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Background: Little is known about the relationship between the disease activity of Behçet disease (BD) and the incidence of inflammatory major organ events., Objectives: In this prospective registry study, we investigated the association between the Behçet Disease Current Activity Form (BDCAF) and incidence of inflammatory major organ events, defined as the inflammation of the ocular, central nervous, intestinal, and vascular systems in BD., Methods: We enrolled participants from Japanese multicenter prospective cohorts. The BDCAF was evaluated annually. BD-related symptoms, including inflammatory major organ events, were monitored. The association between BDCAF and inflammatory major organ events was analyzed by time-to-event analysis. An unsupervised clustering of the participants' BDCAF, therapeutic agents, and multiple serum cytokines was also performed to examine their association with inflammatory major organ events., Results: A total of 260 patients were included. The patients had a median BDCAF score of 2 [Interquartile range, 1-3] at the enrolment and remained disease active at 1- and 2-year follow-ups, indicating residual disease activity in BD. Patients with a BDCAF score of 0 had a longer inflammatory major organ event-free survival at 52 weeks than those with a score of 1 or higher (p=2.2 x 10 -4 ). Clustering analysis revealed that patients who did not achieve remission despite treatment with tumor necrosis factor inhibitors had high serum inflammatory cytokine levels and incidences of inflammatory major organ events. Among the elevated cytokines, IL-6 was associated with inflammatory major organ events., Conclusion: This study suggests that treatment strategies targeting overall disease activity and monitoring residual serum IL-6 may help prevent inflammatory major organ events in BD., Competing Interests: YK has received support from Amgen speaking fees, support for attending meetings and travel, and advisory board, Novartis speaking fees and advisory board, and Nippon Shinyaku grants. Mitsuhiro Takeno has received consulting and speaking fees from Amgen; research grants and speaking fees from AbbVie, Asahi Kasei, Chugai, Eisai, Tanabe-Mitsubishi, and Taisyo; and speaking fees from Astellas, Asympti, Boehringer-Ingelheim, Eli Lily, Jansen Pharma, Nippon Shinyaku, Novartis, Ono Pharmaceuticals, Takeda, UBC Japan, and Viatris. Tatsuya Atsumi has received grants from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Nippon Boehringer Ingelheim Co., Ltd., TEIJIN PHARMA LIMITED., Eisai Co., Ltd., and Eli Lilly Japan K.K. Tetsuya Atsumi has also received consulting fees from Sanofi K.K, GlaxoSmithKline plc, AbbVie Inc., AstraZeneca plc, Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Janssen Pharmaceutical K.K., Gilead Sciences, Inc., Eli Lilly Japan K.K., and ONO PHARMACEUTICAL CO., LTD. TA has also received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Pfizer Inc., Alexion Inc., Novartis Pharma K.K., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., AbbVie Inc., Nippon Boehringer Ingelheim Co., Ltd., Amgen Inc. UCB Japan Co. Ltd., AstraZeneca plc, and Eisai Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hirahara, Kirino, Soejima, Iizuka, Yoshimi, Fujieda, Atsumi, Tono, Kobayashi, Meguro, Takeuchi, Sakamaki, Takeno, Mizuki and Nakajima.)

Objectives: Approximately 30-60% of Behçet's disease patients exhibit joint symptoms. The aim of this study was to determine the clinical characteristics of such patients in Japan., Methods: This study retrospectively analyzed 151 Behçet's disease patients with joint symptoms who had been treated at seven cooperative medical institutions from 2007 to 2017. We investigated their clinical characteristics and treatments., Results: The most commonly affected joints were the knee, ankle, and proximal interphalangeal joints. Of the cases with pain and swelling, 18 of 293 joints (11 cases) displayed narrowing of the cleft or deformity by X-ray analysis. Improvement in their arthritis was observed in 80% of the patients who received steroids as initial treatment; however, the rate of improvement was lower in patients who had received prednisolone (PSL) at <10 mg/day. The recurrence of joint symptoms was significantly less common in the colchicine group than in the PSL group., Conclusions: These results suggest that PSL is effective for remission induction for the treatment of joint symptoms of Behçet's disease. Additionally, colchicine is effective in preventing the recurrence of joint symptoms in Behçet's disease. Furthermore, joint damages like joint space narrowing or with any deformity can often be observed in Behçet's disease., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: In Japan, the 57S and 67S single syllable lists have been used to test speech perception in cochlear implant (CI) users. However, due to advances in implants and processors, these lists have become too simple for CI users. In 2019, the Japan Otological Society created a new list, referred to as the iCI2004. The objective of this study was to compare the performance of these lists., Methods: The Japanese single syllable speech perception tests, iCI2004, 57S, and 67S, were administered to 70 patients with CI users. The effects of single syllable characteristics on the test scores were examined. The type and number of single syllables used in each list were different. Therefore, we compared the scores for normal lists, shared single syllables, and non-shared single syllables., Results: The average test results were 52% for iCI2004, 64% for 57S, and 77% for 67S; 67S performed the best, followed by 57S and iCI2004. The test results were significantly different. In a comparison of shared single syllables, the average scores were 58% for iCI2004 and 63% for 57S (45 pieces). A comparison of iCI2004 and 67S (17 pieces) showed that the average scores were 63% for iCI2004 and 75% for 67S. A comparison of 57S and 67S (20 pieces) showed that the average score for 57S was 70% and the average scored for 67S was 77%. No significant differences were detected under all conditions. Based on these results, the type of single syllable adopted affected the result., Conclusion: The data gives no clear indication that the selection of the word table or presentation of sound pressure affects listening to sound for CI users in Japan. Based on the type and number of single syllables used, iCI2004 seems appropriate for evaluation of hearing in patients using CI., Competing Interests: Declaration of Competing Interest The authors have no financial conflicts of interest to declare., (Copyright © 2021. Published by Elsevier B.V.)

Objective: This study was aimed to determine the characteristics of middle ear cholesteatoma and to investigate short-term outcomes regarding the rates of residual and recurrent cholesteatoma and the postoperative hearing results in Japan, via a nationwide survey using staging and classification criteria for middle ear cholesteatoma, as proposed by the Japan Otological Society (JOS)., Methods: The first-round survey was conducted in 2016. The target was patients with middle ear cholesteatoma who were surgically treated in Japan between January and December 2015. Medical information on the patients was anonymized. The questionnaire entries were age, sex, cholesteatoma classification and stage, preoperative hearing level, mastoid development, status of the stapes, and surgical method. There were a total of 1,787 registered patients from 74 facilities from all over Japan. The second survey was conducted in January 2018 and received 1,456 responses from 49 facilities in Japan. Of the 1,456 cases, 1,060 were conducted in the postoperative hearing survey and 1,084 in the residual recurrence survey., Results: The most common cholesteatoma type was pars flaccida cholesteatoma (63.3%), followed by pars tensa cholesteatoma (13.0%), congenital cholesteatoma (12.9%), and cholesteatoma secondary to chronic tensa perforation (5.6%). Cholesteatoma of uncertain origin accounted for 5.0% (90 cases). Stage II was predominant in pars flaccida and pars tensa cholesteatoma, which frequently involves the mastoid, whereas about half of cases of cholesteatoma secondary to chronic tensa perforation and congenital cholesteatoma were classified as stage I. One hundred fifty-two of 1,084 cases (14.0%) had recurrent cholesteatoma, residual cholesteatoma, or both following first surgeries. The postoperative rates of hearing success rate was 63.3%., Conclusion: We were able to clarify not only the current epidemiological status of middle ear cholesteatoma but also the current trends of cholesteatoma surgery in Japan. The development of a staging system by the JOS Committee serving an epidemiological database for international or time-dependent comparison. It is possible to use this staging system with reasonable reliability., Competing Interests: Declaration of Competing Interest All authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020. Published by Elsevier B.V.)

Background: Speech perception tests are commonly used as indices reflecting hearing ability in daily life. In Japan, the CI-2004 test, first developed in 2004, is widely used as standard, but it was not validated against a large number of normal hearing controls and hearing loss patients., Aims/objectives: The primary objective of the present study was to develop and validate iPad-based software for the Japanese monosyllable speech perception test, 'iCI2004'., Material and Methods: Seven universities and two medical centers participated in this study. The hearing threshold and Japanese monosyllable speech perception test results of 77 people with normal hearing and 459 people with hearing loss were collected., Results: All participants with normal hearing achieved almost perfect perception results both in quiet and in noise. For cochlear implant users, the average monosyllable speech perception score was 55.1 ± 19.6% in quiet and 40.3 ± 19.2% in noise (SNR + 10dB)., Conclusions and Significance: We developed iPad-based Japanese monosyllable speech perception test software and validated it by testing a large number of controls and hearing loss patients with cochlear implants or hearing aids. The developed monosyllable speech perception test has a sufficiently large dynamic range for assessing improvement in speech perception in Japanese cochlear implant users.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a form of necrotizing vasculitis with few or no immune deposits. It primarily affects small and medium blood vessels. AAV is classified into three categories, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA), and two major ANCAs, proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA are involved in their pathogenesis. Intractable otitis media frequently occurs in patients with GPA, MPA or EGPA, although all patients show similar clinical features, regardless of the type of AAV. Furthermore, approximately 15% patients with otitis media caused by AAV do not show ANCA positivity, histopathological evidence, or any other AAV-related lesions at the initial visit; therefore, these patients do not fulfill the ordinary diagnostic criteria for systemic AAV. Thus, we first proposed that this condition could be categorized as "otitis media with AAV (OMAAV)". Subsequently, the Japanese Otological Society (JOS) conducted a nationwide survey between December 2013 and February 2014 and identified 297 patients with OMAAV. The survey revealed that OMAAV is a disease that initially occurs in the middle ear and subsequently spreads to other organs such as the lungs and kidneys, with eventual involvement of all body organs. Severe sequelae such as facial palsy, hypertrophic pachymeningitis, complete deafness, and subarachnoid hemorrhage resulting in death can also occur. In this review, we introduce the clinical features, diagnostic criteria, and treatment strategies recommended by JOS for early diagnosis and treatment of OMAAV., Competing Interests: Declaration of Competing Interest All authors require neither any financial support nor other benefits from commercial sources for the work, nor any other financial interests that any of the authors may have, which could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The Chronic Otitis Media Questionnaire-12 (COMQ-12) assesses patient-reported health-related quality of life. A multinational collaborative project was performed to translate and appraise the psychometric properties of the COMQ-12 across Europe, Asia, and South America., Methods: Eight otology units from seven countries (China, Colombia, France, Italy, Japan, Korea, Turkey) created native versions of the COMQ-12 by the process of translation and back-translation. Questionnaire reliability was assessed on the basis of internal consistency by calculating Cronbach's coefficient alpha. Exploratory factor analysis was performed to identify underlying correlations between individual questionnaire items., Results: This study included 478 participants from 8 countries. Calculated values for Cronbach's coefficient alpha were between 0.71 and 0.90. Exploratory factor analysis allowed the identification of three dominant factors, the primary factor (related to hearing problems) explaining 42% of the total variance, the secondary factor (related to daily activities) explaining 30% of the variance, and the third factor (related to acute disease activity) explaining 28% of the variance., Conclusions: This is a large study of patients with chronic otitis media, from centers from within many different countries spanning Europe, Asia, and South America. This study supports the use of the COMQ-12 within the individual countries where it was tested.

A 40-year-old man with systemic lupus erythematosus taking consecutive oral corticosteroids developed a high-grade fever and disorder of consciousness following acute rhinitis. Haemophilus influenzae type f (Hif) was found and isolated from the blood and cerebrospinal fluid by culture, leading to a diagnosis of meningitis. The prevalence of H. influenzae type b (Hib) infections has decreased due to routine immunization. As a result, the prevalence of invasive non-Hib, including Hif infection, is increasing as a common H. influenzae infection in children and adults. Physicians should be aware of non-Hib H. influenzae infection, even though the Hib vaccine is widely used in Japan.

Objective: In 2010, we established the Miyazaki Comprehensive Hearing Care Network (MCHCN) for early identification and intervention in children with congenital and late-onset/acquired hearing loss with the cooperation of related administrative bodies in Miyazaki prefecture. The central roles of the MCHCN program are played by the Hearing Care Center (HCC) at the University of Miyazaki Hospital established in 2010 to facilitate audiological diagnoses, hearing aid interventions, and educational efforts, as well as linkage with the Department of Otolaryngology for surgical interventions. Herein, we aimed to present the main outcomes of the MCHCN program organized by the HCC at the University of Miyazaki Hospital., Methods: The MCHCN consists of two different networks, the Newborn Hearing Screening Network (NHSN) and the Pediatric Hearing Care Network (PHCN). All children suspected of having hearing loss by Newborn Hearing Screening (NHS) are referred to the HCC via the NHSN. In addition, children suspected of late-onset/acquired hearing loss by municipality-led health checkups, pediatricians, public health nurses, and childcare workers are referred to the HCC via the PHCN. Children who were born in Miyazaki prefecture between January 2010 and December 2017 and referred to the HCC for detailed hearing examination were included in this study., Results: Within the study period, 89,390 infants were born in Miyazaki prefecture, and 84,737 (94.9%) of them underwent NHS. A total of 698 infants and 182 children with suspected hearing loss were referred to the HCC via the NHSN and PHCN, respectively. Of the 880 referrals, 169 were diagnosed with hearing loss, which included 80 children with bilateral hearing loss and 89 children with unilateral hearing loss. Of the 80 children with bilateral hearing loss, 76 began wearing hearing aids and 15 had cochlear implants in the follow-up period. In children with bilateral conductive hearing loss, 4 children with bilateral middle ear anomalies underwent ossiculoplasty, following which two of these children no longer required hearing aids. Imaging assessments performed on 71 of the 89 children with unilateral hearing loss revealed that 20 of the 30 (66%) children who underwent CT exhibited ossicular anomalies and 28 out of the 48 (58%) children who underwent MRI were found to have ipsilateral cochlear nerve hypoplasia. Among the 169 children with hearing loss, no follow-up loss was observed during the period of this study., Conclusion: The MCHCN that was organized at the initiative of the HCC at the University of Miyazaki Hospital has enabled the provision of comprehensive and continuous support, ranging from diagnosis to intervention, not only for children with suspected hearing loss referred based on their NHS results but also for those who pass the screening. Via this system, children with late-onset/acquired hearing loss can be identified early and can receive medical interventions tailored to the cause of their hearing loss while simultaneously avoiding a loss to follow-up., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Objective: This study was undertaken to determine the characteristics of congenital cholesteatoma (CC) in Japan, via a nationwide survey using staging and classification criteria for middle ear cholesteatoma, as proposed by the Japan Otological Society (JOS)., Methods: A nationwide survey regarding middle ear cholesteatoma treated in 2015 was performed. There were 1787 registrations from 74 facilities, among which, CC accounted for 12.9% (231 cases) of all middle ear cholesteatoma cases. The extent of the disease was classified according to the classification and staging of cholesteatoma proposed by JOS in 2015., Results: The age of the patients ranged from 1 to 55 years (mean, 8.2 years; median, 6 years; 149 ears of males; 82 ears of females). Among these cases, 105 (45.5%) were classified as stage I, 121 (52.4%) as stage II, and 5 (2.1%) as stage III, with no cases in stage IV. In the sub classification of stage I, 35 (33%), 43 (41%) and 27 (26%) ears were classified as stages I-a, I-b and I-c, respectively. Stage I-b (cholesteatoma confined to the posterior half of the tympanic cavity) was more frequent than stage I-a (the anterior half of tympanic cavity). Pre-operative hearing level of air-conduction was 20.5dB for stage I-a, 34.5dB for stage I-b, 30.5dB for stage I-c, 38.6dB for stage II, and 59.0dB for stage III. The rate of missing stapes superstructure increased as the disease progressed. In the same way, the mastoid development lowered as the stage of the disease progressed. There were significant differences in the age at operation, pre-operative hearing level, status of stapes, and major ossiculoplasty, between stage l-a and l-b., Conclusions: The current condition of CC in Japan was been evaluated; in particular, it was observed that the cases limited to the posterior part of tympanic cavity were not rare. The JOS stage classification based on the progression of the disease seemed simple and efficient., (Copyright © 2018. Published by Elsevier B.V.)

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.

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.

Background: Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands., Methods: We examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient's clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon-intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2(-ΔΔCT)) method were used to determine the pathogenicity associated with gene substitutions., Results: SLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A., Conclusions: The substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA.

Objective: To clarify the mortality rates, causes of death, and contributing clinical factors in Japanese patients with systemic sclerosis (SSc)., Methods: A cohort of 405 patients with SSc, who attended our institution during the period 1973 to 2008, was retrospectively analyzed until the end of 2009. Clinical data were obtained from medical records or autopsy reports., Results: The 405 patients with SSc consisted of 310 (76.5%) survivors, 86 (21.2%) who died, and 9 who were lost to followup. Diffuse cutaneous SSc and involvement of organs other than the gastrointestinal tract were more frequent in patients who died, and were associated with a worse prognosis according to Kaplan-Meier analysis. Female sex, limited cutaneous SSc, anticentromere antibody (ACA), and overlap with Sjögren's syndrome (SS) were factors favoring a better prognosis, while overlap with myositis contributed to a poor prognosis. The overall 10-year survival rate was 88%. The patients with SSc had a significantly higher mortality than the general population (standardized mortality ratio 2.76), but the patients with ACA or overlapping SS did not. The most common causes of death were unknown ones including sudden death, followed by malignancy and infection. In patients with pulmonary arterial hypertension, sudden death was the most common cause of mortality., Conclusion: The overall mortality rate of patients with SSc was higher than that of the general population, probably because of poor prognostic factors including organ involvement. These factors should be carefully monitored during followup.

Objective: The objective of this study was to demonstrate the prevalence and severity of external auditory canal exostoses in a population of competitive surfers in Japan. The authors used a “surfing index,” the product of the period (years) as an active surfer and the frequency (number of surfing days per week), to predict external auditory exostoses formation., Study Design: Cross-sectional study., Setting: A total of 5 surfing competitions that were held in Miyazaki, Japan., Materials and Methods: The ear canals of 373 surfers with an average age of 33.1 years (range, 11-80 years) were examined with an otoscope. The severity of exostosis was classified into 4 groups, ranging from grade 0 to 3, according to otoscopic findings. Subjects also completed a questionnaire detailing their surfing habits., Results: There was a 59.8% overall prevalence of exostoses in 373 surfers. The incidences of grade 1, 2, and 3 exostoses were 118 (31.6%), 71 (19.0%), and 34 (9.1%), respectively. The prevalences of grade 2 and 3 exostoses were higher in surfers with a surfing index of more than 20 (P < .0001)., Conclusions: The authors determined that a positive association exists between the surfing index and the severity of exostoses. The findings suggest that it is possible to assume the likelihood of exostosis formation from the surfing index, and this may be of help to spread awareness of exostosis among surfers.

To evaluate whether nystagmus has clinical significance in psychiatric patients who have functional and/or organic brain dysfunction. We performed gaze, positional and positioning nystagmus tests on 227 patients with psychiatric diseases (144 men, 83 women, with an average age +/- SD of 62.5 +/- 14.0 years) in order to evaluate the frequency and characteristics of nystagmus. Patients were classified according to the underlying disease. Normal control subjects were 107 subjects (26 men, 81 women, with an average age +/- SD of 35.6 +/- 10.0 years). Nystagmus was observed in 56 (24.7%) of 227 cases. Nystagmus was seen in 16 (59.3%) of 27 cases of alcoholism, 14 (22.2%) of 63 cases of organic psychiatric disorders, 25 (20.2%) of 124 cases of schizophrenia, 1 (20.0%) of 5 cases of excited mental retardation, 0 (0.0%) of 7 cases of mood disorders, 0 (0.0%) of 1 case of anxiety disorders and 1 (0.9%) of 107 subjects of normal control. There was a significant difference between psychiatric diseases and normal control. These results indicate that nystagmus may also be a very important clinical finding not only in patients with neurological and neuro-otological diseases, but also in patients with psychiatric diseases.

Background: There are many cases of breast cancer with axillary lymph node metastases without lymphatic invasion. We hypothesized that in these cases cancer cells may pass through the retro-mammary space (RS) into lymph nodes and that axillary lymph node metastases may correlate with the tumor invasion of the RS., Methods: A total of 127 patients who had undergone radical operation between April 1997 and April 2001 were studied. Whether or not the tumor had invaded the RS was histologically examined with hematoxylin and eosin staining of sections made at the point where the distance between the tumor and the fascia of the major pectoral muscle was the shortest., Results: Eighty-five cases did not have lymphatic invasion. Twenty-nine of these 85 cases had RS invasion and 56 cases did not. Among the 29 cases with RS invasion, 14 cases had lymph node metastases. In contrast, of 56 cases without RS invasion only 3 cases had lymph node involvement. Of the 85 cases without lymphatic invasion, the relationship between RS invasion and lymph node invasion was statistically significant (RS(+) vs. RS(-), p<0.0001, chi-square test). For all 127 cases, if cases showing either lymphatic invasion or RS invasion were diagnosed with lymph node involvement, the sensitivity, specificity, accuracy, and negative predictive value were 93.5%, 65.4%, 75.6% and 94.6%, respectively., Conclusion: These data suggest that lymph node metastases may occur via the tumor cell migration through lymphatic vessels and the RS.

Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule. The susceptibility of tumors to fluoropyrimidines is reported to correlate with tumor levels of these enzymes. To obtain some insight into the tumor types susceptible to fluoropyrimidine therapy, we measured expression levels of these two enzymes in various types of human cancer tissues (241 tissue samples) by the ELISA methods. DPD exists in all the cancer types studied, such as bladder, breast, cervical, colorectal, esophageal, gastric, hepatic, pancreatic, prostate, and renal cancers. Among them, the cervical, hepatic, pancreatic, esophageal, and breast cancer tissues expressed high levels of DPD (median >70 U/mg protein), while high concentrations of the dThdPase were expressed in esophageal, cervical, breast, and pancreatic cancers and hepatoma (median >150 U/mg protein). The dThdPase/DPD ratio, which was reported to correlate with the susceptibility of human cancer xenografts to capecitabine, was high in esophageal, renal, breast, colorectal, and gastric cancers (median ratio of >1.5). In any of these three parameters, the inter-patient DPD variability for each cancer type was much larger than the DPD variability among cancer types; highest/lowest ratios for dThdPase, DPD, and dThdPase/DPD were 10-321, 7-513, and 2-293, respectively. These results indicate that measurements of the three parameters, DPD, dThdPase and dThdPase/DPD, would be useful criteria for selecting cancer patients suitable for fluoropyrimidine therapy rather than for selecting cancer types.

The frequency of three mitochondrial point mutations, 1555A-->G, 3243A-->G, and 7445A-->G, known to be associated with hearing impairment, was examined using restriction fragment length polymorphism (RFLP) analysis in two Japanese groups: (1) 319 unrelated SNHL outpatients (including 21 with aminoglycoside antibiotic injection history), and (2) 140 cochlear implantation patients (including 22 with aminoglycoside induced hearing loss). Approximately 3% of the outpatients and 10% of the cochlear implantation patients had the 1555A-->G mutation. The frequency was higher in the patients with a history of aminoglycoside injection (outpatient group 33%, cochlear implantation group 59%). One outpatient (0.314%) had the 3243A-->G mutation, but no outpatients had the 7445A-->G mutation and neither were found in the cochlear implantation group. The significance of the 1555A-->G mutation, the most prevalent mitochondrial mutation found in this study of a hearing impaired population in Japan, among subjects with specific backgrounds, such as aminoglycoside induced hearing loss, is evident.