Background: Asthma is a heterogeneous disease. Diagnosis relies on symptom evaluation and lung function tests using spirometry. Symptoms can be vague. Spirometry is effort-dependent and does not reliably evaluate small airways. Allergic asthma in preschool children is not easily separated from episodic wheeze. Exhaled NO (FeNO) is a marker of allergic Th2-cytokine-driven airway inflammation. However, FeNO is not feasible in preschoolers with current devices and algorithms. Alveolar NO is an estimate of small airway involvement. Forced oscillometry (FOT) is an effort-independent lung function test assessing both large and small airways. Aims: To study clinical and methodological aspects of FeNO, alveolar NO and lung function indices by FOT. Methods: Asthmatic children and young adults and healthy controls, were included in the studies. FeNO at 50 mL/s was performed in all studies (in study III with an adapted single-breath method with age-adjusted exhalation times). FeNO at multiple exhalation flow rates were performed in studies I, II and IV to calculate alveolar NO, as was spirometry. FOT indices were assessed in study IV. Results: The exhalation time needed to reach steady-state NO was < 4 s in subjects aged 3-4 years, and was related to subject height. FeNO was higher in ICS-naïve asthmatic children than in controls. ICS-naïve asthmatic preschool children had FeNO < 20 ppb. The oral contribution to FeNO was similar in asthmatic and healthy youths. Multiple flow rates and modelling of alveolar NO were feasible in children aged 10-18 years. Alveolar NO correlated to asthma characteristics, though not when axial diffusion correction was applied. FOT resistance measures were associated with asthma diagnosis, and small airway FOT measures were associated with asthma control, in adolescents. Conclusion: An adapted FeNO method is feasible from 4 years, and exhalation time is related to child height. Our findings emphasise the need to refine clinical cut-offs for FeNO in younger children. FOT variables discriminate between asthmatics and controls, much like spirometry. The information provided by FOT is additive to that from spirometry. Further studies of exhaled NO dynamics and FOT indices of small airways are warranted to evaluate new treatment options and possibly improve asthma control.

UA Open Access Publishing Fund / Background: Noninvasive positive-pressure ventilation (NIPPV) use has increased in the treatment of patients with respiratory failure. However, despite decreasing the need for intubation in some patients, there are no data regarding the risk of intubation-related complications associated with delayed intubation in adult patients who fail NIPPV. The objective of this study is to evaluate the odds of a composite complication of intubation following failed NIPPV compared to patients intubated primarily in the medical intensive care unit (ICU). Methods: This is a single-center retrospective cohort study of 235 patients intubated between 1 January 2012 and 30 June 2013 in a medical ICU of a university medical center. A total of 125 patients were intubated after failing NIPPV, 110 patients were intubated without a trial of NIPPV. Intubation-related data were collected prospectively through a continuous quality improvement (CQI) program and retrospectively extracted from the medical record on all patients intubated on the medical ICU. A propensity adjustment for the factors expected to affect the decision to initially use NIPPV was used, and the adjusted multivariate regression analysis was performed to evaluate the odds of a composite complication (desaturation, hypotension, or aspiration) with intubation following failed NIPPV versus primary intubation. Results: A propensity-adjusted multivariate regression analysis revealed that the odds of a composite complication of intubation in patients who fail NIPPV was 2.20 (CI 1.14 to 4.25), when corrected for the presence of pneumonia or acute respiratory distress syndrome (ARDS), and adjusted for factors known to increase complications of intubation (total attempts and operator experience). When a composite complication occurred, the unadjusted odds of death in the ICU were 1.79 (95% CI 1.03 to 3.12). Conclusions: After controlling for potential confounders, this propensity-adjusted analysis demonstrates an increased odds of a composite complication with intubation following failed NIPPV. Further, the presence of a composite complication during intubation is associated with an increased odds of death in the ICU.

A common problem following general anesthesia is postoperative sore throat (POST) and postoperative hoarseness (PH). Symptoms directly correlated with less satisfaction according to the patients. The overall aim of this thesis was to describe patients' postoperative sore throat and hoarseness after general anesthesia with endotracheal intubation or laryngeal mask airway. As well as to investigate the risk factors that are associated with the symptoms, and to test methods that may prevent sore throat and hoarseness after a general anaesthetics. A total of 889 patients are included in the four studies. Incidence of POST varied from 21% up to 52 % depending on endotracheal tube (ETT) size in women (I-IV) and in men was the incidence 32-38% (III-IV). There were no gender difference in POST in study III and IV. The overall incidence of PH varied from 42- 59% (I-IV) in all patients, with no gender differences (III-IV). Following a laryngeal mask airway (LMA) 19% of the patients had POST and 33% of the patients reported PH. Patients with POST do seem to be able to localize their pain in the throat (IV). Different risk factors are shown to contribute to both POST and PH in men and women (II-III). To intubate with a smaller ETT size, 6.0 vs. 7.0 decreased POST in women in the early postoperative period as well as their discomfort from their POST (I). Only 6% of men who needed a laryngeal mask airway had POST compared to 26% of women. The symptoms are more discomforting after an ETT vs. an LMA up to 24 hours (IV). More patients have sore throat and hoarseness in the early postoperative period, but the symptoms can remain up to almost 5 days postoperatively (I, IV). In summary, sore throat and hoarseness following general anesthesia, affects many patients postoperatively. To intubate women with endotracheal size 6.0 decreases both sore throat and hoarseness postoperatively. Women are more likely than men to have a sore throat when a laryngeal mask airway is used.

No description available.

The dynamics of particle laden flows are integral to the analysis of toxic particle deposition and medical respiratory aerosol delivery. Computational fluid-particle dynamics (CFPD) can play a critical role in developing a better understanding of particle laden flows, especially in a number of under-explored areas. The applications considered in this study include both the numerical aspects and the physical phenomena of respiratory aerosol transport. Objective I: Considering the effects of mesh type and grid convergence, four commonly implemented mesh styles were applied to a double bifurcation respiratory geometry and tested for flow patterns and aerosol deposition. Results indicated that the mesh style employed had a significant effect on the transport and deposition of aerosols with hexahedral meshes being most accurate. Objective II: In order to evaluate the effects of bronchoconstriction under exhalation conditions, normal and constricted pediatric airway models were considered. Results include (i) a significant increase in deposition for constricted airways, and (ii) a novel correlation for deposition during exhalation based on the Dean and Stokes numbers. Objective IIIa: Considering evaluation of an aerosol size sampler, an eight-stage Andersen cascade impactor (ACI) was numerically analyzed. The numerical simulations indicated high non-uniformity and recirculation in the flow field. Numerical predictions of retention fraction matched well with existing experiments (0.5 – 11% error). Objective IIIb: As an extension to this study, numerical predictions of electrostatic charge effects on aerosol transport and deposition in the ACI were presented. Charges consistent with standard pharmaceutical pressurized metered dose inhalers and dry powder inhalers were considered. The numerical predictions indicated that charged aerosols deposit as if they were 5 – 85% larger due to electrostatic effects. Applications of the studies considered include (i) quantitative guidance in selecting numerical mesh styles and development of standard grid convergence criteria, (ii) the development of more accurate whole-lung deposition models that better evaluate exhalation conditions,(iii) improvements in the design of pharmaceutical assessment and delivery devices, and (vi) correction values to account for electrostatic charge on pharmaceutical aerosols.

Obstructive sleep apnea is a chronic illness with increasing prevalence. In addition to associated cardiovascular comorbidities, obstructive sleep apnea syndrome has been linked to poor quality of life, occupational accidents, and motor vehicle crashes secondary to excessive daytime sleepiness. Although continuous positive airway pressure is the gold standard for sleep apnea treatment, its effects on quality of life are not well defined. In the current study we investigated the effects of treatment on quality of life using the data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), a randomized controlled trial of continuous positive airway pressure (CPAP) versus sham CPAP. The Calgary Sleep Apnea Quality of Life Index (SAQLI) was used to assess quality of life. Overall we found no significant improvement in quality of life among sleep apnea patients after CPAP treatment. However, after stratifying by OSA severity, it was found that long-term improvement in quality of life might occur with the use of CPAP in people with severe and possibly moderate sleep apnea, and no demonstrable improvement in quality of life was noted among participants with mild obstructive sleep apnea.

<p>The lungs are vital organs whose airways are lined with a continuous layer of epithelial cells. Epithelial cells in the distal most part of the lung, the alveolar space, are specialized to facilitate gas exchange. Proximal to the alveoli is the airway epithelium, which provides an essential barrier and is the first line of defense against inhaled toxicants, pollutants, and pathogens. Although the postnatal lung is a quiescent organ, it has an inherent ability to regenerate in response to injury. Proper balance between maintaining quiescence and undergoing repair is crucial, with imbalances in these processes leading to fibrosis or tumor development. Stem and progenitor cells are central to maintaining balance, given that they proliferate and renew both themselves and the various differentiated cells of the lung. However, the precise mechanisms regulating quiescence and repair in the lungs are largely unknown. In this dissertation, ionizing radiation is used as a physiologically relevant injury model to better understand the repair process of the airway epithelium. We use in vitro and in vivo mouse models to study the response of a secretory progenitor, the club cell, to various doses and qualities of ionizing radiation. Exposure to radiation found in space environments and in some types of radiotherapy caused clonal expansion of club cells specifically in the most distal branches of the airway epithelium, indicating that the progenitors residing in the terminal bronchioles are radiosensitive. This clonal expansion is due to an increase in p53-dependent apoptosis, senescence, and mitotic defects. Through the course of this work, we discovered that p53 is not only involved in radiation response, but is also a novel regulator of airway epithelial homeostasis. p53 acts in a gene dose-dependent manner to regulate the composition of airway epithelium by maintaining quiescence and regulating differentiation of club progenitor cells in the steady-state lung. The work presented in this dissertation represents an advance in our understanding of the molecular mechanisms underlying maintenance of airway epithelial progenitor cells as well as their repair following ionizing radiation exposure.</p> / Dissertation

A asma é uma doença crônica das vias aéreas, cuja fisiopatologia compreende inflamação, hiper-responsividade e remodelação. As características clínicas e a espirometria são usadas para avaliar o controle da doença. Alguns asmáticos não conseguem controlar tomando altas doses de medicações de controle (asma de difícil controle). A tomografia computadorizada quantitativa de tórax (TCQ) é pouco usada na asma, mas pode fornecer biomarcadores da doença. Objetivos: Comparar os achados de TCQ de indivíduos sem doenças respiratórias (grupo controle - GC), com asma controlada (ABC) e com asma de difícil controle (ADC), visando prioritariamente parâmetros substitutivos do remodelamento das vias aéreas. Investigar se há correlações entre os parâmetros QCT e espirometria. Materiais e Métodos: Recrutamos sujeitos com ADC e ABC em um hospital terciário. Usamos registros médicos e convite pessoal para obter dados de CG. Todos os indivíduos foram submetidos a tomografia computadorizada de alta resolução e espirometria. Um software (Yacta) foi usado para obter dados de TCQ. O teste t de Student, o one-way ANOVA e o teste exato de Fisher foram realizados para comparar os dados dos grupos. Os coeficientes de correlação de Pearson foram calculados para avaliar as correlações entre os parâmetros espirométricos e TCQ. Resultados: O GC foi composto por 21 sujeitos; ABC, de 28 e ADC, de 27. Estes últimos eram mais idosos que GC e ABC (50,85 (10,11); 41,27 (11,57); 42,04 (10,11) anos; p = 0,002). A espessura relativa das vias aéreas (ERP3-8) foi significativamente diferente entre GC e ADC (45,31% (3,71); 49,38% (3,38); p = 0,001) e entre GC e ABC (45,31%, 71); 48,25 (4,51); p = 0,001). A espessura normalizada das vias aéreas (Pi10) foi significativamente diferente entre ADC e ABC (0,51 (0,10); 0,44 (0,10); p = 0,0001) e entre ADC e CG (0,51 (0,10), 0,39 (0,08), p = 0,0001). A área da parede das vias aéreas (AP/ASC-mm2) da terceira geração brônquica foi significativamente diferente entre o ADC e o GC (37,14 (9,70); 30,18 (5,06); p = 0,005) e entre ABC e GC (35, 54 (6,37); 30,18 (5,06); p = 0,005). A área da luz da via aérea da terceira geração brônquica (LA/ASC-mm2) foi significativamente diferente entre ADC e ABC (28,81 (10,08); 35,88 (7,12); p = 0,002) e entre ADC e GC (28 81 (10,08); 36,14 (7,29); p = 0,002). A atenuação máxima média (MMA-Hounsfield Units) da terceira geração brônquica foi significativamente diferente entre ADC e GC (-128,68 (67,15); -232,01 (75,20); p = 0,0001) e entre ABC e CG (-147,81 (75,31); -232,01 (75,20); p = 0,0001). Encontramos correlações negativas entre o volume expiratório forçado no primeiro segundo (VEF1) e a ERP na terceira, quarta e quinta gerações brônquicas; entre o índice Tiffeneau e a ERP nessas gerações; entre fluxo expiratório forçado (FEF25-75%) e ERP nas mesmas gerações. Encontramos correlações negativas entre VEF1 e AMMna terceira e quarta gerações e entre o índice de Tiffeneau e AMM nessas gerações. Encontramos correlações negativas entre o FEF(25-75%) e o AMM nessas gerações. Conclusões: Mesmo os asmáticos com doença controlada apresentaram evidências radiológicas de comprometimento da parede das vias aéreas; as evidências foram maiores em asma de difícil controle. Características tomográficas podem ser devido a inflamação ou remodelação. Encontramos correlações entre os parâmetros espirométricos e TCQ. Nossos achados reforçam a utilidade potencial dos parâmetros do TCQ como biomarcadores do controle da asma e da resposta ao tratamento, em pesquisa e em bases clínicas / Asthma is a chronic airway disease whose pathophysiology comprises inflammation, hyperresponsivenes and remodelling. Clinical characteristics and spirometry are used to assess disease control. Some asthmatics do not achieve control taking high doses of controller therapy (difficult to control asthma). Quantitative lung computed tomography (QCT) is seldom used in asthma but may provide asthma biomarkers. Objectives: To compare QCT findings of subjects without respiratory diseases (control group - CG), with controlled asthma (CA) and with difficult to control asthma (DCA), aiming primarily at surrogate parameters of airway remodelling. To investigate whether there are correlations between QCT and spirometry parameters. Materials and Methods: We recruited subjects with DCA and CA from a tertiary hospital. We used medical records and personal invitation to obtain CG data. All subjects underwent high resolution computed tomography and spirometry. A software (Yacta) was used to obtain QCT data. Student\'s t-test, one-way ANOVA and Fisher\'s exact test were performed to compare data from the groups. Pearson correlation coefficients were calculated to assess correlations between spirometric and QTC parameters. Results: The CG was comprised of 21 subjects; CA, of 28 and DCA, of 27. The latter had older subjects than CG and CA (50,85 (10,11); 41,27 (11,57); 42,04 (10,11) years; p=0,002). Relative airway thickness (RT) was significantly different between CG and DCA (45,31% (3,71); 49,38% (3,38); p=0,001) and between CG and CA (45,31% (3,71); 48,25 (4,51); p=0,001). Normalised airway thickness (Pi10) were significantly different between DCA and CA (0,51 (0,10); 0,44 (0,10); p=0,0001) and between DCA and CG (0,51 (0,10); 0,39 (0,08); p=0,0001). Airway wall area (AWAmm2) of the third bronchial generation was significantly different between DCA and CG (37,14 (9,70); 30,18 (5,06); p=0,005) and between CA and CG (35,54 (6,37); 30,18 (5,06); p=0,005). Airway lumen area of the third bronchial generation (ALA-mm2) was significantly different between DCA and CA (28,81 (10,08); 35,88 (7,12); p=0,002) and between DCA and CG (28,81 (10,08); 36,14 (7,29); p=0,002). Mean maximum attenuation (MMA-Hounsfield Units) of the third bronchial generation was significantly different between DCA and CG (-128,68 (67,15); -232,01 (75,20); p=0,0001) and between CA and CG (-147,81 (75,31); -232,01 (75,20); p=0,0001). We found negative correlations between forced expiratory volume on the first second (FEV1) and RT on the third, fourth and fifth bronchial generations ; between the Tiffeneau index and RT on those generations; between forced expiratory flow (FEF25-75) and RT on the same generations. We found negative correlations between FEV1 and MMA on the third and fourth generations and between the Tiffeneau index and MMA on those geneations. We found negative correlations between FEF25-75 and MMA on those generations.Conclusions: Even asthmatics with controlled disease had radiological evidence of airway wall involvement; the evidences were greater in difficult to control asthma. Tomographic features can be due to inflammation or remodelling. We found correlations between spirometric and QTC parameters. Our findings reinforce the potential usefulness of QTC parameters as biomarkers of asthma control and of response to treatment, on research and clinical grounds

La Broncho-pneumopathie Chronique Obstructive (BPCO) est une maladie respiratoire grave caractérisée par une inflammation chronique entrainant des lésions irréversibles de l’épithélium respiratoire et du parenchyme pulmonaire. Le principal facteur de risque est le tabagisme mais des études d’association génétique pangénomiques ont montré que certains polymorphismes nucléotidiques simples (SNP) des récepteurs nicotiniques (nAChRs) sont associés à l’incidence de la BPCO. Un de ces polymorphisme est le variant rs16969968 dans le 5ème exon du gène CHRNA5 codant la sous-unité α5. Le but de ce travail a été d’évaluer in vivo l’implication du SNP α5 dans les lésions pulmonaires caractérisant la BPCO et d’étudier l’impact fonctionnel du polymorphisme sur les voies de signalisation mises en jeu en aval des nAChRs. A l’aide de différents modèles in vivo murins et humains, nous avons pu montrer qu’indépendamment du tabagisme, le SNPα5 est associé à une inflammation cellulaire plus marquée, une sécrétion de cytokines pro-inflammatoires, des lésions emphysémateuses, une hyperplasie des cellules mucipares et des cellules Club moins fréquentes par rapport au génotype sauvage. Le SNPα5 est associé à une altération de la perméabilité calcique des cellules épithéliales et une modulation de la voie de signalisation AC3-PKA/C. Cette étude apporte pour la première fois une explication biologique à l’association entre le SNPα5 et la BPCO décrite dans les études d’association génétique pangénomiques à travers un rôle pro-inflammatoire du SNPα5 au niveau pulmonaire. / Chronic Obstructive Pulmonary Disease (COPD) is a critical respiratory disease characterized by a chronic inflammation leading to irreversible epithelial and parenchymal injuries. The main risk factor is tobacco consumption but several genome-wide association studies (GWAS) described some single-associated polymorphisms (SNP) on nicotinic acetylcholine receptors (nACHR) genes associated with COPD incidence. One of these polymorphisms is the rs16969968 variant in the 5th exon of CHRNA5 gene coding the α5 subunit (SNP α5). The aim of this study was to determine in vivo the involvement of SNPα5 in COPD-associated lung injuries and to deciphere the functional impact of the polymorphism on nAChR signaling pathways. Thanks to several in vivo models (mouse and human), we describe here that the SNPα5 is associated, irrespective of the tobacco consumption, to an increased inflammation, pro-inflammatory cytokines secretion, emphysema, goblet cell hyperplasia, and Club cell diminution compared to the wild-type genotype. The SNPα5 is associated with a decreased calcium influx and a modulation of AC3-PKA/C pathway in airway epithelial cells. Our study describe for the first time a biological explanation for the association between SNPα5 and COPD shown in GWAS with a pro-inflammatory role of SNPα5 in the lung.

Objetivos: Comparar os efeitos dos tratamentos com montelucaste e dexametasona no recrutamento eosinofílico e na avaliação de células positivas para eotaxina, RANTES, fibronectina, IGF-I e NF-B tanto no parênquima pulmonar distal, quanto nas vias aéreas de cobaias com inflamação alérgica crônica. Métodos: As cobaias receberam inalação com ovoalbumina (grupo OVA- 2 vezes semanais, durante 4 semanas, totalizando 7 inalações). Após a quarta inalação, as cobaias foram tratadas com montelucaste (grupo OVA-M: 10mg/Kg/VO/dia) ou dexametasona ( grupo OVA-D: 5mg/Kg/IP/dia). Após 72 horas da sétima inalação, as cobaias foram anestesiadas e os pulmões foram removidos e submetidos a avaliação histopatológica. Resultados: Os tratamentos com montelucaste e dexametasona reduziram o número de eosinófilos tanto no parênquima pulmonar distal quanto nas vias aéreas, quando comparados ao grupo OVA (p<0.05). No parênquima pulmonary distal, ambos os tratamentos foram efetivos na redução de células positivas para RANTES, NF-B e fibronectina, quando comparados ao grupo OVA (p<0.001). O tratamento com montelucaste mostrou melhor eficácia na redução de células positivas para eotaxina, quando comparado ao tratamento com dexametasona (p<0.001), por outro lado, o tratamento com dexametasona mostrou-se mais significativo na redução de células positivas para IGF-I, quando comparado ao tratamento com montelucaste (p<0.001). Nas vias aéreas, ambos os tratamentos foram efetivos na redução de células positivas para IGF-I, RANTES e fibronectina, quando comparados ao grupo OVA (p<0.05). O tratamento com dexametasona foi mais efetivo na redução de células positivas para eotaxina e NF-B, quando comparado ao tratamento com montelucaste (p<0.05). Conclusões: Neste modelo animal, ambos os tratamentos foram efetivos no controle da resposta inflamatória, tanto no parênquima pulmonar distal, quanto nas vias aéreas / Aims: Compare the effects of montelukast or dexamethasone treatments on eosinophilic recruitment, eotaxin, RANTES, fibronectin, IGF-I and NF-B positive cells of distal lung parenchyma and also in airway walls of guinea pigs (GP) with chronic allergic inflammation. Methods: GP were inhaled with ovalbumin (OVA group-2x/week/4weeks). After 4th inhalation, GP were treated with montelukast (M group: 10mg/Kg/PO/day) or dexamethasone (D group: 5mg/Kg/IP/day). After 72 hrs of 7th inhalation, GP were anesthetised, lungs were removed and submitted to histopathological evaluation. Results: Montelukast and dexamethasone treatments reduced the number of eosinophils both in airway wall as well as in distal lung parenchyma compared to OVA group (p<0.05). On distal parenchyma both montelukast and dexamethasone were effective in reducing RANTES, NF-B and fibronectin positive cells compared to OVA group (p<0.001). Montelukast was more effective in reducing the eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (p<0.001), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (p<0.001). On airway walls, both montelukast and dexamethasone were effective in reducing IGF-I, RANTES and fibronectin positive cells compared to OVA group (p<0.05). Dexamethasone was more effective reducing the number of eotaxin and NF-kB positive cells than Montelukast (p<0.05). Conclusions: In this animal model, both treatments were effective in modulating the eosinophilic response in distal lung parenchyma and in airway wall, contributing to a better control of the inflammatory response in distal lung parenchyma as well as in airway walls. Dexamethasone treatment induced a greater reduction of NF-B expression in airway walls which suggests one of the mechanisms that explains the higher efficacy of this therapeutic approach