Abstract Despite the common recommendations of the criteria for the diagnosis of asthma there is still a wide variation within different regions in diagnoses, use of medications and hospitalisation rates especially among young children. This thesis elucidates the role of spesified environmental risk factors associated with the development of atopic diseases in childhood. In two prospective follow-up surveys we found that allergies and asthma associate with the consumption of margarines, butter and fish and that the common infection of childhood, RS-virus infection, does not increase asthma morbidity in adolescence. In a randomised set-up we were able to verify that the common childhood infections do not protect from allergies and asthma. In a retrospective survey we found that hospitalisation rates can reflect medication practices in different regions. Our results indicate that consumption of fat in the diet can be one triggering factor for allergies but common childhood infections are merely markers of susceptibility to allergies and asthma rather than the cause of it.

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Background: A subtype of inflammatory bowel disease, Crohn’s disease is thought to represent a complex interaction between environmental factors, a defective immune system, the gastrointestinal microbiome and genetic susceptibility. Aim: The focus of this study was to investigate the association between environmental exposures during childhood and the subsequent development of Crohn’s disease, thus the two primary aims were to: 1) conduct a systematic review of the literature evaluating environmental risk factors during childhood, defined by studies either as, age intervals (e.g., 0-5, 6-10 and 11-18 years), or more 'broadly' as 0-18 years; and 2) investigate the association between childhood environmental exposures during three age intervals (0-5, 6-10 and 11-18 years), as well as frequency of childhood infections and the future development of Crohn's disease based on a score analysis, using a subset of previously collected data from a completed doctoral thesis involving a case control study design in study population, in the Western Cape, South Africa. The aim included a primary analysis of the latter dataset for childhood infections. Design: For the first aim of the study, a systematic search was conducted during March 2015 in electronic databases, such as EMBASE, EBSCOhost (Medline), Ovid, Scopus and World Cat, PubMed and Biomed Central, to identify epidemiological studies that examined the association between childhood environmental exposures and the subsequent development of Crohn's disease. Studies evaluating childhood exposure either by age intervals, or more broadly, from birth until 18 years were included. The environmental exposures evaluated in the review were; farm animal contact, place of upbringing, sibship size, household pets, primary water source and hot water availability. Of the 181 identified articles, 16 were included in the final systematic review. The second aim of the study involved a post hoc analysis of a subset of findings from the completed doctoral research by Abigail Basson with regard to the multiple logistic regression analysis evaluating environmental risk factor exposure during three age intervals; 0-5 years, 6-10 years and 11-18 years. In the present research, two different methodological approaches were undertaken. Briefly, exposure variables, of similar nature, were combined into subgroups and assigned weighting scores. The two 'subgroup models' were designated as: Group A and Group B. Based on these premises, a score analysis was performed, and the difference in scores, between case and control groups, was compared. In addition, multiple logistic regression models were conducted on a subset of original data from the aforementioned completed doctoral study to assess the association between the frequency of childhood infections between 0-20 years and risk of Crohn’s disease development. Following this, a score analysis was again performed. Results: Sixteen studies were included in the systematic review. Of the five studies that investigated the association between place of upbringing during the age interval 0-5 years and the subsequent development of Crohn's disease, three found no significant association; however of the three studies evaluating place of upbringing during the age intervals 6-10 and 11-18 years, only one study identified a significant association. Three studies investigated exposure to farm animals during the age interval 0-5 years, of which, two identified a significant association. Of the latter three studies, two investigated farm animal contact during the age intervals 6-10 and 11-18 years, but only one reported a significant association during these age intervals. Notably, this was the study which had failed to identify an association during the 0-5 year age interval. Both studies which broadly evaluated farm animal exposure during 'childhood' reported that not having contact with animals significantly increased the risk of developing Crohn's disease. Of the five studies that investigated exposure to pets during the age interval 0-5 years, only one identified a significant risk association, namely with exposure to cats. Of the three which investigated pet exposure during the age intervals 6-10 years and 11-18 years, one identified a significant association, for both age intervals. Five studies investigated pet exposure during 'childhood'; one found that having a pet significantly increased the risk of developing Crohn's disease, two reported that not having a pet significantly increased risk in developing Crohn's disease, whereas the remaining studies found no significant association. Only one study evaluated primary water source during the three age intervals; during the age interval 0-5 years and 11-18 years, having piped tap or bottled water was significantly associated with CD development. Of the four studies investigating primary water source during ‘childhood’, only one reported a significant association between primary water source and the development of Crohn's disease. The availability of hot water during the age interval 0-5 years was significantly associated with Crohn's disease development in one of the three relevant studies. Two studies investigated hot water availability during 6-10 and 11-18 years, however both failed to identify a significant association. When broadly evaluated, hot water availability during 'childhood' was significantly associated with Crohn's disease risk, in two of the three relevant studies. None of the studies which investigated sibship size and the risk of future Crohn's disease development during defined age intervals reported a significant association. Only two of the seven studies that evaluated sibship size during childhood reported a significant association. Results of the score analysis revealed a significant difference during all three age intervals between the case and control groups with Group A and Group B, with cases having significantly lower exposure scores (approximately 30% and 40% lower, respectively), when compared with that of controls. On multiple logistic regression analysis, subjects who never had tooth decay/cavity (OR = 1.78; 95% CI, 1.05-3.04), periodontitis (OR = 1.95; 95% CI, 1.10, 3.48), diarrhoea (OR = 2.71; 95% CI, 1.62-4.62), gastritis (OR = 2.13; 95% CI, 1.30-3.35), or mouth ulcers (OR = 2.02; 95% CI, 1.12-3.70), at least once per year or more, were at an increased risk for later development of Crohn's disease, when compared to those who were exposed to these infections at least once per year or more. There was a significant difference in exposure scores between the case and control groups (OR = 0.88; 95% CI, 0.82-0.94), thus indicating that cases had 12% less exposure to childhood infections from birth until the age of 20 years, when compared to the controls. Conclusion: The systematic review of the literature provides evidence in support of the hygiene hypothesis, in that delayed exposure to immunostimulatory microbes through the environmental exposures increases the risk for future CD development, in genetically susceptible individuals. In addition, the literature supports that the childhood environment plays an important role in the aetiology of Crohn's disease. However, the lack of consistent findings between studies, particularly those which have broadly defined ‘childhood’ implies that timing of exposure plays a crucial role in this ever evolving paradigm. Results from the score analysis provide insight into the 'compound' effects from multiple environmental exposures in the aetiology of Crohn's disease. While the present research was unable to provide any explanation for the underlying mechanism of disease pathogenesis, overall, the findings have important implications for future IBD-related studies as they demonstrate the importance of accounting for environment as a 'whole' when conducting epidemiological studies, as opposed to focusing on individual environmental factors, as well as that it is imperative to investigate environmental exposures within the context of defined age intervals.

Bibliographische Beschreibung: Christian Dick „Schützen Impfungen vor der Entstehung von Allergien?“ Universität Leipzig, Dissertation 68 S., 72 Lit., 9 Abb., 19 Tab., 7 Anlagen. Referat: Die Anzahl von Kindern mit allergischen Erkrankungen steigt in den industrialisierten Staaten dieser Welt stetig. Nach der „Hygiene-Hypothese“ ist dafür ein moderner „westlicher“ Lebensstil mitverantwortlich. Dieser führt dazu, dass Menschen einer immer geringeren Anzahl von Infektionen und mikrobiellen Expositionen ausgesetzt sind. Diese scheinen jedoch gerade in den ersten Lebensjahren ein wichtiges Stimulans des Immunsystems darzustellen. Die Folge davon scheint eine Imbalance zwischen T1- und T2-Helferzellen zu sein, welche zu einem verstärkten Auftreten von allergischen Erkrankungen führt. Entsprechend dieser „Hygiene-Hypothese“ könnten im Umkehrschluss Impfungen im frühen Kindesalter als eine Art „Ersatzinfektion“ einen protektiven Effekt auf allergische Erkrankungen besitzen. Anhand der Daten einer prospektiven Geburtskohortenstudie mit einer Anfangsteilnehmerzahl von 3097 Kindern wurde zum Ende des 6. Lebensjahres die Lebenszeitprävalenz des atopischen Ekzems von geimpften und nicht geimpften Kindern verglichen. Der Vergleich wurde zum einen für drei unterschiedliche Impfungen -Tetanus, Haemophilus influenzae b und Masern- einzeln durchgeführt. Zum anderen wurden Kinder mit einem hohen Impfstatus, welche drei Mal als erfolgreich geimpft gewertet wurden, Kindern mit niedrigem Impfstatus gegenübergestellt, die nur einmal oder gar nicht als erfolgreich geimpft gewertet wurden. Für keine der drei einzeln untersuchten Impfungen konnte ein signifikanter Einfluss auf die Ekzemlebenszeitprävalenz zum Ende des 6. Lebensjahrs festgestellt werden. Dagegen erwies sich ein hoher Impfstatus als protektiver Faktor in Bezug auf die Ekzemlebenszeitprävalenz zum vollendeten 6. Lebensjahr (OR=0,29, 95% Konfidenzintervall=0,12 - 0,71 /p=0,006). Ergebnis dieser Arbeit ist, dass sich ein hoher Impfstatus protektiv auf die Allergieentwicklung auswirkt. Damit stützen die Ergebnisse die „Hygiene-Hypothese“.

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<p>This thesis examines patterns in poliomyelitis mortality in Wentworth and York Counties of southern Ontario, Canada, from 1900 to 1937. This period marked polio’s shift from endemic to epidemic status. It was also a time of shifting social, cultural, demographic, and economic patterns. Contemporaries struggled to understand polio’s epidemiology, and even today, with the poliovirus on the verge of global eradication, models to explain its changing patterns and impact continue to be revised.</p> <p>This thesis uses both qualitative and quantitative data collected from a variety of archival sources, including death, birth, and marriage registrations, census records, and newspaper articles, among other records. This information was used to build a geodatabase which forms the basis for analyses of mortality patterns in relation to age and sex, illness duration, seasonality, nativity, birthplace, ethnicity, and religion. Further analyses included family size, birth order, socioeconomic status, and place of residence patterns.</p> <p>Examined in the context of Wentworth and York Counties in the early 20^th century, the results both reveal a local pattern to polio’s epidemic emergence and provide a means to test broader hypotheses regarding polio’s epidemiological patterns. Specifically, results from this study were compared to the expectations of the intensive-exposure and cross-sex transmission hypotheses proposed by Nielsen and colleagues. Among the most important contributions of this thesis are the results showing a pattern of change over the study period, with two distinct stages. Stage One (1910 to 1927) is characterized by an equal sex ratio and a median known family size of four. Stage Two (1928 to 1937) is characterized by excess male deaths and a median known family size of two. These results link polio mortality patterns to demographic and ecological shifts in the early 20^th century and confirm that there is still much to learn from the history of this disease.</p> / Doctor of Philosophy (PhD)

Background It is debated whether a low total diversity of the gut microbiota in early childhood is more important than an altered prevalence of particular bacterial species for the increasing incidence of allergic disease. The advent of powerful, cultivation-free molecular methods makes it possible to characterize the total microbiome down to the genus level in large cohorts. Objective We sought to assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to atopic eczema development. Methods Microbial diversity and composition were analyzed with barcoded 16S rDNA 454-pyrosequencing in stool samples at 1 week, 1 month, and 12 months of age in 20 infants with IgE-associated eczema and 20 infants without any allergic manifestation until 2 years of age (ClinicalTrials.gov ID NCT01285830). Results Infants with IgE-associated eczema had a lower diversity of the total microbiota at 1 month (P = .004) and a lower diversity of the bacterial phylum Bacteroidetes and the genus Bacteroides at 1 month (P = .02 and P = .01) and the phylum Proteobacteria at 12 months of age (P = .02). The microbiota was less uniform at 1 month than at 12 months of age, with a high interindividual variability. At 12 months, when the microbiota had stabilized, Proteobacteria, comprising gram-negative organisms, were more abundant in infants without allergic manifestation (Empirical Analysis of Digital Gene Expression in R [edgeR] test: P = .008, q = 0.02). Conclusion Low intestinal microbial diversity during the first month of life was associated with subsequent atopic eczema. / <p>Funding Agencies|BioGaia AB, Stockholm, Sweden||Ekhaga Foundation, the Heart and Lung foundation||Research Council for the South-East Sweden|F2000-106|Olle Engqvist Foundation||Swedish Asthma and Allergy Association||Swedish Research Council||University Hospital of Linkoping||Soderberg Foundation||Vardal Foundation for Health Care Science and Allergy Research, Sweden||BioGaia AB||</p>

Asthma is the leading chronic illness in children in the United States. Since children in the U.S. spend a majority of their time indoors there is an increased need to understand key sources of daily asthma triggers in the home. Bacterial endotoxin, dust mite allergens and β-D-glucan have been shown to be potent inducers of asthma attacks, and high levels of these allergens in homes can trigger attacks in those with asthma. We aim to better understand the risks to those with asthma that might be associated with evaporative cooler (EC) use in low-income homes. ECs are often promoted because of their low energy consumption and decreased environmental impact compared to central air conditioning (AC). Because of their lower cost, ECs are more widely used in low-income homes. ECs use evaporation to cool the air, which leads to higher indoor relative humidity. This may create an ecological niche for house dust mites in semi-arid climates where they are normally absent. EC sump water also provides an ideal environment for bacteria and fungi to grow, possibly resulting in EC loading the air with more potential asthma triggers than central air conditioning. We sampled low-income homes around Utah county with central air and evaporative cooling and tested them for the presence of dust mite allergens, β-D-glucan and endotoxin. There were significantly higher levels of endotoxins and β-(1→3)-D-glucans in the EC homes compared to the AC homes, with increased odds of dust mite allergen prevalence but not at clinically significant levels. These findings suggest that in semi-arid environments, endotoxin and β-(1→3)-D-glucan levels in homes with evaporative coolers are more elevated than dust mite allergens.

La maladie de Crohn (MC) pédiatrique a des conséquences majeures sur la qualité de vie des patients atteints (troubles de croissance, absentéisme scolaire, etc). L’étiologie de la MC est inconnue. La théorie de l’hygiène (TH) stipule que les conditions de vie sanitaires des pays industrialisés préviennent l’exposition antigénique et empêchent le développement de la tolérance immunitaire chez les enfants. Ceci mènerait à une réaction excessive du système immunitaire lors d’expositions subséquentes et engendrerait le développement de maladies inflammatoires chroniques telles la MC. Objectif: Analyser l’association entre la fréquence, la temporalité et le type d’infections infantiles (indicateurs d’environnements pourvus d’antigènes) et le risque de MC pédiatrique. Une étude cas-témoin fût réalisée, les cas de MC provenant d’un centre hospitalier tertiaire montréalais. Les témoins, provenant des registres de la Régie d’assurance maladie du Québec (RAMQ), furent appariés aux cas selon leur âge, sexe et lieu de résidence. L’exposition aux infections fût déterminée grâce aux codes de diagnostic ICD-9 inscrits dans la base de données de la RAMQ. Un modèle de régression logistique conditionnelle fût construit afin d’analyser l’association entre infections et MC. Des ratios de cotes (RC) et intervalles de confiance à 95% (IC 95%) furent calculés. Résultats: 409 cas et 1621 témoins furent recrutés. Les résultats de l’analyse suggèrent un effet protecteur des infections infantiles sur le risque de MC (RC: 0,67 [IC: 0,48-0,93], p=0,018), plus particulièrement au cours des 5 premières années de vie (RC: 0.74 [IC: 0,57-0,96], p=0,025). Les infections rénales et urinaires, ainsi que les infections des voies orales et du système nerveux central (virale), semblent particulièrement associées à l’effet protecteur. Les résultats de l’étude appuient la théorie de l’hygiène: l’exposition aux infections infantiles pourrait réduire le risque de MC pédiatrique. / Crohn’s disease (CD) poses specific challenges in the paediatric population (growth failure, depression, etc). The environmental contributors to CD aetiology remain largely unknown. There are suggestions that sanitary living conditions prevailing in developed countries prevent antigen exposure and impede the development of immunological tolerance amongst children, resulting in abnormally heightened immunological responses with subsequent exposures (hygiene hypothesis). Evidence for the hygiene hypothesis in CD aetiology remains unclear. Objectives: To assess the role of the frequency, timing and type of childhood infections (measures of antigen exposure) on the risk of paediatric CD. A case-control study was carried out. Confirmed cases of CD were recruited from a tertiary care paediatric hospital. Controls matched to the cases on calendar age, gender, and area of residence, were selected using the provincial health insurance files. Infection exposure was ascertained using ICD-9 diagnostic codes provided by the provincial insurer’s administrative databases. Conditional logistic regression analysis was used to assess the relationship between childhood infections and CD. Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were estimated. 409 cases and 1621 controls were recruited. A diagnosis of infection was associated with reduced risks for paediatric CD (OR=0.67, 95% CI:[0.48-0.93], p=0.018), attributable to infection exposures primarily during the first 5 years since birth [OR=0.74, 95% CI=0.57-0.96, p=0.025]. Infections affecting the kidney and urinary tract, oral tract and viral CNS infections, were most significantly associated with protective effects. Our study provides support for the hygiene hypothesis in CD whereby exposure to infections in early childhood could potentially reduce risks for CD.

Background Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. It usually strikes during young adulthood, and 2.5 million individuals are estimated to have the disease worldwide. The causes of MS are not known, but several factors have been shown to be associated with the risk of the disease, including certain genes, vitamin D, smoking and Epstein- Barr virus infection. Little is known about how/if these factors interact. Methods Study I: The risk of MS by month of birth was investigated using MS cases from the Swedish MS registry and using general population controls. Studies II–V: We identified MS cases who had donated blood prior to disease onset, and MS cases whose mothers had donated blood during pregnancy, by cross-linking a database of MS cases, and a database of mothers of MS cases, to two local biobank cohorts. One of them consisted of blood samples collected during early pregnancy, and one with samples collected during health controls. Levels of 25(OH)D (25-hydroxyvitamin D), RBP (retinol binding protein, a surrogate marker for vitamin A), CRP (C- reactive protein), cotinine (a nicotine metabolite) and anti Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibodies were measured in cases and matched controls. The risk of MS by categories of these exposures was estimated in bi- and multivariable matched logistic regression models. Results Subjects born in spring had a higher risk of MS, but no influence of early gestational levels of the measured risk factors on the risk of MS in the offspring was observed. In prospective samples from MS cases and controls, 25(OH)D levels ≥75 nmol/l, intermediate RBP levels, and elevated CRP levels in young were associated with a decreased risk of MS. Elevated cotinine levels (suggestive of smoking) and high antibody reactivity against EBNA-1 were associated with an increased risk of MS. All factors but RBP were more clearly associated with MS in young subjects. Conclusion All factors analyzed in prospectively collected samples were associated with the risk of MS, and taken together, the data indicate that the key etiopathological events that lead to MS occur before the age of 20–30. Study II provides support for trials exploring the primary preventive potential of oral vitamin D supplementation.

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2017-07-04T16:01:12Z No. of bitstreams: 1 rafaelvalenteveiga.pdf: 4234191 bytes, checksum: 215e887a2d4ac1ec9993886981d707eb (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-08-08T15:16:30Z (GMT) No. of bitstreams: 1 rafaelvalenteveiga.pdf: 4234191 bytes, checksum: 215e887a2d4ac1ec9993886981d707eb (MD5) / Made available in DSpace on 2017-08-08T15:16:30Z (GMT). No. of bitstreams: 1 rafaelvalenteveiga.pdf: 4234191 bytes, checksum: 215e887a2d4ac1ec9993886981d707eb (MD5) Previous issue date: 2017-03-08 / Nas últimas décadas os casos de asma e demais doenças alérgicas tiveram grande aumento em todo o mundo, sendo atualmente um grande problema de saúde pública. As causas do aumento da prevalência destas patologias são desconhecidas, porém a hipótese mais aceita é que seja oriunda da redução de infecções na infância como consequência da recente melhora nas condições de higiene. Esta redução das infecções pode levar ao desenvolvimento anômalo do sistema imune, aumentando assim a chance de desenvolver alergias e a asma. Tanto a asma como as demais alergias são patologias complexas, causadas por fatores genéticos e ambientais, de modo que o uso de ferramentas computacionais, tais como a programação genética podem contribuir para a compreensão destas doenças. Aplicou-se a técnica de Programação Genética Gramatical Multiobjetivo (MGGP) em dados obtidos de um coorte de 1445 crianças entre 4 e 11 anos para gerar modelos os quais possam representar como as relações entre infecções e ambiente podem explicar o desenvolvimento de atopia e asma. Para avaliar a presença de asma foi usado um questionário do ISAAC fase II e para avaliar atopia foram realizadas medições de anticorpos IgE contra alérgenos comuns e teste de reatividade cutânea. Os resultados obtidos mostram que os modelos gerados pela MGGP apresentam desempenho em acurácia competitivos aos obtidos pelo algoritmo C4.5 e regressão logística múltipla para os diferentes desfechos. Os resultados obtidos pela MGGP são de fácil interpretação, e capazes de encontrar relações complexas relevantes para o entendimento destas patologias, sendo assim, a MGGP é uma poderosa ferramenta para ajudar a compreender essas condições. / In the last decades cases of asthma and other allergic diseases have increased greatly throughout the world, being nowadays a major public health problem. The causes of this increased prevalence are unknown, however the most accepted hypothesis is that it comes from the reduction of childhood infections as a consequence of the recent improvement in hygiene conditions. This reduction of infections can lead to anomalous development of the immune system, thus increasing the chance of developing allergies, including asthma. Asthma and other allergies are complex pathologies caused by genetical and environmental factors, so the use of computational tools such as genetic programming can contribute to the understanding of these diseases. We applied the Multiobjective Grammatical Genetic Programming (MGGP) technique to data obtained from a cohort of 1445 children to generate models which may represent how the relationships between infections and environment may explain the development of allergies and asthma. To assess the presence of asthma, a questionnaire was used and allergy measurements were performed on IgE antibodies against common allergens and skin reactivity test. The results obtained show that the models generated by MGGP show a performance in accuracy that is competitive with those obtained by the algorithm C4.5 and multiple logistic regression for the different outcomes. The results obtained by MGGP are easy to interpret, and capable of finding complex relationship relevant to the understanding of these complex pathologies, therefore MGGP is a powerful tool to help understand these conditions.