1742-2094-4-3 1742-2094 Case study <p>Effect of pioglitazone treatment on behavioral symptoms in autistic children</p> Boris Marvin mboris@pol.net Kaiser C Claudia ckaiser@uic.edu Goldblatt Allan mboris@pol.net Elice W Michael mboris@pol.net Edelson M Stephen edelson4@comcast.net Adams B James jim.adams@asu.edu Feinstein L Douglas dlfeins@uic.edu

77 Froehlich Farm Blvd Woodbury, New York 11797, USA

Department of Anesthesiology, University of Illinois, Chicago, IL, 60612, USA

Autism Research Institute, 4182 Adams Ave, San Diego, CA 92116, USA

Arizona State University, PO Box 876006, Tempe, AZ 85287-6006, USA

 Journal of Neuroinflammation 1742-2094 2007 4 1 3 http://www.jneuroinflammation.com/content/4/1/3 17207275 10.1186/1742-2094-4-3 13 11 2006 05 1 2007 05 1 2007 2007 Boris et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction

Autism is complex neuro-developmental disorder which has a symptomatic diagnosis in patients characterized by disorders in language/communication, behavior, and social interactions. The exact causes for autism are largely unknown, but is has been speculated that immune and inflammatory responses, particularly those of Th2 type, may be involved. Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator activated receptor gamma (PPARγ), a nuclear hormone receptor which modulates insulin sensitivity, and have been shown to induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. The TZD pioglitazone (Actos) is an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile, currently being tested in clinical trials of other neurological diseases including AD and MS. We therefore tested the safety and therapeutic potential of oral pioglitazone in a small cohort of children with diagnosed autism.

Case description

The rationale and risks of taking pioglitazone were explained to the parents, consent was obtained, and treatment was initiated at either 30 or 60 mg per day p.o. A total of 25 children (average age 7.9 ± 0.7 year old) were enrolled. Safety was assessed by measurements of metabolic profiles and blood pressure; effects on behavioral symptoms were assessed by the Aberrant Behavior Checklist (ABC), which measures hyperactivity, inappropriate speech, irritability, lethargy, and stereotypy, done at baseline and after 3–4 months of treatment.

Discussion and evaluation

In a small cohort of autistic children, daily treatment with 30 or 60 mg p.o. pioglitazone for 3–4 months induced apparent clinical improvement without adverse events. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients.

Conclusion

Pioglitazone should be considered for further testing of therapeutic potential in autistic patients.

Introduction

Autism, the most common of the group of disorders collectively referred to as Autism Spectrum Disorders (ASD), is a complex neurological disease of unknown etiology. The incidence of autism is estimated to be 1 per 166 1 with a male to female ratio of 4:1. Autism has been found throughout the world in families of all racial, ethnic and social backgrounds. Although accumulating evidence suggests that genetic, environmental, inflammatory, immunological, and metabolic factors play a prominent role in this disease 234567, the precise causes remain to be determined.

Altered immune responses in children with ASD are well documented. Autoimmune disorders of thyroiditis, colitis, myelin basic protein autoantibodies, and diabetes are prevalent in children with ASD. Stubbs (1976) published that 5 of 13 autistic children had no detectable rubella antibodies despite prior immunization 7. An additional study showed peripheral mononuclear cells had a decreased proliferative response to mitogenic stimulation compared to normal children 8. These findings of abnormal T-lymphocyte function have been replicated by other investigators 910. Inflammatory responses in ASD have also been reported to occur in brain, for example neuroinflammatory processes involving both microglia and astroglia were found on post mortem examination in autistic children with elevated cytokine levels in the cerebral spinal fluid 1112. Children with ASD have increased cytokines of Th2 and Th1 arms of the immune response with Th2 predominant without an increase in IL10 13.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor originally characterized by its ability to regulate adipocyte differentiation and gene transcription 14. PPARγ agonists include fatty acids, non-steroidal anti-inflammatory drugs (NSAIDs), the natural compound 15-deoxy12,14-prostaglandin-J2 (PGJ2), and members of the class of synthetic drugs termed thiazolidinediones (TZDs) which include pioglitazone (Actos) and rosiglitazone (Avandia). TZDs were originally designed as anti-diabetic drugs due to their insulin sensitizing effects, and several are now in clinical use. In addition to insulin sensitizing effects, TZDs also exert anti-inflammatory effects on a variety of cell types, and for this reason some are being considered for treatment of inflammatory diseases including artherosclerosis 15, psoriasis 1617, and inflammatory bowel disease 18192021. TZDs also reduce inflammatory activation of brain glial cells, and increase metabolic activities in glial cells which can lead to increased glucose uptake, lactate production, and mitochondrial function 2223. Furthermore, pioglitazone can cross the BBB, 24 suggesting possible direct effects on brain physiology, which could positively influence possible abnormalities in regional brain glucose utilization 25 or dysregulation of functional activity 26 as reported to occur ASD.

The safety and efficacy of pioglitazone has been established by clinical studies worldwide 2728 and since FDA approval, pioglitazone has been prescribed to several million patients. The adverse events associated with TZDs including pioglitazone are generally mild and transient, and those effects returned to baseline upon withdrawal from, or completion of the studies. Two recent studies for the treatment of diabetes in adolescents point to a good safety profile for Actos in younger populations 2930. Studies with PPARγ drugs in animal models of neurological conditions have led to clinical testing of these drugs in Alzheimer's disease (AD) and multiple sclerosis (MS) 3132. These properties of PPARγ agonists make them promising candidates for a therapeutic approach to influence the clinical course of ASD. In this report we discuss initial findings using pioglitazone to treat children with autism, which provides the rationale for design of larger clinical trials.

Case description

Population

The autistic children all were patients of Marvin Boris, MD, Allan Goldblatt, PA, and Michael Elice, MD. Twenty-five children and adolescents participated in this study. The mean age was 7.9 ± 3.5 years, with a range from 3 to 17 years. There were 22 males and 3 females. All of the participants received an independent diagnosis of Autism Spectrums Disorder (ASD) from an independent clinician and/or agency. None of the children had diagnosed Asperger's Disorder (a mild variant of ASD with higher social functioning) or PDDNOS (Pervasive Developmental Disorder – Not Otherwise Specified, a condition with social or behavioral impairments but which do not meet the DSM-IV criteria for ASD). The diagnosis of autism was initially established by a board certified pediatric neurologist, developmental pediatrician, or psychiatrist with experience in ASD. In addition, at the first visit to the offices of the treating physician, the child had to meet the DSM-IV checklist criteria for ASD. All the children had been receiving behavioral and educational therapies. These included speech, occupational, and physical therapy, applied behavioral analysis, and auditory integration therapy. The children had also received various biomedical interventions for at least one year. These included dairy and gluten free diet, metabolic treatment with supplements to known deficiencies such as MTHFR (methylenetetrahydrofolate reductase), treatment with intravenous gamma globulin or secretin, vitamin supplementation, and heavy metal chelation. The children who responded poorly (no noticeable improvements in cognitive, social, behavior, or language skills) for at least one year to biomedical, behavioral, or educational therapies were selected to be treated with pioglitazone as part of the routine health care treatment, based on papers suggesting that ASD includes an auto-immune or inflammatory component 3334, and that pioglitazone can reduce T-cell activation and Th2-type cytokine production, both implicated in ASD 35363738. The rationale and risks of taking pioglitazone were explained to the parents, and parental written consents were obtained for all participants. A retrospective review of their personal medical records was approved by the Internal Review Board of Arizona State University.

Comorbities

The autistic population has well-known auto-immunne comorbidities. In this group of autistic children, 7/25 (28%) had thyroiditis, 8/25 (32%) had colitis, 8/25 (32%) had PANDAS (Pediatric acquired neurological disorder associated with streptococcus), 20/25 (80%) had allergic diseases, and 7/25 (28%) were positive for serum antibodies to myelin basic protein. In addition 2/25 had seizures prior to being treated with pioglitazone.

Treatment

Children were prescribed pioglitazone either 30 mg per day, p.o. for ages 3–5 years old; or 60 mg per day for ages 6–17 years old. These children were followed with monthly complete blood counts, glucose and insulin levels, and serum metabolic assays.

Analysis

The participants' parents completed the Aberrant Behavior Checklist (ABC) prior to the administration of pioglitazone and then at a follow-up assessment, 12 or 16 weeks later. There are five subscales on the ABC, consisting of 58 questions. The subscales are: hyperactivity, inappropriate speech, irritability, lethargy, and stereotypy. Each question was rated on a 4-point scale: 0 = 'not a problem,' 1 = 'the behavior is a problem but slight in degree,' 2 = 'the problem is moderately serious,' and 3 = 'the problem is severe in degree.' 'The ABC has been shown to be a valid and reliable procedure to evaluate treatment efficacy 394041. Each of the five subscales was analyzed using paired t-tests. The relationship between age and amount of behavior change was examined using Pearson product correlations

Outcomes

There were no significant abnormalities observed in standard blood analyses in the group of 25 autistic children treated with pioglitazone for up to 4 months (Table 1). Over the course of treatment, there were no elevations in hemoglobin, creatine, BUN (blood urea nitrogen) or insulin levels. There were 2 incidents of slightly and transiently elevated white blood counts and glucose levels, and 3 incidents of slightly and transiently elevated liver enzyme (ALT and AST) levels. All elevations resolved without interventions.

<p>Table 1</p>

Incidents of elevated blood values

#

Pre 6

Mid

Post

WBC 1

2

0

1

1

Glucose 2

2

1

1

0

AST 3

3

0

2

1

ALT 4,5

3

0

3

0

1White blood cell counts, normal range 3.8 to 10.5 × 1000 cells per mcl. Values of 11.0 and 12.0 recorded. 2Glucose, normal range 70–99 mg/dl. Values of 102 and 106 recorded. 3Aspartate aminotransferase, normal range 10–40 IU/L. Values of 42, 48, and 45 recorded. 4Alanine aminotransferase, normal range 10–45 IU/L. Values of 56, 60, and 48 recorded. 5ALT and AST elevations occurred in the same three patients. 6Pre, pre-trial; Mid, mid-trial; Post, post-trial.

A comparison of the mean scores for ABC subscales between baseline and end of treatment for each of the patients revealed that four of the five ABC subscales decreased significantly following the administration of pioglitazone (Figure 1). These subscales were hyperactivity, irritability, lethargy, and stereotypy. There was no change in inappropriate speech; however, it should be noted that the speech subscale is of limited value in children with autism who lack or have very limited speech.

<p>Figure 1</p>

Effect of Pioglitazone on behavior improvement

Effect of Pioglitazone on behavior improvement. The average (mean ± s.d.) of the total scores for the 5 subscales of the ABC was calculated for 25 patients before treatment (baseline) and after 3–4 months of treatment with Pioglitazone. *, P < .05 unpaired T-test.

Of the 25 patients, 76% showed an improvement (defined as >50% decrease in score) in at least one subgroup; while 56% showed an improvement in two or more subgroups, and 40% showed improvements in 3 or more subcategories. If response rate is estimated as those who showed >25% decrease in at least 2 of the 5 subscales, then the percentage is much higher 71%. The majority of patients (52%) showed an improvement (>50%) in the hyperactivity subscale.

Significant inverse correlations (Figure 2) were detected between age and the improvements calculated for irritability (P = 0.03), lethargy (P = 0.02) and hyperactivity (P = 0.007). This indicates a tendency for younger participants to benefit more from pioglitazone than the older participants.

<p>Figure 2</p>

Relationship of behavioral improvements to age

Relationship of behavioral improvements to age. Differences in scores for the 5 subscales of the ABC were calculated and plotted versus patient age, and analyzed using Graphpad Prism V4 assuming Gaussian distributions.

Discussion and evaluation

The current study provides evidence that treatment with the PPARγ agonist pioglitazone (Actos) does not induce any significant adverse effects, and may have a beneficial effect on patterns of aberrant social behavior in children with diagnosed autism. Despite the small sample size (n = 25 total), we observed statistically significant decreases in 4 of the 5 subscales of the ABC after a relatively short (4 months) treatment with pioglitazone. It is yet not known if these improvements are long lasting, or if they will continue after treatment is withdrawn. Although originally approved for treatment of Type 2 diabetes in adults, recent clinical trials of pioglitazone for treatment of diabetes in adolescents suggest this drug will be well tolerated in younger populations 2930.

There is increasing evidence for an association of ASD with various immune syndromes. It was reported that 66% of children with autism have a relative with an autoimmune disease 42, and families of children with PDD (Pervasive Development Disorder) have a higher average number of autoimmune diseases than families of healthy children 43. Recently the occurrence of AITD (Autoimmune Thyroid Disease) in first or second order relatives was concluded to be a risk factor for those ASD children who show regression (the early loss of already established skills of communication or of social interactions) 44. The possibility therefore exists that pioglitazone influences some aspect of auto-immune nature in ASD children.

It has been suggested that a Th2-like dysfunction may contribute to the causes of ASD. In children with ASD, a preponderance of Th2-like (IL4, IL6, IL10) over Th1-like (IL2, IFNg, IL1β) cytokines has been reported 45464748. These studies support the idea that a predominance of Th2 cytokines may be a factor in ASD. PPARγ agonists are known to influence T-cell physiology, and although most often they have been shown to reduce Th1-like cytokine (IL1β, TNFa, IL12) production, in several studies they also reduced Th2 responses. In CD4 cells, PGJ2 and the TZD ciglitazone reduced IL4 production 35 and in EAE, the animal model of Multiple Sclerosis, PGJ2 blocked splenic T cell production of IL10 and IL4 36. PPARγ agonists also reduce the clinical symptoms in animal models of asthma, a disease which is also thought to be predominantly Th2 type involving IL4, IL5, and IL13 37. PPARγ agonists have been shown to reduce IL4, IL5, and IL13 production from Tcells of mice with induced lung inflammation 3849. However, in one study the TZDs increased IL4 and IL10, and stimulated GATA3 expression (a transcription factor which shifts cells towards Th2 phenotype) 50; although in other studies PPARγ drugs were shown to inhibit GATA3 activity 5152. Nevertheless, taken together these studies demonstrate that PPARγ agonists have the potential to shift the T-cell response from Th2 to Th1, or to reduce Th2 cytokine expression, which may be of therapeutic benefit in ASD.

Despite observing significant improvements in 4 of 5 subscales of the ABC, the open-label nature of this study limits the ability to draw strong conclusions regarding treatment-dependent benefits. In addition, well-known expectancy effects in the parent population make interpretation of the ABC subject to potential bias 5354. The placebo effect in ASD has been reported to be high in some studies where improvement was assessed using the ABC. Improvements occurred in 25% of patients following atomoxetine treatment for 6 weeks, 55; 34% after 8 week treatment with risperidone 56; and 37% after 3 weeks treatment with amantadine 54. In the current study, the number of responders (those showing >50% improvement in at least one subscale) was 76%, considerably higher than the values reported in the above studies.

An additional confound of the current study is the diversity of auto-immune comorbidities that are common in the autistic population. It is possible that pioglitazone effects are, in part or in full, an indirect consequence of reducing symptoms of the autoimmune diseases present in the study population (thyroiditis, colitis, and PANDAS). For example, in autoimmune thyroiditis (AITD), pioglitazone could increase levels of suppressor T-cells that are deficient 57 and as a result reduce circulating levels of Th1 or Th2 cytokines. Similarly, activation of PPARγ can suppress experimentally induced colitis 58 which could also reduce plasma cytokine levels, and in fact several clinical trials of PPARγ agonists for treating colitis are in progress 1959. PANDAS, a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections is defined by obsessive-compulsive (OCD) and or tic disorders, is thought to be due to the actions of auto-immune antibodies on basal ganglia neurons 60, and is improved by immunomodulatory therapies 61; anti-inflammatory effects of PPARγ agonists could therefore influence the course of this disease. However, since the precise relationships between autoimmune diseases and the penetrance of autistic symptoms remains to be established, deciphering the relative importance of indirect effect of pioglitazone on behavior will be a formidable task.

The recent increase in type 2 diabetes in children has resulted in an increased interest of researchers to explore the use of anti-diabetic drugs including TZDs in children, therefore providing additional information regarding the safety of TZDs in this population. A recent clinical trial tested the effects of rosiglitazone (2 mg bid increased to 4 mg bid after 8 weeks), a related TZD, in 195 obese type 2 diabetic children (age range 8–17 years), in a 24-week double-blind, randomized, metformin-controlled, parallel group design. The rosiglitazone group gained ~3 kg after 24 weeks with the occurrence of peripheral edema in 1 child 29. However, no other adverse effects were reported, suggesting that TZDs are well tolerated in children as in adults. More recently 30 pioglitazone (15 mg po escalated to 30 mg po after 4 weeks) was tested as an adjunct therapy for the treatment of type 1 diabetes in a small group of young adolescents (age range 10–17.9 years). After 6 months treatment the pioglitazone subjects showed a small but significant increase in BMI z-score (body mass index standard deviation for age) suggesting treatment-related weight gain. In the 35 subjects who completed the study, there was no evidence of edema, anemia, or of any significant increase in the frequency of hypoglycemia in the treatment group versus the placebo group. However, it is clear that the safety of pioglitazone, and of other TZDs, in the pediatric population requires additional testing.

Conclusion

In view of its established safety profile, the current results provide the rationale for further testing of pioglitazone in autism and other forms of ASD.

Abbreviations

ABC: Aberrant Behavior Checklist

AD: Alzheimer's disease

ASD: Autism Spectrum Disorder

BBB: Blood brain barrier

CBC: Complete blood count

CD: Cluster of differentiation

IL: Interleukin

MS: Multiple Sclerosis

NSAID: Non steroidal anti-inflammatory drug

PANDAS: Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections

PGJ2: 15-deoxy-delta12,14-prostaglandin J2

PDD: pervasive developmental disorder

PPAR: Peroxisome proliferator activated receptor

TNF: Tumor necrosis factor

TZD: thiazolidinedione

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

MB and AG were the primary physicians who treated the patients, and carried out behavioral testing to determine if the medication was helping their patients. CK prepared the first draft of the paper, and analyzed the data. DLF organized and analyzed the data, contributed to the original idea to treat ASD patients, helped write and edit the manuscript.

Acknowledgements

The authors wish to acknowledge the financial assistance of the Autism Research Institute (San Diego, CA) and dedicate this study to the memory of its founder Dr Bernard Rimland,

 <p>Protective effects of a peroxisome proliferator-activated receptor-beta/delta agonist in experimental autoimmune encephalomyelitis</p> Polak PE Kalinin S Dello RC Gavrilyuk V Sharp A Peters JM Richardson J Willson TM Weinberg G Feinstein DL J Neuroimmunol 2005 168 65 75 10.1016/j.jneuroim.2005.07.006 16098614 <p>Neurobiology of autism</p> Rapin I Katzman R Ann Neurol 1998 43 7 14 10.1002/ana.410430106 9450763 <p>Heritable and nonheritable risk factors for autism spectrum disorders</p> Newschaffer CJ Fallin D Lee NL Epidemiol Rev 2002 24 137 153 10.1093/epirev/mxf010 12762089 <p>Genetics of autism: complex aetiology for a heterogeneous disorder</p> Folstein SE Rosen-Sheidley B Nat Rev Genet 2001 2 943 955 10.1038/35103559 11733747 <p>Genetic and immunologic considerations in autism</p> Korvatska E Van de WJ Anders TF Gershwin ME Neurobiol Dis 2002 9 107 125 10.1006/nbdi.2002.0479 11895365 <p>Microbiology and immunology of autism spectrum disorders</p> Lipkin WI Hornig M Novartis Found Symp 2003 251 129 143 14521191 <p>Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination</p> Stubbs EG J Autism Child Schizophr 1976 6 269 274 10.1007/BF01543467 1036494 <p>Depressed lymphocyte responsiveness in autistic children</p> Stubbs EG Crawford ML J Autism Child Schizophr 1977 7 49 55 10.1007/BF01531114 139400 <p>Immune abnormalities in patients with autism</p> Warren RP Margaretten NC Pace NC Foster A J Autism Dev Disord 1986 16 189 197 10.1007/BF01531729 2941410 <p>Lymphocyte subsets and interleukin-2 receptors in autistic children</p> Denney DR Frei BW Gaffney GR J Autism Dev Disord 1996 26 87 97 10.1007/BF02276236 8819772 <p>Neuroglial activation and neuroinflammation in the brain of patients with autism</p> Vargas DL Nascimbene C Krishnan C Zimmerman AW Pardo CA Ann Neurol 2005 57 67 81 10.1002/ana.20315 15546155 <p>Immunity, neuroglia and neuroinflammation in autism</p> Pardo CA Vargas DL Zimmerman AW Int Rev Psychiatry 2005 17 485 495 10.1080/02646830500381930 16401547 <p>Elevated cytokine levels in children with autism spectrum disorder</p> Molloy CA Morrow AL Meinzen-Derr J Schleifer K Dienger K Manning-Court Altaye M Wills-Karp M J Neuroimmunol 2006 172 198 205 10.1016/j.jneuroim.2005.11.007 16360218 <p>Physiological and therapeutic roles of peroxisome proliferator-activated receptors</p> Berger J Wagner JA Diabetes Technol Ther 2002 4 163 174 10.1089/15209150260007381 12079620 <p>The role of PPARs in atherosclerosis</p> Duval C Chinetti G Trottein F Fruchart JC Staels B Trends Mol Med 2002 8 422 430 10.1016/S1471-4914(02)02385-7 12223313 <p>Treatment of active psoriatic arthritis with the PPARgamma ligand pioglitazone: an open-label pilot study</p> Bongartz T Coras B Vogt T Scholmerich J Muller-Ladner U Rheumatology (Oxford) 2005 44 126 129 10.1093/rheumatology/keh423 15479756 <p>Emerging drugs in psoriasis</p> Gniadecki R Calverley MJ Expert Opin Emerg Drugs 2002 7 69 90 10.1517/14728214.7.1.69 15989537 <p>A novel PPAR gamma gene therapy to control inflammation associated with inflammatory bowel disease in a murine model</p> Katayama K Wada K Nakajima A Mizuguchi H Hayakawa T Nakagawa S Kadowaki T Nagai R Kamisaki Y Blumberg RS Mayumi T Gastroenterology 2003 124 1315 1324 10.1016/S0016-5085(03)00262-2 12730872 <p>[A clinical trial of rosiglitazone and 5-aminosalicylate combination for ulcerative colitis]</p> Liang HL Ouyang Q Zhonghua Nei Ke Za Zhi 2006 45 548 551 17074107 <p>An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis</p> Lewis JD Lichtenstein GR Stein RB Deren JJ Judge TA Fogt F Furth EE Demissie EJ Hurd LB Su CG Keilbaugh SA Lazar MA Wu GD Am J Gastroenterol 2001 96 3323 3328 11774944 <p>PPARgamma and inflammatory bowel disease: a new therapeutic target for ulcerative colitis and Crohn's disease</p> Wada K Nakajima A Blumberg RS Trends Mol Med 2001 7 329 331 10.1016/S1471-4914(01)02076-7 11516972 <p>Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists increase glucose metabolism in astrocytes</p> Dello Russo C Gavrilyuk V Weinberg G Almeida A Bolanos JP Palmer J Pelligrino D Galea E Feinstein DL J Biol Chem 2003 278 5828 5836 10.1074/jbc.M208132200 12486128 <p>Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key?</p> Feinstein DL Spagnolo A Akar C Weinberg G Murphy P Gavrilyuk V Dello RC Biochem Pharmacol 2005 70 177 188 10.1016/j.bcp.2005.03.033 15925327 <p>Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys</p> Maeshiba Y Kiyota Y Yamashita K Yoshimura Y Motohashi M Tanayama S Arzneimittelforschung 1997 47 29 35 9037440 <p>Volumetric analysis and three-dimensional glucose metabolic mapping of the striatum and thalamus in patients with autism spectrum disorders</p> Haznedar MM Buchsbaum MS Hazlett EA LiCalzi EM Cartwright C Hollander E Am J Psychiatry 2006 163 1252 1263 10.1176/appi.ajp.163.7.1252 16816232 <p>Failing to deactivate: resting functional abnormalities in autism</p> Kennedy DP Redcay E Courchesne E Proc Natl Acad Sci U S A 2006 103 8275 8280 1472462 16702548 10.1073/pnas.0600674103 <p>Pioglitazone</p> Gillies PS Dunn CJ Drugs 2000 60 333 343 10.2165/00003495-200060020-00009 10983737 <p>Safety profile of pioglitazone</p> Hanefeld M Belcher G Int J Clin Pract Suppl 2001 27 31 11594241 <p>Diabetes in childhood - Benefits of rosiglitazone in children with type 2 diabetes mellitus</p> Saenger P Dabiri G Jones K Krebs J Sun Y Mudd P Weston WM Cobitz AR Freed MI Porter LE Program and abstracts of the European Association for the Study of Diabetes 41st Annual Meeting 2005 133 <p>Pioglitazone as adjunctive therapy in adolescents with type 1 diabetes</p> Zdravkovic V Hamilton JK Daneman D Cummings EA J Pediatr 2006 149 845 849 10.1016/j.jpeds.2006.08.049 17137905 <p>PPARgamma agonists as new therapeutic agents for the treatment of Alzheimer's disease</p> Landreth G Exp Neurol 2006 199 245 248 10.1016/j.expneurol.2006.04.006 16733054 <p>Therapeutic potential of peroxisome proliferator-activated receptor agonists for neurological disease</p> Feinstein DL Diabetes Technol Ther 2003 5 67 73 10.1089/152091503763816481 12725709 <p>Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics</p> Gupta S Aggarwal S Heads C J Autism Dev Disord 1996 26 439 452 10.1007/BF02172828 8863094 <p>Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism</p> Singh VK J Neuroimmunol 1996 66 143 145 10.1016/0165-5728(96)00014-8 8964908 <p>Peroxisome proliferator activator receptor-gamma ligands, 15-deoxy-Delta(12,14)-prostaglandin J2 and ciglitazone, reduce systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways</p> Zingarelli B Sheehan M Hake PW O'Connor M Denenberg A Cook JA J Immunol 2003 171 6827 6837 14662889 <p>Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis</p> Diab A Deng C Smith JD Hussain RZ Phanavanh B Lovett-Racke AE Drew PD Racke MK J Immunol 2002 168 2508 2515 11859145 <p>Cytokines or their antagonists for the treatment of asthma</p> O'Byrne PM Chest 2006 130 244 250 10.1378/chest.130.1.244 16840409 <p>Peroxisome proliferator-activated receptor gamma ligands attenuate immunological symptoms of experimental allergic asthma</p> Mueller C Weaver V Vanden Heuvel JP August A Cantorna MT Arch Biochem Biophys 2003 418 186 196 10.1016/j.abb.2003.08.006 14522590 <p>Validity of Autism Behavior Checklist (ABC): preliminary study</p> Marteleto MR Pedromonico MR Rev Bras Psiquiatr 2005 27 295 301 16358111 <p>A closer look at the Autism Behavior Checklist: discriminant validity and factor structure</p> Wadden NP Bryson SE Rodger RS J Autism Dev Disord 1991 21 529 541 10.1007/BF02206875 1778965 <p>An evaluation of the Autism Behavior Checklist</p> Volkmar FR Cicchetti DV Dykens E Sparrow SS Leckman JF Cohen DJ J Autism Dev Disord 1988 18 81 97 10.1007/BF02211820 3372461 <p>Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism</p> Comi AM Zimmerman AW Frye VH Law PA Peeden JN J Child Neurol 1999 14 388 394 10385847 <p>Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders</p> Sweeten TL Bowyer SL Posey DJ Halberstadt GM McDougle CJ Pediatrics 2003 112 e420 10.1542/peds.112.5.e420 14595086 <p>Familial autoimmune thyroid disease as a risk factor for regression in children with Autism Spectrum Disorder: a CPEA Study</p> Molloy CA Morrow AL Meinzen-Derr J Dawson G Bernier R Dunn M Hyman SL McMahon WM Goudie-Nice J Hepburn S Minshew N Rogers S Sigman M Spence MA Tager-Flusberg H Volkmar FR Lord C J Autism Dev Disord 2006 36 317 324 10.1007/s10803-005-0071-0 16598435 <p>Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism</p> Gupta S Aggarwal S Rashanravan B Lee T J Neuroimmunol 1998 85 106 109 10.1016/S0165-5728(98)00021-6 9627004 <p>Changes of soluble interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in the serum of autistic children</p> Singh VK Warren RP Odell JD Cole P Clin Immunol Immunopathol 1991 61 448 455 10.1016/S0090-1229(05)80015-7 1934632 <p>Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism</p> Warren RP Yonk LJ Burger RA Cole P Odell JD Warren WL White E Singh VK Immunol Invest 1990 19 245 251 2142123 <p>CD4+ helper T cell depression in autism</p> Yonk LJ Warren RP Burger RA Cole P Odell JD Warren WL White E Singh VK Immunol Lett 1990 25 341 345 10.1016/0165-2478(90)90205-5 1979061 <p>PPAR-gamma modulates allergic inflammation through up-regulation of PTEN</p> Lee KS Park SJ Hwang PH Yi HK Song CH Chai OH Kim JS Lee MK Lee YC FASEB J 2005 19 1033 1035 10.1096/fj.04-2591hyp 15788448 <p>Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis</p> Saubermann LJ Nakajima A Wada K Zhao S Terauchi Y Kadowaki T Aburatani H Matsuhashi N Nagai R Blumberg RS Inflamm Bowel Dis 2002 8 330 339 10.1097/00054725-200209000-00004 12479648 <p>The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells</p> Zheng W Flavell RA Cell 1997 89 587 596 10.1016/S0092-8674(00)80240-8 9160750 <p>Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses</p> Zhu J Min B Hu-Li J Watson CJ Grinberg A Wang Q Killeen N Urban JF Jr. Guo L Paul WE Nat Immunol 2004 5 1157 1165 10.1038/ni1128 15475959 <p>An open-label trial of escitalopram in pervasive developmental disorders</p> Owley T Walton L Salt J Guter SJ Jr. Winnega M Leventhal BL Cook EH Jr. J Am Acad Child Adolesc Psychiatry 2005 44 343 348 10.1097/01.chi.0000153229.80215.a0 15782081 <p>Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder</p> King BH Wright DM Handen BL Sikich L Zimmerman AW McMahon W Cantwell E Davanzo PA Dourish CT Dykens EM Hooper SR Jaselskis CA Leventhal BL Levitt J Lord C Lubetsky MJ Myers SM Ozonoff S Shah BG Snape M Shernoff EW Williamson K Cook EH Jr. J Am Acad Child Adolesc Psychiatry 2001 40 658 665 10.1097/00004583-200106000-00010 11392343 <p>Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled crossover pilot trial</p> Arnold LE Aman MG Cook AM Witwer AN Hall KL Thompson S Ramadan Y J Am Acad Child Adolesc Psychiatry 2006 45 1196 1205 10.1097/01.chi.0000231976.28719.2a 17003665 <p>Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders</p> Shea S Turgay A Carroll A Schulz M Orlik H Smith I Dunbar F Pediatrics 2004 114 e634 e641 10.1542/peds.2003-0264-F 15492353 <p>In vitro effects of cytokines and human thyroglobulin on the induction of antibody-secreting cells in patients with auto-immune thyroid disease</p> Resetkova E Morita T Akasu F Carayon P Volpe R Clin Invest Med 1993 16 256 264 8306534 <p>Expression of Peroxisome Proliferator-Activated Receptor-{gamma} in Macrophage Suppresses Experimentally-Induced Colitis</p> Shah Y Morimura K Gonzalez F Am J Physiol Gastrointest Liver Physiol 2006 <p>PPARgamma as a new therapeutic target in inflammatory bowel diseases</p> Dubuquoy L Rousseaux C Thuru X Peyrin-Biroulet L Romano O Chavatte P Chamaillard M Desreumaux P Gut 2006 55 1341 1349 10.1136/gut.2006.093484 16905700 <p>PANDAS: current status and directions for research</p> Snider LA Swedo SE Mol Psychiatry 2004 9 900 907 10.1038/sj.mp.4001542 15241433 <p>The PANDAS subgroup: recognition and treatment</p> Swedo SE Garvey M Snider L Hamilton C Leonard HL CNS Spectr 2001 6 419 6 15999030