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For assessment of the potential of the Beppu Bay sediments as a Global boundary Stratotype Section and Point (GSSP) candidate for the Anthropocene, we have integrated datasets of 99 proxies. The datasets for the sequences date back 100 years for most proxy records and 1300 years for several records. The cumulative number of occurrences of the anthropogenic fingerprint reveal unprecedented increases above the base of the 1953 flood layer at 64.6 cm (1953 CE), which coincides with an initial increase in global fallout of 239Pu+240Pu. The onset of the proliferation of anthropogenic fingerprints was followed by diverse human-associated events, including a rapid increase in percent modern 14C in anchovy scales, changes in nitrogen and carbon cycling as recorded by anchovy δ15N and δ13C, elevated pollution of heavy metals, increased deposition of novel materials (spheroidal carbonaceous particles, microplastics, polychlorinated biphenyls), the occurrence of hypoxia (Re/Mo ratio) and eutrophication (biogenic opal, TOC, TN, diatoms, chlorophyll a), unprecedented microplankton community changes (compositions of carotenoids, diatoms, dinoflagellates), abnormally high spring air temperatures as inferred from diatom fossils, and lithological changes. These lines of evidence indicate that the base of the 1953 layer is the best GSSP level candidate in the stratigraphy at this site.

Heterozygous variants in TUBB encoding one of β-tubulin isotypes are known to cause two overlapping developmental brain disorders, complex cortical dysplasia with other brain malformations (CDCBM) and congenital symmetric circumferential skin creases (CSCSC). To date, six cases of CSCSC and eight cases of CDCBM caused by nine heterozygous variants have been reported. Here we report two cases with novel de novo missense TUBB variants (NM_178014.4:c.863A>G, p.(Glu288Gly) and c.869C>T, p.(Thr290Ile)). Case 1 presented brain malformations consistent with tubulinopathies including abnormalities in cortex, basal ganglia, corpus callosum, brain stem, and cerebellum along with other systemic features such as coloboma, facial dysmorphisms, vesicoureteral reflux, hypoplastic kidney, and cutis laxa-like mild skin loosening. Another case presented abnormalities of the corpus callosum, brain stem, and cerebellum along with facial dysmorphisms. We reviewed previous literature and suggest the diversity of clinical findings of TUBB-related disorders.

Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated.Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments.A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD), with an estimated frequency of 1 per 2,200,000 births in Japan. Patients with ARG1 deficiency develop symptoms in late infancy or pre-school age with progressive neurological manifestations and sometimes present with severe hepatic disease. We previously investigated the status of UCDs in Japan; however, only one patient was identified as having ARG1 deficiency. Therefore, we aimed to investigate the current status of patients with ARG1 deficiency in 2018–2021 because almost 10 years have passed since the previous study. We present the disease history, clinical outcome, and treatment of five surviving patients with ARG1 deficiency and discuss the features of ARG1 deficiency in Japan. We found that clinicians often face difficulty in diagnosing ARG1 deficiency at the early stage of onset because of interpatient variability in onset time and clinical manifestations. Blood L-arginine and guanidino compounds were considered to be the major factors causing adverse neurodevelopmental outcomes. Therefore, early detection and intervention of ARG1 deficiency is essential for improved neurodevelopmental outcomes. Liver transplantation has been considered an effective treatment option that can dramatically improve the quality of life of patients, prior to the neurological manifestation of symptoms caused by ARG1 deficiency.

This multicenter study examined the effectiveness and tolerability of lacosamide (LCM) for children and young adults with epilepsy, particularly in patients who had previously been treated with other sodium channel blockers (SCBs) and the difference in effectiveness and tolerability when using other concomitant SCBs.We retrospectively studied the clinical information of patients aged30 years given LCM to treat epilepsy. The effectiveness and adverse events (AEs) of LCM and the other SCBs were investigated. Factors related to the effectiveness and AEs of LCM, such as the number of antiepileptic drugs (AEDs) tried before LCM and concomitantly used SCBs, were also studied.We enrolled 112 patients (median age = 11 years). One year after starting LCM, 29% of the patients were seizure free, and 50% had a ≥50% seizure reduction. Of the patients, 17% experienced AEs, the most common being somnolence. A ≥50% seizure reduction was observed for LCM in 30% of patients in whom other SCBs had not been effective. Lacosamide produced a ≥50% seizure reduction in 35% of the patients taking one concomitant SCB. By contrast, no patients had ≥50% seizure reduction, and 33% developed AEs, when LCM was administered concomitantly with two SCBs.Lacosamide was effective in 30% of children and young adults in whom other SCBs had not been effective. The effectiveness of LCM may differ from that of other SCBs, and it is worth trying in patients with epilepsy resistant to other AEDs.

Volcanoes in the East Asian/Pacific region have been the source of some of the largest magnitude eruptions during the Late Quaternary, and accurately evaluating their eruptive histories is essential for hazard assessments. To overcome difficulties in resolving and precisely dating eruptions in the near‐source realm, the high‐resolution (varved) sediments of Lake Suigetsu (central Honshu, Japan) were examined for the presence of non‐visible (cryptotephra) layers from 50 ka up until the 30 ka Aira‐Tanzawa (AT) caldera‐forming event of Aira volcano. Cryptotephra layers are four times more frequently preserved than visible markers in the Suigetsu sediments, meaning that this archive provides a unique and unprecedented record of eruptions that were dispersed over the densely populated regions of central Honshu. Major and trace element volcanic glass chemistry is used to fingerprint the ash layers and pinpoint their volcanic origin. Tephras are found throughout the investigated sediments, but the highest abundance of ash fall events are recorded between 39 and 30 ka, capturing a period of intense volcanism at calderas on Kyushu Island (Japan). The augmented Suigetsu tephrostratigraphy records at least seven eruptions from Aso caldera (southern Kyushu) that post‐date the widespread ACP‐4 Plinian eruption (ca. 50 ka) and four explosive events from Aira (central Kyushu) that occurred leading up to the catastrophic caldera‐forming AT eruption (ca. 30 ka).

Objectives Long‐term adrenocorticotropic therapy (LT‐ACTH), which consisted of 2‐4 weeks of daily injections of adrenocorticotropic hormone (ACTH) and subsequent months of weekly injections, was tried for relapsed West syndrome (WS) or other intractable epilepsies in small case reports. Our aim was to explore the efficacy of LT‐ACTH for preventing WS relapse, as well as the prevalence of its adverse events. Methods This is a retrospective, nationwide, multicenter case series of patients with WS who underwent LT‐ACTH. Clinical information of the patients and protocol of LT‐ACTH were collected from participating institutes in this study. We defined clinical response to ACTH as achievement of hypsarrhythmia and epileptic spasms resolution. Patients who responded to daily ACTH injections were identified and assessed whether they experienced WS relapse during/after the weekly ACTH injection period. The outcome was measured by the nonrelapse rate at 24 months after daily ACTH injections using the Kaplan‐Meier method. Results Clinical information of 16 children with WS was analyzed. The median age at LT‐ACTH initiation was 14.5 months (range: 7‐68 months). Thirteen (81%) patients had previously undergone conventional ACTH treatment. The LT‐ACTH regimens comprised a median of 16 days of daily injections (range: 11‐28 days) and 10 months of weekly injections (range: 3‐22 months). Seven patients experienced WS relapse during/after subsequent weekly ACTH period, and the nonrelapse rate at 24 months after daily injections was estimated at 60.6% (95% confidence interval: 32.3%‐80.0%). Height stagnation, hypertension, and irritability were observed; lethal adverse events were not reported. Significance Our study firstly explored the efficacy of LT‐ACTH for preventing WS relapse. LT‐ACTH might be a treatment option for patients with relapsed or intractable WS; however, we note that our study is limited by its small sample size and the lack of an appropriate control group.

Background There are few studies on hiragana reading skill and phonological awareness in Japanese schoolchildren with periventricular leukomalacia (PVL). Methods Three seven-year-old children with PVL who had no intellectual disabilities or dysarthria were recruited. Their perinatal information, brain magnetic resonance image (MRI) at term equivalent age, accompanying neurodevelopmental disorders, ophthalmologic features, Kaufman Assessment Battery for Children (K-ABC), a hiragana reading test (four tasks), and a phonological awareness task (mora reversal tasks) were analyzed. Results Patient (Pt) 1 and pt2 were male. Pt2 and pt3 were siblings of triplets. Their gestational age was 28 or 32 weeks, and their birth weights were 1196, 1554, and 1848 g, respectively. Their brain MRI revealed cystic or non-cystic periventricular white matter injury involving the deep white matter at the trigone of both lateral ventricles. Pt1 had attention-deficit/hyperactivity disorder and pt3 had pervasive developmental disorder not otherwise specified. All patients had strabismus with spared best-corrected visual acuity. Scores of Reading/Decoding in K-ABC ranged from 89 to 99. As for the single mora reading task or the non-word reading task in the kana reading test, Z scores of their reading time ranged from 2.3 to 5.9 compared to control children. Pt1 and pt3 made significant errors in the mora reversal task of three-mora words, whereas all patients could answer all words correctly in the mora reversal task of two-mora words. Conclusion All children showed significantly prolonged reading time despite their adequate letter recognition. Two patients showed delayed phonological awareness. It was suggested that hiragana decoding impairment due to subcortical and/or cortical injury related to PVL affected their reading ability.

Tephra (volcanic ash) layers have the potential to synchronise disparate palaeoenvironmental archives on regional to hemispheric scales. Highly productive arc regions, like those in East Asia, offer a considerable number of widespread isochrons, but before records can be confidently correlated using these layers, a refined and integrated framework of these eruptive events is required. Here we present the first high-resolution Holocene cryptotephra study in East Asia, using the Lake Suigetsu sedimentary archive in central Japan. The Holocene tephrostratigraphy has been extended from four to twenty ash layers using cryptotephra extraction techniques, which integrates the deposits from explosive eruptions from North Korea/China, South Korea and along the Japanese arc. This Lake Suigetsu tephrostratigraphy is now the most comprehensive record of East Asian volcanism, and the linchpin site for correlating sequences across this region. Major element glass geochemical compositions are presented for the tephra layers in the sequence, which have been compared to proximal datasets to correlate them to their volcanic source and specific eruptions. This study has significantly extended the ash dispersal of many key Holocene marker layers, and has identified the first distal occurrence of isochrons from Ulleungdo and Changbaishan volcanoes. Utilising the high-precision Lake Suigetsu chronology, we are able to provide constrained eruption ages for the tephra layers, which can be transferred into other site-specific age models containing these markers. This new framework indicates that several isochrons stratigraphically bracket abrupt climate intervals in Japan, and could be used to precisely assess the regional and hemispheric synchronicity of these events.

A self-assembled nanofiber film of octabutoxy-phthalocyanine (H2PCOC4) was prepared by a simple spin-coating method with a mixed solvent. This film indicated a high vertical hole mobility up to 0.12 cm2 V−1 s−1 when the nanofiber structure is formed from a mixed solvent of chloroform and o-dichlorobenzene. The high vertical mobility is attributed to the unique crystal structure of H2PCOC4 and molecular arrangement in the fiber film. Quantum chemical calculations reveal that the crystal structure of H2PCOC4 enables two-dimensional carrier transport that is advantageous for the vertical transport. The nanofiber films were applied to vertical-type organic transistors, resulting in higher output current compared to a non-structured film.

Fossil pollen grains have long been recognised as potentially ideal materials for radiocarbon dating. In recent years, the development of cell sorter technology has made it possible to date fossil pollen grains. Although various approaches have been proposed, none of them is being practiced routinely because of the difficulty in stably and efficiently extracting small fossil grains at high enough purity from a variety of sediments. Here we show a new method which allows routine extraction and reliable radiocarbon dating of fossil pollen grains, even from organic-rich sediments. The improved physicochemical pre-treatment enables efficient enrichment from large volume of organic-rich sediments without the use of an oxidant. We also propose new sorting criteria consisting of multi-step ‘gates’, each of which is based upon fluorescence characteristics and scattered light of the particles. The sorting method, combined with the improved physicochemical pre-treatments, makes it possible to separate small fossil pollen grains from impurities such as green algae, micro charcoal, spores and plant fragments using a cell sorter. In particular, relatively small fossil pollen grains, with which previously proposed methods tended to suffer, could be extracted from organic-rich lacustrine sediments and organic peats in a remarkably high purity and velocity using our method. Radiocarbon ages subsequently measured on fossil pollen concentrates prepared by our method show very good agreement with those of terrestrial leaf fossils extracted from the same sediments of Lake Suigetsu, which directly record atmospheric 14C. The extraction method provides a new opportunity to routinely determine ages of sediments that do not contain contemporaneous macrofossil remains, and allow us to increase the precision of age models by strategically selecting horizons for dating prior to incorporation into Bayesian chronological modelling.

Background The characteristics of epilepsy in patients with Kabuki syndrome with KMT2D mutations (KABUK1) have not yet been well documented. This is the first review to explore this. Materials & methods We enrolled 14 patients with KABUK1, whose median age was 13.6 years (range = 4.1–21.3 years). Their medical records from October 1981 to May 2016 were retrospectively analyzed. Results Epilepsy was present in 5 (36%) patients. Four of these patients presented with nonsense mutations and one with missense mutations. None presented with brain abnormalities. Four patients presented with annual or monthly focal seizures, of which three evolved to bilateral convulsive seizures. Median onset age of focal epilepsy was 11.8 years (range = 9.5–12.8 years). One presented with monthly myoclonic seizures from age 11.2, whose mother with no other KABUK1 features, had focal epilepsy. The cumulative incidence of epilepsy related to KABUK1 up until age 13 was 45%. Interictal electroencephalogram revealed focal paroxysmal epileptiform discharges (in frontal, central, and parietal regions) in three patients, diffuse high-voltage spike-and-waves in one patient, and normal sleep record in one patient. Myoclonic seizures were rapidly controlled by levetiracetam. In contrast, focal seizures were not controlled in the early period of antiepileptic therapy. Conclusion This long-term follow-up of patients with KABUK1 revealed a higher prevalence of epilepsy than previously reported. The age of epilepsy onset and rate of focal seizures evolving to bilateral convulsive seizures in KABUK1 were also higher than previously reported in patients with clinically diagnosed Kabuki syndrome. Although seizure outcome is reported to be favorable in Kabuki syndrome, focal seizures in patients with KABUK1 were not immediately responsive to medication.

In this study, we revised eruptive ages, especially the Aso and Yufu volcanoes, central Kyushu, by analyzing a sediment core of southwestern Beppu Bay, southwest Japan, where undisturbed sediments are continuously deposited in a dysoxic basin. We identified two ash-fall layers in the sequence covering the last ca. 3000 years by using the refractive index of volcanic glasses and other parameters. These layers were likely correlated with N2 ash of the Aso volcano and Yufu-dake 1 ash (Yf1) of the Yufu volcano on the basis of the refractive indices of volcanic glasses, heavy mineral compositions, special distribution, and facies. According to high precision age models, the eruptive ages (68.2% probability range) of these tephras were 1470–1490 and 2010–2100 cal yr BP, respectively, and concordant with reported ages of previous research. These precise ages of tephras improve linking or dating in the various environments, and contribute to investigation of environmental changes or sedimentary process from source to sink.

High vertical carrier mobilities in organic semiconductor films are a challenging issue for fundamentally improving the performance of vertical devices. To achieve improvement in the vertical direction, a reduced graphene oxide (rGO) template is used with pentacene and DNTT having a herringbone structure enabling two-dimensional (2D) transport in comparison with CuPc having a slipped-stack structure. A thin-film structure and the optoelectrical properties of the oriented films are investigated with respect to molecular structures and packing modes. The rGO template induces a "laid-down" herringbone structure for pentacene and DNTT with a face-on orientation. Our results reveal that intermolecular dispersion energy is an additional important factor to form face-on states of molecules and influences face-on ratios in the films on rGO. Vertical charge mobilities of the films are significantly enhanced by the rGO template. Particularly, the DNTT film with a laid-down herringbone structure produces a vertical mobility as high as 0.27 cm

The eruptive histories of Ulleungdo (South Korea) and Changbaishan (North Korea/China border) volcanoes are not well constrained since their proximal stratigraphies are poorly exposed or largely inaccessible. However, determining the past behaviour of these volcanoes is critical since future eruptions are likely to disperse ash over some of the world’s largest metropolitan regions. Alkaline tephra deposits erupted from both centres are routinely identified in marine cores extracted from the Sea of Japan, as well as high-resolution lacustrine records east of the volcanoes. Here, we review the distal ash occurrences derived from Ulleungdo and Changbaishan and provide new data from the Lake Suigetsu (central Honshu, Japan) sediment core, in order to provide a more complete and constrained eruption framework. The intensely-dated Lake Suigetsu archive provides one of the most comprehensive distal eruption records for both centres, despite being located ca. 500 km E of Ulleungdo and ca. 1000 km SSE of Changbaishan. The Suigetsu record is utilised to precisely date and geochemically fingerprint (using major, minor and trace element glass compositions) ash fall events that reached central Honshu. Here, we identify a new non-visible (cryptotephra) layer in the Suigetsu sediments, which reveals a previously unreported explosive event from Changbaishan at 42,750 – 42,323 IntCal13 yrs BP (95.4 % confidence interval). This event is chronologically and geochemically distinct from the B-J (Baegdusan-Japan Basin) tephra reported in the Sea of Japan (ca. 50 ka). Furthermore, we also confirm that the widespread U-Ym tephra erupted from Ulleungdo reached central Japan, and is herein dated to 40,332 – 39,816 IntCal13 yrs BP (95.4 % confidence interval). This terrestrial 14C-derived age of the U-Ym can be used to constrain the chronology of marine records containing the same marker layer. This reviewed and integrated tephrostratigraphic framework highlights the pivotal role that distal sedimentary records can play in evaluating the eruptive histories and hazard potential of Ulleungdo and Changbaishan.

A reduced graphene oxide (rGO) film is first applied to a surface template layer to control the molecular orientation of crystalline organic semiconductors. The ultrathin and ultrasmooth rGO layer was successfully prepared on a substrate without a transfer process by spin-coating a carefully purified GO aqueous dispersion. This rGO layer exhibited a strong templating effect rivaling monolayer graphene, inducing a face-on orientation of copper phthalocyanine molecules leading to significant improvement of vertical carrier mobilities. The highly-conductive and transparent rGO film does not hamper charge transport at the interface and photoabsorption unlike conventional templating materials. This method can be widely used for vertical organic devices that require high carrier mobilities and strong photoabsorption/emission.

Tsunami deposit studies have progressed and provided extensive information on the presence of tsunami deposits, their ages, and physical parameters especially after the devastating tsunamis from the 2004 Sumatra earthquake and 2011 Tohoku-oki earthquake. However, the abundance of such information makes it challenging to assess its uncertainty and reliability. These issues associated with the tsunami deposit studies are significant and should be resolved for the benefit of people using tsunami deposit data. In this study, we used multisite drilling cores to elucidate the sediment distribution in the study area. Additionally, we conducted micro-X-ray fluorescence core scanning, roundness analysis, and radiocarbon dating to obtain a certain identification of tsunami deposits and a reliable lateral correlation of sediments. Herein, we present a long-term tsunami history and tsunami deposit distribution at Koyadori on the Sanriku Coast in northeast Japan. Adding to tsunami deposits including the 2011 CE tsunami deposits reported in our previous studies, three tsunami deposits widely distributed in the Koyadori lowland were newly identified, concluding 14 tsunami deposits during the last 6000 years. This continuous and long record of large tsunamis in the central part of the Sanriku Coast provides an insight into the mechanisms of earthquakes and tsunamis occurring in the Japan Trench and is also expected to contribute to improvement in hazard assessment of earthquakes and tsunamis. Quantitative data (geochemical signature and gravel roundness) are also useful for a lateral correlation of tsunami deposits. In addition, the correlated sediment distribution enables the identification of an area with high preservation potential of tsunami deposits and estimation of paleoenvironment since 6 ka. Therefore, detailed information on tsunami deposits in one area is as necessary as revealing tsunami deposits across a wider area for future studies.

Here we present four unrelated families with six individuals that have infantile-onset developmental delay/regression and epilepsy. Whole-exome sequencing revealed compound heterozygous mutations, c.[283G>A];[607G>A] in a gene encoding prolyl-tRNA synthetase (PARS2) in one family. Two pairs of compound heterozygous mutations, c.[151C>T];[1184T>G] and c.[707T>G];[594+1G>A], and a homozygous mutation, c.[500A>G];[500A>G], in a gene encoding asparaginyl-tRNA synthetase (NARS2) were also identified in the other three families. Mutations in genes encoding aminoacyl-tRNA synthetases cause gene-specific mitochondrial disorders. Biallelic PARS2 or NARS2 mutations are reported to cause Alpers' syndrome, which is an autosomal recessive neurodegenerative disorder characterized by psychomotor regression and epilepsy with variable degree of liver involvement. Moreover, it is known that NARS2 mutations cause various clinical phenotypes, including non-syndromic hearing loss, Leigh syndrome, intellectual disability with epilepsy and severe myopathy. The individuals with PARS2 and NARS2 mutations, we have reported here demonstrate similar neurological features as those previously reported, with diversity in clinical presentation such as hearing loss and seizure type. Our data broaden the clinical and mutational spectrum of PARS2- and NARS2-related disorders.

Arts syndrome is characterized by early-onset hypotonia, ataxia, intellectual disability, sensorineural hearing impairment, progressive optic atrophy, and a tendency to develop infections. Arts syndrome is an X-linked disorder caused by a loss-of-function mutation in the PRPS1 gene, which encodes phosphoribosylpyrophosphate synthetase 1. Only three families have been reported. Here, we report another family with Arts syndrome. The initial symptoms of the 1-year-old proband were hypotonia and ataxia, worsening recurrent infection-triggered muscle weakness, motor and intellectual developmental delay, and hearing loss. Both central nervous system involvement and peripheral neuropathy were demonstrated. His three maternal uncles had died before the age of 3years. A genetic analysis of PRPS1 revealed a novel missense mutation, c.367C>G (p.His123Asp). PRPS enzymatic activity was markedly reduced in the patient. His mother was supposed to be an asymptomatic carrier. Arts syndrome should be included in the differential diagnosis of infantile hypotonia and weakness aggravated by recurrent infection with a family history of X-linked inheritance.

Purpose Although it has been reported that some antiepileptic drugs have inducing or inhibiting effects on lamotrigine (LTG) clearance, whether they have the same effects in Asian epilepsy patients as in those in other countries has not been clarified, especially in children. The aim of this study was to determine the effects of co-medications on LTG clearance in Japanese children with epilepsy. Methods A total of 342 routine serum concentration measurements of LTG in 102 Japanese epilepsy patients under 20 years of age were reviewed. The dose-corrected concentration (DCC) of LTG was calculated as [concentration]/[dose/(body weight)], and the DCC of LTG was compared by co-medication. The difference in the DCC of LTG was compared between patients with and without valproic acid (VPA) and between those with and without drugs inducing glucuronic acid conjugation (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB)). Results The DCC of LTG was significantly higher in patients on VPA and significantly lower in patients on drugs inducing glucuronic acid conjugation than in patients on LTG monotherapy. The DCC of LTG was significantly higher in patients on CBZ than in patients on PHT or PB. There was no correlation between the DCC of LTG and the concentration of VPA or metabolic inducers within the therapeutic range. Other antiepileptic drugs including clobazam, clonazepam, zonisamide, and levetiracetam had little effect on LTG concentration. Conclusion LTG concentration changes dramatically with concomitant antiepileptic drugs in Japanese children, as previously reported from other countries, and special attention is required. Although the dose of LTG should be adjusted when starting or discontinuing VPA or metabolic inducers, no adjustment is needed when changing the dose of VPA or metabolic inducers in the therapeutic range.

Strike-slip basins are one of the most important accumulation spaces for sediment of terrigenous, biogenic, and volcanic origins, and generally include large amount of event deposits. Although these event deposits are important basin filling process, research on this topic, particularly the effects of event deposits, is insufficient. In this study, we discuss sedimentation features based on grain composition and other properties for ca. 3000 year periods in Beppu Bay, which is strike-slip basin located at the western end of an arc-bisecting dextral fault known as Median Tectonic Line (MTL) associated with the northwestward subduction of the Philippine Sea Plate. This sediment is composed of hemipelagic clay and coarser event layers of turbidites referred to as types A, B, and C; ash layers referred to as type D; and other referred to as type E. The turbidite event layers, which accounted for 92% of the total major event layer, with >1 cm thickness, consist of particles related to volcanism, including hydrothermal activity. The events control the regional filling rate and transportation of coarse and heavy volcaniclastic materials. In particular, type A, which accounted for 73% of the total major event layer thickness, is likely induced by earthquakes related to the MTL, according to its age. As a result, the basin filling processes are controlled mainly by tectonics related to the subduction of the Philippine Sea Plate.

Background The tricarboxylic acid (TCA) cycle is a sequence of catabolic reactions within the mitochondrial matrix, and is a central pathway for cellular energy metabolism. Genetic defects affecting the TCA cycle are known to cause severe multisystem disorders. Methods We performed whole exome sequencing of genomic DNA of a patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. We also performed biochemical studies using patient fibroblasts. Results We identified new compound heterozygous mutations (c.1534G > A, p.Asp512Asn and c.1997G > C, p.Gly666Ala) in ACO2, which encodes aconitase 2, a component of the TCA cycle. In patient fibroblasts, the aconitase activity was reduced to 15% of that of the control, and the aconitase 2 level decreased to 36% of that of the control. As such a decrease in aconitase 2 in patient fibroblasts was partially restored by proteasome inhibition, mutant aconitase 2 was suggested to be relatively unstable and rapidly degraded after being synthesized. In addition, the activity of the father‐derived variant of aconitase 2 (p.Gly666Ala), which had a mutation near the active center, was 55% of that of wild‐type. Conclusion The marked reduction of aconitase activity in patient fibroblasts was due to the combination of decreased aconitase 2 amount and activity due to mutations. Reduced aconitase activity directly suppresses the TCA cycle, resulting in mitochondrial dysfunction, which may lead to symptoms similar to those observed in mitochondrial diseases.

Tandem intramolecular electrophilic arene borylation was developed to facilitate access to B-doped polycyclic aromatic hydrocarbons (PAHs). DFT calculations revealed that electrophilic arene borylation occurred via a four-membered ring transition state, in which C-B and H-Br bonds formed in a concerted manner. An organic light-emitting diode employing the B-doped PAH as an emitter and a B-doped PAH-based field-effect transistor were successfully fabricated, demonstrating the potential of B-doped PAHs in materials science.

Background We aimed to assess the characteristics of thalamic lesions in children with acute encephalopathy with biphasic seizures and late reduced diffusion. Methods Using the Tokai Pediatric Neurology Society database, we identified and enrolled 18 children with acute encephalopathy with biphasic seizures and late reduced diffusion from 2008 to 2010. Using diffusion-weighted images, we identified patients with thalamic lesions and compared their clinical factors with those of patients without thalamic lesions. We analyzed the time sequence of thalamic, sucortical, and cortical lesions. To study the topography of thalamic lesions, we divided the thalamus into five sections: anterior, medial, anterolateral, posterolateral, and posterior. Subsequently, we analyzed the relationship between the topography of thalamic lesions and the presence of central-sparing. Results Seven children presented with symmetrical thalamic lesions associated with bilateral subcortical or cortical lesions. No statistical difference in the clinical features was observed between individuals with and without thalamic lesions. These lesions were observed only when subcortical or cortical lesions were present. In 5 children, thalamic lesions were present in bilateral anterior or anterolateral sections and were associated with subcortical or cortical lesions in bilateral frontal lobes with central-sparing. In the other two children, thalamic lesions were extensive and accompanied by diffuse subcortical and cortical lesions without central-sparing. Conclusion Thalamic lesions in patients with acute encephalopathy with biphasic seizures and late reduced diffusion involve the anterior sections. The thalamocortical network may play a role in development of thalamic lesions in patients with acute encephalopathy with biphasic seizures and late reduced diffusion.

Purpose To evaluate the prognostic importance of electroencephalography (EEG) findings at cessation of epileptic spasms for seizure outcome. Methods We reviewed 71 children with West syndrome (cryptogenic 14) who had obtained control of epileptic spasms with initial treatment (adrenocorticotropic hormone (ACTH) 37, high-dose vitamin B 6 2, and antiepileptic drugs 32). According to the EEG findings at control of epileptic spasms, the subjects were divided into three groups: normal group (no epileptic activity, n =12), abnormal group (residual epileptic activity without hypsarrhythmia, n =53), and hypsarrhythmic group (persisting hypsarrhythmia, n =6). Results Overall, 47 (66%) of the 71 patients (cryptogenic 4) had experienced relapses of seizures (epileptic spasms 23 and focal seizure 24) after initial control of epileptic spasms. Within symptomatic cases, seizure relapse rate varied widely from 0% (Down syndrome) to 100% (tuberous sclerosis), depending on underlying causes. Seizure relapse depended on the EEG findings at control of epileptic spasms. The normal group had a significantly lower seizure relapse rate (17%) in comparison with the abnormal group (75%), the hypsarrhythmic group (83%), and the epileptiform (abnormal plus hypsarrhythmic, 76%) group. No significant difference in seizure relapse rate was observed between non-hypsarrhythmic (normal plus abnormal, 65%) and hypsarrhythmic groups. At the last follow-up, normal group children also showed a favorable seizure prognosis (seizure control 100%). Conclusions A favorable seizure prognosis is associated with the disappearance of epileptic activity, but not the resolution of hypsarrhythmic pattern on EEG at control of epileptic spasms. We suggest that effective treatment for West syndrome should produce both cessation of epileptic spasms and disappearance of epileptic activity on EEG.

To elucidate the time course of neuronal cell death after the clinical criteria for brain death are met, the authors reviewed serial changes of serum neuron-specific enolase levels in 3 children (age range, 3-15 years) clinically diagnosed as brain dead due to cardiopulmonary arrest. All patients survived for more than 2 months after brain death. Children with brain death had higher peak neuron-specific enolase values (1069-2849 ng/mL) than did 3 control children (256-1800 ng/mL) who did not become brain dead but had poor neurological outcome (1 death, 2 vegetative state) after cardiopulmonary arrest. A major finding is that children with brain death showed persistent elevation of neuron-specific enolase at 4 weeks (>400 ng/mL) and 8 weeks (>50 ng/mL) after cardiopulmonary arrest, in comparison with 2 surviving patients without brain death (

Background: Indomethacin is used to treat the hemodynamically significant patent ductus arteriosus in premature infants. Some infants show ductus arteriosus reopening after effective constriction by the drug. The purpose of this study was to examine the clinical characteristics of such infants. Methods: We studied 57 very-low-birthweight infants with effective constriction of patent ductus arteriosus by the initial course of indomethacin. They were classified into the reopened group if they developed hemodynamically significant patent ductus arteriosus again or into the closed group if they showed complete closure. Clinical characteristics were compared between the two groups. Results: Ductus arteriosus reopening was shown in 15 (26%) of the 57 infants. These 15 infants had successful clinical ductal closure after a subsequent course of indomethacin or oral mefenamic acid treatment or surgical ligation without any severe complications. Infants in the reopened group showed significantly higher rates of developing chronic lung disease at 36 weeks of gestation than those in the closed group (53% vs 18%; P= 0.009). Furthermore, multivariate logistic regression analysis revealed ductus arteriosus reopening was the only independent risk factor for developing chronic lung disease at 36 postconceptional weeks in this population (adjusted odds ratio, 6.1; 95% confidence interval, 1.4–31.2; P= 0.02). Conclusions: Incomplete closure of the ductus arteriosus is associated with recurrence of a clinically significant patent ductus arteriosus and reopening of the ductus after initial closure with indomethacin is associated with chronic lung disease.

Molecular orientation to the substrate surface is a fundamental problem in organic semiconductor devices due to the anisotropic nature of optoelectronic properties of organic semiconductors. A face-on molecular orientation with the molecular planes parallel to the substrate, is ideal for out-of-plane charge carrier transport for vertical-type organic transistors where charge carriers flow perpendicularly to the substrate. It is usually difficult to induce the face-on molecular orientation on the substrate where intermolecular interactions are stronger than the molecule–substrate surface interactions. Most of the organic semiconductor materials show an edge-on orientation with the molecular planes vertical to the substrate, which is unsuitable for out-of-plane charge carrier transport. Template layer techniques have been proven to enhance the molecule–substrate surface interactions by inserting template materials between the substrate and organic layer. One of the template materials, perylene 3,4,8,9-tetracarboxylic dianhydride (PTCDA) exceptionally show the face-on orientation on the substrate and act as the template layer due to the π-π interactions between PTCDA and the upper side molecules. It has been known that PTCDA is effective for orientation control of phthalocyanine and its derivatives. However, it is still not clear about templating effect for other materials and vertical carrier transport property of organic semiconductors oriented with PTCDA. In this study, we investigated molecular orientation of various π-conjugated crystalline molecules on PTCDA, and the mechanism of orientation control from the crystal structure view point. We also measured the vertical carrier mobility of the oriented molecules and the performance of vertical-type organic transistors, and revealed the effect of orientation control for vertical carrier transport. Dimethyl-3,4,8,9-perylenedicarboximide (MePTC), copper-phthalocyanine (CuPc), dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene (DNTT), pentacene, and diindenoperylene (DIP) were deposited on glass substrates by thermal vacuum evaporation after deposition of PTCDA. X-ray diffraction (XRD) measurements were carried out in the out-of-plane configuration to evaluate molecular orientation. In these organic semiconductor molecules, MePTC and CuPc on PTCDA gave a diffraction peak at 27.7° with d-spacing of 3.33 Å corresponding to the distance of π-π stacking, which indicates the face-on orientation of the molecules. DNTT, pentacene, and DIP had no diffraction peaks showing the face-on orientation. The difference of molecular orientation results from molecular packing in the crystal structure. Vertical carrier mobility of MePTC was measured by the space charge limited current (SCLC) technique. The electron mobility improved from 1.3×10-4 cm2/Vs to 4.3×10-4 cm2/Vs due to the face-on orientation control. The MePTC film oriented with PTCDA was applied to the metal base organic transisitor (MBOT) which is one of the vertical-type organic transistors, resulting in higher output current compared to the device without PTCDA.

We report the case of a boy with a de novo partial monosomy 16p13-pter and partial trisomy 16q22-qter detected by fluorescence in situ hybridization using subtelomeric probes for 16p and 16q. The boy had facial characteristics, skeletal features, congenital heart defects, an imperforate anus, urogenital malformations, pre/postnatal growth retardation, and psychomotor retardation, most of which have been reported both in partial monosomy 16p and partial trisomy 16q. In addition, he suffered from upper airway stenosis due to possible laryngeal stenosis with subglottic webs. The upper airway stenosis could be a rare complication of partial monosomy 16p or partial trisomy 16q, or a nonspecific malformation resulting from chromosomal abnormalities.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT, EC 2.8.3.5) is the key enzyme for ketone body utilization. Hereditary SCOT deficiency (MIM 245050) causes episodes of severe ketoacidosis. We identified a homozygous point mutation (c.671G>A) , which is a single-base substitution at the last nucleotide of exon 6, in a Turkish patient (GS12) with SCOT deficiency. This point mutation resulted in the skipping of exon 6, and exons 6 and 7 in human SCOT genes. To understand why the c.671G>A causes exons 6 and 7 skipping, nuclear RNA was separated from cytoplasmic RNA and both were analyzed by RT-PCR. In nuclear RNA, SCOT mRNA with exon 6 skipping was predominant and mRNA with exons 6 and 7 skipping was hardly detected, whereas the latter became one of major mRNA species in cytoplasmic RNA. This discrepancy was interpreted as follows: exon 6 skipping causes a frameshift and nonsense-mediated RNA decay in the cytosol, so mRNA with exon 6 skipping was unstable. On the other hand, SCOT mRNA with exons 6 and 7 is a minor transcript but it retains the reading-frame and is stable in cytosol. As a result, the latter mRNA is more abundant under steady-state conditions as compared to the former mRNA.

Since vitamin K2 (VitK2) syrup prophylaxis has become a routine measure for neonates and young infants, the incidence of vitamin K deficiency (VitK-D) in infancy has markedly decreased. However, we recently experienced 2 infantile cases of VitK deficiency, in whom intracranial hemorrhage (ICH) was the first clinical sign of CMV hepatitis. Case 1 is a breast-fed boy who received VitK2 syrup orally at birth and at the age of 1 month. He did not suckle well and developed a generalized tonic convulsion twice at the age of 8 weeks. Case 2 is a mixed-fed boy who also received VitK2 syrup twice but developed vomiting and drowsiness at the age of 4 months. In both cases, laboratory tests showed anemia, leukocytosis, liver dysfunction with cholestasis, and coagulopathy, consistent with VitK-D abnormality. Their serological analyses showed that cytomegalovirus (CMV) IgG and IgM were both positive. In case 1, CMV DNA was positive, as judged by the PCR method. In case 2, CMV antigenemia was positive. Hence we diagnosed these two patients as having VitK-D ICH caused by CMV hepatitis with cholestasis. CMV hepatitis is a risk factor of VitK-D ICH.