XMRV Study No. 4

[kurt]

Hi Kurt,

Okay...now I'm confused (even more than usual!).

You use the term 'glutathione overload'. Isn't it Rich's hypothesis that ME/CFIDS is due to possible methylation blocks and glutathione depletion?

Thanks in advance,

Dan

Overload = overwhelming glutathione load. Since glutathione is part of the antioxidant system you might think of it as carrying an oxidative stress load.

Maybe I should have said 'overloaded glutathione processes' or something like that. (I just updated the post above to try and clarify)

This is a different way to think about the glutathione problem, rather than a focus on depletion, focusing on the load factors that are chronically depleting the glutathione system and eventually blocking its production. So treatments would seek first to identify and reduce total glutatione load, perhaps even before addressing the methylation cycle itself with the 'genetic bypass' strategy.

 

[natasa778]

Late onset autism is unknown other than post trauma

not really, unless you count post herpes encephalitis as post trauma, several case reports in literature describe late-onset of autism following herpes encephalitis, ages being 11, 14 and 31 if I remember correctly


Autistic syndrome with onset at age 31 years: herpes encephalitis as a possible model for childhood autism.
The author describes a previously healthy man who contracted herpes encephalitis at the age of 31 years, and over the following months developed all the symptoms considered diagnostic of autism. This case report casts doubt on the notion of autism as an exclusively developmental disorder. It is suggested that temporal lobe damage may cause autism in some cases Gillberg IC. Dev Med Child Neurol. 1991 Oct;33(10):920-4.

There is also something called P something xxx syndrome (memory gone , sounds a bit like pick's but isn't) happens in early twenties and later, with all symptoms of autism according to any DSM or ADOS or 'triad' criteria, you name it... but isn't diagnosed as autism, probably political reasons as poor "experts" would have to rethink their expertise. will post if I ever remember the name of the syndrome, sorry

 

[Gerwyn]

not really, unless you count post herpes encephalitis as post trauma, several case reports in literature describe late-onset of autism following herpes encephalitis, ages being 11, 14 and 31 if I remember correctly


Autistic syndrome with onset at age 31 years: herpes encephalitis as a possible model for childhood autism.
The author describes a previously healthy man who contracted herpes encephalitis at the age of 31 years, and over the following months developed all the symptoms considered diagnostic of autism. This case report casts doubt on the notion of autism as an exclusively developmental disorder. It is suggested that temporal lobe damage may cause autism in some cases Gillberg IC. Dev Med Child Neurol. 1991 Oct;33(10):920-4.

There is also something called P something xxx syndrome (memory gone , sounds a bit like pick's but isn't) happens in early twenties and later, with all symptoms of autism according to any DSM or ADOS or 'triad' criteria, you name it... but isn't diagnosed as autism, probably political reasons as poor "experts" would have to rethink their expertise. will post if I ever remember the name of the syndrome, sorry

encephalitis is a form of trauma --anything that damages the brain.

If glutathione depletion was a cause the everyone who had a chronic viral infection would go on to have CFS.

Glutathione suppliments do bring up levels in Autism but not usually ME. Obviously it is the same size molecule in each case

The Reno results dont appear to have generalised

.Aids TAT directly depletes glutathione the higher the load the greater the depletion,

Survival is connected to severity of load replicative rate etc. lower the load the higher the intracellular gluthione.

There is correlation here between survival and glutathione levels but it is not causative.

The methylation block in autism is at the level of methionine synthase.this is inhibited by nitric oxide.This is a common denominator in glutathione depletion as well.INOSi is upregulated by Creb CRe systems.

Xmrv binds within CREB genes.

So only a specific retrovirus insertion is needed in this causal hypothesis any old retro or any other virus would not do

 

[kurt]

encephalitis is a form of trauma --anything that damages the brain.
If glutathione depletion was a cause the everyone who had a chronic viral infection would go on to have CFS.
Glutathione suppliments do bring up levels in Autism but not usually ME. Obviously it is the same size molecule in each case
The Reno results dont appear to have generalised
.Aids TAT directly depletes glutathione the higher the load the greater the depletion,
Survival is connected to severity of load replicative rate etc. lower the load the higher the intracellular gluthione.
There is correlation here between survival and glutathione levels but it is not causative.
The methylation block in autism is at the level of methionine synthase.this is inhibited by nitric oxide.This is a common denominator in glutathione depletion as well.INOSi is upregulated by Creb CRe systems.
Xmrv binds within CREB genes.
So only a specific retrovirus insertion is needed in this causal hypothesis any old retro or any other virus would not do

Gluathoine Depletion may not be the sole factor, I don't think we know that yet. There are over 7,000 studies of glutathione, and 90,000 studies that mention the word, clearly it is involved in many conditions. Also, glutathione can be depleted in specific organ systems I believe including just in the brain. So there may be a complex interaction between GD and various co-morbid conditions. Also, the degree of depletion may vary, the SNPs of the patient and also the existing viral load figure in to whether or not a given level of depletion will lead to viral re-activation, methylation cycle blocks, or some other problem due to the oxidative stress level. Without pre-activated bad SNPs a person may tolerate much more glutathione depletion. Maybe a virus or retrovirus plays a role in activating bad SNPs, much more research is needed.

Glutathione in supplement form is not the solution, the methylation cycle has to be corrected so the cells can produce their own, so specific activated supplements may help differentially depending on specific pathologies and interactions between them.

The Reno GD-MB study needs to be validated with other studies, too early to say whether it can generalize, this is a recent report, in 2009. So not correct to say it can't be generalized, at least not yet.

The blocks are more complicated than just NO, I don't know all the details, but there are many different steps in the cycle that can be broken. Heavy metal load is a common block, for example. What can be easily blocked depends on one's specific SNPs and also the biochemistry of the total load on the system.

I have not studied how XMRV blocks CREB but thought the specific attachment location was still unknown, although you have made an interesting connection, with the NOS upregulation. If that is a high-level factor and XMRV is involved, then improving glutathione metabolism becomes an important part of the treatment of XMRV related disease. And given that we already know this may be important for ME/CFS, maybe glutathione load/block is a good direction to focus on for treatments, regardless of the future outcome of the XMRV hypothesis.

 

[bel canto]

Autism and ASD are defined as development disorders - look at the many sources of information available to see this. Autism-like symptoms in adulthood is not Autism or ASD. It's just a description of symptoms, which may be labeled a "syndrome", but is NOT autism.

It's helpful to be precise in the terms that get used in these discussions. Sticking to facts and science rather than opinion and speculation is also helpful.

We are all on edge with all the uncertainty out there, so let's try not to add to the confusion. I'm sure that everyone who takes the time to write on this forum means well.

 

[bel canto]

Sorry - didn't mean to sound so preachy!

 

[natasa778]

Autism-like symptoms in adulthood is not Autism or ASD.

Autism is defined and diagnosed solely by its symptoms, there is NOTHING else to its diagnosis and definition apart from symptoms. If someone has symptoms, he/she has autism - and that is by every diagnostic criteria out there. "Autism-like symptoms" term is ridiculous, as every single individual diagnosed with autism earned his/her diagnosis SOLELY as a result of displaying those autism symptoms. Nothing else. There are only symptoms. They are not autism-like, symptoms are just that, symptoms.

A child who is diagnosed with autism age 2 grows up to display exactly the same range of "autism symptoms" as your new-onset adult "autism-like" would display. Generally speaking there would be no difference whatsoever between the two of them - imaging blind-assessing them by an experienced diagnostician, who be looking and scoring their symptoms. And as autism is described, defined and diagnosed solely by the surface symptoms, it would be impossible to diagnose those two individuals differently. Everything else is politics.

 

[Gerwyn]

Thus far only one block has appeared in a published peer reviewed journal--Methionine synthase Prolonged elevated nitric oxide levels can deplete glutathione and inhibit methionine synthase.

I agree that glutathione can be depleted by any prolonged or chronic infection and the resultant oxidative processes

It is the fact that it is so common that being causative in ME seems so unlikely.You would expect glutathione depletion and the resultant block in the methylation to go on to produce symptoms of ME but they dont

I agree that there must be other factors involved the question is what?

Rick proposes genetic factors re gene expression this is where the argument becomes nebulous

Comorbid conditions and viral load as factors are certainly worthy of consideration.I cant find anything published in this area.The infectous processes leading to Glutathione depletion are triggered by interferon alpa and beta binding at the IFNalpha gene

The interferon respose appears to be activated at amout 100 virions per ml higher tites would not seem to be an issue if by comorbidity you mean coinfection with another virus the same would apply


.Variations in the innate system can affect viral load however

I agree it is to soon to make any conclusions about the RENO paper The reports about infectiveness are mixed.

If It works it would be marvelous but we need to assess the method scientifically to find out.That has not yet even been done in autism

The high nitric oxide levels have been shown to inhibit viral replication and maintain latentcy even in the presence of Glutathione depletion so level of glutathione depletion is not critical in this regard.

I am suggesting that XMRV integration within regualory sequences would produce the variation in gene expression observed by Rich in children dianosed as having autism.

.Deletion sequences in Gamma retroviruses are causative of their pathological mode of action and related to their ability to dysregulate gene function

The fact that not everyone suffering a viral infection gets ME can be explained by a mechanism in which a virus causes prolonged and intractable upregulation of Nitric oxide which exhausts glutathione production because the raw materials needed to produce glutathione are not inexhaustabke This is a high glutathione load caused by the virus

Nitric oxide at a high prolonged level will block methionine synthase both directly and indirectly and directly damages Mitochondria

Interestingly Retroviruses are also associated with polymorphisms.

P.S I also believe that XMRV is causative in Autism via vertical transfer. The main difference is the amount of damage which can be done to a forming mind by lack of mitochondrial function.The integrative processes in particular are severly damaged.I really hope that The methylation block treatment works .I have seen many desperate parents over many years and any effective treatment would be so welcome

 

[Gerwyn]

Gluathoine Depletion may not be the sole factor, I don't think we know that yet. There are over 7,000 studies of glutathione, and 90,000 studies that mention the word, clearly it is involved in many conditions. Also, glutathione can be depleted in specific organ systems I believe including just in the brain. So there may be a complex interaction between GD and various co-morbid conditions. Also, the degree of depletion may vary, the SNPs of the patient and also the existing viral load figure in to whether or not a given level of depletion will lead to viral re-activation, methylation cycle blocks, or some other problem due to the oxidative stress level. Without pre-activated bad SNPs a person may tolerate much more glutathione depletion. Maybe a virus or retrovirus plays a role in activating bad SNPs, much more research is needed.

Glutathione in supplement form is not the solution, the methylation cycle has to be corrected so the cells can produce their own, so specific activated supplements may help differentially depending on specific pathologies and interactions between them.

The Reno GD-MB study needs to be validated with other studies, too early to say whether it can generalize, this is a recent report, in 2009. So not correct to say it can't be generalized, at least not yet.

The blocks are more complicated than just NO, I don't know all the details, but there are many different steps in the cycle that can be broken. Heavy metal load is a common block, for example. What can be easily blocked depends on one's specific SNPs and also the biochemistry of the total load on the system.

I have not studied how XMRV blocks CREB but thought the specific attachment location was still unknown, although you have made an interesting connection, with the NOS upregulation. If that is a high-level factor and XMRV is involved, then improving glutathione metabolism becomes an important part of the treatment of XMRV related disease. And given that we already know this may be important for ME/CFS, maybe glutathione load/block is a good direction to focus on for treatments, regardless of the future outcome of the XMRV hypothesis.

The only published block is methionine synthase prolonged elevation of NO would inhibit this enzyme

The fact that glutathione depletion is so common disturbs me --why doesnt everyone go on to develop ME

Rich proposes genetic factors but the argument here becomes nebulous

The cellular mechanisms ultimately responsible for glutathione depletion are stimulated by the INF alpha gene activated in turn by ifalpa and beta binding.These responses kick in at about 100 virond per ml.this suggests that viral load is not a factor.The same argument applies to viral coinfection

Deficiencies in the innate system can influence viral load though.

High nitric oxide levels inhibit viral replication and maintain latency even when glutathione levels are depleted.

XMRV inserted could cause variation in gene expression especially in terms of nitric oxide because that mechanism is CRE?CREB dependent.

Prolonged elevated No would have a near lethal effect on mitochondria massively increasing glutathione load leading to its exhaustiion while also inhibiting methioine synthase cusing a methylation cycle block

The pathogenicity of gamma retroviruses is highly dependent on deletions in their genome.XMRV has by far the most so you would expect it to be the most pathogenic of all gammas

It is worth noting that there is a strong relationship between polymorphisms and retroviruse.

I akso think that vertically transmitted XMRV is causative in autism.

The main difference is the havok that mitochondrial dysfunction can wreak when the mind is developing integrative processes networks and circuits---Can this be treated later I really hope so

I look forward to a scientific assessment of Rich's protocol

 

[Mithriel]

I don't think equating autism and CFS is very useful to anyone. It might be of peripheral interest but we've seen this sort of thing before and it leads to the point of people saying they have had a "touch of autism" but got over it by XXXX, choose your own word.

It might be interesting for basic science if XMRV causes both but we are a long way from showing that. The original question of how an insignificant virus like XMRV can cause all our symptoms is a good one but has been lost in the byways.

We already know that viruses can cause different diseases, Coxsackie B gives ME and Bornholm's disease for instance and we know that there are categories of disease.

Fever is a symptom that is common to most acute infections and finding a way to treat can be useful, but to work out what is causing each infection you have to look at the differences, not the commonalities.

We have the mess we are in nowadays because fatigue, a common symptom, has been used as the defining thing instead of ME as neurological with an abnormal response to exercise something that separated it from other illnesses.

Many of us have to limit our time on the computer so we have to be very selective about what we read. It would be helpful if things like autism and CFS were put into their own thread so we could chose to read it or not.

Mithriel

 

[Gerwyn]

I don't think equating autism and CFS is very useful to anyone. It might be of peripheral interest but we've seen this sort of thing before and it leads to the point of people saying they have had a "touch of autism" but got over it by XXXX, choose your own word.

It might be interesting for basic science if XMRV causes both but we are a long way from showing that. The original question of how an insignificant virus like XMRV can cause all our symptoms is a good one but has been lost in the byways.

We already know that viruses can cause different diseases, Coxsackie B gives ME and Bornholm's disease for instance and we know that there are categories of disease.

Fever is a symptom that is common to most acute infections and finding a way to treat can be useful, but to work out what is causing each infection you have to look at the differences, not the commonalities.

We have the mess we are in nowadays because fatigue, a common symptom, has been used as the defining thing instead of ME as neurological with an abnormal response to exercise something that separated it from other illnesses.

Many of us have to limit our time on the computer so we have to be very selective about what we read. It would be helpful if things like autism and CFS were put into their own thread so we could chose to read it or not.

Mithriel

I dont think that autism and cfs is the same I do believe the same virus may be causative in both but with totally different consequences.I was trying to show how the virus could account for all the symptoms and biochem abnormalities that we display----I was trying to fill in the holes present in the glutathione hypothesis

 

[Marco]

Gerwyn and Kurt.

You may wish to check what I posted in this thread. Neither XMRV nor methylation blocks per se may be the problem :

http://www.forums.aboutmecfs.org/showthread.php?3732-Postulated-Vasoactive-Neuropeptide-Autoimmunity-in-fatigue-related-Conditions&p=56146#post56146

 

[ukxmrv]

The problem with getting excited about a paper like that Marco, is that we have seen them all before. There have been many papers arguing plausible mechanisms for CFS. Until someone has actually carried out some research it sits in the "interesting" area.

Same with methylation blocks. Rich VK work is tremendous and I'm glad to see it. However, I'm not seeing very much success in people I know and have been following (including the group set up to follow it). That may change over time but too soon to get excited.

I'd like to see this thread stay on topic so I can follow it.

 

[Gerwyn]

Gerwyn and Kurt.

You may wish to check what I posted in this thread. Neither XMRV nor methylation blocks per se may be the problem :

http://www.forums.aboutmecfs.org/showthread.php?3732-Postulated-Vasoactive-Neuropeptide-Autoimmunity-in-fatigue-related-Conditions&p=56146#post56146

Thanks Marco interesting High No again involved. CREB/CRE disruption leads to problems with functioning PVNs I have also just found out that the CREB/CRE system is involved in scarring and delayed wound healing that i suffer from. XMRV appears to be a common link in both these areas

 

[Marco]

The problem with getting excited about a paper like that Marco, is that we have seen them all before. There have been many papers arguing plausible mechanisms for CFS. Until someone has actually carried out some research it sits in the "interesting" area.

Same with methylation blocks. Rich VK work is tremendous and I'm glad to see it. However, I'm not seeing very much success in people I know and have been following (including the group set up to follow it). That may change over time but too soon to get excited.

I'd like to see this thread stay on topic so I can follow it.

No problems. I wasn't so much over-excited as in 'this is the cure' as finding it very interesting and a plausible alternative and wanted to hear what those with strong science backgrounds thought.

Apologies - back on topic.

 

[ukxmrv]

Thanks for your kindness Marco. Sorry to be a pain.

 

[kurt]

Do we need a thread for a ME/CFS causal model discussion, with a focus on the role of retroviral infection? I can pull out related posts from here and place them in a new thread if members would like that.

 

[ukxmrv]

Maybe causal comparing all the different models?

Thanks Kurt, great idea.

Anyone else?