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Competing Interests: KS received consulting fees from Moderna and Takeda; honoraria for lectures from Gilead Sciences, Moderna, and Shionogi & Co; and is supported by the Agency for Medical Research and Development (AMED) Adopting Sustainable Partnerships for Innovative Research Ecosystem (ASPIRE), AMED Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA) Japan Initiative for World-leading Vaccine Research and Development Centers UTOPIA, AMED SCARDA Program on R&D of new generation vaccine including new modality application, AMED Research Program on Emerging and Re-emerging Infectious Diseases, Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (KAKENHI), and Mitsubishi UFJ Financial Group Vaccine Development Research Support. SL received consulting fees from EcoHealth Alliance. JI received consulting fees and honoraria for lectures from Takeda; and is supported by grants from Japan Science and Technology Agency PRESTO, JSPS KAKENHI Grant-in-Aid for Early-Career Scientists, and Mitsubishi UFJ Financial Group Vaccine Development Research Support. ECH received consulting fees and honoraria for lectures from Moderna and Pfizer; and is supported by grants from the National Health and Medical Research Council (NHMRC) Investigator award and AIR@InnoHK from the Innovation and Technology Commission (Hong Kong, China). JET is supported by a grant from the Japanese Government MEXT Scholarship-Research Category and declares no competing interests.

Telomere length (TL) and mitochondrial DNA copy number (mt-cn) are associated with embryonic development. Here, we investigated the correlation between TL and mt-cn in bovine embryos to determine whether TL regulates mt-cn. TL and mt-cn were closely correlated in embryos derived from six bulls. Treatment of embryos with a telomerase inhibitor (TMPyP) and siTERT shortened the TL and reduced mt-cn in blastocysts. RNA-sequencing of blastocysts developed with TMPyP revealed differentially expressed genes associated with transforming growth factor-β1 signaling and inflammation. In conclusion, TL regulates mt-cn in embryos., 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 © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Objective: In the present study, we examined the effects of high-dose betahistine on dizziness handicap inventory (DHI) scores in patients with unilateral vestibulopathy., Methods: An uncontrolled, open-label, multicenter clinical trial was conducted. Fifteen patients with unilateral vestibulopathy, such as vestibular neuritis, who complained of intractable dizziness for more than three months were enrolled. Initially, all patients were orally administered betahistine at a dose of 36 mg/day for four weeks, which is the standard dose and dosing period for the treatment of dizziness in Japan. The patients were then administered betahistine at a double dose of 72 mg/day for four weeks. Six patients who became aware of the benefits of high-dose betahistine were further administered betahistine at 72 mg/day for an additional 12 weeks (a total of 16 weeks). Perceived disability due to dizziness was assessed by DHI scores., Results: In all 15 patients, short-term administration with high-dose (72 mg/day) betahistine for four weeks, but not low-dose betahistine (36 mg/day) for four weeks significantly decreased DHI scores. In particular, in six responding patients with self-reported benefits after short-term administration with high-dose betahistine, long-term administration with high-dose betahistine for 16 weeks further significantly decreased DHI scores. However, DHI scores of the remaining nine non-responding patients were not changed after short-term administration with high-dose betahistine for four weeks., Conclusion: Short-term administration with the standard dose and dosing period of betahistine did not improve DHI scores in the enrolled patients, indicating that they were not compensated for unilateral vestibulopathy with intractable dizziness. The present findings suggest that long-term administration with high-dose betahistine facilitates vestibular compensation to improve intractable dizziness in some, but not all patients with uncompensated unilateral vestibulopathy., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest in this study., (Copyright © 2023. Published by Elsevier B.V.)

Objective: This study aimed to longitudinally evaluate speech perception ability and sound-field thresholds with the first, second, or bilateral cochlear implants (CIs) and MAP parameters of second CI in children., Methods: Eighteen children who underwent bilateral cochlear implantation at Kyoto University Hospital were included. We evaluated speech perception under quiet and noisy conditions using the first, second, or bilateral CIs, CI-aided sound-field thresholds using the first or second CI, and MAP parameter values (C-levels, T-levels, and dynamic range) of the second CI of more than 5 years after the second implantation., Results: Patients with a second CI after 7 years of age had significantly worse speech perception ability with the second CI even long after the surgery than those with a second CI before 7 years of age. CI-aided sound-field thresholds using the first or second CI were similar, regardless of the second implantation timing. Speech perception in noise with bilateral CIs was enhanced by the addition of a second CI, even after 7 years of age. Patients undergoing second cochlear implantation before 3.5 years of age showed significantly higher C-levels and wider dynamic ranges in the second CI MAP parameters., Conclusions: When the second implantation was performed after 7 years of age, the second CI effects were limited even with long-term use, which is attributed to unstable MAP parameters. The second CI-aided sound-field threshold contributed to the better outcome of bilateral CIs in noise, even if the second implantation was performed at age of ≥7 years., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Mitochondrial DNA (mtDNA) copy number and telomere length (TL) in blastocysts derived from the same male mice at young (10-19-week-old) and aged (40-49-week-old) time points and mtDNA and TL in the hearts of offspring derived from young and aged male mice were examined. Paternal aging correlated with reduced mtDNA and TL in blastocysts. mtDNA and TL were significantly correlated, which was also observed in bovine blastocysts. Moreover, mtDNA in the heart of offspring was reduced in male mice with paternal aging. In conclusion, paternal aging affects embryonic mtDNA and TL, potentially impacting their offspring., 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 © 2022 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.)

Objective: This study aims to evaluate the speech perception with first, second, or bilateral cochlear implants (CI) and to reveal the effects of wearing bilateral CI in children., Methods: After reviewing the medical records, a total of 19 children who underwent bilateral cochlear implantation serially between 2012 and 2015 at Kyoto University Hospital (tertiary referral center) were included in this study. All patients had no delay in language development. The study group comprised nine boys and ten girls, and their age ranged from 3 years 8 months to 12 years 5 months when they underwent the tests in this study. The mean and median ages were 8 years 6 months and 9 years 2 months, respectively. We measured the appropriate signal/noise ratio (SNR) to test speech perception of Japanese language in noise by testing the hearing ability of unilateral CI patients with or without noise and by surveying the sound environment in a classroom of a mainstream elementary school. Speech perception in quiet and noise and the left-right localization ability were examined using first, second, or bilateral cochlear implants in all patients., Results: Considering the results of hearing ability tests with noise and the SNR of the elementary school classrooms, we decided to use SNR of +10 dB to evaluate the speech perception ability in noise. The speech perception ability using the second CI was significantly worse in patients undergoing second cochlear implantation after 7 years old than in those who underwent surgery before 3.5 years old. Moreover, patients undergoing second cochlear implantation before 7 years old showed significantly better left-right localization of high-frequency sound., Conclusions: Second cochlear implantation before 7 years old is a critical factor in acquiring beneficial speech perception ability with the second CI and sound localization ability with the bilateral CI., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To confirm the distribution of functional nerves involved in erectile function at the posterior of the prostate base, intraoperative nerve stimulation was performed during robot-assisted radical prostatectomy (RARP) METHODS: Several points at the posterior of the prostate and the posterolateral typical neurovascular bundle (NVB) were electrically stimulated at the level of the prostate base during RARP in patients with clinically localized prostate cancer. The prostate pedicle (PP), medial side of the PP (MPP), Denonvilliers' fascia (DF), and typical NVB were stimulated using bipolar electrodes. The changes in pressure at the middle of the urethra were measured using an inserted balloon-catheter to detect the increase in cavernosal pressure., Results: Although the study included only 12 patients, each stimulation of the PP, MPP, and NVB induced evident urethral pressure responses in all patients. The median amplitude of the pressure responses was 5.49 (IQR 3.11-8.42), 6.00 (IQR 3.70-8.30), and 3.22 (IQR 2.48-7.19) cm H2O at the PP, MPP, and NVB, respectively. The amplitude of responses at the PP and MPP was not small compared with the responses at the typical NVB. Stimulations at the DF induced unstable weak urethral response alone or no response in all patients., Conclusion: We showed that electrostimulation of the PP and MPP increases the cavernosal pressure similar to the typical NVB stimulation. These findings indicate that maximal preservation of the tissues at the posterior area of the prostate base can contribute to optimal recovery of postoperative erectile function after nerve-sparing RARP., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: (1) To compare temporal bone anatomy comprehension taught to speech therapy students with or without a papercraft model. (2) To explore the effect of papercraft simulation on the understanding of surgical approaches in first-year residents., Methods: (1) One-hundred and ten speech therapy students were divided into three classes. The first class was taught with a lecture only. The students in the second class were given a lecture and a papercraft modeling task without instruction. The third class modeled a papercraft with instruction after the lecture. The students were tested on their understanding of temporal bone anatomy. (2) A questionnaire on the understanding of surgical approaches was completed by 10 residents before and after the papercraft modeling. The papercraft models were cut with scissors to simulate surgical approaches., Results: (1) The average scores were 4.4/8 for the first class, 4.3/8 for the second class, and 6.3/8 for the third class. The third class had significantly better results than the other classes (p<0.01, Kruskal-Wallis test). (2) The average scores before and after the papercraft modeling and cutting were 2.6/7 and 4.9/7, respectively. The numerical rating scale score significantly improved (p<0.01, Wilcoxon signed-rank test)., Conclusion: The instruction of the anatomy using a papercraft temporal bone model is effective in the first step of learning temporal bone anatomy and surgical approaches., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Patients with nonalcoholic fatty liver disease may subsequently develop nonalcoholic steatohepatitis after suffering from a second insult, such as oxidative stress. Aim of this study was to investigate the pathogenesis of the liver injury caused when lipids accumulate under conditions of intrinsic oxidative stress using mice that are deficient in superoxide dismutase 1 (SOD1) and the leptin receptor (Lepr). We established Sod1 -/- ::Lepr db/db mice and carried out analyses of four groups of genetically modified mice, namely, wild type, Sod1 -/- , Lepr db/db and Sod1 -/- ::Lepr db/db mice. Mice with defects in the SOD1 or Lepr gene are vulnerable to developing fatty livers, even when fed a normal diet. Feeding a high-fat diet (HFD) caused an increase in the number of lipid droplets in the liver to different extents in each genotypic mouse. an HFD caused the accelerated death of db/db mice, but contradictory to our expectations, the death rates for the Sod1-deficient mice were decreased by feeding HFD. Consistent with the improved probability of survival, liver damage was significantly ameliorated by feeding an HFD compared to a normal diet in the mice with an Sod1-deficient background. Oxidative stress markers, hyperoxidized peroxiredoxin and lipid peroxidation products, were decreased somewhat in Sod1 -/- mice by feeding HFD. We conclude that lipids reacted with reactive oxygen species and eliminated them in the livers of the young mice, which resulted in the alleviation of oxidative stress, but in advanced age oxidized products accumulated, leading to the aggravation of the liver injury and an increase in fatality rate., (Copyright © 2016 Elsevier Inc. 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.)

We report a case of temporal bone chondroblastoma that was totally invisible on MRI. The patient was a 64-year-old man who presented with several months history of vertigo. The CT scan with bone window setting showed destruction of the temporomandibular joint, the floor of the middle cranial fossa, and the superior semicircular canal. Calcific foci were seen within the tumor. On MR imaging, the tumor, situating mainly medial to the temporomandibular joint, showed no signal on both T1- and T2-weighted images. The tumor was not enhanced with gadolinium. In summary, the tumor was totally signal negative or "invisible" on pre- and postcontrast T1- and T2-weighted images. The tumor was resected through transpetrosal - transzygomatic approach., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Transoral surgery is a less invasive treatment that is becoming a major strategy in the treatment of laryngo-pharyngeal cancer. It is a minimally invasive approach that has no skin incision and limits the extent of tissue dissection, disruption of speech and swallowing muscles, blood loss, damage to major neurovascular structures, and injury to normal tissue. Transoral approaches to the laryngo-pharynx, except for early glottis cancer, had been limited traditionally to tumors that can be observed directly and manipulated with standard instrumentation and lighting. Since the 1990s, transoral laser microsurgery (TLM) has been used as an organ preservation strategy with good oncological control and good functional results, although it has not been widely used because of its technical difficulty. Recently, transoral robotic surgery (TORS) is becoming popular as a new treatment modality for laryngo-pharyngeal cancer, and surgical robots are used widely in the world since United States FDA approval in 2009. In spite of the global spread of TORS, it has not been approved by the Japan FDA, which has led to the development of other low-cost transoral surgical techniques in Japan. Transoral videolaryngoscopic surgery (TOVS) was developed as a new transoral surgery system for laryngo-pharyngeal lesions to address the problems of TLM. In TOVS, a rigid endoscope is used to visualize the surgical field instead of a microscope and the advantages of TOVS include the wide operative field and working space achieved using the distending laryngoscope and videolaryngoscope. Also, with the spread of narrow band imaging (NBI), endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), which are widely used for superficial cancers in the gastrointestinal tract, have been applied for the superficial laryngo-pharyngeal cancer. Both EMR and ESD are performed mainly by gastroenterologists with a sharp dissector and magnifying endoscopy (ME)-NBI with minimal surgical margin. Endoscopic laryngo-pharyngeal surgery (ELPS) was developed to treat laryngo-pharyngeal superficial cancer by modifying the ESD procedure. The concept of ELPS is the same as that of ESD, however, the resection procedure is performed by a head and neck surgeon with both hands using a ME-NBI and rigid curved laryngo-pharyngoscope. These four procedures are low cost with similar oncological and functional outcomes to TORS. TORS may be less expensive than chemoradiotherapy, but the number of hospitals that can afford da Vinci surgical systems is limited. Even in the era of robotic surgery, these four procedures will be good options for laryngo-pharyngeal cancer., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

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.)

Inflammatory bone diseases have been attributed to increased bone resorption by augmented and activated bone-resorbing osteoclasts in response to inflammation. Although the production of diverse proinflammatory cytokines is induced at the inflamed sites, the inflammation also generates reactive oxygen species that modify many biological compounds, including lipids. Among the oxidized low-density lipoprotein (LDL) receptors, lectin-like oxidized LDL receptor-1 (LOX-1), which is a key molecule in the pathogenesis of multifactorial inflammatory atherosclerosis, was downregulated with osteoclast differentiation. Here, we demonstrate that LOX-1 negatively regulates osteoclast differentiation by basically suppressing the cell-cell fusion of preosteoclasts. The LOX-1-deleted (LOX-1(-/-)) mice consistently decreased the trabecular bone mass because of elevated bone resorption during the growing phase. In contrast, when the calvaria was inflamed by a local lipopolysaccharide-injection, the inflammation-induced bone destruction accompanied by the elevated expression of osteoclastogenesis-related genes was reduced by LOX-1 deficiency. Moreover, the expression of receptor activator of NF-κB ligand (RANKL), a trigger molecule for osteoclast differentiation, evoked by the inflammation was also abrogated in the LOX-1(-/-) mice. Osteoblasts, the major producers of RANKL, also expressed LOX-1 in response to proinflammatory agents, interleukin-1β and prostaglandin E2. In the co-culture of LOX-1(-/-) osteoblasts and wild-type osteoclast precursors, the osteoclastogenesis induced by interleukin-1β and prostaglandin E2 decreased; this process occurred in parallel with the downregulation of osteoblastic RANKL expression. Collectively, LOX-1 abrogation results in resistance to inflammatory bone destruction, despite promoting osteoclastogenesis in the steady state. Our findings indicate the novel involvement of LOX-1 in physiological bone homeostasis and inflammatory bone diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Spasmodic dysphonia (SD) is a complex neurological communication disorder characterized by a choked, strain-strangled vocal quality with voice stoppages in phonation. Its symptoms are exacerbated by situations where communication failures are anticipated, and reduced when talking with animals or small children. Symptoms are also reduced following selected forms of treatment. It is reasonable to assume that surgical alteration reducing symptoms would also alter brain activity, though demonstration of such a phenomenon has not been documented. The objective of this study is to reveal brain activity of SD patients before and after surgical treatment., Methods: We performed lateralization thyroplasties on three adductor SD patients and compared pre- and post-operative positron emission tomography recordings made during vocalization., Results: Pre-operatively, cordal supplementary motor area (SMA), bilateral auditory association areas, and thalamus were activated while reading aloud. Such activity was not observed in normal subjects. Type II thyroplasty was performed according to Isshiki's method and the strained voice was significantly reduced or eliminated in all three patients. Post-operative PET showed normal brain activation pattern with a significant decrease in cordal SMA, bilateral auditory association areas and thalamus, and a significant increase in rostral SMA compared with pre-operative recordings., Conclusion: This is the first report showing that treatment to a peripheral organ, which reverses voice symptoms, also reverses dysfunctional patterns of the central nervous system in patients with SD., (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.)

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.)

Objective: The objective of this study was to evaluate the relationship between developmental delays and speech perception in pre-lingually deafened cochlear implant recipients., Methods: This study was a retrospective review of patient charts conducted at a tertiary referral center. Thirty-five pre-lingually deafened children underwent multichannel cochlear implantation and habilitation at the Kyoto University Hospital Department of Otolaryngology-Head and Neck Surgery. A pre-operative cognitive-adaptive developmental quotient was evaluated using the Kyoto scale of psychological development. Post-operative speech performance was evaluated with speech perception tests two years after cochlear implantation. We computed partial correlation coefficients (controlled for age at the time of implantation and the average pre-operative aided hearing level) between the cognitive-adaptive developmental quotient and speech performance., Results: A developmental delay in the cognitive-adaptive area was weakly correlated with speech perception (partial correlation coefficients for consonant-vowel syllables and phrases were 0.38 and 0.36, respectively)., Conclusion: A pre-operative developmental delay was only weakly associated with poor post-operative speech perception in pre-lingually deafened cochlear implant recipients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: We investigated the association between income inequality and social capital with measles-containing vaccine (MCV) coverage rates in Japan., Methods: MCV coverage data for all 1750 municipalities were collected from statistics publicized by the Ministry of Health, Labour and Welfare of Japan in 2010. Prefectural Gini coefficients in 2009 (an indicator of income inequality) and social capital indicators (including voting rates, volunteer rates at the prefectural level, and move-in ratios at the municipal level) were linked to MCV coverage using a multilevel analysis adjusting for covariates (population, age distribution, average income, average number of household members)., Results: Coverage of the first dose of MCV (MCV1), and second dose (MCV2), decreased by 3.98% (95% confidence interval [CI]: 0.26-7.71) and 4.28% (95% CI: 0.60-7.60) per each 0.1-unit increase in Gini coefficients within large municipalities (with a population 50,000 or more), respectively. Conversely, coverage of MCV2 increased by 0.26% (95% CI: 0.08-0.45) per 1% increase in voting rate within large municipalities. Volunteer rates were inversely associated with MCV2 coverage within large municipalities. Move-in ratios at the municipal level were inversely associated with MCV2 coverage within medium-sized municipalities (with a population between 10,000 and 50,000)., Conclusions: While higher income inequality at a prefectural level was associated with lower MCV coverage rates, higher social capital was associated with higher coverage in large municipalities. To enhance MCV coverage in Japan, we recommend that income inequality be addressed and social capital boosted at the prefectural level., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Lipid metabolism in a child may be altered when the mother has a high-fat diet (HFD), but it is unclear whether the lipid metabolism of future offspring (grandchildren) is also changed under these circumstances. In this study, we examined the influence of intake of an HFD beyond one generation on offspring in normal mice. Parent mice fed an HFD were bred and the resultant second and third generations were also fed an HFD. The diets used in the study had approximately 20% more energy than a standard chow diet. Changes in lipid metabolism were examined in each generation. Intake of an HFD from generation to generation promoted lipid accumulation in the white adipose tissue of female mice, increased lipid, glucose and insulin levels in the serum, increased the activities of enzymes associated with fatty acid metabolism in the liver, promoted lipid accumulation in hepatocytes and adipocytes and increased the mRNA levels of Cdkn1a in the liver and white adipose tissue. These results suggest that activation of Cdkn1a promoted lipid accumulation in the liver and white adipose tissue of third-generation female mice that were offspring from earlier generations fed HFDs. Moreover, intake of a high-energy diet beyond one generation led to offspring with obesity, fatty liver and hyperinsulinemia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Although extensive studies have done much to clarify the molecular mechanisms of osteoclastogenesis during the last ten years, there may still be unknown molecules associated with osteoclast differentiation. Thus, we used fluorescent differential display to screen for genes whose expression is induced by receptor activator of NF-κB ligand (RANKL), a crucial molecule for osteoclast formation. We identified caveolin-1 (Cav-1) as a RANKL-induced gene. Cav-1 is a major structural protein of caveolae and lipid rafts, cholesterol-enriched microdomains in the plasma membrane (PM). The RANKL-induced Cav-1 was immediately conveyed to lipid rafts. Conversely, expression of flotillin-1 (Flot-1), another scaffolding protein of lipid rafts, was reduced during osteoclastogenesis, indicating conversion of Flot-1-predominant rafts into Cav-1-enriched rafts. However, in vitro osteoclastogenesis of precursor cells from Cav-1-null mice was comparable to that of wild-type mice, while Cav-2 expression in the knockout osteoclasts was maintained. Conversely, Cav-2 gene silencing in Cav-1-null osteoclast precursors using siRNA for Cav-2 increased osteoclast formation, suggesting that the Cav-1/Cav-2 complex may act as a negative regulator for osteoclastogenesis. On the other hand, destruction of lipid rafts by removal of cholesterol from the PM by methyl-ß-cyclodextrin (MCD) treatment caused disordered signal transductions for osteoclastogenesis, such as hyperactivation of Erk1/2 and insensitivity of Akt to RANKL stimulus. The abnormal signaling was reproduced by deleting exogenous lipoproteins from the culture medium, which also resulted in reduced osteoclast formation. In addition, the deletion caused delayed expression of nuclear factor of activated T cells c1 (NFATc1), and depressed its activation in the cytosol and inhibited its translocation into nuclei. Simultaneously, the deletion reduced the level of FcRγ, a trigger protein for initiating the calcium signaling needed to activate NFATc1, and decreased Cav-1 in lipid rafts. These findings indicate that the molecular mechanisms of osteoclastogenesis are highly dependent on extracellular lipoprotein and the integrity of lipid rafts, and suggest possible involvement of cholesterol., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We present 4 cases with metastasis to the thyroid gland (MTG), and discussed the diagnosis and treatment of MTG. It is not always easy to correctly diagnose MTG from primary thyroid cancer. Although fine needle aspiration biopsy is useful for the diagnosis of MTG, it is important to take other imaging studies and/or tumor marker into consideration. Thyroidectomy for MTG is controversial, but the good indication of thyroidectomy is considered for the patient whose primary tumor is controllable. Thyroidectomy may also be useful even for the patient with uncontrollable disease to prevent respiratory and swallowing problems caused by MTG., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Endolaryngeal microsurgery using a direct laryngoscope is a well-established procedure in phonosurgery. Adequate laryngeal exposure is essential, but in some cases sufficient view of the glottis cannot be obtained, leading to treatment failure. This study reports how to manage vocal fold lesions in difficult laryngeal exposure (DLE) cases., Methods: From 2003 to 2009, 212 patients underwent endolaryngeal microsurgery at Kyoto Medical Center and Kyoto University Hospital. Phonomicrosurgery was performed under sniffing (Boyce-Jackson) position with triangular shaped laryngoscope for laryngeal exposure. However, in DLE cases, the posture and laryngoscope were modified as needed to adequately expose the lesion. Fiberoptic laryngeal surgery (FLS) with local anesthesia was also used for the most difficult cases., Results: The number of the patients with DLE was 14 (6.6%). Endolaryngeal microsurgery was possible in DLE cases by selecting the appropriate posture and laryngoscope. However, the procedure could not be completed in two patients with an anterior web and a vocal fold cyst, both of which required a subsequent revision procedure. Fiberoptic laryngeal surgery with topical anesthesia was a feasible alternative for these cases., Conclusions: Phonosurgery was possible even in DLE cases. It is important to modify the setup of direct laryngoscopy as needed to obtain adequate exposure. Fiberoptic surgery may also be used in certain difficult cases., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Expansion of the progenitor pool of oligodendrocytes (OLs) is a critical process for obtaining appropriate amounts of mature myelin-forming OLs in the developing and regenerating central nervous system. In vitro, fibroblast growth factor-2 (FGF2), together with platelet-derived growth factor (PDGF), is required to expand oligodendrocyte progenitor cells (OLPs) in an unlimited manner, maintaining them in the early progenitor stage. However, the intracellular mechanisms that prevent OLP maturation remain elusive. In order to investigate these mechanisms, we established a mouse OLP primary culture, which enabled us to undertake biochemical analyses. We found that the suppressive effects on maturation of early OLP to the late O4(+) progenitor by PDGF+FGF2 treatment was abrogated by Mek inhibitor, while transfecting cells with a constitutively active Mek1 construct prevented OLP maturation, suggesting that the Mek-Erk pathway is implicated in the effects of the growth factor treatment. The activation of Mek-Erk pathway promoted proliferation of OLP suggesting that cell cycle progression has suppressive effects to the maturation of OLP. Furthermore, molecular screening using DNA microarrays revealed that Hes1, a negative regulator of bHLH transcription factors, is one of the downstream molecules induced by PDGF+FGF2 treatment. We confirmed that forced activation of Mek-Erk pathway is sufficient to induce Hes1 expression and that Hes1, in turn, exerts suppressive effects on the maturation of OL lineage by itself. Our observations thus indicate that Mek-Erk pathway plays pivotal role in preventing early OLP maturation to late OLPs and the effect is mediated by cell cycle progression as well as Hes1 induction., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

The design, synthesis and structure-activity relationships of a novel class of N-phenylpyridone MCH1R antagonists are described. The core part of the N-phenylpyridone structure was newly designed and the side chain moieties that were attached to the core part were extensively explored. As a result of optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese (DIO) mice., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Pancreatic polypeptide is released mainly from the pancreas, and is thought to be one of the major endogenous agonists of the neuropeptide Y Y(4) receptor. Pancreatic polypeptide has been shown to stimulate colonic muscle contraction, but whether pancreatic polypeptide has in vivo functional activity with respect to colonic transit is unclear. The present report investigated the effects of pancreatic polypeptide on fecal output as an index of colonic transit as well as intestinal motor activity, using wild-type (WT) and neuropeptide Y Y(4) receptor-deficient (KO) mice. Peripheral administration of pancreatic polypeptide increased fecal weight and caused diarrhea in WT mice in a dose-dependent manner (0.01-3mg/kg s.c.). Pancreatic polypeptide-induced increases in fecal weight and diarrhea completely disappeared in KO mice, while basal fecal weights did not differ between WT and KO mice. In longitudinal and circular muscles of mouse isolated colon, pancreatic polypeptide (0.01-1 microM) increased basal tone and frequency of spontaneous contraction in WT mice, but not in KO mice. Atropine did not affect pancreatic polypeptide-induced fecal output or increase in colonic muscle tone, indicating that the actions of pancreatic polypeptide are not mediated through cholinergic mechanisms. The present findings demonstrate that pancreatic polypeptide enhances colonic contractile activity and fecal output through neuropeptide Y Y(4) receptor, and a neuropeptide Y Y(4) receptor agonist might offer a novel therapeutic approach to ameliorate constipation., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Melanin-concentrating hormone (MCH), which is a neuropeptide expressed in the hypothalamus of the brain, is involved in regulating feeding behavior and energy homeostasis via the MCH(1) receptor in rodents. It is widely considered that MCH(1) receptor antagonists are worthy of development for medical treatment of obesity. Here we report on the development of an ex vivo receptor occupancy assay using a new radiolabeled MCH(1) receptor antagonist, [(35)S]-compound D. An MCH(1) receptor antagonist inhibited the binding of [(35)S]-compound D to brain slices in a dose-dependent manner. The result showed a good correlation between the receptor occupancy levels and plasma or brain levels of the MCH(1) receptor antagonist, suggesting that the ex vivo receptor binding assay using this radioligand is practical. Quantitative analysis in diet-induced obese mice showed that the efficacy of body weight reduction correlated with the receptor occupancy levels at 24h. Furthermore, more than 90% occupancy levels of MCH(1) receptor antagonists during 24h post-dosing are required for potent efficacy on body weight reduction. The present occupancy assay could be a useful pharmacodynamic marker to quantitatively estimate anti-obese efficacy, and would accelerate the development of MCH(1) receptor antagonists for treatment of obesity.

A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.

Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure-activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice.

Prostaglandin E(1) is frequently used for the clinical treatment of acute sensorineural hearing loss. However, the mechanisms underlying the effects of prostaglandin E(1) on the inner ear have not yet been elucidated. The physiological effects of prostaglandin E(1) are mediated by the prostanoid receptors prostaglandin I receptor and the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, the respective agonists for which have been purified. In the current study, we examined the efficacy of a local EP4 agonist application for the treatment of sensorineural hearing loss. We examined EP4 expression in the mouse cochlea using the reverse transcription-polymerase chain reaction and immunohistochemistry. The protective effects of local EP4 agonist treatment before or after noise exposure were tested in guinea pigs using measurements of auditory brain-stem responses and histological analysis. The results demonstrated EP4 expression in the cochlea, and showed that pre- and post-treatment with an EP4 agonist significantly attenuated threshold shifts of auditory brain stem responses, and significant attenuation in the loss of outer hair cells was found in local EP4 agonist treatment before noise exposure. These findings indicate that EP4 is involved in mechanisms for prostaglandin E(1) actions on the cochlea, and local EP4 agonist treatment could attenuate acute sensorineural hearing loss.

Hyperthyroidism due to thyroid carcinoma is rare, and most cases are caused by hyperfunctioning metastatic thyroid carcinoma rather than primary carcinoma. Among primary hyperfunctioning thyroid carcinoma, multifocal thyroid carcinoma is exceedingly rare, with the only one case being reported in the literature. Here, we describe the case of a 62-year-old woman with multifocal functioning thyroid carcinoma. Technetium-99m (99m Tc) scintigraphic imaging showed four hot areas in the thyroid gland. Histopathological examination of all four nodules revealed papillary carcinoma, corresponding to hot areas in the 99m Tc scintigram. DNA sequencing of the thyrotropin receptor (TSH-R) gene from all nodules revealed no mutation, indicating that activation of TSH-R was unlikely in the pathophysiogenesis of hyperfunctioning thyroid carcinoma in the present case.

Three new sesquiterpenoid quinones, nakijiquinones G-I (1-3), containing a different amino group derived from amino acids have been isolated from Okinawan marine sponges of the family Spongiidae, and the structures and relative stereochemistry of 1-3 were elucidated on the basis of the spectral data. Nakijiquinones G-I (1-3) showed modest cytotoxicity and inhibitory activity against HER2 kinase, while nakijiquinone H (2) exhibited antimicrobial activity.

This report describes a very rare case of myasthenia gravis (MG) localized to the larynx, with the onset of dyspnea requiring tracheotomy. The vocal cords of this patient were fixed in the paramedian position. Under fiberscopic observation, improvement of laryngeal function was demonstrated after intravenous injection of edrophonium. However, no voice change occurred. The posterior crico-arytenoid muscle has the sole responsibility of abducting the vocal cord; thus, it is concluded that the dyspnea was caused by the selective paralysis of this muscle. We suggest that MG should be considered in cases of vocal cord paralysis of unknown etiology.

A new operative technique for the treatment of floppy epiglottis is introduced in this report. Though its diagnosis is not so difficult by close observations using a flexible fiberscope, it is likely to be treated as an asthma attack or a paradoxical vocal cord movement. In previous reports of upper airway obstruction caused by adult floppy epiglottis: epiglottis prolapse during inspiration, the cause of this condition has been divided broadly into two categories: idiopathic cases and secondary cases. Partial or total epiglottectomy has been usually reported for the treatment of the relief of airway obstruction caused by a floppy epiglottis. It is very difficult to decide adequately how much volume of epiglottis to cut without postoperative sequelae. A V-shaped partial epiglottidectomy is described for its treatment. This technique is very easy, simple, and effective.

A series of stereoisomers for the azetidine ring of penaresidin B was synthesized and their cytotoxic and antimicrobial activities were evaluated. Among six synthetic isomers 1-6, isomers 4 and 5 showed relatively potent cytotoxic activity against A549 (lung) and HT29 (colon) tumor cells as well as antibacterial activity.

A series of phenylpiperazine derivatives were synthesized and evaluated for their neuropeptide Y (NPY) Y5 receptor antagonistic activities. The benzindane portion of 2 was replaced by 1-phenylpiperazine, resulting in novel urea derivative 3f. Subsequent optimization of the phenylpiperazine template by substitution of the phenyl moiety resulted in a series of (2-methanesulfonamidephenyl)piperazine derivatives that showed potent binding affinity and antagonistic activity for the Y5 receptor.

The aim of this study was to investigate validity and limitation of the novel infrared system to record and analyze horizontal visual-vestibular interaction using whole-body rotation rapidly and conveniently in the routine vestibular clinic. We examined 11 patients with cerebellar dysequilibrium and 25 patients with peripheral dysequilibrium for vestibulo-ocular reflex in darkness (DVOR), visually-enhanced vestibulo-ocular reflex (VEVOR), and fixation suppression of vestibulo-ocular reflex (FSVOR), and compared the results with those of examination for head-fixed smooth pursuit and fixation suppression during caloric stimulation. The manual rotation stimuli were 0.5-0.75 Hz in frequency and 60-90 degrees /s in maximal angular velocity. Gain of vestibulo-ocular reflex in darkness was not significantly correlated with maximal slow phase velocity (MSPV) of caloric-induced nystagmus at that stimulus condition either in patients with peripheral dysequilibrium or in those with cerebellar dysequilibrium. An index for fixation suppression of vestibulo-ocular reflex during rotation stimulus was significantly lower in patients with cerebellar dysequilibrium than in normal control subjects and those with peripheral dysequilibrium. On the other hand, there was no significant difference among the two disease groups and the normal control group in gain of visually-enhanced vestibulo-ocular reflex. In about a half of patients with cerebellar dysequilibrium, measured smooth pursuit gain was lower than estimated smooth pursuit gain calculated based on a simple superposition theory of vestibulo-ocular reflex and smooth pursuit. Testing fixation suppression using the present system is an unusually convenient tool for detection of cerebellar dysequilibrium.

The generation of superoxide has been implicated as a cause of cochlear damage from excessive noise. Cu/Zn superoxide dismutase (SOD1) generally will protect against superoxide-mediated tissue injury but protection by this enzyme against noise trauma is controversial. This study assessed auditory function in C57BL/6 mice overexpressing SOD1 or treated with lecithinized SOD1 (PC-SOD1). Noise exposure caused significantly higher threshold shifts in PC-SOD1-treated animals than physiological saline-treated animals. Cochlear tissues of PC-SOD1-treated animals exhibited significant elevation of the levels in the SOD activity, not in the catalase activity, in comparison with those of saline-treated animals. Likewise, transgenic mice overexpressing SOD1 tended to suffer higher threshold shifts than nontransgenic littermates from noise exposure. The findings indicate that increasing SOD1 enhances auditory dysfunction following noise exposure.

We studied the neural correlates for the performance of auditory verbal memory using fMRI in 28 normal right-handed volunteers who had to encode and retrieve 50 related word-pair associates. Since the effectiveness of encoding and retrieval processes contribute to memory performance, we combined them in one analysis in addition to examining each condition. Between-subjects analyses were performed by a two-sample t-test in which brain activation in the good-performance group was compared with that of the poor-performance group. Regression analysis was also carried out to find the regions whose activations were linearly correlated to the number of correct recalls by all subjects. In addition to the positive correlates of memory performance, the areas whose activations have a negative effect were also examined. The results indicate that the brain networks of positive correlates including the parahippocampal gyrus and negative correlates including the right prefrontal cortex constitute neural substrates for the performance of auditory verbal memory.

We investigated the effects of neuroactive steroids on N-methyl-D-aspartate (NMDA) cytotoxicity in cultured rat cortical neurons. 3alpha-hydroxy-5beta-pregnan-20-one sulfate (3alpha5betaS) attenuated, whereas pregnenolone sulfate and pregnenolone hemisuccinate exacerbated, NMDA neurotoxicity in cortical slice cultures. These actions of steroids were not affected by inhibition of protein synthesis, by blockade of GABA(A) receptors, or by blockade of sigma receptors. In addition, the actions of steroids were not affected by manipulation of cyclic AMP levels or protein kinase C activity. We found that 3alpha5betaS attenuated and pregnenolone hemisuccinate augmented NMDA-induced currents in cortical neurons, whereas pregnenolone sulfate exerted no significant effect. Fluorometric measurements revealed that 3alpha5betaS attenuated and pregnenolone hemisuccinate augmented glutamate-induced increase in intracellular Ca(2+). Pregnenolone sulfate slowed the decay of Ca(2+) increase induced by glutamate, without significant effect on the peak amplitude of Ca(2+) increase. These results indicate that neuroactive steroids affect NMDA cytotoxicity by modulation of Ca(2+) influx through NMDA receptor-associated channels.

A simple method was established for determination of the stereospecificity of C-4' hydrogen transfer of the coenzymes (pyridoxal and pyridoxamine). The method is based on the findings that aspartate aminotransferase of pig heart and D-amino acid aminotransferase of Bacillus sp. YM-1 catalyze the abstraction of the pro-S and pro-R proton at C-4' of pyridoxamine, respectively. Pyridoxal is a poor coenzyme, but readily released from the enzyme. It reacts in 3H2O with a substrate amino acid and an apo-aminotransferase whose stereospecificity for C-4' hydrogen transfer is to be determined. The resultant pyridoxamine which is tritiated at C-4' is incubated with an apo form of aspartate aminotransferase or D-amino acid aminotransferase and a substrate, alpha-keto acid. The stereospecificity for the C-4' hydrogen transfer examined is determined by measurement of radioactivity retained in the pyridoxal formed. We showed by means of this method that C-4' hydrogen transfer of coenzyme occurs on the si face of the external Schiff base in the transamination reactions of two aspartate aminotransferases of Bacillus sp. YM-2 and Escherichia coli, and aromatic amino acid aminotransferase of E. coli.