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Article: 2010 ME/CFS Research Overview Pt II: The Exercise Studies...Validation and Progress

Good recap, and it all looked so promising in 2010.
Small Studies - Most of these studies are quite promising, but one unfortunate similarity in them is their small size; often under 20 patients indicating that these researchers are probably strapped for funds. These studies are small enough to make them quite preliminary; bigger studies will be needed to validate these findings.
Unfortunately, the latest study from Pacific Labs looks like it doesn't validate their earlier findings on exercise. (my commentary on the study).

I agree this is an intersting and very important area but we're not there yet.
 
I think its not true to say that mitochondria are working normal, the study of Vermeulen just showed that oxidative phosphorylation was normal. The Myhill et al study is still the best prove of the abnormalities in ME/CFS there are also studies that show that the TL-protein can be blocked by toxins as well as by wrong pH. I dont think that protons can be the only reason for mitochondrial dysfunction because loss of membranpotential is also described in ME/CFS. Lots of PWCs profit from taking nutrition and there are some studies that show this e.g. Mg and higher energy production as a result. Mitochonrial therapy together with the methylation cycle therapy and NO/ONOO cycle therapy are one of the most promising therapies so far available. Dont dismiss earlier findings until newe ones are really something new. The higher lactic acid in ME/CFS is long know and pumping protons costs ATP and dysfunction of ion channels was also described earlier.
 
I think its not true to say that mitochondria are working normal, the study of Vermeulen just showed that oxidative phosphorylation was normal. The Myhill et al study is still the best prove of the abnormalities in ME/CFS there are also studies that show that the TL-protein can be blocked by toxins as well as by wrong pH. I dont think that protons can be the only reason for mitochondrial dysfunction because loss of membranpotential is also described in ME/CFS. Lots of PWCs profit from taking nutrition and there are some studies that show this e.g. Mg and higher energy production as a result. Mitochonrial therapy together with the methylation cycle therapy and NO/ONOO cycle therapy are one of the most promising therapies so far available. Dont dismiss earlier findings until newe ones are really something new. The higher lactic acid in ME/CFS is long know and pumping protons costs ATP and dysfunction of ion channels was also described earlier.

I don't think you can say one way or another - all we can say is that some findings support 'x' and some findings support 'y'. I agree that the treatment successes - mostly modest - but still there - are a good line of evidence supporting mitochondrial issues. Lot more work to be done on these issues.
 
A New Possibility Emerges - The Suarez Spanish group didnt dally around with a submaximal exercise test; instead they pushed their participants to the limit with a maximal exercise test. This interesting study didnt find any increases in glucose or lactate but they did find increases in nitrates and not small differences either; they were large enough (300% higher) to warrant a p>.0001 figure, far more than needed to reach significance in a research study (typically p<.05). Interestingly, the nitrate levels at baseline were normal in both groups and then went up in the people with CFS when they exercised.

This is a fascinating finding. Nitric oxide produced by the blood vessels (eNOS) is a vasodilator it opens up blood vessels to allow for more blood flow which is generally thought of as a very good thing; physicians, after all, use nitroglycerin and another nitrates to increase NO levels and blood flows in their heart patients. This type of NO production, which is prompted by the endothelial tissues in blood vessels in response to increased blood flow through them, is entirely appropriate.

But high NO levels in ME/CFS could conceivably reflect a very different process of NO formation. High free radicals (ie the F2 Isoprostanes in the MERUK study) or pro-inflammatory cytokines (e.g. Light) in the blood can trigger the iNOS enzyme to produce very high levels of NO. Maes, in fact, has found that high levels of the bad nitric oxide enzyme (iNOS) correlated with increased cytokines in CFS patients. These high NO levels can then contribute to the production of free radicals (e.g. peroxynitrate) that can damage the mitochondria.

The high findings suggest that, instead of opening blood vessels, the NO in CFS patients is producing free radicals that could possibly shut down the mitochondria. The rise in nitrate levels during exercise suggests that an inflammatory reaction is driving this process although its cause is still unclear. This study also validated the reduction in VO2 max found in the Pacific Fatigue Lab study.

Inflammation, immune activation, validation of the VO2 max findings this was an informative study.

The main result of the present study is that nitric oxide (NO) metabolites (nitrates) showed a much higher increase after a maximal physical test in CFS patients than in a group of matched subjects. This combination (exercise plus NO response evaluation) may be useful in the assessment of CFS. http://www.ncbi.nlm.nih.gov/pubmed/20469961

Doesn't this support what Dr Martin Pall said in his 2007 book "Explaining 'Unexplained Illnesses'"? The one Dr Bell summarized in "Cellular Hypoxia and Neuroimmune Fatigue"? He talked about how increases in nitric oxide and therefore peroxynitrite initiate a cascade that he calls the NO/OONO- cycle. In his paradigm, this becomes a feedback loop that perpetuates illness.

He isn't saying that this is the initiating cause of the illness, but the mechanism that produces most of the symptoms. He believes that treatment should target down-regulating the NO/OONO- cycle, so that you treat the cause of the symptoms, instead of just treating the symptoms. I still think his model makes a lot of sense.
 


Doesn't this support what Dr Martin Pall said in his 2007 book "Explaining 'Unexplained Illnesses'"? The one Dr Bell summarized in "Cellular Hypoxia and Neuroimmune Fatigue"? He talked about how increases in nitric oxide and therefore peroxynitrite initiate a cascade that he calls the NO/OONO- cycle. In his paradigm, this becomes a feedback loop that perpetuates illness.

He isn't saying that this is the initiating cause of the illness, but the mechanism that produces most of the symptoms. He believes that treatment should target down-regulating the NO/OONO- cycle, so that you treat the cause of the symptoms, instead of just treating the symptoms. I still think his model makes a lot of sense.

Yes absolutely it does and, in fact, the paper mentioned the peroxynitrite hypothesis. There are two NO producing enzymes; ironically separate theories positive one is up (iNOS) and one is down (eNOS). I don't know if they are mutually exclusive or not.
 
Thanks for this summary, Cort!

I know there is still a long way to go, but for me, reading this took some of the sting out of the terrible, horrible, no good, very bad PACE results. These new studies are absolutely critical for (eventual) doctor education.
 
Yes absolutely it does and, in fact, the paper mentioned the peroxynitrite hypothesis. There are two NO producing enzymes; ironically separate theories positive one is up (iNOS) and one is down (eNOS). I don't know if they are mutually exclusive or not.

I was reading a about nitric oxide quite recently, and since the info is still floating about in my brain, I thought I'd throw out a few things:

The iNOS enzyme (inducible nitric oxide synthase) is induced (created) by the immune system as an when needed. The immune system uses iNOS to make nitric oxide (NO) simply because nitric oxide is a potent antiviral and antibacterial agent. So it makes sense that in CFS, iNOS is thought to be high, as the body is constantly fighting off viruses and bacteria, and often uses nitric oxide to do this.

The eNOS enzyme (epithelial nitric oxide synthase) is used to make nitric oxide for a different purpose: to contract and dilate the blood vessels. That eNOS is thought to be down in CFS probably corresponds to the cold hands and feet symptoms, and may relate to the generally impeded blood flow in CFS.

There is also a third type of nitric oxide generating enzyme in the body called nNOS (neuronal nitric oxide synthase), which is produced in the brain. In the brain, nitric oxide acts as a signaling molecule (a neurotransmitter), and an important one. Maternal bonding behavior with newborns / offspring is triggered by nitric oxide in the brain, and experimentally inhibiting brain nitric oxide will prevent the natural bonding behavior animals exhibit towards their newborns from occurring.

So nitric oxide has multiple uses and functions in the body.

Incidentally, Dave Whitlock has an interesting theory that autism and CFS are underpinned by low nitric oxide in the brain. He thinks that low brain nitric oxide causes the behavioral changes found in autism, and to an extent, in CFS too.

In addition, apparently, ambient nitric oxide levels control the rate of mitochondrial biogenesis - the producing of new mitochondria and replacement and removal of the older mitochondria in cells. Whitlock says that mitochondria in cells have a normal lifespan of a few months, and they get regularly replaced because they wear out pretty quickly.

When mitochondria wear out, they become leaky (leaking out protons, which then lead to more reactive oxygen species being produced in the cell) and much less efficient. So there needs to be a constant process of creating new mitochondrial, and replacement and removal of the older ones in the cell (otherwise cellular production is impaired, and the amount of damaging reactive oxygen species being created in the cell goes up).

Whitlock thinks that the supposed mitochondrial problems in CFS / autism come from a lowered rate of turnover of mitochondria, simply due (according to Whitlock) to levels of nitric oxide being low (since the nitric oxide level sets the mitochondrial turnover rate). This lowered turnover means that we are not replacing the old and leaky mitochondria.

In others words, people with CFS / autism may be going around with damaged mitochondria, because their mitochondria are not getting renewed, due to low nitric oxide.

Certainly a very intriguing idea.
 
Well, this is just out, so it doesn't fall under the 2010 umbrella, but it's more research on oxidative stress in ME/CFS, so it fits in with the NO/OONO- theory:

Med Sci Monit. 2011 Apr 1;17(4):SC11-15.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:eek:ffice:eek:ffice" /><o:p></o:p>
<o:p></o:p>
Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).<o:p></o:p>
Maes M, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E.<o:p></o:p>
<o:p></o:p>
Maes Clinics@TRIA, Thailand.<o:p></o:p>
<o:p></o:p>
Abstract<o:p></o:p>
Background: There is evidence that myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by activation of immune, inflammatory, oxidative and nitrosative stress (IO&NS) pathways. The present study was carried out in order to examine whether ME/CFS is accompanied by increased levels of plasma peroxides and serum oxidized LDL (oxLDL) antibodies, two biomarkers of oxidative stress.
Material/Methods: Blood was collected from 56 patients with ME/CFS and 37 normal volunteers. Severity of ME/CFS was measured using the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.
Results: Plasma peroxide concentrations were significantly higher in patients with ME/CFS than in normal controls. There was a trend towards significantly higher serum oxLDL antibodies in ME/CFS than in controls. Both biomarkers contributed significantly in discriminating between patients with ME/CFS and normal controls. Plasma peroxide and serum oxLDL antibody levels were both significantly related to one of the FF symptoms.
Conclusions: The results show that ME/CFS is characterized by increased oxidative stress.
<o:p></o:p>
<o:p></o:p>
PMID: 21455120 [PubMed - in process]<o:p></o:p>
 
I guess it raises some questions about coherent symptom presentation...but we're still good on the VO2 max abnormalities?
Not sure at all. The point I made in my commentary was that it appears they did all the work to give us confirmation of the VO2 max abnormalities etc (and I got the impression from other posts that you were expecting such data yourself) but no such data was published. Which makes me wonder if they had failed to validate their own findings.
 
I wonder why most of these studies only look at female M.E./CFS subjects. I'd like to see a representation of male patients ;) included to see if these types of results extrapolate across the board!
 
Thanks Cort. I've plugged this in a few places.

If anyone wants to discuss these studies individually, or read other comments on them, the Latest Research subforum:
http://forums.phoenixrising.me/forumdisplay.php?23-Latest-Research has threads on many/most of them (and anyone can start a thread where there isn't already a thread on a paper):
e.g.

'Exercise Tolerance Testing in a Prospective Cohort of Adolescents
with Chronic Fatigue Syndrome and Recovered Controls Following
Infectious Mononucleosis'
http://forums.phoenixrising.me/show...ecovered-Controls-after-Mono&highlight=Taylor


Pain inhibition and post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome
http://forums.phoenixrising.me/show...tional-malaise-in-ME-CFS&highlight=Huybrechts

Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta
http://forums.phoenixrising.me/show...nt-C4a-and-interleukin-1?&highlight=Lambrecht

Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome
http://forums.phoenixrising.me/show...rcise-is-linked-to-cytokine&highlight=Martins

Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study
http://forums.phoenixrising.me/show...se-in-CFS-A-Case-Control-Study&highlight=Roig

Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome
http://forums.phoenixrising.me/show...ntial-regulation-by-.......&highlight=Blamire
 
Thanks Hip! Very interesting. I look forward to looking up Whitlocks ideas - I hadn't heard of him before.

I think several of the parties believe that mitochondrial functioning is low - the question is that due to something outside mitochondria impacting them (low NO, poor oxygen delivery to them, high ONOO levels) or is it due to problems inside the mitochondria themselves? I think thats an accurate distinction but am aware that it may not be :)

My guess is that high NO levels caused by iNOS do not necessarily mean high NO levels produced by eNOS in the blood vessel wall; that you could have both - but I don't know.
 
Not sure at all. The point I made in my commentary was that it appears they did all the work to give us confirmation of the VO2 max abnormalities etc (and I got the impression from other posts that you were expecting such data yourself) but no such data was published. Which makes me wonder if they had failed to validate their own findings.

I see what you mean! There was no mention of VO2 Max results......ach!!!!:eek::eek:

OK here's my hopeful solution - they did a slew of analyses on this group and that paper is coming up shortly....:confused::confused: I sure hope it is...I will talk to Staci Stevens at the Workshop and get the scoop on what's going on.
 
I wonder why most of these studies only look at female M.E./CFS subjects. I'd like to see a representation of male patients ;) included to see if these types of results extrapolate across the board!

As a male I know what you mean....They are cutting the minority group out more and more....In a way I think this is good because it shows they are being very careful to document their results in a group that they know works (my guess is). It shows an increased concern for the type of patients looked at - which I think given the Light results is a good thing. I hope that every exercise study now subsets according to patients with low and high symptom flares (PER) after exercise.
 
Thanks Hip! Very interesting. I look forward to looking up Whitlocks ideas - I hadn't heard of him before.

I think several of the parties believe that mitochondrial functioning is low - the question is that due to something outside mitochondria impacting them (low NO, poor oxygen delivery to them, high ONOO levels) or is it due to problems inside the mitochondria themselves? I think thats an accurate distinction but am aware that it may not be :)

My guess is that high NO levels caused by iNOS do not necessarily mean high NO levels produced by eNOS in the blood vessel wall; that you could have both - but I don't know.

I just came across Whitlock's autism/CFS ideas recently. He is actually from a chemical engineering background, and I think he started seriously studying biochemistry in his own time, in order to try to understand and remedy his asperger/autism condition, which he says has have made progress in doing, using some rather strange and unusual techniques to raise the body's basal nitric oxide (NO) level techniques which he thinks should also work for CFS.

On the face of it, it seems that his low NO view of CFS is in contradiction with Prof. Martin Pall's high NO view of CFS. Whitlock even says on his blog that his view differs from Pall's view. However, as you hinted, maybe people can have low NO in parts of the body (like the brain), and high NO in other parts.

It all seems so fascinating, and I wish I was not so mired in brain fog, so that I might understand it better.
 
iNOS and nNOS can suppress the eNOS so this is the point why you can have very high levels in some areas (of the cells) and low levels outside. if someone is interested in what NO and its reaction product peroxynitrite are causing in the body, then have a look at
Pacher et al. Nitric oxide and peroxynitrite in health and disease: http://physrev.physiology.org/content/87/1/315.full#VI._NITRIC_OXIDE_AND_PEROXYNITRITE_IN_DISEASE
if you need a short overview about diseases caused by peroxynitrite have a look at the tables. There is much much more evidence than pall cited in his book, about the things that occur in CFS. So everybody with CFS should test for nitrotyrosine and if possible for tetrahydrobiopterine. All my results fit with Prof. Palls publications.

if Ca flows into the cells much too much which is typical for CFS because of the NMDA rceptor activity then Ca cant be bufferd and so it binds to other proteins in the cells where it does not go away from very easily. So the Ca dependent NO-Synthases produce much more NO and use up the BH4 which all raises peroxynitrite which again stimulates NMDA and lowers ATP by inhibiting the respiratory chain. This again leads to an increase in NMDA activity because NMDA is ATP dependent so more Ca comes into the cell and so on. The CA also binds to proteins outside the mitochondria which can lead to a mitochondrial clumping and which affects the normal cell motility. So this could also be a reason why mitochondria cant duplicate as usual. Another point is the during duplication mitochondria are very very oxygen sensitive, they turn of their respiratory chain because the even in healthy people generated superoxide would damage the new and young mitochondrial membran during division. So this may be another point why they cant replicate.