Validation of the Tinnitus Acceptance Questionnaire: Japanese Version.

This study aimed to develop and validate a Japanese version of the Tinnitus Acceptance Questionnaire (TAQ), an instrument that measures the process of intentional acceptance of adverse experiences associated with tinnitus. A total of 125 patients with chronic tinnitus from multiple institutions participated in this study. Participants completed the Japanese versions of the TAQ, Tinnitus Handicap Inventory, Valuing Questionnaire, Acceptance and Action Questionnaire-II, and Hospital Anxiety and Depression Scale. A second TAQ was administered 1-2 weeks later. Because the model fitted poorly in confirmatory factor analysis, exploratory factor analysis was conducted, which yielded a two-factor structure that was divided into forward and reversed item groups. Hypotheses regarding criterion and construct validity were clearly supported. A high Cronbach's α coefficient value was obtained for the TAQ total score (0.88). The interclass correlation coefficient for test-retest reliability was within the acceptable range (0.95). The results of the exploratory factor analysis were considered to be due to artifacts caused by the characteristics of the Japanese language. The present study confirmed the validity and reliability of the Japanese version of the TAQ in measuring tinnitus-specific receptivity.

Relationship between cognition and the severity of chronic tinnitus: Validation of the Japanese version of the Tinnitus Cognitions Questionnaire.

OBJECTIVE: The Tinnitus Cognitions Questionnaire (TCQ) is a scale designed to assess the positive and negative cognitions associated with tinnitus. The purpose of this study was to validate the Japanese version of the TCQ and to analyze the relationship between cognition and the severity of chronic tinnitus. METHODS: This was a cross-sectional, multicenter study. Patients with chronic tinnitus persisting for longer than 3 months were included. Participants completed the TCQ, the Tinnitus Handicap Inventory (THI), and the Hospital Anxiety and Depression Scale (HADS). They also completed the TCQ a second time 3-7 days later. The questionnaire was translated into Japanese. A factor analysis was performed and the convergent and discriminant validity, internal consistency, and test-retest reliability were evaluated. RESULTS: The total sample consisted of 75 participants. We obtained high Cronbach's α coefficients for the total score and subscales, ranging from 0.933 to 0.974. The total score and subscale interclass correlation coefficients for test-retest reliability ranged from 0.631 to 0.963. The factor analysis yielded a two-factor structure: negative and positive subscales. The convergent and discriminative validity was sufficiently clear. The negative subscale of the TCQ was strongly correlated with the THI and the HADS. CONCLUSION: The Japanese version of the TCQ was validated here. It also exhibited a two-factor structure that was well matched with previous data. And it was a highly consistent and reliable measure that can be used to evaluate cognitions in patients with chronic tinnitus. Negative cognition for tinnitus was greatly related to handicap and psychological state.

An improved system for grading and treating tinnitus.

OBJECTIVE: Tinnitus is an auditory sensation that can cause discomfort or even pain. Because patients with tinnitus frequently have psychological problems, self-reporting of the severity of tinnitus is unreliable. We developed a new grading system and practical protocol for the systematic treatment of tinnitus that accounts for its severity, patients' psychological problems, and the frequency of catastrophic episodes. The aim of this study is to employ and validate the new system in patients with tinnitus. METHODS: This study comprised two parts: (i) We identified 113 patients, who were then analyzed in terms of severity of tinnitus, psychological problems, and catastrophic episodes. They were then classified into 5 grades, and the records of their previous treatments were scrutinized. From these records, we designed a practical treatment protocol suitable for each of the 5 grades. (ii) We then identified 82 new patients, and graded and treated them according to the system developed in part (i). Patients were followed-up for at least 6 months; treatment efficacy was evaluated using the pre- and post-treatment scores on the Tinnitus Handicap Inventory (THI) and Hospital Anxiety and Depression Scale (HADS). Psychological status was also assessed with the DSM-IV. RESULTS: (i) The overall patient group was categorized as follows: Grade I, 38 patients, average THI=37.6 points, average HADS=10.9 points, catastrophic episodes=0 points; Grade II, 24 patients, THI=70.6, HADS=13.1, catastrophic episodes=0; Grade III, 5 patients, THI=73.2, HADS=28.4, catastrophic episodes=0; Grade IV, 33 patients, THI=63.5, HADS=18.8, catastrophic episodes=1.0; Grade V, 13 patients, THI=73.2, HADS=22.4, catastrophic episodes=2.2. The treatment records revealed treatment via psychotropic drugs for 40% of Grade III, 45.5% of Grade IV, and 84.6% of Grade V patients; psychiatric consultation was provided for 20% of Grade III, 12.5% of Grade IV, and 53.8% of Grade V patients. (ii) THI scores improved significantly in Grades II, IV, and V after treatment using the new protocol; HADS scores improved significantly in Grades IV and V. Catastrophic episode scores improved significantly in Grades IV and V. CONCLUSION: We found large enough differences in THI and HADS scores to successfully classify patients with tinnitus into 5 distinct grades that accounted for tinnitus severity, psychological problems, and catastrophic episodes. We found significant improvements in tinnitus severity and psychological problems in the higher (more severe) grades when this system was used to guide treatment. This system not only provided a reasonably reliable categorization system, it simplified treatment without sacrificing efficacy.

Broadened population-level frequency tuning in the auditory cortex of tinnitus patients.

Tinnitus is a phantom auditory perception without an external sound source and is one of the most common public health concerns that impair the quality of life of many individuals. However, its neural mechanisms remain unclear. We herein examined population-level frequency tuning in the auditory cortex of unilateral tinnitus patients with similar hearing levels in both ears using magnetoencephalography. We compared auditory-evoked neural activities elicited by a stimulation to the tinnitus and nontinnitus ears. Objective magnetoencephalographic data suggested that population-level frequency tuning corresponding to the tinnitus ear was significantly broader than that corresponding to the nontinnitus ear in the human auditory cortex. The results obtained support the hypothesis that pathological alterations in inhibitory neural networks play an important role in the perception of subjective tinnitus.NEW & NOTEWORTHY Although subjective tinnitus is one of the most common public health concerns that impair the quality of life of many individuals, no standard treatment or objective diagnostic method currently exists. We herein revealed that population-level frequency tuning was significantly broader in the tinnitus ear than in the nontinnitus ear. The results of the present study provide an insight into the development of an objective diagnostic method for subjective tinnitus.

Neuro-rehabilitation Approach for Sudden Sensorineural Hearing Loss.

Sudden sensorineural hearing loss (SSHL) is characterized by acute, idiopathic hearing loss. The estimated incidence rate is 5-30 cases per 100,000 people per year. The causes of SSHL and the mechanisms underlying SSHL currently remain unknown. Based on several hypotheses such as a circulatory disturbance to the cochlea, viral infection, and autoimmune disease, pharmaco-therapeutic approaches have been applied to treat SSHL patients; however, the efficacy of the standard treatment, corticosteroid therapy, is still under debate. Exposure to intense sounds has been shown to cause permanent damage to the auditory system; however, exposure to a moderate level enriched acoustic environment after noise trauma may reduce hearing impairments. Several neuroimaging studies recently suggested that the onset of SSHL induced maladaptive cortical reorganization in the human auditory cortex, and that the degree of cortical reorganization in the acute SSHL phase negatively correlated with the recovery rate from hearing loss. This article reports the development of a novel neuro-rehabilitation approach for SSHL, "constraint-induced sound therapy (CIST)". The aim of the CIST protocol is to prevent or reduce maladaptive cortical reorganization by using an enriched acoustic environment. The canal of the intact ear of SSHL patients is plugged in order to motivate them to actively use the affected ear and thereby prevent progress of maladaptive cortical reorganization. The affected ear is also exposed to music via a headphone for 6 hr per day during hospitalization. The CIST protocol appears to be a safe, easy, inexpensive, and effective treatment for SSHL.

Inhibitory effect of low-dose inorganic iodine on thyroidal radioactive iodine uptake in healthy Japanese adults.

In the event of a nuclear power plant accident, prophylactic administration of potassium iodide (KI) is recommended to prevent thyroid damage due to uptake of radioiodine. To assess the inhibitory effect of low-dose inorganic iodine on thyroidal radioactive iodine uptake (RAIU) in healthy adults without dietary iodine restriction, single or repeated doses of 10 mg inorganic iodine solution were given to 22 Japanese volunteers, 18 men and 4 women with the mean age of 35.7 years, between 2011 and 2013. Changes in urinary iodine excretion, thyroid function and 24-hour RAIU were also evaluated. The median 24-hour RAIU without iodine restriction was 13% (range, 5-26%). A single-dose of 10 mg inorganic iodine suppressed the median 24-hour RAIU measured one hour after iodine administration to 3% (range, 1-7 %) and, in 90.9% of 22 participants their 24-hour RAIU was < 5%. For seven participants given 10 mg of inorganic iodine daily for 14 days, the median 24-hour RAIU measured at 24 hours after the last administration of iodine was 6% (range, 2-12%), although the inhibitory effect was diminished in two participants. Serum thyroid stimulating hormone concentration was slightly elevated in three participants without decreased serum FT3 and FT4 levels. We conclude that a single-dose of 10 mg inorganic iodine is sufficient to inhibit RAIU in adults, although the inhibitory effect of repeated-dose on RAIU is diminished when KI is given once daily. The dose, duration or interval of iodine administration should be evaluated in iodine-sufficient regions in a future.

Radioiodine-Associated Exacerbation of Graves' Orbitopathy in the Japanese Population: Randomized Prospective Study.

CONTEXT: Exacerbation of Graves' orbitopathy (GO) after radioiodine (RAI) therapy has been examined in some populations but has not been fully described in Japanese populations. OBJECTIVE: The purpose of this study was to clarify the characteristics of GO exacerbation after RAI therapy and the effectiveness of low-dose prophylactic corticosteroid (PCS). DESIGN AND SETTING: This was a prospective randomized study in Tokyo, Japan. PATIENTS: Between June 2011 and June 2012, 295 patients with Graves' disease with either inactive GO or no GO received RAI therapy. Of these, 147 received no PCS (PCS-Off group), whereas 148 received low-dose PCS (starting dose, 15 mg/day of prednisolone) for 6 weeks (PCS-On group). We used magnetic resonance imaging to thoroughly evaluate GO before and 1 year after RAI therapy. MAIN OUTCOME MEASURES: Outcomes of GO 1 year after RAI therapy were determined. RESULTS: GO exacerbation occurred in 29 patients (9.8%), and only 7 patients (2.4%) required ophthalmic treatment. No significant difference in the frequency of GO exacerbation was seen between the groups (PCS-On group: n = 18 [12.1%]; PCS-Off group: n = 11 [7.5%]; P = .17). Significant prognostic factors were identified as thyroid-stimulating antibody (by 100% linear increase: risk ratio, 1.15; 95% confidence interval, 1.07-1.24; P = .0003) and clinical activity score (≥1 vs 0: risk ratio, 6.40; 95% confidence interval, 2.17-19.7; P = .0009). CONCLUSION: Exacerbation of GO after RAI therapy in the Japanese population appears less common than in other populations. Low-dose PCS did not produce a significant preventive effect and appeared insufficient. Patients presenting with risk factors would thus be recommended to receive higher-dose PCS.

Rituximab-including combined modality treatment for primary thyroid lymphoma: an effective regimen for elderly patients.

BACKGROUND: Primary thyroid lymphoma (PTL) develops mostly in middle-aged and older females. However, the optimal treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL), which accounts for most PTL cases, is unclear. Rituximab is a promising drug that, in combination with traditional combination therapy, has demonstrated an increased antitumor effect without a substantial increase in toxicity. In this study, treatment outcomes of elderly patients with thyroid DLBCL who underwent rituximab-including combination therapy were analyzed. METHOD: Between January 2005 and December 2011, 43 patients 60 years of age or older (median 71 years, range 60-80 years) were diagnosed as having stage IE (n=12) or stage IIE (n=31) DLBCL, and three courses of R-CHOP therapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, adriamycin 40 mg/m2, vincristine 1.4 mg/m2, and prednisolone 100 mg/body) and involved field irradiation were planned. Treatment outcomes of these patients were retrospectively reviewed. RESULTS: Two patients terminated the treatment because of interstitial pneumonia during R-CHOP therapy. Only one patient showed treatment resistance and the regimen was changed; 42 patients (98%) responded to the treatment. Five-year overall survival and event-free survival were 87% (95% confidence interval [95% CI], 64-96%) and 74% (95% CI, 50-89%), respectively. CONCLUSION: The results of the present study indicate that rituximab-including combination therapy was effective for elderly patients with thyroid DLBCL. A multicenter, long-term observational study is needed to confirm this, and additional refinement of the treatment protocol is required to optimize the antitumor effect.

Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis.

BACKGROUND: Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto thyroiditis (HT), which partially share immunological features. Determining the genetic basis that distinguishes GD and HT is a key to understanding the differences between these 2 related diseases. AIM: The aims of this study were to identify HLA antigens that can explain the immunopathological difference between GD and HT and to elucidate epistatic interactions between protective and susceptible HLA alleles, which can delineate the distinct function of HLA in AITD etiology. DESIGN: We genotyped 991 patients with AITD (547 patients with GD and 444 patients with HT) and 481 control subjects at the HLA-A, HLA-C, HLA-B, DRB1, DQB1, and DPB1 loci. A direct comparison of HLA antigen frequencies between GD and HT was performed. We further analyzed an epistatic interaction between the susceptible and protective HLA alleles in the development of GD and HT. RESULTS: We identified 4 and 2 susceptible HLA molecules primarily associated with GD and HT, respectively, HLA-B*35:01, HLA-B*46:01, HLA-DRB1*14:03, and HLA-DPB1*05:01 for GD and HLA-A*02:07 and HLA-DRB4 for HT. In a direct comparison between GD and HT, we identified GD-specific susceptible class II molecules, HLA-DP5 (HLA-DPB1*05:01; Pc = 1.0 × 10(-9)) and HLA-DR14 (HLA-DRB*14:03; Pc = .0018). In contrast, HLA components on 3 common haplotypes in Japanese showed significant protective effects against the development of GD and HT (HLA-A*24:02-C*12:02-B*52:01-DRB1*15:02-DQB1*06:01-DPB1*09:01 and HLA-A*24:02-C*07:02-B*07:02-DRB1*01:01-DQB1*05:01-DPB1*04:02 haplotypes for GD and HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01 haplotype for GD and HT). Interestingly, the representative protective HLA, HLA-DR13 (HLA-DRB1*13:02), was epistatic to susceptible HLA-DP5 in controlling the development of GD. CONCLUSION: We show that HLA exerts a dual function, susceptibility and resistance, in controlling the development of GD and HT. We also show that the protective HLA allele is partially epistatic to the susceptible HLA allele in GD.

Determination of pediatric reference levels of FT3, FT4 and TSH measured with ECLusys kits.

Reference ranges for serum thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in children were set using the assay kits currently used in clinical settings. A total of 342 children (111 males and 231 females) who were negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonographic examination of the thyroid gland were divided into 6 age groups: 4-6 years (45 children), 7-8 years (40), 9-10 years (53), 11-12 years (65), 13-14 years (83), and 15 years (56) for the study. FT3, FT4 and TSH levels were determined by electrochemiluminescence immunoassay (ECLIA) (ECLusys FT3, FT4 and TSH).The reference range for FT3 (pg/mL) was 2.91-4.70 for the age group of 4-6 years, 3.10-5.10 for the age group of 7-8 years, 3.10-4.87 for the age group of 9-10 years, 2.78-4.90 for the age group of 11-12 years, 2.77-4.59 for the age group of 13-14 years, and 2.50-4.64 for the age group of 15 years . The reference range for FT4 (ng/dL) was 1.12-1.67, 1.07-1.61, 0.96-1.60, 1.02-1.52, 0.96-1.52, 0.95-1.53. The reference range for TSH (µU/mL) was 0.62-4.90, 0.53-5.16, 0.67-4.52, 0.62-3.36, 0.54-2.78, 0.32-3.00. Serum FT3, FT4 and TSH levels in children differ from those in adults. It is, therefore, of importance to perform evaluation of thyroid function in children using reference values appropriate for the chronological ages, because misdiagnosis of hypothyroidism or inappropriate secretion of TSH (SITSH) and oversight of mild subclinical hypothyroidism could occur if the diagnosis is made using reference values for adults.

Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation.

BACKGROUND: Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy. OBJECTIVES: We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women. METHODS: We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations. RESULTS: The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation. CONCLUSIONS: In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly.

Reference limits for serum thyrotropin in a Japanese population.

The aim of the present study was to establish new reference intervals for serum thyrotropin (TSH) levels in Japanese subjects without antithyroid antibodies. We reviewed the serum TSH level of all patients 20 years of age and over who attended the outpatient clinic of our hospital between January 1, 2003, and September 20, 2010. The thyroid gland of every patient was examined by ultrasonography, and subjects found to have a normal thyroid were chosen. The following subjects were excluded: subjects with past history of thyroid diseases; subjects whose serum was positive for antithyroid antibodies; pregnant women; patients taking medication that might affect their free thyroxine (fT(4)) level or TSH levels. Ultimately, 1388 subjects were included in the reference population. The serum TSH levels shifted to higher ranges as the age of the groups increased. The calculated reference range was 0.39-4.29 mIU/L in the 20-29-year-old group, 0.34-3.90 mIU/L in the 30-39-year-old group, 0.56-5.02 mIU/L in the 40-49-year-old group, 0.51-5.30 mIU/L in the 50-59-year-old group, 0.60-4.85 mIU/L in the 60-69-year-old group, 0.62-6.15 mIU/L in the over 70-year-old group. The results of this study showed that the upper limit of the normal range of serum TSH levels increased with age in a Japanese population. Since the number of elderly reference subjects was relatively small, further study is needed. Setting the age- and race-specific reference limits for serum TSH levels is important in order to prevent significant misclassifications of patients with abnormal TSH levels.

Severe thyroid-associated orbitopathy in Hashimoto's thyroiditis. Report of 2 cases.

Thyroid-associated orbitopathy (TAO) is characterized by immune-mediated inflammation of the extraocular muscles surrounding orbital connective tissue and adipose tissue. Severe orbitopathy related to autoimmune thyroid disease often occurs in patients with Grave's disease, but it is rare in patients with Hashimoto's thyroiditis. The pathogenesis of TAO is unclear. Several studies have noted a strong correlation between the levels of antibodies to thyrotropin receptor antibody (TRAb) and TAO in Graves' disease. Mild upper eyelid retraction has been reported to be common in Hashimoto's thyroiditis patients, however severe orbitopathy is rare. We report two cases of severe TAO in patients with Hashimoto's thyroiditis who required systemic glucocorticoid therapy and orbital irradiation to treat the TAO. The activity of the TAO was high in both patients, because their clinical activity scores (CAS) for the orbitopathy were high, and magnetic resonance imaging (MRI) showed enlargement of the extraocular muscles and an increase in T2 signal intensity and prolonged T2 relaxation time which indicate an active stage of inflammation. We tested the presence of TRAb by three different assays and were negative in both patients. Since the eye muscle damage cannot be due to TSH receptor antibodies, other pathogenetic mechanisms may be responsible for the orbitopathy in patients with Hashimoto's thyroiditis.