This diploma thesis is a loose continuation of the bachelor thesis titled Impact of the Advertising Campaign on the Sales of Products of Pharmaceutical Companies and its Impact on the Consumer. The theoretical part was appropriately expanded to include new findings mentioned in modern literature in order to identify all protective factors that may affect the use or purchase of nasal hygiene products. Attention is paid to the associated processes such as marketing, marketing communications and consumer behavior of the customer. In connection with the subsequent analysis health issues are also mentioned. In the practical part, the success rate of individual advertising campaigns in the years 2007 - 2010 on Nasivin and Sterimar in connection with sales that occur subsequent to influenza, non- influenza diseases and allergic diseases morbidity in the population of the Czech Republic is evaluated. Buying habits of a customer ? a possible Nasivin consumer, what medication he/she uses to treat rhinitis, and what brands of nasal decongestants he/she knows are analyzed. In connection with the product Nasivin and Sterimar, the relationship of a customer and a pharmacist, with regard to the product brand and practices in recommendations, is analyzed. The data were obtained from several sources. The company Merck Serono provided me with information on advertising campaigns and sales results in 2007 - 2010. The market research agency Median provided the data for the target customer analysis. The third data source was the agency STEM / MARK, from which I received background data on consumers' buying habits and practices of pharmacists when recommending products. The fourth source of data was the State Institute of Public Health with information relating to respiratory and allergic diseases. By the carried out analysis a close correlation between the sale of products and the occurrence of respiratory diseases, but not allergic diseases, was proved. The company knows well how to target customers and their needs and it respects the products seasonality. It should focus primarily on acquiring new customers and stop the existing customers´ move to competition. In the discussion and the conclusion the issues of health, the Czech health care system and the prevention of civilization-related diseases are mentioned.

Esta tese investiga a aquisição fonológica variável da nasal velar em coda silábica final (como em living ‘vivendo’ e singing ‘cantando’, por exemplo) por aprendizes brasileiros de inglês como segunda língua. O estudo é motivado pela diferença de status da nasal velar em português (L1, primeira língua) e inglês (L2, segunda língua): enquanto na L1 o segmento é realização fonética resultante de assimilação de ponto de articulação (como em atum, em que a nasal bilabial assimila o traço [+dorsal] da vogal precedente realizando-se como velar), na L2 a nasal velar é fonema (como em sin ‘pecado’ x sing ‘cantar’, realizados com a nasal alveolar e velar, respectivamente). Em algumas comunidades de falantes nativos de inglês, palavras derivadas pelo sufixo {ing} (como read.ing ‘lendo’ e study.ing ‘estudando’, por exemplo) constituem um fenômeno de variação linguística estável, em que os falantes alternam a produção das nasais velar e alveolar no final das palavras. Essa variação é estrutural e socialmente condicionada (LABOV, 1994; 2001). Os dados empíricos deste estudo provêm da fala coletada através de gravações com aprendizes de inglês, que pertecem a dois níveis de proficiência: básico e pré-intermediário. São realizadas duas análises formais: uma que explica a variação sistemática na interlíngua, observável no desempenho dos aprendizes, através do software Goldvarb (SANKOFF, TAGLIAMONTE e SMITH, 2015), e outra que formaliza a organização interna dessa gramática variável, através de algoritmos de aprendizagem vinculados à Teoria da Otimidade Estocástica, o Algoritmo de Aprendizagem Gradual (GLA) (BOERSMA e HAYES, 2001) e o ORTO Ajuste Paramétrico (DORNELLES FILHO, 2014). A Análise de Regra Variável demonstrou que a interlíngua é um sistema linguístico sujeito à variação ordenada como as demais línguas naturais, condicionada por aspectos linguísticos (classe morfológica) e extralinguísticos (nível de proficiência). A variação é verificada pela produção oral dos aprendizes, examinada de oitiva, que alterna as nasais palatal (63,6%) e velar (36,4%) em coda silábica final. A análise estocástica revelou um sistema de interlíngua dominado por restrições de Marcação, cuja variação é decorrente do aumento dos valores de ponto de seleção de restrições de Fidelidade. As restrições diretamente envolvidas na aquisição fonológica variável da nasal velar são AGREEplaceVN#, que exige que a sequência Vogal+Nasal em coda final partilhem ponto de articulação, e IDENTnasal, que requer identidade de traço nasal entre as formas presentes no input e no output. As análises realizadas, que representam a língua dos aprendizes em seus aspectos interno e externo, ou, conforme a terminologia de Chomsky ([1965]1 1975), a competência e o desempenho linguísticos, comprovaram a natureza variável da interlíngua e proporcionaram uma reflexão teórica acerca da possibilidade de diálogo entre o estrutural e o social para a explicação de fenômenos linguísticos variáveis. / This thesis investigates the variable phonological acquisition of the velar nasal in final syllabic coda (such as in living ‘vivendo’ and singing ‘cantando’, for example) by Brazilian learners of English as a second language. The study is motivated by the different status of the velar nasal in Portuguese (L1, first language) and in English (L2, second language): while the segment is a phonetic realization of assimilation of place of articulation in the L1 (‘atum’, where the bilabial nasal assimilates the feature [+dorsal] of the preceding vowel, being realized as velar), the velar nasal is a phoneme in the L2 (sin ‘pecado’ x sing ‘cantar’, realized as the alveolar and velar nasal, respectively). In some native English-speaking communities, words derived from the suffix {ing} (such as read.ing ‘lendo’, study.ing ‘estudando’, for example) are in linguistic stable variation, in which the speakers alternate the production of the alveolar and velar nasal the velar nasal at the end of words. This variation is both structurally and socially conditioned (LABOV, 1994; 2001). The empirical data of this study were collected through recordings with the informants, who belong to two levels of proficiency: basic and pre-intermediate. Two formal analysis are made: one that explains the observable systematic variation in the Interlanguage, through the software Goldvarb (SANKOFF, TAGLIAMONTE and SMITH, 2015) and another that formalizes the internal organization of this variable grammar, through gradual learning algorithms associated to the Stochastic Optimality Theory, the Gradual Learning Algorithm (GLA) (BOERSMA and HAYES, 2001) and the ORTO Ajuste Paramétrico (DORNELLES FILHO, 2014). The Variable Rule Analysis has demonstrated that interlanguage is a linguistic system subject to ordered variation as in all the other natural languages, conditioned by linguistic aspects (morphological class) and extralinguistic ones (level of proficiency). The variation is verified by the oral production of the learners, examined by hearing analysis, which alternates the palatal nasal (63,6%) The stochastic analysis has revealed an Interlanguage system dominated by Markedness constraints, where variation is due to the increase on the values of selection points for Faithfulness constraints. The constraints directly involved in the variable phonological acquisition of the velar nasal are AGREEplaceVN#, which demands the sequence Vowel+Nasal in final coda to share place of articulation, and IDENTnasal, which demands feature identity [+nasal] between input and output forms. The analyses made, which represent the learners’ language in its internal and external aspects, or, according to Chomsky’s terminology ([1965] 1975), the linguistic competence and performance, have proved the variable nature of the Interlanguage and have enabled a theoretical reflection upon the possibility of dialogue between the structural and the social to the explanation of variable linguistic phenomena.

O trabalho tem como tema o estudo da variação do ditongo nasal ão em sílaba final de vocábulo (ex. pão ~ pon; tiravam ~ tiravon) por falantes bilíngues de português-alemão e português-italiano das comunidades de Panambi e Flores da Cunha, respectivamente. A decisão por investigar essas comunidades deve-se à constatação preliminar de que tal fenômeno é característico de comunidades bilíngues cujas línguas de origem não possuem ditongos nasais. A amostra constitui-se de 16 entrevistas do PROJETO VARSUL (Variação Linguística Urbana na Região Sul). Dados do PROJETO ALERS (Atlas Linguístico-Etnográfico da Região Sul do Brasil) de comunidades bilíngues de alemão e de italiano contribuíram para enriquecer a discussão. No presente estudo, a variável dependente, a alternância do ditongo nasal ão/am ~on em final de vocábulo, é examinada frente a possíveis condicionadores linguísticos e extralinguísticos, suas variáveis independentes. As variáveis linguísticas analisadas são Tonicidade do Alvo, Extensão do Vocábulo, Classe Gramatical, Número (Singular ou Plural) e Contexto Precedente. De forma geral, o fenômeno se aplica em sílabas finais tônicas de palavras no singular, fazendo uma leve distinção entre palavras longas e curtas. Além disso, como se trata de uma variação fonética de superfície, a classe gramatical não parece ser relevante nesse processo, ainda que deva incidir mais significativamente sobre alguns itens lexicais em específico. Quanto às variáveis extralinguísticas, foram analisados Localidade Bilíngue, Idade, Sexo e Escolaridade. De forma geral, o processo não faz distinção importante entre as duas localidades bilíngues analisadas, mas se aplica mais entre os menos escolarizados, por seu menor contato com a modalidade padrão da língua portuguesa. Além disso, o processo aplica-se mais entre homens com mais de 50 anos, em virtude de seu grau de bilinguismo e, possivelmente, por as mulheres dessas comunidades evitarem mais do que os homens variantes desprestigiadas. Os resultados foram analisados estatisticamente pelo programa GOLDVARB X e discutidos na perspectiva da Teoria da Variação, proposta por Labov (1969, 1972). / This dissertation deals with the variation of the nasal diphthong [ãw] in final syllable of word position (ex. pão ~ pon; tiravam ~ tiravon) by bilingual speakers of German and Italian communities from Panambi and Flores da Cunha, respectively. The decision to investigate these communities due to the preliminary conclusion, that this phenomenon is characteristic of bilingual communities whose languages of origin do not have nasal diphthongs. The sample is constituted of 16 interviews from VARSUL PROJECT (Urban Linguistic Variation in South Region). Data from ALERS PROJECT (Linguistic-Ethnographic Atlas of Southern Brazil) communities bilingual German and Italian contributed to enrich the discussion. In this study, the dependent variable, the alternation of the nasal diphthong ão/am ~ on at the end of word, is examined against possible linguistic and extra linguistic conditioners, their independent variables. The linguistic variables analyzed are Target Toning, Extension of the Word totally, Grammar Class, Number (singular or plural) and Previous Context. In general, the phenomenon applies in tonic final syllables of words in the singular, making a slight distinction between long and short words. Moreover, as it is a phonetic variation of surface, the grammar class is not relevant in this process, although it should focus more significantly on some lexical items in particular. Concerning to the extralinguistic variables, were analyzed bilingual Place, Age, Gender and Education. In general, the process does not distinguish between the two major bilingual cities analyzed, but applies more among the less educated, on the slightest contact with the standard form of the Portuguese language. Furthermore, the process applies more among men over 50 years, because of their degree of bilingualism and, possibly, by the fact the women these communities more than men discredited variants. The results were statistically analyzed by the GOLDVARB X and discussed from the perspective of the Theory of Change, proposed by Labov (1969, 1972).

Orientador: Carlos Takahiro Chone / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T17:38:33Z (GMT). No. of bitstreams: 1 Ortiz_Erica_M.pdf: 2620936 bytes, checksum: e99104f6d864e8b71f9b41dcfe9763c4 (MD5) Previous issue date: 2009 / Resumo: A imunossupressão é a principal causa de rinossinusite recorrente no transplante de células tronco hematopoiéticas (TCTH) com uma incidência aumentada na Doença do Enxerto contra o Hospedeiro (DECH) pós-TCTH. Descrições histológicas de mucosas oral, pulmonar e intestinal associadas ao TCTH e a DECH têm sido descritas. Porem, para entender melhor a fisiopatogenia da resposta imune nos pacientes transplantados, verificou-se a histologia e ultraestrutura da mucosa nasossinusal dos pacientes TCTH com e sem DECH. O processo unciforme de 24 pacientes submetidos ao TCTH (19 com DECH e 5 sem) foi submetido à análise histológica através das microscopias óptica e eletrônica de transmissão (ME). A ME mostrou alterações na estrutura ciliar, quantidade de mitocôndria, microvilos e vacuolização citoplasmática. Todos os transplantados com rinossinusite apresentaram perda ou ausência significante de cílios (P=0.018). Corpúsculos apoptóticos estavam aumentados e células caliciformes, diminuídas no epitélio nasossinusal dos pacientes transplantados com DECH crônica (P=0.04). Esta destruição epitelial poderia facilitar a penetração bacteriana ou viral, desencadeando uma recorrência ou exacerbação da infecção. / Abstract: Immunosuppression is the leading cause of recurrent sinus infections following Hematopoietic Stem Cell Transplantation (HSCT) with increased incidence of sinusitis in patients with chronic graft versus host disease (GVHD) following HSCT. Histological descriptions of the oral mucosa, lung ciliary epithelium and intestinal mucosa related to HSCT and GVHD have been described. However, we sought to verify the histological and ultra structural aspects of nasal mucosa in patients following HSCT with and without GVHD in order to better understand the pathophysiology of the immune response. The uncinate processes from 24 HSCT (19 with GVHD, 5 without) patients were subjected to histological analyses via light and transmission electron microscopy (TEM). TEM revealed altered cilia structure, mitochondria quantity, microvilli, cytoplasm vacuolization. All HSCT patients with rhinosinusitis had significant loss or absence of cilia (P=0.018). Apoptotic bodies were increased and Goblet cells decreased in nasal epithelium from patients with chronic GVHD (P=0.04).This tissue destruction would facilitate the bacterial and viral penetration and may result in a recurrence or exacerbation of the infection. / Mestrado / Otorrinolaringologia / Mestre em Ciências Médicas

Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2014-11-26T19:51:25Z No. of bitstreams: 2 Tese- Gisélia Brito dos Santos - 2013.pdf: 4152384 bytes, checksum: 0d7d314119a6b433c433012852e4d3ab (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2014-12-04T14:09:16Z (GMT) No. of bitstreams: 2 Tese- Gisélia Brito dos Santos - 2013.pdf: 4152384 bytes, checksum: 0d7d314119a6b433c433012852e4d3ab (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-12-04T14:09:16Z (GMT). No. of bitstreams: 2 Tese- Gisélia Brito dos Santos - 2013.pdf: 4152384 bytes, checksum: 0d7d314119a6b433c433012852e4d3ab (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-11-05 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / This Thesis presents an acoustic-phonetic analysis of the oral and nasal vowels of Brazilian Portuguese, specifically those of the speech community of Fortaleza dos Nogueiras, Maranhão and European Portuguese, in some speech data from the region of Lisbon, Portugal. The theoretical foundation is sustained on the postulates of Camara Jr. (1970 ), Mateus (1982), de Morais Barbosa (1994) and Moraes and Wetzels (1992), concerning nasality in Portuguese, especially in Brazilian Portuguese. The theoretical framework of Acoustic Phonetics is composed mainly by the work of Ladefoged (2003, 2006 and 2007), Ladefoged, Johnson (2008), Mateus et al. (2005), Delgado-Martins (1988), Morais Barbosa (1994), Malmberg (1998), Medeiros (2007), Medeiros et al. (2008) and Sousa, E. (1994). The informants used as subjects in this research, both Brazilian and Portuguese, are people with low education, low turnover, 50 years of age or older. The Brazilian informants were born and lived most of their lives in rural Fortaleza dos Nogueiras; the Portuguese live in the outskirts of Lisbon. The speech data in Brazil are a result of our field research conducted in 2011. The data from Portugal were provided by the Instituto de Linguística da Universidade de Lisboa and form part of the speech collection of ALEPG (Linguistic and Ethnographic Atlas of Portugal and Galicia). The acoustic-phonetic analysis of the data is made through the program of Speech Station by Sensimetrics for visualization of expectograms and to extract measurements of F1 and F2. We present the values of formants 1 and 2 of the oral and nasal vowels and these are compared in order to show what happens with the nasal vowel in relation to the corresponding oral; we highlight the acoustical characteristics of oral and nasal vowels; we show the articulatory triangle of vowels of the informants of the research highlighting the contours the vowels assume in articulation and the frequency bands in which each vowel stands. Finally, we carry out a comparative investigation of oral and nasal vowels in these two varieties of Portuguese. / Este trabalho apresenta uma análise fonético-acústica das vogais orais e nasais do português brasileiro, mais especificamente da comunidade de fala de Fortaleza dos Nogueiras, Maranhão e do português europeu, em alguns dados de fala da região de Lisboa, Portugal. O embasamento teórico pauta-se nos postulados de Camara Jr. (1970), de Mateus (1982), de Morais Barbosa (1994) e de Moraes e Wetzels (1992), acerca da nasalidade na língua portuguesa, especialmente, no português brasileiro. O referencial teórico de Fonética Acústica compõe-se, principalmente, pelos trabalhos de Ladefoged (2003, 2006 e 2007), Ladefoged; Jonhson (2008), Mateus et al. (2005), Delgado-Martins (1988), Morais Barbosa (1994), Malmberg (1998), Medeiros (2007), Medeiros et al. (2008) e Sousa, E. (1994). Os informantes sujeitos desta pesquisa, tanto brasileiros como portugueses, são pessoas com baixa escolaridade, baixa rotatividade, que têm a partir de 50 anos de idade. Os brasileiros nasceram e viveram a maior parte de suas vidas na zona rural de Fortaleza dos Nogueiras; os portugueses são moradores do entorno de Lisboa. Os dados de fala do Brasil são resultado de nossa pesquisa de campo realizada em 2011. Os de Portugal foram-nos cedidos pelo Instituto de Linguística da Universidade de Lisboa e fazem parte do acervo de fala do ALEPG (Atlas Linguístico e Etnográfico de Portugal e da Galiza). A análise fonético-acústica dos dados é feita por meio do programa Speech Station da Sensimetrics, para a visualização dos expectogramas e para a extração das medidas de F1 e de F2. Apresentam-se os valores dos formantes 1 e 2 das vogais orais e nasais e estes são comparados com o intuito de mostrar o que acontece com a vogal nasal em relação à correspondente oral; evidenciam-se quais as características acústicas das vogais orais e nasais; apresenta-se o triângulo articulatório das vogais desses informantes da pesquisa com evidência para os contornos que elas assumem na articulação e para as faixas de frequência em que cada vogal se posiciona. Por fim, realiza-se uma investigação comparativa das vogais orais e nasais nessas duas variedades da língua portuguesa.

Introdução: A rinossinusite crônica com polipose nasal constitui um subgrupo particular da rinossinusite crônica, caracterizado por uma inflamação da mucosa que leva a um espessamento da mesma e à formação de pólipos, podendo ser especialmente difícil de tratar. A Doxiciclina é um antibiótico bacteriostático, de largo espectro, que também tem uma ação antiinflamatória, e tem se mostrado útil no controle dos sintomas das recidivas desta doença, promovendo inclusive uma diminuição do pólipo. Objetivo: avaliar se o uso de baixas doses de Doxiciclina, por períodos prolongados, pode melhorar o controle clínico da rinossinusite crônica com polipose nasal, de difícil tratamento. Métodos: este é um estudo prospectivo, aberto, realizado em 60 pacientes com rinossinusite crônica de difícil tratamento que se submeteram a cirurgia endoscópica nasal. Os pacientes foram divididos em 2 grupos: 28 pacientes receberam corticóide nasal, lavagem nasal com soro fisiológico, e Doxiciclina (200mg no primeiro dia, seguido por 100mg uma vez ao dia) por 12 semanas, enquanto 30 pacientes receberam apenas corticóide nasal e lavagem nasal com soro fisiológico. O principal resultado avaliado foi a existência de uma melhora, dose efeito, clinicamente significativa do SNOT-20 após o tratamento com a Doxiciclina. Outros resultados avaliados foram os valores do SNOT-20, NOSE e do Lund-Kennedy. Os seguintes parâmetros também foram analisados: asma, rinite, doença respiratória exacerbada pela Aspirina (DREA), níveis séricos de IgG, IgA, IgE, IgM, ANCA e contagem de eosinófilos. Resultados: oy tratamento com a Doxiciclina promoveu uma melhora, dose efeito, clinicamente significativa do SNOT-20. Pacientes que receberam a Doxiciclina também tiveram resultados significativamente melhores do SNOT-20, NOSE e Lund-Kennedy. Houve uma associação negativa entre a melhora clinicamente significativa do SNOT-20 e a presença de asma, DREA e níveis séricos elevados de IgE pré-tratamento. Conclusão: os achados sugerem que a doxiciclina pode ter uma ação benéfica nos pacientes com rinossinusite crônica com polipose nasal, especialmente naqueles pacientes sem asma, DREA ou níveis séricos elevados de IgE prétratamento / Introduction: Chronic rhinosinusitis with nasal polyps is a particular subset of chronic rhinosinusitis characterized by a mucosal inflammation that leads to mucosal thickening and polyp formation, and can be especially difficult to treat. Doxycycline is an oral, available, broad-spectrum bacteriostatic antibiotic which also has anti-inflammatory action, that has been used to treat this disease and has shown a successful control of symptoms even reducing the volume of polyps. Objective: Evaluate if long-term low-dose doxycycline is effective in controlling clinical symptoms of difficult-to-treat chronic rhinosinusitis with nasal polyps. Methods: This was a prospective, open-label study of 60 patients with difficultto- treat chronic rhinosinusitis with nasal polyps who had undergone endoscopic sinus surgery. Patients were divided into two groups: 28 received nasal steroids, saline irrigation, and doxycycline (200 mg on the first day, followed by 100 mg daily) for 12 weeks, while 30 received only nasal steroids and saline irrigation. The main outcome measure was an adequate effect size of doxycycline treatment on clinically meaningful significant improvement of SNOT-20. Other outcome measures were the SNOT-20, NOSE, and Lund-Kennedy scores. The following parameters were also analyzed: asthma, rhinitis, non-steroidal-exacerbated respiratory disease (NERD), and baseline serum IgG, IgA, IgE, IgM, ANCA, and eosinophil count. Results: There was an adequate effect size of doxycycline treatment on clinically meaningful significant improvement of SNOT-20. Patients who received doxycycline also had significantly better outcomes regarding SNOT-20, NOSE, and Lund-Kennedy scores. There was a negative association among a clinically significant improvement of SNOT-20 and presence of asthma, NERD, and elevated serum IgE levels before treatment. Conclusion: These findings suggest that doxycycline may have a beneficial role for chronic rhinosinusitis with nasal polyps patients, especially for those without asthma, NERD or high levels of serum IgE before treatment

Avec l’identification des antigènes tumoraux et la compréhension de la réponse immunitaire mucosale, la vaccination par voie respiratoire est devenue un champ d’investigation prometteur pour le traitement du cancer. L’objectif de cette thèse était de concevoir des vaccins peptidiques nanoparticulaires à base de liposomes, destinés à la vaccination antitumorale par voie respiratoire ou nasale. Ainsi, nous avons formulé des liposomes vectorisant un épitope peptidique TCD8+ dérivé de l’oncogène ErbB2, un épitope TCD4+ et une molécule adjuvante. Cette construction a ensuite été optimisée en faisant varier les caractéristiques physicochimiques du vecteur liposomique (taille, structure, composition) ou de la formulation (viscosité). L’efficacité antitumorale des différents vaccins ainsi obtenus a été évaluée après administration respiratoire ou nasale, prophylactique ou thérapeutique, dans un modèle de tumeurs pulmonaires ou de tumeurs sous-cutanées chez la souris. L’ensemble de ces travaux a montré un intérêt indéniable des vaccins peptidiques à base de liposomes dans la vaccination antitumorale par voie respiratoire et nasale, ouvrant de nouvelles perspectives pour le traitement du cancer. / With the identification of tumor antigens and the better understanding of the mucosal immune response, the vaccination by the respiratory route has become a promising field of investigation for cancer treatment. The purpose of this study was to develop nanoparticulate peptide-based liposomal vaccines for antitumor vaccination by respiratory or nasal route. Thus, we have prepared liposomes associating ErbB2 TCD8+ and HA TCD4+ peptide epitopes with an adjuvant molecule. This construct was then optimized by varying its physicochemical characteristics (size, structure, composition) or its formulation (viscosity). The antitumor efficacy of the various vaccines obtained thereby was evaluated in a model of pulmonary or subcutaneous tumors in mice after prophylactic or therapeutic, nasal or respiratory immunization. All our data showed an undeniable interest of peptide vaccines based on liposomes in the antitumor vaccination by the respiratory and nasal routes, opening new perspectives for cancer treatment.

La mucoviscidose est la maladie héréditaire autosomique récessive, rare, létale, la plus fréquente dans la population caucasienne. Cette maladie est causée par des mutations du gène CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) codant la protéine CFTR. Cette protéine est principalement un canal chlorure (Cl-) AMPc-dépendant localisé dans la membrane apicale des cellules épithéliales. La mutation F508del entraîne un défaut de maturation de la protéine qui est retenue dans le réticulum endoplasmique avant d’être dégradée. Cependant, une faible quantité de protéines malformées échappe à ce système de contrôle et parvient à la membrane plasmique.Des travaux de notre équipe ont montré une augmentation des efflux ioniques dépendants du CFTR dans des lignées cellulaires épithéliales bronchiques (CFBE41o-), exprimant le CFTR sauvage ou le CFTR muté F508del, après un traitement par une hormone: la gonadolibérine (GnRH, Gonadotropin releasing hormone, 1h, 10-9M). Cette augmentation est vraisemblablement due à un nombre plus important de canaux CFTR à la membrane plasmique.L’objectif de cette thèse a été de tester un analogue de la GnRH comme modulateur de l’exportation membranaire et/ou de l’activité canal du CFTR muté, sur des cultures primaires de cellules épithéliales nasales humaines homozygotes pour la mutation F508del. Dans un premier temps, nous avons vérifié la présence du récepteur à la GnRH (R-GnRH) dans notre modèle cellulaire. Puis, nous avons étudié l’effet de l’analogue sur la fonction du CFTR par des techniques d’électrophysiologie. Nous avons observé une augmentation des efflux d’ions Cl- médiés par le canal CFTR après un traitement à l’analogue (2h, 10-12M). Enfin, une étude protéomique nous a permis d’identifier des protéines différentiellement exprimées après traitement. Certaines protéines mises en évidence pourraient appartenir à des voies de signalisation intracellulaires ayant un rôle dans la régulation de la protéine CFTR et être des cibles thérapeutiques.Par ailleurs, le canal CFTR est régulé par le Mg2+ intracellulaire ([Mg2+]i). Le canal TRPM7 est le principal régulateur du [Mg2+]i. La [Mg2+]i a été mesurée et l’expression de TRPM7 vérifiée dans des cellules Hela transfectées avec le CFTR sauvage (wt) ou mutés (G551D et F508del). Nous avons étudié la localisation, la fonction et la régulation de TRPM7 dans nos modèles cellulaires avant de rechercher un possible lien fonctionnel entre le CFTR et TRPM7. Dans les modèles CF, l’expression, la fonction et la localisation du canal TRPM7 sont altérées. Il existerait un lien fonctionnel entre TRPM7 et le CFTR par l’intermédiaire de la diminution du [Mg2+]i impliquant TRPM7 dans la physiopathologie de la mucoviscidose. / Cystic fibrosis is the most common lethal autosomal recessive disease in the Caucasian population. This disease is caused by mutations in the gene encoding the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) protein. This protein is a cAMP-regulated chloride channel expressed at the apical membrane of epithelial cells. The F508del mutation causes a defect in CFTR protein folding preventing its maturation. Some misfolded proteins escape the control system and reach the plasma membrane.We previously showed a rise of CFTR-dependent ion efflux in wt- and F508del-CFTR human bronchial epithelial expressing cells (CFBE41o-) after incubation with GnRH (Gonadotropin releasing hormone; 1h, 10-9M). This increase was probably due to an increased cell surface expression of CFTR.The aim of the present study was to test a GnRH analog as a modulator of CFTR delivery to the plasma membrane and/or activity of CFTR on primary culture of human nasal epithelial cells (F508del/F508del).We checked the GnRH receptor expression in our model. Then, we studied the GnRH effect on CFTR’s function by electrophysiology. We found a significant increase of CFTR dependent chloride efflux in cells pretreated with analogue (2h, 10-12M). Proteomic study enabled us to identify differentially expressed proteins after treatment. Some highlighted proteins could be part of signalling pathways regulating CFTR and could be therapeutic targets.Moreover, CFTR is regulated by intracellular Mg2+ ([Mg2+]i). TRPM7 (Transient Receptor Potential Melastatin 7) is the main channel regulating [Mg2+]i. [Mg2+]i and TRPM7 expression were measured in Hela cells stably expressing wildtype and two CFTR mutants (F508del-CFTR and G551D-CFTR). We studied TRPM7 expression, function and regulation in our cell models before examining a functional link between TRPM7 and CFTR. In CF models, TRPM7 expression, localization and function are altered. There should be a functional link between TRPM7 and CFTR through the decreased [Mg2+]i involving TRPM7 in cystic fibrosis physiopathology.

As proteínas de classe 3 são candidatas na preparação de uma vacina contra a doença meningocócica. O objetivo deste estudo é determinar a imunogenicidade da proteína de classe 3 purificada da cepa de Neisseria meningitidis do sorogrupo B juntamente com a capacidade adjuvante de whole cells de Bordetella pertussis. Foram imunizados camundongos BALB/c neonatos em um intervalo de 3 a 12 dias entre 1 e 4 doses da proteína de classe 3 mais adjuvante, pela via intranasal e no 21º dia pela via intramuscular com a proteína de classe 3 emulsificada com hidróxido de alumínio. Os resultados demonstraram que após 2 doses pela via intranasal e 1 dose pela via intramuscular houve rápido estímulo das células imunes nos camundongos adultos BALB/c e neonatos BALB/c e outbred. Todos os soros foram analisados por ELISA e immunoblot. O adjuvante B. pertussis administrado pelas vias intranasal ou intramuscular, aumentou a resposta imune comparada com os controles. Anticorpos bactericidas e de alta afinidade foram produzidos. / Proteins of class 3 sound candidates in the preparation of vaccine against meningococcal illness. The aim of this study was to determine the immunogenicity of class 3 proteins purified of Neisseria meningitidis of the serogroup B along with whole cells of Bordetella pertussis as adjuvant. BALB/c and outbred neonate mice between 3 and 12 days old were immunized with 1 to 4 doses of the purified class 3 proteins with or without adjuvant given by the intranasal route, and on the 21st day the animals received an intramuscular dose of the class 3 proteins with or without aluminum hydroxide. The results demonstrated that after 2 doses by the intranasal route and 1 dose intramuscular there was a rapid stimulation of the immune cells in BALB/c adult mice as well as BALB/c and outbred neonates mice. All sera were analyzed by ELISA and immunoblot. The adjuvant B. pertussis used in the present investigation and given via the intranasal or intramuscular route increased the immune response compared with the controls. High affinity and bactericidal antibodies were produced.

<p>Funkcija nosa povezana je sa različitim anatomskim, fiziolo&scaron;kim i emocionalnim faktorima. Postoji mnogo teorija koje su poku&scaron;ale da objasne efekat ženskih polnih hormona (estrogena i progesterona) na fiziologiju nosa, ali sam mehanizam njihovog dejstva jo&scaron; uvek ostaje izazov za mnoge istraživače. Prethodno je opisano da ženski polni hormoni mogu da izazovu nazalnu opstrukciju, povećavajući ekspresiju histaminskih H1 receptora i menjajući koncentraciju neurotransmitera, &scaron;to dovodi do edema nosne sluznice i modifikacije nazalnog otpora. Kada je reč o mirisnoj funkciji na malom broju ispitanika i u različito dizajniranim studijama je pokazano da je u fazi ovulacije mirisni prag značajno niži u odnosu na folikularnu i luteinsku fazu, međutim ne postoje podaci o identifikaciji i diskriminaciji mirisa u menstrualnom ciklusu. Nizak nivo estrogena prouzrokovan fiziolo&scaron;kom atrofijom jajnika u postmenopauzi može dovesti do hiposmije ili čak anosmije, &scaron;to predstavlja jo&scaron; jedan dokaz o osetljivosti nazalne sluznice na estrogen.&nbsp; Cilj ovog istraživanja je bio da se ispita uticaj ženskih polnih hormona na respiratornu i mirisnu funkciju nosa u menstrualnom ciklusu i postmenopauzi. Istraživanje je u celosti prospektivno, sprovedeno je na Zavodu za fiziologiju, Medicinskog fakulteta, Univerziteta u Novom Sadu. Uključeno je 204 osoba ženskog pola koje su bile podeljene u dve grupe. Prvu grupu su činile 103 devojke uzrasta 23,126 &plusmn; 4,597 godina u reproduktivnom periodu sa regularnim menstrualnim ciklusom i 101 žena prosečnog uzrasta 60,069 &plusmn; 5,570 u postmenopauzi. Respiratorna i mirisna funkcija nosa procenjene su uz pomoć odgovarajućih standaradizovanih objektivnih i subjektivnih metoda. Funkcija donjih disajnih puteva ispitana je uz pomoć spirometrije. Kod žena u reproduktivnom periodu testiranje se vr&scaron;ilo u fazi ovulacije i lutealnoj fazi menstrualnog ciklusa, a kod ispitanica u postmenopauzi jednom. Nakon određivanja prvog plodnog dana ispitanice su uz pomoć standardizovanih urin - tračica za određivanje pika luteinizirajućeg hormona u urinu utvrđivale momenat ovulacije, dok se drugo testiranje u lutealnoj fazi vr&scaron;ilo sedam dana nakon prvog. Respiratorna funkcija nosa je značajno lo&scaron;ija u fazi ovulacije u odnosu na progesteronsku fazu menstrualnog ciklusa,ali se značajno ne razlikuje između žena u reproduktivnom periodu i žena u postmenopauzi. Subjektivni osećaj nazalne opstrukcije značajno se ne razlikuje u različitim fazama menstrualnog ciklusa, kao ni između testiranih populacija zdravih žena. Sposobnost identifikacije mirisa je statistički značajno slabija, a subjektivni osećaj intenziteta mirisa izraženiji u fazi ovulacije u odnosu na luteinsku fazu menstrualnog ciklusa. Međutim, sposobnost identifikacije mirisa značajno je lo&scaron;ija kod žena u postmenopauzi u odnosu na obe faze menstrualnog ciklusa. Reaktivnost nosne sluznice značajno je veća u fazi ovulacije u odnosu na lutealnu fazu menstrualnog ciklusa, ali se ista ne razlikuje između žena u reproduktivnom period i žena u postmenopauzi. Respiratorna i mirisna funkcije nosa u testiranim populacijama zdravih žena nisu značajno povezane.</p> / <p>The nasal function is associated with various anatomical, physiological and emotional factors. There are many theories that have tried to explain the effect of female sex hormones (estrogen and progesterone) on the nasal physiology, but the mechanism still remains unknown for many researchers. It has been previously described that female sex hormones can cause nasal obstruction by increasing the expression of histamine H1 receptors and altering the concentration of neurotransmitters, which leads to edema of the nasal mucosa and modification of nasal resistance. When it comes to olfaction on a small number of subjects and in differently designed studies, it was shown that in the ovulatory phase the olfactory threshold is significantly lower compared to the follicular and luteal phase, however there are no data on the identification and discrimination of odors in the menstrual cycle. Low estrogen levels caused by physiological atrophy of the ovaries in postmenopause can lead to hyposmia or even anosmia, which is another proof of the sensitivity of the nasal mucosa to estrogen.&nbsp; The aim of this study was to examine the effect of female sex hormones on respiratory and olfactory function of the nose in the menstrual cycle and postmenopause. The research is prospective and it was conducted at the Department of Physiology, Faculty of Medicine, University of Novi Sad. It included 204 females who were divided into two groups. The first group consisted of 103 women aged 23.126 &plusmn; 4.597 years in the reproductive period with a regular menstrual cycle and 101 women with an average age of 60.069 &plusmn; 5.570 in the postmenopausal period. The respiratory and olfactory function of the nose were assessed using appropriate standardized objective and subjective methods. The lower airway function was examined using spirometry. Young women in reproductive period were tested twice, in the ovulatory and luteal phase of the menstrual cycle, and the postmenopausal women were tested only once. After menstrual bleeding the participans used standardized urine strips consecutively day by day to determine ovulation (the peak of the luteinizing hormone (LH) in plasma which pointed out the estrogen plasma peak). The test was positive if two horizontal pink streaks appeared on the strip 5 to 10 minutes after the contact with the urine. One pink streak indicates a correctly performed test, while the second streak appears only if there is an LH peak. Within 24 hours of confirmed LH peak, the subjects were tested for the first time. The second measurement was performed in the luteal phase of the menstrual cycle (the progesterone plasma peak) seven days after the first one.&nbsp; The nasal respiratory function is significantly worse in the ovulatory phase compared to the luteal phase of the menstrual cycle, but it does not differ significantly between women in the reproductive period and postmenopausal women. The subjective sense of the nasal obstruction does not differ significantly in different phases of the menstrual cycle, as well as between tested populations of healthy women. The odor identification ability is statistically significant weaker and the subjective sense of odor intensity is more pronounced in the ovulatory phase compared to the luteal phase of the menstrual cycle. However, the ability to identify odors is significantly worse in postmenopausal women compared to both phases of the menstrual cycle. The reactivity of the nasal mucosa is significantly higher in the ovulatory phase compared to the luteal phase of the menstrual cycle, but it does not differ between women in the reproductive period and postmenopausal women. The respiratory and olfactory nasal functions in these tested populations are not significantly corelated.</p>