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    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

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Wolfe Hypothesis ~ Key causative processes involved in CFS/CFIDS/M.E.

Does this theory seem plausible?

  • Yes

    Votes: 9 23.7%
  • Didn't read it

    Votes: 5 13.2%
  • Not sure I fully understand it

    Votes: 5 13.2%
  • No

    Votes: 19 50.0%

  • Total voters
    38

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
Yeah, when someone tries to squish different papers from a traditionally dodgy area of research (psychology) into one integrated theory, they're going to get some weird results.

How shocking - you managed to find a way to suggest that most of us are likely to have certain unflattering psychological disorders, while safely extracting yourself from the group.

For the third time, you seem to have spectacularly failed to read the research sufficiently to answer some basic questions: how are they diagnosing or defining depression? Is "depressive symptoms" as mentioned in the study the same thing as crossing a threshold for a depression diagnosis? Were physical ME/CFS symptoms considered indicative of depression?

I know you don't have answers to any of the questions, because the paper doesn't answer them. Though the researchers are not psychobabblers themselves, most of their sources are psychobabblers, and heavily skewed toward psychogenic theories. The odds are extremely good that anxiety and depression assessment was based on having certain symptoms which have physical causation for ME/CFS patients.

Of course, no appropriate control group involving patients with a better-understood chronic and multi-system was used, and the results for mood disorders among the healthy patients was not shown either. Because the the controls were certainly assessed for the purpose of making comparisons between genetics and mood disorders, it is rather suspect that those results have been withheld, indicating that they were likely quite overzealous in labeling participants as having "depressive symptoms".

I think you need to stop trying to warp the world to fit your anecdotal picture. You're starting with a conclusion, and working backward, which means the only question is how you're going to present the data to best support your conclusions. Good research should involve looking for answers, rather than looking for justification for your pre-emptive conclusions.

Your anecdotal picture also seems highly incorrect and insulting, which is not helping.

Better run or hide, John H Wolfe - the Hulk approaches..:aghhh::D

Just please promise us that your next project is not "The Wolfe Therapy"...at a (high) price. If it is, you may find an army of Hulks after you...

Oh - and please test it on yourself first before presenting it to the world.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
Yeah, when someone tries to squish different papers from a traditionally dodgy area of research (psychology) into one integrated theory, they're going to get some weird results.

How shocking - you managed to find a way to suggest that most of us are likely to have certain unflattering psychological disorders, while safely extracting yourself from the group.

For the third time, you seem to have spectacularly failed to read the research sufficiently to answer some basic questions: how are they diagnosing or defining depression? Is "depressive symptoms" as mentioned in the study the same thing as crossing a threshold for a depression diagnosis? Were physical ME/CFS symptoms considered indicative of depression?

I know you don't have answers to any of the questions, because the paper doesn't answer them. Though the researchers are not psychobabblers themselves, most of their sources are psychobabblers, and heavily skewed toward psychogenic theories. The odds are extremely good that anxiety and depression assessment was based on having certain symptoms which have physical causation for ME/CFS patients.

Of course, no appropriate control group involving patients with a better-understood chronic and multi-system was used, and the results for mood disorders among the healthy patients was not shown either. Because the the controls were certainly assessed for the purpose of making comparisons between genetics and mood disorders, it is rather suspect that those results have been withheld, indicating that they were likely quite overzealous in labeling participants as having "depressive symptoms".

I think you need to stop trying to warp the world to fit your anecdotal picture. You're starting with a conclusion, and working backward, which means the only question is how you're going to present the data to best support your conclusions. Good research should involve looking for answers, rather than looking for justification for your pre-emptive conclusions.

Your anecdotal picture also seems highly incorrect and insulting, which is not helping.

Better run or hide, John H Wolfe - the Hulk approaches..:aghhh::D

Just please promise us that your next project is not "The Wolfe Therapy"...at a (high) price. If it is, you may find an army of Hulks after you...

Oh - and please test it on yourself first before presenting it to the world.
 

John H Wolfe

Senior Member
Messages
220
Location
London
you managed to find a way to suggest that most of us are likely to have certain unflattering psychological disorders, while safely extracting yourself from the group
Just noting some interesting observations. Personally I have no problem talking about my own sub-disorders (e.g. compulsive behaviours, above) but I have no history of depressive/anxiety disorders :)

how are they diagnosing or defining depression? Is "depressive symptoms" as mentioned in the study the same thing as crossing a threshold for a depression diagnosis? Were physical ME/CFS symptoms considered indicative of depression?
You'd have to ask the study organisers these things (I'm guessing not re: your 2nd question though)

At some stage I will critically evaluate as many references as possible but as I'm still writing the 1st draft of the paper and the references amount to over 150 papers

The odds are extremely good that anxiety and depression assessment was based on having certain symptoms which have physical causation for ME/CFS patients
If you take the time to read my discussion with MeSci you'll note my thoughts on psychophysiology

the results for mood disorders among the healthy patients was not shown either
That would be handy to know for the purposes of relative comparison aye

You're starting with a conclusion, and working backward
I'm afraid not, anyone following my work will note that I keep moving the goal posts re: my theories the more I learn about different pathophysiological explanations and their possible interplay
 

John H Wolfe

Senior Member
Messages
220
Location
London
Just please promise us that your next project is not "The Wolfe Therapy"...at a (high) price. If it is, you may find an army of Hulks after you
I've always helped people for free but what's wrong with folks providing therapy (at any price)?

Giving false hope/lending credence to psychobabble/unsustainable GET is of course hazardous, but otherwise.. people are free to pick and chose/take or leave the various therapies out there, and we are lucky we're living in the internet age where word of mouth/reviews are relatively easy to come by :)

I am not a (qualified) health practitioner, and have no plans to/am not currently in a position to/interested in delivering therapy in a professional setting. My main aims are:

1) To construct this systems biology disease model that provides a platform for better understanding of the illness by all (especially medical researchers/trial designers)

2) Off the back of that, to provide insights/ideas for protocol design that may enhance wellness, chances of remission and possibly recovery
 
Messages
15,786
You'd have to ask the study organisers these things (I'm guessing not re: your 2nd question though)
You can't rely on bad sources ... it's not good enough to say "well it got published, so it must check out." If you read it thoroughly, and basic questions like the ones above are not answered, then the conclusions drawn by that paper simply cannot be trusted and used to support any theories or arguments.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
I've always helped people for free but what's wrong with folks providing therapy (at any price)?

What's wrong is when the 'therapy' is based on poor evidence or no evidence and has the potential to cause harm. For example, at your second link you say

You should aim to drink a minimum of 2 ltrs of water during the day

Many people with ME are deficient in minerals/electrolytes due to passing large quantities in urine - osmotic or solute diuresis. Drinking water - a hypotonic fluid - will further dilute the blood and exacerbate the deficiency. I ended up seriously ill in hospital from hyponatraemia, for example. I was not far off dying. People with this type of osmotic diuresis/polyuria need to drink fluids that are at least isotonic and ideally hypertonic. In any case, I believe that the advice to drink 2 litres a day is based on poor evidence, even for healthy people.
 

John H Wolfe

Senior Member
Messages
220
Location
London
What's wrong is when the 'therapy' is based on poor evidence or no evidence and has the potential to cause harm
No evidence and potential harm are of course an undesirable basis for any treatment. However evidence for efficacy is often limited (nature of the beast) and owing to the complex and enigmatic nature of the illness, plus the wide variety of presentations and relationships with changes in this or that parameter, the potential for harm cannot ever fully be removed

I have responded to your other points in the appropriate thread
 

John H Wolfe

Senior Member
Messages
220
Location
London
ATP depletion from exertion leads to increase in symptoms universally via numerous pathways potentially including glutamate excitotoxicity due to failure of voltage gated calcium channels which are ATPase dependent. Hence glutamate significantly worsens sensory overload, pain and other symptoms
Indeed..

"The detection of ATP activity by receptors on ATP potassium channels determines glutamate and GABA production and hence the glutamate:GABA ratio. ATP depletion is associated with NMDA stimulation and when cells containing NMDA receptors become ATP depleted, these receptors become hypersensitive to further stimulation.(Pall, 2003) Furthermore, low neuronal energy production markedly increases sensitivity to glutamate excitotoxicity.(Blaylock & Maroon, 2012)" ~ Draft paper

This rudimentary/rough (unfinished) diagram I put together just yesterday to help illustrate the central component of my disease model may be of interest here (elements on the right hand side relate to what you mentioned)
 

John H Wolfe

Senior Member
Messages
220
Location
London
Updated working draft abstract:

A NEUROIMMUNE MODEL FOR THE ETIOPATHOGENESIS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) a debilitating condition of unknown aetiology, classified as a disease of the central nervous system by the World Health Organisation. In recent years the disease has been linked to neural sensitivity and sensitisation. In this speculative article I describe a new neuroimmune model for the etiopathogenesis of ME/CFS in this context

Drawing upon relevant findings from the neurology literature, and in the light of the reported efficacy of Rituximab and Naltrexone, as well as purported overlaps with migraine pathophysiology, I present a rudimentary model for the etiopathogenesis of ME/CFS centred on glial activity and neural (hyper)sensitivity. The model holds the following as central to etiopathogenesis: glial priming, and possible gliopathy - relating to a synergistic (neuro-glial) dysfunction and/or (fungal) glio-toxin exposure, in the context of persistent pathogenic and/or biomechanical sources of chronic peripheral nerve infection/inflammation/nociceptive signalling. This results ultimately in neural sensitivity and central sensitisation effects

wprx.jpg

Neural sensitivity associated with excitotoxicity, neuroinflammation, and possibly also central sensitisation and subsequent sensory gating irregularities, enhances the potential for pathogen activation and adverse neuroimmune responses including glial dysfunction and autoimmunity, as well as the central initiation of ‘sickness behaviour’ and dysautonomia

This neuroimmunological model may explain why only a small proportion of the general population infected with pathogens commonly associated with ME/CFS go on to develop the condition. The model provides a platform, and suggestions for, future exploration and testing of component pathophysiological links, as well as insights into the efficacy of existing treatment strategies and ideas for the development of fresh approaches

Keywords
ME/CFS; Myalgic encephalomyelitis; M.E; Chronic fatigue syndrome; CFS; Neural sensitivity; Microglial activation; Neuroimmune; Neuroexcitation; Excitotoxicity; Neuroinflammation; Neural sensitivity; Central sensitisation; Etiopathogenesis; Pathophysiology;

Wolfe Hypothesis © John H Wolfe (2013)​
 

beaverfury

beaverfury
Messages
503
Location
West Australia
Updated working draft abstract:

A NEUROIMMUNE MODEL FOR THE ETIOPATHOGENESIS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME


wprx.jpg

Looks good! Well done. A lot of work.

Theoretically, microglial inhibitors could have a useful role to play in this model. Especially at onset.

There doesn't seem to be much evidence of their use or effectiveness in me/cfs at the moment.
Maybe low dose naltrexone for fibro. http://www.ncbi.nlm.nih.gov/pubmed/23359310

Probably early days yet.
 

John H Wolfe

Senior Member
Messages
220
Location
London
Looks good! Well done. A lot of work
Thanks, yes indeed, getting that diagram alone worked out/put together took me the best part of an afternoon! hehe

Theoretically, microglial inhibitors could have a useful role to play in this model
Aye

There doesn't seem to be much evidence of their use or effectiveness in me/cfs at the moment
Do you know if there is any?

Maybe low dose naltrexone for fibro
From my infection and immune status section:

"One or more of these themes [B cells/microglial autoantibody relations] may, in part, help explain why Rituximab and Low-dose naltrexone (LDN) have been shown to improve symptoms in ME/CFS (Fluge et al, 2011) and the overlapping condition fibromyalgia [FM] (Younger et al. 2013) respectively in early trials.

Naltrexone is a drug that blocks the opioid/endorphin receptors in the brain, apparently resulting in increased compensatory endorphin production, and inhibits microglial activation.(Younger et al. 2013) Endorphins relieve pain and are produced by the hypothalamic pituitary adrenal (HPA) axis, a glandular system broadly held as being dysfunctional among patients with ME/CFS and FM.(Papadopoulos, 2012)" ~ Draft paper
 

beaverfury

beaverfury
Messages
503
Location
West Australia
Do you know if there is any?

Good point.
I took a quick lazy look through the ncbi pubmed archives and couldn't find any. I'm out of my league here though.

Ibudilast, a drug used for asthma, has been mentioned as a possibilty, http://www.mecfsforums.com/index.php?topic=4512.0
but i can't find any research directly relating it to me/cfs treatment.

Cort and Marco, over at Healthrising have done a good job of discussing possible neuroinflammation models, with microglial activation in me/cfs.
http://www.cortjohnson.org/blog/201...py-implications-for-chronic-fatigue-syndrome/
 

John H Wolfe

Senior Member
Messages
220
Location
London
couldn't find any. I'm out of my league here though
Me either, and me too really (not as learned or in the loop as professional/qualified experts)

Ibudilast, a drug used for asthma, has been mentioned as a possibilty, http://www.mecfsforums.com/index.php?topic=4512.0 but i can't find any research directly relating it to me/cfs treatment
I'll look into that, thanks - very interesting!

Cort and Marco, over at Healthrising have done a good job of discussing possible neuroinflammation models
Yes indeed, speaking to Marco/incorporating bits and bobs from his series into my discussion, and Cort's site more generally, has been extremely helpful indeed :)
 

John H Wolfe

Senior Member
Messages
220
Location
London
The 2nd draft of the paper I am writing off the back of this work is now complete. Updated abstract:

A NEUROIMMUNE MODEL FOR THE ETIOPATHOGENESIS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) a debilitating condition of unknown aetiology, classified as a disease of the central nervous system by the World Health Organisation. In recent years the disease has been linked to neural sensitivity and sensitisation. In this speculative article I describe a new neuroimmune model for the etiopathogenesis of ME/CFS, in this context.

Drawing upon relevant findings from a diverse literature, I present a rudimentary model for the etiopathogenesis of ME/CFS, centred on glial activity, neuronal hypersensitivity, and related neuroinflammation. The model holds the following as central to etiopathogenesis: glial priming, and possible synergistic neuro-glial dysfunction, in the context of (fungal) glio-toxin exposure, and/or persistent pathogenic and/or biomechanical sources of chronic peripheral nerve infection/inflammation and associated distortions, and chronicity, in nociceptive and ‘sickness behaviour’ signalling.

wprx.jpg

Neural sensitivity and central sensitisation effects associated with cytokine and excitotoxic products of glial activation enhance the potential for pathogen activation and adverse neuroimmune responses including immune dysregulation, glial dysfunction and autoimmunity. Central initiation of sickness behaviour, neuroendocrine dysfunction, and related hypothalamic pituitary adrenal (HPA) axis dysfunction and dysautonomia, are also a corollary.

This neuroimmunological model may explain why only a small proportion of the general population infected with pathogens commonly associated with ME/CFS go on to develop the condition. It provides a platform to help direct more focused future research into component pathological thematics, and elucidates important probable pathophysiological links within those thematics, as well as conceptual insights into the efficacy of existing treatment strategies and a broad array of ideas for the development of fresh approaches.

Keywords
ME/CFS; Myalgic encephalomyelitis; M.E; Chronic fatigue syndrome; CFS; Neural sensitivity; Microglial activation; Neuroimmune; Neuroexcitation; Excitotoxicity; Neuroinflammation; Neural sensitivity; Central sensitisation; Etiopathogenesis; Pathophysiology;
 

John H Wolfe

Senior Member
Messages
220
Location
London
Updated abstract:

A PSYCHONEUROIMMUNOLOGICAL MODEL FOR THE AETIOPATHOGENESIS OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) a debilitating condition of unknown aetiology, classified as a disease of the central nervous system by the World Health Organisation. In recent years the disease has been linked theoretically to neural sensitivity and sensitisation. In this speculative article I describe a new neuroimmune model for the etiopathogenesis of ME/CFS, in line with this increasingly prevalent conception.

Drawing upon relevant findings from a diverse literature, I present a rudimentary model for the etiopathogenesis of ME/CFS, centred on glial activity, neuronal hypersensitivity, and related neuroinflammation. The model holds the following as central to etiopathogenesis: glial priming, neuroinflammation, and possible synergistic neuro-glial dysfunction, in the context of (fungal) glio-toxin exposure, and/or biomechanical and/or persistent pathogenic sources of chronic peripheral nerve inflammation/infection and associated distortions, and chronicity, in nociceptive and ‘sickness behaviour’ signalling.
wprx.jpg

Neural sensitivity and central sensitisation effects associated with products of glial activation enhance the potential for pathogen activation and adverse neuroimmune responses including immune dysregulation, glial dysfunction and autoimmunity. Central initiation of sickness behaviour, neuroendocrine dysfunction, and related hypothalamic pituitary adrenal (HPA) axis dysfunction and dysautonomia, are also a corollary.

The proposed model may explain why only a small proportion of the general population infected with pathogens commonly associated with ME/CFS go on to develop the condition. It provides a platform intended to help direct future research towards potentially key component pathological thematics, and elucidates important probable pathophysiological links within those thematics, as well as conceptual insights into the efficacy of existing treatment strategies and a broad array of ideas for the development of fresh approaches.

Keywords
ME/CFS; Myalgic encephalomyelitis; M.E; Chronic fatigue syndrome; CFS; Neuronal sensitivity; Microglial activation; Neuroimmune; Neuroexcitation; Excitotoxicity; Neuroinflammation; Central sensitisation; Etiopathogenesis; Pathophysiology; Etiology.​
 
Messages
48
Location
UK
In any case, I believe that the advice to drink 2 litres a day is based on poor evidence, even for healthy people.
http://www.nhs.uk/Livewell/Goodfood/Pages/water-drinks.aspx

"The European Food Safety Authority recommends that women should drink about 1.6 litres of fluid and men should drink about 2.0 litres of fluid per day. That's about eight 200ml glasses for a woman and 10 200ml glasses for a man."

Regards.
 
Messages
48
Location
UK
John, you write some good stuff and there are some thought provoking items in there and for me this as it should be. Until someone has a clear cut answer on the cause of ME/CFS and which can be scientifically proven we should stimulate discussion and different ways of thinking about things.

Regards.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
http://www.nhs.uk/Livewell/Goodfood/Pages/water-drinks.aspx

"The European Food Safety Authority recommends that women should drink about 1.6 litres of fluid and men should drink about 2.0 litres of fluid per day. That's about eight 200ml glasses for a woman and 10 200ml glasses for a man."

Regards.

That's not evidence, but advice, and it refers to fluid, not water.

Here is the rest of my post that you quoted from:

Many people with ME are deficient in minerals/electrolytes due to passing large quantities in urine - osmotic or solute diuresis. Drinking water - a hypotonic fluid - will further dilute the blood and exacerbate the deficiency. I ended up seriously ill in hospital from hyponatraemia, for example. I was not far off dying. People with this type of osmotic diuresis/polyuria need to drink fluids that are at least isotonic and ideally hypertonic. In any case, I believe that the advice to drink 2 litres a day is based on poor evidence, even for healthy people.
 
Messages
48
Location
UK
That's not evidence, but advice, and it refers to fluid, not water. Here is the rest of my post that you quoted from:

Thank you for replying to my post. :) The link etc., is from a National Health Service and which is regulated by the Government. Actually there are lots of such links and we have all over the internet doctors saying things one year which are then found to be nonsense years later and so on.

So if these people cannot even get it right over a simple thing like water then how can we really ever be sure about 'evidence' on the things related to ME/CFS? All the scientific evidence would appear to be 'dodgy', all of it.

Are we going to wait for some doctor to come up with a solution and then provide umpteen scientific studies in order to prove that pill/operation will work before we take it? If we do then decades of our lives will be gone because that is how long it is going to take......do you want to waste your life?

You have an MSc, so do tell me what is missing here and what opportunity exists to do something about it? I believe we have here a group of people who have a vested interest in getting better and we have an illness or illnesses which are a little bit complicated. How do we solve complicated? Shall we formulate an approach to solving complicated and then work together collectively on it and in a more organised way?

I believe we can do this but I do think in order for us to do so we have to also be prepared to critically analyse ourselves along the way and proceed with open minds, logic and reason and not be going into running each other down. If in the meantime some doctor comes up with the magic pill then great we'll take it.

Regards.