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Biomedical Treatments for Neurodevelopmental, Autoimmune and other Chronic Disorders David Berger, MD Medical Director Wholistic Pediatrics Tampa, FL  (813) 960-3415 www.wholisticpeds.com
Is there an Autism Epidemic? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Autistic Spectrum Disorders ,[object Object],[object Object],[object Object]
Discover Magazine, 3/14/07
Intestinal ,[object Object],[object Object],[object Object],[object Object]
Immune System ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Biochemical Abnormalities ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Robert Cade, MD, Professor,  University of Florida Medical School “ 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 ,[object Object],[object Object],[object Object],[object Object]
DPP-IV 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 essential starting point for a gluten and casein free diet.
Milk: It does your body good? ,[object Object],[object Object]
Causes of Autism? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Evaluating Children ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
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 Autism  February 28, 2007
Abnormal Stool & Urine Findings ,[object Object],[object Object],[object Object]
Treat Stool & Urine Findings ,[object Object],[object Object],[object Object]
OAT test
OAT After Culturelle and Nystatin
Nicholas (8 y/o)After Culturelle and Nystatin (3 months later) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Sulfation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
 
After Epsom Salt Baths
Eric’s (6 y/o) Response to Epson Salt Baths ,[object Object],[object Object],[object Object],[object Object],[object Object]
Ammonia ,[object Object],[object Object],[object Object],[object Object]
Connor’s original Ammonia level
Connor’s ammonia after 2 capsules of alpha ketoglutaric acid ,[object Object],[object Object],[object Object],[object Object]
Connor After 4 capsules of  Alpha Ketoglutaric Acid ,[object Object],[object Object],[object Object],[object Object],[object Object]
Essential Fatty Acids The Omega Factor
 
 
Omega-3 Fatty Acid Depletion in Post-Partum Women ,[object Object],[object Object],[object Object],[object Object]
Omega 3’s in Autism ,[object Object],[object Object],[object Object],[object Object],[object Object]
 
Immunity is complex and impacts every system in the body.  It isn’t surprising that it effects child behavior and development.
Immune System ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
PPARS  (Peroxisome Proliferator-Activated Receptors) ,[object Object],[object Object],[object Object],[object Object]
IMMUNIZATIONS ,[object Object],[object Object],[object Object]
Concerns about Vaccines ,[object Object],[object Object],[object Object],[object Object]
What’s Going On? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
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” MERCURY Statement: Pediatrics 2001 Jul, American Academy of Pediatrics: Committee on Environmental Health.
Mercury/Thimerosal ,[object Object],[object Object],[object Object],[object Object],[object Object]
Mercury/Thimerosal ,[object Object],[object Object],[object Object],[object Object],[object Object]
Mercury/Thimerosal ,[object Object],[object Object],[object Object]
Mercury/Thimerosal ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Mercury/Thimerosal ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Mercury/Thimerosal ,[object Object],[object Object],[object Object],[object Object],[object Object]
Heavy Metal Exposures ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Who’s looking into all of this?!?!?! Mark R. Geier, MD, Ph.D. (Submitted to the Institute of Medicine, of the US National Academy of Sciences, January 2004   ,[object Object],[object Object],[object Object],[object Object]
Who’s looking into all of this? ,[object Object],[object Object],[object Object]
Who’s looking into all of this?!?!?! ,[object Object],[object Object],[object Object]
Who’s looking into this (cont) ,[object Object],[object Object]
Who’s looking into this (cont) ,[object Object],[object Object]
Mercury Testing ,[object Object],[object Object],[object Object]
Mercury Removal: Chelation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Mercury Removal: Chelation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Single dose chelation challenge ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
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 stopped. 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 After Chelation ,[object Object],[object Object],[object Object],[object Object],[object Object],Richard Before Chelation ,[object Object],[object Object],[object Object],[object Object]
Baseline
DMPS/Glutathione-IV
DMPS/Glutathione-Rectal
Urine Porphyrins ,[object Object],[object Object],[object Object],[object Object]
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 ,[object Object],[object Object],[object Object],[object Object],What can cause an enzyme not to work? A + B   0  C  0  D
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Urine Porphyrins
[object Object],[object Object],[object Object],[object Object],Urine Porphyrins
[object Object],[object Object],[object Object],Urine Porphyrins
 
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Urine Porphyrins ( how/when I use the test)
SAM SAH MTase SAHH Homocysteine B6 THF MS CBS MB12 Protein synthesis BHMT Choline Betaine Overview of The Methylation / Transsulfuration Pathway THF: tetrahydrofolate Betaine:TMG 5-CH 3 THF Methylation of DNA, RNA, proteins,  membrane phospholipids, creatine, neurotransmittors Cystathionine Cysteine Glutathione Methionine Adenosine AK ADA Inosine AMP MAT B6 MTHFR
The Methylation / Transsulfuration Pathway The Enzymes: MS: Methionine synthase MAT:  Methionine adenosyltransferase MTase: Methyltransferase MTHFR: Methylenetetrahydrofolate Reductase SAHH:  S-adenosylhomocysteine Hydrolase CBS: Cystathione beta synthase BHMT: betaine-homocysteine methyltransferase
SAM SAH MTase SAHH Homocysteine THF MS MB12 Protein synthesis The Methionine Cycle: Remethylation of Homocysteine THF: tetrahydrofolate 5-CH 3 THF Methylation of DNA, RNA, proteins,  histones,  membrane phospholipids,  neurotransmitters Methionine Adenosine AK ADA Inosine AMP MAT
SAM SAH MTase SAHH Homocysteine THF MS B12 Protein synthesis The Methionine Cycle: Remethylation of Homocysteine THF: tetrahydrofolate 5-CH 3 THF Methylation of DNA, RNA, proteins,  histones,  membrane phospholipids,  neurotransmitters Methionine Adenosine AK ADA Inosine AMP MAT
SAM SAH MTase SAHH Homocysteine THF MS B12 Protein synthesis BHMT Choline Betaine The Methionine Cycle: Remethylation of Homocysteine Betaine: TMG 5-CH 3 THF Methylation of DNA, RNA, proteins,  histones,  membrane phospholipids,  neurotransmitters Methionine Adenosine AK ADA Inosine AMP MAT
SAM SAH MTase SAHH Homocysteine B6 THF MS CBS B12 Protein synthesis BHMT Choline Betaine Methionine Transsulfuration to Cysteine and Glutathione Transsulfuration Pathway THF: tetrahydrofolate 5-CH 3 THF Methylation of DNA, RNA, proteins,  membrane phospholipids, creatine, neurotransmittors Cystathionine Cysteine Glutathione Methionine Adenosine AK ADA Inosine AMP MAT B6
SAM SAH MTase SAHH Homocysteine B6 THF MS CBS B12 Protein synthesis BHMT Choline Betaine Effect of Oxidative Stress on Methionine Transsulfuration THF: tetrahydrofolate 5-CH 3 THF Methylation of DNA, RNA, proteins,  membrane phospholipids, creatine, neurotransmittors Cystathionine Cysteine GSH  GSSG Methionine Adenosine (  AK and/or ADA) MAT B6
Neurotoxicity of Thimerosal in Human Brain Cells is Associated with Glutathione Depletion:  Protective Effect of Cysteine or Glutathione  Supplementation S. Jill James, William Slikker, Elizabeth New,  Stefanie Jernigan, Stepan Melnyk Department of Pediatrics University of Arkansas for Medical Sciences Little Rock, AR
[object Object],[object Object],[object Object],[object Object],Neurotoxicity of Thimerosal in Human Brain Cells is Associated with Glutathione Depletion:  Protective Effect of Cysteine or Glutathione  Supplementation
0  2.5  5  10  20 VIABILITY OF GLIOBLASTOMA AND NEUROBLASTOMA CELLS WITH INCREASING DOSE OF THIMEROSAL Viability (MTT OD) Glioblastoma Cells Neuroblastoma Cells ( 48 hr Exposure )   ( 3 hr Exposure ) 0  2.5  5  10  20  0  2.5  5  10  20  M Thimerosal   M Thimerosal
Control  Thimerosal  +GSH  + Cystine  +NAC  + Methionine O.D. (Viability) Viability of Glioblastoma cells exposed to 15   M Thimerasol in the presence of GSH-ester, Cystine, N-acetylcysteine (NAC), or Methionine
Control  Thimerosal  +GSH  + Cystine  +NAC  + Methionine O.D. (Viability) Viability of Neuroblastoma cells exposed to 15   M Thimerosal  Pretreated with 100   M   GSH-ester, Cystine, N-acetylcysteine (NAC), or 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 B12
Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Methionine S-Adenosylmethionine S-Adenosylhomocysteine Adenosine Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Transmethyation Metabolites after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children
Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Homocysteine Cysteine Cystinyl-Glycine Total Glutathione tGSH) Transsulfuration Metabolites after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children
Total Glutathione (tGSH) Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Oxidized Glutathione (fGSSG) GSH/GSSG Ratio Glutathione Redox Potential after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children Control  Before  Folinic  Folinic   Betaine  Betaine   Me-B12 Control    Folinic  Folinic Before  Betaine  Betaine   Me-B12
So, Why is this happening? ,[object Object],[object Object],[object Object]
JAMES A. NEUBRANDER, M.D., F.A.A.E.M. EDISON, N.J.  08837 OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY
OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY Total number of children included in the data: 85 • 71 males •14 females • 84% males •16 % females 51 males responded 12 females responded 74.1 % of the children responded positively!
OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY THE TOP TEN Symptoms Parents Reported Were Helped Most Often Language  71% Awareness  65% Cognition  52% Engagement  43% Eye Contact  37% Better Behavior  35% More Focused  35% Understanding  35% Vocalization  35% Trying“New Things”  33%
Side Effects Parents Reported OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY Hyperactivity  10% Sleep Patterns Disrupted Or  W orsened  6% Uncontrolled Or Unusual   Laughter  3% Increased Aggression  2% Biting Objects  2% More Distractible  2% Eczematous Symptoms  W orse  2% Increased Stimming  2% Silliness, Unusual And   Unexplained  2% Teeth Grinding  2% Tongue Tingles  2% ,[object Object],[object Object]
Oxalates ,[object Object],[object Object],[object Object],[object Object],[object Object]
Oxalates ,[object Object],[object Object],[object Object],[object Object],[object Object]
Testing for High Oxalates ,[object Object],[object Object],[object Object],[object Object]
Treating High Oxalates ,[object Object],[object Object]
Treating High Oxalates ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Elevated Male Hormones/Androgens ,[object Object],[object Object],[object Object],[object Object]
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 testosterone
Treating elevated Androgens ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Treating elevated Androgens ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Armanini D et al. N Engl J Med 1999;341:1158 Serum Hormone Concentrations in Seven Men Given Licorice for Seven Days
Risperdal ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Vaccine Update (time permitting)
Varicella / Chicken Pox Vaccine ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Influenza Vaccine ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
HPV/Cervical Cancer/Genital Warts ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Rotavirus ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy ,[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Laws of Physics ,[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy History ,[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Cunningham’s Sanitarium  - 1921 ,[object Object]
Hyperbaric Oxygen Therapy History ,[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Hyperbaric Oxygen Therapy Official Medical Indications
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action Rossignol DA, Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism. Med Hypotheses (2006) ,[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Before After Mild HBO SPECT Scans in a 4 year old autistic child  after 10 dives mHBOT at 1.3 atm and 24% oxygen Heuser et al., 2002 Best Publications; 2002:109-15
HBOT 1.3 ATA, 24% Oxygen: 4 year old child Before and after 40 dives
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Proposed Mechanisms of Action ,[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Hard vs. Soft Chamber ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy  And Seizure Risk ,[object Object],[object Object],[object Object]
 
Hyperbaric Oxygen Therapy
Hyperbaric Oxygen Therapy
Hyperbaric Oxygen Therapy ,[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Our Proposed Study ,[object Object],[object Object]
Hyperbaric Oxygen Therapy Our Proposed Study ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hyperbaric Oxygen Therapy Our Proposed Study ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
We Need More Research! The Bottom Line: ----The Bottom Line----The Bottom Line----The Bottom Line----The Bottom Line---
 

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2007-03 Louisville Autism Lecture

  • 1. Biomedical Treatments for Neurodevelopmental, Autoimmune and other Chronic Disorders David Berger, MD Medical Director Wholistic Pediatrics Tampa, FL (813) 960-3415 www.wholisticpeds.com
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  • 8. Robert Cade, MD, Professor, University of Florida Medical School “ A gluten and casein free diet resulted in significant improvement in 81% of children with autism within three months.”
  • 9.
  • 10. DPP-IV 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
  • 11. Dr. Lewis’ book is the essential starting point for a gluten and casein free diet.
  • 12.
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  • 14.
  • 15. 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 Autism February 28, 2007
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  • 19. OAT After Culturelle and Nystatin
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  • 29. Essential Fatty Acids The Omega Factor
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  • 35. Immunity is complex and impacts every system in the body. It isn’t surprising that it effects child behavior and development.
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  • 41. 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” MERCURY Statement: Pediatrics 2001 Jul, American Academy of Pediatrics: Committee on Environmental Health.
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  • 58. Antonio (7 y/o) on first chelation challenge with DMSA
  • 59. Antonio, after 4 cycles of DMSA
  • 60. Antonio, after 8 cycles of DMSA
  • 61. 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 stopped. At this point language is the major barrier, behaviors and stemming are under control
  • 62. Richard (6 y/o) on first DMSA Challenge
  • 63. Richard after 2 mo of DMSA
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  • 69. 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
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  • 75.
  • 76. SAM SAH MTase SAHH Homocysteine B6 THF MS CBS MB12 Protein synthesis BHMT Choline Betaine Overview of The Methylation / Transsulfuration Pathway THF: tetrahydrofolate Betaine:TMG 5-CH 3 THF Methylation of DNA, RNA, proteins, membrane phospholipids, creatine, neurotransmittors Cystathionine Cysteine Glutathione Methionine Adenosine AK ADA Inosine AMP MAT B6 MTHFR
  • 77. The Methylation / Transsulfuration Pathway The Enzymes: MS: Methionine synthase MAT: Methionine adenosyltransferase MTase: Methyltransferase MTHFR: Methylenetetrahydrofolate Reductase SAHH: S-adenosylhomocysteine Hydrolase CBS: Cystathione beta synthase BHMT: betaine-homocysteine methyltransferase
  • 78. SAM SAH MTase SAHH Homocysteine THF MS MB12 Protein synthesis The Methionine Cycle: Remethylation of Homocysteine THF: tetrahydrofolate 5-CH 3 THF Methylation of DNA, RNA, proteins, histones, membrane phospholipids, neurotransmitters Methionine Adenosine AK ADA Inosine AMP MAT
  • 79. SAM SAH MTase SAHH Homocysteine THF MS B12 Protein synthesis The Methionine Cycle: Remethylation of Homocysteine THF: tetrahydrofolate 5-CH 3 THF Methylation of DNA, RNA, proteins, histones, membrane phospholipids, neurotransmitters Methionine Adenosine AK ADA Inosine AMP MAT
  • 80. SAM SAH MTase SAHH Homocysteine THF MS B12 Protein synthesis BHMT Choline Betaine The Methionine Cycle: Remethylation of Homocysteine Betaine: TMG 5-CH 3 THF Methylation of DNA, RNA, proteins, histones, membrane phospholipids, neurotransmitters Methionine Adenosine AK ADA Inosine AMP MAT
  • 81. SAM SAH MTase SAHH Homocysteine B6 THF MS CBS B12 Protein synthesis BHMT Choline Betaine Methionine Transsulfuration to Cysteine and Glutathione Transsulfuration Pathway THF: tetrahydrofolate 5-CH 3 THF Methylation of DNA, RNA, proteins, membrane phospholipids, creatine, neurotransmittors Cystathionine Cysteine Glutathione Methionine Adenosine AK ADA Inosine AMP MAT B6
  • 82. SAM SAH MTase SAHH Homocysteine B6 THF MS CBS B12 Protein synthesis BHMT Choline Betaine Effect of Oxidative Stress on Methionine Transsulfuration THF: tetrahydrofolate 5-CH 3 THF Methylation of DNA, RNA, proteins, membrane phospholipids, creatine, neurotransmittors Cystathionine Cysteine GSH GSSG Methionine Adenosine ( AK and/or ADA) MAT B6
  • 83. Neurotoxicity of Thimerosal in Human Brain Cells is Associated with Glutathione Depletion: Protective Effect of Cysteine or Glutathione Supplementation S. Jill James, William Slikker, Elizabeth New, Stefanie Jernigan, Stepan Melnyk Department of Pediatrics University of Arkansas for Medical Sciences Little Rock, AR
  • 84.
  • 85. 0 2.5 5 10 20 VIABILITY OF GLIOBLASTOMA AND NEUROBLASTOMA CELLS WITH INCREASING DOSE OF THIMEROSAL Viability (MTT OD) Glioblastoma Cells Neuroblastoma Cells ( 48 hr Exposure ) ( 3 hr Exposure ) 0 2.5 5 10 20 0 2.5 5 10 20  M Thimerosal  M Thimerosal
  • 86. Control Thimerosal +GSH + Cystine +NAC + Methionine O.D. (Viability) Viability of Glioblastoma cells exposed to 15  M Thimerasol in the presence of GSH-ester, Cystine, N-acetylcysteine (NAC), or Methionine
  • 87. Control Thimerosal +GSH + Cystine +NAC + Methionine O.D. (Viability) Viability of Neuroblastoma cells exposed to 15  M Thimerosal Pretreated with 100  M GSH-ester, Cystine, N-acetylcysteine (NAC), or Methionine
  • 88. 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 B12
  • 89. Control Before Folinic Folinic Betaine Betaine Me-B12 Methionine S-Adenosylmethionine S-Adenosylhomocysteine Adenosine Control Before Folinic Folinic Betaine Betaine Me-B12 Control Before Folinic Folinic Betaine Betaine Me-B12 Control Before Folinic Folinic Betaine Betaine Me-B12 Transmethyation Metabolites after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children
  • 90. Control Before Folinic Folinic Betaine Betaine Me-B12 Control Before Folinic Folinic Betaine Betaine Me-B12 Control Before Folinic Folinic Betaine Betaine Me-B12 Control Before Folinic Folinic Betaine Betaine Me-B12 Homocysteine Cysteine Cystinyl-Glycine Total Glutathione tGSH) Transsulfuration Metabolites after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children
  • 91. Total Glutathione (tGSH) Control Before Folinic Folinic Betaine Betaine Me-B12 Oxidized Glutathione (fGSSG) GSH/GSSG Ratio Glutathione Redox Potential after addition of Methyl-B12 to Folinic Acid and Betaine Supplementation in 8 Autistic Children Control Before Folinic Folinic Betaine Betaine Me-B12 Control Folinic Folinic Before Betaine Betaine Me-B12
  • 92.
  • 93. JAMES A. NEUBRANDER, M.D., F.A.A.E.M. EDISON, N.J. 08837 OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY
  • 94. OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY Total number of children included in the data: 85 • 71 males •14 females • 84% males •16 % females 51 males responded 12 females responded 74.1 % of the children responded positively!
  • 95. OPEN CLINICAL TRIAL METHYLCOBALAMIN STUDY THE TOP TEN Symptoms Parents Reported Were Helped Most Often Language 71% Awareness 65% Cognition 52% Engagement 43% Eye Contact 37% Better Behavior 35% More Focused 35% Understanding 35% Vocalization 35% Trying“New Things” 33%
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  • 103. 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 testosterone
  • 104.
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  • 106. Armanini D et al. N Engl J Med 1999;341:1158 Serum Hormone Concentrations in Seven Men Given Licorice for Seven Days
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  • 108. Vaccine Update (time permitting)
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  • 123. Before After Mild HBO SPECT Scans in a 4 year old autistic child after 10 dives mHBOT at 1.3 atm and 24% oxygen Heuser et al., 2002 Best Publications; 2002:109-15
  • 124. HBOT 1.3 ATA, 24% Oxygen: 4 year old child Before and after 40 dives
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  • 145. We Need More Research! The Bottom Line: ----The Bottom Line----The Bottom Line----The Bottom Line----The Bottom Line---
  • 146.