Springer Science and Business Media LLC Acta Medica Okayama 2168-8184 17 8 2025 A Higher Liver Fibrosis-4 Index Is Associated With More Severe Hearing Loss in Idiopathic Sudden Sensorineural Hearing Loss e89864 EN Yukihide Maeda Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Soshi Takao Department of Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryotaro Omichi Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mizuo Ando Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Background Liver fibrosis is an important medical issue increasing over time in developed countries. Aims/objectives This study aimed to investigate whether liver fibrosis, as indicated by routine blood test parameters, influences the risk and severity of idiopathic sudden sensorineural hearing loss (ISSNHL). Material and methods Sixty-six patients with ISSNHL and 198 patients with benign parotid gland tumors (BPTs) (controls) were enrolled. Indices for liver fibrosis (Liver Fibrosis-4 index (FIB-4 index) and aspartate aminotransferase-to-platelet ratio index (APRI)) were calculated from the blood laboratory data. The pure tone average (PTA) was calculated as the mean of hearing levels at the six frequencies at the onset of ISSNHL. Severe hearing loss was defined as PTA≥60 decibels Hearing Level (dB HL). Results In risk evaluation, the FIB-4 index did not differ significantly between ISSNHL patients and controls. Regarding the severity of ISSNHL, the FIB-4 index was significantly higher in ISSNHL patients with severe hearing loss than in those with PTA<60 dB HL (P<0.05) on univariate comparison. After adjusting for age, sex, and indices of inflammation, both the FIB-4 index and APRI showed a significant association with severe hearing loss (odds ratio (OR): 5.9, 95% confidence interval (CI): 1.3-25.7, and OR: 2.2, 95% CI: 1.1-4.7). Conclusions and significance Higher liver fibrosis indices (FIB-4 index and APRI), derived from routine blood laboratory data, are associated with a more severe phenotype of ISSNHL. No potential conflict of interest relevant to this article was reported.

Nature Portfolio Acta Medica Okayama 2045-2322 15 1 2025 A glucocorticoid-regulating molecule, Fkbp5, may interact with mitogen-activated protein kinase signaling in the organ of Corti of mice cochleae 7506 EN Asuka Sato Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryotaro Omichi Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yukihide Maeda Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mizuo Ando Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences FKBP5 is a 51-Da FK506-binding protein and member of the immunophilin family involved in controlling the signaling of glucocorticoid receptor from the cytosol to nucleus. Fkbp5 has previously been shown to be expressed in murine cochlear tissue, including the organ of Corti (i.e., the sensory epithelium of the cochlea). Fkbp5-/- mice as used in this study show hearing loss in the low-frequency (8-kHz) range and click-evoked auditory brainstem response (ABR) threshold compared to wild-type mice. Both Fkbp5-/- and wild-type mice showed hearing loss at all frequencies and click-ABR thresholds at 24 h and 14 days following acoustic overexposure (AO). Tissues of the organ of Corti were subjected to RNA sequencing and KEGG pathway analysis. In Fkbp5-/- mice before AO, the mitogen-activated protein kinase (MAPK) signaling pathway was dysregulated compared to wild-type mice. In wild-type mice at 12 h following AO, the most significantly modulated KEGG pathway was the TNF signaling pathway and major MAPK molecules p38 and Jun were involved in the TNF signaling pathway. In Fkbp5-/- mice at 12 h following AO, the MAPK signaling pathway was dysregulated compared to wild-type mice following AO. In conclusion, Fkbp5 interacts with MAPK signaling in the organ of Corti in mice cochleae. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 6 2023 Cochlear Implantation in the Poorer-Hearing Ear Is a Reasonable Choice 589 593 EN Ryotaro Omichi Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Kariya Department of Otolaryngology-Head and Neck Surgery, Kawasaki Medial University Yukihide Maeda Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kunihiro Fukushima Hayashima Clinic of Otolaryngology and Dermatology Yuko Kataoka Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akiko Sugaya Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazunori Nishizaki Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mizuo Ando Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Original Article 10.18926/AMO/66150 Choosing the optimal side for cochlear implantation (CI) remains a major challenge because of the lack of evidence. We investigated the choice of the surgery side for CI (i.e., the better- or poorer-hearing ear) in patients with asymmetric hearing. Audiological records of 74 adults with a unilateral hearing aid who had undergone surgery at Okayama University Hospital were reviewed. The definition of ‘better-hearing ear’ was the aided ear, and the unaided ear was considered the poorer-hearing ear. We performed a multiple regression analysis to identify potential predictors of speech recognition performance after unilateral CI in the patients. Fifty-two patients underwent CI in the poorer-hearing ear. The post-Ci bimodal hearing rate was far higher in the poorer-ear group (77.8% vs. 22.2%). A multivariate analysis revealed that prelingual hearing loss and the patient’s age at CI significantly affected the speech recognition outcome (beta coefficients: 24.6 and －0.33, 95% confidence intervals [11.75-37.45] and [－0.58 to －0.09], respectively), but the CI surgery side did not (－6.76, [－14.92-1.39]). Unilateral CI in the poorer-hearing ear may therefore be a reasonable choice for adult patients with postlingual severe hearing loss, providing a greater opportunity for postoperative bimodal hearing. No potential conflict of interest relevant to this article was reported.

Public Library Science Acta Medica Okayama 1932-6203 16 10 2021 Upregulation of a nuclear factor-kappa B-interacting immune gene network in mice cochleae with age-related hearing loss e0258977 EN Kensuke Uraguchi Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yukihide Maeda Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junko Takahara Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryotaro Omichi Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shohei Fujimoto Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Kariya Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazunori Nishizaki Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mizuo Ando Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Epidemiological data suggest that inflammation and innate immunity play significant roles in the pathogenesis of age-related hearing loss (ARHL) in humans. In this mouse study, real-time RT-PCR array targeting 84 immune-related genes revealed that the expressions of 40 genes (47.6%) were differentially regulated with greater than a twofold change in 12-month-old cochleae with ARHL relative to young control mice, 33 (39.3%) of which were upregulated. These differentially regulated genes (DEGs) were involved in functional pathways for cytokine-cytokine receptor interaction, chemokine signaling, TNF signaling, and Toll-like receptor signaling. An NF-kappa B subunit, Nfkb1, was upregulated in aged cochleae, and bioinformatic analyses predicted that NF-kappa B would interact with the genomic regulatory regions of eight upregulated DEGs, including Tnf and Ptgs2. In aging cochleae, major proinflammatory molecules, IL1B and IL18rap, were upregulated by 6 months of age and thereafter. Remarkable upregulations of seven immune-related genes (Casp1, IL18r1, IL1B, Card9, Clec4e, Ifit1, and Tlr9) occurred at an advanced stage (between 9 and 12 months of age) of ARHL. Immunohistochemistry analysis of cochlear sections from the 12-month-old mice indicated that IL-18r1 and IL-1B were localized to the spiral ligament, spiral limbus, and organ of Corti. The two NF-kappa B-interacting inflammatory molecules, TNF alpha and PTGS2, immunolocalized ubiquitously in cochlear structures, including the lateral wall (the stria vascularis and spiral ligament), in the histological sections of aged cochleae. IBA1-positive macrophages were observed in the stria vascularis and spiral ligament in aged mice. Therefore, inflammatory and immune reactions are modulated in aged cochlear tissues with ARHL. No potential conflict of interest relevant to this article was reported.

Public Library Science Acta Medica Okayama 1932-6203 16 4 2021 Lack of collagen alpha 6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation e0249909 EN Shaoying Tang Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoko Yonezawa Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yukihide Maeda Department of Otolaryngology-Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mitsuaki Ono Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takahiro Maeba Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Toru Miyoshi Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Ryusuke Momota Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yasuko Tomono Division of Molecular and Cell Biology, Shigei Medical Research Institute Toshitaka Oohashi Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6, encoding the basement membrane (BM) collagen alpha 6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the COL4A6 mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated Col4a6 knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen alpha 6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner's membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of Col4a6 KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of Col4a6 KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the COL4A6 missense mutation c.1771G>A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in COL4A6 are likely due to the dominant-negative effects of the alpha 6(IV) chain and/or alpha 5 alpha 6 alpha 5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 01680102 2020 Immediate changes in transcription factors and synaptic transmission in the cochlea following acoustic trauma: A gene transcriptome study EN Yukihide Maeda Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shin Kariya Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kensuke Uraguchi Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Junko Takahara Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shohei Fujimoto Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akiko Sugaya Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazunori Nishizaki Department of Otolaryngology- Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Pathologic mechanisms in cochleae immediately following the onset of noise-induced hearing loss (NIHL) remain unclear. In this study, mice were exposed to 120 dB of octave band noise for 2 h to induce NIHL. Three hours after noise exposure, expression levels of the whole mouse genome in cochleae were analyzed by RNA-seq and DNA microarray. Differentially expressed genes (DEGs) exhibiting >2-fold upregulation or downregulation in noise-exposed cochleae compared to controls without noise exposure were identified. RNA-seq and microarray analyses identified 273 DEGs regulated at 3 h post-noise (51 upregulated and 222 downregulated). Bioinformatic analysis revealed that these DEGs were associated with the functional gene pathway "neuroactive ligand-receptor interaction" and included 28 genes encoding receptors for neurotransmitters such as gamma-aminobutyric acid and glutamate. Other DEGs included 25 genes encoding transcription factors. Downregulation of 4 neurotransmitter receptors (Gabra3, Gabra5, Gabrb1, Grm1) and upregulations of 5 transcription factors (Atf3, Dbp, Helt, Maff, Nr1d1) were validated by RT-PCR. The differentially regulated transcription factor Atf3 immunolocalized to supporting cells and hair cells in the organ of Corti at 12-h post-noise. The present data serve as a basis for further studies aimed at developing medical treatments for acute sensorineural hearing loss. No potential conflict of interest relevant to this article was reported.

Lippincott, Williams & Wilkins Acta Medica Okayama 15317129 41 3 2020 Role of Macrophage Migration Inhibitory Factor in NLRP3 Inflammasome Expression in Otitis Media 364 370 EN Shin Kariya Department of Otolaryngology―Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mitsuhiro Okano Department of Otolaryngology―Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Pengfei Zhao Department of Otolaryngology―Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yukihide Maeda Department of Otolaryngology―Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Yuko Kataoka Department of Otolaryngology―Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takaya Higaki Department of Otolaryngology―Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Seiichiro Makihara Department of Otolaryngology―Head and Neck Surgery, Kagawa Rosai Hospital Jun Nishihira Department of Medical Bioinformatics, Hokkaido Information University Tomoyasu Tachibana Departments of Otolaryngology, Japanese Red Cross Society Himeji Hospital Kazunori Nishizaki Department of Otolaryngology―Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hypothesis: Macrophage migration inhibitory factor plays an important role in the expression of interleukin (IL)-1β and the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in lipopolysaccharide-induced otitis media. Background: NLRP3 inflammasome and macrophage migration inhibitory factor are critical molecules mediating inflammation. However, the interaction between the NLRP3 inflammasome and macrophage migration inhibitory factor has not been fully examined. Methods: Wild-type mice and macrophage migration inhibitory factor gene-deficient (MIF－/－) mice received a transtympanic injection of either lipopolysaccharide or phosphate-buffered saline. The mice were sacrificed 24 hours after the injection. Concentrations of IL-1β, NLRP3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain and a pyrin domain), and caspase-1 in the middle ear effusions were measured by enzyme-linked immunosorbent assay. Temporal bones were processed for histologic examination and immunohistochemistry. Results: In the immunohistochemical study using the wild-type mice, positive staining of macrophage migration inhibitory factor, NLRP3, ASC, and caspase-1 were observed in infiltrating inflammatory cells induced by lipopolysaccharide in the middle ear. The number of inflammatory cells caused by lipopolysaccharide administration decreased remarkably in the MIF－/－ mice as compared with the wild-type mice. The concentrations of IL-1β, NLRP3, ASC, and caspase-1 increased in the lipopolysaccharide-treated wild-type mice. The MIF－/－ mice with lipopolysaccharide had decreased levels of IL-1β, NLRP3, ASC, and caspase-1 as compared with the wild-type mice. Conclusion: Macrophage migration inhibitory factor has an important role in the production of IL-1β and the NLRP3 inflammasome. Controlling the inflammation by modulating macrophage migration inhibitory factor and the NLRP3 inflammasome may be a novel therapeutic strategy for otitis media. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0959-4965 22 13 2011 Expression analysis of microRNAs in murine cochlear explants 652 654 EN Misato Hirai Yukihide Maeda Kunihiro Fukushima Akiko Sugaya Yuko Kataoka Kazunori Nishizaki MicroRNAs (miRNAs) play functional roles in sound transduction in cochlea. This study focuses on the validity of cochlear culture as an in vitro experimental tool, in view of miRNA expression. E15 cochleae were dissected and maintained in vitro for 48 h before extraction of miRNAs. MiRNA expression was comprehensively screened in explanted cochleae using a miRNA array that covers 380 miRNAs. A strong correlation was observed between expression levels of miRNAs in in vitro and in in vivo cochleae. Levels of 43 miRNAs were altered in vitro and these changes were reproducible over three trials. These findings indicate that in vitro miRNA profiling is a viable method for analysis of gene expression and action of chemical compounds on cochleae. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2000 Regional differences in the expression of DNA topoisomerase IIbeta in the pyramidal neurons of the rat hippocampus EN Yukihide Maeda A detailed analysis of the differential expression of a nuclear enzyme, DNA topoisomerase (topo) IIβ, was performed in the rat hippocampal pyramidal layer. Three-dimensional (3-D) reconstruction from serial sections immunostained with anti-topo IIβ antibody showed that the immunoreactivity was apparently weak in the entire CA3 region. Almost all CA1 pyramidal cells showed similar immunoreactivity to that seen in the dentate granular cells, the subicular neurons, and the cerebral neocortical neurons. In addition, immunoblotting analysis in the adult dorsal hippocampus showed that the expression level of topo IIβ in the CA3 was significantly lower than that in the CA1 region. The dissociation in the expression level between CA1 and CA3 occurred in postnatal days 4 (P4) through P6. The present finding suggests that the enzyme is possibly involved in activities of the hippocampal pyramidal neurons. No potential conflict of interest relevant to this article was reported.