No description available.

No description available.

No description available.

No description available.

Background: Lung function is a highly heritable trait. So far there is limited knowledge of the genetic factors that influence lung function. Vascular endothelial growth factor A (VEGF-A) is expressed in the lung at high levels and is known to play a role in angiogenesis and lung remodelling, both in utero and throughout life. A candidate gene study was carried out in order to investigate the role of variants within the VEGF-A gene in determining lung function in childhood and adult life.Methods: Using available longitudinal data previously collected for an unselected birth cohort (Manchester Asthma and Allergy Study-MAAS) the relationship between lung function and single-nucleotide polymorphisms (SNPs) in VEGF-A was assessed. Replication studies were performed in cross-sectional studies of adults from Manchester and children with asthma from Croatia, in whom FEV1/FVC ratio was measured using spirometry. The potential functional roles of two consistently associated SNPs were then further investigated. Finally, using the genome-wide data generated in the discovery cohort (MAAS) I assessed why associations between VEGF-A and lung function had not been reported in recent genome-wide association studies of lung function.Results: Two VEGF-A SNPs, rs10434 and rs3025028, were significantly associated with lung function at multiple ages in a discovery population (MAAS). Subjects with a GG genotype for either SNP had significantly diminished lung function compared to subjects with other genotypes. These findings were replicated in two additional populations (631 parents of children participating in MAAS and in 410 Croatian children with physician-diagnosed asthma aged 6-18 years). SNP rs10434 is located in the 3’UTR and based on its location I hypothesised that it may affect mRNA stability. No significant difference in the rate of VEGF-A mRNA degradation was found between GG and the AA homozygotes. SNP rs3025028 is an intronic SNP in a close proximity to the splice site involved in alternative splicing which generates two different isoforms of VEGF-A; I therefore tested the hypothesis that a change of base at this position could affect the splicing mechanism and cause a change in the ratio of the isoforms. Western blot analysis was used to demonstrate a difference in the ratio of the splice variants VEGF-A165b and total VEGF-A165 (relative to a reference sample) between genotype groups. The VEGF-A165b/panVEGF-A165 ratio was significantly higher at birth (cord plasma), in school-age children and in adults amongst CC compared to GG homozygotes at rs3025038 (p<0.03). Finally, the genome-wide data for the discovery cohort showed that the region containing VEGF-A was not well targeted by either genotyped or imputed SNPs in genome-wide arrays. Conclusion: Evidence was provided to demonstrate that variants within the VEGF-A gene are significantly associated with lung function in both children and adults. Furthermore, data was presented to support a functional role for one of the SNPs (rs3025028). I investigated why associations between VEGF-A and lung function had not previously been reported in recent GWAS and concluded that the region containing VEGF-A was poorly covered by all of the currently available arrays.

É feita a análise da evolução de provas funcionais ventilatórias de dois grupos de crianças clinicamente sadias, residentes no Município de Cubatão, examinadas inicialmente em dois estudos transversais realizados respectivamente em 1983 (verão) e em 1985 (inverno). O princípio epidemiológico que norteou essa pesquisa foi a realização de um estudo de Coorte Não-Controlada, ou mais apropriadamente, um Estudo Ecológico Longitudinal, onde esses dois grupos de crianças foram anualmente submetidos a exames espirométricos no período de 1987 a 1989, mantida a estrita sazonalidade, ou seja, o Grupo de 1983 foi sempre reexaminado no verão, enquanto que o Grupo de 1985 sempre no inverno. Aproximadamente 1.110 crianças, oriundas de todas as áreas do Município foram submetidas a provas de função pulmonar utilizando-se espirômetro seco, com especial ênfase na análise do comportamento da Capacidade Vital Forçada (CVF), do Volume Expiratório Forçado no Primeiro Segundo (VEF1,0), do \"Peak-Flow\" ou Pico de Fluxo Expiratório (PFE), e do Fluxo Médio Expiratório Forçado (FMF25-75 por cento ), todos considerados como indicadores sensíveis às influências dos níveis de poluição atmosférica registrados em Cubatão. As informações concernentes à poluição do ar foram obtidas através dos relatórios de pesquisas efetuadas pela Companhia de Tecnologia de Saneamento Ambiental do Estado de São Paulo (CETESB) e envolveram a análise das estimativas de emissões das indústrias prioritárias de Cubatão, das concentrações horárias de material particulado (MP), dióxido de enxofre (SO2) e do ozona (O3) registradss nas estações amostradoras de Vila Parisi, Cubatão-Centro e Vila Nova no período de Novembro de 1983 a Dezembro de 1989. Também integrou o contexto de análise, a avaliação das principais metas do Programa de Controle de Poluição do Ar instituído pela CETESB na região a partir de 1984, com o objetivo de se verificar se as reduções pretendidas nos níveis de poluição do ar se fizeram acompanhar de melhorias nas provas funcionais pulmonares das crianças estudadas. Verificou-se que os episódios agudos de poluição do ar, principalmente devidos ao material particulado, mostraram algum decréscimo. No entanto, aqueles devidos a oxidantes fotoquímicos, representados pelos níveis de ozona, tiveram progressivo incremento no período de 1984 a 1988, tanto em relação ao número de episódios, como na persistência e gravidade dos mesmos. Os resultados espirométricos indicaram que em ambos os grupos de crianças a função pulmonar mostrou decrementos significativos, com perdas em tomo de 5 a 8 por cento ao ano, em média, quando comparados com os valores inicialmente registrados por ocasião dos estudos transversais. Apesar das reduções terem sido observadas em todas as variáveis espirométricas, os maiores decrementos verificaram-se principalmente nas medidas de fluxo (PFE e FMF25_75 por cento ), e coincidiram com o ano em que foram assinalados os mais graves episódios de poluição devida a oxidantes fotoquímicos. Os bairros Cota 95, Cota 200, Jardim das Indústrias e Vila Natal, localizados na área de influência do núcleo industrial químicofpetroquímico sobressairam-se como os mais críticos em função dos piores resultados espirométricos apresentados ao longo de todo o estudo. Pôde-se concluir que apesar da função pulmonar das crianças ainda não ter atingido níveis considerados como patológicos, mesmo registrando valores inferiores aos limites da normalidade nas variáveis de fluxo no ano de 1988, verificou-se que de ano para ano a função pulmonar vem decrescendo progressivamente indicando que esta vai sendo afetada pela exposição as poluentes da região e que as medidas de controle da poluição instituídas em Cubatão não tiveram a eficácia esperada. Continuando nessa mesma trajetória evolutiva, isso poderá acarretar sérios e irreparáveis prejuízos à saúde da população. É necessário, portanto, a adoção de urgentes medidas para a melhoria da qualidade do ar em Cubatão nos anos futuros, no intuito de prevenir sérios agravos à Saúde Pública. / The purpose of this study was to investigate the effects of exposure to air pollution on lung function of children. Two groups of clinically healthy children, living at different areas of the city of Cubatão, who had been submitted to lung function tests in a previous cross-sectional study (1983 summertime and 1985 wintertime) were annually reexamined using the same type of test during the period 1987 to 1989. On epidemiological basis this is a longitudinal study, where every individual of the two groups of children was measured at each ocasion, always in the same season of the previous examination. About 1,110 children from all areas of the city were examined once a year using dry spirometer, with special emphasis on FVC, FEV 1,0, PEF and FMF25-75 per cent measurements, since they were considered as those which could be most affected by the local air pollution. Information regarding the conditions of air pollution were obtained from the CETESB\'s written reports. They include the estimate emissions of the main industries of the region; the hourly concentrations of particulate matter, sulfur dioxide and ozone measured in the sampling stations located in Vila Parisi, Cubatão-Centro and Vila Nova during the October/1983 to December/1989 period and also the results of the Source Control Strategy introduced by CETESB since 1984. It was observed that the acute episodes of air pollution due to PM were reduced in number. However, those due to photochemicaf oxidants, mainly represented by ozone leveis, were progressively more frequent during the period from 1984 to 1988; both their number and their severity increased during this period. Spirometric results shows that in both groups of children the lung function was significantly impaired, with losses of 5 to 8 per cent per year, when compared with the initial values of the cross-sectional studies. Despite the fact that all lung function parameters decline, the flow (PFE and FMF2s-7s per cent ) values were those most affected and closely related to the most serious episodes of air pollution due to photochemical oxidants mainly those observed in 1988. Children living in the areas of Cota 95, Cota 200, Jardim das Indústrias and Vila Natal, situated in the nearest area of influence of the chemical and petrochemical industries, presented worst spirometric results than children living in other places of Cubatão. The lung function of the examined children did not attain pathological values, despite the fact of presenting the worst results in flow parameters during the year of 1988. It was observed that their lung function is progressively impaired year by year, a clear indication of the progressive effects of air pollution on their lung function, and if such impairment continues there will carne the time when lung function will probably reach a pathologicallevel. It is concluded that there is an urgent need of improving the quality of air of Cubatão to avoid serious Public Health problems in a quite near future.

É feita a análise da evolução de provas funcionais ventilatórias de dois grupos de crianças clinicamente sadias, residentes no Município de Cubatão, examinadas inicialmente em dois estudos transversais realizados respectivamente em 1983 (verão) e em 1985 (inverno). O princípio epidemiológico que norteou essa pesquisa foi a realização de um estudo de Coorte Não-Controlada, ou mais apropriadamente, um Estudo Ecológico Longitudinal, onde esses dois grupos de crianças foram anualmente submetidos a exames espirométricos no período de 1987 a 1989, mantida a estrita sazonalidade, ou seja, o Grupo de 1983 foi sempre reexaminado no verão, enquanto que o Grupo de 1985 sempre no inverno. Aproximadamente 1.110 crianças, oriundas de todas as áreas do Município foram submetidas a provas de função pulmonar utilizando-se espirômetro seco, com especial ênfase na análise do comportamento da Capacidade Vital Forçada (CVF), do Volume Expiratório Forçado no Primeiro Segundo (VEF1,0), do \"Peak-Flow\" ou Pico de Fluxo Expiratório (PFE), e do Fluxo Médio Expiratório Forçado (FMF25-75 por cento ), todos considerados como indicadores sensíveis às influências dos níveis de poluição atmosférica registrados em Cubatão. As informações concernentes à poluição do ar foram obtidas através dos relatórios de pesquisas efetuadas pela Companhia de Tecnologia de Saneamento Ambiental do Estado de São Paulo (CETESB) e envolveram a análise das estimativas de emissões das indústrias prioritárias de Cubatão, das concentrações horárias de material particulado (MP), dióxido de enxofre (SO2) e do ozona (O3) registradss nas estações amostradoras de Vila Parisi, Cubatão-Centro e Vila Nova no período de Novembro de 1983 a Dezembro de 1989. Também integrou o contexto de análise, a avaliação das principais metas do Programa de Controle de Poluição do Ar instituído pela CETESB na região a partir de 1984, com o objetivo de se verificar se as reduções pretendidas nos níveis de poluição do ar se fizeram acompanhar de melhorias nas provas funcionais pulmonares das crianças estudadas. Verificou-se que os episódios agudos de poluição do ar, principalmente devidos ao material particulado, mostraram algum decréscimo. No entanto, aqueles devidos a oxidantes fotoquímicos, representados pelos níveis de ozona, tiveram progressivo incremento no período de 1984 a 1988, tanto em relação ao número de episódios, como na persistência e gravidade dos mesmos. Os resultados espirométricos indicaram que em ambos os grupos de crianças a função pulmonar mostrou decrementos significativos, com perdas em tomo de 5 a 8 por cento ao ano, em média, quando comparados com os valores inicialmente registrados por ocasião dos estudos transversais. Apesar das reduções terem sido observadas em todas as variáveis espirométricas, os maiores decrementos verificaram-se principalmente nas medidas de fluxo (PFE e FMF25_75 por cento ), e coincidiram com o ano em que foram assinalados os mais graves episódios de poluição devida a oxidantes fotoquímicos. Os bairros Cota 95, Cota 200, Jardim das Indústrias e Vila Natal, localizados na área de influência do núcleo industrial químicofpetroquímico sobressairam-se como os mais críticos em função dos piores resultados espirométricos apresentados ao longo de todo o estudo. Pôde-se concluir que apesar da função pulmonar das crianças ainda não ter atingido níveis considerados como patológicos, mesmo registrando valores inferiores aos limites da normalidade nas variáveis de fluxo no ano de 1988, verificou-se que de ano para ano a função pulmonar vem decrescendo progressivamente indicando que esta vai sendo afetada pela exposição as poluentes da região e que as medidas de controle da poluição instituídas em Cubatão não tiveram a eficácia esperada. Continuando nessa mesma trajetória evolutiva, isso poderá acarretar sérios e irreparáveis prejuízos à saúde da população. É necessário, portanto, a adoção de urgentes medidas para a melhoria da qualidade do ar em Cubatão nos anos futuros, no intuito de prevenir sérios agravos à Saúde Pública. / The purpose of this study was to investigate the effects of exposure to air pollution on lung function of children. Two groups of clinically healthy children, living at different areas of the city of Cubatão, who had been submitted to lung function tests in a previous cross-sectional study (1983 summertime and 1985 wintertime) were annually reexamined using the same type of test during the period 1987 to 1989. On epidemiological basis this is a longitudinal study, where every individual of the two groups of children was measured at each ocasion, always in the same season of the previous examination. About 1,110 children from all areas of the city were examined once a year using dry spirometer, with special emphasis on FVC, FEV 1,0, PEF and FMF25-75 per cent measurements, since they were considered as those which could be most affected by the local air pollution. Information regarding the conditions of air pollution were obtained from the CETESB\'s written reports. They include the estimate emissions of the main industries of the region; the hourly concentrations of particulate matter, sulfur dioxide and ozone measured in the sampling stations located in Vila Parisi, Cubatão-Centro and Vila Nova during the October/1983 to December/1989 period and also the results of the Source Control Strategy introduced by CETESB since 1984. It was observed that the acute episodes of air pollution due to PM were reduced in number. However, those due to photochemicaf oxidants, mainly represented by ozone leveis, were progressively more frequent during the period from 1984 to 1988; both their number and their severity increased during this period. Spirometric results shows that in both groups of children the lung function was significantly impaired, with losses of 5 to 8 per cent per year, when compared with the initial values of the cross-sectional studies. Despite the fact that all lung function parameters decline, the flow (PFE and FMF2s-7s per cent ) values were those most affected and closely related to the most serious episodes of air pollution due to photochemical oxidants mainly those observed in 1988. Children living in the areas of Cota 95, Cota 200, Jardim das Indústrias and Vila Natal, situated in the nearest area of influence of the chemical and petrochemical industries, presented worst spirometric results than children living in other places of Cubatão. The lung function of the examined children did not attain pathological values, despite the fact of presenting the worst results in flow parameters during the year of 1988. It was observed that their lung function is progressively impaired year by year, a clear indication of the progressive effects of air pollution on their lung function, and if such impairment continues there will carne the time when lung function will probably reach a pathologicallevel. It is concluded that there is an urgent need of improving the quality of air of Cubatão to avoid serious Public Health problems in a quite near future.

Doctor of Philosophy(PhD) / Over the last 20 years both asthma and obesity have increased in prevalence. What is the link? There are data to suggest that increasing obesity is a risk for the increase in prevalence of asthma. A number of mechanisms have been postulated including the effects of reduced lung volume on bronchial reactivity and mechanical changes with lower lung volumes. Other possibilities include other obesity-induced co-morbidities including gastro-oesophageal reflux. The aim of this thesis was to evaluate the link between asthma and obesity in both adult and childhood populations and to undertake experimental studies to examine the effects of changes in lung volume on bronchial reactivity. In chapter 1, the literature is reviewed. The current literature suggests that there is a link between diagnosis of asthma, new onset of asthma, symptoms of shortness of breath and wheeze. In chapter 2, data on 1997 adults in 3 population studies were analysed and the association between body mass index (BMI) and symptoms of shortness of breath and wheeze, diagnosis of asthma, medication usage for asthma, lung function and bronchial responsiveness were studied. This study showed that obesity was a risk for recent asthma (OR 2.04; 95%CI 1.02-3.76, p=0.048), symptoms of shortness of breath and wheeze (OR 2.6; 95%CI 1.46- 4.70, p=0.001), and medication usage for asthma (OR 2.53; 95%CI 1.36-4.70, p=0.003). There was a reduction in lung volume as measured by forced vital capacity (FVC), but there was no increase in bronchial hyperresponsiveness (BHR) (OR 0.87; 95% CI 0.35-2.21, p=0.78). Thus although the symptoms of asthma are increased there were no increases in BHR, despite significantly reduced lung volumes. The increase the medication usage is unlikely to have normalised the BHR, as there were ongoing symptoms suggestive of asthma. In chapter 3, data on 5993 children in 7 population studies were analysed and the association between BMI percentile and symptoms of cough, wheeze, ix diagnosis of asthma, medication usage for asthma, atopy, lung function and bronchial responsiveness was studied. After adjusting for atopy, sex, age, smoking and family history, BMI was a significant risk factor for wheeze ever (OR=1.06; 95%CI 1.01-1.10, p=0.008) and cough (OR=1.09; 95%CI 1.05-1.14, p=0.001) but not for recent asthma (OR=1.02; 95%CI 0.98-1.07 p=0.43), or bronchial hyperresponsiveness (OR=0.97; 95%CI 0.95-1.04 p=0.77). In girls, a higher BMI was significantly associated with higher prevalence of atopy (x2 trend 7.9, p=0.005), wheeze ever (x2 trend 10.4, p=0.001), and cough (x2 trend 12.3, p<0.001). These were not significant in boys. With increasing BMI in children, there was no reduction in lung volume, no increase in airway obstruction and no increase in bronchial responsiveness. In chapter 4, the hypothesis that obesity per se is associated with bronchial responsiveness was tested. Six obese women without asthma were compared to 6 non-obese women without asthma with high dose methacholine challenges to assess the bronchial responsiveness. There was no increase in bronchial responsiveness, and no difference in the position or shape of the high dose methacholine curve despite the fact that these women had reduced lung volumes associated with their obesity. In chapter 5, the hypothesis whether reduced lung volume per se would cause a change in greater mechanical effect, ie more marked airway narrowing in both non-asthmatic and asthmatic subjects was tested. Lung volumes and methacholine challenges were undertaken in the supine and erect position on different days. As expected in normal subjects there was a small reduction in lung volume on lying down, this was associated with an increase in the measure of bronchial reactivity DRR. In contrast, in asthmatics, there was no acute fall in lung volume and there were variable changes in the index of reactivity suggesting non-homogeneity in the lung function abnormality. This suggests changes in bronchial reactivity can occur without any relationship to lung volume change. These negative results suggest that lung volume changes that may occur in obesity are unlikely contributors to the apparent increase in asthma symptoms. In chapter 6, the hypothesis that the supposed increase in asthma symptoms in the obese were due to the effects of gastro-oesophageal reflux were assessed in 147 obese subjects graded for gastro-oesophageal reflux severity using manometry and gastroscopy. This study showed that subjects with increased gastro-oesophageal reflux did not have subjective increases in asthma prevalence, obstructive sleep apnoea, or snoring however they had a clear worsening of gas transfer as measured by carbon monoxide transfer suggesting a greater level of parenchymal disease. The overall results are that there is an increase of diagnosis of asthma, increase in symptoms of asthma and medication usage for the treatment of asthma in the obese. Objectively despite reductions in lung volume, there is no increase in bronchial responsiveness in this group suggesting that these symptoms are not related to true asthma, but to alternative co-morbidities associated with obesity such as gastro-oesophageal reflux. Notably gastrooesophageal reflux was not associated with increased asthma prevalence or airway obstruction. However it was associated with reduced gas transfer suggesting parenchymal disease. This suggests that the increase in symptoms of wheeze and shortness of breath in the obese should not be attributed to asthma in the absence of variable airflow limitation that is reversible spontaneously or with treatment, or with an increase in the existing bronchial hyperresponsiveness (BHR) to a variety of stimuli.

The human immunodeficiency virus (HIV)-1 can compromise pulmonary function at all stages of the disease. The present study examined whether there were differences in resting and exercising pulmonary function among sedentary, resistance-trained and aerobically-trained, early symptomatic, HIV-1+ men. Forty five subjects, 15 per group, were enrolled. An analysis of variance (ANOVA) showed differences in demographics for age [F (2, 42) = 5.14, p<0.01)], weight [F (2, 42) = 4.84, p<0.01)], body mass index [F (2, 42) = 9.50, p<0.01)] and average years HIV-1+ [F (2, 42) = 4.78, p<0.01)]. A multiple analysis of covariance (MANCOVA) showed differences in resting pulmonary function [F (8, 72) = 7.164, P = 0.01]. Univariate ANOVA's and Bonferroni post-hoc comparisons showed the aerobically-trained group had higher forced expiratory volume in one second (FEV1) than the resistance-trained and sedentary groups (p<0.05 and p<0.01, respectively), higher forced vital capacity (FVC) (p<0.01, for both), higher maximum voluntary ventilation (p<0.01, for both) and higher FEV1/FVC ratios than the sedentary group only (p<0.01). The resistance-trained group also showed higher FEV1 (p<0.01) and FEV1/FVC (p<0.01) than the sedentary group. For exercising pulmonary function, significant differences in our MANCOVA were found [F (12, 68) = 12.73, P = 0.001]. Univariate ANOVA's and Bonferroni post-hoc comparisons showed that the aerobically-trained group had higher dyspnea index than the resistance-trained and sedentary groups (p<0.01 and p<0.05, respectively), higher ventilatory efficiency (RR/VE max) than the resistance-trained and sedentary groups (p<0.05 and p<0.01, respectively), higher maximum minute ventilation (VE max) (p<0.01, for both), higher peak oxygen consumption (peak VO2) (p<0.01, for both) and lower dead space (VD/VT) (p<0.01, for both). The resistance-trained group also showed higher peak VO2 (p<0.01), lower VD/VT (p<0.01) and lower RR/VE max (p<0.01) than the sedentary group. Results suggest that aerobically-trained, and to a lesser extent, resistance-trained seropositives possessed superior resting and exercising pulmonary function compared to sedentary seropositive males.

Genetic studies of lung disease in Cystic Fibrosis are faced with the challenge of identifying a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. This thesis uses data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies (CGS), Johns Hopkins University Twins and Siblings Study (TSS), and University of North Carolina/Case Western Reserve University Gene Modifier Study (GMS)), to calculate two novel phenotypes using age-specific CF percentile values of FEV1 (Forced Expiratory Volume in 1 second), with adjustment for CF age-specific mortality. The normalized residual, mortality adjusted (NoRMA) was designed for population based samples, while KNoRMA, using Kulich percentiles, is robust to sample ascertainment; both account for the effects of age-related disease progression and mortality attrition. NoRMA was computed for 2122 patients representing the Canadian CF population. KNoRMA was computed for these 2122 patients and also 1137 extreme phenotype patients in the GMS study and 1323 patients from multiple CF sib families in the TSS study. Phenotype was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype was highly correlated with the previously recommended mixed model phenotype1; 2, but computationally much easier and suited to studies with limited follow up time. As an example of its use, KNoRMA was used to test the association between locus variants in a previously published candidate gene, Transforming Growth Factor β1(TGFβ1), and lung function in CF, in an attempt to provide insight into discrepant results in the literature. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible interpolation distortions.