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Asthma is a heterogeneous group of conditions that typically begin in early life and result in recurrent, reversible bronchial obstruction. The role played by epigenetic mechanisms in the pathogenesis of childhood asthma is understood only in part. Here we discuss asthma epigenetics within a developmental perspective based on our recent demonstration that the epigenetic trajectory to childhood asthma begins at birth. We next discuss how this trajectory may be affected by prenatal environmental exposures. Finally, we examine in vitro studies that model the impact of asthma-associated exposures on the epigenome. All of these studies specifically surveyed human DNA methylation and involved a genome-wide component. In combination, their results broaden our understanding of asthma pathogenesis and the role the methylome plays in this process.

Introduction. The atopic diseases of asthma, eczema and hayfever are immunologically mediated diseases initiated and perpetuated by T-helper (Th) cells of the Th2 phenotype, in affluent countries the prevalence of atopic diseases has increased dramatically in the last 40 years. This increase has been attributed to declining dietary intake of naturally occurring antioxidants. Epidemiological data and in vitro studies demonstrating that antioxidant deficiency is associated with Th2 differentiation support this 'antioxidant' hypothesis. The 'hygiene' hypothesis attributes the recent increase in atopic disease to declining childhood infections. This proposal originated from the observation of an inverse association between atopic disease and birth order. There is increasing interest that in utero influences play a critical role in determining the development of childhood atopic disease. There are reports that Th-cells from genetically susceptible neonates and neonates who subsequently develop atopic disease exhibit altered in vitro proliferative and cytokine responses. A proposed in utero influence is the sensitisation of fetal Th- cells by allergens and this concept is supported by indirect evidence. This thesis describes a prospective study designed to test the hypothesis that maternal allergen exposure and dietary antioxidant intake during pregnancy influence fetal Th-cell differentiation and the subsequent development of childhood atopic disease. Methods. Advantage was taken of a prospective cohort study of 2,000 pregnant women. Cord blood samples were obtained from a random sample of the neonates at birth. Cord blood mononuclear cells (CBMC) were stimulated with mitogen, control antigens and allergens. CBMC proliferative responses were quantified and CBMC interleukin-4 (IL-4) and interferon-y (IFN-y) secretion was measured by the celELISA method. These responses were related to antenatal data collected prospectively relating to the pregnancy. In a small number of samples the CD45 isoform of the responding CBMC was determined to investigate whether in utero allergen sensitisation of fetal Th-cells occurs. CBMC responses were also related to respiratory symptoms and atopic disease during the first year of infant life. Results. CBMC responses from 223 cord blood samples were characterised. CBMC culture conditions were optimised and the celELISA successfully detected secreted IFN-y and IL-4. CBMC proliferative responses were detected in 27-91% of cord blood samples, IL-4 responses in 18-31% and IFN-y responses in 19-88%. CD45 isoform analysis indicated that in utero sensitisation of timothy grass specific Th-cells occurs in 38% of pregnancies. CBMC proliferative responses were positively associated with a family history of atopic disease and maternal smoking. CBMC proliferative responses were negatively associated with birth order and maternal dietary vitamin E intake during pregnancy. CBMC IFN-gamma and IL-4 cytokine responses were positively associated with each other and a family history of atopic disease. CBMC IFN-gamma responses were negatively associated with birth order. Wheezing illness in the first year tended to be associated with increased CBMC proliferative responses at birth. Conclusions. Previously identified risk factors for atopic disease, which have been considered to be manifestations of post-natal influences, exert significant antenatal influences. The accepted adverse effects of maternal smoking on children's respiratory health may be a consequence of in utero influences. This study demonstrates a major in utero component to the association between birth order and atopy, contradicting the widely held assumption that it is a consequence of the protective effect of childhood infections. The maternal influence of dietary vitamin E intake raises the possibility of preventing childhood allergy by modifying the maternal diet during pregnancy. This study also provides the most direct evidence to date of the in utero sensitisation of Th-cells by allergens.

PhD, Faculty of Health Sciences, University of the Witwatersrand / Background: Dental procedures associated with dental unit waterlines (DUWLs) in dental health care settings generate aerosolised droplets that have the potential to cause adverse health effects in exposed workers. Aim: The aim of this study was to evaluate the risk of work-related asthma associated with endotoxin exposure in dental health care workers. Materials and methods: The study population included dental personnel (n = 454) from 5 academic dental institutions in South Africa. Personal air samples (n = 413) in various dental jobs as well as airborne area and water samples from dental handpieces and basin taps were collected. A self-administered modified European Community Respiratory Health Survey questionnaire was used to obtain information on respiratory symptoms and the occupational history. Serum samples were collected to determine atopic status, specific IgE to composite latex (k82) extract and 8 recombinant latex proteins, myeloperoxidase (MPO), eosinophilic cationic protein (ECP), inflammatory cytokines, and endotoxin levels. Spirometry including pre- and post-bronchodilator testing was conducted according to ATS/ERS guidelines. Multivariate linear and logistic regression and factor analysis was used in the data analysis. Results: Airborne endotoxin levels were variable across departments with administration having the lowest and laboratories the highest mean exposures (geometric mean: 2.38 versus 5.63 EU/m3). Job status as a student (compared to staff member) and dental unit characteristics (age, model type, number of units) were important predictors of airborne endotoxin. The most common asthma phenotypes were atopic asthma (6.9%), non-atopic asthma (5.9%) and work-aggravated asthma (4%). Four inflammatory groups related to eosinophilic versus neutrophilic inflammation and chronicity of the response were identified. Acute neutrophilic response was associated with work-related chest symptoms (OR = 4.99, 95% CI: 1.32 - 18.92). Cumulative endotoxin exposures (>51.12 EU/m3-year) was an important predictor of work-related ocular-nasal symptoms (OR = 3.82, 95% CI: 1.01 – 14.41) in non-atopic workers. Borderline significant associations were also observed between current airborne endotoxin concentrations (>5.83 EU/m3) and asthma-related symptoms (OR = 2.24, 95% CI: 0.97 – 5.17) as well as suboptimal lung function (FEV1<80% predicted) (OR = 8.02, 95% CI: 0.94 – 68.35) in non-atopic workers. Dental workers using latex gloves and concurrently exposed to low-grade (> 5.83 EU/m3) elevated endotoxin levels were at increased risk (OR = 2.59, 95% CI: 1.20 – 5.60) of presenting with latex sensitisation. Conclusion: This study demonstrated that endotoxin exposures from DUWLs play an important role in the manifestation of non-atopic asthma through the neutrophilic-response mechanism. Neutrophilic inflammatory cell asthma phenotypes coexist with eosinophilic inflammatory cell asthma phenotypes in this group of workers. Furthermore, low-grade elevated endotoxin levels increase the risk of sensitisation to latex among dental workers using latex gloves. This is the first study to demonstrate airway effects associated with low-grade elevated endotoxin exposures in dental settings.

Background: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) measured the global prevalence of symptoms of asthma in children. We undertook comprehensive analyses addressing risk factors for asthma symptoms in combination, at both the individual and the school level, to explore the potential role of reverse causation due to selective avoidance or confounding by indication. Objective: To explore the role of reverse causation in risk factors of asthma symptoms. Methods: We compared two sets of multilevel logistic regression analyses, using (a) individual level exposure data and (b) school level average exposure (ie prevalence), in two different age groups. In individual level analyses, reverse causation is a possible concern if individual level exposure statuses were changed as a result of asthma symptoms or diagnosis. School level analyses may suffer from ecologic confounding, but reverse causation is less of a concern because individual changes in exposure status as a result of asthma symptoms would only have a small effect on overall school exposure levels. Results: There were 131 924 children aged 6-7 years (2428 schools, 25 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (odds ratio = 2.06; 95% confidence interval 1.97-2.16), early life antibiotic use (1.65; 1.58-1.73) and open fire cooking (1.44; 1.26-1.65). In school level analyses, these risk factors again showed increased risks. There were 238 586 adolescents aged 13-14 years (2072 schools, 42 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (1.80; 1.75-1.86), cooking on an open fire (1.32; 1.22-1.43) and maternal tobacco use (1.23; 1.18-1.27). In school level analyses, these risk factors again showed increased risks. Conclusions & clinical relevance: These analyses strengthen the potentially causal interpretation of previously reported individual level findings, by providing evidence against reverse causation. / Revisión por pares

by Ng Wun Wai. / Thesis (M.S.S.)--Chinese University of Hong Kong, 1990. / Bibliography: leaves 45-53. / ABSTRACT --- p.i / ACKNOWLEDGMENTS --- p.ii / TABLE OF CONTENTS --- p.iii / LISTS OF TABLES --- p.iv / INTRODUCTION --- p.1 / METHOD / Subjects --- p.9 / Instruments --- p.11 / Apparatus --- p.15 / Procedure --- p.15 / RESULTS --- p.19 / DISCUSSION --- p.22 / TABLES --- p.30 / APPENDICES --- p.38 / REFERENCES --- p.45

Thesis (M.Sc.Eng.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Status asthmaticus (SA) is a severe, acute exacerbation of asthma that is refractory to traditional therapies using standard bronchodilators such as β-agonists and corticosteroids. Inhaled volatile anesthetics are currently used as a rescue therapy for SA due to their potent bronchodilator effects. However, it is unclear whether these agents act in vivo via 1) direct action on airway smooth muscle (ASM); 2) systemic re-circulation; or 3) autonomic reflexes from the central nervous system. Treatment with these agents can also lead to negative side effects, notably hypotension and arrhythmias, especially during prolonged pediatric use. The goals of this thesis were to compare direct versus systemic effects of these inhaled anesthetic agents, and to determine whether sufficient bronchodilation can be achieved via direct diffusion from the airway lumen to the ASM. We designed and developed a computer-actuated, ventilator-valve system to control the serial composition of the inspired gas. Using this system, we delivered inhaled anesthetic agents either a) to the anatomic dead space selectively (direct), or b) continuously throughout inspiration (systemic) in three mongrel canines (20-25 kg) with methacholine-induced bronchoconstriction. Measurements of lung resistance (RL), elastance (EL), and anatomic dead space (VD) demonstrated that isoflurane and sevoflurane result in bronchodilation for both delivery regimes. This suggests that the mechanism of action for these agents is at least partly via direct effects. Fluctuations in VD were not directly coupled with those for RL or EL. Furthermore, there may exist a limit to maximal bronchodilation using inhaled anesthetics, with isoflurane being more potent. In summary, this study illustrates the feasibility of using a targeted anesthetic delivery to treat severe, acute bronchoconstriction. Such a delivery system has the potential to define a rapidly translatable treatment paradigm for SA while increasing patient safety. / 2031-01-01

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O planejamento para direcionar o cuidado e fundamentar o conhecimento de enfermagem em situaÃÃes clÃnicas especÃficas se baseia na utilizaÃÃo de diagnÃsticos de enfermagem precisos. O uso de bons indicadores clÃnicos para predizer diagnÃsticos à fundamental para que se alcance essa precisÃo. Este estudo teve como objetivo geral determinar as medidas de acurÃcia dos indicadores clÃnicos dos diagnÃsticos de enfermagem respiratÃrios: DesobstruÃÃo ineficaz de vias aÃreas, PadrÃo respiratÃrio ineficaz, Troca de gases prejudicada e VentilaÃÃo espontÃnea prejudicada em crianÃas asmÃticas. Estudo transversal, realizado em um hospital de nÃvel secundÃrio da rede pÃblica de Fortaleza (CE), nos meses de abril a setembro de 2013. A amostra foi composta por 205 crianÃas. Os dados foram coletados por meio de uma avaliaÃÃo pulmonar e entrevista com os responsÃveis. As informaÃÃes obtidas foram analisadas para determinar a presenÃa ou ausÃncia dos indicadores clÃnicos dos diagnÃsticos em estudo. Posteriormente, esses dados foram encaminhados a enfermeiros diagnosticadores para inferÃncia diagnÃstica. Foram utilizados os softwares Excel e SPSS para organizaÃÃo e anÃlise estatÃstica dos dados. O nÃvel de significÃncia adotado foi de 5%. O estudo adotou os princÃpios Ãticos e recebeu parecer Ãtico favorÃvel (parecer n 237.389/13). Houve uma discreta prevalÃncia para o sexo masculino (52,3%) e mediana de idade de 36 meses. Das crianÃas avaliadas, 89,3% desenvolveram DesobstruÃÃo ineficaz de vias aÃreas; 86,8%, PadrÃo respiratÃrio ineficaz; 28,8%, Troca de gases prejudicada e 5,9%, VentilaÃÃo espontÃnea prejudicada. DesobstruÃÃo ineficaz de vias aÃreas apresentou dispneia, mudanÃa na frequÃncia respiratÃria, mudanÃa no ritmo respiratÃrio, ortopneia, ruÃdos adventÃcios e tosse ineficaz como indicadores mais prevalentes. MudanÃa na frequÃncia respiratÃria, mudanÃa no ritmo respiratÃrio, ortopneia, ruÃdos adventÃcios respiratÃrios, sons respiratÃrios diminuÃdo e tosse ineficaz apresentaram associaÃÃo estatisticamente significante com este diagnÃstico. E ruÃdos adventÃcios respiratÃrios e tosse ineficaz mostraram-se como os indicadores mais acurados. PadrÃo respiratÃrio ineficaz apresentou ortopneia, taquipneia e uso da musculatura acessÃria para respirar como os indicadores mais prevalentes. Evidenciou-se associaÃÃo estatisticamente significante de alteraÃÃes na profundidade respiratÃria, taquipneia, uso da musculatura acessÃria e ortopneia com PadrÃo respiratÃrio ineficaz. Uso da musculatura acessÃria para respirar, alteraÃÃes da profundidade respiratÃria e ortopneia apresentaram-se como mais acurados para padrÃo respiratÃrio ineficaz. Troca de gases prejudicada apresentou dispneia, respiraÃÃo anormal, taquicardia e hipoxemia como os indicadores mais prevalentes. Hipoxemia foi o Ãnico indicador que mostrou associaÃÃo estatisticamente significativa, alÃm de manifestar-se como mais acurado para troca de gases prejudicada. Para VentilaÃÃo espontÃnea prejudicada, dispneia, frequÃncia cardÃaca aumentada e SaO2 diminuÃda foram os indicadores mais prevalentes. CooperaÃÃo diminuÃda, SaO2 diminuÃda e uso aumentado da musculatura acessÃria para respirar estiveram associados significativamente com ventilaÃÃo espontÃnea prejudicada e uso aumentado da musculatura acessÃria para respirar apresentou-se com melhor acurÃcia. Para a associaÃÃo entre os diagnÃsticos, desobstruÃÃo ineficaz de vias aÃreas manteve relaÃÃo com padrÃo respiratÃrio ineficaz e padrÃo respiratÃrio ineficaz com Troca de gases prejudicada. VentilaÃÃo espontÃnea prejudicada nÃo apresentou associaÃÃo. Acredita-se que o conhecimento do perfil diagnÃstico de populaÃÃes especÃficas possa contribuir para que as intervenÃÃes de enfermagem sejam orientadas por decisÃes diagnÃsticas, facilitando assim, escolha de aÃÃes adequadas. / The planning to lead the care and to support the nursing knowledge in specific clinical situations is based on the use of accurate nursing diagnoses. The use of good clinical indicators for predicting diagnosis is essential in order to reach this precision. This study aimed at determining the measures of accuracy of clinical indicators for nursing diagnosis, such as: Ineffective airway clearance, Ineffective breathing pattern, Impaired gas exchange and Impaired spontaneous ventilation in asthmatic children through a cross-sectional study held in a secondary level public hospital in Fortaleza (CE), from April to September 2013. The sample consisted of 205 children with asthma whose data were collected through a pulmonary assessment and interviews with their parents. The data were analyzed by the researcher to determine the presence or absence of: Ineffective airway clearance; Ineffective breathing pattern; Impaired gas exchange and Impaired spontaneous ventilation indicators based on a research protocol and then diagnostician nurses analyzed this information for diagnostic inference. For statistical analysis, SPSS and Excel were used with a significance level of 5 %. The study adopted the ethical principles and received the assent of the Federal University of Cearà Ethics and Research (opinion No. 237.389/13). There was a slight prevalence for males (52.3 %) and average age of 36 months. 89.3% of the children assessed developed Ineffective airway clearance; 86.8 % developed Ineffective breathing pattern; 28.8 % developed Impaired gas exchange and 5.9 % of the children developed Impaired spontaneous ventilation. Ineffective airway clearance presented dyspnea, change in respiratory rate, change in respiratory rhythm, orthopnea, rales and ineffective cough as the most prevalent indicators. Change in respiratory rate, change in respiratory rhythm, orthopnea, respiratory rales, decreased breath sounds and ineffective cough showed a significant association with this diagnosis whereas ineffective cough and respiratory rales appeared as the most accurate indicators. Ineffective breathing pattern had orthopnea, tachypnea and use of accessory muscles to breathe as the most prevalent indicator. A statistically significant association between changes in respiratory depth, tachypnea, accessory muscle use and orthopnea with Ineffective breathing pattern was also observed in this study. The Use of accessory muscles for breathing, changes in respiratory depth and orthopnea were observed as more accurate for Ineffective breathing pattern. Impaired gas exchange presented dyspnea, abnormal breathing, tachycardia and hypoxemia as the most prevalent indicators. Hypoxemia was the only indicator that showed a statistically significant association, and were seen as more accurate for Impaired gas exchange. For Impaired spontaneous ventilation dyspnea, increased heart rate and decreased SaO2 were the most prevalent indicators. Decreased cooperation, decreased SaO2 and increased use of accessory muscles to breathe were significantly associated with Impaired spontaneous ventilation and increased use of accessory muscles to breathe was presented with better accuracy. For the association between diagnoses, Ineffective airway clearance remained related to Ineffective breathing pattern and Impaired gas exchange and Ineffective breathing pattern remained related to Impaired gas exchange. Impaired spontaneous ventilation showed no association. It is believed that knowledge of the diagnostic profile of specific populations may contribute to nursing interventions so that they are guided by diagnostic decisions, thus facilitating the choice of the most appropriate actions.