The Montreal ME/CFS Conference: Pt I
I thought I was in Paris, so much French was being spoken. The conversations in the cafes, on the streets, in the subways – everywhere – were in French. It turns out that with its 4,000,000 plus residents, Montreal is the second largest French speaking city in the world. I couldn’t understand a word anyone was saying but the beauty of the language was evident. (Thankfully, they quickly switch to English when needed.)
My Parisian Uber driver told me, however, that Canadian French is not correct French at all – it is, he sniffed, anglicized French which he had trouble understanding at first. French, he assured me, is the easiest language to learn because, in contrast to English, it actually has rules that it follows. Plus, in French you actually say all the letters. He demonstrated that by pronouncing Toronto the way it should be pronounced (Tor-on-To) and then the way he said Torontonians pronounce it (Tor-an-do). (A Torontonian informs me the pronunciation is more like “tronno”). He also informed me, that because the French were first on the green and gentle isle that is England, English is actually French spoken poorly. 🙂
The conference took place in auditoriums in a French hospital – the CHU Sainte-Justine (there are French and English hospitals in Montreal) – home to one of the four most important pediatric centers in North America. The auditoriums, which tended to be packed (Ron Davis’s talk was standing room only), were a step up from the usual hotel conference room. Having the conference off-site from the hotel, on the other hand, required some extra work and expense. The food, which was generous, included the most interesting hors d’oeuvres I’ve ever seen. The only real miss was the “rest room” which consisted of a very small room with a pad on the floor and a chair.
The CHU Sainte-Justine is one of four important pediatric centers in North America.
Canada has recovered nicely from the weird rejection a couple of years ago of all grant applications for federally funded research studies on the grounds that chronic fatigue syndrome (ME/CFS) is not a real disease. The conference was funded by the second grant, plus Canadian and U.S. groups (Solve ME/CFS Initiative, Open Medicine Foundation). Plus, Canada is going to fund a small research center that will collaborate with the NIH-funded research centers in the U.S.
The conference came about from a few key actions. Christian Godbout, a Montreal patient who was too ill to attend but whose father was present (and regularly attends ME/CFS conferences), pressed an influential doctor to get Montreal to do more. The doctor got in touch with the best researcher he knew of – Alain Moreau – and asked him to produce an overview of ME/CFS research with the idea of identifying research needs.
As Moreau worked his way through the overview, he became intrigued with the disease and applied for both the first, rejected grant, as well as the grant which helped pay for the conference. The NIH funding of the ME/CFS centers prompted Canada to provide funds towards a small research center that will collaborate with the U.S. ones. Plus, I was told Canadian officials have promised to be more proactive about getting the word out about ME/CFS.
This is just to show that individuals can make a difference and that you never know the impact your actions may end up having.
As with every conference, the talks were a jumble of snoozers, moderately exciting ones and positively scintillating ones. Alain Moreau and his counterparts did a good job highlighting Canadian researchers and doctors while bringing in some excellent outside researchers.
It was particularly good to see Carmen Scheibenbogen show up. Scheibenbogen, a German researcher with her fingers in many pies, was there attending her first (but hopefully not her last) North American ME/CFS conference. Roland Staud, one of the rare researchers to cross over from fibromyalgia to ME/CFS, made, I believe, his first appearance at an ME/CFS conference as well. I missed several presentations but Maureen Hanson, Betsy Keller and Nancy Klimas provided particularly thought-provoking presentations.
Maureen Hanson – The One Problem to Rule Them All?
Hanson headed off the Metabolic section, and as she did so, she noted Canada’s excellent, free Human Metabolite Database (HMDB) which contains detailed information about 114,100 metabolites. It wasn’t a groundbreaking new study result that made Maureen Hanson’s talk so interesting: it was her conclusions.
Hanson – known to be a rigorous researcher – has been comparing the results of past metabolome studies to see if the results match up. Are we getting more or less consistent results or are the results all over the map?
Could metabolism be ground zero for chronic fatigue syndrome (ME/CFS?)
Whether we’re getting consistent results or getting a jumble of results from metabolomics studies is a very important question given the amount of interest and effort that has gone into the field recently. Ian Lipkin is adding metabolomic studies to his portfolio. After finding some darn interesting cytokine findings, the Simmaron Research Foundation is exploring the metabolomics of spinal fluid.
I still go back to Ron Davis’s findings with his son; after doing test after test after test, it was only the metabolomics results that impressed him. This field needs to replicate those results, though, for them to be considered solid.
It wasn’t looking good early on as Hanson noted the different platforms used, the different sample types used (serum vs plasma), the different extraction methods, the different ways samples were stored, etc. All these possible confounding factors in a rather finicky field seemed to presage disaster, but in the end the news was good. Except for the studies which used plasma vs. serum, the findings were actually very consistent, and even in the plasma vs. serum studies, the numbers weren’t that far off.
As to the applicability of metabolomics to ME/CFS, Hanson reported she was able to identify 95% of ME/CFS patients correctly using 41 metabolites. Her search for metabolomic subsets failed – suggesting perhaps that metabolic problems are at the core of ME/CFS; that they may be THE central driver which gives rise to the subsets that are probably found in ME/CFS.
Hanson perhaps gave a clue to what she thinks is going on when she noted the 2014 Vermoulen study which suggested low oxygen flow to the tissues was causing the problems with exercise in ME/CFS.
Hanson is currently doing or will do a two-day metabolomic and exercise study, which I believe is part of her NIH research center grant. If ME/CFS is indeed a hypometabolic state that’s held in place by problems with energy production, the results of the two-day exercise study will be fascinating. Will that hypometabolic state – always measured during rest so far – get even more hypometabolic after the two-day exercise trials? This is the kind of big, complex and expensive study that we need the NIH for.
Betsy Keller – The Ever-Evolving Exercise Picture in ME/CFS
Keller first thanked the Workwell Foundation for getting her into this field. Most of the patients she sees are there for disability evaluations.
Quite a few groups are doing exercise studies, but it’s the Workwell Foundation – composed of exercise physiologists – which has contributed the most eye-opening finding of all: that the ability of ME/CFS patients to generate energy gets whacked by exercise. That finding is all too obvious to anyone with ME/CFS, but it turns out that that finding may be unique to ME/CFS.
Keller stated that people with lung disease, heart disease or sedentary controls are able to replicate their energy production to a surprisingly precise degree (differing by 1-7%) on the second day of a two-day maximal exercise test. Many people with ME/CFS cannot – something happens to them during or after exercise to disturb one of the most fundamental biological processes of all: their ability to turn oxygen into energy goes down, sometimes quite severely. Hanson reported that a former marathon runner’s ability to produce energy went down a staggering 44% after one maximal exercise test.
Ventilation is proving to be a major issue in ME/CFS. (By John Pierce [CC0], from Wikimedia Commons).
The ventilatory response – the breathing we do to remove the CO2 waste products and get more oxygen to our tissues – is often deranged in ME/CFS as well. If you can’t remove the excess CO2 produced during exercise, you’re going to be in pain fairly quickly. (Of my two single exercise tests done years ago, my ventilatory response was the only measure that was off — and it was way off.) Dr. Systrom has said that breathing problems during exercise are almost universally found in ME/CFS.
The heart rate should increase at a certain rate during exercise in order to propel more blood to the tissues. It’s becoming clear that a problem called chronotropic incompetence – or, the inability to properly increase the heart rate during exercise – is common in ME/CFS.
After exercise, the heart rate should drop at a certain rate as the person recovers. Within six minutes, their systolic blood pressure should come down to resting levels. Each of these can also be off in ME/CFS.
One might expect a lot of lactate production in aerobically challenged ME/CFS patients, but sometimes Hanson sees little lactate production. (Lactate – a toxin – is a function of anaerobic energy production). This odd situation is probably occurring not because the patients aren’t energetically impaired but because they’re so lousy at producing energy anaerobically. Their tests, Dr. Hanson said, are over very quickly – too quickly to produce a lot of lactate. Ventilation is a better measure in these patients.
Dr. Keller has a paper in review. It’s great to see Dr. Keller digging deeper into this oh-so-fundamental problem in ME/CFS.
Cara Tomas – Energy Production Sagging in ME/CFS Patients’ Immune Cells
Cara Tomas – from Julia Newton’s group in the U.K – noted some of the different results we’re getting in mitochondrial studies. Every study is finding something wrong, but at times, quite different things wrong. As Maureen Hanson did, Cara went over some of the possible confounding factors.
She used the Seahorse machine in the Newton group’s latest study – that machine, at least, shows some consistency. The Seahorse is currently being used in several studies (Hanson, Barao, Newton). She was surprised to find that mitochondrial function was not worse in the severely ill ME/CFS patients, when compared to moderately ill patients. That finding, which needs to be replicated, could suggest that factors other than the ability to produce energy are needed to produce more severe ME/CFS.
Because Tomas used PBMC’s isolated from whole blood, no factors in the blood could have contributed to the results. Tomas first assessed the ability of ME/CFS patients’ and healthy controls’ immune cells to create energy in low and high glucose concentrations. Adding glucose should boost up glycolysis – the anaerobic portion of the energy cycle – and it did – but only in the healthy controls. The inability of the ME/CFS patients’ cells to utilize the extra glucose seemed to suggest that something had gone wrong with glycolysis in ME/CFS, but then came a twist: a glycolysis stress test indicated that glycolysis was operating normally.
The ME/CFS patients’ immune cells couldn’t generate nearly as much energy as the healthy controls.
As Tomas went through her tests and found that ME/CFS patients’ immune cells underperformed in every situation she put them in, suggesting they were stuck in a kind of low energy mode. When given extra glucose, they weren’t able to use it. When deprived of glucose, they weren’t able to increase their mitochondrial energy production.
The fact that ME/CFS patients’ cells had lower reserve capacity suggested they may have already been operating near their maximum level. The low coupling efficiency suggested that, when pushed, they simply didn’t have the resources to respond. When asked to respond, the ME/CFS cells were able to generate only about a quarter of the energy of the healthy controls.
The study was on immune cells, not muscle cells, but each finding seemed to make sense given ME/CFS patients’ inability to mount the energy to engage in exercise.
The healthy controls’ cells, on the other hand, demonstrated the flexibility and adaptability healthy cells need to have to respond to the different situations they will inevitably face.
All in all, it was a remarkable set of findings which made several of the Ramsay Award studies the SMCI has funded of double interest. A couple of years ago, the SMCI made investigating the energy production of immune cells a top priority. Ramsay award winner Chris Armstrong is studying the metabolism of B-cells under a variety of conditions. Isabel Barao is using the Seahorse machine to see if problems with energy production are hampering NK cells’ notorious problems killing other cells in ME/CFS, and Brupesh Prusty is determining if HHV-6 infections are hampering mitochondrial functioning in ME/CFS. Those studies should be finished or finishing up soon.
In fact, Ramsay Award winners were on full display at this conference: they included Carmen Scheibenbogen (2 Ramsay studies), Jonas Bergquist, Chris Armstrong and Maureen Hanson.
Roland Staud – Fatigue and the ME/CFS Brain
Staud was an inspired choice as he’s one of the very few researchers to study both ME/CFS and FM – and we could dearly use researchers who have a foot in both worlds. This is the first time, I believe, that he’s shown up at an ME/CFS conference.
A rheumatologist based in Florida, Staud has for many years focused entirely on FM and pain, but in the last three years, this well published researcher has produced no less than six studies on ME/CFS.
Bad Brain Motor?
Could the brain not be activating the muscles in ME/CFS properly?
Staud stated that his recent brain imaging study used a different, more precise kind of brain imaging called spin labeling which provides better imaging of neuronal functioning. His goal was to see whether blood flow to the brain overall was reduced, and whether blood flow to brain areas that are associated with fatigue is altered in ME/CFS. Since blood flow is an indirect measure of energy – the brain directs more blood to areas of it that are active – the study measured blood flow during a fatiguing cognitive task.
Staud found that, in contrast to some studies, there were no differences in overall blood flow to the brains of people with ME/CFS, but found a paradoxical result when brain blood flow was looked at in more detail. Increased blood flow to parts of the brain associated with memory and cognition (superior temporal gyri (STG), precuneus, and fusiform gyrus) were associated with decreased fatigue in healthy controls but increased fatigue in the ME/CFS patients during the cognitive task and afterwards.
In other words, blood flow to one part of the brain produced exactly opposite fatigue responses in the ME/CFS patients vs. the healthy controls. Patients with the greatest reductions in blood flow to one part of the brain (precuneus, left fusiform gyrus) after the cognitive task experienced the least fatigue. These parts of the brain are believed to affect attention, motor coordination, and sense of self/self-reflection.
That suggests that some sort of flip has occurred in ME/CFS and the fatigue reduction pathways are now responsible for producing fatigue in ME/CFS – a bizarre finding, but then again bizarre findings are not unusual in ME/CFS.
A currently embargoed paper by Staud is expanding on his findings. It found altered “connectivity” i.e. transmission between the precuneus and portions of the brain associated with movement planning and motor function (supplementary motor area, precentral gyrus, basal ganglia), cognitive control (superior frontal gyrus), and sensory function (thalamus) both during resting state and during cognitive tests.
Notice the possible issues with movement planning and “motor functioning” (movement) Staud is finding. He’s not the first – others in the rather distant past uncovered possible issues with engaging the muscles in ME/CFS, but the research mostly lapsed. Miller’s basal ganglia studies of a couple of years ago underlined possible problems with “motor functioning” in ME/CFS. Now Staud is adding to that oh-so-interesting theme. If the brain is not engaging the muscles properly – they should be sequentially engaged as the need arises – then fatigue is an inevitable result.
A big question is why decreased blood flow to the regions of the brain responsible for movement or motor activities would be associated with more fatigue in ME/CFS. Because some research indicates that the motor system might be left “on” in ME/CFS during the recovery period, perhaps reduced blood flow could ameliorate that (?).
In response to a question, Staud said the brain areas he found that make a difference in ME/CFS highly correlated with those that Dr. Hyde asserts are most relevant. The difficulty in accessing the brain makes it a problematic feature to change, but transcranial magnetic stimulation (TMS) is having some success redirecting the flows from one part of the brain to another. If the connectivity between different regions in the brain is indeed a major problem, it’s possible TMS could be helpful.
Next Up: Montreal Pt II – the Immune System
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“…paradoxical result when brain blood flow was looked at in more detail… …Increased blood flow to parts of the brain associated with memory and cognition … were associated with decreased fatigue in healthy controls but increased fatigue in the ME/CFS patients during the cognitive task and afterwards.”
I wouldn’t call that necessarily paradoxical. Compare it to healthy people walking. A short walk in a park doesn’t swell up feet. But a long hike in the mountains does. Mountain guides tell people not to remove their shoes while resting if their feet hurt, because their feet could be swollen so much they are unable to put their shoes back on. Likewise a friend told me that after running a marathon feet swell up 1 to 1.5 European sizes. That’s a lot.
This would not be far off from having a mental task the mind can cope well with compared to one that is far too much for the mind. For a ME patient trying to read 5 lines of text may be far too much. For a healthy student the same state may be reached only after studying 14 hours a day with few fresh air and unhealthy food for an entire month. I tend to see it more as a sliding scale rather then an opposite reaction. Unfortunately we’re stuck at the end of the scale for even the smallest tasks.
In both the walking example as the mental task example I believe the larger blood flow goes hand-in-hand with large inflammation. Inflammation is related by many researchers to pain and fatigue. As such pain in FM/ME and fatigue in ME/FM is not faulty nor excessive when comparing the loading of the body to what the body can handle. Mental tasks to heavy very often go hand-in-hand with mind blowing sphere like pain too in my experience. A sphere the size of a big golf to tennis ball hurting like it’s exploded would be about the size of the overexerted brain area.
The view of migraine as a brain blood flow related disease that can be triggered by allergic reactions is almost logic. Dis-regulated blood flow in the brain goes hand in hand with inflammation and thus pain and fatigue. Allergic reactions are prime causes of very strong and sudden inflammatory reactions. Whilst the reaction may be against food and it’s prime center may be in the digestive tract, inflammatory chemicals flood the body in an allergic reaction. For mold sensitive people being exposed to mold could do just the same. It’s said to trigger near instant severity of ME. That’ll include fatigue and pain that are well linked to inflammation. The importance of inflammation in fatigue correlates with the majority of pain killers being also anti-inflammatory.
Not seeing massive swelling in the body is probably linked to the massive amount of anti-inflammatory stuff keeping truly excessive inflammation at bay. Imagine all body parts having as much swelling as their dire state would entitle. Then we’d likely end up with the effect of purple swollen toes with gout but applied to the whole body from head to toes. That’d be probably even more deadly then sepsis so the body can’t allow for that and has to compensate the massive amount of pro-inflammatory stuff with nearly as much anti-inflammatory stuff and measures. Low blood volumes and often low body temperatures are part of these measures.
As it’s hard to guess if the body has reached the optimal balance between inflammation for healing and reducing inflammation in order to not strongly hamper functioning I prefer to reduce activities/situations that necessitate increased inflammation/healing or increased immune functioning over trying to force inflammation down by anti-inflammatory agents only modulating inflammatory response. Unfortunately every little thing we do is an excessive load to our bodies. Even doing nothing at all is inflammatory due to it’s stagnating effect on the blood flow. So it’s a daunting task prone to failure.
I see it as paradoxical because that part of the brain was relieving fatigue in healthy controls. If it had been a part of the brain that was associated with muscle activity or producing energy, I could see how too much stimulation could be a problem but here I would think the more stimulation the better?
“I could see how too much stimulation could be a problem but here I would think the more stimulation the better?”
A muscle cell producing ATP to create a mechanical movement or a brain cell producing ATP to create useful electric impulses isn’t that different to me. Both are metabolic processes creating waste and some sort of damage to repair. For example all overexerted cells switch after a while from producing ATP to hydrogen peroxide. That does cost oxygen/blood too but impairs functioning.
Maybe we differ in view were the extra blood flow is used for? Is the extra blood flow driven to these parts of the brain in order to enable increased activity or is it driven in order to repair/clean up the mess after overexertion? The latter would resemble an inflammatory mechanism IMO. Probably the extra blood flow does initially increase ability to think but quickly inflammation takes the upper hand.
“Because Tomas used PBMC’s isolated from whole blood, no factors in the blood could have contributed to the results.”
“When asked to respond the ME/CFS cells were able to generate only about a quarter of the energy of the healthy controls.”
“As Tomas went through her tests and found that ME/CFS patients’ immune cells under performed in every situation she put them in, suggesting they were stuck in a kind of low energy model.”
=> I guess that would be still out of healthy blood? Weren’t studies on immune cells in healthy blood showing them to function normal?
If so, then combining all quotes would say that the immune cells aren’t permanently damaged, but can be regenerated rather quickly to a normal state of functioning. From a quarter of functioning to normal functioning in ?an instant? by putting our immune cells into healthy blood would be very impressive and suggest a few things:
* the immune cells are not defect nor unable to perform better, but not willing or inhibited
* as this inhibition remains when putting our immune cells out of the blood, the inhibition must be “remembered” by the immune cells for example by setting a switch or containing some of the inhibiting chemicals in the cell
* if the memory would be caused by containing some of the inhibiting chemicals in the cell, then it seems they do not easily/quickly diffuse out of the cell into a water/glucose solution
* if the cells wouldn’t gradually perform better over time when dipped long enough in a large enough pool of water/glucose then the inhibiting chemicals are very resilient to leave the cells to the water/glucose solution, giving a small clue to the sort of chemicals, or it’s then more likely a switch rather then chemicals after all
* if dripping our immune cells in healthy blood would switch them on quickly, then I can see either a switch being flipped by the chemicals in the blood, the cell seeing an influx of “pro-functioning” chemicals from the blood overwhelming the inhibiting chemicals in the cell and/or chemicals in the blood being able to transport the inhibiting chemical out of the immune cell.
If that would work out, switching the cells back on by a certain drug would probably go against natures intent. It seems that the body does work hard to put immune cells (and other cells too) functioning down. It resembles the inflammatory state that seems to increase pain and fatigue. That is another way to decrease activity. In the case of the immune system, putting it to full power rather then quarter power could cause all kind of nasty things like even deeper depletion of energy or very severe auto-immune reactions.
If I read you message correctly you were asking if the serum test should be done? as I think the test you mention has been done by by Dr Ron Davis, i.e. putting ME/CFS cells in the blood serum from a healthy person and the ME/CFS cells woke up, He then put healthy cells in the blood serum of an ME/CFS patient and the healthy cells shut down. meaning theres something in the blood of ME/CFS patients. That something (I read somewhere since) is thought to be an antibody that possibly attacks pyruvate (sorry I’m not sure on the spelling) which is essential in converting glucose to energy/ATP.
My thoughts are if it is an antibody, then using other methods of waking up ME/CFS patients hibernating cells won’t work, because chances are it will make the antibody wake up too and attack pyruvate harder.
I think we need to be focussing on finding whats in the ME/CFS blood serum, apparently its not a metabolite as they were filtered out in the test.
I may have interpreted that wrong, but thats how I understood it.
Its a damn interesting study as it gives me hope, because if our mitochondria were damaged then they would’t wake up in a healthy person’s blood serum.
however blocking an auto antibody could prove difficult
Here’s Ron Davis talking on this test
https://youtu.be/sGBXXlQO49g?t=710
what would the cost of running batches of samples of this waking up and shutting down of cells be?
I’m confused about “A big question is why decreased blood flow to the regions of the brain responsible for movement or motor activities would be associated with more fatigue in ME/CFS. Because some research indicates that the motor system might be left “on” in ME/CFS during the recovery period, perhaps reduced blood flow could ameliorate that (?)”
=> Is the first decreased correct or should that be increased? It seems to conflict with the text above it and with “perhaps reduced blood flow could ameliorate that (?)”
Bye the way: thanks for going through the effort of going all the way to Canada, trying to focus on the conference and doing a great write-up to our benefit as usual. It must have been quite an exhausting undertaking everything combined. Thanks Cort and don’t forget to pace! You deserved it ;-).
Good catch. I think it should have been increased. ??
Yes, Cort, thank you for going and for this excellent synopsis of the conference.
Thanks. It was fun visiting Canada.
Hi Cort,
Um, as a French Quebecoise, I’d like to set the record straight concerning the Uber driver’s expert opinion about our language. 🙂 A little off-topic, I know, but I wouldn’t want you to get the wrong impression. Our way of speaking French in Canada varies from region to region and the very same goes for France! In fact, it’s the same with varying English accents and expressions across the USA.
So, don’t listen to Parisians looking down their nose at the way Québécois speak; when we go over there, we hardly understand a word THEY say! France does not have a monopoly on a language used around the globe anymore than England does on your language.
Thank you,
A Montreal native.
Fascinating and well said! 🙂
Nice writeup Cort.
“Because Tomas used PBMC’s isolated from whole blood, no factors in the blood could have contributed to the results.”
I wonder if Tomas can really conclude that:
If the putative factor in the blood that blocks energy metabolism in ME/CFS were an anti-mitochondrial autoantibody, possibly once that autoantibody is “glued” onto the mitochondria, it might remain stuck there even if the PBMC’s are removed from the blood.
An anti-mitochondrial autoantibody is known to be produced in chronic enterovirus infection of the heart muscle (chronic coxsackievirus B myocarditis), as German researchers observed this autoantibody in myocarditis decades back (see this thread: http://forums.phoenixrising.me/index.php?threads/enterovirus-induced-ant-autoantibodies-the-cause-of-me-cfs.51145/ ). I have always wondered whether the chronic enterovirus infections of the skeletal muscles found in ME/CFS might produce the same anti-mitochondrial autoantibody, thereby explaining the poor energy production in ME/CFS.
It would be interesting to see if cells from healthy controls that were immersed for a time in the blood serum of ME/CFS patients would also start to display the same energy metabolism blockages that Cara Thomas finds in ME/CFS patients’ cells using the Seahorse machine.
If they did, then it would confirm Fluge and Mella’s finding of “something in the serum”.
Nice point! And a very interesting one. I have heard that Ron Davis has found problems in energy production in cells isolated from the blood or serum as well. The plot keeps thickening!
Didn’t Dr. Naviaux conclude in his metabolomics studies that CFS patients are in a hibernative-type state that the body went into as a defense mechanism against death? If that’s so, then wouldn’t you still have to find the reason it went into the hibernative state and fix THAT? If you bring it out of the hibernative state before the cause is fixed, then wouldn’t you die?
My guess is that if there is still a reason for the body to be in a hibernative state then yes. I think though that Naviaux mostly believes that the hibernative state is a mistake, something which should have been turned off long ago.
You make a good point, Step 1 of Dr. Naviaux’s 3-step treatment strategy is to eliminate the “trigger.” Perhaps Mark Davis’ T-cell research to determine the cause of T-cell clonal expansion (infection or autoimmune) will enlighten? It is known chronically activated immune cells undergo profound alterations in metabolism integral to their bioenergic needs.
When I read all these informations, I have the impression that the theory of metabolic trap developped by robert phair is the good way to solve me/cfs Isn’t it ?
It would be a great way to solve it. Robert Phair is a very smart guy and let’s hope he’s correct. And as you can see there are other options and other avenues being explored. We shall see!
I am a severelly ill patient and read this blog laying in my bed in pieces. II was looking for some hope, a solution, a cure, even if it was only for a part of the multi symptom f….ng desease.But I did not see much … I saw many small studies but I am desperate for tests and treatments.
Yes, no treatments yet but Dr. Klimas is planning a small trial later this year – that’s in the next blog.
I have POTS and CFS/ME and blood flow (blood pooling) is a major issue contributing to my fatigue. When exercising or standing still it is the worst. But mental tasks and anything that is not lying down tax me. I didn’t see mention of POTS, which most many/most CFS/ME patients have.
There wasn’t too much on POTS or orthostatic intolerance although Peter Rowe did talk about OI and POTS. One of the interesting things he said was that since OI severely impacts ones ability to exercise that treating it successfully can help ME/CFS patients ability to exercise.
Maureen Hanson continues to impress me. She is thorough and a very solid researcher. We are lucky to have her. I hope she is right…no subsets would be great if that’s what she is suggesting? That was my interpretation!
That’s my interpretation too – a new twist. How nice it would be if there was one core abnormality in ME/CFS….
Here is a comment Ron Davis made recently about subsets. The quote is from the OMFwebsite, WBUR Interview with Ronald W. Davis, PhD, for MA Dept Public Health April 2018
“We also see a large number of mutations that are probably affecting the patients. Some of them are probably causing some of their symptoms. Every patient has a different collection of mutations. So you can account easily for all the varied symptoms that the patients experience. There is a tendency to want to group these into different categories of the disease. My suspicions are there are as many categories as there are patients and therefore it is not a useful thing to do.”
That’s very similar to what Naviaux says about autism
Fascinating! Thank you , Cort!
Thanks Hip and Brendan for your contributions on anti-bodies. Ron Davis indeed tested ME cells in healthy blood. It’s still unclear to me how healthy patients blood could clear out the anti-bodies from immune cells, so I’m open to ideas ;-). It did however lead me to another take on the memory idea.
Ron Davis appears to assume some sort of protein in the plasma is responsible for converting healthy cells to ME cells in ME blood. And ME cells can covert back to healthy ones (or at least act like healthy ones) by putting them in healthy blood. To be more correct he assumes it may be multiple protein sized components.
Maybe it could be poorly folded and/or damaged protein? Heat shock proteins (HSP) do more then their original name suggests https://en.wikipedia.org/wiki/Heat_shock_protein. “Production of high levels of heat shock proteins can also be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the cell to toxins (ethanol, arsenic, trace metals, and ultraviolet light, among many others), starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants), or water deprivation.” “As a consequence, the heat shock proteins are also referred to as stress proteins and their upregulation is sometimes described more generally as part of the stress response.”
The only thing in that list that does not apply to ME patients is the nitrogen deficiency for plants. Remark the inclusion of exercise and ethanol in the list.
As bacteria are simpler to study, more is known about HSP in them. “However, some studies suggest that an increase in damaged or abnormal proteins brings HSPs into action.” This would indicate that also external “plain faulty” (poorly digested?) proteins could trigger HSP.
Now HSP are in fact protective, used by the body to correct faulty folding (or damaged proteins?) so they are an indicator for how much protein damage there is in the cell and in the adjacent plasma.
I can only get the abstract of https://www.ncbi.nlm.nih.gov/pubmed/20700702 for free. “we will discuss the mechanisms by which misfolded proteins lead to the generation of oxidative stress” “the effects of oxidative stress will be discussed… …and related to the generation and cellular effects of oxidatively modified proteins, which closes a vicious cycle of protein misfolding and oxidative stress.”
Now we potentially have a physical memory remaining in the cell (badly folded proteins); badly folded proteins generate oxidate stress in said cell; oxidative stress causes oxidatively modified proteins which leads to oxidative stress…
In dr Tomans her experiments their is no protein in the liquid IMO. So the only protein available to the cell is the one that was already in it. It’s not going to release that in large quantities IMO. If it’s faulty it will cause oxidative stress and that will cause the refolding of said protein to be faulty too: memory! The oxidative stress in the process produces H202, which is known to put cells in CDR or low energy production.
Now let us assume that much of the proteins in healthy peoples blood are fine and in ME patients blood are faulty. Dip ME patients cells in healthy blood and let them work. It has at least some chance to replace faulty proteins by good ones and clear the faulty ones out (and thus switch to “on”). Put the healthy cells in ME patients blood with supposedly plenty of faulty proteins and they go into oxidative stress and CDR and remain stuck in there.
Faulty protein folding leads to https://en.wikipedia.org/wiki/Unfolded_protein_response: “degrading misfolded proteins” (eg break down) among others. That could reduce protein levels in blood as seen in ME research. Another way of reducing faulty proteins is consuming them for energy if possible. Some research suggests protein is preferred over glucose as a source of energy in ME patients if I recall well. Now their are glucogenic amino acids that can produce glucose for energy production. Next to it there are ketogenic amino acids that cannot produce glucose and hence cannot directly be consumed for energy production. But they can be turned into ketones: https://en.wikipedia.org/wiki/Ketogenic_amino_acid. Could this help people on a keto diet to clear out faulty proteins?
Note: faulty protein folding is mentioned in Alzheimer, Parkinson, Huntington and MS disease;
Note: I did recently found indications that a large part of ME patients have either immune reactions to proteins or protein digestion problems; vegan proteins are often said to be better digestible then animal ones: a plus for the vegan diet?; keto diet has low milk but other dairy, paleo has no dairy.
Note: milk protein and soy protein are major suspects, so vegan diets without soy for the intolerant people? for another time ;-).
Apparently others had the same thoughts before me ;-):
https://www.healthrising.org/forums/threads/er-stress-protein-misfolding-tudca.3961/
https://forums.phoenixrising.me/index.php?threads/unfolded-protein-response-and-a-possible-treatment-for-cfs.37244/
The last one has a whopping 94 pages of comments and the original poster claims “After many years of Brain Fog, Psychological Problems, Orthostatic Intolerance, Thyroid Problems, Testosterone Problems, i am totally recovered.”
I didn’t got past the first page of comments yet but it is promising. I’m on a very early two weeks of remarkable improvement using likewise concepts, but I do far less than this poster did. What I do is cheap and easy. If this rate of improvement would keep up another month or two I’d go into detail, but I don’t want to risk that it is just a fluke.
Maybe the single new idea I posted could be the idea that this could be the elusive thing in plasma that links dr. Tomas and Davis research, if someone else didn’t linked those yet.
I came up with this idea as apparently I do not have cold sores *very* frequently but https://en.wikipedia.org/wiki/Aphthous_stomatitis and “When early aphthous ulcers are biopsied, the histologic appearance shows a dense inflammatory infiltrate, 80% of which is made up of T cells.[5] Persons with aphthous stomatitis also have circulating lymphocytes which react with peptides 91–105 of heat shock protein 65–60”
So basically I likely have a very active “benign” auto-immunity reaction against something looking an awful lot related to “wrong” proteins.
I read somewhere (ME patient survey?) that a whopping 40% of ME patients would have aphthous stomatitis aka canker sores so it could apply to many of us. As well, 31% of ME patients have been found to be intolerant to milk protein https://onlinelibrary.wiley.com/doi/full/10.1111/apa.13476. Poor protein digestion could be a big source of this protein-folding stress response IMO. Milk protein and soy protein are somewhat similar so looking into that may be worthwhile if you use soy products too.
I wonder if a biologic drug could target its (manmade antibodies) to attach to these miss-folded proteins and have the body’s natural T-cells then remove them from the blood serum. That would be a nice fix
German Doctor about COMT-Polymorphism
http://cfs-aktuell.de/januar11_7.htm
(use deepl.com for translation)
Maybe this is one reason why many (all?) ME patients where active people before they got ill.
Due to low COMT they “see everything” but on the other hand this reduces immunsystem power
Dear Cort
Thanks for this brilliant write-up.
Very much appreciated, but I’m quite distressed that there wasn’t much practical take-away for the suffering patient,who endures this horrific illness hourly.
On the subject of French, I’ll just say that technically Quebec French is closest to 17 th c French. Also, many of the colonists came from Normandy and so had their own specific dialects and expressions.
Your ‘french’ Uber driver is technically only partially correct. Quebec french and Canadian French ( the language (in pockets) is spoken in New Brunswick and in Acadia and in manitoba) actually have not only antique french expressions, like Breuvage ( drink)rather than boisson, but have Amerindian words. It was only later during the industrial years particularly after the war, that English terms, were grafted onto Quebec french, like brake for brakes.
It’s a colourful language, and the joual is hard to understand for those from France. But the level of education is fairly high now, so the spoken french now is more international. Yes, the accent or pronunciation can still be a challenge. But the educated classes are easy to understand, and speak beautifully.
I’m glad you enjoyed the city. I hoped to come by and say hello but did not spot you— but then I was only there for the Friday.
Merci.
Dear Cort, I think your taxidriver might have made some erroneous statements.
French language is rather full of exceptions in grammartic rules. Spanish, another latin language, has much less exceptions and is therefore more straightforward to learn. German has very few exceptions in its grammatic rules.
When it comes to pronounciation of all characters of written words, French spoken language sort of always omit the last character. But it may be true that Canadians omit phonemes in the middle of words.
Canadians speak like the French spoke very far back in time. The French pronounciation has developed over hundreds of years, but the French spoken in Canada is an imprint of the settlers that emigrated to Canada far back in the 17th and 18th century. It is a known effect that people that emigrate converve the pronounciation, while the pronounciation in a larger society has a tencency to develop over time. I think that for example the pronounciation of French and Spanish has been influenced by how their royal court spoke. I think the people in Quebec speak more or less like the plebs (common people) spoke around three hundreds years ago in Paris, but it is true that it has also been influensed by english.
Aha!
Interesting. Very interesting particularly about French being spoken more as it was by the people who emigrated to Canada – more the common people. Ha! Thanks.
You might enjoy the English in Newfoundland. Many communities were accessible by boat only until they joined confederation in 1949 (I think). In some places the English is more Shakespearan in its expression.
Thanks for always delivering, Cort.
Cort, I can assure you Staud, along with all of the other UF MDs, has ZERO interest in ME. FMS perhaps, ME: absolutely not. Occasionally we’ll run into a lot of nuttiness in the ME forums with patients attacking researchers saying ridiculous things like “follow the money” as if it were some political game, and sadly it’s directed at the people working their hardest to help up. Other times, you run into physicians who blow you away when you find out they actually fall into the category people fear. In the future, I’d recommend going elsewhere for the data. He doesn’t take legit ME patients who have received a proper ME diagnosis from a qualified position. Whenever I read that he’s received another grant, I cringe thinking of the other researchers who actually do care and want to get to the root of the problem vs. draw a check and slap another grant on his resume to make UF appear as if they’re doing anything at all for ME. Not a single physician in their employment understands ME. If they do, none of the Dept. Heads are aware. I have to travel a very long way for help because of this. It’s unconscionable, and frankly as a Gator Alum, it’s pretty embarrassing as well. Thank goodness for Miami VA, UM, and NSU as UF is WORTHLESS when it comes to helping PWMEs.
I get that he’s not a doctor to see – obviously I have no idea about that – but he’s doing pretty good work on the research end.
Dear Cort, I would like to know how ME/CFS patients have been diagnosed. I refer to the Hanson study in which she was able to identify 95% of ME/CFS patients correctly. Have the patients been dignosed with ccc? For me this question is interesting because in reverse conclusion it should mean that the ccc are very good criteria for diagnostics?!
For better understanding.. if in 95% of the via ccc diagnosed ME/CFS patients the metabolomics is different to healthy people the ccc have to be very good (eg if they would include other patients like patients with depression the metabolomics wouldn’t be the same).
Thanks in advance
Antje
I’m sorry you were so poorly informed by your French driver. There is more English in Spoken French from Paris than in French from Canada. The fact that he has trouble understanding the North American accent has nothing to do with the quality of French spoken in Quebec. I beg to differ…