from this study is that the diagnostic yield of the standard anti-GM1 antibody ELISA can be improved upon through use of the combinatorial glcyoarray]
 

wastwater

Senior Member
Messages
1,271
Location
uk
I find that codeine has a positive effect on me especially on mood,but has a terrible day after effect,so I never take it now.
 

Snow Leopard

Hibernating
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5,902
Location
South Australia
Some more info for those who enjoy confirmation bias.



Gq-Coupled Receptors in Autoimmunity
Lu Zhang and Guixiu Shi

https://www.hindawi.com/journals/jir/2016/3969023/

4. The Diversity of Gq-Coupled GPCRs Mediates Activation of Signal-Regulated Pathways

Binding partners to GqPCR distinct from PLC-β include novel activators (Ric-8A and tubulin), candidate effectors (RhoGEFs, PI3K, GPCR kinases (GRKs), Btk, and complex regulator of G-protein signaling (RGS) proteins), regulators (RGS proteins and GRKs), and scaffold/adaptor proteins (EBP50/NHERF1, CDP/CD81, caveolin-1, and TPR1) [1, 4, 6, 50]. Downstream of these signaling proteins, signals through GPCR to Gq family members exhibit unexpected differences in signaling pathways and the regulation of gene expression profiles [8, 50].

4.1. Gq-Related PLC-β and PKC/Calcium Pathways

PLC-β is the most well-known downstream effector molecule of GqPCR (Figure 1). The canonical pathway for the Gq/11 family is the activation of PLC-β enzymes, which catalyze the hydrolysis of the minor membrane phospholipid phosphatidylinositol bisphosphate (PIP2) to release IP3 and DAG [4–7, 13, 14]. These second messengers serve to propagate and amplify the GqPCR-mediated signal with calcium mobilization following release from IP3-regulated intracellular stores and DAG-mediated stimulation of PKC activity [4, 5]. Inositol lipids, DAG, PKC, and calcium each participate in multiple signaling networks, linking Gq family members through a host of different cellular events [1]. This pathway has been widely studied as a marker of GqPCR signaling [8]. As the aforementioned chemokine receptors, there are classic (Gi) and alternative (Gq) coupled GPCR pathways depending on the specific type of the chemokines and chemokine-stimulated cells [38]. The Gi is through AC pathway mentioned in the introduction part. The Gq activates the PLC family that can regulate the extracellular calcium entry in chemokine-stimulated cell and also subsequently influence the downstream effectors such as PI3K/Akt for survival of the cell.

4.2. The PI3K-Akt-Mammalian Target of Rapamycin (mTOR) Pathway

Multiple reports have documented the negative influence of Gq-coupled receptors on the growth factor-directed activation of PI3K and Akt isoforms [1, 4–7, 13]. One report showed that Gαq directly inhibits the PI3K p110a catalytic subunit in vitro [51]. In addition, a previous study also showed that Gαq represses Akt activation in fibroblast cell lines [52–54] and cardiomyocytes [55, 56]; however, overexpression of Gαq in cardiomyocytes leads to cardiac hypertrophy and cardiomyocyte apoptosis [10, 57].

PI3K can be activated by the βγ dimers released from Gi-coupled receptors [5]. In contrast, Gq normally inhibits PI3K activation and prevents activation of Akt [6, 7, 10, 14, 38]. Furthermore, Gαq inhibits the activation of the PI3K-Akt pathway, as has been demonstrated in Gnαq−/− mice. Indeed, by measurement of the phosphorylation of Akt at Ser473 (phospho-Akt), a phosphorylation site under the control of PI3K demonstrated that the level of phospho-Akt was higher in Gnαq−/− mice than in WT B cells [58]. Furthermore, deletion of phosphatase and tensin homolog (PTEN), an inhibitor of PI3K, also promotes mature B-cell survival [59] and can rescue autoreactive B cells from anergy [60]. Interestingly, the autoreactive prone marine zone-like B (MZB) cell compartment is also expanded in mice expressing activated p110 or lacking PTEN [61]. In the absence of Gαq, B cells constitutively express higher levels of activated Akt and preferentially survive BCR-induced cell death signals and BAFF (B-cell-activating factor of the TNF family, also known as BLyS, for B lymphocyte stimulator) withdrawal in vitro and in vivo [10, 58, 62]. The B cells isolated from multiple models of autoimmunity have been reported to express elevated levels of phospho-Akt [62], and perturbations in the PI3K/Akt axis can lead to the development of autoimmunity [51, 62].

4.3. The MAPK/ERK Pathway

In addition to PLC-β and PI3K, many studies have demonstrated that Gq-coupled receptors can also regulate other intracellular signaling molecules, such as members of the MAPK family [6, 7, 50, 57]. The MAPK signaling cascade is one of the most ancient and evolutionarily conserved signaling pathways and responds to a broad range of extracellular and intracellular changes [63–67]. Among the MAPKs, p38 MAPK regulates the expression of tumor necrosis factor- (TNF-) α, interferon- (IFN-) γ, and other cytokines via transcriptional and posttranscriptional mechanisms. Therefore, inhibiting p38 MAPK may abrogate TNF-α, providing potential anti-inflammatory effects [65, 68, 69]. Predominant Th1 and Th17 cytokine production are characteristic of many organ-specific autoimmune diseases, and the dysregulation of p38 MAPK activity specifically in autoreactive lymphocytes appears to enhance IL-17 and IFN-γ expression [66, 70–72]. Additionally, the ERK pathway can be activated by the small G protein Ras via the Raf group of MAP kinase kinase kinases (MKKKs) [66]. Solid evidence has supported that endothelin-dependent ERK/MAPK activation depends on the GqPCR/PLC-β/Ca2+/Src signaling cascade [64]. Taken together, these studies have shown that GqPCR and Gαq are involved in the activation of ERK.

Thus, complex GPCR signaling should be studied as a concerted network at the systems level [73]. The detailed “cross-talk” mechanism between these GqPCR pathways still needs to be explored in the future.


Examples of Gq-coupled receptors

Examples of Gi-coupled receptors
Additional info you might be wondering about - beta adrenergic receptors couple to Gs subunit.

"Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217865/


"The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation"
http://pharmrev.aspetjournals.org/content/67/1/36
 

Belbyr

Senior Member
Messages
602
Location
Memphis
Yes, that is one very deep article but I think it is one of the best I have read in a while. I need to re-read it about 15 more times and pass along to some other groups!
 
Messages
516
@Snow Leopard That list of g receptor examples is a great launchpad for things to look at and it looks mostly as you'd expect with some extra very interesting tidbits... But those parts you bolded about B cells... Is this trying to imply that elevated mTor localized to B cells could be an issue? This isn't the first time localization questions or "paradox" about mTor comes up but it's the first time it's sounded relevant... Or is this invoking the other "paradox" where the B cells in CFS might behave opposite to those in autoimmunity?... Or...? (I can't post a lot and very tired so just trying to get the point)
 
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Anne

Senior Member
Messages
295
PS I wonder how diagnostic we could make an NK cell function test in ME. If we test NK cells in our own serum, and isolated NK cells, and compare function, would this be diagnostic? Would that be an easy test? This would be a way to turn the inconsistencies in our NK cell tests to our advantage, presuming it works and is reliable.

There are two types of tests. Normally you get the same result from both. In us you get opposite results. So I would like to know if that were diagnostic, as the tests are available NOW and have been for many years.

No. Sigh. This has been discussed, even came up at the IACFSME conference, but its not formally published.

You might recall that NK function tests have had wildly variable results. It turns out that tests in our serum show low NK function, and tests out of our serum show OK NK cell function. That includes in the sera of healthy people. That appears to be potentially diagnostic to me. BOTH these tests are NK function tests, but done two different ways.

This is about some factor in our blood, or lack thereof, turning NK cell function off.

Some tests of NK cell function leave the cells in the patient's blood when testing. This is the test that would give you usable information.

Other tests of NK cell function take the cells out of the patient's blood. From what we know so far, it appears that something in the blood is depressing NK cell function, so if your cells were taken out of the serum they could be expected to perform normally. These tests would be essentially useless in determining your NK cell function.

@alex3619 and @Cheesus - Could you help me by pointing me to more information on this? Is there a discussion in other threads here? And do you know who mentioned it at the IACFS/ME conference?

I also have information pointing towards there not being a problem in the NK cells (when isolated), but possibly a problem with a soluble factor in the blood/serum of ME patients (could, in speculation, be an autoantibody - or something else) which seems to be inhibiting NK cell function. Grateful for help, I am in touch with researchers and would like to contribute to moving this discussion forward.

Also tagging @mango and @Johannawj FYI