Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Chronic obstructive pulmonary disease (COPD) has a severe impact on quality of life (QOL). Using the Health Promotion Model as a guide, a cross-sectional, correlational design was used to describe relationships among individual characteristics and experiences (age, gender, race, severity of illness, resilience), behavior-specific cognitions and affect (self-efficacy, barriers, social support), behavioral outcomes (health promoting lifestyle), and QOL in this patient population. One hundred and twenty participants were recruited from three clinics at Virginia Commonwealth University Health System. In addition to a demographic survey, participants completed a 151-item questionnaire incorporating measures resilience, severity of illness, self-efficacy, and barriers to a health-promoting lifestyle, social support, lifestyle, and QOL. Spirometric evaluation of lung function and the 6-minute walking test were also completed. Structural equation modeling was used to determine the effect of nine independent variables on QOL.Participants were white (51.2%), female (63.6%), and approximately 60.5 years old. Severity of illness, characterized by symptoms and functional capacity, suggested they were not severely ill (mean = 3.18, S.D.= 2.69). They were somewhat resilient (mean = 136.01, S.D.= 23.01), had adequate social support (mean = 68.10, S.D.= 19.95), were uncertain about their competency (self-efficacy) to manage their health (mean = 24.91, S.D.= 4.92), sometimes experienced barriers (mean = 33.33, S.D.= 9.02), and sometimes included attributes of a healthy lifestyle in their lives (mean = 123.93, S.D.= 25.22). Their QOL was fair to poor (mean = 6.10, S.D.= 2.39).A series of analyses using structural equation modeling was conducted. The first model that was tested did not fit the data χ2(df = 13)= 67.989,p = 0.000, GFI = 0.895, CFI = 0.781, RMSEA = 0.189). Next, modification indices were use to reexamine for fit. Using the recommended modifications, a good fit model was obtained χ2(df = 9)=5.016, p = 0.833, GFI = 0.992, CFI = 1.0, RMSEA = 0.0); however, non-significant paths were present. An alternative model was tested and fit the data very well χ2(df=18)= 10.011, p = 0.932, GFI = 0.981, CFI = 1.0, RMSEA = 0.0). The independent variables explained about 45.1% of the variance in health-promoting lifestyle. All the variables explained 45.3% of variance in QOL. The most significant predictor of a healthy lifestyle was social support (0.383) and the most significant predictor of QOL was self-efficacy (0.364). The findings confirmed the utility of the HPM.

Pulmonary emphysema is a serious worldwide illness, causing progressive and irreversible alveolar wall loss and difficulty in breathing. It is caused mostly by cigarette smoking. However, its unresolved complex and multiple pathogenic mechanisms have left this disease without effective pharmacotherapy. This project hypothesized that cinnamic acid-based dehydropolymers (DHPs), originally discovered as novel anti-coagulants, protect against emphysema through their potent triple inhibitory actions against oxidative stress, inflammation and elastase, some of the pathogenic mechanisms associated with this disease. Three in vitro inhibitory activity assays for oxidative stress, lung inflammation and neutrophil elastase (NE) were developed and used to identify the most potent triple inhibitor DHP. These activities were determined by chromogenic free radical generation in chemical oxidation, lung epithelial (Calu-3) repression of pro-inflammatory nuclear factor κB (NFκB) upon its plasmid transfection and chromogenic substrate NE hydrolysis, respectively. The sulfated caffeic acid DHP, CDS was shown to be the most potent in all three assessments, yielding the half-maximal inhibitory concentrations of 3.52, ~10 and 0.43 µM, respectively. CDS was tested with pulmonary delivery in an in vivo rat model of emphysema induced by elastase and cigarette smoke extract (HSE/CSE). CDS at 5 and 30 μg/kg was instilled into the lung at 2 h prior to HSE/CSE instillation. The lung tissues and bronchoalveolar lavage fluids (BALFs) were taken 1 or 48 h post-HSE/CSE instillation to determine the tissue reduced glutathione (rGSH), airway infiltration of inflammatory neutrophils and airway luminal elastase alongside lung hemorrhage. The HSE/CSE instillation significantly caused 43.0 % decrease in rGSH, 104.8-fold greater neutrophil infiltration, 2.8-fold higher elastase activity and 9.3-fold increased lung hemorrhage, compared to the saline (negative) control. However, all these inductions were significantly protected by CDS at 30 μg/kg, exhibiting 92.9, 76.6, 59.7 and 70.4 % inhibition, respectively; reduced effects were seen at 5 μg/kg, showing its dose-related responses. As a result, the HSE/CSE-induced airspace enlargement assessed on 28th day was also prevented by CDS at 30 μg/kg, yet not at 5 μg/kg. In conclusion, this study has demonstrated the in vitro and in vivo effectiveness of CDS for its possible use in the protection against emphysema development, specifically via inhalation.

Introduction: Chronic obstructive pulmonary disease (COPD) is one of the most common chronic respiratory diseases. Impairments in exercise capacity, kinesiology and skeletal muscle function are well established in these patients. Recently presented data also suggests impairments in postural balance and increased risk of falls in patients with COPD. The aim of this study is to examine postural balance functions in a group of patients and compare the results with a control group. Methods: Twelve patients (the average age 65,6 ± 7,1, 5 women, 7 men) with COPD hospitalized at the Pulmonary Clinic at the Faculty Hospital, Prague Motol and 10 healthy control subjects (the average age 58,6 ± 5,2, 7 women, 3 men) participated in this study. Participants were measured by The Activities-specific Balance Confidence Scale (ABC) and The Balance Evaluation Systems Test (BESTest). Results: COPD patients scored significantly worse (0,0099, p < 0,05) on the ABC scale total score compared to healthy controls, 78,38 ± 21,14 for COPD versus 97,78 ± 3,88 for controls. The total score and the six subsystem categories score of the BESTest were lower in COPD patients, but not significantly, compared to controls. Conclusion: Patients with COPD showed a lower degree of balance confidence and postural balance functions....

The thesis deals with the possibility to influence the values of the lung function in patiens with chronic obstructive pulmonary disease (COPD) after exercise carried out according to the Methodology of sensorimotor training. The thesis contains a summary of theoretical knowledge about the pathophysiologic expresion of COPD, including their consequences not only for the respiratory system, but musculoskeletal system as well. Furthermore the thesis includes the information about the Methodology of sensorimotor training, that was used to influence the posture correction in our research. Methods: The spirometric examination of flow-volume curves monitor the changes prior to and after the exercise according to sensorimotor training in patiens with COPD (mean age 60, 733 ± 11,817). Results: The using of sensorimotor training can provide correction of the position of the whole body, of the chest, and change a chest mobility and in total to set up conditions for more economical muscle activation. This enable the changes in the values of the lung functions in the patiens with COPD, that we measured. Not all changes showed statistically significant change. Conclusion: Using sensorimotor training have an objective effect on the values of the lung function in patiens with COPD.

Healthcare utilizations are typically measured independently of each other; neglecting the interdependencies between services. An episode of care is suitable for measuring healthcare utilizations of patients with complex health conditions because it tracks all contacts throughout the healthcare system. The overall goal of this research was to construct an episode of care data system to study healthcare utilizations and costs of chronic obstructive pulmonary disease (COPD) exacerbations. To achieve this goal, four related studies were undertaken. The first study (Chapter 2) evaluated the agreement between emergency department (ED) data and hospital records for capturing transitions between the two care settings. Using the κ statistic as a measure of concordance, we found good agreement between the two data sources for intra-facility transfers; but only fair agreement for inter-facility transfers. The results show that linking multiple data sources would be important to identify all related healthcare utilization across care settings. The second study (Chapter 3) linked hospital data, ED data, physician billing claims, and outpatient drug records to construct an episode of care data system for COPD patients. Latent class analysis was used to identify COPD patient groups with distinct healthcare pathways. Pathways were associated with outcomes such as mortality and costs. A few individuals followed complex pathways and incurred high costs. Building on the previous study, the next one (Chapter 4) predicted whether high-cost patients in one episode also incurred high costs in subsequent episodes. Using logistic regression models, we found that patient information routinely collected in administrative health data could satisfactorily predict those who become persistent high users. The final study (Chapter 5) used a cross-validation approach to compare the performance of eight alternative linear regression models for predicting costs of episodes of COPD exacerbations. The results indicate that the robust regression model, a model not often considered for cost prediction, was among the best models for predicting episode-based costs. Overall, this research demonstrated how population-based administrative health databases could be linked to construct an episode of care data system for a chronic health condition. The resulting data system supported novel investigations of healthcare system-wide utilizations and costs. / May 2016

Dans le but d'obtenir des composés originaux ayant une activité inhibitrice envers la NE, des triazoles et des 2-aminofuranes diversement substitués ont été synthétisés. Une réaction de "click chemistry" catalysée par le cuivre entre un azide et un alcyne a été appliquée pour la synthèse des triazoles. La synthèse des composés de type 2-aminofuranes est basée sur l'attaque nucléophile d'un isonitrile sur un γ-oxo butynoate d'alkyle en présence d'un aldéhyde aromatique.Les tests biologiques ont été réalisés tout au long de la thèse. Les composés présentant les meilleures IC50 envers la NE ont été sélectionnées pour une évaluation en terme de sélectivité vs les autres sérines protéases du PN (la cathepsine G et la protéinase 3). Enfin, les meilleurs inhibiteurs ont subi une évaluation de leur activité anti-oxydante selon deux méthodes: méthode au DPPH (1,1-diphényl-2-picryl-hydrazyl) et méthode au thiocyanate ferrique. / To prepare new compounds with an inhibitory activity towards NE, diversely substituted triazoles and 2-aminofuranes were synthesized. Triazoles were obtained using the copper catalyzed "click chemistry" between an azide and an alkyne. The synthesis of 2-aminofuranes is based on the nucleophilic attack of an isonitrile on an alkyl γ-oxo-butynoate in the presence of an aromatic aldehyde.Biological assays were carried out throughout the thesis. Compounds owning the best IC50 towards NE were selected for evaluation in terms of selectivity vs the two other serine-proteases of the PN (cathepsin G and proteinase 3). Finally, evaluation of antioxidant activity of the best compounds was achieved using by two approachs: DPPH (1,1-diphenyl -2-picrylhydrazyl) method and ferric thiocyanate method.

Le maintien de l'intégrité de l'épithélium des voies aériennes est assuré par un mécanisme de réparation épithéliale pouvant être dérégulé dans la bronchopneumopathie chronique obstructive (BPCO). La BPCO, définie par une obstruction irréversible des débits aériens et émaillée d'épisodes d'exacerbation, présente différents phénotypes, pour lesquels l'évaluation de la sévérité tient compte de la fonction respiratoire et de données cliniques. L'objectif de cette thèse était d'étudier du point de vue phénotypique des patients BPCO lors des exacerbations virales et au cours du processus de réparation épithéliale. Nous avons étudié prospectivement 51 patients BPCO suivis mensuellement et lors des exacerbations. Virus et bactéries étaient recherchés dans l'expectoration induite par PCR et culture. Les résultats analysés en fonction des données cliniques et fonctionnelles respiratoires ont montré qu'une coinfection, présente dans 25% des exacerbations, n'était pas associée au phénotype des patients ni à la sévérité ou à la récidive de l'exacerbation. Nous avons ensuite étudié la réparation de cellules épithéliales bronchiques primaires dans un modèle de réparation de lésion. L'analyse des paramètres de fermeture de lésion (vitesse de fermeture, sécrétions, prolifération cellulaire) en fonction des données cliniques, fonctionnelles et histologiques a montré notamment que la vitesse de fermeture était associée à la sévérité de l'obstruction bronchique. Ces résultats suggèrent le rôle d'anomalies de réparation épithéliale dans la physiopathologie de la BPCO et soulignent la complexité du phénotypage des patients atteints de BPCO. / The integrity of airway epithelium is provided by a complex mechanism of epithelial repair that can be dysegulated in chronic obstructive pulmonary disease (COPD). COPD is a heterogeneous condition defined by an irreversible obstructive airflow limitation with frequent acute episodes of exacerbations. COPD patients can present different phenotypes, for which severity evaluation must take into account the severity of lung function and clinical data. The aim of this thesis was to study the COPD patients in a phenotypic point of view during viral exacerbations and during the process of epithelial repair.We prospectively studied 51 COPD patients monitored monthly and during exacerbations. Induce sputum were analyzed for viruses and bacteria detection by PCR and culture. These results analyzed according to the clinical and functional respiratory data showed that co-infection was present in 25 % of exacerbations and was not associated with the phenotype of patients or the severity or recurrence of exacerbation.We then studied primary bronchial epithelial cells repair in a model of wound closure. Associations between wound closure parameters (speed of wound closure, secretions, cell proliferation) and clinical, histological and functional data were analyzed. We showed that the speed of wound closure was associated with the severity of bronchial obstruction. These results suggest the role of abnormal epithelial repair in the pathogenesis of COPD and highlight the complexity of phenotypic characterization of COPD patients.

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.

Kombinierte Ventilations- und Inhalationsszintigraphie Während konventionelle Lungenfunktionsparameter zur Bestimmung ventilatorisch und atemmechanisch bedingten Verteilungsstörungen nur eine funktionelle Beurteilung erlauben, ermöglichen die Methoden der Ventilations- und Inhalationsszintigraphie eine regional funktionelle Zuordnung. Bei obstruktiven Lungenerkrankungen kann durch den Einsatz von Aerosolen gezielt eine Verteilungsstörung nachgewiesen werden, die um so ausgeprägter ist, je weniger sich im Szintigramm (regional) die Lungenperipherie darstellen läßt. Mit einer gleichzeitig durchgeführten Xenon-133-Ventilation kann differenziert werden, ob es sich um eine obstruktionsbedingte Minderbelüftung handelt ( Ventilations-Inhalations-Mismatch), oder ob die Belüftung bestimmter Lungenareale funktionell ausgefallen ist ( Ventilations-Inhalations-Match). Ziel unserer Untersuchung war es herauszufinden, in welcher Beziehung die regionale Darstellung der Ventilations-Inhalations-Konstellationen zu konventionellen Inhomogenitätsparametern der Lungenfunktion bei Patienten mit COPD steht und inwieweit Informationen über die Lungenfunktion hinaus erlangt werden können. Patienten: Wir untersuchten 32 Patienten mit chronisch obstruktiver Lungenkrankheit (COPD) im Alter zwischen 17 und 68 Jahren. Die Untersuchung der Patienten wurde in einem möglichst beschwerdefreien Intervall unter klinischer Fragestellung durchgeführt. Methodik: Die Patienten wurden mittels folgender Methoden untersucht:1. Lungenfunktionsdiagnostik: Fluß-Volumen-Kurve, Bodyplethysmographie, FRC-Rebreathing, Diffusionsmessung und Impulsoszillometrie. 2. Szintigraphische Untersuchung: Alle Patienten wurden zur Darstellung der belüfteten Lungenabschnitte einer Xenon-133-Ventilationsszintigraphie und im Anschluß daran einer Technetium-99m-DTPA-Inhalationsszintigraphie unterzogen. Xenon-133 wurde im single-breath Verfahren mit 10 Sekunden Atemanhaltezeit verabreicht. Die Inhalation von Technetium markierten Aerosolpartikeln erfolgte mittels eines Verneblersystems. Die Patienten atmeten das Aerosol 7 Minuten langsam und ruhig ein. Die quantitative Auswertung erfolgte mittels interessierender Regionen (ROI) und eines Scores. Statische Szintigramme wurden nach einem Score in 4 Gruppen entsprechen verschiedener Ventilations-Inhalations-Konstellationstypen ( Mismatch, Match) eingeteilt. Ergebnisse: Bei Patienten mit COPD wurden nuklearmedizinisch 3 Schweregrade von Ventilationsstörungen unterschieden: geringgradiges Ventilations-Inhalations-Mismatch, ausgeprägtes Ventilations-Inhalations-Match, pathologisches Ventilations-Inhalations-Match. Im Vergleich der Schweregradeinteilung der Verteilungsstörungen durch Methoden der konventionellen Lungenfunktionsdiagnostik und der Nuklearmedizin ergibt sich eine hochsignifikante Korrelation. Von den 22 Patienten, die pathologische Lungenfunktionswerte aufwiesen, ergaben sich auch zu 95 % Veränderungen in der Szintigraphie, währenddessen zeigten von den 28 Patienten mit pathologischer nuklearmedizinischer Bewertung nur 75% pathologische Inhomogenitätsparameter. Die Methode der Ventilations- und Inhalationsszintigraphie erwies sich somit als sensitiver. / Combination of ventilation and inhalation scintigraphy While conventional parameters to determine the ventilatory and respiratory-mechanical distribution disturbances allow a functional assessment only, the methods of ventilation and inhalation scintigraphy enable a regional functional categorization. With obstructive pulmonary diseases, a disturbance of distribution can be traced with the help of aerosols, the disturbance of distribution being the more severe the less the regional periphery of the lung can be imaged in the scintigram. A simultaneous xenon-133-ventiation, which is performed in selected cases, allows to differentiate between an obstructive underventilation (ventilation-inhalation mismatch) and the functional failure of ventilation of definite areas of the lung (ventilation-inhalation match). It was the aim of our investigation to find out the relation between the regional demonstration of the different ventilation-inhalation patterns and conventional parameters of inhomogeneity in patients with COPD. Is it possible to get more informations by scitigraphic methods and is there perhaps a parameter in conventional pulmonary function that reflects the degree of the disturbance of nuclear medical measures best? Patients: We examined 32 patients with chronic obstructive pulmonary disease (COPD) between 17 and 68 years of age. The patients were examined during a complaint-free period, so it was possible. Methodology: The following methods were applied to examine the patients: 1. Pulmonary function: flow-volume curves, bodyplethysmography, FRC-rebreathing, diffusion measuring and impulse oscillometry. 2. Scintigraphic examination: For imaging the ventilated parts of the lung, all patients underwent a xenon-133-ventilation scintigraphy followed by a technetium-99m-DTPA-inhalation scitigraphy with 10 seconds of breath-holding. The inhalation of technetium-marked particles of aerosol was enabled by mechanical atomising system. The patients inhale the aerosol for 7 minutes slowly and calmly. Quantitative evaluation was based on the regions of interest (ROI) and score. Static scitigrams were devided into 4 groups according to a score and to the different types of ventilation-inhalation patterns (match, mismatch). Results: In patients with COPD three degrees of severity of ventilation disturbances are defined by nuclear medical examinations: low-grade ventilation-inhalation mismatch, moderate ventilation-inhalation mismatch, pathological ventilation-inhalation match. A comparison of the classification of severity of distribution disturbances according to conventional pulmonary function diagnosis and nuclear medicine results in a highly significant correlation. Of the 22 patients with pathological values of pulmonary function, 95% showed pathological changes in the scintigram, whereas in the 28 patients who underwent nuclear medical examinations pathological inhomogeneity parameters were found in only 75%. Hence it follows that the method of ventilation and inhalation scintigraphy is the more sensitive one.