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The Karolinska Conference was a success
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Prof Trevor Marshall
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 Posted: Fri May 26th, 2006 15:46

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Well, it is early Saturday morning here in Stockholm, and the DMM2006 conference at the Karolinska Institut is winding down into its final sessions. A half day today, and I suspect many of the International participants will be leaving early, flying home for the weekend. I am staying until tomorrow, to make sure I get the chance to talk with everybody I can.

With the help of several MP members we managed to get our key messages condensed down to just a few words on a 30 inch x 40inch poster board. There are copies of that poster available for download from URL
http://autoimmunityResearch.org/karolinska.jpg

The actual text has been re-arranged into a more easily printed form at
http://autoimmunityResearch.org/karolinska-handout.pdf

Please print them out, discuss the core points, and make sure your physicians and friends get to understand the message that we presented to the experts gathered here.

This conference is the sixth in the series “Days of Molecular Medicine” with the theme “Inflammation in Chronic Disease.” There are about 300 scientists here, with another 150 graduates, interns, and students from this most excellent University and Hospital complex. The ‘locals’ are watching the proceedings on a video link in an adjacent conference room, as the main lecture hall is full.

The conference is being held in the same lecture hall where Nobel Laureates deliver their orations after the yearly prize has been announced. It is quite an experience to realize how influential this one location has become to the advance of medical knowledge.

The keynote was delivered by 1997 Nobel Laureate, Prof Rolf Zinkernagel, from the University Hospital of Zurich. Rolf must have been reading our presentation right before his lecture, as he told the delegates that signs that ‘autoimmune’ inflammation was linked to bacteria were becoming unmistakable, and that maybe 30% of diseases could be linked to “intra-cytoplasmic” infection. Further, he emphasized that ‘immuno-pathology’ (what we call herx) was the key to attainable recovery rate. I was just sitting there dumbfounded, while most of this went straight over the heads of those seated around me:):) Still, now that the conference has wound down, I am starting to get some really good questions and comments. The bacterial pathogenesis will become accepted sooner, rather than later, IMO.

I hate to tinge this optimistic scientific note with reality, but there was also a presentation about Sarcoidosis from a Pulmonologist-led study group. I took photos of their poster, and will make it available for discussion when I get a few spare moments (probably Monday). In summary, however, it was striking that the first few lines of both posters emphasized TLR2 and TLR4 as key to Sarcoid inflammation, with the primary difference being that our poster explained that they were transcribed by VDR, with the pulmonologists still content to merely observe their presence. I was told that they need to be thorough and methodical’ as they move forward. Which I guess explains why there is this constant pressure upon us to slow down the rate of change.. gotta be more ‘thorough’ –LOL

Anyway, I have to get some more sleep and prepare for the morning sessions. Take a look at the material, try and understand why we are focusing the emphasis on ‘VDR Competence’ and away from “which species of bacteria is it?” (still the most common question I get) and help people focus on plasmids, with horizontal transfer of DNA between multiple species accumulated during a lifetime.

Indeed, it was Rolf's opening lecture that had emphasized these same polymicrobial concepts, and sent me scurrying for the library to incorporate some of his excellent references into my upcoming presentation(s) for LAX:X

John McDonald
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 Posted: Fri May 26th, 2006 21:09

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Trevor, it sounds like a brilliant conference and a breakthrough for you (and us). 

I really want to understand this science but I am having trouble with bits of it.  In the spirit of discussing the core points:

From the Karolinska handout:

During Th1 immune challenge, the VDR is activated by the endogenous secosteroid 1,25 dihydroxyvitaminD.'Vitamin D' is actually a seco-steroid, disables VDR, and strongly supresses Th1 innate immunity.
...25-D (which is commonly tested in clinical trials), 24,25-D; 25,26-D; and even cholecalciferol itself will displace the activating metabolite 1,25-D from the VDR, thus inactivating innate immunity.
The 1st quote seems to say or might say that an activated VDR is bad.  2nd quote seems to say that an inactivated VDR is bad.  Third quote seems to say that docked 1,25D is good.  In fact the 3rd quote might argue for having lots of 1,25D in the body.  Maybe I need to stick to physical science because I find this to be terribly confusing.

  1. Does an activated VDR fight bacteria or suppress the fight?
  2. Do we actually want 1,25-D docked to the VDR?  If so, wouldn't we like to have more of it rather than less of it?
  3. I believe the 2nd quote above argues for staying out of sunlight (cholicalciferol) and avoiding dietary D.  That seems familiar and reassuring.
  4. I believe that the 3rd quote above would argue that having high measured levels of 1,25-D is a good thing.
  5. What exactly does Olmesartin do to the VDR?  I can't quite make it out, but I get the idea that it stablizes the 1,25-D that is docked to the VDR and prevents the other 'D's from dislodging it.
Help!

Last edited on Fri May 26th, 2006 21:17 by John McDonald



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Morris W. Milnes
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 Posted: Fri May 26th, 2006 22:50

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John,

      Your question got me curious and I went looking. 

I went to our post of the importance of avoiding Vitamin D

http://www.marshallprotocol.com/forum2/4062.html

and I think it in combination with the parts you quoted clarify the matter a little better.  It's different than I had thought I understood it.  It appears that 1,25 D does activate the vdr but needs to be dampend by olmesarten to keep us from killing ourselves with herx.  You also don't want excess 1,25 D because of the other bad things it does to our system such as dissolve bones and redeposit calcium in soft tissue and organs.  Excess 25- D  competes with 1,25 D and stops the immunes system like prednisone by displacing the 1,25 D on the receptor.  If I have  overstepped myself, staff, or misinterpreted please feel free to delete this.  I really don't like to say stupid things.

Morris

Last edited on Fri May 26th, 2006 23:33 by Morris W. Milnes



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Prof Trevor Marshall
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 Posted: Sat May 27th, 2006 03:18

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John, Morris,
The conference is over now, and I can focus on returning to reality:):)

First, Olmesartan has an effect on many receptors in the human body, and probably also some receptors expressed from bacterial genomes (see the MRSA model in my Karolinska presentation).

1,25-D, and the other Vitamins-D, have a high affinity for a number of receptors. Generally, 1,25-D activates VDR, but it also has a high affinity for the Glucocorticoid Receptor and for the Alpha and Beta Thyroid receptors. So, as the concentration of 1,25-D in the body rises, it displaces Cortisol out of the GCR, T3 and T4 out of the Thyroid receptors. Some of us have had practical experience of this:):)

As the level of Vitamin D itself, or its metabolite 25-D, rises in the bloodstream some of them will enter the phagocytes, and, if the concentration of cholecalciferol or 25-D is high enough, they will displace 1,25-D from the VDR and inactivate it.

This means that they have disabled the body's last line of defense against intracellular pathogens. Which is not good. I think that a level of 25-D above 20ng/ml is totally suppressive of VDR activation, and therefore of innate immunity, and that levels of 25-D below 12 ng/ml seem to allow it to function moderately well. Olmesartan should be handy in this transition region. Once somebody has their 25-D into the single digits, and is not ingesting cholecalciferol, the VDR should be sufficiently active without needing any more Olmesartan intervention to activate innate immunity.

But Olmesartan also acts on other receptors- producing a palliative action in addition to the antibacterial effects it has when it interacts with VDR. I have identified one of these receptors, and over the next few days I think I will be able to track down another (based on a presentation I just saw...). These palliative actions include anti-anxiolytic and anti-panic effects, as well as pain palliation.

Hmm... John... I haven't really directly answered your questions exactly as they were asked. But have I clarified what is happening?

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 Posted: Sat May 27th, 2006 03:57

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Very nice conference and poster.
I got lost like John, the VDR science starts to be more and more complicated for me too

Last edited on Sat May 27th, 2006 04:29 by wrotek



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 Posted: Sat May 27th, 2006 05:45

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Trevor,

Congratulations on the conference.  Things are hotting up! :)

Once somebody has their 25-D into the single digits, and is not ingesting cholecalciferol, the VDR should be sufficiently active without needing any more Olmesartan intervention to activate innate immunity. But Olmesartan also acts on other receptors- producing a palliative action in addition to the antibacterial effects it has when it interacts with VDR.In the light of this, would it be a good idea to experiment with continuing the abx regime without olmesartan, for someone like me who has done over two years of MP (25D 8.8)?  Presumably if the herx got too bad, one could always start up the olmesartan again.  Can you foresee any possible drawbacks to this experiment?

Julia 

Prof Trevor Marshall
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 Posted: Sat May 27th, 2006 05:54

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Julia,
Try to stretch out the dosing intervals. That will tell you whether it is worth saving the money on Olmesartan. Its palliative effects are excellent, and will last as long as you get herx from the abx. If cost is not a factor, the organ-protective effects of Olmesartan are pretty convincing, and I would keep a blockade in place...

As for the complexity of the science - yes, the science is becoming more precise all the time, and the depth of knowledge is increasing by leaps and bounds. I sometimes shudder to read a lot of what I wrote just 12 months ago:X:X

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 Posted: Sat May 27th, 2006 08:54

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But Olmesartan also acts on other receptors- producing a palliative action in addition to the antibacterial effects it has when it interacts with VDR. I have identified one of these receptors, and over the next few days I think I will be able to track down another (based on a presentation I just saw...). These palliative actions include anti-anxiolytic and anti-panic effects, as well as pain palliation.
Bolding is my emphasis :)

Recently I have been going through the anxiety of waiting for test results for a serious condition. I can attest to being much less anxious, in this waiting period, than I would have been pre-MP. I assumed this is because I have improved enough on the MP to cause the "less anxious" effect, but perhaps it is a combination of improvement *and* the beneficial effects of the Olmesartan.

Thanks for the excellent new handout, Dr. Marshall. :cool:

Catlady



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John McDonald
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 Posted: Sat May 27th, 2006 10:19

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There are too many kinds of D and the web sources aren't consistent about which D is which. Also for the moment, the role of the Olmesartin is confusing. I scrambled too many questions into my previous post so I am going to be a reductionist. Leaving aside Olmesartin only for the moment:
  • Do I want my VDR activated or not? I do, right? It is embarrasing to ask this but I am trying to be crystal clear about whether an active VDR or inactive VDR supports bacterial destruction.
  • I think you responded that 1,25 D activates the VDR (good?) but does bad things elsewhere.
  • Previously I believed that the bacteria synthesize 1,25 D for their own prosperity. Do we still think that?
  • I think I get the ingested 25-D. It deactivates the VDR (bad?).
Please bear with me, once I get this I will retain it. ::::::::::::john

P.S. I have had a heck of a time this week reaclimating to my home time zone. Jet lag can be as bad as a herx and I often think of the day after a long flight as a time of convalesence. You have gone equally far in the opposite direction. I hope you recover quickly. ::::::::::j



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 Posted: Sat May 27th, 2006 10:56

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Congratulations, Trevor, for the excellent poster presentation and on the well-deserved accolades from the distinguished attendees!  Yes, I also predict that it will be sooner than later for the overdue respect and appreciation of your efforts!  :D

We all THANK YOU! . . . Carole



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Prof Trevor Marshall
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 Posted: Sat May 27th, 2006 11:17

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John,
Jet lag is easier to manage when you have your health back. I did arrive on Tuesday morning and the first conference event was Wed evening, but I missed nothing due to zone problems. Which is a nice warm feeling after all these years of struggling with travel...

So, question 1 - yes, the VDR must be activated as part of innate immunity.

Q2 - The Vitamins-D have a high affinity for the Glucocorticoid receptor, and the thyroid receptors, where presumably they do immunosuppressive, feedback, or other yet-to-be defined things. These apparently occur at higher concentrations of 1,25-D - after the VDR has been activated.

Q3 - I am not sure what the bacterial defense mechanism is, although it is clearly based in the properties of those biofilms we keep photgraphing in the blood under darkfield.

I did show the world expert on cell apoptosis (Dr Kristoff Binder) the video I had from Andy Wright, and Kristoff assured me that the filaments we were imaging were like nothing associated with apoptosis, where the cell memberane breaks into much larger 'blebs' as the cell disintegrates.

Q4 - both Vitamin D (cholecalciferol) and its hydroxylated metabolite 25-D displace 1,25-D from the VDR in a concentration-dependent manner, and deactivate the VDR.

..Trevor..

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 Posted: Sat May 27th, 2006 11:53

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John,

I can empathize with you on the VDR and D questions and although Trevor's answers are just above this post and may be clear to you, I'd like to add my nickel's worth. :cool:

It took me a little while to get that (I hope this is right ;)) it's not as simple as yes or no in regards to 1,25-D and VDR, but also HOW MUCH. 

In other words, we need some 1,25-D but more is not better.  That's when we run into problems and why ingesting D foods, (especially supplements and foods that add D) create problems in those of us with Th1 illnesses that can't regulate the proper amounts necessary of all of the Ds for proper functioning, especially once the CWD have entered our immune cells causing havoc. 

John McDonald
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 Posted: Sat May 27th, 2006 11:53

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Excellent.  Now I know in which direction to throw the VDR light switch.  I want it activated.  Now again from the handout:

During Th1 immune challenge, the VDR is activated by the endogenous secosteroid 1,25 dihydroxyvitaminD.

So a bit of 1,25D seems to be good, to activate the VDR.  But from this:

Q2 - The Vitamins-D have a high affinity for the Glucocorticoid receptor, and the thyroid receptors, where presumably they do immunosuppressive, feedback, or other yet-to-be defined things. These apparently occur at higher concentrations of 1,25-D - after the VDR has been activated.

Too much 1,25-D is not a good thing, probably immunosuppresive.  Presumably if we have Th1 symptoms then we have too much 1,25-D, though some small fraction of it is doing us good and may be essential.

Do you know if anything else switches on the VDR?  Is it just 1,25-D?

thanks,        john



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Prof Trevor Marshall
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 Posted: Sat May 27th, 2006 12:10

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The VDR is unique among the Nuclear Receptors in having only one known activator, 1,25-dihydroxyvitamin-D. But, as the years go by, other endogenous receptor activators may well be identified, just as there are with the other nuclear receptors.

I can tell you that 1,25-D and the VDR are totally below the radar of everybody here. Nobody laughed at the Vitamin D connection, as many physicians do back home, but I guess 'bewilderment' and 'consternation' were the best description of reactions here.

Milk is not routinely supplemented here (Sweden is one of the countries with the least sunshine in the world) but butter is, only a little, about 9% RDA per serving. You can buy enriched milk, and they are just starting to put it in infant formulas. One of the pediatricians confided that she had wondered why the recent surge in Autism, so I suspect her patients' kids will no longer be supplemented:):)

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 Posted: Sat May 27th, 2006 12:40

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but I guess 'bewilderment' and 'consternation' were the best description of reactions here.

Years ago I got a valuable lesson in self psychology.  I was taking my modern physics survey course and I found Relativity Theory and Quantum Mechanics to be outrageously counter-intuitive, maybe preposterous.  I wondered how anybody could believe that stuff no matter how solid the mathematical evidence.  Then a few weeks later I noticed that I no longer felt that way.  It seemed intuitively reasonable.  Nothing changed except I had a few weeks to habituate to the ideas.  So this "common sense" or intuition in my case simply required adjustment to "feel" true.  So my intuition was and is pretty suspect.  I reckon that is true for all of us.  Please use small words and speak slowly to your colleagues (and to me).  They have a lot of "common sense" and antiquated intuition to overcome.

There must be 4 or 5 vitamins-D.  How many in the conference, do you suppose, can tell them apart?

john



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 Posted: Sat May 27th, 2006 13:23

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I am at the conference in spirit feeling your awesome progress Dr. Marshall. Keep up the great work you are doing and sleep to keep going! Much happiness comes from reading your enthusiasm about finally figuring this all out and fine tuning.

10,000 Thankyous



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 Posted: Sat May 27th, 2006 13:57

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Milk is not routinely supplemented here (one of the countries with the least sunshine in the world) but butter is, only a little, about 9% RDA per serving. You can buy enriched milk, and they are just starting to put it in infant formulas. One of the pediatricians confided that she had wondered why the recent surge in Autism, so I suspect her patients' kids will no longer be supplemented:):)

Here neither, except butter is enriched. Do other european MPers know or their countries are enriching things other then butter? When I saw the "Foods to Avoid" list, where could be putten Vitamin D in, I realised that the US situation is really different then the European. I cannot find a normal food wich lists added Vitamin D, except butter.

Bw,
Jeroen

GC
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 Posted: Sat May 27th, 2006 15:44

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Dr Trevor Marshall wrote:

As the level of Vitamin D itself, or its metabolite 25-D, rises in the bloodstream some of them will enter the phagocytes, and, if the concentration of cholecalciferol or 25-D is high enough, they will displace 1,25-D from the VDR and inactivate it.

This means that they have disabled the body's last line of defense against intracellular pathogens. Which is not good. I think that a level of 25-D above 20ng/ml is totally suppressive of VDR activation, and therefore of innate immunity, and that levels of 25-D below 12 ng/ml seem to allow it to function moderately well. Olmesartan should be


I have some problems with this interpretation. Do you have any references to show that 25OHD3 is capable of displacing 1,25D3 from the VDR? My understanding is that 1,25D3 binds over 400x more strongly to the VDR than 25D3.

In Prof. R Veith's chaper 61, page 5, of the book "Vitamin D" he explains that

There are
two ways to improve capacity for 1,25(OH)2D production
at kidney, and at peripheral tissues: provide more
substrate, or increase 1-hydroxylase content of the tissue.
This is fundamentally different from the situation relevant
to every other part of the endocrine system. No other
hormone is so dependent on the arbitrary, external supply
of its structural raw material. The concept of a mass action
relationship for 1,25(OH)2D production is the basis
of the argument that operation of paracrine control
systems dependent on vitamin D supply can be improved
by improving vitamin D nutrition."

So, increasing 25D3 nutrition will lead to increased synthesis of 1,25D3 in the paracrine system, and therefore improved function of the innate immune system.

Prof Trevor Marshall
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 Posted: Sat May 27th, 2006 16:25

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GC,
If you are representing his position accurately, then Veith is totally incorrect (again).

I have given my receptor affinity data at Karolinska. I will be happy to share it with Reinhold, if he requests it. There is less than a factor of 3 difference in affinity for the VDR between 1,25-D and 25-D. This difference is easily swamped by the higher available concentration of (exogenous) 25-D (untethered by DBP). Take a look at the figure on my poster which shows all the metabolites docked into the VDR. There is no significant difference in conformation between all of them. Neither are there any significznt differences between the binding affinities.

But only endogenous 1,25-D has the hydroxylated 1-alpha position. Only 1,25-D can activate the VDR.

I will not joust at phantoms when discussing scientific issues. If you wish to challenge the scientific integrity of my work, then you will need to identify yourself, and come out from behind the nom-de-plume. Because of the proliferation of your 'hostile' posts over the last several hours, you have been banned from further such comments until you comply with this professional courtesy.

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 Posted: Sat May 27th, 2006 18:59

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MPers, welcome to the wild,wild west of molecular genomics:) Sam



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