But thyroid autoantibodies are increased in a range of other autoimmune diseases and may be an indirect clue to autoimmune goings on. At least one US study claimed a higher rate in ME/CFS.
I found a metanalysis by Park et al. 2022 on thyroid autoimmunity and fibromyalgia. Link between thyroid antibodies and FM.
In ME/CFS there's Loebel et al. 2016 who found correlations between "b AdR and M AChR antibodies with immunoglobulin levels, T cell activation, and elevated ANA and TPO antibodies." But unclear if either ANA or TPO/TG rates elevated in their sample.
Quickly reading through the thread and with reference to PET I think I remember in an earlier presentation (possibly in the MECFS roadmap series) by Michelle James that bone marrow showed signals. I forget the details. The healthy and MECFS weren’t well matched for BMI if i remember. Dr James made no comment on bone marrow in her recent Stanford presentation. Her paper due out in next few months.
General musculoskeletal pain, often very serious, has always been a major and almost constant feature for me. It has what feels like a very deep component, like it is underneath the muscle, and the bones themselves are hurting.
Would bone marrow experiencing altered pressure dynamics be consistent with that?
I see an interesting methodological catch22 in some of these questions.
What I realised with the DecodeME data is that we are looking at the causal effects of little packets of linked SNPs by and large. You might say that once you have checked the effect of each SNP independently you can tell you the effect is achieved. But if the SNPs never normally occur separately then you are proposing a 'cause' by reference to a counterfactual that never occurs. Although we like to think causes act on their own the reality is that all causation involves everything antecedent in a system and that we can only talk of causes in terms of legitimate possible counterfactuals.
An example of where this runs into trouble is the potential claim that 15% of the causation of RA is smoking. But for people who don't smoke that statement is meaningless and if in 30 years time nobody smokes it will be false.
The genes on the X chromosome are a gross example of 'linkage disequilibrium'. And the counterfactual of having all the genes on X except TLR7 might be possible in a mouse but it is not going to be in humans. You might say that we can still use indirect evidence to work out the exact causal role of TRL7. But potentially there is a worse problem still. That is that an absence of a TLR7 might in infancy lead to some other disease that makes you die before you ever get old enough to get ME/CFS.
An extreme analogy might be that if you wanted to test exactly which section of a clay pot on a wheel was making it wobble you cannot take out each bit of the pot and put in a new perfect bit to see what happens because you then get a wobble because of the joins.
Possibly. I was tempted to suggest that you 'feel ME/CFS in your bones' but decided it was a red mullet. Interestingly, apart from osetomyelitis and cancer deposits, pain from bone marrow is not often considered in medicine. In myeloma pain occurs when bones crumble but probably not just because of the plasma cells. I think it may be a red mullet.
Quickly reading through the thread and with reference to PET I think I remember in an earlier presentation (possibly in the MECFS roadmap series) by Michelle James that bone marrow showed signals. I forget the details.
PURPOSE
CD38 is a glycoprotein highly specific to multiple myeloma (MM). Therapeutics using antibodies targeting CD38 have shown promising efficacy. However, the efficient stratification of patients who may benefit from daratumumab (Dara) therapy and timely monitoring of therapeutic responses remain significant clinical challenges. To address these issues, we developed a novel nanobody-based PET tracer, [68Ga]Ga-TOHP-CD3813, which exhibits rapid clearance from the blood and rapid accumulation in targeted tumor lesions, facilitating the detection of CD38 expression in murine models of MM and lymphoma. Furthermore, we conducted the world’s first-in-human trials using CD38-targeted nanobodies to validate and assess the clinical imaging effectiveness of [68Ga]Ga-TOHP-CD3813 in guiding cancer immunotherapy.
MATERIALS AND METHODS
We prepared a new PET imaging probe based on a CD38-targeted nanobody CD3813, [68Ga]Ga-TOHP-CD3813, via the site-specific radiolabeling for noninvasive PET imaging of CD38 expression. [68Ga]Ga-TOHP-CD3813 was assessed for its affinity and specificity to CD38 and its ability to image CD38 expression in MM and lymphoma xenograft models. Biodistribution and the relationship between tumor uptake and CD38 expression were evaluated. Subsequently, we conducted a translational PET imaging of 2 MM patients using [68Ga]Ga-TOHP-CD3813, while compared with [18F]FDG PET/CT head-to-head. Dosimetry was also calculated based on the animal data.
RESULTS
TOHP-CD3813 retained a high affinity for CD38 with a KD of 0.0826 nmol/L. [68Ga]Ga-TOHP-CD3813 was successfully synthesized at room temperature within 10 min, exhibiting optimal radiochemical properties. Preclinical assessments revealed rapid blood clearance, high CD38 affinity, and significant uptake in CD38-positive xenograft mouse models (6.50 ± 2.69%ID/g). [68Ga]Ga-TOHP-CD3813 showed pronounced accumulation in the kidneys and bladder, with moderate liver uptake, indicating its potential as a viable clinical PET radiotracer for diagnosing MM. Additionally, in first-in-human trials, [68Ga]Ga-TOHP-CD3813 PET/CT provides a substantial improvement over [18F]FDG PET/CT for the visualization of MM.
CONCLUSIONS
[68Ga]Ga-TOHP-CD3813, with its high affinity, specificity, and robust imaging capabilities, rapidly and specifically accumulates in tumors with high CD38 expression, offering a significant advantage over [18F]FDG PET/CT for visualizing MM and enabling same-day PET imaging. Initial human trial results are promising, suggesting its potential as a companion diagnostic tool for optimizing CD38-targeted treatments in tumors. Ongoing larger trials aim to further confirm these findings.
Web | PDF | European Journal of Nuclear Medicine and Molecular Imaging | Paywall
I see an interesting methodological catch22 in some of these questions.
What I realised with the DecodeME data is that we are looking at the causal effects of little packets of linked SNPs by and large. You might say that once you have checked the effect of each SNP independently you can tell you the effect is achieved. But if the SNPs never normally occur separately then you are proposing a 'cause' by reference to a counterfactual that never occurs. Although we like to think causes act on their own the reality is that all causation involves everything antecedent in a system and that we can only talk of causes in terms of legitimate possible counterfactuals.
An example of where this runs into trouble is the potential claim that 15% of the causation of RA is smoking. But for people who don't smoke that statement is meaningless and if in 30 years time nobody smokes it will be false.
The genes on the X chromosome are a gross example of 'linkage disequilibrium'. And the counterfactual of having all the genes on X except TLR7 might be possible in a mouse but it is not going to be in humans. You might say that we can still use indirect evidence to work out the exact causal role of TRL7. But potentially there is a worse problem still. That is that an absence of a TLR7 might in infancy lead to some other disease that makes you die before you ever get old enough to get ME/CFS.
An extreme analogy might be that if you wanted to test exactly which section of a clay pot on a wheel was making it wobble you cannot take out each bit of the pot and put in a new perfect bit to see what happens because you then get a wobble because of the joins.
Which question does DecodeME attempt to answer? Is it «does pwME/CFS have this gene more/less often than others?»
If so, wouldn’t that solve the issue of proving causality because a gene can’t make a difference for the rate of ME/CFS if it isn’t involved in one ore more of the disease processes?
Smoking would also be involved in the disease processes of RA, but smoking isn’t required to develop RA.
This would be different from e.g. HD where you need to have the mutation to get the disease.
Perhaps someone should contact Michelle James about this then. If she isn't interested in studying cd38 herself she may be able to advise how best to go about it.
If so, wouldn’t that solve the issue of proving causality because a gene can’t make a difference for the rate of ME/CFS if it isn’t involved in one ore more of the disease processes?
I think things are a lot more complicated. The whole body and every gene are in some sense involved. A risk associated with a variant of a gene implies that the gene is particularly directly involved but the variant is not going to be necessary (in the way the HD gene is). But the bigger problem is that we may not be able to tell which of a string of 6 linked genes are involved because each possible combination of variant options may induce confounding effects that override the role of any one gene. I am being pessimistic, but I think we need to be cautious.
For the X chromosome, where all the genes are linked 100%, the problem becomes major unless you have SNPs associated with variants that confer risk, but there is no guarantee that for the relevant genes such variants exist and they apply to a different quetion from the one about sex ratio.
Michelle James and Vicky Wittemore discuss PET scan. Search document for “marrow” and it is discussed on page 10-11. Not much detail but they seem to think bone marrow and salivary glands are areas of interest.
My immediate thought is that this theory fails to explain abrupt switching between ME and non-ME states, since marrow cell production doesn't, AFAIK, change rapidly enough. It's possible that the mechanism that does allow that switching is affected by differences in cell production, but the marrow isn't key to ME. It might affect the likelihood of developing ME.
Another flaw: wouldn't such changes in marrow function likely cause longer-term changes in severity or responses to various factors? My ME has short-term (typically weeks or months) fluctuations, but I ascribe most of those to microbiome alterations. I'd call my baseline ME quite stable over 25 years.
Possibly. I was tempted to suggest that you 'feel ME/CFS in your bones' but decided it was a red mullet. Interestingly, apart from osetomyelitis and cancer deposits, pain from bone marrow is not often considered in medicine. In myeloma pain occurs when bones crumble but probably not just because of the plasma cells. I think it may be a red mullet.
Interesting. I experience an overwhelming"flu like ache" which at times can occur seemingly solely due to a rapidly falling barometric pressure. I live somewhere where large and steep drops in barometric pressure occur in the fall, winter and spring seasons. I have quizzed medical practitioners constantly about this flu like ache phenomenonfor 30+ years and never received any response but a puzzled look.
A normal TLR7 gene couldn't tell us anything because nearly everyone has one, and half of us have two.
A TLR7 gene with a gain or loss of function mutation is unlikely to tell us anything because that's probably a rare occurrence and ME/CFS isn't rare.
A normal (or abnormal for that matter) TLR7 gene could be involved in a chain of events that are difficult to find because it's like looking for a fish called Susan in a fish market.
If I've got that right, it means we either have to work out theoretically what Susan is up to, or shut Susan up?
[Apologies – I had to edit this because while trying to space out my bullet points I accidentally discovered a keyboard command that presses the Post button.]
My immediate thought is that this theory fails to explain abrupt switching between ME and non-ME states, since marrow cell production doesn't, AFAIK, change rapidly enough.
I think that is a useful point but bone marrow output of myeloid cells can respond pretty rapidly. I don't know details but after haemorrhage platelet numbers can go up within a few hours and I presume that is from marrow release. Similarly, with infection the neutrophil count can rise fivefold in a few hours.
I think the sort of mechanism proposed might be subject to overriding with acute signals much in the way that people talk of adrenaline overriding PEM in the very short term. Some also talk of getting better ME/CFS wise during infections. In RA we think there are underlying loops in immune memory but joint inflammation can appear and disappear over hours too.
I also think it is likely that any model like this might be one module of the process with neurological loops being other modules with some people's disease being almost entirely driven by immune loops and others' by brain loops but with both being involved to some degree in all.
If the immune loop is anything like the ones in RA and psoriasis (a B cell loop and a T cell loop) it seems they are consistent with just about any long term dynamic pattern in different cases. I think that may be an argument for invoking an adaptive clonal element but I am not sure. Just basing things on the rules of myeloid cells I would expect monozygotic twin concordance to be almost complete because they would meet relevant infections at some point and the pathways and regulatory steps engaged ought to be much the same.
Barometric pressure would not impact marrow because there is free flow of blood in and out. Pressure gradients would only be sustained over a second or so (as with sucking out marrow in a biopsy) before blood re-equalised the pressure.
I am not sure what that means. It may be that the fact that women have two TLR7 genes and men one tells us all we need to know about why women have more ME/CFS than men. But a normal TLR7 gene does not tell you why one woman had ME/CFS and another doesn't.
TLR7 gene with gain or less of function might tell us a huge amount, just as it has done in lupus where uncommon variants confer risk for the disease. But that has nothing to do with whether they are male or female. Such a rare variant would probably not even be put on the list for a GWAS but a rare gene search using WGS could pick it up. It might tell us why more women have ME/CFS than men, not because it made a big contribution to that, because it would be rare, but because it could explain why having two doses of TLR7, as a woman, might confer risk (the implication being that a gene with increased or less controlled expression would confer risk as well as having two of them).
A normal (or abnormal for that matter) TLR7 gene could be involved in a chain of events that are difficult to find because it's like looking for a fish called Susan in a fish market.
It would be a bit like looking to see if there are a higher proportion big John Dory's to small Brill on the market stalls today when you have no chance of getting round all the stalls before they have mostly been bought up and how fast they are bought will depend on the sizes of both.
Possibly. I was tempted to suggest that you 'feel ME/CFS in your bones' but decided it was a red mullet. Interestingly, apart from osetomyelitis and cancer deposits, pain from bone marrow is not often considered in medicine. In myeloma pain occurs when bones crumble but probably not just because of the plasma cells. I think it may be a red mullet.
My mum experienced pain in her legs and hip that she kept saying was 'in the bones'. It was pretty severe. A locum GP said it was probably muscular. A couple of weeks after this she was rushed into hospital, had blood tests, was given a bed on a ward and started chemo the next day. That was Friday night, we were told if she'd waited the weekend, it might have been too late. She had NH lymphoma. She was an impatient for 3 months receiving very strong chemo (inc rituximab). Remarkably, it worked. I feel there may be a genetic link between NHL and ME as I know of a few other families who have had both in the family. If anyone is experiencing new pain that feels like it is 'in bones' and hasn't had blood tests done for a while, I would recommend speaking to GP, especially if it accompanied by any other new symptoms.
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