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This study numerically investigated the characteristics of unsteady aerodynamic forces around a pitching airfoil in the transonic flow regime. The unsteady Reynolds-averaged compressible Navier–Stokes (URANS) equations were solved using a Spalart–Allmaras (SA) turbulence model. The pitching NACA64A010 airfoil at mean angles of attack of 0, 2, 4, and 6 deg with the amplitude of 1 deg and reduced frequency of 0.2 was parametrically simulated. The study found that the trend of the unsteady aerodynamic characteristics around the pitching airfoil, particularly that of the unsteady lift force, significantly changes with the mean-angle-of-attack conditions. The shock-induced boundary-layer separation and reattachment during the pitching oscillation have a crucial role in determining the trend of the unsteady aerodynamic forces, such as the phase-delayed or phase-advanced features for the variation in the angle of attack. The boundary-layer separation during the oscillation, observed at a high mean angle of attack of 6 deg, produces the phase-advanced feature of the lift force. Because the phase-advanced feature is associated with a positive damping effect, the result indicates that the boundary-layer separation may serve as a stabilizing effect on the pitching airfoil motion. The boundary-layer reattachment from separation during the airfoil oscillation, observed at an intermediate mean angle of attack of 4 deg, generates an unusual shock wave movement, resulting in a unique lift loop for the variation in the angle of attack. The study also demonstrated a good prediction accuracy of the URANS with the SA model for the unsteady aerodynamics around the pitching airfoil with the shock and shock-induced boundary-layer separation.

Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked recessive developmental disorder characterized by initially marked truncal hypotonia, later athetotic posturing, and severe intellectual disability caused by mutations in SLC16A2, which is responsible for the transport of triiodothyronine (T3) into neurons. We conducted a nationwide survey of patients with MCT8 deficiency to clarify their current status.Primary survey: In 2016-2017, we assessed the number of patients diagnosed with MCT8 deficiency from 1027 hospitals. Secondary survey: in 2017-2018, we sent case surveys to 31 hospitals (45 cases of genetic diagnosis), who responded in the primary survey. We asked for: 1) perinatal history, 2) developmental history, 3) head MRI findings, 4) neurophysiological findings, 5) thyroid function tests, and 5) genetic test findings.We estimated the prevalence of MCT8 deficiency to be 1 in 1,890,000 and the incidence of MCT8 deficiency per million births to be 2.12 (95 % CI: 0.99-3.25). All patients showed severe psychomotor retardation, and none were able to walk or speak. The significantly higher value of the free T3/free T4 (fT3/fT4) ratio found in our study can be a simple and useful diagnostic biomarker (Our value 11.60 ± 4.14 vs control 3.03 ± 0.38). Initial white matter signal abnormalities on head MRI showed recovery, but somatosensory evoked potentials (SEP) showed no improvement, suggesting that the patient remained dysfunctional.For early diagnosis, including in mild cases, it might be important to consider the clinical course, early head MRI, SEP, and fT3/fT4 ratio.

Panayiotopoulos syndrome (PS) is a common benign epilepsy in childhood, characterized by predominantly autonomic symptoms such as emesis, pallor, and seizures, which are often prolonged. In an emergency room (ER), particularly when unconsciousness is prolonged, differentiating PS from acute encephalopathy is challenging. In this study, we aimed to elucidate the differences in clinical features of patients with PS and acute encephalopathy who visited our ER.We retrospectively reviewed 18 patients who were transferred to our ER because of status epilepticus later diagnosed as PS, and 30 patients with acute encephalopathy, between July 2012 and July 2017. We compared patient demographics, clinical characteristics, and treatment.Most patients (90%) with acute encephalopathy had convulsive seizures of greater than or equal to 15 min, whereas only three patients (17%) with PS had convulsive seizures of greater than or equal to 15 min (P 0.001). In addition, seizures were treatable in all patients with PS with a small dose of midazolam (0.1 mg/kg), but all patients with acute encephalopathy required midazolam at 0.3 mg/kg or more (P 0.001). More patients with PS had autonomic symptoms compared to those with acute encephalopathy (e.g., vomiting [78% vs. 3%, P 0.001]). Non-convulsive status epilepticus was observed in 22% of PS patients, but not in any acute encephalopathy patients. In contrast, fever was observed in all patients with acute encephalopathy (100%), but less frequently in those with PS (11%, P 0.001).PS was characterized by 1) convulsive seizures shorter than 15 min, 2) seizures treatable with small doses of midazolam, and 3) autonomic symptoms. PS could be differentiated from acute encephalopathy in the early stages of the syndrome.

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in all cases analyzed. Exonization of intronic sequences was observed in 15 cases and exon skipping in one case; 13 single nucleotide variants and three structural rearrangements were identified as causal genomic variations. DMD transcripts were aberrantly spliced and polyadenylated in two cases in which chromosome rearrangements were detected. In one case, DMD transcripts were terminated due to nucleotide repeat expansion. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed, because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in 19 of 20 cases; Exonization of intronic sequences in 15 cases, exon skipping in one case, aberrantly spliced and polyadenylated transcripts in two cases and transcription termination in one case. Intronic single nucleotide variants, chromosomal rearrangements and nucleotide repeat expansion were identified in DMD gene as pathogenic causes of transcript alteration. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.

We summarize the long-term motor outcome and disability level in a cluster of pediatric patients with acute flaccid myelitis (AFM) associated with the enterovirus D68 outbreak in 2015.This is a nationwide follow-up questionnaire analysis study. Clinical data including the motor function (manual muscle strength test) and other neurological symptoms were collected at the acute (nadir), recovery (six months), and chronic (three years) stages. We use the Barthel index, which measures 10 variables describing activity of daily living and mobility to assess the disability level.Clinical data of 33 patients with AFM (13 females, 20 males; median age = 4.1 years) were available. Among patients with tetraplegia or triplegia, paraplegia, and monoplegia at the acute stage, two of seven, four of thirteen, and two of thirteen exhibited complete recovery without paralysis; of those five of seven, eight of thirteen, and two of thirteen showed improvement with lesser limb involvement at the chronic stage, respectively. Nine patients (27%) demonstrated improvement at the recovery-to-chronic period. All six patients with positive isolation of enterovirus D68 from biological samples at the acute stage showed persistent motor deficits. Other neurological findings had better prognosis than motor weakness. Better Barthel index score at the chronic stage was observed (P 0.001; median difference [95% confidence interval], 53 [40 to 63]), implying an improved disability level even in patients with persistent motor deficits.AFM has a high rate of persistent motor deficits showing one- to two-limb paralysis. Disability level of patients with AFM, however, generally improved at the three-year time point.

This study highlights the importance of heat release rate in low-temperature oxidation (LTO) on non-uniform end-gas autoignition and strong pressure wave generation, which are substantially relevant to knocking combustion. The simulations are conducted using the compressible Navier–Stokes equations with detailed transport and chemical kinetics models in a one-dimensional constant-volume reactor. Four fuel/air stoichiometric mixtures, n-butane, i-octane, n-heptane, and dimethyl ether (DME)/air mixtures, are simulated. The results show that larger knocking intensities are produced with n-heptane and DME in their negative temperature coefficient (NTC) regimes because of the stronger non-uniformity of end-gas autoignition. The non-uniformity of end-gas autoignition is enhanced by a pressure wave disturbance that is caused by the rapid temperature rise of the end-gas region in LTO. In particular, the high heat release rate with the DME/air mixture generates a distinct pressure wave disturbance in the reactor, which considerably enhances the non-uniformity of end-gas autoignition through the reflection of the wave at the wall. In contrast, the heat release rate in the n-heptane case is milder than that in the DME case, and therefore, the knocking intensity in the n-heptane case is smaller compared to that of DME due to less enhancement of the non-uniform end-gas autoignition. No large knocking intensities are produced with n-butane and i-octane, which have weak NTC, because of the absence of a temperature rise in LTO. Thus, this study concludes that the high heat release rate in LTO and the generated pressure wave disturbance play a significant role in the generation of large knocking intensities through the enhancement of non-uniform end-gas autoignition.

The present study proposes a localized thickened flame (LTF) model for the accurate prediction of flame propagation and autoignition timing. The unresolved-scale terms appeared in spatially-filtered governing equations due to thin flame structures are constructed under a physical constraint in which laminar flame speed is maintained. A high-order derivative is introduced to dynamically localize the effects of the LTF in the regions of unresolved propagating flame. The model is also designed such that the thickened flame is resolved by the same number of grid points for any grid size used. Therefore, a user-specified constant in the model does not need to be adjusted depending on the employed grid size. Laminar flame propagation problems are used to validate the performance of the proposed LTF model and determine the appropriate value of the user-specified constant. The results using a one-dimensional constant-volume reactor demonstrate that the LTF successfully captures the accurate flame propagation behaviors under elevated pressure conditions, while not affecting the end-gas autoignition timing, even on relatively coarse grid resolutions. The high-order derivative in the LTF serves as a dynamic parameter for detecting the thinning flame under elevated pressure conditions.

BackgroundVariants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.MethodsWe examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.ResultsPathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.ConclusionsPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Recent advances in human genetics identified genetic variants involved in causing autism spectrum disorders (ASDs). Mouse models that mimic mutations found in patients with ASD exhibit behavioral phenotypes consistent with ASD symptoms. These mouse models suggest critical biological factors of ASD etiology. Another important implication of ASD genetics is the enrichment of ASD risk genes in molecules involved in developing synapses and regulating neural circuit function. Sophisticated in vivo imaging technologies applied to ASD mouse models identify common synaptic impairments in the neocortex, with genetic-mutation-specific defects in local neural circuits. In this article, we review synapse- and circuit-level phenotypes identified by in vivo two-photon imaging in multiple mouse models of ASD and discuss the contributions of altered synapse properties and neural circuit activity to ASD pathogenesis.

The present study addresses effects of pressure wave disturbance on end-gas autoignition behavior and subsequent pressure wave development, which are of particular interest for understanding a fundamental process of knocking combustion in spark-assisted ignition engines. Such pressure wave disturbance is initiated by a compression wave generated from spark-like ignition and continuously exists in a combustion chamber. The investigation is conducted through a direct numerical simulation with a 1-D constant volume reactor, where the compressible Navier–Stokes equations are solved with detailed reaction mechanisms of n − C 7 H 16 and n − C 4 H 10 /air mixtures. The width of an ignition kernel parametrically changes in order to control the strength of an initial compression wave and thus pressure wave disturbance. The result showed that stronger compression waves with larger kernel widths enhance the progress of the autoignition process at the wall through the transient increase in pressure and temperature due to the wave reflection. Consequently, stronger pressure waves such as a developing detonation are generated with the enhanced inhomogeneous end-gas autoignition starting from the wall. In contrast, weak pressure wave disturbance produces no strong pressure waves due to the lower inhomogeneity of autoignition timing in an end-gas region. An analysis with temperature variation in an end-gas region indicates that cool flame generation helps maintain the superiority of the wall for earlier autoignition through the heat release at an earlier stage. Therefore, a stronger pressure wave associated with inhomogeneous end-gas autoignition is likely generated around 650 K in the case of an n − C 7 H 16 /air mixture, which corresponds to a distinct peak generation of knocking intensity in the negative temperature coefficient regime. For lower temperature conditions such as 500 K, the end-gas autoignition first takes place in a region away from the wall. This is because the initially induced temperature inhomogeneity in the end-gas region is considerably weakened due to wave interactions and dissipation effects during longer ignition delay times. Thus, multiple end-gas points including the wall can become a preferred point for earlier end-gas autoignition, resulting in a variation of end-gas autoignition locations. The result for an n − C 4 H 10 /air mixture is finally shown and the difference from that for the n − C 7 H 16 /air mixture is highlighted.

A front tracking/ghost fluid method was used to simulate fluid interfaces in a shock–bubble interaction problem. The method captures fluid interfaces, using explicit front-tracking and defines interface conditions, using the ghost-fluid method. In order to demonstrate the accuracy and the capability tracking of the approach used, an air-helium and anair-R22 shock-bubble interaction cases were simulated. The computational results were compared with reliable experimental and computational studies, showing close agreements.

Purpose Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by prolonged febrile seizures at onset and subsequent damage to the cerebral cortex of infants and children. The pathogenesis is suspected to be excitotoxicity leading to neuronal death. SCN1A and KCNQ2 are causative genes of genetic epilepsy including Dravet syndrome and Ohtahara syndrome. Here we conducted a case-control rare-variant association study of the two genes in AESD. Methods The coding regions of SCN1A and KCNQ2 were sequenced by the Sanger method for 175 and 111 patients, respectively, with AESD. As control subjects, we used genetic data from 3554 subjects provided by the Integrative Japanese Genome Variation Database (iJGVD). Then we performed a case-control association study of rare missense and splice region variants (minor allele frequency Results SCN1A rare variants had a significant association with AESD after correction for multiple tests (WSS, permutated p value 4.00 × 10−3: SKAT, p value 2.51 × 10−4). The association was more significant when we focused on deleterious variants (WSS, permutated p = 9.00 × 10−4; SKAT, p = 4.99 × 10−5). Although KCNQ2 rare nonsynonymous variants tended to be more frequent in patients than in controls, there was no significant difference. Conclusion Our study provided statistical evidence of an association between SCN1A and AESD for the first time, and established SCN1A as one of the susceptibility genes for AESD.

Variants in the type IV collagen gene (We examinedPathogenicPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and

This study numerically investigates the effects of stratified temperature distributions on the end-gas combustion mode in a constant volume reactor. The initial temperature in the reactor was globally stratified with linear gradients. The effects of negative temperature coefficient (NTC) characteristics are addressed through a comparison between the results of a non-NTC fuel and an NTC fuel. The compressible Navier–Stokes equations are solved with detailed chemistry. The results show that the addition of large temperature gradients such as −10 or −5 K/cm can prevent the pressure wave development associated with end-gas autoignition, and the knocking intensity is significantly reduced. In contrast, small temperature gradients such as −1 K/cm lead to the generation of the developing detonation mode and thus to large knocking intensities. In the NTC fuel case, the knocking intensity becomes relatively large because the spatial gradient of the ignition delay time decreases even with the addition of large temperature gradients, especially in the NTC regime. Based on all the results, a correlation is presented between the initial temperature and the reaction front speed (the spatial gradient of the ignition delay time) for the prediction of end-gas combustion mode. The correlation suggests that the possibility of preventing large knocking intensities by temperature gradients is reduced under high-pressure conditions because of the increase in the reaction front speed. Consequently, this study suggests that very large temperature gradients would be required under high-pressure conditions to prevent large knocking intensities under the concept of thermal stratification.

A knocking combustion in a one-dimensional constant volume reactor has been simulated with a detailed chemical kinetic mechanism of n-heptane premixed gases by using the compressible Navier-Stokes equations. This study focuses on the impact of the various equivalence ratios (0.6–1.4) in the pressure wave development during knocking combustion in an account of different initial temperature (600–900K). The result demonstrates the autoignition process in the end-gas region and explains the knocking phenomenon on different equivalence ratio. In an adiabatic wall condition, the largest knocking intensity occurs in equivalence ratio 1.4 whereas the lowest knocking intensity found in equivalence ratio 0.6. Regarding to initial temperatures, a strong peak of knocking is generated around 650K in all the equivalence ratios (0.8–1.4). However, yet a small perceptivity of knocking is found in around 750K for each equivalence ratio. In case of smaller equivalence ratios, a weak knocking occurs, which can be identified by the behavior of the pressure wave generation in the end-gas region.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2017-11-03, 資料番号: PA1810069000

The present study deals with the mechanisms for the hot-spot formation and pressure wave development associated with end-gas autoignition during knocking combustion of n -heptane/air mixture. The discussion is based on a one-dimensional (1-D) direct numerical simulation, where the compressible Navier–Stokes equations are solved with a detailed chemical kinetic mechanism of n -heptane, involving 373 species and 1071 reactions. The result demonstrates that the first trigger for a hot-spot formation is a compression wave generated by forced autoignition of a hot kernel and its reflection at a wall. The wall reflection of the propagating compression wave periodically produces an instantaneous temperature increase, which leads to the production of a larger amount of chemical species compared to that of other end-gas points. This non-uniform progress of chemical reaction process continues to exist at the wall, although the temperature increase is transient, resulting in faster autoignition and pressure wave generation at the wall. Thus, an important aspect of observing chemistry behaviors rather than temperature is demonstrated on the mechanism of hot-spot formation. The present study further addresses the reactivity of hot-spots on the relevance to pressure wave developments, wherein a zero-dimensional (0-D) ignition problem with pulsed compression waves is introduced. The higher reactivity of n -heptane/air mixture against pulse waves is observed with the faster ignition delay times in lower and higher initial temperature conditions. Conversely, the result at initial temperatures of 750—800 K indicates the lower reactivity with no significant effects of pulse waves on the ignition delay times. This is connected with the fuel characteristics of a negative temperature coefficient. Thus, in the 1-D simulations, a hot-spot with the high reactivity enhances spatial temperature difference in the end-gas region, leading to strong pressure wave generations. In contrast, a hot-spot with the low reactivity suppresses the pressure wave development with little spatial variation in temperature. The result demonstrates a significant aspect of hot-spot formation and reactivity on pressure wave development during knocking combustion.

The diffusive-thermal effect plays an important role in the intrinsic instability of premixed flames. A two-dimensional direct numerical simulation of the propagation of premixed hydrogen–air flames was performed using a detailed chemical kinetics model. The cellular behavior of a lean hydrogen–air flame was analyzed on the basis of its chemical structure. The primary consequence of the diffusive-thermal effect was found to be a change in the buildup process of reactive intermediates by the chain reaction mechanism at the preheat zone. The resultant chemical structure at the main reaction zone can be explained by the local composition change of the gas flowing into the reaction zone from the preheat zone.

DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown–Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML. © 2016 Wiley Periodicals, Inc.

BACKGROUND Acute encephalopathy (AE) is defined by the Japanese guidelines as the acute disturbance of consciousness (Glasgow coma scale [GCS] score ≤11) that persists for >24 h. We have often encountered, however, cases of prolonged mild disturbance of consciousness (PMDC) with GCS score >11, meaning that they do not fit the guideline definition of AE. The reports of these cases have been relatively sparse, and the nosological position, prognosis, and other characteristics remain unknown. To clarify the characteristics of PMDC we compared cases of PMDC with cases of AE. METHODS This study was a retrospective observational study at a tertiary children's hospital in Japan. We studied children with a diagnosis of AE or PMDC between January 2011 and August 2016. RESULTS Thirteen cases of PMDC and 19 cases of AE were identified during the study period. PMDC patients more frequently had hyponatremia (P < 0.01), paradoxical arousal response on electroencephalogram (P = 0.010), normal computed tomography (CT; P = 0.025), and normal magnetic resonance imaging (MRI; P < 0.01) than the AE patients. Sequelae were more frequently observed in AE than in PMDC patients (P = 0.011). CONCLUSIONS PMDC has different characteristics to AE with regard to hyponatremia, paradoxical arousal response, CT or MRI findings, and prognosis. Despite the differences, PMDC might also be regarded as being a milder member of the wide variety of AE and related diseases.

Febrile infection-related epilepsy syndrome (FIRES), or acute encephalitis with refractory, repetitive partial seizures (AERRPS), is an epileptic encephalopathy beginning with fever-mediated seizures. The etiology remains unclear. To elucidate the genetic background of FIRES/AERRPS (hereafter FIRES), we recruited 19 Japanese patients, genotyped polymorphisms of the IL1B , IL6 , IL10 , TNFA , IL1RN , SCN1A and SCN2A genes, and compared their frequency between the patients and controls. For IL1RN , the frequency of a variable number of tandem repeat (VNTR) allele, RN2, was significantly higher in the patients than in controls ( p =0.0067), and A allele at rs4251981 in 5′ upstream of IL1RN with borderline significance (p =0.015). Haplotype containing RN2 was associated with an increased risk of FIRES (OR 3.88, 95%CI 1.40–10.8, p =0.0057). For SCN1A , no polymorphisms showed a significant association, whereas a missense mutation, R1575C, was found in two patients. For SCN2A , the minor allele frequency of G allele at rs1864885 was higher in patients with borderline significance ( p =0.011). We demonstrated the association of IL1RN haplotype containing RN2 with FIRES, and showed a possible association of IL1RN rs4251981 G>A and SCN2A rs1864885 A>G, in Japanese patients. These preliminary findings suggest the involvement of multiple genetic factors in FIRES, which needs to be confirmed by future studies in a larger number of FIRES cases.

Mutations in SPATA5 have recently been shown to result in a phenotype of microcephaly, intellectual disability, seizures, and hearing loss in childhood. Our aim in this report is to delineate the SPATA5 syndrome as a clinical entity, including the facial appearance, neurophysiological, and neuroimaging findings. Using whole-exome sequencing and Sanger sequencing, we identified three children with SPATA5 mutations from two families. Two siblings carried compound heterozygous mutations, c.989_991del (p.Thr330del) and c.2130_2133del (p.Glu711Profs*21), and the third child had c.967T>A (p.Phe323Ile) and c.2146G>C (p.Ala716Pro) mutations. The three patients manifested microcephaly, psychomotor retardation, hypotonus or hypertonus, and bilateral hearing loss from early infancy. Common facies were a depressed nasal bridge/ridge, broad eyebrows, and retrognathia. Epileptic spasms or tonic seizures emerged at 6-12 months of age. Interictal electroencephalography showed multifocal spikes and bursts of asynchronous diffuse spike-wave complexes. Augmented amplitudes of visually evoked potentials were detected in two patients. Magnetic resonance imaging revealed hypomyelination, thin corpus callosum, and progressive cerebral atrophy. Blood copper levels were also elevated or close to the upper normal levels in these children. Clinical delineation of the SPATA5-related encephalopathy should improve diagnosis, facilitating further clinical and molecular investigation.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted: 2016-06-14, 資料番号: PA1710033000

Objective Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures. The pathogenesis of AESD is considered to be fever-induced seizure susceptibility and excitotoxicity, which may be caused by sodium channel dysfunction in some cases. Here we studied whether mutations in genes encoding sodium channels, SCN1A and SCN2A , predispose children to AESD. Methods We recruited 92 AESD patients in a nationwide survey of acute encephalopathy in Japan from 2008 to 2011. We collected their genomic DNA samples, and sequenced the entire coding region of SCN1A and SCN2A . Results Five out of 92 patients (5.4%) had missense mutations either in SCN1A or SCN2A . After a preceding infection with fever, all the patients showed status epilepticus at the onset. Hemiconvulsion–hemiplegia was recognized in three patients during the acute/subacute phase. One patient had taken theophylline for the treatment of bronchial asthma just before the onset of AESD. Familial history was not remarkable except one patient with a SCN1A mutation (G1647S) whose mother had a similar episode of AESD in her childhood. A different substitution (G1674R) at the same amino acid position, as well as two other SCN1A mutations found in this study, had previously been reported in Dravet syndrome. Another SCN1A mutation (R1575C) had been detected in other types of acute encephahlitis/encephalopathy. One patient had SCN2A mutation, F328V, which had previously been reported in Dravet syndrome. Another SCN2A mutation, I172V, was novel. None of the patients were diagnosed with Dravet syndrome or genetic (generalized) epilepsy with febrile seizure plus in the following-up period. Conclusions Mutations in SCN1A and SCN2A are a predisposing factor of AESD. Altered channel activity caused by these mutations may provoke seizures and excitotoxic brain damage.

This paper addresses issues in high-fidelity numerical simulations of transcritical turbulent flows at supercritical pressure. The proposed strategy builds on a tabulated look-up table method based on REFPROP database for an accurate estimation of non-linear behaviors of thermodynamic and fluid transport properties at the transcritical conditions. Based on the look-up table method we propose a numerical method that satisfies high-order spatial accuracy, spurious-oscillation-free property, and capability of capturing the abrupt variation in thermodynamic properties across the transcritical contact surface. The method introduces artificial mass diffusivity to the continuity and momentum equations in a physically-consistent manner in order to capture the steep transcritical thermodynamic variations robustly while maintaining spurious-oscillation-free property in the velocity field. The pressure evolution equation is derived from the full compressible Navier-Stokes equations and solved instead of solving the total energy equation to achieve the spurious pressure oscillation free property with an arbitrary equation of state including the present look-up table method. Flow problems with and without physical diffusion are employed for the numerical tests to validate the robustness, accuracy, and consistency of the proposed approach.