Chihiro Sawai

Seizure Susceptibility Due to Antihistamines in Febrile Seizures

The aim of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures. The study population comprised 14 patients with simple febrile seizures and 35 patients with complex febrile seizures. Detailed clinical manifestations were compared between patients with and without administration of antihistamine. The time from fever detection to the seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than that in nonantihistamine group. Interleukin-1beta is thought to be associated with causing febrile seizures via its dual role as a pyrogen and convulsant substance. Moreover, interleukin-1beta may activate the turnover of hypothalamic neural histamine. These considerations, along with the present results, suggest that the depletion of hypothalamic neuronal histamine induced by antihistamines may increase neuronal excitability, thereby increasing seizure susceptibility in patients with febrile seizures.

Radial and Tangential Neuronal Migration Disorder in Ibotenate-Induced Cortical Lesions in Hamsters: Immunohistochemical Study of Reelin, Vimentin, and Calretinin

To investigate the mechanisms of radial and tangential neuronal migration disorders, immunohistochemical expressions of reelin, vimentin, and calretinin were examined in brain lesions induced by ibotenate (an agonist of the N-methyl-D-aspartate [NMDA] complex receptor) in hamsters. Thirty-four newborn hamsters were subjected to intracerebral injections of ibotenate, and 12 animals served as the control. These hamsters were examined at 1, 2, 3, 5, and 7 days after injections. The cortical lesions observed after ibotenate injections had a strong resemblance to the following neuronal migration disorders: (1) microgyria, (2) focal subcortical heterotopia, and (3) leptomeningeal glioneuronal heterotopia. In microgyria, the radial glial fibers were sparsely distributed, but in leptomeningeal glioneuronal heterotopia, vimentin-positive fibers extended into this abnormal neural tissue. Calretinin-immunoreactive neurons and fibers were present along the lesion forming the microgyria and abnormal neuronal arrangement. Focal subcortical heterotopia also included a small number of calretinin-expressing neurons originating from the subplate neuronal population. These results imply that the neuronal migration disorders produced by ibotenate show not only the migrational arrest of neurons but also interference from the termination of the migration process. We also suggest that the heterotopic neurons constituting the focal subcortical heterotopia originate in the lateral or medial ganglionic eminence of the ventral telencephalon, probably caused by the abnormal tangential neuronal migration. (J Child Neurol 2004;19:107—115).

Effect of additional auditory and visual stimuli on continuous performance test (noise-generated CPT) in AD/HD children - usefulness of noise-generated CPT

The continuous performance test (CPT) is designed to measure sustained attention quantitatively. Several CPTs are used clinically. We have made changes to the conventional type of visual CPT, by displaying auditory and visual noise along with target or non-target stimuli. By influencing the recognition of the subjects in this way, the changes were intended to increase the sensitivity of detection of inattention and impulsiveness, to make CPT more useful for diagnosis, and to examine the effect of noise on AD/HD children during CPT performance. Its usefulness for AD/HD diagnosis and the reaction of AD/HD children to noise were examined using newly developed computer software. Using this CPT analysis, a significant difference was observed in all measurements, except mean reaction time, between the control and AD/HD groups, showing that it was useful as a supplementary diagnostic method for AD/HD, and was more useful in the younger age group than in the older age group, as the same for conventional CPTs. As compared to no-noise sessions, commission and omission errors both increased significantly in auditory and visual noise sessions. Thus, analyzing the changes in measurements during noise sessions will improve the diagnosis of inattention and combined AD/HD subtypes. Furthermore, it was suggested that analysis of the effects of noise on AD/HD children will benefit their handling in an educational environment. Since omission errors were decreased in AD/HD children by noise during the CPT performance as compared to the control group, noise may induce attention in AD/HD children. The present study presents new findings on the responses to noise of AD/HD children during the CPT.

A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders

Fecal and blood samples of infants with autism spectrum disorders (ASD) and healthy infants were analyzed to investigate the association of altered gut microbiota and ASD development. 16S rRNA gene-based sequencing found that, unlike those of healthy infants, feces of ASD infants had significantly higher and lower abundance of genera Faecalibacterium and Blautia, respectively. Moreover, DNA microarray analysis of peripheral blood mononuclear cells (PBMC) detected more highly than low expressed genes in ASD infants than in healthy infants. Gene Ontology analysis revealed that differentially expressed genes between ASD and healthy infants were involved in interferon (IFN)-γ and type-I IFN signaling pathways. Finally, strong positive correlations between expression of IFN signaling-associated genes in PBMC and fecal abundance of Faecalibacterium were found. Our results strongly suggested that altered gut microbiota in infants resulted from ASD development and was associated with systemic immunity dysregulation, especially chronic inflammation. Graphical abstract Altered gut microbiota in autistic infants play a role in chronic inflammation induced by interferon signaling that may cause further inflammation in central nervous system.

Polymicrogyria without epilepsy by aberrantly migrating inhibitory interneurons.

Polymicrogyria is the presence of an excess number of abnormally small gyri that produce an irregular cortical surface. Although polymicrogyria is associated with severe epilepsy in 65% of patients [1], few data concerning the epileptogenic zone and its relationship with the polymicrogyric tissue are available because patients with polymicrogyria are rarely considered suitable candidates for epilepsy surgery [2]. An experimental model in which a single or few microgyri are generated by a freezing insult suggests a widespread area of functional disruption that extends beyond the visualized abnormality [3]. However, the detailed mechanism of epileptogenesis has not yet been well characterized for polymicrogyria [4]. We previously demonstrated that the intracerebral injection of ibotenate produces excitotoxic brain lesions to mimic neuronal migration disorders [5]. We also reported that subventricular zone cells play an important role in the formation of cortical dysplasia [6]. Based on these experimental studies, we conducted a neuronal tracing study for progenitor cells in the ganglionic eminence, and thereby demonstrated that the interneurons are mobilized to the microgyric area out of the ganglionic eminence, which thus leads to the construction of a part of the abnormal neuronal arrangement of this microgyria. All procedures used in the study described here were approved by the Committee on Animal Experimentation and Animal Care of Shiga University of Medical Science, Japan. One microgram (1 μL) of ibotenate (Sigma, St. Louis, MO, USA) was injected intracerebrally into 18 Syrian hamsters within 24 hours of birth (postnatal day 0 [P0]) using stereotaxic methods as described previously [5]. Biotinylated dextran amine (BDA-10000 Neuronal Tracer Kit, N7167; Molecular Probes, Eugene, OR, USA) was used as a neuronal tracer. BDA is a highly sensitive tool in anterograde and retrograde pathway tracing studies of the nervous system. The high-molecularweight BDA employed in this experiment yields sensitive and exquisitely detailed labeling of axons and terminals using preferentially anterograde transport. After the ibotenate injection, 1 μL (0.05 μg) of BDA was injected into the ganglionic eminence of the identical hemisphere with a 5-μl Hamilton syringe at P0, as also described previously [6]. Seven animals injected in the same manner with the same amount of phosphate-buffered saline served as the control group. BDA immunohistochemistry and hematoxylin and eosin staining were performed on P1, P2, and P5. One day after ibotenate injection (P1), the resultant cortical lesion was recognized as a disorganized neuronal arrangement, extending from the marginal zone to the ventricular zone. On P5, the cortical lesions were restricted to the marginal zone and superficial layer of the

Experimental cortical dysplasia following ibotenate administration in hamsters: Pathogenesis of microgyria and associated gray matter heterotopia

ABSTRACT  The study presented here investigated the pathogenetic relationship among different types of neuronal migration disorders occurring simultaneously in the brain using an experimental model induced by ibotenate in hamsters. In the cerebral cortex, abnormal neuronal arrangement was induced 1 day after ibotenate injection. This brain lesion resulted in microgyria in the rostral portion, focal subcortical heterotopia in the mid‐portion, and focal subependymal heterotopia in the caudal portion in the same specimen. Vimentin‐immunoreactive radial glial fibers were lacking in the area of disorganized neuronal arrangement, but were detected around the microgyria and the intermediate zone surrounding focal subcortical heterotopia. The focal subependymal heterotopia did not include radial glial elements. Glial fibrillary acidic protein (GFAP)‐positive glial reaction was weak in these cortical lesions. We suggest that the occurrence of each type of migration disorder depends on the depth of the cortical lesion, that is, the production of microgyria, focal subcortical heterotopia and focal subependymal heterotopia are closely related to the lesions including the cortical plate, subplate and ventricular zone, respectively.

Peters' anomaly with bilateral perisylvian polymicrogyria and abdominal calcification

ABSTRACT  We report a neonatal case of Peters’ anomaly with bilateral perisylvian polymicrogyria and abdominal calcification. The male infant was born after a normal labor. Bilateral central corneal opacities with iridocorneal strands indicated Peters’ anomaly. The X‐ray and abdominal computed tomography demonstrated multiple calcifications beneath the diaphragma around the liver and the spleen. TORCH serology was negative. Intracranial calcification was not detected. Brain magnetic resonance imaging demonstrated bilateral perisylvian polymicrogyria. Abdominal calcification was suspected to be related to vascular disruption. Bilateral perisylvian polymicrogyria has been thought to result from ischemic events such as intrauterine hypotension or vascular occlusions. Based on these considerations, we conclude that a vascular disruption sequence may an important pathogenetic mechanism of Peters’ anomaly.

High molecular weight microtubule-associated protein 2 over-expression in neuronal migration disorders caused by N-methyl-D-aspartate receptor activation in hamsters.

ABSTRACT  To evaluate the neuronal cytoarchitectural changes in neuronal migration disorders, the immunohistochemical expression of microtubule‐associated proteins (MAPs) was analyzed using the experimental model induced by ibotenate in newborn hamsters. The cortical lesions observed after intracerebral ibotenate injections strongly resembled the following neuronal migration disorders: (1) microgyria; (2) focal subcortical heterotopia; (3) focal subependymal heterotopia; and (4) leptomeningeal glioneuronal heterotopia. Microgyria and leptomeningeal glioneuronal heterotopia had MAP2 (HM‐2: high and low‐molecular‐weight forms of MAP2) immunoreactive dendritic processes or neuronal elements. The high molecular weight isoform of MAP2 (AP‐20), which is more characteristic of mature neurons, showed enhanced expression in neurons of focal subcortical or subependymal heterotopia, although MAP1B (AA6: early form of MAP) immunoreactive elements were not detected in these heterotopic areas. We conclude that high molecular weight isoform of MAP2 is closely associated with cytoarchitectural repair and remodeling of neuronal processes, resulting in neuronal heterotopia after NMDA receptor activation.

A preliminary study of gut dysbiosis in children with food allergy

Gut microbiota of food allergic children was analyzed by high throughput 16S rRNA gene sequencing. Signs of gut dysbiosis, which is likely associated with gut inflammation, was observed in children with food allergies. For example, decreased abundance of genus Akkermansia but increased abundance of Veillonella was found in children with food allergy in comparison with healthy control children.