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Supplementary figure 1. Characterization of the cisplatin-resistant HNSCC cell lines. Supplementary figure 2. Genetic or pharmacological inhibition of G9a promotes cisplatin-induced apoptosis in SAS-CR cells.Supplementary figure 3. Depletion of G9a increases the sensitivity to cisplatin in OECM-1 cells.Supplementary figure 4. Depletion of G9a increases the platinum-DNA adduct accumulation. Supplementary figure 5. Inhibition of G9a by shRNA or enzymatic inhibitor decreases intracellular GSH levels. Supplementary figure 6. Multi-drug resistance to chemotherapeutic agents in G9a-overexpressed SAS cells. Supplementary figure 7. Effect of G9a on the expression of GSH synthesis enzymes. Supplementary figure 8. The expression of GSH synthesis enzymes in mouse xenograft tumors. Supplementary figure 9. ATF4 upregulates GCLC in cisplatin-resistant cells. Supplementary figure 10. Upregulated GCLC is required for G9a to promote cisplatin resistance.

Hypoxia-inducible factor-1α (HIF-1α) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1α, acting through direct binding to the HIF-1α 3′ untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1α protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1α protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1α–mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c–overexpressing cells exhibited dramatically reduced HIF-1α levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1α inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells. Cancer Res; 70(7); 2675–85

Supplementary Figures 1-7 from MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

Background: The world’s age-related health concerns continue to rise. Audio-vestibular disorders, such as hearing loss, tinnitus, and vertigo, are common complaints in the elderly and are associated with social and public health burdens. Various preventative measures can ease their impact, including healthy food consumption, nutritional supplementation, and lifestyle modification. We aim to provide a comprehensive summary of current possible strategies for preventing the age-related audio-vestibular dysfunction. Methods: A PubMed, Embase, and Cochrane review databases search was conducted to identify the relationship between diet, lifestyle, and audio-vestibular dysfunction. “Diet”, “nutritional supplement”, “lifestyle”, “exercise”, “physical activity”, “tinnitus”, “vertigo” and “age-related hearing loss” were used as keywords. Results: Audio-vestibular dysfunction develops and progresses as a result of age-related inflammation and oxidative stress. Diets with anti-inflammatory and antioxidant effects have been proposed to alleviate this illness. A high-fat diet may induce oxidative stress and low protein intake is associated with hearing discomfort in the elderly. Increased carbohydrate and sugar intake positively correlate with the incidence of audio-vestibular dysfunction, whereas a Mediterranean-style diet can protect against the disease. Antioxidants in the form of vitamins A, C, and E; physical activity; good sleep quality; smoking cessation; moderate alcohol consumption; and avoiding noise exposure are also beneficial. Conclusions: Adequate diet or nutritional interventions with lifestyle modification may protect against developing audio-vestibular dysfunction in elderly individuals.

The most prevalent oral cancer globally is oral squamous cell carcinoma (OSCC). The invasion of adjacent bones and the metastasis to regional lymph nodes often lead to poor prognoses and shortened survival times in patients with OSCC. Encouraging immunotherapeutic responses have been seen with immune checkpoint inhibitors (ICIs); however, these positive responses to monotherapy have been limited to a small subset of patients. Therefore, it is urgent that further investigations into optimizing immunotherapies are conducted. Areas of research include identifying novel immune checkpoints and targets and tailoring treatment programs to meet the needs of individual patients. Furthermore, the advancement of combination therapies against OSCC is also critical. Thus, additional studies are needed to ensure clinical trials are successful. Mice models are advantageous in immunotherapy research with several advantages, such as relatively low costs and high tumor growth success rate. This review paper divided methods for establishing OSCC mouse models into four categories: syngeneic tumor models, chemical carcinogen induction, genetically engineered mouse, and humanized mouse. Each method has advantages and disadvantages that influence its application in OSCC research. This review comprehensively surveys the literature and summarizes the current mouse models used in immunotherapy, their advantages and disadvantages, and details relating to the cell lines for oral cancer growth. This review aims to present evidence and considerations for choosing a suitable model establishment method to investigate the early diagnosis, clinical treatment, and related pathogenesis of OSCC.

Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti–programmed cell death-1 (anti-PD1) agents. In addition, early-phase clinical trials of combination of anti–PD-1 and antiangiogenic agents have shown very promising anti-tumor activity in patients with advanced HCC. Therefore, the critical research questions at present are whether this combination strategy will be the next generation of standard therapy and which antiangiogenic agents will be the optimal partner for the combination. All of the 4 multikinase inhibitors for HCC (sorafenib, regorafenib, lenvatinib, and cabozantinib) have been reported to have immune modulatory effects. The authors systematically reviewed the pre-clinical evidence of their immune modulatory effects to explore whether these effects were mediated by angiogenesis inhibition or by other “off-target” effects on the tumor microenvironment. Studies of sorafenib comprised the majority (58 of the 71) of the research articles reviewed. Potentially beneficial effects on anti-tumor immunity may result from increased M1 polarization of macrophages and stimulation of CD8 T cell function. On the other hand, high dosage of the kinase inhibitors in pre-clinical models and hypoxia associated with angiogenesis may contribute to immune suppression in the tumor microenvironment. Sorafenib and other multikinase inhibitors may promote anti-tumor immunity through modulation of multiple immune cell types as well as the tumor microenvironment. The optimal immune modulatory dosage should be defined to facilitate design of future combination regimens.

Summary Objectives Although a variety of therapeutic techniques have been suggested for patients with unilateral adductor vocal fold paralysis (UAVFP), they were not aimed specifically at determining the efficacy of early intervention for these patients. The purposes of this study are to explore a protocol of voice therapy and to investigate its efficacy in voice therapy for patients with early UAVFP. A 12-week planned voice therapy protocol, including vocal function exercise, hard attack, and resonance voice therapy, was given to 10 patients within 6 months of initial diagnosis. Additionally, nine patients diagnosed with UAVFP within 6 months served as controls. Methods Multidimensional evaluations of voice function were obtained for statistical analyses. Results Compared to a control group, the experimental group receiving voice therapy exhibited significant improvement in the following: (1) glottal closure; (2) voice quality of grade, breathiness, monotone, and resonance; (3) acoustic measurements of jitter, shimmer, and noise-to-harmonic ratio; (4) aerodynamics measurements of maximum phonation time, phonation threshold pressure, and phonation quotient; and (5) Voice Handicap Index of functional subscale. Conclusion This prospective study established an effective protocol of early intervention of voice therapy in patients with UAVFP and demonstrated its efficacy in data on laryngeal physiology, voice quality, voice stability, voice efficiency, and communication function.

This study explored the curriculum-related beliefs and practices reported by Singapore kindergarten teachers at a time when concerted efforts are being made to promote children’s holistic development through a child-centered curriculum that emphasizes active learning through play and interaction. A questionnaire was administered to a sample of 167 teachers of 4- to 5-year-olds. Factor analyses revealed three reliable factors for teachers’ beliefs and four factors for their classroom practices. Teachers endorsed philosophies in child-centeredness and teacher-centeredness but there was stronger endorsement of child-centered approach. Correlation and regression analyses conducted revealed some relationships between beliefs and reported practices as well as associations of beliefs and practices with certain personal and kindergarten factors. Overall, beliefs in child-centeredness and teacher-centeredness predicted interactive academic activities, and beliefs in teacher-centeredness influenced reports of engaging in structured academic and teacher-led activities after controlling for demographic and contextual variables.

Almost all children in Singapore complete 1 year of preschool before entering primary school. However, preschool education (PSE) is not compulsory and is provided primarily by the private sector. Taking the national agenda for reforming PSE at the start of the twenty-first century as the point of departure, this paper describes and discusses the policies and strategies that have been introduced and implemented for preschool quality enhancement in the past 15 years. Three major waves of preschool policy reviews were undertaken in 2000, 2008, and 2012 attesting to the seriousness the government attaches to improving PSE for encouraging a strong start for every child. The key recommendations of these reviews were related to uplifting teacher, center, and program quality, and enhancing the affordability and accessibility of PSE. Opportunities and challenges associated with implementing recommendations for quality enhancement are discussed and suggestions to further enhance PSE in Singapore are explored.

Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatin-resistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC. Mol Cancer Ther; 16(7); 1421–34. ©2017 AACR.

B-cell lymphoma/leukemia 10 (BCL10) is an apoptotic regulatory protein related to advanced TNM stage and disease recurrence in oral squamous cell carcinoma (OSCC). However, the regulatory mechanism of BCL10 in OSCC progression is still unknown. Here, we showed that knockdown of endogenous BCL10 could significantly reduce cell migration and invasion abilities, retard cell proliferation by G0/G1 phase accumulation and inhibit tumorigenicity in vivo. In molecular level, we identified S100P as a crucial downstream effector of BCL10-inhibited OSCC progression by high-throughput microarray analysis. S100P messenger RNA and protein expression levels were significantly diminished in silenced-BCL10 clones, and transfected S100P expression plasmids restored migration, invasion, proliferation abilities and tumorigenicity in shBCL10 transfectants. Furthermore, we provided evidence that BCL10 regulated S100P expression through signal transducers and activators of transcription 1 (STAT1) and activating transcription factor 4 (ATF4). Knockdown of BCL10 decreased S100P promoter activity, but showed no effect in truncated STAT1/ATF4 S100P promoter. In addition, we also found that the P50/P65 signaling pathway was involved in BCL10-enhanced OSCC progression. Restored S100P in silenced-BCL10 clones could markedly reverse P65 activation via outside-in signaling. Taken together, we discovered a novel axis of BCL10-regulated OSCC progression via STAT1/ATF4/S100P/P65 signaling, which could predict the prognosis of OSCC and will be beneficial for developing therapeutic strategy against advanced OSCC.

The editors were made aware of concerns by a reader regarding potential manipulation of data in [this article][1] ([1][2]). An internal review by the editors determined that the same RT-PCR bands appear to be duplicated in the A549/HIF-1α and MDA-MB-231/GAPDH panels in Fig. 1B. In addition, it

Background Higher CXCR4 expression enhances basal cell carcinoma (BCC) invasion and angiogenesis. The underlying mechanism of increased CXCR4 expression in invasive BCC is still not well understood. Objective To investigate the mechanisms involved in the regulation of CXCR4 expression in invasive BCC. Methods We used qRT-PCR, RT-PCR, Western blot, and flow cytometric analyses to examine different CXCR4 levels among the clinical samples, co-cultured BCC cells and BCC cells treated with recombinant transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF). Immunohistochemical studies were used to demonstrate the correlation between TGF-β1 and CXCR4 expressions. The signal transduction pathway and transcriptional regulation were confirmed by treatments with chemical inhibitors, neutralizing antibodies, or short interfering RNAs, as well as luciferase reporter activity. Results Invasive BCC has higher TGF-β1 and CTGF levels compared to non-invasive BCC. Non-contact dermal fibroblasts co-culture with human BCC cells also increases the expression of CXCR4 in BCC cells. Treatment with recombinant human TGF-β1, but not CTGF, enhanced the CXCR4 levels in time- and dose-dependent manners. The protein level and surface expression of CXCR4 in human BCC cells was increased by TGF-β1 treatment. TGF-β1 was intensely expressed in the surrounding fibroblasts of invasive BCC and was positively correlated with the CXCR4 expression of BCC cells. The transcriptional regulation of CXCR4 by TGF-β1 is mediated by its binding to the TGF-β receptor II and phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2)-ETS-1 pathway. Conclusion TGF-β1 induces upregulation of CXCR4 in human BCC cells by phosphorylation of ERK1/2-ETS-1 pathway.

Stromal cell-derived factor-1 (SDF-1) (CXCL12) has been observed to promote laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) invasion through cooperation with its receptor CXCR4. Here, we further explore the angiogenesis mechanism induced by SDF-1/CXCR4 interaction in LHSCCs. Immunohistochemistry (IHC) reveals the significant correlation between CXCR4 and angiogenesis in tumors. After blocking the function of CXCR4 by specific inhibitor AMD3100 and neutralized antibody 12G5 or inhibiting the expression by siRNA, we were able to disrupt the HUVECs tube formation, demonstrating that SDF-1/CXCR4 indeed regulated the angiogenesis mechanism. The angiogenesis profiling from angiogenesis array and reverse transcription polymerase chain reaction indicates that IL-8 can be significantly triggered by SDF-1/CXCR4 interaction in LHSCCs. We also demonstrate that IL-8 secretion mechanism is regulated by Akt phosphorylation after SDF-1 stimulation. These results point out the importance of SDF-1/CXCR4 interaction in LHSCCs angiogenesis. The angiogenic factor IL-8 would be triggered by the cooperation of SDF-1 and CXCR4 through an Akt-dependent pathway. This provides a new targeting therapy utility, disrupting SDF-1/CXCR4 interaction combined with downstream-induced angiogenic factors in LHSCCs would be beneficial to improve clinical outcome.

The aim of this study was to investigate whether physical evaluations could be used for predicting the presence and severity of obstructive sleep apnea (OSA) in non-obese snoring patients.This is a retrospective study, and a total of 244 non-obese (body mass index, BMI,27 kg/m(2)) snoring patients (178 men and 66 women; mean age = 43.1 ± 12.1 years) were included. Each patient underwent polysomnography and a thorough physical examination, including flexible nasopharyngoscopy and Müller maneuver. Patients were divided into four groups based on apnea-hypopnea index (AHI) scores: normal (simple snoring), AHI5; mild OSA, 5 ≦ AHI15; moderate OSA, 15 ≦ AHI30; severe OSA, AHI ≧ 30. Logistic regression was used to identify risk factors for OSA severity.Fifty-nine patients (24%) were simple snorers. The prevalence of sleep apnea (mild, moderate, or severe OSA) for our non-obese snoring patients was 76%. Univariate logistic analyses showed that higher BMI, male gender and retropalatal Müller grades were significantly associated with OSA severity. Multivariate logistic regression analysis identified male gender and retropalatal Müller grade as risk factors for OSA in non-obese snoring patients.Physical examination may be useful for studying the upper airway in non-obese snoring patients. Flexible nasopharyngoscopy with Müller maneuver appears to be useful for evaluating the severity of OSA in non-obese patients. Retropalatal Müller grade is highly related to both the presence and severity of OSA, particularly in males.

Background: The aim of this study was to investigate the role of temperature and humidity in positive continuous pressure flow-induced apnea. Methods: Forty-two adult male Sprague-Dawley rats were used in a functionally isolated laryngeal animal model. In study 1, animals were challenged with laryngeal stimulation for 1 minute to detect the possibility of adaptation. In study 2, different airflow conditions (25°C dry–25°C dry, 25°C dry–25°C wet, 25°C dry–37°C dry and 25°C dry–37°C wet) were delivered to determine the role of temperature and humidity in the flow-induced apneic response of the larynx. The apneic index was calculated by prolonged expiratory time/baseline expiratory time. Results: Laryngeal dry room temperature air exposure induced an apneic response, and this response was reproducible and could be eliminated by humidification. In contrast, this apneic response could not be inhibited by increasing temperature alone. In addition, prolonged cold dry air stimulation did not evoke a tachyphylactic effect to normalize the breathing pattern. Conclusion: Laryngeal cold dry air stimulation triggered an apneic response, which could be eliminated by humidification but not by the heating of air. These results suggest that using continuous positive airway pressure (CPAP) with humidified air decreases CPAP-induced apnea. [J Chin Med Assoc 2010;73(7):369–374]

To investigate the incidence and prenatal risk factors for allergic rhinitis among elementary school children in an urban city.Risk factor data were collected by questionnaire and direct physical examination. Multiple logistic regression analysis was used to calculate the odds ratios of developing allergic rhinitis among children 6-13 years of age.From January 2006 to December 2006, we enrolled 1368 elementary school children in the study. Sampling was done by a multi-stage clustered-stratified random method to determine the study subject. All the children studied attended 12 elementary schools located in the six districts in Taipei, with two schools in each district. Odds ratios were adjusted for the confounding effects of gender, parity, maternal age at childbirth, maternal education, gestational complications, tobacco smokers in the residence, pets, carpets, molds, and air pollution.The incidence of allergic rhinitis in the study was 50.1% (685/1368). Factors like gender (p.001), parity (p.05), carpets (p.025), and air pollution (p.001) increased risk, while the other factors did not (p.05 for all).Gender, parity, carpets, and air pollution increased the risk of developing allergic rhinitis among elementary school children. Other potential factors such as low birth weight, maternal age at childbirth, parental education, gestational complications, presence of tobacco smokers, and exposure to pets and molds did not significantly increase risk of developing allergic rhinitis.

Objectives/Hypothesis: The purpose of this study is to investigate whether diabetes impairs the recovery from noised-induced temporary hearing loss. Methods: Twenty-eight male Wistar rats were divided into three groups: control, diabetes with insulin control (DI), and diabetes without insulin control (DM). Diabetes was induced by intraperitoneal injection of streptozotocin. All animals were exposed to white noise at 110 dB SPL for 8 hours. Auditory brainstem response (ABR) thresholds and distortion product otoacoustic emission (DPOAE) amplitudes were measured for all animals 1 day prior to noise exposure to obtain a baseline for hearing function, and then 1 hour, 1 day, 2 days, 4 days, 7 days, and 14 days after noise exposure. Results: One hour post exposure, ABR thresholds shifted markedly, and DPOAE was reduced similarly in all groups. Both ABR thresholds and DPOAE returned to the baseline in the control group at day 1, but they were not back to the baseline in the DM group even by day 14. Compared with the control group, the ABR threshold shifts and DPOAE returned to baseline more slowly in the DI group. Conclusions: The present study suggests that diabetic patients need proper blood sugar control and probably need more effective preventive measures to preserve their hearing from the effects of noise.

Introduction Craniofacial anatomic abnormalities related to structural narrowing of the upper airway have been reported in patients with obstructive sleep apnea syndrome (OSAS). The purpose of this study was to test whether there are sex differences in the relative contributions of specific anthropometric and cephalometric measurements of OSAS severity. Methods The subjects were Taiwanese patients who visited the Ear, Nose, and Throat Department of National Taiwan University Hospital with complaints of snoring or sleep apnea. The anthropometric, cephalometric, and overnight polysomnographic records of 109 subjects were evaluated. Results There are obvious sex differences in the craniofacial skeletal characteristics that contribute to OSAS severity. Male patients with the following risk factors are likely to have more severe type OSAS: increased neck size, inferiorly positioned hyoid bone, and greater anterior lower facial height. The risk factors related to the severity of OSAS in female patients include smaller posterior facial height and anteriorly positioned hyoid bone. Conclusions To evaluate OSAS severity, different anthropometric and cephalometric measurements should be used for men and women. The craniofacial skeletal characteristics that contribute to OSAS severity were in the anterior lower portion of the profile in men and in the posterior portion of the profile in women.

Epigenetic reprogramming has been associated with the functional plasticity of cancer-initiating cells (CICs); however, the regulatory pathway has yet to be elucidated. A siRNA screen targeting known epigenetic genes revealed that G9a profoundly impairs the chemo-resistance, self-renewal and metastasis of CICs obtained from patients with colorectal cancer (CRC). Patients with elevated G9a were shown to face a high risk of relapse and poor survival rates. From a mechanistic perspective, G9a binds with and stabilizes RelB, thereby recruiting DNA methyltransferase 3 on the Let-7b promoter and repressing its expression. This leads to the activation of the K-RAS/β-catenin pathway and regulates self-renewal and function of CICs. These findings indicate that the G9a/RelB/Let-7b axis acts as a critical regulator in the maintenance of CIC phenotypes and is strongly associated with negative clinical outcomes. Thus, these findings may have diagnostic as well as therapeutic implications for the treatment of chemotherapy-resistant or metastatic CRC.

The effects of taicatoxin on the slow motility of isolated outer hair cells of guinea pig were studied in the experiments. Pretreatment with taicatoxin (0.19 microM) was able to prevent both the cell shortening induced by high K(+) (50mM), and the cell elongation induced by ionomycin (10 microM). These effects of taicatoxin can be mimicked by pretreatment of cells with Ca(2+)-free medium on the slow motility in response to ionomycin or high K(+). Pretreatment with neither calcium channel blockers such as nifedipine (L-type blocker), omega-conotoxin GVIA (N-type blocker), and omega-agatoxin IVA (P-type blocker); nor potassium channel blockers, such as tetraethylammonium chloride (TEA) and 3,4-diaminopyridine (3,4-DAP) can antagonize the cell shortening effect induced by high K(+) and cell elongation induced by ionomycin. The calcium-imaging experiment indicated that taicatoxin, but not nifedipine, did prevent an increase of intracellular Ca(2+) level significantly induced by high K(+). These results demonstrate that the effect of taicatoxin was to block the calcium entry through calcium channels of cell membrane, without relative to its properties of potassium channel blockers. We conclude that taicatoxin-sensitive-calcium channels at least impart, play a significant role in the slow motility of outer hair cell.

INTRODUCTIONAcute alcohol (ethanol) challenge is known to inducevarious cognitive disturbances. Alcohol can also affecthearing by acting on the human central nervoussystem. Significant reductions in the amplitude ofauditory cortical potentials have been reported afteralcohol ingestion (1). Subcortical alterations of audi-bility under the influence of alcohol in humans havealso been studied. Several investigators showed thatacute and chronic ethanol ingestion could alterauditory brainstem potentials and middle latencyresponses (2, 3). Studies of the effects of alcohol onhuman auditory thresholds yielded varying results.Murata et al. (4) reported that drinking even verysmall amounts of alcohol induces a temporary reduc-tion in auditory threshold. It was also reported thatmoderate alcohol consumption (

Observing the pattern changes of inpatient fall and validating the Fall Prevention Tool Kit (FPTK) are essential for developing fall prevention strategies. However, the work requires the collection, calculation, and comparison of large amount of data. The information is often scattered in diverse information systems and lack of integration, which makes the work difficult and often neglected. This study demonstrates the development of an Interactive Data Repository System (IDRS) and uses it in the analysis of the pattern changes of inpatient fall within the institute, and validates efficiency of the FPTK across time. This study collected the incident data of year 2011 and compared it with the previous analysis in 2001. The result shows that reasons for patient fall had turned from physical disability to impaired conscious or cognition. The scoring result may be too sensitive in identifying patient falls. Patients with high scores needed to reinforce in functional strength.

Noise and aminoglycosides initially attack cochlear outer hair cells (OHCs). Distortion product otoacoustic emissions (DPOAEs) are used for the early diagnosis of damage to OHCs. The effects of sub-damaging doses of amikacin, an aminoglycoside antibiotic agent, on noise-induced hearing loss (NIHL) were examined in guinea pigs. Animals were grouped by gender and exposed to broadband noise at 105 dB SPL for 12 h and/or injected i.m. with either amikacin (100 mg/kg/day) or saline for 10 days. Auditory brainstem response (ABR) thresholds, along with DPOAE amplitudes, were measured serially before and after noise exposure. DPOAE amplitudes decreased and ABR thresholds elevated immediately after noise exposure and then gradually recovered. At all frequencies, the emission amplitudes recovered completely to pre-exposure baseline values by 4 days after noise exposure. There was no effect of amikacin on either the ABR threshold or DPOAE amplitudes, in animals treated with amikacin only. However, amikacin significantly prolonged the effect of noise exposure on DPOAE amplitude but not on the noise-induced temporary threshold shift (TTS) of the ABR. In animals treated with a combination of noise and amikacin, significant changes in DPOAE amplitudes were still observed at 4 weeks after cessation of noise exposure. No gender difference in the responses to noise and/or amikacin could be demonstrated. The present findings indicate that even sub-damaging dosages of amikacin might impair recovery from NIHL in guinea pigs.

Na+,K+-ATPase and Ca2+-ATPase activities have not been studied quantitatively in the cochlea affected by endolymphatic hydrops. The present study was designed to measure quantitatively the Na+,K+-ATPase and Ca2+-ATPase activities in the cochlear lateral wall and the threshold of auditory brainstem response (ABR) for guinea pigs in the early stages (=2 months) of experimentally induced endolymphatic hydrops. A significant negative association was demonstrated between Ca2+-ATPase activity and the change in ABR threshold for hydropic cochleae (P=0.014), but not for control cochleae (P=0.123), although no such significant association was revealed between Na+,K+-ATPase activity and any change in ABR threshold for both hydropic cochleae (P=0.751) and control cochleae (P=0.352). A significant increase in Ca2+-ATPase activity in the cochlear lateral wall was observed for the hydropic ear, in which normal ABR thresholds were maintained, as compared to the control ear. On the contrary, a mild decrease in Ca2+-ATPase activity in the cochlear lateral wall was observed for the hydropic ear, in which ABR thresholds increased significantly. The present findings suggest that alterations of Ca2+-ATPase activity in the cochlear lateral wall may implicate disturbed calcium-homeostasis in the inner ear, resulting in hearing dysfunction in the early stages of experimentally induced endolymphatic hydrops.

Aminoglycosides are widely used antibiotics and frequently produce acute ototoxicity. In this study we attempted to comparatively investigate the effects of gentamicin on Ca2+ influx of apical and basal outer hair cells (OHCs) isolated from guinea-pig cochlea. Since the solution of gentamicin sulfate salt is acidic (pH 3.1-3.3), we also explored the effect of external acidification on Ca2+ influx. By means of fura-2 microspectrofluorimetry, we measured the intracellular calcium concentration ([Ca2+]i) of OHCs bathed in Hanks' balanced salt solution (pH 7.40) during either a resting state or high K+-induced depolarization. Our results show that at the resting state, the baseline [Ca2+]i in apical OHCs (94+/-2.0 nM) was slightly lower than that in basal OHCs (101.1+/-2.4 nM). By contrast, the increase in [Ca2+]i evoked by high K+ depolarization in apical OHCs was about two-fold greater than that in basal OHCs. Nifedipine (30 microM) abolished the increased [Ca2+]i in both types of OHCs, suggesting that Ca2+ influx was mainly through L-type Ca2+ channels of OHCs. While gentamicin and extracellular acidification (pH 7.14) can separately attenuate this increase in [Ca2+]i in both types of OHCs, their suppressive effects are additive in basal OHCs, but not in apical OHCs. The implications of these findings are that: (1) apical and basal OHCs behave differently in response to depolarization-increased [Ca2+]i, and (2) basal OHCs are more vulnerable to the impairment of Ca2+ entry during depolarization by a combination of gentamicin and extracellular acidification, which is correlated with the clinical observation that ototoxicity of aminoglycosides at the basal coil of OHCs is more severe than that at the apical coils. Moreover, the possibility that extracellular acidification may enhance the acute ototoxic effects of aminoglycosides should be considered especially in topical applications.

The purpose of this study is to investigate whether suramin is capable of preventing the neurotoxic effects of Ca(2+) channel inhibitors at the presynaptic sites. Mouse diaphragm and triangularis sterni preparations were used for this study in order to measure the muscle tension and nerve terminal Ca(2+) current, respectively. Both omega-conotoxin MVIIC and omega-agatoxin IVA markedly inhibit the nerve-evoked muscle contractions as well as the nerve terminal Ca(2+) current respectively. Pretreatment with suramin (0.3 mM) significantly reduced the inhibitory effect of nerve-evoked muscle contractions and Ca(2+) current induced by either omega-conotoxin MVIIC or omega-agatoxin IVA but not that induced by the non-selective Ca(2+) channel blocker, Cd(2+). Neither suramin nor Ca(2+)-channel toxins significantly affect Na(+)- and K(+) currents of the nerve terminals. These findings indicate that suramin selectively interferes the action of presynaptic Ca(2+) channel neurotoxins and thus reduces their depressant effects on the muscle contractions. The implication of these findings is that suramin and its derivatives may potentially become useful agents in management of intoxication of Ca(2+) channel neurotoxins.

This study examined 11,333 rigid endoscopy procedures performed in the Department of Otolaryngology, National Taiwan University Hospital, during a 27-year period from 1970 to 1996. Among these cases, 3217 were performed to remove foreign bodies from the airway (459 cases, 14.3%) and esophagus (2758 cases, 85.7%). Retrospective analysis of these data revealed that peanuts (217 cases) and animal bones (1184 cases) were the most frequent foreign bodies encountered in the airway and esophagus, respectively. The successful rate of removal of these foreign bodies was 99.9% (3213/3217). The complication rate was only 0.2% (8/3217), and the mortality rate was less than 0.1% (2/3217). On the basis of these results, we conclude that foreign bodies in the airway and esophagus can be removed safely under direct visualization through rigid endoscopy with relatively few complications. A significant finding in this study is the declining trend in the number of cases in recent years. Despite the decline in the number of procedures, endoscopic removal of foreign bodies remains as a vital skill of the aerodigestive tract surgeon.

Otitis media with effusion is characterized by the presence of an inflammatory cellular infiltrate of the submucosa and a poor ventilation of the middle ear. This results in hypersecretion of mucus and alteration of the mucociliary clearance, which produce accumulation of fluid and cellular debris in the middle ear. The aim of this work was to investigate whether inflammatory mediators such as prostaglandins and oxygen metabolites modulate the absorptive function of the middle ear epithelium. The data we present demonstrated that: (i) among prostanoids, only prostaglandin E2 modulated the rate of sodium transport; (ii) oxidants had a stimulatory effect on ion transport; (iii) the role of reactive oxygen species was mediated by prostaglandin E2. This process might be involved in the impairment of the mucociliary clearance.

Mucus and cellular debris are eliminated from the middle-ear cavity through the E-tube by the mucocuiary system. Depth of the periciliary fluid layer is thought to be regulated by epithelial ion trans

Oral cancer, a subtype of head and neck cancer, is one of the leading causes of cancer death and is difficult to detect in the early stages. Improved methods of detecting primary oral lesions during endoscopy would significantly improve cancer survival rates. Here we report a high-performance nanoparticle for photodynamic detection of oral cancer. Succinate-modified chitosan (SCHI) is physically complexed with folic-acid-modified chitosan to form nanoparticles with a high drug loading efficiency and to improve drug release in the cellular lysosome. The z-average diameter and zeta potential of the prepared nanoparticles (fSCN) were 110.0 nm and 18.6 mV, respectively, enough to keep the nanoparticles stable in aqueous suspension without aggregating. When loaded with 5-aminolaevulinic acid (5-ALA; 72.8% loading efficiency) in the prepared fSCNA, there were no significant differences between the fSCN and fSCNA in particle size or zeta potential. Moreover, the fSCNA nanoparticles were readily engulfed by oral cancer cells via folate-receptor-mediated endocytosis. The release of loaded 5-ALA in the lysosome was promoted by the reduced attraction intensity between chitosan and 5-ALA via the deprotonated SCHI molecules, which resulted in a higher accumulation of intracellular protoporphyrin IX (PpIX) for photodynamic detection. These results demonstrate that N-succinyl-chitosan-incorporated and folic-acid-conjugated chitosan nanoparticles are an excellent vector for oral-specific delivery of 5-ALA for fluorescent endoscopic detection.