Introdução: A assistência ventilatória adequada é imprescindível para o tratamento do paciente ventilado artificialmente. A busca por parâmetros para realizar o ajuste ótimo e que tenham aplicação fácil a beira leito como, por exemplo, métodos não-invasivos, são desejáveis. Objetivo: analisar a acurácia diagnóstica das variáveis do padrão respiratório, da P0.1 esofágica e traqueal, para o ajuste da assistência ventilatória em pressão de suporte. Métodos: Vinte e sete pacientes internados em unidade de terapia intensiva foram consecutivamente incluídos no estudo. Todos pacientes estavam no modo de pressão de suporte, que foi aumentada para 20 cmH2O e diminui em passos de 3 cmH2O, até 2 cmH2O ou antes se o paciente apresentasse sinais de desconforto respiratório. Os pacientes foram monitorizados com cateteres para medidas de pressão esofágica e gástrica, com uma peça proximal ao tubo para mensurar a pressão traqueal a partir da oclusão da via aérea e com um pneumotacógrafo para medidas de fluxo. Durante todos níveis de suporte, foram gravados os dados dos cateteres esofágicos, gástricos, da traquéia, dados hemodinâmicos e do padrão respiratório. O ajuste da assistência ventilatória foi classificado como adequado, insuficiente e excessivo de acordo com critérios pré-estabelecidos. Resultados: Foram analisados 210 períodos com diferentes pressões de suporte e em 49% destes períodos a assistência foi excessiva, enquanto em 3,8% a assistência foi insuficiente. No início do estudo, enquanto os pacientes ainda estavam com a assistência ventilatória ajustada pela equipe assistente, 48,2% apresentavam assistência ventilatória excessiva. Pela pequena incidência de períodos com assistência ventilatória insuficiente, não foi avaliado a acurácia das variáveis para diagnóstico de assistência insuficiente. Para diagnosticar assistência ventilatória excessiva, a variável do padrão respiratório que se mostrou mais acurada foi a frequência respiratória, com sensibilidade de 90% e especificidade de 88% quando a frequência respiratória foi menor que 17 incursões por minuto. Outras variáveis do padrão respiratório não mostraram elevada acurácia. Também para o diagnóstico de assistência excessiva, foi elevada a acurácia da P0.1 esofágica (sensibilidade de 81% e especificidade de 70% quando P0.1 <= 1,9) e da P0.1 traqueal (sensibilidade de 81% e especificidade de 70% quando P0.1 <= 2,1). Conclusão: A ocorrência de assistência ventilatória excessiva foi significativamente maior que a assistência ventilatória insuficiente. A frequência respiratória menor que 17 foi a variável do padrão respiratório com maior acurácia para diagnosticar assistência ventilatória excessiva. As P0.1 esofágica e traqueal também tiveram acurácia elevas, mas menores que a frequência respiratória . / Introdution: The adequate assistance is essential for the treatment of mechanically ventilated patient. The search of parameters to achieve the optimal adjustment and with easy application to bedside, for example, non-invasive methods. Objective: Analyze the diagnostic accuracy of the breathing pattern variables, esophageal and tracheal P0.1 for adjustment of mechanical ventilation in pressure support ventilation. Methods: Twenty-seven patients in intensive care unit were consecutively included in the study. All patients were in the pressure support mode, which was raised to 20 cmH2O and decreased in steps of 3 cmH2O up to 2 cmH2O or earlier if the patient had signs of respiratory distress. Patients were monitored with catheters for esophageal and gastric pressure measurements, with the T-piece was used close to the tube to measure tracheal pressure during an airway occlusion and a pneumotachograph for flow measurements. Data was recorded for all support levels to esophageal, gastric, and tracheal pressures, also hemodynamic data and ventilatory pattern. The adjustment of mechanical ventilation was classified as adequate assistance, overassistance and underassistance according to pre-established criteria. Results: Two hundred and ten periods were analyzed with different pressures of support and 49% of these periods were overassistance, while 3,8% these periods were underassistance. At baseline, while patients were still ventilatory assistance set by assistance staff, 48,2% had overassistance. Due to the low incidence of periods with underassistance, the variables accurancy has not been evaluated. The variable breathing pattern that was more accurate diagnosing overassistance was the respiratory rate (90% sensitivity and specificity of 88 % when the respiratory rate was less than 17 breaths per minute). Other variables of the breathing pattern did not show high accuracy although esophageal P0.1 (sensitivity 81 % and specificity of 70 % when P0.1 <= 1,9) and tracheal P0.1 (sensitivity 81 % and specificity of 70 % when P0.1 <= 2,1) were high accuracy diagnosing overassistance. Conclusion: The occurrence of overassistance was significantly higher than underassistance. The respiratory rate below 17 was the variable breathing pattern more accurate to predict overassistance. The esophageal and tracheal P0.1 also had high accuracy but lower than the respiratory rate

Acute respiratory infections (ARI) are a major global cause of morbidity and mortality. Vitamin D deficiency has been reported to associate with susceptibility to ARI and with greater severity and poorer control of asthma and chronic obstructive pulmonary disease (COPD). Clinical trials of vitamin D for the prevention of ARI have yielded heterogeneous results, with some showing protection and others not. This may reflect variation in the frequency of genetic variants influencing response to vitamin D supplementation in different populations. The impact that genetic variation in the vitamin D pathway has on vitamin D status, disease phenotype and response to vitamin D supplementation in prevention of ARI has not been comprehensively investigated. Methods: I conducted: 1. A systematic review and meta-analysis of clinical studies which have investigated vitamin D as a potential therapy for ARI; 2. Three cross-sectional studies (in n=297 adult asthma patients, n=278 COPD patients, and n=272 older adults) to investigate potential environmental determinants (lifestyle and anthropometric) and genetic determinants (35 single nucleotide polymorphisms [SNP] in 11 vitamin D related genes) of serum 25-hydroxyvitamin D concentration (25[OH]D) and clinical phenotype; 3. Three prospective studies investigating the influence of genetic variation in the vitamin D pathway on a) susceptibility to ARI (main effects analysis) and b) efficacy of vitamin D supplementation for the prevention of ARI (interaction analysis). Results: My systematic review identified consistent reports of an inverse association between vitamin D status and risk of ARI in observational studies, and heterogeneous reports from clinical trials. My cross-sectional studies identified a range of classical environmental factors which predict vitamin D status in the three study populations, but did not identify any genetic variants in the vitamin D pathway that associate with vitamin D status. I identified an association between vitamin D deficiency and decreased lung function in COPD patients, but no associations between vitamin D deficiency and asthma phenotype. Finally, my analysis identified a haplotype of 5 single nucleotide polymorphisms in the vitamin D receptor (VDR) gene which significantly modify the effect of vitamin D supplementation on risk of upper respiratory infection in COPD patients. Conclusions: I identified environmental determinants that predict 25(OH)D concentrations in all three study populations, but only found an association between vitamin D deficiency and disease severity in COPD patients. Furthermore, I identified a haplotype in VDR which modifies the effect of vitamin D supplementation in COPD patients to result in a significantly reduced risk of ARI.

The relationship between respiratory muscle fatigue and the function of swallowing is examined here. The main objective of this study is to examine the effects of respiratory muscle fatigue on swallowing physiology in healthy young adults. Specifically, this study aims to determine if differences exist in several swallowing-related parameters (a. the muscle recruitment pattern of the submentals and infrahyoids associated with swallowing, b. the pattern of breathing and swallowing coordination, c. the duration of the breath phases associated with swallowing, d. the duration of swallowing apnea, and e. the secondary swallow frequency) during several different swallowing conditions before, following respiratory muscle fatigue and following recovery. Fifty-four healthy young adults were randomly assigned into two groups, either an inspiratory (MIP) or an expiratory (MEP) muscle fatigue group. Respiratory and swallowing measurements were obtained, during 3 experimental conditions: a baseline condition, after exercise-induced fatigue, and finally, after a 15min rest period. A loaded breathing device was used in order to induce fatigue to the respiratory muscles. Presence of fatigue was determined with the assessment of Maximum Expiratory (PEmax)/Maximum Inspiratory (PImax) Pressures measured with a mouth pressure manometer. Electrophysiologic data were obtained with the use of sEMG on the submental and infrahyoid muscle groups, and with the use of three respiratory belt transducers, placed around the thorax, abdomen and neck. The Borg Scale was used to behaviourally assess perceived sense of breathing effort. Descriptive and inferential statistics were conducted to allow for detailed analysis of differing measures and variances between individuals. Results revealed significant differences between the three experimental conditions in the muscle recruitment patterns of the submental and infrahyoids, in the pattern of breathing and swallowing coordination, in the duration of the swallow-related respiratory cycle and in the frequency of secondary swallows. The duration of the deglutitive apnea was not affected by the presence of respiratory muscle fatigue. In particular, the sEMG Integral of the infahyoids was significantly reduced during the fatigued condition compared to the baseline and post-rest conditions, as opposed to an increase in sEMG integral of the submental muscles observed only in the MEP subject group. Additionally, the occurrence of swallows followed by inspiration was significantly increased during the fatigued condition. Secondary swallow frequency was significantly increased during the fatigued condition. These results suggest an effect of respiratory muscle fatigue on selective swallowing related parameters. These results are of great clinical importance since the observed patterns may increase the risk of aspiration. Results will be discussed with respects to the implications for patients and their therapeutic interventions.

Cough is common but has been under-researched. In tuberculosis cough is probably of particular relevance in transmitting infection. This thesis explores several interlinking areas. Regarding how best to measure cough, coughs are shown to be recognizable to the human ear, but automated cough monitors can disagree with auditory cough counting. A novel approach to testing cough reflex sensitivity is described, E62.5. There was no evidence to support the hypothesis that cough has unique characteristics in tuberculosis, in terms of symptoms, frequency and clustering. A significant reduction of cough frequency in tuberculosis is demonstrated overnight. Clinical correlates of 24hour cough frequency were explored; female sex in unexplained chronic cough, and sputum smear status in tuberculosis were important, and possibly transfer factor in pulmonary fibrosis and duration of symptoms prior to treatment in COPD exacerbations. Cough frequency correlated poorly with symptoms. There seem to be both generic and disease-specific mechanisms associated with cough. This was further suggested by a faster reduction in cough frequency with treatment in pneumonia than in acute asthma and COPD exacerbations, correlating with C-reactive protein decline only in pneumonia. A serial reduction in 24-hour cough frequency in tuberculosis during the whole course of treatment was demonstrated, a potentially novel approach to measuring treatment response. The role of genetic polymorphism in the cough receptor gene TRPV1 was explored, but, at least in chronic cough was not demonstrated to predict coughing. Regarding the infectiousness of coughs, an airborne particle counter was shown not to be sensitive enough for measuring droplets released during coughing in room air. However, I demonstrate for the first time a significant association between 24-hour cough frequency in TB and household infection. This work has set a foundation for the further investigation of the mechanisms, processes and patterns of coughing with respect to tuberculosis transmission and other contexts.

Ma Shuang-Cheng. / "March 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 289-324). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Orientador: Roberto Calderon Gonçalves / Banca: Rogério Martins Amorim / Banca: Simone Biagio Chiacchio / Banca: Alice Maria Melville paiva Della Libera / Banca: Giovana Wingeter Di Santis / Resumo: A expansão econômica da ovinocultura acarreta no aumento do número de animais mantidos em confinamento e seu maior trânsito entre as propriedades. Com isso há aumento dos índices de doenças respiratórias nessa espécie, que estão entre as enfermidades que ocasionam maiores perdas econômicas em rebanhos de vários países. Grande parte das doenças respiratórias de mortalidade elevada e sintomatologia clínica evidente está associada a infecções por Mannheimia (Pasteurella) haemolytica. Entretanto, outras enfermidades também acometem os ovinos e são pouco definidas etiológica e morfologicamente, especialmente as de etiologia viral. Os vírus têm sido incriminados como agentes precursores e agravantes quando em associação com infecção bacteriana secundária. Os métodos mais utilizados para identificação viral são a sorologia, isolamento viral, teste de vírus neutralização e reação em cadeia pela polimerase. Contudo, essas técnicas apresentam limitações quanto ao tempo de execução e a necessidade de equipamentos dispendiosos. Com a necessidade da detecção rápida de antígenos virais, métodos como imunofluorescência e ensaios imunoenzimáticos vem sendo mais estudados no diagnóstico de agentes etiológicos. A imunoistoquímica é uma opção para a identificação de diversos agentes etiológicos e vem sendo amplamente estudada nos casos de enfermidades respiratórias, devido a facilidade na execução e não necessitar equipamentos dispendiosos nem técnicas trabalhosas para armazenamento de amostras. Neste contexto, o propósito deste estudo foi avaliar ovinos com comprometimento de vias aéreas anteriores e processos broncopulmonares, detectados no exame clínico e exame histopatológico, e correlacionar os achados com a sorologia, citologia de vias aéreas anteriores e posteriores, com a imunoistoquímica para os Vírus sincicial respiratório... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The economic expansion of sheep breeding cause an increase in the number of animals kept in confinement and increased traffic between these properties, increasing the rates of respiratory diseases in this species, which are among the diseases that cause major economic losses in herds in several countries. Much of respiratory diseases and high mortality evident clinical symptoms are associated with infections by Mannheimia (Pasteurella) haemolytica, however, other diseases also affect sheep and are poorly defined etiology and morphology, especially viral diseases. Viruses have long been incriminated as agents precursors and aggravating when combined with secondary bacterial infection. The methods used for viral identification are serology, virus isolation, virus neutralization test, polymerase chain reaction. However, these techniques have limitations as to time of execution and the need for expensive equipment. With the need for rapid detection of viral antigens, methods such as immunofluorescence and enzyme immunoassays has been most studied in the search for etiologic agents. Immunohistochemistry is an option for the identification of other agents and has been widely studied in cases of respiratory illnesses due to ease of execution and does not require expensive equipment or laborious techniques for sample storage. In this context, the purposes of this research was to evaluate sheep with involvement of upper airways and bronchopulmonary cases, detected on clinical examination and histopathology, and correlate the findings with serology, cytology airways before and after, and immunohistochemistry for Virus Respiratory Syncytial and Parainfluenza virus. Was detected by serology 27.5% for the BIS-3 and 40% for BRSV positive samples. There was a predominance of interstitial pneumonia type (56.7%) and immunohistochemistry detected the presence of BPI-3 antigens in 13.3% and 20.0% ...(Complete abstract click electronic access below) / Doutor

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / Chronic obstructive pulmonary disease is a common, avoidable and treatable disease characterized by persistent obstruction of the airways and lungs. This disease is usually progressive and associated with a chronic inflammatory response set off by noxious particles or gases. Patients with chronic obstructive pulmonary disease, represents a great impact on the increase of clinical care, as well as the economic health spending to provide better quality of life. This study characterizes the pharmacoepidemiological profile, adherence to drug therapy, pharmacotherapy complexity and performance of using inhalation devices in outpatientâs subjects of a referral hospital for treatment of pulmonary diseases. This is a descriptive, exploratory and transversal study. 83 individuals were interviewed, with a predominance of males, a mean age of 68.22 years, and low schooling. The average number of medications per patient was 5.58, characterizing the polypharmacy, and 81.9% had some type of comorbidity. The founded prevalence was mean adherence rate (45.8%). The most frequent response among the questions asked to measure adherence was related to forgettings (38.6%). The complexity therapy had a mean value of 15.9 points, a high score that reveals the difficulties in following the treatment. After evaluation of inhalation devices was found that as the use of dry powder inhaler Aerolizer, the technique was considered good in 62.5% of patients, the use of Respimat  inhaler was "good" in 70.96% of cases and the use of metered-dose aerosol showed to be regular in 64.7%. The evaluation of the use of the devices found flaws in several steps considered essential for their proper management. From these data, are needed strategies that aimed at enhancing actions to improve adherence to therapy and ongoing evaluation of inhalation devices, minimizing complications for the patient. / A DoenÃa pulmonar obstrutiva crÃnica, à uma doenÃa comum, evitÃvel e tratÃvel, caracterizada por obstruÃÃo persistente das vias aÃreas e dos pulmÃes, geralmente progressiva e associada a uma resposta inflamatÃria crÃnica desencadeada por partÃculas ou gases nocivos. Os pacientes portadores de DoenÃa pulmonar obstrutiva crÃnica representam um grande impacto no aumento dos atendimentos clÃnicos, assim como nos gastos econÃmicos com a saÃde para proporcionar melhor qualidade de vida. Este trabalho caracteriza o perfil farmacoepidemiolÃgico, a adesÃo à terapia medicamentosa, complexidade da farmacoterapia e o desempenho do uso de dispositivos inalatÃrios em indivÃduos atendidos em um ambulatÃrio de um hospital de referÃncia em tratamento de doenÃas pulmonares. Trata-se de um estudo descritivo, exploratÃrio e transversal. Foram entrevistados 83 indivÃduos, com predominÃncia do sexo masculino, idade mÃdia de 68,22 anos e baixa escolaridade. A mÃdia do nÃmero de medicamentos por paciente foi de 5,58, caracterizando a polifarmÃcia, e 81,9% tinham algum tipo de comorbidade. A prevalÃncia encontrada foi de mÃdia adesÃo (45,8%). A resposta mais frequente entre as perguntas realizadas para mensurar a adesÃo foi a referente aos esquecimentos dos pacientes em tomarem seus medicamentos diariamente (38,6%). A complexidade terapÃutica teve valor mÃdio de 15,9 pontos, um escore elevado que revela as dificuldades existentes no seguimento do tratamento. ApÃs avaliaÃÃo dos dispositivos inalatÃrios constatou-se que quanto ao uso de inaladores de pà seco Aerolizer a tÃcnica foi considerada boa em 62,5% dos pacientes, o uso de inalador Respimat foi âbomâ em 70,96% dos casos e o uso de aerossol dosimetrado mostrou-se regular em 64,7%. A avaliaÃÃo do uso dos dispositivos encontrou falhas em vÃrias etapas consideradas essenciais para o seu manejo adequado. A partir destes dados, se fazem necessÃrias estratÃgias que visem potencializar aÃÃes para melhorar a adesÃo à terapia e uma avaliaÃÃo contÃnua do uso dos dispositivos inalatÃrios, minimizando complicaÃÃes para o paciente.

Introdução: A assistência ventilatória adequada é imprescindível para o tratamento do paciente ventilado artificialmente. A busca por parâmetros para realizar o ajuste ótimo e que tenham aplicação fácil a beira leito como, por exemplo, métodos não-invasivos, são desejáveis. Objetivo: analisar a acurácia diagnóstica das variáveis do padrão respiratório, da P0.1 esofágica e traqueal, para o ajuste da assistência ventilatória em pressão de suporte. Métodos: Vinte e sete pacientes internados em unidade de terapia intensiva foram consecutivamente incluídos no estudo. Todos pacientes estavam no modo de pressão de suporte, que foi aumentada para 20 cmH2O e diminui em passos de 3 cmH2O, até 2 cmH2O ou antes se o paciente apresentasse sinais de desconforto respiratório. Os pacientes foram monitorizados com cateteres para medidas de pressão esofágica e gástrica, com uma peça proximal ao tubo para mensurar a pressão traqueal a partir da oclusão da via aérea e com um pneumotacógrafo para medidas de fluxo. Durante todos níveis de suporte, foram gravados os dados dos cateteres esofágicos, gástricos, da traquéia, dados hemodinâmicos e do padrão respiratório. O ajuste da assistência ventilatória foi classificado como adequado, insuficiente e excessivo de acordo com critérios pré-estabelecidos. Resultados: Foram analisados 210 períodos com diferentes pressões de suporte e em 49% destes períodos a assistência foi excessiva, enquanto em 3,8% a assistência foi insuficiente. No início do estudo, enquanto os pacientes ainda estavam com a assistência ventilatória ajustada pela equipe assistente, 48,2% apresentavam assistência ventilatória excessiva. Pela pequena incidência de períodos com assistência ventilatória insuficiente, não foi avaliado a acurácia das variáveis para diagnóstico de assistência insuficiente. Para diagnosticar assistência ventilatória excessiva, a variável do padrão respiratório que se mostrou mais acurada foi a frequência respiratória, com sensibilidade de 90% e especificidade de 88% quando a frequência respiratória foi menor que 17 incursões por minuto. Outras variáveis do padrão respiratório não mostraram elevada acurácia. Também para o diagnóstico de assistência excessiva, foi elevada a acurácia da P0.1 esofágica (sensibilidade de 81% e especificidade de 70% quando P0.1 <= 1,9) e da P0.1 traqueal (sensibilidade de 81% e especificidade de 70% quando P0.1 <= 2,1). Conclusão: A ocorrência de assistência ventilatória excessiva foi significativamente maior que a assistência ventilatória insuficiente. A frequência respiratória menor que 17 foi a variável do padrão respiratório com maior acurácia para diagnosticar assistência ventilatória excessiva. As P0.1 esofágica e traqueal também tiveram acurácia elevas, mas menores que a frequência respiratória . / Introdution: The adequate assistance is essential for the treatment of mechanically ventilated patient. The search of parameters to achieve the optimal adjustment and with easy application to bedside, for example, non-invasive methods. Objective: Analyze the diagnostic accuracy of the breathing pattern variables, esophageal and tracheal P0.1 for adjustment of mechanical ventilation in pressure support ventilation. Methods: Twenty-seven patients in intensive care unit were consecutively included in the study. All patients were in the pressure support mode, which was raised to 20 cmH2O and decreased in steps of 3 cmH2O up to 2 cmH2O or earlier if the patient had signs of respiratory distress. Patients were monitored with catheters for esophageal and gastric pressure measurements, with the T-piece was used close to the tube to measure tracheal pressure during an airway occlusion and a pneumotachograph for flow measurements. Data was recorded for all support levels to esophageal, gastric, and tracheal pressures, also hemodynamic data and ventilatory pattern. The adjustment of mechanical ventilation was classified as adequate assistance, overassistance and underassistance according to pre-established criteria. Results: Two hundred and ten periods were analyzed with different pressures of support and 49% of these periods were overassistance, while 3,8% these periods were underassistance. At baseline, while patients were still ventilatory assistance set by assistance staff, 48,2% had overassistance. Due to the low incidence of periods with underassistance, the variables accurancy has not been evaluated. The variable breathing pattern that was more accurate diagnosing overassistance was the respiratory rate (90% sensitivity and specificity of 88 % when the respiratory rate was less than 17 breaths per minute). Other variables of the breathing pattern did not show high accuracy although esophageal P0.1 (sensitivity 81 % and specificity of 70 % when P0.1 <= 1,9) and tracheal P0.1 (sensitivity 81 % and specificity of 70 % when P0.1 <= 2,1) were high accuracy diagnosing overassistance. Conclusion: The occurrence of overassistance was significantly higher than underassistance. The respiratory rate below 17 was the variable breathing pattern more accurate to predict overassistance. The esophageal and tracheal P0.1 also had high accuracy but lower than the respiratory rate

Recurrent infection with human respiratory syncytial virus (RSV) is one of the most common causes for lower respiratory tract illness (LRI) in infants, the elderly, and immunocompromised individuals. Due to lack of vaccines and therapeutic interventions, medical care of acute RSV bronchiolitis is mostly limited to supportive measures. Thus, novel treatment options to control RSV infection are desperately required. The cationic host defence peptide human cathelicidin LL-37 possesses both microbicidal and immunomodulatory properties. This essential effector of the innate immune system holds potent antiviral activity against a variety of viruses, including influenza virus, and has been proposed as a promising candidate for antiviral drug development. Previous studies revealed that lower cathelicidin levels put RSV infected infants at risk for more severe RSV disease, while infection of lung epithelial cells induced cathelicidin up-regulation. These findings suggest that LL-37 might possess antiviral activity against RSV. However, its potential antiviral function on RSV remains to be elucidated. This thesis therefore aimed to evaluate the antiviral activity of cathelicidins against RSV, by assessing its relevance in vitro and in vivo and elucidating the underlying antiviral mechanism. Firstly, the antiviral effects of human cathelicidin LL-37 against RSV were addressed in vitro. Presence of LL-37 during infection potently reduced viral titres and protected cells against virus-associated cytopathic effects. Experiments revealed that only the core region of LL-37 holds antiviral activity against RSV. Antiviral effects were also observed for the murine LL-37 orthologue mCRAMP. Administration of LL-37 at different stages in the infection cycle provided evidence that LL-37 can be used preventatively, protecting against RSV infection by directly acting on both cells and viral particles. When given therapeutically, once an infection was established, LL-37 also limited viral spread. Next, the molecular mechanism mediating the peptide’s antiviral activity was investigated. It was demonstrated that LL-37 does not affect the interferon-mediated cellular antiviral immune response to RSV. Experiments established that LL-37 does not contribute to viral clearance by inducing epithelial cell death. Further mechanistic studies revealed that the peptide directly binds to RSV particles, destabilises the integrity of the viral envelope, and prevents adsorption of RSV to epithelial cells during the entry stage of infection. Finally, the in vivo relevance of LL-37 treatment and endogenous cathelicidin expression was examined, employing both murine and human model systems. It was established that LL-37 has protective antiviral effects against RSV in vivo. In contrast to the cell culture model, only co-administration of LL-37 and RSV, but not treatment prior or post infection, protects mice from clinical signs of infection. Levels of the murine LL-37 orthologue mCRAMP were increased in RSV infected lungs, pointing towards its importance in antiviral defence. In keeping with this, mCRAMP-deficient mice were more susceptible to RSV induced disease. Equally, individuals with low nasal LL-37 baseline levels that were experimentally challenged with RSV, were more susceptible to infection. This highlights the importance of endogenous cathelicidin expression to fight and control RSV infection. Overall, these results identify LL-37 as an important antiviral agent against RSV in vitro and in vivo, and emphasise the role of endogenous cathelicidins in the defence against this pathogen. Moreover, unravelling the underlying antiviral mechanism of LL-37 against RSV adds to our understanding of how CHDP act on enveloped viruses, thus supporting the development of new antiviral treatment options.

Measuring the level of exhaled NO (eNO) in the breath is a new method to monitor airway inflammation in asthma and may have a role in the management of asthma. The hypotheses were that eNO will reflect the degree of inflammation in chronic asthma, and will indicate how anti- inflammatory therapy should be altered to improve asthma control. Three studies were performed to test the hypotheses. A cross sectional study was performed to define the normal range of eNO and to compare this range with those who have asthma or atopy. The second study was observational, to compare the level of eNO during and after an exacerbation of asthma. The third study was an interventional study to evaluate eNO in management of paediatric asthma. In this latter study the level of eNO was measured to monitor airway inflammation in asthmatic children with the intention of adjusting antiinflammatory drugs (inhaled glucocorticosteroids) according to the level of eNO. These studies have shown that the mean level of eNO was significantly higher in asthmatic compared with normal subjects, but not significantly different when compared with atopic non-asthmatic subjects. eNO was correlated with the number of positive skin prick tests in atopic subjects whether asthmatic or nonasthmatic. The eNO level was increased during acute exacerbations of asthma and decreased after two weeks with therapy of GCS. In a pilot study eNO appeared to be superior to FEV1 in adjusting the dose of iGCS to control asthmatic children, but this needs to be confirmed with a larger sample size. Another non-invasive method to detect inflammatory markers is the technique of exhaled breath condensate (EBC). Although NO is degraded to NOx, it was found that eNO had no significant correlation with EBC NOx but had a significant correlation with pH. Hypertonic saline challenge, an artificial model of an asthmatic exacerbation was associated with an increase in EBC volume and the release of histamine, implicating mast cell activation. These novel findings suggest that non-invasive markers can be used both for clinical and mechanistic proposes.