This shows you the differences between two versions of the page.

Link to this comparison view

Both sides previous revision Previous revision
Next revision
Previous revision
home:publications:marshall_american_academy_of_environmental_medicine_2006 [04.21.2009] external edit
home:publications:marshall_american_academy_of_environmental_medicine_2006 [01.03.2012] (current)
Line 1: Line 1:
 +====== Presentation - A new approach to treating intraphagocytic CWD bacterial pathogens in sarcoidosis, CFS, Lyme and other inflammatory diseases ======
 +{{ youtube>-FzYARFQ9ZE}}
 +**Type:** Conference presentation\\
 +**Presenter:**  Trevor Marshall PhD\\
 +**Conference:**  41st Annual Meeting of AAEM\\
 +**Location:**  Hilton Head, SC \\
 +**Date:**  Oct. 26-29, 2006\\
 +**Additional content:** [[http://autoimmunityresearch.org/transcripts/marshall_aaem_2006.pdf|Transcript and slides]]
 +===== Transcript =====
 +Thank you John, and thank you to the academy for inviting me to
 +Well the first two slides are just links to some of the papers that
 +we've published on these topics. They are there for your references.
 +Our FDA coordinator also told me to make sure that I point out
 +that there are FDA applications current for both Sarcoidosis,
 +designations in the drugs in Sarcoidosis, and also in PTLDS or Post
 +Treatment Lyme Disease Syndrome(what most of you would know
 +as chronic Lyme) active; and the numbers are all at the bottom
 +and you can find a copies of all of those applications on the
 +Internet if you want to look in more detail at the regulatory issues.
 +The disclaimers. Many of the disease states that I am going to
 +cover in this presentation, including neurological states are not
 +generally accepted as being caused by pathogens. Much of this
 +presentation is based on leading edge science and not on weight
 +of evidence. The Phase 2 clinical trial is ongoing.
 +Even when shown the science and the microscopy, some experts
 +still disagree to the existence of persistent pathogens.
 +The FDA has now designated trials for long term use of
 +Minocycline and Clindamycin in the treatment of Sarcoidosis but
 +not in the other indications I am going to discuss. We are going to
 +Phase 3 trials over the next year or two.
 +Now in addition to our previous papers, the list of which I've just
 +gone through, many of the slides have Pub Med ID numbers on
 +them. Those are citations to support the science in any specific
 +slide. So if there is something on a specific slide that you feel I'm
 +reaching a bit with, make sure you look at the Pub Med ID
 +citations first.
 +And there are also a few new slides resulting from recently
 +published peer review papers which are not in the syllabus and
 +which have not been reviewed by AAEM. These have that little red
 +logo at the bottom saying "NOT IN SYLLABUS."
 +So here is the first one, "Not in Syllabus." Well, actually, the top
 +part is in the syllabus but I changed the text on the bottom, as you
 +will see on the next slide.
 +The quotation at the top, from a gentleman called John Arbuthnot,
 +from Sixteen Hundred and Ninety two. Believe it or not, this
 +quotation really forms the basis of evidence-based medicine. This
 +is the gentleman that wrote the first book on statistics of the laws 
 +of chance in 1692 and as you would all know, without statistics and
 +without the concepts of statistics, we wouldn't have the clinical
 +evidence-base that we have at the moment.
 +What John said ... [read quote from slide].
 +The primary difference between mathematical science, which is
 +primarily what I'm going to deal with in this presentation, and
 +evidence-based medicine is that one is definitive and one is
 +interpretive. Mathematical science tries to define relationships
 +between metabolites. Tries to define what's going on. Evidence-
 +based medicine tries to interpret the results of observations in a
 +reliable manner.
 +As we enter the 21st century, the tools to reduce some important
 +medical dilemma to mathematical precision are now available in
 +Molecular Genomics. Now one thing I want to point out is that
 +true science has no concept of weight of evidence. It doesn't
 +matter how many times you add up the balance in your checking
 +account, you can start at the bottom of the page and work up, you
 +can start at the top of the page and work down, the numbers you
 +are going to get are exactly the same and any body who has done
 +high school arithmetic can sit down and check your calculations
 +for you. So therefore, there is no need for weight of evidence.
 +As a hypothesis is advanced, it can be tested and it stands until it is
 +rejected or improved. E=MC2 has been improved many times
 +over the years, but the basic E=MC2 is still there, still in place.
 +If the problem is deterministic, then there is a solution.
 +This is a new slide, and as an example of how molecular and
 +evidence-based knowledge are symbiotic and the need for both
 +fields to work in closer cooperation, last week The Lancet
 +published my answer to a question which had been posed in July
 +(2006) by Dr DS Grimes. Dr Grimes posed the hypothesis, "Are
 +statins analogues of Vitamin D?"
 +Now that's my paraphrase and I'm being a little bit cruel but I
 +wanted to give you a quick encapsulation of what the hypothesis is
 +about. This is a hypothesis which cannot be solved by evidence-
 +based medicine. It cannot be solved because the variables that are
 +involved, the number of variables that are involved is too high and
 +they are not appreciated by the investigator.
 +When you have too many degrees of freedom, your statistical
 +analyses of the epidemiology just break down. However, the
 +evidence-based dilemma is easily solved by Molecular Biology and
 +I'll show you this later in the presentation. I'm going to be talking
 +about statins. That was actually in the syllabus.
 +But I wanted to point out that biochemists are also failing. [Read
 +slide to 'Vitamins D']. The VDR stands for Vitamin D Receptor.
 +[Continue reading slide to knowledge] Yet the insights that are
 +resulting from science that the biochemists are producing [continue
 +First I need to say little bit about Th1 inflammatory disease. [Read
 +slide first Paragraph]
 +Unfortunately, interferon-gamma is a paracrine cytokine. It exists
 +only in the tissues and it's not an endocrine hormone. It doesn't
 +circulate through the bloodstream. [Read 2nd Paragraph to tissue]
 +if you want to do a biopsy [finish 2nd Paragraph].
 +Consequently, a number of other paracrine cytokine have
 +historically been measured in order to try and infer whether a
 +patient is presenting with a type Th1 inflammation, or a type Th2
 +inflammation. A type Th1 inflammation is typically those which
 +result from infection, such as Tuberculosis, Leprosy, Syphilis. All
 +those are Th1 or they cause Th1 immune responses. Th2 is more
 +typically those which result from what we call allergies. However,
 +none of these other cytokine are specific and this has led to
 +considerable confusion. People think in terms of Th1 and Th2, but
 +basically all of the autoimmune diseases are Th1.
 +Louis Pasteur once noted that in science, chance favors the
 +prepared mind. There are 2 factors: Chance, it's all based on luck
 +(chuckle), being in the right place at the right time. But the
 +prepared mind is important. You have to be able to observe what
 +you see, when you are there. We were lucky, we were able to
 +break that particular nexus and realized that all of these diseases
 +we were dealing with were in fact, Th1 diseases.
 +... Suicidal idealation, this is not something I've heard anybody
 +speak about, so far at the conference. It's a big problem with us.
 +As the immunopathology takes over, the cytokine storm hits.
 +Suicidal idealationoccurs in a significant number of these people
 +and it's treatable. As a matter of fact, it's avoidable.
 +Now those of you that know about the Marshall Protocol and have
 +been following what we have been doing over the last five or six
 +years would know that we've conducted this on the Internet as an
 +open study. Any physician such as yourselves can register and get
 +full access to the database of all the reporting from the patients in
 +the study going right back to day one, right back to about 2001.
 +A year ago, this was heresy. Everybody said you can't do an open
 +study. You can't do an adaptive study. You can't change the
 +conditions as you are going along. You can't do anything on the
 +Well, things change. The drug pipeline is now nearly empty and
 +the FDA is getting quite concerned that not only is the drug
 +pipeline nearly empty, but the drugs that are there don't work
 +properly anyway.
 +And so I put a quote in there now which is given by the FDA
 +Deputy Commissioner for Medical and Scientific Affairs, who is
 +actually in charge of clinical trial evaluation at the FDA, Dr Scott
 +Gottlieb, from an actual conference that was held earlier this year
 +on adaptive trial design. And basically, I'll save time by saying that
 +he says [paraphrase] "we've got to figure out better ways of doing
 +these things, guys." And whenever I read the stuff he writes, it
 +makes me think of the things we are doing.
 +Now we published our initial results in 2004 in the Th1 syndrome
 +called Sarcoidosis. Sarcoidosis is a rare disease and it's a disease
 +that we chose to investigate first. We were lucky to choose this
 +one, it happens to be a prototypical case for all of the Th1
 +diseases. And there are a number of things in Sarcoidosis which
 +makes the analysis of the disease state very much easier than it is
 +in some of the more complex conditions.
 +And in particular, by the time the inflammation has advanced to
 +the stage where it forms self-perpetuating granuloma, there are
 +very few antibodies being formed. So there is no longer the red
 +herring of the antibody formation and perhaps the antibodies
 +making people sick. We knew the antibodies weren't making
 +people sick because there weren't any. We knew there was
 +something else that was making people sick, probably a cytokine
 +storm. Where was it coming from?
 +That was the other Pasteur piece of luck. We happened to be
 +studying the correct disease that turned out to be the prototype for
 +many, many other Th1 diseases.
 +So at Karolinska institutet in Stokholm, at DMM 2006, I gave the
 +following figures for the recovery rate in several key autoimmune
 +diagnoses. These were extracted from the Phase 2 and 3 reports.
 +These are people that have mainly been on the protocol for twelve
 +months or so on average.
 +As you can see, Rheumatoid Arthritis has very good success. Eight
 +have a primary diagnosis of Rheumatoid Arthritis, seven of them
 +are reporting improvement in their condition.
 +With Hashimoto's Thyroiditis it is a lot easier. Either they need the
 +supplements or they don't. There the ratio is twenty out of twenty-
 +five are improving.
 +Osteo Arthritis is an interesting one. I was surprised how many
 +people with Osteo Arthritis we had in the cohort.
 +And then the ones that we are known for: CFS/CFIDS/Myalgia
 +Encephalmyelitis. Let me stick with Chronic Fatigue Syndrome.
 +Seventy-seven with about forty reporting ongoing resolution.
 +Cardiac Arrhythmia is an interesting one. This came up in a case
 +study yesterday. And I would like to have an opportunity to join this
 +group again in about five years time when we have more data and
 +a lot more history under our belts. And talking again about
 +cardiac arrhythmia, this is a very classic symptom of late stage Th1
 +Sarcoidosis of course, ninety-two with fifty seven recovering.
 +Diabetes, five and three.
 +Uveitis, eighteen and twelve.
 +34/20 in Fibromyalgia and 10/8 in Irritable bowel syndrome.
 +It is an open study, we don't put any preselection conditions on the
 +patients that want to join, and that's why we have accumulated
 +such a wide range of diagnoses. There are about 500 patients at
 +the moment that are regularly reporting and about ten times that
 +number that we are aware of... of course, that don't report.
 +There are a few more diagnoses on this slide. It is in your syllabus
 +so I won't go over them in too much detail. Point out Psoriatic
 +Arthritis is a new one, also Multiple Sclerosis. We have quite a few
 +Multiple Sclerosis patients now, at least it is getting up to statistical
 +significance. Most of those are being looked after by Dr Greg
 +Blaney in Canada.
 +Tinnitus resolves. Usually acute Tinnitus resolves quite quickly and
 +then takes quite a lot longer to resolve fully, several years to
 +resolve fully. Like peripheral neuropathy, Tinnitus is one of the slow
 +symptoms to resolve.
 +Juvenile ADHD, I've got two out of two and I've already chatted
 +with the autism, the people that are interested in autism. That was
 +quite a surprise to us. Both of those patients had primary diagnosis
 +in other areas. One had a Lyme disease diagnosis, the other had
 +Sarcoidosis and Uveitis diagnosis. The uveitis being key there. The
 +patient was going blind. All of the problems have resolved. As the
 +primary inflammatory diagnosis resolved, the attention and other
 +problems, psychological problems, resolved as well. Resolved
 +spectacularly. Both are back at school and doing very well.
 +Well, five steps basically. [Read to end of step 2]
 +Olmesartan is licensed for sale throughout the world as an
 +angiotensin-receptor blocker. But it has significant activity in other
 +receptors. One of the receptors it is very active in is the VDR. It
 +activates the VDR.
 +[Read step 3, to "25"] And when the patients start with 25mg every
 +48 hours it is usually all they can handle. And then increasing to
 +100mg over about three months.
 +[Read step 4] The choice is made based on suicidal ideation.
 +Clindamycin tends to exacerbate any suicidal ideation or
 +depression that is present and we avoid it in the early stages of the
 +protocol with people who have that tendency.
 +[Read step 5 to 3 antibiotic combo] "Low dose?", well
 +Azythromycin, some of them can handle 1/8 of a tablet every ten
 +days when they start. They eventually work up to about half of an
 +Azythromycin tablet as ultimately the bacterial load is totally
 +removed, and then they can just guzzle the antibiotic like candy,
 +like a healthy person can.
 +But initially, when the immune system is working, those antibiotics
 +do an incredible job of killing the bacteria.
 +So, this was a warning that my FDA liaison — contact — said
 +"please put in."
 +[Read warning to apoptosis] programmed cell death [continue
 +Immunopathology. That is the word that is being used instead of
 +"Jarisch-Herxheimer." Jarisch-Herxheimer typically refers to the
 +cytokine storm that occurs in acute episodes. "Immunopathology," I
 +first heard Rolf Zinkernagle use it at Karolinska and it is becoming
 +more and more commonly used. It is basically what happens to
 +the body when the immune system is doing its job. It includes
 +apoptosis, cytokene storm, all of the other effects on the body from
 +the immune system doing its job. Immunopathology.
 +[Read Steps needed].
 +The moment pathogens start being recognized and start being
 +killed, your white and red blood cell counts are going to go all
 +over the place.
 +[Read Step 1 to receptors], which is rather handy to reduces
 +fibriotic tissue deposition.
 +Now we use special antibiotics. You might not think they are
 +special, but they are special in their interaction. The antibiotics
 +have a direct action on a part of the bacterial genome which is
 +called the ribosome. The ribosome, if you cast your mind back to
 +molecular biology, is where the messenger RNA from gene
 +transcription, are turned into protein.
 +In bacteria, they only have one ribosome. The human body has
 +two ribosomes. Bacteria only have one, called the 70S ribosome,
 +and the antibiotics that we use block the action of the 70S
 +ribosome. They block the ability of the bacteria to produce protein.
 +Particularly to use the protein that they use to evade the immune
 +system. Because clearly, the bacteria wouldn't be capable of living
 +within the phagocytes unless they had a mechanism evolved
 +probably over centuries that allows them to evade phagocytosis.
 +So the rate of bacterial death is controlled by inhibiting the protein
 +synthesis, using only intermittent low doses of bacteriostatic
 +The other advantage of going after the ribosome is a small
 +amount of antibiotics kills a small number of bacteria. In fact, one
 +molecule binds into one ribosome. So it is not quite linear, but it is
 +a proportional response.
 +So why? Why does this intervention work when all the previous
 +antibiotic therapies used for these diseases didn't induce recovery?
 +[Read 1]
 +In other words, there is a model. We can fit the disease that we
 +observe to a model. So when I say that five MS patients is a good
 +sized sample, its because they are behaving exactly as the model
 +predicts. So we have the extra statistical guidance from the model
 +as well as from the data.
 +It works because [Read 2].
 +[Read 3] The VDR, which was long thought to be 'just' associated
 +with 'vitamin D', is now known to be at the heart of innate
 +immunity. And I'll talk a LOT more about this as we go forward.
 +[emphasis repeat] Vitamin D is at the heart of innate immunity.
 +[Read 4]. That is part of the model. We have to know how the
 +people get sick, and how the sickness progresses over the years.
 +[Reference 5]. For example, sequencing the bacterial genomes
 +have shown that many of the common bacteria, even Staph
 +aurious, has got plasmids. Plasmids are little self-replicating loops
 +or sticks of DNA that can exist and replicate on their own without
 +the main chromosome. And many bacteria have these plasmids.
 +The plasmids can persist and if they are not destroyed by the
 +immune system, they can interact with other species of bacteria.
 +Toward the end, I will show you exactly how that happens with a
 +bacterium species called antrhax.
 +So the plasmids are persistent and prolific. So when you have a
 +chronic disease which is accumulating over a lifetime, certainly
 +over many years, you're not going to have just one species that is
 +active. You are going to have a number of species that are active.
 +You are going to have a number of plasmids that are active. You
 +are going to have a number of viruses that are active.
 +The ubiquitous EBV. I think I can find a paper for just about any
 +disease you like name which blames EBV as the cause of that
 +disease. No. But EBV is very hard to kill off. Its plasmids is just two
 +genomes long; something like a 160,000 base pairs long; it's very,
 +very small; very, very hard for the immune system to recognize and
 +kill; and it persists. And it interacts with any other species of
 +pathogens in exactly the same way as it interacts with the human
 +genome. And it will cause mutations. The bacteria cause
 +And the last reason the intervention works is [reference 6] because
 +the MODEL recognizes that neo-natal pathogens persist in the
 +brain. [Repeat intended] Neo-natal pathogens persist in the brain.
 +Well, now we get into some pretty pictures.
 +These are pictures of a receptor, it is a G-Protein Coupled
 +Receptor that goes through a membrane. And each of the little
 +colored balls are atoms. Each of the similarly colored atoms form
 +part of an amino acid, which together make the protein which is
 +folded into the receptor.
 +Well it's not very easy analyzing that sort of diagram, so
 +biochemists tend to draw everything in terms of spirals and loops.
 +Each one of these spirals is a cascade of amino acids. It is shown
 +diagramatically as a spiral so that we can see more easily what it
 +is actually doing.
 +We also have a more precise 2-dimensional representation that
 +you will find in some of my papers. And here we have the actual
 +amino acid of the protein (see lower right "Leu 293" highlighted in
 +video) and it shows which are the atoms or ligand of the chemical.
 +In this case it is olmesartan but it could be any of the vitamins D.
 +It shows which of the atoms interact with the ammino acid residues
 +(see lower right O1 red atom highlighted in video), and it also
 +shows the hydrogen bonds when they exist as well. Making it very
 +easy to try and figure out whether we are dealing with an agonist,
 +or an ANtagonist. Much harder to do that in 3-dimensions.
 +I want to talk about the nuclear receptor type one family because it
 +turns out that this family is most closely related to the operation of
 +the immune system — both the innate immune system, and the
 +adaptive immune system.
 +The key receptors for which we have known structure models. In
 +other words, we not only know that the bacterial genome looks like
 +this but we also know in 3-dimensional space that x-ray
 +spectroscopy has told us exactly where each atom is in the
 +molecule. In this case, we're talking about the human genome. But
 +it's the same theory, we've got the VDR (Vitamin D Receptor), the
 +Progesterone Receptor, PPAR-alpha (which is one of the lipid and
 +immune system mediators), PPAR-gamma (which is also lipid and
 +immune system), Androgen Receptor, the Estrogen Receptor,
 +glucocorticoid receptor, Thyroid-alpha-1, Thyroid-beta-1, and the
 +mineralcorticoid receptor.
 +Now surprisingly, if you look at the pictures of each of these drawn
 +as spirals (I guess maybe I should have done a slide of it for you),
 +but they are all very, very similar. And that is why they are the type
 +1 nuclear receptors.
 +And you know molecules that will go into the VDR usually only go
 +into PPAR-gamma and some of the other type 1 receptors as well.
 +They affect more than one function of the body.
 +So nuclear receptors are responsible for the transcription of the
 +DNA genes to strands of RNA, which are then translated into
 +proteins in the ribosomes. And they are very important.
 +I've put a link there to a simplified set of flash animations for those
 +of you that want a crash course on how this all works. It is a very
 +simple crash course. I really recommend you have a look at it.
 +Now we're going to look at some simplified 3-D animations of the
 +transcription molecules, just to give us an overview.
 +What we have here, we have a strand or double strand of DNA
 +(highlight blue/grey/red/pink balls base right of diagram). These
 +are the base pairs that run across (highlight on video shows
 +vertical ball lines at bottom center of diagram) the two backbones
 +of the DNA. Across the center you have the hydrogen bonds that
 +hold the DNA together (highlight moves L-R across center of
 +vertical ball lines). Hydrogen bonds that are peeled apart is when
 +the RNA is produced. The RNA is basically ½ of the DNA double
 +So when the nuclear receptors do their job and transcribe a gene,
 +what they are actually doing is breaking the hydrogen bonds and
 +producing the RNA in a very complex and clever fashion which
 +doesn't occur very fast because it requires a lot of things, the
 +statistically drift around and come together in exactly the right way.
 +Nuclear receptors typically take days to effect their action.
 +Key to nuclear receptors are the zinc fingers here (video highlights
 +upper left center large yellow/green balls). The green atoms are
 +zinc, the yellow, sulpher-disulfides. Actually cystines to be honest.
 +And they are a key part to positioning the helixes which go through
 +the (video highlights lower left solid light grey spiral) DNA and find
 +the exact chain that needs to be translated based on the exact
 +mapping of attractive and repulsive forces and then do the DNA
 +It is an amazing system. I've shown here that there two receptors
 +because usually one nuclear receptor doesn't do it by itself. It can
 +form a homodimer but it usually forms a Heterodimer. So you have
 +a VDR coupled with a retinoid-X receptor and then the two of them
 +transcribe genes. There is also a cofacter that gets involved as
 +well. Quite complex and we really don't know a lot about it yet.
 +I mean we now have the genes to transcribe, but we don't know
 +exactly which co-factors go with which receptors.
 +The biggest surprise we got when we started doing this modeling,
 +was the high affinity of the ARBs and Statins for VDR and PPAR-
 +gamma, Nuclear Receptors which are both key to the immune
 +Now these are very flexible, highly polar ligands. And we thought
 +they might have an affinity for other G-protein coupled receptor
 +membrane receptors, in other words receptors that go through a
 +membrane rather than exist in the nucleus of the atom.
 +But their affinity for the Nuclear receptors was a real surprise.
 +Here's a big table which represents months of computing.
 +But what we have done here is used special software that
 +computes the interaction between thousands of atoms and figures
 +out for each of the (video highlights drug names in the sartan
 +group) ARBs and each of the Statins (video highlights drug names
 +in the statin group), which receptors they are going to have an
 +affinity for — if any — and which receptors they are going to
 +switch on or switch off.
 +And if we just look at the statins first, thinking back to the question
 +posed by Grimes in The Lancet: "Are statins analogues of vitamin
 +D?" Well the first thing that pops out is that the VDR here (video
 +highlights VDR column head), there is a huge difference between
 +the statins.
 +Simvastatin (video highlights 4 at base of the VDR column) hs got
 +quite a low number which means quite a high affinity, but
 +Rosuvastatin, fluvastatin, and particularly Atorvastatin (Lipitor) don't
 +have any affinity for the VDR at all. Pravastatin that is effectively no
 +affinity. Lovastatin would have a little affinity if a low dose is used
 +in vivo.
 +So there is a huge difference between the statins. Just thinking of
 +the statins as a group is a concept that is dangerous clinically, let
 +alone to try and extrapolate that to talking about the statins
 +functioning as a hormone would.
 +But you can also see if you take Simvastatin, not only does it have
 +a high affinity for the VDR, it's got 10x higher affinity for the PPAR-
 +gamma, same for PPAR-alpha as the VDR. The Gluco-corticoid
 +receptor -the home for cortisole- it has a high affinity for, also the
 +MCR. The Progesterone receptor, the Alpha-Thyroid and the Beta-
 +Thyroid. Simvastatin is a very, very active statin.
 +Whereas Atorvastatin for example, primarily hits PPAR-gamma and
 +alpha and incidently hits the Gluco-cortisole axis for the GCR.
 +However, some of the ARBs are a little bit better behaved than that.
 +Telmisartan is very poorly behaved. It totally shuts off the VDR the
 +moment you give it to somebody. This is NOT good.
 +Olmesartan, here (video highlights 10 in the VDR column) has got
 +a moderately low affinity for the VDR, and that is one of the
 +reasons why we have to use a higher dose when we are using it to
 +modify the VDR than when we are modifying the Angiotensen-
 +receptor where it has a much higher affinity. But it is nicely
 +controlled in the PPAR-gamma and -alpha (video highlight across
 +Olmesartan Estimated Ki row) and GCR. It hits the progestrone
 +receptor but it doesn't really hit Alpha-Thyroid.
 +Beta-Thyroid it hits but we're not really sure what Beta-Thyroiod
 +does yet. What we know about Beta Thyroid is that if you breed
 +mice that don't have the beta thyroid receptor, then they are born
 +deaf. Otherwise they seem to be fine. (Audience chuckles) So we're
 +still trying to figure out what the Beta Thyroid does.
 +The ability to breed mice with gene knock-outs without these
 +receptors is a PRIMARY new tool that has become available to the
 +biochemist. It is invaluable. Unfortunately with the GCR, if you
 +knock out the GCR the mice never survive past gestation. So we
 +don't know a heck of a lot about the GCR either except it is at the
 +root of the Cortisole axis of the adrenal.
 +But anyway, it is a big table and I have it printed on a sheet of
 +paper and I have to refer to it all the time, so I'm not going to
 +expect any of you to commit that to memory.
 +Now I'm going to look at a very simple hormonal system. The
 +adrenal axis. And up here (video highlights top word
 +"GlucoCortocoid Receptor"), I'm just looking at part of it and I'm
 +looking at the GlucoCortocoid Receptor, the nuclear receptor, with
 +a promotor which is "c" AMP (cAMP). Promotor binds to the
 +receptors, and then the promotor and the receptor together bind
 +to the DNA and transcribe the gene.
 +The GlucoCortocoid Receptor is responsible for producing
 +Corticotrophin Releasing Hormone (CRH highlighted), and that in
 +turn produces the Pro-Opeo-Milleno Cortin and when that is
 +metabolized, you get Beta-endorphin and also an ACTH
 +produced. ACTH of course you know, that catalyzes the conversion
 +of Cholesterol into Cortisol. Then Cortisol goes up and docs into
 +the GlucoCortocoid Receptor (highlight shows arrow line path left
 +and up to GCR) and you have a feedback loop, which keeps the
 +Cortisol levels of the body at roughly constant levels.
 +That is a very simple, straight forward hormone loop.
 +Unfortunately, with 'vitamin' D, it is a little bit more complex. As you
 +would expect for something that is at the heart of the immune
 +system. It has adapted over many, many millennia.
 +The "not in Syllabus" flag indicates some of the enzymes here have
 +shifted from what is printed in your syllabus. Also, since that
 +syllabus was published, there has been new studies showing that
 +the Androgens (video highlights lower left corner word
 +"Androgens"), particularly testosterone, reduce the breakdown of
 +1,25-D by the enzyme CYP24.
 +But basically, the body starts off with 7-dehydro-Cholesterol, which
 +is part of the sterol subsystem. It is a cholesterol derivative (video
 +highlights upper left 7-dehydro-Cholesterol), and that is converted
 +to pre-Vitamin D by energy. Conventionally thought to be UVB, but
 +the biochemists will easily tell you it doesn't have to be UVB and it
 +can even be an enzyme. Enzyme at this point, we have no idea
 +what that enzyme would be if it is an enzyme. But it certainly
 +doesn't have to be UVB to convert to Pre-Vitamin D (Pre-Vitamin D
 +highlighted). All you need is a contra-rotatory electrocyclic reaction
 +which occurs in other substances and which is pretty well
 +(Vitamin D highlighted) Then, Pre-Vitamin D is formed into Vitamin
 +D by a Sigmatrophic shift. A very small shift of the electrons (????).
 +Vitamin D is converted by the enzyme CYP27A1 -or- CYP2R1 and
 +both of these are P450 digestive system enzymes into 25-
 +hydroxyvitamin-D (highlight drops to 25-hydroxyvitamin-D) and this
 +is the one that most of you are measuring when you measure
 +somebody's 'vitamin' D levels, you are almost certainly measuring
 +the 25-hydroxyvitamin-D.
 +(Highlight drops to 1,25-dihydroxyvitamin-D) That then is
 +converted to 1,25-dihydroxyvitamin-D, hydroxillation by enzyme
 +either CYP27A1 or CYP27B1, both of them will hydroxyllate. And
 +that 1,25-dihydroxillate with activate (highlight moves to
 +*activate*) the VDR and allow the VDR to do the gene transcription
 +that is at the heart of innate immunity.
 +And then finally, the 1,25-D is inactivated (highlight opens on
 +lower left "Inactive 24,25 & 25,26") by the VDR up regulating this
 +CYP24 enzyme so that you don't end up with too much of it in the
 +And that is what goes wrong in Th1 disease. You end up with too
 +much 1,25-D in the body because the VDR inactivation path —
 +something goes wrong with it.
 +Well, OK. Here we have some pretty pictures. We have atoms and
 +bonds. The grey atoms (highlight upper left picture, left grey atom
 +selected highlight in video) are carbons, the red ones are oxygen,
 +that green is a fluorine, That's a hydroxy OH there (highlight
 +moving from green to lower center red/grey center bottom), the
 +light blue is the H of the hydroxy. And this molecule is
 +Dexamethasone in exactly the configuration where it binds into the
 +Gluco-Corticoid Receptor (GCR binding pocket), you know the
 +adrenal axis, the Gluco-corticoid receptor.
 +And here (video highlights lower right figure center), we see 1,25-
 +Dihydroxyvitamin D competing with Dexamethasone for the
 +binding pocket of the GlucoCortocoid receptor.
 +1,25-D has a very high affinity for the adrenal axis. This is new, it
 +is not in the syllabus, it's taken from a paper which was accepted
 +for the nuclear receptors conference next week, actually.
 +So what does that mean? If we go back to our nice simple adrenal
 +axis, what does that mean?
 +Well it means that (highlight focuses on top black box 25-D and
 +1,25-D) 25-D and 1,25-D can both bind into the GlucoCortocoid
 +Receptor and displace Cortisol from doing that.
 +When it does that, the amount of CRH and particularly ACTH is
 +down regulated, and you end up with Adrenal Insufficiency
 +(highlight on lower black box "Adrenal Insufficiency").
 +OK, the vitamins D also compete for the Thyroid binding pocket.
 +I'm talking about the alpha thyroid here, the important one.
 +There we have T3 as it docs into the alpha thyroid to activate the
 +alpha thyroid (highlight shows green end molecules on the top left
 +illustration). These are the iodine molecules, three of them of
 +Here we have 1,25-D competing (highlight center of lower R
 +figure) with T3 for the alpha thyroid Binding Pocket. It wants to
 +dock in exactly the same binding pockets as the T3 would. And by
 +doing that in high enough concentration, it will stop the T3 from
 +binding. It will stop the alpha thyroid from working properly.
 +We end up with, among other things, hypothyroidism.
 +So I've done a summary slide here of the operation of the VDR. It
 +is key to both the endocrine and immune systems.
 +The VDR is responsible for decreasing parathyroid Hormone
 +Transcription. [Reference slide to TLR4], and therefore the
 +bacterial response.
 +Toll-like Receptor 4 is responsible for sensing
 +lipopolysaccarhride. Toll-like Receptor 2 is responsible for
 +sensing the presence of other bacteria protein. When the VDR is
 +not working, because you have administered vitamin D and are
 +experiencing the immuno suppressive action of the vitamin D,
 +when the VDR is not working, you do not have a functioning TLR2
 +and TLR4 system.
 +But you also lose the antimicrobial peptides. It transcribes the
 +cathelicidin antimicrobial peptide (cAMP) and it's also responsible
 +for beta defensins. The beta defensins are absolutely key to the
 +proper operation of small intestine. The small intestine, in fact,
 +the whole GI tract is critically dependent on the defensins and
 +especially the beta defensins and the cathelicidins to work
 +properly. When you knock out the VDR with immunosupression
 +— either a steroid or 'vitamin' D — you lose that ability.
 +And finally, the VDR is responsible for binding the interluken 2
 +(IL2) promoter. Now you all probably know that you measure
 +interluken 2 when you want to measure a Th1 reaction. Well, that
 +is why, because the VDR actually produces the interluken 2, even
 +if you can't measure it.
 +I've got some other functions there, I guess the main one there is
 +it regulates the TACO gene, which is responsible for
 +mycobacterium tuberculosis intraphagocytic survival, and it
 +promotes transcription of Insulin Receptors.
 +Let's skip the rest because we're running a little late bit short in
 +The current status of the VDR is that the VDR is responsible for
 +TLR2 and TLR4 expression, as well as cAMP... hey, I just said that
 +on the previous slide! Sorry.
 +What we've got here is two pictures and we have all the vitamin
 +D's (video highlights left image) superimposed. We've got 1,25-
 +Dihydroxyvitamin-D, that's the one that has the activating hydroxyl
 +(highlight arrow and red atom in lower right of left image) here,
 +the only one that can activate the VDR. Various other atoms can
 +activate the GCR or de-activate the GCR and the thyroid, but the
 +only one that will activate the VDR is this one (highlight again on
 +arrow and red atom) on the 1,25-Dihydroxy. But you can see that
 +all the vitamins D fit into the receptor in almost identical
 +positions. Whether it is 24,25-D, 25,26-D or 1,25-D. Even
 +vitamin D itself fits in there as well and they are all competitive.
 +If you're giving people 40mg, if you're giving people vitamin D
 +such as such as to get the blood concentration at 25-D to 40
 +nanograms per ml, then you're sitting with 25-D in most of your
 +VDRs and they are NOT activated, it is immuno-suppressive. The
 +patient will feel better short term because the inflammation is
 +suppressed. Long term, with the bacterial pathogens running right,
 +it's a different situation.
 +The picture on the right hand side just shows olmesartan binding
 +into the VDR pocket and you can see if you look at it carefully, you
 +can see that the olmesartan hydroxyl here (video highlights upper
 +right atoms O1 and O2 in lower right of right image) are actual
 +capable of activating the VDR in the same way as 1,25-D does.
 +So, we've got some little pictures here. We have 2 molecules.
 +What we have here is the steroid rings (video highlights right
 +image, upper right rings of molecule) of prednisone. This is
 +actually prednisone.
 +We have the steroid rings of prednisone, and over here (video
 +highlights middle two rings on left figure) we have the steroid rings
 +of "vitamin" D. What I wanted to show you was that you've got the
 +steroid rings.... I want to show you the only difference between the
 +secosteroid and the steroid is one bond. It's this carbon to carbon
 +bond across here (highlight shows critical top left ring closure of
 +right image, in 2nd ring from left). And it is missing across here
 +(highlight now shows open ring in left image in the 2nd ring from
 +left) in the seco-steroid. And that is why it is a secosteroid rather
 +than a steroid.
 +It is a very subtle change, it actually gives the [vitamin D] [not VDR]
 +more flexibility to move in a socket and that is one of the reasons
 +why it binds into so many of the nuclear receptors. The structural
 +similarity (video highlights cortisone bond again) between
 +prednisone and vitamin D basically come down to that one carbon
 +bond. And that is why it is a secosteroid and not a corticosteroid.
 +So I have a slide here on Vitamin D in Bone Remodeling because I
 +know all of you are going to say "well, If I withdraw vitamin D from
 +my patients, their bones are going to get weaker." This gives you
 +some up to date citations you can go away and look at, which
 +show that actually "vitamin" D is not really responsible for calcium
 +at all. It's the Calcium Sensing Receptor and the Parathyroid
 +hormone that are responsible for Calcium homeostasis. And
 +secondly, even the cannabinoid receptors play a key role in bone
 +remodeling and bone mass. That paper is only a few weeks old.
 +The sex hormones are also players in bone density, I think you
 +know that one.
 +And that elevated levels of 1,25-dihydroxyvitamin-D, such as we
 +have found to be associated with Th1 immune disease, actually
 +encourage osteoclastic actions and breakdown of bone and
 +deposition of bone into soft tissue. The last thing you want in these
 +patients is high levels of 1,25-Dihydroxyvitamin-D.
 +So this has got a "not in syllabus" picture because the text that I
 +had in the syllabus was a lot more caustic. This is diluted.
 +Public-Health Consequences of Regarding 'vitamin D' as a
 +'Vitamin.' Sometime during the 20th century, we began to view
 +"Cholecarciferol' as a 'Vitamin' rather than recognizing its steroidal
 +and hormonal activity. And we put the seco-steroid
 +'Cholecarciferol' into the food chain, in a futile attempt to eliminate
 +the rare disease, Rickets. And as physicians, you would know the
 +side effects from administration of steroids.
 +So the CDC now says we are heading towards half of all US
 +seniors being Diabetic by the year 2050.
 +And, Oh, steroids often induce obesity. I'll leave you to connect the
 +I haven't said anything about bacteria yet. When I was trying to
 +figure out how Sarcoidosis patients could be made sick in the
 +absence of antibodies, this paper was published back in late 2001
 +on the Internet, and what it showed was Rickettsia Helvetica inside
 +Phagocytes (video highlights upper right image E at two arrows).
 +Persistent inside phagocytes, not broken down by phagocytosis but
 +actually living in the phagocytes of Sarcoidosis patients.
 +That was the Eureka moment for me. I should have known it, there
 +is plenty of other literature talking about mycobacterium being
 +intraphagocytic, but that was the actual paper.
 +And then the real studies that you all will want to see if you are
 +interested in the actual pathogens, were the Wirostko Studies from
 +Columbia University in the late 80's. There are bout 30 or 40
 +electron transmisional microscopy photographs showing stained
 +bacteria. Tiny, tiny colonies (video highlight shows lower left arrow
 +circle of bacteria, then moves to second to left arrow colony, to
 +middle arrow pointing to colony and then to upper right arrow) of
 +stained bacteria in the phagocytes. This is a quarter of a
 +And they were very thorough, they did macrophages, monocytes,
 +lymphocytes and neutrophils. And they found that in the
 +Sarcoidosis patient, they found the intraphagocytic bacteria
 +persistent in all of them.
 +And in fact, the nucleus here (video highlights heavy bolded arrow
 +left of center pointing to nucleus) is breaking away a little bit near
 +this larger colony of bacteria (video highlights second lower left
 +small arrow). That's why it has the big arrow on it.
 +Fascinating photographs. Very important if you want to understand
 +the actual bacterial pathogens, the L-forms that cause these
 +diseases (cell wall deficient bacteria called L-forms for the Lister
 +institute where they were first identified). They are tiny pathogens.
 +They are so small. They are hundredths the diameter of the
 +macrophage. I've got 200 nanometers here (video highlights lower
 +right slide legend). We're talking about cocciodes, tiny little dots
 +that are about 10-15 nanometers in diameter.
 +These are pictures that show the diagrammatically show the
 +survival of bacteria in the phagocyte. I've covered these in my 30th
 +anniversary of Lyme meeting and with your permission, I'll skip over
 +this. You can find it in any book. (because we're running late on
 +Bacterial protein synthesis, and remember I talked about the 70S
 +Ribosome, the bacterial Ribosome. Here we actually have the
 +structure of the bacterial Ribosome, it is primarily made up of RNA,
 +unlike the human ribosomes which are primarily protein based.
 +But the 16S RNA (video highlights the lower left 16S rRNA on
 +figure), which you would all recognize as being the PCR, the
 +substance which is used as the target for most PCR tests. 16S rRNA
 +forms the 30S side of the ribosome (video highlights upper left 30S
 +figure subhead). The top of this 30S we have a heliacal structure
 +(video highlights top left ribbons) which is responsible for translate
 +but actually for ... translating the mRNA into a protein.
 +The actual translation is done on the 50S side, you can see a
 +protein (video highlights lower right quadrant) coming out the
 +bottom here and it's in yellow. The protein transferase center
 +(video highlights middle, slightly right) is right in the center which
 +you see, and there we have tRNA (video highlights blue grape
 +cluster mid top) which is donating the amino acid into the growing
 +And this is an Xray structure, which was produced from the Max
 +Planck group in Germany, and this x-ray structure shows a
 +number of antibiotic molecules found in, you can look at them in
 +your syllabus', but the one's we're interested in primarily are the
 +tetracycline. And in fact, the tetracycline binds right at the top
 +(video highlights top of 30S Sub-unit, see Orange color), and
 +inhibits RNA translation.
 +On the 50S side, you can see how the protein is assembled and
 +exits the exit tube a little more easily. And in particular, the
 +important thing is here, you will notice that Clindamycin (video
 +highlights center formation), just the light orange one, sits right at
 +the PTC. And the Azythromycin sits a little bit below it, so they are
 +actually symbiotic antibiotics.
 +All three antibiotics that we use are symbiotic. That means that
 +each of them progressively reduces the function of the [bacterial]
 +ribosome. That means that when you give them together, they are
 +not competing with each other, they're complementary. It is
 +symbiotic. Very important. Something that the genome, the
 +bacterial genome, has told us quite clearly.
 +So now we talk about the species.
 +Which species of bugs is it?
 +Well, it is not a single species. We're dealing with a polymicrobial
 +disease. If you look at the various diseases, and the bacteria that
 +have been reported with them all, the common ones like Staph-
 +aureus and Propionibacterium-acnes, Propionibacterium-
 +granulosum, seem to be the ones that crop up most of all, with the
 +nasty bugs, micobactera cropping up far less frequently. And
 +certainly less than 100%.
 +So we're almost certainly dealing with a polymicrobial disease.
 +And depending on the exact mix of pathogens, determines which
 +of the Th1 diseases, which of the Th1 symptom syndromes the
 +patient will progress to. Whether it turns into Rheumatoid Arthritis,
 +Multiple Sclerosis, or Anorexia Nervosa.
 +It's become obvious that most bacteria species are not
 +homogenous. They've got not only the chromosome, but also the
 +self-replicating plasmids which carry DNA and genes. Borrelia
 +burgdorferi has got a large number of plasmids, in fact, nearly half
 +of its genome exists on 21 self-replicating plasmids sub-units.
 +Now I'm not saying that makes it any more strong of a pathogen,
 +but it certainly adds quite a lot to the "Pea Soup" which I like to
 +think of as mix of DNA which accumulates in the chronic diseases.
 +Yet even Staph. epidermidis gives rise to plasmids. It's got about
 +10% of its DNA spread over six self-replicating plasmids.
 +These can be shared between species. But the plasmids are not
 +targeted by antibiotics. Antibiotics don't target plasmids. Only the
 +innate immune system can go after the plasmids. So unless the
 +plasmids are destroyed by the immune system, they will persist in
 +chronic intra-cellular infections.
 +And I think of it as a "DNA Pea-Soup."
 +Plasmids do transmit DNA horizontally. Notice the citation here, it
 +was published in the Proceedings of the National Academy of
 +Sciences in 2004. And what you had was, you had a patient that
 +got very, very ill with a species of Bacillus cereus. Now, Bacillus
 +cereus, we all know is a [relatively] harmless bacteria. It's a
 +Bacillus that doesn't cause the body [much] trouble, it clears it
 +(video highlights B.cereus yellow circle on figure, upper right of
 +Whereas just a little bit further around on the phylogeny here, we
 +have Bacillus-anthracus (video highlights red spike circle far upper
 +right). And what distinguishes Bacillus-anthracus is 2 plasmids.
 +One plasmids contains the ability to evade the immune system, the
 +proteins that give it the ability to evade the immune system, the
 +other plasmids carries the ability to produce a cytokine storm and
 +kill the host.
 +Now what happened in this case was the two plasmids from
 +anthracus were transferred into cereus and formed an extremely
 +toxic combination.
 +And you can see that the mice that were just challenged with
 +cereus, they all survived (video highlights upper center double red
 +circles on figure 4).
 +Those that were challenged with anthrax (video moves down to
 +yellow circle dropping line) -which color is anthrax? yellow- most
 +of them died.
 +BUT they died a lot quicker if they were the hybrid (video highlights
 +green circle line) of the anthrax plasmids and the cereus genome.
 +This is a big, big problem!
 +Why is it a problem?
 +Well, (video returns to first horizontally slide) if you look further
 +around on this phylogeny (video highlights B thuringiensis
 +israeliensis, mid far left green triangle), you'll find here Bacillus
 +thuringiensis Israelensis. That one is sprayed onto agricultural
 +crops as a herbicide. Sorry, it is an insecticide.
 +Anyway, you might have noticed, for example, Garth Nicholson
 +found a higher incidence of autism in the agricultural areas. This
 +fellow (video highlights B thuringiensis israeliensis) is sprayed in the
 +agricultural areas.
 +If the chronic infection allows the plasmids to spread, these people
 +will get very ill.
 +The final thing that I want to show is that the pathogens actually
 +persist in the brain.
 +This [slide] is taken from a paper by Rolf Zinkernagle, whom I was
 +lucky to meet at Karolinska, the home of Team Nobel. Rolf gave
 +the keynote speech there back in May [2006]. And what they
 +found they've done, is they injected the brains of mice at a very
 +young age (video highlights A - neonate mice figure upper right
 +figure), neonatal in fact, with a virus. And this is injected before the
 +mice have an adaptive immune system.
 +As you all know, the adaptive immune system in humans and mice
 +takes some time to kick in (video highlights top time line center,
 +showing Time after rLCMV/INDG). I think these are helper cells
 +coming up to indicate the adaptive immune system has kicked in
 +after about 7 days.
 +But when the mice are born, the only thing they have to protect
 +themselves is the innate immune system. You know, the thing we're
 +knocking out with 'vitamin' D.
 +Anyway, what Rolf did was, he showed that if they injected this virus
 +during this period, it remained dormant in the mouse. And later,
 +when a similar virus was used to challenge the mouse, It killed
 +them (video highlights upper right dead mouse figure).
 +Whereas mice that were challenged in adulthood by the same
 +virus (video highlights lower left time line, far left), injected by the
 +same pathway were not killed when they were re-challenged, in
 +fact, they survived primarily.
 +This is a fascinating paper, it is quite detailed with citations there at
 +the bottom [of the slide]. And Rolf is working on dispelling a myth
 +of autoimmunity — or response to self — by showing occult
 +viruses can, in fact, can exist and they can indeed persist in the
 +brain. Very important when we are trying to understand the
 +symptoms of our patients.
 +And here is the slide from Professor Bach, Jean-Francois Bach,
 +which was presented in Budapest in 2004. Jean-Francois Bach
 +was the person who proposed the hygiene synthesis.
 +But what he found was that bacteria, the particular strain of mice
 +called non-obese diabetic mice (NOD), where typically 60% of
 +them died (video highlights upper right dark dot line) from
 +diabetes — type 1 diabetes during their lifetime — that if he
 +injected them early enough with a mix of common bacterial
 +proteins, that they survived (video highlights cyan and yellow end
 +point line).
 +And the ones that survived best were the ones that got the
 +bacterial proteins earlier in life than later in life (video highlights
 +magenta square dotted line lower right).
 +Again, another fascinating insight into exactly how these diseases
 +persist and why some people get ill, and other people carry the
 +bacteria and don't get ill.
 +Because it is no secret that the NIH/NHLBI did a study in 2001
 +where they tested with PCR, they tested the blood of controls. No,
 +they didn't use PCR, they cultured the L-form using Wayne State
 +Lyda Mattman's technology. And they found 60% of their controls
 +were carrying L-forms in the blood. Supposedly a sterile
 +This has since been confirmed by the Relman Lab, Dave Relman
 +up at Stanford published a paper in the last year, where he too has
 +noted that 60-80% of the population are carrying around bacterial
 +RNA in their blood. It should not be there. Many of them, most of
 +them in fact, are not ill or certainly not diagnosably ill. Some
 +however, regress to really serious illness. It all depends on the DNA
 +mix and how the mutations progress in life.
 +So just a few quick final thoughts that my colleagues at FDA felt I
 +had to put in because I am talking to clinicians here, [are] just the
 +simple stuff again.
 +Final thoughts, if you are thinking if your patient might in fact be
 +suffering from Th1 diseases, then the therapeutic probe is really
 +the gold standard. That's because it is greater than 95% response
 +rate. Most of the patients will immediately feel immunopathology.
 +They'll immediately feel more ill when they start taking the
 +antibiotics. At that point you know that you are killing bugs. You
 +know that these people are responding.
 +The only thing I would say is 25-D levels above about 20ng/ml
 +you will be getting immuno-suppression there and it will be
 +suppressing the therapeutic probe. So you need to be somewhat
 +careful about the 25-D level before initiating a therapeutic probe.
 +Hypotension is not a concern, even though we are using an
 +angiotensin-receptor blocker. These are the graphs from the FDA
 +describing insert, the package insert [see slide figure]. As you can
 +see, the maximum drop is about 12 millimeters of mercury [12mm
 +Hg], and that value is independent of dose. You can see the dose
 +along the bottom here the response tops at 40mg. It is not a very
 +good hypotensive. Benicar is not a very good hypotensive. Luckily,
 +it does other things as well like protect the kidneys, and protect the
 +eyes and all the other things that you are reading about in the
 +clinical literature right now.
 +Hypotension is not a concern.
 +Dizziness. When the patients get dizziness, especially in the first
 +month, it's usually a sign of the disease process. It is not
 +hypotension. It's actually better to increase the Benicar to give
 +them a better blockade than to back off the Benicar.
 +There is no way you can start with a low dose and work up. You've
 +got to have those receptors being blocked, all the receptors being
 +blocked, or it doesn't work properly. You will increase the
 +immunopathology with only a low dose. That means the patient
 +will get, "Herxheimer" if you wish, they will get ill from only a low
 +dose of Benicar, but they won't get the palliative effects, they won't
 +get the renal-protective effects, until the dose goes up.
 +So it is very important to give them the correct dose so they are
 +actually going to make it through the therapy and kill those bugs
 +The only thing I didn't mention was how long it would take: three
 +to five years for the seriously-ill patients to totally get their lives
 +back. Most of them are happy with some form of recovery. They
 +see the light at the end of the tunnel after about six months. Very
 +few have not seen the light by twelve months but actually, they are
 +symptom free or say they are symptom free at about two years. But
 +all that means is they are getting along from day to day very nicely
 +and much better than they were before. There is still a lot of
 +disease present, they are still getting a lot of reaction to the
 +It takes about another two years to where they can just guzzle the
 +antibiotics like candy. At that point, the bacterial load is low
 +enough for them to pronounce recovery.
 +Thank you.
 +{{tag>presentations videos Trevor_Marshall_PhD AAEM 2006}}
home/publications/marshall_american_academy_of_environmental_medicine_2006.txt · Last modified: 01.03.2012 (external edit)
© 2015, Autoimmunity Research Foundation. All Rights Reserved.