New video: Is acetylcholine toxicity the cause of CFS?

[richvank]

If there was a high expression of acetylcholine receptors you would expect a high peak response and no prolonged response. The Vance Spence's group found a normal peak response and a prolonged response in the CFS patients which is consistent with low cholinesterase levels.

Hi, Emootje.

That would be true if the gene expression of cholinesterase were the same in the normals and the PWCs, but suppose the expression of cholinesterase drops in PWCs, as another adaptation to lower acetylcholine production in addition to a rise in expression of the acetylcholine receptors, both due in turn to choline deficiency resulting from the methylation deficit? I think this would be likely, if acetylcholine is indeed low in PWCs. I think all this fits together well. I would like to see some good measurements of absolute choline and acetylcholine levels. I don't know why the pyridostigmine seemed to help some PWCs, while the galantamine did not.

Best regards,

Rich

 

[Emootje]

I would like to see some good measurements of absolute choline and acetylcholine levels.

I agree

 

[Emootje]

Aerotoxic syndrome is a syndrome caused by contamination of cabin air with an organophosphate (tricresyl phosphate). The symptoms of aerotoxic syndrome have a lot in common with the symptoms of ME/CFS.

Symptoms of Aerotoxic Syndrome:
Fatigue feeling exhausted, even after sleep
Blurred or tunnel vision
Shaking and tremors
Loss of balance and vertigo
Seizures
Loss of consciousness
Memory impairment
Headache
Tinnitus
Light-headedness, dizziness
Confusion / cognitive problems
Feeling intoxicated
Nausea
Diarrhoea
Vomiting
Coughs
Breathing difficulties (shortness of breath)
Tightness in chest
Respiratory failure requiring oxygen
Increased heart rate and palpitations
Irritation of eyes, nose and upper airways.

It makes you wonder.......same etiology different organophosphate?
For more information:
http://www.aerotoxic.org/
http://www.youtube.com/watch?v=ienEGWtlW8w

 

[Hip]

I found a write-up by Cort on this subject, that supports the high acetylcholine idea (or at least gives evidence of high choline, the precursor of acetylcholine). An excerpt:

Putting It All Together CFS is a Disease of Increased Phospholipase (PLA) Activity - Chaudhuri and Behan suggest increased choline levels contribute to cognitive dysfunction (effortful task processing) and reduced ATP levels impair aerobic metabolism and contribute to the exercise intolerance seen in CFS. What might increased brain choline and decreased ATP production have in common? Chaudhuri and Behan believe both are due to increased phospholipase (PLA) activity. This appears to suggest they believe increased PLA activity occurs not just in the brain but is system wide. Since PLA is ubiquitous in the body increased PLA activity could affect a wide variety of tissues.

The rest of Cort's article is here: http://aboutmecfs.org.violet.arvixe.com/RsRch/CholineBrain.aspx



Though I must say that I also do well with supplements that boost the output or effects of acetylcholine, including: phosphatidylcholine, alpha GPC, sulbutiamine (a form of vitamin B1), L-carnitine, piracetam, aniracetam, centrophenoxine (Lucidril). These supplements reduce my brain fog considerably: my working memory is much improved with them. So I am not sure what is going on here. Sometimes I take a whole bunch of these supplements simultaneously, and my concentration and brain powder return to their pre-CFS normal level, perhaps even higher. Try them!

One point that may be of relevance here is that acetylcholine is found both in the brain and central nervous system (CNS), and in the peripheral nervous system (PNS), including the sympathetic nervous system, parasympathetic nervous system, and in nerve ganglia. So acetylcholine levels may have effects even beyond the CNS. When I take acetylcholine boosting supplements, my muscles can feel a little stiff.

I also found this: Neuropeptide Y is high in CFS, and I think neuropeptide Y inhibits the release of acetylcholine.

 

[Snow Leopard]

Could decreased Acetylcholine be one of the reasons for the elevated heart rate in patients? Acetylcholine also plays a role in Alzheimer's disease, along with a disregulated CDK5 pathway. This pathway was also found to be unusually expressed in CFS patients in the recent Schutzer et al. spinal fluid study.

There doesn't seem to be much literature besides this and the articles already mentioned:
http://www.ncbi.nlm.nih.gov/pubmed/12950326

 

[Sing]

Aricept

I do well with 5 to 7.5 mg of Aricept at night. It helps the body hold onto acetylcholine. It helps me have some dreams to remember--These are important to me as a dreamworker! vs. no memory of dreams without Aricept. And I think it helps me have somewhat better cognitive function during the day. Not a cure all but a help.

Perhaps I could benefit from some of the supplements Rich recommends too.

I also was diagnosed with Partial Central Diabetes Insipidus years ago. All my symptoms seem to come from a Hypo state rather than any forms of Hyper-activations, so boosters of various kinds provide some symptomatic help.

 

[richvank]

I found a write-up by Cort on this subject, that supports the high acetylcholine idea (or at least gives evidence of high choline, the precursor of acetylcholine). An excerpt:

Putting It All Together CFS is a Disease of Increased Phospholipase (PLA) Activity - Chaudhuri and Behan suggest increased choline levels contribute to cognitive dysfunction (effortful task processing) and reduced ATP levels impair aerobic metabolism and contribute to the exercise intolerance seen in CFS. What might increased brain choline and decreased ATP production have in common? Chaudhuri and Behan believe both are due to increased phospholipase (PLA) activity. This appears to suggest they believe increased PLA activity occurs not just in the brain but is system wide. Since PLA is ubiquitous in the body increased PLA activity could affect a wide variety of tissues.

The rest of Cort's article is here: http://aboutmecfs.org.violet.arvixe.com/RsRch/CholineBrain.aspx



Though I must say that I also do well with supplements that boost the output or effects of acetylcholine, including: phosphatidylcholine, alpha GPC, sulbutiamine (a form of vitamin B1), L-carnitine, piracetam, aniracetam, centrophenoxine (Lucidril). These supplements reduce my brain fog considerably: my working memory is much improved with them. So I am not sure what is going on here. Sometimes I take a whole bunch of these supplements simultaneously, and my concentration and brain powder return to their pre-CFS normal level, perhaps even higher. Try them!

One point that may be of relevance here is that acetylcholine is found both in the brain and central nervous system (CNS), and in the peripheral nervous system (PNS), including the sympathetic nervous system, parasympathetic nervous system, and in nerve ganglia. So acetylcholine levels may have effects even beyond the CNS. When I take acetylcholine boosting supplements, my muscles can feel a little stiff.

I also found this: Neuropeptide Y is high in CFS, and I think neuropeptide Y inhibits the release of acetylcholine.

Hi, Hip.

In my opinion, Chaudhuri, Behan, and also Puri have misinterpreted their magnetic resonance spectroscopy data. They extrapolated from observing a high ratio of choline to creatine (and in one paper, a high ratio of choline to water) to concluding that choline was high. This assumed normal levels of creatine and water in the brains of the CFS patients. However, the synthesis of creatine and choline are known to be the first and second major users of methylation in the body, and I believe that we have good evidence of a methylation deficit in CFS because of a partial block of methionine synthase. In 24-hour urine test results from PWCs, I also often see low creatinine, which indicates low creatine. Furthermore, water is likely to be low in the brain as it is in the blood in many PWCs, because of the diabetes insipidus that many have. Thus, my opinion is that this assumption was not valid. Until we have measurements of the absolute levels of choline and creatine in the brain, this issue will remain unsettled. It is possible to do such measurements, and Dr. Shungu, who is studying CFS with CAAA support, has the capability to do this, by comparing scans of the human brain to scans of known phantoms for calibration. I'm hoping that he will do it.

Vance Spence and his group accepted this interpretation, and my opinion is that this threw off their interpretation of their own results, which I believe are consistent with low acetylcholine. I discussed this with Vance some years ago, but I don't think he was convinced.

Acetylcholine can be measured in blood platelets by Health Diagnostics and Research Institute.

I think that your positive experience with boosting acetylcholine is in agreement with my interpretation of these experiments. I suspect that the reason you feel muscle stiffness when you boost acetylcholine is that your body has compensated for the low acetylcholine by expressing a lower a lower level of acetylcholinesterase. Then, when you raise acetylcholine suddenly, your muscles contract in response, but the contraction isn't released as soon, because acetylcholine stays high in the synapses longer than normal. This leads to the stiffness.

Yes, neuropeptide Y does inhibit release of acetylcholine.

Best regards,

Rich

 

[WillowJ]

regarding dry mouth, here is one possible explanation:

Calabrese LH, Davis ME, Wilke WS. "Chronic fatigue syndrome and a disorder resembling Sjgren's syndrome: preliminary report." Clin Infect Dis. 1994 Jan;18 Suppl 1:S28-31. PMID: 8148449

Results of Schirmer's test were abnormal for 16 of 27, and results of minor salivary-gland biopsy were abnormal for 20 of 25. Antibodies to nuclear antigen were present in 16 of 27, but anti-Ro was present in only 1 of 21.

I'm not sure if they biopsied mouth glands as well. Sjogren's typically affects both eyes and mouth, but Schirmer's test is just for eye moisture.

 

[lucy]

I will have to do the schirmers and gland biopsy in a few months to follow up possible sjogrens diagnosis. I had high ana and positive anti ssa/ro. Nevertheless, I noticed only dry eyes (and only after I was told that this ssa/ro is pretty specific, it basically means sjogrens) - before, I was attributing the feeling to the exhaustion. So now, with the artificial tears, I reduce the feeling of exhaustion, which is an improvement. For women with sjogrens it is quite common to have vaginal dryness, not that it is something easy to discuss. Another interesting thing- while asking my family members, I found out one of my siblings was using eye drops.
And btw, there is a do it yourself schirmers test: blend an onion or two and hold it in front of your eyes. I found out that one of my eyes was not lacrimating.

 

[Hip]

Hi, Hip.

In my opinion, Chaudhuri, Behan, and also Puri have misinterpreted their magnetic resonance spectroscopy data. They extrapolated from observing a high ratio of choline to creatine (and in one paper, a high ratio of choline to water) to concluding that choline was high. This assumed normal levels of creatine and water in the brains of the CFS patients. However, the synthesis of creatine and choline are known to be the first and second major users of methylation in the body, and I believe that we have good evidence of a methylation deficit in CFS because of a partial block of methionine synthase. In 24-hour urine test results from PWCs, I also often see low creatinine, which indicates low creatine. Furthermore, water is likely to be low in the brain as it is in the blood in many PWCs, because of the diabetes insipidus that many have. Thus, my opinion is that this assumption was not valid. Until we have measurements of the absolute levels of choline and creatine in the brain, this issue will remain unsettled. It is possible to do such measurements, and Dr. Shungu, who is studying CFS with CAAA support, has the capability to do this, by comparing scans of the human brain to scans of known phantoms for calibration. I'm hoping that he will do it.

Vance Spence and his group accepted this interpretation, and my opinion is that this threw off their interpretation of their own results, which I believe are consistent with low acetylcholine. I discussed this with Vance some years ago, but I don't think he was convinced.

Acetylcholine can be measured in blood platelets by Health Diagnostics and Research Institute.

I think that your positive experience with boosting acetylcholine is in agreement with my interpretation of these experiments. I suspect that the reason you feel muscle stiffness when you boost acetylcholine is that your body has compensated for the low acetylcholine by expressing a lower a lower level of acetylcholinesterase. Then, when you raise acetylcholine suddenly, your muscles contract in response, but the contraction isn't released as soon, because acetylcholine stays high in the synapses longer than normal. This leads to the stiffness.

Yes, neuropeptide Y does inhibit release of acetylcholine.

Best regards,

Rich

Thanks Rich, it is always good to have the benefit of your expertise in uncovering any flawed assumptions in these papers.

Interesting what you say about low acetylcholinesterase explaining the muscle stiffness -it makes sense.

Funny how organophosphates are connected to precipitating CFS/ME (or at least to precipitating a CFS/ME like condition), as Emootje has noted.

Since organophosphates are acetylcholinesterase inhibitors, you might at first glance think that very mild exposure to organophosphates might even help CFS/ME symptoms (WHICH IS ABSOLUTELY NOT THE CASE, BY THE WAY, SO ANYONE READING THIS, STAY WELL AWAY FROM ORGANOPHOSPHATES!!).

However, I guess it may well be that other toxic actions of organophosphates, unrelated to its irreversible acetylcholinesterase inhibition, may be the problem, such as the mitochondrial damage that organophosphates are known to cause. Organophosphates are also known to damage the basal ganglia malfunction of which has been often implicated in CFS/ME, as well as, of course, in Parkinson's

 

[Snow Leopard]

Funny how organophosphates are connected to precipitating CFS/ME (or at least to precipitating a CFS/ME like condition), as Emootje has noted.

No, they have been implicated in Gulf War Syndrome. But GWS cases aren't necessarily biologically similar. Nevertheless, it is possible that such exposure pushed the associated system out of equilibrium.

 

[Hip]

No, they have been implicated in Gulf War Syndrome. But GWS cases aren't necessarily biologically similar. Nevertheless, it is possible that such exposure pushed the associated system out of equilibrium.

Gulf War Syndrome too, but there is a long history of famers using sheep dip (which contains high levels of OPs) getting CFS-like illnesses, and as a group, of such farmers having higher incidence of CFS-like illnesses. Though I read that some researchers are saying that it may not be a good idea to band together CFS and OP poisoning as one illness, even though they are very similar.

However, you can imagine that if someone was exposed to a CFS-associated virus, plus some organophosphates, they are likely going to have an additive effect.

 

[Emootje]

@Hip
Corts article is awesome! Chaudhuri and Behan explanation (inflammation - phosholipase? - choline?) makes a lot of sense. Maybe a natural PLA2 inhibitors will be helpful in ME/CFS.

Funny how organophosphates are connected to precipitating CFS/ME (or at least to precipitating a CFS/ME like condition), as Emootje has noted.

Since organophosphates are acetylcholinesterase inhibitors, you might at first glance think that very mild exposure to organophosphates might even help CFS/ME symptoms (WHICH IS ABSOLUTELY NOT THE CASE, BY THE WAY, SO ANYONE READING THIS, STAY WELL AWAY FROM ORGANOPHOSPHATES!!).

However, I guess it may well be that other toxic actions of organophosphates, unrelated to its irreversible acetylcholinesterase inhibition, may be the problem, such as the mitochondrial damage that organophosphates are known to cause. Organophosphates are also known to damage the basal ganglia malfunction of which has been often implicated in CFS/ME, as well as, of course, in Parkinson's

Toxic actions of organophosphates:

According to dr. Shattock, OP insecticides will inhibit any enzymes with an active serine site
In his article he mentioned four enzymes:
- tryptophan hydroxylase
- trypsin
- chymotrypsin
- di-peptyl peptidase IV
http://www.espa-research.org.uk/linked/iagandtryptophan.pdf

I found the last enzyme very interesting because the Klimas article mentioned earlier by Hip, stated that di-peptyl peptidase IV (DPPIV) is low in CFS and is involved in the biologic effects of neuropeptide Y.

Recently, our group reported that soluble as well as cell surface associated dipeptidyl peptidase IV (DPPIV) is decreased in CFS cases relative to controls [20]. NPYs biologic effects require interaction with its receptors. Native NPY 1-36 in the periphery is a major mediator of stress, responsible for prolonged vasoconstriction via Y1 receptors [29]. By cleaving the N-terminal Tyr-Pro dipeptide from NPY, DPPIV generates the Y2/Y5 receptor agonist NPY 3-36, that loses its affinity for the Y1 receptor and is angiogenic and inhibitory of NE release [30,63]. The low DPPIV observed in CFS coupled with high NPY would favor the Y1 receptor agonist form of NPY

Organophosphates and the immune system:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024290/pdf/1744-9081-6-76.pdf

Organophosphates and NMDA activation:


Another interesting thing:
"Residential areas in Lake Tahoe were fogged with OP's in the middle of the night in the 1980's to kill snow-melt mosquitoes at the time the Yuppie-Flu made headlines in nearby Incline Village"
http://www.sharecareprayer.org/subpages/CFS/organophosphates.html

Conclusion:
Organophosphates sucks!

 

[Emootje]

Could decreased Acetylcholine be one of the reasons for the elevated heart rate in patients?

In theory, decreased acetylcholine would decrease sympathetic tone (= decreased heart rate) and decrease parasympathetic tone (= increased heart rate)
It depends therefore on which system is more dominance.

In acute cholinestrase inhibitor poisoning (acetylcholine toxicity) the muscarinic symptoms are more dominance.



I think that a subgroup of ME/CFS patients have a prolonged action of acetylcholine (acetylcholine toxicity)
These patients have high levels of norepinephrine, excess salivation, excess sweating, blurred vision, rhinorrhea, fasciculations and lacrimation.
In my opinion this subgroup would benefit from acetylcholine lowering therapy.

 

[Sing]

Hi, Hip.

In my opinion, Chaudhuri, Behan, and also Puri have misinterpreted their magnetic resonance spectroscopy data. They extrapolated from observing a high ratio of choline to creatine (and in one paper, a high ratio of choline to water) to concluding that choline was high. This assumed normal levels of creatine and water in the brains of the CFS patients. However, the synthesis of creatine and choline are known to be the first and second major users of methylation in the body, and I believe that we have good evidence of a methylation deficit in CFS because of a partial block of methionine synthase. In 24-hour urine test results from PWCs, I also often see low creatinine, which indicates low creatine. Furthermore, water is likely to be low in the brain as it is in the blood in many PWCs, because of the diabetes insipidus that many have. Thus, my opinion is that this assumption was not valid. Until we have measurements of the absolute levels of choline and creatine in the brain, this issue will remain unsettled. It is possible to do such measurements, and Dr. Shungu, who is studying CFS with CAAA support, has the capability to do this, by comparing scans of the human brain to scans of known phantoms for calibration. I'm hoping that he will do it.

Vance Spence and his group accepted this interpretation, and my opinion is that this threw off their interpretation of their own results, which I believe are consistent with low acetylcholine. I discussed this with Vance some years ago, but I don't think he was convinced.

Acetylcholine can be measured in blood platelets by Health Diagnostics and Research Institute.

I think that your positive experience with boosting acetylcholine is in agreement with my interpretation of these experiments. I suspect that the reason you feel muscle stiffness when you boost acetylcholine is that your body has compensated for the low acetylcholine by expressing a lower a lower level of acetylcholinesterase. Then, when you raise acetylcholine suddenly, your muscles contract in response, but the contraction isn't released as soon, because acetylcholine stays high in the synapses longer than normal. This leads to the stiffness.

Yes, neuropeptide Y does inhibit release of acetylcholine.

Best regards,

Rich

Thank you, Rich. I understood most all of that, and relate well to what you said. Low choline, creatine and water in the brain producing the familiar symptoms. Plus a lack of the enzyme which breaks down the acetylcholine, which then causes the muscle stiffness. Yes!

 

[richvank]

According to dr. Shattock, OP insecticides will inhibit any enzymes with an active serine site
In his article he mentioned four enzymes:
- tryptophan hydroxylase
- trypsin
- chymotrypsin
- di-peptyl peptidase IV
http://www.espa-research.org.uk/linked/iagandtryptophan.pdf

I found the last enzyme very interesting because the Klimas article mentioned earlier by Hip, stated that di-peptyl peptidase IV (DPPIV) is low in CFS and is involved in the biologic effects of neuropeptide Y.

Recently, our group reported that soluble as well as cell surface associated dipeptidyl peptidase IV (DPPIV) is decreased in CFS cases relative to controls [20]. NPYs biologic effects require interaction with its receptors. Native NPY 1-36 in the periphery is a major mediator of stress, responsible for prolonged vasoconstriction via Y1 receptors [29]. By cleaving the N-terminal Tyr-Pro dipeptide from NPY, DPPIV generates the Y2/Y5 receptor agonist NPY 3-36, that loses its affinity for the Y1 receptor and is angiogenic and inhibitory of NE release [30,63]. The low DPPIV observed in CFS coupled with high NPY would favor the Y1 receptor agonist form of NPY

Hi, Emootje.

I'd like to comment on DPPIV, also known as CD26 in the immune system.

Lack of this enzyme has been found to be associated with food sensitivities to casein and gluten in autism patients. Some of the digestive enzyme products used in autism therefore include it.

As you may know, I believe that autism and ME/CFS are the same disorder from the biochemical perspective (symptoms and epidemiology differing only because of different ages at onset in relation to brain development and puberty). I think this is consistent with the fact that many PWCs are gluten and casein sensitive, and that Dr. Klimas's group has found low DPPIV in ME/CFS.

I have a hypothesis for the cause of the low DPPIV in autism and CFS. This hypothesis also applies to other secretory proteins that are found to be low in ME/CFS, including several of the peptide hormones (for examples, ACTH, antidiuretic hormone, and and growth hormone) as well as perforin. Here it is:

These proteins that show deficits all normally contain cysteine. When a protein is synthesized inside a cell, the amino acids are first joined together in an appropriate chain by the ribosomes within the cytosol. Then the chain is passed into the endoplasmic reticulum, where the tertiary structure of the protein is formed by linking cysteine residues together with their proper partners to form disulfide cystine bonds. If it is to be a secretory protein, it is then exported from the cell.

In order for this process to occur properly, the cysteine molecules must be maintained in their reduced state as cysteine, and not be allowed to bind together to form cystine until the appropriate stage of the process in the endoplasmic reticulum.

Here's where the problem arises in autism and CFS. Glutathione is depleted in the cytosol of cells. Without sufficient glutathione to control the redox potential in the cystosol, the cysteine molecules form disulfide bonds too early. This causes the quality control mechanism to send the malformed proteins to the proteasomes, which take them appart and recycle the amino acids. The result of this continuing recycling is that not enough of the proteins are formed.

The problem seems to be worst with proteins that contain a lot of cysteine residues. Perforin contains 20. DPPIV contains 12. It also seems to be worse for proteins that are made by cells that do not have a completely functioning transsulfuration pathway, and thus are not able to make cysteine from methionine, so that a scarcity of cysteine shows up first in them. Beside being an important constituent of these proteins, cysteine is also the rate-limiting amino acid for the synthesis of glutathione.

A counterexample is insulin. It is usually not low in ME/CFS, but does contain cysteine. I suggest that the reason it is O.K. is that it is made in the pancreas, and pancreatic cells do have a complete transsulfuration pathway.

DPPIV also has an important role (as CD26) on the lymphocytes. Lymphocytes do not have a complete transsulfuration pathway, as far as I know. So low CD26 in ME/CFS would again be consistent with this hypothesis.

Best regards,

Rich

 

[Hip]

... Here's where the problem arises in autism and CFS. Glutathione is depleted in the cytosol of cells. Without sufficient glutathione to control the redox potential in the cystosol, the cysteine molecules form disulfide bonds too early. This causes the quality control mechanism to send the malformed proteins to the proteasomes, which take them appart and recycle the amino acids. The result of this continuing recycling is that not enough of the proteins are formed...

Very interesting, Rich.

A while ago I was looking into the possibly of inhibiting coxsackievirus B using something that can attack the 3c cysteine protease of coxsackievirus B.

It seems that sodium selenite, a specific form of selenium (and not to be confused with sodium selenATE), can inhibit coxsackievirus B5, due to its toxicity following its interaction with thiols: see here: Selenite inhibition of Coxsackie virus B5 replication: implications on the etiology of Keshan disease. I do not have the full paper, but I believe selenite forms the toxin hydrogen selenide on reaction with cysteine or other thiols, so I assume that selenite is reacting with the 3c cysteine protease of coxsackievirus B5, to make this toxic hydrogen selenide in situ that may destroy the virally-infected cell.

Sodium selenite has proved quite effective as a chemotherapy for treatment-resistant cancers, because resistant cancers cells have thiols (cysteine) on their surfaces, and it is precisely these thiols that selenite reacts with to produce toxic hydrogen selenide, which helps kill the cancer cell. Some people have taken as much as 5,000 mcg of elemental selenium daily in the sodium selenite form, over many months, to cure treatment-resistant cancers. Note that the maximum daily dose of selenium is 800 mcg.

Anyway, I wonder whether sodium selenite might have any benefit in coxsackievirus B associated CFS.

Any idea how cellular glutathione levels (high or low) would interact with this apparent cysteine-mediated antiviral action of selenite on coxsackievirus B?

 

[Hip]

Toxic actions of organophosphates:

According to dr. Shattock, OP insecticides will inhibit any enzymes with an active serine site
In his article he mentioned four enzymes:
- tryptophan hydroxylase
- trypsin
- chymotrypsin
- di-peptyl peptidase IV
http://www.espa-research.org.uk/link...tryptophan.pdf

I heard a story of a researcher who was exposed to a very small leak of sarin (a super-potent organophosphate), and was plunged into a mental abyss so dire and depressed, he killed himself within a few weeks. Looking at the fact that organophosphates can inhibit the enzyme tryptophan hydroxylase, which converts tryptophan to serotonin, perhaps a complete block of serotonin was the reason for this dire depression.

In terms of avoiding organophosphate insecticides in everyday life, apparently the greatest dose we are exposed to comes from garden use of insecticides, not from food. Pesticide residues in food are generally very low, and so most of our yearly exposure to insecticides comes from garden use (or your neighbor's garden use, or the local municipal authorities spraying grass verges or flowerbeds around the town). Also, golf courses are heavy sprayed with insecticides, so golfers have a higher exposure to these chemicals.

I just mention this, because a lot of people think that by eating organic that can safely avoid pesticides; but eating organic will not reduce your yearly exposure to insecticides by very much at all.

 

[globalpilot]

Hi Rich,
This is very interesting. I wonder if this would also apply to other enzymes such as the disacharidase ?

Regards, GP

 

[Emootje]

Hi, Emootje.

I'd like to comment on DPPIV, also known as CD26 in the immune system.

Lack of this enzyme has been found to be associated with food sensitivities to casein and gluten in autism patients. Some of the digestive enzyme products used in autism therefore include it.

As you may know, I believe that autism and ME/CFS are the same disorder from the biochemical perspective (symptoms and epidemiology differing only because of different ages at onset in relation to brain development and puberty). I think this is consistent with the fact that many PWCs are gluten and casein sensitive, and that Dr. Klimas's group has found low DPPIV in ME/CFS.

I have a hypothesis for the cause of the low DPPIV in autism and CFS. This hypothesis also applies to other secretory proteins that are found to be low in ME/CFS, including several of the peptide hormones (for examples, ACTH, antidiuretic hormone, and and growth hormone) as well as perforin. Here it is:

These proteins that show deficits all normally contain cysteine. When a protein is synthesized inside a cell, the amino acids are first joined together in an appropriate chain by the ribosomes within the cytosol. Then the chain is passed into the endoplasmic reticulum, where the tertiary structure of the protein is formed by linking cysteine residues together with their proper partners to form disulfide cystine bonds. If it is to be a secretory protein, it is then exported from the cell.

In order for this process to occur properly, the cysteine molecules must be maintained in their reduced state as cysteine, and not be allowed to bind together to form cystine until the appropriate stage of the process in the endoplasmic reticulum.

Here's where the problem arises in autism and CFS. Glutathione is depleted in the cytosol of cells. Without sufficient glutathione to control the redox potential in the cystosol, the cysteine molecules form disulfide bonds too early. This causes the quality control mechanism to send the malformed proteins to the proteasomes, which take them appart and recycle the amino acids. The result of this continuing recycling is that not enough of the proteins are formed.

The problem seems to be worst with proteins that contain a lot of cysteine residues. Perforin contains 20. DPPIV contains 12. It also seems to be worse for proteins that are made by cells that do not have a completely functioning transsulfuration pathway, and thus are not able to make cysteine from methionine, so that a scarcity of cysteine shows up first in them. Beside being an important constituent of these proteins, cysteine is also the rate-limiting amino acid for the synthesis of glutathione.

A counterexample is insulin. It is usually not low in ME/CFS, but does contain cysteine. I suggest that the reason it is O.K. is that it is made in the pancreas, and pancreatic cells do have a complete transsulfuration pathway.

DPPIV also has an important role (as CD26) on the lymphocytes. Lymphocytes do not have a complete transsulfuration pathway, as far as I know. So low CD26 in ME/CFS would again be consistent with this hypothesis.

Best regards,

Rich

Hi Rich.
Interesting alternative hypothesis on the low DPPIV findings.
I am very interested in the treatment options.
Athene has posted the same therapy question on another thread, so maybe thats a better place to discuss the low DPPIV findings? http://forums.phoenixrising.me/showthread.php?5186-Klimas-London-presentation-CD26-DPPIV-impaired-in-CFS-retroviral-involvement&p=176700#post176700
Greetings Emootje