Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

Hantaviruses are members of the virus family Bunyaviridaethat cause two potentially life-threatening diseases in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (BPS). HFRS is caused by Old World hantaviruses that are endemic in many Asian and European countries. Infections with Old World hantaviruses can range in severity from asymptomatic to moderate or severe, depending primarily on the infecting serotype of virus. HPS is caused by New World hantaviruses in North and South America. New World hantaviruses are rarely asymptomatic and are severe in the majority of cases. These syndromes are distinct from one another in the primary target organ of virus infection (kidney vs. lung), but have important clinical features in common, including fever, thrombocytopenia, and a capillary leak syndrome. These common clinical manifestations suggest that the underlying mechanisms of disease may be similar in the two syndromes. The precise mechanisms of pathogenesis of HFRS and HPS are poorly characterized, but may be mediated in part by immunopathology. Hantaviruses are able to establish infections in many human cell types, including primary human endothelial cells, without having any cytopathic effect on these cells. Human infections with hantavirus result in a robust activation of the humoral and cellular immune response, and we hypothesize that these immune responses contribute to the pathology of disease. Evidence for the activation of T lymphocytes, and their potential involvement in immunopathology, includes increases in the number of circulating, activated CD8+ T cells during HFRS, the presence of lymphocytic infiltrates (predominantly CD8+T cells) in kidney biopsies from patients with acute HFRS, and associations between certain HLA haplotype and disease severity following hantavirus infection. This thesis is the first examination of human T lymphocyte responses that are generated during HFRS. Initially, we studied memory T cell responses in scientists who were sub-clinically infected with Hantaan virus (HTNV), the prototype hantavirus. We later investigated memory T cell responses in healthy Finnish adults who had HFRS caused by Puumala virus (PUUV), a hantavirus endemic primarily in Scandinavia. At the onset of these studies, there was no available information on human T lymphocyte responses to Old World hantaviruses. Virus-specific CD8+ and CD4+human T cell lines had been isolated from patients with acute HPS caused by Sin Nombre virus (SNV) infection. In that study, conducted in our laboratory, several human T cell epitopes on the nucleocapsid (N) protein and G2 envelope glycoprotein of SNV were identified and characterized. We decided to perform similar analyses on PBMC from donors who had been infected with HTNV and PUUV, in order to determine the specificity and diversity of the T cell response to Old World hantaviruses. The initial study of three donors who had sub-clinical infections with HTNV demonstrated that virus-specific T cell responses could be detected in all the donors following in vitro stimulation of PBMC with inactivated virus. In two of the donors, the virus-specific cytolytic T cells (CTL) recognized the HTNV N protein, and in the third donor the virus-specific CTLs recognized the HTNV G1 glycoprotein. Isolation and characterization of virus-specific T cells from two donors resulted in the identification of two CD8+ T cell epitopes on the HTNV N protein, which were restricted by either HLA A1 or B51. These CTL lines included both HTNV-specific (HLA B51-restricted) and serotype-cross reactive (HLA A1 restricted) lines. In one subject, these virus-specific T cell responses were detectable in IFN-γ ELISPOT assays following peptide stimulation, and in bulk cultures after short-term stimulation with inactivated HTNV. These results indicated that the CD8+CTL responses of humans after sub-clinical infection with HTNV were readily detectable and were directed against a limited number of viral proteins and epitopes. In addition, sub-clinical infection resulted in the generation of both virus-specific and cross-reactive CTL responses. We reasoned that hantavirus infections that lead to clinical illness may result in the generation of more robust and/or diverse virus-specific T cell responses than in sub-clinical infections. To address this question, we studied the memory CD8+ T cell responses in a group of healthy adults from Finland who had HFRS caused by PUUV infection between the years 1984 and 1995. We detected virus-specific CTL in the bulk cultures of seven of eleven immune individuals tested following stimulation with infectious virus. The PUUV proteins N, G1 and G2 were recognized by CTLs in six, five, and two donors respectively. Extensive cloning of T cells from two donors resulted in the isolation of sixty-three virus-specific CTL lines, the majority of which (61/63) were specific for the PUUV N protein. Six novel CD8+ CTL epitopes and one CD4+ CTL epitope were identified on the N protein, all of which clustered in the center of the protein between amino acids 173 and 251. The CTL lines specific for these epitopes were restricted by a variety of HLA alleles including A2, A28, B7 and B8, and were primarily serotype specific when tested against target cells expressing HTNV or SNV N protein. IFN-γ ELISPOT analysis using the defined epitopes to stimulated PBMC, revealed high frequencies of circulating N-specific CD8+ T cells in eight of thirteen individuals tested. Finally, T cell receptor (TCR) Vβ analysis of CTL clones specific for one epitope (N204-12) demonstrated that cells in this population expressed up to five different Vβ chains. These results demonstrated that the PUUV N protein may be the dominant target of the CTL response, that the N-specific CD8+ CTL responses are diverse, heterogeneous, and primarily serotype specific, and that virus-specific memory CD8+T cells can persist at high levels for up to 15 years after the primary infection. In order to understand the pathology of HFRS and HPS, we must be able to assess the contribution of various factors that could potentially contribute to disease. The virus burden in the infected individual is likely to be an important factor in the severity of the resulting disease. Quantitative RT-PCR analysis of plasma samples from acute HPS patients demonstrated that a higher virus burden (as reflected by viral RNA copy number) is associated with more severe HPS. In order to perform similar analyses in patients with HFRS caused by PUUV, we established a quantitative RT-PCR assay for the detection of PUUV S segment RNA in patient plasma. The design and optimization of the PUUV-specific RT-PCR is described in this report. This assay will allow us to measure the virus burden in patients and compare these data with levels of T cell activation and with parameters of disease severity. In this way, we hope to gain an understanding of the kinetics and magnitude of both the virus burden and virus-specific T cell response during the acute illness. This thesis provides the first description of human virus-specific T cell responses to HTNV and PUUV. These data shed light on the nature of the CD8+ T cell responses that are generated following natural infections with PUUV and sub-clinical infections with HTNV. The studies of memory CD8+ T cell responses to PUUV, and the development of a PUUV-specific quantitative RT-PCR assay, establish the framework for future studies of the immunopathology of acute HFRS. Quantitative analysis of both virus burden and T cell responses during acute illness will provide insight into their relative contributions to the pathology of disease.

Patients admitted to intensive care unit (ICU) are known to develop significant impairments in physical function. Patients with critical illness suffer up to 30% reductions in muscle size within the first ten days of admission to the ICU. Muscle strength testing, Medical Research Council-sum score, is current gold-standard to diagnosis ICU-acquired weakness and predicts risk of mortality and long-term physical function. Muscle power different from muscle strength in that it accounts for velocity of movement, is potentially a better independent predictor of function that has not been studied in this population. In addition, we hypothesize that muscle size and quality measured through ultrasound imaging has better applicability and prediction that strength testing. Therefore, we prospectively collected data surrounding these muscle parameters in patients admitted to the medicine ICU at University of Kentucky. Primary outcomes included physical function, muscle power with a novel assessment tool for the critically ill population, muscle strength, and muscle size and quality assess through ultrasound imaging. 36 patients admitted to ICU and 18 aged-matched controlled were enrolled. Patients had significantly lower scores on muscle power assessment at ICU discharge (33.6 ±19.0 W; t= 4.01, p < 0.001) and at hospital discharge (40.9 ±16.5 W; t= 4.81, p < 0.001) in comparison to controls (59.3± 14.7 W). Patients with better scores on muscle power assessment had significantly better scores on physical function measures (Six-minute walk test; rs = 0.548, p = 0.0001). Muscle size (cross-sectional area of rectus femoris muscle) and muscle power were strongly correlated (rs = 0.66, p < 0.0001). These data suggest that patients with critical illness have significantly reduced muscle power which directly related to deficits in physical function.

Human influenza is a contagious respiratory disease resulting in substantial morbidity and mortality worldwide. With the recent cases of avian influenza infections in humans and the heightened concern for an influenza pandemic arising from these infections, it is essential to understand host responses that would confer protective immunity to influenza. The cell-mediated immune responses to influenza virus play an important role during influenza infection. To analyze the specificity and diversity of memory T-cell responses, we performed a genome-wide screening of T cell epitopes to influenza A virus in healthy adult donors. We identified a total of 83 peptides, 54 of them novel, to which specific T cells were detectable in interferon-(IFN-γ) enzyme-linked immunosorbent spot assays (ELISPOT) using peripheral blood mononuclear cells (PBMCs) from four healthy adult donors. We found that among 11 influenza viral proteins, hemagglutinin (HA) and matrix protein 1 (M1) had more T-cell epitopes than other viral proteins. The donors were not previously exposed to H5N1 subtype, but we detected H5 HA T cell responses in two of the four donors. To confirm that HA is a major target of T cell responses we also analyzed H1 and H3 HA-specific T-cell responses using PBMC of additional 30 adult donors. Fifteen out of thirty donors gave a positive response to H3 HA peptides, whereas five of thirty donors gave a positive response to H1 HA peptides. Because we detected T cell responses to the H5 HA peptides in donors without prior exposure to H5N1 subtype, we asked if cross-reactive T cells to H5 HA peptides can be attributed to a prior exposure to H2N2 subtype, the closest HA to the H5 based on their phylogeny. We compared younger donors who have no prior exposure to H2N2 subtype and older donors who were likely to be exposed to H2N2 subtype, and both groups responded H2N2 peptides at similar level, suggesting that memory T cells cross-reactive to H5 HA peptides can be generated by prior exposure to the H1N1 and H3N2 subtypes, and the exposure to H2N2 subtype is not necessary. We subsequently identified a CD4+ T cell epitope that lies in the fusion peptide of the HA. This epitope is well conserved in all 16 subtypes of HA of influenza A and the HA of the influenza B virus. A CD4+ T cell line specific to this epitope recognizes target cells infected with various influenza A viruses including seasonal H1N1 and H3N2, a reassortant H2N1, the 2009 pandemic H1N1, H5N1 and influenza B virus in cytotoxicity assays and intracellular cytokine staining assays. Individuals who have the HLA-DRB1*09 allele have ex vivo IFN-γ responses to this epitope peptide in ELISPOT. Although natural infection or standard vaccination may not induce strong T and B cell responses to this very conserved epitope in the fusion peptide, it may be possible to develop a vaccination strategy to induce these CD4+ T cells which are cross-reactive to both influenza A and B viruses.

<p>Systemic fungal infections brought about by <em>Cryptococcus</em> species are associated with some of the highest mortality rates of any infectious disease. Alarmingly these pathogens have overtaken tuberculosis as the second greatest killer among Sub-Saharan AIDS patients and are an emerging disease among immunocompetent populations on the Pacific Coast of North America. This clinical threat has been exacerbated by our inability to discover novel compounds that specifically target fungal cellular architecture at the genus level. To confront this challenge, we have made a concerted effort to biologically prospect the vast chemical potential of Actinomycete bacteria isolated from diverse and underexplored niches around the world. A novel phenotypic screen was developed whereby bacterial small molecule producers were co-cultured on agar plates in an intimate setting with evolutionary distant fungal pathogens <em>Candida albicans</em> and <em>Cryptococcus neoformans</em>. Diffusible small molecules released by the organisms created a signaling environment that stimulated profound phenotypic changes both in the Actinomycetes and the pathogens. We were able to discern a unique relationship whereby the growth of <em>C. neoformans</em> was specifically inhibited by Nigerian soil Actinomycete isolate curated as WAC 2288. Further bioactivity guided purification and chemical analysis lead to the identification of ibomycin, a previously undescribed 34 membered macrolactone decorated with seven sugar moieties. A draft genome of WAC 2288 revealed a 140kb gene cluster containing 12 type I PKS modules and downstream capacity to generate rare sugars are responsible for ibomycin biosynthesis. Purification of ibomycin analogs has revealed that the terminal vancosamine on the molecule is dispensable for bioactivity, establishing a chemical antecedent for target identification through affinity chromatography. Throughout these studies the unprecedented anticryptococcal activity of ibomycin is consistently recapitulated. Future work on the molecule may validate ibomycin as an effective antifungal therapy.</p> / Master of Science (MSc)

<p>Asthma involves a systemic element that includes the mobilization and lung-accumulation of bone marrow-derived endothelial progenitor cells (EPC). This traffic may be driven by the stromal cell derived factor-1α (SDF-1α)/CXCR4 axis, where SDF1-α is a potent progenitor cell chemoattractant.</p> <p>Interfering with EPC lung-accumulation by administering AMD3100, a CXCR4 antagonist, was previously shown to be associated with the modulation of airway angiogenesis and airway hyperresponsiveness. However, since eosinophils express CXCR4, it is unknown whether AMD3100 acted directly on EPC or indirectly through its anti-inflammatory effects on eosinophils.</p> <p>We investigated the role that eosinophilic inflammation plays in the lung-homing of EPCs and airway angiogenesis in allergic asthmatic response by utilizing eosinophil deficient (PHIL) mice.</p> <p>Wild-type BALB/c (WT) and PHIL mice underwent a chronic house dust mite (HDM) exposure protocol. Treatment groups were administered AMD3100. Outcome measurements were made 24hrs post final exposure and included: flow cytometry to enumerate lung-extracted EPCs, immunostaining for von Willebrand factor to assess bronchial vascularity, bronchoalveolar lavage for airway inflammation, haematoxylin and eosin stain to enumerate eosinophils, picrosirius red stain to assess collagen deposition, and measurement of airway resistance to increasing intranasal doses of methacholine.</p> <p>HDM exposed mice had a significant increase in EPC lung accumulation, bronchial vascularity, airway inflammation, collagen deposition and airway hyperresponsiveness (AHR) in both WT and PHIL groups, with some indices at lower levels in PHIL mice. Concurrent treatment with AMD3100 significantly attenuated EPC lung homing, bronchial vascularity, eosinophil numbers in lung tissue and AHR, but not collagen deposition in WT mice. AMD3100 treatment significantly attenuated all indices in PHIL mice.</p> <p>The findings of this study show that, EPC-driven angiogenesis and the development of AHR in allergic airway responses are independent of eosinophils, the presence of these cells, however, may have a role in worsening of the pathology of allergic airways disease.</p> / Master of Science (MSc)

<p>Obstructive lung diseases limit airflow and gas exchange and have a major impact on a patient’s long-term health. Asthma and chronic obstructive pulmonary disease (COPD) are the most prevalent obstructive lung diseases and represent a major burden on healthcare systems worldwide. It is now accepted that the pathologies associated with these diseases are heterogeneous in nature, and as the function of the lung is determined by its three-dimensional structure, methods to volumetrically evaluate the lung are important tools in furthering the study of these pathologies.</p> <p>Three-dimensional imaging methodologies, such as computed tomography (CT) and single photon emission computed tomography (SPECT), are used clinically in the diagnosis of lung disease, but results are not commonly quantified. In addition, asthma and COPD develop slowly over time and diagnosis normally takes place after the underlying pathologies are well established. Experimental models in small animals, such as rats and mice, allow for the study of disease pathogenesis in a controlled setting and development of quantitative imaging practices for these models provides translational tools for relating results back to the clinic.</p> <p>In this thesis, CT densitometry and ventilation/perfusion (V/Q) SPECT are explored as methods to investigate models of asthma and COPD. CT densitometry is shown to be capable of quantifying allergic inflammation in an asthma model but is of less use in a model of COPD, predominantly due to the relative amounts of inflammation present. However, V/Q imaging is shown to be quite sensitive to the effects of cigarette smoke in a model of COPD and has been used to better understand how pathologies associated with COPD contribute to gas exchange limitation in the lung.</p> <p>The models, imaging techniques, and analysis methods described in this work provide insight into chronic obstructive lung disease and allow for future investigations into how pathologies effect gas exchange. Further, the characterization of the models described in this thesis allows for drug efficacy studies to be performed, both on established and novel treatments. Future research into asthma and COPD will benefit further from the use of threedimensional imaging methodologies because they provide volumetric information on structure and function and can act as a translational bridge between clinical disease and preclinical animal models.</p> / Doctor of Philosophy (Medical Science)

No / Zinc oxide (ZnO) nanoparticles are the mostly used engineered metal oxide nanoparticles in consumer products. This has increased the likelihood of human exposure to this engineered nanoparticle (ENPs) through different routes. At present, the majority of the studies concerning ZnO ENPs toxicity have been conducted using in vitro and in vivo systems. In this study, for the first time we assessed the effect of ZnO ENPs on the major cellular pathways in the lymphocytes of healthy individuals as well as in susceptible patients suffering from lung cancer, chronic obstructive pulmonary disease (COPD) and asthma. Using the differential expression analysis, we observed a significant (P < 0.05) dose-dependent (10, 20 and 40 microg/ml for 6h) increase in the expression of tumour suppressor protein p53 (40, 60 and 110%); Ras p21 (30, 52 and 80%); c-Jun N-terminal kinases; JNKs) (28, 47 and 78%) in lung cancer patient samples treated with ZnO ENPs compared to healthy controls. A similar trend was also seen in COPD patient samples where a significant (P < 0.05) dose-dependent increase in the expression of tumour suppressor protein p53 (26, 45 and 84%), Ras p21 (21, 40 and 77%), JNKs (17, 32 and 69%) was observed after 6h of ZnO ENPs treatment at the aforesaid concentrations. However, the increase in the expression profile of tested protein was not significant in the asthma patients as compared to controls. Our results reiterate the concern about the safety of ZnO ENPs in consumer products and suggest the need for a complete risk assessment of any new ENPs before its use.

O etanol de cana-de-açúcar se consolida como combustível renovável, o que promove nova expansão da cultura da cana-de-açúcar no Brasil e, principalmente, no Estado de São Paulo. Como a queima prévia controlada da palha de cana-de-açúcar ainda é considerada uma prática agrícola necessária para a viabilização econômica da colheita, em mais de 70% dos municípios do Estado de São Paulo a população é obrigada a conviver com essa poluição. Para estudar a distribuição desse fator de risco e sua relação com a saúde, realizei um estudo epidemiológico ecológico nos 645 municípios de São Paulo. Usei um modelo Bayesiano de regressão multivariada relacionando os efeitos na saúde com a exposição à queima prévia da palha de cana-de-açúcar, sendo controlados os efeitos das variações socioeconômicas (saneamento, educação e renda) e climáticas (temperatura máxima, umidade mínima e precipitação), através da inserção das mesmas no modelo. O efeito sobre a saúde foi medido por meio da Razão de Mortalidade e Morbidade Padronizada (RMP) dos desfechos: óbitos por doenças respiratórias nas faixas etárias acima de 65 anos e internações por doença respiratória, nas faixas etárias menores de 5 anos e acima de 65 anos de cada um dos municípios. Usei como medida de exposição à queima prévia dados obtidos no INPE: percentual da área de cana colhida com queima (PMQ), níveis médios de Aerossol e Focos de queima, testadas separadamente. Para resolver a autocorrelação entre os dados, estes foram considerados conforme sua disposição espacial, através da construção de uma matriz de vizinhança dos 645 municípios do Estado. Utilizei o método de simulação de Monte Carlo via Cadeias de Markov (MCMC) para \'suavizar\' as estimativas da RMP. A análise demonstrou que existe associação entre a queima prévia da palha de cana-de-açúcar e a ocorrência de doenças respiratórias, porque o aumento nos focos de queima (Focos) esteve associado significativamente com o aumento das internações por doenças respiratórias, na faixa etária de menores de cinco anos. Os resultados mostraram que a queima prévia da palha da cana-de-açúcar oferece efetivamente risco à saúde da população e, adicionados aos mapas coropléticos gerados, oferecem subsídios para a vigilância epidemiológica e contribuem para o estabelecimento de políticas públicas para controle da poluição do ar, que contemplem além dos grandes centros urbanos, os pequenos municípios. A eliminação desse fator de risco deve fazer parte das medidas primordiais de prevenção à saúde a serem adotadas no Estado / Ethanol from sugarcane is consolidated as a renewable fuel which promotes further expansion of the culture of sugarcane in Brazil and especially in the State of São Paulo. As the controlled pre-harvest burning of sugarcane straw is still considered an agricultural practice necessary for the economic viability of this crop in more than 70% of municipalities in the State of São Paulo the population is forced to live with this pollution. To study the distribution of this risk factor and its relationship with the health of the population, I conducted an ecological study in the 645 municipalities of São Paulo. I used a Bayesian multivariate regression model relating the health effects and the exposure to previous straw burning of sugarcane, controlling the effects of socioeconomic factors (sanitation, education and income) and climate (maximum temperature, minimum humidity and precipitation) by the insertion of these variables in the model. The effect on health was measured by Standardized Mortality and Morbidity Ratio (SMR) of the outcomes: deaths from respiratory diseases in the age group above 65 years old and admissions for respiratory disease in children less than 5 years old and above 65 years old of each of the municipalities. I used as a measure of exposure to the pre-harvest burning data obtained at INPE: percent of sugarcane area harvest with burning (PMQ), levels of Aerosol and Spotlights of burning, tested separately. To solve the autocorrelation in the data these were considered as their spatial arrangement, by building a neighborhood matrix of the 645 municipalities in the state. I used the Markov Chain-Monte Carlo simulation method (MCMC) to \'soften\' the estimates of the SMR. The analysis showed that there is an association between previous straw burning of sugarcane and respiratory diseases, because the increase in outbreaks of burning (Spotlights) was significantly associated with increased hospital admissions for respiratory diseases in children aged under five years old. The results show that the previous straw burning of sugarcane effectively offers health risk to the population and added to the choropleth maps generated provide valuable information for epidemiological surveillance and contribute to the establishment of public policies for the control of air pollution, which should contemplate beyond the major urban centers, the small towns. The elimination of this risk factor should be part of a primordial prevention measure to be taken in the state

In conclusion, the current air pollution levels in Hong Kong had a risk for school children's respiratory and cardiovascular health. In comparison between the highly- and least-polluted districts, a rise of 8 mug/m 3 annual mean for PM10 concentration was significantly associated with increased risks for some respiratory symptoms such as wheezing, cough, and phlegm, with decreased lung function in FEF25-75% and FEF75%, and with decreased cardiopulmonary fitness in predicted VO2max, after adjustment for confounding factors. An increase of 13 mug/m3 annual mean for NO2 in the moderately-polluted district did not individually cause adverse effects on children's respiratory and cardiopulmonary health. Physical activity appears to have no positive health effects on the children's VO2max in moderately- and highly-polluted districts. / In the past year preceding the study (May 2003 to April 2004), the annual means for PM10, NO2, SO2 and O3 were respectively 55.1 mug/m3, 51.4 mug/m3, 15.4 mug/m3, and 42.5 mug/m3 in the least-polluted district (LPD); 56.3 mug/m3, 64.7 mug/m3, 15.2 mug/m3, and 35.2 mug/m3 in the moderately-polluted district (MPD); and 63.8 mug/m3, 64.1 mug/m3, 22.2 mug/m3, and 31.7 mug/m3 in the highly-polluted district (HPD). The 99th percentiles were 178 mug/m3, 158 mug/m 3, 104 mug/m3, and 140 mug/m3 in the LPD; 169 mug/m3, 181 mug/m3, 106 mug/m 3, and 113 mug/m3 in the MPD; and 226 mug/m 3, 177 mug/m3, 140 mug/m3, and 137 mug/m 3 in the HPD. The average daily 1-h maximum O3 (peak O 3) was 83.7 mug/m3 in the LPD, 73.6 mug/m 3 in the MPD, and 64.8 mug/m3 in the HPD. / Lung function indices included FVC, FEV1, FEV 1/FVC, FEF25-75%, FEF25%, and FEF75%. Children in the HPD had lower FEV 1/FVC, FEF25-75%, and FEF25% than those in both the LPD and MPD, after controlling for their corresponding confounders. In comparison between the LPD and HPD, the adjusted mean differences for FEV1/FVC, FEF25-75%, and FEF25% were respectively 1.39%, 85 ml, and 113 ml in boys, and 1.60%, 86 ml, and 225 ml in girls. In addition, the decreased FEF75% of HPD was found in boys (62 ml) but not in girls. When comparing the MPD with LPD, the increased FEF25% was observed in girls in the LPD (158 ml), whereas boys in the LPD had lower FEF75% than those in the MPD (81 ml). There were no significant differences in children's FVC and FEV1 between districts. / The multistage fitness test (MFT) with the Matsuzaka's function was employed to predict cardiopulmonary fitness (VO2max) of children. After adjustment for the factors, girls in the LPD had significantly higher VO 2max than those in the MPD and HPD by 0.19 and 0.75 ml&middot;kg -1 &middot;min-1 respectively. The VO 2max among boys in the LPD was 0.48 ml&middot;kg-1 &middot;min -1 higher than those in the HPD. When we compared the VO 2max between students in MPD and HPD, higher VO2max in both boys and girls in the MPD were observed---by 0.49 and 0.56 ml&middot;kg -1 &middot;min-1 respectively. In LPD, significantly higher VO2max values were observed in both boys and girls who were physically active (children who took part in sports and/or vigorous free play at least three times a week for at least 30 minutes each time) compared with those who were not (0.71 and 0.65 ml&middot;kg-1 &middot;min -1 respectively), but those differences in VO2max among students in MPD and HPD were small and insignificant. / There were totally 2,641 (82.9%) children who participated in the study, and 2,203 participants were involved in analyses. After adjustment for confounding factors, girls living in the HPD had significantly increased odds ratios (ORs) for wheezing without cold (4.75), cough at night (1.71), phlegm without cold (3.61), compared with those in the LPD. Boys in the HPD had increased OR only for phlegm without cold (1.88). When comparing the MPD with LPD, the adjusted OR for cough at night achieved significance in girls (1.74) and marginal significance in boys (1.40). Sneeze with itchy-watery eyes and current/ever allergic rhinitis had negative associations with district. In comparison with LPD, the decreased OR for sneeze with itchy-watery eye in girls in HPD (0.65) reached statistical significance. Both boys and girls in MPD had significantly decreased ORs for current allergic rhinitis (0.72 and 0.50 respectively) and for ever allergic rhinitis (0.74 and 0.55 respectively). There were no significant differences in the prevalence rates of asthma and bronchitis between districts. / To explore associations between air pollution and respiratory and cardiovascular health of school children, a cross-sectional study was conducted among 3,186 primary school children in P3 and P4 from three districts with different air pollution levels in Hong Kong during March to June in 2004. / Gao Yang. / "August 2005." / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6339. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 137-154). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.