Search

Objective: The "Summary of Japanese clinical practice guidelines for Bell's palsy (idiopathic facial palsy) - 2023 update edited by the Japan Society of Facial Nerve Research" aims to review the latest evidence regarding the treatment of Bell's palsy and to provide appropriate recommendations., Method: Regarding the treatment of Bell's palsy, a guideline panel identified key clinical questions using an analytic PICO framework. The panel produced recommendations following the standards for trustworthy guidelines and the GRADE approach. The panel considered the balance of benefits, harm, and preferences when making recommendations., Results: The panel identified nine key clinical questions: systemic (high/standard dose) corticosteroids, intratympanic corticosteroids, systemic antivirals, decompression surgery, acupuncture, physical therapy, botulinum toxin, and reanimation surgery., Conclusion: These guidelines strongly recommend systemic standard-dose corticosteroids for the clinical management of Bell's palsy. Other treatments are weakly recommended due to insufficient evidence. The absolute risk reduction of each treatment differed according to the disease severity. Therefore, physicians and patients should decide on treatment based on the disease severity., Competing Interests: Declaration of competing interest No financial conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare malignant neoplasm of the nasal vault and anterior skull base. The results of treatment for ONB are relatively good; however, regional and distant metastases can develop several years after definitive treatment. This study aimed to validate the treatment modality of ONB for oncological outcomes, especially for regional recurrence., Methods: We retrospectively reviewed the medical records of 22 patients diagnosed with ONB at Kyoto University Hospital between 2009 and 2020. Descriptive statistics were calculated, and Kaplan-Meier curves were used., Results: The median follow-up time was 58.2 months. One (4.5%) patient was clinically node positive, (cN+) and the remaining 21 (95.5%) were clinically node negative (cN0) at presentation. Eighteen patients underwent an endoscopic endonasal approach (EEA) for primary resection, and the remaining four patients underwent a combined EEA and transcranial approach. Elective neck dissection was not performed for 21 patients with cN0 ONB, whereas unilateral neck dissection with removal of ipsilateral lateral retropharyngeal node was performed for one patient with cN+ ONB. Postoperative radiotherapy without concurrent chemotherapy was performed only at the primary tumor bed for 21 patients with cN0 ONB, and at the primary tumor bed and bilateral neck for one patient with cN+ ONB. The 5-year overall, disease-specific, and disease-free survival rates were 94.1%, 100%, and 69.6%, respectively. No patients developed local recurrence, but 6 (27.2%) patients experienced recurrence with a median time to recurrence of 36.4 months, including four and two patients who initially developed regional recurrences and bone metastases, respectively. Five (22.7%) patients had delayed neck recurrence. The salvage rate was only 60.0% in the five patients who had delayed neck recurrence. Regarding the level of delayed neck recurrence, 4 (18.2%) patients had lateral retropharyngeal lymph node metastases., Conclusion: Patients with ONB have excellent survival outcomes after endoscopic surgical resection of the primary lesion with postoperative radiotherapy only to the primary tumor bed. Despite excellent survival, delayed neck recurrence, including the lateral retropharyngeal lymph node, remains high. Because salvage surgery for lateral retropharyngeal lymph node recurrence is sometimes technically difficult, it may be better to extend the field of postoperative radiotherapy from the primary tumor bed only to include bilateral lateral retropharyngeal lymph node regions in patients with clinically N0 ONB. Further prospective studies with a large number of patients are needed to determine the extent of postoperative radiotherapy., Competing Interests: Declaration of Competing Interest The authors have no funding, financial relationships, or conflicts of interest to disclose., (Copyright © 2022 Japanese Society of Otorhinolaryngology-Head and Neck Surgery, Inc. Published by Elsevier B.V. All rights reserved.)

Over the past couple of decades, endoscopic skull base surgery (ESBS) has significantly evolved and is applied to a broad range of skull base pathologies, including sinonasal malignancies. Recent studies have demonstrated remarkable progress of ESBS in complete resection with low morbidity and extension of its application to larger and more complex lesions. In this review, we focus on the evolution of functional preservation and multiportal approaches. Progress in preoperative assessments and surgical techniques improved the preservation of olfactory function after ESBS. The technical feasibility of olfaction preservation even after resection of olfactory groove lesions has been reported. To overcome the limitations of extending use of the endoscopic endonasal approach in surgical fields, various types of multiportal approaches, including combinations of the endoscopic endonasal and transorbital, transmaxillary, or transoral approach, have been reported, as they are useful for complete resection of extensive pathologies while limiting morbidity. These innovative techniques are still in the process of maturation. Hence, an ongoing critical evaluation is essential to ensure efficacy., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest related to this research., (Copyright © 2022. Published by Elsevier B.V.)

Objective: In recent decades, posterior nasal neurectomy (PNN) with submucosal inferior turbinectomy (ST) has been increasingly used for the treatment of intractable severe rhinitis; however, to the best of our knowledge, there have been few studies regarding its long-term therapeutic effects or its influence on patient quality of life (QOL). Therefore, this study examined the long-term therapeutic effects in patients who underwent PNN with ST, as well as their QOL and medication use after surgery., Methods: This retrospective cohort study initially included 16 consecutive patients who underwent PNN with ST from January 2010 to December 2011. Ten of the 16 patients participated in a paper-based survey questionnaire between June 2018 and November 2018; the responses of these 10 patients were used for analysis in this study. To clarify the effects of surgical treatment on symptoms, QOL, and medication status, data recorded before and 3 months after surgery were compared with data recorded at 8 years after surgery using the Japan Rhinoconjunctivitis Quality of Life Questionnaire No. 1 and Classification of the Severity of Allergic Rhinitis Symptoms I and II., Results: Nasal symptoms including runny nose and nasal congestion, medication score, respective total symptoms medication scores (i.e., combined average total symptoms score and medication score), and the scores of troubles with daily life and total QOL were significantly improved at 3 months and 8 years after surgery, compared with before surgery; scores were not significantly worsened at 8 years after surgery, compared with 3 months after surgery. In addition, there were no adverse events requiring treatment after surgery., Conclusion: Our findings suggest that PNN with ST is effective and safe for long-term treatment of severe chronic rhinitis symptoms, as well as reduction of medication use and improvement of QOL., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Rapid epithelialization is crucial to maintain tracheal patency and prevent potential graft failure in tracheal reconstruction after tracheal resection for cancer with tracheal infiltration or tracheal stenosis. Insulin-like growth factor 1 is a liver-secreted endocrine molecule that controls cell proliferation, differentiation, and apoptosis and has been reported to promote epithelialization in several organs. Here, we utilized mouse tracheal organ cultures to examine the effect of insulin-like growth factor 1 on tracheal epithelialization., Methods: The trachea was resected from thirteen-week-old female ICR mice, and cut into small plate-shaped tracheal sections. First, the expression of insulin-like growth factor 1 receptor was assessed by immunohistochemistry. Secondly, the tracheal sections were cultured for seven days in the culture medium, and the morphological change during the seven-day culture was assessed by immunohistochemistry, hematoxylin and eosin staining, and scanning electron microscopy. Moreover, the tracheal sections were cultured for 48 h with different concentration of insulin-like growth factor 1 (0, 0.1, 1 and 10 µg/mL) in the culture medium, and the extension length of the tracheal epithelium during culture was measured in order to assess the effect of topical IGF1 on tracheal epithelialization., Results: Immunohistochemistry showed that insulin-like growth factor 1 receptor was expressed in tracheal epithelium. Immunohistochemistry, hematoxylin and eosin staining, and scanning electron microscopy showed that the tracheal organ cultures were stable for at least seven days without apparent morphological damage. The effect of insulin-like growth factor 1 on tracheal epithelialization was examined in plate-shaped tracheal sections cultured in medium supplemented with or without insulin-like growth factor 1 for 48 h. We also found that the epithelial edge of plate-shaped tracheal sections extended further along the surface of the tracheal section in culture medium containing insulin-like growth factor 1 compared with that in culture medium without insulin-like growth factor 1., Conclusion: The current study using an in vitro mouse tracheal organ culture model demonstrated that topical insulin-like growth factor 1 treatment promoted the extension of tracheal epithelium, suggesting the potential utility of insulin-like growth factor 1 in aiding rapid tracheal epithelialization in patients requiring tracheal reconstruction using tissue-engineered tracheas., (Copyright © 2020. Published by Elsevier B.V.)

Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

ELOVL fatty acid elongase 6 (ELOVL6) is a long-chain fatty acid elongase, and the hepatic expression of the Elovl6 gene and accumulation of triglycerides (TG) are enhanced by long-term high-fructose intake. Fatty acid synthesis genes, including Elovl6, are regulated by lipogenic transcription factors, sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP). In addition, carbohydrate signals induce the expression of fatty acid synthase not only via these transcription factors but also via histone acetylation. Since a major lipotrope, myo-inositol (MI), can repress short-term high-fructose-induced fatty liver and the expression of fatty acid synthesis genes, we hypothesized that MI might influence SREBP-1c, ChREBP, and histone acetylation of Elovl6 in fatty liver induced by even short-term high-fructose intake. This study aimed to investigate whether dietary supplementation with MI affects Elovl6 expression, SREBP-1 and ChREBP binding, and acetylation of histones H3 and H4 at the Elovl6 promoter in short-term high-fructose diet-induced fatty liver in rats. Rats were fed a control diet, high-fructose diet, or high-fructose diet supplemented with 0.5% MI for 10 days. This study showed that MI supplementation reduced short-term high-fructose diet-induced hepatic expression of the Elovl6 gene, ChREBP binding, but not SREBP-1 binding, and acetylation of histones H3 and H4 at the Elovl6 promoter., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Classic glucocorticoids have been prescribed for various inflammatory diseases, such as rheumatoid arthritis, due to their outstanding anti-inflammatory effects. However, glucocorticoids cause numerous unwanted side effects, including osteoporosis and diabetes. Hence, selective glucocorticoid receptor modulators (SGRMs), which retain anti-inflammatory effects with minimized side effects, are among the most anticipated drugs in the clinical field. The assumption is that there are two major mechanisms of action via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, anti-inflammatory effects of glucocorticoids are largely due to TR, while the side effects associated with glucocorticoids are mostly mediated through TA. We previously reported that JTP-117968, a novel SGRM, maintained partial TR activity while remarkably reducing the TA activity. In this study, we investigated the anti-inflammatory effect of JTP-117968 on a lipopolysaccharide (LPS) challenge model and collagen-induced arthritis (CIA) model in mice. Meanwhile, we tested the effect of JTP-117968 on the bone mineral density (BMD) in mouse femur to evaluate the side effect. Based on the evaluation, JTP-117968 reduced the plasma levels of tumor necrosis factor α induced by LPS challenge in mice significantly. Remarkably, CIA development was suppressed by JTP-117968 comparably with prednisolone and PF-802, an active form of fosdagrocorat that has been developed clinically as an orally available SGRM. Strikingly, the side effect of JTP-117968 on mouse femoral BMD was much lower than those of PF-802 and prednisolone. Therefore, JTP-117968 has attractive potential as a new therapeutic option against inflammatory diseases with minimized side effects compared to classic glucocorticoids., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: We used real-ear insertion gain (REIG), with the international speech test signal (ISTS), to evaluate the amplifying characteristics of hearing aids, set for patients who have been wearing such aids for a long time in a stable manner. We further compared this to the target values of the DSLv5 and NAL-NL2 methods., Methods: The subjects were adults with moderate sensorineural hearing loss. We examined 40 ears in 25 individuals (15 people wearing hearing aids in both ears and ten people wearing aid in only one ear). Fit assessments were performed based on the speech performance-intensity functions and tolerance of environmental noise, and the ears studied were categorized as either ears with sufficient benefit or ears with insufficient benefit. Additionally, we evaluated the REIG for international speech test signals at 65-dB and 80-dB sound pressure level (SPL). We compared the REIG and target values for voice input at 65-dB and 80-dB SPL, calculated from the DSLv5 and NAL-NL2 methods., Results: Among the 40 ears, 34 received sufficient benefit and six received an insufficient benefit from hearing aids. The REIG for ISTS at 65-dB in the sufficient benefit ears, at frequencies of 1,000 Hz and 2,000 Hz, were similar to the target values of NAL-NL2 and DSLv5 but were significantly lower at 250 Hz, 500 Hz, and 4,000 Hz frequencies. The compression ratio of REIG for sufficient benefit ears was similar to that of DSLv5. The REIG for ISTS at 65-dB in the insufficient benefit ears was smaller than that in the sufficient benefit ears at frequencies of 2,000 Hz and 4,000 Hz., Conclusion: This study suggested that the target values of NAL-NL2 and DSLv5 are appropriate, even for Japanese-speaking individuals, at mid-pitch sounds. Although it is necessary to investigate the necessity for low-pitch and high-pitch gains further in the future, this study provides meaningful data regarding the amplifying characteristics in Japanese-speaking individuals who have been wearing hearing aids in a stable manner., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Objective: The immune checkpoint inhibitor Nivolumab was approved for the treatment of platinum-refractory head and neck squamous cell carcinoma (SCC), expanding the treatment options for recurrent or advanced head and neck SCC. However, since temporal bone squamous cell carcinoma (TB-SCC) is very rare cancer, the effectiveness of Nivolumab remains unclear. We investigated the effects of Nivolumab for TB-SCC., Method: Chart information was collected for all patients who underwent the first administration of Nivolumab for recurrent or residual TB-SCC in our hospital between September 2017 and December 2019. Tumor staging followed the modified Pittsburgh classification. Changes in the tumor burden and survival outcome were examined., Results: We examined 9 patients with recurrent or residual TB-SCC who started administration of Nivolumab. In these cases, recurrent or residual SCC was observed after chemotherapy and/or chemoradiotherapy including platinum. The duration of Nivolumab was 2-54 weeks (median 20.0 weeks). The evaluation of the therapeutic effect according to the RECIST method showed partial response in 1 case, stable disease in 2 cases, progressive disease in 4 cases, and size unevaluated in 2 case. Although the number of cases was small, comparing with 5 cases without Nivolumab, these cases showed longer overall survival (1-year OS 33.3% vs 20.0%)., Conclusion: We used Nivolumab as palliative chemotherapy in 9 patients with recurrent/residual TB-SCC, and we were able to obtain a certain therapeutic effect on TB-SCC as well as other head and neck SCC., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objective: This study aimed to investigate the incidence of postoperative pneumonia (PP) and surgical site infection (SSI) in head and neck cancer (HNC) patients and clarify the relationship between oral care and postoperative infection., Methods: We conducted a retrospective observation survey based on the medical records of 209 HNC surgery patients managed at a University Hospital in 2016-2018. The incidence of PP and SSI were assessed in patients who underwent operations of the nose and paranasal sinuses to the larynx. Factors associated with PP and SSI in a univariate analysis were included in a multiple logistic regression analysis. A Cox proportional hazards model was used analyze the incidence of PP according to time after surgery. The present study was approved by the ethical review board of our Institute., Results: The rates of PP and SSI in our study population were 20.5% and 23.0%. Operative time (P < 0.01), blood loss (P = 0.004), tracheostomy (P < 0.01), reconstruction (P < 0.01), and preoperative plaque control record (PCR) (P < 0.01) were significantly associated with PP. The PCR depicted the oral hygiene based on the percentage of plaque attached to the tooth neck. A multiple logistic regression analysis indicated that the incidence of PP was significantly higher in patients with PCR values of ≥50% after preoperative oral care (OR=10.174, 95% CI 2.14-48.32, P = 0.004). Tracheostomy (P < 0.01), reconstruction (P = 0.044), a lower preoperative albumin level (P = 0.019), and a lower preoperative hemoglobin level (P < 0.01) were significantly associated with SSI., Conclusions: The incidence of PP among patients who received oral care was high in those patients with high PCR values, indicating the importance of increasing compliance to preoperative oral care., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in association with the present study., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate long-term olfactory outcomes in patients who underwent pituitary surgery through the endoscopic endonasal transsphenoidal approach (EETSA) by T&T olfactometer., Methods: We retrospectively reviewed 26 patients who underwent pituitary surgery via EETSA. Olfactory function was assessed by T&T olfactometer before and 6 months after surgery. The mean of recognition thresholds for five different odorants was used. The change in the mean recognition threshold values was evaluated in the entire cohort and the subgroup analysis was performed according to the age, sex, past history of pituitary surgery (primary surgery or revision surgery), histopathology (non-functioning adenoma (NFA) or functioning adenoma (FA)), reconstruction procedure (rescue flap or nasoseptal flap), and superior turbinate management (preserved or resected)., Results: Of the 26 patients (12 men and 14 women, median age 53 years), 21 patients were newly diagnosed with pituitary gland tumor (16 NFAs, 5 FAs) and the remaining 5 were diagnosed with recurrent pituitary gland tumor (4 NFAs and 1 FA). In the whole cohort, the mean recognition threshold values of T&T olfactometer significantly improved after surgery (P=0.01). Thirteen out of 26 patients (50%) showed olfactory improvement, whereas only 3 (12%) showed deterioration. In the subgroup analysis, olfactory function outcomes were not significantly different between the subgroups with respect to the age, sex, past history of pituitary surgery, histopathology, reconstruction procedure, or superior turbinate management. The olfactory function tended to worsen in the revision surgery group compared to that in the primary surgery group, but not significantly (P=0.06)., Conclusions: The olfactory function was improved or maintained after pituitary surgery via EETSA in 88% of patients, indicating the benefits of low invasiveness of our surgical treatment. On the other hand, three patients (12%) demonstrated deterioration of olfactory function, suggesting that the risk of postoperative olfactory dysfunction should be informed to patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Although nivolumab treatment is effective in extending the overall survival (OS) in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), only a few patients benefit from this treatment. Recent studies have reported that chemotherapy and cetuximab might be effective for R/M HNSCC after nivolumab treatment. In the present study, we aimed to elucidate the effectiveness of chemotherapy after nivolumab treatment in patients with R/M HNSCC., Methods: This retrospective study included 10 patients with R/M HNSCC who were mainly treated with paclitaxel plus cetuximab (7/10, 70%) or S-1 (3/10, 30%) following nivolumab treatment. Chemotherapy was administered as a second-line or higher palliative treatment. The performance status of all patients ranged from 0 to 2. The progression-free survival (PFS) was analyzed using the Kaplan-Meier method., Results: The response rate (RR), clinical benefit rate, and median PFS were 60%, 90%, and 5.4 months, respectively. Regarding adverse effects, Grade 3 neutropenia and hypomagnesemia due to salvage chemotherapy administered after immunotherapy were observed in one patient. The treatment significantly increased the RR compared to that achieved with other palliative chemotherapies reported so far., Conclusion: A higher RR and clinical benefit rate were observed for our strategy than for any first-line regimen, suggesting that our strategy might improve the PFS. Palliative chemotherapy with/without cetuximab after nivolumab treatment might be useful in patients with R/M HNSCC. Although the results of this retrospective study are limited, this strategy can be a good treatment option for patients with R/M HNSCC because of its strong clinical benefits and acceptable toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The present cross-sectional study investigated the relationship between serum 25-hydroxyvitamin D 3 (25[OH]D 3 ) levels and the presence of poor sleep quality in a community-based Japanese adult population., Methods: Poor sleep quality, defined as poor subjective sleep quality and/or use of sleep medications, was assessed using a self-administered questionnaire. The prevalence of poor sleep quality was compared among 512 Japanese participants aged 35-79 years, based on serum 25(OH)D 3 levels, which were determined using tandem mass spectrometry. A logistic regression model was used to calculate the odds ratios (ORs) for the presence of poor sleep quality in each group with the highest quartile of 25(OH)D 3 serving as the reference group., Results: Poor sleep quality was reported by 33.2% of the total study population. The prevalence of poor sleep quality was higher in the first quartile group (25[OH]D 3 : 2.08-18.13 ng/mL) than in the second, third and fourth quartile groups (18.14-23.07 ng/mL, 23.08-28.32 ng/mL, and 28.33-78.83 ng/mL, respectively). The ORs for poor sleep quality were 1.86 (95% confidence interval, 1.08-3.20) for the first quartile group, 0.73 (0.41-1.29) for the second quartile group, and 0.73 (0.42-1.27) for the third quartile group after adjusting for age, sex, and sociodemographic, lifestyle, physical and environmental factors, while the ORs were 1.68 (0.96-2.95), 0.69 (0.39-1.24), and 0.65 (0.37-1.15) after further adjustment for overall health status and depression status., Conclusions: The first quartile group of serum 25(OH)D 3 was associated with the presence of poor sleep quality., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Optical coherence tomography (OCT) is an imaging tool that exploits the coherence of infrared light and is clinically utilized in the field of ophthalmology and dermatology. This study aimed to examine the feasibility of using OCT for diagnosing degeneration and regeneration of the olfactory epithelium in mice., Methods: The olfactory and respiratory epithelia in excised nasal septa of adult mice were observed using OCT. Subsequently, histological assessments were performed with hematoxylin and eosin (H-E) staining. The thicknesses of the olfactory or respiratory epithelia were measured in both OCT images and H-E-stained paraffin sections. The ability of OCT to distinguish olfactory epithelia from respiratory epithelia in normal mice was compared with that of H-E staining. The feasibility of using OCT assessments for detecting changes in the thickness of olfactory epithelia was tested in a mouse model of the degeneration and regeneration of olfactory epithelia., Results: OCT allowed visualization of the gross morphology of the olfactory and respiratory epithelium in normal mice, although it was limited in terms of visualizing cellular components. OCT-based measurements of epithelial thickness helped to distinguish olfactory epithelia from respiratory epithelia. Similar to H-E staining, OCT also clarified changes in the olfactory epithelium thickness after methimazole application., Conclusions: These findings indicate the utility of OCT for assessment of olfactory epithelial thickness and its potential for clinical evaluation of human olfactory epithelia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dietary supplementation with the major lipotrope myo-inositol (MI) potently reduces triglyceride (TG) content and expression levels of the fatty acid synthesis genes, for example, fatty acid synthase (FASN), in rat nonalcoholic fatty liver induced by high-fructose diet. Fatty acid synthesis genes are regulated by the carbohydrate-responsive element-binding protein (ChREBP) that exists in 2 isoforms: ChREBP-α and ChREBP-β. The gene encoding the latter isoform is more responsive to fructose. Because MI repressed the induction of fatty acid synthesis gene expression by high-fructose diet, we hypothesized that MI may reduce binding of ChREBP to the carbohydrate response elements (ChoREs) in the ChREBP-β gene as well as in fatty acid synthesis genes in the liver. Rats were fed high-glucose, high-fructose, or high-fructose diets supplemented with MI (0.05% and 0.25%) for 2 weeks. Hepatic TG content and expression levels of the glucose-6-phosphate dehydrogenase, malic enzyme 1, FASN, acetyl-CoA carboxylase alpha, S14, and ChREBP-β were remarkably elevated in rats fed with high fructose compared with the corresponding levels in high-glucose group. Notably, elevated values of these parameters in high-fructose group were reduced by MI. Similarly, high-fructose-induced ChREBP binding to the ChoREs of the ChREBP-β and FASN genes was nominally decreased by MI. This study showed that treatment with MI reduced elevated TG content and expression of genes related to fatty acid synthesis, such as FASN and ChREBP-β, in rat nonalcoholic fatty liver induced by high-fructose diet. Furthermore, MI treatment nominally decreased increased binding of ChREBP to the ChoREs of ChREBP-β and FASN genes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The usefulness of pretreatment measurement of SCC antigen in patients with head and neck SCC is still controversial. Our aim of this study was to evaluate the clinical usefulness of serum SCC antigen, SCCA1 and SCCA2 in the management of patients with head and neck SCC., Methods: Serum samples for the analysis of SCCA1, SCCA2 and SCC antigen were taken from head and neck SCC patients before treatment. Serum SCC antigen was assayed with a solid phase immunoradiometric assay. The SCCA1 and SCCA2 protein level was determined by a sandwich ELISA., Results: Fifty-two of 96 cases (54%) showed evaluated serum SCC antigen levels above the upper limit. The serum SCCA2 level was significantly higher in the head and neck SCC patients than in control group, whereas there were no significant differences in the serum SCCA1 level between head and neck SCC patients and control group. 72% of head and neck SCC patients demonstrated SCCA2 levels higher than 0.15, whereas 68% of the control subjects had SCCA2 levels less than 0.15., Conclusion: The serum SCCA2 levels were increased during the progression of cancer and might be a useful tool for the management of head and neck SCC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD) is an important co-factor involved in numerous physiological processes, including metabolism, post-translational protein modification, and DNA repair. In living organisms, a careful balance between NAD production and degradation serves to regulate NAD levels. Recently, a number of studies have demonstrated that NAD levels decrease with age, and the deterioration of NAD metabolism promotes several aging-associated diseases, including metabolic and neurodegenerative diseases and various cancers. Conversely, the upregulation of NAD metabolism, including dietary supplementation with NAD precursors, has been shown to prevent the decline of NAD and exhibits beneficial effects against aging and aging-associated diseases. In addition, many studies have demonstrated that genetic and/or nutritional activation of NAD metabolism can extend the lifespan of diverse organisms. Collectively, it is clear that NAD metabolism plays important roles in aging and longevity. In this review, we summarize the basic functions of the enzymes involved in NAD synthesis and degradation, as well as the outcomes of their dysregulation in various aging processes. In addition, a particular focus is given on the role of NAD metabolism in the longevity of various organisms, with a discussion of the remaining obstacles in this research field., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Voice-aligned compression (VAC) is a method used in Oticon's hearing aids to provide more comfortable hearing without sacrificing speech discrimination. The complex, non-linear compression curve for the VAC strategy is designed based on the frequency profile of certain spoken Western languages. We hypothesized that hearing aids could be further customized for Japanese-speaking users by modifying the compression curve using the frequency profile of spoken Japanese., Methods: A double-blind randomized controlled crossover study was performed to determine whether or not Oticon's modified amplification strategy (VAC-J) provides subjectively preferable hearing aids for Japanese-speaking hearing aid users compared to the same company's original amplification strategy (VAC). The participants were randomized to two groups. The VAC-first group received a pair of hearing aids programmed using the VAC strategy and wore them for three weeks, and then received a pair of hearing aids programmed using VAC-J strategy and wore them for three weeks. The VAC-J-first group underwent the same study, but they received hearing aids in the reverse sequence. A Speech, Spatial and Qualities (SSQ) questionnaire was administered before beginning to use the hearing aids, at the end of using the first pair of hearing aids, and at the end of using the second pair of hearing aids., Results: Twenty-five participants that met the inclusion/exclusion criteria from January 1 to October 31, 2016, were randomized to two groups. Twenty-two participants completed the study. There were no statistically significant differences in the increment of SSQ scores between the participants when using the VAC- or the VAC-J-programmed hearing aids. However, participants preferred the VAC-J strategy to the VAC strategy at the end of the study, and this difference was statistically significant., Conclusion: Japanese-speaking hearing aid users preferred using hearing aids that were fitted with the VAC-J strategy. Our results show that the VAC strategy can be adjusted to the frequency profile of different languages and that participants expressed their subjective preference more clearly than was reflected in the SSQ scores. A similar language-specific strategy may improve user's satisfaction while using hearing devices, and this concept may be extended to implantable hearing devices., Clinical Research Registration Number: R000023191., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Primary squamous cell carcinoma (SCC) of the thyroid is a rare disease. It usually presents with locally advanced disease and has an overall poor prognosis. In this study, we investigated the characteristics and outcomes of patients with SCC of the thyroid, and reported our experience with chemotherapy with lenvatinib in the treatment of SCC of the thyroid., Methods: The management outcome of 10 patients who had SCC of the thyroid between January 2000 and 2015 at Kyushu University Hospital or associated facilities was reviewed., Results: There were 3 males and 7 females, ranging in age from 53 to 77 years. Extent of disease was staged as follows: stage IVA, 3 cases; stage IVB, 3 cases; stage IVC, 4 cases. Only tracheostomy was applied for 2 cases, surgical resection, such as total thyroidectomy and neck dissection, for the other 8 cases. Radiotherapy following surgical treatment was applied for 9 cases. Four patients started on oral lenvatinib due to recurrent or progressive SCC of the thyroid. The one year actuarial survival rate of patients was 22.7%. There was no 2-year survivor of all patients., Conclusions: Treatment should primarily be targeted at surgical resection with negative margins in patients with resectable disease. Lenvatinib may show promise to potentially extend survival., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The aim of the present study was to illustrate the safety and utility of the endoscopic endonasal approach (EEA) for the treatment of esthesioneuroblastomas (ENB)., Methods: We retrospectively reviewed patients with a diagnosis of ENB between March 2008 and February 2016 at 10 tertiary referral hospitals in Japan, and assessed demographic data, stage of disease, surgical approach, outcomes and postoperative complications., Results: A total of 22 patients (10 males and 12 females; mean age at presentation, 49.0 years) underwent endoscopic endonasal resection of newly diagnosed ENBs. Dulguerov staging at presentation was T1, 6 patients; T2, 9 patients; T3, 5 patients; and T4, 2 patients. As surgical procedures, unilateral resection via EEA was performed in 12 patients aiming preservation of the contralateral olfactory system, and bilateral resection via EEA was done in 10 patients. Post-operative radiotherapy was done in 20 patients. Pathological margin studies revealed margin-free resections in 21 patients (95.5%). The mean period of follow-up was 44 months. Local recurrence was observed in one T2 patient 12 months after bilateral resection. All patients were alive at the last follow-up, and 21 patients showed no evidence of disease. No post-operative complications including bleeding, CSF leak and meningitis were identified. Preservation of olfactory function was achieved in 11 patients (91.7%)., Conclusion: The results of the present study indicate the safety and utility of multilayer resection using EEA for treatment of ENBs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: This study aimed to verify cutoff values for G width (the width of bimodal peaks for the waveform obtained when measuring conductance at 2000Hz) in Japanese individuals diagnosed with Ménière's disease (MD) using multifrequency tympanometry (MFT) and to determine the relationship between the G width and ability to hear low-pitched sounds using measurements over time., Methods: The study included 51 patients with clinically diagnosed MD, who had not undergone endolymphatic sac surgery, but had no other known ear disease (57 ears in patients aged 22-80 years were affected, and 45 ears in patients aged 18-83 years were unaffected; mean age: 53.3±16.9 years). We also enlisted 80 healthy controls with no prior history of ear disease (160 ears, aged 22-76 years, mean age: 40.8±15.7 years). MFT was used to measure the bimodal peak width of the waveform obtained when measuring conductance at resonance frequency of 2000Hz. For patients who had G width measured several times over multiple outpatient visits, we used initial test data to analyze cutoff values. In nine cases with four or more measurements over time, we evaluated a possible correlation between G width and the sum of the hearing threshold for three low-pitched frequencies (125Hz, 250Hz, and 500Hz). We used Student's t-test to determine significance., Results: The both ears in the MD patients had a G width wider than the distribution in the control group. There was a significant difference between G width in the control group and in affected ears with MD (p=0.00026) and there was also a significant difference between G width in the control group and in unaffected ears of MD patients (p=0.0056). The cutoff value set with a specificity of 95% was 200daPa, with a sensitivity of 35.1% and specificity of 95.6%. The cutoff value set with a sensitivity of 50% was 140daPa, with sensitivity of 50.9% and specificity of 78.8%. There was no significant difference between resonance frequency of ears in the control group and ears with MD (p=0.41). In nine cases with four or more measurements over time, a case showed a statistically significant positive correlation between the G width and hearing ability threshold for low-pitched sounds (125Hz, 250Hz, and 500Hz) (p=0.03), while an another case showed a tendency toward a positive correlation, which was not statistically significant (p=0.08). Further, there were cases that did not show significant differences in the present study, but might have shown a negative correlation if the number of measurements had been increased., Conclusion: Measurement of G width using MFT may have accuracy as the traditional endolymphatic hydrops test. MFT is non-invasive, causes little discomfort for patients, requires little time to perform, and can be performed by paramedics. MFT was shown to be useful in screening for MD and it is effective in diagnosing MD to measure the change over time of G width using MFT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Olfactory neuroblastoma (ONB) is a relatively rare nasal or paranasal malignant tumor. This tumor is rarely accompanied by paraneoplastic syndromes such as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Here, we report a 31-year-old female with histologically confirmed ONB who had been diagnosed with SIADH three years prior. She was treated with surgery followed by concurrent chemoradiotherapy. SIADH resolved immediately after surgical tumor resection. Immunohistochemically, both biopsy and resected specimens from the nasal cavity had been negative for ADH. Although extremely rare, ONB may be associated with SIADH, and the possibility of this cancer should be taken into account during the follow-up of idiopathic SIADH., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Phosphatidylcholines (PCs), a major class of human plasma phospholipids, are composed of highly diverse fatty acids. Because the dietary carbohydrate-fat ratio alters the hepatic fatty acid metabolism, plasma fatty acids that bind PCs, which are secreted as lipoproteins from the liver, may be affected by long-term consumption of a high-carbohydrate diet or a high-fat diet. Therefore, in this study, we profiled the plasma PC species comprehensively in formulated dieting conditions to identify those phospholipid molecules that reflect the dietary carbohydrate-fat ratio. C57BL6J mice were fed diets containing different amounts of fat for 8 weeks, and plasma PC species were analyzed under fasting conditions using liquid chromatography-mass spectrometry. In addition, a cross-sectional study of 78 middle-aged Japanese men, who participated in health checkups, was conducted. Nutrient intakes were estimated by a brief self-administered diet-history questionnaire. The plasma PC profiles changed depending on the dietary carbohydrate-fat ratio. Especially, PC (16:0/16:1) and PC (16:0/18:1) levels increased as the dietary carbohydrate-fat ratio increased in human and mouse, suggesting that these PC species reflected the increase in de novo lipogenesis and might become useful biomarkers of the dietary carbohydrate-fat ratio. Since these PCs act as ligands for peroxisome proliferator-activated receptor α, PC species reflecting the dietary carbohydrate-fat ratio may influence metabolism of glucose and lipids., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Combined small cell carcinoma (SCC) and squamous cell carcinoma (SqCC) of the oropharynx is extremely rare and shows an aggressive clinical course. There are only 5 reported cases of combined SCC and SqCC in the English language literature. Here, we report a 59-year-old male presenting with a right tonsillar mass. The mass was biopsied, and the histological findings showed a proliferation of small-sized tumor cells with scant cytoplasm. Immunohistochemically, the tumor cells were positive for neuroendocrine markers (synaptophysin, chromogranin A, and CD56). Our first diagnosis was tonsillar small cell carcinoma. We treated the patient with concurrent chemoradiotherapy together with cisplatin followed by surgery. The resected tonsillar specimen showed a residual tumor composed of SCC and SqCC, and lymph nodes showed metastatic tumor cells of the SCC component. Immunohistochemically, the SCC component was positive for all neuroendocrine markers and p16; on the other hand, the SqCC component was positive for p40, p63, p16, and EGFR. Fluorescence in situ hybridization revealed that neither component showed any EGFR gene copy number gain. The patient was treated with adjuvant chemotherapy consisting of irinotecan and cisplatin. Liver and bone metastases developed, resulting in the death of the patient. We discuss the present case and review similar cases. Most cases of combined SCC and SqCC occur regardless of p16 status, and a therapeutic strategy has yet to be determined. Further examination of this kind of combined tumor is necessary., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Classic glucocorticoids that have outstanding anti-inflammatory effects are still widely prescribed for the treatment of various inflammatory and autoimmune diseases. Conversely, glucocorticoids cause numerous unwanted side effects, particularly systemically dosed glucocorticoids. Therefore, selective glucocorticoid receptor modulator (SGRM), which maintains beneficial anti-inflammatory effects while reducing the occurrence of side effects, is one of the most anticipated drugs. However, there have been no SGRMs marketed to date. The assumption is that there are two major mechanisms of action of glucocorticoids via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, the anti-inflammatory effects of glucocorticoids are mostly mediated through TR, while the side effects associated with glucocorticoids are largely caused by TA. We started to evaluate novel orally available SGRMs that maintain anti-inflammatory effects while minimizing adverse effects by favoring TR over TA. Based on this evaluation, we discovered JTP-117968, (4b'S,7'R,8a'S)-4b'-benzyl-7'-hydroxy-N-(2-methylpyridin-3-yl)-7'-(trifluoromethyl)-4b',6',7',8',8a',10'-hexahydro-5'H-spiro[cyclopropane-1,9'-phenanthrene]-2'-carboxamide, a non-steroidal SGRM. JTP-117968 has partial TR activity, but exhibits extremely low TA activity. The maximum TR efficacy of JTP-117968 was comparable to its structural analogue, PF-802, (4bS,7R,8aR)-4b-Benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide, which is the active form of Fosdagrocorat that has been developed clinically as a first-in-class orally available SGRM. Remarkably, the TA activity of JTP-117968 was much weaker than PF-802 not only in in vitro assays, but also in in vivo mice experiments. These findings indicate that JTP-117968 exhibits improved TR/TA dissociation because the compound has significantly lower TA activity compared with an already reported SGRM. Therefore, JTP-117968 is expected to be a useful compound for evaluating ideal SGRMs in the future., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to investigate the clinical features and prognosis of patients with squamous cell carcinoma (SCC) associated with sinonasal inverted papilloma (IP)., Methods: The medical records of 95 patients who were diagnosed with IP or SCC associated with IP were retrospectively reviewed. Out of 95 patients, 15 were diagnosed with SCC associated with IP. The clinical characteristics, treatment modalities, and survival outcomes of the patients were analyzed., Results: The incidence of SCC associated with IP was 15.8%. Although differential diagnosis between IP and SCC associated with IP is difficult, epistaxis may be the specific symptom in SCC associated with IP cases. The 3-year disease-specific survival rate was higher in cases with T1, 2 and 3 than in cases with T4. There was no significant difference in survival rate between maxillary sinus and other primary sites. On the other hand, there was a significant difference in survival rate between the microscopic SCC with IP cases and the other cases. In addition, the patients with <70 years old better than those with >70 years old with a 3-year disease free survival of 80% versus 0%., Conclusions: Some T4 patients were found to have a highly aggressive disease. Therefore, complete surgical resection followed by chemo-radiation therapy is the recommended treatment for patients with T4 disease to control of the primary tumor site., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Epidemiological studies suggest that chronic kidney disease (CKD) is a significant risk factor in the development of cognitive decline. However, the exact role of CKD in cognitive impairment or dementia is unclear. This work was performed to examine the potential impact of CKD on cognitive impairment in Alzheimer's disease (AD), focusing on angiotensin II. (1) CKD was induced in 5XFAD mice, an AD model mouse, and wild-type mice by feeding an adenine-containing diet and the effect on cognitive function was compared between both strains. There was no significant difference regarding the severity of CKD induced by adenine between the strains. In 5XFAD mice, the CKD group exhibited significant cognitive impairment while the control group (control diet-fed group) did not, as evidenced by a passive avoidance test. On the other hand, in wild-type mice, neither the CKD group nor the control group showed cognitive impairment. Thus, CKD itself appears to accelerate cognitive impairment in AD mice. (2) We also examined the effect of olmesartan, an angiotensin II receptor blocker, on 5XFAD mice with CKD to elucidate the potential involvement of angiotensin II. As evidenced by the findings of the water maze test, olmesartan treatment significantly ameliorated the impairment of spatial learning and memory function induced by CKD in 5XFAD mice. Olmesartan treatment significantly ameliorated blood-brain barrier (BBB) disruption induced by CKD in 5XFAD mice. Furthermore, olmesartan reduced hippocampal oxidative stress in 5XFAD with CKD to similar levels to the control group of 5XFAD fed standard diet. Hence, the amelioration of CKD-induced cognitive impairment in 5XFAD mice by olmesartan appears to be mediated by the suppression of BBB disruption or oxidative stress. In conclusion, we obtained the evidence suggesting that CKD itself accelerates cognitive impairment in AD mice, through angiotensin II. Thus, our work provides a novel insight into the underlying mechanism of the link between CKD and AD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Eyelid carcinomas are rare, and the management strategy of regional lymph node metastasis linked to eyelid carcinomas has not been standardized to date. The aim of the present study was to analyze the patterns of regional metastasis and to assess the optimal extent of surgical treatment for lymph node metastasis of eyelid carcinoma., Methods: This study was a retrospective review of patient data from a single institution. From a series of 268 eyelid carcinomas, we selected the 21 patients with lymph node metastasis, and we analyzed the patterns of lymphatic spread, approach to treatment and outcomes., Results: The most common histological type of eyelid carcinoma with regional metastasis was sebaceous carcinoma (17/21, 81.0%). Submandibular area metastases were seen only in the patients with the primary tumor originating in the medial half of the eyelid, but parotid area metastases were seen in both the patients whose tumors had a medial-half origin and those with a lateral-half origin. Although 11 of the 16 patients with parotid-area metastases underwent a tumorectomy or superficial parotidectomy (which resulted in four cases of recurrence in the parotid area), none of the five patients who underwent a total parotidectomy developed parotid-area recurrence. The incidence of regional recurrence of the patients who received adjuvant radiotherapy (14.3%) was lower than that of the patients without adjuvant radiotherapy (57.1%)., Conclusion: Continued surveillance and optimal management of regional lymph node metastases are important for the control and survival of eyelid carcinomas., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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.)

Background: As of 2014, routine vaccination strategies in Japan have included the varicella vaccine. Given the widespread use of the vaccine, it is important to investigate the safety profile of the vaccine strain, Oka/Biken varicella, in Japanese patients., Methods: Reports of adverse events associated with varicella vaccination between 2005 and 2015 were retrospectively reviewed. Virological analysis was performed on clinical specimens collected from some of the reported cases to determine whether the etiological agent was the wild-type or Oka vaccine-strains., Results: There were 351 reports (3.71/100,000 doses) of adverse events during the observation period. Among the 351 reports, there were 88 reports (0.93/100,000 doses) of varicella-like and 66 reports (0.70/100,000 doses) of zoster-like skin rashes. The wild-type strain induced varicella-like skin rashes earlier than the Oka vaccine strain. The Oka vaccine strain induced zoster-like skin rashes in younger patients compared to the wild-type strain. The onset of zoster-like skin rashes after vaccination was earlier in patients vaccinated with the Oka vaccine-type strain., Conclusion: The Oka/Biken vaccine is generally safe and well tolerated in Japan. Clinical aspects of adverse reactions caused by the Oka vaccine strain were consistent with previous reports from the United States and Europe., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Uric acid, once viewed as an inert metabolic end-product of purine metabolism, has been recently incriminated in a number of chronic disease states, including hypertension, metabolic syndrome, diabetes, non-alcoholic fatty liver disease, and chronic kidney disease. Several experimental and clinical studies support a role for uric acid as a contributory causal factor in these conditions. Here we discuss some of the major mechanisms linking uric acid to metabolic and cardiovascular diseases. At this time the key to understanding the importance of uric acid in these diseases will be the conduct of large clinical trials in which the effect of lowering uric acid on hard clinical outcomes is assessed. Elevated uric acid may turn out to be one of the more important remediable risk factors for metabolic and cardiovascular diseases., (Copyright © 2015 European Federation of Internal Medicine. All rights reserved.)

Mycobacterium avium complex (MAC) infections are increasing annually in many countries. MAC strains are the most common nontuberculous mycobacterial pathogens isolated from respiratory samples and predominantly consist of two species, Mycobacterium avium and Mycobacterium intracellulare. The aim of this study was to analyze the molecular epidemiology and genetic backgrounds of clinical MAC isolates collected from The Netherlands, Germany, United States, Korea and Japan. Variable numbers of tandem repeats (VNTR) analysis was used to examine the genetic relatedness of clinical isolates of M. avium subsp. hominissuis (n=261) and M. intracellulare (n=116). Minimum spanning tree and unweighted pair group method using arithmetic averages analyses based on the VNTR data indicated that M. avium subsp. hominissuis isolates from Japan shared a high degree of genetic relatedness with Korean isolates, but not with isolates from Europe or the United States, whereas M. intracellulare isolates did not show any specific clustering by geographic origin. The findings from the present study indicate that strains of M. avium subsp. hominissuis, but not M. intracellulare, exhibit geographical differences in genetic diversity and imply that MAC strains may have different sources, routes of transmission and perhaps clinical manifestations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The contribution of endothelial nitric oxide synthase (eNOS) to podocyte integrity remains unclear. This study therefore examined podocytes and mitochondrial abnormalities in eNOS deficient mice. Absence of eNOS caused glomerular hypertrophy, along with occasional glomerular sclerosis and mesangiolysis. While many glomeruli did not have such advanced lesions, ultrastructural analysis showed cellular hypertrophy, vacuolization, lysosomal enlargement, and microvillus formation in podocytes of eNOS knockout (KO) mice. Increased oxidative stress was associated with mitochondrial abnormalities, including an increase in number, coupled with a reduction in size, of mitochondria in podocytes of eNOS-KO mice. While the levels of expression of several mitochondrial proteins were not altered, the d-17 mutation in mitochondrial DNA was significantly associated with the eNOS deficiency. Renal ATP level in the renal cortex and mitochondrial respiration in the primary podocytes were significantly lower in eNOS-KO mice, suggesting that renal mitochondria may be functionally impaired. Podocytes cultured with endothelial conditioned medium lacking NO consistently showed a greater degree of mitochondrial fragmentation and an increase in mitochondrial oxidative stress, with these mitochondrial alterations rescued by an NO donor. In conclusion, eNOS may be necessary to maintain podocyte integrity, especially mitochondrial function., (Copyright © 2015. Published by Elsevier Inc.)

Objective: To examine the efficacy of a three-dimensional (3D) endoscope for endoscopic sinus and skull base surgery., Methods: The study design was a retrospective case series and qualitative research. The clinical efficacy of 3D endoscopes was examined on five cadavers. We performed conventional endoscopic sinus surgery (ESS) in five cases and hypophysectomy in two cases using a 3D endoscope. The educational advantages of the 3D endoscope were assessed using questionnaires given to the participants of cadaver dissection courses., Results: In the posterior portion of the nasal cavity, images captured via 3D endoscopy provided a superior perception of depth of information than those via two-dimensional (2D) endoscopy. All endonasal surgeries were completed in clinical settings using a 3D endoscope without perioperative complications. In terms of the operative time and amount of bleeding, the results of 3D endoscopic surgeries were not inferior to those of 2D endoscopic surgeries. Fatigue from 3D viewing through polarized glasses did not adversely affect performance of the surgery. Moreover, questionnaires for the evaluation of educational efficacy were completed by 73 surgeons. Of the respondents, 89% agreed that 3D endoscopy provided a better understanding of the surgical anatomy than did 2D endoscopy. As for the site where 3D endoscopy would be the most useful for understanding surgical anatomy, 40% of the respondents named the skull base; 29%, the posterior ethmoid sinuses; and 26%, the sphenoid sinus; and 9%, the ethmoid bulla and middle turbinate., Conclusion: The 3D endoscope contributes to a more precise anatomical understanding of the posterior structures of the sinuses and skull base and ensures a more precise operation of the instruments. Thus, 3D endoscopes will likely become a standard device for endonasal surgery in the near future., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Esthesioneuroblastoma (ENB), or olfactory neuroblastoma, is a rare malignant neoplasm arising from the olfactory neuroepithelium. Typically, ENBs are found in the olfactory cleft with extension to the ethmoid sinuses or anterior skull base. Here we report a case of ENB located in the sphenoid sinus, which had been considered as an ectopic ENB. However, endoscopic resection revealed the continuity of the tumor with the hindmost olfactory filament. The present case suggests that an ENB in the sphenoid sinus was not ectopic, but arose from the normal olfactory neuroepithelium. This continuity of the ENB with this filament indicated that the tumor was not ectopic, and that there was possible tumor invasion into the olfactory neuroepithelium in the cribriform niche. Therefore, pathological examination of the olfactory neuroepithelium in the cribriform niche may be necessary in case of sphenoid ENBs., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

High fructose intake is associated with increased plasma triglyceride concentration, hepatic steatosis, impaired glucose tolerance, insulin resistance, and high blood pressure. In addition, increased fructose intake has recently been supposed to be a risk factor for dementia. However, direct effects of fructose on the brain function remain to be clarified. The localization of glucose transporter 5 (Glut5), a representative transporter of fructose, was immunohistochemically examined in the brains of humans, rats, and mice to clarify whether fructose was transported from the blood into the brain. Glut5 immunoreactivity was demonstrated to be located in the epithelial cells of the choroid plexus and the ependymal cells in the brains of humans and rats using commercial antibodies for Glut5. In addition, mRNA expression of mouse Glut5 was confirmed in the brains of mice. Immunohistochemical examination using a custom-made antibody against two regions of amino acid sequences of mouse Glut5 revealed that Glut5 immunoreactivity was also seen in the epithelial cells of the choroid plexus and the ependymal cells in the brains of mice. These findings show that Glut5 immunoreactivity is located in the epithelial cells of the choroid plexus and the ependymal cells, suggesting the possibility of the direct transportation of intravascular fructose into the brain parenchyma., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: The present study aimed to examine whether an E-prostanoid receptor 4 (EP4) agonist has superior protective effects to those of prostaglandin E1 (PGE1) in a guinea pig model of noise trauma., Methods: Drugs were locally applied on the round window membrane of guinea pig cochleae, followed by exposure of the test animals to intense noise. Protective effects mediated by an EP4 agonist were compared with those mediated by PGE1. Auditory function was monitored by measurements of the auditory brainstem response (ABR), and histological damage was assessed by immunohistochemical analysis of cochlear specimens., Results: Animals treated with an EP4 agonist exhibited significantly better hearing recovery than those pretreated with PGE1. Histologically, the numbers of remaining outer hair cells in cochleae treated with the EP4 agonist were significantly higher than in those treated with PGE1., Conclusion: The selective activation of EP4 has a stronger protective effect on cochleae against noise trauma than does the broad activation of EPs by PGE1., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Because of its high oxygen demands, neural tissue is predisposed to oxidative stress. Here, our aim was to clarify the cellular localization of antioxidant enzymes in the trigeminal ganglion. We found that the transcriptional factor Sox10 is localized exclusively in satellite glial cells (SGCs) in the adult trigeminal ganglion. The use of transgenic mice that express the fluorescent protein Venus under the Sox10 promoter enabled us to distinguish between neurons and SGCs. Although both superoxide dismutases 1 and 2 were present in the neurons, only superoxide dismutase 1 was identified in SGCs. The enzymes relevant to hydrogen peroxide degradation displayed differential cellular localization, such that neurons were endowed with glutathione peroxidase 1 and thioredoxin 2, and catalase and thioredoxin 2 were present in SGCs. Our immunohistochemical finding showed that only SGCs were labeled by the oxidative damage marker 8-hydroxy-2'-deoxyguanosine, which indicates that the antioxidant systems of SGCs were less potent. The transient receptor potential vanilloid subfamily member 1 (TRPV1), the capsaicin receptor, is implicated in inflammatory hyperalgesia, and we demonstrated that topical capsaicin application causes short-lasting mechanical hyperalgesia in the face. Our cell-based assay revealed that TRPV1 agonist stimulation in the presence of TRPV1 overexpression caused reactive oxygen species-mediated caspase-3 activation. Moreover, capsaicin induced the cellular demise of primary TRPV1-positive trigeminal ganglion neurons in a dose-dependent manner, and this effect was inhibited by a free radical scavenger and a pancaspase inhibitor. This study delineates the localization of antioxidative stress-related enzymes in the trigeminal ganglion and reveals the importance of the pivotal role of reactive oxygen species in the TRPV1-mediated caspase-dependent cell death of trigeminal ganglion neurons. Therapeutic measures for antioxidative stress should be taken to prevent damage to trigeminal primary sensory neurons in inflammatory pain disorders., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Yokukansan (YKS) is a traditional Japanese medicine consisting of seven medicinal herbs that is used for the treatment of neurosis, insomnia, and the behavioral/psychological symptoms of dementia. This study examined the effects of YKS on morphine tolerance and physical dependence in mice. Daily oral administration of YKS (0.5 or 1.0 g/kg) for 3 weeks significantly attenuated morphine tolerance and naloxone-precipitated morphine withdrawal signs (jumps and body weight loss) without affecting the analgesic effect of morphine. The inhibitory effect of YKS on withdrawal jumps in morphine-dependent mice was blocked by a single pretreatment with an α(2)-adrenoceptor antagonist, yohimbine, but not by an α(1)-adrenoceptor antagonist, prazosin. A similar inhibitory effect on withdrawal jumps was observed by repeated administration of yohimbine. The membrane expression of α(2A)-adrenoceptors in the pons/medulla was decreased in morphine withdrawn animals; this reduction was prevented by repeated administration of YKS or yohimbine. Competitive radioligand and [(35)S]guanosine-5'-O-(3-thiotriphosphate) binding assays revealed that YKS and its constituent herbs, Glycyrrhiza (GR) and Uncaria hook (UH), had specific binding affinity for and antagonist activity against the α(2A)-adrenoceptor. Certain chemical constituents, including GR -derived glycyrrhizin and its metabolite, 18β-glycyrrhetinic acid, and UH-derived geissoschizine methyl ether (GME), shared such activities. Repeated administration of GR, UH, glycyrrhizin or GME significantly inhibited morphine withdrawal signs. These results suggest that YKS and its active constituents inhibit morphine tolerance and physical dependence, and that the latter is due at least in part to the prevention of the decreased membrane expression of the α(2A)-adrenoceptor in the brainstem by its prolonged blockade., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

There is increased interest in the Bn-receptor family because they are frequently over/ectopically expressed by tumors and thus useful as targets for imaging or receptor-targeted-cytotoxicity. The synthetic Bn-analog, [D-Tyr(6), β-Ala(11), Phe(13), Nle(14)]Bn(6-14) [Univ.Lig] has the unique property of having high affinity for all three human BNRs (GRPR, NMBR, BRS-3), and thus could be especially useful for this approach. However, the molecular basis of this property is unclear and is the subject of this study. To accomplish this, site-directed mutagenesis was used after identifying potentially important amino acids using sequence homology analysis of all BnRs with high affinity for Univ.Lig compared to the Cholecystokinin-receptor (CCK(A)R), which has low affinity. Using various criteria 74 amino acids were identified and 101 mutations made in GRPR by changing each to those of CCK(A)R or to alanine. 22 GRPR mutations showed a significant decrease in affinity for Univ.Lig (>2-fold) with 2 in EC2[D97N, G112V], 1 in UTM6[Y284A], 2 in EC4[R287N, H300S] showing >10-fold decrease in Univ.Lig affinity. Additional mutations were made to explore the molecular basis for these changes. Our results show that high affinity for Univ.Lig by human Bn-receptors requires positively charged amino acids in extracellular (EC)-domain 4 and to a lesser extent EC2 and EC3 suggesting charge-charge interactions may be particularly important for determining the general high affinity of this ligand. Furthermore, transmembrane amino acids particularly in UTM6 are important contributing both charge-charge interactions as well as interaction with a tyrosine residue in close proximity suggesting possible receptor-peptide cation-π or H-bonding interactions are also important for determining its high affinity., (Published by Elsevier Inc.)

Objective: Patients with acute sensorineural hearing loss (ASNHL) often complain of a feeling of ear fullness (FEF) that is similar to the sensation experienced during barometric pressure changes. This suggests that modulation of somatosensory abilities may relate to the manifestation of FEF, whereas it cannot simply be assumed that somatosensory abilities would be directly affected by ASNHL. To examine this possible relationship, we estimated somatosensory abilities of the tympanic membrane, and investigated the relationship between them and the manifestation of FEF., Methods: To estimate somatosensory abilities of the tympanic membrane, 83 new patients demonstrating unilateral sudden deafness were studied. The air pressure was loaded through an exclusive device on the external auditory canals in order to measure the minimum change in air pressure sensed by the subjects. The minimum pressure was defined as the minimum sensory threshold for air pressure loading (MSTAP; daPa). We estimated patient's somatosensory abilities and inquired about their experiences with FEF at the first medical examination (point 1) and at the time a steady audiogram was obtained (point 2). We also estimated MSTAP in 65 volunteers (130 ears) with no history of ear diseases and compared their MSTAP with that of sudden deafness patients., Results: MSTAP values (-64.0±32.2daPa, 60.5±26.0daPa) on the affected side with both negative pressure and positive pressure measured at point 1 were significantly higher than those (-40.7±15.0daPa, 40.0±12.7daPa) obtained at point 2 in all sudden deafness patients (p=0.0001, p=0.0001). There was no difference between MSTAP values (-39.6±10.7daPa, 39.9±11.4daPa) in normal subjects and those obtained at point 2 in all sudden deafness patients. On the other hand, significant differences of MSTAP with negative pressures between the affected and unaffected sides at point 1 were seen in 32 patients, and manifestation of FEF showed an insignificant association in these 32 patients (p<0.05)., Conclusion: Modulation of somatosensory abilities in ASNHL seemed to be the best possible explanation for results, suggesting that a rise in MSTAP may somehow be associated with FEF. Although it cannot be verified by result of the current study, consideration of the previous literature suggests that the phenomenon may be caused by cross-modality of hearing and somatosensory abilities., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To investigate the corneal higher-order aberrations (HOAs) of the anterior and posterior corneal surfaces in eyes that underwent penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK), and Descemet stripping automated endothelial keratoplasty (DSAEK)., Design: Retrospective, case-control study., Methods: study population: Twenty-four eyes underwent PK, 28 eyes underwent DALK, and 19 eyes underwent DSAEK; 29 normal eyes served as controls. observation procedures: The anterior and posterior corneal heights and pachymetric data were obtained with a Scheimpflug-based corneal topographer. Corneal HOAs for 4-mm pupils were calculated from the height data and were expanded with normalized Zernike polynomials. The HOAs resulting from the anterior and posterior corneal surfaces were compared among the procedures. main outcome measures: Anterior and posterior corneal HOAs (root mean square)., Results: Control eyes had significantly lower total HOAs and Zernike vector terms of the anterior and posterior surfaces than the other groups, except for spherical aberration. The mean anterior corneal surface total HOAs in the PK, DALK, DSAEK, and control groups were 1.38 ± 0.67 μm, 1.19 ± 0.57 μm, 0.61 ± 0.33 μm, and 0.21 ± 0.07 μm, respectively. The anterior corneal HOAs in the DSAEK group were significantly less than those in the PK group (P < .001) and DALK group (P < .001). The mean posterior corneal surface total HOAs were, respectively, 0.20 ± 0.09 μm, 0.24 ± 0.11 μm, 0.27 ± 0.15 μm, and 0.07 ± 0.02 μm. There were no significant differences in the posterior corneal HOAs among the treatment groups., Conclusions: Because the refractive indices between the anterior and the posterior surfaces differed greatly, eyes that undergo DSAEK have lower anterior corneal HOAs compared with PK or DALK eyes. However, the anterior and posterior corneal HOAs in DSAEK eyes still were greater than those in control eyes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Intermittent administration of parathyroid hormone (PTH) has a potent anabolic effect on bone in humans and animals. Calcium-sensing receptor (CaSR) antagonists stimulate endogenous PTH secretion through CaSR on the surface of parathyroid cells and thereby may be anabolic agents for osteoporosis. JTT-305 is a potent oral short-acting CaSR antagonist and transiently stimulates endogenous PTH secretion. The objective of the present study was to investigate the effects of JTT-305 on PTH secretion and bone in ovariectomized rats. Female rats, immediately after ovariectomy (OVX), were orally administered vehicle or JTT-305 (0.3, 1, or 3 mg/kg) for 12 weeks. The serum PTH concentrations were transiently elevated with increasing doses of JTT-305. In the proximal tibia, JTT-305 prevented OVX-induced decreases in both the cancellous and total bone mineral density (BMD) except for the 0.3mg/kg dose. At the 3mg/kg dose, JTT-305 increased the mineralizing surface and bone formation rate in histomorphometry. The efficacy of JTT-305 at the 3mg/kg dose on the BMD corresponded to that of exogenous rat PTH1-84 injection at doses between 3 and 10 μg/kg. In conclusion, JTT-305 stimulated endogenous transient PTH secretion and bone formation, and consequently prevented bone loss in OVX rats. These results suggest that JTT-305 is orally active and has the potential to be an anabolic agent for the treatment of osteoporosis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC(50)=1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Eosinophilic otitis media (EOM) is a newly recognized intractable middle ear disease, characterised by the accumulation of eosinophils in middle ear effusion and middle ear mucosa. Since EOM patients show gradual or sudden deterioration of hearing, it is important to properly diagnose EOM and to start adequate treatment for EOM. We aimed to investigate the clinical risk factors of EOM and to establish the diagnostic criteria of EOM., Patients and Methods: We reviewed 138 patients with EOM and 134 age-matched patients with the common type of otitis media with effusion or chronic otitis media as controls. We analyzed the incidence of the following clinical variables in both groups: bilaterality of otitis media, viscosity of middle ear effusion, formation of granulation tissue in the middle ear, response to the treatment for otitis media, deterioration of bone conduction hearing level, and association with other diseases such as bronchial asthma, chronic rhinosinusitis, nasal polyposis, and allergic rhinitis., Results: A high odds ratio was obtained from an association with bronchial asthma (584.5), resistance to conventional treatment for otitis media (232.2), viscous middle ear effusion (201.6), association with nasal polyposis (42.17), association with chronic rhinosinusitis (26.49), bilaterality (12.93), and granulation tissue formation (12.62). The percentage of patients with EOM who were positive for two or more among the highest four items was 98.55%., Conclusion: A patient who shows otitis media with effusion or chronic otitis media with eosinophil-dominant effusion (major criterion) and with two or more among the highest four items (minor criteria), can be diagnosed as having EOM. Patients with ear symptoms should have the proper diagnosis of EOM using the proposed diagnostic criteria, and then can receive adequate treatment, resulting in prevention of deterioration of hearing and quality of life., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Objective: Although radiotherapy is effective for head and neck cancer patients, the local pain evoked by the irradiation itself reduces food intake and frequently halts the treatment. Thus, pain control is an important problem in radiotherapy for head and neck cancer. We performed to examine whether early induction of low-dose, opioid from mild pain improves dietary and caloric intake, while reducing weight loss., Methods: The subjects were 43 patients who were hospitalized for head and neck cancer from 2004 to 2008. They were patients who underwent radiation treatment but those who did not undergo preoperative treatment. They were divided into two groups, depending on whether the pain was mild or moderate when an opioid was introduced (MILD and MODERATE, N=23 and 20, respectively)., Results: The visual analog scale scores for pain were significantly lower in the MILD than in the MODERATE group at between 25 and 50 Gy. The amount of oxycodone used for pain was significantly lower in the MILD than the MODERATE group. A regular diet was maintained for significantly longer in the MILD group. Caloric intake was significantly higher in the MILD group at over 20 Gy. Weight loss was significantly lower in the MILD group at over 20 Gy. The incidence of side effects was equal in both groups., Conclusion: Our results indicated that the introduction of opioids for mild pain during radiotherapy controls the level of pain, improving food intake in head and neck cancer patients., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)