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Cystic fibrosis (CF) is a common lethal hereditary disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction affects multiple organ systems and most morbidity and mortality in CF results from lung disease. The CF lung appears healthy at birth, but spontaneously develops airway disease characterized by infection, inflammation, mucus plugging and airway remodeling. A CF pig model was recently generated to determine the events that initiate lung disease. CF pigs recapitulate many findings seen in humans with CF, including the spontaneous development of lung disease. I used newborn CF pigs to investigate two leading hypotheses regarding CF disease initiation: abnormal airway surface liquid (ASL) composition and defective mucociliary transport (MCT). I developed an assay to study ASL composition and found that CF ASL contained similar sodium concentrations, elevated potassium concentrations, and a decreased fraction of volatile material. I developed an assay to measure MCT in vivo. By tracking individual particles in 3-dimensions I found that newborn pigs exhibit a ventrally directed cilia orientation in the trachea. I also found that MCT is highly heterogeneous and particles traveled at different speeds within airways and between airways, challenging the classic view that airway mucus exists as continuous blanket. Comparing particle transport revealed that non-CF and CF newborn pigs exhibit similar basal particle clearance and speeds. Cholinergic stimulation induces mucus and fluid secretion. Particles became stuck in newborn CF pigs after cholinergic stimulation and stasis persisted with tissue submersion. This challenged the leading hypothesis that attributes CF airway disease pathogenesis to ASL depletion. I hypothesized that adherent mucus impairs mucociliary transport in CF airways and I developed an assay to visualize mucus stasis in submerged tracheal segments ex vivo. CF trachea stimulated in vivo exhibited highly adhesive mucus entities that emerged exclusively from submucosal gland ducts. These adherent entities impaired MCT even with extremely high ASL depths. Non-CF trachea with combinatorial disruption of HCO3- and Cl- transport reproduced the defect in CF signifying that anion transport disruption was responsible for adherent mucus. These data suggest that CFTR disruption directly produces multiple host defense defects, including defective bacterial killing and abnormally adherent mucus. Therapeutic targeting of the described defects may provide new opportunities to intervene early and improve the lives of those with CF.

Η ρινοκολπίτιδα οδηγεί τους ασθενείς σε συχνές ιατρικές επισκέψεις. Συντελεί σημαντικά στις δαπάνες για την υγεία, τόσο στις άμεσες λόγω ιατρικών επισκέψεων και φαρμακευτικής αγωγής, όσο και στις έμμεσες που συνδέονται με την απουσία από την εργασία, καθώς και με μια γενικότερη πτώση της παραγωγικότητας που οφείλεται σε μείωση της ποιότητας ζωής των ατόμων που πάσχουν. Η βαθύτερη κατανόηση της παθογένειας και αιτιολογίας της χρόνιας ρινοκολπίτιδας είναι απαραίτητη προκειμένου να αναπτυχθούν αποτελεσματικές θεραπείες. Το ιγμόρειο άντρο αποτελεί το συχνότερο κλινικό εντοπισμό της και χώρο εύκολα προσπελάσιμο για την μελέτη της παθογένειας των παθήσεων των παραρρινίων κόλπων. Η καταστροφή του κροσσωτού επιθήλιου ή η δυσλειτουργία των κροσσών του βλεννογόνου της μύτης και των παραρρινίων κόλπων επηρεάζουν αρνητικά την κάθαρση του βλεννοκροσσωτού επιθηλίου, η οποία αποτελεί έναν από τους μηχανισμούς που διαταράσσεται σε ρινοκολπίτιδα. Η ταχύτητα μεταφοράς του βλεννοκροσσωτού επιθηλίου (mucociliary transport velocity – MTV) που εκτιμάται με το ρινοσπινθηρογράφημα θεωρείται μια αξιόπιστη μέτρηση της κάθαρσης του βλεννοκροσσωτού επιθηλίου. Σχεδιάσαμε την παρούσα μελέτη με σκοπό τη διερεύνηση, μέσω του ρινοσπινθηρογραφήματος, της κάθαρσης του βλεννοκροσσωτού επιθηλίου σε ασθενείς με χρόνια ιγμορίτιδα που αντιμετωπίστηκαν συντηρητικά ή χειρουργικά. Επίσης μελετήσαμε την συσχέτιση της με ευρήματα από την αξονική τομογραφία καθώς και με τη βαρύτητα των συμπτωμάτων του ασθενούς. / Rhinosinusitis leads patients to frequent visits to medical doctors. It greatly contributes to healthcare expenses, directly due to medical visits and medication, as well as indirectly due to the subsequent absence from work and a productivity loss due to patients’ life quality deterioration. The deeper understanding of the cause and pathogenesis of the chronic rhinosinusitis is essential to the development of an effective treatment. The maxillary sinus is the most frequent location and it is easily accessible for the study of the pathogenesis of facial sinuses diseases. The ciliary epithelium destruction or the dysfunction of the nose mucosa’s cilia, negatively influences the mucociliary epithelium clearance, which constitutes one of the mechanisms disrupted in a rhinosinusitis. The Mucociliary Transport Velocity (MTV) which is estimated by the use of rhinoscintigraphy, is concerned a reliable measurement of the clearance of the mucociliary epithelium. We have designed the current study, in order to investigate, through the rhinoscintigraphy, the clearance of the mucociliary epithelium in patients with chronic maxillary sinusitis who were treated conservatively or surgically. Also, we studied its correlation with the CT findings, as well as with the quality of patients’ life.

Submitted by Jakeline Ortega (jakortega@unoeste.br) on 2018-12-07T19:24:10Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Danillo Nascimento Vicente1.pdf: 1177674 bytes, checksum: 5cbafc336ec745db7de7b00c859677f1 (MD5) / Made available in DSpace on 2018-12-07T19:24:10Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Danillo Nascimento Vicente1.pdf: 1177674 bytes, checksum: 5cbafc336ec745db7de7b00c859677f1 (MD5) Previous issue date: 2017-12-18 / Introduction: Urban air pollution has been one of the biggest problems in society. In Pontal do Paranapanema there are several factors that contribute to this pollution, among them the increase in the vehicle fleet registered in Presidente Prudente, the lack of suitable places for solid waste disposal and the burning of sugarcane straw. Due to the large area of contact between the surface of the respiratory system and the environment, air quality directly interferes with respiratory health. Thus, it can cause a mucociliary dysfunction that is responsible for episodes of exacerbations, which causes hypersecretion, recurrent infections and, consequently, dyspnea. The mucociliary system is the first mechanical barrier to come into contact with these air pollutants and its integrity is fundamental for the protection of the respiratory system. Currently the most accepted concepts of quality of life aim at a multiplicity of dimensions. Objective: to evaluate the influence of air pollution residues on respiratory health and quality of life of public urban transport drivers in a city of Pontal do Paranapanema. Methodology: 30 individuals of both sexes were evaluated, divided into two groups: Control Group - GC, consisting of 10 employees from the administrative sector and the Motorists - GM Group, made up of 20 drivers who are directly exposed to pollution. Measurement of carbon monoxide from expired air (COex) was performed to evaluate the nasal mucociliary transport, the saccharine transit time test (TTS) was used. Both carried out at the beginning and end of the working day in the three moments measured. The perception of quality of life (QOL) was analyzed through the application of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), applied before the beginning of the working day on the first day of evaluation. Results: The results of the TTS test for the group drivers showed increased transport speed from the first to the third day of research. Already the perception of QoL was observed that in the pain domain was higher for the Workers of the Control Group (p <0.05). Conclusion: Exposure to air pollution residues affects mucociliary transport of urban public transport drivers and that administrative employees feel more pain than drivers. We hope to contribute with these results to preventive health policies according to the needs of this population / Introdução: A poluição atmosférica urbana vem sendo um dos maiores problemas que assolam a sociedade. No Pontal do Paranapanema existem vários fatores que contribuem para essa poluição, dentre eles ao aumento da frota de veículos registrado em Presidente Prudente, a falta de locais apropriados para destinação de resíduos sólidos e ainda a queima da palha da cana-de-açucar. Devido à grande área de contato entre a superfície do sistema respiratório e o meio ambiente, a qualidade do ar interfere diretamente na saúde respiratória. Assim podendo causar uma disfunção mucociliar que é responsável por episódios de exacerbações, o que ocasiona quadros de hipersecreção, infecções recorrentes e, consequentemente, dispneia. O sistema mucociliar é a primeira barreira mecânica a entrar em contato com esses poluentes atmosféricos e sua integridade é fundamental para a proteção do sistema respiratório. Atualmente os conceitos mais aceitos de qualidade de vida visam uma multiplicidade de dimensões. Objetivo: avaliar a influência dos resíduos da poluição atmosférica na saúde respiratória e qualidade de vida dos motoristas de transporte coletivo urbano em uma cidade do Pontal do Paranapanema. Metodologia: foram avaliados 30 indivíduos de ambos os sexos, que foram divididos em dois grupos: Grupo Controle – GC, constituído por 10 funcionários do setor administrativo e Grupo Motoristas – GM, constituído por 20 motoristas que ficam diretamente expostos à poluição. Foi realizada a mensuração de monóxido de carbono do ar expirado (COex), para a avaliação do transporte mucociliar nasal, foi utilizado o teste de tempo de trânsito de sacarina (TTS). Ambos realizados ao início e término da jornada de trabalho nos três momentos aferidos. A percepção da qualidade de vida (QV) foi analisada através da aplicação do questionário Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), aplicado antes do início da jornada de trabalho no primeiro dia de avaliação. Resultados: os resultados do teste TTS para o grupo motoristas apresentaram aumento da velocidade do transporte do primeiro para o terceiro dia de pesquisa. Já a percepção da QV foi observada que no domínio dor foi maior para os trabalhadores do Grupo Controle (p<0,05). Conclusão: exposição aos resíduos da poluição atmosférica afeta o transporte mucociliar de motoristas de transporte coletivo urbano e que os funcionários do setor administrativo, sentem mais dor do que os motoristas. Esperamos contribuir com esses resultados para as políticas preventivas de saúde de acordo com as necessidades dessa população.

Submitted by JULIANA SOUZA UZELOTO null (juliana_uzeloto@hotmail.com) on 2016-06-21T17:32:29Z No. of bitstreams: 1 Defesa corrigida.pdf: 733210 bytes, checksum: 1fa0d39c72ee0d5ab9cc81d7c1b4bf2b (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-06-23T16:35:36Z (GMT) No. of bitstreams: 1 uzeloto_js_me_prud.pdf: 733210 bytes, checksum: 1fa0d39c72ee0d5ab9cc81d7c1b4bf2b (MD5) / Made available in DSpace on 2016-06-23T16:35:36Z (GMT). No. of bitstreams: 1 uzeloto_js_me_prud.pdf: 733210 bytes, checksum: 1fa0d39c72ee0d5ab9cc81d7c1b4bf2b (MD5) Previous issue date: 2016-05-20 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução: Mulheres tabagistas apresentam maior susceptibilidade para diversas doenças, em relação ao sexo oposto. Porém não há estudos que mostrem se há diferença no comportamento do transporte mucociliar nasal entre tabagistas homens e mulheres. É certo que nem todos os tabagistas desenvolvem doenças respiratórias crônicas, no entanto, o tabagismo é considerado um importante fator de risco para essas doenças. Assim, entende-se que além de avaliar o sistema respiratório dos tabagistas, a pesquisa no desfecho da saúde do pulmão de tabagistas é essencial, já que a maioria dos pacientes atendidos na fisioterapia respiratória é doente pulmonar crônico. Objetivos: Comparar a transportabilidade mucociliar nasal de homens e mulheres tabagistas levando em consideração a idade, dados antropométricos, carga tabagística, variáveis hemodinâmicas e função pulmonar. Além de avaliar sistematicamente a qualidade de diretrizes para doenças respiratórias crônicas, relevantes para a prática da fisioterapia, por meio do instrumento AGREE II e também avaliar a confiabilidade entre os avaliadores do instrumento AGREE II. Métodos: Foram inclusos na análise um total de 70 indivíduos tabagistas (33 homens e 37 mulheres). Todos responderam a uma entrevista inicial para obtenção dos dados pessoais e carga tabagística, foram mensurados os dados antropométricos, sinais vitais e monóxido de carbono no ar exalado, além disso, foram submetidos ao teste de função pulmonar e ao teste do tempo de trânsito de sacarina (TTS). Para análise do segundo objetivo foram avaliados, por quatro avaliadores, diretrizes sobre doença respiratória crônica, indexadas na base de dados PEDro, por meio do instrumento AGREE II (seis domínios e dois itens globais). Resultados e Conclusões: Na comparação da transportabilidade mucociliar nasal entre homens e mulheres, não foi encontrada diferenças significativas dentre as análises realizadas, mesmo realizando estratificações das variáveis, ou seja, o transporte mucociliar nasal de homens e mulheres adultos tabagistas, aparentemente saudáveis, é semelhante. Além disso, a qualidade das diretrizes de prática clínica baseadas em evidência, para doenças respiratórias crônicas, relevantes para a prática da fisioterapia podem ser melhoradas, particularmente no domínio aplicabilidade. A boa confiabilidade apresentada sugere que o número de avaliadores para o AGREE II possa ser reduzido. / Introduction: Female smokers have increased susceptibility to various diseases in the opposite sex. But there are no studies that show if there are differences in the behavior of nasal mucociliary transport between smokers men and women. It is sure that not all smokers develop chronic respiratory diseases, however, smoking is considered a major risk factor for these diseases. Thus, it is understood that in addition to evaluating the respiratory system of smokers, research in the outcome of smokers lung health is essential, since most of the patients seen in respiratory therapy is chronic pulmonary patient. Objectives: To compare the nasal mucociliary transportability of male and female smokers taking into consideration the age, anthropometric data, smoking load, hemodynamics and lung function. In addition to systematically assess the quality of guidelines for chronic respiratory diseases relevant to the practice of physiotherapy, through the AGREE II instrument and also assess the reliability of the evaluators of the AGREE II instrument. Methods: We included in the analysis a total of 70 smokers (33 men and 37 women). All responded to an initial interview to obtain personal data and smoking load, anthropometric data were measured, vital signs and carbon monoxide in exhaled air, moreover, underwent lung function test and the saccharin transit time test (STT). For analysis of the second objective guidelines indexed in the Physiotherapy Evidence Database (PEDro) on chronic respiratory diseases were evaluated by four assessors using AGREE II (six domains and two global items). Results and Conclusions: In comparison of nasal mucociliary transportability between men and women, there was no significant difference among the analyzes, even performing stratifications of variables, so the nasal mucociliary transport of men and women smokers adult apparently healthy, is similar. Moreover, the quality of evidence-based clinical practice guidelines for chronic respiratory diseases relevant to physiotherapy could be improved, particularly with regard to applicability. The number of assessors for AGREE II could be reduced because of the good inter-rater reliability. / FAPESP: 2014/11970-3 / FAPESP: 2015/13353-4

Introdução: A desobstrução rinofaríngea retrógrada (DRR) é uma técnica de fisioterapia respiratória aplicada em lactentes para desobstrução de vias aéreas superiores, podendo, inclusive, ser associada à irrigação nasal com salina isotônica para remoção de muco viscoso aderido às paredes das vias aéreas. Objetivo: Caracterizar o perfil de motociclistas profissionais expostos à poluição urbana no que se refere a transporte mucociliar nasal (TMCN), inflamação das vias aéreas superiores e sintomas nasais, e comparar o efeito da DRR isolada e associada à instilação de salina isotônica (DRR+S) nesta população. Métodos: Vinte e quatro voluntários divididos aleatoriamente em dois grupos (DRR e DRR+S) submeteram-se a 15 dias consecutivos de tratamento. A avaliação basal e a pós-intervenção constituíram-se da análise do teste de trânsito da sacarina, da celularidade total e diferencial do lavado nasal e dos sintomas de vias aéreas superiores por meio do questionário SNOT-20, bem como do estudo da exposição pessoal à poluição do ar, por meio da análise da concentração do NO2 de amostradores passivos. O TMCN foi avaliado pelo teste ANOVA não paramétrico com medidas repetidas e o SNOT-20 pelo teste Mann-Whitney. As correlações entre a concentração de NO2 e os desfechos das vias aéreas superiores foram testadas por meio do coeficiente de correlação de Spearman. Resultados: Os grupos apresentaram dados clínicos e demográficos semelhantes. O TMCN apresentou-se alterado em 25% dos voluntários e 100% deles apresentavam sintomas de vias aéreas superiores. Após os tratamentos, os sintomas de vias aéreas e o TMCN evidenciaram melhora significativa, apesar do aumento no número de macrófagos e células ciliadas do lavado nasal. Não houve correlação entre o NO2 e o TMCN, tampouco em relação aos sintomas de vias aéreas superiores. CONCLUSÃO: Técnicas não farmacológicas, simples e de baixo custo são efetivas para recuperar o TMCN alterado e melhorar os sintomas de vias aéreas superiores em adultos não tabagistas / Introduction: Rhinopharyngeal Retrograde Clearance (RRC) is a respiratory therapy technique applied to infants with upper airway obstruction that may also be associated with nasal irrigation with isotonic saline for removal of viscous mucus adhered to the walls of the airways. OBJECTIVE: Characterize the profile of professional motorcycles exposed to urban pollution in relation to the nasal mucociliary transport (NMCT), inflammation of the upper airways and nasal symptoms and compare the effect of DRR alone and associated with instillation of isotonic saline (RCC + S). Methods: Twenty-four volunteers were randomly divided into two groups (RCC and RCC + S) and were submitted to 15 consecutive days of treatment. The baseline and post-intervention consisted of analysis of the transit saccharin test, the total and differential cellularity nasal lavage, and symptoms of upper airway through the SNOT-20, as well as the study of personal exposure to air pollution, by analyzing the concentration of diffuse nitrogen dioxide monitoring system. The NMCT was evaluated with ANOVA for repeated measures and the SNOT-20 with the Mann-Whitney test. The correlations between the concentration of NO2 and the upper airway outcomes were tested using the Spearman correlation coefficient. Results: The groups showed similar demographic and clinical data. The NMCT was abnormal in 25% of the volunteers and 100% of the volunteers had symptoms of upper airways. After treatment the upper airway symptoms and the NMCT showed significant improvement despite the increase in the number of macrophages and ciliated cells on the nasal lavage. No correlation was observed between dioxide nitrogen and TMCN and with the symptoms of the upper airways. Conclusion: Nonpharmacological, simple and inexpensive techniques are effective to treat abnormal NMCT and improve symptoms of upper airway in nonsmoking adults

Introdução: A desobstrução rinofaríngea retrógrada (DRR) é uma técnica de fisioterapia respiratória aplicada em lactentes para desobstrução de vias aéreas superiores, podendo, inclusive, ser associada à irrigação nasal com salina isotônica para remoção de muco viscoso aderido às paredes das vias aéreas. Objetivo: Caracterizar o perfil de motociclistas profissionais expostos à poluição urbana no que se refere a transporte mucociliar nasal (TMCN), inflamação das vias aéreas superiores e sintomas nasais, e comparar o efeito da DRR isolada e associada à instilação de salina isotônica (DRR+S) nesta população. Métodos: Vinte e quatro voluntários divididos aleatoriamente em dois grupos (DRR e DRR+S) submeteram-se a 15 dias consecutivos de tratamento. A avaliação basal e a pós-intervenção constituíram-se da análise do teste de trânsito da sacarina, da celularidade total e diferencial do lavado nasal e dos sintomas de vias aéreas superiores por meio do questionário SNOT-20, bem como do estudo da exposição pessoal à poluição do ar, por meio da análise da concentração do NO2 de amostradores passivos. O TMCN foi avaliado pelo teste ANOVA não paramétrico com medidas repetidas e o SNOT-20 pelo teste Mann-Whitney. As correlações entre a concentração de NO2 e os desfechos das vias aéreas superiores foram testadas por meio do coeficiente de correlação de Spearman. Resultados: Os grupos apresentaram dados clínicos e demográficos semelhantes. O TMCN apresentou-se alterado em 25% dos voluntários e 100% deles apresentavam sintomas de vias aéreas superiores. Após os tratamentos, os sintomas de vias aéreas e o TMCN evidenciaram melhora significativa, apesar do aumento no número de macrófagos e células ciliadas do lavado nasal. Não houve correlação entre o NO2 e o TMCN, tampouco em relação aos sintomas de vias aéreas superiores. CONCLUSÃO: Técnicas não farmacológicas, simples e de baixo custo são efetivas para recuperar o TMCN alterado e melhorar os sintomas de vias aéreas superiores em adultos não tabagistas / Introduction: Rhinopharyngeal Retrograde Clearance (RRC) is a respiratory therapy technique applied to infants with upper airway obstruction that may also be associated with nasal irrigation with isotonic saline for removal of viscous mucus adhered to the walls of the airways. OBJECTIVE: Characterize the profile of professional motorcycles exposed to urban pollution in relation to the nasal mucociliary transport (NMCT), inflammation of the upper airways and nasal symptoms and compare the effect of DRR alone and associated with instillation of isotonic saline (RCC + S). Methods: Twenty-four volunteers were randomly divided into two groups (RCC and RCC + S) and were submitted to 15 consecutive days of treatment. The baseline and post-intervention consisted of analysis of the transit saccharin test, the total and differential cellularity nasal lavage, and symptoms of upper airway through the SNOT-20, as well as the study of personal exposure to air pollution, by analyzing the concentration of diffuse nitrogen dioxide monitoring system. The NMCT was evaluated with ANOVA for repeated measures and the SNOT-20 with the Mann-Whitney test. The correlations between the concentration of NO2 and the upper airway outcomes were tested using the Spearman correlation coefficient. Results: The groups showed similar demographic and clinical data. The NMCT was abnormal in 25% of the volunteers and 100% of the volunteers had symptoms of upper airways. After treatment the upper airway symptoms and the NMCT showed significant improvement despite the increase in the number of macrophages and ciliated cells on the nasal lavage. No correlation was observed between dioxide nitrogen and TMCN and with the symptoms of the upper airways. Conclusion: Nonpharmacological, simple and inexpensive techniques are effective to treat abnormal NMCT and improve symptoms of upper airway in nonsmoking adults