Search

Post-surgery failure of dental implants due to alveolar bone loss is currently critical, disturbing the quality of life of senior dental patients. To overcome this problem, bioceramic or bone graft material is loaded into the defect. However, connective tissue invasion instead of osteogenic tissue limits bone tissue regeneration. The guided bone regeneration concept was adapted to solve this problem and still has room for improvements, such as biochemical similarity or oriented structure. In this article, an aligned electrospun-guided bone regeneration barrier with xenograft equine bone-derived nano hydroxyapatite (EBNH-RB) was fabricated by electrospinning EBNH/PCL solution on high-speed rotating drum collector and fiber characterization, viability and differentiation enhancing properties of mesenchymal dental pulp stem cell on the barrier was determined. EBNH-RB showed biochemical and structural similarity to natural bone tissue electron microscopy image analysis and x-ray diffractometer analysis, and had a significantly better effect in promoting osteogenesis based on the increased bioceramic content by promoting cell viability, calcium deposition and osteogenic marker expression, suggesting that they can be successfully applied to regenerate alveolar bone as a guided bone regeneration barrier.

It is known that hyperlipidemia is a risk factor for sensorineural hearing loss. However, the biological mechanisms underlying hyperlipidemia and hearing impairment have not been completely elucidated in the cochlea. Based on our previous study of human subjects, elderly people taking drugs for hyperlipidemia showed better hearing than those not taking any medications. We hypothesized that drugs for hyperlipidemia, such as statins, may have the potential to prevent hearing impairment. The aim of this study was to investigate the correlation between hyperlipidemia and hearing impairment and the hearing preservation effect of atorvastatin using a hyperlipidemic mouse model with diet-induced obesity (DIO). Here, we demonstrate that DIO mice had a significant hearing impairment as well as increased levels of reactive oxygen species (ROS) and hair cell death due to reduced levels of pAKT and superoxide dismutase 2 (SOD2). However, these changes were significantly prevented by atorvastatin. Oxidative stress-induced intrinsic apoptosis was decreased by the high expression of Nrf2 and antioxidant genes, which improved mitochondrial function and ROS via activation of the PI3K-pAKT pathway by atorvastatin. Therefore, atorvastatin has the potential to prevent hearing impairment via redox balance in the presence of hyperlipidemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: A speech discrimination score (SDS) is a predictor for the successful use of hearing aids (HAs). This study is to evaluate the efficacy of HAs in patients with a low or poor SDS., Methods: We enrolled 186 ears using HAs, with an unaided SDS ≤ 64%. They were categorized into four groups by their unaided SDS: 0-16% for Group 1, 20-32% for Group 2, 36-48% for Group 3, and 52-64% for Group 4. Aided SDS was measured 1, 3, 6, and 12 months after the use. The Hearing In Noise Test (HINT), the Hearing Handicap Inventory for the Elderly (HHIE), and the International Outcome Inventory for Hearing Aids (IOI-HA) were assessed., Results: The SDS increased by 27.4% (12.0 to 39.4%) in Group 1, 26.4% (26.9 to 53.3%) in Group 2, 24.6% (42.2 to 66.8%) in Group 3, and 10.5% (59.5% to 70.0%) in Group 4. HINT composite scores significantly decreased from 22.5 to 15.1 in Group 1, 9.4 to 7.0 in Group 2, and 4.4 to 2.4 in Group 4. Total HHIE score changed from 48.2 to 24.2 in Group 1, 64.0 to 32.8 in Group 2, 37.1 to 16.6 in Group 3, and 55.8 to 40.1 in Group 4 (P < 0.05 in Groups 2, 3, and 4)., Conclusion: In patients with a low SDS, a significant increase in SDS was achieved after the use of HAs, and subjective satisfaction was also acceptable. Low SDS might not be a contraindication for HAs.

The relationship between type 1 diabetes and hearing loss is not well known, although based on many pathological studies, type 2 diabetes induced hearing loss is associated with microcirculation problems in the inner ear. The purpose of this study was to investigate the correlation between type 1 diabetes and hearing loss through hearing function and immunohistochemical analyses using type 1 diabetic Akita or wild-type (WT) mice. The Akita mice had a significant increase in hearing thresholds, blood glucose, and insulin tolerance compared to WT mice. Histological analysis showed that the loss of cells and damage to mitochondria in the spiral ganglion neurons of Akita mice were significantly increased compared to WT. Also, the stria vascularis showed decreased thickness, loss of intermediate cells, and disturbance in blood capillary shape in the Akita mice. Moreover, a reduction in type I, II, and IV fibrocytes and Na + /K + -ATPase α1 expression in spiral ligament was also observed. Cleaved caspase-3 expression was highly expressed in spiral ganglion neurons. In conclusion, hearing loss in type 1 diabetes is caused not only by ion imbalance and blood flow disorders of cochlear endolymph, but through the degenerative nervous system via apoptosis-mediated cell death.

Background: Clinically, steroids have been used for hearing preservation both topically and systemically during cochlear implantation. Objective: This study compared steroid efficacy for hearing preservation among different types of delivery modes using an animal experiment. Materials and methods: For 76 guinea pigs, topical and systemic delivery methods, four pump types with different infusion rates, delivery durations, and total steroid amounts were used. Threshold changes of 8, 16, and 32 kHz after dummy electrode insertion were evaluated at 1 and 4 weeks and compared among delivery method and pump types. Inflammatory response in the cochlea was histologically compared. Results: For topical delivery groups, long-term release showed advantages in preserving hearing. Systemic delivery groups showed smaller threshold shifts than control group in all frequencies ( p  > .05). In short-term low dose application, compared to topical delivery, systemic delivery showed advantage in hearing preservation at both time point. However, others fail to show significant difference between two methods. Histologically, inflammatory response in the scala tympani at the basal turn was less in systemic delivery, especially in high dose and long-term. Conclusion and significance: The difference of hearing preservation was not obvious between two delivery methods. Higher dose and longer duration might have advantages in hearing preservation.

Purpose: Timely diagnosis and identification of etiology of pediatric mild-to-moderate sensorineural hearing loss (SNHL) are both medically and socioeconomically important. However, the exact etiologic spectrum remains uncertain. We aimed to establish a genetic etiological spectrum, including copy-number variations (CNVs) and efficient genetic testing pipeline, of this defect., Methods: A cohort of prospectively recruited pediatric patients with mild-to-moderate nonsyndromic SNHL from 2014 through 2018 (n = 110) was established. Exome sequencing, multiplex ligation-dependent probe amplification (MLPA), and nested customized polymerase chain reaction (PCR) for exclusion of a pseudogene, STRCP, from a subset (n = 83) of the cohort, were performed. Semen analysis was also performed to determine infertility (n = 2)., Results: Genetic etiology was confirmed in nearly two-thirds (52/83 = 62.7%) of subjects, with STRC-related deafness (n = 29, 34.9%) being the most prevalent, followed by MPZL2-related deafness (n = 9, 10.8%). This strikingly high proportion of Mendelian genetic contribution was due particularly to the frequent detection of CNVs involving STRC in one-third (27/83) of our subjects. We also questioned the association of homozygous continuous gene deletion of STRC and CATSPER2 with deafness-infertility syndrome (MIM61102)., Conclusion: Approximately two-thirds of sporadic pediatric mild-to-moderate SNHL have a clear Mendelian genetic etiology, and one-third is associated with CNVs involving STRC. Based on this, we propose a new guideline for molecular diagnosis of these children.

Age-dependent decrease of mitochondrial energy production and cellular redox imbalance play significant roles in age-related hearing loss (ARHL). Lactate dehydrogenase B (LDHB) is a key glycolytic enzyme that catalyzes the interconversion of pyruvate and lactate. LDH activity and isoenzyme patterns are known to be changed with aging, but the role of LDHB in ARHL has not been studied yet. Here, we found that LDHB knockout mice showed hearing loss at high frequencies, which is the typical feature of ARHL. LDHB knockdown caused downregulation of mitochondrial functions in auditory cell line, University of Bristol/organ of Corti 1 (UB/OC1) with decreased NAD + and increased hypoxia inducing factor-1α. LDHB knockdown also enhanced the death of UB/OC1 cells with ototoxic gentamicin treatment. On the contrary, the induction of LDHB expression caused enhanced mitochondrial functions, including changes in mitochondrial respiratory subunits, mitochondrial membrane potentials, ATP, and the NAD + /NADH ratio. Thus, we concluded that suppression of LDHB activity may be closely related with the early onset or progression of ARHL.

The 'Bow and Lean Test' (BLT) was developed for proper diagnosis of horizontal semicircular canal benign paroxysmal positional vertigo (HSC-BPPV). Occasionally, down- and/or up-beating vertical nystagmus is observed during the BLT. This study analyzed patients who exhibited vertical nystagmus in the BLT to comprehend the clinical significance of this sign. Of 2872 patients with vertigo between 2010 and 2015, 225 patients who showed vertical nystagmus in the BLT were enrolled. All patterns of vertical nystagmus were described based on their types of BPPV. After performing therapeutic maneuvers for BPPV, remnant symptoms in the BLT findings were investigated. Of the 225 patients with vertical nystagmus, 163 were posterior semicircular canal BPPV (PSC-BPPV). Down-beating in the bowing position and no nystagmus in the leaning position ('Down/-') was the most common type (190 of 225 patients). In addition, the nystagmus occurred in the form of '-/Up', 'Down/Up', and '-/Down'. The pattern of vertical nystagmus may be related to the position of otoconia in the canals. The location of the otoconia enables the diagnosis of hidden PSC-BPPV. Even after treatment for BPPV, patients with vertical nystagmus in the BLT tended to complain remnant vertigo symptoms (44.8% vs. 23.9%, P = 0.022, in PSC-BPPV; 70.0% vs. 24.0%, P = 0.020, in HSC-BPPV). We thought that they actually had hidden PSC-BPPV and the otoconial debris may still in the PSC; this untreated PSC-BPPV might cause the remnant symptoms. In conclusion, vertical nystagmus in the BLT may indicate the presence of PSC-BPPV. Moreover, vertical nystagmus during the BLT may occur in patients with hidden PSC-BPPV who complain of remnant vertigo symptoms. Vertical nystagmus shown in the BLT may not include the possibility of central vertigo.

Background: This study was performed to identify acute tinnitus and evaluate the efficacy of steroids for noise-induced acute tinnitus by measuring the gap-prepulse inhibition of the acoustic startle (GPIAS) value in an animal model., Methods: Nineteen rats (the noise group [n = 7] and the noise + dexamethasone [DEX] group [n = 12]) were exposed to narrow-band noise centered at 16 kHz from a sound generator for 4 hours. The noise + DEX group received intraperitoneal steroid administration daily for 5 days (1.5 mg/kg/day) after completing noise exposure. Auditory brainstem response and GPIAS value were measured just prior to, and 1 day after noise exposure and on days 1 and 10 days after completing steroid administration. The changes in cochlear structure were evaluated by histological analysis., Results: The threshold shift was checked 1 and 10 days after intraperitoneal steroid injection, and no differences in threshold shift were observed between the two groups in each frequency except for 32 kHz 1 day after steroid injection. The mean GPIAS value in the noise + DEX group (36.4% ± 14.1%) was significantly higher than that in the noise group (16.4% ± 18.8%) 10 days after intraperitoneal steroid administration ( P = 0.017). There were no pathological changes associated with noise trauma in the two groups as determined on hematoxylin and eosin and immunohistochemical staining., Conclusion: An acute tinnitus model with minimal structural changes by noise exposure was set up, and used to verify tinnitus objectively by measuring the GPIAS value. Steroid therapy for control of tinnitus was validated in this animal model., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

The clinical use of aminoglycoside antibiotics is partly limited by their ototoxicity. The pathogenesis of aminoglycoside-induced ototoxicity still remains unknown. Here, RNA-sequencing was conducted to identify differentially expressed genes in rat cochlear organotypic cultures treated with gentamicin (GM), and 232 and 43 genes were commonly up- and downregulated, respectively, at day 1 and 2 after exposure. Ubiquitin carboxyl-terminal hydrolase isozyme L1 (Uchl1) was one of the downregulated genes whose expression was prominent in spiral ganglion cells (SGCs), lateral walls, as well as efferent nerve terminal and nerve fibers. We further investigated if a deficit of Uchl1 in organotypic cochlea and the House Ear Institute-Organ of Corti 1 (HEI-OC1) cells accelerates ototoxicity. We found that a deficit in Uchl1 accelerated GM-induced ototoxicity by showing a decreased number of SGCs and nerve fibers in organotypic cochlear cultures and HEI-OC1 cells. Furthermore, Uchl1-depleted HEI-OC1 cells revealed an increased number of autophagosomes accompanied by decreased lysosomal fusion. These data indicate that the downregulation of Uchl1 following GM treatment is deleterious to auditory cell survival, which results from the impaired autophagic flux. Our results provide evidence that UCHL1-dependent autophagic flux may have a potential as an otoprotective target for the treatment of GM-induced auditory cell death.

Vertically aligned nanomaterials, such as nanowires and nanoneedles, hold strong potential as efficient platforms onto which living cells or tissues can be interfaced for use in advanced biomedical applications. However, their rigid mechanical properties and complex fabrication processes hinder their integration onto flexible, tissue-adaptable, and large-area patch-type scaffolds, limiting their practical applications. In this study, we present a highly flexible patch that possesses a spiky hydrogel nanostructure array as a transplantable platform for enhancing the growth and differentiation of stem cells and efficiently suppressing biofilm formation. In vitro studies show that the hydrogel nanospike patch imposes a strong physical stimulus to the membranes of stem cells and enhances their osteogenic, chondrogenic, and adipogenic differentiation and the secretion of crucial soluble factors without altering cell viability. At the same time, the array exhibits effective bactericidal properties against Gram-positive and Gram-negative bacteria. In vivo studies further demonstrate that the flexible hydrogel patch with its spiky vertical nanostructures significantly promotes the regeneration of damaged cranial bone tissues while suppressing pathogenic bacterial infections in mouse models.

In cochlear implants, the electrode insertion trauma during surgery can cause damage residual hearing. Preserving the residual hearing is an important challenge and the localized administration of drugs, such as steroids, is one of the most promising ways, but remains a challenge. Here, a microscaffold cochlear electrode array (MiSCEA) consisting of a microfabricated flexible electrode array and a 3D microscaffold for steroid reservoir is reported. The MiSCEA without loaded drug is tested by measuring the electrically evoked auditory brainstem response of the cochlea in guinea pigs (n = 4). The scaffold is then coated with steroid (dexamethasone) encapsulated in polylactic-co-glycolic acid and the continuous release of the steroid into artificial perilymph during six weeks is monitored. The steroid-containing scaffolds are then implanted into guinea pigs (n = 4) and threshold shifts are analyzed for four weeks by measuring the acoustically evoked auditory brainstem response. The threshold shifts tend to be lower in the group implanted with the steroid-containing MiSCEAs. The feasibility of 3D MiSCEA opens up the development of potential next-generation cochlear electrode with improved steroid release dynamics into cochlea., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: This study was designed to evaluate the relationship between the degree of round window membrane (RWM) exposure and hearing outcome. Materials and methods: Forty-six ears with cochlear implantation (CI) were enrolled. The degree of RWM exposure was divided into Grade I (<25%), Grade II (25-50%), and Grade III (>50%). The hearing outcomes were evaluated at 1.5 and 12 months postoperatively. Results: Twenty-seven ears were Grade I, 13 were Grade II, and 6 were Grade III. RW approach was used in all ears of Grades II and III and 20 ears of Grade I and cochleostomy was used in 7 ears of Grade I. The pattern of bony overhang was multidirectional in 41 ears. Threshold shift significantly decreased proportional to the increase of RWM exposure after CI. The mean RWM exposure was 32.1 ± 24.4% in ears with more than partial preservation ( n  = 17), and 13.3 ± 11.7% in the other ears ( n  = 6) at 12 months post-CI ( p  = .061). Age at CI differed significantly between ears that had more than partial preservation and the other ears at 1.5 months post-CI. Conclusions and significance: Degree of RWM exposure and age at CI might be factors predicting hearing outcome after CI using the RW approach.

Objective: The outcome of cochlear implantation (CI) is affected by various factors, including the manufacturer of the device. We validated the factors contributing to postoperative performance and evaluated the influence of different company devices on pure tone thresholds and postoperative performance., Methods: Our study included 56 postlingually deaf adults who underwent CI between June 2005 and March 2016. The ears were divided into groups according to the implant manufacturer: A (n=32 ears) and B (n=24 ears) groups. The prognostic factors for CI outcome were evaluated using speech perception at 3, 6 and 12 months postoperatively and compared across devices., Results: The duration of hearing aid use, age at CI, and mean pure tone threshold with the implant were correlated with postoperative speech perception. The mean pure tone thresholds with the implant (averages of 0.25, 0.5, 1, 2, 4 and 6kHz) were 27.9±3.7dB HL in the group A and 33.5±5.6dB HL in the group B (P<0.01). The open-set monosyllabic word, open-set disyllabic word and open-set sentence scores were not significantly different between the groups at 3, 6 and 12 months postoperatively., Conclusion: The mean pure tone threshold with implant differed between the devices; however, no device-related effect on postoperative performance was observed. Additional multifactorial analyses are needed to clarify the relationship between free-field pure tone threshold with implant and postoperative speech perception., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: The aim of this study was to report a novel POU Class 3 Homeobox 4 ( POU3F4) variant and to provide further guidance on genetic counseling for incomplete partition (IP) type III families in the Korean population by showing two new contrasting cases in terms of genotypes and inheritance. Materials and Methods: Two consecutively recruited hearing-impaired probands with seemingly nonsyndromic features and their biological mothers were included in this study. Sanger sequencing and quantitative polymerase chain reaction (PCR) assays were performed for POU3F4 . Results: A novel frameshift variant of POU3F4 , c.852delC (p.Ile285Serfs*3), was identified in one of the patients. This mutation is predicted to truncate the protein within the POU homeodomain, resulting in the complete loss of the last nucleus localization signal. The proband's biological mother was also shown to be a carrier of this c.852delC (p.Ile285Serfs*3) mutant allele. A de novo genomic deletion on chromosome Xq21.2 was confirmed in another subject via quantitative PCR. This subject's biological mother, however, was not a carrier of this deletion. This indicates that the large upstream deletion of POU3F4 in the second proband occurred de novo. This finding is compatible with the previously proposed tendency for a high de novo rate of large genomic deletions involving the X-linked deafness-2 ( DFNX2 ) locus. Conclusion: This study adds a novel, probably pathogenic POU3F4 truncation variant to the literature and provides guidance toward effective genetic counseling for IP III subjects based on more frequent de novo occurrence of POU3F4 deletions than POU3F4 point variants.

Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague-Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H & E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis., Competing Interests: The authors declare no conflict of interest.

Hearing loss in the elderly causes communication difficulties, decreased quality of life, isolation, loneliness and frustration. The aim of this study was to identify the modifiable variables that may affect the progression of hearing loss in the elderly. A case-control study was conducted using two data sets. Data were extracted from the health examination survey of Ajou University Hospital (2010-2014) and the Korea National Health and Nutrition Examination Survey (2009-2012) data sets. Audiometry data were evaluated according to variables such as age, sex and drug use for underlying diseases. Logistic regression analysis was performed on the entire study population, and middle-aged and elderly groups using odds ratios (ORs). Factors including older age, female gender and diabetes mellitus were significantly associated with hearing levels in all age groups (OR [95% confidence interval, 95% CI], 0.375 [0.388-0.415], 1.202 [1.195-1.208], and 1.427 [1.183-1.721], respectively). However, when the results from the middle-aged and elderly groups were compared, medication for hyperlipidaemia had a significantly positive effect on the preservation of hearing in the elderly group (OR [95% CI], 0.713 [0.567-0.897]), but not in the middle-aged group (OR [95% CI], 0.967 [0.791-1.183]). People, especially those in the elderly group, exposed to medication for hyperlipidaemia are likely to have better hearing than those not exposed to such drugs. Thus, drugs prescribed for hyperlipidaemia may maintain hearing in the elderly. However, to overcome potential confounding-by unmeasured variables-that is present in this study, further studies must be performed with more elaborate research design and methodology., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Chronic tympanic membrane (TM) perforations can cause otorrhea. To date, various types of tissue engineering techniques have been applied for the regeneration of chronic TM perforations. However, the application of nanofibers with radially aligned nanostructures and the simultaneous release of growth factors have never been applied in the regeneration of chronic TM perforations. Here, epidermal growth factor (EGF)-releasing radially aligned nanofibrous patches (ERA-NFPs) are developed and applied for the regeneration of chronic perforated TMs. First, radial alignments and the presence of EGF in the ERA-NFPs are analyzed. EGF is confirmed to be released from the ERA-NFPs until 8 weeks. In an in vitro study, cell viability assay, immunocytochemistry, and wound-healing assay indicate rational enhancement of healing by the combination of radial alignments and EGF release. The effect of ERA-NFPs on TM cells is revealed by quantitative real-time polymerase chain reaction. An in vivo animal study shows that the ERA-NFPs effectively stimulates the healing of the chronic TM perforations. The TMs healed by ERA-NFPs show histological properties similar to those of normal TMs. These results indicate that ERA-NFPs may be an efficient platform for the regeneration of chronic TM perforations, laying the foundation for nonsurgical treatments of chronic otitis media., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: This study evaluated the influence of the performance of the first cochlear implant (CI-1) on the second implant (CI-2) and the significance of inter-implant intervals in children with sequential cochlear implantation., Method: Thirty-four patients were included for speech perception outcome and 38 patients were included for subjective hearing satisfaction in daily life in this study. The patients were classified into 3 groups according to inter-implant interval: group I, <4 years; group II, 4-7 years; group III, >7 years. Open-set speech perception scores before and at 3, 6, 12, and 24 months after the second implantation was compared among the CI-1, CI-2, and bilateral CI conditions. Subjective hearing benefits in daily life were measured using a questionnaire of Speech, Spatial, and Qualities of Hearing Scale (SSQ) for parents of children with impaired hearing, and device use and preference were evaluated (by phone interview.) Results: The speech perception of children using the CI-2 only improved quickly within 3 months postoperatively and were similar to those using the CI-1 only. The results of monosyllabic and disyllabic word tests using CI-2 at 3 months after second implantation were not significantly different from those in patients using the CI-1 only. In the sentence test, the scores using the CI-2 only were not significantly different from those using the first implant only at 6 months after second implantation. SSQ scores were similar among groups and the worst score in each section was shown from the questions about performance under noisy conditions in each section. Device usage habits showed that 17 (44.7%) and 16 (42.1%) patients preferred bilateral and the CI-1, respectively. Only 5 (13.2%) patients wanted the CI-2 rather than the CI-1. While group I and II showed a prominent positive attitude to bilateral use, group III, for which the inter-implant interval was 7 years or more, showed a definite preference for the CI-1 (p < 0.01)., Conclusions: Functional binaural benefits were achieved in patients who were good performers with the CI-1 after the second implantation irrespective of the inter-implant interval. Sequential CI should be strongly recommended for patients with unilateral CI showing a good performance., (© 2019 S. Karger AG, Basel.)

Objectives: The aims of this study are to analyze the clinical characteristics of congenital middle ear cholesteatoma (CMC), to evaluate the treatment results according to the types of surgical approach, and to suggest the appropriate surgical treatment option in each stage., Methods: One hundred fifteen children (≤15 years old) with surgically confirmed CMC, who underwent surgery at a tertiary hospital during 1994-2012 and were followed up more than 2 years, were enrolled in this study. CMC was classified into four stages by the staging system proposed by Potsic. Clinical characteristics of CMC were analyzed and its association with the rate of residual disease was evaluated., Results: Based on the location of the lesion, posterior-origin CMCs were detected significantly later (5.5 years old, P = 0.018) and more likely to be in the Stage 3 or 4 (P < 0.001). Residual CMCs were observed in 10 out of 115 cases (8.7%) and were more frequent in the Stage 3 or 4 patients (P = 0.007). However, the rate of the residual disease was not statistically different between anterior- and posterior-origin CMCs (P = 0.101). All 58 cases of CMC in the Stage 1 or 2 were successfully removed by transcanal tympanoplasty with only one residual case (1.7%). In the Stage 3 cases, transcanal tympanoplasty was conducted in 24 out of 29 patients, and the residual disease rate was 12.5% (3 out of 24)., Conclusions: The early stages of CMC were likely to be diagnosed at younger age, and the early diagnosis seemed to show better surgical outcomes with less invasive techniques. Transcanal tympanoplasty can be an effective surgical option for CMCs in the Stage 3., (Copyright © 2018. Published by Elsevier B.V.)

c-Jun N-terminal kinase 2 (JNK2) is primarily responsible for the oncogenic transformation of the transcription factor c-Jun. Expression of the proto-oncogene c-Jun progresses the cell cycle from G1 to S phase, but when its expression becomes awry it leads to uncontrolled proliferation and angiogenesis. Delivering a JNK2 siRNA (siJNK2) in tumor tissue was anticipated to reverse the condition with subsequent onset of apoptosis which predominantly requires an efficient delivering system capable of penetrating through the compact tumor mass. In the present study, it was demonstrated that polymannitol-based vector (PMGT) with inherent hyperosmotic properties was able to penetrate through and deliver the siJNK2 in the subcutaneous tumor of xenograft mice. Hyperosmotic activity of polymannitol was shown to account for the enhanced therapeutic delivery both in vitro and in vivo because of the induction of cyclooxygenase-2 (COX-2) which stimulates caveolin-1 for caveolae-mediated endocytosis of the polyplexes. Further suppression of JNK2 and hence c-Jun expression led to the activation of caspase-9 to induce apoptosis and inhibition of tumor growth in xenograft mice model. The study exemplifies PMGT as an efficient vector for delivering therapeutic molecules in compact tumor tissue and suppression of JNK2 introduces a strategy to inhibit tumor progression., (Copyright © 2018. Published by Elsevier B.V.)

Significant technical and optical advances are required for intraoperative optical coherence tomography (OCT) to be utilized during otological surgeries. Integrating OCT with surgical microscopy makes it possible to evaluate soft tissue in real-time and at a high resolution. Herein, we describe an augmented-reality, intraoperative OCT/microscope system with an extended working distance of 280 mm, providing more space for surgical manipulation than conventional techniques. We initially performed ex vivo experiments to evaluate system performance. In addition, we validated the system by performing preliminary clinical assessments of tympanomastoidectomy outcomes in six patients with chronic otitis media. The system evaluated residual inflammation in the region-of-interest of the mastoid bone. Most importantly, the system intraoperatively revealed the connection between the graft and the remnant tympanic membrane. The extended working distance allows otological surgeons to evaluate the status of both the mastoid bone and tympanic membrane during manipulation, affording full intraoperative imaging.

Background: While auditory neuropathy spectrum disorder (ANSD) is a heterogeneous disorder and its management quite varies depending upon the etiology, even including self-resolution, OTOF is an important molecular etiology of prelingual ANSD and has emerged as an attractive target for implementation of precision medicine in terms of timing and prognosis prediction of auditory rehabilitation. However, to date, the literature is lacking in the genotype-phenotype relationship of this gene as well as efficient molecular testing strategy in the clinic in many populations and to make things more complicated in Koreans, the most prevalent variant p.Arg1939Gln among Korean ANSD children frequently evaded detection by next generation sequencing (NGS), resulting in delayed genetic diagnosis and late cochlear implantation (CI). The aims of this study are to document the mutational and phenotypic spectrum of OTOF-related ANSD (DFNB9) in the Korean population, further establishing genotype-phenotype correlation and proposing a set of the most commonly found OTOF variants to be screened first., Methods: Genetic diagnosis through the NGS-based sequencing was made on patients with ANSD in two tertiary hospitals. Genotype and phenotypes of eleven DFNB9 patients were reviewed. For data analysis, Mann-Whitney test and Fisher's exact test were applied., Results: This study disclosed four prevalent variants in Koreans: p.Arg1939Gln with an allele frequency of 40.9%, p.Glu841Lys (13.6%), p.Leu1011Pro and p.Arg1856Trp (9.1%). Three novel variants (c.4227 + 5G > C, p.Gly1845Glu, and p.Pro1931Thr) were identified. Interestingly, a significant association of p.Arg1939Gln with worse ASSR thresholds was observed despite consistently no ABR response. Ten of 11 DFNB9 patients received CI for auditory rehabilitation, showing favorable outcomes with more rapid improvement on early-CI group (age at CI ≤ 18 mo.) than late-CI group., Conclusions: This study included the largest Korean DFNB9 cohort to date and proposed a set of the most frequent four OTOF variants, allowing the potential prioritization of exons during Sanger sequencing. Further, a significant association of p.Arg1939Gln homozygotes with poor residual hearing was observed. We may have to suspect p.Arg1939Gln homozygosity in cases of poor auditory thresholds in ANSD children with putative negative OTOF variants solely screened by NGS. Reciprocal feedback between bench and clinics regarding DFNB9 would complement each other.

Objectives: The aim of this multicenter registry study was to investigate the effectiveness of ventilation tube insertion and the microbiology of otitis media with effusion (OME) in children. This part I study was conducted to evaluate the microbiological profile of children with OME who needed ventilation tube insertion., Methods: Patients <15 years old who were diagnosed as having OME and received ventilation tube insertion were prospectively enrolled in 16 tertiary hospitals from June 2014 to December 2016. After excluding patients with missing data, the data of 397 patients were analyzed among a total of 433 enrolled patients. The clinical symptoms, findings of the tympanic membrane, hearing level, and microbiological findings were collected., Results: In 103 patients (25.9%), antibiotics were used within 3 weeks before surgery. Ventilation tube insertion was performed in a total of 710 ears (626 in both ears in 313 patients, 55 in the left ear only, and 29 in the right ear only). Culture of middle ear effusion was done in at least one ear in 221 patients (55.7%), and in a total of 346 ears. Only 46 ears (13.3%) showed positive results in middle ear effusion culture. Haemophilus influenzae (17.3%, followed by coagulase-negative Staphylococcus and Staphylococcus auricularis ) was the most common bacteria detected., Conclusion: H. influenzae was the most commonly found bacteria in middle ear effusion. Relatively low rates of culture positivity were noted in middle ear effusion of patients with OME in Korea.

Objective: To assess the usefulness of cone beam computed tomography (CBCT) for characterizing electrode insertion and evaluate the influence of electrode insertion status on post-cochlear implantation (CI) outcomes., Design: Twenty-six ears with post-CI CBCT scans were included. The devices were MED-EL Flex28 (n = 21) and Nucleus slim straight (n = 5). The parameters including cochlear duct length (CDL), insertion depth angle (IDA), insertion length of electrode (IL), and cochlear coverage (CC) were analyzed and compared with aided pure-tone threshold (PTA) with implant in free field, and open-set sentence score., Results: The mean CDL was 36.8 ± 1.4 mm. Electrode array was dislocated into scala tympani in two ears. The mean IL and IDA were 26.5 ± 1.9 mm and 541.4 ± 70.2°. The mean linear CC (IL/CDL, 0.73 ± 0.06) was larger than the mean angular CC (IDA/900, 0.60 ± 0.08). The CBCT parameters showed correlation one another. While the aided pure-tone threshold was correlated with IL and IDA, there were no significant correlations in the open-set sentence score. For the postlingually deaf patients with single electrode (Flex 28), the sentence score had no significant correlation and the aided PTA was positively correlated with IL (R = 0.517, p = .028)., Conclusions: This study validated the CBCT evaluating the electrode array position. The CBCT could be helpful for the preoperative selection of the optimal array and prediction of the CC.

Objectives: Combined mastoidectomy is generally preferred to tympanoplasty alone when treating patients with chronic otitis media (COM), particularly when temporal bone computed tomography (TBCT) shows that the mastoid cavity contains opacification of soft tissue density. However, in cases with Eustachian tube dysfunction, a mastoid cavity volume may be a burden to its function. We hypothesized that tympanoplasty alone might be better than tympanoplasty combined with mastoidectomy because soft tissue in the mastoid cavity is a sequel to a protective physiological response. Thus, we explored the efficacy of tympanoplasty without mastoidectomy in COM patients exhibiting mastoid air cell opacification on TBCT., Methods: Between 2010 and 2014, a total of 33 patients, diagnosed with COM and with evidence of mastoid cavity opacification on TBCT, underwent tympanoplasty without mastoidectomy. All ears had been dry for ≥3 months before surgery. All procedures were performed by the same surgeon. We retrospectively analyzed the preoperative otoscopic findings, pre- and postoperative pure tone averages (PTAs; the mean of the values at 0.5, 1, 2, and 4 kHz), surgical procedures, and complications or recurrence., Results: Of the 33 patients, 28 (84.8%) exhibited hearing improvement after surgery. The mean pre- and postoperative PTAs were 46.9±21.2 dB and 29.4±17.0 dB, respectively ( P <0.001). The air-bone gap decreased from 25.7±10.7 dB to 10.3±8.7 dB ( P <0.001). Thirty-two patients (97.0%) did not develop any COM recurrence or cholesteatoma; one patient developed attic retraction of the tympanic membrane. Other minor complications were transient otorrhea caused by myringitis (two cases) and a pinpoint perforation (one case)., Conclusion: Tympanoplasty alone, i.e., without mastoidectomy, may adequately control COM, if it shows dry-up status for at least 3 months even though mastoid cavity opacification is detected in TBCT.

Damage to the eardrum causes acute pain and can lead to chronic otitis media if it develops into chronic tympanic membrane (TM) perforations. Chronic TM perforations are usually treated with surgical methods such as tympanoplasty and myringoplasty. However, these surgeries are not only complicated and difficult but also cost a lot of money. Our research team developed chitosan patches (E-CPs) that release epidermal growth factor (EGF) as a patch therapy to replace surgical methods. However, there was a limitation in the healing ratio of the treatment compared to the surgical methods. In this study, we developed EGF and epidermal growth factor receptor (EGFR) gene-releasing polyethyleneimine (PEI)/chitosan patches (EErP-CPs) to increase the regeneration of TM perforations. The addition of PEI increased the adhesion and migration ability of TM cells on the patches. The simultaneous release of the EGF and the EGFR gene further enhanced TM cell proliferation, adhesion and migratory ability. It was confirmed that the EGF protein and EGFR gene were released for 30 days; however, EGF was released and increased TM cell viability almost immediately after treatment and EGFR took a minimum of 3 days before showing its effect on improved cell viability. It was also shown that EErP-CPs are more hydrophilic and have more positive charge than E-CP because of added amine groups from PEI. In conclusion, the developed EErP-CPs resulted in the improved healing of TM perforations and can potentially be applied to the regeneration of both chronic and acute tympanic membrane perforations.

Objective: Steroids have been widely used to treat inner-ear diseases such as sudden sensorineural hearing loss, tinnitus, and Meniere's disease. They can be given via either systemic or intratympanic (IT) injection. The purpose of the present study was to explore differences in intracochlear steroid distribution by the administration method employed (systemic vs. IT injection)., Study Design: Animal study., Methods: Twenty-three Sprague-Dawley rats were given fluorescein isothiocyanate-labeled dexamethasone (FITC-DEX) three times (on successive days) via intraperitoneal (IP) or IT injection. Cochlear uptake of FITC-DEX was evaluated via immunohistochemistry and flow cytometry at 6 hours, and 3 and 7 days after the final injection., Results: FITC-DEX uptake was evident in spiral ganglion cells (SGs), the organ of Corti (OC), and the lateral walls (LWs), the basal turns of which were stained relatively prominently in both groups. Animals receiving IP injections exhibited higher FITC-DEX uptakes by the SGs and OC, whereas IT injection triggered higher-level FITC-DEX accumulation by the OC and LWs. Flow cytometry revealed that intracochlear FITC-DEX uptake by IT-injected animals was higher and more prolonged than in animals subjected to IP injections., Conclusion: We thus describe differences in cochlear steroid distributions after systemic and IT injections. This finding could help our understanding of the pharmacokinetics of steroids in the cochlea., Level of Evidence: NA. Laryngoscope, 128:189-194, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Mastoidectomy, the removal of infected mastoid bones, is a common surgical procedure for the treatment of chronic otitis media. Persistent and recurrent otorrhea and accumulation of keratin debris following open cavity mastoidectomy are still bothersome issues for both patients and otologists. In this study, we used human ear adipose-derived stromal cells (hEASCs) in combination with polycaprolactone (PCL) scaffolds and osteogenic differentiation medium (ODM) to regenerate temporal bone defects. The hEASCs showed stem cell phenotypes, and these characteristics were maintained up to passage 5. Mastoid bulla and cranial bone defects were induced in Sprague-Dawley rats using AgNO 3 and burr hole drilling, respectively, and the rats were then divided into five groups: (1) control, (2) hEASCs, (3) hEASCs + ODM, (4) hEASCs + PCL scaffolds, and (5) hEASCs + PCL scaffolds + ODM. Osteogenesis was evaluated by micro-computed tomography and histology. Compared with the control group, the groups transplanted with hEASCs and PCL scaffolds had significantly higher bone formation along the periphery of the mastoid bulla area. Moreover, ODM synergistically enhanced bone formation in mastoid bulla defects. Our results suggest that combining hEASCs with PCL scaffolds represents a promising method for anatomical and functional reconstruction of postoperative temporal bone defects following mastoidectomy. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3493-3501, 2017., (© 2017 Wiley Periodicals, Inc.)

Topographic features play a crucial role in the regulation of physiologically relevant cell and tissue functions. Here, an analysis of feature-size-dependent cell-nanoarchitecture interactions is reported using an array of scaffolds in the form of uniformly spaced ridge/groove structures for engineering wound healing. The ridge and groove widths of nanopatterns are varied from 300 to 800 nm and the nanotopography features are classified into three size ranges: dense (300-400 nm), intermediate (500-600 nm), and sparse (700-800 nm). On these matrices, fibroblasts demonstrate a biphasic trend of cell body and nucleus elongation showing the maximum at intermediate feature density, whereas maximum migration speed is observed at the dense case with monotonic decrease upon increasing feature size. The directional organization of cell-synthesized fibronectin fibers can be regulated differently via the nanotopographical features. In an in vitro wound healing model, the covering rate of cell-free regions is maximized on the dense nanotopography and decreased with increasing feature size, showing direct correlation with the trend of migration speed. It is demonstrated that the properties of repaired tissue matrices in the process of wound healing may be controlled via the feature-size-dependent cell-nanoarchitecture interactions, which can be an important consideration for designing tissue engineering scaffolds., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives/hypothesis: We compared the clinical characteristics between acute low- and high-frequency hearing loss (LF and HF, respectively) patients, and the efficacy of three different treatment protocols (systemic steroids, intratympanic steroid injection, and combination therapy)., Study Design: Prospective, randomized controlled study., Methods: A total of 111 patients diagnosed with LF or HF were treated on an outpatient basis. Each group was randomly divided into three equal subgroups based on therapy: oral steroid, intratympanic dexamethasone injection (IT), and combination therapy. Hearing gain was estimated by comparing pre- and post-treatment pure-tone averages. Recovery rate was assessed by Clinical Practice Guideline: Sudden Hearing Loss from the American Academy of Otolaryngology-Head and Neck Surgery., Results: In comparison of chief complaints, ear fullness and hearing loss were more common in the LF and HF group, respectively (P = .033 and P = .001, respectively). Hearing recovery rates were significantly different between the two groups (i.e., 74.1% [40/54] in the LF group and 45.6% [26/57] in the HF group; P < .001). Oral steroid therapy was most effective in the LF group (P = .017). In the HF group, all three modalities showed similar results, although IT tended to be the most effective (P = .390)., Conclusions: There were differences in chief complaints and treatment responses between LF and HF patients. Although they showed similar partial damage in the cochlea, the pathophysiology of LF and HF may be quite different., Level of Evidence: 1b. Laryngoscope, 127:1878-1884, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Hearing Aids amplify sounds at certain frequencies to help patients, who have hearing loss, to improve the quality of life. Variables affecting hearing improvement include the characteristics of the patients' hearing loss, the characteristics of the hearing aids, and the characteristics of the frequencies. Although the two former characteristics have been studied, there are only limited studies predicting hearing gain, after wearing Hearing Aids, with utilizing all three characteristics. Therefore, we propose a new machine learning algorithm that can present the degree of hearing improvement expected from the wearing of hearing aids., Methods: The proposed algorithm consists of cascade structure, recurrent structure and deep network structure. For cascade structure, it reflects correlations between frequency bands. For recurrent structure, output variables in one particular network of frequency bands are reused as input variables for other networks. Furthermore, it is of deep network structure with many hidden layers. We denote such networks as cascade recurring deep network where training consists of two phases; cascade phase and tuning phase., Results: When applied to medical records of 2,182 patients treated for hearing loss, the proposed algorithm reduced the error rate by 58% from the other neural networks., Conclusions: The proposed algorithm is a novel algorithm that can be utilized for signal or sequential data. Clinically, the proposed algorithm can serve as a medical assistance tool that fulfill the patients' satisfaction.

Objective: The study was designed to evaluate the outcomes of early surgical intervention, and to suggest the accurate operation time and surgical strategies., Methods: A total of 190 cases (144 patients) of PAS excision were classified into 2 groups according to their time of surgery; early intervention group (n = 53), and non-early intervention group (n = 137). Early intervention was defined as excision performed within 3 weeks from their first hospital visit, and after acute infection control, surgical removal was followed regardless of their infection status. The mean age of patients was 18.3 ± 15.7 years old (62 male, 82 female). During surgery, a parallel incision was added when iatrogenic fistula due to incision and drainage (I &D) or additionally opened wounds caused by infection was present., Results: Cases of I & D history, revision cases, use of preoperative antibiotics were significantly higher in the early intervention group compared to the non-early intervention group, however, the time of surgery did not affect the complication rate (p = 0.533). Within the infected cases, only 1 patient from the non-early intervention group showed a minor complication of keloid scar. During our follow up period of minimum of 6 months, there was no recurrence in either groups., Conclusion: The early intervention of PASs does not seem to increase postoperative complication or recurrence rates. A double parallel skin incision is a simple but adequate technique to treat infected PASs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Microbial infection is one of the most significant causes of ear diseases, but microbial profiles are very diverse according to the diseases and change over time. The purpose of the study was to clarify differences and chronological changes in causative pathogens among infectious ear diseases over the last 20 years, and to identify antibiotic resistance. In total, 1191 isolates were included from patients diagnosed with chronic otitis media without cholesteatoma (COM), cholesteatomatous otitis media (Chole), middle ear effusion (MEE), including acute otitis media and otitis media with effusion, and external otitis (EO). Data were collected periodically for the years 1995, 2000, 2004, 2009, and 2013. Culture results and antibiotic resistance were assessed. The most common microorganism identified was S. aureus. The microbial profiles differed significant among the COM, Chole, and MEE groups (p < 0.001). In contrast, there was no distinct difference between COM and EO (p = 0.332). COM, Chole, and MEE also showed significant chronological changes in microbial profiles over time. The frequency of CNS increased markedly in COM and Chole (p = 0.029 and 0.028, respectively); however, S. pneumoniae infection decreased significantly in MEE (p = 0.016). Methicillin-resistant S. aureus (MRSA) demonstrated a constant trend (p = 0.564), whereas ciprofloxacin-resistant P. aeruginosa increased over time (p < 0.001). Microbial profiles have changed over a 20-year period. Increases in the frequency of coagulase-negative Staphylococcus (CNS) and bacterial resistance to ciprofloxacin, used widely in treating ear infections, are noteworthy.

Aminoglycoside antibiotics including gentamicin (GM) induce delayed ototoxic effects such as hearing loss after long-term use, unlike the early-onset ototoxicity caused by cisplatin. The purpose of the study was to identify the mechanism of the delayed GM-induced ototoxicity by exploring the role of autophagy in vitro and in vivo. Treating HEI-OC1 auditory cells with GM led to a time-dependent increase of the autophagosome marker LC3-II, which was accompanied by cell death. In contrast, cisplatin and penicillin caused a rapid increase and had no effect on LC3-II levels, respectively. LC3-II-expressing autophagosomes co-localized with the labeled GM. GM-treated autophagosomes expressed reduced levels of Rab7, which is necessary for the fusion of autophagosomes with lysosomes. When the autophagic flux enhancer rapamycin was applied to GM-treated cells, Rab7 and the lysosomal enzyme cathepsin D were upregulated, and increased cell survival was observed. In animal studies, the intraperitoneal injection of GM worsened hearing thresholds and induced the accumulation of LC3 in the organ of Corti. This hearing impairment was attenuated by rapamycin. These findings suggest that the delayed onset-ototoxicity of GM may be closely related to the accumulation of autophagosomes via impaired autophagy. This GM-induced auditory cell death could be inhibited by enhancing autophagic flux., Competing Interests: The authors declare no competing financial interests.

Aims: Gap junction coupling is known to play a role in intercellular communication by the Good Samaritan effect or bystander effect. Nonjunctional connexins (Cxs) may also play certain gap junction-independent roles in cell death or survival. The purpose of the present study was to investigate the role of junctional and nonjunctional Cxs in ototoxic drug-induced auditory cell death by focusing on Cx43 in the cochlea., Results: Nonjunctional Cx43 conditions were prepared by low confluence culture (5 × 10 3 /cm 2 ) or a trafficking inhibitor, brefeldin A (BFA), in auditory cells, and short lengthened Cx43s with amino-terminal (NT; amino acids 1-256) or carboxy-terminal (CT; amino acids 257-382) were transfected into Cx-deficient HeLa cells to avoid gap junction formation. Knockdown of nonchannel Cx43 (small interfering RNA [siRNA]) inhibited Cis-diamminedichloroplatinum (cisplatin)-induced cell death regardless of gap junction formation; however, a gap junction blocker, 18 alpha-glycyrrhetinic acid (18α-GA), showed inhibitory effect only under the junctional condition. BFA did not show any additive influence on the inhibitory effect of siRNA Cx43. Shortened Cx43-transfected HeLa cells also resulted in a significant increase in cell death under cisplatin. In the animal studies with cisplatin-treated rats, hearing thresholds of auditory brainstem response were significantly preserved by a gap junction blocker, carbenoxolone, showing much more preserved stereocilia of hair cells in scanning electron microscopic findings. Innovation and Conclusion: Cx43 plays a proapoptotic role in cisplatin-induced auditory cell death in both junctional and nonjunctional conditions. Targeting the Cx-mediated signaling control may be helpful in designing new therapeutic strategies for drug-induced ototoxicity. Antioxid. Redox Signal. 25, 623-636.

Objective: To investigate the time course of tinnitus changes in patients receiving cochlear implantation (CI) in a prospective, multicenter setting and to determine related factors., Materials and Methods: A total of 79 adult patients who underwent CI were included in this study. We used the same questionnaires sequentially 5 times. The questionnaires included the Visual Analog Scale (VAS) for tinnitus severity, the Tinnitus Handicap Inventory (THI), Beck's Depression Index (BDI), and the Brief Encounter Psychosocial Instrument (BEPSI) for stress assessment., Results: Tinnitus was present in 59 (74.7%) of the 79 study subjects. After CI, tinnitus was eliminated in 10 patients (25%) and improved in 16 patients (40%) of the 40 patients who completed the final questionnaires, and most of the tinnitus reduction occurred in the early period of CI use. In an analysis of psychological functioning with CI, BDI was reduced significantly after CI. Multiple linear regression analysis revealed that preoperative auditory steady-state response (ASSR), THI, and final BDI score were significantly associated with the changes in tinnitus after CI., Conclusions: Most of the tinnitus reduction occurred within 1 month after CI use, and the changes were significantly associated with THI, ASSR, and BDI scores 6 months after CI. CI is a valuable therapeutic modality in tinnitus of a deafened ear., (© 2016 S. Karger AG, Basel.)

The development of an efficient platform for the growth and neuronal differentiation of stem cells is crucial for autologous cell therapy and tissue engineering to treat various neuronal disorders and neurodegenerative diseases. In this study, we describe the use of highly uniform graphene platforms that provide unique environments where unusual three-dimensional spheroids of human mesenchymal stem cells (hMSCs) are formed, which is advantageous for the differentiation of hMSCs into neurons. We suppose that graphene regulates the interactions at cell-substrate or cell-cell interfaces, consequently promoting the neurogenesis of hMSCs as well as the outgrowth of neurites, which was evidenced by the graphene-induced upregulation of early neurogenesis-related genes. We also demonstrated that the differentiated neurons from hMSCs on graphene are notably sensitive to external ion stimulation, and their neuronal properties can be maintained even after detaching and re-seeding onto a normal cell culture substrate, suggesting the enhanced maturity of resulting neuronal cells. Thus, we conclude that monolayer graphene is capable of regulating the growth and neural differentiation of hMSCs, which would provide new insight and strategy not only for autologous stem cell therapy but for tissue engineering and regenerative medicine based on graphene scaffolds.

Inspired by the hierarchically organized protein fibers in extracellular matrix (ECM) as well as the physiological importance of multiscale topography, we developed a simple but robust method for the design and manipulation of precisely controllable multiscale hierarchical structures using capillary force lithography in combination with an original wrinkling technique. In this study, based on our proposed fabrication technology, we approached a conceptual platform that can mimic the hierarchically multiscale topographical and orientation cues of the ECM for controlling cell structure and function. We patterned the polyurethane acrylate-based nanotopography with various orientations on the microgrooves, which could provide multiscale topography signals of ECM to control single and multicellular morphology and orientation with precision. Using our platforms, we found that the structures and orientations of fibroblast cells were greatly influenced by the nanotopography, rather than the microtopography. We also proposed a new approach that enables the generation of native ECM having nanofibers in specific three-dimensional (3D) configurations by culturing fibroblast cells on the multiscale substrata. We suggest that our methodology could be used as efficient strategies for the design and manipulation of various functional platforms, including well-defined 3D tissue structures for advanced regenerative medicine applications., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Engineering complex extracellular matrix (ECM) is an important challenge for cell and tissue engineering applications as well as for understanding fundamental cell biology. We developed the methodology for fabrication of precisely controllable multiscale hierarchical structures using capillary force lithography in combination with original wrinkling technique for the generation of well-defined native ECM-like platforms by culturing fibroblast cells on the multiscale substrata [1]. This paper provides information on detailed characteristics of polyethylene glycol-diacrylate multiscale substrata. In addition, a possible model for guided extracellular matrix formation from fibroblast cells cultured on bio-inspired configurable multiscale substrata is proposed.

In recent years, cell chip-based platforms have begun to show promise as a means of corroborating the findings of in vivo animal tests for cytotoxicity, and perhaps in the future partially replacing the need for such animal models. In contrast to the conventional culture methods, micro- and nanofabrication techniques can be utilized to provide a set of mechanostimulatory signals to the cells that mimic the context of extracellular matrix (ECM) of the tissue in which a particular cell line resides. Here, we report periodic lateral topographic striations, with a pitch ranging approximately from 200 to 800 nm with an intention to mimic a common geometry of fibrils in the ECM such as collagen or elastin, as a platform for investigating anticancer drug-induced cytotoxicity in stem cells. The ECM cues could facilitate perimeter, elongation, and gap junction formation of mesenchymal stem cells (MSCs), which eventually influenced the fate of cells in terms of death and survival against the common chemotherapeutic agent cisplatin. Interestingly, the appropriate inhibition of gap junctions of MSCs on the ECM mimicking substrates could prevent the cisplatin-induced cytotoxicity through the inhibition of the cisplatin-induced 'death signal communication' as compared to that on the flat substrates. Our results imply that nanoscale topography is an important consideration for chip-based cytotoxicity assays, which uniquely enable the consideration and rational design of ECM-like topographic features, and furthermore, that the natural topography of the ECM in the context of stem cell niches may serve as an important indicator for chemotherapeutic agent sensitivity., (© 2014 Wiley Periodicals, Inc.)

Intralabyrinthine schwannomas (ILSs) are rare benign tumors arising from the distal part of the cochleovestibular nerve confined within the labyrinth. Patients with ILSs complain of hearing loss, vertigo, tinnitus, and ear fullness. Surgical treatment of ILS is performed in special cases such as in cases of patients with nonserviceable hearing, progressive hearing loss, intractable vertigo, or tumor extension. We present an unusual case of a patient with intralabyrinthine schwannoma who underwent surgery to treat progressive hearing loss and recovered his hearing after surgery., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Tympanic membrane (TM) perforation, in particular chronic otitis media, is one of the most common clinical problems in the world and can present with sensorineural healing loss. Here, we explored an approach for TM regeneration where the latent progenitor or stem cells within TM epithelial layers may play an important regulatory role. We showed that potential TM stem cells present highly positive staining for epithelial stem cell markers in all areas of normal TM tissue. Additionally, they are present at high levels in perforated TMs, especially in proximity to the holes, regardless of acute or chronic status, suggesting that TM stem cells may be a potential factor for TM regeneration. Our study suggests that latent TM stem cells could be potential regulators of regeneration, which provides a new insight into this clinically important process and a potential target for new therapies for chronic otitis media and other eardrum injuries.

Purpose: The purpose of this study was to examine the validity of student ratings of instruction by analyzing their relationships with several variables, including gender, academic rank, specialty, teaching time, and teaching method, at a medical school., Methods: This study analyzed the student ratings of 297 courses at Ajou University School of Medicine in 2013. SPSS version 12.0 was used to analyze the data and statistics by t-test, analysis of variance, and Scheffe test., Results: There were no statistically significant differences in student ratings between gender, rank, and specialty. However, student ratings were significantly influenced by teaching times and methods (p<0.05). Student ratings were high for teaching times of 10 hours or more and small-group learning, compared with lectures. There was relatively mean differences in students ratings by teaching times, specialty and rank, although the difference in ratings was not statistically significant., Conclusion: Student ratings can be classified by teaching time and method for summative purposes. To apply student ratings to the evaluation of the performance of faculty, further studies are needed to analyze the variables that influence student ratings.

Here, we introduce a polydixylitol based highly osmotic polymer that not only transmigrates the BBB by intra-arterial infusion of osmotic polyol but also triggers cellular uptake via modulation of caveolae mediated endocytosis.

Serine hydroxymethyltransferase isoforms (SHMT1 & SHMT2α), which serve as scaffold protein for the formation of a multi-enzyme complex and generate one-carbon unit for the de novo thymidylate biosynthesis pathway during DNA synthesis, are vitamin B6 (VB6)-dependent enzyme. Cancer cells with high proliferation intensity need increased SHMT activation which enforces the facilitated-diffusion of VB6 for the continuous functioning of thymidylate synthase cycle. Therefore, SHMT knockdown presents an alternative approach to prevent DNA synthesis in cancer cells; however, its potential to inhibit cancer growth remains unknown so far. Here we demonstrated that VB6 coupled to poly(ester amine) (VBPEA) enforces a high level of VTC (VB6-transporting membrane carriers)-mediated endocytosis of the complexed SHMT1 siRNA (siSHMT1) to interrupt the thymidylate biosynthesis pathway of cancer cells. The detrimental effect of SHMT1 knockdown on the disintegration of multi-enzyme complex resulted in cell cycle arrest and a decrease in cell's genomic DNA content, leading to enhanced apoptotic events in cancer cells. A reduction in tumor size was observed with constant SHMT1 suppression in xenograft mice. This study illustrates how silencing the SHMT1 expression inhibits cancer growth and the increased VB6 channeling for sustenance of cancer cells promotes VB6-coupled vector to elicit enhanced delivery of siSHMT1., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cis-diamminedichloroplatinum (cisplatin) is an effective chemotherapeutic drug for cancer therapy. However, most patients treated with cisplatin are at a high risk of ototoxicity, which causes severe hearing loss. Inspired by the "Good Samaritan effect" or "bystander effect" from gap junction coupling, we investigated the role of gap junctions in cisplatin-induced ototoxicity as a potential therapeutic method. We showed that connexin 43 (Cx43) was highly expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, mediating cell-cell communication. The viability of HEI-OC1 cells was greatly decreased by cisplatin treatment, and cisplatin-treated HEI-OC1 cells showed lower Cx43 expression compared to that of untreated HEI-OC1 cells. In particular, high accumulation of Cx43 was observed around the nucleus of cisplatin-treated cells, whereas scattered punctuate expression of Cx43 was observed in the cytoplasm and membrane in normal cells, suggesting that cisplatin may interrupt the normal gap junction communication by inhibiting the trafficking of Cx43 to cell membranes in HEI-OC1 cells. Interestingly, we found that the inhibition of gap junction activity reduced cisplatin-induced apoptosis of auditory hair cells. Cx43 siRNA- or 18α-GA-treated HEI-OC1 cells showed higher cell viability compared to control HEI-OC1 cells during cisplatin treatment; this was also supported by fluorescence recovery after photobleaching studies. Inhibition of gap junction activity reduced recovery of calcein acetoxymethyl ester fluorescence compared to control cells. Additionally, analysis of the mechanisms involved demonstrated that highly activate extracellular signal-regulated kinase and protein kinase B, combined with inhibition of gap junctions may promote cell viability during cisplatin treatment.

Since Korean red ginseng (KRG) has been proven to protect against gentamicin-induced vestibular and hearing dysfunction, the effects of KRG on age-related inner ear disorder in C57BL/6 mice were investigated. While age-related hearing loss was detected at the age of 6months (32kHz) and 9months (16kHz) in the control group, it was significantly delayed (p<0.05) in the 150mg/kg KRG-treated group. Vestibular dysfunction was observed in the tail-hanging and swimming tests, with significantly different severity scores and swimming times detected between the control and 150mg/kg KRG-treated group at the age of 12months (p<0.05). Mice treated with 500mg/kg KRG exhibited irritability and aggravated inner ear dysfunction. Histological observation supported the findings of hearing and vestibular function defects. In conclusion, C57BL/6 mice showed early-onset hearing loss and progressive vestibular dysfunction with aging, which were delayed by treatment with 150mg/kg KRG. However, 500mg/kg KRG treatment may induce aggressive behavior., (Copyright © 2014 Elsevier Inc. All rights reserved.)