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Background: There is controversy regarding the efficacy and side effects of proactive administration of allergenic foods in early infancy to prevent food allergies. This is the first trial involving the gradual introduction of trace amounts of multiple foods to infants. Methods: Infants under 4 months old with atopic dermatitis from 14 primary care pediatric clinics in Japan were enrolled in this randomized, double-blind, placebo-controlled trial. The infants were administered either mixed allergenic food powder (MP) containing eggs, milk, wheat, soybeans, buckwheat, and peanuts, or placebo powder (PP). The amount of powder was increased in a stepwise manner on weeks 2 and 4 and continued until week 12. Weaning food was started subsequently according to the Japanese guidelines for nursing/bottle feeding, and for baby food. The occurrence of food allergy episodes after powder intervention was assessed at 18 months old by the physician responsible for each participant. Findings: A total of 163 participants were randomly allocated to either the MP group (n = 83, 50.9%) or the PP group (n = 80, 49.1%). There was a significant difference in the incidence of food allergy episodes by 18 months between the MP and PP groups (7/83 vs. 19/80, respectively; risk ratio 0.301 [95% CI 0.116 – 0.784]; P = 0.008). No serious adverse events attributable to MP were observed. Interpretation: Gradually increasing the intake of trace amounts of multiple foods in early infancy can safely reduce the incidence of food allergies. Clinical Trial Registration Details: UMIN000027837. The protocol for this study and the subsequent changes are available on the UMIN-CTR Trial website. Funding Information: This study was self-funded and did not receive any other support. Declaration of Interests: The authors declare that no conflicts of interest exist. Ethics Approval Statement: Written informed consent was obtained from the parents of the participants at the time of enrollment. The study was approved by the institutional review board of Umezu Clinic.

Background Bow Hunter’s Syndrome (BHS) is known as one of cervical diseases which causes vertigo, but the details of its vertigo, especially nystagmus and eye movement, are still incompletely understood. This time, we reported the first case of BHS with a nystagmus chart with video record of transitional nystagmus. Case presentation The patient, a 47-year-old female, complained of vertigo caused by head rotation. When she turned her head leftward, leftward nystagmus appeared, and this was followed by dullness of the right arm. After her head was returned to the central position, downbeat nystagmus appeared, which changed to rightward nystagmus. She was diagnosed with BHS by her symptoms and images. We recorded a nystagmus video and nystagmus chart of this transitional nystagmus including downbeat nystagmus. Her vertigo was cured by the modification of a prescription for her past medical history: hypertension. Conclusion The vertigo of BHS accompanies nystagmus. In this present case, the transitional nystagmus was observed, and it occurred toward the healthy side. Then the nystagmus direction was changed to the affected side via downbeat nystagmus. This is the first report with both a nystagmus chart with video of BHS. Nowadays, various kinds of vertigo induced by neck movement are known. BHS is a rare disease among vertigo diseases, but we should consider it as a different diagnosis of vertigo patients. A precise interview and proper examination are required to make the final diagnosis.

Molecular chaperon SERPINA3 colocalizes with accumulated amyloid peptide in Alzheimer’s disease (AD) patient’s brain. From the QTL analysis, we narrowed down Serpina3 with two SNPs in senescence-accelerated mouse prone (SAMP) 8 strain. Our study showed SAMP8 type Serpina3 prolonged retention of oligomeric Aβ 42 for longer duration (72 hr) while observing under transmission electron microscope (TEM). From Western blot results, we confirmed presence of Aβ 42 oligomeric forms (trimers, tetramers) were maintained for longer duration only in the presences of SAMP8 type Serpina3. Using SH-SY5Y neuroblastoma cell line, we observed until 36 hr preincubated Aβ 42 with SAMP8 type Serpina3 caused neuronal cell death compared to 12 hr preincubated Aβ 42 with SAMR1 or JF1 type Serpina3 proteins. Similar results were found by extending this study to analyze the effect of polymorphism of SERPINA3 gene of the Japanese SNP database for geriatric research (JG-SNP). We observed that polymorphic SERPINA3 I308T (rs142398813) prolonged toxic oligomeric Aβ 42 forms till 48 hr in comparison to the presence wild type SERPINA3 protein, resulting neuronal cell death. From this study, we first clarified pathogenic regulatory role of polymorphic SERPINA3 in neurodegeneration.

Background Quantification of gene expression such as RNA-Seq is a popular approach to study various biological phenomena. Despite the development of RNA-Seq library preparation methods and sequencing platforms in the last decade, RNA extraction remains the most laborious and costly step in RNA-Seq of tissue samples of various organisms. Thus, it is still difficult to examine gene expression in thousands of samples. Results Here, we developed Direct-RT buffer in which homogenization of tissue samples and direct-lysate reverse transcription can be conducted without RNA purification. The DTT concentration in Direct-RT buffer prevented RNA degradation but not RT in the lysates of several plant tissues, yeast, and zebrafish larvae. Direct reverse transcription on these lysates in Direct-RT buffer produced comparable amounts of cDNA to those synthesized from purified RNA. To maximize the advantage of the Direct-RT buffer, we integrated Direct-RT and targeted RNA-Seq to develop a cost-effective, high-throughput quantification method for the expressions of hundreds of genes: DeLTa-Seq (Direct-Lysate reverse transcription and Targeted RNA-Seq). The DeLTa-Seq method could drastically improve the efficiency and accuracy of gene expression analysis. DeLTa-Seq analysis of 1056 samples revealed the temperature-dependent effects of jasmonic acid and salicylic acid in Arabidopsis thaliana. Conclusions The DeLTa-Seq method can realize large-scale studies using thousands of animal, plant, and microorganism samples, such as chemical screening, field experiments, and studies focusing on individual variability. In addition, Direct-RT is also beneficial for gene expression analysis in small tissues from which it is difficult to purify enough RNA for the experiments.

Reproductive isolation plays an important role in population differentiation and speciation, thus enhancing biodiversity in wild plants. Hybridisation sometimes involves rapid reproductive isolation between parents and their hybrids through the novel traits of hybrids derived from a new combination of genomes. Here, we report how a hybrids’ new phenotype contributes to rapid reproductive isolation between two ecotypes ofImperata cylindrica. The two ecotypes differ in their flowering phenology and habitats. An analysis with genetic markers revealed that hybrid populations consisted of only F1individuals. Both parental ecotypes flowered in spring, but F1s flowered in fall. This drastic shift in flowering phenology prevented backcrossing parental ecotypes to F1. F1s flowered in fall and dispersed seeds in winter. The germination percentage of seeds set on F1was extremely low in their habitats, and seedlings did not survive due to the low temperatures in winter, resulting in the absence of a F2generation. In conclusion, flowering phenology mismatch promotes reproductive isolation between parents and F1, resulting in a hybrid population consisting of only F1s.

Acclimation to high temperature increases plants’ tolerance of subsequent lethal high temperatures. Although epigenetic regulation of plant gene expression is well studied, how plants maintain a memory of environmental changes over time remains unclear. Here, we show that JUMONJI (JMJ) proteins, demethylases involved in histone H3 lysine 27 trimethylation (H3K27me3), are necessary for Arabidopsis thaliana heat acclimation. Acclimation induces sustained H3K27me3 demethylation at HEAT SHOCK PROTEIN22 (HSP22) and HSP17.6C loci by JMJs, poising the HSP genes for subsequent activation. Upon sensing heat after a 3-day interval, JMJs directly reactivate these HSP genes. Finally, jmj mutants fail to maintain heat memory under fluctuating field temperature conditions. Our findings of an epigenetic memory mechanism involving histone demethylases may have implications for environmental adaptation of field plants., Acclimation to high temperature increases tolerance of heat shock in plants. Here the authors show that JUMONJI H3K27me3 demethylases are needed for heat acclimation in Arabidopsis and act at loci encoding HEAT SHOCK PROTEINS to facilitate induction upon heat stress.

AIM:This study aimed to investigate the current progression status from screening phase to further investigation phase in the Japanese school urine mass screening (SUS) project., METHODS:This retrospective cohort study on the SUS project across the Shiga Prefecture during 2012 to 2017 analysed data from school life instruction sheets, which are principal documents in the SUS project, regarding urinalysis, attendance at follow-up and diagnoses., RESULTS:Between the years 2012 to 2017, a median of 107 out of 83 749 elementary school students (aged 6-11 years) and 215 out of 42 870 junior high students (aged 12-14 years) had urine abnormalities identified for the first time in the SUS project. Among those with urine abnormalities, a mean of 4.2% of elementary school and 1.8% of junior high school students, respectively, were diagnosed with suspected glomerulonephritis for the first time. Overall, 5.9% (95% confidence interval [CI] 4.1, 7.7) and 23.6% (95% CI 21.3, 25.9) of proteinuria-positive elementary and junior high school students, respectively, did not undergo further investigations. The probability of a student undergoing further investigations was not affected by the local availability of medical care benefits., CONCLUSION:In the current SUS project, screening frequently does not lead to further investigation, especially among junior high school students. To maintain the integrity of the SUS project and to prevent the progression of renal disease in young students, efforts including elucidation of barriers to further investigations should be made to reduce the proportions of students not undergoing further investigations for abnormal urinalysis findings.

Neurodevelopmental disorders are congenital impairments, impeding the growth and development of the central nervous system. These disorders include autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder in Diagnostic and Statistical Manual of Mental Disorders-5. ASD is caused by a gene defect and chromosomal duplication. Despite numerous reports on ASD, the pathogenic mechanisms are not clear. The optimal methods to prevent ASD and to treat it are also not clear. Other studies have reported that endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative diseases. In this study, we have investigated ER stress condition and neuronal maturation in an ASD mice model employing male ICR mice. An ASD mice model was established by injecting with valproic acid (VPA) into pregnant mice. The offspring born from VPA-treated mothers were subjected to the experiments as the ASD model mice. The cerebral cortex and hippocampus of ASD model mice were found to be under high ER stress. The mRNA levels of Hes1 and Pax6 were decreased in the cerebral cortex of the ASD model mice, but not in the hippocampus. In addition, the mRNA level in Math1 was increased in the cerebral cortex. ER stress inhibited dendrite and axon extension in primary culture derived from the cerebral cortex of E14.5 mice. Furthermore, dendrite outgrowth was suppressed in primary culture derived from the cerebral cortex of ASD model mice by the same method. These results indicated the possibility that ER stress induces abnormal neuronal maturation in the embryonal cerebral cortex of ASD model mice employing male ICR mice. Therefore, ER stress may contribute to the pathogenesis of ASD.

Impairment of epithelial barrier integrity caused by environmental triggers is associated with the pathogenesis of airway inflammation. Using human airway epithelial cells, we attempted to identify molecule(s) that promote airway epithelial barrier integrity. Microarray analyses were conducted using the Affimetrix human whole genome gene chip, and we identified the N-myc downstream-regulated gene 1 (NDRG1) gene, which was induced during the development of the epithelial cell barrier. Immunohistochemical analysis revealed strong NDRG1 expression in ciliated epithelial cells in nasal tissues sampled from patients with chronic rhinosinusitis (CRS), and the low expression of NDRG1 was observed in goblet cells or damaged epithelial cells. NDRG1 gene knockdown with its specific siRNA decreased the transepithelial electrical resistance and increased the dextran permeability. Immunocytochemistry revealed that NDRG1 knockdown disrupted tight junctions of airway epithelial cells. Next, we analyzed the effects of NDRG1 knockdown on the expression of tight and adhesion junction molecules. NDRG1 knockdown significantly decreased only claudin-9 expression, but did not decrease other claudin family molecules, such as E-cadherin, and ZO-1, -2, or -3. Knockdown of claudin-9 markedly impaired the barrier function in airway epithelial cells. These results suggest that NDRG1 is important for the barrier integrity in airway epithelial cells.

The aim of this study is to elucidate the detailed mechanism of endoplasmic reticulum (ER) stress-induced auditory cell death based on the function of the initiator caspases and molecular complex of necroptosis. Here, we demonstrated that ER stress initiates not only caspase-9-dependent intrinsic apoptosis along with caspase-3, but also receptor-interacting serine/threonine kinase (RIPK)1-dependent necroptosis in auditory cells. We observed the ultrastructural characteristics of both apoptosis and necroptosis in tunicamycin-treated cells under transmission electron microscopy (TEM). We demonstrated that ER stress-induced necroptosis was dependent on the induction of RIPK1, negatively regulated by caspase-8 in auditory cells. Our data suggested that ER stress-induced intrinsic apoptosis depends on the induction of caspase-9 along with caspase-3 in auditory cells. The results of this study reveal that necroptosis could exist for the alternative backup cell death route of apoptosis in auditory cells under ER stress. Interestingly, our data results in a surge in the recognition that therapies aimed at the inner ear protection effect by caspase inhibitors like zVAD-fmk might arrest apoptosis but can also have the unanticipated effect of promoting necroptosis. Thus, RIPK1-dependent necroptosis would be a new therapeutic target for the treatment of sensorineural hearing loss due to ER stress.

A 43-year-old Japanese man presented with a history of bacterial meningitis (BM). He was admitted to our department with a one-day history of headache and was diagnosed with relapse of BM based on the cerebrospinal fluid findings. The conventional imaging studies showed serial findings suggesting left otitis media, a temporal cephalocele, and meningitis. Three-dimensional multi-detector computed tomography (3D-MDCT) showed left petrous bone defects caused by the otitis media, and curative surgical treatment was performed. Skull bone structural abnormalities should be considered a cause of relapsed BM. 3D-MDCT was useful for revealing the causal minimal bone abnormality and performing pre-surgical mapping.

ObjectivesWe aimed to elucidate the prognostic factors of the patients with taste disorders who were treated with popular and common medication in Japan.Materials and methodsA retrospective study on the medical charts of a total of 255 patients with taste disorders who were treated primarily with oral medication including a zinc agent.ResultsThe factors below were significantly linked with poor prognosis: 1) male gender, 2) taste disorders that began 3 months before starting treatment and 3) a severe taste disorder grade at the initial visit.ConclusionsWe have concluded that the prognosis for the patients with taste disorders who were treated by popular and standard medication therapy in Japan recently was significantly linked to gender, the period of 3 months before starting the treatment and the severity of the disorder at the time of diagnosis. In addition, we recognized some limitations we should resolve in further research including a method of measuring "umami" and so on.Clinical relevanceBetter awareness of these factors should be clinically useful when we manage patients with taste disorders. Earlier treatment should be started to cure the symptoms.

Cases of dizziness caused by multiple sclerosis are commonly reported, but those caused by mitochondrial encephalomyopathy have been rarely reported. Particularly, the description of eye nystagmography (ENG) using caloric and optokinetic nystagmus tests has not been reported to date. We encountered the case of a 40-year-old woman with mitochondrial encephalomyopathy who visited us with the chief complaint of dizziness. At first, we considered multiple sclerosis based on the magnetic resonance imaging (MRI) findings and dizziness. Repeated attacks of dizziness and serum lactic acid levels suggested mitochondrial encephalomyopathy. A muscle biopsy confirmed the diagnosis. ENG findings suggested central vestibular disorder of the cerebellum and brainstem. This case suggests that we should not rule out the differential diagnosis of a very rare mitochondrial encephalomyopathy in patients who experience dizziness with MRI findings indicative of multiple sclerosis.

Summary Imperata cylindrica (cogongrass) is one of the most invasive grass weeds found worldwide. In Japan, this grass grows as three climate types: cool temperate (CT), common (CM) and subtropical (ST). An early flowering (E) type has been also reported. Among them, the CM type is large and most invasive. Recent global warming may cause the extension of distribution of the CM type to northern parts of Japan and may allow hybrids to form between the CM and CT or E types. The hybrids sometimes show heterosis and this leads to new weed problems. Distinguishing between the hybrids and parents on a morphological basis is difficult. We investigated polymorphisms of eight cpDNAs to enable distinction between the ecotypes and the hybrids. Fourteen haplotypes were detected in 33 Japanese clones, based on variations in eight cpDNA regions. Based on three substitutions in the psbA–matK spacer, the ORF170 intron1, the trnL(UAA) intron–trnF(GAA) spacer and indels in the trnL(UAA) intron–trnF(GAA) spacer, the haplotypes were clustered into three phylogenetic groups: I, IIa and IIb, which corresponded with the CM and ST, E and CT types, respectively. The polymorphism in the cpDNA therefore enables us to distinguish among the ecotypes and is useful for prediction of the range expansion of the CM type.

Increasing evidence suggests that endoplasmic reticulum (ER) stress and autophagy play an important role in regulating brain function. ER stress activates three major branches of the unfolded protein response (UPR) pathways, namely inositol-requiring enzyme-1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6)-mediated pathways. Recent studies have suggested that these UPR signals may be linked to autophagy. In this review article, we summarize recent evidence and discuss a possible link between ER stress and autophagy with regard to neurodegenerative diseases. Furthermore, possible pharmacological strategies targeting UPR and autophagy are discussed.

The purpose of this study was to clarify the relationship among X-box-binding protein 1 unspliced, spliced (XBP1u, s), Forkhead box O1 (FoxO1) and autophagy in the auditory cells under endoplasmic reticulum (ER) stress. In addition, the relationship between ER stress that causes unfolded protein response (UPR) and autophagy was also investigated. The present study reported ER stress induction by tunicamycin treatment that resulted in IRE1α-mediated XBP1 mRNA splicing and autophagy. XBP1 mRNA splicing and FoxO1 were found to be involved in ER stress-induced autophagy. This inference was based on the observation that the expression of LC3-II was suppressed by knockdown of IRE1α, XBP1 or FoxO1. In addition, XBP1u was found to interact with XBP1s in auditory cells under ER stress, functioning as a negative feedback regulator that was based on two important findings. Firstly, there was a significant inverse correlation between XBP1u and XBP1s expressions, and secondly, the expression of XBP1 protein showed different dynamics compared to the XBP1 mRNA level. Furthermore, our results regarding the relationship between XBP1 and FoxO1 by small interfering RNA (siRNA) paradoxically showed negative regulation of FoxO1 expression by XBP1. Our findings revealed that the XBP1-FoxO1 interaction regulated the ER stress-induced autophagy in auditory cells.

Conclusion: Patients with incapacitating Meniere Disease (MD) suffer in their daily lives and activities because of the dizziness and anxiety induced by MD. Minimally Invasive Vestibular Neurotomy (MIVN) is a safe and effective surgical treatment for these individuals, and improved their dizziness and anxiety.Objectives: This study aimed to assess the state of dizziness and anxiety of patients with incapacitating MD and its improvement through MIVN.Method: A total of 118 patients with incapacitating MD who underwent MIVN in France and Japan were evaluated. The DHI (Dizziness Handicap Inventory), SAST (Short Anxiety Screening Test), and STAI (State Trait Anxiety Index) questionnaires were used to evaluate disequilibrium and anxiety.Results: The MIVN method appears safe and effective for patients with incapacitating MD. Pre-operative assessment results by DHI and SAST were significantly related to each other, and were influenced by lifestyle and profession. This prospective study showed that MIVN im...

// Nana Akagi Tsuchihashi 1, 2 , Ken Hayashi 1, 3 , Katsuaki Dan 4 , Fumiyuki Goto 1 , Yasuyuki Nomura 5 , Masato Fujioka 1 , Sho Kanzaki 1 , Shizuo Komune 2 , Kaoru Ogawa 1 1 Department of Otorhinolaryngology, Head and Neck Surgery, Keio University, School of Medicine, Tokyo 160–8582, Japan 2 Department of Otorhinolaryngology, Head and Neck Surgery, Kyushu University, School of Medicine, Fukuoka 812–0054, Japan 3 Department of Otorhinolaryngology, Kamio Memorial Hospital, Tokyo 101–0063, Japan 4 Collaborative Research Resources, Core Instrumentation Facility, Keio University, Tokyo 160–8582, Japan 5 Department of Otorhinolaryngology-Head and Neck Surgery, Nihon University, School of Medicine, Tokyo 173–8610, Japan Correspondence to: Kaoru Ogawa, e-mail: ogawak@a5.keio.jp Keywords: premature senescence, autophagy, AMPK, oxidative stress, auditory cell Received: November 17, 2014 Accepted: December 08, 2014 Published: December 30, 2014 ABSTRACT The aim of this study was to determine whether autophagy and AMPK contribute to premature senescence in auditory cells. Incubating HEI-OC1 auditory cells with 5 mM H 2 O 2 for 1 h induced senescence, as demonstrated by senescence-associated β-galactosidase (SA-β-gal) staining. H 2 O 2 treatment significantly delayed population-doubling time, leaving cell viability unchanged. Furthermore, the proportion of SA-β-gal-positive cells significantly increased. Autophagy-related protein expression increased, with Atg7 and LC3-II peaking 6 h and Lamp2 peaking 24 h after H 2 O 2 treatment. The expression of these proteins decreased 48 h after treatment. Transmission electron microscopy revealed lipofuscin and aggregates within autolysosomes, which accumulated markedly in the cytoplasm of HEI-OC1 cells 48 h after treatment. Akt and P70S6 phosphorylation markedly decreased after H 2 O 2 treatment, but 4EBP1 phosphorylation significantly increased 48 h after treatment. After RNAi-mediated knockdown (KD) of Atg7 and AMPK, H 2 O 2 -treated cells displayed dense SA-β-gal staining. Also, premature senescence was significantly induced. These suggest that a negative feedback loop may exist between autophagy and AMPK signaling pathways in HEI-OC1 cells. In our model, oxidative stress-induced premature senescence occurred due to impaired autophagy function through 4EBP1 phosphorylation. Our results also indicate that AMPK may regulate premature senescence in auditory cells in an autophagy-dependent and independent manner.

Neural stem cells (NSCs) play an essential role in development of the central nervous system. Endoplasmic reticulum (ER) stress induces neuronal death. After neuronal death, neurogenesis is generally enhanced to repair the damaged regions. However, it is unclear whether ER stress directly affects neurogenesis-related processes such as neuronal differentiation and dendrite outgrowth. We evaluated whether neuronal differentiation and dendrite outgrowth were regulated by HRD1, a ubiquitin ligase that was induced under mild conditions of tunicamycin-induced ER stress. Neurons were differentiated from mouse embryonic carcinoma P19 cells by using retinoic acid. The differentiated cells were cultured for 8 days with or without tunicamycin and HRD1 knockdown. The ER stressor led to markedly increased levels of ER stress. ER stress increased the expression levels of neuronal marker βIII-tubulin in 8-day-differentiated cells. However, the neurites of dendrite marker microtubule-associated protein-2 (MAP-2)-positive cells appeared to retract in response to ER stress. Moreover, ER stress markedly reduced the dendrite length and MAP-2 expression levels, whereas it did not affect the number of surviving mature neurons. In contrast, HRD1 knockdown abolished the changes in expression of proteins such as βIII-tubulin and MAP-2. These results suggested that ER stress caused aberrant neuronal differentiation from NSCs followed by the inhibition of neurite outgrowth. These events may be mediated by increased HRD1 expression.

Endoplasmic reticulum (ER) stress has recently been implicated in human diseases such as Alzheimer׳s disease (AD) and Parkinson׳s disease (PD). However, the link between the immune system, ER stress, and the development of neurodegenerative diseases has not yet been clarified in detail. Mouse primary cultured astrocytes were treated with lipopolysaccharide (LPS) and/or tunicamycin (Tm), and inducible nitric oxide synthase (iNOS) and interleukin (IL)-1β levels were then measured using RT-PCR, ELISA, and Western blotting. Activation of the immune system by LPS triggered inflammatory responses in astrocytes, as measured by the induction of iNOS and IL-1β. Tm-induced ER stress inhibited the LPS-induced expression of IL-1β and iNOS at the protein level. On the other hand, ER stress alone did not induce the expression of IL-1β or iNOS. The inhibitory effect of ER stress on iNOS and IL-1β may not be mediated transcriptionally as we did not observe inhibition at the mRNA level. LPS-induced iNOS protein levels were attenuated by the Tm post-treatment in the absence of LPS. Overall, these results suggest that ER stress negatively regulates the expression of IL-1β and iNOS in LPS-activated astrocytes.

Mutations in SLC26A4 cause a broad phenotypic spectrum, from typical Pendred syndrome to nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Identification of these mutations is important for accurate diagnosis, proper medical management and appropriate genetic counseling and requires updated information regarding spectrum, clinical characteristics and genotype-phenotype correlations, based on a large cohort. In 100 patients with bilateral enlarged vestibular aqueduct among 1511 Japanese hearing loss probands registered in our gene bank, goiter data were available for 79, of whom 15 had Pendred syndrome and 64 had nonsyndromic hearing loss. We clarified the mutation spectrum for the SLC26A4 mutations and also summarized hearing levels, progression, fluctuation and existence of genotype-phenotype correlation. SLC26A4 mutations were identified in 82 of the 100 patients (82.0%). Of the Pendred syndrome patients, 93% (14/15) were carriers, as were 77% (49/64) of the nonsyndromic hearing loss patients. Clinical characteristics of patients with SLC26A4 mutations were congenital, fluctuating and progressive hearing loss usually associated with vertigo and/or goiter. We found no genotype-phenotype correlations, indicating that, unlike in the case of GJB2 mutations, the phenotype cannot be predicted from the genotype. Our mutation analysis confirmed the importance of mutations in the SLC26A4 gene among hearing loss patients with enlarged vestibular aqueduct and revealed the mutation spectrum, essential information when performing genetic testing.

SAMP8 exhibits accelerated aging and a short lifespan. Insulin-like growth factor-1 receptor (IGF-1R)/FOXO pathway is associated with aging. Phosphorylation of IGF-1R, Akt, and FOXO1 was found to be increased during aging in the liver of SAMR1 normal aging mice. However, significant decreases in the phosphorylation of IGF-1R and Akt were observed in the liver of SAMP8 during aging compared with that in SAMR1, whereas phosphorylation of FOXO1 was markedly increased with age in SAMP8. In addition, the protein level of FOXO1 was decreased with age in SAMP8. Protein phosphatase 2A (PP2A) directly dephosphorylates FOXO1. Significant reduction of PP2A activity was observed in the liver nucleus of SAMP8. These results suggest the possibility that the increased FOXO1 phosphorylation might occur by the decreased activity of PP2A, resulting in the decrease in the protein level of FOXO1 in SAMP8. Furthermore, FOXO1 regulates longevity and the expression of antioxidant enzymes such as Mn-SOD and catalase. The expression of Mn-SOD and catalase was significantly decreased in the liver of SAMP8. Therefore, it is possible that the elevation of phosphorylated FOXO1 level with age causes a short lifespan in SAMP8.

This letter describes the mechanism behind the protective effect of 4-phenylbutyric acid (4-PBA) against endoplasmic reticulum (ER) stress-induced neuronal cell death using three simple 4-(p-substituted phenyl) butyric acids (4-PBA derivatives). Their relative human histone deacetylase (HDAC) inhibitory activities were consistent with a structural model of their binding to HDAC7, and their ability to suppress neuronal cell death and activity of chemical chaperone in vitro. These data suggest that 4-PBA protects against neuronal cell death mediated by the chemical chaperone activity rather than by inhibition of histone deacetylase.

While fibromyalgia is frequently associated with ear-related symptoms such as feeling of ear fullness, earache, and tinnitus, the pathogenesis of these ear-related symptoms in fibromyalgia patients is unknown. Here, we focused on clarifying the pathogenesis of ear fullness, a particularly common symptom observed in fibromyalgia patients. Twenty patients diagnosed with fibromyalgia on outpatient psychosomatic treatment complaining of ear-related symptoms answered our questionnaire and underwent neurotological examination, including pure tone audiometry and Eustachian tube function testing. While ear-related symptoms were significantly exacerbated after onset of fibromyalgia, we noted no correlation between the presence or absence of feeling of ear fullness and abnormal findings on neurotological examination. Given our findings, we suspect that onset of ear fullness may be associated not with abnormal findings in the middle and inner ear function tests but with other causes, such as central desensitization.

Impairment of epithelial barrier integrity caused by environmental triggers is associated with the pathogenesis of airway inflammation. Using human airway epithelial cells, we attempted to identify molecule(s) that promote airway epithelial barrier integrity. Microarray analyses were conducted using the Affimetrix human whole genome gene chip, and we identified the N-myc downstream-regulated gene 1 (NDRG1) gene, which was induced during the development of the epithelial cell barrier. Immunohistochemical analysis revealed strong NDRG1 expression in ciliated epithelial cells in nasal tissues sampled from patients with chronic rhinosinusitis (CRS), and the low expression of NDRG1 was observed in goblet cells or damaged epithelial cells. NDRG1 gene knockdown with its specific siRNA decreased the transepithelial electrical resistance and increased the dextran permeability. Immunocytochemistry revealed that NDRG1 knockdown disrupted tight junctions of airway epithelial cells. Next, we analyzed the effects of NDRG1 knockdown on the expression of tight and adhesion junction molecules. NDRG1 knockdown significantly decreased only claudin-9 expression, but did not decrease other claudin family molecules, such as E-cadherin, and ZO-1, -2, or -3. Knockdown of claudin-9 markedly impaired the barrier function in airway epithelial cells. These results suggest that NDRG1 is important for the barrier integrity in airway epithelial cells.

Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders with a severe medical and social impact. Further insights from clinical and scientific studies are essential to develop effective therapies. Various stresses on the endoplasmic reticulum (ER) cause unfolded/misfolded proteins to aggregate, initiating unfolded protein responses (UPR), one of which is the induction of neuronal cell death. Some of the pathogenic factors for AD and PD are associated with UPR. ER molecules such as ubiquitin ligases (E3s) and chaperones are also produced during UPR to degrade and refold aberrant proteins that accumulate in the ER. In this review, we examine the role of HMG-CoA reductase degradation protein 1 (HRD1) and the chaperone protein-disulfide isomerase (PDI), which are both produced in the ER in response to stress. We discuss the importance of HRD1 in degrading amyloid precursor protein (APP) and Parkin-associated endothelin receptor-like receptor (Pael-R) to protect against neuronal death. PDI and the chemical chaperone 4-phenyl-butyrate also exert neuroprotective effects. We discuss the pathophysiological roles of ER stress, UPR, and the induction and neuroprotective effects of HRD1 and PDI, which may represent significant targets for novel AD and PD therapies.

Background: Bilastine, a novel non-sedating second-generation H1 antihistamine, has been approved in most European countries since 2010. This study aimed to evaluate the superiority of bilastine over placebo in Japanese patients with perennial allergic rhinitis (PAR). Methods: This randomized, double-blind, placebo-controlled, parallel-group, phase III study (trial registration number JapicCTI-142600) evaluated the effect of a 2-week treatment period with bilastine (20 mg once daily), fexofenadine (60 mg twice daily), or a matched placebo (double dummy) in patients with PAR. All patients were instructed to record individual nasal and ocular symptoms in diaries daily. The primary endpoint was the mean change in total nasal symptom scores (TNSS) from baseline to Week 2 (Days 10–13). Results: A total of 765 patients were randomly allocated to receive bilastine, fexofenadine, or placebo (256, 254, and 255 patients, respectively). The mean change in TNSS from baseline at Week 2 was significantly decreased by bilastine (−0.98) compared to placebo (−0.63, P = 0.023). Bilastine and fexofenadine showed no significant difference in the primary endpoint. However, the mean change in TNSS from baseline on Day 1 was more significantly decreased by bilastine (−0.99) than by placebo (−0.28, P

Neurodevelopmental disorders, which include autism spectrum disorder, are congenital impairments in the growth and development of the central nervous system. They are mainly accentuated during infancy and childhood. Autism spectrum disorder may be caused by environmental factors, genomic imprinting of chromosome 15q11-q13 regions, and gene defects such as those in genes encoding neurexin and neuroligin, which are involved in synaptogenesis and synaptic signaling. However, regardless of the many reports on neurodevelopmental disorders, the pathogenic mechanism and treatment of neurodevelopmental disorders remain unclear. Conversely, it has been reported that endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases. ER stress is increased by environmental factors such as alcohol consumption and smoking. Here we show the recent results on ER stress-induced neurodevelopmental disorders. ER stress led to a decrease in the mRNA levels of the proneural factors Hes1/5 and Pax6, which maintain an undifferentiated state of the neural cells. This stress also led to a decrease in nestin expression and an increase in beta-III tubulin expression. In addition, dendrite length was shortened by ER stress in microtubule-associated protein-2 (MAP-2) positive cells. However, the ubiquitin ligase HRD1 expression was increased by ER stress. By suppressing HRD1 expression, the ER stress-induced decrease in nestin and MAP-2 expression and increase in beta-III tubulin returned to control levels. Therefore, we suggest that ER stress induces abnormalities in neuronal differentiation and maturation via HRD1 expression. These results suggest that targeting ER stress may facilitate quicker approaches toward the prevention and treatment of neurodevelopmental disorders.

Endoplasmic reticulum (ER) stress responses play an important role in neurodegenerative diseases. Sodium 4-phenylbutyrate (4-PBA) is a terminal aromatic substituted fatty acid that has been used for the treatment of urea cycle disorders. 4-PBA possesses in vitro chemical chaperone activity and reduces the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R), which is involved in autosomal recessive juvenile parkinsonism (AR-JP). In this study, we show that terminal aromatic substituted fatty acids, including 3-phenylpropionate (3-PPA), 4-PBA, 5-phenylvaleric acid, and 6-phenylhexanoic acid, prevented the aggregation of lactalbumin and bovine serum albumin. Aggregation inhibition increased relative to the number of carbons in the fatty acids. Moreover, these compounds protected cells against ER stress-induced neuronal cell death. The cytoprotective effect correlated with the in vitro chemical chaperone activity. Similarly, cell viability decreased on treatment with tunicamycin, an ER stress inducer, and was dependent on the number of carbons in the fatty acids. Moreover, the expression of glucose-regulated proteins 94 and 78 (GRP94, 78) decreased according to the number of carbons in the fatty acids. Furthermore, we investigated the effects of these compounds on the accumulation of Pael-R in neuroblastoma cells. 3-PPA and 4-PBA significantly suppressed neuronal cell death caused by ER stress induced by the overexpression of Pael-R. Overexpressed Pael-R accumulated in the ER of cells. With 3-PPA and 4-PBA treatment, the localization of the overexpressed Pael-R shifted away from the ER to the cytoplasmic membrane. These results suggest that terminal aromatic substituted fatty acids are potential candidates for the treatment of neurodegenerative diseases., This work was partly supported by a Sasakawa Scientific Research Grant from the Japan Science Society. In addition, this work was supported by Grants-in-Aid for Scientific Research (21590101, 21300142, 20659013, and 21590120) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

SAMP8 mice show spontaneously accelerated aging and a short life span with systemic accumulation of oxidative stress. Nrf2 translocates into the nucleus upon oxidative stress and induces the expression of detoxifying and antioxidant enzymes. Recently, several studies reported that Nrf2 is associated with aging and various diseases. In the present study, we investigated the levels of Nrf2 nuclear translocation and phosphorylation of Akt and GSK-3β in livers of SAMP8 and normal aging SAMR1 mice. The protein level of Nrf2 in the nucleus of the liver was significantly decreased in SAMP8 at 10 months old compared with that in age-matched SAMR1. The protein level of Keap1, which anchors Nrf2 in the cytoplasm, did not differ between SAMP8 and SAMR1. In addition, the mRNA expression of Nrf2 in the liver of SAMP8 was significantly lower than that of SAMR1. Moreover, mRNA levels of detoxification and antioxidant enzymes, GSTa1 and NQO1, were significantly decreased in SAMP8 compared with SAMR1. These results indicate that a higher level of oxidative stress in SAMP8 might be caused by a lower level of Nrf2. Furthermore, the phosphorylation of Akt and GSK-3β was significantly decreased in the liver of SAMP8 at 10 months old. Recent studies have suggested that the Akt/GSK-3β signaling pathway is involved in the nuclear translocation of Nrf2. Therefore, it is suggested that the reduction of the translocation of Nrf2 into the nucleus might be induced by a decrease of GSK-3β phosphorylation, resulting in an increase of oxidative stress in SAMP8 mice.