Search

Conclusions. The present study confirmed the clinical characteristics of patients with SLC26A4 mutations: congenital, fluctuating, and progressive hearing loss usually associated with vertigo and/or goiter during long-term follow-up. This clarification should help to facilitate appropriate genetic counseling and proper medical management for patients with these mutations, but there was no particular genotype-phenotype correlation among them, suggesting that other factors may contribute to such variability. Objectives. Due to the wide range of phenotypes caused by SLC26A4 mutations, there is controversy with regard to genotype-phenotype correlation. The present study was performed: (1) to determine phenotypic range in patients with biallelic SLC26A4 mutations, and (2) to evaluate whether possible genotype-phenotype correlation exists. Subjects and methods. Phenotypes in 39 hearing loss patients with SLC26A4 mutations were summarized and genotype-phenotype correlation was analyzed. Results. Hearing level varied in the individuals from mild to profound severity. Most of the patients had fluctuating and progressive hearing loss that may have been of prelingual onset. Twenty-four (70.6%) patients had episodes of vertigo, and 10 (27.8%) patients had goiter, which had appeared at age 12 or older. In contrast to such phenotypic variabilities, no apparent correlation was found between these phenotypes and their genotypes. [ABSTRACT FROM AUTHOR]

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ -associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ -associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ -associated HL and may be relevant in clinical practice.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients., (© 2021. The Author(s).)

Epstein syndrome is a rare disease characterized by macrothrombocytopenia, nephritis and progressive sensorineural hearing loss (SNHL). This syndrome is presently recognized as an autosomal dominant disease caused by mutations of non-muscle myosin heavy chain 9 (MYH9). Little information is available about the progress of SNHL, the efficacy of cochlear implants (CI) or the perioperative management of thrombocytopenia in patients with Epstein syndrome. We herein report a case of a patient with Epstein syndrome with the MYH9:c.2105G>A:p.R702H variant who underwent cochlear implantation after 27 years of follow-up for her progressive SNHL. The deterioration rates of hearing were 3.48 dB/year on the right ear and 2.46 dB/year on the left ear. The patient derived benefits from CI and had a speech recognition test result (for sentences) of 93% at 6-months postoperatively. Thrombocytopenia was successfully managed without any bleeding complications by using eltrombopag, an oral thrombopoietic agent, making transfusion of platelets unnecessary. The accurate diagnosis of Epstein syndrome was made only after long-term follow-up as the thrombocytopenia was initially diagnosed as idiopathic thrombocytopenic purpura. This case report highlights the perioperative management of thrombocytopenia, the progress of SNHL and the potential pitfalls of diagnosis., Competing Interests: Declaration of Competing Interest All authors declare that there are no conflicts of interest associated with this manuscript., (Copyright © 2020 Japanese Society of Otorhinolaryngology-Head and Neck Surgery, Inc. Published by Elsevier B.V. All rights reserved.)

Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease-associated pruritus (CKD-aP), subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n = 12) and CKD-aP (mild, moderate, or severe pruritus; n = 11). Skin samples were obtained from the forearm or elbow during operations on arteriovenous fistulas. We measured ion channels expressed at the skin, including peripheral nerve endings by RT-PCR: Nav1.8, Kv1.4, Cav2.2, Cav3.2, BK Ca , Anoctamin1, TRPV1, TRPA1, and ASIC. Results: Expression of Cav3.2, BK Ca , and anoctamin1 was significantly elevated in patients with CKD-aP. On the other hand, expression of TRPV1 was significantly reduced in these patients. We observed no significant difference in the levels of Cav2.2 or ASIC between subjects with and without CKD-aP. TRPA1, Nav1.8, and Kv1.4 were not expressed. Conclusions: It was concluded that this greater difference in the expression of ion channels in the skin tissue including, specially cutaneous peripheral nerve endings in CKD patients with CKD-aP may increase generator potential related to itching.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.

Sensorineural hearing loss is a common deficit and mainly occurs due to genetic factors. Recently, copy number variants (CNVs) in the STRC gene have also been recognized as a major cause of genetic hearing loss. We investigated the frequency of STRC deletions in the Japanese population and the characteristics of associated hearing loss. For CNV analysis, we employed a specialized method of Ion AmpliSeq TM sequencing, and confirmed the CNV results via custom array comparative genomic hybridization. We identified 17 probands with STRC homozygous deletions. The prevalence of STRC homozygous deletions was 1.7% in the hearing loss population overall, and 4.3% among mild-to-moderate hearing loss patients. A 2.63% carrier deletion rate was identified in both the hearing loss and the control population with normal hearing. In conclusion, our results show that STRC deletions are the second most common cause of mild-to-moderate hearing loss after the GJB2 gene, which accounts for the majority of genetic hearing loss. The phenotype of hearing loss is congenital and appears to be moderate, and is most likely to be stable without deterioration even after the age of 50. The present study highlights the importance of the STRC gene as a major cause of mild-to-moderate hearing loss.

Objective: To report on the safety and efficacy of an investigational active middle ear implant (AMEI) in Japan, and to compare results to preoperative results with a hearing aid., Design: Prospective study conducted in Japan in which 23 Japanese-speaking adults suffering from conductive or mixed hearing loss received a VIBRANT SOUNDBRIDGE with implantation at the round window. Postoperative thresholds, speech perception results (word recognition scores, speech reception thresholds, signal-to-noise ratio [SNR]), and quality of life questionnaires at 20 weeks were compared with preoperative results with all patients receiving the same, best available hearing aid (HA)., Results: Statistically significant improvements in postoperative AMEI-aided thresholds (1, 2, 4, and 8 kHz) and on the speech reception thresholds and word recognition scores tests, compared with preoperative HA-aided results, were observed. On the SNR, the subjects' mean values showed statistically significant improvement, with -5.7 dB SNR for the AMEI-aided mean and -2.1 dB SNR for the preoperative HA-assisted mean. The APHAB quality of life questionnaire also showed statistically significant improvement with the AMEI., Conclusion: Results with the AMEI applied to the round window exceeded those of the best available hearing aid in speech perception as well as quality of life questionnaires. There were minimal adverse events or changes to patients' residual hearing.

A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.

We report a case of a nine-year-old male who presented with facial nerve stimulation four years after cochlear implantation. Computed tomography was performed revealing a dilated internal auditory meatus and the cochlear implant electrode was found to be protruding into the fallopian canal at the level of the geniculate ganglion. Subsequent genetic analysis demonstrated X-linked deafness type 2 (DFNX2) caused by a novel c.769C > T nucleotide change in the POU domain, class 3, transcription factor 4 gene (POU3F4). Inactivation of electrodes 1 and 19-21 successfully abated facial nerve stimulation., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Objective: To determine the prognostic factors for hearing recovery in patients with sudden sensorineural hearing loss (SSHL) refractory to systemic corticosteroids following salvage treatment., Methods: This is a retrospective observational study at nine tertiary referral hospitals. A total of 120 patients with sudden deafness refractory to systemic corticosteroids were enrolled. The patients were randomly assigned to receive topical application of recombinant human IGF-1 or intratympanic injection of dexamethasone as salvage treatment. Multiple regression analysis was performed to identify determinants of hearing recovery using pure tone audiometry results at 8 weeks after treatment. Clinical predictors that were evaluated included age, sex, pretreatment hearing level, presence of vertiginous symptoms, days to study entry from symptom onset and salvage treatment assignment (IGF-1 vs. dexamethasone)., Results: The linear regression model identified age (P=0.001), pretreatment hearing level (P<0.001), days to study entry from symptom onset (P=0.011) and treatment assignment (P=0.033) at 8 weeks after treatment as significant variables influencing the recovery of pure tone audiometry average thresholds. Younger age (<60 years), early initiation of salvage treatment and treatment with topical IGF-1 therapy had significant effects on hearing recovery., Conclusion: The results indicate that early initiation and choice of treatment modalities for salvage treatment may be important for the prognosis of patients with refractory SSHL. The positive effect of topical IGF-1 therapy on hearing recovery indicates its utility as salvage treatment., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To analyze the difficulty of discriminating Japanese nonsense monosyllables in each of several grades of high-frequency hearing loss and to evaluate the limitations of amplification., Methods: We collected retrospective data on the discrimination of Japanese nonsense monosyllables by patients with three grades of high-frequency hearing loss who fulfilled or nearly fulfilled the Japanese criteria for EAS. Discrimination of the twenty monosyllables included in the 67-S speech audiometric test, which is approved by the Japan Audiological Society, was evaluated under quiet conditions., Results: One hundred and five ears of ninety-one adults with high-frequency hearing loss were tested. We classified the ears according to hearing threshold at 1000 Hz; Group 1: <45 dB; Group 2: ≥45 dB and <70 dB; Group 3: ≥70 dB. Under the best conditions, the best speech discrimination scores were 72.3 ± 18.6% (mean ± SD, N=11), 56.9 ± 19.9% (N=57) and 38.1 ± 22.6% (N=37) in Group 1, Group 2 and Group 3, respectively. For most of the monosyllables, discrimination score declined gradually as high-frequency hearing loss became more severe. The high incidence in the Japanese language of [k], an easy consonant to distinguish, may be an advantage for patients with high-frequency hearing loss who use hearing aids. By employing a new confusion matrix that displays consonants and the following vowels separately, we were able to reveal the interactions of those two components. We observed that discrimination of preceding nasal consonants and that of the following vowels were not independent in patients with high-frequency hearing loss., Conclusion: Our classification based on threshold at 1000 Hz was useful to predict the effectiveness and limitations of amplification in high-frequency hearing loss. Threshold at 1000 Hz can be an index enabling us to refine the indications of EAS for native Japanese speakers to maximize its effectiveness against high-frequency hearing loss., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Usher syndrome type 1 (USH1) is the most severe of the three USH subtypes due to its profound hearing loss, absent vestibular response and retinitis pigmentosa appearing at a prepubescent age. Six causative genes have been identified for USH1, making early diagnosis and therapy possible through DNA testing. Targeted exon sequencing of selected genes using massively parallel DNA sequencing (MPS) technology enables clinicians to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using MPS along with direct sequence analysis, we screened 227 unrelated non-syndromic deaf children and detected recessive mutations in USH1 causative genes in five patients (2.2%): three patients harbored MYO7A mutations and one each carried CDH23 or PCDH15 mutations. As indicated by an earlier genotype-phenotype correlation study of the CDH23 and PCDH15 genes, we considered the latter two patients to have USH1. Based on clinical findings, it was also highly likely that one patient with MYO7A mutations possessed USH1 due to a late onset age of walking. This first report describing the frequency (1.3-2.2%) of USH1 among non-syndromic deaf children highlights the importance of comprehensive genetic testing for early disease diagnosis.

Middle ear implants (MEIs) such as the Vibrant Soundbridge (VSB) are attractive and alternative treatments for patients with conductive, sensorineural, and mixed hearing loss who do not benefit from, or who choose not to wear, conventional hearing aids (HAs). Recent studies suggest that MEIs can provide better improvements in functional gain, speech perception, and quality of life than HAs, although there are certain risks associated with the surgery which should be taken into consideration, including facial nerve or chorda tympanic nerve damage, dysfunctions of the middle and inner ears, and future device failure/explantation. In Japan, a multi-center clinical trial of VSB was conducted between 2011-2014. A round window vibroplasty via the transmastoid approach was adopted in the protocol. The bony lip overhanging the round window membrane (RWM) was extensively but very carefully drilled to introduce the Floating Mass Transducer (FMT). Perichondrium sheets were used to stabilize the FMT onto the RWM. According to the audiological criteria, the upper limit of bone conduction should be 45 dB, 50 dB, and 65 dB from 500 Hz to 4, 000 Hz. Twenty-five patients underwent the surgery so far at 13 different medical centers. The age at the surgery was between 26-79 years old, and there were 15 males and 10 females. The cause of conductive or mixed hearing loss was middle ear diseases in 23 cases and congenital aural atresia in two cases. The data concerning on the effectiveness and safety of VSB was collected before the surgery and 20 weeks after the surgery. Significant improvements of free-field Pure Tone Audiogram (PTA) from 250 Hz to 8, 000 Hz were confirmed (p < 0.001). Hearing gain up to 40 dB was achieved in the 1, 000 Hz to 4, 000 Hz range. No deterioration in either air conduction or bone conduction at PTA was noted at 20 weeks after the surgery. Monosyllable speech perception in both quiet and noisy conditions improved significantly (p < 0.001). The speech discrimination score in both quiet and noisy conditions improved significantly too (p < 0.001). In the future, it is likely that there will be an increasing population even in Japan that will meet the criteria for MEIs such as VSB. However, the long-term efficacy and safety of these devices should be established.

The Vibrant Soundbridge (VSB) is an active middle ear implant with the Floating Mass Transducer (FMT). We performed a multicenter study to study the efficacy of the VSB by means of "the 10 Questionnaire on Hearing 2002" and "the APHAB questionnaire" at 13 hospitals between 2011 and 2013. In all, 23 patients with mixed or conductive hearing loss received VSB implantation by the round window placement technique. These individuals were generally unable to use, or gained little from conventional hearing aids or bone conduction hearing aids. Two questionnaires were administrated before the surgery and 20 weeks after the VSB implantation. Scores on every item of "the 10 Questionnaire on Hearing 2002" showed significant improvement under noise after VSB implantation. On the APHAB, the scores for Ease of Communication, Reverberation, and Background subscales improved significantly after the VSB implantation, while the score for the Aversiveness subscale alone failed to show a positive improvement from the inexperience to the new sound. Analysis of the responses to these subjective questionnaires revealed better results after VSB implantation as compared to the preoperative data. In conclusion, RW vibroplasty with the use of VSB provided subjective benefit in patients with conductive and mixed hearing loss.

Objectives: To elucidate the involvement of MYO6 mutations, known to be responsible for DFNA22/DFNB37, in Japanese hearing loss patients through the use of genetic analysis., Methods: Genomic variations responsible for hearing loss were identified by massively parallel DNA sequencing (MPS) of 63 target candidate genes in 1120 Japanese hearing loss patients, and the detailed clinical features for the patients with MYO6 mutations were collected and analyzed., Results: Four mutations were successfully found in 7 families exhibiting autosomal dominant inheritance. All of the patients showed progressive hearing loss, but hearing type and onset age varied. Further, none of the affected patients showed any associated symptoms, such as hypertrophic cardiomyopathy or retinitis pigmentosa., Conclusions: MPS is powerful tool for the identification of rare causative deafness gene mutations, such as MYO6. The clinical characteristics noted in the present study not only confirmed the findings of previous reports but provided important new clinical information., (© The Author(s) 2015.)

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.

Conclusions: Our results indicated that electric acoustic stimulation (EAS) is beneficial for Japanese-speaking patients, including those with less residual hearing at lower frequencies. Comparable outcomes for the patients with less residual hearing indicated that current audiological criteria for EAS could be expanded. Successful hearing preservation results, together with the progressive nature of loss of residual hearing in these patients, mean that minimally invasive full insertion of medium/long electrodes in cochlear implantation (CI) surgery is a desirable solution. The minimally invasive concepts that have been obtained through EAS surgery are, in fact, crucial for all CI patients., Objectives: This study was conducted to evaluate hearing preservation results and speech discrimination outcomes of hearing preservation surgeries using medium/long electrodes., Methods: A total of 32 consecutive minimally invasive hearing preservation CIs (using a round window approach with deep insertion of a flexible electrode) were performed in 30 Japanese patients (two were bilateral cases), including patients with less residual hearing. Hearing preservation rates as well as speech discrimination/perception scores were investigated on a multicenter basis., Results: Postoperative evaluation after full insertion of the flexible electrodes (24 mm, 31.5 mm) showed that residual hearing was well preserved in all 32 ears. In all patients, speech discrimination and perception scores were improved postoperatively.

Objective: To clarify the responsible gene for a family associated with hearing loss but having no well-known mitochondrial mutations., Subjects: A Japanese family showing late-onset, progressive, and ski-sloping sensorineural hearing loss., Results: Whole mitochondrial genome sequencing identified the 1673T>C mutation, a novel mitochondrial DNA mutation in the 16S ribosomal RNA gene., Conclusion: Whole mitochondrial genome sequencing is a powerful tool to identify the responsible gene for plausible mitochondrially inherited families. This is additional evidence that mitochondrial gene mutations may cause late-onset, progressive, and ski-sloping sensorineural hearing loss.

Usher syndrome is an autosomal recessive disorder manifesting hearing loss, retinitis pigmentosa and vestibular dysfunction, and having three clinical subtypes. Usher syndrome type 1 is the most severe subtype due to its profound hearing loss, lack of vestibular responses, and retinitis pigmentosa that appears in prepuberty. Six of the corresponding genes have been identified, making early diagnosis through DNA testing possible, with many immediate and several long-term advantages for patients and their families. However, the conventional genetic techniques, such as direct sequence analysis, are both time-consuming and expensive. Targeted exon sequencing of selected genes using the massively parallel DNA sequencing technology will potentially enable us to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using this technique combined with direct sequence analysis, we screened 17 unrelated Usher syndrome type 1 patients and detected probable pathogenic variants in the 16 of them (94.1%) who carried at least one mutation. Seven patients had the MYO7A mutation (41.2%), which is the most common type in Japanese. Most of the mutations were detected by only the massively parallel DNA sequencing. We report here four patients, who had probable pathogenic mutations in two different Usher syndrome type 1 genes, and one case of MYO7A/PCDH15 digenic inheritance. This is the first report of Usher syndrome mutation analysis using massively parallel DNA sequencing and the frequency of Usher syndrome type 1 genes in Japanese. Mutation screening using this technique has the power to quickly identify mutations of many causative genes while maintaining cost-benefit performance. In addition, the simultaneous mutation analysis of large numbers of genes is useful for detecting mutations in different genes that are possibly disease modifiers or of digenic inheritance.

Background: Auditory neuropathy spectrum disorder (ANSD) is a unique form of hearing loss that involves absence or severe abnormality of auditory brainstem response (ABR), but also the presence of otoacoustic emissions (OAEs). However, with age, the OAEs disappear, making it difficult to distinguish this condition from other nonsyndromic hearing loss. Therefore, the frequency of ANSD may be underestimated. The aim of this study was to determine what portion of nonsyndromic hearing loss is caused by mutations of OTOF, the major responsible gene for nonsyndromic ANSD., Methods: We screened 160 unrelated Japanese with severe to profound recessive nonsyndromic hearing loss (ARNSHL) without GJB2 or SLC26A4 mutations, and 192 controls with normal hearing., Results: We identified five pathogenic OTOF mutations (p.D398E, p.Y474X, p.N727S, p.R1856Q and p.R1939Q) and six novel, possibly pathogenic variants (p.D450E, p.W717X, p.S1368X, p.R1583H, p.V1778I, and p.E1803A)., Conclusions: The present study showed that OTOF mutations accounted for 3.2-7.3% of severe to profound ARNSHL patients in Japan. OTOF mutations are thus a frequent cause in the Japanese deafness population and mutation screening should be considered regardless of the presence/absence of OAEs.

The present study of KCNQ4 mutations was carried out to 1) determine the prevalence by unbiased population-based genetic screening, 2) clarify the mutation spectrum and genotype/phenotype correlations, and 3) summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL) families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287). While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC) showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.

This prospective study aimed to determine speech understanding in neurofibromatosis type II (NF2) patients following implantation of a MED-EL COMBI 40+ auditory brainstem implant (ABI). Patients (n = 32) were enrolled postsurgically. Nonauditory side effects were evaluated at fitting and audiological performance was determined using the Sound Effects Recognition Test (SERT), Monosyllable-Trochee-Polysyllable (MTP) test and open-set sentence tests. Subjective benefits were determined by questionnaire. ABI activation was documented in 27 patients, 2 patients were too ill for testing and 3 patients were without any auditory perception. SERT and MTP outcomes under auditory-only conditions improved significantly between first fitting and 12-month follow-up. Open-set sentence recognition improved from 5% at first fitting to 37% after 12 months. The number of active electrodes had no significant effect on performance. All questionnaire respondents were 'satisfied' to 'very satisfied' with their ABI. An ABI is an effective treatment option in NF2 patients with the potential to provide open-set speech recognition and subjective benefits. To our knowledge, the data presented herein is exceptional in terms of the open-set speech perception achieved in NF2 patients., (© 2013 S. Karger AG, Basel.)

Usher syndrome is an autosomal-recessive disorder that causes bilateral sensorineural hearing loss, retinitis pigmentosa (RP), and occasionally vestibular dysfunction. Usher syndrome types 1, 2, and 3 can be distinguished by differences in audiovestibular features. The objectives of this retrospective study were to evaluate 26 patients with Usher syndrome clinically. The 26 patients (male: 12 cases, female: 14 cases) with Usher syndrome, with a clinical diagnosis based on symptoms of bilateral sensorineural hearing loss and RP, had been registered from 13 hospitals as a multicenter study. We assessed the clinical history and performed audiovestibular and ophthalmologic examinations, and genetic testing. Eleven of the patients were classified as having Usher type 1 (38.5%), 6 with Usher type 2 (23.1%), and 9 with Usher type 3 (38.5%). However, many patients with atypical Usher type 1 (70%) and type 2 (83.3%) were found compared with Usher type 3 (10%). The conductive rate of vestibular examinations including the caloric test (50%) was low. There were many variations in the clinical symptoms in Usher syndrome patients, therefore the classification of Usher types 1, 2, and 3 has been complicated. We have proposed a flowchart for the diagnosis of Usher types 1, 2, and 3.

The effectiveness of bone anchored hearing aid (BAHA) for the patients with congenital aural atresia was evaluated by multicenter clinical study in Japan. Twenty patients (17 bilateral and 3 hemilateral) of congenital auricular atresia were registered for this study and finally, 18 of them (15 bilateral and 3 unilateral) were subjected to further evaluation. Primary endpoint of this study was free sound-field pure-tone audiometory and speech threshold hearing test in quiet and noisy circumstances. Secondary endpoint of this study was patient's satisfaction based upon APHAB (Abbreviated Profile of Hearing Aid Benefit) questionnaire survey. These results were compared between before and 12 weeks after BAHA surgery. Both hearing level of pure tone and speech threshold significantly improved after BAHA surgery. APHAB scores also suggested the improvement of the QOL after BAHA usage, except for the scores that concerned with unpleasantness of noisy sound. BAHA is one of the useful options for the treatment of congenital auricular atresia.

Purpose: Even in the cases of localized prostate cancer, there are a substantial number of patients who undergo endocrine therapy, and their prognosis is affected by the treatment. We evaluated the histological effect of endocrine therapy and analyzed its correlation with prognosis., Methods and Subjects: Seventy-seven cases with localized prostate cancer who underwent maximal androgen blockade (MAB) therapy 1 year or longer were pathologically evaluated using repeat biopsy specimens from November 1994 to October 2001. The relationship between clinical parameters and histological effect in repeat biopsy specimens was examined. Biopsy was conducted mainly by the 6-site systematic method, and the histological effect was judged in accordance with the General Rules for Clinical and Pathological Study of Prostate Cancer (3rd edition). The median re-biopsy and follow-up periods were 13 months and 41 months, respectively., Results: Using this criteria for the histological effects of anti-cancer treatment, the histological effect of endocrine therapy was most frequently observed in class G3b with 61.0%, and correlations with PSA nadir and initial biopsy positive number before endocrine therapy were observed. After biopsy, radical prostatectomy was performed on 9 patients (endocrine therapy was concurrently performed on 4), endocrine therapy on 67 (intermittent administration on 21), and radiation therapy on 1 (MAB was concurrently performed). Outcomes included PSA failure in 14, of whom 2 died of cancer. Three-year and 5-year PSA-failure free survival rates were 91.1% and 76.3%, respectively. Pathological disease stage in radical prostatectomy specimens was examined by dividing it into class G0-2 and class G0-3. This revealed a significant correlation between histological effect and pathological disease stage (pT2-3). PSA-failure free survival was analyzed in 67 of the 77 patients who underwent endocrine therapy. A significantly large number of PSA-failures occurred in class G0-2. Multivariate analysis revealed that the histological effect alone was the influencing factor in PSA-failure., Conclusion: A strong histological effect by MAB 1 year or longer after treatment was observed on localized prostate cancer. Evaluation of the histological effect by the present method was considered to be a useful predictor for organ-confined disease after radical prostatectomy and endocrine therapy for PSA-failure.

Prostatic phyllodes tumor is an unusual lesion for which there are only occasional reports in the literature. We encountered a phyllodes tumor of the prostate in a 36-year-old man who had complained of urinary frequency and dysuria for one month. In October 1998, he visited our hospital and had a transurethral resection of the prostate (TUR-P) for obstructive symptoms. He experienced recurrent same symptoms in September 1999 and underwent another TUR-P. The pathologic examination at this time revealed phyllodes tumor. In the tumor, despite its regular alternating growth of ducts and stroma, the stromal element appeared histologically malignant, showing marked atypia and rhabdomyosarcoma-like components. Consequently, in December 1999, the patient underwent radical prostatectomy with lymph node dissection. The resection margins and pelvic lymph nodes were free of tumor. The patient remains alive and well after 14 months.

Auditory brainstem implant (ABI) is a central prosthesis that directly stimulates the cochlear nucleus in the brainstem for those who have interrupted auditory nerves and cannot benefit from the cochlear implantation. Speech perception in a recipient of the Nuclues 8 channel ABI, the first in Japan, is reported. A 25-year-old man with bilateral acoustic nerve tumors postlingually deafened due to tumor resection received auditory sensations with 5 channels. The correct answer using a coding strategy, SPEAK, was 35% for 5 vowels and 36% for 5 monosyllables. The use of ABI also improved his lip-reading ability on monosyllables and open-set words. This indicated that he benefited from ABI, although it was limited. Even after 1 year and 3 months of follow-up, he had no serious side effects such an infection or implant rejection.

A 25-year-old male with neurofibromatosis type 2 had hearing restored with an auditory brainstem implant (ABI) after removal of an acoustic schwannoma. The ABI allows the patient to discern many different environment sounds and is a significant adjunct to lip-reading, enabling conversation with people who have clear pronunciation without the necessity for writing.

We ranked prognostic factors to retrospectively evaluate the clinical significance of interferon alpha (IFN-alpha) therapy in patients with Robson stage IVB renal cell carcinoma. A total of 44 Robson stage IVB renal cancer patients were divided into 2 groups, one with more than 6 months administration of IFN-alpha (3-7 times a week: group A) and another without any IFN-alpha administration. The distribution of these 2 groups was not randomized. In addition to IFN-alpha therapy, survival was analyzed with respect to performance status (PS), mass reductive nephrectomy, concomitant use of other cytotoxic therapies, the number of metastatic organs, growth type, site of metastasis and the period of diagnosis, using a multivariate method with Cox proportional hazards regression. The multivariate analysis showed administration of IFN-alpha to be the most significant factor influencing a good prognosis. Improved survival was also significantly correlated with slow growing type and good PS. Among group A, a significant favorable prognosis was obtained in patients with the responses of no change (NC), partial response (PR) and complete remission (CR) 6 months after initiating administration of IFN-alpha, as well as with good PS and a slow growing type carcinoma. We conclude that IFN-alpha therapy might improve the prognosis of patients with Robson stage IVB renal cell carcinoma, especially, in cases when a greater than NC response is obtained after 6 months administration of IFN-alpha.

A 57-year-old woman presented with tinnitus and complete hearing loss in her right ear and a mild right-sided facial palsy. She was found to have an atypical acoustic neuroma involving the internal auditory canal, labyrinth, and middle ear, extending into both the cerebellopontine angle and the external auditory canal. The tumour was completely removed as a two-stage surgical procedure. The underlying mechanism for the atypical extension is discussed.

Between April 1994 and March 1995, transurethral balloon laser thermotherapy (TUBAL-T) using Prostalase was performed on 53 patients with benign prostatic hyperplasia. Clinical efficacy was evaluated at 3 months after TUBAL-T. The mean international prostate symptom score (I-PSS) decreased from 21.5 at baseline to 11.3 after 3 months (p < 0.0001). Irritative (the sum of items 1, 2, 4 and 7 of I-PSS) decreased by 55%, while obstructive symptoms (the sum of items 3, 5 and 6 of I-PSS) by 45%. However, other objective parameters such as maximum flow rate, voided volume, percent postvoid residual volume and prostate volume showed no significant change (7.8 to 7.2 ml/s, 130 to 147 ml, 33 to 28% and 39.7 to 41.0 ml, respectively). In conclusion, significant improvement after TUBAL-T was observed for subjective symptoms, especially irritative symptoms, but not for objective parameters.

Sound lateralization is considered useful in diagnosing retrocochlear lesions. Interaural time difference (ITD) discrimination has been considered more important than interaural intensity difference (IID) discrimination in diagnosing retrocochlear lesions. The purpose of this study was to determine whether testing sound lateralization by IID and ITD discrimination is useful in patients with acoustic neurinomas (AN). Twenty patients (15 to 74 years old) with unilateral AN were studied by testing IID and ITD discrimination using a self-recording device by delivering 500 Hz band noise through head-phones. Auditory brainstem response (ABR) testing and magnetic resonance imaging (MRI) were also performed in all patients. IID discrimination abnormalities were found in 25% of all patients, and ITD discrimination abnormalities in 85%. Five patients (25%) showed both IID and ITD discrimination abnormalities. One of the three patients with both normal IID and ITD discrimination showed waves I and V, and two of them showed waves I, III and V. One of the five patients with both IID and ITD discrimination abnormalities showed no response, two of them showed only wave I, the other two showed waves I, III and V. Two patients with latency prolongation between waves III and V had both IID and ITD discrimination abnormalities, and seven patients with latency prolongation between waves I and III had normal ITD discrimination or slightly abnormal ITD discrimination and normal IID discrimination. Three of the four patients with large tumors (> 3 cm) had both IID and ITD discrimination abnormalities, while two patients with small ear tumors (< 1 cm) had both normal IID discrimination and normal ITD discrimination. Normal ITD discrimination or slightly abnormal ITD discrimination was found in the majority of patients with wave III. Impairment of ITD discrimination was well correlated with wave III abnormalities. Patients with latency prolongation between waves III and V showed a high degree of ITD discrimination abnormality. Impairment of IID discrimination was related to a high degree of cochlear nerve damage or brainstem damage. We emphasize that IID discrimination is important in the neurological diagnosis of AN, in addition to ITD discrimination. Sound lateralization testing was a useful screening test for diagnosing AN, because tumor size influenced lateralization in every patient, and ITD discrimination was closely correlated with the ABR findings.

A 21-year-old man with hearing loss and recurrent otorrhagia was shown angiographically to have an aneurysm arising from the intrapetrous internal carotid artery (ICA). Endovascular balloon occlusion of the aneurysm with preservation of the parent ICA was attempted twice, but each time the balloon deflated and the aneurysm reappeared two weeks and three months, respectively, following the endovascular procedures. The patient was then successfully treated with a surgical trapping procedure combined with superficial temporal artery-middle cerebral artery bypass.

Recent progress in magnetic resonance imaging (MRI) has made it possible to obtain detailed images of the inner ear by delineating the lymphatic fluid within the labyrinth. We analyzed CT scans and MR images in 70 ears manifesting profound deafness owing to inner ear lesions and compared their detective ability for inner ear lesions. The following results were obtained. 1) CT scan examination showed slight to extensive ossification of the labyrinth in six ears (9%), whereas MRI examination revealed low to absent signal intensity of the inner ear in nine ears (13%). Therefore, it was concluded that MRI is more sensitive in detecting abnormalities of the inner ear than CT scan. 2) MRI provided useful information as to whether the cochlear turn is filled with lymphatic fluid or obstructed. This point was one of the greatest advantages of MRI over CT scan. 3) Abnormal findings in either or both the CT scan and the MRI were detected in suppurative labyrinthitis occurring secondary to chronic otitis media, bacterial meningitis and in inner ear trauma. However, such abnormal findings were not detected in patients with idiopathic progressive sensorineural hearing loss, ototoxicity or sudden deafness. These findings should be taken into consideration in pre-operative assessment of cochlear implant candidates.

Intravesical instillation of pirarubicin (THP) was performed on 66 patients with superficial bladder cancer after transurethral resection to evaluate the prophylactic effect against tumor recurrence. Intravesical chemotherapy was carried out at the concentration of 20mg/40ml. THP was initially instilled three times for one week, following instillation of every two weeks for ten times, and then every one month for seven times. Bladder irritability was demonstrated 21 of 66 cases (31.8%). Although there was a case of contracted bladder, generalized side effect was no case. Eligible cases for evaluation of efficacy were 43 out of 66 patients. The non-recurrence rate (by Kaplan-Meier's method) at one and two years were 90.4% and 77.8%, respectively. Intravesical THP instillation seems to be effective for the purpose of prophylaxis against the recurrence of superficial bladder tumor.

A study was carried out to determine which factors contributed to the vowel and consonant recognition ability of recipients of the 22-channel cochlear implant system. On the basis of the statistical analysis, no isolated factor showed a strong correlation with vowel recognition score. On the other hand, negative correlations were found between patients' consonant recognition scores and postoperative psychophysical percepts such as threshold levels and maximum comfortable loudness levels. However, multiple regression analysis also showed that the combination of lower threshold levels, a larger number of usable electrodes, and wider dynamic ranges contributed to higher consonant recognition scores.

A new alpha 1-adrenergic receptor antagonist, KT-611 (naftopidil) antagonized dose dependently the contraction induced by agonists, noradrenaline and phenylephrine in the human prostatic tissue. KT-611 at a dosage of once or twice a day was evaluated for its effects on 49 patients with benign prostatic hypertrophy. The drug improved subjective and objective symptoms significantly. The residual urine was reduced in volume and percentage significantly. The average and maximum flow rates increased significantly. The optimal dosage was presumed to be in the range of 25 to 75 mg once a day or 25 to 100 mg twice a day. Adverse reactions and abnormal laboratory findings were all slight. KT-611 was concluded to be useful in the treatment of patients with benign prostatic hypertrophy.

Immediate recall of serial 6 digits was examined in order to clarify whether the electrical information heard via a 22-channel cochlear implant can give rise to normal acoustic memory or not. Serial 6 digits were generated randomly using the digits 1 through 6. Following results were obtained in 2 patients with the implant prosthesis. 1) There was a normal primary effect, i.e., good performance of recall at the first or two digits, and also a normal recency effect, i.e., an increased probability of recall at the last one or two digits. 2) There was a normal suffix effect or attenuation of the recency effect when the digits were followed by an another irrelevant speech suffix, the "8". 3) The suffix effect, however, was not observed when the digits were followed by a non-speech noise suffix. Thus, in noise suffix mode, probability of recall was increased at the last one or two digits as similarly with in no suffix mode. The primary effect, the recency effect and the suffix effect are already regarded as the characteristic items of acoustic memory produced in subjects with normal hearing ability. Therefore, it was suggested that a speech perception with a 22-channel cochlear implant prosthesis can produce an normal acoustic memory, and that there is a similarity of neurophysiological functions between natural audition and electrical audition. Moreover, it was demonstrated that the patients with the cochlear implant can distinguish between speech and noise.