Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration.

Cell transplantation therapy has long been investigated as a therapeutic intervention for neurodegenerative disorders, including spinal cord injury, Parkinson's disease, and amyotrophic lateral sclerosis. Indeed, patients have high hopes for a cell-based therapy. However, there are numerous practical challenges for clinical translation. One major problem is that only very low numbers of donor cells survive and achieve functional integration into the host. Glial scar tissue in chronic neurodegenerative disorders strongly inhibits regeneration, and this inhibition must be overcome to accomplish successful cell transplantation. Intraneural cell transplantation is considered to be the best way to deliver cells to the host. We questioned this view with experiments in vivo on a rat glial scar model of the auditory system. Our results show that intraneural transplantation to the auditory nerve, preceded by chondroitinase ABC (ChABC)-treatment, is ineffective. There is no functional recovery, and almost all transplanted cells die within a few weeks. However, when donor cells are placed on the surface of a ChABC-treated gliotic auditory nerve, they autonomously migrate into it and recapitulate glia- and neuron-guided cell migration modes to repair the auditory pathway and recover auditory function. Surface transplantation may thus pave the way for improved functional integration of donor cells into host tissue, providing a less invasive approach to rescue clinically important neural tracts.

Septin7 regulates inner ear formation at an early developmental stage.

Septins are guanosine triphosphate-binding proteins that are evolutionally conserved in all eukaryotes other than plants. They function as multimeric complexes that interact with membrane lipids, actomyosin, and microtubules. Based on these interactions, septins play essential roles in the morphogenesis and physiological functions of many mammalian cell types including the regulation of microtubule stability, vesicle trafficking, cortical rigidity, planar cell polarity, and apoptosis. The inner ear, which perceives auditory and equilibrium sensation with highly differentiated hair cells, has a complicated gross morphology. Furthermore, its development including morphogenesis is dependent on various molecular mechanisms, such as apoptosis, convergent extension, and cell fate determination. To determine the roles of septins in the development of the inner ear, we specifically deleted Septin7 (Sept7), the non-redundant subunit in the canonical septin complex, in the inner ear at different times during development. Foxg1Cre-mediated deletion of Sept7, which achieved the complete knockout of Sept7 within the inner ear at E9.5, caused cystic malformation of inner ears and a reduced numbers of sensory epithelial cells despite the existence of mature hair cells. Excessive apoptosis was observed at E10.5,E11.5 and E12.5 in all inner ear epithelial cells and at E10.5 and E11.5 in prosensory epithelial cells of the inner ears of Foxg1Cre;Septin7floxed/floxed mice. In contrast with apoptosis, cell proliferation in the inner ear did not significantly change between control and mutant mice. Deletion of Sept7 within the cochlea at a later stage (around E15.5) with Emx2Cre did not result in any apparent morphological anomalies observed in Foxg1Cre;Septin7floxed/floxed mice. These results suggest that SEPT7 regulates gross morphogenesis of the inner ear and maintains the size of the inner ear sensory epithelial area and exerts its effects at an early developmental stage of the inner ear.

TGF-ß induces the differentiation of human CXCL13-producing CD4(+) T cells.

In the ectopic lymphoid-like structures present in chronic inflammatory conditions such as rheumatoid arthritis, a subset of human effector memory CD4(+) T cells that lacks features of follicular helper T (Tfh) cells produces CXCL13. Here, we report that TGF-ß induces the differentiation of human CXCL13-producing CD4(+) T cells from naïve CD4(+) T cells. The TGF-ß-induced CXCL13-producing CD4(+) T cells do not express CXCR5, B-cell lymphoma 6 (BCL6), and other Tfh-cell markers. Furthermore, expression levels of CD25 (IL-2Rα) in CXCL13-producing CD4(+) T cells are significantly lower than those in FoxP3(+) in vitro induced Treg cells. Consistent with this, neutralization of IL-2 and knockdown of STAT5 clearly upregulate CXCL13 production by CD4(+) T cells, while downregulating the expression of FoxP3. Furthermore, overexpression of FoxP3 in naïve CD4(+) T cells downregulates CXCL13 production, and knockdown of FoxP3 fails to inhibit the differentiation of CXCL13-producing CD4(+) T cells. As reported in rheumatoid arthritis, proinflammatory cytokines enhance secondary CXCL13 production from reactivated CXCL13-producing CD4(+) T cells. Our findings demonstrate that CXCL13-producing CD4(+) T cells lacking Tfh-cell features differentiate via TGF-ß signaling but not via FoxP3, and exert their function in IL-2-limited but TGF-ß-rich and proinflammatory cytokine-rich inflammatory conditions.

Histopathological evaluation and long-term results of soft tissue preservation technique in cholesteatoma surgery.

The goal of cholesteatoma surgery is total removal of the cholesteatoma matrix and prevention of recurrence. Preservation of soft tissue in the attic is reported to improve post-operative middle ear aeration, and thus prevents recurrence. However, the histology and nature of the preserved tissue have rarely been reported. The aim of this study is to clarify the histology of the preserved soft tissue in cholesteatoma surgery, and to show its relationship to the clinical course. Surgical specimens were obtained from ten patients with pars flaccida-type cholesteatoma. In these patients, cholesteatoma occupied the attic and the mastoid cavity. The cholesteatoma was removed so as not to expose the bone in the attic. After the removal of the lesions, soft tissue was harvested from the floor of the attic, using cupped forceps. The specimens were fixed with 10 % formalin, and stained with hematoxylin-eosin. The patients were followed-up for 8 years after the surgery. No patients showed post-operative inner ear disturbance or facial nerve palsy. In one patient, residual lesion was found during the revision surgery. The area of residual lesion was not explored during the first operation. Two other patients showed recurrent cholesteatoma in the pars tensa; one of these patients had accompanying otorrhea. The other seven patients showed no residual or recurrent cholesteatoma 8 years after the surgery. The histological examination showed that the harvested tissue was mainly composed of collagen fiber and fibroblasts. Ciliary epithelial cells were found in one patient. In three patients, cysts of mucosal remnants (glandular cysts), were embedded in the connective tissue. Two of these three patients experienced recurrent cholesteatoma, while the other seven patients were without recurrence at follow-up. Preservation of soft tissue behind the cholesteatoma matrix is a safe technique if the surgical field is fully visible. In most cases, the preserved tissue was fibrous connective tissue and lacked the characteristics of mucosa. The glandular cysts in the preserved soft tissue seem to be related to the recurrence of cholesteatoma.

Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea.

Mechanosensory hair cells and supporting cells develop from common precursors located in the prosensory domain of the developing cochlear epithelium. Prosensory cell differentiation into hair cells or supporting cells proceeds from the basal to the apical region of the cochleae, but the mechanism and significance of this basal-to-apical wave of differentiation remain to be elucidated. Here, we investigated the role of Hedgehog (Hh) signaling in cochlear development by examining the effects of up- and downregulation of Hh signaling in vivo. The Hh effector smoothened (Smo) was genetically activated or inactivated specifically in the developing cochlear epithelium after prosensory domain formation. Cochleae expressing a constitutively active allele of Smo showed only one row of inner hair cells with no outer hair cells (OHCs); abnormal undifferentiated prosensory-like cells were present in the lateral compartment instead of OHCs and their adjacent supporting cells. This suggests that Hh signaling inhibits prosensory cell differentiation into hair cells or supporting cells and maintains their properties as prosensory cells. Conversely, in cochlea with the Smo conditional knockout (Smo CKO), hair cell differentiation was preferentially accelerated in the apical region. Smo CKO mice survived after birth, and exhibited hair cell disarrangement in the apical region, a decrease in hair cell number, and hearing impairment. These results indicate that Hh signaling delays hair cell and supporting cell differentiation in the apical region, which forms the basal-to-apical wave of development, and is required for the proper differentiation, arrangement and survival of hair cells and for hearing ability.

Endoscopic laryngo-pharyngeal surgery for superficial laryngo-pharyngeal cancer.

BACKGROUND AND STUDY AIMS: Narrow band imaging (NBI) combined with magnifying endoscopy enables us to detect superficial laryngo-pharyngeal cancers, which are difficult to detect by standard endoscopy. Endoscopic laryngo-pharyngeal surgery (ELPS) is a technique developed to treat such lesions and the purpose of this study is to evaluate the usefulness of ELPS for superficial laryngo-pharyngeal cancer. PATIENTS AND METHODS: Seventy five consecutive patients with 104 fresh superficial laryngo-pharyngeal cancers are included in this study. Under general anesthesia, a specially-designed curved laryngoscope was inserted to create a working space in the pharyngeal lumen. A magnifying endoscope was inserted transorally to visualize the field and a head & neck surgeon dissected the lesion using the combination of the orally-inserted curved grasping forceps and electrosurgical needle knife in both hands. The safely, functional outcomes, and oncologic outcomes of ELPS were evaluated retrospectively. RESULTS: Median operation time per lesion was 35 min. Post-operative bleeding occurred in 3 cases and temporal subcutaneous emphysema occurred in 10 cases. No vocal fold impairment occurred after surgery. The median fasting period was 2 days and all patients except one have a normal diet with no limitations. Local recurrence occurred in 1 case, and the 3-year overall survival rate and the 3-year disease specific survival rate was 90% and 100%, respectively. CONCLUSIONS: ELPS is a hybrid of head and neck surgery and gastrointestinal endoscopic treatment, and enjoys the merit of both procedures. ELPS makes it possible to perform minimally-invasive surgery, preserving both the swallowing and phonation functions.

The sensitivity and accuracy of a cone beam CT in detecting the chorda tympani.

The facial recess approach through posterior tympanotomy is the standard approach in cochlear implantation surgery. The size of the facial recess is highly variable, depending on the course of the chorda tympani. Despite their clinical importance, little is known about the sensitivity and accuracy of imaging studies in the detection of the chorda tympani. A total of 13 human temporal bones were included in this study. All of the temporal bones were submitted to a cone beam CT (Accuitomo, Morita, Japan). The multi-planar reconstruction images were rotated around the mastoid portion of the facial nerve to locate the branches of the facial nerve. A branch was diagnosed as the chorda tympani when it entered the tympanic cavity near the notch of Rivinus. The distance between the bifurcation and the tip of the short crus of the incus was measured. In all temporal bones, the canal of the chorda tympani or the posterior canaliculus was detected. In the CT-based evaluation, the average distance from the bifurcation to the incus short crus was 12.6 mm (8.3-15.8 mm). The actual distance after dissection was 12.4 mm (8.2-16.4 mm). The largest difference between the distances evaluated with the two procedures was 1.1 mm. Cone beam CT is very useful in detecting the course of the chorda tympani within the temporal bone. The measured distance is accurate.

Carrier frequency of the GJB2 mutations that cause hereditary hearing loss in the Japanese population.

Hearing impairment is one of the most common sensory disorders that affect ~1 in 1000 children, and half of them are considered to be hereditary. Information about the carrier frequencies of mutations that underlie autosomal recessive disorders is indispensable for accurate genetic counseling to predict the probability of patients' children's disease. However, there have been few reports specific to the Japanese population. GJB2 mutations are reported to be the most frequent cause of hereditary hearing loss, and the mutation spectrum and frequency of GJB2 mutations were reported to vary among different ethnic groups. In this study, we investigated the carrier frequency of GJB2 mutations and the mutation spectrum in 509 individuals randomly selected from the general Japanese population. We show that the carrier frequencies of the two most common pathogenic mutations are 1.57% (8/509) for c.235delC and 1.77% (9/509) for p.Val37Ile. In addition to these mutations, we found two pathogenic variants (p.[Gly45Glu;Tyr136*] and p.Arg143Trp), and the total carrier frequency was estimated to be around 3.73% (19/509). We also detected six unclassified variants, including two novel variants (p.Cys60Tyr and p.Phe106Leu), with the former predicted to be pathogenic. These findings will provide indispensable information for genetic counseling in the Japanese population.

Biocompatibility and efficacy of collagen/gelatin sponge scaffold with sustained release of basic fibroblast growth factor on vocal fold fibroblasts in 3-dimensional culture.

OBJECTIVE: Treatment of vocal fold scarring remains challenging. We have previously reported the therapeutic effects of local injection of basic fibroblast growth factor (bFGF) in animal models and humans. A novel collagen/gelatin sponge (CGS) is capable of sustained release of bFGF, which compensates for its quick absorption in vivo, avoiding multiple injections. This study aimed to evaluate the biocompatibility and efficacy of the CGS in rat vocal fold fibroblasts prior to human trials. METHODS: Fibroblasts extracted from Sprague-Dawley rat vocal folds were seeded onto a CGS and then cultivated with bFGF at concentrations of 0, 10, and 100 ng/mL. Vocal fold fibroblast morphology, adhesion, proliferation, and gene expression were measured under these 3-dimensional conditions. RESULTS: Cells adhered to the CGS from day 1. Although no significant differences in cell morphology were detected, cell proliferation was accelerated by bFGF administration. Expression of endogenous bFGF and hepatocyte growth factor was significantly up-regulated at 10 ng/mL bFGF. The expression of procollagen I and procollagen III was significantly suppressed, whereas HAS-1 and HAS-2 were up-regulated at 10 and 100 ng/mL bFGF. CONCLUSION: The collagen/gelatin sponge is biocompatible with vocal fold fibroblasts and may be useful as a bFGF drug delivery system for the treatment of scarred vocal folds.

A randomized controlled clinical trial of topical insulin-like growth factor-1 therapy for sudden deafness refractory to systemic corticosteroid treatment.

BACKGROUND: To date, no therapeutic option has been established for sudden deafness refractory to systemic corticosteroids. This study aimed to examine the efficacy and safety of topical insulin-like growth factor-1 (IGF-1) therapy in comparison to intratympanic corticosteroid therapy. METHODS: We randomly assigned patients with sudden deafness refractory to systemic corticosteroids to receive either gelatin hydrogels impregnated with IGF-1 in the middle ear (62 patients) or four intratympanic injections with dexamethasone (Dex; 58 patients). The primary outcome was the proportion of patients showing hearing improvement (10 decibels or greater in pure-tone average hearing thresholds) 8 weeks after treatment. The secondary outcomes included the change in pure-tone average hearing thresholds over time and the incidence of adverse events. RESULTS: In the IGF-1 group, 66.7% (95% confidence interval [CI], 52.9-78.6%) of the patients showed hearing improvement compared to 53.6% (95% CI, 39.7-67.0%) of the patients in the Dex group (P = 0.109). The difference in changes in pure-tone average hearing thresholds over time between the two treatments was statistically significant (P = 0.003). No serious adverse events were observed in either treatment group. Tympanic membrane perforation did not persist in any patient in the IGF-1 group, but did persist in 15.5% (95% CI, 7.3-27.4%) of the patients in the Dex group (P = 0.001). CONCLUSIONS: The positive effect of topical IGF-1 application on hearing levels and its favorable safety profile suggest utility for topical IGF-1 therapy in patients with sudden deafness. TRIAL REGISTRATION: UMIN Clinical Trials Registry Number UMIN000004366, October 30th, 2010.

Growth factor-eluting cochlear implant electrode: impact on residual auditory function, insertional trauma, and fibrosis.

BACKGROUND: A cochlear implant (CI) is an artificial hearing device that can replace a damaged cochlea. The present study examined the use of growth factor-eluting gelatin hydrogel coatings on the electrodes to minimize inner ear trauma during electrode insertion. Insulin-like growth factor 1 (IGF1) and/or hepatocyte growth factor (HGF) were chosen as the agents to be administered. METHODS: Silicone CI electrode analogs were prepared and coated with gelatin hydrogels. Adsorption/release profile of the hydrogel was measured using (125)I-radiolabeled IGF. Hydrogel-coated electrodes were absorbed with IGF1, HGF, IGF1 plus HGF, or saline (control) and implanted into the basal turns of guinea pig cochleae (n = 5). Auditory sensitivity was determined pre-operatively, immediately after, and 3, 7, 14, 21, and 28 days post-operatively by using auditory brainstem response (ABR; 4-16 kHz). In addition, histological analysis was performed and auditory hair cell (HC) survival, spiral ganglion neuron (SGN) densities, and fibrous tissue thickness were measured. RESULTS: Compared to non-coated arrays, hydrogel-coated electrodes adsorbed significantly greater amounts of IGF1 and continuously released it for 48 h. Residual hearing measured by ABR thresholds after surgery were elevated by 50-70 dB in all of the electrode-implanted animals, and was maximal immediately after operation. Thresholds were less elevated after hydrogel treatment, and the hearing protection improved when IGF1 or HGF was applied. Histopathologically, hair cell survival, spiral ganglion cell survival, and fibrous tissue thickness were not different between the experimental groups. No serious adverse events were observed during the 4-week observation period. CONCLUSIONS: Our findings provide the first evidence that hydrogel-coated, growth factor-releasing CI electrodes could attenuate insertional trauma and promote recovery from it, suggesting that this combination might be a new drug delivery strategy not only in cochlear implantation but also in treating clinical conditions characterized by inner ear damage.

Effects of mouse utricle stromal tissues on hair cell induction from induced pluripotent stem cells.

BACKGROUND: Hair cells are important for maintaining our sense of hearing and balance. However, they are difficult to regenerate in mammals once they are lost. Clarification of the molecular mechanisms underlying inner ear disorders is also impeded by the anatomical limitation of experimental access to the human inner ear. Therefore, the generation of hair cells, possibly from induced pluripotent stem (iPS) cells, is important for regenerative therapy and studies of inner ear diseases. RESULTS: We generated hair cells from mouse iPS cells using an established stepwise induction protocol. First, iPS cells were differentiated into the ectodermal lineage by floating culture. Next, they were treated with basic fibroblast growth factor to induce otic progenitor cells. Finally, the cells were co-cultured with three kinds of mouse utricle tissues: stromal tissue, stromal tissue + sensory epithelium, and the extracellular matrix of stromal tissue. Hair cell-like cells were successfully generated from iPS cells using mouse utricle stromal tissues. However, no hair cell-like cells with hair bundle-like structures were formed using other tissues. CONCLUSIONS: Hair cell-like cells were induced from mouse iPS cells using mouse utricle stromal tissues. Certain soluble factors from mouse utricle stromal cells might be important for induction of hair cells from iPS cells.

Therapeutic potential of a gamma-secretase inhibitor for hearing restoration in a guinea pig model with noise-induced hearing loss.

BACKGROUND: Notch signaling plays a crucial role in the fate determination of cochlear progenitor cells, hair cells, and supporting cells in the developing cochlea. Recent studies have demonstrated the temporal activation of Notch signaling in damaged mature cochleae, and have demonstrated the induction of new hair cells by pharmacologically inhibiting Notch signaling. The present study aimed to illustrate the feasibility of pharmacologically inhibiting Notch signaling by using a gamma-secretase inhibitor for treating sensorineural hearing loss. RESULTS: The effect of the sustained local delivery of MDL28170, a gamma-secretase inhibitor, on hearing and hair cell induction was tested in a guinea pig model with noise-induced hearing loss. MDL28170 was directly delivered into the cochlear fluids via a micro-osmotic pump. Drug application was initiated 7 days after noise exposure. Measurements of auditory brainstem responses revealed better hearing in the MDL28170-treated animals than in the vehicle controls. Histological analysis demonstrated a higher number of outer hair cells in the MDL28170-treated cochleae than the vehicle-treated cochleae. CONCLUSION: These findings strongly suggest that local sustained delivery of a gamma-secretase inhibitor into the cochlea could be a novel strategy for treating acute hearing loss that is refractory to conventional treatment.

The clinical utility of reduced-distortion readout-segmented echo-planar imaging in the head and neck region: initial experience.

OBJECTIVES: To evaluate whether readout-segmented echo-planar imaging (RS-EPI) diffusion weighted image (DWI) can diminish image distortion in the head and neck area, compared with single-shot (SS)-EPI DWI. METHODS: We conducted phantom and patient studies using 3 T magnetic resonance imaging (MRI) with a 16-channel coil. For the phantom study, we evaluated distortion and signal homogeneity in gel phantoms. For the patient study, 29 consecutive patients with clinically suspicious parotid lesions were prospectively enrolled. RS-EPI and SS-EPI DWI were evaluated by two independent readers for identification of organ/lesion and distortion, using semiquantitative scales and quantitative scores. Apparent diffusion coefficient (ADC) values and contrast-noise ratios of parotid tumours (if present; n = 15) were also compared. RESULTS: The phantom experiments showed that RS-EPI provided less distorted and more homogeneous ADC maps than SS-EPI. In the patient study, RS-EPI was found to provide significantly less distortion in almost all organs/lesions (p < 0.05), according to both semiquantitative scales and quantitative scores. There was no significant difference in ADC values and contrast-noise ratios between the two DWI techniques. CONCLUSIONS: The distortion in DWI was significantly reduced with RS-EPI in both phantom and patient studies. The RS-EPI technique provided more homogenous images than SS-EPI, and can potentially offer higher image quality in the head and neck area. KEY POINTS: The distortion in DWI is significantly reduced with RS-EPI compared with SS-EPI. Structures in the head and neck were identified more clearly using RS-EPI. No significant difference in ADC values was found between the techniques.

A distinct human CD4+ T cell subset that secretes CXCL13 in rheumatoid synovium.

OBJECTIVE: A subset of CD4+ T cells in the synovium of patients with rheumatoid arthritis (RA) produce CXCL13, a chemokine that is crucial for the formation of germinal centers. This study was undertaken to determine the relevance of this population to known subsets of T helper cells and to proinflammatory cytokines, and how these cells are generated. METHODS: The expression of Th markers and CXCL13 by CD4+ T cells in RA synovium and the involvement of proinflammatory cytokines in CXCL13 production were assessed. We also investigated whether CXCL13+CD4+ T cells could be newly induced. RESULTS: CXCL13+CD4+ T cells in RA synovium were negative for interferon-γ (IFNγ), interleukin-4 (IL-4), IL-17, FoxP3, and CXCR5 and expressed low levels of inducible T cell costimulator, indicating that this population is a distinct human CD4 subset. T cell receptor (TCR) stimulation of CD4+ T cells, obtained from RA synovium with low expression of CXCL13, promptly induced CXCL13 production and addition of proinflammatory cytokines supported the long-term production of CXCL13. These findings indicate that CXCL13-producing CD4+ T cells can be in a memory state ready to be reactivated upon TCR stimulation and that proinflammatory cytokines are involved in persistent CXCL13 production. TCR stimulation of CD4+ T cells from the blood of healthy volunteers, together with proinflammatory cytokine supplementation, induced a population that produced CXCL13, but not IFNγ. Synovial T cells recruited CXCR5+ cells in a CXCL13-dependent manner. CONCLUSION: CXCL13-producing CD4+ T cells induced in RA synovium may play a role in the recruitment of CXCR5+ cells, such as B cells and circulating follicular helper T cells, and in ectopic lymphoid neogenesis at sites of inflammation.

Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice.

Sensorineural hearing loss, which is mainly caused by cochlear hair cell damage, is an intractable disease, as cochlear hair cells and supporting cells are unable to proliferate in postnatal mammals. As a novel and potent treatment for sensorineural hearing loss, we have studied IGF-1 and found that it protects cochlear hair cells from the damage caused by noise and ischemic trauma. Through a clinical trial, we have also confirmed that IGF-1 is an effective treatment for idiopathic sudden sensorineural hearing loss. In the current study, we attempted to identify the downstream pathways of the IGF-1 signal and the mechanisms by which IGF-1 protects the neonatal mouse cochlear hair cells that have been damaged by neomycin. IGF-1 activated both the PI3K/Akt and MEK/ERK pathways to maintain the hair cell numbers in the injured cochlea. The PI3K/Akt pathway specifically protected the cochlear inner hair cells through the inhibition of apoptosis. In contrast, the MEK/ERK pathway induced the cell cycle promotion of Hensen's and Claudius' cells, the supporting cells that are located lateral to the outer hair cells of the cochlea. This cell cycle promotion of the supporting cells resulted in the maintenance of the outer hair cell numbers. These results indicate that IGF-1 is a growth factor that efficiently regulates different mechanisms through different downstream cascades, thereby protecting cochlear hair cells.

Piezoelectric materials mimic the function of the cochlear sensory epithelium.

Cochlear hair cells convert sound vibration into electrical potential, and loss of these cells diminishes auditory function. In response to mechanical stimuli, piezoelectric materials generate electricity, suggesting that they could be used in place of hair cells to create an artificial cochlear epithelium. Here, we report that a piezoelectric membrane generated electrical potentials in response to sound stimuli that were able to induce auditory brainstem responses in deafened guinea pigs, indicating its capacity to mimic basilar membrane function. In addition, sound stimuli were transmitted through the external auditory canal to a piezoelectric membrane implanted in the cochlea, inducing it to vibrate. The application of sound to the middle ear ossicle induced voltage output from the implanted piezoelectric membrane. These findings establish the fundamental principles for the development of hearing devices using piezoelectric materials, although there are many problems to be overcome before practical application.

[A clinical study on 106 infant cases who received detailed hearing tests after newborn hearing screening].

Newborn hearing screening (NHS) has been conducted widely in Japan in the last decade, however, there seems to be some confusion regarding the significance of NHS or management of the results obtained from NHS among clinics and practitioners. The system of NHS in Japan should be improved and refined through continuous evaluation of NHS, in terms of cost effectiveness in particular, so that NHS can be conducted more efficiently and effectively. To achieve this goal, the authors thought it important to clarify the current status and roles of our department as a facility for infants with congenital hearing impairment. In the present study, we studied 106 infant cases who were referred to the Department of Otolaryngology in Kyoto University Hospital after NHS before the age of twelve months in a period of seven years from 2006 to 2012 via retrospective chart reviewing. 79.2% of 96 infants who were qualified as referred either unilaterally or bilaterally following NHS were diagnosed as having hearing impairment in any form, either unilateral or bilateral, or conductive and/or sensorineural. The positive agreement rate was 88.7% in 53 cases who were qualified as referred bilaterally in NHS, demonstrating a high reliability of the NHS system. Twenty-four cases were diagnosed as having the need for hearing aids and were assigned to treatment and education. All the infants who underwent cochlear implantation in our department had severe bilateral hearing impairment of more than 105 dBnHL in both ears at the first examination. Moreover, a number of infants who were qualified as having passed in both ears in NHS or who had failed to receive NHS at birth were revealed as having hearing impairment and needed treatment later in the first year of their life, suggesting that NHS should be conducted in combination with periodical health checkups by family practitioners in order to identify infants with hearing impairment earlier in their life with higher efficacy.

Long-term effects of second cochlear implantation with sequential bilateral cochlear implantation in Japanese children.

OBJECTIVE: This study aimed to longitudinally evaluate speech perception ability and sound-field thresholds with the first, second, or bilateral cochlear implants (CIs) and MAP parameters of second CI in children. METHODS: Eighteen children who underwent bilateral cochlear implantation at Kyoto University Hospital were included. We evaluated speech perception under quiet and noisy conditions using the first, second, or bilateral CIs, CI-aided sound-field thresholds using the first or second CI, and MAP parameter values (C-levels, T-levels, and dynamic range) of the second CI of more than 5 years after the second implantation. RESULTS: Patients with a second CI after 7 years of age had significantly worse speech perception ability with the second CI even long after the surgery than those with a second CI before 7 years of age. CI-aided sound-field thresholds using the first or second CI were similar, regardless of the second implantation timing. Speech perception in noise with bilateral CIs was enhanced by the addition of a second CI, even after 7 years of age. Patients undergoing second cochlear implantation before 3.5 years of age showed significantly higher C-levels and wider dynamic ranges in the second CI MAP parameters. CONCLUSIONS: When the second implantation was performed after 7 years of age, the second CI effects were limited even with long-term use, which is attributed to unstable MAP parameters. The second CI-aided sound-field threshold contributed to the better outcome of bilateral CIs in noise, even if the second implantation was performed at age of ≥7 years.

Effects of high-dose betahistine on intractable dizziness in patients with uncompensated unilateral vestibulopathy.

OBJECTIVE: In the present study, we examined the effects of high-dose betahistine on dizziness handicap inventory (DHI) scores in patients with unilateral vestibulopathy. METHODS: An uncontrolled, open-label, multicenter clinical trial was conducted. Fifteen patients with unilateral vestibulopathy, such as vestibular neuritis, who complained of intractable dizziness for more than three months were enrolled. Initially, all patients were orally administered betahistine at a dose of 36 mg/day for four weeks, which is the standard dose and dosing period for the treatment of dizziness in Japan. The patients were then administered betahistine at a double dose of 72 mg/day for four weeks. Six patients who became aware of the benefits of high-dose betahistine were further administered betahistine at 72 mg/day for an additional 12 weeks (a total of 16 weeks). Perceived disability due to dizziness was assessed by DHI scores. RESULTS: In all 15 patients, short-term administration with high-dose (72 mg/day) betahistine for four weeks, but not low-dose betahistine (36 mg/day) for four weeks significantly decreased DHI scores. In particular, in six responding patients with self-reported benefits after short-term administration with high-dose betahistine, long-term administration with high-dose betahistine for 16 weeks further significantly decreased DHI scores. However, DHI scores of the remaining nine non-responding patients were not changed after short-term administration with high-dose betahistine for four weeks. CONCLUSION: Short-term administration with the standard dose and dosing period of betahistine did not improve DHI scores in the enrolled patients, indicating that they were not compensated for unilateral vestibulopathy with intractable dizziness. The present findings suggest that long-term administration with high-dose betahistine facilitates vestibular compensation to improve intractable dizziness in some, but not all patients with uncompensated unilateral vestibulopathy.