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									  Biomedical Treatments for
Autoimmune and other Chronic
        David Berger, MD
        Medical Director
       Wholistic Pediatrics
           Tampa, FL
         (813) 960-3415
Autistic Spectrum Disorders

ADHD     Asperger’s      PDD        Autism

 In many of our patients, there are multiple
          biological abnormalities
Discover Magazine, 3/14/07
 Abnormal flora (dysbiosis)
 Abnormal permeability (leaky gut)
 Illeal lymphoid hyperplasia
 Persistent Measles virus
            Immune System
 Th1       Th2 type of WBC
 Low TH1 can cause susceptibility to
  infections, with potential increased
  exposure to antibiotics.
  – Related Yeast Overgrowth in Intestinal Tract
    as well as Clostridia and Parasites

 High TH2 can lead to inappropriate
  antibody formation
  – Auto-antibodies
  – Food antibodies
      Biochemical Abnormalities
   Low sulfur amino acids
   Low zinc levels
   Low selenium levels
   High copper to zinc ratios
   Low omega – 3 fatty acids
   High ammonia levels
   Abnormal methylation metabolism
   High microbial metabolites
   Elemental Toxins: Mercury, Lead, etc
Robert Cade, MD, Professor,
University of Florida Medical
“A gluten and casein free
diet resulted in significant
improvement in 81% of
children with autism within
three months.”
      Rationale for Casein/Gluten
               Free Diet
 Gluten and casein have immune, as well as
  neurotransmitter impacts.
 Many ASD children have food hypersensitivities
 Improper digestion leads to buildup of opiate-like
  peptides. These can be identified in the urine of
  many children with ASD.
 Dr Cade at UF recently injected rats with
  casomorphin, causing the rats to develop autistic-
  like behaviors

Dipeptidyl Peptidase IV, carboxypeptidase A, and aminopeptidase are some
of the main enzymes that brake down the opiate peptides.
Some of the enzymes are zinc dependent, and it’s activity can be inhibited
by mercury, among other things.
A first generation enzyme containing DPP-IV is available from Kirkman
Labs. Although for most children it can not serve as a sole replacement for
the C/G free diet, giving it with these foods allow some children to take c/g
foods with out negative reactions, and it can be administered in cases of
accidental exposure
Dr. Lewis’
book is the
starting point
for a gluten
and casein
free diet.
Milk: It does your body good?
                Frank Oski -
                  Past chairman of
                  Johns Hopkins
                  Department of
                  Pediatrics and Past-
                  President of the
                  American Academy of
         Evaluating Children
   Urine and Stool Studies
   Thyroid profile
   Toxic Metals
   Inborn Errors of Amino Acids
   Fragile X, Chromosomal Analysis
   Metallothionein analysis
   RBC Fatty Acids
   Brain auto-antibodies
   Immunoglobulins, WBC activity
   Detoxification Metabolism
   Hormone Profiles
 Autism Speaks Launches Pediatrician
Outreach Initiative to Increase Awareness
 about the Diagnosis and Treatment of
       Gastrointestinal Problems

Consensus Statement Developed by Expert Panel Includes
  Recommendations for Care Specific to Children with

                                    February 28, 2007
      Abnormal Stool & Urine
 Best, and in some cases imperative to treat these
  prior to starting more advanced therapies such as
 Stool : Yeast (Candida), Parasites (Giardia,
  Dientameoba, and others), Malabsorption, Blood,
 Urine : Yeast and Bacterial metabolites, abnormal
  Kreb’s cycle metabolites, oxalates, opiate
  peptides, etc
Treat Stool & Urine Findings
 Yeast Killers: Nystatin, Diflucan, Sporonox,
  Uva Ursi, MCT, goldenseal, Garlic, Candex
  (digestive enzyme) and others.
 Clostridia Killers: high dose lactobacillus,
  Metronidazole (benzoate by compounding),
 Parasites: the ones we see most often are
  also sensitive to Metronidazole Benzoate,
  other specific natural and pharmacological
  agents used depending on the particular
OAT test
OAT After Culturelle and Nystatin
    Nicholas (8 y/o)After Culturelle and
                     (3 months later)
   Attention span has definitely improved since the last visit.
   getting very good reports fro the teachers
   more "with it", not spacey
   now will respond much faster when spoken to.
   Reading skills vastly improved, with good comprehension skills.
    Reading instruction manuals and understanding it. Wants to
    keep reading on and on.
   performing skills at school that he never did before. Amazing
    memory for spelling.
   Learned how to tell time.
   Can perform addition.
   less problems with interactions with his peers, but he prefers
    solitary play when in his house. When visiting others he will
    interact more. He does much better in small and quiet groups
   getting better balance of his body.
 Sulfur is an element critical to the structure and
    functioning of body mechanisms.
   Dr. Rosemary Waring reports that most autistic children
    show a deficiency of sulfates in their plasma. Of the
    autistic children she tested, 92% had sulfate levels that
    were only 12% of normal
   Low sulfates can lead to a leaky gut, as well as a
    weakness in the phenolsulfotransferase (PST) system.
   the PST pathway is important in removing toxins
   A weakness in the PST system is often characterized by
    night sweats, red face and ears, allergies, and keratosis
    pilaris (red bumps on back of arms)
   Tx: Epsom Salt by bath or transdermal application, or
    oral sulfates such as glucosamine sulfate and MSM
After Epsom Salt Baths
Eric’s (6 y/o) Response to Epson
Salt Baths
 •Making new statements. Becoming more creative with
 language. Responding to answers appropriately
 •still needs help focusing for long periods of time, but
 paying more attention
 •echolalia is gone
 •showed much more interest in presents that he received
 for the holidays.
 •getting more involved with his brother, they are fighting a
 bit now.
•Ammonia is a known toxin to the brain.
•High enough levels can cause can cause neurological
symptoms, even coma. This is usually associated with liver
•About 5-10% of ASD patients we check have mild to moderate
elevations in Ammonia levels (in the presence of normal liver
•Proposed mechanism: Proteins >> Amino Acids >>Ammonia
>>liver fuses 2 ammonia molecules to form urea >> excreted
in urine. Gut pathogens >> leaky gut. Urease enzyme made by
certain gut pathogens >> Urease enters the bloodstream >>
splits urea back to ammonia at a pace faster then urea can be
Connor’s original Ammonia level
  Connor’s ammonia after 2 capsules of
        alpha ketoglutaric acid

•Increased speech, repeating everything
•socializing better, especially with sister
•Separation still a problem when school starts
•When peer tantrums, Conor gets upset. He did approach a
crying child instead of running away, and when sister was crying
he sought help instead of withdrawing
Connor After 4 capsules of Alpha Ketoglutaric

•No more episodes of the rapid eye blinking or enlarged pupils
•interacting better with sister
•less melt-downs when others tantrum
•speech improving on a weekly basis
sound sensitivities seem to no longer be a problem
Essential Fatty Acids

The Omega Factor
   Omega 3’s in Autism
 Replacing and Omega-3 deficiency
       (source independent)
 Addressing Omega deficiency and
Supplementing with natural Vitamin A
          (Cod Liver Oil)
Immunity is complex and impacts
every system in the body. It
isn’t surprising that it effects
child behavior and development.
Immune System
 TH1         TH2 type of WBC
 Viral Stimulation
 Inappropriate antibody formation
   – Auto-antibodies
   – Food antibodies
 Frequent Infections - Especially Ear
 Related Yeast Overgrowth in Intestinal
  Tract w/ Clostridia and Parasites
 I am not suggesting that we abandon our
  vaccination policy
 I am concerned about the growing number
  of chronically ill children
 There are more children with learning
  disabilities and autoimmune disorders then
  there has ever been in the history of
      Concerns about Vaccines
 Are we unnaturally stressing underdeveloped
  immune systems beyond their capabilities in our
  effort to keep the children from becoming ill?
 There are inadequate safety studies for the
  vaccines that are currently on the market
 Are we giving too many vaccines over a short
  time span?
 We do not have a clear understanding of the
  effects of some of the vaccine components such as
  thimerosal, aluminum, formaldehyde, and human
  fetal tissue.
                 What’s Going On?
 Social deficits, shyness, social withdrawal
 Repetitive, perseverative, stereotypic behaviors; obsessive-compulsive
   Irritability, aggression, temper tantrums
   Lacks eye contact; impaired visual fixation
   Loss of speech, delayed language, failure to develop speech
   Speech comprehension deficits
   Sound sensitivity; mild to profound hearing loss
   Abnormal touch sensations; touch aversion
   Flapping, myoclonal jerks, choreiform movements, circling, rocking, toe
    walking, unusual postures
   Poor concentration, attention, response inhibition
   Self injurious behavior, e.g. head banging
   ADHD traits
   Sleep difficulties
   Diarrhea; abdominal pain/discomfort, constipation
                    MERCURY TOXICITY
Statement:Pediatrics 2001 Jul, American Academy of Pediatrics: Committee on
Environmental Health.

   The developing fetus and young children are thought to be disproportionately
   affected by mercury exposure, because many aspects of development,
   particularly brain maturation, can be disturbed by the presence of mercury.
   Minimizing mercury exposure is, therefore, essential to optimal child
   health…..Mercury in all of its forms is toxic to the fetus and children, and
   efforts should be made to reduce exposure to the extent possible to
   pregnant women and children as well as the general population.
   Vaccine inserts would typically say “0.01% thimerosal as a preservative”, which
   to anyone would sound like an extremely small amount. When called to testify
   in front of the Institute of Medicine, an independent group formed by our
   government to monitor safety issues, Dr. Neil Halsey of Johns Hopkins
   University, and head of the vaccine recommendation committee that reports to
   the CDC, went on record as saying “No one ever did the math…. No one
   knows what dose of mercury, if any, from vaccines is safe. We can say there is
   no evidence of harm but the truth is no one has looked”
 Thimerosal is Ethylmercury, a neurotoxin
 Mercury was found in the blood of
  newborns even before Hepatitis B shot, and
  higher levels after the shot.
  •   Journal of Pediatrics, May 2000
 In some pre-term infants, mercury levels
  were 10 times that of term infants
 Pre-term babies are vaccinated according to
  chronological age, not gestational age.
 Intrauterine sources may include:

• maternal fish consumption
• mercury amalgam fillings
•Rhogam (given to Rh (-) mothers, no longer present)
•Influenza vaccine (still present)
 Hepatitis B vaccine was introduced in 1991-
  with most newborns getting the first dose
  before leaving the hospital
 Hep B vaccine had contained 12.5 mcg of
  thimerosal = 6.25mcg mercury
 EPA established the “safe limit” at 0.1
  mcg/kg/day, approximately 0.4 mcg/day for
  an 8 pound newborn
Typical Thimerosal Exposure for 2 month old infant:
Hep B       12.5 mcg
DTaP        25    mcg
Hib         25 mcg
Total       62.5 mcg
of which 50% is ethylmercury = 31.25mcg

Total “safe” dose for 10 pound (2 month old) baby
  by EPA standards: 0.5 mcg. The average 2 month
  old received ~60x the EPA limit
 By 6 months of age, a fully vaccinated infant
  would have received:
   – 3 DTP          75 mcg thimerosal
   – 3 Hib          75 mcg thimerosal
   – 3 Hep B        37.5 mcg thimerosal

   Total            187.5 mcg thimerosal
                    93.75 mcg mercury

   1999 FDA Center for Biologics Evaluation and Research
         Heavy Metal Exposures
After exposure to mercury, the length of time to be eliminated
  varies for different organs:

 Blood and Hair: 4-6 months
 Non CNS organs: several years
 Brain: 20 years
(Boyd Haley, PhD, University of Kentucky, Dept of

Lead typically deposits into brain and bone. After exposure to
  lead, within several months the blood and urine levels will
  be normal even if the lead is still in the bone and brain
  (Clarkson, 2002)
           Who’s looking into all of this?
Boyd Haley, PhD, Department of Chemistry Chairman,
University of Kentucky. Dr Haley is considered one of the
leading researchers in America on Heavy Metal toxicity
   • He reports that exposing neurons to thimerosal rapidly
   results in the stripping of tubuluin from the nerve axon,
   and also reduces the viability of actin. Actin and tubulin
   are proteins that are critically important for the growth of
   dendrites and to maintain the structure of the axon.
   •On exposing neurons grown in culture for 24 hours, then
   exposed to vaccines with thimerosal and thimerosal-free
   vaccines. There was significantly more cell death in those
   exposed to thimerosal vaccines. The most concerning part
   about this was that there was an extremely low amount of
   thimerosal used in the study, 10K less then the
   concentration found in most vaccines
   Who’s looking into this (cont)
•Holloway et al, Arizona State:Oral antibiotics have been shown in rats
to increase the half-life for excretion of mercury from 10 days to over
100 days. (Doctors have been told it is OK to vaccinate children as
long as they are not seriously sick, with high fevers, and there is no
recommendations not to vaccinate children on antibiotics)
•Holloway et all, Arizona State 2002 carried out a DMSA challenge
study involving 15 children with autism and 15 typical children. The
children received a single dose of meso-2,3-dimercaptosuccinic acid
(DMSA), at a dose of 10 mg/kg, followed by a 10-hour urine collection.
The DMSA resulted in a much greater increase in heavy metal
excretion in the children with autism compared to the controls. Many
of the children with autism excreted high levels of one or more heavy
metals, although there was wide variation in the amount and type of
metal excreted. (The data suggests that many children with autism
have a greatly diminished ability to excrete heavy metals, and thus
would be unusually vulnerable to exposures to those metals)
                Mercury Testing
 As there is a relative short half life of mercury in serum,
  blood and urine testing will often be negative if more then
  6 months have passed between exposure and testing
 Hair tests can be falsely positive if there are metals in
  shampoos, conditioners, or water. Also, there is evidence
  that mercury levels in the hair of autistic children is less
  than in controls (Cave and Holmes)

 For me, the best test is an oral chelation challenge,
  extracting the heavy metal and excreting it in the urine.
  This can document that the metal is present, it is not being
  excreted under normal circumstances, AND that the
  chelation agent and the route of administration given
  works for the individual
  Mercury Removal: Chelation
EDTA, Dimercaprol (BAL), DMSA, DMPS, and DMPA all have
   heavy metal binding activity
Marked specificity for heavy metals, but also can cause decreases in
   trace elements and micronutrients (and these should be tested for
Mercury is essentially irreversibly bound to DMSA, so mercury is
   not deposited in other tissues, even the kidney.
DMSA/DMPS works through increasing urinary excretion.
DMSA/DMPS does not cross the blood-brain barrier, so no risk of
   delivering bound mercury to the brain
Very low toxicity. Side effects may include anorexia, nausea,
   vomiting, diarrhea, rash and a transient increase in liver enzymes.
There are no known adverse drug interactions with DMSA/DMPS.
EDTA: disodium vs Calcium disodium. Disodium EDTA given
   rapidly by IV can suddenly drop serum calcium levels. Only
   should use CaNa2 EDTA
Mercury Removal: Chelation
  •   oral (DMPS and DMSA)
  •   IV (DMPS and CaNa2 EDTA)
  •   Rectal (DMPS, DMSA, CaNa2 EDTA
      –   best to have stool passage before insertion
      –   CaNa2 EDTA seems to cause less yeast
  •   TD – emu oil seems the best vehicle
      –   seen very little benefit/movement with DMPS
      –   seen some positive excretions with DMSA
      –   CaNa2 very difficult to keep in suspension without
Single dose chelation challenge
     – baseline urine taken before dose given
     – 8 hour urine collection regardless of
     – empty bladder before giving dose
     – DMSA (oral or rectal 25mg/kg)
     – DMPS (3mg/kg for IV, 10mg/kg for
       rectal, 5-10mg/kg oral)
     – CaNA2 EDTA (25-50mg/kg regardless
       of rout, maximum of 1500mg)
     – May need to do more than 1 challenge
       with different agents/routes
     (DAN! 2005 Consensus Paper)
Antonio (7 y/o) on first chelation challenge with DMSA
Antonio, after 4 cycles of DMSA
Antonio, after 8 cycles of DMSA
         Antonio After Chelation with DMSA

Has bad gas during the DMSA days, and is moody,
then this goes away when the DMSA is finished.
Doing better and better in speech therapy
If he does not want to do things he cries.
Teachers are reporting improvements seen on a
month-to-month basis
More hand gesturing
In a more advanced class. The mimicry behavior has
At this point language is the major barrier, behaviors
and stemming are under control
Richard (6 y/o) on first DMSA Challenge
Richard after 2 mo of DMSA
           Richard Before Chelation
•No self help skills
•No bathroom skills
•No attention span
•No learning anything at school

                  Richard After Chelation
•Using the bathroom appropriately
•Will sit still for haircuts
•Focus and attention significantly improved
•Knows his letter, numbers and colors
•Excelling in all areas of education except for verbal speech, though is
vocalizing more then every before
           Urine Porphyrins
Porphyrins represent a group of uniquely
  structured compounds that can surround
  different types of ions/metals. Each has a
  specific biological function
  – Hemoglobin
  – Myoglobin
  – Chlorophyll
     Biochemistry 101
Enzymes – the keys to life

A+B         0     C     0     D
A & B are substrates, the ingredients being
“mixed” together
0 is the enzyme, the catalyst that makes the
reaction proceed.
C & D are products made by the reaction,
which can then go on to be substrates
(ingredients) in other reactions
Some enzyme reactions can go both directions
         Biochemistry 101
       A+B         0     C     0      D
    What can cause an enzyme not to work?
•Not enough or particular substrate
•The genes that code for the enzyme are
abnormal, creating a damaged or inefficient
•Something “poisons” the enzyme so it won’t
•Too much of a product (D) drives the reaction
in the other direction
                Urine Porphyrins
 Certain toxins, such as heavy metals and pesticides can inhibit
  certain enzymes in the heme porphyrin pathway, leading to
  specific porphyrin profiles being excreted into the urine. If an
  enzyme is inhibited, the substrate “upstream” can build up.
 Aluminum and dioxin inhibit uropophyrin decaboxylase.
 Mercury inhibits coproporphyrinogen oxidase.
 Lead inhibits coproporphyrinogen oxidase and aminolevulinic
  acid dehydratase.
(Woods, 1996)

Second urine void of the day is the best collection, as supplements
   that cause oxidation if mixed with the porphyrins overnight in
   the bladder can change the structure of the porphyrin lead to
   false values (Martin, 1996)
            Urine Porphyrins
 Coproporphyrin (copro) is a general marker for
  overall toxic metal burden. It is seen elevated in
  the presence of mercury, lead and arsenic
 Precoproporphyrin (preco) – an atypical porphyrin
  that only appears in the presence of mercury
 Heptacarboxyporhyrin and uroporphyrin is high
  on exposure to pesticides, PCBs, arsenic and
(Woods, 2005)
            Urine Porphyrins
 Children with autism have significantly higher
  levels of copro and preco porphyrins compared to
  controls (Nataf, 2006; Geier, 2006)
 Nataf also found that the severity of autistic
  symptoms correlated with the copro level, and that
  children with autism and seizures had the highest
  copro levels.
 Urine porphyrin levels decrease with chelation
  (Pingree, 2001)
                  Urine Porphyrins
               (how/when I use the test)
 I only send to Dr Nataf’s lab in France. They are the only
  commercial lab that has ranges for children and that autistic
  children has been studied at. The large US labs are not
  calibrated to test for levels under that which is seen in genetic
  porphyrin diseases which produce much higher porphyrin levels
 I prefer using the chelation challenge test, as it also tells me if
  the chelation agent/route of administration is working, not just if
  the metals are present.
 I order this test for:
   – families who do not wish to expose their children to a
      chelation agent unless there is proof of metals.
   – If chelation challenge tests are negative but we still suspect
      metals are present
   – Once chelation challenge tests are negative after cycles of
      chelation, if we still suspect metals are present
 Overview of The Methylation / Transsulfuration Pathway
                            Methionine          Protein synthesis
                                                Methylation of DNA, RNA,
                                                proteins, membrane
        MS    BHMT                              phospholipids, creatine,
      MB12                    SAH               neurotransmittors
                           SAHH                         AK
   5-CH3THF      Choline                   Adenosine         AMP

                           Homocysteine          ADA

                              B6 CBS
THF: tetrahydrofolate
Betaine:TMG                Cystathionine


The Methylation / Transsulfuration Pathway

 The Enzymes:

 MS:            Methionine synthase
 MAT:           Methionine adenosyltransferase
 MTHFR:         Methylenetetrahydrofolate Reductase
 SAHH:          S-adenosylhomocysteine Hydrolase
 CBS:           Cystathione beta synthase
 BHMT:          betaine-homocysteine methyltransferase
              The Methionine Cycle: Remethylation of Homocysteine

                            Methionine         Protein synthesis
    THF                                        Methylation of DNA, RNA,
                                               proteins, histones,
                                  MTase        membrane phospholipids,
       MS                                      neurotransmitters
     MB12                     SAH

                           SAHH                        AK
   5-CH3THF                               Adenosine         AMP

                           Homocysteine         ADA
THF: tetrahydrofolate
     The Methionine Cycle: Remethylation of Homocysteine
                         Methionine         Protein synthesis
                                            Methylation of DNA, RNA,
                               MTase        proteins, histones,
       MS                                   membrane phospholipids,
       B12                SAH               neurotransmitters

                        SAHH                        AK
   5-CH3THF                            Adenosine         AMP

                        Homocysteine         ADA
THF: tetrahydrofolate
 Effect of Oxidative Stress on Methionine Transsulfuration

                            Methionine         Protein synthesis
                                   MTase         Methylation of DNA, RNA,
       MS                                        proteins, membrane
                                                 phospholipids, creatine,
       B12                    SAH                neurotransmittors

   5-CH3THF      Choline   SAHH            Adenosine ( AK and/or ADA)


                              B6   CBS
THF: tetrahydrofolate

                             GSH     GSSG
Neurotoxicity of Thimerosal in Human Brain Cells
   is Associated with Glutathione Depletion:

  Protective Effect of Cysteine or Glutathione

        S. Jill James, William Slikker, Elizabeth New,
                Stefanie Jernigan, Stepan Melnyk
                     Department of Pediatrics
           University of Arkansas for Medical Sciences
                          Little Rock, AR
Neurotoxicity of Thimerosal in Human Brain Cells
   is Associated with Glutathione Depletion:

  Protective Effect of Cysteine or Glutathione

• Ethyl mercury in Thimerosal binds to cysteine thiol (–
SH) groups on intracellular proteins and inactivates

• The cysteine-rich antioxidant, glutathione, binds
mercury and protects essential proteins from functional

• The neurotoxicity of Thimerosal is associated with
depletion of glutathione, the major intracellular
Viability (MTT OD)

                     1.2   Glioblastoma Cells                Neuroblastoma Cells
                            (48 hr Exposure)                    (3 hr Exposure)


                     0.0                             0.0
                           0   2.5   5    10    20         0 0 2.52.5 5   510 10 20
                               M Thimerosal                        M Thimerosal
  Viability of Glioblastoma cells exposed to 15 M
Thimerasol in the presence of GSH-ester, Cystine, N-
         acetylcysteine (NAC), or Methionine

   O.D. (Viability)

                            Control Thimerosal +GSH   + Cystine +NAC + Methionine
 Methyl-B12, Folinic Acid, and Betaine
Supplementation in 8 Children with Autism

Injectible Methyl-B12 (75 µg/Kg b.i.d.) was given to the 8
children who had been taking folinic and and betaine
supplements for 3-4 months

Plasma thiol profile was repeated in the 8 children after
4 weeks of combined folinic acid, betaine, and methyl
 Transmethyation Metabolites after addition of Methyl-B12 to
Folinic Acid and Betaine Supplementation in 8 Autistic Children

                  Methionine                                  S-Adenosylmethionine
50                                               140
40                                               120
20                                                60
      Control    Before    Folinic    Folinic     40
10                                                         Control    Before    Folinic    Folinic
                           Betaine    Betaine                                   Betaine    Betaine
                                      Me-B12      20

       S-Adenosylhomocysteine                                         Adenosine
 30                                                0.4
       Control    Before    Folinic    Folinic
 10                                                         Control    Before    Folinic    Folinic
                            Betaine    Betaine     0.1                           Betaine    Betaine
                                       Me-B12                                               Me-B12
 0                                                     0
       Transsulfuration Metabolites after addition of Methyl-B12 to
      Folinic Acid and Betaine Supplementation in 8 Autistic Children

                    Homocysteine                                        Cysteine
10                                                  250

8                                                   200

6                                                   150

4                                                   100
                                                          Control   Before   Folinic   Folinic
         Control    Before    Folinic    Folinic    50
2                                                                            Betaine   Betaine
                              Betaine    Betaine
0                                                    0

                   Cystinyl-Glycine                 12          Total Glutathione tGSH)
 60                                                 10
 50                                                  8
 20                                                       Control   Before   Folinic    Folinic
          Control    Before    Folinic    Folinic
 10                            Betaine    Betaine    2                       Betaine    Betaine
  0                                                  0
       Glutathione Redox Potential after addition of Methyl-B12 to
     Folinic Acid and Betaine Supplementation in 8 Autistic Children

          Total Glutathione (tGSH)                   0.8
                                                           Oxidized Glutathione (fGSSG)
6                                                    0.4
4        Control   Before   Folinic   Folinic        0.2        Control   Before   Folinic   Folinic
2                           Betaine   Betaine                                      Betaine   Betaine
                                      Me-B12                                                 Me-B12
0                                                     0
                                        GSH/GSSG Ratio



                       10         Control            Folinic   Folinic
                                            Before   Betaine   Betaine
     So, Why is this happening?
 Certain toxins such as mercury can inhibit the
  enzymes of this pathway.
 Dr James has looked at the DNA sequences that
  code for the proteins that make up these enzymes
  and has found that autistic children have up to 3
  times as many single DNA mutations
  (polymorphisms, SNPs) as do children without
 We have identified these SNPs in children with
  other neurodevelopmental disorders

    EDISON, N.J. 08837

Total number of children included in the data: 85

•71 males                 51 males responded
•14 females               12 females responded

•84% males
                              74.1 % of the
•16 % females

                 THE TOP TEN
Symptoms Parents Reported Were Helped Most Often

  Language      71%   Better Behavior      35%
  Awareness     65%   More Focused         35%
  Cognition     52%   Understanding        35%
  Engagement    43%   Vocalization         35%
  Eye Contact   37%   Trying“New Things”   33%
            Side Effects Parents Reported
  Hyperactivity                                10%
  Sleep Patterns Disrupted Or Worsened         6%
  Uncontrolled Or Unusual Laughter             3%
  Increased Aggression                         2%
  Biting Objects                               2%
  More Distractible                            2%
  Eczematous Symptoms Worse                    2%
  Increased Stimming                           2%
  Silliness, Unusual And Unexplained           2%
  Teeth Grinding                               2%
  Tongue Tingles                               2%

•All reported side effects faded upon stopping therapy
• Most parents chose to resume therapy b/c benefits
outweighed the side-effects
 Oxalates are small carbon and oxygen containing molecules that
   are found in certain types of fruits and vegetables. Also most
   nuts and seeds have oxalates.

 For most people, oxalates in the diet are not absorbed in great
  amounts into the bloodstream. They are usually metabolized by
  intestinal flora and excreted in the feces.
 In the presence of intestinal inflammation and leaky gut, larger
  amounts of oxalates can get into the bloodstream and be
  transported to tissues
 Under certain conditions they can crystallize and become
  deposited in tissues. The crystals can grow and become stones
  (kidney stones are calcium oxalate)
 When lodged in tissues, these crystals can produce irritation and
 Oxalates seem to accumulate more in conditions of
    glutathione deficiency and oxidative stress.
   Vitamin B6 (pyridoxine) is a necessary cofactor for
    enzymes that help prevent the formation of oxalates
   When sulfur is deficient, it becomes extremely difficult to
    keep the body from making excess oxalates.
   High oxalates are associated with certain conditions like
    vulvodynia, prostatitis, irritable bowel syndrome,
    fibromyalgia, interstitial cystitis, and skin sensitivity. Some
    people may get a sense of urinary urgency and frequent
    urination, and sometimes the patient would have trouble
    urinating (Solomon, VP Foundation)
   High oxalates are often seen in patients with
    recurrent/resistant yeast infections and glycine intolerance.
       Testing for High Oxalates
 There is no perfect test right now.
 Urine testing is most often used. If high values are seen
  then this is a strong indicator, but people secrete oxalates
  in their urine at different times of the day (it may be most
  accurate to collect multiple urine specimens during the
  day), and relative to food intake so there can be false
 Great Plains Lab full organic acid test reports a spot oxalic
  acid value. They also report other substances that are high
  when there are oxalate issues: glyceric and glycolic acid
 Quest Labs has both random and 24 hour urine oxalate
  tests, both as an individual value as well as relative to
  oxalate. I usually get 24 hour collection with oxalate.
       Treating High Oxalates
 The low oxalate diet. Full information can
  be found at several sources:
  – Yahoo Group: Trying_Low_Oxalates
          Treating High Oxalates
 The Low Oxalate Cookbook is published by the Vulvar
    Pain Foundation, contains over 250 recipes.
   The book has lists of foods with actual amount of oxate per
    serving of a food.
   Aim to keep oxalate intake down to under 40-60mg oxalate
    a day.
   Food Lists and summary can be found on “Medical
    Topics” section of my webpage
   Probiotics: VSL#3: 1/2 to 1 capsule daily or ¼ to ½
    packet of the unflavored powder daily
   Reduce vitamin C to 250mg or less a day, including foods
    (oxalates can be converted to vitamin C)
   Calcium citrate supplementation - given with meals to
    help bind and excrete the oxalates.
Elevated Male Hormones/Androgens
 Several studies have demonstrated that children with
  Autism Spectrum Disorders have elevated androgens,
  including testosterone, dihydrotestosterone,
  androstendione and DHEA (Torjman, 1997; Knickmeyer,
  2005; Geier,2006)
 Although not exclusive, increased androgens have been
  associated with increased masturbation and genital
  rubbing, aggressiveness, hyperactivity, self-stimming, and
  increased body hair (legs and back),
 Elevations have been seen in male and female patients
 I use LabCorp for my testing. They have the most specific
  reference ranges for both sex and age of patient.
Elevated Male Hormones/Androgens

          The enzyme that converts DHEA to DHEA-S
          (storage hormone) is sulfotransferase, which is
          glutathione dependant. When this enzyme is not
          working, there is a build up of DHEA which then
          gets sent to androstenedione and then
Treating elevated Androgens
 Geier – Lupron.
   – belongs to a class of drugs called gonadotropin-releasing
     hormone (GnRH) agonists.
   – It is used to decrease the body’s production of specific
     hormones, natural chemicals that influence the behavior of
     certain cells. Because Lupron Depot can reduce the
     production of both male and female hormones, it is used to
     treat specific conditions in men, women, and children
 Bradstreet – Spironolactone,
   – a potassium sparing diuretic, also has action of blocking the
     receptor for dihydrotestosterone.
   – Androgen levels should not go down with this treatment, but
     the effects of the hormone are blocked.
Treating elevated Androgens
 Berger (VERY NEW)
   – Glycyrrhizin – the active ingredient in licorice root
   – decreases testosterone level by inhibiting the enzyme which
     converts of 17-OH progesterone to DHEA (Armanini, 1999)
   – Inhibits the enzyme that converts Androstendiaone to Testosterone
     (Fukui, 2003).
   – High doses can affect blood pressure and fluid retention, but doses
     < 0.2mg/kg/d should not cause these side effects (van Gelderen,
   – Current trials underway.
   – In addition to monitoring the androgens, also monitoring cortisol,
     ACTH and blood pressure
Serum Hormone Concentrations in Seven Men Given Licorice for Seven Days

Armanini D et al. N Engl J Med 1999;341:1158
–   1st medicine specifically approved for
–   For use in children with aggressiveness,
    extreme hyperactivity
–   Specific weight dosing is known
–   Effects are immediate, often seen the first
–   Pretty easy to titrate for affective dose
–   Pretty easy to get kids off of once the
    underlying reason is uncovered
–   Fewer incidences of side effects compared to
    other psychotropic drugs
Vaccine Update
  (time permitting)
Varicella / Chicken Pox Vaccine
   •   Brand Name: Varivax
   •   my initial concerns over long term protection
   •   when first released, one of the main “talking points”
       was that each shot saved “the system” $42 .
   •   now we are seeing failures:
       – Either it didn't “take” in the first place
       – or long term protection was not conferred
   •   now 2nd dose is being recommended between 4-6
       years old
   •   My recommendation: as morbidity increases with age,
       if not with vaccine or definitive disease by age ~11,
       get titer to see if immune and if not, consider the
         Influenza Vaccine
•   No guarantee that the strain of flu one is exposed to is
    1 of the 3 that are in the vaccine
•   Thimerosal-free shot now available but not
    guaranteed. Must view package insert
•   Nasal spray
    – now available for children 5 and older
    – is mercury-free
    – is a live virus
    – makes some sense, as it uses the natural lines of
       defense to convey immunity
    – Contraindicated for those who likely could benefit
       from it the most….those with asthma and
•   Article at
HPV/Cervical Cancer/Genital Warts
   •   Brand Name: Gardasil
   •   Not contagious disease, except for sexual contact.
       Raises ethical questions.
   •   Not protecting against all strains of HPV
       –   protects against 70% of strains causing cervical cancer
       –   protects against 90% of strains causing cervical warts
   •   being recommended for females 11-26 y/o, but
       can be given as early as 9 y/o
   •   for me, it is to early to assess safety, as often less
       common side effects are not seen until large
       groups of people are vaccinated such as was seen
•   1st vaccine, called RotaShield was made available in
    the late 1990’s deemed safe in pre market studies
•   Then within the first year of widespread use there were
    at least 100 cases of intussusception, an acute form of
    bowel obstruction
•   The vaccine was pulled in 1999
•   2006, a new, “safer” vaccine was introduced, called
•   So far, 28 cases reported so far, about half of them
    occurred within 21 days of vaccination and 16 of the
    infants had to have surgery.
•   Lactobacillus has been demonstrated to significantly
    shorten the length of time with diarrhea (Shornikova,
    1997) and frequency of stools (Van Neil, 2002)
     Hyperbaric Oxygen Therapy

 Definition – A therapeutic modality that employs
  the application of pressures greater than ambient
  atmospheric pressure, at oxygen levels greater
  than atmospheric oxygen (>21%)

 Traditional HBOT – a hard walled chamber that
  exposes the patient to a maximum of 3ATA
  (monoplace-1 patient) or 6ATA (multiplace - >1
  patient) at 100% oxygen
 Mild HBOT (mHBOT) - a soft walled chamber
  that exposes the patient to a maximum of 1.3ATA
  and <100% oxygen
      Hyperbaric Oxygen Therapy
                        Laws of Physics
 Henry’s Law - the amount of a gas absorbed by a
  liquid is in proportion to the pressure of the gas
  above the liquid, provided that no chemical action
 Boyle’s Law - at a constant temperature, the
  volume and the pressure of a gas are inversely
  proportional. In other words, a gas will compress
  proportionately to the amount of pressure exerted
  on it.
 Examples of these laws:
   – a bottle of soda
   – A scuba diver
      Hyperbaric Oxygen Therapy
 In 1662, British Physician Dr. Henshaw first used
  compressed air in an attempt to treat pulmonary disease.
  His first chamber was called the “Domicilium”. Chamber
  pressure was either raised or lowered with organ bellows
 In 1879, French surgeon Fontaine created a mobile
  chamber. He was able to increase the amount of oxygen
  carried in the blood during the administration of nitrous
  oxide anesthesia. This prevented blood oxygen levels from
  decreasing, which typically happened from surgical
 In 1921 Cunningham constructed a 20 meter round ball
  that was the largest Hyperbaric Chamber ever built. It
  contained a smoking lounge, dining facilities, rich
  carpeting, and private quarters.
     Hyperbaric Oxygen Therapy
         Cunningham’s Sanitarium -1921

Later it was scraped for metal during World War II.
      Hyperbaric Oxygen Therapy
 In 1934, US Naval Submarine Officer, Dr. Behnke
  proposed using oxygen plus recompression for
  Decompression Sickness (the bends). This information was
  ignored until 1967
 In 1955, Dutch thoracic surgeon, Dr. Boerma removed the
  red blood cells from pigs and found they could survive
  with oxygen dissolved in plasma by use of hyperbaric
 In 1961 Danish Dr. Brummelkamp, Published on the
  ability of HBOT to inhibit the growth of anaerobic
  bacteria - organisms that live where there is low or no
  oxygen, such as gangrene or tetanus.
 In June 2006 Tampa Pediatrician David Berger obtained
  his first mHBOT chamber, getting a second one the month
  later. The world has never been the same since.
Hyperbaric Oxygen Therapy
            Official Medical Indications
 •   Air or Gas Embolism          •   Exceptional Blood Loss
 •   Carbon Monoxide                  (Anemia)
     Poisoning and Smoke          •   Necrotizing Soft Tissue
     Inhalation                       Infections
 •   Carbon Monoxide              •   Osteomyelitis
     Poisoning Complicated            (Refractory)
     by Cyanide Poisoning         •   Radiation Tissue
 •   Clostridial Myonecrosis          Damage
     (Gas Gangrene)                   (Osteoradionecrosis)
 •   Crush Injury,                •   Skin Grafts and Flaps
     Compartment                      (Compromised)
     Syndrome, and other          •   Thermal Burns
     Acute Traumatic
 •   Decompression Sickness
     (the "Bends")
 •   Enhancement of Healing
     in Selected Problem
Hyperbaric Oxygen Therapy
         Proposed Mechanisms of Action
•    Correct Cerebral hypoperfusion (low blood flow)
•    Correct Cerebral Hypoxia (low oxygen levels)
•    Decrease Neuroinflammation
•    Decrease Intestinal Inflammation
•    Improve Immune Function
•    Reduce Oxidative Stress
•    Correct Neurotransmitter Abnormalities
•    Treat Intestinal Dysbiosis

Rossignol DA, Hyperbaric oxygen therapy might improve certain
     pathophysiological findings in autism. Med Hypotheses (2006)
    Hyperbaric Oxygen Therapy
           Proposed Mechanisms of Action

Rossignol DA, Hyperbaric oxygen therapy might
 improve certain pathophysiological findings in
       autism. Med Hypotheses (2006)
•   Differing levels of pressure and oxygen were used in
    the various studies that are discussed
•   Some may be at pressures that are not being
    recommended for children with Neurodevelomental
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action
Cerebral Hypoperfusion and Hypoxia in Autism

•   Multiple studies have shown hypoperfusion to areas of the
    brain of children with autism, especially the temporal lobes.
    (Rye, 1999; Zilbovicius, 2000; Ohnishi, 2000)
•   The low blood flow was more profound the older a child is.
    (Wilcox, 2002)
•   Autistic children often do not increase their cerebral blood
    flow when doing tasks and when listening and trying to
    speak, as seen in neurotypical children. (Critchley 2000,
    Allen 2003).
•   Decreased blood flow to the thalamus as seen on SPECT
    scans has been associated with repetitive and self-stimming
    behaviors (Starkstein, 2000)
•   Decreased blood flow to Wernicke’s and Brodmann’s areas
    (speech areas of the brain) has been associated with
    decreased auditory processing (Bodaert, 2002) and
    language development (Wilcox, 2002)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action
      Treating Hypoperfusion with HBOT
•   HBOT may overcome the effects of the hypoperfusion by
    providing the brain with more oxygen (Sheffield, 1976;
    Neubauer, 1998)
•   HBOT may increase new blood vessel growth (Al-Waili,
•   Hypoperfusion may be due to inflammation. Inflamed
    vascular cells can lead to diminished blood flow, and
    inflammation in tissue prevents maximal uptake of oxygen
    by cells
•   HBOT can increase the distance that Oxygen can travel
    between cells (Williams, 1997)
•   Increased blood flow to the brain also means increased
    blood flow from the brain, potentially increasing the flow of
    toxins away from the brain. This could bring a synergistic
    effect with chelation.
     SPECT Scans in a 4 year old autistic child
after 10 dives mHBOT at 1.3 atm and 24% oxygen

    Before                         After Mild HBO

                                   Heuser et al., 2002
                                   Best Publications; 2002:109-15
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

      Neuroinflammation and Autism
•   Of recent, several studies have demonstrated
    evidence that children with autism have increased
•   Increased inflammatory cells and pro-
    inflammatory chemical mediators (cytokines)
    have been found in the CSF of Autistic Children
    (Weizman, 1982; Vargas, 2005).
•   Increased brain auto-antibodies have been
    demonstrated in children with Autism (Connolly,
    1999; Singh, 1997; Vojdani, 2002; Singer, 2006)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

    Gastrointestinal Inflammation and Autism
•   A subset of children with Autism have demonstratable
    inflammation of their stomach, small intestine and colon
    (Furlano, 2001; Uhlmann, 2002; Balzola, 2005; Wakefield,
•   Both inflammatory cell and cytokines (TNF-ά, IL-1Β, IL-6)
    have been seen in increased amounts in the gastrointestinal
    lining in some children with Autism (Jyonouchi, 2001;
    Ashwood, 2003 & 2004)
•   Many children with autism have increased serum antibodies
    directed against casein and gluten based peptides (Vojdani,
    2003; & 2004)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

       Treating Inflammation with HBOT
•   HBOT had been demonstrated to have anti-inflammatory
    affects on tissues (Al-Waili, 2006)
•   HBOT can decrease the production of the cyctokines that
    are pro-inflammatory such as IL-6 and IL-1(Weisz, 1997)
    and TNF-ά, (Yang, 2006)
•   HBOT can increase the production of cytokines that
    decrease inflammation such as IL-10 (Buras, 2006)
•   HBOT has been shown in animal studies to reduce
    symptoms and inflammation of arthritis (Warren, 1979) and
    peritonitis (Tokar, 2003)
•   There is evidence that HBOT can facilitate remission for
    non-responsive Crohn’s Disease (Brady, 1989; Columbel,
    1995) and Ulcerative Colitis (Buchman, 2001; Gurbuz,
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

       Abnormal Immune Function and Autism

•   5% of Children with Autism have low serum IgA levels
    (Gupta, 1996)
•   Compared to typical children, many Autistic children have
    elevated IgE levels (Gupta, 1996; Lucarelli, 1995)
•   Some children with Autism have reduced levels of T-helper
    cells (Warren, 1986)
•   Some children with Autism have decreased lymphocyte
    activity/responsiveness (Stubbs, 1977)
•   Warren (1987) demonstrated decreased Natural Killer Cells
    in Autistic Children compared to controls
Hyperbaric Oxygen Therapy
         Proposed Mechanisms of Action

    Treating Immune Abnormalities with HBOT

•     In patients with MS, HBOT significantly
      increased the production in total an helper T-
      Lymphocyte levels as well as IgA serum levels
      (Nyland, 1989)
•     In patients with atopic dermatitis, HBOT
      decreased IGE levels as well as symptoms
      (Olszanski, 1992).
•     In mice studies, Lymphocyte activity and
      lymphocyte counts were increased by HBOT
      (Lee, 1993&1994)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action
        Increased Oxidative Stress and Autism

•   Many children with Autism show the presence of increased
    oxidative stress/free radicals
•   They have lower levels of glutathione (James, 2004)
•   Increased RBC nitric oxide has been seen in some Autistic
    children. This is a free radical and is a neurotoxin. (Sogut,
•   Children with Autism demonstrate increased markers of
    oxidative stress and lipid peroxidation such as
    malondialdehyde (Chauhan, 2004)
•   Children with Autism often have decreased activity of the
    enzymes that produce antioxidants such as glutathione
    peroxidase and superoxide dismutase (Yorbik, 2002)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

         Treating Oxidative Stress with HBOT

•   There has been concern that HBOT could, thought increased
    production of reactive oxygen species, increase oxidative
    stress, and that taking alpha-liopic acid (an antioxidant)
    could ameliorate this problem (Alleva, 2005).
•   In animal studies, there is evidence that oxidative stress is
    less of a concern at pressures < 2.0 ATA (Wada, 2001).
•   Other animal studies have shown that at < 2.0 ATA, HBOT
    may reduce oxidative stress by decreasing the peroxidation
    of lipids (Ozden, 2004, Kudchakar, 2000).
•   In other animal studies, HBOT has been demonstrated to
    increase superoxide dismutase (Gregorevic, 2001) and
    glutathione peroxidase (Gulec, 2004)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

    Abnormalities in Neurotransmitters and Autism

•   Serotonin levels man be lower in children with autism
    (Chugani, 1999; Connors, 2006)
•   Compared to controls, children with Autism have lower
    plasma tryptophan levels. Tryptophan is the amino acid
    precursor of serotonin.
•   Tryptophan uptake into brain cells was decreased in children
    with Autism compared to controls when studies with PET
    scans (Chugani, 1999)
•   Some children with Autism may have increased dopamine
    activity (Gillberg, 1997)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

    Correcting Neurotransmitter Abnormalities with

•   Serotonin uptake by endothelial cells of the lung
    has been shown to be reduced [the same
    mechanism as SSRIs] when HBOT was used
    (Fisher, 1980; Block, 1981)
•   Following brain injury, HBOT was demonstrated
    to decrease dopamine release (Yang, 2002)
•   Oxygen alone, without increased pressure, may
    decrease brain extracellular dopamine levels
    (Adachi, 2001)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

            Intestinal Dysbiosis and Autism

•   Overgrowth of certain abnormal bacteria, and in particular
    clostridia (anaerobic) bacteria, have been seen in many
    children with autism compared to controls (Feingold, 2002;
    Song, 2004; Parracho, 2005)
•   An increased clostridial byproduct (HPHPA) is often seen
    on urine organic acid testing of children with Autism.
•   Improvements in Autistic symptoms have been
    demonstrated in serial blinded psychological evaluations
    after the administration of oral Vancomycin (Sandler, 2000)
•   Intestinal overgrowth of yeast, viruses and parasites have
    been documented in children with Autism (Cave, 2001)
Hyperbaric Oxygen Therapy
       Proposed Mechanisms of Action

    Treating Intestinal Dysbiosis with HBOT

•   HBOT has been shown to decrease levels of
    atypical bacteria overgrowth in the distal ileum
    (Akin, 2001).
•   HBOT has been demonstrated to be able to kill
    many different types of bacteria, including
    clostridia (Gotleib, 1971;Unsworth, 1984)
•   Phagocytes, white blood cells that engulf bacteria,
    depend on oxygen to kill the bacteria (Babior,
    1978). Killing of Staph Aureus by these
    leukocytes is enhanced by HBOT (Mader, 1980)
Hyperbaric Oxygen Therapy
            Hard vs. Soft Chamber
•   Cost: Hard chamber dives cost 2-6x that of mHBOT
•   Time to depressurize if need to get out quickly. The higher
    the pressure, the longer it takes to depressurize
•   Oxygen Dangers/Flammability/fire and building codes
•   Oxygen Delivery
    –   100% in Hard Chamber. In most units, no special masks or
        tubes are needed. Compliance may be easier with the Hard
    –   24 – 40% in mHBOT depending on how O2 is delivered
•   Breaks vs. no breaks in therapy
•   Accessibility/home use approval
•   Is more better?
•   Some may respond to hard but not soft (often see 1.75ATA
    used for ASD, never more than 2.0ATA)
    –   certain conditions such as crush injuries, CP, anaerobic bone
Hyperbaric Oxygen Therapy
             And Seizure Risk
•   There is a known entity called Oxygen seizures.
•   Incidence of seizures has never been reported with
    pressures <2.0ATA for 1 hour or less
•   Davis (1989): In chart review, Overall incidence
    of seizures was 0.01%, looking at 1505 patients
    who did a total of 52,700 dives. 5 patients
    developed seizures, all recovered completely.
Hyperbaric Oxygen Therapy
Hyperbaric Oxygen Therapy
     Hyperbaric Oxygen Therapy
               Our Proposed Study
   This would be the first University based,
    placebo-controlled, blinded study ever
    performed using HBOT on children with
   Joint project between Wholistic Pediatrics and
    USF Child Psychiatry, Child Neurology and
    Child Development teams
     Hyperbaric Oxygen Therapy
                     Our Proposed Study
   Subjects:
         –      Children with formal diagnosis of Autism
         –      Selecting kids that have not done any biomedical/dietary
                interventions, only educational interventions
         –      Only educational changes allowed during treatment
         –      10 children to receive treatment, 10 placebo. Will cross-
                over the placebo group.
         –      6-8 year old
         –      Must be able to comply with use of non-rebreather mask
     Hyperbaric Oxygen Therapy
                 Our Proposed Study
   Outcome measures:
            •   ADOS
            •   full neuropsychological evaluation
            •   Single subject design – since multiple N=1
            •   GI checklist

            Will do evaluations at:
            3 months prior to starting mHBOT
            The week before starting mHBOT (to determine what a typical
                 3 months bring in terms of symptom changes)
            At the end of 3 months of dives
            3 months after dives start
            Also will take selected data during 1-2 week intervals during
                 the dive phase for the single subject design
              The Bottom Line:
                       We Need More

----The Bottom Line----The Bottom Line----The Bottom Line----The Bottom Line---

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