Introdução: As afecções nasais e sinonasais em cães possuem causas variadas, e algumas vezes cursam com sinusites, sendo raros os casos que não há doença nasal pré-existente. O diagnóstico presuntivo é baseado nas manifestações clínicas como secreção nasal uni ou bilateral anormais, esternutações, esternutações reversas paroxísticas, respiração estertorosa, engasgos, halitose, epistaxes, rinorragia, tosse, distrição respiratória, dor e deformação facial. Para concluir o diagnóstico, são indicados exames de imagem, rinoscopia, culturas, citologia e histopatológico. Objetivo: O presente estudo observacional teve como objetivo avaliar a contribuição ao diagnóstico das afecções da cavidade nasal e seios paranasais de cães, da radiografia, tomografia computadorizada e rinoscopia, realizando-se a comparação dos métodos diagnósticos mediante ao escore comparativo idealizado para este fim. Materiais e métodos: Foram utilizados 20 cães atendidos do Hospital Veterinário da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, com manifestações clínicas compatíveis com afecção nasal e submetidos a exame radiográfico, tomográfico e rinoscópico. A biópsia foi realizada, em 18 cães, por meio da rinoscopia, nos casos em que visibilizou-se proliferação tecidual, úlcera ou alteração na mucosa nasal sendo encaminhadas para estudo histológico. Resultados: Foram observados resultados estatisticamente significativos, baseados pelo escore, a radiografia em conjunto com a tomografia computadorizada, a rinoscopia associada à tomografia computadorizada e, também, a rinoscopia isoladamente, como métodos diagnósticos mais específicos na diferenciação de lesão maligna. A rinoscopia demonstrou como vantagem a visibilização direta diferenciando a presença ou não de inflamação ou proliferação tecidual, alteração anatômica, corpo estranho e placa fúngica. Conclusão: Os resultados do presente estudo indicam que embora possuam especifidade diferentes a utilização da radiografia, tomografia computadorizada e rinoscopia se complementaram como métodos diagnósticos nas afecções nasais e sinonasais dos cães avaliados. Nos casos de proliferação tecidual o estudo histológico demonstrou ser mais útil para conclusão diagnóstica em comparação aos exames de imagem e a rinoscopia. / Introduction: The nasal and sinus disorders in dogs have various causes, and sometimes go with sinusitis that there is no pre-existing nasal disease. The presumptive diagnosis is based on clinical manifestations as nasal discharge, sneezing, reverse sneezing, gagging, stertor, halitosis, epistaxis, cough, open-mouth breathing, pain and facial deformation. To complete the diagnosis, image examinations, rhinoscopy, cultures, cytology and histopathological fidings. Objectives: This observational study aimed to evaluate the contribution to the diagnosis of disorders of the nasal cavity and paranasal in dogs, radiography, computed tomography and rhinoscopy, performing comparison of diagnostic methods through the comparative score conceived for this purpose. Materials and methods: This study used 20 dogs of Veterinary Hospital of the Faculty of Veterinary Medicine and Zootechny of the University of São Paulo, with clinical signs compatible with nasal disorder and undergone radiographic examination, computed tomography and rhinoscopy. The biopsy was performed on 18 dogs through rhinoscopy, where is tissue proliferation, ulcer or change in the nasal mucosa histology study being forwarded to. Results: Significant results were observed by the score with radiography, computed tomography, rhinoscopy associated with computed tomography, and also, separately, as rhinoscopy diagnostic methods more specific differentiation of malignant lesion. The rhinoscopy demonstrated how advantage to visualize directly differentiating presence or not of inflammation or tissue proliferation, alteration, foreign body and fungal plaques. Conclusion: The results of this study indicate that although having different specific utilization, radiography, computed tomography and rhinoscopy as diagnostic methods arranged in nasal disorders of dogs and evaluated. In cases of tissue proliferation, histological study proved most useful in final diagnostic compared to the image exams and rhinoscopy.

Este trabalho teve como objetivos a avaliação da cavidade nasal, através de rinoscopia, de cães portadores de afecção nasal crônica, identificando o tipo e a localização das lesões, correlacionando-as com os achados clínicos e radiográficos; verificar a epidemiologia segundo a raça, idade, peso e sexo dos; e definir o resultado qualitativo da biópsia. Foram utilizados 38 cães com sinais clínicos e alterações radiográficas compatíveis com afecção nasal crônica. Sobre a epidemiologia das afecções nasais, tivemos maior ocorrência de cães sem raça definida (SRD), adultos, macho, de porte médio e grande. As alterações mais encontradas em cavidade nasal foram as tumorais, sendo a afecção de maior ocorrência o TVT, representado em sua maioria pelo SRD adulto e macho, seguido de neoplasia de origem mesenquimal, neoplasia de origem epitelial, pólipo, rinite crônica, corpo estranho e aspergilose. A biópsia guiada por rinoscopia foi efetiva, com exceção dos tumores de origem mesenquimal. A rinoscopia neste estudo comprovou ser um meio diagnóstico efetivo, não invasivo complementar aos exames físico e radiográfico, que permite, pela técnica anterógrada associada à retrógrada, ampla visibilização da cavidade nasal, escolha do local de biópsia e colheita de material para cultivo, e em casos de corpos estranhos permite sua remoção, servindo como método diagnóstico e terapêutico. / The aim of this study was to evaluate the nasal cavity of dogs, presented with chronic nasal disease, through rhinoscopy. In addition to checking the reliability of nasal biopsy results, rhinoscopy was used to identify the type and location of lesions and to relate them to the clinical and radiographic findings. Furthermore, we also gathered epidemiology data related to breed, age, weight and gender. For the purpose of this study we used 38 dogs that presented clinical signs and radiographic alterations compatible with chronic nasal disease. Regarding the epidemiology, the highest incidence of nasal diseases was noticed in mixed breed dogs. Also, nasal disease was more frequent in adult, male, large or medium sized dogs. The majority of nasal diseases were due to tumors, and in this regard the transmissible venereal tumor (TVT) was the most frequent and was mainly diagnosed in mixed breed, male, adult dogs. Mesenchymal neoplasia were the second most frequent alteration of the nasal cavity, followed by, epithelial neoplasia, polyps, chronic rhinitis, foreign bodies and aspergillosis. Rhinoscopy guided biopsy proved to be effective except in the case of mesenchymal tumors. The results of this study prove that rhinoscopy is an effective non-invasive diagnostic tool, which complements physical and radiological examination. Moreover, this study also shows that the association of anterior and posterior rhinoscopy techniques, allow for a wide visualization of the nasal cavity and determination of the biopsy location and collection of samples for culture. In additional, rhinoscopy is a useful tool for diagnosis and removal of foreign bodies.

TITLE: Teaching of French pronunciation aimed at nasal vowels SUMMARY: The thesis deals with the issues of French pronunciation teaching at Czech schools. The theoretical part is aimed at teaching of pronunciation, the key concepts of phonetics and its importance in learning of foreign language. Then the thesis deals with the base of French phonetic system, especially the nasal vowels, the comparison of Czech and French phonetics and the main methods of teaching phonetics. The nasal vowels and their pronunciation are the starting point for the practical part - research in the field of the ability of Czech students to recognize and pronounce the nasal vowels in a good way. The research is based on 95 recordings of Czech students from different classes (from high school to bachelor's programme). KEYWORDS: French language, phonetics, phonology, teaching of phonetics, nasal vowels

Superior Ethmoidal Breadth (SEB = the maximum breadth between the left and right frontoethmoidal sutures) has been widely employed by anthropologists as a proxy for internal nasal airway dimensions since it is easily measured without imaging. SEB is also commonly argued to evince climatic adaption in modern humans, as populations living in cold-dry environments predictably exhibit narrower SEB dimensions than those inhabiting tropical environments. However, given uncertaintiy regarding its relationship with internal nasal anatomy, the accuracy of SEB as a proxy for airway dimensions remains questionable. Here, I evaluate the correlation between SEB and internal airway dimensions using linear measurements collected on CT scans from a mixed-sex sample of human crania (n=215) ancestrally derived from sub-Saharan Africa, the Arctic Circle, East Asia, and Europe. My results demonstrate that SEB is often located superior to the anatomcial roof of the nasal passages but is highly correlated (R= 0.8119, p<0.0001) with ethmoidal breadth taken at the functional level of the upper airways (i.e., functional airway breadth [FEB]). ANOVA results indicate, in addition to significant differences in SEB (χ2 = 82.20, p<0.0001), regional differences also exist for FEB (χ2 = 54.21, p<0.0001) and its components: the combined superior and superior common meatal breadths (χ2 = 19.03, p< 0.0001) and ethmoid air cell (EAC) breadth (χ2 = 27.67, p<0.0001). Further, following theoretrical expecations, the African-derived sample generally exhibits the widest internal nasal dimensions and the Arctic-derived sample the narrowest. Specifically, the Arctic sample exhibits significantly narrower airway breadths compared to all other groups. Conversely, the African sample possesses significantly wider EAC breadths comapred to all other groups. Cumulatively, these results empirically support use of SEB as proxy for upper nasal airway breadth and bolster claims that clinal variation in internal airway dimensions across human populations is likely attributable to climatic factors.

For many years, the nasal route of administration as part of a therapeutic treatment has been used. This route of administration is easy to implement, especially due to its non-invasiveness the ease of administration that it affords for the patient. In addition, it is suitable for chronic treatment as well as for an emergency situation when the patient is unconscious. For instance, the administration of benzodiazepines, such as midazolam, may be done to stop convulsions in a patient.Traditionally, intranasal administration was mainly borrowed to target a local effect (e.g. treatment of a cold with a decongestant agent). Subsequently, its application for systemic delivery (e.g. treatment of migraine with triptans) was more and more frequently considered. However, the administration of a drug in the nasal cavities for systemic delivery still remains limited. Indeed, even if the intravenous route has several major limitations such as its invasiveness or the pain generated during administration, it remains more widely used than the intranasal route. This can be explained, on the one hand, by the knowledge that was relatively limited regarding the nasal delivery but also because of the unavailability of nasal devices allowing precise control of the nasal administration (i.e. accurate dose delivery, strong deposition in the nasal cavity, etc).Subsequently, the intranasal route has led to a third therapeutic targeting, namely, the “nose-to-brain pathway”. In that case, the nasal cavity was considered as an opportunity to access the central nervous system (CNS). Indeed, the nose-to-brain delivery allows reaching the brain while bypassing the blood-brain barrier which is known to be a major obstacle to the diffusion of drugs in the CNS. Moreover, the passage through the nasal cavity would allow the administration of sensitive molecules (e.g. biopharmaceuticals) while avoiding excessive enzymatic degradation.Therefore, the nose-to-brain pathway appears to be an attractive route for the delivery of unstable molecules, requiring an access to the brain to reach their site of action. In this context, the therapeutic target that has been selected was "cachexia". It is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. It usually results in particular from undernutrition and a generalized inflammatory state in the patient. In order to treat this syndrome and to restore the appetite in these patients, the goal was to use ghrelin (GHRL) as a model drug. GHRL is a peptide hormone that exhibits, among other effects, an orexigenic action. This biopharmaceutical needs to reach its receptors, located in the hypothalamus, to exert its therapeutic effect.In this study, the goal was to develop a formulation that was able to protect GHRL during its nasal administration, while increasing its residence time to promote its diffusion through the nasal olfactory epithelium.In the first part of the project, GHRL was mainly characterized in terms of stability (e.g. temperature and pH), but also in terms of surface charge. These results allowed selecting the most suitable strategy of formulation as well as the optimal storage conditions. After these preformulation evaluations, it was decided to work on the development of a liquid formulation. The first formulation was based on micelles composed of lipids with polyethylene glycol "DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol) -2000] (ammonium salt)" as hydrophilic group. This type of pegylated lipids have already shown, in many scientific studies, interesting properties in the context of intranasal administration, especially in terms of mucopenetration. With a slight adaptation of the protocol found in the literature, it was possible to obtain micelles of an adequate size (~15 nm). The micelles produced also showed good ability to encapsulate GHRL with an encapsulation rate of 98%, but micelles of DSPE-PEG failed to increase the GHRL diffusion through epithelial layer. This step is essential in order to obtain high GHRL levels in the brain. The formulation containing DSPE-PEG micelles has thus been abandoned.Still in the goal of combining lipid excipients with hydrophilic polymer, another formulation strategy based on liposomes coated with chitosan has been considered. Since GHRL has a positive charge at physiological pH, anionic liposomes have been developed to get a high loading. Three types of liposomes have been produced: anionic, neutral and cationic. The objective was to evaluate the influence of the liposomes charge on GHRL encapsulation. By working with anionic liposomes, the loading could be 46% higher than that obtained from the cationic liposomes. In order to evaluate a potential relation between the amount of GHRL that was encapsulated in the liposomes and the amount of GHRL that could potentially be degraded in the presence of enzyme, the three types of liposomes were exposed to trypsin. Following enzyme exposure, anionic liposomes showed enzymatic protection 4 times higher than cationic liposomes. These anionic liposomes have also shown high GHRL protection in the presence of another enzyme with another mechanism of digestion, namely, carboxylesterase-1. Subsequently, isothermal titration calorimetry tests were performed to better understand the interaction mechanisms between GHRL and anionic liposomes. This technique showed that hydrophobic interactions between both compounds were predominant. The coating of anionic liposomes by chitosans was performed and confirmed by an increase of the mean diameter (+48 nm) and charge (+6 mV) as well as by the modification of the morphology of the liposomes. This coating of liposomes with chitosans was supposed to confer additional properties to the formulation such as mucoadhesion and permeation enhancement. These both effects can be obtained thanks to the positive charge of chitosans which allows adhering to the mucins of the mucus, on the one hand, and thanks to the opening of the epithelial tight junctions that enhances drug permeation, on the other hand. The chitosan coating allowed increasing the fixation of the liposomes to mucins by about twenty percent compared to uncoated liposomes. In addition, the "absorption promoter" effect of chitosans was confirmed on cells culture. Then, the formulation was introduced into two distinct nasal devices intended for the administration of liquid nasal sprays, namely, the VP3 device from Aptar Pharma and the SP270 device from Nemera. The aerosols produced by each device allowed generating droplets characterized by a mean diameter higher than 10µm, leading to potential satisfactory impaction onto the olfactory region instead of diffusion throughout posterior region of the nasal cavities. In the second part of the work, a dry formulation was produced by spray-drying from the liquid dispersion of coated liposomes. The objective was to increase the stability of GHRL during storage as well as to enhance its remanence and diffusion through the olfactory epithelium. The optimized parameters allowed producing a powder characterized by a mean diameter higher than 10 μm with an acceptable yield. The powder produced exhibited a low residual moisture and showed good homogeneity in terms of GHRL content. Then, a comparative study was carried out between the powder and the liquid formulation to compare the GHRL stability over time during storage at different temperatures (4°C and 25°C) but also their ability to fix mucins. In both cases, the dry powder showed better results The powder was also re-dispersed in aqueous phase to evaluate the ability of the liposomes to be reconstituted without modifying their physicochemical properties (e.g. size distribution, charges, stability). It was demonstrated that the majority of the initial properties could be preserved after reconstitution (i.e. rate of encapsulation). Similarly to the liquid formulation, the powder was loaded into a specific device developed for the nasal administration of powders that allows targeting the olfactory region to optimize the nose-to-brain transfer. The device, "UDS - Unit Dose System " from Aptar Pharma, has shown excellent properties in terms of particle size distribution in the aerosol but also in terms of targeting the olfactory zone. The latest was studied by means of "nasal cast" that is a 3-printed model of artificial nasal cavities. After impaction in the different cavities of the cast, it was possible to quantify the amount of GHRL that was deposited in the olfactory zone. Using our optimized formulation in combination with the device developed by Aptar, it was shown that 52% of the powder was impacted onto the area corresponding to the olfactory region. Such data demonstrated the relative difficulty to target this section of the nasal cavities.Finally, the formulation loaded with fluorescent GHRL was intranasally administered in mice. It was demonstrated that GHRL could reach the brain after intranasal administration of the formulation and that the formulation was essential to allow this transfer to the brain.The administration of such biopharmaceutical by nose-to-brain with this formulation seems to be an interesting alternative to exploit. However, additional studies to quantify this transfer more precisely, to better define its kinetics and also to evaluate the efficacy of the treatment should be carried out. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / The aim of this study was to determine the prevalence of nasal skin cancer, its location by facial aesthetic subunits and the type of reconstructive procedures performed for each nasal subunit after excision for nasal skin tumors. Observational cross-sectional study of all consecutive patients with the diagnosis of skin tumor located in the nasal unit, treated from 2018 to 2019 by the department of head and neck surgery of a general hospital. 60 patients were treated with nasal skin tumors excisions. A total of 52 patients (86,6%) had basal cell skin cancer, 7 (11,6%) had squamous cell skin cancer and 1 (1,6%) had melanoma. Fifty-nine patients (98.33%) presented a primary tumor and just 1 case (1,66%) recived a previous surgical treatment. Regardless of the type of tumor, the tip subunit was the most often involved with 29 (48,33%) cases in total. Despite of the nasal aesthetic subunit affected, the most frequent type of procedure used for reconstruction was the rotation or advancement flap, based on aesthetic nasal subunits, which was performed in 39 cases (65%). Nasal reconstruction after skin cancer can be very complex, especially since all patients have high expectations about the results. In order to achieve good results, there is a necessity for careful analysis of the defect, correct planning and excellent technical execution of the procedures Frequently, staged procedures will be needed to achieve an optimal result. / Revisión por pares

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24129号 / 医博第4869号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 中島 貴子, 教授 森本 尚樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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