You may wonder why the CAA treats XMRV the way they do... So:

[V99]

Dr Yes

I am both perplexed and deeply concerned that Vernon considered this paper an authoritative source for information on the lack of physical findings in CFS and, even more so, on the successful psychosocial approach to management of the disease! Are these views representative of Dr. Vernon's own on CFS, or on the CAA's as a whole??.

Justinreilly

Yes! This is outrageous.

I agree with justinreilly and Dr Yes. In fact, I find this really disturbing.

I have no strong opinion of the CAA, however I have wanted to ask questions about them. As they deal with organisations like the CDC and NIH, I feel entitled to know where they stand on issues. So far I have had a mixture of thoughts about how they are performing, from disappointment to reasonable satisfaction. This reference however, fills me with dread.

I will leave it there, as the drugs I am currently taking are having a weird effect. :tongue:

 

[CBS]

The CAA research strategy has been to cast a wide net and look for anything that correlates to (rather vaguely defined) illness in CFS patients, but with necessarily limited funding this has never seemed to me like an efficient approach. And even in the search for biomarkers they seem to have ignored two of the most compelling findings in ME/CFS research: abnormal SPECT, PET, and fMRI scans, and low circulating blood volume. To complement the work being done by the WPI and others, I would love to see the CAA expand efforts to look for these abnormalities in CCC-defined cohorts. The studies with Drs. Medow and Shungu hint in this direction, but are again essentially looking for different markers.

Dr. Yes,

I'm wondering if you'd agree that the work of Drs. Medow & Shungu touch on ('covers' wasn't the best word here) both of the areas about which you have expressed concern?

MM: Splanchnic vasoconstriction is impaired by microbiomic nitric oxide production reducing cerebral blood flow in CFS (http://www.cfids.org/cfidslink/2009/050601.pdf) and

DS: MR neuroimaging assessment of cerebral metabolic substrates and regional blood flow in CFS (http://www.cfids.org/cfidslink/2009/030403.pdf)

There may be other ways to study abnormal brain scans and low blood volume but in my book, these two CAA sponsored researchers are doing an excellent job of covering the bases while doing work that may be synergistic. It doesn't get much better than that, specially on such a limited budget.

http://www.cfids.org/about/acceleratecfsresearch.asp

Just last week Dr. Shungu co-authored an impressive paper on ventricular lactate in CFS, MDD and control subjects.

Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder.

Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, Levine SM, Mathew SJ, Shungu DC.

NMR Biomed. 2010 Jul;23(6):643-50.

Correspondence to: D. C. Shungu, Professor of Physics in Radiology, Citigroup
Biomedical Imaging Center, Weill Medical College of Cornell University, 516 E
72nd Street, New York, NY 10021, USA.
E-mail: dcs7001@med.cornell.edu

Contract/grant sponsor: CFIDS Association of America, Inc.
Contract/grant sponsor: National Institutes of Health; contract/grant number:
R01- MH075895, K23-MH-069656, MO1-RR-00071.

Abstract

Chronic fatigue syndrome (CFS), a complex illness characterized by fatigue, impaired concentration, and musculoskeletal pain, is often misdiagnosed as a psychiatric illness due to the overlap of its symptoms with mood and anxiety disorders. Using proton magnetic resonance spectroscopic imaging ((1)H MRSI), we previously measured levels of the major brain metabolites in CFS, in generalized anxiety disorder (GAD), and in healthy control subjects, and found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in CFS compared to the other two groups. In the present study, we sought to assess the specificity of this observation for CFS by comparing ventricular lactate levels in a new cohort of 17 CFS subjects with those in 19 healthy volunteers and in 21 subjects with major depressive disorder (MDD), which, like GAD, is a neuropsychiatric disorder that has significant symptom overlap with CFS. Ventricular CSF lactate was significantly elevated in CFS compared to healthy volunteers, replicating the major result of our previous study. Ventricular lactate measures in MDD did not differ from those in either CFS or healthy volunteers. We found a significant correlation between ventricular CSF lactate and severity of mental fatigue that was specific to the CFS group. In an exploratory analysis, we did not find evidence for altered levels of the amino acid neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate + glutamine ('Glx'), in CFS compared to MDD or healthy controls. Future (1)H MRS studies with larger sample sizes and well-characterized populations will be necessary to further clarify the sensitivity and specificity of neurometabolic abnormalities in CFS and MDD.

 

[CBS]

Low Blood Volume & the CAA

Slow Flow

By Suzanne D. Vernon, PhD
Scientific Director
The CFIDS Association of America


http://www.cfids.org/cfidslink/2009/070102.asp


Chronic fatigue syndrome: comments on deconditioning, blood volume and resulting cardiac function.

Stewart JM.
Department of Pediatrics and Physiology, New York Medical College, Hawthorne, NY 10532, USA. stewart@nymc.edu

Clin Sci (Lond). 2009 Oct 19;118(2):121-3.

Abstract

Cardiovascular and autonomic dysfunction have been suggested to underlie the symptoms accompanying CFS (chronic fatigue syndrome). In the present issue of Clinical Science, Hurwitz and co-workers have investigated whether deficits were present in cardiac output and blood volume in a cohort of patients with CFS and if these were linked to illness severity and sedentary lifestyle. The results clearly demonstrate reduced cardiac stroke volume and cardiac output in more severely afflicted patients with CFS, which is primarily attributable to a measurable reduction in blood volume. Similar findings are observed in microgravity and bed rest deconditioning, in forms of orthostatic intolerance and, to a lesser extent, in sedentary people. The circulatory consequences of reduced cardiac output may help to account for many of the findings of the syndrome.


While Marvin Medow, MD is the PI funded by the CAA, Dr. Stewart is in the same lab and is listed as a collaborator on the CAA grant list.

 

[CBS]

CAA Research: Research Grants Program
http://www.cfids.org/about-cfids/research-update.asp

 

[Robyn]

If deconditioning is the problem then why don't all obese or sedentary people have CFS? I'm sorry but this carries no weight as far as i'm concerned. I had alwaysbeen very active and have attempted several exercise programs since becoming ill. I have lost over 60 pounds and eat very healthy. I am also far from sedentary and have continued working full time the whole 15 years I have been sick. Blaming this on deconditioning isn't working. I can assure you. I'm far from well. I just barely manage with some days being worse than others.

 

[CBS]

If deconditioning is the problem then why don't all obese or sedentary people have CFS? I'm sorry but this carries no weight as far as i'm concerned. I had alwaysbeen very active and have attempted several exercise programs since becoming ill. I have lost over 60 pounds and eat very healthy. I am also far from sedentary and have continued working full time the whole 15 years I have been sick. Blaming this on deconditioning isn't working. I can assure you. I'm far from well. I just barely manage with some days being worse than others.

Go back and read the abstract. The citation is a comment on a study done by N. Klimas and friends. The author of the comment wasn't attributing cardiovascular problems to deconditioning, they were comparing the results to bed rest deconditioning as had been done in the original study. I listed it because the author is part of the group funded by the CAA and it clearly shows that the group takes the issue of low blood volume seriously.

No one is blaming this on deconditioning. That said, I'm sorry you're doing so poorly.

 

[Dr. Yes]

Hi CBS

Thanks for the Shungu article!

It is not clear to me whether the Medow study looks at circulating erythrocyte volume. If it will, using a technique or analysis not described in the CAA description, that would be great. It appears Medow will be looking at abdominal pooling and general blood flow - which may of course yield important results, but so far I don't think he is looking at blood volume in general, which as you noted had been found to be abnormal in many ME/CFS patients. Including, as you pointed out, in the Stewart study:

While Marvin Medow, MD is the PI funded by the CAA, Dr. Stewart is in the same lab and is listed as a collaborator on the CAA grant list.

If Medow is actually going to integrate some of Stewart's techniques into his study, that would be very cool, but it would mean adding experiments to those originally proposed.

Dr. Shungu's work is very impressive, and I was in no way trying to minimize it. My point was that he appears to be looking at one marker, brain lactate (again, I am only going by what I read in the CAA proposal literature); it would be great if even a single complementary study to Dr. Shungu's for the evaluation of blood brain flow via, say, fMRI, as was done recently for GWI patients, could be funded for ME/CFS patients. The general presentation of brain blood flow in these patients at rest or post-exertion, etc, would cover even more bases without breaking the bank.

I definitely feel that his study is an excellent project, and that the CAA did well to fund it. I don't feel that his and Medow's studies, between them (and from what I understand of them) fully address the areas I mentioned, though Shungu's in particular has the potential to answer some of the brain metabolism questions I had.

What I was trying to argue is that, given a limited budget, and limited research going on in the 'field' at all, a better research strategy by the CAA would be to focus on testing explanatory hypotheses for ME/CFS based on parameters with a long history of documented abnormalities, or on postulated causative mechanisms that best explain the breadth of ME/CFS clinical and patient experience. That would mean more profound and numerous studies on viral (or other pathogen) involvement. My criticism was of the general approach that has informed the CAA strategy up to this point, not of these two studies in particular.

Hope that made sense; my brain is now officially fondue.

 

[CBS]

Hi Dr. Yes,

It is my understanding (from a recent (March 2010) webinar on the subject - http://www.cfids.org/webinar/oi-slides-32510.pdf - see slides 38 & 39 for what appears to be a reference to unpublished research - although tit says published in May, 2009 in Clinical Science - I looked through their index and didn't see it) that Medow (and Stewart) are looking at directly at blood volume.

The CAA has an upcoming webinar on OI

Managing Orthostatic Intolerance
Date: Tuesday, September 7, 2010
Time: 12:30 PM - 2:00 PM EDT
Registration page:
https://www1.gotomeeting.com/register/702557728
Orthostatic intolerance (OI) is an umbrella term for several conditions in which symptoms are made worse by upright posture. When a healthy individual stands up, gravity causes about 10 – 15 percent of her blood to settle in the abdomen or limbs. This pooling of blood means that less blood reaches the brain, resulting in a feeling of lightheadedness, seeing stars, darkening of vision or even fainting. For most of us, this lightheaded feeling is infrequent when we stand up because the body turns on a series of rapid reflex responses, including releasing epinephrine and norepinephrine, that return more blood to the heart and brain.
When a person suffers from OI and goes to an upright position, he appears to pool a larger amount of blood in vessels below the heart. More blood settles in the limbs the longer he remains upright. The body responds by releasing even more epinephrine and norepinephrine in order to tighten vessels to send blood back to the heart and brain. But for a variety of reasons, not all of which are well understood, the blood vessels don’t seem to respond normally and the heart rate increases or blood pressure falls, or both.
Dr. Peter Rowe was the first person to establish a substantial overlap between OI and CFS (although not everyone with OI suffers from CFS, and not everyone with CFS experiences OI). Join him for an informative presentation that details the various forms of OI, explores the condition’s relationship to CFS and offers tips and tricks to manage OI.
Peter Rowe, M.D.
Professor of Pediatrics & Director of the Chronic Fatigue Clinic
Johns Hopkins Children’s Center, Baltimore, Md.
​

The notion of an abnormality in the vessels that would lead to a loss of vessel integrity is interesting as it could explain a functional hypovolemia (no less blood but rather a bigger pond).

Regardless, I do not think the this would be a comprehensive explanation for all CFS patients. As I have written in other posts, I have florid diabetes insipidus caused by a complete absence of ADH (treated very successfully with DDAVP). For years this caused a persistent low volume state which was the direct result of a hormonal deficiency (most likely caused by low grade chronic encephalitis). And even though my actual volume issues have been addressed, I do still have some periods of lightheadedness and cardiovascular instability (both HR and BP).

As for FMRI specifically, I have been told that this is being investigated further (not necessarily by the CAA - personal communication as a potential subject and discussion of my subjective experience with CFS doc). If I hear more on this I'll let you know.

 

[Cort]

But the only unifying hypothesis I can think of that can account for all those abnormalities, without requiring new understandings of human biology, is one of pathogenic causation or co-causation. And as acer2000 pointed out, those things by themselves represent a diffuse constellation of potential markers with only limited insight into pathophysiology.

The CAA has been fishing for biomarkers too exclusively for too long; there are many problems with this approach, including the poor definition of the disease itself (even Fukuda would include overlapping, unrelated conditions) and therefore of 'true' patient cohorts, but also the basic problem that the search parameters are too wide... Looking for biomarkers is like looking for a needle in a colossal haystack (i.e. the sum of possible biological parameters interacting with the sum of biological and environmental variables). It would make far more sense for an organization with a very limited research budget like the CAA to formulate, based on available biomedical research, a set of co-existing hypotheses for the pathophysiology of ME/CFS and to look for evidence of the causal mechanisms posited by those hypotheses. This is exactly what the WPI did. Instead, the CAA - and many other researchers - have tended to investigate rather peripheral associations between disease and certain biological parameters that do not encompass a central hypothesis of disease causation and that in themselves would, at best, only suggest a possible correlating pathophysiology. As I said this has been the sort of piecemeal approach prevalent in the research community as a whole towards CFS, but the CAA was in the position to do what the WPI ultimately did: to focus on investigating a particular hypothesis of what is going on in ME/CFS, particularly one involving viral pathogenesis, for which the biomedical evidence (despite what Dr. Vernon asserts in the linked article) has always been the strongest.

The CAA research strategy has been to cast a wide net and look for anything that correlates to (rather vaguely defined) illness in CFS patients, but with necessarily limited funding this has never seemed to me like an efficient approach. And even in the search for biomarkers they seem to have ignored two of the most compelling findings in ME/CFS research: abnormal SPECT, PET, and fMRI scans, and low circulating blood volume. To complement the work being done by the WPI and others, I would love to see the CAA expand efforts to look for these abnormalities in CCC-defined cohorts. The studies with Drs. Medow and Shungu hint in this direction, but are again essentially looking for different markers.

My apologies for spamming!

It struck me at one point that everyone was trying to figure out WHAT was wrong rather than figuring how it all went wrong. I think I concluded that we were at such a basic level of understanding this disorder that researchers were simply trying to determine what went wrong. Part of that is obviously due to the definition as you pointed out.

if you look at the studies that Dr. Vernon has integrated in with each other I think you'll see that she's attempting to tie in blood pooling in the gut, reduced blood flows to the brain (causing all sorts of symptoms) and I believe Shungu's mitochondrial problems in the brain (complicated enough that its hard to remember). That group of studies as a whole is very hypothesis driven and quite ingeniously done. Its rare that different research teams collaborate so closely - so closely, in fact, that they can adjust their research protocols relative to other teams findings to take advantage of them (Before they publish).

Of course one problem is the the CAA's very limited budget which does not allow them to fund really expansive single studies. I'm not sure the WPI's research efforts, other than XMRV, will satisfy you either. I couldn't get in to their research section but I remember studies on cytokines and chemokines - secondary manifestations of whatever is going on - as well as the broad pathogen searches. Its a very interesting program but I don't know if anyone, prior to XMRV, was directly getting to cause. Researchers have really been stuck simply on finding consistent abnormalities. Even diastolic dysfunction is not really cause (?) - its an unexplained abnormality - but each documented abnormality does give researchers a string to pull on - and potentially find the cause.

You could take the repeat exercise studies at the Pacfic Fatigue lab the CAA funded. Is that getting at cause? No - it's demonstrating an abnormality for which is there is no explanation - but those studies have changed the field more than any other, I would think, up until XMRV. Repeat exercise - stress testing - is becoming almost a necessity for many researchers because they now recognize that they are going to pick up more abnormalities that way. That study was solely funded by the CFIDS Association I believe.

 

[Cort]

Dr Yes


Justinreilly


I agree with justinreilly and Dr Yes. In fact, I find this really disturbing.

I have no strong opinion of the CAA, however I have wanted to ask questions about them. As they deal with organisations like the CDC and NIH, I feel entitled to know where they stand on issues. So far I have had a mixture of thoughts about how they are performing, from disappointment to reasonable satisfaction. This reference however, fills me with dread.

I will leave it there, as the drugs I am currently taking are having a weird effect. :tongue:

I would note that that paper apparently had at least 132 references. i think one has been mentioned. Do you have any idea how representative it is? Have you checked out any of the others?

 

[Cort]

I agree. It's been said before, but what ever happen to the science in ME.

if you're looking in the scientific literature there basically are no published studies on ME after 1985 and just a handful of small papers - mostly doctors clinical notes prior to then. Its always been a niche topic - and a very small niche at that.

 

[Cort]

CBS- I don't see what you're saying. What V99 said is that Vernon said that ME is not caused by a retrovirus and that Vernon's statement is unsupported. CAA and other orgs should have been on top of XMRV. I totally agree with her.

Cort- You stated that noone else (but WPI) was looking at XMRV so why single out CAA? I agree with V99 that every org should have funded this work. In this country the only orgs that fund any science on ME are WPI, CAA, NIH and CDC (and to a much lesser extent NCA) and we know we NIH and CDC have to be bludgened into funding any valid research, much less retroviral research.

Also, you are claiming again that CAA is funding XMRV research, but when questioned about this on the last thread, you said that you thought they weren't funding it (just providing samples) and good for them for getting someone else to fund it instead of them.

They aren't funding any grants on XMRV; they haven't funded any new grants since well before XMRV hit the scene. They and GSK are collaborating on an XMRV study. I have no idea who is paying for what - what matters to me is that we have a good XMRV study going on - and kudo's to the CAA for working one out however they did.

 

[Cort]

I totally agree- all the new human retroviruses need to be researched re ME: HTLV III, HTLV IV, but especially XMRV, the 'related' MuLV's that Dr. Alter reported he found in humans in the NIH/FDA study, and DeFreitas retrovirus. It's crazy this is not being done.

• The CDC didn't find HTLV
• The Japanese researchers didn't find HTLV
• The Gow team couldn't find HTLV
• At the last go around Dr. DeFreitas couldn't find HTLV
• The National CFIDS Association didn't find HTLV
• The WPI didn't find HTLV

I don't think anyones going to find HTLV and, quite frankly, looking for it at this point is probably a waste of precious research dollars.

Mulv's are obviously a new story and I'm sure that other viruses will continue to crop up over time. The WPI used the largest most sophisticated pathogen array to date - I'm sure they're pretty caught up on the different pathogens in CFS patients blood - at least the ones we know to look for.

 

[CBS]

Medow and Stewart on POTS

Clinical Science (2006) 110, (255263) (Printed in Great Britain)
PDF


Increased plasma angiotensin II in postural tachycardia syndrome (POTS) is related to reduced blood flow and blood volume

Julian M. STEWART, June L. GLOVER and Marvin S. MEDOW
Center for Pediatric Hypotension, New York Medical College, Valhalla, NY 10595, U.S.A.

Abstract
POTS (postural tachycardia syndrome) is associated with low blood volume and reduced renin and aldosterone; however, the role of Ang (angiotensin) II has not been investigated. Previous studies have suggested that a subset of POTS patients with increased vasoconstriction related to decreased bioavailable NO (nitric oxide) have decreased blood volume. Ang II reduces bioavailable NO and is integral to the reninAng system. Thus, in the present study, we investigated the relationship between blood volume, Ang II, renin, aldosterone and peripheral blood flow in POTS patients. POTS was diagnosed by 70 upright tilt, and supine calf blood flow, measured by venous occlusion plethysmography, was used to subgroup POTS patients. A total of 23 POTS patients were partitioned; ten with low blood flow, eight with normal flow and five with high flow. There were ten healthy volunteers. Blood volume was measured by dye dilution. All biochemical measurements were performed whilst supine. Blood volume was decreased in low-flow POTS (2.140.12 litres/m2) compared with controls (2.760.20 litres/m2), but not in the other subgroups. PRA (plasma renin activity) was decreased in low-flow POTS compared with controls (0.490.12 compared with 0.900.18 ng of Ang Iml-1h-1 respectively), whereas plasma Ang II was increased (8920 compared with 324 ng/l), but not in the other subgroups. PRA correlated with aldosterone (r=+0.71) in all subjects. PRA correlated negatively with blood volume (r=-0.72) in normal- and high-flow POTS, but positively (r=+0.65) in low-flow POTS. PRA correlated positively with Ang II (r=+0.76) in normal- and high-flow POTS, but negatively (r=-0.83) in low-flow POTS. Blood volume was negatively correlated with Ang II (r=-0.66) in normal- and high-flow POTS and in five low-flow POTS patients. The remaining five low-flow POTS patients had reduced blood volume and increased Ang II which was not correlated with blood volume. The data suggest that plasma Ang II is increased in low-flow POTS patients with hypovolaemia, which may contribute to local blood flow dysregulation and reduced NO bioavailability.

 

[Robyn]

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[Robyn]

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[judderwocky]

just to throw this out... people keep pointing to not finding a few retroviruses... there are so many out there which could be crossing over.... no matter who you want to do the research... it seems like at some point... somebody should be looking for more of these in CFS patients... I don't just mean XMRV and MLV's ... i mean we really need to start canvasing wider ... in this illness... and i think autism might benefit similarly...

i think that retroviruses cause illnesses almost identical to these types of disorders in every other species and in our own... there are so many at this point, we need to look beyond the short list of ones we are familiar with in studies... we need to be broadening our focus base on that....

 

[CBS]

Well I did read it so maybe I don't fully understand. Since I do work all day it ends up taking a toll on me. But it looks as if it says that bed rest deconditioning is attributing to the cardiac issues and orthostatic intolerance. Is that correct? If so I would not understand it because I am not bed rest deconditioned and have never been. I do however have cardiac issues that include orthostatic intolreance an tachycardia almost all the time. I'm not doing as poor as most since I am able to get out of bed and make it through a a full day of work. I also walk around all day long during the day. But the heart problems have been there since I became ill and are unchanged (for 15 years). I've had 3 echocardiagrams, numerous ekg's, been on a heart monitor 5 times, and and they can't figure it out. Some days I can move like about a 60 year old although I'm in my 40's (this has been going on since my 30's) and at it's worse I move about like some 90 years old. My whole body feeling like I'm carrying weights on every muscle. So what would cause such difference when this can change day by day or even from one hour to the next. Sometimes within minutes. Oh and I have perfect cholesteral and weigh 125 lbs.

Hi Robin,

My read of the commentary is that Stewart is on blood volume and is saying that CFS patients have cardiovascular problems that resemble someone that has either been on bed rest or who has been in a "microgravity environment" and has deconditioned when they haven't been in either. Specifically he states that he feels that "reduced cardiac stroke volume and cardiac output in more severely afflicted patients with CFS, which is primarily attributable to a measurable reduction in blood volume."

Stewart and Medow have been studying POTS for a long time and are in a very good position to assess a whole host of potential mechanisms involved in cardiovascular dysfunction. As you can see from their 2006 article, they recognize low blood volume and hormonal imbalances (amongst other processes delineated in other studies).

Low blood volume and hormonal issues that lead to a loss of vascular tone would mean that your tissues aren't getting the oxygen they need and it's no wonder you feel like you're 60 or even 90 yo.

 

[judderwocky]

So I guess what I'm wondering is what else could cause the POTS and tachycardia if it's not from bed rest deconditioning? Could a retrovirus that's infected the heart or brain cause the problem with blood flow? I thought I've heard that Dr. Cheney said this is one possibility. An infection in the heart.

Its more than just that... its my understanding that XMRV has a number of protein homologues similar to human proteins... so when your body fights the virus off... some of these anti bodies attack chemical systems in the cell that are good.... the homologues receptors for a couple really important energy and receptor systems.... so there is a potential that it could be the source of some of the auto immune issues... that would certainly impact muscles like the heart that rely heavily on the systems that are disrupted...

http://xmrvaction.org/content/nature-proceedings-proteins-xmrv-retrovirus-implicated-cfs-and-pc

 

[thegodofpleasure]

The WPI used the largest most sophisticated pathogen array to date

It seems to me that the WPI did the blindingly obvious and in doing so, made those government funded agencies, who should have been advocating / doing this already, look inept. Those agencies' consequent embarrassment (together with a large dose of hubris) perhaps explains much of what has subsequently come to pass.