Maybe this is better for a members only thread?
In general, I like the OMF approach because it is a consortium of researchers not just a single researcher/research group.
Having said that, Polybio is also a research consortium , but…..well you know.
News From Jarred Younger / Neuroinflammation, Pain, and Fatigue Laboratory at UAB, From Aug 2020
- Thread starter wigglethemouse
- Start date
Maybe this is better for a members only thread?
In general, I like the OMF approach because it is a consortium of researchers not just a single researcher/research group.
Having said that, Polybio is also a research consortium , but…..well you know.
I think the point was to simulate the immune system activation without actual infection using LPS to show how ME/CFS feels. The theory is that over-active immune system is making us feel sick.
The tracers bind to activated microglial cells as far as I know. So, the tracers lighting up the image means activated microglia, which presumably means inflammatory cytokines. Whether the images are interpretable I have no idea. I suppose the peer reviewers will tell us if it means something or nothing.
His team already made the imaging for FMS available. I suspect the ME/CFS study will be similar, except that it'll get wider scrutiny given the controversy around ME/CFS and LC.
jnmaciuch
Senior Member (Voting Rights)
I get the theory, he kept repeating it as if it was proven fact over and over again.
LPS is a widely used tool for TLR stimulation on immune cells in an experimental context. Like I said before, the only thing he’s modeling is actual bacterial infection.
Personally I think there’s a good case for suspecting some part of the immune response is involve in ME/CFS, but I also think there’s a world of difference between suspecting there’s immune involvement and using LPS stimulation to “model” ME/CFS when you don’t know what’s going on in ME/CFS.
I’m pretty familiar with the method, it was something an old department member presented on multiple times in the context of neurolupus.
There’s no specific PET marker for “activated microglia,” only some proteins which we think get expressed at relatively higher levels on microglia in an extremely-broadly-defined phenotypic state that may or may not correlate with specific cytokine release in other contexts. I’m guessing they used TSPO, maybe CSF1R if they’re really keeping up with the field.
The entire category of “activated microglia” is more or less an empty concept for anyone who studies immunology. It’s as coherent as assuming someone will have 27 particular food items in their fridge at home based solely off of whether they chose a meat or vegetarian entree at a restaurant.
Jonathan Edwards
Senior Member (Voting Rights)
Why so? Surely it just means there is a protein on the microglia that has been associated in other situations in which microglia change expression in response to signals and which maybe are associated in other situations with some cytokines being produced. What if ME/CFS is a conditions where the chain of events does not follow usual rules (which is pretty much a certainty in one way or another).
Would these be cytokines stimulating the microglia or cytokines produced by the activated microglia, for instance? And since there is no inflammation present what more does it tell us anyway, since these so called inflammatory cytokines are not being pro-inflammatory?
Very early on I learnt that building theories using plug-in dogma modules is the quickest route to nowhere.
ChronicallyOverIt
Established Member (Voting Rights)
I think there’s tactful ways of doing this. Presenting it weekly on youtube to the patient population of sick individuals with high hopes is not one of those
Jesse
Senior Member (Voting Rights)
@jnmaciuch @Jonathan Edwards Given that DecodeME has started pointing us more towards the brain and Jarred's lab focusses on the brain in ME/CFS, do we have any leads that would be more interesting for him to pursue? Considering the disappointment here with his current endeavours..
If there is a protein that is more frequently expressed by microglia in people who have conditions effecting the brain, would it not be useful to know if that increased expression occurs in ME/CFS? There seems to be good evidence that TSPO is elevated in certain conditions and after brain injury, so it must be measuring some process related to these conditions. Even if we don't know why this protein is expressed more frequently, knowing if it is the case could be worthwhile.
I think Younger would agree that ME/CFS is a condition where the chain of events do not follow the usual rules. He thinks it is an abnormal glial response to some stimulus; when some process along the chain of events reacts far too strongly compared to the usual case. If it is the case that LPS triggers increased TSPO expression in ME/CFS compared to healthy people that could be interesting too. I don't LPS is "modeling" ME/CFS just controlling the stimulus variable to see if there is a difference response to a controlled challenge. Would exercise be a better challenge I don't know, but the goal is to see if the TSPO activation is stronger in ME/CFS.
In what sense can cells be following different sets of rules? To me cells can only follow rules, an autoimmune B cell is just following the rules and pumping out antibodies that happen to cause other issues. Cancer cells are just following a set of rules to rapidly multiply. If the usual rules are the set of rules that happen in a healthy person, every condition does not follow the usual rules or there would be no pathology.
I think you are missing the point. It’s actually better that he is doing these under-evidenced videos.
I don’t have any confidence that he would be able to execute a high-level science project. Basically every year since I started on these forums maybe eight years ago he has been talking about how he was going to do a huge screening of all of these great candidate anti-neuro inflammatory compounds he has.
Crickets.
Jonathan Edwards
Senior Member (Voting Rights)
Absolutely, I am not disagreeing with that. I am disagreeing with the use of the term 'neuroinflammation' when nobody knows what they mean by it. Specifically, we do not know that the presence of a molecule on microglia means that cytokines are causing inflammation nearby.
Certainly, each cell will follow rules that apply at the level of individual molecular event sequences but I am talking of higher level 'rules'.
A simple example is IL-6 production by Kupffer cells. IL-6 might be considered a 'pro-inflammatory cytokine' but because Kupffer cells are located inside venules rather than outside there is no inflammatory action - there is nowhere for white cells to be attracted out to. The effect is acute phase protein production by nearby hepatocytes.
Microglia are rather like macrophages but their environment differs in all sort of way, like Kupffer cells. Saying that because there is a molecule on their surface they must be responding to, or maybe producing (even this is unclear) 'inflammatory cytokines', does not necessarily follow.
But the key point is that when you come to individual diseases the hold-all bag concept of 'inflammation' becomes not just unhelpful but dangerously misleading because it implies all sorts of things that may well not happen and treatments that are almost certain to fail.
Jonathan Edwards
Senior Member (Voting Rights)
As an example of why one has to think which cell is making the cytokine and which cell is responding I am reminded of the years wasted on T cells in RA. Everyone was obsessed with the idea that the inflammation was due to T cells and that they must be TH1 cells because the main cytokine present was TNF. What they seemed blind to was that macrophages make about 00 times as much TNF as T cells in response to immune complexes and macrophage activation had been documented as the most consistent early change in the tissue (not T cell infiltration).
So it turned out that the T cells were there in response to the inflammation (resulting from macrophage TNF) rather than the inflammation there in response to T cells.
If brain microglia are important in ME/CFS, and they may well be, we need a specific story of what cell tells what other cell what and where that originates and how it might fit the specific clinical picture.
So it turned out that the T cells were there in response to the inflammation (resulting from macrophage TNF) rather than the inflammation there in response to T cells.
If brain microglia are important in ME/CFS, and they may well be, we need a specific story of what cell tells what other cell what and where that originates and how it might fit the specific clinical picture.
DigitalDrifter
Senior Member (Voting Rights)
Not sure why he thinks placebo worked better than CBD because there was eventual regression to mean by the time the trial had finished (no difference between active group and placebo group).
shak8
Senior Member (Voting Rights)
Well, that's useful. FM pain levels high this month and I was just going to spend some money on a trial of CBD:THC 30:1 tincture.
So now I have to read the clinical trial data (re any FM patients) on suzetrigene (Nav1.8) trade name Journax might work for me....that's expensive as well. For acute pain only.
My pain feels pretty acute. I might ask for a trial of it and get a coupon/discount. Either that or ask for an opioid. Pain at a level of 8/10 lasting days is scary and not fun.
So now I have to read the clinical trial data (re any FM patients) on suzetrigene (Nav1.8) trade name Journax might work for me....that's expensive as well. For acute pain only.
My pain feels pretty acute. I might ask for a trial of it and get a coupon/discount. Either that or ask for an opioid. Pain at a level of 8/10 lasting days is scary and not fun.
My understanding was that the treatment ended at 24 weeks, however they collected an additional datapoint at 36 weeks, and that is the one where the two groups had no difference. So it appears they reverted after 12 weeks of no treatment.
Mij
Senior Member (Voting Rights)
@shak8
My retired financial advisor has very good results with CBD for his back pain. He no longer needs prescription meds that negatively affected his liver enzymes. He has a prescription for CBD and also buys another product online. It was the difference between being able to walk again or debilitating back pain.
He explained that taking CBD was about timing, he took it early in the morning hrs before getting up.
Only side affect was the munchies.
I hope you can finally get relief!
My retired financial advisor has very good results with CBD for his back pain. He no longer needs prescription meds that negatively affected his liver enzymes. He has a prescription for CBD and also buys another product online. It was the difference between being able to walk again or debilitating back pain.
He explained that taking CBD was about timing, he took it early in the morning hrs before getting up.
Only side affect was the munchies.
I hope you can finally get relief!
DigitalDrifter
Senior Member (Voting Rights)
May be the CBD actually made the patients' Fibromyalgia pain a little worse but there was still some response bias, but the placebo group had more response bias.
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