New Klimas Paper- NPY, Stress, HPA Axis and CFS

[Cort]

Here are the conclusions of the paper.. It is all pathophysiological - disorder is caused by complex interactions by many systems and should be studied that way....Infections could trigger NPY activity....

Conclusions
This study is the first in the CFS literature to report that plasma NPY is significantly
elevated over healthy controls and also over a comparision group of lated to symptom severity. elevation of NPY is associated with severity of stress, negative mood and clinical symptoms.

The pattern, in some CFS cases, of high NPY noted here, along with previously observed low DPPIV and hypocortisolism [20,57,58] supports the hypothesis of HPA axis dysregulation in CFS. Duration of this illness typically exceeds 10 years. Persistence is likely to involve complex interaction of immune, autonomic and neuroendocrine regulation and remains poorly understood. Investigation of CFS biology has focused on the detailed characterization of individual neuroendocrine and immune components taken in isolation.

Current CFS treatments are directed at reducing symptom severity but no cure exists for this condition. In a review of CFS, published in Lancet, Prins, et al. stated: Techniques such as bioimaging and proteomic strategies, and perhaps a systems biology approach, should be applied to try to elucidate such complicated interactions[68]. It is clear that further understanding of disease mechanisms and development of effective treatments will require more than a list of the abundance of gene products, proteins or cells. These various cellular and molecular components are highly inter-dependent. Our research group has undertaken a systems biology approach [69]. We are presently incorporating data from plasma NPY measurements, along with other plasma and cellular biomarkers into a network analysis.

The renewed interest in viral infections in CFS suggests further studies. It is possible that NPY is induced by such infections. As reliable assays become available it will be important to determine the relationship of plasma NPY to potential pathogens.

 

[Cort]

More on Neuropeptide Y from the paper

They covered NPY with regard to stress, SNS activity, exercise (?), depression, blood pressure and heart rate, the limbic system, autoimmune disorders...this peptide gets around....

Neuropeptide Y (NPY) is found in both the central and peripheral nervous systems. In the peripheral nervous system, NPY is concentrated in and released from sympathetic nerve endings, either alone or with catecholamines. Irwin reported NPY increased in depressed and stressed subjects, and suggested that “circulating levels of this neuropeptide serves as a tonic measure of sympathetic activity“[25]. NPY release follows stress such as strenuous exercise [26], panic disorders [27], and cold exposure [28].

In the periphery, NPY is activating and stimulates the stress response, but in the brain, NPY is anxiolytic, inhibitory of sympathetic activity and causes lowering of blood pressure and heart rate [29, 30]. Concentrations of NPY in the brain are higher than other neuropeptides, particularly in the limbic system, including the amygdala and the hypothalamus, all areas of the brain involved with emotion [31, 32]. 


Plasma levels of NPY are reported to be elevated in other complex multi-symptom
illnesses associated with immunologic dysfunction, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [33]. A recent study compared 51 fibromyalgia patients to 25 healthy controls and reported elevated plasma NPY [34]. However, an earlier study found lower NPY in 12 fibromyalgia cases [35]

Given these reports, it seemed likely that plasma NPY would be elevated in CFS.
Elevated NPY would be anticipated to correlate with psychological measures of stress and other aspects of CFS symptoms. However, we could find no such studies. There is a clear need for CFS biomarkers that are useful in diagnosis, in defining patient subgroups and in therapeutic trials. We tested and confirmed the hypotheses that elevation of peripheral NPY occurs in CFS and that elevation of NPY is associated with severity of stress, negative mood and clinical symptoms.

I don't why Nancy didn't go for those other functional measures..one reason might be the small sample size inhibited the the number of variables she could use and she was more sure of getting a positive result using what she did. I wish she had looked at the others.

 

[OurDayWillCome]

NPY has been noted in POTS as well.

Conversely, our results indicate that exercise can lead to MCA, presumably through sympathetic activation. In this regard, neuropeptide Y (NPY), a 36-aa neuropeptide that is coreleased with norepinephrine from noradrenergic neurons, has been shown to induce mast cell degranulation with the release of preformed mediators in purified rat peritoneal21,22 and human jejunal mast cells23 and to induce hypotension in animals secondary to MCA in vivo.24 This appears to be a nonreceptor-mediated effect related to the presence of positively charged amino acid residues of the C terminus of NPY. Therefore, the physiological significance of NPY-mediated MCA remains speculative.

http://hyper.ahajournals.org/cgi/content/full/hypertensionaha;45/3/385

I just hope they keep looking until they can definitely separate physical stress from psychological once and for all.

 

[Cort]

NPY has been noted in POTS as well.



http://hyper.ahajournals.org/cgi/content/full/hypertensionaha;45/3/385

I just hope they keep looking until they can definitely separate physical stress from psychological once and for all.

My gosh Ourday - what a nice tie-in to CFS...that they missed...a shame. I wonder if they can link mast cell degranulation to complement findings in exercise......I'm on the skinny branches here...

 

[OurDayWillCome]

Good question, but I have no idea. Now will go looking. I do know my Tryptase (a marker for mast cell burden) is elevated.

 

[Cort]

Theorharides proposed mast cell degranulation is a factor in CFS.....NPY is a potent mast cell degranulator

http://www.cfids-cab.org/rc/Theoharides.pdf

How interesting that NPY mediates mast cell degranulation in ischemia - which could be occurring, I would think, given the low blood volume state in CFS (?)

Mast cells: A unique source of renin
Adenosine and neuropeptide Y (NPY) are two of many potential mediators of mast cell degranulation in ischemia.

Here's the complement connection:

Complement activation resulting in significant increase of C4a split product may be a marker of post-exertional malaise in chronic fatigue syndrome (CFS) subjects. This study was focused to identify the transcriptional control that may contribute to the increased C4a in CFS subjects post-exercise.

I don't know if they trigger mast cell degranulation, though...Yes it does

Anaphylotoxins
C4a, C3a and C5a (in increasing order of activity) are all anaphylotoxins which cause basophil/mast cell degranulation and smooth muscle contraction. Undesirable effects of these peptides are controlled by carboxypeptidase B (C3a-INA).

 

[Angela Kennedy]

NPY has been noted in POTS as well.



http://hyper.ahajournals.org/cgi/content/full/hypertensionaha;45/3/385

I just hope they keep looking until they can definitely separate physical stress from psychological once and for all.

But because that is currently impossible, and 'they' mostly won't accept that 'stress' explanations are flawed in both methodology and theory with regard to many illnesses, but ME/CFS in particular, people are likely to be waiting a very long time- possibly will die waiting.

 

[Angela Kennedy]

More on Neuropeptide Y from the paper

They covered NPY with regard to stress, SNS activity, exercise (?), depression, blood pressure and heart rate, the limbic system, autoimmune disorders...this peptide gets around....



I don't why Nancy didn't go for those other functional measures..one reason might be the small sample size inhibited the the number of variables she could use and she was more sure of getting a positive result using what she did. I wish she had looked at the others.

But even looking at this nice little bit of 'pathophysiologico-speak' it is still all related to notions of stress and negative thinking. This confounds the whole project and places it in the context of psychogenic explanations.

 

[Cort]

OKay here we go - a theory

Exercise induces both abnormally high levels of both NPY and C4. Both of these substances degranulate mast cells triggering blood vessel contraction and ischemia (low blood flows causing high levels of oxidative stress) and, in some patients, hypotension - lowered blood pressure (a bit at odds with the blood vessel contraction or maybe not -blood vessels should contract in response to reduced blood pressure.)

 

[OurDayWillCome]

Well, you beat me to the connection.


Mast cells release gobs of Histamine, which dilates blood vessels. I believe the working hypothesis in this group of POTS patients is that the Histamine triggers the release of Norepinephrine to combat the Histamine, which triggers the release of Histamine, and on and on. Histamine can cause many problems.

Angela .... I know that some things cannot be answered at this point. But I still hope.

 

[Angela Kennedy]

Well, you beat me to the connection.



Angela .... I know that some things cannot be answered at this point. But I still hope.

But in the meantime, a fundamentally flawed edifice is being propagated while we wait and hope. This has meant funds for biological research into ME/CFS are diverted towards extremely flawed projects that set back progress for this community further and further. So I might hope as much as you, but I have to add my voice to those who bring to public attention the fallacies in this type of thinking, because while people like Nancy Klimas do not appear to understand the problems of the 'science' being done here, things can only get worse for those people waiting, as science regresses even further under the prevailing ideology of fallacious psychogenic explanations.

 

[OurDayWillCome]

???? I am not a proponent for Klimas or the type of research that was presented.

 

[aruschima]

But in the meantime, a fundamentally flawed edifice is being propagated while we wait and hope. This has meant funds for biological research into ME/CFS are diverted towards extremely flawed projects that set back progress for this community further and further. So I might hope as much as you, but I have to add my voice to those who bring to public attention the fallacies in this type of thinking, because while people like Nancy Klimas do not appear to understand the problems of the 'science' being done here, things can only get worse for those people waiting, as science regresses even further under the prevailing ideology of fallacious psychogenic explanations.

I agree, once more diverting attention away from important biomedical research . It could have been a step further in validating the disease, if the interpretation would have been directed and had highlighted the very serious issues association to Hypothalamus/ brain abnormalities/ white/grey matter reduction and so forth or pointed out the possible link to cancers (Leukemia).
I am very disappointed about Nancy and can not understand that she allowed such a fallacy, especially at this point of time.

 

[Angela Kennedy]

???? I am not a proponent for Klimas or the type of research that was presented.

I understand. But because your comment was directed at me it seemed to close off my own discussion slightly (not your intent, I'm sure) which is why I felt the need to explain why just 'hoping' on this issue in particular is not something I personally can do.

 

[lancelot]

Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome.

Conclusions
This study is the first in the CFS literature to report that plasma NPY is elevated compared to healthy controls and to a fatigued comparison group, GWI patients. The significant correlations of NPY with stress, negative mood, general health, depression and cognitive function strongly suggest that this peptide be considered as a biomarker to distinguish subsets of CFS.

http://www.behavioralandbrainfunctions.com/content/6/1/76

I'm very surprised to see this kind of research from Dr Klimas. How does one correlate any biomarker for CFS with stress, negative mood, general health, depression and cognitive function??? Why can't she correlate it with severe fatigue(mental and physical), unrefreshing sleep, sleep disturbance(insomnia or hypersomnia), OI/POTS/NMH, pain, sickness/nausea/malaise, PEM/DPEM or walking distance instead of purely mental symptoms that are not the key nor main symptoms of CFS/ME?

If anyone has heard Dr Klimas speak at the CFSAC or seen her other good CFS research, we must give her the benefit( in the big picture) of the doubt regardless of how this study looks.

 

[OurDayWillCome]

Angela...." just 'hoping' ".

I don't know how that can be concluded by what I write, or don't write, on this thread.

But because your comment was directed at me it seemed to close off my own discussion slightly (not your intent, I'm sure) ...

Nope, not my intention at all.

 

[WillowJ]

The NPY connection to the blood vein stuff and epilepsy and anorexia (as in just not feeling hungry like in many medical diseases) is very interesting and could be pertinent.

It's very unfortunate that this study was done in this context and in this manner (particularly the Background).

I did hear back from Dr. Klimas who was kind and replied to my somewhat grumpy email, and she noted that she was not the lead author so had not written the manuscript, and that some of the others use "psychology speak" (although she doesn't feel they are coming at it from a psychogenic or Wessely school standpoint), but that no subgroup is being left behind, and to please take her work in the larger context where this disease is being studied from all angles with the other pathologies being covered as well.

This last point is what lancelot just said, and it's a good point because Klimas generally does wonderful work and speaks up for us all the time.

But it doesn't take away the fact that some aspects of this study come pretty close to giving aid and comfort to, and shockingly echoing, the psychobabble crowd. Even though that was, as I suspected, completely unintended. I'm a bit discouraged that this happened and there isn't a move to revise the Background to include other pathologies and actually describe this disease.

I have not heard back from Fletcher, but I am still hoping she will write back.

 

[FunkOdyssey]

Man this thread is ridiculous, do you want to learn more about this disease or do you want to selectively hear only what supports your agenda? Its new data and it's interesting, take it for what it's worth. Just because CFS is a physiological disorder with infectious causes doesn't mean there isn't ALSO mental stuff going on (as a secondary consequence) that may be correlated with various biomarkers. For crying out loud.

 

[WillowJ]

can anyone tell me if there is any other use for the term "psychoneuroimmunology" than the study of psychogenic and/or psychosomatic illness?

 

[WillowJ]

Man this thread is ridiculous, do you want to learn more about this disease or do you want to selectively hear only what supports your agenda? Its new data and it's interesting, take it for what it's worth. Just because CFS is a physiological disorder with infectious causes doesn't mean there isn't ALSO mental stuff going on (as a secondary consequence) that may be correlated with various biomarkers. For crying out loud.

we want to learn about this disease and we want this disease to be taken seriously. At the moment and for the past 25 years and counting (USA) and much longer (UK), the theory that stress and maladaptive coping causes this disease has prevented this disease and therefore any patient labelled with CFS (correctly or misdiagnosed, doesn't matter) from being taken seriously.

Meaning the patients are ridiculed and fail to get medical care for this condition or any other condition they may happen to have, especially if the other condition has symptom overlap (asthma, for instance). In some cases the patient abuse is even much more serious than this. Patients also have trouble getting social support or disability aids.

Perception of the disease also influences whether any researchers are interested in the disease and how much funding is available (and whether even the small amount of funds will actually be spent productively or whether it will be frittered away and diverted to other things).

How a disease is percieved is very serious, because the consequenses to the patients are very serious.

The question isn't whether there may be secondary stress (there is, just the same as in any other chronic debilitating disease).

The question is: did the paper do a good job of explaining what ME/CFS is (because that explanation is so badly needed) or what they meant by the terms they used? The Discussion was pretty good but the Background was dismal. Since the background comes right at the beginning, this is a problem. Also since the buzzword "maladaptive coping" was used without explaining what the authors meant (they evidently didn't mean the usual; Klimas interpreted it to mean "pushing through"), that's a very serious problem because it won't be interpreted in this way.