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Purpose: KRAS is among the most commonly mutated oncogene in cancer including non–small cell lung cancer (NSCLC). In early clinical trials, inhibitors targeting G12C-mutant KRAS have achieved responses in some patients with NSCLC. Possible intrinsic and acquired resistance mechanisms to KRAS G12C inhibitors are not fully elucidated and will likely become important to identify. Experimental Design: To identify potential resistance mechanisms, we defined the sensitivity of a panel of KRAS G12C–mutant lung cancer cell lines to a KRAS G12C inhibitor, AMG510. Gene set enrichment analyses were performed to identify pathways related to the sensitivity, which was further confirmed biochemically. In addition, we created two cell lines that acquired resistance to AMG510 and the underlying resistance mechanisms were analyzed. Results: KRAS expression and activation were associated with sensitivity to KRAS G12C inhibitor. Induction of epithelial-to-mesenchymal transition (EMT) led to both intrinsic and acquired resistance to KRAS G12C inhibition. In these EMT-induced cells, PI3K remained activated in the presence of KRAS G12C inhibitor and was dominantly regulated by the IGFR–IRS1 pathway. We found SHP2 plays a minimal role in the activation of the PI3K pathway in contrast to its critical role in the activation of the MAPK pathway. The combination of KRAS G12C inhibitor, PI3K inhibitor, and SHP2 inhibitor resulted in tumor regressions in mouse models of acquired resistance to AMG510. Conclusions: Our findings suggest that EMT is a cause of both intrinsic and acquired resistance by activating the PI3K pathway in the presence of KRAS G12C inhibitor.

Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

Attention deficit-hyperactivity disorder (ADHD) is a prevalent neuropsychiatric disorder found in children. It is characterized by inattention, hyperactivity, and impulsivity. Methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed for the treatment of ADHD. In the present study, we examined the behavioral and brain transcriptome changes in MPH-treated and ATX-treated zebrafish. In behavioral analysis, zebrafish showed opposite response to each treatment. MPH-treated fish showed higher anxiety-like behavior while ATX-treated fish showed lower anxiety-like behavior. Further, we performed RNA sequencing analysis of zebrafish brain to elucidate the underlying biological pathways associated with MPH and ATX treatment. Interestingly, we found that shared differentially expressed genes in MPH-treated and ATX-treated fish were instrumental in cholesterol biosynthesis pathway and were regulated in opposite manner. Our findings highlight the contrast between MTH and ATX, and may suggest the alterations in clinical practice for these medications and drug development for ADHD., 2種類のADHD治療薬が対照的な作用を持つことを発見 --ゼブラフィッシュで行動や脳での働きを探る--. 京都大学プレスリリース. 2020-05-18.

Background Williams syndrome (WS) is a neurodevelopmental disorder that has been attributed to heterozygous deletions in chromosome 7q11.23 and exhibits a variety of physical, cognitive, and behavioral features. However, the genetic basis of this phenotypic variability is unclear. In this study, we identified genetic clues underlying these complex phenotypes. Methods Neurobehavioral function was assessed in WS patients and healthy controls. Total RNA was extracted from peripheral blood and subjected to microarray analysis, RNA‐sequencing, and qRT‐PCR. Weighted gene co‐expression network analysis was performed to identify specific alterations related to intermediate disease phenotypes. To functionally interpret each WS‐related module, gene ontology and disease‐related gene enrichment were examined. We also investigated the micro (mi)RNA expression profiles and miRNA co‐expression networks to better explain the regulation of the transcriptome in WS. Results Our analysis identified four significant co‐expression modules related to intermediate WS phenotypes. Notably, the three upregulated WS‐related modules were composed exclusively of genes located outside the 7q11.23 region. They were significantly enriched in genes related to B‐cell activation, RNA processing, and RNA transport. BCL11A, which is known for its association with speech disorders and intellectual disabilities, was identified as one of the hub genes in the top WS‐related module. Finally, these key upregulated mRNA co‐expression modules appear to be inversely correlated with a specific downregulated WS‐related miRNA co‐expression module. Conclusions Dysregulation of the mRNA/miRNA network involving genes outside of the 7q11.23 region is likely related to the complex phenotypes observed in WS patients., Read the Commentary on this article at doi: 10.1111/jcpp.13056

Summary: Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. : Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci. Keywords: autism spectrum disorder, schizophrenia, copy-number variation, array comparative genomic hybridization, genetic overlap, Japanese population, oxidative stress response, genome integrity, lipid metabolism, gene ontology

Increasing evidence suggests that epigenetic mechanisms play a role in the etiology of autism spectrum disorder (ASD). To date, several studies have attempted to identify epigenetic biomarkers for ASD. However, reliable markers remain to be established and most of these studies have focused on pediatric patients with ASD. In this study, we sought to find an epigenetic DNA methylation biomarker from peripheral blood for adult patients with high-functioning ASD. DNA methylation profiles were analyzed using the Illumina 450 K methylation array. To identify robust candidate markers, we employed two types of machine-learning algorithms for marker selection. We identified a potential marker (cg20793532) for which is the AUC value was 0.79. Notably, cg20793532 was annotated to the PPP2R2C gene, which was hypermethylated and down-regulated in blood from ASD patients compared to that in the controls. Although requiring careful interpretation, this pilot study seems to provide a potential blood biomarker for identifying individuals with high-functioning ASD.

Williams syndrome (WS) is caused by a microdeletion of chromosome 7q11.23, and is characterized by various physical and cognitive symptoms. In particular, WS is characterized by hypersocial (overfriendly) behavior; WS has gained attention as aspects of the WS phenotype contrast with those of autism spectrum disorder (ASD). The oxytocin receptor gene (OXTR) contributes to social phenotypes in relation to regulation of oxytocin (OXT) secretion. Additionally, mounting evidence has recently shown that DNA methylation of OXTR is associated with human social behavior. However, the role of OXTR in WS remains unclear. This study investigated the regulation of OXTR in WS. We examined the gene expression levels in blood from WS patients and controls, and then analyzed the methylation levels in two independent cohorts. We showed that OXTR was down-regulated and hypermethylated in WS patients compared to controls. Our findings may provide an insight into OXTR in mediating complex social phenotypes in WS.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and repetitive behaviors. Owing to the difficulty of clinical diagnosis, ASD without intellectual disability (i.e., high-functioning ASD) is often overlooked. MicroRNAs (miRNAs) have been recently recognized as potential biomarkers of ASD as they are dysregulated in various tissues of individuals with ASD. However, it remains unclear whether miRNA expression is altered in individuals with high-functioning ASD. Here, we investigated the miRNA expression profile in peripheral blood from adults with high-functioning ASD, and age and gender-matched healthy controls. We identified miR-6126 as being robustly down-regulated in ASD and correlated with the severity of social deficits. Enrichment analysis of predicted target genes revealed potential association with neurons, synapses, and oxytocin signaling pathways. Our findings may provide insights regarding the molecular clues for recognizing high-functioning ASD.

Williams syndrome (WS) is a clinical condition, involving cognitive deficits and an uneven language profile, which has been the object of intense inquiry over the last decades. Although WS results from the hemideletion of around two dozen genes in chromosome 7, no gene has yet been probed to account for, or contribute significantly to, the language problems exhibited by the affected people. In this paper we have relied on gene expression profiles in the peripheral blood of WS patients obtained by microarray analysis and show that several robust candidates for language disorders and/or for language evolution in the species, all of them located outside the hemideleted region, are up- or downregulated in the blood of subjects with WS. Most of these genes play a role in the development and function of brain areas involved in language processing, which exhibit structural and functional anomalies in people with this condition. Overall, these genes emerge as robust candidates for language dysfunction in WS.

Williams–Beuren syndrome (WBS) is a multisystemic neurodevelopmental disorder caused by a hemizygous deletion on chromosome 7q11.23. Though at present there is a limited number of reports on WBS patients with tumors, most cases are related to blood cancer in children with WBS. We describe a case of Burkitt lymphoma in a 21-year-old man with WBS. In addition to providing a summary of published reports describing tumors observed in patients with WBS, we present a hypothesis about a possible mechanism of oncogenesis. In particular, we identified some significantly dysregulated cancer-related genes using blood samples from this patient at the age of 19 years (who have not yet developed Burkitt lymphoma). Our findings may provide a new perspective on the relation between WBS and Burkitt lymphoma.

Pompe disease is caused by an inborn defect of lysosomal acid α-glucosidase (GAA) and is characterized by lysosomal glycogen accumulation primarily in the skeletal muscle and heart. Patients with the severe type of the disease, infantile-onset Pompe disease (IOPD), show generalized muscle weakness and heart failure in early infancy. They cannot survive over two years. Enzyme replacement therapy with recombinant human GAA (rhGAA) improves the survival rate, but its effect on skeletal muscle is insufficient compared to other organs. Moreover, the patho-mechanism of skeletal muscle damage in IOPD is still unclear. Here we generated induced pluripotent stem cells (iPSCs) from patients with IOPD and differentiated them into myocytes. Differentiated myocytes showed lysosomal glycogen accumulation, which was dose-dependently rescued by rhGAA. We further demonstrated that mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity was impaired in IOPD iPSC-derived myocytes. Comprehensive metabolomic and transcriptomic analyses suggested the disturbance of mTORC1-related signaling, including deteriorated energy status and suppressed mitochondrial oxidative function. In summary, we successfully established an in vitro skeletal muscle model of IOPD using patient-specific iPSCs. Disturbed mTORC1 signaling may contribute to the pathogenesis of skeletal muscle damage in IOPD, and may be a potential therapeutic target for Pompe disease.

Based on an observational study of astronomy education using a tangible globe system, this paper aims to elicit implications for effective learning procedure for tangible learning environments. By analyzing the experiment based on “embodied design” concept, we found that, when appropriate instruction is not provided, intuitive operability of tangible user interface at times rather disturbs learners’ thinking opportunities. We also found that by properly limiting the information to show learners, the system can make learners be more conscious of the meaning of manipulating tangible objects and result in better understanding of the learning content.

Background A history of psychiatric disorders is a high risk for suicide. The present study compared the clinical features of psychiatric patients in Japan who attempted suicide by jumping from a height and those who attempted suicide by self-stabbing. Methods We compared two groups of suicide attempters who were hospitalized for both physical and psychiatric treatment (n=202). We compared the psychiatric diagnoses and clinical features between those who attempted suicide by jumping from a height (N=147) and those who did so by self-stabbing (N=55). Results The self-stabbing group (mean age 52.3 years) was significantly older compared to the jumping group (mean age 37.9 years). A significantly higher proportion of females were found in the jumping group. Jumping from a height was significantly associated with schizophrenia spectrum disorders, whereas self-stabbing was significantly associated with mood disorders. Limitations The results were drawn from data from a single hospital in a large urban city, and the study population did not include subjects who completed their suicide attempts. Conclusions Our findings show that differences in suicide methods (here, between jumping from a height and self-stabbing) may be related to suicide attempters' psychiatric diagnosis, gender and age. It is thus important to obtain a more detailed background information about a patient's suicide attempt and to create suicide prevention plans in accord with individuals' psychiatric diagnosis, age and gender, especially among those who have attempted suicide by jumping from a height or self-stabbing.

We analyzed the association between PPP2R2B gene CAG repeat length and Alzheimer disease (AD) susceptibility in the Japanese population. Blood samples were collected from 218 late-onset AD patients and 86 controls. DNA fragments containing the target CAG repeat region were amplified using polymerase chain reaction (PCR). PCR products were sequenced using ABI PRISM 310 genetic analyzer. The mean CAG repeat length did not differ significantly between the control and AD groups. In contrast, the frequency of CAG repeats shorter than 15 was significantly higher in AD group, specifically in the AD with APOE4 subgroup, than in the control group. The results suggest that CAG repeat lengths in the PPP2R2B gene may be potential genetic markers for AD susceptibility in the Japanese population.

Background Refugees and displaced populations after natural disasters have been vulnerable to tuberculosis. We report an active pulmonary tuberculosis case at a shelter and the subsequent contact investigation and review lessons learned from the 2011 Great East Japan Earthquake. Methods The contact investigation was conducted to identify latent tuberculosis infection among a total of 95 contact persons, including 78 evacuees at the shelter, who were exposed to the index tuberculosis patient. The association between exposure time of contacts to a patient with active tuberculosis and results of interferon-γ release assay (IGRA) was also examined. Results IGRA was positive in 9 (12.3%) of 73 evacuees at the shelter. Contacts who were exposed to active tuberculosis for more than 25 days were significantly more likely to be IGRA positive, compared with contacts exposed for less than 20 days. All of the 4 evacuees with latent tuberculosis infection who initiated treatment completed the regimen successfully. Conclusion When a disaster strikes and many people are living in shelters, it is essential for health care personnel to first suspect tuberculosis and implement prevention and control in collaboration with referral hospitals and public health centers.

Background/Aims: A single-nucleotide polymorphism (SNP) in the KIBRA gene, rs17070145, was reported to be significantly associated with episodic memory in cognitively normal cohorts. This observation has expanded genetic studies on KIBRA to Alzheimer’s disease (AD). Importantly, the association between KIBRA and episodic memory in AD has never been addressed. In this study, we investigated whether the KIBRA rs17070145 SNP influences AD episodic memory and the disease in a Japanese cohort. Methods: Blood samples from 346 AD patients and 375 normal cognitive controls were collected and genotyped for rs17070145. Episodic memory was measured in 32 AD patients, diagnosed for the first time, by use of the Rivermead Behavioral Memory Test (RBMT). Results: We found that KIBRA C allele carriers scored significantly lower than KIBRA non-C carriers on both RBMT total profile score (p = 0.042, effect size = 0.84) and RBMT total screening score (p < 0.001, effect size = 1.42). The KIBRA gene did not show association with AD in our Japanese cohort. Conclusion: Our results evidence a strong association between the KIBRA gene and episodic memory impairment in AD, but show no influence on AD in our Japanese cohort. We propose that KIBRA might have an effect similar to cognitive reserve.

A recent study reported that variants of the neuronal sortilin-related receptor gene ( SORL1 ) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-ɛ4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD.

Relationships between otolith and somatic sizes were examined for Japanese anchovy Engraulis japonicus and sardine Sardinops melanostictus larvae collected broadly in the western North Pacific, based on a substantial data set derived from a previous paper. Allometric formulae showed close fits to the relationships between otolith radius and standard length, and the formulae differed between anchovy and sardine larvae. Despite the high correlations, the effect of somatic growth rate on the otolith and somatic size relationship (the ‘growth effect’) was significantly detected for both anchovy and sardine larvae. Slower growing larvae tended to have larger otoliths than faster growing conspecifics at the same somatic size. This growth effect was more obvious for sardine larvae than for anchovy larvae, probably because of their differential responses of somatic growth to temperature shifts. The growth effect could lead to the possibility of biases in the backcalculation and size estimation processes. As the growth effect is considered to be a general phenomenon and its extent to be species-specific, the relationship between otolith and somatic size and its uncoupling should be scrutinized before application of techniques based on the otolith and somatic size correlation.

Alzheimer disease (AD) is characterized by progressive cognitive decline caused by synaptic dysfunction and neurodegeneration in the brain, and late-onset AD (LOAD), genetically classified as a polygenetic disease, is the major form of dementia in the elderly. It has been shown that beta amyloid, deposited in the AD brain, interacts with dynamin 1 and that the dynamin 2 (DNM2) gene homologous to the dynamin 1 gene is encoded at chromosome 19p13.2 where a susceptibility locus has been detected by linkage analysis. To test the genetic association of LOAD with the DNM2 gene, we performed a case-control study of 429 patients with LOAD and 438 sex- and age-matched control subjects in a Japanese population. We found a significant association of LOAD with single nucleotide polymorphism markers of the DNM2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele. Even though subjects with the genotype homozygous for the risk allele at rs892086 showed no mutation in exons of the DNM2 gene, expression of DNM2 mRNA in the hippocampus was decreased in the patients compared to non-demented controls. We propose that the DNM2 gene is a novel susceptibility gene for LOAD.

Alzheimer disease (AD), the major cause of dementia in the elderly, is characterized by β-amyloid deposition in senile plaques and hyperphosphorylated tau in neurofibrillary tangles. Since albumin, binding and transporting free fatty acids is also the major transporter of β-amyloid, we examined the association between the albumin (ALB) gene and the occurrence of late-onset AD (LOAD). We found that the allele distribution of the intron 4 microsatellite of the ALB gene showed a significant difference (P

The canonical pathway of Notch signaling is mediated by regulated intramembrane proteolysis (RIP). In the pathway, ligand binding results in sequential proteolysis of the Notch receptor, and presenilin (PS)-dependent intramembrane proteolysis at the interface between the membrane and cytosol liberates the Notch-1 intracellular domain (NICD), a transcription modifier. Because the degradation of the Notch-1 transmembrane domain is thought to require an additional cleavage near the middle of the transmembrane domain, extracellular small peptides (Notch-1 Abeta-like peptide (Nbeta)) should be produced. Here we showed that Nbeta species are indeed secreted during the process of Notch signaling. We identified mainly two distinct molecular species of novel Nbeta, Nbeta21 and C-terminally elongated Nbeta25, which were produced in an approximately 5:1 ratio. This process is reminiscent of the production of Alzheimer disease-associated Abeta. PS pathogenic mutants increased the production of the longer species of Abeta (Abeta42) from beta-amyloid protein precursor. We revealed that several Alzheimer disease mutants also cause a parallel increase in the secretion of the longer form of Nbeta. Strikingly, chemicals that modify the Abeta42 level caused parallel changes in the Nbeta25 level. These results demonstrated that the characteristics of C-terminal elongation of Nbeta and Abeta are almost identical. In addition, because many other type 1 membrane-bound receptors release intracellular domains by PS-dependent intramembrane proteolysis, we suspect that the release of Abeta- or Nbeta-like peptides is a common feature of the proteolysis during RIP signaling. We anticipate that this study will open the door to searches for markers of RIP signaling and surrogate markers for Abeta42 production.

Objective The aim of the present study was to determine the efficacy of ramelteon for treating delirium. Methods Three patients were prescribed ramelteon for delirium. The severity of the delirium was assessed using the Japanese version of the Memorial Delirium Assessment Scale. Results Memorial Delirium Assessment Scale scores improved after treatment with ramelteon in all cases. Conclusion These cases suggest that ramelteon may be beneficial in the treatment of delirium. Randomized controlled studies are needed to confirm the therapeutic benefits.

Young-of-the-year (YOY) bay anchovy Anchoa mitchilli occur in higher proportion rel- ative to larvae in the upper Chesapeake Bay. This has led to the hypothesis that up-bay dispersal favors recruitment. Here we test whether recruitment of bay anchovy to different parts of the Chesa- peake Bay results from differential dispersal rates. Electron microprobe analysis of otolith strontium was used to hind-cast patterns and rates of movement across salinity zones. Individual chronologies of strontium were constructed for 55 bay anchovy aged 43 to 103 d collected at 5 Chesapeake Bay mainstem sites representing upper, middle, and lower regions of the bay during September 1998. Most YOY anchovy were estimated to have originated in the lower bay. Those collected at 5 and 11 psu sites exhibited the highest past dispersal rates, all in an up-estuary direction. No significant net dispersal up- or down-estuary occurred for recruits captured at the polyhaline (♢18 psu) site. Ini- tiation of ingress to lower salinity waters (

Citrin deficiency, caused by a mutation of the SLC25A13 gene, s an autosomal recessive disorder that leads to neonatal intraheptic cholestasis caused by citrin deficiency (NICCD) and adult-onset ype II citrullinemia (CTLN2) [1]. The function of citrin is imporant in translocating cytosolic NADH reducing equivalents into he mitochondria as part of the malate-aspartate shuttle [2]. In ddition, citrin plays an important role in supplying aspartate o argininosuccinate synthetase (ASS) in the cytosol to generte argininosuccinate in the urea cycle [2]. Thus, a deficiency f citrin results in dysfunction of the urea cycle and hyperamonemia [1]. Patients with CTLN2 present with sudden onset of arious encephalopathic manifestations due to hyperammonemia 2]. One of the distinct features of citrin deficiency is that the ajority of patients have a peculiar fondness for proteinand at-rich foods, such as beans and peanuts, and an aversion to arbohydrate-rich foods, such as rice, sweets, and alcohol [2]. It is ssumed that their unique food preference may be directly related

We experienced a leiomyosarcoma of the breast in an 18-year-old female. No specific treatment has been established. In order to clarify appropriate therapeutic management methods, the limited data available from our and previous case reports were assessed. A leiomyosarcoma of the breast must be excised with a negative margin. If the tumor size is large and an adequate margin, greater than 3-cm margin around the excised tumor, is not achieved due to anatomical constraints, radiotherapy may be indicated.

Objective To highlight the association between posterior reversible encephalopathy syndrome (PRES) and chronic alcoholism. Methods We present a case report, a review of the literature and a discussion. Results We report on the case of a 51-year-old man with chronic alcoholism, who suddenly developed visual disturbance and confusion. Magnetic resonance imaging (MRI) on admission demonstrated abnormal findings. However, clinical symptoms and imaging promptly improved, indicating the diagnosis of PRES. Conclusion PRES should be considered when making a diagnosis for disturbed consciousness in alcoholic patients.

QT延長症候群(LQTS)は,死に至る重篤な不整脈を呈することがあり,周術期の管理が重要である.術後,Torsade de Pointes (TdP)型心室性頻拍を呈した症例を経験したので報告する.症例は,69歳女性.盲腸癌のため結腸切除手術施行.術後,第1病日にTdPを起こした.リドカイン静注に反応無く,DCショックで洞調律に回復した.手術前後の心電図でQTcの延長が見られ,遺伝性,二次性の原因はなく,散発ILQTSと診断された.本症は,QT延長があるため手術ストレス等によりTdPを起こしたと考えられる.本症例の麻酔に際しては,不整脈予防のため,十分な鎮静,麻酔深度,使用薬剤の選択が重要であり,また,万一に備えて心臓ペースメーカー,除細動装置等の準備と周術期の監視体制が必要と考えられる.

The endoplasmic reticulum (ER) stress response is a defense system for dealing with the accumulation of unfolded proteins in the ER lumen. Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases and cerebral ischemia. In a screen for compounds that induce the ER-mediated chaperone BiP (immunoglobulin heavy-chain binding protein)/GRP78 (78 kDa glucose-regulated protein), we identified BiP inducer X (BIX). BIX preferentially induced BiP with slight inductions of GRP94 (94 kDa glucose-regulated protein), calreticulin, and C/EBP homologous protein. The induction of BiP mRNA by BIX was mediated by activation of ER stress response elements upstream of the BiP gene, through the ATF6 (activating transcription factor 6) pathway. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of apoptotic cells. Considering these results together, it appears that BIX induces BiP to prevent neuronal death by ER stress, suggesting that it may be a potential therapeutic agent for cerebral diseases caused by ER stress.

We scanned throughout chromosome 21 to assess genetic associations with late-onset Alzheimer disease (AD) using 374 Japanese patients and 375 population-based controls, because trisomy 21 is known to be associated with early deposition of beta-amyloid (Abeta) in the brain. Among 417 markers spanning 33 Mb, 22 markers showed associations with either the allele or the genotype frequency (P < 0.05). Logistic regression analysis with age, sex and apolipoprotein E (APOE)-epsilon4 dose supported genetic risk of 17 markers, of which eight markers were linked to the SAMSN1, PRSS7, NCAM2, RUNX1, DYRK1A and KCNJ6 genes. In logistic regression, the DYRK1A (dual-specificity tyrosine-regulated kinase 1A) gene, located in the Down syndrome critical region, showed the highest significance [OR = 2.99 (95% CI: 1.72-5.19), P = 0.001], whereas the RUNX1 gene showed a high odds ratio [OR = 23.3 (95% CI: 2.76-196.5), P = 0.038]. DYRK1A mRNA level in the hippocampus was significantly elevated in patients with AD when compared with pathological controls (P < 0.01). DYRK1A mRNA level was upregulated along with an increase in the Abeta-level in the brain of transgenic mice, overproducing Abeta at 9 months of age. In neuroblastoma cells, Abeta induced an increase in the DYRK1A transcript, which also led to tau phosphorylation at Thr212 under the overexpression of tau. Therefore, the upregulation of DYRK1A transcription results from Abeta loading, further leading to tau phosphorylation. Our result indicates that DYRK1A could be a key molecule bridging between beta-amyloid production and tau phosphorylation in AD.

Recent reports have shown that the endoplasmic reticulum (ER) stress is relevant to the pathogenesis of Alzheimer disease. Following the amyloid cascade hypothesis, we therefore attempted to investigate the effects of ER stress on amyloid-beta peptide (Abeta) generation. In this study, we found that ER stress altered the localization of amyloid precursor protein (APP) from late compartments to early compartments of the secretory pathway, and decreased the level of Abeta 40 and Abeta 42 release by beta- and gamma-cutting. Transient transfection with BiP/GRP78 also caused a shift of APP and a reduction in Abeta secretion. It was revealed that the ER stress response facilitated binding of BiP/GRP78 to APP, thereby causing it to be retained in the early compartments apart from a location suitable for the cleavages of Abeta. These findings suggest that induction of BiP/GRP78 during ER stress may be one of the regulatory mechanisms of Abeta generation.

Objective Memantine has been reported to have positive effects on visual hallucinations and cognition in patients with dementia with Lewy bodies (DLB). We hypothesized that memantine would have similar effects on a patient having Charles Bonnet syndrome, preclinical DLB. Method We evaluated the effect of memantine on visual hallucination, cognitive abilities and so on from baseline to 4 months after the start of medication. Results Treatment of the patient with memantine resulted in the disappearance of visual hallucinations but could not stop the progression to dementia. Conclusions Our results suggested that, for a patient having preclinical DLB, memantine had some degree of positive effects, but the mechanism remains to be revealed.

Objective To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD). Design Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies. Setting Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy. Participants All published white and Asian case-control data sets, which included a total of 12 464 cases and 17 929 controls. Main Outcome Measures Alzheimer disease according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association). Results In the white data sets, several markers were associated with AD after correction for multiple testing, including previously reported SNPs 8, 9, and 10 (P < .001). In addition, the C-G-C haplotype at SNPs 8 through 10 was associated with AD risk (P < .001). In the combined Asian data sets, SNPs 19 and 23 through 25 were associated with AD risk (P < .001). The disease-associated alleles at SNPs 8, 9, and 10 (120 873 131-120 886 175 base pairs [bp]; C-G-C alleles), at SNP 19 (120 953 300 bp; G allele), and at SNPs 24 through 25 (120 988 611 bp; T and C alleles) were the same previously reported alleles. The SNPs 4 through 5, 8 through 10, 12, and 19 through 25 belong to distinct linkage disequilibrium blocks. The same alleles at SNPs 8 through 10 (C-G-C), 19 (G), and 24 and 25 (T and C) have also been associated with AD endophenotypes, including white matter hyperintensities and hippocampal atrophy on magnetic resonance imaging, cerebrospinal fluid measures of amyloid β-peptide 42, and full-length SORL1 expression in the human brain. Conclusion This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.

Pulmonary interstitial fibrosis (PIF) is a morphological term which in part can be defined as accumulation of collagen in the extracellular matrix. Previously we showed that hamsters sensitized with 2,4,6-trinitro-1-chlorobenzene (TNCB) developed PIF 14 days after an intratracheal challenge with 2,4,6-trinitrobenzene sulfonic acid (TNBS). The participation of delayed-type hypersensitivity (DTH) in lung collagen deposition was clearly demonstrated. In this paper, we use an adaptation of this model to mice and show that the lung collagen deposition observed was related to the genetic ability of the strain to maintain a DTH response to the immunizing hapten (TNP). Specifically, the lung collagen deposition on Day 14 in hapten-sensitized, challenged animals in high responder to TNP (BALB/c, H-2d) was higher than that in low responder mouse (C57BL/6, H-2b). Furthermore, aged C57BL/6 strain (retired breeders) possessed a DTH response to TNP and produced significantly higher accumulation of hydroxyproline than that of TNBS-challenged-only animals. A DTH mechanism for the induction of the fibrosis is consistent with the observation that responder mice that were made tolerant to the antigen were unable to respond to the lung challenge with a specific increase in lung index or collagen deposition. These results suggest that effector T lymphocytes that are important in DTH play a key role in the regulation of lung collagen deposition in hapten-immune pulmonary interstitial fibrosis (HIPIF) in mice.

We assessed the ability to discriminate local stocks of walleye pollock Theragra chalcogramma based on data from five elements (Na, K, P, Ca and Sr) using electron probe micro analyzer (EPMA) from the otoliths of 26 adult fish (standard length 339–576 mm) caught at four sites (Rausu, Kushiro, Minami-kayabe and Musashi Bank) around Hokkaido, Japan in 1998 and 1999. To compare the elemental compositions, the otolith formation periods were arranged based on the annual rings to allow analysis of comparative winter periods. Elemental concentrations of Na and K remained at a stable level throughout the otolith development. The pattern of Sr concentration differed for each individual. The 1999 winter samples collected from Kushiro and Minami-kayabe distributed similarly and were discriminated at a near-significant level from samples at Rausu. These results indicate that we might be able to discriminate the local Nemuro and Pacific stocks of walleye pollock spawned around Hokkaido using their otolith elements by comparing portions of otoliths formed in the same year.