1	AUTISM - DEVELOPMENTAL DISORDER or . . . DISEASE ? THE CRITICAL QUESTION Michael J. Goldberg, M.D., F.A.A.P. 5620 WILBUR AVENUE, SUITE 318 TARZANA, CALIFORNIA 91356 TELEPHONE (818) 343 - 1010 FAX (818) 343 – 6585 Director – NIDS Research Institute E-mail – office@neuroimmunedr.com On the web: www.neuroimmunedr.com
2	What's going on? The question of time trends in autism. Blaxill MF. SafeMinds, Cranford, NJ, USA Public Health Rep. 2004 Nov-Dec;119(6):536-51 Reported rates of autism in the United States increased from < 3 per 10,000 children in the 1970s to > 30 per 10,000 children in the 1990s, a 10-fold increase In the United Kingdom, autism rates rose from < 10 per 10,000 in the 1980s to roughly 30 per 10,000 in the 1990s Reported rates for the full spectrum of autistic disorders rose from the 5 to 10 per 10,000 range to the 50 to 80 per 10,000 range in the two countries A precautionary approach suggests that the rising incidence of autism should be a matter of urgent public concern
3	Although exact statistics are controversial It is known that the incidence of autism has skyrocketed from 1 in 10,000 to 1 in 166 Some places in the United States report 1 in 100 Brick Township, New Jersey, the incidence is reported at 1 in 10 to 1 in 50, depending on the source of the statistic CDC Autism - $11.3 million 2002 AIDS - $932 million 2002 Diabetes - $62 million 2002 NIH Autism - $56 million 2002 AIDS - $2.2 billion 2002 Diabetes - $688 million 2002 *source of figures Sen. Dan Burton Is society prepared financially and emotionally to handle adults at a rate of 1 in 166 at the least to an estimate of 1 in 50, who are autistic and need supervision and help to cope with daily life?
4	All United Together In Something Miserable THE “A” word: Faster than ALL efforts at science and logic . . . Able to paralyze parents and professionals with the sheer thought Able to leap over all logic, skepticism, past established clinical medical principles and policies with a single expression
5	THE “A” word: Disguised as “Autism,” “Mercury toxicity,” “ASD/PDD/CDD et al” fights a strong, never ending battle against TRUTH – scientific logic and reasoning JUSTICE – for your children The “American Way” . . . . A chance for a optimistic future and life A chance for equal education / equality Improved health care and quality of life for children and families
6	SCIENCE says: An epidemic can NOT be due to a developmental or genetic disorder ONE MUST have a disease process The ONLY possible CAUSE for this type of disorder / dysfunction has become immune and / or viral in origin
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8	The Human Brain - a “Black Box” Could “define” patterns of dysfunction Very little understanding objectively as to cause, reason, or origin Reasons for disease / dysfunction Structural Congenital / developmental malformation Vascular malformation – Aneurysm, etc. Injury Neoplasm - Tumor Metabolic Infectious Disposition of Herpes viruses - temporal lobes!! Immunologic Evolution of information s/p HIV
9	1980’s Change in disease patterns becoming obvious in clinical practice Early discussion of a new entity in adults causing chronic tiredness, cognitive dysfunction, combination of muscle, joint, autonomic, endocrine symptoms Children being “labeled” atypical ADD, quiet ADD, “mixed” ADD ADHD with Hyperactivity ADHD without Hyperactivity Autism > PDD (“atypical” autism)
10	1990’s Increased discussions of cognitive dysfunction, school difficulties for children ADHD variants LD Autism / PDD – beginning to “surface” in preschools Dr. Byron Hyde “Emerging epidemic” in children School phobia, cognitive dysfunction, unexplained physical dysfunction’s, expanding teenage drug addiction, teenage suicide
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14	EXPLOSION of auto-immune, immune mediated disorders adults and children Diabetes NOW known to be immune and viral mediated Allergies, migraines, sinus infections Adults and children IBS, Crohn’s Disease, Ulcerative Collitis Rheumatoid disease, FMS Auto-immune links to Alzheimer’s, Parkinson’s, MS, and other adult neurological disorders “Neuro-Immune” has become the research pathway of the future
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16	CURRENTLY: Neuro-Immune linkage acknowledged, being invested in childhood states of: Tourette’s syndrome NOT discussed or recognized before the 1980’s OCD – PANDAS Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections Autism / PDD CFS / CFIDS ADHD / ADD Adults routinely discussed as ADHD
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18	Autism - associated medical conditions in the past: Tuberous Sclerosis (genetic) PKU (metabolic) Congenital Rubella (viral) Down Syndrome (genetic - chromosome 21) Fragile X (genetic) Others . . .
19	GENETIC AND IMMUNOLOGIC CONSIDERATIONS IN AUTISM Korvatska E, Van de Water J, Anders TF, Gershwin ME Neurobiol Dis 2002 Mar;9(2):107-25 Erratum in: Neurobiol Dis 2002 Jun;10(1):69 Division of Rheumatology, Allergy, and Clinical Immunology, University ofCalifornia at Davis, Davis, California Recent epidemiological surveys Recognized as common childhood psychopathologies Strong genetic determinant consistent with a polygenicmode of inheritance Parallel evidence of immune abnormalities in autistic patients argues for an implication of the immune system in pathogenesis Emerging concerns addressing the disease incidence and triggering factors Neurochemical and immunologic findings are analyzed in the context of a neuroimmune hypothesis for autism Studies of disorders with established neuroimmune nature indicate multiple pathways of the pathogenesis
20	MATERNAL INFECTION: WINDOW ON NEUROIMMUNE INTERACTIONS IN FETAL BRAIN DEVELOPMENT AND MENTAL ILLNESS Patterson PH. : Curr Opin Neurobiol 2002 Feb;12(1):115-8 Biology Division, California Institute of Technology, Pasadena, California Direct viral infection of the developing brain can have disastrous consequences for the fetus More insidious are viral infections of the pregnant mother Recent mouse model - respiratory infection in the pregnant mother leads to marked behavioral and pharmacological abnormalities in the offspring Some of which are relevant for schizophrenia and autism This effect on fetal brain development might be caused by the maternal antiviral immune response, possibly mediated by cytokines
21	Elaborate interactions between the immune and nervous systems REVIEW: Nature Immunology 5, 575 - 581 (2004) Published online: 26 May 2004; \| doi:10.1038/ni1078 Lawrence Steinman Department of Neurological Sciences and Neurology and Pediatrics, Interdepartmental Program in Immunology, Beckman Center for Molecular Medicine, Stanford, California 94305. The immune system and the nervous system maintain extensive communication, including 'hardwiring' of sympathetic and parasympathetic nerves to lymphoid organs. Neurotransmitters such as acetylcholine, norepinephrine, vasoactive intestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and -melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior. Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.
22	With the Relatively New Thinking That Autism Has Medical Origins Have Come Several . . . . Theories Some doctors believe autism is a result of a metabolic, enzyme, or genetic defect Although a few children (??) may suffer a built-in genetic or functional defect present since early gestation, our clinical observation and our rCBF findings for Autism do not support these theories for the majority of children afflicted These theories do not fit or begin to explain the large increase in the number of children diagnosed with autism today
23	Past “Flavor of the week” Therapies – “Autism” Purine metabolism Phenol metabolism Strict ABA Vitamin B6, B12, Magnesium, Calcium, et al .. Anticonvulsants – EEG’s Steroids Vitamin A – cod liver oil Chelation Secretin
24	Mercury – A “New Disease” Model ?? Some feel Autism has never been described as a mercury-induced disease, because the disorder must arise from a mode of mercury administration which has not been studied before But Mercury (Hg) - symptoms, methods of detection, negative effects, etc. HAS BEEN STUDIED for MANY, MANY years NO support in past literature: Celiac Disease = Autism – NOT Mercury = CFS, Autism, etc. - NOT
25	Thimerosal and Autism? PEDIATRICS Vol. 111 No. 3 March 2003, pp. 674-679 Karin B. Nelson, MD Neuroepidemiology Branch National Institute of Neurological Disorders and StrokeBethesda, MD 20892-1447 Margaret L. Bauman, MD Children’s Neurology Service Harvard Medical School Boston, MA 02114-2620 ?? - Whether current evidence indicates that mercury atany known dose, form, duration, age, or route of exposure leadsto autism. In mercury poisoning, the characteristic motor findings areataxia, dysarthria, and spasticity. In autism, the only common motor manifestations are repetitivebehaviors (stereotypies) such as flapping, circling, or rocking.
26	Thimerosal and Autism? (cont.) Frequency ofclumsiness and hypotonia in autism spectrum disorders is notestablished The presence of ataxia or dysarthria in a child whosebehavior has autistic features should lead to careful medicalevaluation for an alternative or additional diagnosis Most characteristic sensory finding of mercury poisoning- highly specific bilateral constriction of visual fields The "Sensory Defensiveness" of Autism Seems toReflect Altered Sensory Processing Within the Brain Rather ThanPeripheral Nerve Involvement
27	Thimerosal and Autism? (cont.) Other signs that may appear in children with chronic mercurytoxicity, such as hypertension,skin eruption,and thrombocytopenia,are seldom seen in autism When severe mercury poisoning occurs in prenatal life or early infancy, head size tends to be small – microcephaly common Prenatal exposure to other neurotoxins – predispose to decreased head size In contrast, in autism - head size tends to be larger than population norms
28	Thimerosal and Autism? (cont.) No paper published in the peer-reviewed literature that reported an abnormal body burden of mercury, or an excess of mercury in hair, urine, or blood. We did not find evidence that chelation therapy has led to improvement in children with autism. Substantial literature - neurotoxicity of methylmercury Relatively little is known - of ethylmercury on the nervous system, especially with repeated low-doseexposure Passage of methyl mercury across the blood-brainbarrier is facilitated by an active transport mechanism The passage of ethyl mercury into the brain does not have sucha transport system - larger molecularsize and faster decomposition
29	Thimerosal and Autism? (cont.) At equivalent doses, higherlevels of mercury have been found in the blood and less in brainfollowing administration of ethyl mercury than methyl mercury Risk of ToxicityFrom Ethyl Mercury Is Overestimated by Comparison With the Riskof Intoxication From Methyl Mercury Ethyl mercury exposurehas been reported to be more likely than methyl mercury to producelesions of the spinal cord, skeletal muscle, and myocardium Extensive pathologic studies contaminatedseafood in Japan contaminated bread in Iraq
30	Thimerosal and Autism?(cont.) MicroscopicFindings Decreased numbers of neurons Increased numbers of glial cells, macrophages In 2 Iraqi infantsexposed prenatally to methyl mercury there was a simplifiedgyral pattern, short frontal lobe, and reduction in white mattervolume, along with derangement and lack of definition of thecortical layers and heterotopic neurons in cerebrum and cerebellum In ethyl mercury toxicity - diffuseproliferation of glia, demyelination of ninth and tenth cranialnerve roots Atrophy of the cerebellar granule cell layerwith relative sparing of Purkinje cells
31	Thimerosal and Autism? (cont.) In Contrast - at Autopsy Brains of autistic persons- commonly enlarged No reports of significant cerebral cortical neuronalloss or calcarine atrophy in autism Most frequently reportedfindings - autistic forebrain - unusually small,closely packed neurons and increased cell packing density Portions of the limbic system, consistent with curtailment ofdevelopment of this circuitry
32	Thimerosal and Autism? Microscopic findings: (cont.) Most consistent finding in the neuropathology of autismis reduction in Purkinje cells in the cerebellum, primarilyin the posterior inferior hemispheres Involvementof granule cells has rarely been reported In contrast, mercury-exposedbrains have shown significant and consistent damage to the cerebellargranule cell layer with relative preservation of Purkinje cells.
33	Thimerosal and Autism? First Half of the 20th Century Mercury was a constituentof medications Use of these compounds was associated with illness inyoung children, affecting chiefly those 8 months old to 2 yearsold Infants showed photophobia, anorexia, skin eruption,and bright pink color of hands and feet “Pink disease" or acrodynia Survivors were not described to have behavioraldisorders suggestive of autism.
34	Thimerosal and Autism? 1950s in Minamata and 1960s in Niigata, Japan Epidemics of methyl mercury poisoning Heavy prenatal exposure resultedin low birth weight, microcephaly, profound developmental delay,cerebral palsy, deafness, blindness, and seizures Affectedadults experienced impairments of speech, constriction of visualfields, ataxia, sensory disturbance, and tremor Was autism recognized with higher frequency in Japanese childrenin the period of these toxic outbreaks Japanese reports in the English language do not indicate thatJapanese clinicians thought so!!!
35	Thimerosal and Autism? Studies that followed victims of high-dose acute or chronicmercury poisoning resulting from contaminated foods in Iraq,Pakistan, Guatemala, and Ghana have not reported manifestationssuggestive of autism in survivors In contrast, many of thesesurvivors had clinical signs such as persisting ataxia and dysarthriathat are seldom seen in autism
36	Thimerosal and Autism? Unpublished retrospective study Canadian Communicable Disease Report 10 years of data A weak but statistically significant(relative risk ratio <2.0) association was found betweenmeasures of cumulative exposures to thimerosal and the presenceof speech delay and attention-deficit/hyperactivity disorder,but not autism A second unpublishedscreening study did not confirm the findings of the first
37	Thimerosal and Autism? Two studies have examined neurologic and psychologic functionin young children associated with lower dose but repeated dietaryexposure to methyl mercury Faeroestudy of 428 to 900 children at 7 years old observed an associationof mercury levels in cord blood or maternal hair with impairedperformance in tests In contrast, in the Sechylles study of >700 children - boys with higher levels of hairmercury performed better on some tests The Faeroe and Seychelles studies were probably large enoughto detect a substantial but not a minor increase in autism,if it was present
38	Thimerosal and Autism? In Summary: Mercury poisoning and autism both affect the central nervoussystem Specific sites of involvement in brain and thebrain cell types affected are different in the two disordersas evidenced clinically and by neuropathology Overall the clinical pictureof mercurism DOES NOT mimic that of AUTISM
39	Vaccination Theory ? In other “proposed” disease models (MS,CFS/CFIDS Fibromyalgia) exposures such as maternal Hg exposures (e.g., from vaccinations, thimerosal-containing RhoGam injections during pregnancy, or dental fillings) has been ruled out in the literature. Vaccines may be possible “triggers” but they are NOT the cause of this disorder / epidemic. There Is Too Much Data Over Decades Supporting the Lack of “Causation” But, action as a potential “trigger” is open to scientific investigation (in some cases)
40	Autism and the Immune System It is our* belief that “Autistic Syndrome" probably is a state of dysfunction induced in the brain by a dysregulated immune system It is possible that this dysfunction may occur in individuals that have a genetic predisposition In theory, this predisposition could be triggered by various stresses placed on the child’s neuro-immune system It’s severity varies with the individual and age of onset * Goldberg, M, Mena, I Frontal and Temporal Lobe Dysfunctiion in autism and Other Related Disorders: ADHDH and OCD. Alasbimn Jouranll (4): July 1999
41	9 yr. Old Girl - quiet-ADD / NIDS
42	NeuroSPECT - 8 y/o F - “Autistic Syndrome”
43	NeuroSPECT - 5 y/o M - "Autistic Syndrome"
44	18 yr. Old Boy - ADHD / NIDS
45	PATHOPHYSIOLOGY
46	PATHOPHYSIOLOGY (cont.)
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48	Findings of brain 99mTc-ECD SPECT in high-functioning autism--3-dimensional stereotactic ROI template analysis of brain SPECT. J Med Invest. 2005 Feb;52(1-2):49-56. Ito H, Mori K, Hashimoto T, Miyazaki M, Hori A, Kagami S, Kuroda Y. Department of Pediatrics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. The aim of this study is confirmation of an abnormal regional cerebral blood flow (rCBF) pattern in high-functioning autism (HFA). Confirmation of an abnormal rCBF pattern in HFA may be useful for elucidate of its pathophysiology and a differential diagnosis, such as with attention-deficit/hyperactivity disorder (AD/HD). Brain 99mTc-ECD SPECT was performed in 16 cases of HFA. We found a significantly low 'relative rCBF (%)' in the left temporal region in the HFA group. We found significant right < left perfusion in the angular region and significant left < right perfusion in the pericallosal, thalamus, and hippocampus region in the HFA group. We also found significant right < left perfusion in the temporal region in the control group. Significant hypoperfusion in the left temporal region due to an unidentified underlying brain pathology and abnormal laterality in the angular, temporal (lack of right < left perfusion), pericallosal, thalamus, and hippocampus regions may influence the symptoms of autism.
49	Multiple Immune abnormalities reported: Changes in T cells (& T cell function) CD4 / CD8 - increased / decreased Low (and elevated) NK cells B cells - increased / decreased Increased DR+ T cells Increased Interleukin 2 Receptors Decreased Mitogen response Altered Delayed hypersensitivity Antibodies to serotonin receptors Antibodies to neuro elements
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51	N.I.D.S. (Neuro –Immune Dysfunction Syndromes) For whatever the reasons (genetic, environmental, a combination of viruses, vaccines, allergies, immune system “insults,” etc.), what is occurring appears to be an immune mediated, abnormal “shut down” of blood flow in the brain and therefore central nervous system function.
52	N.I.D.S. (Neuro –Immune Dysfunction Syndromes) (cont.) The multiple secondary metabolic, physiologic, and immune markers that are abnormal in these children, "make sense" when you think of the bigger picture and consider the primary cause of autism as immune dysfunction, creating multiple cellular / mitochondrial dysfunctions
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54	N.I.D.S. (Neuro–Immune Dysfunction Syndromes) In adolescents and adults, this dysfunction may manifest itself as CFIDS (Chronic Fatigue Immune Dysfunction Syndrome), ADHD “variants”, and various other atypical auto-immune disorders associated with neuro-immune dysfunction In older children, it is seen as variants of ADD (Attention Deficit Disorder) / ADHD And in younger children/infants, it appears as “Autism, Autistic syndrome, PDD, etc.
55	NIDS – Family “Connections” Mother or Father with CFS or “other” immune mediated disorder Older child (or two) with ADHD (or other learning disorder LD) Younger child (or two) with Autism / PDD
56	NeuroSPECT - 5 y/o M - "Autistic Syndrome"
57	NeuroSPECT - 8 y/o F - “Autistic Syndrome”
58	FRONTAL AND TEMPORAL LOBE DYSFUNCTION IN AUTISM AND OTHER RELATED DISORDERS: ADHD AND OCD Michael Goldberg, M.D Ismael Mena, M.D., Bruce Miller, M.D. Clínica Las Condes, Santiago,Chile, Dept of Neurology, UCSF Medical Center. Alasbimn Journal1(4):July 1999 Autism, Pervasive Development Disorder (PDD), Attention Deficit Hyperactive Disorder (ADHD), and Obsessive and Compulsive Disorder (OCD) involve significant frontal and temporal lobe dysfunction. This conclusion is based on NeuroSPECT work now in progress on children afflicted with these disorders. We have been using NeuroSPECT to image cerebral abnormalities of perfusion/function in Autism, ADHD, OCD, and other neuro-cognitive disorders. With increased incidence of learning disorders, comes a greater need to understand and define the dysfunction in these children by objective "functional" quantification, .
59	FRONTAL AND TEMPORAL LOBE DYSFUNCTION IN AUTISM AND OTHER RELATED DISORDERS: ADHD AND OCD (cont) This offers an explanation for the progressive process of the autistic syndrome that occurs sometime between 15-24 months of age. It is this immune mediated, abnormal "shut down" of blood flow in the brain that affect the language and social skills area of the brain and central nervous system function. The dysfunction / lack of blood flow can eventually lead to injury of nerve cells Possible explanation for the abnormal brain waves and the large numbers of autistic syndrome children suddenly being labeled as "Landau-Kleffner."
60	NeuroSPECT Findings: Quantitative rCBF measurements with Xenon 133 were found to be higher than normal in autistic children, with maximal values in the frontal lobes and visual cortex Minimal perfusion was observed in the temporal lobes. Decreased flow was also noted in the cerebellum and occipital lobes
61	NeuroSPECT Findings: The areas of increased perfusion, most frequently located in lateral frontal lobes, are similar to our observations in obsessive compulsive disorder (OCD children) Tc 99m HMPAO images (Prado et al.) demonstrate increased frontal perfusion, and demonstrating also temporal, occipital and cerebellar hypoperfusion
62	4 yr. old female “Autistic”
63	6 yr. old “Autistic” female
64	Autism:
65	N.I.D.S. (Neuro –Immune Dysfunction Syndromes) Symptomotology - Brain Dysfunction: Severe speech and language development (Left temporal lobe) Severe social difficulties (Right temporal lobe) Often some fine, not usually gross, motor difficulties (Cerebellar involvement) Various learning difficulties and attention deficit dysfunctions consistent with involvement of frontal and temporal lobes, and links to areas of parietal-occipital dysfunction May also have many symptoms consistent with OCD characteristics, associated with these areas of dysfunction
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68	Past Medical History “PMH = ILLNESS” Eczema or hives Frequent ear infections Enuresis Frequent urination Very fidgety Trouble concentrating Self stemming Eye contact variable PHOTOSENSITIVY
69	“PMH = ILLNESS” ( cont.) Disturbs others in class Sensory processing difficulty Vestibular dysfunction Auditory processing difficulties Abnormal EEG or SEIZURE disorder “convulsions (maybe)” Behavioral issues Very affectionate Hyperactive Easily fatigued Sleep difficulties Wakes tired in AM
70	“PMH = ILLNESS” ( cont.) Tuned out Impairment with non-verbal behaviors Failure to develop peer relationships Lack of sharing interests Impairment to initiate or sustain speech OCD Lack of varied or spontaneous play Inflexible adherence to rituals Repetitive motor mannerisms Fine / Gross motor abnormal
71	Disease(di-zez´): 1. An interruption, cessation, or disorder of body functions, systems, or organs.illness, morbus, sickness; something is wrong with a bodily function. 2. A morbid entity characterized usually by at least two of these criteria:
72	Disease(di-zez´): (cont.) Recognized etiologic agent(s) Associated with Herpes and other viral infections Identifiable group of signs and symptoms “Autism” - DSMIV 299.00 “Potential Immune and other Markers” Consistent anatomical alterations NeuroSPECT!
73	SCIENCE says: An epidemic can NOT be due to a developmental or genetic disorder SCIENTIFICALLY IMPOSSIBLE!!! ONE MUST have a disease process The ONLY possible CAUSE for this type of disorder / dysfunction has become immune and / or viral in origin
74	More Pertinent Articles: Biochemical dysregulation of the 2-5A I Rnase L antiviral defense pathway in Chronic Fatigue Syndrome Authors:Robert 1. Suhadolnik, Daniel L Pecerson, Paul R Cheney+, Susan E Horvath, Nancy L Reichenbach. Karen OlBrien, Vincent Lombardi, Suzanne Welsch++, Elizaoeth G. Furr+, Ramamurthy Charubala, and Wolfgang Pfleiderer*Temple University School of Medicine, Philadelphia, PA - IMMUNE ACTIVATION Increased activation of human herpesvirus-6 (HHV-6, but not human herpesvirus-7 (HHV-7) or human herpesvirus-8 (HHV-8), in Chronic Fatigue Syndrome (CFS) patients Authors:D.V. AhIashi+. S. Marsh, M. Handy, J. Whilman, D. Viza, 0. Krueger and P.H. Leviine**Advanced Biotechnologies Inc. Columbia, MD)+Georgetown University School of Medicine, Washington, DC - PERSISTENT REACTIVATION
75	Persistent active human herpesvirus six (HHV-6) infections in patients with Chronic Fatigue Syndrome Authors: Konstance K Knox Ph.D.; Joseph H. Brewer, M.D., and Donald R. Carrigan, Ph.d. Herpesvirus Diagnostics, Inc. and Institute for Viral Pathogenesis; 12346W. Layton Ave. Greenfield, Wisconsin 532281 and*lnfectious Diseases; St. Luke's Hospital; Kansas City, Missouri. Conclusion: These studies demonstrate that a sizable proportion (30% to 70%) of patients with CFS suffer from an active persistent infection with HHV-6. Active HHV-6 infections may be especially prevalent in CFS patients with CNS involvement, consistent with the highly neuro-invasive nature of HHV-6
76	Human Herpesvirus-6 and -7 Infections in Children: Agents of Roseola and Other Syndromes Leach CT Department of Pediatrics, University of Texas Health Science Center at San Antonio Curr Opin Pediatr 2000 Jun;12(3):269-74 Human herpesvirus-6 (HHV-6) and -7 (HHV-7) infections Typically silent or mild febrile illnesses (Roseola) Rare occurrence of HHV-6 encephalitis In immunocompromised / immunocompetent subjects Many other diseases – putatively associated Nevertheless, treatment may be considered for patients with serious HHV-6- or HHV-7-associated disease confirmed with accurate virologic tests
77	Human Herpesvirus-6 Associated Encephalitis With Subsequent Infantile Spasms and Cerebellar Astrocytoma Rantala H, Mannonen L, Ahtiluoto S, Linnavuori K, Herva R, Vaheri A, Koskiniemi M Department of Paediatrics, University of Oulu, Finland. Heikki.Rantala@oulu.fiDev Med Child Neurol 2000 Jun;42(6):418-21 14 month-old girl 3 days of fever, floppiness, and diffuse urticarial exanthem. Developed encephalitis and carditis 1 week later > intractable seizures On days 14 and 34 (after the onset of symptoms) a human herpesvirus-6 (HHV-6) genome in cerebrospinal fluid was identified by polymerase chain reaction (PCR) Convulsions > “typical” infantile spasms with hypsarrhythmic Gradually lost her social contact and ability to walk and sit
78	Epidemiology of Human Herpesvirus 6 (HHV-6) Infection in Pregnant and Nonpregnant Women Baillargeon J, Piper J, Leach CT Departments of Pediatrics, The University of Texas Health Science Center at San Antonio J Clin Virol 2000 May;16(3):149-57 Little information available regarding HHV-6 infection in women of reproductive age University Family Planning Clinic RESULTS: All subjects were HHV-6 antibody positive Geometric mean titers of HHV-6 antibodies were significantly higher among non-pregnant versus pregnant women. Moreover, a higher proportion of non-pregnant versus pregnant women had antibody titers >/=160 and >/=320. Low rates of HHV-6 shedding in the genital tract were observed for both groups Further longitudinal studies are required to assess the consequences of maternal HHV-6 infection.
79	Encephalitis Caused by Human Herpesvirus-6 in Transplant Recipients: Relevance of a Novel Neurotropic Virus Singh N, Paterson DL Veterans Affairs Medical Center and University of Pittsburgh, Thomas E Starzl Transplantation Center Transplantation 2000 Jun 27;69(12):2474-9 BACKGROUND: Human herpesvirus-6 (HHV-6) is a neurotropic virus HHV-6 encephalitis occurred a median of 45 days (range 10 days to 15 months) after transplantation Mental status changes Confusion to coma Seizures Headache Focal neurologic findings occurred in only 17% of the patients Cerebrospinal fluid pleocytosis was generally lacking CONCLUSIONS: HHV-6 may be associated with encephalitis after transplantation and warrants consideration in transplant recipients with encephalitis of unidentifiable etiology
80	Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, Nemeroff CB JAMA 2000 Aug 2;284(5):592-7 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine CONTEXT: Evidence suggests that early adverse experiences play a preeminent role in development of mood and anxiety disorders and that corticotropin-releasing factor (CRF) systems may mediate this association RESULTS: Women with a history of childhood abuse exhibited increased pituitary-adrenal and autonomic responses to stress compared with controls Women with a history of childhood abuse and a current major depression diagnosis exhibited a more than 6-fold greater ACTH response to stress than age-matched controls
81	Autistic Regression With Rolandic Spikes Nass R, Devinsky O New York University Medical Center, Department of Neurology,Neuropsychiatry Neuropsychol Behav Neurol 1999 Jul;12(3):193-7 OBJECTIVE: Define the electroencephphic abnormalities seen in the Landau-Kleffner syndrome variants and the associated clinical features METHOD: Two patients - centro-temporal spikes, autistic epileptiform regression, and variably prominent oro-motor symptoms RESULTS: The epileptic aphasia pattern - may more frequently involve expressive language than is seen in the typical Landau-Kleffner syndrome > verbal auditory agnosia CONCLUSIONS: This clinical difference likely reflects the location of the epileptiform activity (centrotemporal as opposed to anterior or mid-temporal)
82	Autism and the serotonin transporter: the long and short of it. Mol Psychiatry. 2005 Aug 16; [Epub ahead of print]Devlin B, Cook EH, Coon H, Dawson G, Grigorenko EL, McMahon W, Minshew N, PaulsD, Smith M, Spence MA, Rodier PM, Stodgell C, Schellenberg GD. 1Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. Some symptoms of autism are alleviated by treatment with selective serotonin reuptake inhibitors, which are known to interact with the serotonin transporter. Variation in the gene that encodes the transporter (SLC6A4),especially the HTTLPR locus, is known to modulate its expression It is natural,therefore, to evaluate whether this variation plays a role in liability to autism Independent family-based sample (390 families, 1528 individuals)
83	Autism and the serotonin transporter: the long and short of it (cont.) From the NIH Collaborative Programs of Excellence in Autism (CPEA) Allele transmissions -individuals diagnosed with autism were biased only for HTTLPR, - narrow diagnosis of autism (P=0.035) and for the broader diagnosis of autism spectrum (P=0.007) The short allele of HTTLPR was significantly over transmitted. Investigation of haplotype transmission suggested that, in our data, biased transmission was only due to HTTLPR. With respect to this locus, there are now seven of 12 studies reporting significant transmission bias of HTTLPR alleles, a noteworthy result in itself. However, the studies with significant findings are almost equally divided between overtransmission of short and overtransmission of long allele Determining the factors influencing the relationship between autism phenotypes and HTTLPRvariation, as well as other loci in SLC6A4, could be an important advance in our understanding of this complex disorder
84	Autistic disorder and viral infections Libbey JE, Sweeten TL, McMahon WM, Fujinami RS.J Neurovirol. 2005 Feb;11(1):1-10.Department of Neurology, University of Utah, Salt Lake City, Utah 84132-2305,USA. One proposed etiology for autism is viral infection very early in development The mechanism, by which viral infection may lead to autism, be it through direct infection - central nervous system (CNS) Through infection elsewhere in the body acting as a trigger for disease in the CNS, through alteration of the immune response of the mother or offspring, or through a combination of these, is not yet known
85	Autistic disorder and viral infections (cont) Animal models in which early viral infection results - behavioral changes later in life include the influenza virus model in pregnant mice and the Borna disease virus model in newborn Lewis rats Many studies over the years have presented evidence both for and against the association of autism with various viral infections The best association to date has been made between congenital rubella and autism; however, members of the herpes virus family may also have a role in autism
86	Clinical efficacy of fluvoxamine and functional polymorphism in a serotonin transporter gene on childhood autism Sugie Y, Sugie H, Fukuda T, Ito M, Sasada Y, Nakabayashi M, Fukashiro K, OhzekiT. J Autism Dev Disord. 2005 Jun;35(3):377-85. Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu,Japan. y-sugie@umin.ac.jp Studied the correlation between response to fluvoxamine and serotonin transporter gene promoter region polymorphism (5-HTTLPR) Eighteen children with autistic disorder completed a 12-week double-blind, placebo controlled,randomized crossover study of fluvoxamine Behavioral assessments were obtained before and at 12 weeks of treatment. 5-HTTLPR (long (l) or short(s)), was analyzed by the PCR method Ten out of 18 patients responded to fluvoxamine treatment Allele type analysis revealed that clinical global effectiveness was noted significantly more in the l allele than in the s allele However, with respect to language use, a significant effectiveness was noted in the allele.5-HTTLPR may influence the individual responses to fluvoxamine administration.
87	Invasion by Human Herpesvirus 6 and Human Herpesvirus 7 of the Central Nervous System in Patients With Neurological Signs and Symptoms Yoshikawa T, Ihira M, Suzuki K, Suga S, Matsubara T, Furukawa S, Asano YDepartment of Pediatrics, Fujita Health University School of Medicine, Aichi,Japan.tetsushi@med.nagoya-u.ac.jpArch Dis Child 2000 Aug;83(2):170-1 Human herpesvirus 6 (HHV-6) and HHV-7 DNA was detected in cerebrospinal fluid (CSF) and peripheral blood mononuclear cells The seven HHV6 CSF viruses were all variant B CONCLUSION: These data suggest that HHV-7 may invade the CNS
88	Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism Diana L. Vargas, MD, Caterina Nascimbene, MD,1Chitra Krishnan, MHS1 Andrew W. Zimmerman, MD, and Carlos A. Pardo, MD Ann Neurol 2005;57:000–000 Investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism Immunocytochemistry, cytokine protein arrays, and enzymelinked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients Determine the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients
89	Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism ( cont.) Suggest - defects in neuronal maturation and cortical organization may be responsible for some of the neurological problems seen in autism Immune dysfunction has been proposed as a potential mechanism for the pathogenesis of autism Several studies in peripheral blood have shown various abnormalities such as T-cell dysfunction, autoantibody The potential role for maternal antibodies- pathogenic factor also has been proposed
90	Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism ( cont.) Despite - growing interest in possible immune mechanisms in its pathogenesis - been no direct evidence linking findings in the peripheral blood to immune activity in the brain of autistic patients Neuropathological studies – little attention to immune and neuroglial activity in autism Most comprehensive postmortem study reported no inflammatory changes or astroglial reactions Only a few reports have described gliosis and inflammatory changes Such neuroinflammation, if present in the brain, might both participate in and result from dysfunctional CNS development and activity in autism
91	Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism ( cont.) Microglial response in autism cases were diffusely distributed in the cortex and subcortical areas, as well as the cerebellum, or were present as microglial nodules or as a part of a prominent accumulation of perivascular macrophages These responses in autism resemble those seen in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotropic lateral sclerosis, and are similar to those seen in dementia associated with human immunodeficiency virus (HIV) infection In these conditions, chronic microglial activations appears to be responsible for a sustained neuroinflammatory response In the case of autism, the presence of microglial activation supports the view that innate immune response are present in cortical and subcortical regions and that a state of chronic activation and reactivity may be involved in the mechanism of neuronal and synaptic dysfunction
92	Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism ( cont.) Immunocytochemical studies - marked activation of microglia and astroglia Findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain. Several lines of research now support the view that genetic, environmental, neurological, and immunological factors contribute to its development
93	HUGE implications “This IS a disease” (NOT a developmental disorder, a congenitally “miswired” brain, etc.) “Disease” means these children were born with normally functioning brains that became dysfunctional That means they can be fixed, in theory they can work normally, again You cannot “fix” / recover from a developmental disorder, you can from a disease All of this has even more profound implications in light of the work from leading institutions showing: The brain is more pliable than we thought (implying late redevelopment is still possible) The importance of early, correct laying down of pathways / tracts – as the brain evolves and develops
94	Implications - Expectations Past focus for autistic children has been on trainability, cooperation, behavior, NOT on improving the cognitive processing As apparent recently noted, a child with “Autism” is not suppose to be able to recover, develop “functions” they are not suppose to have . . .rather one tries to compensate and work with the dysfunctions / “injury” A shift to the idea of "rehabilitation" is beginning A full review of techniques and goals is urgently needed
95	Therapist comments: When presented with a novel task Wayne will avert his gaze and attention and perseveratively manipulate the item presented, rather than engage in purposeful exploration. Each new step in play must be taught. o It is felt that Wayne would benefit from an intensive educational program that includes one-to-one instruction of repetitive drills and structured play, as well as services to address needs in the areas of receptive and expressive language, FINE MOTOR, GROSS MOTOR, and sensory processing.
96	Unlike the “Old” Ideas of NOT Expecting Speech OR Development Past ?? 5 or 6 Years Old, This Means Older Children (10 – 14 / 18 / 20 Years Old) Can Be Helped! Behaviorally, it has become apparent that one must treat these children age appropriate for where they are psychosocially, not chronologically, NOT as “retarded” With the realization that most of these children are truly intelligent . . . Much of the negative behaviors seen, are because these children are not “disciplined” as one would discipline a normal 2, 4, 6 years old child (again where is the child psychosocially, not current “calendar” age) or are outright miserable, in pain, frustrated, angry, and NEVER looked at or truly understood in that way
97	"While for most children," While for most children, it will probably take the advent and usage of new drugs that are immune modulators, to truly shut off their dysregulated immune system Although these drugs are already in existence and are now going to begin new usage testing in adults, they still await testing for children In theory, they will have the ability (used correctly) to adjust the dysregulated function and put the immune system back on track – in a “healthy” / potentially very safe manner
98	Significant Cognitive Improvements by “Combining” Steps of Therapy Regular classes – top of their class, or most subjects “academically” above average “Older” 8, 10, 12, 14 yr. old children “talking” with combined medical / excellent speech pathology “rehab” / “redevelopment” technique Doing things “never before seen” by the therapists working with these children
99	A Disease State Exists! This dysfunction IS a disease state, NOT a developmental or congenital disorder The multiple children I have seen improve, many “normalize” could not have changed the way they have if they were born “defective,” “miswired,” “damaged,” etc. The emerging understanding of that dysfunction, has given an insight to these children and adolescents . . . helping me to function as a clinician, as a Pediatrician. . . dealing with an “ill” child
100	Case Study: H.C. D.O.B. 5/93 Large head- could not get down birth canal Jaundice Limited success with breast feeding – then formula Enjoyed interacting with mom & dad Some words at 9 months At about 1 yr. – whole milk Realized not developing language as she should Sometimes refuses to cooperate National Naval Medical Center – possible “storage problem” in head – decision – nothing abnormal Didn’t potty train
101	Lab: H.C 11/98 ANA – Neg HHV6 IGG <20 CD4 1180 CD8 502 NK Cells 8% Interferon alpha: 439 Gliadin - Neg. Folate 11.7 Vit. B12 – 911.4 3/00 Ferritin – 43 3/01 HHV6 IGG 1:80 CD4 1144 CD8 506 NK Cells 5.0% 5/01 Interferon alpha <5 ASO - 695
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109	Clinical Therapy – for NOW: My clinical therapy approach has been developed over 20 years of hands-on treatment. My approach is to “attack” the various parts of these disorders. In my therapy I utilize: Food elimination regimens Antivirals and antifungals SSRI’s and other appropriate pharmaceuticals Certain supportive supplements when produced in pharmaceutical grade I am opposed to any “megadosing,” “chelation” or “hyperbaric” processes with 99.999% of these children
110	Oxygen for Newborns: How Much is Too Much? Journal of Perinatology (2005) 25, S45−S49. doi: 10.1038/sj.jp.7211321 Ola Didrik Saugstad: Department of Pediatric Research, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway correspondence: Ola Didrik Saugstad, MD, PhD, Department of Pediatric Research, Rikshospitale, 0027 Oslo, Norway Abstract: International guidelines for newborn resuscitation recommend the use of 100% oxygen. However, high concentrations of oxygen after asphyxiation activate reactive oxygen species that may contribute to a number of morbidities. It has been demonstrated that neonates recover faster when resuscitated with room air as opposed to pure oxygen and neonatal mortality rates are improved. Increases in saturation are equal with oxygen and room air resuscitation. Studies of normal oxygen saturation immediately after birth suggest that clinicians may unnecessarily be rushing to high saturations. In the first weeks of life, lower saturation targets in preterm infants reduce retinopathy of prematurity and pulmonary complications and may improve growth. The neonatologist would be well served to think of oxygen as a medication, and use it sparingly.
111	GABA puts the brake on stem cells Nature Neuroscience 8, 1132 - 1133 (2005) doi:10.1038/nn0905-1132 Arnold R Kriegstein Arnold Kriegstein is at the Department of Neurology and the Program in Developmental and Stem Cell Biology, University of California, San Francisco, California 94143, USA. In the adult brain, new neurons are generated from neural stem cells residing in the subventricular zone. Newborn neuroblasts release the transmitter GABA, which reduces the proliferation of stem cells—and thereby neurogenesis—by a nonsynaptic mechanism.
112	Glutamatergic Dysfunction in OCD Neuropsychopharmacology (2005) 30, 1735-1740.doi:10.1038/sj.npp.1300733; published online 20 April 2005 Kaushik Chakrabarty1, Sagnik Bhattacharyya2,5, Rita Christopher3 and Sumant Khanna4,5 ABSTRACT: Recent reports implicating glutamatergic dysfunction in OCD. We decided to investigate CSF glutamate levels in adult OCD probands compared to psychiatrically normal controls CSF glutamate (mol/l) level was found to be significantly higher [F(1,31)=6.846, p=0.014] in OCD patients (47.12±4.25) compared to control subjects (41.36±3.63) on analysis of covariance There was no effect of gender, age, duration of illness, Y-BOCS score, or CGI-S score on CSF glutamate levels Our study provides preliminary evidence implicating glutamatergic excess in the pathophysiology of OCD, which needs to be further explored by studies from other centers involving larger sample sets from different age groups
113	Glutamatergic Dysfunction (CONT.) The findings of our study that glutamatergic dysfunction is related to the pathophysiology of OCD has been supported also by findings from animal studies, in addition to the MRS-imaging studies in pediatric OCD (Moore et al, 1998; Rosenberg et al, 2000; Bolton et al, 2001). McGrath et al (2000) have shown that MK-801, a noncompetitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated a transgene-dependent abnormal behavior (repetitive climbing and leaping) in a transgenic mouse model of comorbid Tourette's syndrome and OCD, at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviours at higher doses.
114	Chelation therapy neither safe nor effective as autism treatment AAP News Vol. 19 No. 2 August 2001, p. 63 © 2001 Michael Shannon, M.D., M.P.H., FAAP, Susan E. Levy, M.D., FAAP and Adrian Sandler, M.D., FAAP Despite years of rigorous scientific investigation, however, there remains no convincing evidence that mercury intoxication causes ASD Pediatricians can point out to parents that it is misleading to compare a list of symptoms of different disorders and then assume the causes are the same. Extensive toxicologic literature indicates that mercury, unlike lead, arsenic and other heavy metals, remains in the body for only a brief period. Mercury is eliminated naturally through urine and stool in as little as 12 weeks, making chelation useless. Furthermore, clinical experience indicates that chelation therapy for any type of metals poisoning (e.g., lead, arsenic or mercury) does not reverse neurologic injury. Consequently, there is little to no hope that chelation therapy for mercury will improve any aspect of neurodevelopment in a child with ASD.
115	Chelation therapy neither safe nor effective as autism treatment There is an additional flaw in this theory. Those who support chelation also contend that mercury in children with autism usually is tightly bound to proteins and is not easily eliminated from the body or detected with laboratory tests. If the mercury is so tightly protein-bound, how could it cause symptoms? Chelation is an invasive treatment that can be harmful. No chelator is completely safe (or effective) and in some, the potential toxicity is substantial. Side effects include liver injury, allergic reaction, kidney damage and extraction of essential minerals and nutrients from the body. Moreover, it is unlikely that providing nutritional supplements while conducting chelation therapy will prevent the loss of all essential micronutrients.
116	Chelation therapy neither safe nor effective as autism treatment There is convincing evidence that resulting changes in toxicokinetics can lead to increased concentrations of the toxin in the central nervous system, producing greater neurodevelopmental injury. Pediatricians can explain to parents that hair has nothing to do with brain function. Substances found on or in the hair also are inert and may reflect either external or internal exposure. Furthermore, those who suggest analyzing hair make no mention of any correlation between hair measurements and other dynamic tissues or organs that would relate to a child’s nervous system function. The use of scientifically proven techniques for diagnosis of mercury intoxication is key; blood and/or urine should be used to establish the presence of a body burden. Consulting a medical toxicologist may be necessary for further guidance on the diagnosis and management of environmental intoxications in children with ASD.
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118	Autism Inflation: On My Mind: By Jerome Kagan – Professor of Psychology at Harvard and Robert Pozen – Chairman, MFS Investment Management –FORBES – June 6, 2005 Doctors should use biology, not only behavior; to evaluate children Reported incidence of Autism has tripled over the last decade Autism’s sharp rise is in large part a matter of definitions . . We will not find effective cures for autism until we add biological markers to behavioral symptoms in diagnosing children
119	Autism Inflation: (cont.) If children with autistic behaviors were evaluated for these biological features . . . . In other words, what we call autism today is likely to constitute two, three or even more quite different disorders Although intensive behavioral therapy can reduce the frequency of certain autistic behaviors for certain children, it does not cure the basic language and emotional deficiencies of most autistic children Perhaps in a few decades, when a young child begins to exhibit autistic symptoms, a physician will order blood tests and brain scans These will lead to a targeted set of therapies that will be far better than the uniform response we offer today
120	Recent PubMed search: 1: Rutherford MD.Related Articles, Links A retrospective journal-based case study of an infant with autism and his twin. Neurocase. 2005 Apr;11(2):129-37. PMID: 16036467 [PubMed - in process] 2: Stahl L, Pry R.Related Articles, Links Attentional flexibility and perseveration: developmental aspects in young children. Neuropsychol Dev Cogn C Child Neuropsychol. 2005 Apr;11(2):175-89. PMID: 16036443 [PubMed - in process] 3: Williams K, Wray J, Wheeler D.Related Articles, Links Intravenous secretin for autism spectrum disorder. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003495. PMID: 16034901 [PubMed - in process] 4: Kratochvil CJ, Findling RL, McDougle CJ, Scahill L, Hamarman S.Related Articles, Links Pharmacological Management of Agitation and Aggression in an Adolescent With Autism. J Am Acad Child Adolesc Psychiatry. 2005 Aug;44(8):829-832. PMID: 16034286 [PubMed - as supplied by publisher] 5: Couturier JL, Speechley KN, Steele M, Norman R, Stringer B, Nicolson R.Related Articles, Links Parental Perception of Sleep Problems in Children of Normal Intelligence With Pervasive Developmental Disorders: Prevalence, Severity, and Pattern. J Am Acad Child Adolesc Psychiatry. 2005 Aug;44(8):815-822. PMID: 16034284 [PubMed - as supplied by publisher]
121	Recent PubMed search: (cont.) 6: Baron-Cohen S, Belmonte MK.Related Articles, Links AUTISM: A Window Onto the Development of the Social and the Analytic Brain. Annu Rev Neurosci. 2005;28:109-26. PMID: 16033325 [PubMed - in process] 7: Sperner-Unterweger B.Related Articles, Links Immunological aetiology of major psychiatric disorders: evidence and therapeutic implications. Drugs. 2005;65(11):1493-520. PMID: 16033289 [PubMed - in process] 8: Peyton RT, Lindauer SE, Richman DM.Related Articles, Links The effects of directive and nondirective prompts on noncompliant vocal behavior exhibited by a child with autism. J Appl Behav Anal. 2005 Summer;38(2):251-5. PMID: 16033173 [PubMed - in process] 9: Volkert VM, Lerman DC, Vorndran C.Related Articles, Links The effects of reinforcement magnitude on functional analysis outcomes. J Appl Behav Anal. 2005 Summer;38(2):147-62. PMID: 16033163 [PubMed - in process] 10: Janusonis S.Related Articles, Links Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities. Theor Biol Med Model. 2005 Jul 19;2(1):27 [Epub ahead of print] PMID: 16029508 [PubMed - as supplied by publisher]
122	Recent PubMed search: (cont.) 11: Philippi A, Roschmann E, Tores F, Lindenbaum P, Benajou A, Germain-Leclerc L, Marcaillou C, Fontaine K, Vanpeene M, Roy S, Maillard S, Decaulne V, Saraiva JP, Brooks P, Rousseau F, Hager J.Related Articles, Links Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism. Mol Psychiatry. 2005 Jul 19; [Epub ahead of print] PMID: 16027742 [PubMed - as supplied by publisher] 12: D'Amelio M, Ricci I, Sacco R, Liu X, D'Agruma L, Muscarella LA, Guarnieri V, Militerni R, Bravaccio C, Elia M, Schneider C, Melmed R, Trillo S, Pascucci T, Puglisi-Allegra S, Reichelt KL, Macciardi F, Holden JJ, Persico AM.Related Articles, Links Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Jul 19; [Epub ahead of print] PMID: 16027737 [PubMed - as supplied by publisher] 13: Ray MA, Graham AJ, Lee M, Perry RH, Court JA, Perry EK.Related Articles, Links Neuronal nicotinic acetylcholine receptor subunits in autism: an immunohistochemical investigation in the thalamus. Neurobiol Dis. 2005 Aug;19(3):366-77. PMID: 16023579 [PubMed - in process] 14: Battaglia A.Related Articles, Links The inv dup(15) or idic(15) syndrome: A clinically recognisable neurogenetic disorder. Brain Dev. 2005 Aug;27(5):365-9. Epub 2005 Apr 22. PMID: 16023554 [PubMed - in process] 15: Tsai SJ.Related Articles, Links TrkB partial agonists: Potential treatment strategy for epilepsy, mania, and autism. Med Hypotheses. 2005 Jul 12; [Epub ahead of print] PMID: 16023301 [PubMed - as supplied by publisher]
123	Autism / PDD ADHD / ADD vs “NIDS” CFIDS / CFS Signs Symptoms Anatomical findings Millions of Dollars of Research ?? NO OBJECTIVE UNDERSTANDING Definable NeuroSPECT abnormalities Definable Immune / Viral Abnormalities Cognitive dysfunction Specific tests open to selection of patients Ability to focus on new therapy applications . . . Logically - NOW
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