Research on Dietary Interventions in ASD

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Below are some abstracts of research done on the link between dietary issues and autism.


Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder-A Randomized, Controlled 12-Month Trial.

Adams JB1, Audhya T2, Geis E3, Gehn E4, Fimbres V5, Pollard EL6, Mitchell J7, Ingram J8, Hellmers R9, Laake D10, Matthews JS11, Li K12, Naviaux JC13, Naviaux RK14, Adams RL15, Coleman DM16, Quig DW17.

Abstract

This study involved a randomized, controlled, single-blind 12-month treatment study of a comprehensive nutritional and dietary intervention. Participants were 67 children and adults with autism spectrum disorder (ASD) ages 3-58 years from Arizona and 50 non-sibling neurotypical controls of similar age and gender. Treatment began with a special vitamin/mineral supplement, and additional treatments were added sequentially, including essential fatty acids, Epsom salt baths, carnitine, digestive enzymes, and a healthy gluten-free, casein-free, soy-free (HGCSF) diet. There was a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group (+6.7 ± 11 IQ points vs. -0.6 ± 11 IQ points, p = 0.009) based on a blinded clinical assessment. Based on semi-blinded assessment, the treatment group, compared to the non-treatment group, had significantly greater improvement in autism symptoms and developmental age. The treatment group had significantly greater increases in EPA, DHA, carnitine, and vitamins A, B2, B5, B6, B12, folic acid, and Coenzyme Q10. The positive results of this study suggest that a comprehensive nutritional and dietary intervention is effective at improving nutritional status, non-verbal IQ, autism symptoms, and other symptoms in most individuals with ASD. Parents reported that the vitamin/mineral supplements, essential fatty acids, and HGCSF diet were the most beneficial.


Williams, B. L., Hornig, M., Buie, T., Bauman, M. L., Cho Paik, M., Wick, I., Bennett, A., et al. (2011). Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances. (S. Jacobson, Ed.) PLoS ONE, 6(9), e24585. doi:10.1371/journal.pone.0024585.t008

Abstract

Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism.

 

Food Allergy and Autism Spectrum Disorders: Is There a Link? Current Allergy and Asthma Reports 2009;9:194–201

Jyonouchi H

Department of Pediatrics, New Jersey Medical School, UMDNJ, Newark, NJ 07101-1709, USA. jyanouha@umdnj.edu

OBJECTIVE: Gastrointestinal (GI) symptoms are common comorbidities in children with autism spectrum disorders (ASDs). Parents often attribute these GI symptoms to food allergy (FA), although an evaluation for IgE-mediated FA is often unrevealing. Our previous studies indicated a high prevalence of non–IgE-mediated FA in young children with ASDs. Therefore, non–IgE-mediated FA may account for some but not all GI symptoms observed in children with ASDs. This raises the question of what treatment measures are applicable to ASD children with GI symptoms. A wide variety of dietary supplements and dietary intervention measures for ASD children have been promoted by medical professionals practicing complementary and alternative medicine despite the lack of rigorous scientifi c validation in most instances. This review summarizes possible (or proposed) etiologies of GI symptoms in ASD children and discusses risks and possible benefi ts of intervention measures promoted by complementary and alternative practitioners, with emphasis on FA.

RESULTS: In summary, convincing data support the presence of chronic GI inflammation in ASD children, but the etiology of this GI infl ammation is not well understood and is likely affected by multiple genetic and environmental factors. NFA can partially explain the GI symptoms and apparent beneficial effects of dietary interventions in some ASD children, especially young ASD children. Apparent effects of oral vancomycin and altered commensal flora reported in ASD children may be explained partially by dysbiosis, which is likely associated with multiple environmental and, possibly, genetic factors. Further studies are required to understand the etiology of GI symptoms observed in ASD children.

Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85.

Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B.

Department of Pediatrics, New Jersey Medical School, UMDNJ, Newark, NJ 07101-1709, USA. jyanouha@umdnj.edu

OBJECTIVE: Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures.

METHODS: This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production.

RESULTS: ASD and NFH PBMCs produced higher levels of TNF-alpha with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-alpha levels produced with LPS and those with cow's milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens. Conclusion: Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities. Copyright 2005 S. Karger AG, Basel.

Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci. 2004 Jun;7(3):151-61.

Vojdani A, O'Bryan T, Green JA, Mccandless J, Woeller KN, Vojdani E, Nourian AA, Cooper EL.

Section of Neuroimmunology, Immunosciences Lab., Inc., 8693 Wilshire Blvd., Ste. 200, Beverly Hills, California 90211, USA. drari@msn.com

The mechanisms behind autoimmune reaction to nervous system antigens in autism are not understood. We assessed the reactivity of sera from 50 autism patients and 50 healthy controls to specific peptides from gliadin and the cerebellum. A significant percentage of autism patients showed elevations in antibodies against gliadin and cerebellar peptides simultaneously. For examining cross-reaction between dietary proteins and cerebellar antigens, antibodies were prepared in rabbits, and binding of rabbit anti-gliadin, anti-cerebellar peptides, anti-MBP, anti-milk, anti-egg, anti-soy and anti-corn to either gliadin- or cerebellar-antigen-coated wells was measured. In comparison to anti-gliadin peptide binding to gliadin peptide at 100%, the reaction of anti-cerebellar peptide to gliadin peptide was 22%, whereas the binding of anti-myelin basic protein (MBP), anti-milk, anti-egg and anti-soy to gliadin was less than 10%. Further examination of rabbit anti-gliadin (EQVPLVQQ) and anti-cerebellar (EDVPLLED) 8 amino acid (AA) peptides with human serum albumin (HSA) and an unrelated peptide showed no binding, but the reaction of these antibodies with both the cerebellar and gliadin peptides was greater than 60%. This cross-reaction was further confirmed by DOT-immunoblot and inhibition studies. We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells and gliadin peptides, which may be responsible for some of the neurological symptoms in autism.

Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clin Diagn Lab Immunol. 2004 May;11(3):515-24.

Vojdani A, Bazargan M, Vojdani E, Samadi J, Nourian AA, Eghbalieh N, Cooper EL.

Section of Neuroimmunology, Immunosciences Lab., Inc., 8693 Wilshire Blvd., Suite 200, Beverly Hills, CA 90211, USA. immunsci@ix.netcom.com

Searching for a mechanism underlying autoimmunity in autism, we postulated that gliadin peptides, heat shock protein 60 (HSP-60), and streptokinase (SK) bind to different peptidases resulting in autoantibody production against these components. We assessed this hypothesis in patients with autism and in those with mixed connective tissue diseases. Associated with antigliadin and anti-HSP antibodies, children with autism and patients with autoimmune disease developed anti-dipeptidylpeptidase I (DPP I), anti-dipeptidylpeptidase IV (DPP IV [or CD26]) and anti-aminopeptidase N (CD13) autoantibodies. A significant percentage of autoimmune and autistic sera were associated with elevated immunoglobulin G (IgG), IgM, or IgA antibodies against three peptidases, gliadin, and HSP-60. These antibodies are specific, since immune absorption demonstrated that only specific antigens (e.g., DPP IV absorption of anti-DPP IV), significantly reduced IgG, IgM, and IgA antibody levels. For direct demonstration of SK, HSP-60, and gliadin peptide binding to DPP IV, microtiter wells coated with DPP IV were reacted with SK, HSP-60, and gliadin. They were then reacted with anti-DPP IV or anti-SK, anti-HSP, and antigliadin antibodies. Adding SK, HSP-60, and gliadin peptides to DPP IV resulted in 27 to 43% inhibition of the DPP IV-anti-DPP IV reaction, but DPP IV-positive peptides caused 18 to 20% enhancement of antigen-antibody reactions. We propose that (i) superantigens (e.g., SK and HSP-60) and dietary proteins (e.g., gliadin peptides) in individuals with predisposing HLA molecules bind to aminopeptidases and (ii) they induce autoantibodies to peptides and tissue antigens. Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity.

Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. J Pediatr. 2005 May;146(5):605-10.

Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B.

Objective To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD). Study design Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy.

Results PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable.

Conclusion A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of NFH in GI symptoms observed in children with ASD.

Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004 Nov;24(6):664-73.

Ashwood P, Anthony A, Torrente F, Wakefield AJ.

Centre for Paediatric Gastroenterology, Royal Free and University College Medical School, London, United Kingdom. pashwood@ucdavis.edu

A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal paediatric controls, of which 38 had signs of histological inflammation. Detection of CD3+ lymphocyte staining for spontaneous intracellular TNFalpha, IL-2, IL-4, IFNgamma, and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p<0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD children was significantly greater compared with noninflamed controls (p<0.002) but not coeliac disease controls. In addition, LP and epithelial CD3(+)IL-2+ and CD3(+)IFNgamma+, and epithelial CD3(+)IL-4+ cells were more numerous in ASD children than in noninflamed controls (p<0.04). In contrast, CD3(+)IL-10+ cells were fewer in ASD children than in noninflamed controls (p<0.05). In the colon, LP CD3(+)TNFalpha+ and CD3(+)IFNgamma+ were more frequent in ASD children than in noninflamed controls (p<0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3(+)IL-10+ cells were fewer in ASD children than in nondisease controls (p<0.01). There was a significantly greater proportion of CD3(+)TNFalpha+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet (p<0.05). There is a consistent profile of CD3+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities. The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.

Mechanisms of non-IgE mediated adverse reaction to common Dietary Proteins (DPs) in children with Autism Spectrum Disorders (ASD) February 2004, Supplement • Volume 113 • Number 2

Rationale We have reported elevated IFN-/TNF- production by peripheral blood mononuclear cells (PBMCs) against cow's milk protein (CMP), soy, and gliadin in a substantial number of ASD children (Neuropsychobiology 46:76, 2002). IFN-/TNF- production is partly regulated by IL-10 (negatively) and IL-12 (positively).

Methods We examined IFN-, IL-5, TNF-, IL-10 and IL-12 production by PBMCs against common DPs in 68 ASD children on a regular diet (Median age 5.4 yr): >50% of them had gastrointestinal symptoms. Controls include 11 children with DP intolerance (DPI) (Median age 2.5 yr), and 10 normal children (Median age 3.3 y).

Results ASD and DPI PBMCs produced larger amounts of IFN- and TNF-; against CMP and gliadin than controls (p<0.01). IL-12 production against CMP was higher in ASD PBMCs (p<0.01). IL-10 production by ASD, DPI, and control PBMCs were equivalent, resulting in higher TNF/IL-10 ratio with CMP/gliadin in ASD and DPI PBMCs (p<0.01). IL-12/IL-10 ratios with CMP/gliadin were also higher in ASD PBMCs (p<0.01), but not in DPI cells. In 11/11 DPI children, TNF-/IL-10 ratios with CMP and/or gliadin were >0.5 with excellent responses to the appropriate elimination diet. TNF-/IL-10 ratios >0.5 with CMP and gliadin were found in 41/68 and 32/68 ASD children, respectively. In these children, the elimination diet based on immune reactivity helped resolve GI symptoms and attenuate autistic behaviors by parental report.

Conclusions Disregulated production of inflammatory and counter-regulatory cytokines may be associated with non-IgE mediated adverse reaction to common DPs in some ASD children, indicating therapeutic significance of dietary interventions in these children.

Jyonouchi H, Sun S, Le H.: Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 2001 Nov 1;120(1-2):170-9

Abstract:
Department of Pediatrics, University ofMinnesota, MMC 610 FUMC, 420 Delaware Street SE, Minneapolis, MN55455, USA. jyono001@tc.umn.edu

We determined innate and adaptive immune responses in children with developmental regression and autism spectrum disorders (ASD, N=71), developmentally normal siblings (N=23), and controls (N=17). With lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory cytokines without stimuli than controls. With stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha depending on stimulants. Our results indicate excessive innate immune responses in a number of ASD children that may be most evident in TNF-alpha production.

White JF.: Intestinal pathophysiology in autism. Exp Biol Med (Maywood). 2003 Jun;228(6):639-49.

Vojdani A, Pangborn JB, Vojdani E, Cooper EL., Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99.

Bull G, Shattock P, Whiteley P, Anderson R, Groundwater PW, Lough JW, Lees G.: Indolyl-3-acryloylglycine (IAG) is a putative diagnostic urinary marker for autism spectrum disorders. Med Sci Monit. 2003 Oct;9(10):CR422-5.

Abstract:

Sunderland General Hospital, Sunderland, UK.

BACKGROUND: Autism is a heterogeneous pervasive developmental disorder with a poorly defined aetiology and pathophysiology. There are indications that the incidence of the disease is rising but still no definitive diagnostic biochemical markers have been isolated. Here we have addressed the hypothesis that urinary levels of trans -indolyl-3-acryloylglycine (IAG) are abnormal in patients diagnosed with autism spectrum disorders (ASD) compared to age-matched controls. MATERIAL/METHODS: Urine samples were collected on an opportunistic basis and analysed for IAG concentration (normalised against creatinine content to account for changes in urinary volume) using reversed phase HPLC with UV detection. RESULTS: Statistical analysis (Mann-Whitney tests) showed highly significant increases (p=0.0002) in the levels of urinary IAG in the ASD group (median 942 microV per mmol/L of creatinine [interquartile range 521-1729], n=22) compared to asymptomatic controls (331 [163-456], n=18). Detailed retrospective analysis showed that gender (boys 625 microV per mmol/L of creatinine [294-1133], n=29; girls 460 [282-1193], n=11: P=0.79) and age (control donor median 10 years [8-14], n=15; ASD median 9 years [7-11] n=22: P=0.54) were not significantly correlated with IAG levels in this non-blinded volunteer study. CONCLUSIONS: Our results strongly suggest that urinary titres of IAG may constitute an objective diagnostic indicator for ASD. Mechanisms for the involvement of IAG in ASD are discussed together with future strategies to address its specificity.

Reichelt KL, Knivsberg AM.: Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Nutr Neurosci. 2003 Feb;6(1):19-28.

Buie T, Winter H, Kushak, R: Preliminary findings in gastrointestinal investigation of autistic patients. 2002.

Summary:

Harvard University and Mass General Hospital, http://www.ladders.org/autism.php

111 patients evaluated, ages 14 Months to 20 Years, all with GI symptoms of pain or diarrhea. Endoscopic findings: Esophagitis in 23 (20%), Gastritis in 14 (12%); 4 had Helicobacter pylori; Duodenitis in 11 (10%); 2 had Celiac Sprue; Eosinophilic Inflammation in 5 (5%). 10 out of 90 tested (11%) had unusually low enzyme activity: 2 with total pancreatic insufficiency and 5 with multiple enzyme defects. Lactase deficiency was found in 55% of ASD children tested, and combined deficiency of disacchraridase enzymes was found in 15%. Enzyme assays correlate well with hydrogen breath tests. Colitis was found in 11 of 89 patients (12%), none with features of Ulcerative Colitis or Crohn's. Histologic (biopsy reviewed) lymphoid nodular hyperplasia was found in 15 of 89 patients (16%). Eosinophilic inflammation was found in 13 of 89 patients (14%); cause or significance is unclear. Conclusions: more than 50% of autistic children appear to have GI symptoms, food allergies, and maldigestion or malabsorption issues. We need large, evidence-based studies need to be done in order to fully understand the gut-brain association in autism.

Krigsman, A, et al: Preliminary data presented at congressional hearing. 2002 Jun.

Summary:

New York University School of  Medicine: www.med.nyu.edu

We examined 43 patients with autism, in whom we demonstrated enterocolitis in 65% and terminal ileal LNH in 90%. As of November, 2002, our total patient population now stands at 82, and the percentages of enterocolitis and LNH are essentially unchanged. Additional studies will follow.

Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2004;(2):CD003498.

Millward C, Ferriter M, Calver S, Connell-Jones G.

BACKGROUND: It has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of persons with autism. If this is the case, diets free of gluten and /or casein should reduce the symptoms associated with autism.

OBJECTIVES: To determine the efficacy of gluten- and/or casein- free diets as an intervention to improve behaviour, cognitive and social functioning in individuals with autism. SEARCH STRATEGY: Electronic searching of abstracts from the Cochrane Library (Issue 3, 2003), PsycINFO (1971- May 2003), EMBASE (1974- May 2003), CINAHL (1982- May 2003), MEDLINE (1986- May 2003), ERIC (1965-2003), LILACS (to 2003) and the specialist register of the Cochrane Complementary Medicine Field (January 2004). Review bibliographies were also examined to identify potential trials. SELECTION CRITERIA: All randomised controlled trials involving programmes which eliminated gluten, casein or both gluten and casein from the diets of individuals diagnosed with autistic spectrum disorder.

DATA COLLECTION AND ANALYSIS: Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. The authors independently selected the relevant studies from the reports identified in this way. As only one trial fitted the inclusion criteria, no meta-analysis is currently possible and data are presented in narrative form.

MAIN RESULTS: The one trial included reported results on four outcomes. Unsurprisingly in such a small-scale study, the results for three of these outcomes (cognitive skills, linguistic ability and motor ability) had wide confidence intervals that spanned the line of nil effect. However, the fourth outcome, reduction in autistic traits, reported a significant beneficial treatment effect for the combined gluten- and casein- free diet. REVIEWERS' CONCLUSIONS: This is an important area of investigation and large scale, good quality randomised controlled trials are needed.

Whiteley P, Shattock P: Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

Abstract:

Autism Research Unit, School of Sciences (Health), University of Sunderland, Sunderland, SR2 7EE, UK. aru@sunderland.ac.uk

Autism is a lifelong condition usually described as affecting social, cognitive and imaginative abilities. For many years, parents and some professionals have observed that in concordance with the behavioural and psychological symptoms of the condition, there are a number of physiological and biochemical correlates which may also be of relevance to the syndrome. One area of interest that encompasses many of these observations is the opioid-excess theory of autism. The main premise of this theory is that autism is the result of a metabolic disorder. Peptides with opioid activity derived from dietary sources, in particular foods that contain gluten and casein, pass through an abnormally permeable intestinal membrane and enter the central nervous system (CNS) to exert an effect on neurotransmission, as well as producing other physiologically-based symptoms. Numerous parents and professionals worldwide have found that removal of these exogenously derived compounds through exclusion diets can produce some amelioration in autistic and related behaviours. There is a surprisingly long history of research accompanying these ideas. The aim of this paper is to review the accompanying evidence in support of this theory and present new directions of intervention as a result of it.

Vojdani A, Campbell AW, Anyanwu E, Kashanian A, Bock K, Vojdani E: Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol 2002 Aug;129(1-2):168-77.

Abstract:

Section of Neuroimmunology, Immunosciences Laboratory, Inc., 8693 Wilshire Boulevard, Suite 200, Beverly Hills, CA 90211, USA. immunsci@ix.netcom.com

We measured autoantibodies against nine different neuron-specific antigens and three cross-reactive peptides in the sera of autistic subjects and healthy controls by means of enzyme-linked immunosorbent assay (ELISA) testing. The antigens were myelin basic protein (MBP), myelin-associated glycoprotein (MAG), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), alpha,beta-crystallin (alpha,beta-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), streptococcal M protein (STM6P) and milk butyrophilin (BTN). Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. These antibodies are specific because immune absorption demonstrated that only neuron-specific antigens or their cross-reactive epitopes could significantly reduce antibody levels. These antibodies may have been synthesized as a result of an alteration in the blood-brain barrier. This barrier promotes access of preexisting T-cells and central nervous system antigens to immunocompetent cells, which may start a vicious cycle. These results suggest a mechanism by which bacterial infections and milk antigens may modulate autoimmune responses in autism.

Knivsberg AM, Reichelt KL, Hoien T, Nodland M: A randomised, controlled study of dietary intervention in autistic syndromes. Nutr Neurosci 2002 Sep;5(4):251-61.

Center for Reading Research, Stavanger University College, Norway. ann-mari.knivsberg@slf.his.no

Abstract:

Impaired social interaction, communication and imaginative skills characterize autistic syndromes. In these syndromes urinary peptide abnormalities, derived from gluten, gliadin, and casein, are reported. They reflect processes with opioid effect. The aim of this single blind study was to evaluate effect of gluten and casein-free diet for children with autistic syndromes and urinary peptide abnormalities. A randomly selected diet and control group with 10 children in each group participated. Observations and tests were done before and after a period of 1 year. The development for the group of children on diet was significantly better than for the controls.

Kidd PM.: Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base. Altern Med Rev. 2002 Aug;7(4):292-316.

Kidd PM.: Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99.

Hadjivassiliou M, Grunewald RA, Davies-Jones GA: Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry. 2002 May;72(5):560-3. [No abstract available]

Hadjivassiliou M, Boscolo S, Davies-Jones GA, Grunewald RA, Not T, Sanders DS, Simpson JE, Tongiorgi E, Williamson CA, Woodroofe NM: The humoral response in the pathogenesis of gluten ataxia. Neurology 2002 Apr 23;58(8):1221-6.

Abstract: Department of Clinical Neurology, The Royal Hallamshire Hospital, Sheffield, UK. m.hadjivassiliou@sheffield.ac.uk

OBJECTIVE: To characterize humoral response to cerebellum in patients with gluten ataxia. BACKGROUND: Gluten ataxia is a common neurologic manifestation of gluten sensitivity. METHODS: The authors assessed the reactivity of sera from patients with gluten ataxia (13), newly diagnosed patients with celiac disease without neurologic dysfunction (24), patients with other causes of cerebellar degeneration (11), and healthy control subjects (17) using indirect immunocytochemistry on human cerebellar and rat CNS tissue. Cross-reactivity of a commercial IgG antigliadin antibody with human cerebellar tissue also was studied. RESULTS: Sera from 12 of 13 patients with gluten ataxia stained Purkinje cells strongly. Less intense staining was seen in some but not all sera from patients with newly diagnosed celiac disease without neurologic dysfunction. At high dilutions (1:800) staining was seen only with sera from patients with gluten ataxia but not in control subjects. Sera from patients with gluten ataxia also stained some brainstem and cortical neurons in rat CNS tissue. Commercial anti-gliadin antibody stained human Purkinje cells in a similar manner. Adsorption of the antigliadin antibodies using crude gliadin abolished the staining in patients with celiac disease without neurologic dysfunction, but not in those with gluten ataxia. CONCLUSIONS: Patients with gluten ataxia have antibodies against Purkinje cells. Antigliadin antibodies cross-react with epitopes on Purkinje cells.

Garvey J: Diet in autism and associated disorders. J Fam Health Care 2002;12(2):34-8.

Abstract: Royal Free Hospital, London.

A dietitian discusses the theory that peptides with opioid activity may cause or trigger autism. The use of an exclusion diet to treat autism is explained, weighing the potential benefits against some of the practical difficulties of keeping to a strict exclusion diet. The use of nutritional supplements is described. An abnormal gut flora has also been implicated in autism and the use of probiotics and prebiotics in improving the integrity of the gut mucosa is also discussed.

Cornish E: Gluten and casein free diets in autism: a study of the effects on food choice and nutrition. J Hum Nutr Diet 2002 Aug;15(4):261-9.

Abstract: Senior Community Dietitian, Community Nutrition Service, South Derbyshire Community Health NHS Trust, Dar es Salaam, Tanzania.

BACKGROUND: There is growing interest in possible dietary involvement in the aetiology and treatment of Autistic Spectrum Disorders (ASD). Research has focused on the physiological and behavioural effects of dietary change but has not examined the effect of exclusion diets on nutritional intake. AIMS: The aim of this study was to examine whether the removal of major dietary staples placed children with autism at risk of nutrient deficiency and compares their food choice with ASD children not following gluten and/or casein free diets. METHODS: A postal questionnaire was sent to parents of children aged 3-16 years, diagnosed with ASD belonging to the National Autistic Society in Leicestershire and southern Derbyshire. Detailed dietary information and a 3-day food diary were collected. The sample size was small: those using gluten/casein free diets (n = 8) and those not following diet (n = 29). RESULTS: Nutrient intakes fell below the Lower Reference Nutrient Intake (LRNI) in 12 children (32%) for zinc, calcium, iron, vitamin A, vitamin B12 and riboflavin in the nondiet group and four children (50%) for zinc and calcium in the diet group. Fruit and vegetable intakes were higher and cereal, bread and potato consumption were lower in those children using gluten and/or casein free diets. CONCLUSION: No significant differences in the energy, protein and micronutrient intakes were found between the two groups of children. A longitudinal prospective study is suggested to examine whether differences in food choice are the result of dietary intervention or the prerequisite for the successful application of diet in this special group of children.

Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'Leary JJ, Murch SH: Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther. 2002 Apr;16(4):663-74.

Inflammatory Bowel Disease Study Group, Centre for Gastroenterology, Department of Medicine, Royal Free and University College Medical School, London, UK. wakers@aol.com

There is growing awareness that primary gastrointestinal pathology may play an important role in the inception and clinical expression of some childhood developmental disorders, including autism. In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical and immunological abnormalities. The gut-brain axis is central to certain encephalopathies of extra-cranial origin, hepatic encephalopathy being the best characterized. Commonalities in the clinical characteristics of hepatic encephalopathy and a form of autism associated with developmental regression in an apparently previously normal child, accompanied by immune-mediated gastrointestinal pathology, have led to the proposal that there may be analogous mechanisms of toxic encephalopathy in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and there is evidence that opioid peptides may mediate certain aspects of the respective syndromes. The generation of plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extra-cranial origin. Therapeutic targets for this autistic phenotype may include: modification of diet and entero-colonic microbial milieu in order to reduce toxin substrates, improve nutritional status and modify mucosal immunity; anti-inflammatory/immunomodulatory therapy; and specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut.

 

Knivsberg AM, Reichelt KL, Nodland M: Reports on dietary intervention in autistic disorders. Nutr Neurosci 2001;4(1):25-37.

Center for Reading Research, Stavanger College, Norway. ann-mari.knivsberg@slf.his.no

Abstract:

Autism is a developmental disorder for which no cure currently exists. Gluten and/or casein free diet has been implemented to reduce autistic behaviour, in addition to special education, since early in the eighties. Over the last twelve years various studies on this dietary intervention have been published in addition to anecdotal, parental reports. The scientific studies include both groups of participants as well as single cases, and beneficial results are reported in all, but one study. While some studies are based on urinary peptide abnormalities, others are not. The reported results are, however, more or less identical; reduction of autistic behaviour, increased social and communicative skills, and reappearance of autistic traits after the diet has been broken.

 

Hadjivassiliou M, Grunewald RA, Lawden M, Davies-Jones GA, Powell T, Smith CM: Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology 2001 Feb 13;56(3):385-8.

Abstract: Department of Clinical Neurology, The Royal HallamshireHospital, Sheffield,UK. m.hadjivassiliou@sheffield.ac.uk

The authors describe 10 patients with gluten sensitivity and abnormal MRI. All experienced episodic headache, six had unsteadiness, and four had gait ataxia. MRI abnormalities varied from confluent areas of high signal throughout the white matter to foci of high signal scattered in both hemispheres. Symptomatic response to gluten-free diet was seen in nine patients.

Dubynin VA , Ivleva IuA, Malinovskaia IV, Kamenskii AA, Andreeva LA, Alfeeva LIu, Miasoedov NF: Changes in beta-casomorphine-7 effect on behavior of albino rat pups in postnatal development [Article in Russian]. Zh Vyssh Nerv Deiat Im I P Pavlova 2001 May-Jun;51(3):386-9.

Abstract: Lomonosov State University, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow.

The analgetic effect of heptapeptide beta-casomorphine-7 in newborn albino rats (20 mg/kg, i.p.) was recorded already 14 days after birth in the "hot plate" test. The first signs of a possible influence of the peptide on motor activity were observed only at the age of 28 days. They are expressed in impairment of motor coordination and change in locomotion level ("Opto-Varimex" test). The obtained evidence probably reflect the processes of discrete maturation of different components of the opioid system of the rat brain.

Furlano RI, Anthony A, Day R, Brown A, McGarvey L, Thomson MA, Davies SE, Berelowitz M, Forbes A, Wakefield AJ, Walker-Smith JA, Murch SH: Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr. 2001 Mar;138(3):366-72.

University Department of Paediatric Gastroenterology, the Inflammatory Bowel Diseases Study Group, Royal Free and University College School of Medicine, London, United Kingdom.

OBJECTIVES: We have reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism. The aims of this study were to characterize this lesion and determine whether LNH is specific for autism. METHODS: Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms. Blinded comparison was made with 8 children with histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn's disease, and 14 with ulcerative colitis. Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness. RESULTS: Histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal gamma delta cell density were significantly increased above those of all other groups including patients with inflammatory bowel disease. CD8(+) density and intraepithelial lymphocyte numbers were higher than those in the Crohn's disease, LNH, and normal control groups; and CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups. Epithelial, but not lamina propria, glycosaminoglycans were disrupted. However, the epithelium was HLA-DR(-), suggesting a predominantly T(H)2 response. INTERPRETATION: Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism.

Cavataio F, Carroccio A, Iacono G.: Milk-induced reflux in infants less than one year of age. J Pediatr Gastroenterol Nutr 2000;30 Suppl:S36-44

Abstract: 1st Divisione Pediatria, Gastroenterologia, Ospedale dei Bambini G. Di Cristina, Palermo, Italy.

Cow's milk allergy (CMA) and gastroesophageal reflux are considered to be among the most common disturbances in infants less than 1 year of age. In recent years, the relationship existing between these two entities has been investigated and some important conclusions have been reached: In just under half the cases of GER in infants less than 1 year of age there is an association with CMA; in a high proportion of cases, GER is not only CMA-associated but also CMA-induced; the frequency of this association should induce pediatricians to screen for possible concomitant CMA in all infants with GER less than 1 year old; with the exception of some patients with mild typical CMA manifestations (diarrhea, dermatitis, or rhinitis), the symptoms of GER associated with CMA are the same as those observed in primary GER; immunologic tests are useful in a suspected association between GER and CMA; and subjects with GER secondary to CMA show a typical pH-monitoring tracing pattern, characterized by a progressive, slow decrease in esophageal pH between feedings. This article reviews the main features of the two diseases, stressing the aspects in common between them and comments on all the listed points.

NOTE: Reflux appears to be common in infants later diagnosed with autism.

Carroccio A, Montalto G, Custro N, Notarbartolo A, Cavataio F, D'Amico D, Alabrese D, Iacono G: Evidence of very delayed clinical reactions to cow's milk in cow's milk-intolerant patients. Allergy 2000 Jun;55(6):574-9.

Abstract: Internal Medicine, University Hospital of Palermo, Italy.

BACKGROUND: In patients with cow's milk protein intolerance (CMPI), delayed clinical reactions to cow's milk (CM) ingestion may be misdiagnosed if the clinical symptoms are not "classical" and there is a long time lapse between ingestion of CM and the clinical reaction. The aim was to evaluate the clinical outcome of CMPI in a cohort of CM-intolerant children, with particular attention to the occurrence of clinical manifestations beyond 72 h after CM challenge. METHODS: Eighty-six consecutive patients (44 boys, 42 girls) with new CMPI diagnoses were enrolled; median age at diagnosis was 4 months. Patients were followed up for a mean period of 40 months. In all patients, CMPI diagnosis was made on the observation of symptoms, their disappearance after elimination diet, and their reappearance on double-blind CM challenge. At CMPI diagnosis, immunologic tests to demonstrate IgE-mediated hypersensitivity were performed. After 12 months of CM-free diet, CM tolerance was re-evaluated with a CM challenge continued at home for up to 30 days, according to a double-blind, placebo-controlled method. Patients who did not achieve CM tolerance continued a CM-free diet and subsequently underwent yearly CM challenge. RESULTS: The percentages of CMPI patients who became CM-tolerant after 1, 2, and 3 years of CM-free diet were 30%, 54.5%, and 70%, respectively. At the end of the follow-up period, 26/86 subjects showed persistent CMPI; these patients had a higher percentage of positivity of total serum IgE (P<0.05), RAST (P<0.01), and cutaneous prick tests for CM antigens (P<0.001) than all the others. At CMPI diagnosis, all patients had a clinical reaction within 72 h from the beginning of the CM challenge; at the subsequent "cure" challenges, we observed patients who first reacted to CM more than 72 h after ingestion. In total, 10 out of 86 patients showed "very delayed reactions"; in these patients, the mean time between the beginning of CM challenge and the onset of a clinical symptom was 13.3 days (range 4-26 days). The number of "very late reactors" increased from the first to the third of the "cure" CM challenges, performed at yearly intervals. The "very delayed" CMPI manifestations in these subjects were constipation (five cases), wheezing (two cases), dermatitis plus constipation (two cases), and dermatitis alone (one case); in 6/10 patients, the symptoms observed at the "cure challenge" were different from those at CMPI onset. CONCLUSIONS: Very delayed clinical reactions to reintroduction of CM in the diet can occur in CMPI patients; thus, accurate follow-up and frequent outpatient observation in patients with a long history of CMPI are probably more useful and safer than prolonged CM challenge.

Cade R, Privette M, Fregly M, Rowland N, Sun Z, Zele V, Wagemaker H, Edlestein C: Autism and schizophrenia: intestinal disorders. Nutritional Neuroscience 3: 57-72, 2000. [No abstract available]

Pedersen OS, Liu Y, Reichelt KL.: Serotonin uptake stimulating peptide found in plasma of normal individuals and in some autistic urines. J Pept Res 1999 Jun;53(6):641-6

Abstract: Research Institute, University of Oslo, Rikshospitalet, Norway.

We have isolated a tripeptide from normal plasma and autistic urines which stimulates the uptake of serotonin (5-HT) into platelets. This peptide was purified by high-performance liquid chromatography (HPLC) and characterized by sequenation and mass-spectrometry. Synthetic peptide showed co-chromatography with the biological sample in the HPLC systems used. Close to 60% of the autistic children diagnosed using the Diagnostic Statistical Manual III-R had an increased HPLC peak eluting like this peptide in their urines compared with controls.

Ek J, Stensrud M, Reichelt KL.: Gluten-free diet decreases urinary peptide levels in children with celiac disease. J Pediatr Gastroenterol Nutr 1999 Sep;29(3):282-5.

Abstract: Department of Pediatrics, Buskerud Central Hospital, Drammen, Norway.

BACKGROUND: Increased urine secretion of peptides has been found in celiac disease, probably resulting from increased intestinal uptake of peptides caused by damage to the small gut mucosa. METHODS: High-performance liquid chromatography of low-molecular-weight peptides in the urine was performed over 6 months, before and after a gluten-free diet was instituted in children who clinically improved while consuming the diet. RESULTS: A significant decrease of peptide levels was observed in children consuming the gluten-free diet. Certain peptide peaks thought to be gluten related decreased the most after the patients began the diet. CONCLUSIONS: Because the peptides decrease in patients consuming a gluten-free diet, it is reasonable to conclude that such peptides have a mostly dietary origin.

Cade JR et al: Autism and schizophrenia linked to malfunctioning enzyme for milk protein digestion. Autism, Mar 1999.

  • Sun Z, Cade JR, Fregly MJ, Privette RM. Caesomorphine induces Fos-like reactivity in discrete brain regions relevant to schizophrenia and autism. Autism 1999;3:67-84
  • Sun Z, Cade JR. A peptide found in schizophrenia and autism causes behavioral changes in rats. Autism 1999;3:85

Cade JR, Privette RM, Fregly M, Rowland N, Sun Z, Zele V, Wagemaker H Edelstein C: Autism and schizophrenia: Intestinal disorders. Nutritional Neuroscience 1999, 2, 57-72.

Alberti A, Pirrone P, Elia M, Waring RH, Romano C: Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry 1999 Aug 1;46(3):420-4.

Abstract: Department of Pediatrics, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy.

BACKGROUND: Parents of autistic children and autism support groups often report that autistic episodes are exacerbated when the children eat certain foodstuffs such as dairy products, chocolates, wheat, corn sugar, apples, and bananas. The hypothesis that autistic behavior might be related to metabolic dysfunctions has led us to investigate in a group of "low functioning" autistic children and in an age-matched control group each made up of 20 subjects, the sulphation capacity available. METHODS: Utilizing the biochemical characteristics of paracetamol we evaluated by high performance liquid chromatography, the urine paracetamol-sulfate/paracetamol-glucuronide (PS/PG) ratio in all subjects following administration of this drug. RESULTS: The PS/PG ratio in the group of autistic subjects gave a significantly lower results than the control group with p < .00002. CONCLUSIONS: The inability to effectively metabolize certain compounds particularly phenolic amines, toxic for the CNS, could exacerbate the wide spectrum of autistic behavior.

Iacono G, Cavataio F, Montalto G, Florena A, Tumminello M, Soresi M, Notarbartolo A, Carroccio A: Intolerance of cow's milk and chronic constipation in children. New England Journal of Medicine 1998 / 339 (16) / 1100-1104.

Abstract: Divisione di Pediatria, Ospedale G. Di Cristina, Palermo, Italy.

BACKGROUND: Chronic diarrhea is the most common gastrointestinal symptom of intolerance of cow's milk among children. On the basis of a prior open study, we hypothesized that intolerance of cow's milk can also cause severe perianal lesions with pain on defecation and consequent constipation in young children. METHODS: We performed a double-blind, crossover study comparing cow's milk with soy milk in 65 children (age range, 11 to 72 months) with chronic constipation (defined as having one bowel movement every 3 to 15 days). All had been referred to a pediatric gastroenterology clinic and had previously been treated with laxatives without success; 49 had anal fissures and perianal erythema or edema. After 15 days of observation, the patients received cow's milk or soy milk for two weeks. After a one-week washout period, the feedings were reversed. A response was defined as eight or more bowel movements during a treatment period. RESULTS: Forty-four of the 65 children (68 percent) had a response while receiving soy milk. Anal fissures and pain with defecation resolved. None of the children who received cow's milk had a response. In all 44 children with a response, the response was confirmed with a double-blind challenge with cow's milk. Children with a response had a higher frequency of coexistent rhinitis, dermatitis, or bronchospasm than those with no response (11 of 44 children vs. 1 of 21, P=0.05); they were also more likely to have anal fissures and erythema or edema at base line (40 of 44 vs. 9 of 21, P<0.001), evidence of inflammation of the rectal mucosa on biopsy (26 of 44 vs. 5 of 21, P=0.008), and signs of hypersensitivity, such as specific IgE antibodies to cow's-milk antigens (31 of 44 vs. 4 of 21, P<0.001). CONCLUSIONS: In young children, chronic constipation can be a manifestation of intolerance of cow's milk.

Below are some abstracts of research done on the link between dietary issues and autism.

Iacono G, Cavataio F, Montalto G, Soresi M, Notarbartolo A, Carroccio A: Persistent cow's milk protein intolerance in infants: the changing faces of the same disease. Clin Exp Allergy 1998 Jul;28(7):817-23.

Abstract: II Divisione di Pediatria, Ospedale Di Cristina, Universita di Palermo, Italy.

BACKGROUND: Recent research has shown that cow's milk protein intolerance (CMPI) often persists beyond 4 years of age. AIMS: To evaluate the clinical and immunological characteristics of a group of infants with persistent CMPI. PATIENTS AND METHODS: Twelve infants (6 m, 6f) with persistent CMPI were followed up from birth until a median age of 5 years. The patients underwent CMP challenge each year to evaluate CMP-tolerance. As controls we followed 26 infants (12 m, 14 f) with CMPI that resolved within 1-2 years. RESULTS: A family history of atopic disease was found in 10/12 patients with persistent CMPI and in 10/26 controls (P<0.01). Clinical presentation changed over time: at onset symptoms were prevalently gastrointestinal, while at the end of the study there was an increased frequency of wheezing and constipation and a higher frequency of delayed reactions to CMP-challenge than at study commencement (9/12 vs 2/12; P<0.007). 11/12 infants with persistent CMPI and 3/26 controls (P<0.0001) presented multiple food intolerance. During the observation period 9/12 infants with persistent CMPI and 2/26 controls showed atopic disease: asthma, rhinitis, eczema (P < 0.0001). CONCLUSIONS: Persistent CMPI forms are characterized by: (a) considerable importance of familial atopic disease; (b) change in CMPI manifestations over time and more prolonged delay between CMP consumption and manifestation of symptoms; (c) very high frequency of multiple food intolerance and allergic diseases.

Teschemacher, H. et al: Milk protein-derived opioid receptor ligands. Biopolymers. 1997 / 43 (2) / 99-117.

Abstract:

Rudolf-Buchheim-Institut fur Pharmakologie, Justus-Liebig-Universitat, Giessen, Germany.

Milk is mammalian characteristic and is of particular importance for humans: Mother's milk or its substitutes from cows' milk are absolutely essential nutriments for the neonate and cows' milk also represents a basic foodstuff for adults. However, in addition to their well-known nutritive role, milk constituents apparently are also able to carry specific information from the milk producer's to the milk receiver's organism: Thus, a number of milk protein fragments has been shown to behave like opioid receptor ligands able to address opioidergic systems in the adult's or in the neonate's organism. With respect to the proteins, which they are derived off these peptides have been named alpha-casein exorphins or casoxin D (alpha-casein), beta-casomorphins or beta-casorphin (beta-casein), casoxin or casoxin A, B, or C (k-casein), alpha-lactorphins (alpha-lactalbumin), beta-lactorphin (beta-lactoglobulin) or lactoferroxins (lactoferrin). Only casoxins and lactoferroxins display antagonistic properties; the other peptides behave like opioid receptor agonists. Most of the information available so far has been collected about beta-casomorphins. These peptides obviously can be released from beta-casein in the adult's or in the neonate's organism, where they might elicit opioid effects in the frame of a regulatory role as "food hormones". Several synthetic beta-casomorphin derivatives have been shown to be highly specific and potent mu-type opioid receptor ligands which frequently have been used as standard tools in opioid research.

Fukudome, S. et al: Release of opioid peptides, gluten exorphins by the action of pancreatic elastase. FEBS Lett. 1997 / 412 (3) / 475-479.

Abstract: Food Research Laboratory, Nisshin Flour Milling Co. Ltd., Saitama, Japan.

The release of opioid peptides, gluten exorphins A, which have been isolated from the pepsin-thermolysin digest of wheat gluten, with gastrointestinal proteases was examined. High levels of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr) immunoreactive materials were detected in the pepsin-pancreatic elastase digest by a competitive ELISA. From this digest, gluten exorphin A5, B5 and B4 were isolated. This means that these peptides are released in the gastrointestinal tracts after ingestion of wheat gluten. The yield of gluten exorphin A5 in the pepsin-elastase digest was larger than that in the pepsin-thermolysin digest. The gluten exorphin A5 sequence is found 15 times in the primary structure of the high molecular weight glutenin. The region from which gluten exorphin A5 was released by the action of pancreatic elastase was identified using synthetic fragment peptides.

Scifo R, Cioni M, Nicolosi A, Batticane N, Tirolo C, Testa N, Quattropani MC, Morale MC, Gallo F, Marchetti B: Opioid-immune interactions in autism: behavioural and immunological assessment during a double-blind treatment with naltrexone. Ann Ist Super Sanita 1996;32(3):351-9.

Abstract: Servizio di Psichiatria, Istituto OASI per lo Studio del Ritardo Mentale e l'Involuzione Cerebrale, Troina (Enna), Italy.

The emerging concept of opioid peptides as a new class of chemical messengers of the neuroimmune axis and the presence of a number of immunological abnormalities in infantile autism prompted us to correlate biological (hormonal and immunological) determinations and behavioural performances during treatment with the potent opiate antagonist, naltrexone (NAL). Twelve autistic patients ranging from7 to 15 years, diagnosed according to DSM-III-R, entered a double-blind crossover study with NAL at the doses of 0.5, 1.0 and 1.5 mg/kg every 48 hours. The behavioural evaluation was conducted using the specific BSE and CARS rating scales NAL treatment produced a significant reduction of the autistic symptomatology in seven ("responders") out of 12 children. The behavioural improvement was accompanied by alterations in the distribution of the major lymphocyte subsets, with a significant increase of the T-helper-inducers (CD4+CD8-) and a significant reduction of the T-cytotoxic-suppressor (CD4-CD8+) resulting in a normalization of the CD4/CD8 ratio. Changes in natural killer cells and activity were inversely related to plasma beta-endorphin levels. It is suggested that the mechanisms underlying opioid-immune interactions are altered in this population of autistic children and that an immunological screening may have prognostic value for the pharmacological therapy with opiate antagonists.

Hadjivassiliou M, Gibson A, Davies-Jones GA , Lobo AJ, Stephenson TJ, Milford-Ward A: Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996 Feb 10;347(8998):369-71.

Abstract:Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK.

BACKGROUND: Antigliadin antibodies are a marker of untreated coeliac disease but can also be found in individuals with normal small-bowel mucosa. Because neurological dysfunction is a known complication of coeliac disease we have investigated the frequency of antigliadin antibodies, as a measure of cryptic gluten sensitivity, and coeliac disease in neurological patients. METHODS: Using ELISA, we estimated serum IgG and IgA antigliadin antibodies in 147 neurological patients who were divided into two groups. There were 53 patients with neurological dysfunction of unknown cause despite full investigation (25 ataxia, 20 peripheral neuropathy, 5 mononeuritis multiplex, 4 myopathy, 3 motor neuropathy, 2 myelopathy). The remaining 94 patients were found to have a specific neurological diagnosis (16 stroke, 12 multiple sclerosis, 10 Parkinson's disease, 56 other diagnoses) and formed the neurological control group. 50 healthy blood donors formed a third group. FINDINGS: The proportions of individuals with positive titres for antigliadin antibodies in the three groups were 30/53, 5/94, and 6/50 respectively (57, 5, and 12%). The difference in proportion between group 1 and the combined control groups was 0.49 (95% CI 0.35-0.63). Distal duodenal biopsies in 26 out of 30 antigliadin-positive patients from group 1 revealed histological evidence of coeliac disease in nine (35%), non-specific duodenitis in ten (38%), and no lesion in seven (26%) individuals. INTERPRETATION: Our data suggest that gluten sensitivity is common in patients with neurological disease of unknown cause and may have aetiological significance.

D'Eufemia P., Celli M., Finocchiaro R., Pacifico L., Viozzi L., Zaccagnini M., Cardi E., Giardini O: Abnormal Intestinal Permeability in Children with Autism. Acta Paediatrica,1996; 85: 1076-1079.

Abstract: Institute ofPediatrics, La Sapienza University of Rome, Italy.

We determined the occurrence of gut mucosal damage using the intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders. An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls. Compared to the controls, these nine patients showed a similar mean mannitol recovery, but a significantly higher mean lactulose recovery (1.64% +/- 1.43 vs 0.38% +/- 0.14; P < 0.001). We speculate that an altered intestinal permeability could represent a possible mechanism for the increased passage through the gut mucosa of peptides derived from foods with subsequent behavioural abnormalities.

Lucarelli, S., Frediani, T., Zingoni, A.M., Ferruzzi, F.,Giardini, O., Quintieri, F., Barbato, M., D'Eufemia, P., Cardi, E.: Food allergy and infantile autism, Panminerva Med., 1995 Sep; 37(3): 137-41.

Abstract: Department of Paediatrics, University of Rome La Sapienza, Italy.

The etiopathogenesis of infantile autism is still unknown. Recently some authors have suggested that food peptides might be able to determine toxic effects at the level of the central nervous system by interacting with neurotransmitters. In fact a worsening of neurological symptoms has been reported in autistic patients after the consumption of milk and wheat. The aim of the present study has been to verify the efficacy of a cow's milk free diet (or other foods which gave a positive result after a skin test) in 36 autistic patients. We also looked for immunological signs of food allergy in autistic patients on a free choice diet. We noticed a marked improvement in the behavioural symptoms of patients after a period of 8 weeks on an elimination diet and we found high levels of IgA antigen specific antibodies for casein, lactalbumin and beta-lactoglobulin and IgG and IgM for casein. The levels of these antibodies were significantly higher than those of a control group which consisted of 20 healthy children. Our results lead us to hypothesise a relationship between food allergy and infantile autism as has already been suggested for other disturbances of the central nervous system.

Lensing P, Schimke H, Klimesch W, Pap V, Szemes G, Klingler D, Panksepp J: Clinical case report: opiate antagonist and event-related desynchronization in 2 autistic boys. Neuropsychobiology 1995;31(1):16-23.

Abstract: Department of Physiological Psychology, University of Salzburg, Austria.

Event-related desynchronization and visual orientational behavior were examined in 2 autistic boys to determine if blockade of endogenous opioid activity facilitates cognitive processing at a cortical level. Before naltrexone, the boys showed no selective alpha blocking during exposure to either mother's pictures or white light. Unlike normals, they exhibited strong alpha band enhancement at temporocentral recording sites. Two hours after administering 0.5 mg/kg naltrexone, mother-as well as light-related alpha blocking appeared at occipital, occipitotemporal, and prefrontal sites. These effects were gone 24 h after dosing in one child, but persisted in the other. A parallel increase in visual pursuit in a social context was observed. These results affirm that autistic gaze aversion can be caused by excessive opioid activity interfering with corticothalamocortical processing of visual stimuli.

Kurek M, Czerwionka-Szaflarska M, Doroszewska G: Pseudoallergic skin reactions to opiate sequences of bovine casein in healthy children. Rocz Akad Med Bialymst 1995;40(3):480-5.

Abstract: Department of Gastroenterology, Academy of Medicine, Gdansk.

Skin tests with opioid peptides naturally occurring in cow's milk: beta-casomorphin-7 and alpha-casein (90-95), were performed in 25 healthy children. Wheal and flare reactions, similiar to histamine and codeine were observed in all children. The area of these reactions was concentration dependent. Pretreatment with H1 antagonist--cetirizine significantly inhibited the skin response to both peptides. Beta-casomorphin-7 and alpha-casein (90-95) are noncytotoxic histamine releasers in humans.

Knivbserg A.M., Reichelt K.L., Nodland M., Hoien T.: Autistic syndromes and diet. A four year follow-up study. Scand J Educat. Res. 1995, 39: 223-236.

Abstract: Dietary intervention was applied to 15 subjects with autistic syndromes, with pathological urine patterns, and increased levels of peptides found in their twenty-four-hour urine samples. The peptides, some of which are probably derived from gluten and casein, are thought to have a negative pharmacological effect on attention, brain maturation, social interaction and learning. Our hypothesis was that a diet without these proteins would facilitate learning. Social behaviour, as well as cognitive and communicative skills, were assessed before diet. The subjects were closely followed for a year, after which their urine was retested blind, and the assessment of behaviors and skills was repeated. Further retesting was made four years after the onset of dietary intervention. Normalization of urine patterns and peptide levels was found after one year. Likewise, a decrease in odd behaviour and an improvement in the use of social, cognitive and communicative skills were registered. This positive development continued through the next three years, though at a lower rate. These promising results encourage further research on the effect of dietary intervention.

Bouvard MP, Leboyer M, Launay JM, Recasens C, Plumet MH, Waller-Perotte D, Tabuteau F, Bondoux D, Dugas M, Lensing P, et al: Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res 1995 Oct 16;58(3):191-201.

Abstract: Service de Psychopathologie de l'Enfant et de l'Adolescent, Hopital Robert Debre, Paris, France.

The effect of month-long naltrexone (NTX) treatment at a daily oral dose of 0.5 mg/kg/day was contrasted with placebo (PLC) in a double-blind study with conjoint clinical and biochemical evaluations of therapeutic effects. Modest clinical benefits were achieved with both PLC and NTX, with marginally better overall results following NTX, and degree of improvement appeared to be related to plasma chemical profiles. Massively elevated levels of beta-endorphin were observed in all children with assays using C-terminal antibody but not with an N-terminal antibody assay. In addition, 70% of the children exhibited abnormally low levels of adrenocorticotropic hormone, and smaller subsets exhibited elevated norepinephrine (60%), arginine-vasopressin (50%), and serotonin (20%). The best clinical responders exhibited the clearest normalization of the elevated plasma chemistries, especially in C-terminal-beta-endorphin and serotonin. There was some evidence of therapeutic carry-over effects in both clinical and biochemical measures in those children who received NTX before PLC. The results suggest that NTX only benefits a subgroup of autistic children, who may be identified by the presence of certain plasma abnormalities. These results suggest a possible linkage between abnormal plasma chemistries, especially those related to the pro-opiomelanocortin system, and autistic symptoms.

Reichelt K.L. Knivsberg AM, Nodland M, Lind G: Nature and consequences of hyperpeptiduria and bovine casomorphin found in autistic syndromes. Develop Brain Dysfunct. 1994, 7: 71-85. [No abstract available]

Gardner M.L.G.: Absorption of intact proteins and peptides. Physiol of gastrointestinal Tract 3rd edit (edit: LR Johnson) Raven press, New York 1994: 1795-1820.

Leboyer M, Bouvard MP, Launay JM, Recasens C, Plumet MH, Waller-Perotte D, Tabuteau F, Bondoux D, Dugas M: Opiate hypothesis in infantile autism? Therapeutic trials with naltrexone [Article in French]. Encephale 1993 Mar-Apr;19(2):95-102.

Abstract: Service de Psychiatrie Adulte, Hopital Pitie-Salpetriere, Paris.

The opioid hypothesis suggests that childhood autism may result from excessive brain opioid activity during neonatal period which may constitutionally inhibit social motivation, yielding autistic isolation and aloofness (Panksepp, 1979). This hypothesis has now received strong support and is currently based on three types of arguments: (1) similarity between autistic symptomatology and abnormal behaviors induced in young animals by injections of exogenous opioids, such as increasing social aloofness and decreasing social vocalization; (2) direct biochemical evidence of abnormalities of peripheral endogenous opioids being reported in autism and (3) therapeutic effects of the long lasting opioid receptor blocking agent naltrexone in autism. In this article, we give description of open and double-blind studies of naltrexone in autism. Naltrexone has been tested in several open studies. We performed an open trial with naltrexone in 2 autistic girls, displaying serious self-injurious behavior, reduced crying and a marked preference for salty and spicy foods, symptoms that could be related to a dysfunction of the opioid system. With dosages of 1 mg/kg/day, we observed an immediate reduction of hyperactivity, self-injurious behavior and aggressiveness, while attention improved. In addition, social behaviors, smiling, social seeking behaviors and play interactions increased (Leboyer, Bouvard et Dugas, 1988). Campbell et al. (1988) has also reported a tranquilizing and a stimulating effect in 6 out of 8 children with autism. We did confirm these preliminary results in a double-blind study performed on 4 children with autism. In a cross-over double-blind study, three dosages of naltrexone (0.5, 1 and 2 mg/kg/day) and placebo were compared. (ABSTRACT TRUNCATED AT 250 WORDS)

Fukudome S, Yoshikawa M: Gluten exorphin C, A novel opioid peptide derived from wheat gluten. FEBS 1993; 316: 17-19.

Abstract: Research Control Department, Nisshin Flour Milling Co., Ltd., Nihonbashi, Tokyo, Japan.

A novel opioid peptide, Tyr-Pro-Ile-Ser-Leu, was isolated from the pepsin-trypsin-chymotrypsin digest of wheat gluten. Its IC50 values were 40 microM and 13.5 microM in the GPI and MVD assays, respectively. This peptide was named gluten exorphin C. Gluten exorphin C had a structure quite different from any of the endogenous and exogenous opioid peptides ever reported in that the N terminal Tyr was the only aromatic amino acid. The analogs containing Tyr-Pro-X-Ser-Leu were synthesized to study its structure-activity relationship. Peptides in which X was an aromatic amino acid or an aliphatic hydrophobic amino acid had opioid activity.

Bidet B, Leboyer M, Descours B, Bouvard MP, Benveniste J: Allergic sensitization in infantile autism. J Autism Dev Disord 1993 Jun;23(2):419-20. [No abstract available.]

McLaughlin P.J., Zagon I.S.: Endogenous opiod systems and clinical implications for infantile autism. Proceedings of the International Symposium on Neurobiology of Infantile Autism, Tokyo , 1990, Neurobiology of Infantile Autism, Excerpta Medica 1992.

Lensing P, Klingler D, Lampl C, Leboyer M, Bouvard M, Plumet MH, Panksepp J: Naltrexone open trial with a 5-year-old-boy. A social rebound reaction. Acta Paedopsychiatr 1992;55(3):169-73.

Abstract: School Psychology of Upper Austria, Linz.

The neurobiological rationale for an opiate antagonist pharmacotherapy of autism is presented. Naltrexone efficacy in decreasing autistic behaviour and in increasing social-affiliative behaviour was explored in a 5-year-old autistic boy. Naltrexone (0.5 mg/kg 3 times peer week) was effective in immediately decreasing gross motor activity and stereotyped behaviour and caused a delayed increase of crying, smiling and rough-and-tumble play. This single case presents preliminary evidence that a therapeutically valuable rebound reaction is possible and that the human opioid system modulates social-affective processes. The possibility of psychological factors being instrumental in achieving this effect is discussed as being suitable for future clinical trials.

Kurek M, Przybilla B, Hermann K, Ring J: A naturally occurring opioid peptide from cow's milk, beta-casomorphine-7, is a direct histamine releaser in man. Int Arch Allergy Immunol 1992;97(2):115-20.

Abstract: Department of Dermatology, Ludwig-Maximilian-University, Munich.

beta-Casomorphine-7, a naturally occurring product of cow's milk with opiate-like activity, was studied for possible direct histamine liberation activities in humans. It was found to cause concentration-dependent in vitro histamine release from peripheral leukocytes of healthy adult volunteers. Intradermal injection of beta-casomorphine-7 induced a wheal and flare reaction in the skin similar to histamine or codeine. Oral pretreatment with the H1 antagonist terfenadine significantly inhibited the skin responses to beta-casomorphine-7. The intradermal injection of an opiate receptor antagonist, naloxone, inhibited in vitro histamine release and skin reactions only in a 100-fold excess over beta-casomorphine-7. These findings suggest that beta-casomorphine-7 can be regarded as a noncytotoxic, direct histamine releaser in humans. The clinical relevance of these findings deserves further studies.

Fukudome S, Yoshikawa M: Opioid peptides derived from wheat gluten: their isolation and characterization. Federation of European Biochemical Societies (FEBS) 1992; 296: 107-111.

Abstract:Research Control Department, Nisshin Flour Milling Co., Ltd., Tokyo, Japan.

Four opioid peptides were isolated from the enzymatic digest of wheat gluten. Their structures were Gly-Tyr-Tyr-Pro-Thr, Gly-Tyr-Tyr-Pro,Tyr-Gly-Gly-Trp-Leu and Tyr-Gly-Gly-Trp, which were named gluten exorphins A5, A4, B5 and B4, respectively. The gluten exorphin A5 sequence was found at 15 sites in the primary structure of the high molecular weight glutenin and was highly specific for delta-receptors. The structure-activity relationships of gluten exorphins A were unique in that the presence of Gly at their N-termini increased their activities. Gluten exorphin B5, which corresponds to [Trp4,Leu5]enkephalin, showed the most potent activity among these peptides. Its IC50 values were 0.05 microM and 0.017 microM, respectively, on the GPI and the MVD assays.

Dubynin VA, Maklakova AS, Nezavibat'ko VN, Alfeeva LA, Kamenskii AA, Ashmarin IP: Effects of systemically-administered beta-casomorphin-7 on nociception in rats. [Article in Russian] Biull Eksp Biol Med 1992 Sep;114(9):284-6.

Abstract: The influence of food-derived heptapeptide beta-casomorphin-7 (beta-CM-7) on pain sensibility of white rats was studied by tail flick test. As shown for doses 10 and 20 mg/kg intraperitoneally, injected beta-CM-7 induced significant analgesia; lower peptide concentration (5 mg/kg) was ineffective. As a whole, there is a significant positive correlation between the intensity of analgesia and the quantity of administered exorphine. These changes of pain sensibility were observed for one hour after injection of heptapeptide; further measurements showed no significant difference of time reaction between control and experimental groups of rats. It was found out that animals with high native level of pain sensibility (4-8 sec) made the main contribution to manifestation of analgesia.

Bouvard M.P., Leboyer M., Launay J.M., Kerdelhue B., Dugas M.: The opiod excess hypothesis of autism: A double-blind study of naltrexone. Proc. of the Intern. Symp. on Neurob. of Inf. Autism, 1990, Neurobiology of Infantile Autism, Exerpta Medica 1992.

Teschemacher H, Koch G: Opioids in the milk. Endocr Regul 1991 Sep;25(3):147-50.

Abstract: Rudolf-Buchheim-Institut fur Pharmakologie, Justus-Liebig-Universitat Giessen, Germany.

In various studies, the milk has been screened for the presence of free or precursor-bound opioids. In fact, various opioid receptor ligands with agonistic or even antagonistic activity were found. Besides the alkaloid morphine, peptides derived from alpha-casein (alpha-casein exorphins), beta-casein (beta-casomorphins; beta-casorphin), alpha-lactalbumin (alpha-lactorphins) and beta-lactoglobulin (beta-lactorphin) were among the agonists. In addition, certain peptides derived from k-casein (casoxins) or from lactoferrin (lactoferroxins) were found to behave like opioid antagonists. Although a functional role in the mammalian organism for all of these compounds appears to be well possible, evidence has only been presented for the functional significance of beta-casomorphins, so far. These peptides might play a role in reproduction or nutrition in the female, in the newborn's or in a milk consumer's organism, respectively. Thus, opioids related to milk might represent essential exogenous extensions of the endogenous opiodergic systems.

Risebro, B.: Gluten-free diet in infantile autism. Tidsskr Nor Laegeforen 1991 Jun 10;111(15):1885-6 [Article in Norwegian]

Reichelt K.L., Knivsberg A.M., Lind G., Nodland M.: The probable etiology and possible treatment of childhood autism. Brain Dysfunct. 1991, 4: 308-319. [No abstract available]

Longoni R, Spina L, Mulas A, Carboni E, Garau L, Melchiorri P, Di Chiara G: (D-Ala2)deltorphin II: D1-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens. J Neurosci 1991 Jun;11(6):1565-76.

Abstract:

Institute of Experimental Pharmacology and Toxicology, University of Cagliari, Italy.

In order to investigate the relative role of central delta- and mu-opioid receptors in behavior, the effects of (D-Ala2)deltorphin II, a natural delta-opioid peptide, and PL017, a beta-casomorphin derivative specific for mu receptors, were compared after local intracerebral and intraventricular administration. Intracerebral infusion of the two peptides was done bilaterally in the limbic nucleus accumbens and in the ventral and dorsal caudate putamen of freely moving rats through chronic intracerebral cannulas. After intra-accumbens infusion, the two peptides elicited marked but opposite behavioral effects: while (D-Ala2)deltorphin II evoked dose-dependent motor stimulation characterized by locomotion, sniffing, and oral stereotypies, PL017 elicited motor inhibition with rigidity and catalepsy. These effects were site specific because they could not be evoked from the ventral or from the dorsal caudate. Low doses of naloxone (0.1 mg/kg, s.c. ) blocked the effects of PL017 but not those of (D-Ala2)deltorphin II, which instead were reduced by high doses of naloxone (1.0 mg/kg) and by the putative delta-antagonist naltrindole; this drug failed to affect the catalepsy induced by PL017. Therefore, while (D-Ala2)deltorphin II effects were delta-mediated, PL017 effects were mu-mediated. Blockade of dopamine D1 receptors by SCH 23390 abolished (D-Ala2)deltorphin II effects, while blockade of dopamine D2 receptors by raclopride or by haloperidol was without effect. Local application by reverse dialysis of (D-Ala2)deltorphin II (5 microM) to the accumbens resulted in a naloxone-sensitive increase of extracellular dopamine concentrations; these effects could not be evoked from the caudate, nor by PL017 in the accumbens. Intracerebroventricular administration of (D-Ala2)deltorphin II or of PL017 elicited behavioral effects qualitatively similar to those obtained from the accumbens.

If deltorphin II is indeed present in the urine, this may explain why low doses of naloxone are often only moderately effective at reducing autistic behaviors.

Fukudome S.-I. and Yoshikawa M.: Opioid peptides derived from wheat gluten: Their isolation and characterization. FEBS Letters 1991, 296: 107-111.

Abstract: Four opioid peptides were isolated from the enzymatic digest of wheat gluten. Their structures were Gly-Tyr-Tyr-Pro-Thr, Gly-Tyr-Tyr-Pro, Tyr-Gly-Gly-Trp-Leu and Tyr-Gly-Gly-Trp, which were named gluten exorphins A5, A4, B5 and B4, respectively. The gluten exorphin A5 sequence was found at 15 sites in the primary structure of the high molecular weight glutenin and was highly specific for delta-receptors. The structure-activity relationships of gluten exorphins A were unique in that the presence of Gly at their N-termini increased their activities. Gluten exorphin B5, which corresponds to [Trp4,Leu5]enkephalin, showed the most potent activity among these peptides. Its IC50 values were 0.05 microM and 0.017 microM, respectively, on the GPI and the MVD assays.

Shattock P. Kennedy A, Rowell F, Berney T: Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunct 1990, 3: 328-346. [No abstract available]

Reichelt K.L., Ekrem J., Scott H.: Gluten, milk proteins and autism: Dietary interventions effects on behavior and peptide secretion. J Appl Nutrition 1990, 42: 1-11. [No abstract available]

Marchetti B, Scifo R, Batticane N, Scapagnini U: Immunological Significance of Opioid Peptide Dysfunction in Infantile Autism. Brain Dysfunction,3: 346-354,1990. [No abstract available]

Leboyer M, Bouvard MP, Lensing P, Launay JM, Tabuteau F, Arnaud P, Waller D, Plumet MH, Recasens C, Kerdelhue B, Dugas M, Panksepp J: Opioid Excess Hypothesis of Autism. Brain Dysfunction 1990; 3: 285-298. [No abstract available]

Knivsberg A.M., Wiig K., Lind G., Nodland M., Reichelt K.L.: Dietary intervention in autistic syndromes. Brain Dysfunc. 1990, 3: 315-327. [No abstract available]

Cade R. et al.: The effects of dialysis and diet in schizophrenia. Psychiatry: A World perspective 1990, 3: 494-500. [No abstract available]

Barthelemy C, Bruneau N, Adrien J, Roux S, Lelord G: Clinical, Biological and Therapeutic Applications of the Functional Analysis of Autistic Disorders. Brain Dysfunction, 3: 271-284, 1990. [No abstract available]

Herrera-Marschitz M, Terenius L, Grehn L, Ungerstedt U: Rotational behaviour produced by intranigral injections of bovine and human beta-casomorphins in rats. Psychopharmacology (Berl) 1989;99(3):357-61.

Abstract: Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.

The biological activity of beta-casein derived beta-casomorphin peptides was evaluated by injecting bovine beta-casomorphin-5 (Tyr-Pro-Phe-Pro-Gly), the homologous sequence in human beta-casein (Tyr-Pro-Phe-Val-Glu) and the corresponding N-terminal tetrapeptides into the left substantia nigra of rats. Their ability to produce rotational behaviour was compared to that produced by three reference compounds, morphine, D-ala2D-leu5 enkephalin and U50,488H, ligands for mu, delta and kappa types of opioid receptors, respectively. The relative potencies of beta-casomorphins and morphine were compared to those tested in two in vitro assays for opioid activity: (1) inhibition of the electrically induced contraction of the isolated myenteric plexus-longitudinal muscle of the guinea-pig ileum and (2) displacement of 3H-dihydromorphine binding to brain membranes. The same ranking order of potency was found in all three assays, the peptides from human beta-casein being about 10-fold less potent than those from bovine beta-casein. The effects of both morphine and bovine beta-casomorphin-5 in producing rotational behaviour were antagonized by naloxone; however, approximately 10-fold more naloxone was required to antagonize the beta-casomorphin-5 effect than that of morphine. The present data are discussed in the light of the recent observation that high concentrations of beta-casomorphin-like peptides are found in the cerebrospinal fluid and plasma of women with postpartum psychosis.

Ramabadran K, Bansinath M: Opioid peptides from milk as a possible cause of sudden infant death syndrome. Med Hypotheses 1988 Nov;27(3):181-7.

Abstract: Department of Anesthesiology, New York University Medical Center, NY 10016.

Milk from breast or baby formula is the exclusive source of nutrition for newborn infants. Short chain opioid peptides such as beta-casomorphins have been isolated from breast milk as well as baby formula. These biologically active peptides are absorbed from the gastrointestinal tract. In infants predisposed to respiratory apnea because of abnormal autonomic nervous system development and respiratory control mechanisms, opioid peptides derived from milk might be one of the etiological factors for sudden infant death syndrome and near miss sudden infant death syndrome.

Paroli E: Opioid Peptides from Food (the Exorphins). World Review of Nutrition and Dietetics 1988; 55: 58-97. [No abstract available]

Hole K. et al.: Attention deficit disorders: A study of peptide-containing urinary complexes. J Develop Behav Pediatrics 1988, 9: 205-212.

Abstract: Department of Physiology, University of Bergen, Norway.

In several behavioral disorders, we have observed that abnormal amounts of peptides and protein-associated peptide complexes are excreted in the urine. The gel filtration patterns of these excreted substances have some specificity for the different disorders. The urinary excretion of peptide-containing complexes was studied in 91 boys and 13 girls (mean age 9.4 years, range 1-23) with the clinical diagnosis of attention deficit disorder (ADD), with or without hyperactivity. The gel filtration of urine precipitate showed patterns in all patients that were different from those seen in 36 normal controls. Sixty-four patients had increased benzoic acid-glycoprotein-peptide complexes in the late peaks. The symptoms of all these patients fit the criteria for diagnosis of attention deficit disorder with hyperactivity (ADDH). Thirty-five patients showed reduced amounts of uric acid complexes in the late peaks. Clinically, this group, with the exception of three patients, fit the criteria for diagnosis of attention deficit disorder without hyperactivity. Five patients showed reduced amounts of all urinary complexes; four of these were hyperactive. Moderate exercise in control children did not change the urinary pattern. One urinary peptide fraction from hyperactive patients, purified to homogeneity, increased the uptake of 14C[5-HT] in platelets. Strict clinical, neuropsychological, and psychophysiological selection of the patients reduced the heterogeneity of the patterns. Although more studies are needed, the findings seem promising for the possibility of developing biochemical tests that may be helpful diagnostically.

Dohan, FC: Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr. Bull. 1988 / 14 (4) / 489-494.

Abstract:Medical College of Pennsylvania, Eastern Pennsylvania, Psychiatric Institute, Philadelphia, 19129.

This brief overview proposes a testable oligogenic model of the inheritance of susceptibility to idiopathic schizophrenia: "abnormal" genes at each of a few complementary loci. The model is based on my assumptions as to the likely genetic abnormalities at possibly four or five interacting loci that would permit exorphins, the opioid peptides from some food proteins, especially glutens and possibly caseins, to go from gut to brain and cause symptoms of schizophrenia. Exorphins may reach the brain cerebrospinal fluid (CSF) in harmful amounts because of their genetically increased, receptor-mediated transcellular passage across the gut epithelial barrier plus decreased catabolism by genetically defective enzymes. A schizophrenia-specific, genetically enhanced affinity for exorphins by opioid receptors influencing dopaminergic and other neurons would permit sustained dysfunction at low CSF exorphin concentrations. Tests of each postulated genetic abnormality are suggested. This model is supported by a variety of evidence, including a significant effect of gluten or its absence on relapsed schizophrenic patients, the high correlation of changes in first admission rates for schizophrenia with changes in grain consumption rates, and the rarity of cases of schizophrenia where grains and milk are rare.

Sahley TL, Panksepp J: Brain opioids and autism: an updated analysis of possible linkages. J Autism Dev Disord 1987 Jun;17(2):201-16.

Abstract:

Considerable clinical evidence suggests that autistic children lack the normal ability or desire to engage others socially, as indicated by their poor social skills and inappropriate use of language for communicative purposes. Specifically, these children seem to lack normal amounts of social-emotional interest in other people, leading perhaps to a decreased initiative to communicate. This paper summarizes experimental evidence supporting a neurological theory, which posits that autism, at least partially, represents in the brain, such as brain opioids. These substances modulate social-emotional processes, and the possibility that blockade of opioid activity in the brain may be therapeutic for early childhood autism is discussed.

Kahn A, Rebuffat E, Blum D, Casimir G, Duchateau J, Mozin MJ, Jost R: Difficulty in initiating and maintaining sleep associated with cow's milk allergy in infants. Sleep 1987 Apr;10(2):116-21.

Abstract: To confirm that sleeplessness in infants can be related to an undiagnosed allergy to cow's milk proteins, 71 infants were studied. Group I consisted of 20 infants referred for chronic insomnia that had appeared in the early days of life. Group II was made up of 31 infants admitted for skin or digestive symptoms attributed to cow's milk intolerance; 13 of these infants were shown to sleep as poorly as the infants of group I. Group III consisted of 20 infants with no history of sleep disturbance or milk allergy. The three groups of infants were comparable for sex and age. Laboratory tests revealed immunologic reactions to milk in all the infants in groups I and II. The sleep of the insomniac infants (group I, and the 13 "poor sleepers" in group II) became normal after cow's milk was eliminated from the diet. Insomnia reappeared when the infants in group I were challenged with milk. We conclude that infants with clinically evident milk allergy may suffer from sleeplessness and that when no evident cause for a chronic insomnia can be found in an infant the possibility of milk allergy should be given serious consideration.

Meisel, H: Chemical characterization and opioid activity of an exorphin isolated from in vivo digests of casein. FEBS Lett. 1986 / 196 (2) / 223-227.

Abstract:

The in vivo formation of an opioid peptide (exorphin) derived from beta-casein has been proved for the first time. It was isolated from duodenal chyme of minipigs after feeding with the milk protein casein. The exorphin has been identified as a beta-casein fragment by end-group determinations and qualitative amino acid analysis of the purified peptide. This peptide, named beta-casomorphin-11, displayed substantial opioid activity in an opiate receptor-binding assay.

Alpers DH: Uptake and fate of absorbed amino acids and peptides in the mammalian intestine. Federation Proc. 1986; 45:2261-2267.

Abstract:Intraluminal and brush-border digestion of proteins results in a mixture of amino acids and small peptides. Thirteen brush-border peptidases have been described. Despite all of these enzymes, some peptides escape digestion and are absorbed intact. The assimilated products of protein digestion can follow multiple paths: absorption into the blood as amino acids or small peptides, metabolism within the enterocyte, incorporation into proteins of the enterocyte, and incorporation into proteins to be secreted into plasma. Unlike other tissues, the intestinal mucosa is not very responsive to metabolic regulation as regards amino acid uptake or regulation of protein synthesis. Most effects after dietary manipulation or drug or hormonal stimulation are modes (two-to fivefold increases). This constitutive metabolism of amino acids in the intestinal mucosa is consistent with its essential role in absorption. The mucosa also is a major contributor to apolipoproteins, which are probably the quantitatively most important proteins secreted from the intestine. Alterations in apoprotein secretion have been noted after fat feeding, and are both transcriptionally and translationally regulated. Although the fractional renewal rate of protein in the intestine is the highest of any tissue in the body, the quantitative importance of alterations in protein synthesis or secretion to the fate of intracellular amino acids is not known.

Svedberg, J.et al: Demonstration of beta-casomorphin immunoreactive materials in in vitro digests of bovine milk and in small intestine contents after bovine milk ingestion in adult humans. Peptides 1985 / 6 / pag.825-830.

Abstract: Healthy young volunteers ingested one liter of cows' milk; then the contents of the small intestine were aspirated through an intestinal tube at various times and assayed for the presence of bovine beta-casomorphin immunoreactive materials. Considerable amounts of beta-casomorphin-7, but no beta-casomorphin-5 and only small amounts of beta-casomorphin-4 or -6 immunoreactive materials were found. Chromatographical characterization showed that most of the beta-casomorphin-7 immunoreactive material was not identical with beta-casomorphin-7, whereas the major part of the beta-casomorphin-4 or -6 immunoreactive materials might be identical with their corresponding beta-casomorphins. Analogous results were obtained for in vitro digestion of bovine milk which had been designed as a rough imitation of the gastrointestinal digestion process. A regulatory influence of beta-casomorphins as "food hormones" on intestinal functions is suggested.

Saelid G, et. al.: Peptide-Containing Fractions in Depression. Biol Psychiatry 1985, 20: 245-256.

Abstract: A mixture of peptides and glycoproteins has been found in benzoic acid-precipitable material from urines of psychomotorically agitated and retarded endogenous depressive patients. This complex mixture of compounds is fractionated on a Sephadex G-25 gel, from which the different peaks are further separated on Biogel P2. The G-25 elution profiles ultraviolet absorbance, 280 nm) from depressive patients deviated from the normal pattern. The increase in hydrolyzable ninhydrin-colorable material of the P2 fractionation step encountered in psychotic depression was several-fold that of the normal population. Neurochemically active peptide-containing fractions were found. As explanation of these findings, it is probable that a genetically determined peptidase insufficiency is present, causing a peptide overflow when the secretion outstrips the breakdown. This model could easily combine more psychodynamic models with the genetic-biological models. The variability of the peptide patterns could possibly reflect the considerable clinical variability of the syndrome. Furthermore, the presence of a group of active compounds with different neuropharmacological activities might reflect the composite nature of the depressive syndrome.

Rix KJ, Ditchfield J, Freed DL, Goldberg DP, Hillier VF: Food antibodies in acute psychoses. Psychol Med 1985 May;15(2):347-54.

Abstract: Antibodies to a variety of foods, and in particular cereals, were measured in serum from 100 patients with acute psychoses and 100 elective surgical patients. For 13 out of 14 foods to which non-IgE antibodies were detected the schizophrenics had slightly more antibodies than the controls. There was an association between a possible secondary mania and the presence of IgE antibodies to wheat or rye. However, neither the schizophrenia nor the mania findings can be regarded as evidence for food allergy causing psychiatric disorder, since the immunological findings in both cases may represent consequences of the illnesses or their treatment, rather than causes of the illness.

Chang, KJ, Su YF, Brent DA, Chang JK: Isolation of a specific mu-opiate receptor peptide, morphiceptin, from an enzymatic digest of milk proteins. J. Biol. Chem. 1985 / 260 (17) / pag. 9706-9712.

Abstract: Specific radioimmunoassays have been developed for the measurement of naturally occurring morphiceptin and beta-casomorphin. These peptides and related exorphins were isolated from an enzymatic digest of caseins by chromatographic techniques including gel filtration, hydrophobic column and multiple-step high pressure liquid chromatography. Three exorphins were purified and characterized in their radioimmunological, biological, and chemical properties. They were identified as morphiceptin, beta-casomorphin, and 8-prolyl-beta-casomorphin. Since morphiceptin is a highly specific mu-agonist and can be derived from a milk protein, it is possible that morphiceptin is an exogenous opioid ligand specific for mu-receptors in the brain and gastrointestinal tract.

Takahashi M, Fukunaga H, Kaneto H, Fukudome S, Yoshikawa M: Behavioral and pharmacological studies on gluten exorphin A5, a newly isolated bioactive food protein fragment, in mice. Jpn J Pharmacol 2000 Nov;1984(3):259-65.

Abstract: Department of Pharmacoinformatics, School of Pharmaceutical Sciences, Nagasaki University, Japan. takahashi@net.nagasaki-u.ac.jp

Central effects of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr), a fragment from wheat gluten, were studied on the pain-inhibitory system, emotionality and learning/memory processes in mice. Orally administered gluten exorphin A5 produced neither an antinociceptive effect nor an effect on morphine analgesia. Intracerebroventricularly (i.c.v.) administered gluten exorphin A5 produced mild but significant antinociception in a dose-depepndent manner, while not affecting the morphine analgesia. On the other hand, oral gluten exorphin A5 suppressed the endogenous pain-inhibitory system, i.e., antinociception induced by socio-psychological- (PSY-) stress (SIA) using a communication box; intraperitoneal gluten exorphin A5 abolished both footshock- (FS-) stress-induced antinociception (SIA) and PSY-SIA; and i.c.v. gluten exorphin A5 suppressed FS-SIA, but rather potentiated PSY-SIA. This peptide given by these routes was without effect on forced swim-SIA. In addition, oral gluten exorphin A5 tended to prolong the retention time on open arms in the elevated plus-maze test. Finally, oral gluten exorphin A5 when given during the post-training period of learning/memory processes significantly increased the latency into the dark compartment in the one-trail step-though type passive avoidance test, indicating that the peptide also facilitates the acquire/consolidation process of learning/memory. Thus, gluten exorphin A5 has been found to produce various effects not only in the peripheral nervous systems but also in the central nervous system.

Pfeiffer CC: Schizophrenia and wheat gluten enteropathy. Biol Psychiatry 1984 Mar;19(3):279-80. [No abstract available]

Lindstrom LH, Nyberg F, Terenius L, Bauer K, Besev G, Gunne LM, Lyrenas S, Willdeck-Lund G, Lindberg B: (1984) CSF and plasma beta-casomorphin-like opioid peptides in post-partum psychosis. Amer. J. Psychiat. 1984, 141: 1059-1066.

Abstract:

The authors measured opioid receptor-active components in the CSF of 11 women with postpartum psychosis, 11 healthy lactating women, and 16 healthy women who were not lactating. Activity that eluted with 0.2 M acetic acid 0.7-0.9 times the total volume of the column (fraction II activity) was significantly higher in the CSF of both healthy and psychotic women in the puerperium than in that of the lactating women. Very high levels of fraction II activity were seen in four psychotic patients. Material from these patients was further characterized by electrophoresis and high-performance liquid chromatography: The material migrated as bovine beta-casomorphin. Receptor-active material with the same characteristics was also found in the plasma of these four patients. The authors conclude that certain cases of postpartum psychosis are associated with the occurrence in plasma and CSF of unique opioid peptides probably related to bovine beta-casomorphin.

Huebner FR, Lieberman KW, Rubino RP, Wall JS: Demonstration of high opioid-like activity in isolated peptides from wheat gluten hydrolysates. Peptides 1984 Nov-Dec;5(6):1139-47.

Abstract: Because of a possible relationship between schizophrenia and celiac disease, a condition in some individuals who are sensitive to wheat gluten proteins in the diet, there has been interest in observations that peptides derived from wheat gluten proteins exhibit opioid-like activity in in vitro tests. To determine the origin of the peptides exhibiting opioid activity, wheat proteins were fractionated by size (gel filtration), by charge differences (ion exchange chromatography) and by differences in hydrophobicity (reversed-phase HPLC). These fractions were hydrolyzed by pepsin or pepsin and trypsin and the resulting peptides separated by gel filtration chromatography. The separated peptides were tested for opioid-like activity by competitive binding to opioid receptor sites in rat brain tissue in the presence of tritium-labeled dihydromorphine. The peptides showed considerable differences in activity; while some peptides exhibited no activity, 0.5 mg of the most active peptides were equivalent to 1 nM of morphine in the binding assay. The most active peptides were derived from the gliadin fraction of the gluten complex.

Dohan et. al: "Is Schizophrenia Rare if Grain is Rare?" Biol Psychiat 1984; 19(3): 385-399.

Abstract: If, as hypothesized, neuroactive peptides from grain glutens are the major agents evoking schizophrenia in those with the genotype(s), it should be rare if grain is rare. To test this, we analyzed the results of our clinical examinations (e.g., kuru) and observations of anthropologists on peoples consuming little or no grain. Only two overtly insane chronic schizophrenics were found among over 65,000 examined or closely observed adults in remote regions of Papua New Guinea (PNG, 1950-1967) and Malaita, Solomon Islands (1980-1981), and on Yap, Micronesia (1947-1948). In preneuroleptic Europe over 130 would have been expected. When these peoples became partially westernized and consumed wheat, barley beer, and rice, the prevalence reached European levels. Our findings agree with previous epidemiologic and experimental results indicating that grain glutens are harmful to schizophrenics.

Loukas, S. et al: Opioid activities and structures of alpha-casein-derived exorphins. Biochemistry 1983 / 22 (19) / 4567-4573.

Gardner MLG: Evidence for, and implications of, passage of intact peptides across the intestinal mucosa. Biochemical Society Transactions 1983; 11: 810-812. [no abstract available]

Morley, JE: Food peptides. A new class of hormones? J. Am. Med. Assoc. 1982 / 247 (17) / 2379-2380. [No abstract available]

Reichelt KL, Hole K, Hamberger A, Saelid G, Edminson PD, Braestrup CB, Lingjaerde O, Ledaal P, Orbeck H: Biologically active peptide-containing fractions in schizophrenia and childhood autism. Adv Biochem Psychopharmacol 1981; 28: 627-643.

Abstract: It is well documented that peptides have a major role in the effective functioning of higher animals at all levels from enzyme stabilization to homeostatic mechanisms governing essential functions such as eating, sexual behavior, and temperature regulation. The effects of exogenously administered peptides on neurotransmitter release, uptake, metabolism and behavioral consequences are also well established. We have attempted to extend these findings by postulating peptidergic neurons as transducers of multisignal inputs, and that development of pathological states may be due to genetically-determined reduced levels of activity of key peptidases, leading to excretion of regulatory peptides into the circulation. We have been able to demonstrate that, in schizophrenia and autism (in well defined clinical cases), the patterns of peptides and associated proteins from urinary samples differ considerably from each other and from normal controls. In addition to this, further purification of the material obtained has led to the discovery of a number of factors capable of modulating the function of major neurotransmitters. Some of these are in the final stages of characterization as peptides, while the remainder are also probably peptides, as purification has been followed by both biological testing and chemical analysis for peptidic material. We have outlined a number of parameters which we consider relevant in any attempt to put psychiatric disorders on a biological foundation. Any new advances in the neurochemical understanding of such disorders must take into consideration the observations of several different disciplines including genetics and psychology. However, at this stage of research it is far too early to speculate on the relevance of the various biological activities to the etiology and symptomatology of schizophrenia and childhood autism.

Trygstad OE, et al: Patterns of peptides and protein-associated-peptide complexes in psychiatric disorders. Br J Psychiatry 1980 Jan;136:59-72.

Abstract: Peptidic neurones may be considered as multisignal intergrators and transducers. When formation or release of peptide outstrips genetically determined breakdown capacity, overflow of peptides to the body fluids and urine may be expected. In this paper, pathological urinary chromatographic patterns of peptides are shown for genetic, functional and mixed disorders. Part symptoms of the disorders may be induced with the biologically isolated and purified peptides as well as with chemically synthesized peptides.

Ross-Smith, P, Jenner FA: Diet (gluten) and Schizophrenia. J. Hum. Nutr. 1980 / 34 (2) / 107-112.

Four aspects of clinical evidence for an association between gluten and schizophrenia are examined. The scientific evidence for the role of gluten is set out. Finally, reference is made to other dietary approaches.

Zioudrou C, Streaty RA, Klee WA: Opioid peptides derived from food proteins. The exorphins. J. Biol. Chem.1979 / 254 (7) / 2446-2449.

Abstract: Peptides with opioid activity are found in pepsin hydrolysates of wheat gluten and alpha-casein. The opioid activity of these peptides was demonstrated by use of the following bioassays: 1) naloxone-reversible inhibition of adenylate cyclase in homogenates of neuroblastoma X-glioma hybrid cells; 2) naloxone-reversible inhibition of electrically stimulated contractions of the mouse vas deferens; 3) displacement of [3H]dihydromorphine and [3H-Tyr, dAla2]met-enkephalin amide from rat brain membranes. Substances which stimulate adenylate cyclase and increase the contractions of the mouse vas deferens but do not bind to opiate receptors are also isolated from gluten hydrolysates. It is suggested that peptides derived from some food proteins may be of physiological importance.

Panksepp J: A neurochemical theory of autism. Point of View, North-Holland Biomedical Press, Jul 1979.

Hole K, Bergslien AA, Jørgensen H, Berge O-G, Reichelt KL & Trygstad OE:(1979) A peptide containing fraction from schizophrenia which stimulates opiate receptors and inhibits dopamine uptake. Neuroscience, 4, 1139-1147. [No abstract available]

Dohan FC: Schizophrenia and neuroactive peptides from food. Lancet 1979 May 12;1(8124):1031. [No abstract available]

Brantl V, Teschemacher H: Naunyn Schmiedebergs Arch Pharmacol 1979 Apr 30;306(3):301-4. A material with opioid activity in bovine milk and milk products.

Abstract: Chloroform-methanol extracts of lyophilized milk, of commercially available dried milk or baby food and of casein digests were tested for opioid activity on the guinea-pig ileum longitudinal muscle-myenteric plexus preparation. Compounds with opioid activity--which proved to be resistant to peptidases--were detected in certain batches of baby food, casein digest, and cow milk in considerably varying amounts.

Ashkenazi et. al: Immunologic reaction of psychotic patients to fractions of gluten Am J Psychiat 1979; 136: 1306-1309.

Abstract: Production of a leukocyte migration inhibition factor by peripheral blood lymphocytes in response to challenge with gluten fractions was studied in hospitalized patients with schizophrenia and other psychoses compared with normal individuals and with children and adolescents with celiac disease. The schizophrenic and other psychotic patients could be subdivided into two groups, one that responded in the leukocyte migration inhibition factor test as the celiac patients did and one that responded as the normal control subjects did. The psychotic and schizophrenic patients did not show any evidence of malabsorption. The authors speculate that gluten may be involved in biological processes in the brain in certain psychotic individuals.

O'Banion D, Armstrong B, Cummings RA, Stange J.: Disruptive behavior: a dietary approach. J Autism Child Schizophr 1978 Sep;8(3):325-37.

Abstract: The effect of particular foods on levels of hyperactivity, uncontrolled laughter, and disruptive behaviors was studied in an 8-year-old autistic boy. The floor of the child's room was taped off into six equal-sized rectangles to measure general activity level. Frequency data were recorded on screaming, biting, scratching, and object throwing. A time-sample technique was used to record data on laughing. Data were gathered during four phases. During an initial 4-day period the child was fed a normal American diet. A 6-day fasting period followed, during which time only spring water was allowed. The third phase lasted 18 days and involved the presentation of individual foods. During the final phase of the study the child was given only foods that had not provoked a reaction in the third phase. Results showed that foods such as wheat, corn, tomatoes, sugar, mushrooms, and dairy products were instrumental in producing behavioral disorders with this child.

Singh MM, Kay SR: Wheat gluten as a pathogenic factor in schizophrenia. Science 1976 Jan 30;191(4225):401-2.

Abstract: Schizophrenics maintained on a cereal grain-free and milk-free diet and receiving optimal treatment with neuropleptics showed an interruption or reversal of their therapeutic progress during a period of "blind" wheat gluten challenge. The exacerbation of the disease process was not due to variations in neuroleptic doses. After termination of the gluten challenge, the course of improvement was reinstated. The observed effects seemed to be due to a primary schizophrenia-promoting effect of wheat gluten.

Dohan FC, Grasberger JC: Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatry. 1973 Jun;130(6):685-8. [No abstract available]

Goodwin MS, Cowen MA, Goodwin TC: Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. J Autism Child Schizophr 1971 Jan-Mar;1(1):48-62. [No abstract available]

Dohan FC: Is celiac disease a clue to pathogenesis of schizophrenia? Mental Hyg 1969; 53: 525-529. [No abstract available]

Dohan FC: Wheat "consumption" and hospital admissions for schizophrenia during World War II. A preliminary report. Am J Clin Nutr. 1966 Jan;18(1):7-10. [No abstract available]

Cooke WT, Smith WT: Neurological disorders associated with adult celiac disease. Brain 1966, 89: 683-722. [No abstract available]

Dohan FC: Cereals and schizophrenia: data and hypothesis. Acta Psychiat Scand 1966; 42: 125-152. [No abstract available]

Below are some abstracts of research done on the link between dietary issues and autism.

The following are listed on http://www.thoughtfulhouse.org/supporting_research.htm

Autism and the Gastrointestinal System

Afzal N, Murch S, Thirrupathy K, Berger L, Fagbemi A, Heuschkel R. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42.

Alberti A, Pirrone P, Elia M, Waring R, Romano C. Sulphation deficit in “low-functioning” autistic children: a pilot study. Biol Psychiatry 1999; 46 (3), 420-424.

Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006 Apr;173(1-2):126-34.

Balzola F, Barbon V, Repici A, Rizzetto M. Panenteric IBD-like disease in a patient with regressive autism shown for the first time by the wireless capsule enteroscopy: another piece in the jigsaw of this gut-brain syndrome? Am J Gastro. 2005; 979-981.

Balzola F, Daniela C, Repici A, Barbon V, Sapino A, Barbera C, Calvo PL, Gandione M, Rigardetto R, Rizzetto M. Autistic enterocolitis: confirmation of a new inflammatory bowel disease in an Italian cohort of patients. Gastroenterology. 2005;128:Suppl.2;A-303.

Black C, Kaye JA, Jick H. Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database. BMJ. 2002 Aug 24;325(7361):419-21.

Bolte ER. Autism and Clostridium tetani. Med Hypotheses. 1998 Aug;51(2):133-44.

Cade R, Privette M, Fregly M, Rowland N, Sun Z, Zele V, Wagemaker H, Edelstein C. Autism and schizophrenia: Intestinal disorders. Nutr Neurosci. 2000; 3, 57–72.

D'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996 Sep;85(9):1076-9.

Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E, McTeague M, Sandler R, Wexler H, Marlowe EM, Collins MD, Lawson PA, Summanen P, Baysallar M, Tomzynski TJ, Read E, Johnson E, Rolfe R, Nasir P, Shah H, Haake DA, Manning P, Kaul A. Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis. 2002 Sep 1;35(Suppl 1):S6-S16.

Furlano RI, Anthony A, Day R, Brown A, McGavery L, Thomson MA, Davies SE, Berelowitz M, Forbes A, Wakefield AJ, Walker-Smith JA, Murch SH. Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. Pediatrics 2001;138:366-72.

Gonzalez L, Lopez K, Navarro D, Negron L, Flores L, Rodriguez R, Martinez M, Sabra A. Endoscopic and Histological Characteristics of the digestive mucosa in autistic children with gastrointestinal symptoms. Arch Venez Pueric Pediatr 69;1:19-25.

Goodwin MS, Cowen MA, Goodwin TC. Malabsorption and cerebral dysfunction. J Autism Child Schizophr. 1971;1:48-62.

Horvath K, Papadimitriou JC, Rabazlan A. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999, 135:559-563.

Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002 Oct;14(5):583-7.

Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B. Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. J Pediatr. 2005 May;146(5):605-10.

Jyonouchi H, Sun S, Le H. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol. 2001 Nov 1;120(1-2):170-9.

Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology. 2002;46(2):76-84.

Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85.

Knivsberg AM, Reichelt KL, Hoien T, Nodland M. A randomised, controlled study of dietary intervention in autistic syndromes. Nutr Neurosci. 2002 Sep;5(4):251-61.

Knivsberg AM, Reichelt KL, Nodland M, Hoein T: Autistic Syndromes and Diet: a follow-up study. Scandinavian Journal of Educational Research 1995; 39: 223-236.

Knivsberg AM, Reichelt KL, Nodland M. Reports on dietary intervention in autistic disorders. Nutr Neurosci. 2001;4(1):25-37.

Krigsman A, Boris M, Goldblatt A. Frequency of histologic enterocolitis and lymphonodular hyperplasia in autistic children presenting for ileocolonoscopy. IMFAR. May 7th, 2004.

Kuddo T, Nelson KB. How common are gastrointestinal disorders in children with autism. Curr Opin Pediatr 2003: 15(3); 339-343.

Kushak R, Winter H, Farber N, Buie T. Gastrointestinal symptoms and intestinal disaccharidase activities in children with autism. Abstract of presentation to the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition, Annual Meeting, October 20-22, 2005, Salt Lake City, Utah.

Levy S, Souders MC, Wray J, Jawad AF, Gallagher PR, Coplan J, Belchic JK, Gerdes M, Mitchell R, Mulberg AE. Children with autistic spectrum disorders. I: Comparison of placebo and single dose of human synthetic secretin. Arch. Dis. Child. 2003;88;731-736.

Melmed RD, Schneider CK, Fabes RA. Metabolic markers and gastrointestinal symptoms in children with autism and related disorders. J Pediatr Gastroenterol Nutr 2000:31(suppl 2)S31-32.

Parent Ratings of Behavioral Effects of Biomedical Interventions. Autism Research Institute. www.autismwebsite.com/ari/treatment/form34q.htm.

Parracho HM, Bingham MO, Gibson GR, McCartney AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. 2005 Oct;54(Pt 10):987-91.

Reichelt KL, Knivsberg AM. Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Nutr Neurosci. 2003 Feb;6(1):19-28.

Reichelt KL, Knivsberg AM, Lind G, Nodland M: Probable Etiology and Possible Treatment of Childhood Autism. Brain Dysfuntion 1991; 4: 308-319.

Reichelt KL, Saelid G, Lindback T, Boler JB. Childhood autism: a complex disorder. Biol Psychiatry. 1986 Nov;21(13):1279-90.

Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000 Jul;15(7):429-35.

Shattock P, Kennedy A, Rowell F, Berney T. Role of neuropeptides in autism and their relationship with classical neurotransmitters. Brain Dysfunction 1990:3: 328-345.

Shattock P, Lowdon G. Proteins, peptides and autism: Part 2: Implications for the education and care of people with autism. Brain Dysfunction. 1991;4: 323-334.

Shaw W, Kassen E, Chaves E. Increased urinary excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features. Clin Chem. 1995 Aug;41(8 Pt 1):1094-104.

Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol. 2004 Nov;70(11):6459-65.

Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe J. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. BMJ. 2002 Feb 16;324(7334):393-6.

Torrente F, Machado N, Perez-Machado M, Furlano R, Thomson M, Davies S, Wakefield AJ, Walker-Smith JA, Murch SH. Enteropathy with T cell infiltration and epithelial IgG deposition in autism. Mol Psychiatry. 2002;7:375-382.

Torrente F, Anthony A. Focal-enhanced gastritis in regressive autism with features distinct from Crohn’s disease and helicobacter Pylori gastritis. Am J Gastroenterol 2004 Apr;99(4):598-605.

Valicenti-McDermott M, McVicar K, Rapin I, Wershil BK, Cohen H, Shinnar S. Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S128-36.

Wakefield AJ, Murch SH, Anthony A et al. Ileal-lymphoid nodular hyperplasia non-specific colitis and pervasive developmental disorder in children. Lancet. 1998;351:637-41.

Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'Leary JJ, Murch SH. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther. 2002 Apr;16(4):663-74.

Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, O'Leary JJ, Berelowitz M, Walker-Smith JA. Enterocolitis in children with developmental disorders. Am J Gastroenterol. 2000 Sep;95(9):2285-95.

Wakefield AJ, Ashwood P, Limb K, Anthony A. The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder. Eur J Gastroenterol Hepatol. 2005 Aug;17(8):827-36.

Walker SJ, Hepner K, Segal J, Krigsman A. Persistent ileal measles virus in a large cohort of regressive autistic children with ileocolitis and lymphonodular hyperplasia: revisitation of an earlier study. IMFAR. June 1, 2006.

Correcting Nutritional Deficiencies

Adams JB, Holloway C. Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder. J Altern Complement Med. 2004 Dec;10(6):1033-9.

Adams JB, George F, Audhya T. Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements. J Altern Complement Med. 2006 Jan-Feb;12(1):59-63.

Aldred S, Moore KM, Fitzgerald M, Waring RH. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord. 2003 Feb;33(1):93-7.

Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K (m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002 Apr;75(4):616-58.

Amminger GP, Berger GE, Schafer MR, Klier C, Friedrich MH, Feucht M. Omega-3 Fatty Acids Supplementation in Children with Autism: A Double-blind Randomized, Placebo-controlled Pilot Study. Biol Psychiatry. 2006 Aug 22; [Epub ahead of print].

Arnold GL, Hyman SL, Mooney RA, Kirby RS. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord. 2003 Aug;33(4):449-54.

Baker SB, Worthley LI. The essentials of calcium, magnesium and phosphate metabolism: part I. Physiology. Crit Care Resusc. 2002 Dec;4(4):301-6.

Barthelemy C, Garreau B, Leddet I, Sauvage D, Domenech J, Muh JP, Lelord G. Biological and clinical effects of oral magnesium and associated magnesium-vitamin B6 administration on certain disorders observed in infantile autism. Therapie. 1980 Sep-Oct;35(5):627-32.

Bell JG, Sargent JR, Tocher DR, Dick JR. Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders? Prostaglandins Leukot Essent Fatty Acids. 2000 Jul-Aug;63(1-2):21-5.

Boris M, Goldblatt A, Galanko J, James SJ. Association of MTHFR gene variants with autism. J Am Phys Surg. 2004: 9(4):106-108.

Bronner F. Extracellular and intracellular regulation of calcium homeostasis. ScientificWorldJournal. 2001 Dec 22;1:919-25.

Bu B, Ashwood P, Harvey D, King IB, Water JV, Jin LW. Fatty acid compositions of red blood cell phospholipids in children with autism. Prostaglandins Leukot Essent Fatty Acids. 2006 Apr;74(4):215-21.

Calingasan NY, Huang PL, Chun HS, Fabian A, Gibson GE. Vascular factors are critical in selective neuronal loss in an animal model of impaired oxidative metabolism. J Neuropathol Exp Neurol. 2000 Mar;59(3):207-17.

Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C, Komen J. Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J Child Neurol. 2002 Nov;17(11):833-7.

Chugani DC, Sundram BS, Behen M, Lee ML, Moore GJ. Evidence of altered energy metabolism in autistic children. Prog Neuropsychopharmacol Biol Psychiatry. 1999 May;23(4):635-41.

Coleman M, Steinberg G, Tippett J, Bhagavan HN, Coursin DB, Gross M, Lewis C, DeVeau L. A preliminary study of the effect of pyridoxine administration in a subgroup of hyperkinetic children: a double-blind crossover comparison with methylphenidate. Biol Psychiatry. 1979 Oct;14(5):741-51.

Deluca HF. The vitamin D system: a view from basic science to the clinic. Clin Biochem. 1981 Oct;14(5):213-22.

Dhawan M, Kachru DN, Tandon SK. Influence of thiamine and ascorbic acid supplementation on the antidotal efficacy of thiol chelators in experimental lead intoxication. Arch Toxicol. 1988;62(4):301-4.

Dickinson VA, Block G, Russek-Cohen E. Supplement use, other dietary and demographic variables, and serum vitamin C in NHANES II. J Am Coll Nutr. 1994 Feb;13(1):22-32.

Dolske MC, Spollen J, McKay S, Lancashire E, Tolbert L. A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog Neuropsychopharmacol Biol Psychiatry. 1993 Sep;17(5):765-74.

Fernstrom JD. Can nutrient supplements modify brain function? Am J Clin Nutr. 2000 Jun;71(6 Suppl):1669S-75S.

Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ. Relative carnitine deficiency in autism. J Autism Dev Disord. 2004 Dec;34(6):615-23.

Friedman SD, Shaw DW, Artru AA, Richards TL, Gardner J, Dawson G, Posse S, Dager SR. Regional brain chemical alterations in young children with autism spectrum disorder. Neurology. 2003 Jan 14;60(1):100-7.

Gaull GE. Taurine in pediatric nutrition: review and update. Pediatrics. 1989 Mar;83(3):433-42.

Geoghegan M, McAuley D, Eaton S, Powell-Tuck J. Selenium in critical illness. Curr Opin Crit Care. 2006 Apr;12(2):136-41.

Goebel L, Driscoll H. Scurvy. www.emedicine.com. 7-15-05.

Grattan-Smith PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord. 1997 Jan;12(1):39-46.

Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002 Oct;14(5):583-7

Hunt C, Chakravorty NK, Annan G, Habibzadeh N, Schorah CJ. The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections. Int J Vitam Nutr Res. 1994;64(3):212-9.

Imura K, Okada A. Amino acid metabolism in pediatric patients. Nutrition. 1998 Jan;14(1):143-8.

James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004 Dec;80(6):1611-7.

Johnson S. Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson's disease? Med Hypotheses. 2001 May;56(5):641-5.

Johnston CS, Thompson LL. Vitamin C status of an outpatient population. J Am Coll Nutr. 1998, 17(4)366-370.

Jonas C, Etienne T, Barthelemy C, Jouve J, Mariotte N. Clinical and biochemical value of Magnesium + vitamin B6 combination in the treatment of residual autism in adults. Therapie. 1984 Nov-Dec;39(6):661-9.

Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99.

Kleijnen J, Knipschild P. Niacin and vitamin B6 in mental functioning: a review of controlled trials in humans. Biol Psychiatry. 1991 May 1;29(9):931-41.

Kornreich L, Bron-Harlev E, Hoffmann C, Schwarz M, Konen O, Schoenfeld T, Straussberg R, Nahum E, Ibrahim AK, Eshel G, Horev G. Thiamine deficiency in infants: MR findings in the brain. Am J Neuroradiol. 2005 Aug;26(7):1668-74.

Kozielec T, Starobrat-Hermelin B. Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD). Magnes Res. 1997 Jun;10(2):143-8.

Kushak R, Winter W, Farber N, Buie T. Gastrointestinal symptoms and intestinal disaccharidase activities in children with autism. J Pediatr Gastroenterol Nutr. 2005 Oct: 41(4):508.

Lelord G, Muh JP, Barthelemy C, Martineau J, Garreau B, Callaway E. Effects of pyridoxine and magnesium on autistic symptoms—initial observations. J Autism Dev Disord. 1981 Jun;11(2):219-30.

Lelord G, Callaway E, Muh JP. Clinical and biological effects of high doses of vitamin B6 and magnesium on autistic children. Acta Vitaminol Enzymol. 1982;4(1-2):27-44.

Levy J. Immunonutrition: the pediatric experience. Nutrition. 1998 Jul-Aug;14(7-8):641-7.

Li J, Lin JC, Wang H, Peterson JW, Furie BC, Furie B, Booth SL, Volpe JJ, Rosenberg PA. Novel role of vitamin K in preventing oxidative injury to developing oligodendrocytes and neurons. J Neuroscience. 2003 Jul: 23(13):5816-5826.

Liebscher DH, Liebscher DE. About the misdiagnosis of magnesium deficiency. J Am Coll Nutr. 2004 Dec;23(6):730S-1S.

Litov RE, Combs GF Jr. Selenium in pediatric nutrition. Pediatrics. 1991 Mar;87(3):339-51.

Lonsdale D, Shamberger RJ, Audhya T. Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. Neuro Endocrinol Lett. 2002 Aug;23(4):303-8.

Mahadik SP, Scheffer RE. Oxidative injury and potential use of antioxidants in schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 1996 Aug;55(1-2):45-54.

Martineau J, Barthelemy C, Garreau B, Lelord G. Vitamin B6, magnesium, and combined B6-Mg: therapeutic effects in childhood autism. Biol Psychiatry. 1985 May;20(5):467-78.

Megson MN. Is autism a G-alpha protein defect reversible with natural vitamin A? Med Hypotheses. 2000 Jun;54(6):979-83.

Moon J. The role of vitamin D in toxic metal absorption: a review. J Am Coll Nutr. 1994 Dec;13(6):559-64.

Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A. Vitamin B12 and folate depletion in cognition: a review. Neurol India. 2004 Sep;52(3):310-8.

Mousain-Bosc M, Roche M, Polge A, Pradal-Prat D, Rapin J, Bali JP. Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. II. Pervasive developmental disorder-autism. Magnes Res. 2006 Mar;19(1):53-62.

Mousain-Bosc M, Roche M, Rapin J, Bali JP. Magnesium VitB6 intake reduces central nervous system hyperexcitability in children. J Am Coll Nutr. 2004 Oct;23(5):545S-548S.

Ohsaki Y, Shirakawa H, Hiwatashi K, Furukawa Y, Mizutani T, Komai M. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci Biotechnol Biochem. 2006 Apr;70(4):926-32.

Olmez A, Yalcin S, Yurdakok K, Coskun T. Serum selenium levels in acute gastroenteritis of possible viral origin. J Trop Pediatr. 2004 Apr;50(2):78-81.

Pangborn J, Baker SM. Autism: Effective Biomedical Treatments (Have We Done Everything We Can For This Child? Individuality In An Epidemic). San Diego: Autism Research Institute; 2nd Edition Sept. 2005:232-235.

Pfeiffer CC, Braverman ER. Zinc, the brain and behavior. Biol Psychiatry. 1982 Apr;17(4):513-32.

Raiten DJ, Massaro T. Perspectives on the nutritional ecology of autistic children. J Autism Dev Disord. 1986 Jun;16(2):133-43.

Reddi K, Henderson B, Meghji S, Wilson M, Poole S, Hopper C, Harris M, Hodges SJ. Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine. 1995 Apr;7(3):287-90.

Richardson AJ. Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int Rev Psychiatry. 2006 Apr;18(2):155-72.

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