CFI Spinal Fluid study from Lipkin and Hornig is out.

[DanME]

It is the other way around, i don't care if i am ''wrong''. I don't want to upset you.... most people are obsessed by the immune system theory. I am just being critical. Some people don't want to hear that.

Just being critical is not enough. I can have unsupported opinions about anything I want. Critic must come with either good logical arguments or in the natural sciences with supporting evidence. Supporting evidence has different degrees of reliability.
A study from one of the best immunology departments in the world, published in a high impact paper and most importantly properly conducted is in fact very good evidence (of course, we need replication to be sure).

In this case for significant and consistent abnormalities of cytokines in the spinal fluid. That's it. What this exactly means is up for discussion and future research. Maybe it means chronic inflammation or autoimmunity. We simply don't know yet.

 

[Sidereal]

 

[Never Give Up]

Interferon gamma inhibits eotaxin:

Th1-derived cytokine IFN-γ is a potent inhibitor of eotaxin synthesis in vitro


Some things that might help with TH-1 shifting, IFN-y production and eotaxin reduction:

Licorice Flavonoids Inhibit Eotaxin-1 Secretion by Human Fetal Lung Fibroblast in vitro

Effects of Astragalus membranaceus in promoting T-helper cell type 1 polarization and interferon-gamma production by up-regulating T-bet expression in patients with asthma

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[Sidereal]

The comparator/control group consisted of 40 subjects with MS (comparators), with 19 relapsing-remitting MS (RRMS) and 21 secondary progressive MS (SPMS), and 19 subjects who had undergone CSF sampling to rule out CNS infection or hemorrhage (ND controls)

In a study like this it must be immensely difficult to get normal controls who would agree to a lumbar puncture so I would question how healthy are the people who were undergoing "CSF sampling to rule out CNS infection or hemorrhage".

I don't know anything about MS but I would imagine RRMS and SPMS could differ quite a bit on these cytokines.

 

[Gijs]

Just being critical is not enough. I can have unsupported opinions about anything I want. Critic must come with either good logical arguments or in the natural sciences with supporting evidence. Supporting evidence has different degrees of reliability.
A study from one of the best immunology departments in the world, published in a high impact paper and most importantly properly conducted is in fact very good evidence (of course, we need replication to be sure).

In this case for significant and consistent abnormalities of cytokines in the spinal fluid. That's it. What this exactly means is up for discussion and future research. Maybe it means chronic inflammation or autoimmunity. We simply don't know yet.

I think you overlooked a real important point here. Ask how they recruit the spinal fluid, did it come from Daniel Peterson? If so, this study is fundamentally wrong (selection bias). I can go into detail ( statistical methodologies) but that will be not a good idea for this discussion.I think this is just one logical argument, no opion. I was very critical when the XMRV study came out (also published in a high paper) it does't 'say anything. Patiënts said the same things as you and others. But let me be wrong! I hope so

 

[snowathlete]

The studies of Lipnkin/Hornig will never be replicated, like every study of ME. So, there is no breakthrough and nothing will be changed at this point in the medical community. They still think we are grazy and it is all in the mind even the IOM report isn't going to change anything. In Europe the doctors 'laugh' about this report and don't take SEID more serious then CFS/ME. For them it is the same mental illness. So what did we have? Nothing.

Not necessarily true. If the finding is deemed significant and it comes from well-respected researchers then it has more chance of someone wanting to replicate it. A spinal fluid study is less likely than a blood study, to get replicated, for obvious reasons. Funding may become more available after the IOM report, we'll have to see; it may not. Without funding researchers have to be more convinced by the initial study to decide to spend limited funds on replication studies.

But the potential significance and the names involved in this study certainly mean that it may get replicated. Definitely too early to throw the towel in on that one; on the day we hear about it.

Personally, I think the immune system is core to the pathology so I'm pleased the researchers are looking where they are looking.

 

[Gijs]

I would like the respons of professor Edward on these findings, maybe he can show some light into the darkness.

 

[deleder2k]

@Gijs, what will you say when phase 3 of the double-blinded Rituximab study is positive? I am willing to bet $1000 on that

 

[Gijs]

Yes some samples are from Peterson.



Collected between 1994 and 2012.

Thank you Lansbergen. All spinal fluids from CFS patiënts came from Daniel Peterson, not the control and MS patiënts. If that is the case, this study is very biased. Also Hornig said that there immune findings are in line with there other study because this cohort are sick for 7 years. If this is the case, i can't see a group who are sick for a shorter time ( e.g. <3 years) to back up her statement.

 

[Sidereal]

After data reduction through feature selection procedures, variables meeting LASSO criteria (Supplementary Tables S4–6) were included along with clinical covariates (age and sex) to construct the final logistic regression model and calculate the associated ORs, 95% CIs and P-values. Tables 3A–C show results for ME/CFS cases vs ND controls, ME/CFS cases vs MS and MS vs ND controls, respectively. In ME/CFS vs ND comparisons, higher levels of CCL11 (the allergy-associated CC chemokine, eotaxin) were strongly associated with ME/CFS caseness (OR, 33.3711; 95% CI, 2.0975, 530.9223; P = 0.0130) as were lower levels of IL1β (OR, 0.0000; 95% CI, 0.0000, 0.9822; P = 0.0498) (Table 3A). In ME/CFS vs MS comparisons, ME/CFS was associated with markedly higher levels of TGFβ (OR, 22.2495; 95% CI, 1.0910, 453.7519; P = 0.0437), as well as elevated levels of CCL2 (OR, 1.1071; 95% CI, 1.0263, 1.1943; P = 0.0085). ME/CFS was also associated with decreased levels of VCAM1 (OR, 0.9581; 95% CI, 0.9270, 0.9903; P = 0.0112) (Table 3B).

Goldstein talked about low IL-1b in the ME/CFS brain, oh, 20 years ago in relation to low CRH (corticotropin releasing hormone) which he viewed as a cardinal feature of this illness. This is one crucial intersection between the immune system and the HPA axis. IL-1b modulates CRH and vasopressin (antidiuretic hormone) release so this would explain a lot. (It's also the opposite of what's going on in depression, I would add.)

It's interesting also that TGF-beta was markedly higher in ME/CFS than in MS (though lower than in normal controls). There's been a lot of discussion on PR about this cytokine recently. @adreno

Our finding that IL1ra has a negative influence on CSF1, CSF2 and IL17F in ME/ CFS, without effects on IL1α or IL1β, suggests a disturbance in IL1 signaling pathways. The role of IL1ra in inhibition of allergic responses42,43 is consistent with reports of an increased prevalence of allergic disorders in some studies of ME/CFS.44,45 IL1ramediated downregulation of responses to allergic stimuli is associated with lower levels of CSF2 (GMCSF), a key regulator of granulocyte and macrophage maturational pathways.46 The inverse relationship we found between IL1ra and CSF2 in the CSF of cases using a network analysis approach suggests that neuroimmune responses may be shifted toward allergic or Th2 (autoimmune) patterns in the CNS of individuals with ME/CFS

 

[Gijs]

@Gijs, what will you say when phase 3 of the double-blinded Rituximab study is positive? I am willing to bet $1000 on that

I hope this will be the case but i won't bet my money on this I am very pleased by the fact that Fluge and Mella are looking fore objective measurements like bloodflow/vessels dysfunction, as you know a believe this is a very important problem in ME/CFS. I think the cause comes from the brainstem or autoimmune reaction against receptors in the vessels (local) esspecially the gut, hart and brain. What i want to say is if we don't find any objective mesurements, we still have 'nothing' to prove that it works and most important: for which subgroup? Will it work for you, or me? I don't know. I would never use rituximab based on this.

 

[deleder2k]

What i want to say is if we don't find any objective mesurements, we still have 'nothing' to prove that it works and most important: for which subgroup? Will it work for you, or me? I don't know. I would never use rituximab based on this.

That is simply not true. The use of a placebo group does not eliminate the problem, but it will be easy - also for the psychobabblers to see that the majority Rituximab group considered themselves significantly better than before the study. 152 patients, multi-center, double-blinded, placebo-controlled.

The fact that they do FMD tests, CPET cycling test, and the use of Sensewear armbands makes this a smaller issue. If the study wasnt blinded and if you didn't have any tools to objectively measure symptoms it would be a major issue.. This is the case for almost every GET/CBT psychobabble study

 

[alex3619]

of course, we need replication

Which in this case will happen. Cytokine studies are done fairly often. Now Lipkin, Hornig et. al. have set a new standard. Future cytokine studies are likely to take this into account and try to do at least as well, unless they are pilot projects using new technology or something.

The people not taking this seriously in Europe .... how many are psychiatrists?

 

[alex3619]

This is the case for almost every GET/CBT psychobabble study

Which makes this study more robust than most CBT/GET studies. So afterward if they object we can point out the evidence is better for Rituximab than CBT/GET, due to blinding, effect size, and multiple objective measures.

 

[adreno]

Goldstein talked about low IL-1b in the ME/CFS brain, oh, 20 years ago in relation to low CRH (corticotropin releasing hormone) which he viewed as a cardinal feature of this illness. This is one crucial intersection between the immune system and the HPA axis. IL-1b modulates CRH and vasopressin (antidiuretic hormone) release so this would explain a lot. (It's also the opposite of what's going on in depression, I would add.)

Yes, and this could possible explain the hypoactive HPA axis in ME/CFS:

A key finding was that interleukin-1 (IL-1) was a potent stimulator of HPA axis activity. The major known mechanism by which the immune system signals the brain involves cytokines, which are the major chemical messengers within the immune system. Certain other cytokines [e.g, IL-6, IL-10, and tumor necrosis factor-α (TNF-α)] can activate the HPA axis. Cytokines exert their effects on the CNS via afferents of nerves, such as the vagus, although some direct actions of circulating cytokines on the nervous system may also occur. Immune cells can penetrate the brain under some circumstances.

The CNS in turn can influence immune function via the autonomic nervous system and various hormones secreted by the pituitary, the adrenal, and other endocrine organs. Cytokines (especially IL-1) can alter the activity of neurotransmitters in the CNS, most notably norepinephrine and corticotropin-releasing factor (CRF), and can have important effects on behavior.

http://www.sciencedirect.com/science/article/pii/S1567744307002013

 

[Sidereal]

http://www.sciencedirect.com/science/article/pii/S1567744307002013

Yep. Our IL-6 is in the toilet as well, check out the figure. So much for "stress" and child abuse causing these HPA axis derangements in ME/CFS.

 

[lansbergen]

Thank you Lansbergen. All spinal fluids from CFS patiënts came from Daniel Peterson, not the control and MS patiënts. .

Show me where that is in the paper.

 

[A.B.]

Interesting how these immune abnormalities could explain the lazy HPA axis.

Does anyone know if these abnormalities would result in the HPA axis reacting normally to stimulation testing while still underfunctioning under real world conditions?

 

[wastwater]

Forgive me if im being dumb,but isn't eotaxin one of the least dramatic findings here according to the graphs.Ahh I see it is the one that is elevated

 

[DanME]

I think you overlooked a real important point here. Ask how they recruit the spinal fluid, did it come from Daniel Peterson? If so, this study is fundamentally wrong (selection bias). I can go into detail ( statistical methodologies) but that will be not a good idea for this discussion.I think this is just one logical argument, no opion. I was very critical when the XMRV study came out (also published in a high paper) it does't 'say anything. Patiënts said the same things as you and others. But let me be wrong! I hope so

I am very open to any logical argument and of course also methological critic. If all or most of the spinal fluid samples came from Daniel Paterson's patients, this is indeed selection bias and we have to talk about that. But even then, they found abnormal cytokines levels in exactly this patient group. So do you know, how many samples are from Paterson, the exact numbers? Or is this just speculation?

On the other hand, you state, nothing will be replicated, it proves nothing, European doctors will continue to laugh at us. I am not so sure about that. Lipkin is a heavy name in the research community and people will take his studies seriously.

Also your favorite theory (autoimmunity, receptors, and the vascular system) isn't disproved by Lipkin's recent studies. The cytokines abnormalities could also be caused by autoimmunity or may lead to autoimmunity. By the way, it is my favorite theory as well. But I don't reject anything, which isn't in line with my most liked hypothesis.

Last point. Subjective endpoints are used in medicine all the time. Look at the RA scores. Or at all pain scores. They are not worthless. Especially not in a very well thought out study with a placebo group, which is double blinded. So it is still possible to attack the results of the phase III RTX study, but it's much harder than you think.