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A Unified View of the Marshall Pathogenesis
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Prof Trevor Marshall
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Location: Thousand Oaks, California USA
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 Posted: Thu Mar 30th, 2006 16:45
Dateline: 30 March 2006.
Collecting my current thoughts on the MP, I recently wrote a brief abstract for the DMM2006 conference at the Karolinska Institut in Stockholm. This is an upcoming International conference on Chronic Disease. The abstract has been accepted for presentation. I wanted to let you know my latest thinking about Th1 disease (and give you all an opportunity to 'peer-review' it).

You will note that the intense research I did prior to my FDA presentation helped me see both the Vitamin D deprivation and the Benicar blockade as being one-and-the-same in their effect, as they both enable the VDR nuclear receptor to do its job as the primary activator of innate immunity (remember that "innate immunity" is the 'last line' of defence, while "acquired immunity" is the first line, driven by the generation and recognition of antibodies, etc - it is innate immunity alone that can protect against intraphagocytic pathogens).
Here it is...

VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease


The VDR Nuclear Receptor is at the heart of human innate immunity, responsible for TLR2, TLR4, CAMP, TACO and IL2 expression[1]. During Th1 immune challenge, the VDR is activated by the endogenous secosteroid 1,25dihydroxyvitamin-D. We have previously described how intra-phagocytic bacterial pathogens are responsible for much chronic inflammatory disease[2,3], and our phase 2 study results have confirmed this pathogenesis. In order to induce recovery from chronic inflammatory disease, it is necessary to restore VDR functionality by removing all exogenous sources of the secosteroid we call ‘Vitamin-D’, and dampen down over-exuberant VDR activity, for example with the ARB Olmesartan[1]. This enables the immune system to recognize the pathogens. To date we have demonstrated recovery from Hashimoto’s Thyroiditis, Rheumatoid Arthritis, Sarcoidosis, and an assortment of chronic inflammatory diagnoses. This breakthrough is the result of a collaboration between molecular scientists and a disparate group of innovative physicians, facilitated by the Internet. However, the widespread application of this pathogenic understanding will require meticulous translation of the molecular science into conventional clinical precepts.


1. 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.
(Video DVD transcript can be ordered, and a low-resolution version is online at
http://AutoimmunityResearch.org/fda-visiting-professor-7mar06.ram )

2. Marshall TG,Marshall FE: Sarcoidosis succumbs to antibiotics-implications for autoimmune disease. Autoimmunity Reviews,2004;3(4):295-3001.
(Fulltext at http://yarcrip.com/sarcoidosissuccumbs-preprint.htm )

3. Marshall TG,Fenter B,Marshall FE: Antibacterial Therapy Induces Remission in Sarcoidosis. Herald MKDTS 2004g;Volume.III:Release.1(The Journal of the Interregional Clinical-Diagnostic Center, Kazan, in Russian translation).ISSN:1726-6149.
(English version at http://www.joimr.org/phorum/read.php?f=2&i=107&t=107 )

(many thanks go to Belinda, for helping me draft this abstract)

Last edited on Sun Apr 30th, 2006 17:24 by Prof Trevor Marshall

John McDonald
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 Posted: Sat Apr 1st, 2006 09:50
It is a very well and concisely written abstract.  I look forward to the full paper. 

"remember that "innate immunity" is the 'last line' of defence, while "acquired immunity" is the first line..."

'Remembering innate immunity' took me about an hour  of searching this site and reading the results for "innate immunity".  If the built in search routine works properly then this is the first time, as I suspected, that you have ever said this on this web site.  I really appreciate this type of information so if you have another link I would be very, very grateful.

I recognize that you are targeting medical researchers and gov't decision makers with your most recent papers.  I have found them to be less easy to read as an 'outside-of-this-field' scientist than your earlier papers.  I accept that gladly if it helps you with your target audience, but I'm dissappointed nonetheless to not understand your 'take away' points.  I love the insights that you offer and I hate it when my jargon and biology limitations make it hard to read your work.  I am a frequent presenter in my own field and from that background I also worry that much of what you had to say to the FDA went over their heads as well.  I find that I can't count on my audiences knowing what they are supposed to know, and that if I use to much jargon I lose them.  I hope this isn't the case at the FDA, but based on the Q&A I wonder.  I hope you don't take this as hostile, I am a big, big supporter.

I'm afraid that I still don't understand the break through respecting Olmesartin and the vitamin D receptor.  I plan to watch your FDA presentation again in hopes that I will get it this time, but I think that 1,25D turns the receptor off and somehow supports cytoplasmic digestion of the CWD bacteria, and it seems that 25D docks to the same receptor and somehow turns it on.  My point is that I am terribly confused about the simple idea of how the VDR is supposed to work, and how 25D and 1,25D and Benicar affect it, and hence us.  Can you offer just a few sentences about this?  Also, could you offer a layman's synopsis, just a paragraph, of the take-away points from the FDA presentation.  I would be ever gratefully yours,   :::::::::::john

 

Last edited on Sat Apr 1st, 2006 09:51 by John McDonald



____________________
RA 125D38, MP 9/05 Ph2 12/05 Ph3 09/06, Oct07 2510, NoIRs lite exp r/t work covered up
Prof Trevor Marshall
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 Posted: Sat Apr 1st, 2006 22:31
John,
1,25-D is the only metabolite that turns the VDR on.
Everything else turns it off, or at least modifies its capabilities. So exogenous Vitamin D and 25-D both bind into the VDR and block it from working properly. They will displace any 1,25-D from the receptor in a dose-dependent manner. The higher the concentration of Vitamin-D or 25-D competing with the endogenous 1,25-D the more of that 1,25-D will be displaced from the VDR. That occurs in a manner represented by the displacement graphs in the FDA presentation.

Sorry, I hadn't spoken about innate immunity before the FDA presentation. That became crystal clear to me in the months while I was preparing the FDA presentation, but I didn't talk about it publicly here.

Benicar also stops the over-excitation of the VDR by inactivating it, but it does so in a dose-dependent and controllable manner. We control Benicar's activity against the VDR by varying the Benicar dose. But Benicar also has profound actions elsewhere in the immune system. Some I am already aware of, some I am not. There will be more about this at the upcoming conference, which has not yet been announced (watch this spot...)

I understand that what I said to the FDA mostly went over the heads of the audience. But there is a copy in the FDA library, and I will be giving written submissions on issues before the FDA in the future, and from these I will be able to refer to this presentation. For example, if the FDA held a hearing aimed at increasing the RDA of Vitamin D you can be pretty sure I would be making a submission. This lecture being on file will make my written submission that much more effective:)

Prof Trevor Marshall
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 Posted: Fri Apr 7th, 2006 12:20
I am pleased to report that the Abstract has been accepted for poster presentation at the 2006 "Days of Molecular Medicine" conference in May, at the Karolinska Institut in Stockholm.

http://www.nature.com/nm/meetings/dmm/index.html

I usually refuse all except oral presentations, but in this case I missed the deadline, and I think this will be an important conference for us to get the message out.

I am interested in what you'all think I should put on the 27 x 39 inch poster board. I am thinking the right-hand one-third should be a list of the Chronic inflammatory diagnoses of folks on the MP, the number who are responding to the MP, and the number of 'recoveries' (if any).

Beyond that, I am interested in what you think TPTB may be interested in finding out. What was the big hang-up your physician had? What was the key thing for him/her to understand?

Last edited on Sat Apr 8th, 2006 08:42 by Prof Trevor Marshall

paulalbert
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 Posted: Fri Apr 7th, 2006 13:49
Trevor,

If I were a disinterested party evaluating such a poster presentation, here is what I would be interested in....

For each condition that is "on your radar", I would be interested to see which are plausible candidates for the MP, which the MP has achieved some measure of success in treating, and which the MP has cured.

I would be interested to know how many patients have achieved cure versus how many are still in treatment, if possible, broken down by condition.

I would be interested in seeing a scatterplot graph of MP patients' 1,25D levels versus the "normal" range. (This always astounds me.) 

I would be interested to know the numbers of patients who report treatment on the Internet versus the number of patients (that you know of) who are doing the MP offline.

I might also be interested in reading a handful of super pithy, and to the extent possible, objective case histories. 

Of course, this isn't a "billboard presentation."

Nice to return to Stockholm, the site of your eureka moment, eh?

Paul

Last edited on Fri Apr 7th, 2006 13:51 by paulalbert



____________________
Diag CFS 6.03 / sympt since 9.02 / exercise, food intol, sleep prob / 1,25D: 16, 4.06; 1,25D:27, 25D:26 7.04; 1,25D:43, 25D:6 6.05; 1,25D:17, 25D:8 8.05; / MP: 7.04 / Ph. 3 / Bacteriality
Rosie
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 Posted: Fri Apr 7th, 2006 16:06
My rheumy (fibro specialist) was okay about drawing the D tests and about me stopping vitamin D supplementation.  His hangup: "there is no proof that bacteria causes FM" or that FM is an autoimmune disease, just related. Also, while both my rheumy and endocrinologist fully accept that autoimmunity runs in families and that an individual can develop several of them, they did not seem to grasp the fact that many symptoms are shared among folks with very different autoimmune diseases.

Rosie

Last edited on Fri Apr 7th, 2006 20:19 by Rosie



____________________
Thyroid Disease, FMS, Functional Cervical Stenosis/ACDF, Osteopenia, Parox Atrial Fib, Insomnia; 9/05: 1,25D=53, 25D=27; stopped D suppl (525iu/day) on 8/3/05, 4/11: 1,25D=49, 25D=15
RobertTownsend
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 Posted: Fri Apr 7th, 2006 17:46
Trevor
I would highlight at least some of the following - to the extent they can be incorporated into your more focused research :

1 Unified parameters of inflammatory /AI conditions - ACE, cytokine profiles , TNF appha etc

2 Similar clinical framework for many AI conditions - extreme variance in disease progression , remission periods etc

3 Wide range of AI conditions with substantial clinical support for, or at least inference of, bacterial pathogenesis ( RA ( from Brown to ODell) Sarco ( the original work to yours) Crohns ( perhaps Tom Barody's latest work)

4 Why bacterial identification of CWD infection is extra-ordinarily difficult

5 And, of course, your latest work on manipulating the VDR

6 The consolidated observations from your Phase 2 clinical trials ( without corrupting them by drawing out inferences which are too premature)

Good luck

Robert Townsend



____________________
CFS 4yrs,crippled knees;Oct05 Phase 1;Feb 06 Phase 2 ; Mar06 1,25D-61pMol/L 25D-23nMol/K;Jul06 Ph3 start ;July 08 dose tapering some abx,daytime fatigue much lower, skin still very light sensitive ;knee mobility very constrained with limited walking
jrfoutin
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 Posted: Fri Apr 7th, 2006 18:31
Faces do make a difference. Suggest a banner of some MP patients along the top border of your poster, maybe short quotes by patients. 

Of those that signed release forms and are available for this event, some included quotes in the email, others have quotes on the success thread. 

Also, flag icons representing the international nature of your work.



____________________
Sarcoidosis 125D61, MP10/05 ModP2 12/05 Ph2 6/06 Ph3 10/06, NoIRs limited outings covered, 2/08 25D6.2, 10/08 25D6.9
Reenie
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 Posted: Sat Apr 8th, 2006 00:14
What was the big hang-up your physician had?

My GP's hang-up is that I don't have sarc and he doesn't "get" how my illness would be connected to or why a treatment for sarc would work for me.  My GP sees one illness, one treatment. (He still has this hang-up)   

What was the key thing for him/her to understand?

I think understanding how do you know that I have a bacterial infection when a routine workup doesn't show that I have one and how do you know that's what is making me ill.  My GP also doesn't see that all of my symptoms are related to the same cause.  

BTW, my GP is still waiting for the "eureka" moment when "someone" finds the cause and cure for CFIDS. 

Oh and that I'm taking antibiotics for a long time and he's afraid I won't have "anything to take" if/when I get some sort of infection that he would routinely treat with a round of abx. 

The other question that keeps coming up is, "How do you know what you're experiencing, via herx, is making you better rather than just your illness flaring?"  That's prob just going to take some time as more and more of us get well and don't have the usual set backs and relapses.  :cool: 

Last edited on Sat Apr 8th, 2006 00:21 by Reenie

Julia
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 Posted: Sat Apr 8th, 2006 02:49
I agree with Janet - people's faces and brief comments across the top.  I know you want to be as scientific as possible, but 27x39 isn't very big, and there's a limit to the amount a person can take in standing reading a poster.  You have to balance just enough science to get them wanting more, with enough popular appeal to attract them to read in the first place.  Too much popular appeal and you look like a snake oil peddler; too much science and it isn't a 'good read'.

I think the problem for my physicians was the high, untested dosage of olmesartan.

Julia 

Prof Trevor Marshall
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 Posted: Sat Apr 8th, 2006 03:55
Reenie,
One of the things we have planned carefully is to leave available to your Doc a key antibiotic from each class of 'macrolide' and 'tetracycline' which he/she can use for emergency infections. The macrolide is Ketek, the tetracyline is Tigecycline. Both are new, 3rd generation antibiotics with wide spectrum which Doc will be happy to use in an emergency. The MP exposes you to neither, so that if any resistance builds, both classes of abx are still available to Doc. You can point this out to him/her on your next visit.

Of course, as I have said so many times, bacteriostatics are unlikely to promote resistant species, as all species, even resistant ones, succumb to them when given for long enough periods. For example, minocycline, very widely over-prescribed for teenage acne, was released in 1968. In nearly 40 years there have been no significant species which have built resistance to it. There is one known major resistant SNP, but those microbes are still susceptible, just less so.

zackone
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 Posted: Sat Apr 8th, 2006 05:52
If we are still experiencing herxes at the antibiotic combos we are each using, doesn't that illustrate in itself that our bacteria has not grown resistant to at least those drug combos??

I would also add that only one of the antibiotics prescribed on the protocol has ever been prescribed to me in the past, for what it's worth.

Fred

Last edited on Sat Apr 8th, 2006 07:17 by zackone



____________________
Sarcoidosis/lungs (2004); Ph1Mar05 Ph3Feb06; no breaks; Lungs, sinuses, skin, eye irritation, suspect kidneys; 25D=18 (Jul15) 1,25D=35 (Jul15)
dougs
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 Posted: Sat Apr 8th, 2006 06:14
I would divide the poster into four quadrants.  In each quadrant I would seek to answer a question:

1.  What is the cause of chronic illness?

2.  What is the mechanism the bacteria use?

3.  What disease conditions result?  What is the impact on society?

4.  How do we fix it and what are the results?

I would have a portable DVD player which continuously played video of the bugs taken from patients with as many illnesses as possible; produced by as many different researchers as possible.  If this could be integrated into the poster so much the better.  But a small hand held device would suffice.  Nothing is more powerful than seeing the bugs.

I would prepare four presentations (30-45min each) fleshing out the simple material shown in 1-4 above.  These I would hand out as dvd's.  I would also make these presentations available for download on this web site.

Everything must be simple designed to appeal to primary care physicians and sick patients. 

dougs



____________________
CFS 7yr,bruxism/tmj,sleep apnea,hypo thyroid/adr; no meds;mm/yy(25d/1,25d)7/04(-/42),12/04(10/45),11/05(11/25); P1 8/16/04;P2 12/1/04;P3 11/14/05
barbski
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 Posted: Sat Apr 8th, 2006 08:34
My doctor's biggest hang-up is the concept that sunlight = daylight, however high a latitude one lives at. I don't know if that is too much detail for a small poster presentation, but I think Northern Europeans (presumably there'll be plenty in Stockholm :) ) often have trouble believing that patients can have too much Vitamin D with long winters and short days. Emphasising that the bacteria can produce Vitamin D themselves and therefore the protocol is globally relevant may be useful.

From a more personal perspective, I reckon that emphasising the MULTI-bacterial nature of the illnesses would be handy. Speaking from a CFS perspective, I know that research to find an infective cause has always concentrated on an individual pathogen as ‘the’ cause. And of course, a percentage of patients test positive each time, but never enough to be significant.

BTW, the ‘et’ on the end of Karonlinska Institutet is the Swedish way of saying ‘the’, so you can either drop the English ‘the’ or the final ‘et’. Just a tip for if you’re speaking to Swedes:)

Best wishes and good luck with the presentation,

Barb

Last edited on Sat Apr 8th, 2006 08:35 by barbski

Prof Trevor Marshall
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 Posted: Sat Apr 8th, 2006 08:49
Fred,
One can generate herx from killing just one or two species. I prefer an multi-species-kill, and that is why I try and get folks to Phase 2 as soon as practicable.

Dougs,
I have a spare laptop, which is an identical copy of my primary machine (I rely totally on this machine, its 100 Gig hard drive contains hundreds of papers, all of Andy Wright's videos, and a stack of other stuff which allows me to basically do anything, anywhere). Liz and I were looking at ways of fastening this to the poster just last night. It is about 11 inches square, but I agree, the space would be well-used. I was going to edit Andy Wright's bacteria videos and have them running on loop so folks could just stand and watch...

paulalbert
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 Posted: Sat Apr 8th, 2006 09:04
Barbski says:My doctor's biggest hang-up is the concept that sunlight = daylight, however high a latitude one lives at. I don't know if that is too much detail for a small poster presentation, but I think Northern Europeans (presumably there'll be plenty in Stockholm :) ) often have trouble believing that patients can have too much Vitamin D with long winters and short days.
Barb,

Does your doctor have any thoughts on why so many patients with Th1 illness have such high values of D? Surely that would suggest that a Th1 patient requires very little light to catalyze production of it.

I agree with you, Barb. That regular exposure to light is absolutely necessary for everyone is one of those fundamental assumptions of which MD's will have a hard time letting go.

Paul



____________________
Diag CFS 6.03 / sympt since 9.02 / exercise, food intol, sleep prob / 1,25D: 16, 4.06; 1,25D:27, 25D:26 7.04; 1,25D:43, 25D:6 6.05; 1,25D:17, 25D:8 8.05; / MP: 7.04 / Ph. 3 / Bacteriality
barbski
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 Posted: Sat Apr 8th, 2006 09:10
Paul,

Good question but... not all of my doctor's patients get their Ds tested, as it can be awkward and expensive in some parts of the UK. And the main lab here insists the blood doesn't need freezing, so many who do test don't bother to get the blood frozen. (I insisted on getting mine frozen, but I'm stubborn). So he doesn't see a proper range of results from UK patients, unfortunately. The same may be true for other UK and even other European docs using the MP.

Barb

Last edited on Sat Apr 8th, 2006 09:10 by barbski

scooker48
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 Posted: Sat Apr 8th, 2006 10:46
Dr. Marshall,

It has been my experience that Poster Sessions are not mentioned or ultimately indexed in the Conference Proceedings, which ultimately work their way into the scientific bibliographic databases such as MedLine, BIOSIS, or Chemical Abstracts.

Possible to start communicating with whoever is putting on the Conference about the published conference proceedings?  And that you request some way that your info be included in the Final Published Conference Proceedings?  That way, down the road, the MP will have more visability and therefore credabillity.

The abstract is great.

Sherry



____________________
D25, Total: 12 measured 11/3/15 Started MP=01/04/05 Diagnosis: Sarc 12/04; "cat scratch disease" or necrotizing graunulomas 10/88; Raynaud's (diagnosed 1980?)
Prof Trevor Marshall
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 Posted: Sat Apr 8th, 2006 11:00
Sherry,
Those abstracts which are not published can be expanded into full papers for another journal or conference. I am not aware than any abstract will be published from this conference. I am more interested in the potential for interaction with the delegates. There are some important folks who will be there.

Reenie
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 Posted: Sat Apr 8th, 2006 12:54
One of the things we have planned carefully is to leave available to your Doc a key antibiotic from each class of 'macrolide' and 'tetracycline' which he/she can use for emergency infections.

Trevor,

In my previous post, I never implied that I didn't get this nor that you haven't carefully strategized the MP abx to take precaution from any possible resistance, but I think it's important to somehow address this concern as to using an extended abx therapy strategy for treatment since the clinicians don't "get it." :cool:

Heck, most of them don't even get that we have a bacterial infection, which brings me back to my previous "hang-up" posted about how/why would I want to use the MP to treat my illness.  It's a vicious cycle I suppose. (GP's hang-up, not mine, btw)   

PS I know the info is on the site, but when you want to peak (or pique) interest, I think knowing the objections before they are asked is always helpful especially since oftentimes people don't ask/say them, (their objections) they only think them.

Last edited on Sat Apr 8th, 2006 14:11 by Reenie


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