PRIME International Symposium, September 28-29 2026

Jonathan Edwards said:
I had a look through the slides on that video presentation. I find it very hard to see how there can be functional capillary narrowing due to BM thickening here. I may be wrong but both frozen section and EM techniques have artefact problems (ice, obliquity, etc etc). I would prefer to see something like a 1 micron plastic section stained with Toluidine Blue on tissue put straight into glutaraldehyde. Individual high power images are always tricky to interpret. You really need to drive around a slide. The measurements look clear cut but I find it hard to see how such a clear cut difference is not reflected clinically. These are presumably static longstanding changes if real, so single CPETs should be well off, i think.
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Have you ever talked to Rob Wust directly about your reservations?
 
Jonathan Edwards said:
I am not sure that capillaries (without a muscular media) dilate much, other than just filling with blood when arterioles open
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No?
SNT Gatchaman

Thread 'Multicentre retrospective detection of nailfold videocapillaroscopy abnormalities in long covid patients, 2025, Ginaldi et al.'

Multicentre retrospective detection of nailfold videocapillaroscopy abnormalities in long covid patients
Lia Ginaldi; Giovanna Cuomo; Study Group on Capillaroscopy and Microcirculation in Rheumatic Diseases of the Italian Society of Rheumatology (Capsir); Emanuele Gotelli; Rosanna Campitiello; Dilia Giuggioli; Maurizio Cutolo; Serena Guiducci; Valeria Riccieri; Carmen Pizzorni; Francesco Carubbi; Evy Di Ruscio; Rossella De Angelis; Emanuela Martinelli; Massimo De Martinis; Vanessa Smith; Alberto Sulli; Silvia Sammorì; Ernesto Aitella; Francesca Ingegnoli; Sabrina Marrone; Marco...
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And this mouse model of myofibre injury showed it with eGFP1790700184911.webp
Jonathan Edwards said:
I am also very unclear how it is thought all these changes alter oxygen exchange, which I don't think has much to do with permeability to water or protein.
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I mean that's just what Wust's team is claiming to be a downstream effect of their findings to explain impaired performance in ME/CFS. But it could just be a red herring, we don't have to take that as true to accept changes in BM thickness downstream of some abnormal signaling. You'd expect reduced lumen diameter to create clinical signs only if it significantly constricted the passage of RBCs. If it's possible for capillaries to dilate somewhat, that can compensate. So long as the blanket of collagen IV doesn't impair oxygen diffusion we can explain normal day 1 CPET. And if exercise induces more of whatever local signaling caused that BM thickness increase over time, it could explain day 2 worsening (assuming that signaling has other effects than inducing BM depositions)
 
jnmaciuch said:
I mean that's just what Wust's team is claiming to be a downstream effect of their findings to explain impaired performance in ME/CFS. But it could just be a red herring, we don't have to take that as true to accept changes in BM thickness downstream of some abnormal signaling.
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Yeah this is my interest as well. I'm mostly really curious about what could be causing the changes in BM thickness, if they're real. (Somewhat analogously, the buspirone-prolactin studies were based on a questionable serotonin hypothesis about ME/CFS, but they may have still have hit on an interesting thread to pull on and look upstream of.)
 
jnmaciuch said:
But it could just be a red herring, we don't have to take that as true to accept changes in BM thickness downstream of some abnormal signaling.
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No, but there is an awful lot of explaining needed to get generalised capillary basement membrane changes in the absence of any detectable causal mechanism like diabetes or amyloid. And in thsoe conditions we see progressive microvascular changes with severe cases showing obvious clinical ischaemia or permeability problems (intractable oedema) and nobody with ME/CFS ever showed anything like that.

I have looked at these data several times. I have had an email exchange with Rob Wüst in relation to the other findings relating to exercise but not this. I remain confused. I would like to see a formal publication.
 
By the way, there are also some LC papers discussing a similar finding. I haven't looked into it much yet though.

SNT Gatchaman said:
Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology (2022)

Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology (2023)

See links to summary images in those papers here and here.
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SNT Gatchaman said:
On their EM findings, reduced capillaries, abnormal endothelial cells and basement membrane thickening / duplication I screen-grabbed in post #48 look to replicate findings (not universal in that n=11 cohort) in Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles (2023)
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This might be a stupid question, but could these measurements be affected by behaviour close to the time of imaging
or sampling?

Even the most active of us are driven to rest in PEM, meaning there can be a substantial change in activity levels or patterns.
 
Jonathan Edwards said:
You can get pathological structural widening of capillaries in things like dermatomyositis but someone would have picked that up on routine histology I think.
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Who says it has to be a pathological structural widening? Is that the only explanation for the nail bed findings? Or could it be something like slightly impaired endothelial tight cell junction binding, which allows capillaries to widen more than normal with active blood flow but would not look wider than normal on a biopsy slice. If only there was a class of signaling molecule that has been shown to have specific effects on collagen production, ECM degradation enzymes, and endothelial tight cell junctions.
Jonathan Edwards said:
No, but there is an awful lot of explaining needed to get generalised capillary basement membrane changes in the absence of any detectable causal mechanism like diabetes or amyloid. And in thsoe conditions we see progressive microvascular changes with severe cases showing obvious clinical ischaemia or permeability problems (intractable oedema) and nobody with ME/CFS ever showed anything like that.
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Well yes, the mechanism would have to be different than other diseases. That's what a pick n' mix signaling theory is for.
 
jnmaciuch said:
Who says it has to be a pathological structural widening? Is that the only explanation for the nail bed findings?
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Yes. They are done under controlled conditions and we know these are structural changes.

There are an awful lot of tricky questions here. Why did Peter and Wilhelmena Behan, who were intensely interested in ME/CFS muscle and reported mitochondrial changes not notivce any of this? Why did Joan ROund, who studied ME/CFS muscle biopsies in an extended research programe find none of this? Why have routine service pathologists looking at the not insignificant number of muscle biopsies done on people with ME/CFS not noticed this?

Changes in capillaries capable of being clinically relevant (which is what is being claimed) are not too hard to see. In dermatomyositis you can sometimes see them from the end of the bed. If the changes are specific to muscle, why? The tissue in the frozen section slides otherwise looks pristine.

I think I have probably said enough.
 
Jonathan Edwards said:
Yes. They are done under controlled conditions and we know these are structural changes.

There are an awful lot of tricky questions here. Why did Peter and Wilhelmena Behan, who were intensely interested in ME/CFS muscle and reported mitochondrial changes not notivce any of this? Why did Joan ROund, who studied ME/CFS muscle biopsies in an extended research programe find none of this? Why have routine service pathologists looking at the not insignificant number of muscle biopsies done on people with ME/CFS not noticed this?

Changes in capillaries capable of being clinically relevant (which is what is being claimed) are not too hard to see. In dermatomyositis you can sometimes see them from the end of the bed. If the changes are specific to muscle, why? The tissue in the frozen section slides otherwise looks pristine.

I think I have probably said enough.
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I've been trying to figure out a testable hypothesis that fits the (apparent) contradictions of a narrowed lumen on a slide vs. no clear clinical signs of impaired tissue oxygenation if the findings turn out to be real. The multiplicity of effects of cytokine signaling is one way of resolving that contradiction, since the same signals could theoretically cause collagen deposition and affect the endothelium in a way that preserves oxygenation during activity.

All that is an entirely separate question from whether or not these results are a fluke, which is what you're getting at here. We'd need an independent group to confirm the findings anyways.
 
jnmaciuch said:
The multiplicity of effects of cytokine signaling is one way of resolving that contradiction, since the same signals could theoretically cause collagen deposition and affect the endothelium in a way that preserves oxygenation during activity.
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Much as Claude might write the Marschallin's soliloquy from the first act of Rosenkavalier ;) .
I am getting old.
 
hotblack said:
Would you envision these changes being transitory @jnmaciuch or would it be a ‘it depends’ situation?
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I don't know if there's a clean answer to that unfortunately. Collagen deposits could be the long term build up of some transient signaling. They could also be the long term build up of some constant signaling. Or the findings could be a batch effect
 
chillier said:
My understanding, which could be wrong is that they replicated multiple (maybe 6?) of the decode hits. decodeME is also one of the cohorts included in their meta analysis.
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I have a couple of the posters from some of the GEM folk and on their gwas plots they appear to replicate 2 loci, arfgef2 and rabgap. The plots from the two posters are different though they've carried out different gwas on different cohort make ups. One of the GEM people said to me they had replicated 6 so I think all this stuff is a work in progress and we'll get a better sense in time.
 
chillier said:
I have a couple of the posters from some of the GEM folk and on their gwas plots they appear to replicate 2 loci, arfgef2 and rabgap. The plots from the two posters are different though they've carried out different gwas on different cohort make ups. One of the GEM people said to me they had replicated 6 so I think all this stuff is a work in progress and we'll get a better sense in time.
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Could you clarify if this is based on a study independent of the DecodeME cohort, or it's a meta-analysis that includes DecodeME?
 
Jonathan Edwards said:
Yes. They are done under controlled conditions and we know these are structural changes.

There are an awful lot of tricky questions here. Why did Peter and Wilhelmena Behan, who were intensely interested in ME/CFS muscle and reported mitochondrial changes not notivce any of this? Why did Joan ROund, who studied ME/CFS muscle biopsies in an extended research programe find none of this? Why have routine service pathologists looking at the not insignificant number of muscle biopsies done on people with ME/CFS not noticed this?

Changes in capillaries capable of being clinically relevant (which is what is being claimed) are not too hard to see. In dermatomyositis you can sometimes see them from the end of the bed. If the changes are specific to muscle, why? The tissue in the frozen section slides otherwise looks pristine.

I think I have probably said enough.
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Well there is one possible explanation to narrower vessels without the other signs of damage. The patients always had narrow capillaries before they even got ME/CFS or Long COVID and that has actually pre-conditioned them. This group would also be more sensitive to elevations in microclots.
 
MelbME said:
Well there is one possible explanation to narrower vessels without the other signs of damage. The patients always had narrow capillaries before they even got ME/CFS or Long COVID and that has actually pre-conditioned them. This group would also be more sensitive to elevations in microclots.
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Except that the narrowing is attributed to basement membrane thickening it seems. Thickening enough to narrow capillaries is not going to be constitutional. Somebody would have seen it on routine histology and given it a name.

I recently had a thought about the "microclots" that clarified my concern there. If these bits of stuff we are shown on slides were present in vivo and then survived centrifugation they must be, by a long way, too small to cause any problems with microvessels. To embolise in narrow vessels they would need to be about the size of a red cell and would centrifuge out easily. The story does not add up.
 
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