The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.

Quantitative analysis of itching in patients with itching dermatitis including atopic dermatitis (AD) is indispensable for the evaluation of disease activity and response to therapy. However, the objective evaluation system for itching is limited. We have developed a new objective and quantitative scratching behavior detection system using a wristwatch-type sound detector. The scratch sound detected on the wrist is recorded on a personal computer through a filtering, squaring and smoothing process by specific hardware. Subsequently, the data is automatically processed and judged for the scratching movement using specific software based on the periodicity and energy of the signal. Twenty-four measurements for healthy volunteers and those with AD by this system were evaluated by comparison with a simultaneously recorded video analysis system. The ratio of scratching time in sleeping time evaluated by these two systems was almost identical. The healthy subjects scratched their skin approximately 2 min during 6 h of sleeping time, while the mean scratching time of AD subjects was 24 min in their sleeping time. In contrast to the time-consuming video analysis system, this system takes only several minutes for evaluation of an overnight record. This scratch sound detection system is expected to serve as a new objective evaluation tool for itching dermatitis, namely, AD, and development of anti-itch therapies for dermatitis.

Callosal injury in preterm infants is a key factor affecting neurodevelopmental outcome. We investigated the characteristics of corpus callosum (CC) in preterm infants without apparent white matter lesions. We studied 58 preterm infants divided into three groups of 23-25, 26 -29, and 30 -33 wk GA. Diffusion tensor imaging (DTI) was obtained at term-equivalent age. The CC was parcellated into the genu, body, isthmus, and splenium. We measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of each CC subdivision using tractography and manual region of interest analysis. The cross-sectional areas were also measured. At the isthmus and splenium in the 23-25 GA group, the FA was significantly lower and the size was also significantly reduced. Furthermore, the FA and cross-sectional areas in the posterior CC decreased linearly with decreasing GA. There were no differences in FA and cross-sectional areas in other CC subdivisions, and no differences in ADC in any CC subdivisions, among the GA groups. We demonstrated that preterm infants without apparent white matter lesions affect development of the posterior CC depending on the degree of prematurity. (Pediatr Res 69: 249-254, 2011)

SUMMARYSyntaxin-binding protein 1 (STXBP1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene, STXBP1, are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of STXBP1 haploinsufficiency has not been elucidated. Using patient-derived induced pluripotent stem cells (iPSCs), we aimed to establish a neuronal model for STXBP1 haploinsufficiency and determine the pathophysiologic basis for STXBP1 encephalopathy. We generated iPSC lines from a patient with Ohtahara syndrome (OS) harboring a heterozygous nonsense mutation of STXBP1 (c.1099C>T; p.R367X) and performed neuronal differentiation. Both STXBP1 messenger RNA (mRNA) and STXBP1 protein expression levels of OS-derived neurons were approximately 50% lower than that of controlderived neurons, suggesting that OS-derived neurons are a suitable model for elucidating the pathophysiology of STXBP1 haploinsufficiency. Through Western blot and immunocytochemistry assays, we found that OS-derived neurons show reduced levels and mislocalization of syntaxin-1, a component of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins. In addition, OS-derived neurons have impaired neurite outgrowth. In conclusion, this model enables us to investigate the neurobiology of STXBP1 encephalopathy throughout the stages of neurodevelopment. Reduced expression of STXBP1 leads to changes in the expression and localization of syntaxin-1 that may contribute to the devastating phenotype of STXBP1 encephalopathy. KEY WORDS: Ohtahara syndrome, Induced pluripotent stem cell, SNARE complex.Epileptic encephalopathies (EEs) are a group of devastating epileptic disorders, occurring at a critical period of brain development, where frequent seizures and/or persistent severe electroencephalography (EEG) abnormalities lead to behavioral, cognitive, and motor deterioration or regression. EEs have numerous causes, including damage to or malformation of the brain. In cases without such identifiable causes, recent investigations have found disease-causing mutations in several genes. Studies of mutations in these genes can help elucidate the pathophysiology of diseasecausing alterations in the nervous system, encouraging progress toward new treatments.Ohtahara syndrome (OS), also known as early infantile EE with suppression-burst (S-B), is one of the most severe and earliest forms of EE. Mutations in STXBP1 are among the most frequent genetic causes of OS.1 In addition, STXBP1 mutations result in not only OS but also West