Infection -> Epigenetic Change -> Systemic Inflammation = ME/CFS

Hip

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I do find this endotoxin tolerance theory they refer to in the paper very intriguing.

Endotoxin tolerance (which is where the body's inflammatory response to LPS becomes diminished with repeated exposure to LPS) is in some ways a diametric opposite to the immune priming theory of ME/CFS (which is where the inflammatory response becomes greatly increased after a prior exposure to LPS or interferon gamma).

I have not yet had the chance to read up much about endotoxin tolerance, which is a new concept for me. But this paper says endotoxin tolerance was first observed back in 1946, so it's an established phenomenon.
 
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percyval577

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Theories are an important part of the process of science. But.

Theories that make everything seem to fit are CHEAP. ... Once one has a good knowledge of biology and an IQ a couple of standard deviations above normal creating plausible theories is trivial. ... It's not surprising Naviaux and Phair can come up with convincing theories. ...

Morris and Maes have made a career of theories. The longer I've been around here the more theories I can come up with too. In my view science is very hard and this approach - looking at data and creating theories - has relatively low productivity. ...

Mark Davis on T-Cells. Norwegians and cyclophosphamide. Klimas and GWI. Ron Davis and his nano-needle and red blood cells deformity findings. Younger and neuroinflammation. Maybe as an outside bet the Griffith researchers ...

None of these findings are replciated and consistent. ...
Rather agreed.
It may sound cruel, but science is a playing, a kind of game. And this even must not change, because it is unpredictibable what will pop up as an relyability. Science is a random process. Reasoning in itself does not already provide for sufficiency.

The real desaster therefore is that the science on our disease ist not granted. It´s of course true that a lot of the money would look as being wasted, in view of the truth as soon as having been found out. But this is how such a process functions.

Asking the right questions. This is also for scientists as much difficult as for non-scientists. Only that scientists can make a lot of elaborated words. In addition, especially today I am a bit afraid that the the discourse of science is corrupted due to non-intrinsic interests.

But I find it not unlikely that the facts that would lead to the idea of a solution/solutions are already on the cards. It´s not needed to be have strict proofs, as most medicals work by still unkown mechanisms, and only more or less good guesses about the machanism by which they work can be made - and sometimes it seems to me here as well that the most guesses (theories) are more less good.

So I agree with you, @Moof , that the ability to come with theories in itself doesn´t say much. But I want to emphasize as well that interpretation of facts or even of possible facts allows for chances.



.
 

perrier

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I attended that conference and found it very depressing to hear, one after the other, the scientists saying, "Don't try this at home." It was infuriating.

The scientists don't have all the answers yet. They are reading the data, playing hunches, and running experiments. They are doing the very best they can, with the resources they have. And, the pace has been accelerating in the past 5 years, and they are coordinsting with each other. It is truly amazing, and they will crack this.

Tragically, it will be too late for some of us. Some of us are in our 50s, 60s, and 70s, and are running out of time. Others are younger, but will succumb to this disease, to cancer, etc.

We can't sit idly by, waiting in our beds to bring us perfect answers. Because we are each unique, with different genetics, environmental factors, and comorbidities, what works for one, or for the perfect patient, wont work for all of us, even after the long wait.

The more we learn about ourselves in this era of p4 medicine will help us each in our quest to get well.

It's not just one theory chosen from amongst competing theories, but using systems biology to weave together compatible theories into a body of knowledge that provides a roadmap of diagnostics and treatments to bring us back to health.

No, and we wont for many years. If we think of an analogy to cancer, if you take 50 patients all with X cancer, they will benefit from a toolbox of diagnostics and treatments that can be applied to each patient's unique situation. Treating people like widgets can be catastrophic. We need to individualize for each of us.

Unfortunately, there have been very few findings that are clinically applicable to all of us.

There was a recent interview with Susan Levine, who characterized ME/CFS like cancer - she thinks well find its a group of diseases with some key similarities but differences between them. Jarred Younger has found different subgroups, Stanford is looking at different subgroups, ...

This is incredibly complex. But, my doctors and I have learned a lot, and the treatments I've had, built upon some of these theories, that we've chosen when my test results seem to match theories, have been paying off, one by one. And, I, for one, have experienced huge benefits from translating and harnessing theories of Maes and Morris, Fluge and Mella, Younger, Armstrong and McGregor, Hanson and Levine, and many others. It is possible to make headway now, with thoughtful choices, and access to doctors, tests, and treatments.

There will be mistakes, but given that there's little alternative today, it's worth trying.

That's why it's good to know what tests exist to examine some of these ideas, so one is not just making educated, and not foolhardy guesses. Because, as I learned un the cancer world, there are some choices one cannot reverse. Being prudent is wise.
I think you are likely correct, though I must say the idea of no choke hold on this for a very long time is very hard to deal with. This is not a merciful illness. The problem with all the meds that so many physicians who are following the research is that very often the sickest folks cannot tolerate these meds. So, it's ok for the tough and resilient, but those severely fragilized by this illness, it ain't looking too inviting.

From the comments about subgroups, well, does this mean that it can also be really a collection of illnesses. Your cancer analogy is pretty good.

This is for the severely ill very discouraging.
 

Wishful

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For example, my kynurenine and quinolonic acid are normal, as is the ratio between them. When they've been high, I've been deficient in B6.
That's the serum measurement I assume? The problem with that is that the chronic microglial activation takes place on the other side of the BBB. We need measurements of CSF, or maybe even intracellular fluid. My serum KYN/TRP ratio was abnormally low, which was contrary to my expectations. Then I checked deeper into the biology, and found that the kynurenines didn't cross the BBB easily, and that most of the kynurenines in the brain were produced by glial cells. Therefore my serum measurements weren't of much value.

My ME symptoms increase when TRP transport into the brain increases, and also when IFN-g (and thus IDO) increases, so I assume increased microglial activation and TRP->KYN conversion in my brain. I doubt that I can get my doctor to order that sort of test, and without a researcher to properly interpret the results and do something with them, there's not much point.
 

Wishful

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I attended that conference and found it very depressing to hear, one after the other, the scientists saying, "Don't try this at home." It was infuriating.
Maybe that's their legal advisors begging them to avoid potential lawsuits. I can understand that. However, I'd rather they find some way to put out the information. I can make my own decision to try or not try some drug, herbal remedy, or whatever. Maybe one of us will have positive results, post that, and have other PWME post positive results too. Free volunteer guinea pigs. Speeds up testing.
 

Wishful

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I think my biggest take away from this is, it seems everyone is converging on 'sickness behavior'. I really don't think we have some mysterious infection that was sought after for a lot of the 90's and 2000's.
Sickness behaviour isn't an infection; it's our bodies' response to infection, and can probably be triggered without an active infection. Perhaps sickness behaviour is triggered by several cytokines at certain abnormal levels, and ME happens to reach those levels--and be stuck there--without an active viral or bacterial infection.

I have no objection to the researchers treating sickness behaviour as a symptom of ME. Finding the cause that would be useful.
 

debored13

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It is. I have come a long way, by reading and interpreting the research that's out there.

It does not seem prudent to wait 30 years for all of this research to be complete and properly translated into clinical standards of care with a big red now around it.

Time is ticking by, and none of us is getting younger, so dealing with imperfect info and translating as best we can is all we have at this point.

What are the tests available to patients, as a start?
In my case I have come to the conclusion that the only thing that will help us is what Hillary Johnson, the author of Oslers Web, calls a “moonshot approach”, with spending increasing more than 100-fold, spending increased with rfas increased and no strings attached funding to top researchers. While personalized medicine is important even for more well-researched diseases , research and research investment still matters a lot. Cancer and HIV may brave individualized treatments but they still have lots more treatments because of research funding on parity with their severity.
I think that we won’t see major advances until funding increases at least ten-fold. Even with the improved tools like metabolomics, researchers are working slowly because of funding constraints. It’s ultimately a political problem. And I don’t know what to do about it in. I’m too tired to protest or anytbibg.
 

Learner1

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We can work on the problems we have, one by one.

I didn't make any headway until I was on Valcyte and IVIG, then IV antibiotics. Got on POTS meds. Got my hormones balanced. Got methylation working. Reduced peroxynitrites and oxidative stress repaired mitochondrial membranes, mito cocktails.

This is complex. And, much as we all want one, there's no magic pill. We are too far doen the cascade of problems for a point solution to cure us. It may stop the cascade, at some point, but we will still hsve to fix the collateral damage.
 

debored13

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We can work on the problems we have, one by one.

I didn't make any headway until I was on Valcyte and IVIG, then IV antibiotics. Got on POTS meds. Got my hormones balanced. Got methylation working. Reduced peroxynitrites and oxidative stress repaired mitochondrial membranes, mito cocktails.

This is complex. And, much as we all want one, there's no magic pill. We are too far doen the cascade of problems for a point solution to cure us. It may stop the cascade, at some point, but we will still hsve to fix the collateral damage.
I respect what you’re saying and many illnesses are multifactorial, but I still think that the research funding needs to improve drastically for many patients to see any benefits. I’m just not sure recovery is possible for all even with seeing the best doctors. I’m sure that because of Ron’s work, Whitney has access to consults with some of the best doctors and to many sought after treatments, for example, and still hasn’t made much improvement at all. That’s just one example but I think it’s common for people to not make improvements even when they are seeing very good doctors, as even the most innovative doctors don’t have that much to go on. The cases where people seem to improve the most is when there’s a straightforward autoimmune issue discovered that can be treated in a targeted manner

Even if there are subgroups , which seems like an important problem to figure out (but lipkin, Hanson, naviaux et al seem to be finding fairly homogenous signature when they use strict patient criteria ), that wouldn’t negate the need for very intense research and research funding. Cancer is a heterogeneous grouping of diseases with common characteristics but still benefited greatly from huge amounts of funding for research.
I do agree with Hillary johnson in oslers web when she says that sometimes, saying a disease is multifactorial is just what happens when you don’t know the ultimate cause of something. I’m not saying she’s right about an infectious cause at all, but there’s so much we don’t know about these clusters of illnesses and even the most brilliant physicians don’t have a good enough success rate, not because of any lack on their part but because there’s so little to go on. So I still stand by what I say about this being an ultimately political problem, need to demand huge investment by the NIH or millions will continue to suffer and die. And what of people that can’t access these very few expert physicians ? Research allows for treatments that can be applied more broadly.
 

Learner1

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I still think that the research funding needs to improve drastically for many patients to see any benefits
I still stand by what I say about this being an ultimately political problem, need to demand huge investment by the NIH or millions will continue to suffer and die. And what of people that can’t access these very few expert physicians ? Research allows for treatments that can be applied more broadly.
I absolutely agree. More must be learned and diagnodus and treatment must become easier to have higher cure rates. It is a tragedy that this had been so underfunded and that the research isnt farther along.

What I was taking isdue with is people wrong their hands and saying nothing csn be fine now, so we must all wait in our beds doing nothing until the tesrarch is complete.
It sure doesnt happen that way in cancer. Educated experimrnts are tried on patients all the time while tesrarch is ongoing.
I’m just not sure recovery is possible for all even with seeing the best doctors. I’m sure that because of Ron’s work, Whitney has access to consults with some of the best doctors and to many sought after treatments, for example, and still hasn’t made much improvement at all. That’s just one example but I think it’s common for people to not make improvements even when they are seeing very good doctors, as even the most innovative doctors don’t have that much to go on. The cases where people seem to improve the most is when there’s a straightforward autoimmune issue discovered that can be treated in a targeted manner
I think that it does matter what genes we have snd which envuronmebrsl factors weve come in contact with ehich can affect our outcome. Also gerting diagnosed and tested earlier, rather than later. And, in working with some brilliant doctors, the order in which problems are tackled can very much matter and make a difference, for better or worse, in the outcome. I don't want to speculate about well-known patients - I dont think we know the whole story about any confounding factors or treatment details.
Even if there are subgroups , which seems like an important problem to figure out (but lipkin, Hanson, naviaux et al seem to be finding fairly homogenous signature when they use strict patient criteria ), that wouldn’t negate the need for very intense research and research funding.
Agreed. I'm just saying they've already done a lot of good work that can be helpful in guessing at trratments today and vsn be used in n=1 experiments without waiting for the body of knowledge to be complete, 30 years from now. I'm 30 years older than you and dont have time to wait.
Cancer is a heterogeneous grouping of diseases with common characteristics but still benefited greatly from huge amounts of funding for research.
Agreed. And, even so, though I got the supposedly well-researched "national standard of care" thst my doctor so confidently shared with me, it triggered my ME/CFS, hammering my immune system and reactivating viruses...

So, yes, we need large investments in rrsearch to make any headway on a large scale with this dreadful disease, and all its variations, but we need to realize that patients will still be unique individuals with factors that will confound even the best research driven diagnostic and treatment protocols.

And, I keep getting rejected for studies because I didn't have a single viral event, but had the cancer treatment reactivate a 40 year old case of EBV and a 25 year old case of CMV, among other things. There are no patients exactly like me, so whatever research they do on these carefully selected groups of patients wont apply to me, so I may as well chart my own course.

So, yes, the research is useful, but it doesnt mean we can't pursue personalized medicine today.
 

debored13

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I absolutely agree. More must be learned and diagnodus and treatment must become easier to have higher cure rates. It is a tragedy that this had been so underfunded and that the research isnt farther along.

What I was taking isdue with is people wrong their hands and saying nothing csn be fine now, so we must all wait in our beds doing nothing until the tesrarch is complete.
It sure doesnt happen that way in cancer. Educated experimrnts are tried on patients all the time while tesrarch is ongoing.

I think that it does matter what genes we have snd which envuronmebrsl factors weve come in contact with ehich can affect our outcome. Also gerting diagnosed and tested earlier, rather than later. And, in working with some brilliant doctors, the order in which problems are tackled can very much matter and make a difference, for better or worse, in the outcome. I don't want to speculate about well-known patients - I dont think we know the whole story about any confounding factors or treatment details.

Agreed. I'm just saying they've already done a lot of good work that can be helpful in guessing at trratments today and vsn be used in n=1 experiments without waiting for the body of knowledge to be complete, 30 years from now. I'm 30 years older than you and dont have time to wait.

Agreed. And, even so, though I got the supposedly well-researched "national standard of care" thst my doctor so confidently shared with me, it triggered my ME/CFS, hammering my immune system and reactivating viruses...

So, yes, we need large investments in rrsearch to make any headway on a large scale with this dreadful disease, and all its variations, but we need to realize that patients will still be unique individuals with factors that will confound even the best research driven diagnostic and treatment protocols.

And, I keep getting rejected for studies because I didn't have a single viral event, but had the cancer treatment reactivate a 40 year old case of EBV and a 25 year old case of CMV, among other things. There are no patients exactly like me, so whatever research they do on these carefully selected groups of patients wont apply to me, so I may as well chart my own course.

So, yes, the research is useful, but it doesnt mean we can't pursue personalized medicine today.
Yes I don’t fundamentally disagree that there are things that can be done now , and I have benefited from some treatments in terms of quality of life for several periods even as my overall trajectory is downward. I just think that it’s sometimes important to note the bleakness of the overall recovery rate from this illness, not to give up, but to make people realize that this situation is not in the least tolerable or acceptable.

I am excited a little bit about my upcoming appointment with doctors chheda and a few treatments but I feel that reaching a low point in this illness has made me appreciate the importance of advocacy and the inadequacy of research funding, because I have access to better care than the average person with this illness and still have deteriorated. I know many in this position. Doesn’t mean we shouldn’t try anything but now I have newfound appreciation for why aids activists burned mattresses and stuff. This situation feels so intolerable and is ultimately politicized
 

Learner1

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As an aside though, @Learner1 did you find martin palls book helpful at all, since you are focused on oxidative stress?
Pall's work is focused mainly on peroxynitrites, and yes, the success of the past 8 months of treatment has been due to carefully reading Pall, Maes and Morris snd Nicolson.

I tested and found peroxynitrites, in addition to depleted ALA, A, C, E, and glutathione. Measured mito function which indicated huge superoxide radical production. Upped vitamin C and glutathione intake, upped NT Factor, and did 16 IVs of phosphatidyl choline, while taking NAD+ or NMN.

Energy has improved, PEM is reduced, and test results show reduced oxidative snd nitrosative stress, and vastly improved mitochondrial function with lower superoxide production.

So, yes it was helpful, and a great example of experimenting with a theory that's already on paper.

But, I will note that I had already been on IVIG, Valcyte, 4 months of IV antibiotics, snd a mictibiome rebuilding program, or I'm not sure this would have been as successful at this point.
 

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Learner1

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Yes I don’t fundamentally disagree that there are things that can be done now , and I have benefited from some treatments in terms of quality of life for several periods even as my overall trajectory is downward. I just think that it’s sometimes important to note the bleakness of the overall recovery rate from this illness, not to give up, but to make people realize that this situation is not in the least tolerable or acceptable.

I am excited a little bit about my upcoming appointment with doctors chheda and a few treatments but I feel that reaching a low point in this illness has made me appreciate the importance of advocacy and the inadequacy of research funding, because I have access to better care than the average person with this illness and still have deteriorated. I know many in this position. Doesn’t mean we shouldn’t try anything but now I have newfound appreciation for why aids activists burned mattresses and stuff. This situation feels so intolerable and is ultimately politicized
Agreed.
 

Learner1

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Oh and I have done plenty of n= 1 experiments in which I extrapolates from research findings but it hasn’t been enough. I also brought my pcp some research on this illness which I very much doubt he read
This goes back to doing things in the right order. Dealing with immune and infection issues comes first. All the ethyl pyruvate in the world won't fix you if you can't fight off the infections you have, which are running amok and causing damage.

I am excited that you will see Dr. Cheddar and have hope that she will help you.
 

debored13

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This goes back to doing things in the right order. Dealing with immune and infection issues comes first. All the ethyl pyruvate in the world won't fix you if you can't fight off the infections you have, which are running amok and causing damage.
Well this kind of comes down to me being too sick to really approach my own care in an organized way. I thought that either a specialist or my pcp would take charge but nobody has an overall plan. Levine is almost impossible to get on the phone (I imagine she’s busy with research) and she basically doesn’t seem to have notes in order or a particular plan for my case. I really want to see a physician or two who can basically handle my care. I mean I want to have input and bring up ideas from research but I don’t wanna have to be the one organizing all my labs and notes and making the full treatment plan, I am too sick for that. If chheda can do that, that would be miraculous.
 

Learner1

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@Learner1 thanks! Do you agree with palls view on emfs and voltage gated sodium channels? I have been considering this stuff although it had at first sounded a little “out there” to me
Yes. Its all related. But, as he says:
However, pathophysiological responses to EMFs may be as a result of nitric oxide-peroxynitrite-oxidative stress pathway of action.
 

debored13

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I mean, I would think that treating metabolism would help with fighting infection to an extent but I see your point. Isn’t there probably an issue in the metabolism of our T cells or something to be overwhelmed by common infections so easily?