The Physicians Approach to Biotoxin Illness

4/24/14

Inflammation and Chronic Fatiguing Illness Ritchie C. Shoemaker MD 4/9, 10/11

www.survivingmold.com.

Keith Berndston MD's Mold Toxicity Syndrome/CIRS Slides provide additional information.

Hopkinton Drug Compounding and Wellness

(508) 435-4441           www.rxandhealth.com

 

Diagnostic Laboratory Panel

CIRS Treatment Protocol

SAIIE; Timeline of Abnormalities in the Sequential Activation of Innate Immune Elements

Visual Contrast Sensitivity Technique

C4a Effects

VIP Trial Protocol

VIP Results

Summary of Lab Tests

Patients PMH Questionnaire; Clues to CIRS

VIP Dosage, Effects & Restrictions

 

Table of Contents;

I Getting Started                                                                                             1

II CIRS is the Common Pathway to Many Syndromes                                  2

III Biotoxin Pathway Overview                                                                     7

IV Genomics in CIRS                                                                         31

V Treatment of CIRS                                                                          32

VI The Biotoxin Pathway                                                                   38

VII Academic Basis of Treatment of CIRS from WDBs                               42

VIII Sequential Activation of Innate Immune Elements                               44

IX CIRS                                                                                              47

X Examples of Biotoxins                                                                               49

XI This is NOT just a Diagnosis of Exclusion                                               51

XII Case Studies                                                                                 53

XIII Clinical Course of CIRS                                                             57

XIV Understanding the Inflammatory Basis of Post-Lyme Syndrome         67

XV Review of Post-Lyme Syndrome                                                75

XVI Post-Lyme Case Reviews                                                                       77

XVII Attendee Questions                                                                   82

XVIII Summary of Medications Used to Treat CIRS                                    82

XIX Chart of Labs to Draw                                                                82

XX PMH Clues to CIRS                                                                     85

XXI At-A-Glance Management of CIRS                                                       88

XXII Lab Summary                                                                            89

XXIII Treatment Overview Summary                                                           95

XXIV Summary of Medications Used to Treat CIRS                                    96

XXV Bibliography

 

I Getting Started

1) What illnesses are we talking about?

A) Mold, Post-Lyme, Fibromyalgia, Chronic Fatigue Syndrome (CFS)

(1) Stachybotrys forms Tricothecene toxins

(a) T2 toxin (associated with “yellow rain”

(b) Satratoxin H (SH)

(i) Disrupts brain endothelial cells/blood-brain barrier

(ii) Induces initial anti-inflammatory response from astrocytes.

(iii) Chronic exposure results in local oxidative stress & neuronal apoptosis C/W lupus, MS, Alzheimer’s

(iv) Chronic immune response to inhaled SH may produce neuronal hypersensitivity/damage additive to exposure to other airborne toxins/inflammagens.

(c) Tricothecene Toxicity Mechanisms

(i) Cell-cycle arrest

(ii) Mitosis disruption

(iii) Protein synthesis inhibition

(iv) Oxidative cell stress with DNA damage

(v) Cell membrane disruption/permeability

(vi) Immunodysregulation (stimulation & suppression)

(vii) Apoptosis induction

(viii) Increased expression of inflammatory & apoptotic mRNA’s

(ix) Ribotoxic stress response producing MAPK induction of cytokine release

(x) Endotoxic reticulum stress with protein misfolding & blocked unfolding

(d) Toxic Bioaerosol Dispersal

(i) <2% of mold toxins are attached to mold spores; they are free-floating particles dispersed by vibration & air turbulence

(ii) Mix with volatile organic compounds (VOC) and are major threats to indoor air quality

B) Ciguatera, Cyanobacteria are not rare

C) Gulf War Syndrome (GWS)?  Gardasil?  LymeRx?

D) Few physicians have an organized approach to Dx & Tx

E) CIRS; (Chronic Inflammatory Response Syndrome)

F) The answers come from data!

2) Water Damaged Buildings (WDB) are a continuing problem.

A) Discolored carpet

B) Musty smell

C) Stained walls/ceilings

D) Smell of Volatile Organic Compounds (VOC’s)

E) Do they have high water bills from a possible “pin-hole” plumbing/water pipe leak inside a wall

F) This interior environment is a complex ecological system with multiple potential sources for inflammation.

(1) These potential sources of inflammation will make people sick if they are damaged by and/or susceptible to innate immune responses from pre-existing illness.

(2) Illnesses in I-A (above) have a final common pathway, which lets us identify “what is wrong with them now”.

(3) That is what we treat!

(a) Not what was wrong with them in the past

3) Ciguatera will occur even in northern cities due to air-freight bringing seafood from the tropics to northern locations

A) Grouper, Amberjack, Barracuda

B) While gathering their history, ask them; “Do you eat fish?” If not, then Ciguatera is low on the list of probable causes.

C) If they eat fish; “Do you ever get sick while eating fish?”

(1) GI, Cardiovascular and skin symptoms, heat/cold reversal esp. around lips followed by chronic fatigue that doesn’t resolve over 3-6 mos.

4) Cyanobacteria can even occur in cold latitudes esp. in summer when rivers dry up, but less likely there.

A) Exposure to shellfish beds; Brevitoxin 2,3,9

5) LymeRx Vaccine has caused problems;

A) What happens if we give people a known agonist of Toll-2 and Toll-4 receptors

(1) Which group of people is sickened if given Toll-2 or Toll-4 Receptors?

(2) HLA-DR4 folks are susceptible, DR4 is actually a Haplotype of 43-53

(3) DRB 1-4 has 12 subtypes

(4) 0401 has the worse illnesses

B) Some of these subtypes are a different type of CFS,

(1) They’ll have lots of things wrong with them.

6) Gardasil vaccine

A) 11-3-53 Haplotypes should avoid this vaccine

(1) Only about 1% of the population

Back to Top of Biotoxin Illness Outline

II Chronic Inflammatory Response Syndrome is the common pathway to all of these.

1) Chronic Immunologic, Rheumatologic, autoimmune diseases, keep an eye out for the problems that are a subset of CIRS

A) Absence of regulatory neuropeptides is the final common denominator.

B) Lack of regulation is a vital concept

(1) Genes load the gun, exposures pull the trigger.

C) Cast out false knowledge

D) Each of these illnesses has a lot of history of opinions and treatments but no consistent protocol for therapy

E) Until recently, there were no biomarkers

F) Each is readily identified by innate immune inflammatory responses in the setting of the absence of normal neuropeptide regulation.

G) We now have biomarkers that let your work be transparent and reproducible.

2) Biotoxin Pathway;

A) MSH (Melanocyte Stimulating Hormone)

B) VIP (Vasoactive intestinal peptide)

C) Vasopressin/Osmolality regulation

D) All interact in the hypothalamus.

E) Defining what is wrong (brings effective treatment);

(1) Regulation of dysregulated systems is necessary

(2) We need to start lowering levels of the elevated levels of inflammagens;

(3) C3a and C4a are anaphylatoxins. C3a reacts to bacterial membrane molecules. C4a reacts to biotoxins. Lyme disease can raise C3a and C4a levels.  CIRS-WDB raises C4a and tends to lower C3a.

(a) C3a

(b) C4a

(i) C3a & C4a can help differentiate between acute Lyme and post-Lyme

(ii) C4a is important in looking at cognitive effects such as brain fog, executive cognitive function, reduced efficiency of recent memory, difficulty with concentration & word finding, confusion, disorientation.

(iii) Effect is exerted via capillary hypoperfusion in the brain.

(iv) (i) Coagulopathies (correctable with DDAVP/Desmopressin by enabling fibrin monomers to form multimers)

(c) MMP9

(d) TGF β-1   

(i) When TGF β-1 issues are fixed, autoimmunity resolves.

(ii) Stimulated by a variety of cell types, not just HIF (Hypoxia Inducible Factor)

(iii) Will down-regulate VEGF

(e) HIF turns them both on, TGF β-1 is slow to react; down-regulates VEGF

(2) Correct hormonal dysregulation

(a) If estradiol is elevated, consider an aromatase inhibitor.

(b) MSH deficiency commonly causes hormonal issues.

(c) ACTH-Cortisol

(3) Deal with autoimmunity

(a) Look for anti-gliadin antibodies

(b) Anti-cardiolipin antibodies (ACLA)

(i) Spontaneous abortions in women of reproductive age, first trimester fetal loss

a. Also, lack of MSH will do this.

b. Mycotoxic exposures can also cause this.

(4) Improve capillary hypoperfusion

(a) What happens to a cell if you starve it but don’t kill it?

(b) Inadequate delivery of oxygen does not mean the problem is due to mitochondrial dysfunction.

(c) Inadequate delivery of sugar and other metabolites doesn’t mean that there is a primary metabolic disorder.

(d) Hypoperfusion will cause reduced glycogen content in muscle and other organs as well as protein wasting

(5)   Eradicate commensal staphs

(a) A multi-headed beast

(b) Biofilm forming coagulase negative Staph

(i) Produce exotoxins that split MSH

(ii) Make hemolysins that set off cytokine responses

(iii) Lower T-Regulatory cell counts as well

(iv) If an aerobe such as staph living in the sinuses can do all of these things, what happens in the gut?

a. There are lots of commensal’s there too!

b. Are they altering our host innate immune responses?

c. Of course they do; look at Ulcerative Colitis!

01. When TGF β-1 is corrected, the patient will convert their ANCA’s to negative.

02. What set it off to begin with?

(c) These staph don’t cause allergic, infectious symptoms;

(i) Cannot survive without adequate MSH.

(ii) What would happen if MSH were added to Biofilm forming Staph?

a. Syngen, a pharmaceutical company

b. Topical MSH wipes out Candida and others

(6) Correct cellular immunity

(a) Dr. Lewis Thomas, 1974, unaware of C4a yet talks of complement activation, didn’t know about TGF β-1 but talks about the many host responses that become a disease related to poor capillary perfusion.

2) Please stop guessing!

A) Assumptions destroy good medicine

(1) “Thou shall not assume!” (The 11th Commandment!)

(2) Use objective parameters

(3) Symptoms alone are non-specific

(a) They’ll tell you something is wrong, not what is wrong

(b) Many of the illnesses listed in A-1 above cause the same symptoms, but all have different causalities and therapies

(c) Symptoms don’t ensure causation of complex multisymptom illness

(d) The field of chronic fatiguing illnesses is filled with assumptions

(e) Let’s stop such nonsense; the data from reliable labs will set you free!

(4) Assumptions of assumptions are fatal to chronic illness management

(a) Ass2

(5) Psychiatric diagnosis are the worst, with Fibromyalgia a close second

(6) “You look good, you couldn’t be ill”

(7) “All labs are normal”

(8)   Reliable labs;

(a)  LabCorp & Quest frequently change their “normal” ranges

(b) “Alternative” labs may not have reproducible data—run the same test several times on the same patient sample—the results should be very similar…

(c) “Split-Samples” can help you decide if lab is good or not; submit same specimen more than once, beware of result disparity

B) Hunting in the dark with a hammer?

(1) A flashlight is a better idea

(2) Let there be light

(3) High light/heat ratios

(4) Always challenge today’s hypothesis tomorrow

(a) Eg; Cellular Immunity

(5) Knowledge is dynamic

(a) Changes daily with new research findings

(6)   Understanding is basic

3) Systems Approach

A) In depositions, the non-systems approach is used; “You are not a toxicologist, an immunologist, a pulmonologist, a geneticist, an epidemiologist, a rheumatologist, a neuroradiologist or any other specialty are you?”

B) Glean from it all!  Absence of a systems approach will guarantee all the specialty care fails to understand the whole picture.

C) The unit of care is the person, not an individual organ system

D) Wooded wetlands can teach you, all you need to do is listen:

(1) Tell the transition zones by the shifts in vegetation

(2) Strength of the forest mat of intertwined root systems; take out one element of the system and the entire system fails

(3) Disrupt one element of a food chain by our actions and watch for disaster

(4) Ecosystems show us systemic thinking!

(5) There will be different “ecosystem” effects in people with the changes wrought by the Chronic Inflammatory Response Syndrome; changes in MSH, TGF β-1 /low VO2max, VIP etc.  It all needs to be re-regulated and brought back into balance!

4) Human Ecology;

A) Who we are, our genetics, changes our response to…

B) Where we are, our environment

C) Creating what we are in health

D) Complex, interacting, ever-changing

E) Influence of what happened to us a year ago affects what will happen to us tomorrow.

F) Why is man created to deteriorate, “suffer and die”?

(1) Why not?

(2) What is causing the suffering?

(a) We’re not looking at the “terminal decay at the end of life”, we’re looking at correctable illnesses.

(3) When is illness irreversible?

(a) Inflammatory problems are reversible!

(4) Goal is then to intervene to stop the pathophysiology, restore health.

(5) Goal in “my illnesses” is to restore regulation.

(6)   But first, we must stop inflammation!

G) Traditional model of chronic illness;

(1) Cancer, trauma, acute infectious diseases—don’t apply here

(2) Degenerative processes are inevitable

(a) Result of small changes adding up over time

(b) Htn, ASCVD, DM, COPD, OA, Osteoporosis, Cognition

(3) Yet, these ideas ignore inflammation

H) Biotoxin Symptoms; (many unusual symptoms)

(1) Fatigue, weak

(2) Ache, cramps

(3) Unusual sharp, claw, electrical pains

(a) May have high osmolalities and low ADH activity with polydypsia, polyuria, extra salt thru sweatąelevated sweat chloride test!

(b) Clawed digits; tetanic contractures in muscles in end-circulation with buildup of lactic acidącapillary hypoperfusion

(4) Light sensitivity, red, blurred, tearing

(5) SOB, Cough, Sinus

(6) Abdominal Pains, Secretory diarrhea

(7) Joints, morning stiffness

(8) Executive, cognitive, memory, concern, word-finding, assimilation, confusion, disorientation

(9)   Mood, Appetite, sweats, Temperature regulation

(10)  Thirst/polydypsia, polyuria, Shocks

(11) Paresthesias, taste disturbances

(12)  Vertigo, tremors, skin changes

(13) Look at “cluster analysis” with logistic regression with Visual Contrast Sensitivity scores

I) Symptom Cluster Analysis; (common in Biotoxin illnesses, check MSH/C3a/C4a/TGF β-1)

(1) Fatigue

(2) Weakness, poor assimilation, aching, headache, light sensitivity

(3) Memory loss, dysphasia

(4) Impaired concentration

(5) AM stiffness, joints, cramps

(6)  Unusual skin sensations, paresthesias

(7) SOB, sinus

(8) Cough, thirst, confusion

(9) Appetite, body temperature regulation, urinary frequency

(10)  Red tearing eyes, blurred vision, sweats, mood, ice pick pains

(11) Abdominal pain, diarrhea, numbness

(12) Tearing, disorientation, metallic taste

(13) Static shocks, vertigo

J) No biomarkers mean No data!

(1) Critics can call the illnesses medically uncertain

(2) Critics can and do label patients and providers as wacko’s

(3) “GOMER”

(4) Litigation, Secondary gain

(5) Munchausen’s; folie a deux

(6)  Revisit the idiocy of assumptions

II Back to Top of Biotoxin Illness Outline

 

III Biotoxin Pathway Overview:

1) Data answers the critics

A) 8,400 patients in one practice

B) 14 collaborating physicians

C) Data collection is updated daily

D) Labs used are all based on literature, new labs will certainly emerge

E)  Number of Published Clinical Trials; 14 studies total by RCS

(1) Mold (6 studies)

(2) Ciguatera (1 study)

(3) Cyanobacteria (1 study)

(4) Lyme (2 studies, including Babesia)

(5) Pfiesteria (Dinoflagellates)  (4 studies, including Grand Rounds in EHP)*

(a) * Double-blinded placebo controlled trial

F) Pending Papers

(1) HLA DR defines environmental genetic interactions in Biotoxin illness

(2) VIP clinical Trial

(3) T regulatory cells in TGF β-1 illnesses

(4) Rx C4a and MR Spectroscopy

(5) How about the collaborative study on VIP?  Everyone here ready?

2) Innate immunity is old, but it isn’t

A) System of antigen detection and inflammatory response is over three billion years old such as TOLL receptors

(1) 1989 Yale, first big studies in innate immunity

(2) This study is <30 years old!

(3) Evolutionarily conserved in mice, men, sea squirts and slime molds

(4) Look what came first; blue-green algae, fungi, Dinoflagellates, spirochetes.

(5) Look at the illnesses

B) Look for the Final Common Pathway:

(1) Abnormalities in innate immune responses (non-specific for cause)

(2) Call it the “host response”

(3) Incredible amplification of multiple pathways following initiation

(4) CHRONIC INFLAMMATORY RESPONSE SYNDROMES!

(5) No single abnormality defines CIRS, look at all eight factors

3) Don’t forget this is the host response

A) How many molecules does it take to set off the inflammatory cascade?

(1) Maybe 6,000 total molecules!

(2) 1X10-23 grams!

(3) Classical equal and opposite physics is not exponential biology

(4) Cytokines, Complement, Cell-Mediated Immunity, Capillary hypoperfusion, tissue regulation of T-regulatory cells, coagulation; all ongoing and interacting.

(5) Check VonWillebrand profile

4) CIRS is systemic, interacting…

A) There is no way to say just one lab result is the source of fatigue, cognitive abnormalities, joint and respiratory problems

B) All of the putative diagnosis’ have the same final common pathway

C) You will see the same combination of multisymptom illness and labs

D) Differential diagnosis is key!

E) Coagulation abnormalities

(1) Check VonWillebrand’s profile

(a) Factor 8 is an acute-phase reactant; will be either hugely elevated or very low

(b) Ristocetin associated cofactor; will be either hugely elevated or very low

(c) VonWillebrand’s Antigen; will be either hugely elevated or very low

(i) With Low Ristocetin associated cofactor and high C4a from a moldy environment, the combination will prevent the ability of the VonWillebrand’s factors to make a multimer to allow coagulation.

a. This will frequently cause mucosal bleeding

b. With normal C4a, multimerization will occur

c. This is an acquired VonWillebrand’s syndrome!

d. It’s part of the CIRS complex

5)  CIRS

A) Once you recognize it; your life as a physician will be changed forever

B) Lack of regulation of inflammation

C) Enhanced innate inflammatory parameters

(1) C3a

(2) C4a

(3) TGF β-1,

(4) MMP9

(5) And more

D) Hormonal dysregulation

E) Hypoxia from capillary hypoperfusion Low VO2max

F)  T-regulatory dysfunction

G) MARCoNS

(1) Multiple antibiotic resistant coagulase negative staph

(2) Drop “a” to make it MRCoNS if methicillin resistant only

(3) Of the MSH-deficient patients, 80% will have MARCoNS

(a) Of those MARCoNS, 60% will be methicillin resistant

(4) Remember that Coagulase negative staph (Eg. Epidermidis) and Coagulase positive staph (aureus) get together and exchange plasmids

(a) Plasmids for antibiotic resistance are generated by the differentiation of these previously planktonic motile forms within Biofilm.

(b) We don’t have a good way to stop the plasmids within the biofilms. 

(c) Coagulase negative staph is a huge reservoir of these plasmids just waiting to be inserted into more pathogenic organisms.

H) Colonizing commensal MARCoNS

I) VonWillebrand’s factor-66% abnormal: Acute reactants?  NO.

J) Autoimmunity like crazy!

(1) AGA, ACLA, ANA, ANCA, Actin

(2) If a (+) ANA, check their TGFβ-1 which should be high, measure these parameters until they resolve

(3) ANCA elevated with TGF β-1 elevations

(4) Cellular immunity: TGF β-1

(5) Activated complement split products (C3a, C4a)

K)  Environment and genetics is a big deal!

(1) SNP studies abound (so what!)

(2) What prospective data do we have using genetic basis for susceptibility?

(3) Where can we link genetics in the pathophysiology of susceptibility?

(4) What can we access now using labs that are commercially accessible?

(5) The concept of susceptibility truly begins with genetics.

L) What is the genetic basis of susceptibility to biotoxin illness?

(1) Look at HLA DR

(2) Immune response genes

(3) Chromosome 6

(4) Two copies code for a recognition structure

(5) Inside dendritic cells; in the surface of macrophages and lymphocytes.

(6)  HLA is a marker on the cell surface for macrophages and monocytes to help them to identify a particular antigen.

(a) With high IL-10, HLA presentation is suppressed.  IL-10 is an anti-inflammatory T2 suppressor, it’s not anti-inflammatory as much as it is immune paralytic

(b) It removes the detection mechanism

M)  Antigen presentation process

(1) Binding to receptor on dendritic WBC

(2) Phagocytosis (a primitive component of innate immunity!)

(3) Endosome must be acidified to open it up and allow…

(4) Fusion with lysosome to produce an endo-phago-lysosome which then

(5) Fuses with endoplasmic reticulum forms a “processed antigen” then is…

(6)   Presented to naēve T cell and

(7)  Presentation to B cell

(8) This pathway can be interrupted many different ways;

(a) Polycyclic ethers, such as dinoflagellotoxins, block the acidification of the endosome.

(b) Environmental acquisition of insulin resistance such that insulin receptors are taken into cells such as hepatocytes which creates an endosome but in the presence of moninsin or nigerisin (both are dinoflagellotoxins) preventing the release of insulin and monosaccharide which would allow monosaccharide delivery to glycogen for polymerization.

(i) Moninsin is added to chicken feed.

a. It’s a compound that kills small predators called Immeria which kills little chickens

b. 100 mg of Moninsin added to the chicken feed is cheaper than vaccinating the chicks against Immeria

c. Insulin resistance can occur up the food chain when the Moninsin treated chicken is consumed.

d. Remember that insulin is an inflammatory agent

e. Prolonged cooking can reduce glycemic index of foods

(ii) Moninsin causes insulin resistance!

(iii) Physicians advise patients with insulin resistance to avoid red meat and eat more chicken!

(iv) Even organic chicken may have Moninsin

(v) Range-fed chicken is probably OK

N)  There are countless ways to go wrong

(1) Receptors must recognize the antigen

(a) Defective antigen presentation is the primary problem in this process.

(b) This problem stays with people once they become ill.

(c) The beauty of VIP is that once people become ill, it appears that VIP may reverse the defective antigen presentation problem that ill people have.

(d) VIP appears to do this by restoring regulation of the inflammatory process.

(2) Endosomes must be acidified

(3) HLA must be loaded onto the phagolysosome by the endoplasmic reticulum (role of autophagy)

(4) There must be clear binding to naēve T cells; this takes time

(5) Disrupted by CTL; can’t tell you about T to B cell

6) What is Susceptibility?  Simply put, it’s Relative risk

A) An epidemiologic term

B) Incidence in cases divided by incidence in controls (cases/controls)

C) >/= 2.0 is what usually is required

D) Several prominent studies from the CDC in CFS looked at 1.5

E) 1.5 just wasn’t powered strongly enough statistically.

F) Relative Risk by illness

(1) Looking at the 54 HLA DR Haplotypes

(2) Mold (CIRS-WDB) has 6 Haplotypes (24% of the total population)

(3) Lyme has 5 Haplotypes (21% of the total population)

(a) Infectious Disease Society of America references that about 20% of patients do not respond to antibiotic therapy (without paying attention to their haplotype).

(4) Ciguatera has 3 Haplotypes

(5) We have data on all 54 total Haplotypes

(6)   Nothing in biology is 100%, BUT…

(7) If you have non-susceptible Haplotypes and get ill, prognosis is better, these patients are easier to treat, get better faster.

7) DREADED GENOTYPES (See Rosetta Stone document)

A) 4-3-53; 12 subtypes (3% incidence) (the worst RA, malaria, autoimmune hepatitis)

(1) -0401, -0402 and -0404 are the worst

B) 11-3-52B (also 12-3-52B in labs) (1% incidence)

(1) Vaccine and long, tall, hypermobile, good athletes

C) 14-5-52B rare but multisusceptible (0.1% incidence)

(1) Incidence is 3%, 1% and 0.1% respectively

D) 13-3-52A is <0.05% incidence

E) HLA DRB1-0401

(1) Worst C4a and worst TGF β-1 elevations

(2) Most commonly seen with multiple lab abnormalities

(3) Worst TB, Malaria, autoimmune hepatitis

(4) LymeRx vaccine (OspA)

(a) Experiment to see if defective antigen presentation actually hurt people

(b) >90% of those who had bad reactions to the LymeRx had this haplotype

(5) Even with these dreaded genotypes, the patient will be asymptomatic until they undergo a “priming event” that causes cytokine release

(a) Lyme disease or vaccine

(b) Mononucleosis

(c) EBF

(d) XMRV

(e) Coxsackie

(f) Enterovirus

(g) Kawasaki’s disease

(h) Pneumovax

(i) Yellow jacket stings

(j) Any other event that causes cytokine release

8) Pfiesteria changed my world forever

A) Who could help? No one

B) Who could teach? No one

C) Who can I believe from the state?  No one (Sad)

D) Who is deliberately trying to minimize the importance of altered environmental conditions?

E) When the first big fish-kills started, the patients started coming in sick

(1) HA, myalgias, arthralgias, cough, memory problems, cognition etc.

(2) Secretory diarrhea—empiric use of Cholestyramine

(a) Cholestyramine can be compounded without Aspartame

F) All other symptoms improved with Cholestyramine, so empiric Cholestyramine was started on everybody symptomatic

(1) All basic labs were negative

(2) Lung disease was restrictive, not obstructive as in asthma.

G) Everyone said it was nutrients in the river (pollutants)

(1) Levels were unchanged

(2) An old mold, now resistant to standard fungicides was devastating crops exactly where fish kills occurred

(a) Use the old copper and Mancozeb (dithiocarbamate fungicide).

(b) Copper was being deposited along the distal bank of river bends (palustrine) linked with new plant growth in the pore water, copper was in the porewater of the mud, not in the free water column.

(c) Pfiesteria blooms occurred with the copper deposition

(d) Copper in the water column from the porewater was killing the Pfiesteria prey by allowing its prey to become free-swimming and motile

(e) Copper was also killing the nematodes that prey upon Pfiesteria

H) Could fungicides be the source?

I) Look to systems biology; find the copper in porewater at palustrine emergent vegetation sites exactly as the model said

J) Confirmation came TEN years later!

K) This illness was fascinating

(1) There were no clear physical findings

(a) The only way to make a diagnosis was by patient history

(2) Toxin binding with Cholestyramine helped clinically

(3) Capillary hypoperfusion was the clearly changing aspect (HRF & VCS) http://www.survivingmold.com/store1/online-screening-test

(a) The EPA for neurotoxicology studies approved the VCS; VCS showed deficits in Pfiesteria patients that weren’t found anywhere else.

(b) VCS was used as a biomarker, within three days of therapy it had improved, and typically within 2 weeks it normalized.

(c)  VCS fell again with re-exposure to the source of the toxin

(d)  Re-treatment resulted in restoration to improved or normal VCS

(e) Symptoms were demonstrated to be linked to reduce retinal capillary perfusion

9) Lyme taught us about cytokines

A) Lyme produced a toxin that diminished retinal capillary perfusion

B) Cholestyramine actually worsened their symptoms of CIRS

(1) Measure MMP9 (rising MMP9 is due to cytokine release-check it before starting antibiotics for Lyme as well), repeat VCS; results will fall in rows E&D, recheck them after Cholestyramine dose 6 to 10).

(2) The intensification of symptoms and drop in VCS correlates with simultaneous cytokine release; “cytokine storm”.

(a) This is probably related to Cholestyramine binding toxin, temporarily reducing the amount of free toxin

(b) With lower free-toxin concentration, receptor-ligands to the bound toxin release resulting in rebound increase in free toxin and increase in symptoms with the cytokine increase from toxin binding to the dendritic cells.

C) Pioglitazone, (Actos) also blocks cytokine production.

(1) Actos pretreatment for 5-10 days didn’t work without…

(2) Low amylase/low glycemic index diet given with Actos worked to block cytokine production/symptom worsening from cytokine Blocks

(a) TNF

(b) MMP9

(c) Plasminogen activator inhibitor-1 (PIE-1)

(d) Leptin levels decreased

(3) HLA yielded individual susceptibility

(4) Who ever heard of biofilm producers splitting MSH?

10) Benomyl (Agricultural uses of Benomyl causing resistance)

A) Blocks of insertion of microtubules during anaphase of mitosis

(1) Benomyl blocks the insertion of the microtubule to the kineticore

(2) Mitosis becomes faulty, thus

(3) Benomyl is a potent mutagen; causing cellular mutations

(4)  TGF β-1 microtubule mutations allowed fungi to overcome the Benomyl fungicidal/mutagen effect.

(5)  Another mutation fungi experienced involving moving an acetyl group on the mycotoxin thus evolving a new mycotoxin that was not a native wild-type toxin

(6) The mutant fungus (Fusarium oxysporin select) producing the mutant mycotoxin produced cyanide in the rhizosome/fungal root which allowed Pseudomonas flourescens used the cyanide as an energy source

(a) This created an altered ecosystem in the soil

(b) Allowing P. flourescens to overgrow other soil consensuals

(7) People living in areas where this were occurring became symptomatic with CIRS

11) Ecosystems and human health

A) A lesson in systems biology

B) Palustrine emergent vegetation with high nitrogen value located where the blooms were occurring

C) Heavy metals deposited in porewater sites

D) There was a huge availability of reduced copper compounds in the porewater sites

12) Lyme changed a lot of early thinking about biotoxins

A) Application of pure biotoxin theories to Lyme just doesn’t work

(1) There are other things going on with Lyme toxin

(2) These seem to involve cell-mediated immunity

(3) TGF β-1 (high levels are bad, therapy aims to reduce level)

(a) Turns on differential gene activation

(b) Affects autoimmunity

(c) Increases T-regulatory cell counts

(i) Initially may appear to exert an anti-inflammatory effect; BUT

(ii) TGF β-1 actually converts T-regulatory cells to become pathogenic T cells/T-Effector Cells.

(iii) This drives a positive-feedback loop that continues tissue damage

a. This concept is more important in Lyme than many of the other conditions

(d) These T-effector cells then generate more TGF β-1

13) Neurotoxins from Dinoflagellates, Cynaophyta (blue green algae/bacteria) and fungi all responded to Cholestyramine

A) 1999 Dr. Donta shows a Lyme neurotoxin

B) Lyme patient’s symptoms intensified

(1) What? Cytokine fluxes (MMP9)!

(2) Blocked by 5-10 day pretreatment with Actos (and/or high-dose omega-3 fatty acids)

(3)   Actos only worked with a no amylose diet

C) If Cytokines are involved with Lyme, what about other biotoxin illnesses?

(1) Cytokines are released by one cell to affect many others

(2) Labs for cytokines aren’t reliable

(3) Autocrine, Paracrine, Endocrine

(a) Autocrine effect; Cytokine activity on cells in an immediately adjacent site next to the cell releasing the cytokine

(b) Paracrine effect; Cytokine affecting nearby cells (i. & ii. Cannot be measured in blood tests, only iii. Can be measured).

(c) Endocrine effect; Cytokine affecting distant cells and tissues. (This is the only effect that can be measured with blood tests).

(d) Measuring cytokines themselves is thus flawed in terms of CIRS

14) Measuring MMP9 directly measures the pro-inflammatory cytokine effect on receptors in endothelium and macrophages

A) Cytokines are pre-formed and stored in intracellular vacuoles

(1) MMP9 is generated after pro-inflammatory cytokines bind to endothelial cells and macrophages which then…

(2) Initiate differential gene activation leading to the production of MMP14 which is then split to MMP9

(a) Interleukin 2 (IL-2) is another important mediator

(3) Sequence of events; Exposure to toxiną symptoms if previously primed and HLA susceptibleąturns on gene activation which leads to manufacture of a “pro-molecule” (MMP14) that is then split to the active compound (MMP9)ą CIRS.

(a) The maximum time for generation of MMP9 after a point source exposure is between 2-3 days

(b) If you want to measure inflammatory markers after hyperacute exposure to toxin, measure C4a, which changes within a day.

(c) Cytokines can cross the blood-brain barrier to bind to a Leptin receptor, which lowers MSH transcription…

(i) Leptin rises with acute receptor resistance on day 2

(ii) MMP9 increases on day 3

(4) Fixing cytokines helped many but not all; what else was there?

(5) Not all people had cytokine excess

(6) VCS helped a lot, but some stayed ill despite corrected VCS

B) 5-year follow-up of Pfiesteria Exposed

(1) Triple-matched controls

(2) Despite symptom-improvement, there was a…

(3) Dramatic increase in death and disability within five years

(4) VCS/MMP9/VEGF (Vascular Endothelial Growth Factor)/ADH/Osmolality were all OK

(a) VEGF released in response to capillary hypoperfusionąreduced oxygen delivery to tissues

(b) Increasing VEGF will bring about greater oxygen delivery after cytokine-induced capillary hypoperfusion

(c) New blood vessel formation also happens with increased VEGF

(d) Remember that cancer is an obligate aerobe; it uses sugar for energy, thus requiring a lot of tissue oxygen delivery…

(e) Increasing VEGF could increase cancer growth

(f) VEGF inhibitors are key oncologic interventions

(g) Low VEGF is quite common in biotoxic patients

(i) They have capillary hypoperfusion

(ii) They’re not delivering more oxygen due to rising VEGF when they should be

(iii) They’re functionally acting like they were exposed to a chemotherapeutic agent for cancer

a. Fumagilin, made by Aspergillus fumagotus inhibits endothelial growth

(iv) Low VEGF can be fixed by Actos/no amylose diet

a. Remember, Actos lowers Leptin, if Leptin<7 then use

b. Omega-3 fatty acids at high doses

01.  2.4 gm. EPA/d

02.  1.8 gm. DHA/d

(5) What was missed?

15) Enter C3a, C4a from work by Dr. Giclas

A) C3a and C4a are produced from cleavage/activation of Complement;

B) C4 activation is accomplished by MASP-2 (Mannose-binding elected associated serum protease)

(1) MASP-2 is activated by

(a) Ficolins

(b) Acetylated environmental compounds

(i) This is similar to what Benomyl did

(c) The toxicity seems to actually be coming from C4a

(i) To aggravate this situation, MASP-2 can actually auto-activate or turn itself on.

(d) So use of Benomyl in 1974 to prevent fungal growth in paint, created new classes of mutant fungi

(e) Generally speaking, without a ficolin or acetylated environmental compounds, MASP-2 doesn’t get turned on.

(i) Thus, C4a won’t be elevated

(2)   Stunning!

16) Biotoxins

A) Very small molecules; ionophores

(1)   Ionophores are able to move from cell to cell

B) Inflammagens bind to receptors

(1) Toll; mannose, ficolins, C-linked lectins

C) Predictable inflammatory results

D) Direct measurement of biotoxins in blood is not helpful

(1) The chance of finding it in the blood is about zero

(2) The chance of finding it on it’s receptor is much higher

(3) The disassociation concentration for Ciguatoxin is about 1X10-14; it’s highly bound to it’s receptor; a blood test won’t help

(4) How can Cholestyramine remove Ciguatoxin?

(a) The answer is that the disassociation constant is not zero.

(b) Although highly bound, it will eventually migrate off of the receptor so that it can be bound in the gut and removed.

(c) Ciguatera responds much more slowly than Pfiesteria or mold toxins, which have much lower disassociation constants.

E) Examples of biotoxins;

Agent

LD50

Molecular Wt.

Source

Botulinum

0.001

150,000

Bacterium

Shiga Toxin

0.002

55,000

Bacterium

Diphtheria Toxin

0.10

62,000

Bacterium

Maitotoxin

0.10

3,400

Marine Dinoflagellate

Ciguatoxin

0.40

1,000

Fish/marine Dinoflagellate

Batrachotoxin

2.0

539

Arrow-Poison Frog

Ricin

3.0

64,000

Castor Bean

Conotoxin

5.0

1,500

Cone Snail

Tetrodotoxin

8.0

319

Puffer fish

αTityustoxin

9.0

8.000

Scorpion

Microcystin

50.0

994

Blue-Green Algae

Sarin

100.0

140

Chemical Agent

Aconntine

100.0

647

Plant (Monkshood)

T-2 Toxin

1,210.0

466

Fungal Mycotoxin

17) What can be fixed about C3a elevations?

A) C3a is generated when C4a & C2a are made by the activation of MASP-2; splitting C4 & C2 together creates C4b and C2a that activate C3 if there is a bacterial membrane present

B) C3a presence indicates that bacterial membranes are still present inside blood

C) C3a increases within 12 hours of a tick bite in people who go on to develop Lyme disease

D) If HLA is Lyme-susceptible, the patient will probably need more than just 3 weeks of antibiotics.

(1) If not HLA susceptible, then resolution of elevated C3a, C4a and VCS should occur without further intervention.

E) If, after 3 weeks of antibiotics, there is still sero-evidence of infection, then it’s time to start therapy for CIRS.

(1) Baseline CIRS serology is drawn before giving antibiotics for Lyme.

(2) If dealing with a new tick-bite patient, the window for inflammatory change is 96 hours, after 96 hours there should be evidence of inflammation if the tick was infected

(a) VCS is a quick/easy test to use before drawing labs; if it’s normal 96 or more hours after tick bite, there was probably no Borrelia

(3) After three weeks of antibiotics, if C3a & C4a are still elevated, a month of Cholestyramine and Actos are given, and then after a week of no medications, repeat C3a and C4a are rechecked.

(a) If C3a is stable with C4a increasing, then the patient has had a concurrent mold toxin exposure.

(b) Labs won’t be available overnight

(i) Check their VCS

(ii) Check their symptom level; are they improving?

(4) If C3a & C4a are stable, repeat them in a month

(a) If there are still live Lyme spirochetes (Borrelia burgdorferi) the C3a (membranes present) and C4a (causing inflammation) will rise within a month.

F) If live organisms are present after 3 weeks of oral antibiotics, it may be time to switch to IV antibiotic therapy

(1) If C3a is still elevated after three weeks of antibiotics, then…

(2) High dose statins had some literature support

(a) Some of the beneficial effect of statins may be due to lowering C3a

(3) Such high doses caused outrageous muscle cramping and rhambdomyolysis

(4) Statins lower ubiquinone and ubiquinol (CoQ10)

(5) Replenishment of CoQ10 with 150 mg/d improves tolerability of statins

(a) Pre-treat with CoQ10 for a few weeks prior to starting statins

(6) C3a was no longer a big problem

18) C4a Appears as an available lab test in June 2005

19) MR Spectroscopy allows measurement of;

A) N-Acetyl aspartate; a marker of CNS white matter disease

(1) Creatine as a control & cell mass measure

B) Acetyl choline

C) Myoinosotol; indicates glial cell injury

D) Lactate

E) Mold Warriors was outdated within 2 months of publication

F) Correcting existing illness helps

G) High C4a is correlated with CNS capillary hypoperfusion

(1) Lactate;

(2) Glutamate (excitatory) to Glutamine (inhibitory) ratio (excite/inhibit) (ate/ine)

(3) With reduced capillary perfusion comes reduced mitochondrial activity (& aerobic respiration)ą increase lactate production from glycolysis.

(4) Brain fog is associated with increased lactate and suppression of the Glutamate/Glutamine ratio (more inhibition than excitation)

H) Lowering C4a with erythropoietin corrected lactate and G/G

(1) Excessive clotting happens with head and neck cancer

(2) HIV is a heavily cytokine influenced disease

(3) Low doses of erythropoietin are used;

(a) Erythropoietin causes tissue remodeling/repair

(b) 8,000 units erythropoietin SQ Monday and Thursday for a total of 5 doses, (1 40,000 unit vial)

(c) Higher doses of erythropoietin once/week show no benefit due to its short half-life of 1.5 days.

(d) Repeat MR Spectroscopy after erythropoietin

(e) Informed consent is signed before erythropoietin therapy.  It’s just “off-label” use of the drug.

(4)   Cognitive effects disappeared

I) This is Lab-Intensive Medicine;

(1) Review and copy morning labs

(2) Prepare data sets constantly

(3) Patterns emerge; look at the correlations that come from reading trends and graphs

(4) Picking out lab errors is easy

(5) HLA DQ3 versus HLA DQ7 in 2004; LabCorp changed their reporting system of these two haplotypes

J) Being a lab-jockey can show flaws in medical dogma

(1) Celiac disease association with HLA DQ2 (and 8 a little bit) right?

(2) Wrong!  It’s associated with 17-2-52 A, B, C and then 7-2-53

(3) Linkage disequilibrium

(4) Mold illness is too; how many AGA (+) people were moldy or Lyme or CFS?  Just about all of them)

20) Sure enough, MMP9 is a problem

A) Esoterix set up an assay for Dr. Shoemaker only

B) The only person in the US with MMP9 data was Dr. Shoemaker

C) Only he knew cases and controls

D) Esoterix lumped all values together to create a “normal” range which was garbage

E) Quest agreed to do the work properly

F) MMP9 must be drawn in a clot or SST tube

(1) Tube is not allowed to set up at room temperature which means macrophage activity is not going to be stopped by room temperature clotting.

(2) MMP9 is generated by macrophages and endothelial cells

(3) If you don’t control how the specimen is handled, your MMP9 levels will double and triple at room temperature in as little as 30 minutes.

(4) The specimen must be drawn into a cold tube, immediately centrifuged and refrigerated.

G)  Only in 2011 is the MMP9 normal range problem corrected;

(1) LabCorp purchased Esoterix in 2004

(2) Continued to use the normal range of <984

(3) Would not listen to logic

(4) Quest does the MMP9 levels

(a) Normal is <332

(5) Quest won’t do this for other physicians

21) MSH

A) ALPCO kit done by LabCorp

B) Normal range is 35-81 pg/ml

C) Suddenly on 9/26/06 normal range is 0-40

(1) “0” is never a normal range for these metabolic regulators

D) The only change was a lawsuit in Maryland 8/15/06 where low MSH was of key importance and the insurance company paid out a lot of money

E) Now <35 is a “critical value”

F) LabCorp “threw Dr. S a bone”

(1) They now label MSH <35 as a panic value requiring immediate notification of ordering provider

(2) They formerly ran the MSH Friday afternoons, necessitating weekend calls

(3) Now they run the tests Friday mornings, fax the result and have an undisturbed weekend

22) Microbiology leads the way to next; Biofilm

A) What is this biofilm?

(1) Bacteria differentiate inside the biofilm

(2) Standard cultures of the nares will show the faster growing organisms, not the organisms in the biofilm, which grow slower. The faster organisms are reported in 48 hours

B) You must use an API Staph Isolate to get the biofilm forming Coagulase (-) Staph https://www.dxos.com/mold-illness-testing/

(1) Swab has a pink-red top

(2) Insert swab as deep into the nare as possible, beyond the turbinates, leave the swab at the back of the nasopharynx for 5 seconds

(3) Most MARCoNS (+) patients will want a second culture to prove eradication.

(4) MARCoNS (+)/MSH deficient patients will get very little improvement with Cholestyramine alone if the infection isn’t also treated.

(5) Knock out toxin carriage with Cholestyramine, then MARCoNS with BEG; follow with VCS to document progress each step of the way.

C) Why do these funny staphs make an exotoxin that splits MSH?

(1) Coagulase Negative Staph develop best in an MSH deficient patient

(2) The staph must be eliminated after the first month of Cholestyramine

(3) Use BEG spray; Bactroban, EDTA & Gentamycin from Hopkinton Compounding Pharmacy

(4) These MARCoNS in MSH deficient patients also lower the T-Regulatory lymphocytes

(a) This is a case of commensals affecting the human body’s immune regulation

(b) Who knows what is also going on in the gut with a billion anaerobes for every 10 aerobes?

D) What does hemolysin do?

(1) If the biofilm formers are true commensals, there must be permissive host factor right?

(2) Guess what?

(3) Staph biofilms also lower CD4+, CD25+ too

(4) The whole idea of commensals altering host response isn’t confined to nasal staphs

(5) Look at the GI tract

(6) Consider; could autism be part of the result of this?

(a) They can be colonized by multiple unusual Clostridia species

(7) Clostridia boltii?

E) Where else is MARCoNS?  Dr. Kulacz

(1) Culture of deep nasal aerobic space

(2) Pulled a tooth the next day

(3) Culture of both sites yielded the same organism

(4) Nothing happened with treatment until the VCS improved

(5) Then Dennis Katz invents the BEG spray

F) BEG Spray (Bactroban/EDTA/Gentamycin from Hopkinton Compounding)

(1) Proprietary formula

(2) Look at all of the EDTA in baby shampoo

(3) Used with oral Rifampin; beware, GI & red staining (do NOT use with Coumadin)

(4) Reduced carriage after Rx to <5%

G) Rifampin Resistance

(1) Bartonella is over-diagnosed

(a) Quinolones are probably overused

(2) Rifampin resistant organisms are very unusual in the wild; are tough to eradicate

(a) Excess use of Rifampin for putative Bartonella can lead to Rifampin resistance in MARCoNS

(3) Crummy diagnosis of Bartonella leads to injury onto which more antibiotics are dumped

(4) We need a good assay for Bartonella

(a) Nasal smears are inadequate to Dx Bartonella

H) Just do the nasal culture!

(1) Is the $50 cost of the nasal culture worth doing if you might spend $20K for Rocephin

(2) API-Staph is needed https://www.dxos.com/mold-illness-testing/

(a) Remember, biofilm forming organisms grow very slowly

(b) They’re outgrown in routine cultures

(3) Best investment anyone can make in low patients with low MSH

(4) If API Staph done for a Lyme patient given antibiotics, the antibiotics may produce a Herxenheimer die-off reaction

(a) The die-off reaction does not mean that MARCoNS were eliminated

(b) MMP9 & VCS will give information on whether MARCoNS is still present

(c) Biofilm formation of Staph CFS Isolates (image below)

I) Description: New Picture

(1)   The more biofilm is present, the worse the disease is

23) VEGF

A) Vascular Endothelial Growth Factor

B) Responsive to Hypoxia Inducible Factor (HIF); feedback from TGF β-1

(1) VEGF rises quickly with hypoxia

(2) In Re-exposure protocol patients, VEGF will also rise quickly initially, but as TGF β-1 is made, the VEGF will decrease

(3) On Day 1 of a re-exposure protocol of a mold patient into a building, it rises, then declines by day 3 when TGF β-1 increases as a feedback interaction from TGF β-1 on VEGF

C) Increases oxygen and new blood vessel formation

(1) Jonah Folkman and anti-angiogenesis knew about VEGF

(2) Blockade of VEGF is a big deal in onco-chemotherapy

(a) It’s most effective at VEGF (+) receptor tumors

D)  But low VEGF is the norm in the worst biotoxin patients

(1) There will be some “U-shaped” Skew, but…

(a) Normal range is 31-86

(b) <31 with biotoxin/CIRS patients

(c) Few normal range patients

(d) Some patients are >86

E) LabCorp “normal” is 0-115 which is meaningless

F) Quest has ranges similar to LabCorp; unreliable.

G) Low VEGF means cell-based starvation.

H) So why are cancer rates lower in CIRS patients than in the general population?

(1)   Is it VEGF related?

(2) Remember, WDB’s have multiple carcinogens!

(a) Mycotoxins are often carcinogenic

I) Remember; do not ignore low VEGF!

(1) The answer must account for the initial rise in VEGF followed by the crash, as we will see in SAIIE.

J) Measure VEGF, Normal range 31-86; don’t ignore low VEGF!

(1) The biology of VEGF is complex!

(a) VEGF is down-regulated by TGF β-1

(b) Actos on Amylose-Free diet and Omega-3’s are key to raising VEGF

K) Capillary hypoperfusion

(1) Bottom line is decreased delivery of nutrients and oxygen into capillary beds

(2) ABG’s won’t help, venous gasses don’t have any academic basis in these illnesses

(3) Use VO2max from Pulmonary stress testing (PST).

(4) Use lactate in MR spectroscopy (which is better than PST)

L) VO2max

(1) Disability examiners frequently use this measurement

(2) Should be >35 in healthy younger people; nomograms are available

(3) 12 ml/kg/min is Stage 4 CHF

(4) Conversely, training to raise VO2max that doesn’t go beyond the anaerobic threshold works in biotoxin patients.

(5) Pulmonary Stress Testing (PST) determining the anaerobic threshold and VO2max is a great way to get disability status for patients and know the reality of that subjective complaint of chronic fatiguing illnesses

(6)   Erythropoietin and VIP will increase VO2max

M) Raising the VO2max shows benefit;

(1) Correcting VEGF must happen

(2) Anaerobic threshold is measured

(3) At exercises; start low, go slow

(4) Must do defined exercise EVERY DAY!

(5) Bike, treadmill, work up to 15 minutes

(6)  Add floor exercises, build up to 15 minutes; then free weights

(7) Go back to first defined work

(8) Increase sequentially on all parameters

(9)  This regimen will dramatically increase exercise capacity.

N) Post-exertional malaise (Mitochondrial Evaluation)

(1) Measure VO2max with PST

(a) It will be low

(2) What about glycogen in exercise?

(a) Remarkably inefficient glucose oxidation

(3) No oxygen, no efficiency

(a) This will rule out mitochondrial illness!

(b) With mitochondrial illness, metabolism will be anaerobic producing pyruvate and lactate.

(c) Capillary hypoperfusion also produces pyruvate and lactate with the anaerobic metabolism

O) Fat storage; after glucose/glycogen are exhausted, fat is used next]

(1) Fat oxidation requires oxygen

(2) Look at Leptin values; there may be Leptin resistance caused by the cytokine activity of CIR, if so, Leptin values will rise

(3) Since fat oxidation requires oxygen, the only thing left to burn for energy is…

P) Protein burning after fat supply is exhausted (Amino Acid Profile)

(1) Alanine and Glutamine the first amino acids to convert to glucose

(2) Remember; exceeding the anaerobic threshold in the absence of carbohydrate leaves only one option; protein catabolism/oxidation for energy.

(3) With Leptin resistance, fat weight is gained due to the high Leptin values as lean body mass decreases.

24) VIP is one of the newest players in the CIRS realm (usually low in CIRS)

A) 26 amino acid neuropeptide in the secretin family

B) Neuromodulatory and immunomodulatory

C) Also affects hormones/endocrine system

D) CIRS patients have a more profound VIP deficiency than their MSH deficiency

E) Elevated VIP at baseline is possible but rare

(1) Requires an octreotide scan looking for a GI VIP-oma (very rare)

F) Neuropeptides that interact with each other include;

(1) Secretin with VIP

(2) Vasopressin with MSH

(3) VIP has a lot of literature describing what it does

(a) Has a strong effect of reducing pulmonary artery systolic pressure

(b) Binds to membrane receptors to raise intracellular cyclic AMP (cAMP)

(c) Down-regulates cytokines

(d) With exercise, it reduces pressure between the right side of the heart and the lung.

(i) Increases Right then Left ventricular stroke volume by doing so.

(ii) Thus increasing exercise tolerance

(e) If Right ventricular stroke volume is reduced or the work required to maintain it is increased, then Left ventricular output will also drop, decreasing Cardiac Output (CO) is (Stroke Volume X Heart Rate)

(i) We depend on venous return to supply Left Atrium to Left Ventricle to enhance stroke volume, which we cannot attain due to increased pulmonary artery pressure, then

(f)  Heart rate must increase to increase the CO/CI producing

(g) Tachycardia, palpitations, SOBOE, tachyarrhythmia’s

(i) Above could be due to pulmonary disease, COPD, Asthma, Fibrosis

(ii) It may be acquired pulmonary hypertension

(4) Dr. Shoemaker did a study on what VIP might be able to do for Pulmonary Hypertension with a clinical trial;

(a) Subjects had low VIP as entry criteria with Hx of elevated C4a & elevated TGF β-1 and a rise >8 Torr Pulmonary Artery Pressure during cardiac stress testing/exercise

(b) 50 mcg dose of VIP was given to subjects qid

(c) NOTE; VIP must be kept refrigerated stored upright in nasal delivery bottle

(d) At the end of a month of qid VIP, repeat lab parameters & pulmonary stress testing was doneąbenefit was provided by qid dosing

(e) Bid dosing was then tried; lab & PA pressuresąall was OK but

(i) Early on there were a number of subjects who felt better on qid than on bid dosing

(ii) This cohort was not decreased to qd dosing but the others were

(f) All subjects were followed for one year then re-tested

(g) Most people, after 6 months can tolerate a reduced dose of VIP from qid to bid, sometimes to qd

(h) This VIP intranasal protocol has essentially cured a large group of chronic fatigue patients.

(5) FDA has designated VIP for treatment of Pulm Htn (other uses are off-label)

G) Remember, if using VIP then sustaining exposure to toxin/WDB etc., everything “goes back to square one”.

(1) The response will be truncated and shortened however after recovery from symptoms by a course of VIP.

(2) Patients will tolerate longer periods of exposure as well.

H) VIP down-regulates MASP-2 (C4 activator to C4a)

I) VIP restores balance of Vitamin D3

J) VIP down-regulates aromatase which breaks down testosterone among other hormones

K) VIP up-regulates (increases low levels of) VEGF

(1) If Actos or fish oil/omega-3 doesn’t work, VIP will correct

L) Warning Re; VIP may cause Lipase to increase a bit; measure baseline and monthly X 3 VO2max

M) VIP’s main effect immediately is endorphin mediated…

(1) Typically within 5 minutes of first dose patients can take a deeper breath

(2) Joint symptoms @ baseline; tight clenched hands will typically open and relax on VIP

(3) Immediate pain relief is a big deal and much appreciated

(4) Cognitive issues respond more slowly

(a) Draw blood at baseline (Lipase, VEGF, C4a, TGF β-1), give VIP, repeat draw (VEGF, C4a, TGF β-1) in 15 minutes

(b) If there is a sudden increase in TGF β-1, there has probably been recent exposure to WDB with ongoing mycotoxin exposure.

N) Followed by lowering Pulmonary Artery Systolic Pressure (PASP) in exercise

25) PA Systolic Pressure (PASP) and VIP

A) 50-mcg qid corrects paradoxical rise in PASP in exercise in days, not weeks, with durable effects with titration to bid and over time, discontinuation!

B) So many people are not diagnosed with acquired Pulmonary Hypertension (PASP elevations) even if they have a stress echo, it MUST precisely measure degree of Tricuspid Regurgitation!

(1) Estimated PASP is; the square of (TRX4) + RV pressure calculated from the Echocardiogram recording.  Calculations are done on the digital reading from the recording.

C) Don’t accept “Normal” on stress-echo report!

26) Measure PASP with exercise (increased SOB with exertion)

A) “Looks like asthma” but it isn’t

B) PASP should not rise more than 8 Torr with exercise

C) Can cause palpitations and SOB

D) Won’t improve with beta-2 agonists (albuterol etc.)

E) Don’t forget EMT and TGF β-1

27) In the face of VIP deficiency, TGF β-1 may increase with exercise

A) TGF β-1 causes cells to transform/tissue remodeling (TRANSFORMING GROWTH factor…) with fibrotic changes in organs…

B) Remodeling occurs in the heart, CNS, liver, lung

(1) Fibrotic changes

(2) Seems to increase alteration of columnar epithelial cells of the airway to fibroblasts

(a) Therapy with agents that reduce TGF β-1 such as VIP will cause IMPROVEMENT in organ function, structure/histology

28) Other VIP Effects;

A) Immunoregulatory; this is a Neuro-Immune link

B) Drives up CD4 + CD25 + FoxP3

(1) CD4+, CD25+ are regulatory T-Cells detected on a flow-cytometry assay

(a) Either CD4+, or CD25+ don’t give useful information

(b) The COMBINATION of CD4+ AND CD25+ provides the useful data

(2) FoxP3 is a nuclear replication factor that provides greater sensitivity than CD4+ and CD25+

C) This demonstrates the link from neuropeptides to humoral factors to T-cell physiology

(1) Role of down-regulation of TGF β-1 has no obvious upper limit in its application.

D) Low TGF β-1in post-Lyme patients treatment with antibiotics

(1) If NOT HLA-susceptible the CD4/CD5’s come back up to normal

(2) HLA-Susceptible pt’s won’t get that effect with antibiotics

(a) Biotoxin/CIRS therapy will bring the CD4/CD5’s back from ~6 which is low up to about 17 (18 is normal)

(b) Adding VIP will drive the number into the mid-20’s

29) Downsides to VIP

A) It’s not cheap

B) Must be refrigerated (OK at room temperature for ~8 hours)

C) Not FDA approved, is FDA designated

D) No Benefit If;

(1) (+) VCS; it’s necessary to clear out the toxin effect before starting VIP

(2) ERMI >2; DO ERMI testing, don’t accept worthless air testing

(a)       ERMI does not account for non-mold inflammagens including VOC’s, endotoxins, Actinomycetes, glucans, glycoproteins & other noxious incitants. 

(3) (+) Nasal MARCoNS (do the test from Cambridge labs!)

30) Is VIP Too good to be true?

A) Reduces SOB/Cognitive problems improve or resolve

B) Reduces joint stiffness in ~10 minutes (causes endorphin release)

C) Improves exercise tolerance

(1) First noted within 2 hours

(2) By 2 days, dramatic effects

D) Global improvement in all modalities

E) Downsides; as above, will increase circulating lipase;

(1) (Maintain index of suspicion if pancreatic/biliary complaints)

F) VIP is safe, basically impossible to overdose

G) Excellent record to date on over 400 patients

H) Easy to use, portable, effective!

(1)   Finally available by Rx

(2)   Just about every Chronic Fatigue Syndrome patient is deficient in VIP

(a)  As soon as word gets out, LOOK OUT!

(b) Concern; people will leap to its use without recognition of what makes it not work.

31) What makes VIP NOT work?

A) ERMI >2 at home/work/school

B) ERMI interpretation; http://www.survivingmold.com/diagnosis/hertsmi-2

C) VCS still positive

D) Untreated

(1) MARCoNS

(2) MMP9

(3) PAI-1 (Plasminogen Activator Inhibitor-1)

(4) High Leptin

(5) High C3a

(6)  High C4a

(7) High TGF β-1

E) Ongoing exposure

32) TGF β-1 Generates TH17 cells, turns on T-regulatory Cells, made by T-effector cells

A) Will have its own section

B) Is the key advancement in assessment of CIRS

(1) Lung symptoms? Ask Re TGF β-1

(2) Neuro problems/Eg resting tremor? Ask Re TGF β-1

(3) Autoimmune? Ask Re TGF β-1

(4) Learning disability? Ask Re TGF β-1

(5) MS? Ask Re TGF β-1

(6) TM? Ask Re TGF β-1

C) First found to have increased tissue effect in those with mutated fibrillin-1

D) Then the switch to plasma measures

E) TGF β-1 normal is <2,380; >5,000 start to worry

F) >10,000 essentially guarantee restrictive lung disease, tremor, cognitive issues and joint problems.

G) Must be done only on double-spun plasma drawn in chilled tubes as platelet-poor plasma.  Need as few platelets as possible

H) If result >40,000 the specimen was not properly handled

(1) Always have a 2nd specimen saved

I) Diagnostic Laboratory Medicine Bedford MA https://www.dxos.com/mold-illness-testing/

33) MR Spectroscopy

A) Requires a 3 Tesla coil; single voxel

B) Examines

(1) Frontal lobes (memory)

(2) Hippocampi (memory and spatial navigation)

C) Measure the same spots/same compounds!

D) High lactate; >1.29 is to high (problematic)

E) Ratio of Glutamate/Glutamine (G/G); <2.19 is to low (problematic)

F) Change in cognition is a tip-off

G) Therapy is aimed at lowering the elevated C4a, causing reversal of high lactate also reverses suppressed G/G

H) Voilaąreversal of cognitive issues!

I) Key concept is that cellular neuronal mechanisms are not permanently injured!

34) T-Regulatory Lymphocytes

A) Thymic derived cells don’t play much of a role in CIRS

B) These are “Induced” T-lymphocytes due to action of high levels of TGF β-1

(1) With active tissue inflammation the three populations of cells below will be hydrolyzed in the inflamed tissues to release T-effector cells which are pathogenic and in turn produce more TGF β-1

(2) CD4+, CD25+, FoxP3 cells

(3) Untreated 6.2; treated 18.7

(4) Controls 17.8; relapse 5.4

(5) Re-treated 19; VIP 24!

C) But FoxP3 unmeasured although LabCorp is setting up an assay for them.

D) Conversion to pathogenic T-cells in tissue (like Einstein’s unknown nuclear factors!)

Back to Top of Biotoxin Illness Outline

 

IV 2011; Genomics time

1) Examining how to stratify patients and controls by differential gene activity

A) Genetic “Fingerprint” is now available for;

(1) Ciguatera

(2) Post-Lyme

(3) WDB pt’s with mycotoxins

B) Chronic fatigue work is ongoing

(1) 500 genes (out of the 40,000 in the human genome) have been selected for evaluation for CFS etiologies

C) Add proteomics

D) Add differential diagnosis, and then try to add in…

E) Epigenetics

F) We’re still back to the essentials of any ecosystem; at 30,000 feet

2) www.mycometrics.com for ERMI testing; $300.00ą2 samples/bldg. analyzed

A) Looks at 9 different fungal types

(1) Wet-wet 80-100% saturation

(a) Ketonium

(b) Stachybotrus

(2) Medium Wet-wet 70-80% saturation

(a)  Aspergillus

(i) Fumagotus

(ii) Niger

(iii) Versicolor

(iv) Penicilloides

(v) Ochraceus

(3) Dry-wet 60-70% saturation, heating duct environments

(a)  Wallemia

(b) Trichoderma

B) Any ERMI >2 with MSH <35 in a susceptible haplotypeą CIRS

Back to Top of Biotoxin Illness Outline

 

V Treatment of Chronic Inflammatory Response Syndrome

1) Remove from exposure!

A) There is no “safe” threshold for exposure; any exposure is bad!

B) This is a host response, not a dose response

C) Remove mycotoxic exposure as above

(1) Big issue with public schools and many other bldgs.

D) We’re assuming that there is no Lyme exposure

E) We’re also assuming that there is no Ciguatera, Pfiesteria etc. exposures

2) Cholestyramine or Welchol are the only therapeutic choices

A) Pediatric dose 60 mg/kg tid

B) Colestid will not work

C) Activated charcoal doesn’t seem to work.

D) Take Cholestyramine at least 30 minutes before meal with extra fluid to wash it out of the stomach and into the duodenum, it needs to be by the sphincter of Oddi for maximum effect.

(1) Dose qid with meals

(2) No benefit from doubling the dose

(3) No benefit from more frequent dosing

E) Welchol has a much gentler/better side effect profile than Cholestyramine.

(1) Welchol has about 20% the efficacy of Cholestyramine due to fewer quaternium ammonium binding sites for the bile acids

(2) Will probably take >2 months to get the effect of 2 months of Cholestyramine therapy

(3) Dosed 2 tabs tid with food

F) It’s OK to take Cholestyramine AM & PM and two doses of Welchol during the day for the sake of convenience.

G) Use VCS to follow progression and document how well that the exposures/toxins that cause cytokine release & capillary hypoperfusion have been removed/resolved

H) Continue the above drugs as long as the VCS is positive

I) When the VCS becomes negative, cut back on or stop the Cholestyramine or Welchol

(1) Provided there are no new exposures or re-exposures!

(2) If there is a new exposure with MSH <35, it’s back to “square one”.

(3) If on VIP patient won’t get as sick as if not on VIP; will tolerate exposure better but will still be susceptible.

(a) Non-VIP patients will “get sicker quicker” after new/re-exposure

(b) Even with continued exposure, Cholestyramine etc. can help lower toxin load and delay maximum illness in CIRS.

(c) The C4a activating system was “primed” by the first encounter

(d) It now responds quicker (in absence of VIP)

(4) If VCS does not improve or normalize after a couple of months of therapy, there must be other sources of exposure.

(a) If there is low MSH with high C4a (especially after C4a goes >20,000), it takes about an hour of exposure to reverse the effect of two weeks of Cholestyramine.

(b) If the original exposure was Lyme, Cholestyramine is started, then there’s exposure to a WDB, and then the patient will relapse back to square one requiring re-initiation of therapy starting with exposure avoidance… (If the mistaken assumption is that this is more Lyme without doing ERMI in all exposure environments (home, work, school, church etc.) then there will be no improvement.

J) After a month of treatment, if VCS normalizes, you need the result of the deep nasal API-Staph culture (which should be done at the initial visit so that the results will be available at the follow-up).

3) MRCoNS

A) To treat API-staph (+) deep nasal cultures https://www.dxos.com/mold-illness-testing/

B) If positive, use BEG Spray each nostril tid (from Hopkinton www.rxandhealth.com) with Rifampin #2 of the 300 mg tabs q AM

(1) If unable to tolerate Rifampin

(a) Maybe wrongly treated for presumed Bartonella

C) Higher-dose VIP is the only other option with BEG but no Rifampin

D) Consider 2 sprays/nostril tid as “double strength” BEG as another option

4) Antigliadin antibodies

A) Gluten is generally more of a problem for children than adults

B) That doesn’t always hold true for CIRS patients

C) Dr. Shoemaker follows anti-gliadin antibodies; IgM, IgG and IgA in blood, no salivary testing

D) In the presence of MSH deficiency, TGF β-1, T-regulatory cell dysfunction, then there are probably ongoing autoimmune problems.

(1) Gliadin happens to be the most common of the autoimmune triggers.

(2) Patient must abstain from gluten for 3 months before the test will convert to negative.

(3) www.celiac.com is a great resource for dealing with gluten-free diets.

E) If there are no symptoms of celiac disease but the antibodies test (+), then IgA Tissue Transglutamase profile is sent off for evaluation

(1) If the IgA TTG profile is negative, it denotes that this is not celiac disease; it’s merely a case of low MSH autoimmune problems.

F) With 3 months of a gluten-free diet, the vast majority of patients will convert to IgG/IgA negative anti-gliadin antibody status.

(1) Then let them eat gluten to see if they convert back to (+), if they do convert…

(2) They probably are gluten sensitive and should abstain from gluten forever.

5) MMP9

A) MMP9/ADH-Osm/Androgens can all be lumped together for the sake of therapy

(1) When they occur, they usually occur in this cluster, all together

B) Will usually fall back to normal with CIRS therapy

C) If it doesn’t, then Actos/low amylose diet and Omega-3’s will help lower it

D) High levels of MMP9 can cause problems

(1) Levels will be <500 in control patients

(2)  CIRS patients will typically be ~/>900

6) ADH/Osmolality

A) ADH/Osmolality will be dysregulated in about 80% of CIRS patients

B) By correcting exposure, binding toxins with Cholestyramine/Welchol and treating MARCoNS, most of the ADH/Osm problems will resolve

C) Look for polydypsia/polyuria/static shocks

(1) ADH in it’s range should match what the Osmolality is in its range

(2) If Osm normal is 280-300 with a patient result of 295, then expect the ADH to be about 12 if the normal range is 1.5-13.3

(3) Formal calculations can be done but are probably not necessary since it will typically auto-correct with initiation of CIRS therapy

(4) If the ADH remains low for a given osmolality, the patient may be drinking enough to keep their osmolality down, but they can’t drink enough to keep their ADH down.

(5) Consider using DDAVP to increase the urine osmolality but it will cause water-retention/weight gain due to decreased serum osmolality.

(6) If ADH is 0.8, the Osm should be around 280, consideration can be given to use of DDAVP, but it will probably correct with CIRS treatment.

(a) DDAVP is best dosed at night every other night for 5 nights, then re-measure serum osmolality and serum Na

(b) DDAVP can cause significant hyponatremia

(c) Then advance to daily dosing (hs) and recheck serum osm and Na

(d) Rarely does a patient need more than two doses of DDAVP/d

(e) Expect to see reduction of thirst, urination, static shocks and headache

7) Androgens

A) Inflammation can cause up-regulation of Aromatase

B) Use of aromatase inhibitors with a low-MSH patient, they will cause them to deteriorate to tenfold worse than before the inhibitor was started.

C) Do not use aromatase inhibitors in patients with MSH<35

D) Consider use of DHEA as an upstream androgen replenisher, which can increase testosterone levels.

E) Monitor Estrone/Estradiol/Estriol to ensure the estrogen levels are not increasing with the additional DHEA.

F) Use of VIP will stabilize aromatase

G) Testosterone/Estrogen ratio’s can be helpful to document excess aromatase effects

8) C3a (increases when bacterial membranes are in the vasculature)

A) Correction of any underlying Lyme is important

B) C3a does not increase in Bartonella patients, probably because there are not many Bartonella cell membranes within blood vessels

C) C3a elevations can be spectacular in people with cardiovascular issues

D) C3a elevations are common with Raynaud’s syndrome as well, correction will help the Raynaud’s

9) C4a

A) Elevations are far more common than C3a elevations

B) Erythropoietin lowers C4a

C) Very good indicator for mycotoxins.

D) Erythropoietin Protocol; Baseline TGF β-1, C4a, D-Dimer, CBC

(1) If Hb goes >16.5, it’s to high (FDA doesn’t want it >10)

(2) Ensure informed consent is signed

(3) Record the Lot Number of the erythropoietin that is used; there have been recalls

(4) Erythropoietin antibody formation was a complication that occurred with one brand of the product that has been removed from the market.

10) TGF β-1

A) Humoral marker for immunity

B) Responds to Losartan (Cozaar) and responds even better to Losartan degradation product; exp3179

(1) Exp3179 doesn’t change BP but does reduce TGF β-1

(2) Unfortunately, a lot of CIRS patients are orthostatic; Losartan wouldn’t be a good idea due to that problem…

C) Losartan 12.5-50 mg qd to bid causes conversion of autoimmune problems as TGF β-1 is lowered.

(1) This effect was probably more to the Losartan effect on T-regulatory cells than TGF β-1 alone

(2) But if there are low T-reg cells and the TGF β-1 remains elevated, give a trial of Losartan before trial of VIP and then, do what you have to do to give them VIP.

11) VIP

A) 50 mcg dose of VIP was given to subjects qid    

B) NOTE; VIP must be kept refrigerated stored upright in nasal delivery bottle

C) Down-regulates MASP-2 (C4 activator to C4a see # XII U 1)

D) Restores balance of Vitamin D3

E) Down-regulates aromatase which breaks down testosterone among other hormones thus raising testosterone and lowering estrogens

F) Up-regulates (increases low levels of) VEGF

(1) If Actos or fish oil/omega-3 doesn’t work, VIP will correct the low VEGF

G) Warning Re; VIP may cause Lipase to increase a bit; measure baseline and monthly X 3 VO2max

H) Immunoregulatory; this is a Neuro-Immune link

I) Drives up CD4 + CD25 + FoxP3

J) Reduced SOB/Cognitive problems

K) Reduced joint stiffness in ~10 minutes (causes endorphin release)

L) Improved exercise tolerance

M) Global improvement in all modalities

N) Main effect immediately is endorphin mediated…

(1) Typically within 5 minutes of first dose pt’s can take a deeper breath

(2) Joint symptoms @ baseline; tight clenched hands will typically open and relax on VIP

(3) Immediate pain relief is a big deal and much appreciated

O) Cognitive issues respond more slowly

(1) Draw blood at baseline (Lipase, VEGF, C4a, TGF β-1), give VIP, repeat draw (VEGF, C4a, TGF β-1) in 15 minutes

(2) If there is a sudden increase in TGF β-1, there has probably been recent exposure to WDB with ongoing mycotoxin exposure.

P) VIP 50-mcg qid corrects paradoxical rise in PASP in exercise in days, not weeks, with durable effects with titration to bid and over time, discontinuation!

Q) VIP Trial Protocol

(1) At the end of a month of qid VIP, repeat lab parameters

(2) Most people, after 6 months can tolerate a reduced dose of VIP from qid to bid, sometimes to qd

(3) This VIP intranasal protocol has essentially cured a large group of chronic fatigue patients.

(4) FDA has designated VIP for treatment of Pulm Htn (other uses are off-label)

(5) Remember, if using VIP then sustaining exposure to toxin/WDB etc., everything “goes back to square one”.

(a)   The response will be truncated and shortened however after recovery from symptoms by a course of VIP.

(b) Patients will tolerate longer periods of exposure as well.

12) CD4+, CD25+

A) CD4+, CD25+ are regulatory T-Cells detected on a flow-cytometry assay

(1) CD4+, or CD25+ don’t give useful information

(2) The COMBINATION of CD4+ AND CD25+ provides the useful data

(3) There really are no “normal” ranges

(a)   Levels <15 abnormal

(b) 17 for controls

(c) 18 for treated

(d) 25 for VIP

(e) 30’s for Multiple Sclerosis patients on Methotrexate

(i) MTX probably helps connective tissue diseases by driving up the CD4+/CD25+, but that’s just Shoemaker’s speculation…

(ii) Plaquenil may work the same way…

B) FoxP3 is a nuclear replication factor that provides greater sensitivity than CD4+ and CD25+

13) What you need to know

A) Symptoms must be present

B) Labs must be done to show…

(1) What is and…

(2) What is not

C) Differential Diagnosis must be present and documented

D) Treat only ONE THING AT A TIME and monitor therapy effect

E) Labs will show you the way

(1) Start looking at innate immunity as a target

(2) Start looking at targets that you can fix

(3) Fix the targets; watch the illness disappear

(4) Wait for relapse

14) Treatment Message:

A) Look for environmental exposures or re-exposures

B) Establish a decent baseline of results of innate immunity testing

(1) A baseline on controls is just as important as a baseline on ill patients

(2) Follow the normal patients with susceptible haplotypes

(a) Intervene when they fall

(b) Look for VCS, MARCoNS

(3) Fix them quickly so that you can have short interventions and minimal suffering

C) Look for biofilm formers; they must be eradicated!

D) Treat the inflammatory physiology

E) What is left?

F) What happens when the injured patient is exposed next week?

G) Repeat illness, requires that the starting point be used to initiate new therapy.

15) Conclusions;

A) An organized, data-driven approach to diagnosis leads to effective treatment

B) Look for the final common pathway

C) Guessing, assumption and “clinical experience” are of no help compared to data collected with a 30,000 foot view

(1) If you must guess or make an assumption, document that you are doing so!

D) Hope for cure is here: let’s not forsake our new knowledge

E) VIP has brought the word “cure” to this syndrome for the first time.

F) VIP is the golden goose; don’t kill it!

16) For more information:

A) www.survivingmold.com

B) www.chronicneurotoxins.com

C) Surviving Mold December 2010

D) Mold Warriors 2005, 2007, 2010

E) Desperation Medicine 2001, 2006, 2009

F) Lose the Weight You Hate 2002, 2005

Back to Top of Biotoxin Illness Outline

 

VI  The Biotoxin Pathway:

1) Key Points

A) There is differential susceptibility based on genetic coding of the individual

B) This a host response, not a dose response

2) Sequence of the pathway

A) Toxin exposure occurs in an HLA non-susceptible individual

(1) In non-susceptible people, toxins are removed by the liver or broken down by the immune system.  Components are excreted harmlessly.

B) Susceptible individuals with appropriate HLA types have a worse outcome;

(1) Nerve cells are affected directly, impairing function

(a) Abnormal VCS test results

(b) Ciguatoxin affects Na channels in axons

(c) Pfiesteria causes a neurotoxic effect

(2) Adipocyte surface Toll receptors bind the toxin

(a) Leptin increases

(i) Fat cells produce more leptin leading to a vicious cycle and obesity, more leptin production, produces more fat cells…

(ii) Leptin receptors of the Hypothalamus are activated

(b) Cytokine levels increase directly from toxins

(i) Hypothalamic leptin receptors can be damaged by cytokines

(c) Hypothalamic Melanocyte Stimulating Hormone (MSH) Decreases causing myriad effects as below

C) Cytokine increase from Toxins and Adipocytes affect;

(1) Capillaries

(a) Hypoxia inducible factor (HIF)

(i) Has many gene activations under its control

(ii) Has a role in a variety of illnesses

(iii) Influences VEGF, TGF β-1, erythropoietin, platelet derived growth factor

(2) Increased WBC activity

(a) The toxins affect sodium channels on dendritic cells directly.

(i) HLA DR is a “signal molecule” that helps phagocytes migrate to antigen quickly after prior exposure

(ii) Cytokines help phagocytes migrate and cause the phagocytes to release more cytokines for an amplification effect

a. Cytokines bind to leptin receptors in the ventral medial nucleus of the hypothalamus blocking it’s activation by leptin

b. Leptin is an adipocyte cytokine that works in the hypothalamus to produce endorphins and MSH

01. This causes fatigue due to the low MSH effects and obesity due to increased leptin amplification and pain due to reduced endorphins

Þ And all the while, people look OK, not ill.

(3) Leptin has it’s own broad range of effects in the hypothalamus causing production of

(a) VIP

(b) MSH (sometimes this reverses with DDAVP)

(c) AVP

(4) Leptin receptor issues cause refractory weight problems

(a) Check Leptin and insulin (or C-peptide) levels in obese patients—they’re probably high, leptin may be >25, but even low leptin levels with these folks don’t help due to low MSH

(b) Actos/low amylose diet and exercise helps

(5) WBC’s without dendrites are immature and circulating, once exposed to antigen however they

(a) Develop dendrites and stay in the lymph nodes etc.

(6) Decreased capillary perfusion

(a) Tissue Hypoxia should increase VEGF, but CIRSą

(b) Reduced VEGF

(i) Deficient if <31

(ii) Fatigue, muscle cramps, SOB

(iii) Can be relieved with erythropoietin

D) Immune System Effects of Cytokines

(1) Inappropriate immunity/autoimmunity

(a) Antibodies (Ab’s) to myelin basic protein (often from mycotoxins)

(b) Gliadin Ab’s affect digestion

(c) Cardiolipins; affect coagulation

(i) Can cause arterial thrombosis’

(ii) Example of a patient who infracted jejunum and ileum after documented chlamydial pneumonia

a. He had been exposed to mold in his greenhouse, cytokine response to his PNA turned on the cardiolipins which maxed out in the several hundred range

E) Complement activation; the “alternative immune system” noted by increased levels of C3a, C4a

(1) Cytokine Related;

(2) Symptoms

(a) Headache

(b) Myalgias

(c) Temperature regulation issues (sweats/fever/chills)

(d) Brain fog

(3) Lab abnormalities;

(a) TNF

(b) MMP9-delivers inflammatory mediators to; blood, brain, muscle, lungs, joints

(c) Interleukin 1b

(d) PAI1 combines with MMP9 to increase clot formation and arterial blockage

(i) PAI1 contributes to ASCVD, is higher in diabetics, explaining their increased risk of ASCVD complications

a. T-Regulatory cells can convert to pathogenic T-cells

F) Effects of low MSH;

(1) Sleep disturbance (reduced melatonin)

(2) Chronic Pain (suppressed endorphin production)

(a) Enthesopathy at muscle-tendon junction due to hypoperfusion

(3) GI problems (malabsorption-fat, B12; diarrhea, leaky gut-may resolve with restoration of MSH/may be permanent, similar to but is not celiac disease, must avoid gluten, whey, amylose)

(4) Prolonged illness (WBC’s lose regulation of cytokine response—recovery from illnesses is slowed)

(5) Resistant Staph (in mucosa 2’ to biofilm and production of substances that exacerbate high cytokine/low MSH levels)

(a) Do the API staph and prepare to start BEG spray

(6) ACTH/Cortisol changes (Pituitary produces high ACTH/Cortisol initially, then adrenal exhaustion produces low levels but pt’s must avoid steroids which further lower ACTH); 65% may have

(a) ACTH >45, Cortisol<6 or Cortisol <12 with ACTH <10

(b) Cortisol>18, ACTH<5 or Cortisol >18 with ACTH <20

(c) This reflects dysregulation of the HPA axis/poor feedback control “adrenal fatigue”

(d) VIP will help re-regulate this

(i) Be careful with steroids!!

(7) Reduced sex hormones

(a) MSH has a huge effect on FSH/LH

(b) Menstrual irregularities probably have a hypothalamic basis, not an ovarian basis, may respond to VIP as well

(8) Reduced ADH from pituitary leading to polydypsia/polyuria/electric shocks

(a) Replenish their intravascular volume before dumping Florinef on them.

G) Phases of Biotoxin Pathway

(1) Stage I; Biotoxin effects

(2) Stage II; Cytokine effects

(3) Stage III; Reduced VEGF effects

(4) Stage IV; Immune effects

(5) Stage V; Low MSH effects

(6) Stage VI; Drug-resistant Staph/biofilm effects

(7) Stage VII; Pituitary effects

3) Genomics

A) There are many gender differences in gene activation with inflammation.

B) This is the cutting edge; where the new advances will occur; it may replace haplotyping as a better, more specific alternative.

Back to Top of Biotoxin Illness Outline

 

VII The Academic basis of treatment of CIRS from WDB’s; Objective Physiologic Measures Characterize Treatable Disease

1) Once recognized, you’ll see it everywhere

2) The approach to the problem:

A) Evidenced-based medicine

B) Rigorous, transparent, thorough

C) Differential diagnosis is ever ongoing

D) No room for assumptions

E) No room for guesses

F) The GAO says to document therapy to confirm causation

3) Define “Damp”

A) Water intrusion > 48 hours; 2 days!

(1) Water heater/plumbing leak etc.

(2) Pfiesteria ecology in the wild parallels indoor mold environment

(3) What you find indoors is not the same as what you find outside

(a) Even within the same species; Aspergillus is different indoors and outdoors

(b) Less competition for the energy sources indoors; fungi grow faster

(c) 1 square inch is 250,000 organisms, all making spores

(d) Spores break into smaller fragments within hours, these are also antigenic/inflammagenic even if they can’t form new fungi

(e) They create volatile organic compounds (VOC’s) and mycotoxins

(f) Adhesive tape applied to the mold colony and send the tape to a lab for ID

(g) ERMI testing is the best way to get adequate data, results in a week for $300.00

B) Presence of microbes

(1) Bacteria

(2) Mycobacteria

(3) Molds

(4) Actinomycetes

(5) Byproducts of above

C) Presence of speciated organisms

D) Presence of visible mold

E) Musty smells

(1) Geosmin is the most common compound to create musty smells from fungi, especially from Actinomycetes which is actually bacterial

4) Don’t call it mold

A) Toxigenic sources of inflammation found in WDB’s are fungi, Actinomycetes, bacteria, mycobateria

B) Inflammagens are VOC, beta glucans, hemolysins, mannans, proteinases and mannose-containing glycoproteins (more)

C) Smaller particles are far more important than larger-sized spores.

D) Get the picture in your mind that adding water to an environment creates a new ecosystem that is colonized.

(1) “If you wet it, they will grow!”

E) Air sampling is worthless; you must use ERMI

F) Comparison of indoor vs. outdoor fungi is also worthless and outdated!

5) Environmental Relative Mold Index (ERMI);

A) 2006 EPA and 1,000 homes

B) Settled dust in two locations

C) 134 species with Quantitative Polymerase Chain Reaction (QPCR)

D) Distilled to 26 species from group I, which were water-damaged buildings, then 10 species from group II, which were non-water damaged buildings.

E) Add sum of logs; subtract II from I

(1) If >2.0 it’s a toxic bldg.; illness will occur, not a question of if but when

F) Index is a number that represents building health ONLY

6) Problems with ERMI;

A) Dividing water saturation into low, middle and high makes sense

B) Organisms in these micro-ecosystems are different

C) 5 Aspergilli (middle-wet conditions)

(1) fumigatus

(2) niger

(3) ochraceus

(4) penicilloides

(5) versicolor

D) Chaetomium and Stachybotrys (Grows in wet-wet)

E) Trichoderma and Wallemia (dry-wet conditions)

F) Air sampling won’t allow speciation to this degree

G) There are about 300 Aspergilli and 200 Penicillii; most are non-toxic

H) Another problem is that periodically fungal nomenclature changes courtesy of the microbiologists

I) The ERMI process was arbitrary

J) The number doesn’t include other organisms that matter or synergism

K) Somehow, there are lab differences;

(1) http://www.mycometrics.com is a good lab

(2) It’s probably best to stick with one lab

L) Swiffer testing allows sampling to proceed without vacuuming

7) ERMI is a building index; what about a human health index?

A) Causality at baseline works (GAO)

B) Case-control studies say a problem exists

(1) This has been reported in over 50,000 patients in 14 separate countries.

C) The gold standard is prospective exposure, amply controlled

D) That’s how we determine risk.

Back to Top of Biotoxin Illness Outline

 

VIII Sequential Activation of Innate Immune Elements (SAIIE)

 

Baseline

Day 1

Day 2

Day 3

VCS

-

Deceasing

Decreasing

Decreasing

C4a

-

Increasing

Increasing

Increasing

VEGF

-

Increasing

Decreasing (2’ to TGF β-1)

Decreasing

Leptin

-

Stable

Increasing

Increasing

MMP9

-

Stable

Spikes

Increasing

vWF Factor VIII

-

Decreasing

Increasing

Normalizes

vWF Ristocetin

-

Normal

Decreasing

Decreasing/may bleed on day 3

CD4+CD25+

-

Decreasing

Decreasing

Decreasing

Compare to baseline;

PC4a, VEGF

PLeptin, MMP9

PMMP9, CD’s, VEGFi, & symptoms

1) There must be NO associated re-exposure activities

2) This is a prospective exposure trial

A) Requires informed consent

B) People who have been sickened and treated, then

C) Without medications on-board, are willing to re-expose themselves to a WDB

3) Measures;

A) A series of labs and health symptoms over 3 consecutive days of exposure to a given building

B) Changes in VCS if available will fall in 1-2 days

(1) Neuronal injury happens after the cytokine response

(2) C4a is another good measurement to take post-exposure

(3) Persistently elevated C4a can be due to Lyme or Lupus; VEGF can remain altered.

C) VEGF will rise on post-exposure day (PED) 1, then…

(1)   TGF β-1 lowers VEGF

(2) If TGF β-1 remains high or symptoms persist despite normal VCS, Clean ERMI, No MRCoNS, treat with nasal VIP.

D) VEGF will spike on day one then start to fall due to the effect of TGF β-1

E) On day 2, Leptin rises

F) MMP9 spikes between day 2 and 3; it’s made in endothelial cells, monocytes and macrophages.

(1) This will have a gene-transcription time delay, then

(2) A conversion of the pro-metabolite MMP14 which is cleaved to produce MMP9

(3) If MMP9 remains elevated, consider infection, autoimmune or neoplastic process.

(4) VIP may help lower refractory elevation of MMP9

G) VonWillebrand’s factors

(1) Factor 8 is an acute-phase reactant; it drops after PED 1, on day 2,3 it reverts back to normal as it recovers

(2) Ristocetin associated cofactor and VonWillebrand’s antigen are slower to react

(a) On day 1 are normal

(b) Decline by day 3

(c) Bleeding, if it will occur, will happen on PED 3.

(3) Check VonWillebrand’s profile if hemoptysis and/or epistaxis

(4) LabCorp does not have a good vWF profile, Quest’s is excellent, but costs $575 

H) People who have already been primed will bleed quicker.

I) “Sicker quicker”

(1) The Human Health Index is based on the previously discussed physiology.

(2) The SEQUENTIAL activation of innate immune elements (SAIIE)

4)  VCS Interpretation

A) The patient should be able to see beyond 6 in row C

B) The patient should be able to see beyond 5 in row D

C) The patient must pass all four of the above measurements (each eye in C & D)

D) First, check to ensure that both eyes are > 20/50 in acuity at 14” (near vision)

E) If patient has a far-vision contact in one eye and a near-vision contact in the other, then only the near-vision eye can be used.

F) This exam is pass/fail; if any one eye can’t see every image necessary, the test is a “fail”; there are no “almost’s”, one miss is a failed test.

G) It’s an ELEGANT tool to show improvement within a week of Cholestyramine

(1) Scores will improve in row E, then row D…

5) What is normal SAIIE?

A) Control buildings; N=50

(1) SAIIE=6.3

B) Remediated buildings: N=12-

(1) Some high (>15)

(2) Some low (<9)

C) WDB without remediation; N=160

(1) Mean 17.9

6) SAIIE meets ERMI

A)  If the MSH is <30, any ERMI >2 is dangerous

B) If any C4a by RIA is >20,000, the “safe” ERMI falls to -1

C) SAIIE assumes no other re-exposure activity; this must be verified with VCS

D) Sequential activation of inflammatory elements is weighted by time of exposure.

7) Definitions;

A) HLA DR is done by PCR

B) C4a

C) TGF β-1

(1) Has an undeserved reputation of being an anti-inflammatory compound

(2) Untrue if it is turning on TH17 cells at the same time with conversion of T-Reg cells in tissue into pathogenic T-cells

D) MSH

E) VIP

F) MMP9

G) VEGF

H) VCS

I) VWF (or vWF) (VonWillebrand’s Factor)

J) Autoimmunity

(1) AntiCardioLipin Ab’s ACLA & AntiGliadin Ab’s AGA

K) T-Reg Cells (activated in the circulation by TGF β-1)

(1) CD4+

(2) CD25+

(3) FoxP3

8) Cases vs. Controls

A) How many of these abnormalities can a given person have?

B) Look at each of these as independent variables, start multiplying p values, the numbers are staggeringly against the possibility of these results being due to chance

C) Then add cohorts of several patients in the same family/environment/home with

D) The same haplotypes

P value <0.001

Cases

Controls

Significant?

Total Symptoms

22.1

3.1

Y

VIP

7.1

35.5

Y

MSH

9.8

34.9

Y

MMP9

510

260

Y

ACLA-IgM

34%

3%

Y

AGA-IgG

41%

4%

Y

C4a

10,640

2,324

Y

TGF β-1

8,296

2,076

Y

9) Results; Labs are not different

A) P>0.05 (usually >0.4)

(1) ESR, CBC, CMP

(2) ESR, CRP

(3) TSH, Cortisol, Testosterone

(4) Lipids

(5) C3, C4

(6)   IgE, Immunoglobulin panel

10) So what is the SAIIE Protocol?

A) Part of the repetitive exposure protocol

B) After showing no other building makes the patient ill, patient comes off of medications, re-enters the suspected building for 8 hours on day 1

C) Measure labs in AM, then re-expose on day 2

D) Measure labs in AM, then re-expose on day 3

E) Measure labs in AM, and then resume medications.

11) Score the SAIIE;

A) Compare the C4a on day 1 to baseline

B) Compare Leptin on day 2 to baseline

C) Compare MMP9 as average of day 2 and 3 to baseline

D) Compare VEGF to baseline; rise on day 1, fall by day 3

E) Compare symptoms day 3 to baseline.

F) Add the values

12) SAIIE Scores are NOT subtle;

A) 5 for 100%; 4 for 80%, 3 for 70%, 2 for 60%, and 1 for 50%

B) Controls mean is 6.3

C) Cases mean is 17.9

D) TGF β-1 is a new player, rapidly changing

E) CD4+CD25+ show promise; it drops rapidly.

13) What is SAIIE really showing?

A) We’re looking at the progression of innate immune responses

B) Hyperacute (C4a and TGF β-1

C) Gene activation following receptor resistance (leptin)

D) Bottom line; this is absolute proof of causation.

E) A/B/B’/A/B research design.

(1) A Person at baseline

(2) B Intervention fixes them

(3) B’ Stop medicine

(4) A Re-expose

(5) B Intervention fixes them again

14) What then, is the illness?

A) Pattern recognition; antigen presentation gone awry

B) Inflammatory responses aren’t controlled

(1) The neuropeptides are gone

C) Innate immune abnormalities become chronic as a host-response syndrome

D) ICD-9 and V-codes are available for these;

(1)  Therefore a chronic systemic inflammatory response syndrome (ICD-9 995.93) or hazardous effect of exposure to mold (v87.31) = CIRS-WDB.

Back to Top of Biotoxin Illness Outline

 

IX CIRS

1) Once you recognize it one time, your life as a physician will be changed forever

2) Lack of regulation of inflammation

3) Enhanced/increased innate inflammatory parameters

A) Numerous;

(1) C4a, possibly C3a if intravascular membranes

(2) TGF β-1

(3) MMP9

(4) Complement activation

(5) Coagulation activation

(6) Cytokine activation

(7) MSH deficiency

(8) VIP deficiency

(9) Regulatory peptide failure

B) Hormone dysregulation

C) Hypoxia from capillary hypoperfusion

D) Cellular immunity (Th-17, Pathogenic T-reg cells)

E) Colonizing commensal MARCoNS

F) vWF factor 66% is abnormal; are these acute reactants? NO

G) Autoimmunity like crazy!

(1) AGA, ACLA, ANA, ANCA, actin

H) Cellular immunity, TGF β-1

I) Activated complement split products

(1) C3a, C4a

J) CIRS is a systemic, interacting syndrome

K) There is no way that just one lab value can be the source of

(1) Fatigue

(2) Cognitive dysfunction

(3) Arthritis

(4) Respiratory problems

L) All of the putative diagnosis’ have the same final common pathway in just about every disease we have

(1) ASCVD

(2) DM

(3) MS

(4) Parkinson’s disease

M) The same combination of multi-symptom illness and lab abnormalities repeat in each patient

N) Differential diagnosis is key!

(1) All of these various diseases have the same common final pathway

(2) Is there something contributing to a known illness that is NOT from WDB? 

(a)   YES!

(b) If you want to help these patients, correct the abnormalities that you look for and find.

4) Let’s not forget genetics

A) Learn HLA DR by PCR (SSOP)

B) Look for 4-3-53 (0401, the worst of 12)

C) Look for 11-3-52B (this one is easy)

(1) Long arms, long fingers, athletic

(2) Fibrillin cross-linking in collagen shortens the range of motion.

(3) Fibrillin cross-linking in collagen binds TGF β-1

(4) With free/unbound TGF β-1, they get “sicker quicker” upon exposure

D) The “dreaded”

(1) Worst TGF β-1

(2) Most abnormalities

HLA Disequilibrium Relative Risk >2.0 Mold Illness Cases

HLA DR

Control

Cases

 

Adult

Child

4-3-53

-

3.6

4.4

7-2/3-53

-

2.3

2.1

11-3-52B

-

2.9

5.3

12-3-52B

-

2.9

2.6

13-6-52ABC

-

2.1

-

17-2-52A

-

2.6

-

48 Other Linkages

-

-

-

N=

457

4,960

470

Back to Top of Biotoxin Illness Outline

X Biotoxins

A) Their very low molecular weight/small size is an indicator of their potential to be ionophores (able to move between cells), they’re made by many different types of organisms.

B)

C) Types of Biotoxins

Types of Biotoxins

Agent

LD50

Molecular Wt.

Source

Botulinum

0.001

150,000

Bacterium

Shiga Toxin

0.002

55,000

Bacterium

Diphtheria Toxin

0.10

62,000

Bacterium

Maitotoxin

0.10

3,400

Marine Dinoflagellate

Ciguatoxin

0.40

1,000

Fish/marine Dinoflagellate

Batrachotoxin

2.0

539

Arrow-Poison Frog

Ricin

3.0

64,000

Castor Bean

Conotoxin

5.0

1,500

Cone Snail

Tetrodotoxin

8.0

319

Puffer fish

αTityustoxin

9.0

8.000

Scorpion

Microcystin

50.0

994

Blue-Green Algae

XI Sarin

100.0

140

Chemical Agent

XII Aconntine

100.0

647

Plant (Monkshood)

T-2 Toxin

1,210.0

466

Fungal Mycotoxin

A) Table above showing size and LD50 of selected toxins

B) Inflammagens bind to receptors

(1) Toll; mannose

(2) Ficolins; C-linked lectins

(3) These produce predictable inflammatory results

C) Direct neurotoxicity

D) Involves defective antigen presentation

2) Antigen presentation

A) Antigen detection will continue until antibody formation occurs

B) Internalization of receptor/antigen complex

(1) Phagocytosis is an innate immune function

C) Acidification of phagoendosome which is then presented to the

D) Endoplasmic reticulum producing the phagoendolysosome, then the

E) ER adds HLA DR in the ER of dendritic cells and present it to

F) Naēve T-cells and to B-cells found in lymph nodes, not in circulations

3) Ways to disrupt the antigen presentation sequence;

A) Trichothecenes disrupt membrane associated liganding CD 80/86

B) Polycyclic ethers stop acidification

C) Bordetella toxins have intracellular targets (pertussis-defective Ag presentation)

D) HLA as ligand is blocked by high IL-10

(1) IL-10 is an immune paralytic!

E) CLTA blocks T-Cell adhesion

F) T to B cell??

4) So what?

A) If we don’t have antigen (Ag) presentation, will there be antibody (Ab) formation?   No

B) If no Ab is formed, will Ag be cleared?  No

C) If no Ag is cleared, will there be a persistent Ag activation of innate immune responses?  Yes

D) And then, if there is persistent Ag activation, will dysregulated innate immune response ever cease?  No

(1) So if you remove the source of exposure, will you heal?  No

(2) If you deal with allergy, irritation or many other noxious agents remove the exposure and the reaction will cease.

(3) Not so with CIRS!

5) Ag detection sets off the amplification cascade

A) Use any image you want

(1) Barking dogs, sentry, firecrackers

B) Complement, cytokines are pre-formed

C) Differential gene activation follows

D) Interaction of endothelial cells, macrophages, monocytes, hypoxia induced factor (HIF) is next, then hopefully it is

E) Controlled by MSH & VIP.

6) Without Ab, neuropeptides won’t control inflammatory responses

A) Uncontrolled amplification cascadeąCIRS

B) MSH is the first to fall

C) Cytokines bind to long isoform of the leptin receptor; no POMC is made.

(1) Another action of circulating pro-inflammatory cytokines is the stimulation of leptin release from adipocytes.

(2) Leptin has two important functions in the biotoxin pathway,

(a) Triggering macrophage synthesis of additional pro-inflammatory cytokines in a positive feedback loop and

(b) The initiation of negative feedback control on cytokine production through the proopiomelanocortin (POMC) pathway in the ventromedial nucleus of the hypothalamus forming MSH & endorphins.

(3) Leptin-POMC lowers cytokine levels.

(4) Leptin links neuroendocrine and immune systems by binding to the long isoform of the leptin receptor, which resembles a gp-130 cytokine receptor, thereby stimulating POMC expression and depolarization of POMC-containing neurons http://www.survivingmold.com/docs/Resources/Shoemaker%20Papers/NTT5863.pdf

D) Without POMC, then no MSH and no beta endorphin

(1) But there is plenty of fatigue, weight gain and pain

E) Next is VIP

(1) cAMP, Regulation Pulmonary Artery Systolic Pressure

Back to Top of Biotoxin Illness Outline

XIII Diagnosis is not just exclusion

A) Chronic multisystem, multisymptom illness refractory to all interventions.

B) Dense innate immune abnormalities are invariably present

C) Genetic basis; (HLA DR by PCR)

D) Onset is the end of the diagnosis

(1) Numerous other aspects/complications are comorbid

E) Ongoing effect of environmental exposures

(1) This is critical; don’t forget this!!

(a) Sicker Quicker

(b) Back to “square one” if re-exposed, starts with removing exposure.

2) Start with VCS if you’re going too start

A) Simple

B) Old neurotoxicology test—but still works well

C) On-line versions vary

D) Diagnosis at baseline and essential for follow-up

(1) Especially with hyperacute patients

E) Correlates with measures of retinal capillary perfusion

F) Used since 1970’s by DOD/USAF and in studies of non-biological toxicants

G) Reproducible, reliable, portable, non-invasive, cheap

H) The best marker beyond day 4 of biotoxin-associated cytokine disease

I) Neurologic function of optic nerve/vision

J) Eliminates near, far, color, static, motion, peripheral vision

K) Visual non-invasive measure of contrast

L) Requires corrected visual acuity >20/50

M) Control light @ >70 foot-lamberts of light intensity with light-meter

(1) Two 15 inch fluorescent lamps

(2) With “daytime color” lamps provides adequate light for the test.

N) Used in prior studies: screening/monitoring.

3) Controls vs. Initial illness;

A) Curves represent; Control, Fungus identified, Visible evidence of fungi only, visible evidence water damage only

(1)

B) Results are not subtle

C) Only air sampling was done to identify fungi,

(1) Genus available only, not species

(2) Not done with more appropriate ERMI testing (precedes ERMI availability)

D) P-value <0.001; highly significant/not due to chance

E) Patients testing positive were highly symptomatic

F) Visual abstract mathematical functions drops out quickly too; ask the patient to mentally divide 91 by 11 (91/11=8.27 “eight with a remainder” is good enough).

G) Bottom curve/worse results of all were water damage and musty smell

(1) No mold was identified at all!

4) Fungi genera identified cohort; Time series

(1)

B) Symptom/Curves represent (top to bottom)

(1)  Initial; Sick patient untreated

(2) AC-1; Treated

(3) HOC; Improved post-therapy

(4) BOC; Stop medication/Cholestyramine (low symptoms)

(5) AC-2; Re-exposed to the WDB without Cholestyramine

(6)   Prophylactic; Returned to the WDB while taking Cholestyramine

C) Similar curves are generated regardless of type of building

(1) Home

(2) Work

(3) School

D) There are usually mixtures of organisms and toxins involved in these cases

(1) It’s generally impossible to say which toxin or which organism caused the damage

(2) Damage was likely caused by numerous organisms and toxins

(3) Genomic studies when available will help to solve this dilemma

E) Pax-gene testing

Back to Top of Biotoxin Illness Outline

 

XIV Case Studies:

1) Case study; 49 yo WF, ill X 4 years, school teacher

A) Delayed recovery from normal activity

B) Unremitting fatigue, cognitive issues, arthritis

C) Differential Dx; nothing confirmed

D) Multisystem/multisymptom illness

E) Denied disability; deemed “psychiatric” by insurance company

F) Fibromyalgia per rheumatologist; trial of Lyrica

G) XMRV said the WPI user per CFS patient

H) Lyme said the Lyme-Literate local DM

I) Innate immunity is at your service, but you must ASK!

(1) Does she have excessive inflammatory responses? (Yes)

(2) Does she lack regulation of immune response (IR) as shown by neuropeptide deficiency? (Yes)

(a) MSH (low/undetectable; <8)

(b) VIP (low/undetectable; <10)

J) What does the VCS show? (+) (Not XMRV which will not cause VCS (+))

K) Are there problems with;

(1) TGF β-1  (elevated; 15,097, normal <2,380)

(2) MMP9 (elevated; 673, should be half of this)

(3) VEGF (depressed; <31, low VEGF expected with high TGF β-1)

(4) Cellular immunity (yes; “c”, below)

(5) ACLA (+ cardiolipins) IgM (revealing T-cell dysfunction)

(6)  Activated complement (C4a) (elevated; 10,344, normal <2,830)

(7) Coagulation (thrombophillic)

(8) ADH <0.9 with Osmolality 316 (dehydrated)

(9)  MARCoNS by API-staph (six classes of resistance!  She had been on different types of antibiotics for 6 months)

(10)  HLA 11-3-52B and 4-3-53 (each of the dreaded)

(11)  (Yes indeed to a-k, 9, 10))

L) Is this CRS

(1) ABSOLUTELY! (ICD-9; 995.93)

2) Case Study; Simple mold case

A) WDB have lots of toxins and inflammagens

(1) Use ERMI!

B) No specific causation (which organism or toxin made her ill?)

(1) Too many complex issues to be able to tell due to so many potential causes that probably interact with each other to cause patient problems.

(2) Bacteria, Actinomycetes, fungi

(3) Beta glucans, mannans, hemolysins, VOC’s, mannosylated lectins/dectins

C) WHO (7/09); GAO (9/08); POA (7/10)

D) Is your differential complete?  Did you look for hypoperfusion

(1) MR Spectroscopy to delineate suppressed Glutamate/Glutamine ratio (takes an hour and twenty minutes in the scanner)

(2) MRS to check for elevated lactate alone (with therapy it takes 3 weeks for scans to normalize)

(3) Can you R/O capillary hypoperfusion in CNS by history?

(a)   Yes, cognitive dysfunction, executive functions (91/11=8+…)

(b) Generally these are the patients that providers consider as “whacko’s”

(4) How about glial cell production of;

(a) C4a

(b) Reduced VIP

(c) Reduced MSH

3) What are environmental sources of innate immune abnormalities/CIRS?

A) WDB’s/mycotoxins most commonly

B) Post-Lyme syndrome (be careful of this)

C) Ciguatera (under-diagnosed)

D) Cyanobacteria (usually, but not always due to tropical fresh water)

E) Pfiesteria (fish kills)

F) Recluse Spider bites with central ulceration (rare)

(1) De-roof the lesion

(2) Topical Cholestyramine binds that reservoir of toxins

(3) Add oral Cholestyramine and Actos together as well to complete the therapy

(4) Cholestyramine topically is also useful for poison ivy patients

(a) Mix a packet of Cholestyramine in a jar of Noxema

G) Can we define CFS or FMR by biomarkers?

4) Biotoxin Symptoms

A) Fatigue

B) Weak

C) Aches

D) Cramps

E) Unusual sharp, claw, electrical

F) Light sensitivity

G) Red eyes

H) Blurred vision

I) Tearing

J) SOB

K) Cough

L) Sinus symptoms

M) Abdominal pains

N) Secretory diarrhea

O) Morning stiffness

P) Arthritis

Q) Executive and Cognitive dysfunction (hold the neurocognitive testing, take an exposure history, Pfiesteria provided a great platform to demonstrate when testing in hyperacute and recovery periods were done in cohorts.

(1) Decreased recent memory

(2) Difficulty concentrating

(3) Word-finding difficulty

(4) Decreased assimilation of new knowledge

(5) Confusion

(6) Disorientation in familiar places

R) Memory loss

S) Impaired concentration

T) Trouble swallowing

U) Assimilation problems

V) Confusion

W) Disorientation

X) Impaired mood

Y) Impaired appetite

Z) Sweats/chills; thermoregulation problems

AA) Frequent urination

BB) Excessively thirsty

CC) Electrical shock sensation when touching skin

DD) Paresthesias/numbness, tingling

EE) Altered taste

FF) Tremor

GG) Vertigo/dizziness

5) Take a careful history

A) If you “hit”, look at what you can save the patient;

(1) Patient’s course and outcome

(2) Untold millions (? billions) of dollars

B) The International Academy of Chronic Fatigue Syndrome changed their approach to Pediatric CFS as their case definition was incomplete

(1) They added mold exposure specifically to their exclusion list

6) How do we know

A) Prospective exposures give us causation

B) Genomic studies from prospective exposures

C) Defined abnormalities in genomics are persistent and may be unique

(1) This could help to separate

(a) Ciguatera from

(b) Lyme from

(c) Pfiesteria from

(d) Mold toxins, etc.

D) Could this be a “fingerprint”?

7) After pattern recognition (involved with Ag presentation)

A) Pro-inflammatory cytokines

(1) Th-1 followed by Th-2

B) Complement activation

(1) C3a, C4a, anaphylatoxins

C) Differential gene activation

D) Interacting exponential cascade

E) TGF β-1 and a newly discovered player: Th-17 immunity!

F) T-reg cell dysfunction

8) TGF β-1

A) There are 58,000 references on PubMed as of 5/20/10

B) Not one commercial lab until 4/08 was testing for it until Cambridge Biomedical began testing

C) ELISA from R and D Systems

D) Controls <1,350

E) Cases average 6,000 pre-therapy

F) After treatment (all factors* corrected), average drops to 1,800

G) * see 1) Biotoxin Pathway High levels of TGF β-1  can also be treated with Losartan (Cozaar) or it’s degradation product; exp3179

H) Treating high levels of TGF β-1 reduces the driving force between pathogenic T-cells and cellular based immunity & use of VIP. 

9) Meet TH-17; Pathogenic T-Cells that are the main drives of Autoimmunity and Collagen-induced arthritis

A) More than Th-1 and Th-2

B) In the presence of IN-6 and TGF β-1, naēve T-cells differentiate into Th-17

(1) In the periphery, they can make IL-10 and pro-inflammatory cytokines

C) High TGF β-1 is associated with abnormalities in T-reg cells

(1) Inducible T-reg’s add to TGF β-1

D) High TGF β-1 I innate immune illness is prolonged

(1) It’s also complicated by autoimmunity.

10) What can go wrong?

A) This is a dynamic process!  Consider

(1) Re-exposure

(2) Absence of antibody formation to stop the process

(3) New exposures

(4) Inflammatory responses are not static

(5) Once the host is altered, the next response will also be altered.

11) Logistic Regression; Methods

A) Using a “forward selection” model, allowing all variables that were present for both groups (those with and without mold illness)

B) Systematically removing variables that produced “quasi-complete separation” (which produces perfect predictability but no measure of variability).

C) By using symptom clusters and VCS the Dx of CIRS can be attained with 98.8% accuracy at the bedside even before lab results are available.

D) Final resolution of the CIRS involves correction of the lab abnormalities

(1) You must do the labs initially to have a baseline as well as to secure the Dx

(2) The labs will also help determine which etiology of the CIRS the patient has:

(3) Lyme?

(4) Ciguatera?

(5) Mycotoxins?

(6) Pfiesteria?

(7) Etc.

12) Does Physical exam help?

A) Nope, may have mild tremor, low grade tachycardia etc.

B) Patients look good and feel terrible

C) Don’t be deceived by their appearances

D) Take the three minutes to get a decent review of symptoms!!

E) When you see the internist comment; “Diffusely positive review of systems” beware; Biotoxin illness lurks!

13) MR Spectroscopy

A) Methods count

(1) Need to use the same head position during the scan and f/u scans.

B) Look at the same areas consistently

(1) Bilateral frontal and hippocampal; 1 cm voxel

C) Look for signal to noise problems

14) Chemical abnormalities on MRS in Biotoxin illness are absent in psychiatric pt’s;

A) N-Acetyl Aspartate (NAA); evaluates white matter

B) Creatine;

C) Choline; provides information on acetyl choline

D) Myoinosotol; status of glial cell elements

E)  All of the above are typically wnl

F) Lactate high (capillary hypoperfusion)

G) Ratio of excitatory Glutamate to inhibitory Glutamine;

(1) Depressed with brain fog

(2) High in ADHD/Manic

H) Total is 5.2 in cases; 0.9 in controls

I) Corrects with erythropoietin in <3 weeks if high C4a

15) Psychiatric symptoms are often related to inflammation/inflammatory biomarkers

A) Peripheral Vasoactive compounds cross the BBB and are found in CSF

B) Central metabolic effects occur (glial apoptosis)

C) Central metabolic changes; Lactate, Glutamate/Glutamine

D) Reversed by correction of inflammatory sources and processes

E) Not corrected by psychiatric medications!

16) MRS & ERMI scores

A) Can be correlated in patients with MSH <35

B) Weighted cognitive symptoms don’t correlate with range of ERMI values

(1) It’s almost “all or none”

C) Total number of lactate and G/G abnormalities

(1) MATCH ERMI!!

(2) MATCH C4a

D) If ERMI >14, MR Spectroscopy abnormalities >7!

E) We need more patient data

17) Biofilm formers; MARCoNS

A) Not your mother’s Coagulase Negative Staphs

B) 80% Methicillin resistance

C) Not seen in one or none resistances

D) Planktonic organisms become differentiated; multicellular?

E) Hemolysins

F) MSH Cleavage factors; low MSH

G) MARCoNS https://www.dxos.com/mold-illness-testing/

H) We have 6,500 cultures

I) Biofilm formation is expected

J) Multiple antibiotic resistance=signifies commensals are present.

K) You won’t see improvement until MRCoNS is eradicated

L) Reservoir in dogs noses and wet buildings

18) MARCoNS Rx is straightforward for now;

A) Rifampin penetrates biofilm;  #2 of the 300 mg tabs q AM

B) EDTA dissolves biofilm

C) Muciprocin/Gentamycin synergistic effect

D) Use above for 1 month

E) IMPERATIVE; MUST DO THE API-STAPH https://www.dxos.com/mold-illness-testing/

 

(1) When doctors skip the culture…

F) Very slow growing cultures

(1) What you don’t know will hurt your patient!

19)  Complement Pathway Gicla

A) Description: Macintosh HD:Users:rjodo:Desktop:Gicla.png

B) Ficolin activates MSP2 as part of the mannose-binding lectin associated serine protease 2 mechanism will split

C) C4 into C4a & C4b then

D) C2 splits into C2a and C2b

E) The combination of C2a & C4b with Magnesium fits onto a bacterial membrane, it will then

F) Split C3 to form C3a (which is an indication of bacteremia/intravascular bacterial membranes).

G) As a matter of practicality, the turn-around time for C3a & C4a lab results is 3-4 weeks. 

(1) LabCorp is considering doing the tests in-house to give results in <1 week

H) Dr. Shoemaker initially measures C3a & C4a at baseline and at the end of each of the 1-month steps to prove that the diagnosis is mycotoxin related, that the illness is not due to bacteremia or Lyme disease.

20) Complement Definitions;

A) C4a; activation of product of C4 by MASP2

(1) No membrane attachment needed

(2) C4a has a very short half-life in blood

(3) The reason for the persistence of C4a in circulation is the absence of clearance of the antigens that turned on the MASP2.

(4) The presence of Ag’s turns on MASP2.

(5) There is an absence of Ab’s to remove the Ag’s thus turning off the MASP2 and the inflammatory cascade.

(6)   CIRS happens when there is a lack of resolution/regulation by neutralizing Ab’s to turn the cascade off by removing the Ag’s which would then disable MASP2

(7) MASP2 will thus no longer “auto-activate”, giving the rise to C4a

(8) MASP2 is the key to “sicker quicker”

(9) Ab’s would turn this off if they were present.

B) C3a; activation product of C3 after C4bC2a combination links to C3 by MASP2 if an intra-vascular bacterial/ricketsial membrane is present for MASP2.

C) MASP2 auto-activates following pattern recognition of particular glycoproteins by Mannose Binding Lectin (MBL)

D) So far there is no definitive proof by data of VIP inactivating MASP2, but it’s suspected that this is part of the mechanism since patients get so much better so much faster when VIP is used.

(1) There is no big rise in C4a after Ag exposure as there was before use of VIP, so it must involve MASP2

E) If MASP2 is involved, there is NO self-healing.

21) C4a;

A) Putative anaphylatoxin

B) Measured as C4a by TRIA @ NJC

C) Split product of complement activation

D) Activates Mast cells and basophils

E) Increases

(1) Smooth muscle contraction

(2) Vascular permeability

(3) Release of chemotactic factors

F) Systemic responses follow activation.

G) C4a elevations are present in patients with dermatographia due to degranulation of Mast cells

(1) Increases vascular permeability

(a)   Fixing C4a elevations can stop pitting edema

(b) ADH deficiency causes dehydration, if there is also edema, look to C4a to be elevated

(i) This patient is not “chronic fatigue”; this is biotoxicity!

(2) C4a activates chemotactic factors

H) C4a is released by cleavage of C4

(1) Ficolin can trigger this reaction

I) No receptor for C4a has been identified

J) C4a is formed by

(1) Activation of the Classical Complement Pathway or

(2) Lectin pathway

(3) Not formed by the Alternate Complement Pathway

K) Rapid rise in C4a is either from

(1) Ag/Ab complex or from

(2) Lectin binding to carbohydrate groups on bacterial surfaces

L) High C4a is associated with

(1) Cognitive deficits

(2) Restrictive lung disease (will also have a rise in TGF β-1)

(3) Hypersensitivity pneumonitis

(4) Multi-system, multi-symptom illnesses dominated by chronic fatigue

M) Re-exposure brings a rise in C4a within

(1) 4 hours in patients exposed to Toxigenic fungi

(2) 12 hours after tick bite in Lyme patients

N) Elevated levels of C4a persist, even though C4a has a short lifespan

(1) Ongoing immune dysregulation/inflammation is the cause

O) “Sicker Quicker” for mold people, C4a levels will come down nicely with treatment, but when re-exposed, instead of a mean C4a of 10,000, C4a will jump right to 20,000; relapsing patients jump much higher than initial treatment patients

P) Treated vs. Untreated Patient C4a Levels

22)  

Untreated Patient C4a Levels C4a Summary Page

Category

N=

Mean

SEM

Lab Control

 

<2,830 ng/ml

 

Control

70

2,985

132

Acute Lyme ECM- Untreated

10

17,646

4,543

Acute Lyme Treated

5

4,196

821

Chronic Lyme Untreated

26

8,872

750

Chronic Lyme after antibiotics

11

9,349

570

Chronic Lyme Treated

41

3,780

217

Acute Mold Untreated

32

16,250

2,946

Acute Mold Treated

16

4,172

521

Acute Mold Relapse

105

22,219

1,886

Chronic Mold Untreated

273

12,266

699

Chronic Mold Treated

273

4,183

157

Chronic Mold Relapse

70

14,138

982

DINO Untreated

11

15,461

1,121

DINO Treated

13

4,402

477

CFS Untreated

24

9,033

865

CFS Treated

11

5,837

532

EPO Before Treated

59

18,807

2,155

EPO After Treated

40

5,741

3,836

EPO After Relapse

31

22,103

3,399

Relapse by all Illness

212

19,762

1,231

23) C4a in a variety of conditions per table above

A) People with long-standing Lyme

(1) After antibiotics; no change

(2) After CIRS therapy it falls nicely

B) Acute mold patients with very high C4a fixed by CIRS down to level of acute Lyme which is close to control patients

C) Dinoflagellate folks with similar pattern after CIRS therapy

D) Erythropoietin for the very worst patients doesn’t work quite as well but brings it down quite a bit

E) Re; C4a and “Sicker Quicker”; the relapsing patients instead of mean around 10K-11K, the mean is 22K

(1) There REALLY is a difference in C4a in the relapsing patients!

(2) To Summarize Treated vs. Untreated C4a

Category

N=

Value

Lab Control

 

2,830

Control

300

2,985

Untreated All

4,888

12,602

Treated All

4,392

4,193

EPO before

259

18,807

EPO After

240

5,741

Relapse All

1,603

19,762

24) Treatment;

A) Remove from exposure

B) Cholestyramine for 30 days

(1) Actos run-up (if Lyme)

C) Eradicate biofilm formers/MARCoNS

D) No gluten if AGA (+)

(1) Do Tissue Trans-Glutaminase IgA, IgG, IgM if Gluten (+)

(a) Expect to find more of the IgG than IgM but measure all 3

E) Actos/low Amylose diet for MMP9, PAI-1, Leptin

F) Correct ADH/Osmolality;

(1) Use DDAVP if abnormal

G) Androgens;

(1) Look at Testosterone/Estrogen ratio’s to determine if up-regulated

(2) Consider DHEA Sulfate to correct from “upstream”

(3) Avoid Aromatase Inhibitors

H) Fix C3a, C4a, TGF β-1

(1) Losartan 12.5-25 mg bid

(2) Consider VIP therapy

(a) VIP Benefits for abnormal values

(i) Lowers elevated C4a, TGF β-1, VEGF, MMP9, Vitamin D3, reactivity to WDB

(ii) Raises low VEGF, Vitamin D3, thymus-derived & induced T-Reg cells

(b) Potential VIP side effects

(i) May raise lipase levels

(ii) Abdominal discomfort 2’ to lowered gastric HCl production

(iii) Excessively low BP due to vasodilation

(iv) Rash

I) Check VEGF

(1) Consider Erythropoietin

25) Low Amylose Diet

A) Foods are converted quickly to sugar in saliva due to amylase

B) This gives a higher glycemic index

C) Amylose is the sugar for developing plants, it’s found in;

(1) Seeds

(2) Roots; any root vegetable will have Amylose in it those that seem OK...

(a) Onions

(b) Garlic

D) Has a different Glucose-Glucose bond than Glycogen

(1) Wheat

(2) Oats

(3) Rice

(4) Barley

(5) Rye

E) Seeds that have an Amylase inhibitor within them are OK to eat, they include;

(1) Corn

(2) Sorghum

(3) Buckwheat

(4) Quinoa

(5) Amaranth

Back to Top of Biotoxin Illness Outline

 

XV Clinical Course  during Treatment of Chronic Inflammatory Response Syndrome (Lab Summary)

1) Usually patients with an elevated MMP9 will feel worse when starting Cholestyramine

2) Lyme patients will often develop an increased MMP9 with therapy, their symptoms and VCS will worsen

A) If treating Lyme and patient feels worse after start Cholestyramine

(1) Look at VCS row D&E

(2) Repeat MMP9

(3) Stop Cholestyramine

(4) Revisit the issue; Do they have Lyme or other toxin

(5) If Lyme, don’t resume Cholestyramine, don’t give antibiotics for Lyme

(6) Give Actos/low amylose diet

3) Some people will get worse initially, but it will only last a couple of days

A) Lyme patients can go 3-4 days

4) How does Cholestyramine Work?

A) Not absorbed, can’t add to host

B) Binds to anion dipole structures such as quaternary amines, has a net (+) charge, also binds

(1) Cholesterol

(2) Bile salts

C) It’s basically a biologic glue

D) Becomes an electron sink

E) Toxins have an anion ring, sharing electrons

F) The toxin thus binds to the Cholestyramine

(1) They’re the same size and shape but with opposite net charges

(2) Binds

(a) Pacific and Caribbean Ciguatoxin

(b) Brevitoxin in Dinoflagellates

(c) Ochratoxin in Mycotoxins

(d) Wortmannin

G) Interrupts enterohepatic recirculation

H) Stops Ionophores

5) Then what?

A) Meet VIP

B) Deficient in 98% of CFS-type illness

C) 50 mcg/ml nasal spray qid

D) An orphan drug used off-label

(1) Designated for Pulmonary Htn

E) First use in CFS-like illness in 11/08

F) Response is immediate and dramatic

G) “VIP puts out the fire and adds a coat of paint”

H) Vasoactive Intestinal Polypeptide “VIP” is a Regulatory neuropeptide

I) Hypothalamic suprachiasmatic nuclear agonist neuropeptide

J) Input from Olfactory bulb and retina

(1) Listen up MCS folks!

(2) One patient uses 8 doses @ bedtime (2 qid didn’t work) great success!

K) Effector neuropeptide

(1) Increases cAMP; the second messenger intracellularly

(2) Controls Pulmonary Artery Pressure

L) Don’t abuse it by prescribing when/where it’s not indicated

(1) Don’t use with

(a) Abnormal VCS & ERMI >2

(b) Untreated MARCoNS or

(c) MSH<35

M) Measuring toxins and cytokines in blood or urine toxins is a huge waste of time/money

(1) They’re not excreted in genetically susceptible people

(2) A new hardware development is a hand-held beta-glucan detector that will show the presence of VOC’s

6) Usual Disclaimers Re; VIP

A) VIP is safe, basically impossible to OD

B) VIP has an excellent record to date

(1) >100 pt’s with Rx filled @ Hopkinton

C) Easy to use, portable

D) It works great!

E) Available by Rx

F) Just about every CFS’er is deficient in VIP

G) When word gets out, look out!

H) Concern; people will leap to it’s use without recognition of what makes it work and when it should NOT be used (L above)

7)  IRB-approved clinical trial

A) 30 patients; open label

B) Titration study

C) Entry criteria include;

(1) ERMI <2, normal VCS

(2) Negative cultures

(3) PASP rise >8 Torr in exercise

(4) MMP9 Normal

(5) C3a Normal

D) QID X 30d, then BID X 30d, then QD X 30d, off 30d then 6 month F/U

8) Clinical Results of VIP Therapy

A) Before giving VIP, draw baseline; Lipase, VEGF, C4a, TGF β-1.

B) VIP Lowers C3a/C4a/TGF β-1, Reduces PASP with exercise, Increases VEGF & VO2max, Stabilizes aromatase & Vitamin D

C) PASP resolved on qid and bid

D) Normalized capillary hypoperfusion

E) Symptoms decreased rapidly on qid, increased with downward titration

F) Normalized C4a & TGF β-1

G) Normalized VEGF, Androgens (normalized aromatase)

H) Normalized Vitamin D (unexpected)

I) At 6 month F/U, no dropouts

J) Ongoing use of 1-3 doses/d

K) Consider the illness as treated/controlled

L) Remember to screen for Lipase with VIP use

M) Down-regulation of reactivity

(1) Stabilizing MASP2? (yields lower C3a, C4a)

N) Reduced chemical sensitivity

O) Enhanced quality of day to day life

P) Cognitive improvement

Q) Reduction in disability; giving life back to the “living dead”

9) Discussion

A) Must use sequential therapy first

B) Do NOT skip steps

C) Don’t be creative with database

D) Don’t fail to correct ERMI, VCS before VIP

E) Must NOT have ongoing exposure!

F) VIP is miraculous

G) VIP has been abused

(1) Not for (+) VCS patients!

(2) Don’t guess about symptoms and PASP; you MUST measure TR/PA pressures!

(3) Don’t even think about starting CIRS therapy with VIP, it’s therapy for THE END!

(4) Document the process

(a) It is off-label use since it’s designed only for Pulm Htn.

10) Autoimmunity in CFS

A) Antigliadin IgA and IgG*

(1) Adults 33%, Children 58%

(2) TTG IgA is used as a F/U confirmation test, not a screening test

B) Anticardiolipins IgA, IgG and IgM*

(1) Adults 15%, kids 28%

C) Anti-Actin (smooth muscle Ab’s)

(1) Adults 10%, kids 18%

(2) Positive in a lot of 11-3-52b’s

(3) Unclear what to do with anti-actin Ab’s in the face of normal LFT’s

D) ANA 5% in Adults and kids

E) Control incidence in all <3%

11) Conclusions

A) An organized data-driven approach to diagnosis leads to effective therapy!

B) Guessing, assumption and “clinical experience” are of no help compared to data

C) Hope for cure is here; let us not forsake our new knowledge

D) This is the Golden Goose; don’t kill it!

12) Discussion/audience questions

A) Chitosan should have the same correct structure to bind anionic toxins

(1) At pH of <9, Chitosan depolymerizes losing an acetyl group

B) Bentonite clay and activated charcoal have not produced reproducible success

C) Currently there is nothing that works as well as Cholestyramine and Welchol

D) Cholestyramine is NOT given to the very severely ill

(1) Use Welchol for these patients

(2) Welchol for MCS patients

(a) Grind it into small pieces and take a looong time to get to therapeutic dose so that it’s tolerable

(3) Cholestyramine is “category C” in pregnancy

(a) You must document that the decision to use the drug has been discussed with the patient, that risk<benefit

(b) The Amish have used Cholestyramine in pregnancy and nursing without any problems.

Back to Top of Biotoxin Illness Outline

 

XVI Understanding the inflammatory basis of Post-Lyme Syndrome; Objective Physiologic Measurements that Characterize this Treatable Disease

1) Goals

A) Discuss inflammatory elements that contribute to Post-Lyme Syndrome

B) Discuss therapy of those elements

C) Provide a framework for evaluating the process of treatment of PLS

D) Provide indication for abnormality in regulation of T-Reg cells

2) Agenda

A) Assumptions are the enemy; don’t guess!

B) What inflammatory pathways can we define?

C) Biotoxin Pathway

D) CIRS

E) TGF β-1 is your buzz word

F) C4a & MASP2 are not your friends

G) CD4+, CD25+, FoxP3+ T-reg’s are key

3) The ongoing argument

A) Antibiotics for never (wrong)

B) Antibiotics forever (wrong)

(1) Is the answer putative co-infections? 

(2) Is there MARCoNS?

(3) What does the differential Dx show?

C) Lyme has been reported from every state in the US including Hawaii!

D) Both sides need to pay attention to;

(1) Genetics

(2) Markers of innate immune inflammatory responses

E) Patient outcomes are the only goal

4) Look at the PLS Assumptions

A) 90% of Lyme patients have ECM rash (no)

B) 95% of Lyme patients only need short-term antibiotics (no)

C) VCS.

D) Just about every Lyme patient has multiple co-infections (no)

E) Lyme always needs long-term antibiotics in everyone (no)

F) Every patient with tick-borne disease has Lyme and every patient with Lyme has tick-borne disease (no)

5) Stop the Assumptions!

A) We must be very careful in data collection

B) Use objective parameters

C) Symptoms alone are nonspecific

(1) I still hear that night sweats mean Babesia

(2) Particular joint symptoms are not specific

D) Symptoms alone don’t ensure causation of complex multi-symptom illness

E) The field of chronic fatiguing illnesses is filled with assumptions

F) Let’s stop such nonsense; the data from reliable labs will set you free

(1) Before starting a new lab, insist on split-samples to test validity of testing

(2) This is especially true for cash-only labs

G) There are numerous lab abnormalities in Lyme that are due to the diffuse inflammation

6) Definitions

A) TGF β-1

B) C4a

C) C3a

D) MMP9

E) VEGF

F) MARCoNS

G) MSH

H) VIP

I) FoxP3 is a nuclear replication factor in CD4+ & CD25+ cells

(1) FoxP3 is made from FoxP0 which is

(2) Acted on by a kinase that sticks a phosphate on FoxP0 to make FoxP3

(3) Without FoxP3, the pathway of injury from CD4+ & CD25+ cells to pathogenic T-cells does not appear to occur.

(4) FoxP3 allows pathogenic T-cell formation but is also involved in stopping inflammation

(5) So if we fix Low CD4+ & CD25+ cells

(a) Including using elements like VIP to drive them up and…

(b) We block FoxP0 to FoxP3

(c) Will we have an additional way to block the cellular mechanism of inflammation?

(d) There are available kinase inhibitors that do exactly that

(6) The mechanism that converts FoxP0 to FoxP3 comes from the phosphatidyl-inositol 1,3 kinase pathway that’s linked to AKT

(7) These pathways are identified, active research is ongoing especially with P1, 3K and its role with AKT as an additional pathway of injury in these people with inflammatory processes suffers from.

J) Innate immunity

K) Ag detection

L) Ag presentation

M) Dendritic cells and Ag Processing; PAPC

N) Ag Delivery

O) CTLA 4

P) Naēve T cells

(1) Cytotoxic Lymphocyte Factor 4 can block passage of an immune signal from a dendritic cell to a naēve T cell.

(2) This works by blocking the attachment of the naēve T cell to its -T cell receptor on the dendritic cell.

Q) B Cells

7) Where Post-Lyme therapy fails

A) Failure of adequate “30,000 feet”

B) Water-damaged buildings lead the list

C) MARCoNS is almost guaranteed if antibiotics have been used for longer than 1 month

D) Ignoring the issues involving;

(1) AGA, ACLS, Actin auto-Ab’s

(2) ADH/Osmolality

(3) MMP9 untreated

(4) C3a not done

(5) C4a not done or wrong assay used

(6) TGF β-1 ignored

E) If there is defective Ag presentation, is it reasonable to use a Lyme Ab test? (Yes)

8) Failure of Post-Lyme Syndrome

A) MSH & VIP deficiency

(1) Antibiotics will never fix this

B) Ignoring T-reg cell physiology

(1) Antibiotics will never fix this in those with HLA susceptibility to Post-Lyme Syndrome

C) Use of Ab testing in the face of HLA-DR associated failure of Ag presentation

D) Assumption that “once Lyme, always Lyme”

(1) Lyme will change the host such that as time goes by, HLA susceptibility to other diseases will be expressed such that

(2) If Lyme was present last year, and they get sick again this year, do not assume that it’s due to Lyme again this year, what else can cause CIRS?  Use your differential diagnostic skills!

(3) Don’t assume that this is a cyst phase, or co-infection that was latent

(4) Look at this as a new illness; it probably will be

E) Does finding Borrelia burgdorferi in tissue mean causation of illness?

F) Dr. Shoemaker mentions that he has atypical mycobacteria alive and reproducing in his lungs, does he have mycobacterial PNA due to granulomas in his lungs? No

G) If there is a spirochete inside of a fibroblast, does that automatically mean Lyme?  No

H) Could there be sequestration of Lyme within granulomata? Possibly

I) Currently we don’t have the lab tests and ability to look at all tissues

(1) If there’s a negative stain for Borrelia, it doesn’t mean no disease, it means we haven’t found disease, we didn’t get it at that time.

9) Look for the final common pathway; Post-Lyme becomes inflammatory CIRS

A) Abnormalities in innate immune responses (non-specific for cause)

(1) Exactly what it is in other etiologies for CIRS

(2) VCS (+) as from all other causes of CIRS

B) Host response must be defined with labs

C) Incredible amplification of multiple pathways follows initiation

D) CIRS!

10) Biotoxin Pathway

11) Putting the Biotoxin Pathway to work

A) 150 patients with confirmed Lyme

B) 60% ECM rash (+)

C) 32% IgG (+) Western Blot

D) 74% IgM (+)

E) Data recorded at baseline, after 3 weeks of oral antibiotics then after CIRS therapy

12) Biotoxin Therapy

A) Done after antibiotic therapy X 3 weeks

(1) Doxycycline for women (Amoxicillin causes to much vaginal candida)

(2) Doxycycline or Amoxicillin for men

(a) Very little Amoxicillin used

(3) If not 100% fine after antibiotics, they were set up for CIRS treatment

B) Differential Diagnosis is negative

C) Cholestyramine or Welchol for 30 days after

(1) Actos and no-amylose diet for 5 days if Leptin >7 or

(2) 2.4 EPA Omega-3 and

(3) 1.8 DHA if Leptin <7

(4) Reducing Leptin to <2, raises MSH production tremendously

(5) Ensure Leptin is at least  <7

D) Eradicate MARCoNS (BEG spray and Rifampin)

E) Correct ADH/Osmolality (DDAVP)

F) Correct Androgens (check Testosterone/Estrogen ratio)

G)  PAI-1

H) Correct Anti-gliadens Abstinence from gluten if TTG (+)

13) C4a by Step

 

C4a base

C4a after abx

C4a after CIRS Rx

Master

9,336

6,797

2,533

ECM Rash (+)

8,025

6,912

2,643

ECM (-)

11,571

6,558

2,321

IgG (+)

6,795

6,154

2,215

IgG (+)

10,691

7,189

2,726

IgM (+)

9,753

6,656

2,797

HLA (+)

9,771

8,307

2,745

HLA (-)

8,348

4,011

1,512

A) HLA doesn’t make much of a difference on whether the patient gets Lyme or not, but it does make a difference in duration of Lyme problems

B) HLA non-susceptible patients do very well with CIRS therapy

C) Antibiotics alone did not cure these patients

D) CIRS therapy did cure these patients.

14) C3a by Step

 

C3a base

C3a after Abx

C3a after CIRS Tx

Master

638

233

126

ECM (+)

652

436

251

ECM (-)

627

443

321

IgG (+)

738

442

188

IgG (-)

587

434

273

IgM (+)

645

443

273

IgM (-)

620

427

245

HLA (+)

620

556

271

HLA (-)

674

296

212

A) None of the numbers are >940

(1) None of these patients are being seen within the first 4-5 days of their illness

B) As expected, there’s a good C3a reduction with antibiotics

(1) C3a forms with bacterial/spirochetal membranes being found in the blood stream.

C) Further reduced C3a after Actos & Cholestyramine

D) High C3a does not automatically mean Lyme, but it does fall with CIRS Rx

15) TGF β-1 by step

 

TGF β-1 Base

TGF β-1 after Abx

TGF β-1 after CIRS Rx

Master

7,378

8,538

3,149

ECM (+)

7,354

8,095

2,522

ECM (-)

7,415

9.335

2,350

IgG (+)

7,704

5.701

3.028

IgG (-)

7,252

9,484

3,194

IgM (+)

7,323

9,716

3,154

IgM (-)

7,568

5,594

3,135

HLA (+)

7,516

11,005

3,250

HLA (-)

7,063

3,331

2,141

A) No significant differences between ECM, IgG, IgM, HLA statuses at baseline

B) Ideal cut-off is 2,380, this is only achieved in the bottom cohort HLA-

C) How much longer should we continue straight biotoxin therapy?

(1) The table above does not include use of Losartan, VIP

(2) Dr. Shoemaker tends to ignore TGF β-1  as long as they’re <5,000

(3) Clinically, he has not seen problems from this approach.

(4) Further lowering can be attained with Losartan or VIP

16) MMP9 By Step;

 

MMP9 Base

MMP9 After Abx

MMP9 after CIRS Rx

Master

459

410

241

ECM (+)

465

350

255

ECM (-)

447

564

210

IgG (+)

549

342

228

IgG (-)

410

464

250

IgM (+)

426

416

219

IgM (-)

551

401

275

HLA (+)

427

504

264

HLA (-)

530

539

189

A) No huge numbers

B) Antibiotics don’t help much, some cohorts actually worsened with higher numbers

C) This is no surprise with the recollection that MMP9 reflects ongoing inflammatory effects, being split from MMP14 from endothelial cells, macrophages and monocytes.

D) After CIRS therapy, MMP9 drops beautifully as it should.

E) There were no measurements of MMP9 at the conclusion of Actos when they would have been at their nadir.

17) VCS by HLA

 

Base

After Abx

After Rx

% Positive

98

68

0

% Negative

2

32

100

% Positive HLA Susceptible

97

96

0

% Positive HLA Non-Susceptible

100

15

0

A) VCS is not 100%

(1) 8% of the negative patients who were sick got better with treatment

(2) They further improved after antibiotics with CIRS therapy

(3) So VCS by itself can be negative.

B) Of the proportion with VCS (-), there is a disproportionate number of teenaged women

C) Of the men and the older VCS (-) patients, there are artists, photographers, baseball players, and interior designers.

D) He doesn’t stop the CIRS Rx until the VCS is fixed;

(1) He monitors VCS as well as all of the other lab parameters, most of which improve before VCS normalizes.

E) HLA Susceptible patients will NOT have VCS improve with antibiotics.

(1) The improvement after abx comes from the group that is not HLA susceptible

F) Let the VCS guide your therapy, treat until there is a VCS plateau.

(1) Some rare folks will never have a fully normalized VCS.

18) Treating Lyme Patients with VCS as an indicator of neurologic effects

A)

B)  Before antibiotics

C) After antibiotics

D) After antibiotics & Cholestyramine

19) CIRS Therapy

A) Think about immunological illnesses

B) Think sepsis (versus bacteremia)

C) Think about Th-1, Th-2, and Th-17 (Th-9!))

(1) More is being learned about Th-17 in immunology journals

(2) Currently, there is no commercially available lab test to assess Th-17 cell level and/or activity

(3) Th-9 is a brand-new player in the field

D) Think about capillary hypoperfusion

E) Think about loss of neuropeptide control of peripheral inflammation

F) Don’t forget coagulation!

G) The complexity of the immune response does not mean that we have the luxury of not treating what we now know.

H) Activation of C4a; (C3a only if bacterial membrane platform is present.)

I) TGF β-1 is the gorilla here

J) We need to look at T-regulatory cells if TGF β-1 is increased

K) T-reg’s are low in Post-Lyme

L) Raising CD4+ CD25+ FoxP3?

20) CD4+ CD25+ FoxP3+

A) Hot in immunology; inducible (i) cells

B) High TGF β-1 increases T-Reg cells (i) that should suppress inflammatory responses, including auto-immunity

C) But the highest TGF β-1 is in auto-immune illness

D) If FoxP3 split off in inflamed tissue pathogenic T cells and more TGF β-1

E) High levels of CD4+ CD25+ & FoxP3+ cells should be suppressing inflammation.

(1) Yet, in autoimmunity is where you find some of the highest levels of TGF β-1

(2) We need additional definition as to why the CD4+ and CD25+ convert to pathogenic T-cells in inflamed tissue

F) Hopefully, in the future, we’ll find that interventions that increase the T-Reg cells will help our Post-Lyme patients

21) T-Reg’s dominate Post-Lyme

A) Interventions to increase T-reg?

B) Drop Pathogenic T-Cells

C) What if the TGF β-1 is blocked?

(1) No rise in T-reg (i)

(2) No rise in TGF β-1 from pathogenic T cells generated in situ

(3) This stops the feed-forward amplification loop

D) Problem appears to be solved by stopping TGF β-1!

E) Newly discovered kinase inhibitors may hold the answer.

22) T-Reg’s are plastic;

A) If FoxP3 added to CD4+ CD25+ cells is needed for suppression of local inflammation (it is) and that induction is driven by TGF β-1  (it is) and then FoxP3 is split off in inflamed tissues (it is) and then FoxP3 negative cells turn on more TGF β-1  (it does), why wouldn’t stopping TGF β-1 work? (It does)

B) So TGF β-1 starts inflammation, FoxP3 stops inflammation

C) Stopping TGF β-1 stops inflammation

D) Interventions that raise the CD4+ and CD25+ activity should help stop auto-immunity even more than what we see in Lyme.

23) Before the leap to T-reg

A) What do we know about who gets Post-Lyme Syndrome?

B) What do Post-Lyme people have?

C) Is the T-reg and TGF β-1 problem unique to Lyme Patients

(1) Nope; just about every biotoxin person has it, like CD-57

(2) CD-57 cells are not unique to Lyme as some investigators once thought; it goes up with mycotoxins too.

D) This is an emerging field.

24) Innate Immunity; is it old?  No

A) System of Ag detection and response is over three billion years old

B) Evolutionarily conserved in mice, men, sea squirts, slime molds and nasturtiums

C) Look what came first; blue green algae, fungi, Dinoflagellates, spirochetes

D) 1989 CSH Symposium; Janeway

E) 1985 First TNF paper; 50,000 more papers in the last 10 yrs.

F) The intra-cellular parasites are incredibly well adapted for life inside of a host cell.

(1) They have their own nuclear DNA

(2) They have their own mitochondria DNA

(3) They have their own 3,200-kilodalton-plasmid ring that codes for enzymes necessary in the dark phase of photosynthesis.

(4) Some early papers on the Rx of malaria included use of Atrazine; a herbicide

(5) Horses with sarcocystis are given a drug called Marque; another herbicide

G) These diseases can up-regulate or down-regulate each other

(1) Lyme down-regulates Babesia

(2) These organisms each make their own toxin Eg.

(a)   Malaria (GPI)

H) To treat these diseases it is necessary to kill

(1) Nuclear DNA

(2) Mitochondrial DNA

(3) Plasmid plant-source DNA of ATPases as well

(4) It’s also necessary to knock out their toxins with Welchol and Cholestyramine

I) Horses and dogs are afflicted by these organisms

J) We probably will never be able to treat humans with herbicides despite massive “informed consent”

Back to Top of Biotoxin Illness Outline

 

XVII Review of Post-Lyme Syndrome

1) Let’s not forget genetics

A) Learn HLA DR by PCR (SSOP)

(1) A DNA-selective assay

B) Look for 4-3-53 (0401, worst of 12)

C) Look for 11-3-52G (this one is easy)

(1) Long arms, long fingers, flexibility

D) The “dreaded”

(1) Worst TGF β-1

(2) Most abnormalities

2) Lyme HLA DR Relative Risk >2 (Lyme RR is a bit different from mycotoxin RR)

A) 21% of the normal population

B) 4-3-53; 11-3-52B; 14-5-52B

C) 15-6-51 and 16-5-51

D) Post-Lyme in 20-25% of the population

E) Antibiotics alone won’t help here

F) Our data (N+1,200) show Post-Lyme almost never occurs in other HLA’s.

3) Do certain HLA haplotypes have worse inflammation in Post-Lyme?

A) You bet!

B) 2003 Shoemaker et al

C) 2006 Steere (JEM)

(1) 4-3-53

(2) 11-3-52B

(3) 15-6-51

(4) 116-5-51

4) Biotoxins

A) VERY small molecules (usually carried by glycoproteins, bind to receptors on dendritic cells and elsewhere).

B) Ionophores; pass cell to cell

C) Inflammagens bind to receptors;

(1) Toll; Mannose

(2) Ficolins; C-linked lectins

(3) Have predictable inflammatory results

D) Direct neurotoxicity

E) Defective Ag presentation

5) Positive-Feedback Loops

A) HLA DR inhibition/withdrawal (IL-10) from surface of macrophages/Ab production

B) Bordetella and Anthrax block Lysosome/ER complex

C) Increasing TGF β-1 leads to T-reg cell dysfunction forming pathogenic T-cells

D) Differential gene activation (genomics to the rescue, we hope!!)

E) Currently, CD4+ CD25+ FoxP3+ dysregulation is front and center for research.

6) Antibiotics don’t fix innate immunity

A) Interestingly however, both Doxycycline and Macrolides have some intrinsic anti-inflammatory properties

(1) There are even patients with multiple sclerosis being treated with Doxycycline

(2) 15-6-51 is an HLA risk factor for MS

B) Lyme, Mold & MS all lower T-Reg cell counts

(1) Treatment currently is somewhat nonspecific in attempts to drive up T-Reg cell counts.

C) Babesia is horribly over-diagnosed but activates innate immunity

(1) Look for smear; hemolysis

(2) Look for low haptoglobins

D) Bartonella diagnosis is so flawed now

E) Ehrlichia persistence?  Confirm?

7) Diagnosis is not just exclusion

A) Chronic, multisystem, multisymptom illness refractory to all interventions

B) Dense innate immune abnormalities are invariably present

C) Genetic basis (HLA DR by PCR)

D) Onset isn’t the end of the diagnosis

E) Ongoing effect of environmental exposures needs to be remembered;

(1) Don’t Forget To Ask!

8)  Shoemaker’s Treatment Message;

A) Look for environmental exposures and repeat of it first and foremost!

B) Establish a decent baseline of results of innate immunity testing

C) Look for and eradicate biofilm formers

D) Treat the inflammatory physiology

E) What do you have left?

F) What happens when the injured patient is exposed next week?

(1) Repeat illness

(2) Always be on the lookout for repeat exposures!

(3) Sicker Quicker

9) What you need to know:

A) Symptoms must be present

B) Get the VCS

C) Labs must be present to show what is and what is not

D) DDx must be there.

E) The labs will show you the way;

(1) Start looking at innate immunity as a target

(2) Start looking at targets you can fix

(3) Fix the targets; watch the illness disappear

(4) Wait for relapse

Back to Top of Biotoxin Illness Outline

 

XVIII Post-Lyme Syndrome Case Reviews

1) Case Review #1

A) Laundry clerk shows you her ECM rash, 3 days old, few symptoms

B) You demand labs and won’t just give her the antibiotics that she requests

C) HLA DR 4-3-53 (0401)

(1) TGF β-1 17,598

(2) C4a 8,705

(3) C3a 1,284

(4) MMP9 739

D) Her friend the hairdresser says it’s not Lyme

E) Send her a certified letter; she takes no Abx (the letter is his CYA)

F) 3 months later she is Dx’ed with “fibromyalgia”, alopecia universalis and vocal cord polyps (and nasal polyps are both caused by TGF β-1) (not the case with colon polyps)

G) She has pretty typical TGF β-1  (catagen hairs; Transformation!!)

(1) Growing hair follicles are anagen

(2) Rest-phase hair is telogen

(3) Dying hair follicles are catagen due to TGF β-1

(a) Dermatologists and others discussing “hair loss” never mention the effect of TGF β-1

H) One year later has restrictive lung disease

2) Case Review #2

A) 59 wm Farmer; 15-6-51 and 7-2-53

B) Wife had ECM (+) Lyme X 3

C) Presents for evaluation of knees and hands; all inflamed, Tap (-) no C4a in joint fluid (C4a is not a good marker in CSF)

D) ANCA (anti-neutrophilic cytoplasmic antibody)  (+) Atypical; no Ulcerative Colitis or Cirrhosis

E) TGF β-1 high, C4a high, C3a Normal, MMP9 837

F) Given antibiotics as the exposure was only 3d old

G) After 1 month on Abx not improving

H) TGF β-1 doubles, MMP9 climbs to 1,329, C4a doesn’t fall, C3a still normal, Lyme Western Blot negative

I) Starts Actos and Cholestyramine 1 month later slightly better

(1) MMP9 312

J) Starts Erythropoietin 8,000 units twice/week for 5 doses

(1) C4a normalizes

K) Then given Losartan 25 mg bid X 6 months

L) TGF β-1 normalizes

(1) Joint symptoms abate

(2) ANCA converts to normal

M) Didn’t need VIP, Losartan was well tolerated

(1) And Losartan is much less expensive than VIP!

3) Case Review #3

A) Mold inspector with remote history of only 4 bands Lyme in CSF, Rx’ed with oral abx

B) Was well until 2004 MRI with contrast, does OK for a few years after Gadolinium exposure

C) Now skin thickening similar to scleroderma, Multiple symptoms, looks like Parkinson’s

D) Had long-term esophageal problems/dysmotility

E) Might have had another tick bite

F) VCS (+)

G) Another physician had treated him with Cholestyramine which didn’t help at all

H) Lung diffusion capacity abnormal

I) All auto-immunity studies were negative/wnl despite looking like he has scleroderma

J) Could he have ongoing mold exposure?

K) Went back on Cholestyramine and had his home remediated

L) VCS Normalized but patient is still ill

M) Losartan provides a ray of hope

N) 3 months later skin is clear, Parkinson’s is gone

O) Was this Lyme, Mold or Gadolinium?

P) Overall, the culprit was probably TGF β-1 causing endo- to epithelial mesenchymal transformation.

(1) It changed his cell types.

Q) Sebhorreic keratosis’, Actinic keratosis’ will often appear at about the same time TGF β-1 is elevated

(1) TGF β-1 changes cell types!

4) Case Review #4

A) Virginia Beach Pre-teen

B) Unequivocal diagnosis of Multiple Sclerosis had plaguing on her CNS MRI

C) Oligoclonal bands; demyelination

D) Rx for Lyme; had 3 bands in CSF

E) Rx steroids for vision compromise, then another physician treats for Lyme with partial improvement

F) Parents defer MS Rx (Betaseron)

G) Patient finally comes in to see Dr. Shoemaker

H) What’s missing?

I) ERMI 10, moldy junction of garage to home

(1) HVAC spreads bioaerosols

J) Cholestyramine started.  Symptoms did not intensify, so probably not Lyme

(1) TGF β-1 >40,000

K) Neuro stabilizes, home remediated

L) F/U TGF β-1  <3,000; CNS lesions melt

M) Neurology wants her to stay on long-term Cholestyramine

5)  Case Review #5

A) Documented ECM rash X 10, HLA 15-6-51

B) Won’t use Permethrin