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Prof Trevor Marshall
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Marshall TG: Vitamin D Discovery outpaces FDA decision making.
BioEssays Volume 30, Issue 2, Pages 173-182, February 2008
Online ISSN: 1521-1878 Print ISSN: 0265-9247
Copyright 2008 Wiley Periodicals, Inc., A Wiley Company
http://www3.interscience.wiley.com/cgi-bin/abstract/117885976/ABSTRACT


In accordance with the copyright assignment agreement I have put a free copy of the preprint of the Full Text on my personal website at
http://TrevorMarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf


Enjoy! :)
..Trevor..

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Dr. Marshall,

Very impressive work and I hope and pray this will help "get the word out."

Sherry

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Sherry,
The whole team deserves Kudos for this - Meg, Barb, Belinda, Joyce, Janet, PB, Vez, Lottie, Carole, and all the folk whose dedication allowed us to collect the data which led  us to this understanding :):):)
 

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Trevor

Great work as far as my limited ability to think straight allows. (but it's getting better - to misquote Monty python)

One question - you mention gliding bacteria and persistent infections on prosthethic joints - do you think that MP will be able help someone with this issue? 

Cheers

Paul

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Any persistent infection is a sign that the immune system has been unable to clear the pathogen. The MP is an easy, safe intervention to try in such situations. The D-metabolites tests will usually give a pretty good idea if there are likely to be Th1 pathogens present in any quantity.

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Cracking article - congratulations to whole team.

Physicians can't ignore this one.

Cheers

Guss

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Thanks for the wonderful article, and congrats to you and the whole team.

I found two typos. Do you want them?

Prof Trevor Marshall
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Arrgh... Hopefully the typos were caught in the final phases of publishing :):) Let's wait until the printed journal comes out...

 

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My thanks to Dr. M and the research team for your good work and for being so open in your methods.

Copernican revolutions are a beautiful thing and I hope we are seeing one now, on the medical side as well as the research side :D

I guess we should tip our hats to Stallman and Torvalds too.

Very exciting times!

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Trevor, I have a question.

In the paper, you state that the conversion of 7-dehydrocholesterol to pre-vitamin D is also observed in macrophages and intestinal cell lines.

I would think this means that (sun)light is not necessary at all to keep sufficient levels of vit. D ??

Sincerely, Frans

Last edited on Wed Jan 16th, 2008 04:04 by Frans

Prof Trevor Marshall
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Frans,
Yes, please move to the top of the class :):)

I wonder how many other folk will notice that subtlety, and that Figure 1 talks about "energy" rather than solely "UVB"?
 

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You make me blush :D

I will be sure to mention this if and when I try to contact reporters who would like to publish this in their newspapers or medical magazines  :cool:

Sincerely, Frans

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Frans,
Belinda is working on finishing a Press Release, which should be available at about the same time that the paper appears in PubMed (it hasn't propagated to their computer yet). Keep an eye open for her announcement :)
 

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Trevor,

I was thinking of producing something like that myself, so I will stay tuned for it.

Sincerely, Frans

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Trevor, a follow up question.

Did these guys understand that they, in fact, have proven that humans do not need (sun)light at all?

Or to be specific, are they looking further to elucidate the probable enzyme that delivers the energy this mechanism needs?

Considering the steps from previtamin D to 1,25D are all also done by enzymes, another wouldn't come as a surprise?

Sincerely, Frans

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This will surely bring attention of other Vitamin D researchers and they will have problems to digest it, but it logically outlines the points that other researchers have simply troubles believing, but cannot argue with. This really must hurt when you are a studying something for years and u find out to be wrong in the end.

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Frans,
Nobody has thought too much about the enzyme/energy issue in Homo sapiens. In nocturnal animals, of course, and in fish (etc) there has been exploration, but in man nobody has been asking questions. It seemed all so simple...

I was recently contacted by a 25-year veteran of a Nuclear power station, who claimed that there were many staff there suffering from Sarcoidosis. Since it is a rare disease, such a cluster would be highly unusual. But it got me thinking about radiation poisoning, and how low-level poisoning produces many symptoms like Th1 disease. I am sure that Vitamin D is not the only sterol which would be catalyzed by radiant energy, but I was certainly intrigued by this line of research too. Now I wonder who would want to fund a study of such workers??:)
 

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I dont think I understood that last post corectly?

Are you stating that those patients sarcoidosis was caused by radiation poisoning? Also, I thought Sarc was not rare at all? I also thought that sarc was caused by bacteria. If there are a cluster of people with sarc from radiation poisoning, wouldnt we have to rethink the causes of sarc? Please help me understand. I am having a hard time as of late..:X

Shandy

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Shandy,
There are about 134,000 people with Sarcoidosis in the USA, it is classified as a rare disease. About 2 in 10,000 suffer from it.

Frans asked about the step in which 7-dehydrocholesterol is changed to pre-Vitamin D. This requires energy, or an enzyme. Medicine currently believes that this can only occur when the body is exposed to UVB radiation, but we have proven this is not the case. Biologists know that some mammals create their own Vitamin D, through processes such as enzymatic conversion. I was suggesting that this could be the case for humans too. We have a lot of members who are not ingesting any vitamin D, and have been diligently avoiding UVB for several years, yet their bodies are functioning well.

I was further suggesting that the transition from 7-dehydrocholesterol to pre-Vitamin-D could very well be caused by the energy coming from low levels of nuclear, or similar, radiation. As an anecdote, I cited a single power station where such a 'Th1 epidemic' seems to have occurred, and I am also aware of at least one case in a nuclear submarine reactor officer. Just a suggestion at this point - an indication for us to watch the papers, and start to gather epidemiological data which might lead to better insight into the factors which cause the initial decline into Th1 disease. We have already identified pregnancy as one such factor.

I hope this helps:)

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Dr Trevor Marshall wrote: Frans,
Belinda is working on finishing a Press Release, which should be available at about the same time that the paper appears in PubMed (it hasn't propagated to their computer yet). Keep an eye open for her announcement :)
 


Trevor,

I completed the snippet I wanted to write to this reporter I have been in contact with, I had it almost ready...

Maybe Belinda can use some things

Here it goes:

Dear Sir, madam,

I would like to draw your attention to a research paper about vitamin D soon to be published in the magazine BioEssays. It is a paper by professor Trevor Marshall.

You can access the abstract here:
- http://www3.interscience.wiley.com/cgi-bin/abstract/117885976/ABSTRACT

You can access the preprint version here:
- http://TrevorMarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf

Marshall's paper comprises a molecularly derived model of vitamin D in relation to (with regards to) cancer and other chronic diseases linked to vitamin D.


You will be aware of the sugestion that vitamin D somehow protects against cancer, despite the critical comments of Professor Colin Cooper, of the Institute of Cancer Research en Dr Mark Metfield, of the Association for International Cancer Research, when confronted with a review paper of prof. Cedric Garland, who found a distinct correlation between several cancers and plasmalevels of vitamin 25 OHD.

Professor Colin Cooper, of the Institute of Cancer Research, commented that 'further research was necessary to provide definitive proof of the benefits of vitamin D.

He commented that the evidence was rather suggestive, but provided no definitive proof.

Furthermore he stated that prof. Garland failed to provide a MECHANISM to explain how exactly low levels of vitamin 25OHD are related to cancers.

Marshall's paper delivers a model explaining just such a mechanism !

Dr Mark Metfield, of the Association for International Cancer Research, agreed with Cooper that prof. Garland's research did not provide ANY PROOF about the benefits of vitamin D.

He further commented that he was conservative, in that there is clearly a correlation, but it is 'just a correlation'.

(see: http://news.bbc.co.uk/1/hi/health/4563336.stm)

 

Several highlights of Marshall's paper:

- reference 16: in this research they found tat several cell-lines have the capability to create pre-vitamin D from 7-dehydrocholesterol, which clearly implies that homo sapiens most probably does not need any (sun)light to create enough vitamin D, rendering the present definition of vitamin D deficiency totally outdated and useless;  considering the steps from pre-vitamin D to 1,25 dihydroxyvitamin D involve several enzymes, it is likely that the conversion from from 7-dehydrocholesterol to pre-vitamin D also involves an as yet undiscovered enzyme

- vitamin 25OHD is an ANTAgonist of the VDR, implying that high levels of 25OHD are immunosuppressive, rendering several key components of the innate immune system useless, amongst which are several beta defensins and antimicrobial peptides AMPs

- Marshall's delivers a schematic model that explains how and why levels of 25OHD get lower in disease; despite all this molecular knowledge, many sufferers of chronic disease are still being supplemented with vitamin D, rendering their already compromised immunesystems even more powerless, in effect acting as oil upon a fire

- the model also provides the clear insight that plasmalevels of vitamin 25OHD are not a constant, but are regulated by several enzymes and only measuring this level just does not cut mustard;  one should ALWAYS (also) measure the level of 1,25 dihydroxyvitamin D to make better assumptions about activity of the VDR

PS:  More background information:

Rickets is not caused, nor cured by vitamin D, see:
- PubmedID: 15976027: Rickets cuased by hypophosphatemia  (from 2005!)
- PubmedID: 17332234: actions of VDR on skeletal development INDIRECT

Osteoporosis linked to high levels of 1,25D dihydroxyvitamin D

Every paper looking into the benefits of 1,25 dihydroxyvitamin D in cancers states that high levels of 1,25D lead to BONE RESORPTION ! (see pubmed and try query: VDR CANCER)


Maybe it helps,

Sincerely, Frans

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Trevor ,

Am I correct in thinking this also explains how the antibiotic Rifampicin works in chronic Lyme. It modulates the VDR by way of the PXR causing an immunosuppressive affect. As long as they’re taking if they feel better but as soon as they stop they relapse.

I opened a bottle of wine and had a toast when I got through reading it just fascinating to see a disease process at the molecular level on paper congratulations

 Ival

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Ival,
It certainly is an interesting possibility, isn't it Ival :)

The effect would be different in chronic disease from what it is in TB.
 

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The paper is now catalogued in PubMed, PMID: 18200565

http://tinyurl.com/ypk53t


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Dr Trevor Marshall wrote: I wonder how many other folk will notice that subtlety, and that Figure 1 talks about "energy" rather than solely "UVB"? 

Does there have to be an external input of energy or does the body literally produce 1,25D all by itself?  I'm thinking of a theoretical situation where a human is exposed to absolutely zero light of any kind (UVB, IR, visible, electromagnetic, etc.).  Would you expect a human in this theoretical situation to still produce a sufficient amount of 1,25D?

Many congratulations on the paper.  I look forward to the day when your work is fully recognized for the amazing discovery that it is.

Prof Trevor Marshall
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Russ,
As far as we can tell, the body can produce all the 1,25-D it needs by itself. It upregulates keratinocyte production of 1,25-D in the presence of the inflammatory cytokine TNF-alpha, for example, and I suspect there are other mechanisms as well.
 

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A press release about the BioEssays paper is available online at
ttp://www.prweb.com/releases/2008/1/prweb639651.htm

We have a discussion of media coverage of the paper at Our Press Release Today January 21.

Belinda

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Trevor,

When you talk about radiation, could it be that radio EM radiations like GSM, DCS, UMTS, BLUETOOTH, WIFI,...may fuel also these conversions?
I am asking this because I am working in a telecommunication company where everything is radio inside our building (LAN, phone, ...) since many years.

Even if it sounds crazy, the period when WIFI was introduced in our building and the more frequently usage of bluetooth devices correspond with an increase of my HypervitaminoseD symptoms. It is most probably a coincidence but...

Didier

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The lower frequency of these sources reduces their energy. Bluetooth is too low power to cause problems. Sources above 1 GHz and high power might be a possible problem. But I am talking about transmission tower power levels here, not WiFi wireless routers.

It is almost impossible to link symptoms with a cause. Just focus on recovery...
 

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Reuters press release a couple of days ago:

"African immigrants with low levels of vitamin D are much more likely to be infected with tuberculosis"

"Their study of all 375 African immigrants treated at one Melbourne hospital showed that those who had low vitamin D levels were far more likely to have TB infections than those with adequate levels"

...so far, so good, and in clear agreement with Dr. Marshall's research.

But then they conclude with a serious lapse in critical thinking...

"Gibney's team said doctors might consider vitamin D supplements as a treatment for TB, or a way to prevent it.":X

(Not sure this is the right place for this post. Feel free to create a new thread if appropriate.):)

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Yes, this is the correct place. And yes, you are correctly identifying their lapse in thinking. The article is at URL
http://www.reuters.com/article/healthNews/idUSN2846942520080128

Maybe this line of thought was suggested by a peer-reviewer, and accepted in order to get the paper published, or maybe they had it in the back of their minds all along. I guess we shall never know unless somebody contacts the study authors, and draws their attention to the correct interpretation, the interpretation which was formed in the 1985 study of TB (my citation 67)(Don't you find it incredible that the authors were not aware of this paper? All it takes is Google or PubMed to find it...).

Maybe some of our Aussie mates could do some helpful follow-up here
:):)

Folk who live in underdeveloped nations are very likely to be carrying a heavy load of Th1 pathogens. Quite apart from their difficulty avoiding contact with nasty pathogens, the West has been exporting our Vitamin D fortified powdered milk and infant formula to these nations since the 1950s:(
 

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Gibney's contact info

http://www.journals.uchicago.edu/doi/abs/10.1086/525268

Russ
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Dr Trevor Marshall wrote: I wonder how many other folk will notice that subtlety, and that Figure 1 talks about "energy" rather than solely "UVB"? 

Since heat is energy (I think), is it possible that all forms of heat, and not just IR, can trigger the Vit D metabolism?  Many TH1 folk complain of symptoms when they get overheated, even in cases where there is no high-energy IR source involved.  For instance, if I go to sleep under too many covers and get real hot in the night, I will wake up feeling terrible.  This is true even when the heat in my apartment is turned off.  Is it possible that the overheating and the resultant heat energy is causing increased 1,25D or are symptoms like these more likely due to something else?

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"Humans perceive infrared radiation as "heat radiation", which is one way of energy transport. This may be why many persons with Th1 disease feel very uncomfortable when they get overheated." ..Trevor.. See Incident Radiation Tutorial

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An increase in body temperature can also increase the effect of antibiotics. Which might also make you feel less comfortable :)
 

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I guess I was wondering which explanation was more likely the cause of the symptoms, since in one case (IR) you'd want to try hard to avoid it and in the other (increased abx effectiveness) it wouldn't be such a bad thing. 

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Vitamin D deficiency paper is stirring up some debate:

http://www.freerepublic.com/focus/f-news/1960227/posts
http://tinyurl.com/39cttp
http://tinyurl.com/2v2w35
http://brain.hastypastry.net/forums/showthread.php?p=208026
http://www.her2support.org/vbulletin/showthread.php?p=150942
http://stopsarcoidosis.clinicahealth.com/comments.pl?sid=08/01/12/167232

I imagine there will be letters to the editor in the next edition or two...

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Thanks Rico, I hadn't had time to go looking myself.

You know, one of the reasons I had to publish that paper was to draw a line in the sand that I had decoded the riddle of chronic disease, and to describe the processes in a way that they would be able to subjected to peer review.

In many ways, by trying to marginalize our thought, these folk are helping us immensely, as they are showing how radical our breakthrough has been. It is not an evolutionary improvement in knowledge, it is truly a break away from commonly accepted pragma.

There have been letters to the editor at BioEssays, and I have responded to one of them. It is tough to respond to letters where the writer, although well meaning, does not comprehend the concept of the VDR or gene expression, or indeed, even include it their in analysis :(

I have also had letters from Biologists that congratulated me on saying what had to be said. They themselves can now be more outspoken in the future, by citing my work.
 

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Trevor,

I am thinking about writing a paper in a Norwegian medical journal on the vitamin d subject. In that regard, it would be helpful to have a reference to vitamin 25-D being an antagonist to the VDR. Do you have one at hand?

Inge

Last edited on Tue Feb 5th, 2008 01:25 by inge

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Oh dear, Inge. That is a like asking me to prove water is wet.  I just can't recall any single paper which shows that, as it is a pragma which forms the underpinning of all the drug discovery in Vitamin D analogs, and has been proven many, many times by individual drug discovery groups.

For example, this study:
http://www.ncbi.nlm.nih.gov/pubmed/10677578
and this one
http://www.ncbi.nlm.nih.gov/pubmed/11179729
are typical of those in drug discovery exploring compounds which activate the VDR. 'Everybody knows' that 25-D is not one of them :X

I proved it for myself in two ways. They can be seen in my Karolinska presentation, and my Harvard presentation.
For Karolinska I provided the 2D plots of the amino acid residue interactions for 1,25-D 25-D and Olmesartan, while for Harvard I showed diagrams of how the Rat and Human VDR were activated - which residues were important. This was based on my own work, and a review of many papers in the literature. But note that by Harvard I had started to use the more accurate molecular dynamics simulations, which showed that Olmesartan actually changed the shape of the VDR a little from that of 1,25-D, so the key residues are a little different for that drug. There was no change between the 25-D and 1,25-D dynamic and static simulations, however. My paper on receptor modeling gives all the background on how one performs the 2D simulations.
Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract presentation, Days of Molecular Medicine, Karolinska Institutet, Stockholm, May 2006.
Copy available from URL http://autoimmunityresearch.org/karolinska-handout.pdf
Marshall TG: Molecular Static and Dynamic Analyses Reveal Flaw in Murine Model used by US FDA to Detect Drug Carcinogenicity. Abstract presentation, Days of Molecular Medicine, Cambridge MA, May 22-24, 2007. doi:10.1038/npre.2007.52.1
Copy available from URL http://autoimmunityresearch.org/dmm2007/dmm2007-handout.pdf
Marshall TG: Molecular genomics offers new insight into the exact mechanism of action of common drugs - ARBs, Statins, and Corticosteroids. FDA CDER Visiting Professor presentation, FDA Biosciences Library, Accession QH447.M27 2006
Online Video available from URL http://autoimmunityresearch.org/fda-visiting-professor-7mar06.ram
Marshall TG, Lee RE, Marshall FE: Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor Biol Med Model. 2006 Jan 10;3(1):1. Available from URL http://www.tbiomed.com/content/3/1/1
I hope that helps.
 

Last edited on Tue Feb 5th, 2008 05:32 by Prof Trevor Marshall

inge
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Thank you, that helps a lot!

Inge

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Rico,

Those are interesting links.  Maybe some people will go to some of those discussions and post a link to Amy's articles on Vitamin D. 

vitamin d -- Bacteriality.com

It answers a number of the issues people bring up in a way that those people will find easier to understand than Dr. Marshall's BioEssay.

Looking at the first one, they don't seem to realize that the FDA is who is pushing to allow more vitamin D and health claims that will encourage more vitamin D in the food.  The worry about Big Pharma, but not the Big Supplement Industry.

Joyce Waterhouse

Last edited on Tue Feb 5th, 2008 08:55 by jcwat101

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Why would the FDA push more VIT D if they are well aware of Dr. Marshall's work with VITD and the MP?? Hasn't he been working with the FDA about this and has some of the meds aproved for the MP??

Last edited on Tue Feb 5th, 2008 09:41 by shandym

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Maybe because the FDA staff who are responsible for making decisions about supplements at FDA/CFSAN were educated before anybody thought to explain to them the importance of genes and VDR and that sort of stuff?:):)
 

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Dr Marshall,

You said: “It is not an evolutionary improvement in knowledge; it is truly a break away from commonly accepted pragma.”

Yes, IMHO, it can be called a paradigm shift, the transition from evidence based medicine (epidemiology studies) to science based (molecular models).

As you know, when a paradigm shift occurs the learning curve indexes back to the zero – zero origin of the curve. 

The new generation of Molecular Biologists will need to step in to replace the clinical dogma of evidence based medicine. 

Gene

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A revolution instead of evolution perhaps?
 
Shandy:
I don’t think it is just a problem with the FDA folks lacking an education in molecular biology. 
Psychologists have long recognized that humans suffer ‘cognitive dissonance’ when presented with facts that do not agree with something they ‘know’ to be true.  This site http://www.learningandteaching.info/learning/dissonance.htm   defines it as follows:

 “Cognitive dissonance is a psychological phenomenon which refers to the discomfort felt at a discrepancy between what you already know or believe, and new information or interpretation. It therefore occurs when there is a need to accommodate new ideas, and it may be necessary for it to develop so that we become "open" to them.”

They also point out “if learning something has been difficult, uncomfortable, or even humiliating enough, people are less likely to concede that the content of what has been learned is useless, pointless or valueless. To do so would be to admit that one has been "had", or "conned".

An example of this occurred when Thomas Watson (a medical professor) originally suggested that doctors themselves were causing the spread of fatal fevers among women during childbirth by failing to wash their hands between patients.  In 1842 there was no understanding of bacteria and viruses, and therefore no good explanation of how this would happen.  Doctors did not rush to congratulate Watson for his new idea that would help them save lives.  They generally refused to believe him, refused to wash their hands and probably desperately hoped Watson would be proved wrong (oh, and killed quite a few more women…).  One prominent obstetrician stated "Doctors are gentlemen, and gentlemen's hands are clean.”  

It is very hard for people who believe themselves to be good people (and that includes just about everybody) to accept that they have harmed others, even unintentionally, through their actions. 

This is one reason why the BioEssays publication is an important one – people can now try as hard as they like to disprove the science behind the MP.  If they fail to do so, they will actually substantiate the MP and the revolution will begin.  You can bet the FDA won’t take too long to jump on board then…. 

Ruth

 
 

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Trevor,

Does it make any sense to start sending this paper to our congressmen and other 'powers that be' to be sure they're aware of the issue?

Jillian

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Jillian,
Yes, it makes a lot of sense to send it to anybody who might be involved in Public Health. The voices who are pushing this country towards the abyss are overwhelming, and we need to let folk know that Vitamin D is turning out to be like smoking all over again, except that, IMO, it will do much more damage to the health and psyche of this nation than that mistake ever did...

The supporters of Vitamin D do not understand the science, and they do not want to understand. They want to believe the epidemiological studies which only looked as a small part of the puzzle, and only found a small treatment effect. High doses (2000 IU+) make them feel so good that they believe, without question, Vit D must be a magic bullet. The inertia behind Vit D supplementation is based on hope and belief, not on science.
 


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Thank you Trevor, that answer sounds like a good starting point for my letters...:D Would it be okay to quote that reasoning, and the Feb. 5th post in total 'Simple Explanation of Vitamin D Metabolism' here:
http://www.marshallprotocol.com/forum2/364.html 
'cuz I think that may help summarize for people new to the concept what the paper is about? If yes to the Simple Explanation, would it be appropriate to put you as the author?

Jillian

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I tried to contact Reuters, see what happens.

I also contacted our Dutch National association of scientific writers/journalists, do you guys have something similar? A freelancer might be interested/tempted to write about this.

Sincerely, Frans

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I spoke with my local Congresswoman's office, and will send them copies of many letters I've already sent to the NIH, FDA.

She asked me to repeat what we want, and I will say something like "read these mainstream articles on the dangers of Vitamin D supplementation" and "authorize Benicar for treatment of Sarcoidosis". 

RIP Morris, Gary and Alan.

Sherry

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Sherry,
Focus on asking just for FDA/Office of Orphan Products Development  (contact OOPD Director Timothy R. Coté DHHS/FDA/OC/OSHC/OOPD via Congressional Affairs Specialist Jeremiah J. Kelly DHHS/FDA/OC/OL) to explain precisely why they have delayed the application from the Autoimmunity Research Foundation for Designation of Olmesartan in the Treatment of Sarcoidosis for 28 months, without supplying a single substantive safety or efficacy objection. Our OOPD designation request number is 05-2131

Everyone all up the FDA chain, to Commissioner von Eschenbach himself, is aware of this problem, but nobody has the guts to face down the pulmonologists, who are desperate to keep slowing down the pace of change.
 
The Vitamin D issue will disappear once Docs start feeling comfortable with the MP.

..Trevor..
 
 

Last edited on Wed Feb 6th, 2008 11:51 by Prof Trevor Marshall

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I was trying to find a good place to post this and I thought this was the best place. :cool:

Oprah aired a show yesterday with Dr Oz and they are recommending Vit D to her and her staff because of "deficiency."  Apparently, Oprah and her staff were tested, according to someone that watched the show (I missed it) and 60% of her staff along with Oprah tested "deficient" and were told to take Vit D. 

When I pulled up a link for the show, I got a pic of a bottle of Vit D, HERE

You can contact Dr Oz for comments.  I just did... HERE

I think if enough of us send in comments, we may get heard and maybe even aired on a show.  I think it's worth a try and we have strength in numbers. 

PS Oprah had Bernie Mac on the show awhile back for an interview after a severe and frightening episode and diagnosis of sarcoidosis. 

Celebrities suffering from Sarcoidosis 

BTW, on Oprah's show today, she said she reads the message boards daily!  :cool:

Last edited on Wed Feb 6th, 2008 16:09 by Reenie

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I just sent my "two cents worth" into the Oprah/ Dr. Oz message board. Thank you Reenie, for the links. I think you're right.....I've given up on the government or any of its agencies.....I believe the press is where to go for attention.....we just have to get their attention.

Maybe by playing the underdog in the battle and pointing that there's no "money to be made" on our side of battle could raise the ire.

It's so frustrating watching history in the making being so ignored when access to information is supposed to be so FREE.

Onward Marshall soldiers!!!

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There has to be something we can organize as group to get the attention and answers from the FDA.

Jeannine

Last edited on Thu Feb 7th, 2008 03:34 by Bella

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When the paper was published, I sent a show idea to Oprah quoting an easy to understand piece from TM's paper and gave his contact information.  Obviously, they ignored that and went ahead with the D deficiency piece.  I will contact them again and tell them that they are missing out on the greatest discovery of our age.  Claire

Here's the link to offering show ideas:  http://www.oprah.com/email/reach/email_showideas.jhtml

I think it might be helpful to say that this is such an exciting, breaking medical story that it could easily take up an whole hour with TM, a moderator, and some people who have gotten well and understand the process.  Also, no doubt TM could show how the model can possibly explain much of the correlative studies that leave researchers either scratching their heads or make tenuous correlations or have reporters making tenuous correlations (that then everyone tends to believe). 

Last edited on Thu Feb 7th, 2008 08:42 by eClaire

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eClaire,

Maybe we have to send them some video links so they can see Trevor in action!  Like maybe when Trevor is talking to the FDA.  I believe there are some links on YouTube.com? 

He's very charismatic, IMO, and I think folks would really enjoy his Aussie accent.  Heck, if it works, let's use it to pique some interest in a show!  :cool:

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I have sent a letter to my local Congresswoman. 

Soldiering on...

Sherry

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I, too, have sent my own thoughts to the Oprah/Oz show.

Two years ago I sent a letter to Laura Hillenbrand of Sea Biscuit fame via her publisher. No reply was expected or received, but I wanted her to at least know of the MP.

I have a fantasy about her currently being on the Protocol but having to maintain anonimity. If a famous person got well, we'd have the kind of publicity that everyone loves.

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Hi Sharon,

Would you be so kind as to post Laura Hillenbrandt's contact info?  She is another very sick ME/CFS person that could use the MP so badly for herself. 

For those not knowing who Laura is, she wrote the novel Seabiscuit almost exclusively from her bed and flat on her back.  This lady was barely able to make it to the premier showing once it was made into a movie. 

There are many other celebrity folks that have these illnesses, much like our own family and friends.  Montel Williams often discusses MS and I believe he has a foundation set up for it.  Cher had done and article in a magazine years ago how she also had CFS. 

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Reenie.............I don't seem to have a copy of the letter, but I know I found that the book was published by Random House and addressed the letter to:

  • Laura Hillenbrand
  • c/o Random House, Inc
  • 1745 Broadway
  • New York, NY 10019
The phone number for Random House is 212-782-9000, and maybe it would be a good idea to call for specific information before trying to contact her again. Have at it one and all.       ............Sharon

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Sherry Asked

"Does it make any sense to start sending this paper to our congressmen?"

May I recommend that everyone cut quickly to their congressional aide in charge of medical issues. 

Find the number of your congress rep and call, then ask for the aide. Keep it short, polite but to the point. Ask if you can email them the pdfs so they don't have to wait for hardcopy mail (anthrax scare changed how hardcopy mail is delivered to your rep).

Tell them you will call back to see what has been done about your information, and that you expect action on this issue as lives are being lost every day there is a stall.

...........

Per Oprah today I left this message, I hope she gets a chance to read it:

Re: Dr. Oz Reveals the Ultimate Checklist For Great Aging Feb 8, 2008 7:07 PM

Please pay attention to the molecular genomics of this century to unravel the truth about what is really going on with the innate immune system and the diseases of aging. In silico mathematical science (like keying in 2+2 to get 4, it comes out the same every time--only with massive computing power required for this equation) is not going to tell us anything except that the molecular receptor responsible for the human immune system responds to a very complex lock and key feedback mechanism with the steroid D's at the heart of turning it on and off.

Yes, the steroid called vitamin D is not just a little important, it is a LOT important, but throwing "vitamin" fortifications and supplements in the form of ingested D in willey-nilley as recommended by OZ actually foils the mechanism and sets up a perfect environment for pathogens to proliferate in the form of diseases that plague mankind. That means the simplistic "vitamin in = goodness out" drivel needs to stop, especially from TV clinicians that base their recommendations on anything but molecular genomics.

Please invite a real expert on what is going on with the VDR, learn about the TWO very important D metabolites tests need to be measured and why one of them is so fragile it must be handled precisely or the results will be flawed. Learn what lab has a proven track record for better success and why it isn't the one your insurance is going to pay for without your insistence, and what that means for your checkbook--and more important, your life.

Learn why animal studies can never get it right, not even with apes. Learn why animal models continue to divert your tax dollars to studies away from the real solution. Learn why Dr Oz and other medical practitioners have no clue yet about the bench to bedside transition that even the FDA director Dr Von Eschenbach told the 2006 NORD conference would change the world of medicine.

When you explore these issues, you will also learn why people with previously incurable diseases are walking away from wheelchairs and putting away their respirators and getting their life back. It all has to do with the genomic science of this century that outstrips the accuracy of opinion-swayed "emperical" studies we all risk our lives with at this time.

If you really want to tell people the truth and have the courage to do so, then you will not ignore this starting point any longer:


1. Marshall TG. Vitamin D discovery outpaces FDA decision
making. Bioessays. 2008 Jan 15;30(2):173-182 Epub ahead of print Online ISSN: 1521-1878 Print ISSN: 0265-9247 PMID: 18200565
Available from publisher's website at URL
http://www3.interscience.wiley.com/cgi-bin/abstract/117885976/ABSTRACT
Available from PubMed at URL
http://www.ncbi.nlm.nih.gov/pubmed/18200565

A pre-print full text copy at URL
http://TrevorMarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf

2. American Academy of Dermatology fact sheet: "Myths and
Realities of Vitamin D and Sun Exposure," at URL http://www.aad.org/media/background/news/skincancer_2004_05_03_myths.html


3. "Rickets .. is not due to vitamin D deficiency but is
caused by not having enough calcium in the diet." U.S. Dept of Agriculture,
Agricultural Research Service, Available from URL http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=169216

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"Cher had done and article in a magazine years ago how she also had CFS."

Hi Reenie,

I just watched an interview with Cher on Entertainment Tonight. The interviewer mentioned her debilitating illness, except he said she had EBV and never mentioned CFS. :? 

Other celebrities who have Chronic Fatigue Syndrome are legendary film director Blake Edwards; musicians Randy Newman, Keith Jarrett and Dennis DeYoung; actors Morgan Fairchild, James Garner, Alana Stewart and Kathy Crosby; and philsopher Ken Wilbur. And of course, author Laura Hillenbrand and soccer player, Michelle Akers. 

Last edited on Fri Feb 8th, 2008 19:07 by Plateletgal

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Great communicating, Janet. Thanks from all of us.        .........Sharon

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One of the producer/distributors in this area of "organic" milk supplemented with Vit A & D is Garelick Farms in Massachusettes (owned by Deans Food). According to their rep, they add commercially prepared D3 (contains lanolin) because "the FDA requires us". If that is the case, does anyone know off hand how distributors who do not add D3 can avoid supplementation? 

Last edited on Mon Feb 11th, 2008 11:08 by JCB

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The FDA does not require the addition of Vitamin D, it regulates its use.

In other words, if a manufacturer wishes to add Vitamin D to their milk, then they have to do it according to the FDA rules. But they can also choose to not add Vitamin D, and several manufacturers do have product lines fortified only with Vitamin A, or with nothing at all.

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The Homestead Creamery of Virginia says they are required to add A to anything that is not cream, half and half, and whole milk.  However, they add less than 6% A.  I think a company that says they have to add D just doesn't want to deal with the concerns of the public.  I don't know how far they distribute; we have difficulty getting it here.

TM, haven't you said before that if all you are using milk for is to splash a little in your tea (say no more than once a day), then the small amount of D you'd get from regular milk probably isn't going to do any harm?  If that's not okay, then I need to know.

Thanks, Claire

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 I have found the answer to avoiding the D in milk by drinking Almond milk  and watering down Goats milk. My husband hates it but it is acquired taste. Another tip for enjoying eggs white only omelettes etc is to add some tobasco sauce to give it some zip!!

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I called my local Congresswoman and spoke with her aide, and used some of Janet's follow up questions.

My strategy in dealing with these people is, first of all, be very friendly.  They are aspiring politicians or just fascinated with politics (aren't we all now?), and warming them up with appreciation, Thanking them in advance, etc. helps.  I also laughing admitted I never tool Molecular Biology in college or graduate school.  Humility helps, in my opion, to make them know you're an approachable human. 

Then I used Janet's follow up words and sentences; she promised me they would try to follow up.  I emphasized the quality of the editorial board for BioEssays, that it represented institutions from around the world.  In addition to our own NIH, etc.  And those people saw fit to publish this article.  The aide got the idea...

Carry onward...

Sherry

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Claire,
If the milk is not fortified then the small amount of Vitamin D from it will not be significant, especially if you only use it in tea, and coffee. Half and Half is OK, too, as it is usually not fortified (check the box). It has more fat, but you need less of it  (in coffee, anyway).

My hot chocolate mix uses a little non-fortified milk powder. Since AmericanSpice.com seems to have gone out of business, I have recently been getting this powder
http://www.frontiercoop.com/prdDisp.php?I=2852&br=&full=y

Amazon.com no longer lists it, and the price has gone up a little. Nevertheless it is good, and the only milk powder I can find which is not fortified :)

ps: I empty the foil bag into a huge plastic food-container, to make it easier to handle.
 

maggie weeks
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 Do  you know if they ship to Canada.?

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No idea, sorry:X

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Organic Valley has powder milk with no Vit D, buttermilk powder too. I also just found this product.

Self Stable milk with no vit D. Their pasture butter looks like it could be ok too.

http://www.organicvalley.coop/products/milk-and-cream/shelf-stable-milks/product/shelf-stable-whole-milk-1-litre/

Last edited on Mon Feb 11th, 2008 14:38 by Bella

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Organic Valley also has regular pasteurized milk with no Vit. D. They also have regular milk with Vit. D so one has to be sure to read the label. Publix in Fla. carries it.

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 I phoned them and they do not ship to Canada. They called me right back very impressive you lucky southern neighbours.I felt like a change from goats and almond milk, of course I can always have our half and half watered down too!!

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I once tried diluting cream (not totally sure, but I think if it was half-and-half) at a ratio roughly 4 parts water to 1 part cream and it was not far from taste of milk...if you want to have it in cereal, for example. Then again, my sense of taste and smell aren't very good - yet! I drink goat's milk without D in it.

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I've been consuming half & half in moderate amounts with no problems.  D levels have been good, well under 10 for 18 months or so.  1:1 with water is a good substitute for whole milk in cooking.

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In CT, among distributors of so-called "organic" milk, I have found 2 distributors of non-D3 supplemented milk-

Organic Valley (Wisconsin)

Wakefern Food Corp (NY)

and the local Stop and Shop manager has promised me he will look into carrying one of these brands and get back to me about it. We shall see. As I mentioned Garelick Farms does not have a non-supplemented product, and stated to me when asked if they could supply an unadulterated "organic" milk, that "Garelick does not care about consumers".   

 

 

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Reenie,

I saw this Oprah show as well. I just posted on the link you provided to Dr. Oz/Oprah. Hope he investigates into the MP.

Martha

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Great!  All we can do is mark time while getting well and do what we can.  And as Kathleen says, no giving up! 

Eventually, someone will listen in the media.  :cool:

As for the half n half, I gave it up long ago for pure heavy cream in my morning coffee.  It tastes MUCH better IMO, but maybe not for cereal. 

Last edited on Mon Feb 11th, 2008 18:35 by Reenie

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I just spoke with the aide to my local Congresswoman, and she assured me my letter has been received. And...my Congresswoman is writing the FDA regarding the designation of Benicar for Sarcoidosis.

When I receive a copy of this letter to the FDA, I will let you know. 

Really not much progress, but I soldier on.

Sherry

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If you are interested in the conflicts of interest swirling around the Vit D advocates, then you will enjoy reading this article from the Canadian Broadcasting Commission:

"The Vitamin D Debate"
http://www.cbc.ca/news/viewpoint/vp_strauss/20080213.html
 

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Ah, so that's why they want us all to ingest more Vitamin D. Now it all adds up! $$$$$
I'm glad to see that we, the population, are served by such well-meaning scientists.

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Oh man, if it weren't such an important issue, I would be rolling on the floor laughing my tushy off...

It surely gives those of us trying to get through to people some ammunition.

Our beloved Vieth's wife made 30.000 times 20 dollars, equalling 600.000 dollars from this paper in two days, but he still says he has no conflicting interests...

Wow, did I make the wrong career choice...

Frans

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Great article! Thanks for sharing it!

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Dr. Marshall,

Just found this article online...don't know if you have seen it or not but it talks about Vit D causing several bladder conditions. Just thought you might be interested in it.

http://jcem.endojournals.org/cgi/content/full/90/2/962

Joe

inge
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I haven't checked things thoroughly, but to me it seems that during the winter months there is no vitamin D production at all in individuals living in countries situated at latitudes far from the equator (PMID: 2839537). Knowing that the skin has the ability to produce vitamin D it seems that it has this ability for a reason. I get the impression from the MP site that you really can't get vitamin D so low that you will experience adverse health effects. But why does the skin then only have the abiltity to produce vitamin d (as it appears from the study I linked to) from sunlight? Is anyone aware of findings showing that a minimum of vitamin D can be produced without sunlight? After all, a minimum of vitamin D production appears to be necessary for optimal health, knowing how many genes are transcribed by the VDR.

Last edited on Tue Jul 22nd, 2008 02:14 by inge

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inge,

Have you considered the possibility that the purpose of the skin producing vitamin D in the presence of sunlight is to activate the innate immune system to repair the damage to the skin caused by sunlight?

kenc

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Inge, that study is based on a model which was absolutely incorrect. Their early in-vitro work was not thorough, yet a generation of researchers did not question it.

The model was based on an in-vitro experiment which showed that skin keratinocytes expressed Vitamin D when exposed to high intensity UV light of a few key wavelengths. Recently, another study found that monocytes and other cell lines also generated D metabolites when exposed to UV radiation. So what is the reason for that? Those cells, unlike keratinocytes, are never exposed to such radiation. It is now clear that an incorrect and insufficient conclusion was drawn from the initial Vit D stidies of UV on keratinocytes.

Every pragma about sunlight on the skin producing Vitamin D or 25-D is probably incorrect, IMO, as there was a study a few years ago which showed that, especially in the presence of the inflammatory cytokine TNF-alpha, the keratinocytes produced 1,25-D directly, and did not stop at 25-D. This is what the model in my recent paper suggests.
http://www.ncbi.nlm.nih.gov/pubmed/15225839

The human body, just like the bodies of the nocturnal mice and rats in which we test all our medicines :):) does not need to be exposed to sunlight in order for its D metabolism to function correctly, and deliver activated 1,25-D to its VDR to enable transcription. Full stop. Holick, Vieth, and the others, were just incorrect.

You might like to read these recent articles by Stephen Strauss of the CBC. The first deals directly with misreading epidemiological studies so that they prove what you expect them to prove:
http://www.cbc.ca/technology/story/2008/07/07/strauss-vitamind.html
and
http://www.cbc.ca/news/viewpoint/vp_strauss/20080213.html

Vitamin D is not a nutrient. A nutrient would have a first-order mass-action model for its metabolism. AFAIK, only Cannell has been reckless enough to claim that it does. Figure 1 of my Bioessay makes it quite clear that we are dealing at least with a 6th order metabolism, probably even higher.
 

Last edited on Tue Jul 22nd, 2008 04:54 by Prof Trevor Marshall

inge
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Dr Trevor Marshall wrote: The model was based on an in-vitro experiment which showed that skin keratinocytes expressed Vitamin D when exposed to high intensity UV light of a few key wavelengths. Recently, another study found that monocytes and other cell lines also generated D metabolites when exposed to UV radiation. So what is the reason for that? Those cells, unlike keratinocytes, are never exposed to such radiation. It is now clear that an incorrect and insufficient conclusion was drawn from the initial Vit D stidies of UV on keratinocytes.



I hope that you can clarify the above a bit:

- why does it matter that monocytes and other cell lines also generated D metabolites? There are no enzymes needed for the 7-DHC to previtamin D conversion are there? So as long as 7-DHC is present in these cells, when they are exposed to radiation vitamin d will be generated (however unnatural radiation may be for them).

- From the abstract of the study you mentioned (http://www.ncbi.nlm.nih.gov/pubmed/15225839) it does not seem that TNF-alpha singlehandedly induced production of vitamin D metabolites (i.e. all cells were exposed to radiation as well) , or does the full text reveal other findings?)

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Inge,
There is a pathway from 7-dehydrocholesterol to pre-vitamin-D which does not involve radiation, but which involves enzymatic, or some other energy (eg body heat) to cleave the benzene ring. It is likely that the reason macrophages and other cell lines react to UVB is that the UVB synthesis is incidental to the normal and usual way that pre-Vitamin-D is synthesised (eg enzymatic).

Other mammalian species, even invertebrates such as the Lamprey, have an active VDR metabolism in the absence of UVB radiation. You need to be thinking of the corollary, the alternate hypothesis, and not the pragma that you have been taught in medical school. That pragma doesn't fit the data:) If high intensity UVB was absolutely necessary for the Vitamin-D metabolism to function, then your countrymen would be sick and weakly by comparison with those in Africa:)

The importance of the TNF-alpha study was to demonstrate that 25-D is not necessarily the result of irradiation of keratinocytes, that the cells are acting under other influences as well, going straight to 1,25-D metabolite.  Again, this is in violation of the pragma in your textbooks:) We are dealing with the complex, multi-factorial feedback metabolism of my Figure 1, not the simple reactions we would expect from a nutrient.
 
 

didierchretien
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Hi,

A recent Belgian epidemiological study on Low-level 21-month microwave exposure on rats shows that there is an increased mortality of the exposed rats with respect to non-exposed rats. They also noticed a loss of some cognitive functions after a few monthes of exposure.

It may due to a weakening of the immune system, favouring the genesis of decay processes wich may result in life-threatening disorders including cardiovascular and pulmonary diseases, cancer or premature aging.

http://home.scarlet.be/~tsf94646/001/documents/Thesis%20Dirk%20Adang%20-%20Synthese.pdf

This would be a good opportunity for our CWD bacteria...

Didier

Prof Trevor Marshall
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Didier,
The answer almost certainly lies in the VDR / Vitamin D axis )that they didn't even bother to measure). Note that in my Figure 1 I note that 7-dehydrocholesterol is changed to Vitamin D by the addition of ENERGY (I have UVB only as an example). There is also strong evidence for enzymatic catalysis.

Monocytes differentiate from hematopoetic stem cells, at least in part based on 1,25-D levels. This study found monocytes to be the most profoundly affected cell type.

I once took a quick look at the Atomic Radiation poisoning after Chernobyl, and certainly the chronic deaths of children there look awfully like an upset innate immune system. What the effect of any Th1 pathogens might be is not clear, as these folk seem to succumb to acute disease pretty readily, probably before the chronic pathogens become a significant factor.
 

Pat McKinzie
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Dear Dr Marshall,
My wife Pat started pn the MP 4 month ago, after years of sickness and declining helth, despite all efforts by her physicians. The protocoll, as harsh as it is to follow, is the first treatment which gave her hope for recovery and I am immensely gratefull to you for that.
She is doing very well in my opinion (she is almost ready for phase 3) but I do have a big concern with the low vitamin D level which are required.
I am not, by far, a medical expert, but have found many publications stating that low level of vitamin D lead to a cerain death, especially by elevating the heart failure's risks.
As far as I have understood the MP, the low vitamin D level is required to prevent the system from producing 25D & 1.25 D.
How long does this process generally last ? Is there a time when it is possible to go back to "normal" vitamin D levels ?
I would be gratefull if you could give me some hints on this topic, as I did not want to discuss it with her without knowing enough, in order to not stress her even more than she  already is.
Many thanks.
Gérald lechault
(Switzerland)

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Gérald,
Next month I will be co-Chairman of a special session on "VDR, Vitamin D, and Autoimmune Disease" at the 6th International Congress on Autoimmunity. I, and my colleagues, will be presenting our data and science to that august gathering of expert researchers:
http://www.marshallprotocol.com/forum39/12376.html

Last year I published a paper which explained why the addition of Vitamin D to the food chain is responsible for the current epidemics of chronic disease. I opined that the mistake of calling Vitamin D a nutrient, which it is most certainly not, will go down in history as the biggest mistake Medicine has ever made:
http://TrevorMarshall.com/BioEssays-Feb08-Marshall-Preprint.pdf

Vitamin D is not a nutrient. The reason that people are recovering their lives on the MP is because it is based on 21st century science, and not on 20th century mistakes:) Vitamin D is a seco-steroid transcriptional activator, the body produces all that it needs.

Anyway, there is a lot of detailed material here, and at the other sites on this topic. I trust it will set your mind at ease. For example:
http://mp-lifestyles.org/forum1/46.html
 

Pat McKinzie
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Dear Dr Marschall,

Many, many thanks for such a prompt reply.
I will read through this material and, hopefully, understand it. Ha !

Gérald

eClaire
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Gerald,

You might also want to read (an easier read) Amy's "The Truth About Vitamin D: Fourteen Reasons Why Misunderstanding Endures." 

http://bacteriality.com/2007/09/15/vitamind/

Claire

inge
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How can massive amounts of vitamin D supplementation lead to hypercalcemia if all other vitamin D forms than vitamin D 1,25 inactivate the VDR?  

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Inge,
Pse look at my Bioessay figure 1.

Note that the VDR transcribes the Calcium Sensing Receptor, CASR. The function of CASR is to regulate the levels of calcium:
http://en.wikipedia.org/wiki/Calcium-sensing_receptor

So, if you knock out the VDR you take away the ability of the CASR to regulate calcium, as you reduce the expression of CASR.

Of course, the complete detail is a lot more complex than this, as there are many other pathways involved in the regulation of such a critical body function as calcium homeostasis.
 

Russ
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I have often wondered why for millions of years primitive man ate no dairy foods and yet did not suffer from calcium deficiency and yet today people risk deficiency if they do not keep calcium intake at the 1000-1500mg RDA which is surely much more calcium than primitive man got on his hunter-gatherer diet.  Is this the answer, that widespread TH1 disease which has shut down VDR function has messed up calcium homeostasis? 

Some of the advocates of a "paleolithic" diet claim that it was the addition of grains and the move to a high carb diet that has caused the need for more calcium and they claim that on a paleo-diet, which forbids dairy foods, one does not need to supplement calcium because the need for it drops.  Since my understanding is that too much calcium can be as bad as too little, I've wondered how much calcium one should aim for if they are eating paleo/low-carb and I guess if one is taking a VDR agonist as we are that might factor in to the amount needed as well.

Knochen
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yet today people risk deficiency if they do not keep calcium intake at the 1000-1500mg RDA which is surely much more calcium than primitive man got on his hunter-gatherer diet.
A real hunter/gatherer ate a lot of small beasties whole, bones and all, just like other animals.  Lots of calcium there!  Same for small birds eggs. Our forebears were not so fastidious as we! :cool:

Russ
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Yeah, I've heard that explanation before, though more in terms of just that they gnawed on bones rather than completely ate them.  So yeah, if that's true, I guess they would have gotten a lot more calcium than I was thinking.

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Calcium is found in leafy vegetables and seeds.
 

JudyBeauty
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I bet primitive man ate lots of insects which contain calcium.  There are many cultures today that still eat insects and seem to enjoy them.

wytnez
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Take a look at this from the Parade Magazine from yesterday.

Vitamin D & Heart Disease

A report published in Archives of Internal Medicine suggests that a vitamin D deficiency can worsen heart disease.  Researchers looked at levels of the vitamin among more than 3000 Austrians who were in the hospital for heart procedures.  Seven years later, those who'd that the lowest vitamin D levels were most likely to have died in the interim.  Another study, in the Journal of Cardiovascular Pharmacology, reports that vitamin D seems to help ward off heart failure-at least in rats.

"The sunshine vitamin" - technically is not a vitamin but a steroid hormone-gets activated when skin is exposed to sunlight.  As little as 10 minutes of exposure daily may be enough to prevent low levels, also linked to broken bones, high blood pressure, cancer, and immune-system problems.

My purpose in sharing this is that I am surprised to finally see somewhere written that vitamin D is a steroid hormone besides from Dr. Marshalls papers.  Looks like they may be trying to catch up.  ;)

All the more reason for those who have chronic diseases to stay out of the sun so that the immune system is not suppressed.

Saj

 

Saj

inge
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In Marshall's Bioessays paper vitamin Ds are metioned as putative PXR-antagonists. While this may not be well documented, is there any doubt at all that 25-vit D and 1,25-vit D will affect CYP27A1, irrespective of the mechanism?  To me it seems that this is well documented, but this is perhaps solely based on animal studies?

One more thing: Why is there a question mark between the two PXR bubbles in Figure 1?

Inge  

Prof Trevor Marshall
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There is now no doubt that the Vitamins D are PXR antagonists. I had correspondence with a wet-biology group who had tested Vitamin D as a PXR agonist, and it failed, so now we know the pathway - antagonism, which is the only one which makes sense, in any case.

The green question mark indicates that we really don't know what ligand activates PXR to transcribe CYP27A1, CYP24 or CYP3A4.
 
 

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Trevor,

I was wondeering if you are keeping the model from the BioEssays paper up to date? Changing colors when pathways are confirmed and perhaps adding pathways ?

I just ran into this paper, that seems to add to the model downregulation of hydroxylation via cyp2R1 and perhaps more, but you be the judge, it is hard to judge from an abstract, but seems promising:

Regulation of human vitamin D(3) 25-hydroxylases in dermal fibroblasts and prostate cancer LNCaP cells.
Ellfolk M, Norlin M, Gyllensten K, Wikvall K.
Department of Pharmaceutical Biosciences, University of Uppsala, Sweden.

In this study, we examined whether 1alpha,25-dihydroxyvitamin D(3) (calcitriol), phenobarbital, and the antiretroviral drug efavirenz, drugs used by patient groups with high incidence of low bone mineral density, could affect the 25-hydroxylase activity or expression of human 25-hydroxylases in dermal fibroblasts and prostate cancer LNCaP cells.

Fibroblasts express the 25-hydroxylating enzymes CYP2R1 and CYP27A1.

LNCaP cells were found to express two potential vitamin D 25-hydroxylases-CYP2R1 and CYP2J2.

The presence in different cells of nuclear receptors vitamin D receptor (VDR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) was also determined.

Phenobarbital suppressed the expression of CYP2R1 in fibroblasts and CYP2J2 in LNCaP cells.

Efavirenz suppressed the expression of CYP2R1 in fibroblasts but not in LNCaP cells.

CYP2J2 was slightly suppressed by efavirenz, whereas CYP27A1 was not affected by any of the two drugs.

Calcitriol suppressed the expression of CYP2R1 in both fibroblasts and LNCaP cells but had no clear effect on the expression of either CYP2J2 or CYP27A1.

The vitamin D(3) 25-hydroxylase activity in fibroblasts was suppressed by both calcitriol and efavirenz.

In LNCaP cells, consumption of substrate (1alpha-hydroxyvitamin D(3)) was used as indicator of metabolism because no 1alpha,25-dihydroxyvitamin D(3) product could be determined. The amount of 1alpha-hydroxyvitamin D(3) remaining in cells treated with calcitriol was significantly increased.

Taken together, 25-hydroxylation of vitamin D(3) was suppressed by calcitriol and drugs.

The present study provides new information indicating that 25-hydroxylation of vitamin D(3) may be regulated. In addition, the current results may offer a possible explanation for the impaired bone health after treatment with certain drugs.

PMID: 19286836 [PubMed - indexed for MEDLINE


This paper seems to confirm that hydroxylation of D3 is indeed downregulated by the VDR.

It seems that in the tissues, 25-Hydroxylation of D3 is done by different cyps, which is no surprise.

I am not sure what 1alpha-hydroxyvitamin D(3) is. It seems to me, this is just the D3 we know and 'love' ... ?

Frans

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Frans,
I have not had to update the Figure 1, although I have been keeping an eye on it. I decided to omit CYP2R1, along with several other enzymes, because I was not happy with evidence for their equivalence to the primary enzymes.

The change in knowledge about the PXR over the last 18 months has had a huge impact on Figure 1. But the same in-vitro study which said PXR was activated by minocycline (a key piece of the scientific puzzle) also said Clindamycin did the same thing, something that I was unable to verify and which makes little sense based on our clinical observations.

Wet biology is an imprecise art, and as more and more orphan nuclear receptors are discovered, I suspect they will factor into the metabolism more than we can possibly imagine. So I am more interested in the overview, rather than enzyme substitution, at this point in time.
 



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