Natural IgG Anti-F (ab')2 Autoantibody Activity in Children with Autism.

Background: Many and diverse autoimmune abnormalities have been reported in children with autism. Natural autoantibodies (NAAbs) play important immunoregulatory roles in recognition of the immune self. The objective of this study was to examine the presence of NAAbs in the sera of children with autism and across severity subgroups of autistic behavioral impairments. Methods: NAAbs were titrated in sera through an ELISA procedure in 60 low-functioning children with autism and 112 typically developing controls matched for age, sex and puberty. Results: Serum titers of IgG anti-F(ab')2 autoantibodies were significantly lower in children with autism compared to typically developing controls (p < 0.0001), and were significantly negatively associated with autism severity (p = 0.0001). This data appears to be related more specifically to autism than to intellectual disability, given that IgG anti-F(ab')2 levels were significantly negatively correlated with IQ scores in the autism group (p = 0.01). Conclusions: This is the first report in autism of abnormally low natural anti-F(ab')2 autoantibody activity. The findings suggest a dysfunction of self-recognition mechanisms which may play a role in the pathogenesis of autism, especially for the severely affected children. These findings strengthen the hypothesis of an autoimmune process in autism and open the prospect of alternative medical treatment. Further neuroimmunological research is warranted to understand the exact mechanisms underlying this reduced natural IgG anti-F (ab')2 autoantibody activity, and to assess its impact on the pathophysiology and behavioral expression of autism.

Relationships Between Self-Injurious Behaviors, Pain Reactivity, and ß-Endorphin in Children and Adolescents With Autism.

OBJECTIVE: Autism and certain associated behaviors including self-injurious behaviors (SIB) and atypical pain reactivity have been hypothesized to result from excessive opioid activity. The objective of this study was to examine the relationships between SIB, pain reactivity, and ß-endorphin levels in autism. METHODS: Study participants were recruited between 2007 and 2012 from day care centers and included 74 children and adolescents diagnosed with autism (according to DSM-IV-TR, ICD-10, and CFTMEA) and intellectual disability. Behavioral pain reactivity and SIB were assessed in 3 observational situations (parents at home, 2 caregivers at day care center, a nurse and child psychiatrist during blood drawing) using validated quantitative and qualitative scales. Plasma ß-endorphin concentrations were measured in 57 participants using 2 different immunoassay methods. RESULTS: A high proportion of individuals with autism displayed SIB (50.0% and 70.3% according to parental and caregiver observation, respectively). The most frequent types of SIB were head banging and hand biting. An absence or decrease of overall behavioral pain reactivity was observed in 68.6% and 34.2% of individuals with autism according to parental and caregiver observation, respectively. Those individuals with hyporeactivity to daily life accidental painful stimuli displayed higher rates of self-biting (P < .01, parental evaluation). No significant correlations were observed between ß-endorphin level and SIB or pain reactivity assessed in any of the 3 observational situations. CONCLUSIONS: The absence of any observed relationships between ß-endorphin level and SIB or pain reactivity and the conflicting results of prior opioid studies in autism tend to undermine support for the opioid theory of autism. New perspectives are discussed regarding the relationships found in this study between SIB and hyporeactivity to pain.

Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders.

In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder). However, the underlying mechanisms of these associations remain to be ascertained and the cause-effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep-wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders). First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep-wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.

Melatonin: Pharmacology, Functions and Therapeutic Benefits.

BACKGROUND: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. METHODS: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. RESULTS: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. CONCLUSION: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.

Suicide attempts in children and adolescents: The place of clock genes and early rhythm dysfunction.

Suicide remains one of the leading causes of death among young people, and suicidal ideation and behavior are relatively common in healthy and clinical populations. Suicide risk in childhood and adolescence is often approached from the perspective of nosographic categories to which predictive variables for suicidal acts are often linked. The cascading effects resulting from altered clock genes in a pediatric population could participate in biological rhythm abnormalities and the emergence of suicide attempts through impaired regulation of circadian rhythms and emotional states with neurodevelopmental effects. Also, early trauma and stressful life events can alter the expression of clock genes and contribute to the emergence of suicide attempts. Alteration of clock genes might lead to desynchronized and abnormal circadian rhythms impairing in turn the synchronization between external and internal rhythms and therefore the adaptation of the individual to his/her internal and external environment with the development of psychiatric disorders associated with increased risk for suicide attempts.