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Ching-Nung Wu,1,2 Yu-Ming Wang,3,4 Wei-Chih Chen,1 Fu-Min Fang,3,4 Shau-Hsuan Li,5 Tai-Lin Huang,5 Chung-Feng Hwang,1 Yu Lee,6 Chung-Ying Lin,2,7– 9 Sheng-Dean Luo1,10,11 1Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Proton and Radiation Therapy Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 5Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 6Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Kaohsiung, Taiwan; 7Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Department of Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 9Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 10Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 11School of Traditional Chinese Medicine, Chang Gung University College of Medicine, Taoyuan, 33302, TaiwanCorrespondence: Chung-Ying Lin, National Cheng Kung University Tainan, 70101, Taiwan, Tel +886-7-731-7123 ext: 2533, Email cylin36933@gmail.com Sheng-Dean Luo, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Road, Niaosong District, Kaohsiung City, 83301, Taiwan, Email rsd0323.tw@gmail.comBackground: Few instruments are available for assessing the otorhinologic-related quality of life (QOL) in nasopharyngeal carcinoma (NPC) patients. Therefore, we evaluated whether the 22-item Sinonasal Outcome Test (SNOT-22) could be applied to these patients.Methods: Patients diagnosed with NPC, who had been treated with standard protocol and followed up in our institute between 2019 and 2022, were invited to join the cross-sectional study during their clinic visits. All participants completed the SNOT-22 and Eustachian Tube Dysfunction Questionnaire-7 once they were recruited. Confirmatory factor analysis (CFA) was performed to decide the most suitable model for the underlying SNOT-22 subdomains, along with various validity and reliability tests.Results: We identified a total of 275 patients, with 84 (30.5%) women and 191 (69.5%) men. The mean age was 54.1 years (standard deviation: 11.2). Among these patients, 171 (62.1%) were in late stages, and 260 (94.5%) received chemoradiotherapy as treatment. The median interval between primary RT treatment and questionnaire completion was 50 months (interquartile range: 29– 93). CFA supported a five-factor model for the SNOT-22 for NPC patients, including nasal, ear/facial, sleep, function, and emotion domains. The internal consistency and test-retest reliability of the SNOT-22 domain score were good. In addition, known-group validity was good for the SNOT-22 total score and domain scores according to the disease recurrence status.Conclusion: Psychometric analyses supported the reliability and validity of a five-domain SNOT-22 for assessing otorhinologic-related QOL in NPC patients.Keywords: SNOT-22, nasopharyngeal carcinoma, quality of life, psychometrics, chronic rhinosinusitis

Chang-Han Chen,1,2 Li-Jen Su,3–5 Hsin-Ting Tsai,1 Chung-Feng Hwang6,71Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510020, People’s Republic of China; 2Department of Applied Chemistry, Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantou, 54561, Taiwan; 3Department of Biomedical Sciences and Engineering, College of Health Sciences and Technology, National Central University, Taoyuan City, Taiwan; 4Education and Research Center for Technology Assisted Substance Abuse Prevention and Management, Taoyuan City, Taiwan; 5IHMed Global, Taipei City, Taiwan; 6Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 7Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, TaiwanBackground: Nasopharyngeal carcinoma (NPC) is a prevalent malignant tumor in Southeast Asia. The management of NPC has remained a challenge until now. ELF-1 is a member of the ETS family of transcription factors that regulate genes involved in cellular growth. ELF-1 expression has been reported in various cancers and is required for tumor growth and angiogenesis; however, its function in NPC remains unclear. In the present study, we characterized the role and underlying mechanism of ELF-1 in NPC.Methods: The biological functions of ELF-1 in NPC cells such as proliferation, migration, invasion, and drug resistance were investigated using MTT, BrdU incorporation, and Transwell assays. To gain more insight into the mechanism of ELF-1 in NPC, we analyzed CCL2/CCR2 signaling by Western blotting, ELISA, siRNAs, and CCR2 antagonist.Results: Gain-of-function of ELF-1 in TW01 and TW04 cells promoted NPC cell proliferation, BrdU incorporation, migration, invasion and cisplatin resistance. By contrast, knockdown of ELF-1 produced opposite results. Overexpression of ELF-1 enhanced the expression of CCL2 via binding to its promoter region and increased the level of the extracellular matrix protein CCL2 in cell culture medium. ELF-1 expression also modulated the downstream targets of CCL2/CCR2 signaling. Most importantly, ELF-1-induced NPC malignant phenotypes were abrogated by a CCR2 inhibitor, implying that the CCL2/CCR2 signaling axis was involved in ELF-1-mediated regulation in NPC.Conclusion: Our data suggest that ELF-1 plays an oncogenic role in NPC development associated with the CCL2/CCR2 signaling pathway and may therefore be a potential target for NPC therapy.Keywords: ELF-1, NPC, CCL2

Schwannoma arising from the tympanic membrane is a rare neoplasm. This report describes an external ear canal mass obscuring the tympanic membrane. A transcanal approach identified a tumour adhered to the tympanic membrane. The tumour was excised without myringoplasty. Pathology confirmed the diagnosis of schwannoma. Clinical examination revealed no evidence of recurrence during a follow-up period of one year. The possible origins of schwannoma of the tympanic membrane and lesion management are also discussed. [ABSTRACT FROM AUTHOR]

Objective: To investigate the differences in the prevalence of sleep disturbance between vestibular migraine (VM) and Meniere's disease (MD), and to determine whether poor sleep quality is correlated with dizziness handicap., Study Design: Observational prospective study., Setting: Tertiary Academic Medical Center., Methods: Patients diagnosed with VM, MD, and healthy controls completed the Mini Sleep Questionnaire (MSQ), which comprises 10 items assessing sleep quality. The MSQ total score was calculated by summing the scores of each item. The Dizziness Handicap Inventory (DHI) was used to evaluate the physical, emotional, and functional impacts of dizziness on daily life., Results: A total of 87 participants (35 with VM, 39 with MD, and 13 healthy controls) were enrolled. Both the VM and MD groups had significantly higher MSQ total scores than the control group (P < .001). The VM group exhibited a higher prevalence of "difficulty falling asleep" (P = .015) and "headaches on awakening" (P = .012) than the MD group. Additionally, the MSQ total score was significantly correlated with the DHI total score in VM patients (P = .001, r = .518). VM patients with severe dizziness handicap had significantly higher MSQ total scores than those with mild handicap (P = .005)., Conclusion: This study highlights the high prevalence of sleep disturbance in both VM and MD patients. The severity of sleep disturbance is correlated with dizziness handicap in VM patients, emphasizing the importance of assessing sleep quality and promoting good sleep habits in the management of VM., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objectives: Pendred syndrome, an autosomal recessive disorder, is often associated with pathogenic variants of the SLC26A4 gene that encodes the pendrin protein. Given its autosomal recessive inheritance, tracing the family history and screening siblings become crucial once a diagnosis of Pendred syndrome is confirmed. This case report aims to underscore the variability in inner ear morphology within a family diagnosed with Pendred syndrome, all carrying the same SLC26A4 gene mutation., Methods: A chart review and a review of the literature., Results: We present a family of 4, all of whom possess sensorineural hearing loss due to the same homozygous SLC26A4 variant c.919-2A>G. Intriguingly, clinical manifestations, especially inner ear deformities, displayed variability among family members. Notably, 1 family member exhibited a normal cochleovestibular structure morphology, which was rarely reported in the literature., Conclusions: This report highlights the significance of genetic testing and familial consultation when a proband exhibits typical Pendred syndrome symptoms. It also underscores that the inner ear morphology can exhibit variability among family members, even with the same homozygous SLC26A4 variant., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Hearing loss has been recognized as a risk factor for dementia and non-motor features of Parkinson's disease (PD). The apolipoprotein E (APOE) protein contributes to maintenance and repair of neuronal cell membranes, causing age-related disorders. This study aimed to analyze the impact of hearing loss on cognitive impairment, PD severity, and APOE gene expression in these patients. Methods: A total of 72 out-patients diagnosed with either PD or hearing loss were enrolled in this study. The hearing assessment included pure-tone audiometry, speech reception thresholds, and speech discrimination ability. Dementia was assessed by filling out the Clinical Dementia Rating and Mini-Mental State Examination questionnaires. The severity of PD was assessed using the Modified Hoehn and Yahr scale. Blood samples were tested for the gene expression of APOE. Results: Out of the 72 cases, there were 44 males and 28 females, with an average age of 64.4 ± 9.1 years. A total of 41 out of 72 cases had dementia and had a worse hearing threshold than those without dementia (47.1 ± 24.4 vs. 31.7 ± 22.1 dB, p = 0.006). A total of 58 patients were diagnosed with PD, with 14 of them classified as having severe symptoms (Modified Hoehn and Yahr scale > 2). Patients with severe PD were found to have a worse hearing threshold (49.6 ± 28.3 vs. 30.3 ± 17.8 dB, p = 0.028) and higher prevalence of dementia (12/14 vs. 18/44, p = 0.006). Among 10 individuals with the APOE ε4 gene, the prevalence of dementia was higher than those without the ε4 allele (9/10 vs. 32/62, p = 0.036). Conclusions: Hearing loss is common in severe PD and in dementia patients. Severe PD has a negative impact on the hearing threshold and cognitive dysfunction. Patients with APOE ε4 have a higher prevalence of dementia.

Objective: To investigate the autonomic symptom burden in patients with sudden sensorineural hearing loss (SSNHL) and its association with the severity and prognosis., Study Design: Observational prospective study., Setting: Tertiary academic medical center., Methods: Patients diagnosed with SSNHL at a single medical center completed the COMPASS 31 questionnaire, which assesses dysautonomia across 6 domains with 31 questions. A total COMPASS 31 score was calculated by summing the scores from each weighted domain. The treatment outcome was evaluated by the percentage of recovery, calculated as the hearing gain in pure tone average (PTA) after treatment divided by the pretreatment PTA difference between the 2 ears. We defined poor recovery as a percentage of recovery <80%., Results: A total of 63 SSNHL patients were included. The mean COMPASS 31 score was 23.4 (SD 14). Patients with poor recovery had significantly higher COMPASS 31 scores than those with good recovery (mean 26.4 [SD 14.4] vs 16.9 [SD 10.4]; 95% confidence interval [CI] 2-17). There was a negative association between COMPASS 31 score and both hearing gain (r = -.323, 95% CI -0.082 to -0.529) and percentage of recovery (r = -.365, 95% CI -0.129 to -0.562). Multivariate analyses of independent factors indicate that patients with higher COMPASS 31 scores had a greater risk for poor recovery (OR 1.06 [95% CI 1.003-1.117])., Conclusion: This study highlights the association between autonomic symptom burden and poor hearing outcomes in SSNHL patients. The findings underscore the importance of evaluating autonomic function during the treatment of SSNHL., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Lymphangioma (LM) is a rare but benign tumor derived from lymphatic malformation, which is extremely rare in the auditory canal or middle ear cavity. We presented a case of acquired lymphangioma of the external auditory canal combined with cholesteatoma in the middle ear cavity. To our best knowledge, this is the first case of combined lesions of lymphangioma and cholesteatoma in English literature., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Meniere's disease (MD) is one of the most complicated diseases in the otologic clinic. The complexity of MD is partially due to the multifactorial etiological mechanisms and the heterogenous symptoms, including episodic vertigo, hearing loss, aural fullness and tinnitus. As a result, the diagnosis of MD and differentiating MD from other diseases with similar symptoms, such as vestibular migraine (VM), is challenging. In addition, it is difficult to predict the progression of hearing loss and the frequency of vertigo attacks. Detailed studies have revealed that functional markers, such as pure tone audiometry (PTA), electrocochleography (ECochG), vestibular evoked myogenic potential (VEMP), caloric test, video head impulse test (vHIT) and magnetic resonance imaging (MRI) could help to evaluate MD with different hearing levels and frequency of vertigo attacks. Investigations of molecular markers such as autoimmunity, inflammation, protein signatures, vasopressin and circadian clock genes in MD are still underway. This review will summarize these functional and molecular markers, address how these markers are associated with hearing loss and vertigo attacks in MD, and analyze the results of the markers between MD and VM.

Objectives: Recessive variants in the MYO15A gene constitute an important cause of sensorineural hearing impairment (SNHI). However, the clinical features of MYO15A-related SNHI have not been systemically investigated. This study aimed to delineate the hearing features and outcomes in patients with pathogenic MYO15A variants., Design: This study recruited 40 patients with biallelic MYO15A variants from 31 unrelated families. The patients were grouped based on the presence of N-terminal domain variants (N variants). The longitudinal audiological data and for those undergoing cochlear implantation, the auditory and speech performance with cochlear implants, were ascertained and compared between patients with different genotypes., Results: At the first audiometric examination, 32 patients (80.0%) presented with severe to profound SNHI. Patients with at least one allele of the N variant exhibited significantly better hearing levels than those with biallelic non-N variants (78.2 ± 23.9 dBHL and 94.7 ± 22.8 dBHL, respectively) (p = 0.033). Progressive SNHI was observed in 82.4% of patients with non-profound SNHI, in whom the average progression rate of hearing loss was 6.3 ± 4.8 dBHL/year irrespective of the genotypes. Most of the 25 patients who underwent cochlear implantation exhibited favorable auditory and speech performances post-implantation., Conclusions: The hearing features of patients with biallelic pathogenic MYO15A variants are characterized by severe to profound SNHI, rapid hearing progression, and favorable outcomes with cochlear implants. Periodic auditory monitoring is warranted for these patients to enable early intervention., Competing Interests: The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Leptin is important in physiological and pathological functions in various cancers, however, the significance and mechanisms of leptin in nasopharyngeal carcinoma remain ambiguous., Methods: Leptin expression was analyzed by QPCR, immunohistochemistry, Western blotting, and TCGA database. The impact of gain- or loss-of-function of leptin were determined by MTT, colony formation, wound healing, and Transwell assays in NPC cells, and by a xenograft tumor model. Leptin-modulated glucose consumption and lactate production were assessed by ELISA. Furthermore, leptin-regulated signaling pathways were examined by QPCR and Western blotting assays. The immunoprecipitation assay was conducted to determine interaction between leptin and EGFR. In addition, miR-874-3p-regulated leptin expression was evaluated using bioinformatics, QPCR, luciferase assay, AGO2-RIP assay, and Western blotting., Results: In this study, we found that leptin was highly expressed in the sera and tumor tissues of patients with NPC, and elevated leptin expression was associated with advanced clinical features and poor prognosis. Functional assays demonstrated that leptin remarkably promoted NPC cell growth, motility, and glycolysis in vitro and in vivo. Mechanistically, leptin associated with EGFR, resulting in enhanced cell growth through the regulation of cell-cycle related markers, glycolysis-related genes, and EGFR/AKT/c-Myc signaling. Moreover, leptin potentiated the invasive capacity of NPC cells by promoting EMT. We further explored that miR-874-3p influenced leptin-mediated NPC progression. Overexpression of miR-874-3p prevented cell growth, motility, glucose consumption, and lactate production in NPC cells, whereas miR-874-3p inhibition had the opposite effects. AGO-RIP assays confirmed that Argonaute 2 (AGO2), a protein associated with miR-874-3p, regulated leptin expression in NPC cells. The rescue assays indicated that inhibition of leptin suppressed the effects of miR-874-3p inhibitor. In clinical specimens, miR-874-3p was negatively correlated with leptin., Conclusions: Leptin may serve as a novel prognostic factor and potential therapeutic target for patients with NPC. In addition, a newly discovered regulatory axis of leptin/EGFR/AKT/c-Myc can provide a novel therapeutic strategy for NPC., (© 2022. The Author(s).)

Objectives: We compared the functional outcomes of fat myringoplasty and areolar tympanoplasty through a small postauricular incision in patients who underwent transcanal endoscopic ear surgery (TEES)., Methods: The study included patients who underwent myringoplasty or type I tympanoplasty using TEES in our Department of Otolaryngology between April 2016 and May 2019. The patients were divided into 2 groups according to the type of graft material used, which was selected based on the available amount of subcutaneous fat and the surgeon's experience., Results: In total, 63 patients received fat tissue grafts (group A) and 77 received areolar tissue grafts (group B). The median operative time was significantly longer in group B (132 minutes) than in group A (65 minutes); perforations were significantly larger in group B than in group A (61.0% vs 29.7% of the eardrum surface). The postoperative air conduction threshold, air-bone gap, and speech reception threshold values were significantly lower than the preoperative values in both groups. The graft success rate did not significantly differ between groups A (96.8%, 61/63) and B (96.1%, 74/77). In group A, the perforation was > 35% of the eardrum surface in 27.0% (17/63) of the patients; the graft success rate was 100% (17/17). In the remaining 46 patients (perforation > 35%), the graft success rate was 95.7% (44/46); this difference was not statistically significant., Conclusions: Transcanal endoscopic ear surgery increases the usefulness of fat myringoplasty for the repair of perforations > 35% of the eardrum surface. Postauricular fatty and areolar tissues are suitable for this simple and rapid technique, which yields excellent outcomes.

Gentamicin is an important aminoglycoside antibiotic used in the treatment of gram‑negative bacterial infections, but nephrotoxicity and ototoxicity reduce its utility. The autophagy pathway is involved in damage of auditory hair cells. With the aim of developing new strategies for attenuating gentamicin ototoxicity, the present study investigated the otoprotective mechanism of 2,3,4',5‑tetrahydroxystilbene‑2‑O‑β‑D-glucoside (THSG) in vitro using the mouse cochlear cell line UB/OC‑2. MTT assay demonstrated that gentamicin reduced UB/OC‑2 cell viability and western blotting showed that gentamicin upregulated autophagy‑related proteins, such as Beclin, autophagy related 5 and LC3‑II. THSG significantly attenuated gentamicin‑induced cytotoxicity, clearly reduced LDH release observed by LDH assay and decreased the expression of autophagy‑related proteins. Reverse‑transcription‑quantitative (RT‑q) PCR and western blotting showed that THSG against gentamicin‑induced autophagy via suppressing the expression of Sesn2, at both the mRNA and protein level and a possible involvement of AMP‑activated protein kinase (AMPK)/mTOR signaling response. Collectively, the present study demonstrated that THSG decreased gentamicin‑induced ototoxicity in UB/OC‑2 cochlear cells via the autophagic signaling in regulating Sesn2/AMPK/mTOR pathway. These results suggested that THSG might be a new therapeutic agent with the potential to attenuate gentamicin ototoxicity.

Background: It is unclear whether neural response telemetric (NRT) thresholds are related to lexical tonal language performance after cochlear implants (CIs). We explored the factors associated with changes in NRT thresholds and postoperative performance of CI patients., Methods: Patients receiving nucleus 24 CIs in our hospital from November 2010 were enrolled. We analyzed medical records and NRT thresholds. Mandarin speech and tone identification were measured in CI patients for at least 1 year postoperatively., Results: Seventy-two patients with an average age of 16.1 years received CIs. The postoperative NRT threshold was lower than the intraoperative threshold. The NRT threshold was higher in the early- than the late-activation group (mapping within 21 vs >21 days postoperatively, respectively). Lower intraoperative NRT thresholds and curved electrodes were significantly associated with lower postoperative NRT thresholds. In multiple linear regression analysis, only postoperative NRT thresholds significantly affected speech and tone perception, including word recognition scores, tone perception, and comprehension of easy and difficult sentences (all p < 0.05). Other clinical parameters, including age, gender, implant type, and activation timing, were not significantly associated with clinical tone or speech outcomes., Conclusion: Curved electrode arrays were associated with lower postoperative NRT thresholds. A lower postoperative NRT threshold might predict better performance of Mandarin-speaking CI patients. Future studies should evaluate factors that affect both postoperative NRT thresholds and lexical tonal language performance., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Objectives: The underlying etiology of Meniere's disease (MD) is not completely clear, but the precipitated triggers may alter the circadian clock in patients with MD. This study aims to survey the expression of circadian clock genes in peripheral blood (PB) leukocytes of MD patients., Methods: We investigated the expression of nine circadian clock genes in the PB leukocytes of patients with MD and normal controls using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR)., Results: We observed significantly lower expression of PER1 gene and higher expression of CLOCK gene in MD patients than those in normal controls ( p  < 0.05). PER1 did not associate with the degree of dizziness handicap in the patients with MD, but a lower expression of PER1 was significantly correlated with higher pure tone average (PTA) and speech reception threshold of the affected ear ( p  < 0.05). Patients with PTA > 30 dB had significantly lower PER1 expression than those with PTA ≤30 dB in the affected ear ( p  < 0.05). Our qRT-PCR result was validated by fewer positively stained leukocytes for PER1 protein in the MD patients using the immunocytochemical study., Conclusion: Our study implies the alteration of the circadian clock in patients with MD. In particular, the downregulation of PER1 correlated with the degree of hearing loss in the affected ear. PER1 in PB leukocytes may be a potential marker for the progression of hearing loss in MD., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

The videonystagmography oculomotor test battery is considered useful method for diagnosing vertigo. However, its role in diagnosing central vestibular disorder has not been clarified due to variations in interpretation. Patients ( n = 103) with vertigo or dizziness symptoms undergoing the oculomotor tests and brain MRI within 1 month were analyzed. Two otology specialists retrospectively interpreted the oculomotor tests, and three neurology and neuroradiology specialists determined whether central lesions were present on brain MRI. Multivariable logistic regression analysis was performed to determine the factors contributing to discordant interpretation between oculomotor tests and brain MRI. Oculomotor tests predicting central lesions were assessed using principal component analysis. The intra- and inter-rater reliability in oculomotor test interpretation was moderate to good. Age > 60 years and multiple comorbidities were significant predictors of a discordant interpretation between MRI and oculomotor tests. Positive neurological symptoms and a higher oculomotor index (according to saccade (vertical axis), smooth pursuit (horizontal axis), and gaze-evoked nystagmus (horizontal/vertical axes) tests) significantly predicted central vestibular disorder in vertigo patients. Caution is required when interpreting the results of the oculomotor test battery for diagnosis of central lesions in older patients, as well as in those with multiple comorbidities.

The Toll-like receptor (TLR) signaling pathway is the key regulator of the innate immune system in response to systemic infection. Several studies have reported that the systemic TLR4 agonist lipopolysaccharide exacerbates aminoglycoside ototoxicity, but the influence of virus-associated TLR7 and TLR9 signaling cascades on the cochlea is unclear. The present study aimed to investigate the auditory effects of systemic TLR7 and TLR9 agonists during chronic kanamycin treatment. CBA/CaJ mice received the TLR7 agonist gardiquimod or TLR9 agonist CpG oligodeoxynucleotides (ODN) one day before kanamycin injection and on the 5th and 10th days during a 14-day course of kanamycin treatment. We observed that systemic gardiquimod or CpG ODN alone did not affect the baseline auditory brainstem response (ABR) threshold. Three weeks after kanamycin treatment, gardiquimod did not significantly change ABR threshold shifts, whereas CpG ODN significantly increased kanamycin-induced ABR threshold shifts. Furthermore, outer hair cell (OHC) evaluation revealed that CpG ODN reduced distortion product otoacoustic emission amplitudes and increased kanamycin-induced OHC loss. CpG ODN significantly elevated cochlear Irf-7, Tnf-α, Il-1, and Il-6 transcript levels. In addition, an increased number of Iba-1 + cells, which represented activated macrophages, was observed in the cochlea treated with CpG ODN. Our results indicated that systemic CpG ODN exacerbated kanamycin-induced ototoxicity and increased cochlear inflammation. This study implies that patients with underlying virus infection may experience more severe aminoglycoside-induced hearing loss if it occurs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Skin flap infection is one of the most common complications of cochlear implantation (CI). We identified the causes of skin flap pressure ulcer over the antenna site and proposed wound management strategies., Methods: A total of 250 consecutive pediatric patients who underwent CI to treat profound hearing loss were retrospectively assessed. Data on demographic characteristics, the cause of skin infection, and the time of onset were obtained., Results: Seventeen patients (17/250, 6.8%) had a total of 23 skin pressure injuries in the area covering the antenna. We used the National Pressure Ulcer Advisory Panel pressure injury staging system to grade injury severity. Twelve patients had 16 (16/23, 69.6.%) stage 1 pressure injuries; the skin reaction resolved after the patients stopped wearing the device for a brief period, loosened the magnet to relieve pressure on the coil, and received topical antibiotics. Five patients with six (6/23, 26.1%) stage 2 pressure injuries and one (1/23, 4.3%) stage 3 injury, were treated with oral antibiotics. The patient with the stage 3 injury was instructed not to wear the external device for 10-14 days. The incidence of skin reactions associated with the ESPrit speech processor (0/17, 0%) was significantly lower than that associated with the Freedom (2/17, 11.8%), N5 (8/17, 47.1%), and N6 (7/17, 41.1%; p < 0.05) processors. Pressure injuries were more common in younger children (≤7 years, 100%) than in older children (>7 years, 0%; p < 0.05) most likely due to their thinner scalps., Conclusions: Early detection and treatment can prevent implant-threatening infections, particularly in younger children. We believe that better antenna designs will reduce this complication., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory system are still little known. Here, we disturbed the circadian clock in the cochlea of male CBA/CaJ mice by constant light (LL) or constant dark. LL significantly repressed circadian rhythmicity of circadian clock genes Per1 , Per2 , Rev-erbα , Bmal1 , and Clock in the cochlea, whereas the auditory brainstem response thresholds were unaffected. After exposure to low-intensity (92 dB) noise, mice under LL condition initially showed similar temporary threshold shifts to mice under normal light-dark cycle, and mice under both conditions returned to normal thresholds after 3 weeks. However, LL augmented high-intensity (106 dB) noise-induced permanent threshold shifts, particularly at 32 kHz. The loss of outer hair cells (OHCs) and the reduction of synaptic ribbons were also higher in mice under LL after noise exposure. Additionally, LL enhanced high-intensity noise-induced 4-hydroxynonenal in the OHCs. Our findings convey new insight into the deleterious effect of an irregular biological clock on the auditory system.

This article contains data concerning the research article entitled "Pressure ulcers and skin infections after cochlear implantation: A delayed yet serious issue" (Hui-Shan Hsieh, Chee-Yee Lee, Hung-Pin Wu, Ming-Ying Zhuo, and Chung-Feng Hwang) [1]. This data article reports the causes of skin flap pressure ulcer over the antenna site and protocol for the clinical managements. The patients with cochlear implant (n = 315) were enrolled. We used the National Pressure Ulcer Advisory Panel (NPUAP) pressure injury staging system to grade injury severity in all patients. The data included in this article are as follows: the clinical characteristics of patients, baselines variables between groups with and without pressure ulcer, the severity of skin flap reactions based on the NPUAP pressure injury system and corresponding interventions, related clinical details of patients with pressure ulcer, This article will be valuable for routine clinical practice as serving as a paradigm., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2020 The Authors.)

Cardiovascular factors are associated with the pathophysiological features and risk of sudden sensorineural hearing loss (SSNHL). However, little is known about the link between carotid intima-media thickness (IMT), SSNHL risk, and their respective treatment outcomes. In this study, we retrospectively reviewed 47 SSNHL cases and 33 control subjects from a single medical center and compared their demographic data and clinical characteristics, including their carotid IMT and audiological data. Of the 80 enrolled subjects, the proportion of those with high carotid IMT was greater in the SSNHL group (53.2%) than in the control group (21.2%), with an odds ratio (OR) of 4.22 (95% confidence interval (CI) [1.53-11.61], P = 0.004). Notably, high carotid IMT was more common in female SSNHL patients than females in the control group (54.2% vs. 12.5%; OR, 8.27 (95% CI [1.53-44.62]), P = 0.008), particularly in female patients ≥50 years of age (75% vs. 25%; OR, 9.0 (95% CI [1.27-63.9]), P = 0.032). The multivariate regression analyses showed the association between high carotid IMT and SSNHL with an adjusted OR of 4.655 (95% CI [1.348-16.076], P = 0.015), particularly in female SSNHL patients (adjusted OR, 9.818 (95% CI [1.064-90.587], P = 0.044). The carotid IMT was not associated with the treatment outcomes of SSNHL. Our results indicate that early-stage atherosclerosis may be associated with SSNHL, particularly in female patients more than 50 years old., Competing Interests: The authors declare that they have no competing interests., (© 2020 Ho et al.)

Leaf shape in plants plays important roles in water use, canopy structure, and physiological tolerances to abiotic stresses; all important traits for the future development and sustainability of grapevine cultivation. Historically, researchers have used ampelography, the study of leaf shape in grapevines, to differentiate Vitis species and cultivars based on finite leaf attributes. However, ampelographic measurements have limitations and new methods for quantifying shape are now available. We paired an analysis of finite trait attributes with a 17-point landmark survey and generalized Procrustes analysis (GPA) to reconstruct grapevine leaves digitally from five interspecific hybrid mapping families. Using the reconstructed leaves, we performed three types of quantitative trait loci (QTL) analyses to determine the genetic architecture that defines leaf shape. In the first analysis, we compared several important ampelographic measurements as finite trait QTL. In the second and third analyses, we identified significant shape variation via principal components analysis (PCA) and using a multivariate least squares interval mapping (MLSIM) approach. In total, we identified 271 significant QTL across the three measures of leaf shape and identified specific QTL hotspots in the grape genome which appear to drive major aspects of grapevine leaf shape., (Copyright © 2019 Demmings, Williams, Lee, Barba, Yang, Hwang, Reisch, Chitwood and Londo.)

Background: This study was performed to investigate the prognostic factors that influence hearing outcomes of children with cleft lip and palate after ventilation tube insertion., Methods: The authors retrospectively reviewed the hearing thresholds of 90 children with cleft lip and palate and performed univariate and multivariate analyses of five prognostic factors for hearing outcomes: age at palatoplasty, age at first ventilation tube insertion, timing of ventilation tube insertion, frequency of ventilation tube insertion, and type of cleft palate., Results: On univariate analysis, the authors found that older age at palatoplasty (p = 0.002), older age at first ventilation tube insertion (p = 0.025), and increased frequency of ventilation tube insertion (p = 0.048) were significant prognostic factors for poorer hearing outcomes in children with cleft lip and palate. Multiple logistic regression analysis showed that late palatoplasty (age older than 1 year) was the most influential factor for poor hearing outcome (OR, 2.83), followed by two or more ventilation tube insertions (OR, 1.94)., Conclusion: The age at palatoplasty and frequency of ventilation tube insertion were found to be significant prognostic factors influencing hearing outcomes in children with cleft lip and palate., Clinical Question/level of Evidence: Risk, III.

Background: Zinc plays a vital antioxidant role in human metabolism. Recent studies have demonstrated a correlation between noise-induced hearing loss (NIHL) and oxidative injury; however, no investigation has focused specifically on the subgroup of NIHL associated tinnitus patients. We aimed to evaluate the effectiveness of zinc supplementation in treating NIHL associated tinnitus., Methods: Twenty patients with tinnitus and a typical NIHL audiogram (38 ears) were included in this study. Another 20 healthy subjects were used as the control group. A full medical history assessment was performed, and each subject underwent an otoscopic examination, basic audiologic evaluation, distortion product otoacoustic emissions (DPOAEs), tinnitus-match testing, Tinnitus Handicap Inventory (THI) and serum zinc level analyses. After 2 months of treatment with zinc, all tests were repeated., Results: There was a significant difference between pretreatment and post-treatment within the tinnitus group (73.6 vs. 84.6 μg/dl). The pre- and post-treatment difference in serum zinc was significantly higher in the young group (≦50 years) compared to the old group (19.4 ± 11.4 vs. 2.6 ± 9.2 μg/dl, respectively; p = 0.002). There were no statistically significant differences in hearing thresholds, speech reception thresholds, or tinnitus frequency and loudness results before and after treatment. In addition, 17 patients (85%) showed statistically significant improvement of THI-total scores post-treatment, from 38.3 to 30 (p = 0.024)., Conclusions: Zinc oral supplementation elevated serum zinc levels, especially in younger patients. THI scores improved significantly following zinc treatment in patients with NIHL associated tinnitus. However, no improvements in objective hearing parameters were observed., (Copyright © 2018 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Key Message: A major QTL for downy mildew resistance was detected on chromosome 18 (Rpv27) in Vitis aestivalis-derived 'Norton' based on a high-resolution linkage map with SNP and SSR markers as well as 2 years of field and laboratory phenotyping data. Grapevine downy mildew caused by the oomycete Plasmopara viticola is one of the most widespread and destructive diseases, particularly in humid viticultural areas where it damages green tissues and defoliates vines. Traditional Vitis vinifera wine grape cultivars are susceptible to downy mildew whereas several North American and a few Asian cultivars possess various levels of resistance to this disease. To identify genetic determinants of downy mildew resistance in V. aestivalis-derived 'Norton,' a mapping population with 182 genotypes was developed from a cross between 'Norton' and V. vinifera 'Cabernet Sauvignon' from which a consensus map was constructed via 411 simple sequence repeat (SSR) markers. Using genotyping-by-sequencing, 3825 single nucleotide polymorphism (SNP) markers were also generated. Of these, 1665 SNP and 407 SSR markers were clustered into 19 linkage groups in 159 genotypes, spanning a genetic distance of 2203.5 cM. Disease progression in response to P. viticola was studied in this population for 2 years under both laboratory and field conditions, and strong correlations were observed among data sets (Spearman correlation coefficient = 0.57-0.79). A quantitative trait loci (QTL) analysis indicated a resistance locus on chromosome 18, here named Rpv27, explaining 33.8% of the total phenotypic variation. Flanking markers closely linked with the trait can be further used for marker-assisted selection in the development of new cultivars with resistance to downy mildew.

S100 calcium binding protein A4 (S100A4) promotes extracellular signal transduction, intercellular adhesion, motility and mobility. Different extracts from Coix lachryma-jobi have been used for the treatment of various types of cancer in Asia. In our previous study, the polysaccharide fraction extact, CP1, induced cell apoptosis of non‑small cell lung cancer cells. In the current study, CP1 inhibited migration and invasion of A549 cells in a scratch wound healing assay and matrigel invasion assay, respectively. Furthermore, reverse transcription‑polymerase chain reaction and western blotting demonstrated that CP1 downregulated the gene and protein expression levels of S100A4. In silico docking analysis demonstrated that polysaccharides may not interfere with dimerization, whereas, the affinity of polysaccharides for an S100A4‑NMIIA pocket was margnially greater than at the dimerization sites. Thus, CP1 inhibited A549 cell migration and invasion potentially via downregulation of S100A4, and may also interact with the binding site of S100A4‑NMIIA, which indicated that CP1 has potential as an alternative cancer chemotherapeutic by targeting S100A4.

Objectives. We evaluated the causes, hearing, and speech performance before and after cochlear implant reimplantation in Mandarin-speaking users. Methods. In total, 589 patients who underwent cochlear implantation in our medical center between 1999 and 2014 were reviewed retrospectively. Data related to demographics, etiologies, implant-related information, complications, and hearing and speech performance were collected. Results. In total, 22 (3.74%) cases were found to have major complications. Infection (n = 12) and hard failure of the device (n = 8) were the most common major complications. Among them, 13 were reimplanted in our hospital. The mean scores of the Categorical Auditory Performance (CAP) and the Speech Intelligibility Rating (SIR) obtained before and after reimplantation were 5.5 versus 5.8 and 3.7 versus 4.3, respectively. The SIR score after reimplantation was significantly better than preoperation. Conclusions. Cochlear implantation is a safe procedure with low rates of postsurgical revisions and device failures. The Mandarin-speaking patients in this study who received reimplantation had restored auditory performance and speech intelligibility after surgery. Device soft failure was rare in our series, calling attention to Mandarin-speaking CI users requiring revision of their implants due to undesirable symptoms or decreasing performance of uncertain cause.

Objectives/hypothesis: Sudden sensorineural hearing loss (SNNHL) is a disease entity that could be caused by multiple etiologies in which the innate immunity status of the patients might be involved. The aim of this study is to investigate the expression of Toll-like receptor (TLR) genes in peripheral blood leukocytes of SNNHL patients., Study Design: Basic research., Methods: We examined the expression of six TLR genes in the peripheral blood leukocytes of SNNHL patients and normal controls using real-time quantitative reverse transcriptase-polymerase chain reaction., Results: We found significantly higher expression of TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 genes in SNNHL patients as compared with normal controls (P < 0.05). Higher expression of the TLR2 gene was found in patients with profound hearing loss compared with those with less severe hearing loss (P < 0.05). The result was validated by the positively stained leukocytes for TLR2 protein in SNNHL patients using the immunocytochemical study. In addition, the percentage of CD14(+) monocytes expressing TLR2 in SNNHL patients was higher than in normal controls assessed by flow cytometry and significantly correlated with the hearing thresholds of the affected ear (P < 0.05)., Conclusion: Our study implies a role for TLRs in SNNHL. The expression of TLR2 in particular correlates with the severity of the disease., Level of Evidence: N/A., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

The cause of sudden sensorineural hearing loss (SSNHL) remains unclear and therefore it is often considered as idiopathic. Sleep disturbance has been linked to SSNHL and circadian rhythm disruption, but the link between circadian rhythm disruption and SSNHL has never been investigated.In this study, we surveyed the sleep quality of 38 patients with SSNHL using a simple insomnia sleep questionnaire. The expression of circadian clock genes in peripheral blood (PB) leukocytes from 38 patients with SSNHL and 71 healthy subjects was accessed using real-time quantitative reverse transcriptase-polymerase chain reaction and validated using immunocytochemical staining.We found that 61.8% of patients with SSNHL suffered from insomnia before the insult of hearing loss. Besides, significantly decreased expression of PER1, CRY1, CRY2, CLOCK, BMAL1, and CKlε was found in PB leukocytes of patients with SSNHL when compared with healthy subjects. SSNHL patients with vertigo had significantly lower expression of CRY1 and CKlε than patients without vertigo symptoms. Our results imply the association of sleep disturbance and disrupted circadian rhythm in SSNHL.

Pluchea indica is used in traditional medicine for the treatment of lumbago, ulcer, tuberculosis and inflammation. The anti-cancer activities and the underlying molecular mechanisms of the ethanolic extracts of P. indica root (PIRE) were characterized in the present study. PIRE strongly inhibited the viability of the human nasopharyngeal carcinoma cells (NPC-TW 01 and NPC-TW 04) in a time- and dose-dependent manner. Migration of cancer cells was also suppressed by PIRE. In addition, PIRE significantly increased the occurrence of the cells in sub-G1 phase and the extent of DNA fragmentation in a dose-dependent manner, which indicates that PIRE significantly increased apoptosis in NPC cells. The apoptotic process triggered by PIRE involved up-regulation of pro-apoptotic Bax protein and down-regulation of anti-apoptotic Bcl-2 protein, consequently increasing the ratios of Bax/Bcl-2 protein levels. Moreover, the p53 protein was up-regulated by PIRE in a concentration-dependent manner. Therefore, PIRE could induce the apoptosis-signaling pathway in NPC cells by activation of p53 and by regulation of apoptosis-related proteins.

Iatrogenic facial nerve injury is one of the most severe complications of cochlear implantation (CI) surgery. Intraoperative facial nerve monitoring (IFNM) is used as an adjunctive modality in a variety of neurotologic surgeries. The purpose of this retrospective study was to assess whether the use of IFNM is associated with postoperative facial nerve injury during CI surgery. The medical charts of 645 patients who underwent CI from 1999 to 2014 were reviewed to identify postoperative facial nerve palsy between those who did and did not receive IFNM. Four patients (3 children and 1 adult) were found to have delayed onset facial nerve weakness. IFNM was used in 273 patients, of whom 2 had postoperative facial nerve weakness (incidence of 0.73%). The incidence of facial nerve weakness was 0.54% (2/372) in the patients who did not receive IFNM. IFNM had no significant effect on postoperative delayed facial palsy (P = 1.000). All patients completely recovered within 3 months after surgery. Interestingly, all 4 cases of facial palsy received right CI, which may be because all of the surgeons in this study used their right hand to hold the drill. When right CI surgery is performed by a right-handed surgeon, the shaft of the drill is closer to the inferior angle of the facial recess, and it is easier to place the drilling shaft against the medial boundary (facial nerve) when the facial recess is small. The facial nerve sheaths of another 3 patients were unexpectedly dissected by a diamond burr during the surgery, and the monitor sounded an alarm. None of these 3 patients developed facial palsy postoperatively. This suggests that IFNM could be used as an alarm system for mechanical compression even without current stimulation. Although there appeared to be no relationship between the use of monitoring and delayed facial nerve palsy, IFNM is of great value in the early identification of a dehiscent facial nerve and assisting in the maintenance of its integrity. IFNM can still be used as an additional technique to optimize surgical success.

Objectives: This study analyzed the long-term hearing loss after treatment of primary nasopharyngeal carcinoma to elucidate its causal factors., Methods: Ninety-two nasopharyngeal carcinoma patients were treated with radiotherapy or chemoradiotherapy. Pure tone audiometry was performed before the therapy and annually up to 9 years after completing treatment. The hearing thresholds were corrected for age-related deterioration and compared to the results without adjusting for age., Results: The mean air and bone conduction threshold with and without correction for age-related deterioration differed significantly 2-9 years after completing radiotherapy (p < 0.05). The audiometry results with age correction showed a flattened configuration compared to the results without age correction. The total radiation dose and radiation modality showed a causal relationship with a greater incidence of hearing loss after therapy (p < 0.05). There was more deterioration in the air and bone hearing thresholds with conformal radiotherapy than intensity-modulated radiotherapy (p < 0.001). A radiation dose >72 cGy resulted in more severe hearing loss than <72 cGy (p < 0.05)., Conclusion: Hearing loss after completing therapy should be corrected for age-related hearing deterioration to reveal the true extent to which the loss is a therapeutic complication. Both the radiation modality used and the dose were significantly associated with hearing loss.

The use of Bacillus thuringiensis (Bt) strains with high insecticidal activity is essential for the preparation of bioinsecticide. In this study, for 60 Bt strains isolated in Taiwan, their genotypes and the correlation of some cry genes as well as the expression levels of cry1 genes, with their insecticidal activities against Plutella xylostella, were investigated. Pulsed field gel electrophoresis (PFGE) and random amplified polymorphic DNA (RAPD) results revealed that the genotypes of these Bt strains are highly diversified. Also, a considerable number of the Bt strains isolated in Taiwan were found to have high insecticidal activities. Since strains that showed individual combined patterns of PFGE and RAPD exhibited distinct insecticidal activities against P. xylostella, thus, these genotypes may be useful for the identification of the new Bt strains and those which have been used in bioinsecticides. In addition, although the presence of cry2Aa1 may have a greater effect on the insecticidal activity of Bt strains in bioassay than other cry genes, only high expression level of cry1 genes plays a key role to determine the insecticidal activity of Bt strains. In conclusion, both RAPD and PFGE are effective in the differentiation of Bt strains. The presence of cry2Aa1 and, especially, the expression level of cry1 genes are useful for the prediction of the insecticidal activities of Bt strains against P. xylostella.

Objective: The protein 14-3-3 sigma plays a role in cell cycle arrest by sequestering cyclin-dependent kinase 1 cyclin B1 complexes, as well as cyclin-dependent kinases 2 and 4, hence its definition as a cyclin-dependent kinase inhibitor. However, the nature of the interaction between these biological markers in nasopharyngeal carcinoma is unknown. This study aimed to investigate whether altered expression of these markers contributes to nasopharyngeal carcinogenesis., Methods: The study population consisted of 30 nasopharyngeal carcinoma patients and 10 patients without nasopharyngeal carcinoma. The nasopharyngeal carcinoma cell lines TW02, TW04 and Hone-1 were also assessed. We analysed levels of messenger RNA and protein for the p16 gene and the 14-3-3 sigma, Epstein-Barr nuclear antigen 1, and cyclin-dependent kinase 2 and 4 proteins, in nasopharyngeal carcinoma tissue specimens and cell lines and in normal nasopharyngeal tissue., Results: Protein and messenger RNA levels for cyclin-dependent kinase 2 and Epstein-Barr nuclear antigen 1 were significantly higher in nasopharyngeal carcinoma compared with normal tissue, while levels of cyclin-dependent kinase 4 generally were not; results for 14-3-3 sigma varied. Nasopharyngeal carcinoma patients had diminished p16 gene expression, compared with normal tissue., Conclusion: Levels of cyclin-dependent kinase 2 and Epstein-Barr nuclear antigen 1 were significantly higher in nasopharyngeal carcinoma than in normal tissue, while p16 gene expression was diminished. These three proteins may contribute to nasopharyngeal carcinogenesis.

Background: Nasopharyngeal carcinoma (NPC) is known for its high metastatic potential and locoregional recurrence, although the molecular alterations that are driving NPC metastasis remain unclear at this time. This study aimed to examine the expression of fibulin-5 in NPC, correlate the results with clinicopathological variables and survival, and to investigate the role of fibulin-5 in human NPC cell lines., Material and Methods: Standard semi-quantitative-RT-PCR, quantitative-RT-PCR, immunoblotting, and immunohistochemistry were used to investigate the mRNA and protein expression profiles of fibulin-5 in normal and NPC tissues. Immunohistochemistry of fibulin-5 was correlated with clinicopathological characteristics by univariate analyses. NPC cells overexpressing fibulin-5 or fibulin-5-siRNA cells were generated by stable transfection to characterize the molecular mechanisms of fibulin-5-elicited cell growth and metastasis., Results: Our results demonstrated that fibulin-5 overexpression in NPC specimens and significantly correlated with advanced tumor metastasis indicating a poor 5-year overall survival. Fibulin-5 was mainly expressed in the nucleus in human NPC specimens and cell lines. Functionally, fibulin-5 overexpression yielded fast growth in NPC cells. In addition, fibulin-5 promotes cell metastasis in NPC cells through increased FLJ10540 and phosphor-AKT activity. In contrast, siRNA depletion of fibulin-5 suppressed FLJ10540 expression and phosphor-AKT activity. Suppression of either fibulin-5 or FLJ10540 can cause significant inhibition with regards to cell motility in NPC cells. Finally, immunohistochemical analysis of human aggressive NPC specimens showed a significant and positive correlation between fibulin-5 and FLJ10540 expression., Conclusion: Higher fibulin-5 expression is not only an important indicator of poor survival, but also contributes to the development of new therapeutic strategies in the FLJ10540/AKT pathway for NPC treatment.

Objective: The objective of this study was to compare the efficacy of intratympanic steroid injection (ITS), hyperbaric oxygen (HBO), and combination therapy as salvage treatment in patients with sudden sensorineural hearing loss (SSNHL) after failure of systemic therapy., Study Design: A historical cohort study., Setting: Academic medical center., Subjects and Methods: One hundred three refractory SSNHL patients are enrolled. Among them, 35 received ITS alone (ITS group), 22 received HBO alone (HBO group), 19 received combined ITS and HBO (combined group), and 27 received no salvage therapies (control group). Hearing outcomes were determined by hearing gains in pure-tone average (PTA), recovery rate, and word recognition score (WRS) measured by audiometry before and after salvage therapies., Results: Significant larger hearing gains in PTA were found in the ITS, HBO, and combined groups than the control group. The combination of ITS and HBO resulted in a significantly larger WRS improvement than the control group (p = 0.035) and larger hearing gains than the ITS and HBO groups in 250 Hz (p < 0.05)., Conclusion: ITS, HBO, and combined therapy offered some benefits in hearing improvement. Combined ITS/HBO may result in a larger WRS improvement and recovery of hearing, especially in lower frequencies. Further randomized prospective studies are needed for confirmation.

Objectives: The purpose of this study was to objectively evaluate the position and migration of the cochlear implant receiver and ball electrode using 3-dimensional (3D) rendering of computed tomography., Study Design: Retrospective case review., Setting: Tertiary referral center., Patients: Thirty-one patients were treated for profound sensorineural hearing loss with cochlear implant. The operative methods were divided into 2 groups: an inverted J-shaped incision with bony tie-down suture, and a minimally invasive incision without tie-down suture., Intervention(s): When the receiver and ball electrode were detected in 3D imaging, the zygomatic process-receiver angle (ZRA), ear canal to receiver distance (ERD), and ear canal to ball electrode distance (EBD) were measured., Main Outcome Measure(s): Comparison and statistical analysis of postoperative angle and distances., Results: The mean ZRA, EBD, and ERD values were 139.1 degrees, 20.7 mm, and 36.0 mm, respectively. The mean ZRA in patients with an inverted J-shaped incision was significantly wider than for those with a minimally invasive incision (151.2 versus 136.9, p = 0.002). In 10 patients who received postoperative computed tomography 2 times, ZRA increased from 138.6 to 144.4 degrees (p < 0.001) and ERD decreased from 37.0 to 34.9 mm (p = 0.001)., Conclusion: 3D computed tomography is a useful tool for localization and migration of the receiver and ball electrode. Micro downward movements of the receiver were found in both bony tie-down and non-tie-down suture groups.

Papillary squamous cell carcinoma (PSCC) is a rare variant of SCC in the head and neck region. The role of human papillomavirus (HPV) infection in PSCC is still unclear. We retrospectively reviewed 11 PSCCs in our institute over a 21-year period and compared the HPV status of PSCCs with 26 squamous cell papillomas (SCPs). Polymerase chain reaction (PCR) amplification to detect HPV DNA and in situ hybridization (ISH) were performed to analyze the relationship between the papillary lesions and HPV infection. Immunohistochemical (IHC) staining for p16 protein expression was used to analyze the PSCC specimens. Nine of 11 (82 %), eight of 11 (73 %), and eight of 11 (73 %) PSCC samples were found to be HPV positive by PCR, ISH, and IHC staining for p16 protein expression, respectively. PSCC had a significantly higher rate of HPV infection than SCP by PCR (p = 0.002) and ISH (p = 0.001) analysis. This study presents different HPV status in two papillary neoplasms and may help to clarify the unique morphological and biological characteristics of head and neck PSCC.

Background: Nasopharyngeal carcinoma (NPC) is well-known for its highly metastatic characteristics, but little is known of its molecular mechanisms. New biomarkers that predict clinical outcome, in particular the ability of the primary tumor to develop metastatic tumors are urgently needed. The aim of this study is to investigate the role of FLJ10540 in human NPC development., Methods: A bioinformatics approach was used to explore the potentially important regulatory genes involved in the growth/metastasis control of NPC. FLJ10540 was chosen for this study. Two co-expression strategies from NPC microarray were employed to identify the relationship between FLJ10540 and osteopontin. Quantitative-RT-PCR, immunoblotting, and immunohistochemistry analysis were used to investigate the mRNA and protein expression profiles of FLJ10540 and osteopontin in the normal and NPC tissues to confirm microarray results. TW01 and Hone1 NPC cells with overexpression FLJ10540 or siRNA to repress endogenous FLJ10540 were generated by stable transfection to further elucidate the molecular mechanisms of FLJ10540-elicited cell growth and metastasis under osteopontin stimulation., Results: We found that osteopontin expression exhibited a positive correlation with FLJ10540 in NPC microarray. We also demonstrated comprehensively that FLJ10540 and osteopontin were not only overexpressed in NPC specimens, but also significantly correlated with advanced tumor and lymph node-metastasis stages, and had a poor 5-year survival rate, respectively. Stimulation of NPC parental cells with osteopontin results in an increase in FLJ10540 mRNA and protein expressions. Functionally, FLJ10540 transfectant alone, or stimulated with osteopontin, exhibited fast growth and increased metastasis as compared to vehicle control with or without osteopontin stimulation. Conversely, knockdown of FLJ10540 by siRNA results in the suppression of NPC cell growth and motility. Treatment with anti-CD44 antibodies in NPC parental cells not only resulted in a decrease of FLJ10540 protein, but also affected the abilities of FLJ10540-elicited cell growth and motility in osteopontin stimulated-NPC cells., Conclusions: These findings suggest that FLJ10540 may be critical regulator of disease progression in NPC, and the underlying mechanism may involve in the osteopontin/CD44 pathway.

Purpose: As a key component of polycomb-repressive complex 2, enhancer of zeste homolog 2 (EZH2) represses target genes through histone methylation and is frequently overexpressed and associated with poor prognosis in common carcinomas. For the first time, we reported EZH2 expression and its biological and clinical significance in nasopharyngeal carcinoma (NPC)., Methods and Materials: In NPC cell lines and specimens, endogenous expression of EZH2 mRNA and protein was determined by semiquantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively. To analyze the effect on cell growth, stable silencing of EZH2 was established in EZH2-expressing TW02 NPC cells with RNA interference. EZH2 immunolabeling was assessable for 89 primary NPC biopsy samples and correlated with clinicopathological variables, disease-specific survival (DSS), and overall survival (OS)., Results: Growth activity of TW02 cells was significantly suppressed (p < 0.001) with stable EZH2 silencing. Compared with normal nasopharyngeal tissue, expression levels of EZH2 transcript and protein were apparently upregulated in NPC specimens. As a continuous variable, higher EZH2 expression preferentially occurred in NPCs of T3 to T4 stages (p = 0.03) and significantly predicted inferior DSS (p = 0.0010) and OS (p = 0.004). The prognostic implications for DSS (p = 0.010) and OS (p = 0.006) still remained valid when using the median (≥ 60%) of EZH2 immunolabeling index to dichotomize the cohort. In the multivariate model, higher EZH2 expression was an independent adverse factor of both DSS (p = 0.012) and OS (p = 0.011), along with American Joint Committee on Cancer Stages III to IV (p = 0.024 for DSS, p = 0.017 for OS)., Conclusion: At least partly through promoting cell growth, EZH2 implicates disease progression, confers tumor aggressiveness, and represents an independent adverse prognosticator in patients with NPC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Multispecies probiotics have been reported to be more effective than monostrain probiotics in health promoting for the host. In this study, 12 lactic acid bacteria (LAB) strains were selected based on the level of induction of tumor necrosis factor (TNF)-α in RAW 264.7 macrophage cells. Their adherence to Caco-2 cells and inhibitory effects on Salmonella invasion of Caco-2 cells were compared. Strains with different probiotic properties were then combined and BALB/c mice were fed with LAB strains for 63 days; then the mice were challenged with Salmonella on day 64. For Salmonella-unchallenged mice that received a multistrain combination of LAB strains that have greater TNF-α production in macrophages, greater adherence and inhibit Salmonella invasion of Caco-2 cells to a greater extent, their peritoneal macrophages had greater phagocytic activity. For Salmonella-challenged mice, a significant reduction of Salmonella cells in the livers and spleens of the mice was observed 8 days post challenge. The addition of 12% skim milk powder together with LAB strain combinations significantly enhanced the reduction of Salmonella cells in the mice livers and spleens. In conclusion, we have shown that LAB strain combinations with particular probiotic properties when fed to mice can inhibit Salmonella invasion of the liver and spleen., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Objectives/hypothesis: The objective of this study was to investigate whether zinc supplementation can enhance the recovery of idiopathic sudden sensorineural hearing loss (SSNHL)., Study Design: Prospective, randomized study., Methods: The 66 SSNHL patients who participated in this study were randomly divided into two groups: 33 were given corticosteroid treatment (control group) and 33 were given oral zinc gluconate plus corticosteroid treatment (zinc group). Serum zinc levels were checked before treatment in both groups and after zinc supplementation in the zinc group. Hearing gain and percentage of recovery were analyzed and compared between the two groups. The correlation between the serum zinc level changes and hearing recovery was also analyzed., Results: A significantly larger hearing gain, an increased percentage of recovery, and an increased rate of successful recovery were seen in the zinc group compared with the control group (all P < .05). There was a significant correlation between serum zinc level changes and posttreatment hearing thresholds by correlation analysis (P < .05), as well as between changes of serum zinc levels and percentage of recovery in the zinc group (P < .05)., Conclusions: Zinc supplementation may enhance the hearing recovery of SSNHL patients. Its antioxidant and anti-inflammatory effects may help reduce the oxidative stress of the cochlea in SSNHL, implying a new direction in the treatment of this disease., (Copyright © 2010 The American Laryngological, Rhinological, and Otological Society, Inc.)

Nasopharyngeal carcinoma (NPC) is known for its highly metastatic character. Recent advances in diagnosis and treatment have not improved the high mortality rate that is attributable to early metastasis. Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear. We demonstrate comprehensively that fibulin-3 is down-regulated in NPC. Loss of fibulin-3 expression is significantly correlated with advanced tumour and lymph node-metastasis stages, and indicates a poor 5-year survival rate. Functionally, fibulin-3 has the ability to suppress cell migration and invasion in NPC cancer cells by decreasing the activity of phospho-AKT. Conversely, its depletion by fibulin-3-mediated siRNAs may elevate phospho-AKT activity and significantly enhance the ability of NPC cancer cells to migrate and invade. Consistent with this negative association between fibulin-3 and phospho-AKT, their expression levels are inversely correlated in NPC specimens by immunohistochemical analysis. Thus, lower fibulin-3 expression is an important indicator of poor survival. It may also contribute to the development of new therapeutic strategies to block the PI3K/AKT pathway in NPC cancer cells., (Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The crucial role of gap junctions, which are composed of connexin (CX) protein, in auditory functions has been confirmed by numerous studies. In this study, we investigate the prevalence and phenotype/genotype correlation of connexin (CX) gene family variants in a cohort of children with nonsyndromic hearing loss (HL). A total of 253 unrelated children with nonsyndromic HL were screened for the presence of variants in 6 genes of the CX gene family. The prevalence of CX gene variants in 253 patients was 19.7% (50/253). We found the frequency of a sloping audiometric configuration was significantly higher for children with GJB2 and GJB3 variants than for those with GJB4 and GJC3 variants (Adjusted OR = 4.89, p < 0.001). Conversely, the frequency of a flat audiometric configuration was significantly higher for children with GJB4 and GJC3 variants than for those with GJB2 and GJB3 variants (adjusted OR = 7.76, p < 0.001). The relative frequencies of multiplex families was significantly higher for children with GJB3 variants than for those with GJB2, GJB4, and GJC3 variants (Adjusted OR = 11.33, p = 0.003). Our results suggest the variants of GJC3, GJB4, and GJB3 may be the common genetic risk factor, after variants of GJB2, for the development of nonsyndromic HL in Taiwan. These data can be effectively applied to direct the clinical evaluation of children with CX gene variants.