Mast cell activation and autism.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social interactions, repetitive and stereotypic behaviors, as well as learning and sensory deficits. Despite the impressive rise in the prevalence of autism during the last two decades, there are few if any clues for its pathogenesis, early detection or treatment. Increasing evidence indicates high brain expression of pro-inflammatory cytokines and the presence of circulating antibodies against brain proteins. A number of papers, mostly based on parental reporting on their children's health problems, suggest that ASD children may present with "allergic-like" problems in the absence of elevated serum IgE and chronic urticaria. These findings suggest non-allergic mast cell activation, probably in response to environmental and stress triggers that could contribute to inflammation. In utero inflammation can lead to preterm labor and has itself been strongly associated with adverse neurodevelopmental outcomes. Premature babies have about four times higher risk of developing ASD and are also more vulnerable to infections, while delayed development of their gut-blood-brain barriers makes exposure to potential neurotoxins likely. Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients. This article is part of a Special Issue entitled: Mast cells in inflammation.

Prevention in Autism Spectrum Disorder: A Lifelong Focused Approach.

Autism Spectrum Disorder (ASD) is a complex highly heritable disorder, in which multiple environmental factors interact with the genes to increase its risk and lead to variable clinical presentations and outcomes. Furthermore, the inherent fundamental deficits of ASD in social attention and interaction critically diverge children from the typical pathways of learning, "creating" what we perceive as autism syndrome during the first three years of life. Later in life, training and education, the presence and management of comorbidities, as well as social and vocational support throughout the lifespan, will define the quality of life and the adaptation of an individual with ASD. Given the overall burden of ASD, prevention strategies seem like a cost-effective endeavour that we have to explore. In this paper, we take a life course approach to prevention. We will review the possibilities of the management of risk factors from preconception until the perinatal period, that of early intervention in the first three years of life and that of effective training and support from childhood until adulthood.

Neurotensin is increased in serum of young children with autistic disorder.

Autism spectrum disorders (ASD) are a group of pervasive neurodevelopmental disorders diagnosed in early childhood. They are associated with a set of "core symptoms" that include disabilities in social interaction skills, verbal and non-verbal communication, as well as repetitive and stereotypic behaviors. There is no definite pathogenetic mechanism or diagnostic tests. Many children with ASD also have "allergic-like" symptoms, but test negative implying mast cell activation by non-allergic triggers. We measured by Milliplex arrays serum levels of 3 neuropeptides that could stimulate mast cells in children with autistic disorder (n = 19; 16 males and 3 females; mean age 3.0 ± 0.4 years) and healthy, unrelated controls (n = 16; 13 males and 3 females; mean age 3 ± 1.2 years). Only neurotensin (NT) was significantly increased from 60.5 ± 6.0 pg/ml in controls to 105.6 ± 12.4 pg/ml in autistic disorder (p = 0.004). There was no statistically significant difference in the serum levels of ß-endorphin or substance P (SP). NT could stimulate immune cells, especially mast cells, and/or have direct effects on brain inflammation and ASD.

Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by difficulties in communication, cognitive and learning deficits, as well as stereotypic behaviors. For the majority of cases there are no reliable biomarkers or distinct pathogenesis. However, increasing evidence indicates ASD may be associated with some immune dysregulation, and may have a neuroimmune component. We recently showed that the peptide neurotensin (NT) is increased in autistic children. We now show that NT induces release of extracellular mitochondrial DNA (mtDNA) that could act as "autoimmune" trigger. We further show that serum from young autistic patients contains mtDNA (n = 20; cytochrome B, p = 0.0002 and 7S, p = 0.006), and anti-mitochondrial antibody Type 2 (n = 14; p = 0.001) as compared to normally developing, unrelated controls (n = 12). Extracellular blood mtDNA and other components may characterize an autistic endophenotype and may contribute to its pathogenesis by activating autoimmune responses.

Novel therapeutic targets for autism.

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. The diagnosis has increased considerably to approximately one in 180 people, but it is not clear whether this is because of a higher prevalence of the disorder, improved awareness by clinicians or a combination of both. There are no defined mechanisms of pathogenesis or curative therapy presently available. Oxidative stress, overactivation of the hypothalamic-pituitary-adrenal axis and increased gut-blood-brain-barrier permeability might be involved. The scope of this article is to integrate these findings and present the opinion that non-allergic activation of gastrointestinal and brain mast cells could contribute to many of the pathologic findings and provide unique targets for ASD therapy. We make suggestions for new research directives and possible novel therapies from readily available molecules.

Subject and Object Pronouns in High-Functioning Children With ASD of a Null-Subject Language.

Although the use of pronouns has been extensively investigated in children with autism spectrum disorders (ASD), most studies have focused on English, and no study to date has investigated the use of subject pronouns in null subject languages. The present study aims to fill this gap by investigating the use of subject and object pronouns in 5- to 8-year-old Greek-speaking high-functioning children with ASD compared to individually matched typically developing age and language controls. The "Frog where are you" (Mayer, 1969) narrative task was used to elicit subject and object pronouns as well as Determiner Phrases (DPs). Greek is a null subject language, and as a result, subject pronouns most often remain without phonological content. The findings showed that both groups used more null than overt subject pronouns, indicating that children with ASD know that Greek is a null subject language. TD children used more null subjects than subject DPs, whereas children with ASD used an equal proportion of null subjects and subject DPs. In terms of object pronouns, both groups produced more clitics and object DPs than strong object pronouns, but the difference between clitics and DPs did not reach significance in either of the groups. Importantly, the groups did not differ from each other in the use of ambiguous pronouns in both the subject and object position. The ASD children's avoidance to use pronominal subjects can be taken as evidence that they use a strategy to avoid infelicitous reference. This would suggest that the ASD children's difficulties with pronouns is not due to difficulties in core grammar.

Psychosocial perspective and suicidal behaviors correlated with adolescent male smoking and illicit drug use.

OBJECTIVES: To assess the prevalence of smoking and drug use among adolescent boys, and to examine adolescents' psychosocial factors, and suicidal behaviors associated with adolescents' substance use. METHODS: The Kuwait Global School-Based Student Health Survey employed a two-stage cluster sample design targeting a representative sample of adolescents. This study focused on the participated 1310 boys. Statistical analysis included Chi-square test, student t-test, and multivariate analysis. RESULTS: The mean age was 14.5 ± 0.03 years. The reported prevalence of: smoking, ever drug use, and both smoking and drug use were 26.6% (95% CI:24.2-29.1%) and 7.4% (95% CI:6.1-9.0%) and 5.5% (95% CI:4.4-6.9%) respectively. Logistic regression model analysis revealed that adolescents whose parents smoke, suffered from insomnia, were victims of bullying, and had negative social school environment, were more likely than others to be smokers, drug users or both. Addendum, suicidal ideation, and its combination with suicidal planning and/or suicidal attempt were significantly associated with smoking. The odds of these life-threatening behaviors increased when drug use was reported and augmented when both smoking and drug use were experienced. CONCLUSIONS: Prevalence of smoking and illicit drug use were high among adolescent boys. This study confirmed the association between adolescents' smoking and substance use with psychosocial context, and suicidal behaviors. Addressing these predictors would be crucial in the development of effective strategies targeting the prevention of smoking and substance use, which might consequently reduce suicidal behaviors among adolescents.

Prevalence and Associated Factors of Peer Victimization (Bullying) among Grades 7 and 8 Middle School Students in Kuwait.

Background. Peer victimization (bullying) is a universal phenomenon with detrimental effects. The aim of this study is to determine the prevalence and factors of bullying among grades 7 and 8 middle school students in Kuwait. Methods. The study is a cross-sectional study that includes a sample of 989 7th and 8th grade middle school students randomly selected from schools. The Revised Olweus Bully/Victim Questionnaire was used to measure different forms of bullying. After adjusting for confounding, logistic regression identified the significant associated factors related to bullying. Results. Prevalence of bullying was 30.2 with 95% CI 27.4 to 33.2% (3.5% bullies, 18.9% victims, 7.8% bully victims). Children with physical disabilities and one or both non-Kuwaiti parents or children with divorced/widowed parents were more prone to be victims. Most victims and bullies were found to be current smokers. Bullies were mostly in the fail/fair final school grade category, whereas victims performed better. The logistic regression showed that male gender (adjusted odds ration = 1.671, p = 0.004), grade 8 student (adjusted odds ratio = 1.650, p = 0.004), and student with physical disabilities (adjusted odds ratio = 1.675, p = 0.003), were independently associated with bullying behavior. Conclusions. There is a need for a school-wide professional intervention program and improvement in the students' adjustment to school environment to control bullying behavior.

Brief report: "allergic symptoms" in children with Autism Spectrum Disorders. More than meets the eye?

Many children with Autism Spectrum Disorders (ASD) have either family and/or personal history of "allergic symptomatology", often in the absence of positive skin or RAST tests. These symptoms may suggest mast cell activation by non-allergic triggers. Moreover, children with mastocytosis or mast cell activation syndrome (MCAS), a spectrum of rare diseases characterized by increased number of activated mast cells in many organs, appear to have ASD at a rate tenfold higher (1/10 children) than that of the general population (1/100 children). Mast cell activation by allergic, infectious, environmental and stress-related triggers, especially perinatally, would release pro-inflammatory and neurotoxic molecules. We speculate these could disrupt the gut-blood-brain barriers, thus contributing to brain inflammation and ASD pathogenesis. Increased mast cell responsiveness may define at least a subgroup of ASD subjects, who could benefit from inhibition of mast cell activation.

Cigarette smoking among Greek adolescents: behavior, attitudes, risk, and preventive factors.

UNLABELLED: This study was produced in the context of the first author's thesis at Athens University and was a collaboration between the Department of Clinical Care Medicine, Athens University, and Attiki Child Psychiatric Hospital. It was supported by a project grant from the THORAX Foundation, Greece. OBJECTIVE: To study the smoking behavior, attitudes, and beliefs of Greek adolescents, as well as the risk and preventive factors for the onset of smoking and to obtain data to serve in the planning of comprehensive antismoking campaigns tailored to the Greek adolescent's specific profile. SAMPLE AND METHOD: A stratified, nationwide, representative, school-based sample of 3827 Greek adolescents was surveyed during the academic year 2001-2002, using a questionnaire on smoking and Achenbach's Youth Self-Report. RESULTS: Cigarette smoking is a serious problem among Greek youth. Family and peers play a primary role in shaping smoking attitudes and habits. Adolescents who smoke regularly have increased rates of psychopathology as indicated by higher scores on the Externalising and Attention Problem scales of Achenbach's Youth Self-Report, compared to adolescents who are non-smokers. The data obtained can indeed guide smoking prevention strategies in Greece.