Mella Finds Hypometabolic State in Chronic Fatigue Syndrome Plus Rituximab and New Drug For ME/CFS?

[Seanko]

@Cort Fluge & Mella are speaking at the upcoming IACFS/ME conference in Fort Lauderdale.

Will you be attending?

 

[Cort]

@Cort Fluge & Mella are speaking at the upcoming IACFS/ME conference in Fort Lauderdale.

Will you be attending?

Yes...I'll be there

 

[dejurgen]

"Problems producing energy appear to be fundamental and extend to the immune cells"

It is a very long shot, but what if our immune cells were as severely exhausted as the rest of our body or worse?
I would call myself "5 tot 10%" functional. I know this does not mean my cells are only functioning at 5 to 10% of their normal abilities, but lets for sake of easiness say both my body cells and white blood cells are active down to 10% compared to healthy controls. What could that mean?

Well, immune cells that exhausted could likely not fight off large numbers of generally harmless pathogens nor small numbers of stronger pathogens. Like with people with untreated AIDS, small normally harmless infections would be fatal soon if nothing compensates this severe lack of defense capabilities.

Instead of having a very short lifespan like people with untreated late stage AIDS, we keep living or something resembling living for decades. Could it be that Dauer isn't a "wrong stuck state that lives long past it's usefulness" but the only thing that keeps us alive for prolonged times?

* Oxidative stress or shielding as Naviaux calls it fights bacteria, molds, yeasts and starting cancerous cells
* CDR causes the cells membrame to toughen up making access of pathogens to cells a lot harder
* CDR reduces cell divisions rate and hence slows viral reproduction and cancer onset
* reducing key nutrients in blood and cells hampers pathogen and cancer growth as much as it hampers growth of our own body, but our own body needs not to grow but only to repair; maintenance has a lower resource cost than construction
* low body temperature reduces speed of both our metabolism as that of main pathogens
* mast cells could indiscriminately mass-bombard our cells and pathogens with toxic chemicals spilling over to our blood; these chemicals are both harmful to the pathogens as our own cells
* low blood flow reduces speed of spreading pathogens
* low blood volume turns down metabolism in non-key areas even further so redirecting defences to key zones.
* our cells have some limited capabilities to repair DNA damage while pathogens likely have less so.

Using all of above tricks, we have the advantage of suffering less under restricted nutrients as we need only to repair rather than grow and we can repair some damage over time. That does match Dauers "outlast the danger" definition of Naviaux. But instead of one big danger, it may be the repeated small dangers like a common cold, keeping retro virusses like Herpes or EBV under control, fending of small or larger mold infections, fighting off normally harmless Borrelia infections...

Physical exercise and brain exertion do increase metabolism, body temperature, blood flow, oxygen delivery, nutrient flow... and all of the above are counterbalancing the proposed hypothetical defense mechanism so exercise and exertion could be virulently countered as they damage our ability to defend ourselves.

That could also match with Lipkins observations: instead of one fast paste war, we live a prolonged guerilla. With such low potential strength of our white blood cells, the maximum threshold for live-endangering-infections may be a factor ten or so lower than in healthy persons just like it is in people with late stage AIDS. All of the mentioned harsh mechanisms could keep the pockets of infection small enough so that our weakened immune cells can just cope with them. But that would be quantities of pathogens that are considered far bellow the typical threshold for infection and the fight against it would rage in slow motion keeping both infection markers as well as markers for immune reaction far below what is typically considered diseased.

Having an adult mononucleosis would make it even worse: EBV cripples the white blood cells themselves, making them possibly the worst affected of all body cells. Maybe that and the other things relate to the successful use of antivirals by myself and so many others despite them slowing down mitochondria. See also http://www.healthrising.org/blog/2016/10/17/pridgen-fibromyalgia-antivirals/

Maybe our disease could be no auto-immune disease after all, but rather the opposite. It could be a lack-off immunity disease? If Dauer is in large part a signal-molecule thing, then many of these molecules will be carried by the blood. The white blood cells have mitochondria too and are hence potentially vulnerable to these signal molecules. As blood is the easiest way of transport for these molecules, the blood could carry the highest quantities and white blood cells are bathing in it and thus could come more in contact with these signal molecules than any other cell. This somewhat fits the pattern seen in the Rituxmab trials: the drug starts by killing the white blood cells off. So at first the immune system is even more hampered. At the beginning the patients get worse. Then it takes quite some time before the patients get better. Could it be that the newly formed white blood cells made to replaced the killed ones take some time to both build up and get exhausted? If so, the other cells could sense that they are guarded better by more functional immune cells and let there defensive guard somewhat down. In this hypothesis, that would reduce the toxicity of our blood and exhaust our white blood cells less. That could start a positive circle.

I know it is a VERY long shot, but does it make no sense at all or quite a lot of sense? It fits my case of the disease quite well. Has anyone an opinion on this going from "that's totally crazy" to "I recognize parts of that"?

 

[Mavis and Max]

Thank you for this excellent update. It would be interesting to hear from Drs. Patrick and Peterson more about the biomarker that they see that suggests a good response from Rituximab.

How the NIH, after the IOM and P2P reports, and its statements that ME/CFS constitutes a serious, unmet need, could find a way not to fund a Rituximab trial in the face of a successful Norwegian trial is unclear, but if any group can find a way, surely the NIH can. If the NIH waits for the results of Fluge/Mella’s trial before proceeding, we might be looking at a U.S. Rituximab trial beginning in 2019 with the results in 2020 or 2021.....

In a public talk given last week at St. Paul's hospital (Vancouver), by Dr. Ric Arseneau, he stated that BC Women's Complex Chronic Disease Program will be participating as part of a larger US/NIH Phase 3 Trial for Rituximab starting in 2018. Although I imagine that that might be off by a year, in which case the 2019 start makes sense. Dr. Arseneau's presentation also covered on the unifying Central Sensitivity Syndrome, microglial cells and LDN - perhaps an interview with him might also be a good topic for a future post. Thanks Cort!

 

[Cort]

Thank you for this excellent update. It would be interesting to hear from Drs. Patrick and Peterson more about the biomarker that they see that suggests a good response from Rituximab.


In a public talk given last week at St. Paul's hospital (Vancouver), by Dr. Ric Arseneau, he stated that BC Women's Complex Chronic Disease Program will be participating as part of a larger US/NIH Phase 3 Trial for Rituximab starting in 2018. Although I imagine that that might be off by a year, in which case the 2019 start makes sense. Dr. Arseneau's presentation also covered on the unifying Central Sensitivity Syndrome, microglial cells and LDN - perhaps an interview with him might also be a good topic for a future post. Thanks Cort!

It certainly would! and thank you for mentioning it Mavis and Max . That is very exciting news. (I don't imagine that a video was made of the talk?)...They could have decided that the evidence is good enough to start a study I will dig deeper.

 

[Cort]

It certainly would! and thank you for mentioning it Mavis and Max . That is very exciting news. (I don't imagine that a video was made of the talk?)...They could have decided that the evidence is good enough to start a study I will dig deeper.

I sent them an email. This is the second time someone has mentioned this - exciting stuff

 

[Cort]

"Problems producing energy appear to be fundamental and extend to the immune cells"

It is a very long shot, but what if our immune cells were as severely exhausted as the rest of our body or worse?
I would call myself "5 tot 10%" functional. I know this does not mean my cells are only functioning at 5 to 10% of their normal abilities, but lets for sake of easiness say both my body cells and white blood cells are active down to 10% compared to healthy controls. What could that mean?

Well, immune cells that exhausted could likely not fight off large numbers of generally harmless pathogens nor small numbers of stronger pathogens. Like with people with untreated AIDS, small normally harmless infections would be fatal soon if nothing compensates this severe lack of defense capabilities.

Instead of having a very short lifespan like people with untreated late stage AIDS, we keep living or something resembling living for decades. Could it be that Dauer isn't a "wrong stuck state that lives long past it's usefulness" but the only thing that keeps us alive for prolonged times?

* Oxidative stress or shielding as Naviaux calls it fights bacteria, molds, yeasts and starting cancerous cells
* CDR causes the cells membrame to toughen up making access of pathogens to cells a lot harder
* CDR reduces cell divisions rate and hence slows viral reproduction and cancer onset
* reducing key nutrients in blood and cells hampers pathogen and cancer growth as much as it hampers growth of our own body, but our own body needs not to grow but only to repair; maintenance has a lower resource cost than construction
* low body temperature reduces speed of both our metabolism as that of main pathogens
* mast cells could indiscriminately mass-bombard our cells and pathogens with toxic chemicals spilling over to our blood; these chemicals are both harmful to the pathogens as our own cells
* low blood flow reduces speed of spreading pathogens
* low blood volume turns down metabolism in non-key areas even further so redirecting defences to key zones.
* our cells have some limited capabilities to repair DNA damage while pathogens likely have less so.

Using all of above tricks, we have the advantage of suffering less under restricted nutrients as we need only to repair rather than grow and we can repair some damage over time. That does match Dauers "outlast the danger" definition of Naviaux. But instead of one big danger, it may be the repeated small dangers like a common cold, keeping retro virusses like Herpes or EBV under control, fending of small or larger mold infections, fighting off normally harmless Borrelia infections...

Physical exercise and brain exertion do increase metabolism, body temperature, blood flow, oxygen delivery, nutrient flow... and all of the above are counterbalancing the proposed hypothetical defense mechanism so exercise and exertion could be virulently countered as they damage our ability to defend ourselves.

That could also match with Lipkins observations: instead of one fast paste war, we live a prolonged guerilla. With such low potential strength of our white blood cells, the maximum threshold for live-endangering-infections may be a factor ten or so lower than in healthy persons just like it is in people with late stage AIDS. All of the mentioned harsh mechanisms could keep the pockets of infection small enough so that our weakened immune cells can just cope with them. But that would be quantities of pathogens that are considered far bellow the typical threshold for infection and the fight against it would rage in slow motion keeping both infection markers as well as markers for immune reaction far below what is typically considered diseased.

Having an adult mononucleosis would make it even worse: EBV cripples the white blood cells themselves, making them possibly the worst affected of all body cells. Maybe that and the other things relate to the successful use of antivirals by myself and so many others despite them slowing down mitochondria. See also http://www.healthrising.org/blog/2016/10/17/pridgen-fibromyalgia-antivirals/

Maybe our disease could be no auto-immune disease after all, but rather the opposite. It could be a lack-off immunity disease? If Dauer is in large part a signal-molecule thing, then many of these molecules will be carried by the blood. The white blood cells have mitochondria too and are hence potentially vulnerable to these signal molecules. As blood is the easiest way of transport for these molecules, the blood could carry the highest quantities and white blood cells are bathing in it and thus could come more in contact with these signal molecules than any other cell. This somewhat fits the pattern seen in the Rituxmab trials: the drug starts by killing the white blood cells off. So at first the immune system is even more hampered. At the beginning the patients get worse. Then it takes quite some time before the patients get better. Could it be that the newly formed white blood cells made to replaced the killed ones take some time to both build up and get exhausted? If so, the other cells could sense that they are guarded better by more functional immune cells and let there defensive guard somewhat down. In this hypothesis, that would reduce the toxicity of our blood and exhaust our white blood cells less. That could start a positive circle.

I know it is a VERY long shot, but does it make no sense at all or quite a lot of sense? It fits my case of the disease quite well. Has anyone an opinion on this going from "that's totally crazy" to "I recognize parts of that"?

I think its a great hypothesis. I really like the way you laid out all the ways a dauer-like state could have us hunker down and thwart infection at the same time. I thought that was fascinating - very well thought out! Thanks!

 

[Forbin]

...I imagine that you could donate to them through the Kavli Foundation or Me and You (???).

One minor thing... It's the Kavli Trust in Norway that supports the work of Fluge and Mella.
https://en.wikipedia.org/wiki/Kavli_Trust

Here's the webpage discussing it:
http://kavlifondet.no/english/hope-for-cfsme-patients/


The only reason I bring this up is because there is a Kavli Foundation in the United States. https://en.wikipedia.org/wiki/Kavli_Foundation_(United_States)

The two seem to be unrelated, although the (Fred) Kavli Foundation also supports research in science and medicine by awarding prizes and funding several university institutes.

I suppose it is possible that the U.S. based Kavli Foundation is also supporting ME/CFS research in Norway (Google produces many hits for "Kavili Foundation" and "ME/CFS") or maybe people are mistakenly thinking that "KalviFondet" means "Kavli Foundation" instead of "Kavli Fund."

Meanwhile, to make things even more confusing, the U.S. Kavli Foundation is funding the "Kavli Microbiome Ideas Challenge," though this is not ME/CFS specific.
http://www.kavlichallenge.org/

 

[Moss]

@Cort @Monica thanks for the donation info.

 

[David Downer]

Someone in Los Angeles got a NIH grant to study the use of Viagra in ME/CFS a long time ago. Some people were upset over that study because they thought it was demeaning but it made sense = viagra opens blood vessels all over the body. THe study never got published, however.

I just added this to the blog regarding NO


http://www.healthrising.org/forums/...nt-on-nitric-oxide-treatment-for-me-cfs.2829/

I just wanted to reply about Viagra for Treatment of ME/CFS.As a patient for nearly 9 years and i am 56 years old and am on many medications for treatment.I can say for sure that when i have taken Viagra for hypogadism i can asure you that Viagra should be a medication added for treatment because it does help decrease fatigue,pain,brain fog and other symptoms temporally.I have only tried it a couple times because its so expensive here in the USA.I have severly restricted veins and arteries in brain according to my neurologist.I have not taken Viagra but only few times but i can tell you i wish it would be trailed and approved for treatment because the few times i have taken it has helped much,

 

[Peter]

Very interesting David. There is a less costly and more natural alternative that has shown good efficacy for mild to moderate ED in several studies. It's even less costly if you buy the ingredients separately.
https://www.ncbi.nlm.nih.gov/pubmed/?term=prelox

It's called Prelox and is a combination of Pycnogenol (French Pine Bark Extract) and l-arginine. L-arginine is a precursor to nitric oxide (NO) and pine bark extract increases NO production. That's how it improves blood flow. The main difference is that it takes around 4 weeks to achieve full benefits.

Approaches to modulate NO levels and blood flow seem to be promising for symptom relief in a subset of CFS patients. There is a discussion about such medications and supplements on this thread:
Fluge/Mella Take out Patent on Nitric Oxide Treatment for ME/CFS

One thing to mention is that L-arginine can activate herpes viruses and l-citrulline might be a safer option for some people as far as I know.

 

[Francis Martin]

The idea that something in ME/CFS patient's blood may be turning off the mitochondria or natural killer cells or what have you is not a new one. Although no new studies have come out, reports indicate that the natural killer cell problems in ME/CFS apparently disappear when NK cells from ME/CFS patients are put into a healthy person's blood. Conversely, healthy NK cells poop out when put into ME/CFS patient's blood. Fluge and Mella are finding that healthy muscle cells act strangely when cultured with ME/CFS patient's blood.

Finding some factor in the blood that turns things off could be very helpful. It could a) directly point to a cause, and b) to clear treatment options that block the factor or stop it from being produced.

Hi I'm interested in the above comments i.e. effect of plasma from ME/CFS patients on healthy muscle cells (and vice versa). If this compound (cell signalling compound?) could be identified then it would appear to be a potential diagnostic marker --- presumably significantly higher/lower levels in some/all ME/CFS patients.

Jonas Bergquist gave a presentation on the use of Mass Spectrometry in ME/CFS research at the Invest In ME conference in London in 2015. He presented data showing comparison of proteins in ME/CFS patients (cerebrospinal fluid) versus controls (healthy people); patients were clearly distinguished from controls. Re Fluge and Mella's observation; on the face of it a similar approach could be used to identify the compound(s) in blood affecting healthy muscle cells. I.e. use Mass Spectrometry to determine the compounds present in blood samples from normal controls and compare these with ME/CFS patients. Mass Spectrometry was also used in the recently published Naviaux and Hanson metabolomics studies, so the technology is available.

If you hear anything more re this then please publish it.

 

[Aidan Walsh]

I think in a lot of people with POTS the blood vessels in their lower body are too dilated - but it helped with this woman and some others. Nobody ever said we were particularly consistent . I imagine this is another instance of subgroups...

I have seen countless Patients with a diagnosis of CFS & EDS Hypermobility wait years to also get diagnosed with 'VEDS' Vascular EDS type it is what is referred to as a 'crossover'. Last Syncope Paper Published in the mid 50's a

young Woman with Syncope had (HFI) hereditary fructose intolerance which I have also seen (HFI) in numerous EDS Patients test Positive...Any of these above would explain the Vascular issues even the increased acid levels.

We need a trial in CFS to look at what percent have VEDS/HFI??? There just might be Diagnostic tests after all. Last I have read that anything over 8 in tryptase blood test is now highly suspicious of multiple copies of the tryptase

gene mine was at 10 in blood test.The Normal range of tryptase is only a cut-off point some Scientists say Normal 10 is wrong & 20%+ of World Population do not have a tryptase gene at all...The first test for (HFI) cost money if

it is Positive then the entire Family pays no money for all to be screened so a way to maybe test for this would be all family members paying part of the first test costs for those who cannot afford the test it is something to think about.