碩士 / 國防醫學院 / 公共衛生學研究所 / 100 / Background: Among all the military branches, the armed forces who work at noise environment have higher risk of hearing loss including the exposure to impulse noise from firearms and continuous noise from helicopter/ armored vehicles. In recent years, military helicopter noise has become an important issue. The severity of hearing loss or accompanied tinnitus become worse among helicopter pilots due to increasing flight years and exposure to continuous noise levels of up to 100 dB(A) in working environment. Objective: The aims of the present study are to evaluate the prevalence of hearing impairment and the noise exposures in the army helicopter aircrew environment, and to examine impact of hearing loss and insomnia on mental health simultaneously. Methods: This cross-sectional study was carried out in 667 military personnel among north and central region in Taiwan. Each participant answered questionnaire about demographic data, life style, medical history, working time in a noisy environment, hearing loss, depression scale,insomnia condition. Results:With controlling confounding variables, the army helicopter personnel were found hearing loss status correlated with family medical history(OR=2.22) and personnel hearing protective equitment usage(OR=2.79). Wereas in civilian aircrew, personnel hearing protectors usage was only the factor related to hearing loss(OR=2.62). Furthermore, in aircraft machnists, risk factors included family medical history(OR=6.57), hearing protectors(OR=10.35), listening noisy music(OR=6.36), and operating mowing machine(OR=12.27). And hearing impairment related factors in aviators were smoking(OR=4.89), working time per month(OR=1.01), flying year(OR=1.30) and total flight hours (OR=8.95). Conclusion: This study suggested that smoking cessation, proper usage hearing protectors and avoidance of noisy activities were correlated with hearing loss in the aircrew. Furthermore our results also showed that synergistic effect of hearing loss and insomnia on depression, indicating that mental health need to be concerned at the noisy working environment.

碩士 / 明新科技大學 / 化學工程與材料科技研究所 / 101 / Armillariella mellea is one of the fungi food-medicine mushroom with ranquilizing central nervous and reducing death rate of mice inducing by nicotine. Simultaneously, it can treat for dizziness, palsy, insomnia, tinnitus, etc. Many researchers demonstrated that A. mellea polysaccharide has excellent anti-tumor activity. This research is to use substrates including oats, wheat and buckwheat by Armillariella mellea solid-state fermentation to produce antioxidant ubstances, and the product of solid-state fermentation was also examined in antioxidant activity. The results will provide a valuable reference for manufacture of Armillariella mellea related antioxidant health-food. Therefore, the purpose of this study is to use a substrate including wheat, oats and buckwheat as a substrate by using solid-state fermentation (SSF) to produce A. mellea mycelia, and antioxidant properties of the extracts from A. mellea mycelia were examined. The maximum antioxidant values are described as follows: for antioxidant activity, antioxidant activity values of polysaccharide extract from mycelia by buckwheat SSF are 74.46%. For reducing power, values of cold water extract from mycelia by oats SSF are 3.4. For scavenging DPPH effects, values of cold water extract from mycelia by oats SSF are 75.43%. For chelating ability, values of polysaccharide extract from mycelia by buckwheat SSF are 83.29%. For scavenging superoxide radical ability, values of polysaccharide extract from mycelia by buckwheat SSF are 62.97%. Based on results obtained, A. mellea mycelia produced by wheat, oats and buckwheat SSF possess better antioxidant properties, and can act as a source potential for application in health food.

碩士 / 中國醫藥學院 / 中國藥學研究所 / 89 / Acori Rhizoma　was first recorded in Shen-Nung-Pen-Ts’ao-Ching（神農本草經）as Upper Category and in the successive Pen-Ta’ao of descending dynasties such as Pieh-Lu（別錄）,Hsin-Hsiu（新修），Kai-Pao（開寶）,Chia-Yu（嘉祐）,Tu-Ching（圖經）,Cheng-Lei（證類）,Ta-Kwang （大觀）,Ching-Yao（精要）,Kang-Mu（綱目）,Chin-Wu-Ming-Shih-Tu- Kao（植物名實圖考）and Chang-Pen（長編）. Acori Rhizoma，a famous Chinese traditional drugs, has been adopted in a lot of traditional Chinese prescriptions. It is used for amnesia, palpitation, insomnia, tinnitus, chronic bronchitis and bronchial asthma. It also promoting the secretion of digestive juice, and relaxing the spasm of intestinal smooth muscles. This study started with the textual research of Pent’t sao to clarify historical development. The recent literatures of Acori Rhizoma on pharmeceutical botany, pharmeceutical and pharmacology were also studied to elucidate these utilization of the drugs. Five species belong to Acori genera were found growing in swampy or wet places near creek in Taiwan. They are as follows: 1. Acorus calamus LINNEAUS 2. Acorus gramineus SOLANDER 3. Acorus gramineus SOLANDER var. pusillus ENGLER 4. Acorus grammineus SOLANDER var. flavo-marginatus K.M.LIU 5. Acorus macrospadiceus (YAMAMOTO) F.N.WEI et Y.K.LI The specimens of these five species were compared by their morphology and histological characters such epidermis， parenchyma, vascular bundle,fiber bundle，particle size of crystals were found in Acori Rhizoma. The anatomical structures of the plants were also documented by hand drawing, and photographic methods the results were in plates.

A reabilitação vestibular sofre influências das doenças metabólicas na resposta final do tratamento. Os processos sistêmicos podem afetar negativamente na adaptação vestibular, levando a uma resposta parcial ou ainda ausência de resposta. Este estudo caracterizou a tontura de origem metabólica em pacientes tratados com reabilitação vestibular, identificando aspectos auditivos, otoneurológicos e aspectos da doença metabólica envolvida. O procedimento da pesquisa foi baseado em análise de questionários de pacientes com diagnóstico de tontura de origem metabólica, entre os anos de 2002 a 2014. Os resultados revelaram a ocorrência de doenças metabólicas em 55%(N=55) da população com a diabetes sendo a principal (N=28), seguida de hipotireoidismo (N=24) e colesterol (N=18), sendo que 15%(N=15) apresentaram essas doenças associadas. A queixa associada de zumbido e hipoacusia foi relatada por 46 pacientes. O padrão audiológico encontrado foi perda auditiva do tipo sensórioneural (42%N=42). A resposta de hiporreflexia unilateral foi a mais frequente (38% N=38). Os fármacos vasodilatadores foram os mais usados pelos pacientes deste estudo com destaque para o dicloridrato de betaistina (32% N=32). Não houve correlação entre tipo de tontura e resposta labiríntica. Houve correlação entre zumbido e hiporreflexia unilateral (r=0,9 p=0,02) e entre a associação de zumbido com hipoacusia e hiporreflexia unilateral (r=0,9 p=0,02). O grupo tratado com reabilitação vestibular isolada apresentou melhora significativa com nove meses (p=0,01). O grupo tratado com reabilitação vestibular e medicamentos apresentou melhora significativa com 45 dias (p=0,01). O grupo em uso de um fármaco não apresentou melhora significativa. O grupo em uso de vários fármacos apresentou melhora significativa com 45 dias (p=0,03). Conclui-se que a ocorrência de doenças metabólicas foi de 55% sendo a mais frequente a Diabetes. O zumbido e a hipoacusia foram relatados por 46% da população. Perda auditiva do tipo sensórioneural foi o padrão audiológico encontrado. Hiporreflexia unilateral foi à 9 resposta labiríntica mais frequente. Os fármacos vasodilatadores foram os mais utilizados pelos pacientes desse estudo. Houve correlação entre manifestações auditivas e hiporreflexia unilateral. Não houve correlação entre o tipo de tontura e resposta labiríntica. A reabilitação vestibular associada a uso de medicamentos no tratamento da tontura resultou em melhora dos sintomas de forma imediata, não colaborando para compensação em longo prazo. A reabilitação vestibular isolada no tratamento da tontura resultou em melhora dos sintomas com o efeito do tempo. As interações medicamentosas foram benéficas para alívio imediato da tontura, porém não contribuiu para compensação em longo prazo. / The vestibular rehabilitation is influenced metabolic diseases in response to therapy. Systemic processes may negatively affect the vestibular adaptation, leading to a partial response or lack of response. This study characterizes the labyrinthine metabolic in patients treated with vestibular rehabilitation, identifying aspects hearing, otoneurological and aspects of metabolic disease involved.The procedure of the research was based on analysis of patient questionnaires diagnosed with dizziness of metabolic origin between the years 2002-2014. The results revealed the occurrence of metabolic disorders in 55% (n = 55) of population with diabetes being the main (N = 28), followed by hypothyroidism (N = 24) and cholesterol (N = 18) and 15% (N = 15) had associated diseases. The complaint associated tinnitus and hearing loss was reported by 46 patients. The audiological pattern was sensorineural hearing loss type (42% N = 42). Unilateral hyporeflexia response was the most frequent (38% N = 38). Vasodilator drugs were the most commonly used by patients in this study highlighting the betahistine dihydrochloride (32% N = 32). There was no correlation between type of dizziness and labyrinthine response. There was a correlation between tinnitus and unilateral hyporeflexia (r = 0.9 p = 0.02) and between tinnitus associated with hearing loss and unilateral hyporeflexia (r = 0.9 p = 0.02). The group treated with isolated vestibular rehabilitation showed significant improvement with nine months (p = 0.01). The group treated with vestibular rehabilitation and medications showed significant improvement at 45 days (p = 0.01). The group using a drug did not show significant improvement. The group using several drugs showed significant improvement at 45 days (p = 0.03). It is concluded that the occurrence of metabolic disorders was 55% and the most frequent diabetes. Tinnitus and hearing loss were reported by 46% of the population. Sensorineural hearing loss type was the standard audiological found. Unilateral hyporeflexia was the most frequent response labyrinthine. Vasodilator drugs were the most commonly used by patients in this study. 11 There was a correlation between auditory events and unilateral hyporeflexia. There was no correlation between the type of dizziness and labyrinthine response. Vestibular rehabilitation associated with use of drugs in the treatment of dizziness resulted in improvement in symptoms immediately, not contributing to long-term compensation. Vestibular rehabilitation alone in the treatment of dizziness results in improvement of symptoms with the effect of time. Drug interactions were beneficial for immediate relief of dizziness, but did not contribute to long-term compensation.

This thesis investigates the distribution and function of neuronal nitric oxide synthase (nNOS) in the inferior colliculus (IC) the principal midbrain nucleus in the auditory pathway. Firstly, experiments using immunocytochemistry and fluorescent microscopy in the rat IC showed two, previously unreported, different subcellular distributions of nNOS in the IC. Secondly, the presence of nNOS positive post-synaptic puncta in the central nucleus suggests that nNOS, contrary to previous reports, is not limited to the IC cortices. Expression of nNOS was observed in both glutamatergic and GABAergic cells. Cells expressing nNOS were shown to often contain calbindin or parvalbumin but rarely calretinin. In vivo electrophysiological experiments were conducted in the anaesthetised guinea pig. Recording of multiunit neuronal activity was combined with local reverse microdialysis of drugs in the IC. Dialysis of NMDA increased both spontaneous and sound driven activity in the IC in a dose dependent manner. These effects were blocked when NMDA was paired with L-MeArg, a NOS inhibitor, or ODQ, a soluble guanylate cyclase (sGC) inhibitor. These results suggest that NMDA receptor-mediated effects in the IC involve NO and its action on sGC. Systemic administration of sodium salicylate, a drug known to induce tinnitus, resulted in a doubling of spontaneous activity in the IC. In contrast, local delivery of salicylate in the IC reduced spontaneous activity in a time/concentration-dependent manner. Both locally and systemically administered salicylate influenced sound driven activity, suggesting these effects are, in part, mediated directly within the IC. No effect of L-MeArg was observed on the salicylate mediated effects, but this could be due to methodological issues. These results demonstrate that NO play plays a role in sound processing in the IC and further work is required to establish its functional significance.

In synaesthesia a sensation in one modality triggers a consciously perceived sensation in another sensory modality or cognitive domain. In this thesis we investigate auditory sensation that are induced by dynamic visual stimuli, akin to hearing-motion synaesthesia (Saenz and Koch, 2008). We term this the Visually-Evoked Auditory Response (vEAR). We first establish the prevalence of vEAR in a random sample, with questionnaire responses indicating a higher prevalence (as many as 1 in 5) than canonical synaesthesias. We report that those who experience vEAR showed better performance compared to controls when discriminating between ‘Morse-code’ style rhythmic sequences in the visual domain, as did Saenz and Koch (2008). We also demonstrate that vEAR is perceptually real enough to interfere with hearing real world sounds. We then demonstrate that in control subjects Transcranial Alternating Current Stimulation (TACS), when applied over the temporal versus the occipital lobes, impairs auditory versus visual sequence discrimination respectively. However, temporal TACS improved visual and occipital TACS improved auditory sequence discrimination performance. This suggests the presence of normally-occurring mutual alpha-mediated competitive inhibition of the two cortices. This TACS effect was not seen in individuals with vEAR, indicating that their auditory and visual cortices are able to cooperate to perform the task despite disruption from TACS. Finally, we investigate the types of visual stimuli that best evoke vEAR, and the types of people who tend to experience it. We conducted a large online survey in which respondents rated the amount of vEAR evoked by a series of silent videos depicting types of motion. The predictiveness of a real-world sound was identified as a major contributor to ratings in all respondents, while motion energy (raw changes in light over space and time) specifically influenced ratings in those who experience vEAR. We also report demographic and trait questions relating to auditory perception that predict higher ratings, including the frequency one experiences music imagery in their head, or whether they have tinnitus or types of synaesthesia. We conclude that vEAR results from both high and low-level connectivity between the visual and auditory cortices and an atypical inhibition of these connections.

My studies provided evidence for nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) function in the central auditory system. The auditory cortical and subcortical distributions of nNOS, sGC, PKG1alpha and PKG1beta proteins were examined, using histochemical and immunocytochemical methods of detection. Few auditory structures exhibited different expression patterns for nNOS and the other proteins. In the central nucleus of the inferior colliculus (CIC), the sGC and PKG1alpha antibodies had increased neuropil immunoreactivity which outlined the entire CIC, while nNOS antibody did not immunostain the neuropil. Other auditory structures, the nNOS immunostaining occurred in to interneurons. The sGC, PKG1alpha, and PKGbeta immunostaining occurred in both interneurons and projection neurons, indicating that interneurons might express all of the proteins. The results indicate two populations of neurons in the central auditory system exist. One population of neurons exhibited immunostaining for all the proteins of the NO/cGMP signaling cascade and other population expressed either nNOS or cGMP signaling cascade proteins. Since NO/cGMP signaling cascade proteins exhibited immunoreactivity in the subcortical and cortical auditory structures, these results signify the importance of NO/cGMP signaling cascade in acoustic processing Next the involvement of the NO/cGMP signaling cascade in sound induced c-Fos expression was determined by using the nNOS selective antagonist, 7-nitroindazole (7-NI). Three groups of rats were injected with vehicle, or with 7-NI or not injected. Half the rats in each group were exposed to sound stimulus for 40 minutes, while the others were not. In animals subjected to sound stimulation with or without vehicle pretreatment showed a significant increase of c-Fos immunoreactivity, compared to animals not exposed to sound with or without vehicle pretreatment. Pretreatment with 7-NI in the absence of sound induced a significant increase in c-Fos expression in DCN, IC, and Au, but not in occipital cortex, or entorhinal cortex. Pretreatment with 7-NI in the presence of sound significantly attenuated the c-Fos levels in DCN, IC, and Au. These data suggest a complex interaction between the effects of sound and nNOS in the central auditory pathway, and a decrease in nNOS activity may be a pathophysiological mechanism in hyperacusis, tinnitus and/or audiogenic seizures / acase@tulane.edu

Ménière's disease (MD) is a complex disorder of the inner ear characterized by the symptoms of hearing loss, tinnitus, and vertigo, with an incidence in Caucasians of one in 1000. The hallmark histopathologic feature of MD is endolymphatic hydrops. Symptoms of MD typically present in the fourth decade of life, and the vertigo attacks experienced by patients with MD can be debilitating. Treatments aimed at alleviating the symptoms of MD are ineffective in approximately 30% of patients. Several studies have attempted to identify genetic factors important in MD through the use of families segregating the disease, but causative genes have not been identified. Many of these studies have been unsuccessful due to the fact that families of sufficient size to generate meaningful linkage results are extremely rare. Attempts to identify a genetic component to MD through the use of candidate gene association studies have been underpowered or poorly designed and therefore also unsuccessful. We hypothesize Ménière's disease is a complex disorder that is due to the interplay of genetic and environmental factors. We tested this hypothesis using linkage and association studies. Initially, we focused on candidate gene replication association studies (KCNE1, KCNE3, iNOS), as well as testing a novel candidate gene (AQP4). We were unable to replicate the previous associations and although we could not identify an association between MD and AQP4 we did discover rare variants of AQP4 in our MD patient population. These variants segregate with a `syndromic' MD phenotype. We also performed a genome-wide linkage study on a large Chilean family segregating MD over three generations and identified a novel MD locus on 1q32.1-1q32.3. Targeted exon capture and pyrosequencing of the region identified two potential disease-causing variants in two genes of unknown function. We next screened a cohort of singleton patients with MD for variants in these same genes. Surprisingly, in both genes, we identified common and rare variants supporting a possible role for either gene in the development of MD. The function of these two genes is unknown. Our results imply that additional studies must be undertaken to determine whether one or both genes has a role in the pathogenesis of MD. Identification of a causative gene will aid in the understanding of disease pathophysiology and lead to improved treatments.

Noise exposure destroys cochlear afferent synapses between inner hair cells and spiral ganglion neurons, even in the absence of hair cell loss or permanent threshold shift. This cochlear “synaptopathy” is a result of excess release of the neurotransmitter glutamate from inner hair cells, and consequent glutamate excitotoxicity. While the focus has typically been on hair cell loss, studies in recent years have identified cochlear synaptopathy as another major contributor to noise- or age-related hearing loss. This noise-induced damage to cochlear synapses or noise-induced synaptopathy is a consequence of excitotoxic trauma to the synapses, that is, entry of Ca2+ to reach toxic intracellular levels because of increased excitation of the synapses in noise. Permanent noise-induced synaptopathy can result from noise even at levels low enough that there is no permanent damage to hair cells. Nevertheless, this reduction of synapses does appear to cause serious hearing impairments, including poor speech comprehension in noisy environments, and even tinnitus. Noise induced cochlear synaptopathy in animal models can be detected as a reduction in the number of synapses on the inner hair cells. Few, if any, synapses normally regenerate, but application of neurotrophic factors such as BDNF or NT-3 promotes regeneration. NT-3 is normally expressed in the organ of Corti, and appears necessary for regeneration. Ciliary Neurotrophic Factor (CNTF) is also normally expressed in the organ of Corti, and we ask here whether CNTF can promote cochlear synapse regeneration after synaptopathy resulting from excitotoxic trauma. Our approach to this issue has been a methodical investigation of the causes of noise-induced synaptopathy and excitotoxicity in the cochlea on the cellular level using combined in vitro and in vivo approaches. These studies have revealed, first, a criticalphysiological cause of synaptopathy and a pharmacological means of blocking it, specifically, a blocker of the neurotransmitter receptor through which Ca2+ ions enter the synapse during excitotoxic trauma; second, and the primary focus, we ask here whether CNTF can promote cochlear synapse regeneration after synaptopathy resulting from excitotoxic trauma; third, that female mice are less susceptible to noise-induced synaptopathy than are males, with susceptibility varying through the estrous cycle.

Introduction: Hyperbaric oxygen therapy (HBOT) is the administration of 100% oxygen at pressures greater than 1 atmosphere. One recurrent criticism that has been made of this field is that treatment is based on little or no good clinical evidence. Aims: The primary objective of this thesis is to make a useful response to that criticism. I planned to collate all the available randomised evidence in the fields of diving and hyperbaric medicine, supply a critical appraisal of each paper, and synthesise that evidence in a series of systematic reviews with meta-analysis. I also intended to use a cost analysis of hyperbaric practice in our own facility to inform formal cost-effectiveness analysis using the estimates of effect generated by the individual meta-analyses. Methods: A comprehensive search strategy was used to identify all clinical RCTs involving the administration of hyperbaric breathing mixtures. Each trial was appraised using the software developed by the Oxford Centre for Evidence Based Medicine. Each critical appraisal was loaded onto a searchable web site at www.hboevidence.com. Each diagnostic category identified was considered for inclusion in a Cochrane systematic review and meta-analysis. Results: The database includes 130 critical appraisals covering 173 separate reports. The site has received more than 17,000 hits. There are 12 formal meta-analytical reviews and all have been accepted for publication in the Cochrane Database of Systematic Reviews at the time of writing. These form the basis of this thesis and include late radiation tissue injury, chronic wounds, acute hearing loss and tinnitus, multiple sclerosis and decompression illness. The meta-analyses in this thesis suggest there are several areas where HBOT is associated with improved clinical outcomes and that routine use is probably justified in some areas (e.g. radiation proctitis healing with HBOT: NNT 3, 95%CI 2 to 11). On the other hand, these analyses suggest there is most unlikely to be significant clinical benefit from the application of HBOT to patients currently referred for HBOT (e.g. multiple sclerosis). Conclusions: The randomised evidence for the use of HBOT is now significantly easier to access. Recommendations for therapy and future research directions can be made on the basis of these analyses.