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

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“.

No description available.

The Hygiene Hypothesis and Old Friends Hypothesis focus attention on the coevolutionary relationship between humans and pathogens, positing that reduced pathogen exposure in economically developed nations is responsible for immune dysregulation and associated increases in chronic inflammation, allergy, and autoimmunity. Despite progress in testing these ideas, few studies have examined these relationships among populations undergoing the transition from traditional to more market-based lifestyles. The present study tests relationships between economic development and social change, altered infectious disease exposure, and immune function among the Shuar forager-horticulturalists of Amazonian Ecuador, a population undergoing rapid economic change associated with increased market participation. Using stool samples to assess soil-transmitted helminth (STHs; parasitic intestinal worms) burden, dried blood spot measurement of the inflammatory marker C-reactive protein (CRP), and interviews to evaluate level of market integration (MI; the suite of social and cultural changes associated with rapid economic development) and disgust sensitivity, this dissertation tests the Hygiene and Old Friends Hypotheses. The first study tests relationships between STH exposure and MI, using geographic location in relation to the regional market center as a proxy for MI. This study documents lower rates of STHs in people living in more market integrated regions. The second study tests the coevolutionary role that STHs and other pathogens have played in shaping human psychology and behavior. Findings suggest that pathogen exposure has acted as a selective pressure, resulting in evolved disgust sensitivity toward pathogen related stimuli. This study provides evidence that disgust sensitivity is calibrated to local environments, acting to decrease STH exposure. The third study tests the role of STHs in immune function. CRP was positively related to age in uninfected individuals. No relationships existed for more traditionally living or infected individuals. These findings suggest that STH exposure may decrease the risk of developing chronic inflammation and associated diseases with advancing age. These studies provide support for the idea that STHs provide stimuli that decrease chronic inflammation, suggesting that altered intestinal microflora in developed nations may be partially responsible for the development of chronic inflammatory disorders like allergy and autoimmunity. This dissertation includes previously published and unpublished coauthored material.

Research on exposure to animals and risk of type 1 diabetes (T1D) has had conflicting results with some researchers finding that animal exposure reduces the risk of T1D and others finding no association between animal exposure and T1D. Previously conducted studies on the association between animal exposure and T1D are case-control studies that have been limited by recall bias. The purpose of this study is to investigate the association between early life animal exposure and the risk of persistent, confirmed islet autoantibodies (IA) and T1D diagnosis among an eligible cohort of genetically high T1D risk participants enrolled in the international prospective cohort study, The Environmental Determinants of Diabetes in the Young (TEDDY). It is hypothesized that children who are exposed to animals in early life will have a lower risk of developing IA and T1D than children who are not exposed to animals in early life. A total of 7,432 TEDDY participants were included in the study. The associations between early life animal exposure and the outcomes of interest were explored using Cox proportional hazards models. In order to control for confounding, a propensity score analysis was applied by three different methods: adjustment for the propensity score variable in the Cox proportional hazards model, stratification on propensity score groups, and propensity score pair matching. Early life animal exposure was not associated with diabetes autoimmunity or T1D onset in this genetically high T1D risk population. These findings were consistent across all three propensity score analysis methods and when directly adjusting for HLA type. The hypothesis that children who are exposed to animals in early life will have a lower risk of developing IA and T1D than children who are not exposed to animals in early life is not supported by this study. The results of this study suggest that there is no association between early life animal exposure and development of T1D. Performing this analysis again after longer follow-up has been completed for the study population is recommended as it may elucidate the effect of animal exposure on T1D and IA risk. Further studies are also needed on animal exposure and T1D in different types of environments (e.g., high residential density) and the effect of different types of animal exposures (e.g., species, duration) on T1D and IA risk. Additionally, studies on differences in perceptions of pets across countries could also aid the interpretation of studies on animal exposure and health outcomes.

Introdução: A frequência de detecção de bandas oligoclonais (BOC) em doentes com esclerose múltipla (EM) na cidade de São Paulo é significativamente mais baixa do que em outras cidades do Brasil e de outros países, principalmente da Europa e da América do Norte. Não se conhece o motivo pelo qual isso ocorre. Uma das hipóteses mais interessantes relacionada à imunopatogenia da EM é a chamada Hipótese Higiênica, que postula uma relação inversamente proporcional entre a prevalência de infecções por parasitas e a frequência da EM. Objetivo: verificar se há relação entre a ocorrência de anticorpos contra parasitas no soro sanguíneo e a detecção de BOC em pacientes diagnosticados com EM na cidade de São Paulo. Métodos: Foram estudados 164 pacientes do Ambulatório de Doenças Desmielinizantes da Divisão de Neurologia Clínica e da Divisão de Anestesia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo dos quais foram obtidas as amostras de LCR e de soro em que foi realizado este estudo. Esses pacientes foram separados em 4 grupos (EM, CIS, Grupo Controle com Pacientes de DNI e Grupo Controle com Pacientes sem Queixas Neurológicas) nos quais foram identificadas as presenças de BOC e de anticorpos parasitários. Para a detecção de anticorpos parasitários, foi utilizada a técnica de eletroforese unidimensional de proteínas em gel de poliacrilamida em sistema descontínuo, com antígenos LV-Tcra (líquido vesicular de Taenia crassiceps) e ES-Tcra (líquido excreção/secreção de Taenia crassiceps). Resultados: Dos 164 pacientes estudados, separados em seus respectivos grupos, foram pesquisados anticorpos antiparasitários de baixo e de alto peso molecular. Esses anticorpos foram observados em 103 pacientes nos quais não havia 13 BOC. Destes, 2 apresentaram anticorpos de baixo peso molecular e 59 anticorpos de alto peso molecular. Dos 61 pacientes em que havia BOC, foram encontrados anticorpos de baixo peso molecular em um; 16 apresentaram anticorpos de alto peso molecular. Conclusão: Em doentes com EM clinicamente definida anticorpos anti-Taenia foram detectados com a mesma frequência em pacientes com BOC e em pacientes sem BOC / Introduction: The frequency of oligoclonal bands (OCB) detection in patients with multiple sclerosis (MS) in the city of São Paulo is significantly lower than in other cities of Brazil and other countries, mainly Europe and North America. To date, the reason for its occurrence is still unknown. One of the most interesting hypotheses related to the immunopathogenesis of MS is the so-called Hygiene Hypothesis, which postulates an inverse relationship between the prevalence of parasitic infections and the frequency of MS. Objective: This study examined whether there is a relationship between the occurrence of antibodies against parasites in blood serum and the detection of OCB in patients diagnosed with MS in the city of São Paulo. Methods: We have studied 164 patients from the Demyelinating Diseases Clinic of the Division of Clinical Neurology and Division of Anesthesia Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo from whom CSF and serum samples were obtained and which were used to conduct the present study. These patients were divided into 4 groups: MS, Clinically Isolated Syndrome (CIS), control group with patients with Inflammatory Neurologic Diseases (IND) and Control Group with patients without neurologic complaints, in whom the presence of OCB and anti- parasitic antibodies was identified. For the detection of parasitic antibodies, the unidimensional electrophoresis of proteins in polyacrylamide gel in a batch system with LV-Tcra antigens (Taenia crassiceps vesicular fluid) and ES-Tcra (net excretion / secretion of Taenia crassiceps) was used. Results: Of the 164 patients studied, separated into their respective groups, anti- parasite antibodies of low and high molecular weight were analyzed. A total of 103 patients presented no OCB, and of these, 2 had antibodies of low molecular weight and 59 presented antibodies of high molecular weight. Of the 61 patients with OCB positive, one showed antibodies of low molecular weight and 16 antibodies of high molecular weight. Conclusion: This study showed that in patients with clinically established MS. anti-Taenia antibodies occurred with the same frequency in patients with OCB and in patients without OCB

Background: Juvenile idiopathic arthritis (JIA) refers to a group of auto-immune conditions involving joint inflammation that first appears before the age of 16. In the United States, about 294,000 children are affected. Although JIA can be widely attributed to genetic factors, the consensus is that environmental factors also play a role. Attempts to assess the role of environmental factors, though scarce, have focused on the role of infections, smoking exposure, and breastfeeding. Hygiene hypothesis, which suggests that adaptive immunological response improves with higher frequencies of pathogen exposure in early childhood, has been used to try to explain the risk of JIA. Common markers of microbe exposure in early life include sibling number, pet number, and maternal parity. Some prior studies conducted outside the U.S. suggests that increasing sibling number is protective against the risk of JIA. This study aimed to evaluate prior findings, using data from the U.S. Methods: The study used data from the 2017 Centers for Disease Control and Prevention National Survey for Child Health. The survey used a sample size of 21599 children to estimate the number of children in the U.S. Descriptive statistics was carried out, and logistic regression was used to determine the association between family number and the odds of developing JIA, while adjusting for sociodemographic variables. Family number was used as a proxy for sibling number. SAS v 9.4 was used for analysis. Results: Complete data on all the variables of interest were available for 17618 children, of which 67 had JIA. Although there was a marginal association between sibling number and JIA in the unadjusted model (OR [95% CI] 0.983-1.602) (P=0.068), in the adjusted model, there was no significant association between JIA and sibling number ([OR 95% CI] 0.8985-1.447) (P=0.29). There was a significant association between JIA and age, low birth weight, highest education level in the family, while sex had a marginal association. Conclusion: There was no association between family size and the development of JIA in this study. While some prior results have supported the observed significant effect of low birth weight, the disparity in results between this study and the Australian study could be due to the use of family number instead of sibling number. Further studies should assess the association of sibling number and developing JIA in the U.S.

The current dissertation tested a model based on a systems perspective, where inflammation was hypothesized to mediate the influence of diet and physical condition on quality of life (base model) in a nationally representative U.S. dataset (NHANES). Three additional hypotheses, regarding social support (The Buffering Hypothesis), early microbial exposure (The Hygiene Hypothesis) and life history theory (The Tradeoff Hypothesis) were tested utilizing the base model. All analysis utilized a structural equation model. This study focused on objective measurements for dietary behavior and physical activity utilizing blood serum values of nutrients and metabolic markers and anthropometric data as well as blood serum concentrations of CRP and white blood cell count. Quality of life was assessed with the number of limitations in daily living, the number of days that were affected by mental, emotional and physical limitations and the self-reported general health condition. The hypothesized model fit well to the data and the results revealed that lower intake of healthy nutrients and reduced physical condition both predicted decreased quality of life, as mediated by inflammation and explained 31.9 % of the variation in quality of life (R² = .319, p<.001). Social support further predicted quality of life directly (β = .417, p<.001) and indirectly through dietary behavior and inflammation (β = -.106, p<.001), microbial exposure significantly moderated the relation between inflammation and quality of life (β = -.127, p<.001) and higher reproductive effort predicted lower intake of vital nutrients (β = .316, p<.001), physical condition (β = .352, p<.001) and subsequent inflammation. Reproductive effort also directly predicted reduced quality of life (β = .278, p<.001). These analyses indicated that inflammation can be considered a strong mediator between lifestyle factors and resulting quality of life and that social support, microbial exposure and reproductive effort each added unique predictive value to this model.

Parasites may express proteins that mimic host proteins such that the host immune system cannot discriminate between host and parasite. An immune response to host proteins results in autoimmunity, and therefore, mechanisms to avert autoimmunity also limit the capacity of the immune system to respond to parasites that are mimics. In failing to elicit an immune response, parasites that are mimics appear to have a selective advantage and so it is unclear why all parasites do not evolve to be mimics. In this thesis, I demonstrate that next-generation methods can be used to perform an evolutionary invasion analysis. Subsequently, I use this method to identify evolutionarily stable strategies and to investigate three hypotheses for why all parasites are not mimics. These are: (1) that mimicry increases the risk of inducing autoimmunity and that hosts with autoimmunity are less likely to transmit the parasite; (2) that proteins which mimic host proteins have a reduced ability to perform the vital functions necessary for parasite replication; and (3) that owing to a feedback between the types of parasites that infect a host and the host's immune response, when parasites are likely to re-infect the same hosts, mimics are more likely to elicit an immune response. I show that each of these hypotheses explain why all parasites are not mimics. The key data needed to assess the applicability of these results is to quantify the number of secondary infections generated by hosts infected with parasites that are molecular mimics. This thesis motivates a new question in evolutionary epidemiology, furthers the field of evolutionary medicine and contributes novel methodologies for host-parasite multi-scale modelling in mathematical biology. / Thesis (Ph.D, Mathematics & Statistics) -- Queen's University, 2011-04-05 10:27:20.49

Introdução: A frequência de detecção de bandas oligoclonais (BOC) em doentes com esclerose múltipla (EM) na cidade de São Paulo é significativamente mais baixa do que em outras cidades do Brasil e de outros países, principalmente da Europa e da América do Norte. Não se conhece o motivo pelo qual isso ocorre. Uma das hipóteses mais interessantes relacionada à imunopatogenia da EM é a chamada Hipótese Higiênica, que postula uma relação inversamente proporcional entre a prevalência de infecções por parasitas e a frequência da EM. Objetivo: verificar se há relação entre a ocorrência de anticorpos contra parasitas no soro sanguíneo e a detecção de BOC em pacientes diagnosticados com EM na cidade de São Paulo. Métodos: Foram estudados 164 pacientes do Ambulatório de Doenças Desmielinizantes da Divisão de Neurologia Clínica e da Divisão de Anestesia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo dos quais foram obtidas as amostras de LCR e de soro em que foi realizado este estudo. Esses pacientes foram separados em 4 grupos (EM, CIS, Grupo Controle com Pacientes de DNI e Grupo Controle com Pacientes sem Queixas Neurológicas) nos quais foram identificadas as presenças de BOC e de anticorpos parasitários. Para a detecção de anticorpos parasitários, foi utilizada a técnica de eletroforese unidimensional de proteínas em gel de poliacrilamida em sistema descontínuo, com antígenos LV-Tcra (líquido vesicular de Taenia crassiceps) e ES-Tcra (líquido excreção/secreção de Taenia crassiceps). Resultados: Dos 164 pacientes estudados, separados em seus respectivos grupos, foram pesquisados anticorpos antiparasitários de baixo e de alto peso molecular. Esses anticorpos foram observados em 103 pacientes nos quais não havia 13 BOC. Destes, 2 apresentaram anticorpos de baixo peso molecular e 59 anticorpos de alto peso molecular. Dos 61 pacientes em que havia BOC, foram encontrados anticorpos de baixo peso molecular em um; 16 apresentaram anticorpos de alto peso molecular. Conclusão: Em doentes com EM clinicamente definida anticorpos anti-Taenia foram detectados com a mesma frequência em pacientes com BOC e em pacientes sem BOC / Introduction: The frequency of oligoclonal bands (OCB) detection in patients with multiple sclerosis (MS) in the city of São Paulo is significantly lower than in other cities of Brazil and other countries, mainly Europe and North America. To date, the reason for its occurrence is still unknown. One of the most interesting hypotheses related to the immunopathogenesis of MS is the so-called Hygiene Hypothesis, which postulates an inverse relationship between the prevalence of parasitic infections and the frequency of MS. Objective: This study examined whether there is a relationship between the occurrence of antibodies against parasites in blood serum and the detection of OCB in patients diagnosed with MS in the city of São Paulo. Methods: We have studied 164 patients from the Demyelinating Diseases Clinic of the Division of Clinical Neurology and Division of Anesthesia Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo from whom CSF and serum samples were obtained and which were used to conduct the present study. These patients were divided into 4 groups: MS, Clinically Isolated Syndrome (CIS), control group with patients with Inflammatory Neurologic Diseases (IND) and Control Group with patients without neurologic complaints, in whom the presence of OCB and anti- parasitic antibodies was identified. For the detection of parasitic antibodies, the unidimensional electrophoresis of proteins in polyacrylamide gel in a batch system with LV-Tcra antigens (Taenia crassiceps vesicular fluid) and ES-Tcra (net excretion / secretion of Taenia crassiceps) was used. Results: Of the 164 patients studied, separated into their respective groups, anti- parasite antibodies of low and high molecular weight were analyzed. A total of 103 patients presented no OCB, and of these, 2 had antibodies of low molecular weight and 59 presented antibodies of high molecular weight. Of the 61 patients with OCB positive, one showed antibodies of low molecular weight and 16 antibodies of high molecular weight. Conclusion: This study showed that in patients with clinically established MS. anti-Taenia antibodies occurred with the same frequency in patients with OCB and in patients without OCB