I think this one.
No confirmation yet that the symptoms improve with treatment though, as far as I can tell.
PRIME International Symposium, September 28-29 2026
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hotblack
Senior Member (Voting Rights)
In the same ballpark one of the avenues I went down early on and have heard others look to rule out was Addison's_disease, possibly supported by a local doc’s interest in cortisol
Jonathan Edwards
Senior Member (Voting Rights)
What puts me off is that the one set of micrographs shown has ice artefact in the picture that seems to be supposed to be abnormal.
And if there really was a dramatic difference in capillary calibre and oxygenation someone should have picked that up clinically long ago.
chillier
Senior Member (Voting Rights)
Interesting, so a possible batch effect of sample storage/handling between groups. The counter argument could be that there is a very strong correlation between lumen diameter * capillary number and power output
jnmaciuch
Senior Member (Voting Rights)
I remember from the paper they showed an increase in type IV collagen deposition—did they show the same in this data?
chillier
Senior Member (Voting Rights)
I can't remember seeing that but it's possible i missed it
As these two days draw to a close, I've been re-reading the piece which Chris Ponting wrote for the Conversation in 2024, two years ago next month
theconversation.com
I want to thank you for this @Chris Ponting
Ignored, blamed, and sometimes left to die – a leading expert in ME explains the origins of a modern medical scandal
The co-lead of the world’s largest ever genetic study into ME calls for a radical change in how society deals with the disease.
theconversation.com
I want to thank you for this @Chris Ponting
In contrast, by 2013, and despite my decades of scientific training and academic privileges, I had done nothing for ME research. Why did I hesitate? “It’s not my scientific area,” I told myself. I trusted other researchers to identify effective and potentially curative treatments soon.
I was unprepared for the shock of my first ME research meetings. When studying other diseases, I had become used to vast conference halls brimming with celebrated scientists, enthusiastic PhD students, science prize winners, funders, and journal editors, all on the hunt for the next big breakthrough, grant or career opportunity.
For ME, however, the rooms were small and half-empty, funders and journal editors were nowhere to be seen, and researchers were talking at cross-purposes, showing sparse data from small-scale studies. These meetings were also empty of robust evidence for what physiologically had gone wrong for so many. At each meeting, a single word came to my mind: “forsaken” – those who others shun, neglect and abandon, whose existence is denied. I could not then, in all conscience, turn my back and walk away.
Not once have I regretted this decision. Its professional cost – measured in traditional markers of esteem, such as “glamour” publications, international conference and seminar invitations – has been more than offset by the fulfilment from working in this long-neglected field.
The extent of scientific disinterest in ME is clear: so far this year, there have been 17-times more publications mentioning “multiple sclerosis” than those mentioning ME or CFS, despite MS being rarer.
New study
My privilege now is to walk ME’s city of stolen futures alongside many people – like Simon – whose lost decades have been spent searching for their disease’s root causes. Together, for two-and-a-half years our team went back-and-forth with the Medical Research Council MRC and the National Institute for Health and Care Research NIHR. Eventually, we managed to secure a £3.2m award for DecodeME, a hunt for ME’s genetic causes.
/SPOILER]
I was unprepared for the shock of my first ME research meetings. When studying other diseases, I had become used to vast conference halls brimming with celebrated scientists, enthusiastic PhD students, science prize winners, funders, and journal editors, all on the hunt for the next big breakthrough, grant or career opportunity.
For ME, however, the rooms were small and half-empty, funders and journal editors were nowhere to be seen, and researchers were talking at cross-purposes, showing sparse data from small-scale studies. These meetings were also empty of robust evidence for what physiologically had gone wrong for so many. At each meeting, a single word came to my mind: “forsaken” – those who others shun, neglect and abandon, whose existence is denied. I could not then, in all conscience, turn my back and walk away.
Not once have I regretted this decision. Its professional cost – measured in traditional markers of esteem, such as “glamour” publications, international conference and seminar invitations – has been more than offset by the fulfilment from working in this long-neglected field.
The extent of scientific disinterest in ME is clear: so far this year, there have been 17-times more publications mentioning “multiple sclerosis” than those mentioning ME or CFS, despite MS being rarer.
New study
My privilege now is to walk ME’s city of stolen futures alongside many people – like Simon – whose lost decades have been spent searching for their disease’s root causes. Together, for two-and-a-half years our team went back-and-forth with the Medical Research Council MRC and the National Institute for Health and Care Research NIHR. Eventually, we managed to secure a £3.2m award for DecodeME, a hunt for ME’s genetic causes.
/SPOILER]
jnmaciuch
Senior Member (Voting Rights)
My sense is that if this is real, it could easily be explained by a “middle range” of diameters, where there’s a clear significant difference from controls but its not so severe that it produces recognizable clinical signs. In which case the diameter reduction is likely to be a downstream consequence of whatever actually causes differences in muscle performance. That’s why I’m thinking of the type IV collagen finding from the paper—there are local signaling events that can change collagen production and explain the finding. IL-1B for example causes a selective increase in type IV deposition in-vitro (though some of the other findings in this model might not be consistent with Wust’s findings): https://www.ahajournals.org/doi/10.1161/01.RES.86.12.1259
There could be other unexplored factors that have a similar local effect, some other immune factor or something soluble that gets released with nearby muscle cell contraction.
V.R.T.
Senior Member (Voting Rights)
Yes thank you for this Chris, it is an affecting and powerful piece of writing.As these two days draw to a close, I've been re-reading the piece which Chris Ponting wrote for the Conversation in 2024, two years ago next month
Ignored, blamed, and sometimes left to die – a leading expert in ME explains the origins of a modern medical scandal
The co-lead of the world’s largest ever genetic study into ME calls for a radical change in how society deals with the disease.
I want to thank you for this @Chris Ponting
In contrast, by 2013, and despite my decades of scientific training and academic privileges, I had done nothing for ME research. Why did I hesitate? “It’s not my scientific area,” I told myself. I trusted other researchers to identify effective and potentially curative treatments soon.
I was unprepared for the shock of my first ME research meetings. When studying other diseases, I had become used to vast conference halls brimming with celebrated scientists, enthusiastic PhD students, science prize winners, funders, and journal editors, all on the hunt for the next big breakthrough, grant or career opportunity.
For ME, however, the rooms were small and half-empty, funders and journal editors were nowhere to be seen, and researchers were talking at cross-purposes, showing sparse data from small-scale studies. These meetings were also empty of robust evidence for what physiologically had gone wrong for so many. At each meeting, a single word came to my mind: “forsaken” – those who others shun, neglect and abandon, whose existence is denied. I could not then, in all conscience, turn my back and walk away.
Not once have I regretted this decision. Its professional cost – measured in traditional markers of esteem, such as “glamour” publications, international conference and seminar invitations – has been more than offset by the fulfilment from working in this long-neglected field.
The extent of scientific disinterest in ME is clear: so far this year, there have been 17-times more publications mentioning “multiple sclerosis” than those mentioning ME or CFS, despite MS being rarer.
New study
My privilege now is to walk ME’s city of stolen futures alongside many people – like Simon – whose lost decades have been spent searching for their disease’s root causes. Together, for two-and-a-half years our team went back-and-forth with the Medical Research Council MRC and the National Institute for Health and Care Research NIHR. Eventually, we managed to secure a £3.2m award for DecodeME, a hunt for ME’s genetic causes.
/SPOILER]
Jonathan Edwards
Senior Member (Voting Rights)
To reduce capillary calibre, type IV collagen increase would have to be huge, like late stage amyloid. I think it would be detectable on standard BM targeting stains.
I would like to see analysis of the material by a routine service clinical pathology unit with a special interest in muscle - like the one led by Joan Round in the 1980s at UCL that found nothing of note on biopsies.
V.R.T.
Senior Member (Voting Rights)
Yeah I remember that study, a replication attempt on that would be good. Did you email Altmann about it and not hear back?Nice work getting in contact. And agree if they can listen, learn and adapt it’s definitely worthwhile. This was an area I thought they may be interested in but haven’t heard anything
hotblack
Senior Member (Voting Rights)
Yep. I obviously don’t have your knack
V.R.T.
Senior Member (Voting Rights)
I never usually get replies from researchers! It was pleasantly surprising to get a prompt response from DA. Not sure what I did right this time!Yep. I obviously don’t have your knack
Hopefully they're aware of this study as they seem very aware of Fluge and Mella's daratumumab research.
hotblack
Senior Member (Voting Rights)
I think it’s probably little to do with us doing anything right or wrong a lot of the time. They’re busy, sometimes things align. As much luck/chance as anything. Just really pleased you keep on trying and that you got a positive response here
I hope so too. You’d expect someone on their team to be familiar but sometimes things ate missed so I don’t think it does any harm to share information where we can.
jnmaciuch
Senior Member (Voting Rights)
I mean that’s exactly what they showed previously in their data. The presenter says they used type IV collagen stains.
Timestamp 1:10
What are the indications for ordering those stains in clinical practice? Would ME/CFS patients meet it?
Jonathan Edwards
Senior Member (Voting Rights)
I was thinking of something simpler and more reliable. I forget what we used to use, but something suitably nineteenth century that a routine lab would have at hand. The structure is going to be easily visible with a standard microscope if the capillary is to be functionally narrowed by it.
Jonathan Edwards
Senior Member (Voting Rights)
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.
jnmaciuch
Senior Member (Voting Rights)
Unless it's adequately compensated by something that helps increase capillary dilation and endothelial permeability during activity. Minus the rubor calor dolor, of course
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jnmaciuch
Senior Member (Voting Rights)
Seems perhaps noteworthy that despite lumen narrowing, there are more CD3+ cells in the tissue at baseline in LC with PEM
Fig 5E https://www.nature.com/articles/s41467-023-44432-3
Fig 5E https://www.nature.com/articles/s41467-023-44432-3
Jonathan Edwards
Senior Member (Voting Rights)
I am not sure that capillaries (without a muscular media) dilate much, other than just filling with blood when arterioles open. 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.
I admit to being confused by these data. It would be good to see a formal publication.