Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways

[JaimeS]

I get worried when I find the description of how the stats were arrived at impenetrable.

I see. I think fewer and fewer people who publish worry about 'how' the statistics work, because you plug them into a program now and it spits out what's significant. Y/N, @Jonathan Edwards ?

Almost everyone in science tweaks their results around until they get something significant because journals do not publish negative data very often. A young scientist cannot afford to write off six months of work just because correctly he found the answer was negative.

Pretty damning. I've seen a lot of studies I've rolled my eyes at, but it can become difficult when, in order to even understand half of what's out there regarding ME you have to be expert in every medical discipline simultaneously.

I was just looking at some research on epigenetic methylation issues, for example, and had to remind myself a dozen times that it wasn't the same as methylation SNPs, because epigenetics? I know next to nothing about epigenetics.

Also, I definitely need to re-take statistics if I'm ever going to be able to understand half of this stuff.

-J

 

[JaimeS]

...that or hire a statistics expert, a geneticist, a GI doctor, an endocrinologist, a neurologist, a pituitary expert in particular, an autonomic specialist in particular, and a partridge in a pear tree.

To sing at them. <3

-J

 

[Snow Leopard]

I see. I think fewer and fewer people who publish worry about 'how' the statistics work, because you plug them into a program now and it spits out what's significant. Y/N, @Jonathan Edwards ?

I think it is just as likely to be due to the incentives involved, I mean often the attitude is basically do the statistics so the study can be published. Rather than do the statistics so that the study can put up the strongest defense against post-publication criticism (due to lack thereof).

 

[SOC]

I see. I think fewer and fewer people who publish worry about 'how' the statistics work, because you plug them into a program now and it spits out what's significant.

Which I find horrifying. Statistics programs were never designed to be used that way. The user is supposed to have a reasonable understanding of what's going on in the program so s/he can put in the data correctly and interpret the results appropriately. Garbage in, garbage out.

I remember as an undergraduate, being appalled at the way PhD-level biological and social scientists were using the popular statistics package of the time. They had absolutely NO idea what they were doing, and were putting complete garbage into the software and (apparently) believing the utterly ridiculous results they were getting out.

I can live with people not being fully knowledgeable about statistics (although anyone who wants to claim to be a researcher should have a decent grounding in stats), but those who don't have the knowledge should hire a statistician to design their experiments and analyze the data --- and accept their hired expert's conclusions rather than ignore it when it's inconvenient. (I'm looking at you, Psychology)

 

[user9876]

Which I find horrifying. Statistics programs were never designed to be used that way. The user is supposed to have a reasonable understanding of what's going on in the program so s/he can put in the data correctly and interpret the results appropriately. Garbage in, garbage out.

I remember as an undergraduate, being appalled at the way PhD-level biological and social scientists were using the popular statistics package of the time. They had absolutely NO idea what they were doing, and were putting complete garbage into the software and (apparently) believing the utterly ridiculous results they were getting out.

I can live with people not being fully knowledgeable about statistics (although anyone who wants to claim to be a researcher should have a decent grounding in stats), but those who don't have the knowledge should hire a statistician to design their experiments and analyze the data --- and accept their hired expert's conclusions rather than ignore it when it's inconvenient. (I'm looking at you, Psychology)

I'm not convinced hiring a statistician works given some trials have them and there stats are shocking.

I see two important things:
1) Are the assumptions required for any tests or summary stats justified by the data. So are any significance tests suitable given likely distributions, scale characteristics and measurement errors. Are the distributions correctly characterised by the summary stats quoted.
2) People should look at their data and get a feel for it. What does it look like, plot it in different ways. This of course helps with point 1. But I get the impression that people don't look at data. Ideally data would be published in a form where others can see clear differences. But stats should only tell you where to look they are not the answer so if there are differences you need to think why how does this relate to an underlying theory and what other evidence would support this and what evidence would counter it.

 

[Sidereal]

I agree User. The problem is much wider than incompetence of individual researchers or statisticians. The whole field of medical and social science statistics is based on insane practices like null hypothesis significance testing, assumptions of normality, reliance on inferential statistics instead of simple graphical presentation of data etc. Most of the time you read a paper and come away from it with no feel for the data.

 

[MeSci]

There's been a particular symptom cluster that I first attributed to ammonia, and after chasing the sources of that, peroxynitrite emerged as the next culprit. Mostly related to my head: not exactly headache, as in pain in the head. Rather, a feeling of fullness in my head, squinty eyes, a taste in my mouth that's not exactly metallic, but similar. Feeling as if I will crash if I don't do something now. If left to go on, then comes restlessness, tendency toward breathlessness. If I then consume antioxidants, the symptoms reduce or clear immediately.

I've been chipping away at this issue for these past 6 months. I found dramatic reduction in the occurance when I added FMN form of B2. And then, following a 3-day water fast, hoping for the advertised immune system/stem cell reset, an even further reduction. When it was at its worst, I was consuming more than 1kg carrots/day, in juice and raw carrots. Plus a range of antioxidant supps, and antihistamine supps. Now, I'm taking none of those supps, my need for carrots is greatly reduced, I'm less prone to PEM (if I'm careful, cautious in my activity.) I am so thrilled to have not only gotten on top of this oxidative stress response to such a degree, but to have stopped spending the bulk of my budget on bi-monthly iherb orders.

So do you think that excessive peroxynitrite produces symptoms that are distinctive from those caused by other oxidants? The fact that antioxidants reduce your symptoms does suggest that they may be due to oxidants, but it perhaps depends on what antioxidants you use, as many have a wide range of physiological properties.

Glad to hear that you have found something that helps anyway!

 

[ahmo]

So do you think that excessive peroxynitrite produces symptoms that are distinctive from those caused by other oxidants?

I have no idea. I only got the awareness about oxidants after finally beginning to understand Martin Pall's work via his 2014 vid, in my signature. This was at the beginning of the year, when I was still trying to differentiate ammonia from peroxynitrite.

From Pall, I switched to Gamma form of Vit E. I'd already been using astaxanthine, added large quantities of green tea and carrots. Also Vit C, which I felt was primarily, combined with Ca, acting to flush out histamines. Now body is never testing + for astaxanthine or C, the 3 liters of strong green tea has reduced to 1, far fewer carrots. Also the large demand for my nut/seed mixture has decreased. (almonds, walnuts, pepita, sunflower, brazil) No extra choline or Ubiquinol these days. ...

 

[MeSci]

I have no idea. I only got the awareness about oxidants after finally beginning to understand Martin Pall's work via his 2014 vid, in my signature. This was at the beginning of the year, when I was still trying to differentiate ammonia from peroxynitrite.

From Pall, I switched to Gamma form of Vit E. I'd already been using astaxanthine, added large quantities of green tea and carrots. Also Vit C, which I felt was primarily, combined with Ca, acting to flush out histamines. Now body is never testing + for astaxanthine or C, the 3 liters of strong green tea has reduced to 1, far fewer carrots. Also the large demand for my nut/seed mixture has decreased. (almonds, walnuts, pepita, sunflower, brazil) No extra choline or Ubiquinol these days. ...

How do you get these tests? I mean as in 'body is never testing + for astaxanthine or C'?

 

[ahmo]

I forgot to add resveratrol, also from Pall's suggestion. I use self-testing. Not the more familiar muscle testing, but a related method, following the rhythmic movement of the lymph. From the world of Visceral Manipulation, originated by Jean-Pierre Barral (related to craniosacral therapy)

I'd not been successful with muscle testing, tho i now can easily use the thumb/index finger method. I was taught the technique I use just as I was falling apart w/ ME. I've had plenty of time to come to trust it. these last 2 years, especially, it's how I've moved forward with detox and methylation dosing. My body no longer feels like a black box. Pathology testing has been almost universally useless for me. Except for Genova showing SIBO and toxic metals.

 

[Bob]

In case anyone is interested, here's a previous (2014) review of metabolism in CFS, by Armstrong and colleagues...


Metabolism in Chronic Fatigue Syndrome.
Christopher W. Armstrong, Neil R. McGregor, Henry L. Butt, Paul R. Gooley.
19 August 2014
Advances in Clinical Chemistry
Volume 66, 2014, Pages 121–172
http://www.sciencedirect.com/science/article/pii/B9780128014011000050

Abstract
Chronic fatigue syndrome (CFS) is a poorly understood condition that presents as long-term physical and mental fatigue with associated symptoms of pain and sensitivity across a broad range of systems in the body. The poor understanding of the disorder comes from the varying clinical diagnostic definitions as well as the broad array of body systems from which its symptoms present.

Studies on metabolism and CFS suggest irregularities in energy metabolism, amino acid metabolism, nucleotide metabolism, nitrogen metabolism, hormone metabolism, and oxidative stress metabolism. The overwhelming body of evidence suggests an oxidative environment with the minimal utilization of mitochondria for efficient energy production. This is coupled with a reduced excretion of amino acids and nitrogen in general.

Metabolomics is a developing field that studies metabolism within a living system under varying conditions of stimuli. Through its development, there has been the optimisation of techniques to do large-scale hypothesis-generating untargeted studies as well as hypothesis-testing targeted studies. These techniques are introduced and show an important future direction for research into complex illnesses such as CFS.

 

[JaimeS]

Most of the time you read a paper and come away from it with no feel for the data.

Which I fear is the point. If you just splatter your data every which-way in a lot of graphs that are frankly next door to impossible to read, the overwhelmed scientist or layperson is tempted to just accept your conclusions because "it was in a study".

-J

 

[JaimeS]

My body no longer feels like a black box.

Fascinating way to put it, @ahmo . Is there a cat inside?

-J

 

[ahmo]

@JaimeS stays outside.But humming brings her pretty close.

 

[JaimeS]

Hahaha, @ahmo... because my phone shows no icons, that appeared to say that I stay outside, but humming brings me pretty close.

....I was so confused.

 

[Gondwanaland]

Glyoxal Formation and Its Role in Endogenous Oxalate Synthesis

Endogenous oxalate synthesis makes an important contribution to the amount of oxalate excreted in urine and hence the development of calcium oxalate kidney stones, a painful condition that afflicts 10% of the adult Caucasian male population in the United States. The biochemical pathways involved in oxalate production are poorly understood despite decades of research. However, it is clear that glyoxylate is the major precursor of oxalate [1]. The metabolism of a number of substances has been proposed as a source of glyoxylate including glycine, phenylalanine, tryptophan, hydroxyproline, glucose, fructose, pentose sugars, ethanolamine, and glycolate. Our research to date indicates that of these potential sources, hydroxyproline makes a modest contribution, 5–10%, and the majority of others provide negligible amounts [2–4]. We have found, however, by incubating a variety of 2 carbon molecules with hepatocytes, that glyoxal is a prominent source of glyoxylate [3]. We hypothesize that glyoxal is one of the most important sources of endogenous oxalate synthesis in humans and possibly other organisms and is one that has been overlooked to date. Mounting evidence is also suggesting that both glyoxal production and oxalate synthesis can be associated with oxidative stress.

 

[JaimeS]

@Gondwanaland , but since mostly men get kidney stones, no one will ever be prescribed an antidepressant for them.

-J

 

[ChrisArmstrong]

Hi all,

Thank you for the interest in this article I wrote, I was looking up whether it had been published yet and I noticed this forum came up. Been looking through the forum and it's refreshing to see such a positive collective of people helping one another like this.
I'm more than happy to answer any questions about the work and discuss some of the thoughts in better detail. I will scan back through the posts over time to answer questions that have already been asked.

Cheers,

Chris

 

[alex3619]

Which I find horrifying. Statistics programs were never designed to be used that way. The user is supposed to have a reasonable understanding of what's going on in the program so s/he can put in the data correctly and interpret the results appropriately. Garbage in, garbage out.

Its very important for anyone doing stats to be able to interpret them. Statistically significant results mean nothing unless you know what is statistically significant. Over interpretation of a statistically significant result is common.

In PACE for example there are methodological biases that might lead to significant results that are simply not there in the real world. Its a methodological issue. Such things need to be considered and investigated. Simply listing a result is problematic. This leads to such nonsense as allowing for patients to be considered recovered even when they qualify for severe disability under standard objective measures.

Further, many results at the usual p values are due to chance or, as I said, bias. Only very low p values are some indication of reliability, not the high p values we see in many papers. This is particularly likely to be the case if effect sizes are very low.

Statistical evaluation never guarantees certainty. Other things must be considered.

 

[alex3619]

One of the issues I think needs explanation, @ChrisArmstrong , is why so many studies point at high lactate in serum, spinal fluid and even in vitro muscle cells, if the problem is poor glycolysis, which I realize is not necessarily an implication of the paper.

Poor glucose utilization, perhaps as a result of a defective insulin response, does not necessarily imply poor glycolysis in terms of mechanism, just output.

There is also a question of what is happening in different tissues, or in tissue versus individual cells.

This study may have involved resting patients as well. Post exercise may lead to different results.

On that theme I find these results consistent, presuming that the samples were taken at rest. At rest we tend to be alkaline, at exercise we are highly acidic. I wonder if this implies different biochemistry at rest and during activity than expected.

A post exercise version of this testing would seem to be the next logical step, or perhaps both pre- and post- exercise (or mental activity) with a comparison of results, versus controls. I realize this requires funding and organization for a disease that is close to blatantly ignored by funding bodies.

There is always a question of circadian variation in these patterns as well, particularly since a large number of us have highly disturbed circadian regulation.