References. Large brains in autism: the challenge of pervasive abnormality. Herbert, M.R., Neuroscientist, (5): p

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References Defining Autism Brain Disorder or disorder that affects the brain? Herbert M. Autism: A Brain disorder or disorder that affects the brain? Clinical Neuropsychiatry 2006; 2:354-79.

The changing prevalence of autism in California J Autism Dev Disord 2003;33:223-6. Newschaffer CJ et al. National Autism prevalence from United States special education data.

1 References Defining Autism Brain Disorder or disorder that affects the brain? Herbert M. Autism: A Brain disorder or disorder that affects the brain? Clinical Neuropsychiatry 2006; 2: Large brains in autism: the challenge of pervasive abnormality. Herbert, M.R., Neuroscientist, (5): p Autism has changed Blaxill MF et al. The changing prevalence of autism in California J Autism Dev Disord 2003;33: Newschaffer CJ et al. National Autism prevalence from United States special education data. Pediatrics 2005;115:e277-e282. Bertrand J et al. Prevalence of autism in a United States population: the Brick township, NJ, investigation. Pediatrics 2001; 108: Validation of the phenomenon of autistic regression using home videotapes. Werner, E. and G. Dawson, Arch Gen Psychiatry, (8): p The Neuroanatomy of Autism Kemper TL, Bauman ML The contribution of neuropathologic studies to the understanding of autism. Neurol Clin 1993;11: Bauman ML, Kemper TL Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci 2005; 23: Start with the Basics Multivitamin

2 Carlton R et al. Rational dosages of nutrients have a prolonged effect on learning disabilities. Alternative Therapies 2000; 6: Shoenthaler S et al. The effect of vitamin-mineral supplementation on the intelligence of American schoolchildren: a randomized, double-blind, placebo-controlled trial. Journal of Alternative and Complementary Medicine 2000;6: Start with the Basics Magnesium and B6 Martineau J et al. Vitamin B6, Magnesium and combined B6-Mg: therapeutic effects in childhood autism. Biological Psychiatry 1985;20: Mousain-Bosc M et al. Magnesium, Vitamin B6 intake reduces central nervous system hyperexcitability in children. J Am Coll Nutr 2004;23:545S-548S. Miodownik, V. et. al. Vitamin B6 versus mianserin and placebo in acute neurolepticinduced akathisia: a randomized, double-blind, controlled study. Clinical Neuropharmacology, Vol. 29, No. 2, March/April 2006, Lerner, V., et. al. Vitamin B6 treatment in acute neuroleptic-induced akathisia: a randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry, Vol. 65, No. 11, November 2004, Start with the Basics: Diet, Probiotics, Probiotics Knivsber, A.M., K.L. Reichelt, and M. Nodland, Reports on dietary intervention in autistic disorders. Nutr Neurosci, (1): p Miraglia del Giudice, M. and M.G. De Luca, The role of probiotics in the clinical management of food allergy and atopic dermatitis. J Clin Gastroenterol, (6 Suppl): p. S84-5 Magliani, W., et al., Yeast killer systems. Clin Microbiol Rev, (3): p Czerucka, D. and P. Rampal, Experimental effects of Saccharomyces boulardii on diarrheal pathogens. Microbes Infect, (7): p

3 Start with the Basics Zinc Arnold LE et al. Does zinc moderate essential fatty acid and amphetamine treatment of attention deficit/hyperactivity disorder? J Child Adolesc Psychopharmacol 2000;10: Sturniolo, G.C., et al., Zinc supplementation tightens "leaky gut" in Crohn's disease. Inflamm Bowel Dis, (2): p Start with the Basics Essential Fatty Acids Stevens LJ et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995;62: Vancassel S et al. Plasma fatty acid levels in autistic children. Prostaglandins Leukot Essent Fatty Acids 2001;65:1-7. Richardson, A.J., Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int Rev Psychiatry, (2): p Hyperbaric Oxygen Therapy (HBOT) Stoller, K.P. Quantification of neurocognitive changes before, during and after hyperbaric oxygen therapy in a case of fetal alcohol syndrome. Pediatrics 2005; 116(4). Starkstein S.E., et al. SPECT findings in mentally retarded autistic individuals. J Neuropsychiatry Clin Neuroscience 2000; 12(3): Rossignol, D.A et. al. Hyperbaric oxygen therapy may improve symptoms in autistic children accepted February Cytokines Reichenberg, A. and et. al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001 May;58(5): Jyonouchi, H., et al., Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism

4 spectrum disorders. J Pediatr, (5): p Immune Dysregulation Vargas DL et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005;57: Pardo CA et al. Immunity, neuroglia and neuroinflammation in autism. International Review of Psychiatry 2005;17: Ashwood, P. and A.J. Wakefield, Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol, (1-2): p Jyonouchi, H., et al., Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology, (2): p Gupta, S., S. Aggarwal, and C. Heads, Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord, (4): p Croonenberghs, J., et al., Activation of the inflammatory response system in autism. Neuropsychobiology, (1): p Warren, R.P., et al., Immune abnormalities in patients with autism. J Autism Dev Disord, (2): p PANDAS March, J.S., Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infection (PANDAS): implications for clinical practice. Arch Pediatr Adolesc Med, (9): p

5 Swedo, S.E., et al., Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry, (2): p Chmelik, E., et al., Varied presentation of PANDAS: a case series. Clin Pediatr (Phila), (4): p Swedo, S.E., et al., Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry, (1): p Snider, L.A. and S.E. Swedo, PANDAS: current status and directions for research. Mol Psychiatry, (10): p Autism and the Gut Valicenti-McDermott, M., et.al. Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. Developmental and Behavioral Pediatrics, Vol. 27, No. 2, April 2006, S128- S136. Wakefield, A.J., et al., Enterocolitis in children with developmental disorders. Am J Gastroenterol, (9): p Horvath, K., et al., Gastrointestinal abnormalities in children with autistic disorder. J Pediatr, (5): p Torrente, F., et al., Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry, (4): p , 334. Ashwood, P., et al., Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol, (6): p Torrente, F., et al., Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis. Am J Gastroenterol, (4): p Ashwood, P., et al., Spontaneous mucosal lymphocyte cytokine profiles in children

6 with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol, (6): p Autism and Inflammation Trebaticka, J., et. al. Treatment of ADHD with French maritime pine bark extract, Pycnogenol. European Child and Adolescent Psychiatry, May 13, Furlano, R.I., et al., Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr, (3): p Hornig, M., et al., An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci U S A, (21): p Messahel, S., et al., Urinary levels of neopterin and biopterin in autism. Neurosci Lett, (1): p Warren, R.P., A. Foster, and N.C. Margaretten, Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry, (3): p Thimerosal and Autism Bernard S et al. Autism: a novel form of mercury poisoning. Med Hypotheses 2001;56: Blaxill MF et al. Thimerosal and autism? A plausible hypothesis that should not be dismissed. Med Hypotheses 2004; 62: Geier MR, Geier DA An assessment of the impact of thimerosal on neurodevelopmental disorders. Pediatr Rehabil 2003; 6: The Effects of Thimerosal Ueha-Ishibashi, T. and et. al. Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. 2004; 195(1): Stajich GV et al. Iatrogenic exposure to mercury after Hepatitis B vaccination in preterm infants. J Pediatrics 2000; 136(5):

7 Pichichero M et al. Mercury concentrations and metabolism in infants receiving vaccines containing thimerosal: a descriptive study. Lancet 2002; 360(9347): Burbacher T et al. Comparison of blood and brain mercury levels in infant monkeys exposed to methylmercury or vaccines containing thimerosal. Environmental Health Perspect 2005; 113(8): Charleston JS et al. Changes in the number of astrocytes and microglia in the thalamus of the monkey Macaca fascicularis following long-term subclinical methylmercury exposure.neurotoxicology1996;17(1): Holmes A et al. Reduced levels of mercury in first baby haircuts of autistic children. Internat J of Toxicology 2003; 22(4): Bradstreet J et al. A case-control study of mercury burden in children with autistic spectrum disorders. J of Amer Phys and Surgeons 2003; 8(3): Mutter, J., et al., Mercury and autism: accelerating evidence? Neuro Endocrinol Lett, (5): p Colman, E., Mercury in infants given vaccines containing thiomersal. Lancet, (9358): p. 698; author reply 699. Detoxification and Oxidative Stress James S.J., et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004; 80: James SJ et al. Low plasma methionine, cysteine and glutathione levels are associated with increased frequency of common polymorphisms affecting methylation and glutathione pathways in children with autism. Experimental Biology 2005; 19: A51- A52. James SJ et al. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors. Neurotoxicology 2005; 26(1):1-8. Bray, T.M. and C.G. Taylor, Tissue glutathione, nutrition, and oxidative stress. Can J Physiol Pharmacol, (9): p

8 Porphyrin Abnormalities Haley, B.E., and Small, T., Medical Veritas 3 (2006) Interview with Dr. Boyd E. Haley: Biomarkers supporting mercury toxicity as the major exacerbator of neurological illness, recent evidence via the urinary porphyrin tests. Woods, J.S., Altered porphyrin metabolism as a biomarker of mercury exposure and toxicity. Can J Physiol Pharmacol, (2): p Woods, J.S., D.L. Eaton, and C.B. Lukens, Studies on porphyrin metabolism in the kidney. Effects of trace metals and glutathione on renal uroporphyrinogen decarboxylase. Mol Pharmacol, (2): p Woods, J.S., et al., Urinary porphyrin profiles as a biomarker of mercury exposure: studies on dentists with occupational exposure to mercury vapor. J Toxicol Environ Health, (2-3): p Woods, J.S. and H.D. Miller, Quantitative measurement of porphyrins in biological tissues and evaluation of tissue porphyrins during toxicant exposures. Fundam Appl Toxicol, (3): p Nataf, Robert, et al. Porphyrinuria in Childhood Autistic Disorder: Implications for Environmental Toxicity. Toxicology and Applied Pharmacology accepted April 2006.

Focusing Biomedical Treatments. Richard S. Lord, Ph.D.

Focusing Biomedical Treatments with Laboratory Data Richard S. Lord, Ph.D. Questions Why autism spectrum disorder epidemic How to treat? How to prevent? A Medical Hypothesis Regressive Autism: A neuronal