Each individual abnormality can be explained to you within the context of the model if you have a few months to spare and are willing. When there is an absence of data the authors of a model apply research from other branches of medicine. This is why the model is not a review but an original model.
Hi Mula, You just made my point for me, as do the authors in several sections of the paper. If it requires months of additional work to show important things, its a promise not an explanation, and hence is not complete. Indeed a whole section of the model has been postponed to a later paper (presumably): "The role of the peripheral nervous system in modulating the initial effects of immune activation and tissue inflammation is complex and beyond the scope of this paper."
There are many good things in this paper, but after reviewing it yet again I have decided it isn't a model at all, its a metamodel. Rather than being a recipe for a model of CFS or ME, its a cookbook showing how to create recipes for CFS and ME based on biochemical stress and immunological disturbances.
I assert again its not complete, nor have you said anything to disuade me.
The general trend in the paper's arguments is to review a large range of possible explanations for each finding they wish to explain. They then go on to establish that some of these pathways are active in ME, which is a good thing. Not all such pathways are established. This is a shot gun approach, and relies on the principle that if enough pathways are mentioned then most of the important onces should be listed. Eventual models might well draw upon this metamodel, but by itself its not specific enough to be a model.
Now that does not mean I think the outline given at the end (the conclusion section is a very lucid summary, well worth reading if someone hasn't the time to read the full paper) is wrong. Far from it.
I actually discovered a scientific inaccuracy in my reading, something which I hope to raise with the authors but is not for discussion here. This was in the early review, and does not affect the main arguments of the paper.
Let me give an example of incompleteness from the paper: "Coxsackie B3 employs a virally-encoded protein, i.e. 3Cpro, to degrade molecules, which function downstream of pattern recognition receptor signaling".
These explanations are not complete. Why? If this were sufficient then everyone with these infections would show the massive viral load found in most ME patients tissues. Now the model does point at other mechanisms which contribute to this, but its not explicit and not fully worked out. Its a promise that as this model unfolds it has the
potential to explain these things, not that it
does explain these things.
That does not mean the comments made are without value. For example it goes on to say : "Chronic and persistent infections can induce prolonged immune system activation, leading to high levels of
localized or systemic O&NS, which leads to oxidative damage to proteins lipids and nucleic acids." [My bolding] This is important. I long ago realized that localized explanations might be necessary, and this was one of the driving forces for me finishing my biochem degree.
Not only does this paper not explain OI properly, the papers it refers to that I can access (including a recent review by Maes) don't either. Its saying that autonomic disturbances are consistent and expected from the model, not that they are explained: "Autonomic symptoms are associated with cardiovascular abnormalities and may be explained by activated immuno-inflammatory, intracellular and O&NS pathways, including increased TNFα, NO-related mechanisms and NF-κB". Saying a model is consistent with the facts is not the same as explaining them, despite their use of the word "explained". It again is a promise not an actual explanation.
I think this metamodel has potential. I think its worth discussing. I do not want to see people thinking it is fully explanatory if there are not good grounds for that conclusion.
I should point out a subsection of this model overlaps with my own earlier models based on the work of Martinovic (there were a series of papers, only one of which is listed on PubMed), who had worked some of this out by 1993 and showed, repeatedly and consistently, that modification of eicosanoid synthesis can lead to symptom remission though typically not full recovery, in at least 60% of patients, with partial remission in another 30%. Indeed my own protocol has at its core an attenuation of the arachidonate dependant eicosanoid synthesis - which is really easy to do but very hard to do reliably. That is one of the things I find fascinating with this paper: it links my own earlier work (mostly unpublished outside of forums) with that of Maes on autoimmunity, Pall on nitrosative and oxidative stress, and even Rich on methylation. There are some bugs in the eicosanoid related section, I am thinking about them.
One point I think well worth pursuing, is the discussion of the NF-KB/p53 axis. If this can be established, and shown to have regional rather than global significance, I think it has immense potential as an explanation of many issues.
Bye, Alex