Community Symposium on the Molecular Basis of ME/CFS Sept 5 (Stanford/Ron Davis)

BrightCandle said:
Jonathan will appreciate Robert Phair's question on whether ME/CFS is an inflammatory process and what actually differs between acute and chronic inflammation and how can we be precise with our language? They seemed to express that its not a precise word but they don't yet know how to express the gradient of responses being seen and what to call it. What I didn't get a good answer to was is the cell types and molecules different and I think he is right that really matters.
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Was thinking the same.
 
I thought @Jonathan Edwards is quite adamant about inflammation actually having a precise meaning that for various reasons people have stopped using.
It is defined as a tissue change mediated by blood vessels, with dilatation, fluid and protein exudation and cell emigration. It makes the part red, hot, swollen, painful and malfunctioning, although these things vary in degree (chronic inflammation is not very red and may be painless).
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ChronicallyOverIt said:
@jnmaciuch in the Stanford PET scan presentation they are using a new tracer called GPR84. I remember from the Jared younger thread you were versed in tracers. Have you heard of this tracer before? Thoughts on it? Also this new TREM1 tracer seems interesting
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Unfortunately wasn’t able to catch this presentation though I saw some of the morning ones.

It’s not a tracer that anyone in my department mentioned using so I don’t have any specifics to pass on about it. From a quick glance, it seems to be a similar story as TSPO—something which has been observed to strongly increase in surface expression in immune cells undergoing phenotypic and metabolic reprogramming under stimulation, but can be induced under many different conditions. You can guess that some other signaling molecules may be likely to be produced by cells with induced expression of that marker, but it would just be a guess.

Having good data showing that this G-coupled protein receptor is strongly upregulated might be interesting in its own right, but I’d caution against assuming any “if there’s smoke there’s fire” situation relationship re: other immune signaling.
 
I haven't seen any of these presentations. Was there talk of an increased signal for a microglial activity marker? It would not come as a surprise if there was but to take it seriously I would want to see a specific distribution pattern different from normal. The thing that worried me about the Nakatomi pictures was that they were just like a normal distribution only slightly stronger. That could easily be due to artefact. A specific distribution would be far more convincing.
 
Jonathan Edwards said:
I haven't seen any of these presentations. Was there talk of an increased signal for a microglial activity marker?
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The PET presentation I did catch from the Stanford group did not go into specifics this deep, it was more of an overview showing full body PET with TSPO was signalling far stronger and different areas than healthy controls, notably the shoulder/neck area (they alluded to “coat hanger syndrome”) and quadriceps. They were mostly talking about using PET for diagnosis of ME/CFS. I believe they said this paper would be out later this year or early next year showing these results.

They then went on to explain they can tune tracers to cross different barriers, BBB, and that development of tracers for ME/CFS could help diagnosis. She also eluded that development of novel tracers at their lab can be quite quick, about 1 year at max speed.
 
ChronicallyOverIt said:
an overview showing full body PET with TSPO was signalling far stronger and different areas than healthy controls, notably the shoulder/neck area (they alluded to “coat hanger syndrome”) and quadriceps.
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Shoulder/neck and quadriceps would be fascinating if real. I cannot think of another situation where that pattern comes up.

Polymyalgia rheumatica shows increased water content on MRI in tissues around the shoulder and hip. That suggests genuine low-level inflammation with increased permeability of vessels to water. The pictures suggest that the changes relate to fascial or epimyseal areas around muscles. There are potential ways to make sense of that in terms of immune complexes. As far as I know MRI shows nothing in ME/CFS in these areas.

I wonder if anyone has imaged flu myalgia with PET/TSPO.

I am probably not holding my breath yet though.
 
Jonathan Edwards said:
Shoulder/neck and quadriceps would be fascinating if real. I cannot think of another situation where that pattern comes up.
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Hopefully it’s real, there was no numbers presented just some screen grabs of the PET scans. She also said people thought she was crazy to do full body scan and after her findings she was grateful she did since they saw such odd results. There was brief mention that the odd quadricep results could point towards POTS causes.

Very interested in your take after the recordings come out, these are my notes and remembrance of the presentation.

Edit: Totally wrong about the numbers, look at post below
 
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Jonathan Edwards said:
Shoulder/neck and quadriceps would be fascinating if real. I cannot think of another situation where that pattern comes up.
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When this was polled years ago in now-defunct groups, the two most frequent sites of pain came up as shoulders/neck and quads. There was quite a gap between that and the next most common, intercostal muscles.

Always stuck in my mind because it was so odd. Usually backs top the list; neck and shoulders must be nearly as common, but why with quads?

Not particularly useful information (I can't even remember who ran it), but if I'd had to place a bet in advance of these results I might have got a return on my ten bob.
 
Is this linked at all to the “crunchy” neck and stiffness people sometimes report:

B

Post in thread 'Muscle and joint stiffness worsened by activity'

jnmaciuch said:
maybe the best way I can describe it is that joints and muscle feel like they’re “styrofoam-y”—when it’s in my neck and I rotate it, I can actually hear a slight crunching sound as if I was crushing styrofoam. It tends to accompany the crackling-feeling.

Does this sound familiar to anyone else? It’s very distinct from soreness or rigidity as if the muscle was contacting.
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mine doesn't crackle and it is more sore and the cracks or pops are I now know not joints (but when it is my wrist it is still hard to realise that when it does a big loud click) but around them and normally in...
 
ChronicallyOverIt said:
Is this linked at all to the “crunchy” neck and stiffness people sometimes report:

B

Post in thread 'Muscle and joint stiffness worsened by activity'

jnmaciuch said:
maybe the best way I can describe it is that joints and muscle feel like they’re “styrofoam-y”—when it’s in my neck and I rotate it, I can actually hear a slight crunching sound as if I was crushing styrofoam. It tends to accompany the crackling-feeling.

Does this sound familiar to anyone else? It’s very distinct from soreness or rigidity as if the muscle was contacting.
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mine doesn't crackle and it is more sore and the cracks or pops are I now know not joints (but when it is my wrist it is still hard to realise that when it does a big loud click) but around them and normally in...
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It is my shoulders/neck and ankle joints where this was most noticeable by far so it could be in line. Not sure if it is the same for others
 
The tracer is DPA-713, a second generation tracer designed by Dr James 20+ years ago. She really seems to know how to design tracers with a long track record of developing different ones since then.

Jonathan Edwards said:
Was there talk of an increased signal for a microglial activity marker?
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What I learned today from the symposium is that the PBR/TSPO receptor lives on the mitochondrial membrane so that is where the tracer binds. TSPO tracer binding is in fact a mitochondrial membrane marker that lights up during cellular stress, one such example being inflammation. Dr Naviaux described in the discussion the biochemical role of the receptor in the mitochondrial membrane as important for cholesterol transport (I wish I could remember more of what was said).

I gather that whole body PET is rather new, so clinical interpretation is helpful to try and understand what the results actually mean for ME/CFS.
 
At these annual events, I find myself wondering how much progress the field has made since the previous year. I realise that the public talks don't represent what is going on in the closed-door talks, and of course DecodeME represents a huge step forward, but I'm curious to know what people's sense is of whether we're seeing much forward movement.
 
Sasha said:
At these annual events, I find myself wondering how much progress the field has made since the previous year. I realise that the public talks don't represent what is going on in the closed-door talks, and of course DecodeME represents a huge step forward, but I'm curious to know what people's sense is of whether we're seeing much forward movement.
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Last year they were talking about the potential for a Zebrafish model and now they have genetically modified some fish and run a number of tests with it. They were also talking about their mouse knockout model and that too is now delivering some results. One of the 4 compounds (one FDA approved, one "natural" and 2 others) could be a big deal if they are right about the Itaconate shunt and activation model. If those models are good then they have made decent progress from where they were last year.

They could go from validating these drugs in mouse to a pilot trial in the coming year and an FDA approved drug can be pretty quick to become a reality as could a natural product. They might also be studying something not really the core of the disease and its not progress at all, we really don't know. The thing is about the Ron Davis and OMF development is they have been hypothesis testing for years now. Its all based on a good understanding of what is different in the disease but the prior hypothesises (like metabolic trap) were not correct so this one could be wrong too. Given the testing of the models responses everything so far looks aligned with the disease and they have been chasing this target now for 4 years.
 
Sasha said:
I'm curious to know what people's sense is of whether we're seeing much forward movement.
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I've grown increasingly sceptical about some of the OMF approaches (and quite a bit of the other US-based work,). So much emphasis seems to be on testing and imaging, as if they're certain it's going to be something you can see on a screen.

They might be right, of course, but aside from Rob Phair's work there doesn't seem to be much theoretical modelling going on. All the hopes seem to hang on the next shiny bit of kit that's going to show us the toadstone.
 
BrightCandle said:
They could go from validating these drugs in mouse to a pilot trial in the coming year
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I would really like to see their model put to the test in this way. I feel like OMF stanford are always claiming they are on the verge of this, and like Kitty have lost faith in their approach somewhat. It's all well and good mucking around with animal models but unless you've tested your model in people you have no idea whether it's valid.

Of course I will be over the moon if they deliver.

The PET scans sound really facinating, and I really hope they can be validated. A diagnostic scan would be gamechanging, even if it wasn't accessible in the clinic just yet.
 
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