Lipid Peroxidation via Regulating the Metabolism of Docosahexaenoic Acid and Arachidonic Acid in Autistic Behavioral Symptoms.

The association between the lipid peroxidation product malondialdehyde (MDA)-modified low-density lipoprotein (MDA-LDL) and the pathophysiology of autism spectrum disorder (ASD) is unclear. This association was studied in 17 children with ASD and seven age-matched controls regarding autistic behaviors. Behavioral symptoms were assessed using the Aberrant Behavior Checklist (ABC). To compensate for the small sample size, adaptive Lasso was used to increase the likelihood of accurate prediction, and a coefficient of variation was calculated for suitable variable selection. Plasma MDA-LDL levels were significantly increased, and plasma SOD levels were significantly decreased in addition to significantly increased plasma docosahexaenoic acid (DHA) levels and significantly decreased plasma arachidonic acid (ARA) levels in the 17 subjects with ASD as compared with those of the seven healthy controls. The total ABC scores were significantly higher in the ASD group than in the control group. The results of multiple linear regression and adaptive Lasso analyses revealed an association between increased plasma DHA levels and decreased plasma ARA levels, which were significantly associated with total ABC score and increased plasma MDA-LDL levels. Therefore, an imbalance between plasma DHA and ARA levels induces ferroptosis via lipid peroxidation. Decreased levels of α-linolenic acid and γ-linolenic acid may be connected to the total ABC scores with regard to lipid peroxidation.

Lipid Peroxidation of the Docosahexaenoic Acid/Arachidonic Acid Ratio Relating to the Social Behaviors of Individuals with Autism Spectrum Disorder: The Relationship with Ferroptosis.

Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy.

Brain Hypothermia Therapy and Targeted Temperature Management for Acute Encephalopathy in Children: Status and Prospects.

In adult intensive care, brain hypothermia therapy (BHT) was reported to be effective in neuroprotection after resuscitation and cardiac arrest. By contrast, in neonatal intensive care, the pathophysiology of brain damage caused by hypoxic-ischemic encephalopathy (HIE) is attributed to circulatory disturbances resulting from ischemia/reperfusion, for which neonatal brain cryotherapy is used. The International Liaison Committee on Resuscitation, 2010, recommends cerebral cryotherapy for HIE associated with severe neonatal pseudoparenchyma death. The usefulness of BHT for neuroprotection in infants and children, especially in pediatric acute encephalopathy, is expected. Theoretically, BHT could be useful in basic medical science and animal experiments. However, there are limitations in clinical planning for treating pediatric acute encephalopathy. No international collaborative study has been conducted, and no clinical evidence exists for neuroprotection using BHT. In this review, we will discuss the pathogenesis of neuronal damage in hypoxic and hypoperfused brains; the history of BHT, its effects, and mechanisms of action; the success of BHT; cooling and monitoring methods of BHT; adverse reactions to BHT; literature on BHT. We will review the latest literature on targeted temperature management, which is used for maintaining and controlling body temperature in adults in intensive care. Finally, we will discuss the development of BHT and targeted temperature management as treatments for pediatric acute encephalopathy.

A Comprehensive Review of Pediatric Acute Encephalopathy.

Acute encephalopathy typically affects previously healthy children and often results in death or severe neurological sequelae. Acute encephalopathy is a group of multiple syndromes characterized by various clinical symptoms, such as loss of consciousness, motor and sensory impairments, and status convulsions. However, there is not only localized encephalopathy but also progression from localized to secondary extensive encephalopathy and to encephalopathy, resulting in a heterogeneous clinical picture. Acute encephalopathy diagnosis has advanced over the years as a result of various causes such as infections, epilepsy, cerebrovascular disorders, electrolyte abnormalities, and medication use, and new types of acute encephalopathies have been identified. In recent years, various tools, including neuroradiological diagnosis, have been developed as methods for analyzing heterogeneous acute encephalopathy. Encephalopathy caused by genetic abnormalities such as CPT2 and SCN1A is also being studied. Researchers were able not only to classify acute encephalopathy from image diagnosis to typology by adjusting the diffusion-weighted imaging/ADC value in magnetic resonance imaging diffusion-weighted images but also fully comprehend the pathogenesis of vascular and cellular edema. Acute encephalopathy is known as a very devastating disease both medically and socially because there are many cases where lifesaving is sometimes difficult. The overall picture of childhood acute encephalopathy is becoming clearer with the emergence of the new acute encephalopathies. Treatment methods such as steroid pulse therapy, immunotherapy, brain hypothermia, and temperature control therapy have also advanced. Acute encephalopathy in children is the result of our predecessor's zealous pursuit of knowledge. It is reasonable to say that it is a field that has advanced dramatically over the years. We would like to provide a comprehensive review of a pediatric acute encephalopathy, highlighting advancements in diagnosis and treatment based on changing disease classification scenarios from the most recent clinical data.

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder.

The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new therapeutic strategies. Prostaglandin E2 is a membrane-derived lipid molecule that contributes to developing ASD associated with canonical Wnt signaling. Cyclooxygenase-2 plays a key role in neuroinflammation and is implicated in the pathogenesis of neurodevelopmental diseases, such as ASD. The endocannabinoid system maintains a balance between inflammatory and redox status and synaptic plasticity and is a potential target for ASD pathophysiology. Redox signaling refers to specific and usually reversible oxidation-reduction reactions, some of which are also involved in pathways accounting for the abnormal behavior observed in ASD. Redox signaling and redox status-sensitive transcription factors contribute to the pathophysiology of ASD. Cannabinoids regulate the redox balance by altering the levels and activity of antioxidant molecules via ROS-producing NADPH oxidase (NOX) and ROS-scavenging superoxide dismutase enzymes. These signaling cascades integrate a broad range of neurodevelopmental processes that may be involved in the pathophysiology of ASD. Based on these pathways, we highlight putative targets that may be used for devising novel therapeutic interventions for ASD.

Current Status of Internet Gaming Disorder (IGD) in Japan: New Lifestyle-Related Disease in Children and Adolescents.

The World Health Organization recognizes internet gaming disorder (IGD) as a disorder that causes problems in daily life as a result of excessive interest in online games. The causes of IGD have become more apparent in recent years. Because of prolonged exposure to games, the mechanisms controlling the reward system, such as the prefrontal cortex, limbic system, and amygdala of the cerebrum, do not function properly in IGD. This mechanism is similar to that of various behavioral addictions, such as gambling addiction. IGD is particularly risky in children and adolescents because it easily causes brain dysfunction, especially in the developing brain. IGD should be regarded as a new lifestyle-related disease in younger individuals, and lifestyle modifications, including counseling and family therapy, are critical for its management.

Increased cytokines/chemokines and hyponatremia as a possible cause of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with acute focal bacterial nephritis.

OBJECTIVE: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), the second most common encephalopathy syndrome in Japan, is most often associated with viral infection. Bacterial MERS has been rarely reported but is mostly associated with acute focal bacterial nephritis (AFBN) for an unknown reason. We examined cytokines and chemokines in four MERS patients with AFBN to determine if they play an important role in the pathogenesis. METHODS: We examined the clinical charts and MRI results in four MERS patients with AFBN, and measured 10 cytokines and chemokines in serum and cerebrospinal fluid in the acute phase. These were analyzed using the Mann-Whitney U test, compared with the control group (cases with a non-inflammatory neurological disease). Longitudinal changes in the serum cytokine and chemokine levels were evaluated in two patients. RESULTS: Hyponatremia was observed in all four patients with MERS associated with AFBN (128-134 mEq/L). CSF analysis revealed increased cytokines/chemokines associated with Th1 (CXCL10, TNF-α, IFN-γ), T reg (IL-10), Th17 (IL-6), and neutrophil (IL-8 and CXCL1). In serum, upregulation was observed in those associated with Th1 (CXCL10, TNF-α, IFN-γ), Th17 (IL-6), and inflammasome (IL-1ß). The increased serum cytokines/chemokines in the acute stage normalized within 2 weeks in patients 1 and 2, so examined, in accordance with their clinical improvement. CONCLUSION: Increased cytokines/chemokines and hyponatremia may be factors that explain why AFBN is likely to cause MERS.

Urinary and Plasma Antioxidants in Behavioral Symptoms of Individuals With Autism Spectrum Disorder.

The balance between antioxidant capacity and oxidative stress-induced free radicals may be crucial in the pathophysiological development factor of autism spectrum disorder (ASD). We measured the following urinary and plasma biomarker levels of oxidative stress and antioxidants. As urinary biomarkers, (1) hexanoyl-lysine (HEL), which is a new biomarker of oxidative stress, (2) the total antioxidant capacity (TAC), and (3) 8-hydroxy-2'-deoxyguanosine (8-OHdG), as a product of oxidative modifications to DNA; and the plasma levels of (4) the antioxidant protein superoxide dismutase (SOD), which is the crucial defense again oxygen reactive species, and (5) transferrin and (6) ceruloplasmin, which are biomarkers of iron and copper neurotransmission and oxidant-antioxidant systems. We examined the relationship between these urinary and plasma biomarkers and behavioral symptoms in 19 individuals with ASD (mean age, 10.8 ± 5.2 years) and 10 age-matched healthy controls (mean age, 14.2 ± 7.0 years). Behavioral symptoms were estimated using the Aberrant Behavior Checklist (ABC). Urinary TAC levels were significantly lower, whereas urinary HEL levels were significantly increased in the ASD group as compared with the control group. The five ABC subscale and total scores were significantly raised in the autism group than in the control group. The results of a linear regression analysis revealed that plasma SOD levels may be a more accurate predictor of differences in ABC scores between individuals with ASD and control individuals. The present study firstly revealed the important findings that the cooperation between the urinary antioxidant TAC and plasma SOD levels may contribute to the ABC subscale scores of stereotypy. Urinary TAC activity and antioxidant protein SOD may be associated with incomplete mineral body store and antioxidant-related transcription factor and browning reactions. Consequently, a critical imbalance between TAC urinary levels and plasma SOD levels may be an important contributor to autistic behavioral symptoms.

Postinfectious Bronchiolitis Obliterans Misdiagnosed as Bronchial Asthma in a Pediatric Patient.

Bronchiolitis obliterans is a chronic obstructive respiratory disease involving stenosis or occlusion of the bronchioles and smaller airways. The prognosis of bronchiolitis obliterans is poor, and the patient might require home oxygen therapy and/or lung transplantation. Bronchiolitis obliterans has various etiologies; in children, the most common causes are infections by respiratory pathogens like adenoviruses. In such cases, the condition is termed as postinfectious bronchiolitis obliterans. A 7-year-old girl was diagnosed with bronchial asthma at the age of 1 year and was on a regimen of a leukotriene receptor antagonist and an inhaled corticosteroid. At 1 year of age, she was admitted to our hospital with a respiratory syncytial virus infection, and despite continued treatment with the above drugs, she required frequent readmissions. At the age of 7 years, she was diagnosed with postinfectious bronchiolitis obliterans based on the following findings: mosaic perfusion on high-resolution chest computed tomography and ventilation-perfusion mismatch on ventilation-perfusion scintigraphy. A lung biopsy was not performed due to its invasiveness. It has been suggested that appropriate treatment during the early stage improves the prognosis of bronchiolitis obliterans. This disease might be misdiagnosed as bronchial asthma because of the clinical similarities. In patients who do not respond to the treatment for bronchial asthma, pediatricians should consider other diseases with similar signs and symptoms, such as bronchiolitis obliterans, in the differential diagnosis.

Lipid Peroxidation With Implication of Organic Pollution in Autistic Behaviors.

Background Lipid metabolism has been associated with the development of autism. The omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) readily undergo lipid peroxidation and conversion to malondialdehyde (MDA). MDA-modified low-density lipoprotein (MDA-LDL) is a marker of lipid peroxidation. However, the association between PUFAs and MDA-LDL in the pathophysiology of autism spectrum disorder (ASD) is unclear. Materials and methods We studied the association between PUFAs and MDA-LDL in 16 individuals with ASD (mean age: 11.5 ± 5.7 years) and seven age- and sex-matched healthy controls (mean age: 10.0 ± 4.1 years). The Aberrant Behavior Checklist (ABC) was used to assess behavioral symptoms. We overcame the small sample size by using the adaptive LASSO for enhancing the accuracy of prediction and interpretability. We also estimated the coefficient of variation for an appropriate variable selection and compared additional prior studies to support the findings. Thus, we conducted a careful selection of appropriate candidates to account for confounding variables. Results The ASD group had significantly higher plasma MDA levels, eicosapentaenoic acid levels, and a higher ratio of plasma docosahexaenoic acid (DHA)/arachidonic acid (ARA) levels than the control group. Plasma levels of the omega-6 PUFA fraction, dihomo-γ-linolenic acid, and superoxide dismutase levels were significantly lower in the ASD group than in the control group. Total ABC scores were significantly higher in the ASD group than in the control group. Multiple linear regression and adaptive LASSO indicated that plasma DHA levels and plasma DHA/ARA ratios were significantly associated with total ABC scores and plasma levels of MDA-LDL. Conclusion Increased plasma levels of DHA and DHA/ARA ratio might be related to organic pollution. These neurobiological bases may induce neuronal deficiency associated with autistic behavioral symptoms in individuals with ASD.

Guidelines for the diagnosis and treatment of acute encephalopathy in childhood.

The cardinal symptom of acute encephalopathy is impairment of consciousness of acute onset during the course of an infectious disease, with duration and severity meeting defined criteria. Acute encephalopathy consists of multiple syndromes such as acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion and clinically mild encephalitis/encephalopathy with reversible splenial lesion. Among these syndromes, there are both similarities and differences. In 2016, the Japanese Society of Child Neurology published 'Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood', which made recommendations and comments on the general aspects of acute encephalopathy in the first half, and on individual syndromes in the latter half. Since the guidelines were written in Japanese, this review article describes extracts from the recommendations and comments in English, in order to introduce the essence of the guidelines to international clinicians and researchers.