Cord blood IgE has previously been studied as a possible predictor of asthma and allergic diseases. Results from different studies have been contradictory, and most have focused on high-risk infants and early infancy. Few studies have followed their study population into adulthood. This study assessed whether cord blood IgE levels and a family history of asthma were associated with, and could predict, asthma medication and allergy-related respiratory symptoms in adults. A follow-up was carried out in a Swedish birth cohort comprising 1701 consecutively born children. In all, 1661 individuals could be linked to the Swedish Prescribed Drug Register and the Medical Birth Register, and 1227 responded to a postal questionnaire. Cord blood IgE and family history of asthma were correlated with reported respiratory symptoms and dispensed asthma medication at 32–34 years. Elevated cord blood IgE was associated with a two- to threefold increased risk of pollen-induced respiratory symptoms and dispensed anti-inflammatory asthma medication. Similarly, a family history of asthma was associated with an increased risk of pollen-induced respiratory symptoms and anti-inflammatory medication. However, only 8% of the individuals with elevated cord blood IgE or a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication at follow-up. Elevated cord blood IgE and a positive family history of asthma were associated with reported respiratory symptoms and dispensed asthma medication in adulthood, but their predictive power was poor in this long-time follow-up. / <p>The status of this article was on the day of the defence date <em>Manuscript</em>.</p>

Earlier retrospective noise exposure assessments for use in epidemiological research were not adequately characterized because they did not properly account for use of hearing protection devices (HPD) which would result in potential misclassification. Exposure misclassification has been shown to attenuate exposure-outcomes relations. In the case of already subtle relationships such as noise and cardiovascular diseases, this would potentially annihilate any association. We investigated two approaches using Workers’ Compensation Board (WorkSafe BC) audiometric surveillance data to (i) re-assess the noise exposure in a cohort of lumber mill workers in British Columbia using data on the use of HPD and the determinants of their use available through WorkSafe BC, and (ii) test the validity of the new exposure measures by testing their predictions of noise-induced hearing loss, a well-established association. Work history, noise exposure measurements, and audiometric surveillance data were merged together, forming job-exposure-audiometric information for each of 13,147 lumber mill workers. Correction factors specific to each type and class of HPD were determined based on research and standards. HPD-relevant correction factors were created using 1) deterministic methods and self-reported HPD use after filling gaps in the exposure history, or 2) a model of the determinants of use of HPD, then adjusting noise estimates according to the methods’ predictions and attenuation factors. For both methods, the HPD-adjusted and unadjusted noise exposure estimates were cumulated across all jobs each worker held in a cohort-participating lumber mill. Finally, these noise metrics were compared by examining how well each predicted hearing loss. Analyses controlled for gender, age, race as well as medical and non-occupational risk factors. Both methods led to a strengthening of the noise-hearing loss relationships compared to methods using HPD-unadjusted noise estimates. The method based on the modeling of HPD use had the best performance with a four-fold increase in the slope compared to the unadjusted noise-hearing loss slope. Accounting for HPD use in noise exposure assessment is necessary since we have shown that misclassification attenuated the exposure-response relationships. Exposure-response analyses subsequent to exposure reassessment provide predictive validity and gives confidence in the exposure adjustment methods.

The transactivator of transcription protein (Tat) of human immunodeficiency virus (HIV) plays an important role in both viral replication and AIDS pathogenesis. Tat is responsible for enhancing HIV-specific transcription, without which production of infectious virus is severely limited. Ongoing research, however, has identified a plethora of additional functions attributable to Tat including regulating additional HIV processes, altering the homeostasis of both infected and uninfected cells, and being directly involved in AIDS-related neuropathology and cancer. Tat thus plays a diverse role in both viral replication and pathogenesis. What is the relative importance of Tat’s additional functions compared to its principle function of transactivation? This question is explored in Chapter 2 in which tat clones from an epidemiologicallylinked transmission cohort were functionally tested. tat sequences were isolated and cloned from the cohort members at various time points and assessed for transactivation potential. The data revealed that transmission of HIV resulted in the selection of mutations in tat that were host specific and that impacted on the Tat clones’ abilities to transactivate. No correlation, however, was observed between the transactivation potentials of the Tat clones and the AIDS progression statuses of the hosts. The host-specific tat mutations may instead reflect the selection of variants fitter in one or more of Tat’s other functions. This therefore leads to the hypothesis that Tat functions in addition to transactivation are influential in AIDS pathogenesis and are subject to selective pressures during HIV transmission. Tat’s flexibility and diversity of functions are mediated by defined functional domains. One of the most important of these is the basic domain, a highly conserved region encompassing a unique nuclear localisation signal (NLS). The NLS allows Tat to localise to the cell nucleus to participate in transactivation. However, many of Tat’s additional functions require Tat to be outside of the nucleus or even outside of the cell. It is currently unknown how the NLS is modulated to enable Tat nuclear egress, but it may involve post-translational modifications of NLS residues. In Chapter 3, protein arginine methyltransferase 6 (PRMT6) is demonstrated to alter the localisation of Tat within the nucleus and increase the half-life of Tat within the cell. Both of these effects require the methylation activity of PRMT6 and two NLS residues, arginines 52 and 53, previously described to be substrates for PRMT6 methylation. The results suggest that PRMT6 primes Tat for functions outside of the nucleus by altering its subcellular localisation and increasing its stability. The critical role of the basic domain in Tat function is highlighted in Chapter 4 in which mutation of the basic domain led to dysregulation of HIV replication. The mutant, referred to as Nullbasic, has characteristics similar to transdominant Tat mutants, such as suppressing transactivation and localising to the cell cytoplasm. Surprisingly, Nullbasic potently inhibits HIV infectivity by strongly downregulating the expression of envelope, the key molecule involved in cell attachment and entry. Part of this downregulation is attributable to Nullbasic interfering with the nuclear export of envelope-encoding mRNA as a result of altering the subcellular localisation of Rev. However, an additional mechanism of interference is required to fully explain the strong suppression of envelope protein observed in cells. The data allude to a role for Tat in promoting envelope mRNA translation, a role subverted by mutating the basic domain. Taken together, these studies highlight the importance of a diversity of Tat functions to HIV replication and AIDS pathogenesis. Further, they emphasise the critical role of the basic domain to Tat function. Modifications of the basic domain not only influence function, but also regulate Tat spatially and temporally. Dysregulation of the basic domain by mutation not only subverts Tat function, but also elicits antiviral activity at multiple steps of the HIV lifecycle. The study of Tat and its basic domain is crucial in order to understand its role in HIV/AIDS and to recognise Tat as a pathogenic agent in its own right.

This thesis describes a study undertaken between 1992 and 2001 to explore the possible health impacts of human exposure to pesticides. The study followed the health outcomes of approximately 4000 outdoor workers over a period of up to sixty-one years. These workers comprised two subcohorts of approximately even size, one composed of agricultural workers with high insecticide exposures, and the other made up of outdoor staff from local councils in the same area with little or no occupational exposure to insecticides. Mortality and morbidity were compared between the two groups, and with the general Australian community. The study identifies significantly increased mortality among both exposed and control subjects when compared to the Australian population. The major cause of this increase was mortality from smoking related diseases. The study also identifies significant increases in mortality among exposed subjects for a number of conditions that do not appear to be the result of smoking patterns, both when compared to the control group and the Australian population. These include pancreatic cancer in some DDT exposed subjects and asthma, diabetes, and leukaemia in subjects working with more modern chemicals. There was also an increase in self reported chronic illness and asthma, and lower neuropsychological functioning scores among surviving exposed subjects when compared to controls. Diabetes was also reported more commonly by subjects reporting occupational use of herbicides.

Diss. Stockholm : Karol. inst., 2002. / S. 1-56: sammanfattning, s. 59-127: 5 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Research Project (M.B.A.) - Simon Fraser University, 2005. / Research Project (Faculty of Business Administration) / Simon Fraser University. MBA-MOT Program. Senior Supervisor : Dr. Aidan Vining.

Research Project (M.B.A.) - Simon Fraser University, 2005. / Research Project (Faculty of Business Administration) / Simon Fraser University. MBA-MOT Program. Senior Supervisor : Dr. Aidan Vining.

Thesis (Ph. D.)--Case Western Reserve University, 2006. / [School of Medicine] Department of Epidemiology and Biostatistics. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Existem muitos estudos sobre determinantes da interrupção precoce do aleitamento materno (AM), tendo sido identificados fatores socioeconômicos, culturais, demográficos e biológicos. Porém, não há estudos sobre os fatores envolvidos na manutenção do AM por dois anos ou mais, como recomenda a Organização Mundial de Saúde (OMS). Este estudo teve o objetivo de identificar os fatores associados à manutenção do aleitamento materno por dois anos ou mais em crianças nascidas no Hospital de Clínicas de Porto Alegre entre junho e novembro de 2003. Estudo de coorte, parte prospectivo e parte retrospectivo, em que foram acompanhadas 151 crianças, do nascimento até a idade entre 3 e 5 anos de idade. A coleta de dados foi realizada em duas etapas: a primeira, do nascimento aos seis meses de idade da criança, e a segunda, quando a criança tinha entre 3 e 5 anos de idade. Na primeira etapa, foram obtidas informações na maternidade por meio de entrevista com as mães, aos 7 e 30 dias nos domicílios e aos 60, 120 e 180 dias por telefone ou nos domicílios, na impossibilidade de contato telefônico. Para a segunda etapa, as mães foram contatadas por telefone e convidadas para uma entrevista, com foco na prática do aleitamento materno e aspectos relacionados ao desmame de suas crianças. Para testar as associações entre o desfecho (aleitamento materno por dois anos ou mais) e variáveis de interesse, utilizou-se regressão de Poisson seguindo modelo hierárquico. O grau de associação foi estimado por meio de risco relativo (RR) e seus respectivos intervalos de confiança (IC95%). A idade mediana das crianças na época da entrevista foi de 49 meses, com variação entre 40 e 64 meses. Cerca de um terço das crianças (n 49) foi amamentado por dois anos ou mais. A duração mediana do aleitamento materno foi de 11,5 meses, ou 345 dias. Nove crianças (6%) permaneciam sendo amamentadas na época da entrevista. Mostraram-se associados de forma positiva com o desfecho: permanência da mãe em casa com a criança nos primeiros seis meses de vida (RR=2,13; IC95% 1,12-4,05), não uso de chupeta (RR=2,45; IC95% 1,58-3,81), época da introdução de outro leite na dieta da criança (RR=1,001; IC95% 1,001 -1,002 por dia sem sua introdução) e de chás e/ou água (RR=1,005; IC 95% 1,001-1,009 a cada dia de adiamento de sua introdução). Coabitação com o pai da criança mostrou associação negativa com o desfecho (RR=0,61; IC95% 0,37-0,99). De acordo com os resultados deste estudo, para aumentar o número de mulheres que cumprem com a recomendação da OMS de AM por dois anos ou mais seria importante, além de desestimular o uso da chupeta e da introdução precoce de outro leite e de água e/ou chá na dieta da criança, incluir a figura paterna nas intervenções e dar maior atenção para as mulheres que ainda não gozam do direito da licença maternidade de seis meses. / Many studies have assessed the determinants of early discontinuation of breastfeeding (BF), and socioeconomic, cultural, demographic, and biological factors have been identified as such. However, no studies have focused on the factors involved in continuation of breastfeeding for two years or longer, as recommended by the World Health Organization (WHO). The present study sought to identify the factors associated with continuation of breastfeeding for two years or longer in children born at the Hospital de Clínicas de Porto Alegre between June and November 2003. In this combined prospective and retrospective cohort study, 151 children were followed from birth to the age of 3 to 5 years. Data were collected in two stages: the first, from birth to the age of 6 months; the second, sometime between the third and fifth year of life. During the first stage, information was obtained from mothers in the maternity ward (after delivery), at home (at 7 and 30 days), and by telephone—or again at home, when attempts at telephone interviews failed—at 60, 120, and 180 days. For the second stage of data collection, mothers were reached by telephone and invited to attend an interview focusing on breastfeeding practices and weaning. Hierarchical Poisson regression modeling was used to test for association between the study endpoint (breastfeeding for two years or longer) and the variables of interest. The degree of association was estimated by means of relative risks (RR) and their respective 95% confidence intervals. The median age of the child at the time of the interview was 49 months (range, 40–64 months). Roughly one-third of children (n=49) were breastfed for two years or longer. The median duration of breastfeeding was 11.5 months (345 days). Nine children (6%) still breastfed at the time of the interview. The following factors were positively associated with the study endpoint: stay-at-home mothering during the first 6 months of life of the child (RR 2.13; 95%CI, 1.12 to 4.05), non-use of pacifier/dummy (RR 2.45; 95%CI, 1.58 to 3.81), and timing of introduction of non-breast milk (RR 1.001; 95%CI, 1.001 to 1.002 for each day introduction of non-breast milk was delayed) and tea and/or water (RR 1.005; 95%CI, 1.001 to 1.009 for each day introduction of non-milk fluids was delayed). Cohabitation with the child’s father was negatively associated with the study endpoint (RR 0.61; 95%CI, 0.37 to 0.99). The results of this study suggest that, in order to increase the number of women who comply with the WHO recommendation of breastfeeding their children for two years or longer, it would be important not only to discourage use of pacifiers/dummies and early introduction of non-breast milk, water, or tea to the child’s diet, but also to include the child’s father figure in breastfeeding-related interventions and place greater emphasis on women who have yet to gain the right to 6-month maternity leave.