Dissertations / Theses on the topic 'Environmental risk factors'

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2006.
Title from first page of PDF file (viewed July 10, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.

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.

Parkinson's disease (PD) is a progressive, degenerative, neurological disease. The progressive disability associated with PD results in substantial burdens for those with the condition, their families and society in terms of increased health resource use, earnings loss of affected individuals and family caregivers, poorer quality of life, caregiver burden, disrupted family relationships, decreased social and leisure activities, and deteriorating emotional well-being. Currently, no cure is available and the efficacy of available treatments, such as medication and surgical interventions, decreases with longer duration of the disease. Whilst the cause of PD is unknown, genetic and environmental factors are believed to contribute to its aetiology. Descriptive and analytical epidemiological studies have been conducted in a number of countries in an effort to elucidate the cause, or causes, of PD. Rural residency, farming, well water consumption, pesticide exposure, metals and solvents have been implicated as potential risk factors for PD in some previous epidemiological studies. However, there is substantial disagreement between the results of existing studies. Therefore, the role of environmental exposures in the aetiology of PD remains unclear. The main component of this thesis consists of a case-control study that assessed the contribution of environmental exposures to the risk of developing PD. An existing, previously unanalysed, dataset from a local case-control study was analysed to inform the design of the new case-control study. The analysis results suggested that regular exposure to pesticides and head injury were important risk factors for PD. However, due to the substantial limitations of this existing study, further confirmation of these results was desirable with a more robustly designed epidemiological study. A new exposure measurement instrument (a structured interviewer-delivered questionnaire) was developed for the new case-control study to obtain data on demographic, lifestyle, environmental and medical factors. Prior to its use in the case-control study, the questionnaire was assessed for test-retest repeatability in a series of 32 PD cases and 29 healthy sex-, age- and residential suburb-matched electoral roll controls. High repeatability was demonstrated for lifestyle exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). The majority of environmental exposures, including use of pesticides, solvents and exposure to metal dusts and fumes, also showed high repeatability (kappas >0.78). A consecutive series of 163 PD case participants was recruited from a neurology clinic in Brisbane. One hundred and fifty-one (151) control participants were randomly selected from the Australian Commonwealth Electoral Roll and individually matched to the PD cases on age (± 2 years), sex and current residential suburb. Participants ranged in age from 40-89 years (mean age 67 years). Exposure data were collected in face-to-face interviews. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets in SAS version 9.1. Consistent with previous studies, ever having been a regular smoker or coffee drinker was inversely associated with PD with dose-response relationships evident for packyears smoked and number of cups of coffee drunk per day. Passive smoking from ever having lived with a smoker or worked in a smoky workplace was also inversely related to PD. Ever having been a regular tea drinker was associated with decreased odds of PD. Hobby gardening was inversely associated with PD. However, use of fungicides in the home garden or occupationally was associated with increased odds of PD. Exposure to welding fumes, cleaning solvents, or thinners occupationally was associated with increased odds of PD. Ever having resided in a rural or remote area was inversely associated with PD. Ever having resided on a farm was only associated with moderately increased odds of PD. Whilst the current study's results suggest that environmental exposures on their own are only modest contributors to overall PD risk, the possibility that interaction with genetic factors may additively or synergistically increase risk should be considered. The results of this research support the theory that PD has a multifactorial aetiology and that environmental exposures are some of a number of factors to contribute to PD risk. There was also evidence of interaction between some factors (eg smoking and welding) to moderate PD risk.

Parkinson's disease (PD) is a progressive, degenerative, neurological disease. The progressive disability associated with PD results in substantial burdens for those with the condition, their families and society in terms of increased health resource use, earnings loss of affected individuals and family caregivers, poorer quality of life, caregiver burden, disrupted family relationships, decreased social and leisure activities, and deteriorating emotional well-being. Currently, no cure is available and the efficacy of available treatments, such as medication and surgical interventions, decreases with longer duration of the disease. Whilst the cause of PD is unknown, genetic and environmental factors are believed to contribute to its aetiology. Descriptive and analytical epidemiological studies have been conducted in a number of countries in an effort to elucidate the cause, or causes, of PD. Rural residency, farming, well water consumption, pesticide exposure, metals and solvents have been implicated as potential risk factors for PD in some previous epidemiological studies. However, there is substantial disagreement between the results of existing studies. Therefore, the role of environmental exposures in the aetiology of PD remains unclear. The main component of this thesis consists of a case-control study that assessed the contribution of environmental exposures to the risk of developing PD. An existing, previously unanalysed, dataset from a local case-control study was analysed to inform the design of the new case-control study. The analysis results suggested that regular exposure to pesticides and head injury were important risk factors for PD. However, due to the substantial limitations of this existing study, further confirmation of these results was desirable with a more robustly designed epidemiological study. A new exposure measurement instrument (a structured interviewer-delivered questionnaire) was developed for the new case-control study to obtain data on demographic, lifestyle, environmental and medical factors. Prior to its use in the case-control study, the questionnaire was assessed for test-retest repeatability in a series of 32 PD cases and 29 healthy sex-, age- and residential suburb-matched electoral roll controls. High repeatability was demonstrated for lifestyle exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). The majority of environmental exposures, including use of pesticides, solvents and exposure to metal dusts and fumes, also showed high repeatability (kappas >0.78). A consecutive series of 163 PD case participants was recruited from a neurology clinic in Brisbane. One hundred and fifty-one (151) control participants were randomly selected from the Australian Commonwealth Electoral Roll and individually matched to the PD cases on age (± 2 years), sex and current residential suburb. Participants ranged in age from 40-89 years (mean age 67 years). Exposure data were collected in face-to-face interviews. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets in SAS version 9.1. Consistent with previous studies, ever having been a regular smoker or coffee drinker was inversely associated with PD with dose-response relationships evident for packyears smoked and number of cups of coffee drunk per day. Passive smoking from ever having lived with a smoker or worked in a smoky workplace was also inversely related to PD. Ever having been a regular tea drinker was associated with decreased odds of PD. Hobby gardening was inversely associated with PD. However, use of fungicides in the home garden or occupationally was associated with increased odds of PD. Exposure to welding fumes, cleaning solvents, or thinners occupationally was associated with increased odds of PD. Ever having resided in a rural or remote area was inversely associated with PD. Ever having resided on a farm was only associated with moderately increased odds of PD. Whilst the current study's results suggest that environmental exposures on their own are only modest contributors to overall PD risk, the possibility that interaction with genetic factors may additively or synergistically increase risk should be considered. The results of this research support the theory that PD has a multifactorial aetiology and that environmental exposures are some of a number of factors to contribute to PD risk. There was also evidence of interaction between some factors (eg smoking and welding) to moderate PD risk.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007.
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on September 19, 2007) Vita. Includes bibliographical references.

Thesis (Ph.D.)--Boston University
Gastroschisis is a rare congenital malformation where loops of bowel are protruding from the abdominal wall of an infant. The prevalence of gastroschisis has been increasing over the past 20 years, particularly in younger women. However, as the number of studies on gastroschisis increases each year, it continues to remain unclear why the prevalence is increasing and why it disproportionately affects younger mothers. Previous research has suggested that environmental or infectious factors may be involved in the pathogenesis of gastroschisis. This dissertation aims to explore the possibility of these two factors in relation to gastroschisis. In study 1, clusters of gastroschisis were identified in space or the combination of space and time. Cases and controls came from the National Birth Defects Study (NBDPS) or for some study centers from the birth defects surveillance systems. Generalized additive models were used to create a continuous map surface of odds ratios (OR) by smoothing over latitude and longitude. Data from the NBDPS were used for the Arkansas, California, and Utah study centers and the highest adjusted ORs detected were 2.0, 1.3, and 2.4, respectively. In Massachusetts and Texas, where surveillance data were used, the highest adjusted ORs observed were 2.4 and 1.3, respectively, with only the latter state achieving statistical significance. Texas had sufficient data to assess the combination of space and time, which identified an increased risk (OR=2.9) in the center of Texas in 2003. The results of this study suggest that clusters of gastroschisis may exist and further exploration of environmental or behavioral factors are warranted. [TRUNCATED]

Contexte : Le neuroblastome est une tumeur embryonnaire qui se développe à partir du système nerveux sympathique. C’est la tumeur maligne solide extra-cérébrale la plus fréquente chez les enfants de moins d’un an. La cause du neuroblastome est encore inconnue dans la majorité des cas. Cependant, les caractéristiques embryonnaires de la tumeur ainsi que sa courte latence de survenue après la naissance suggèrent l’origine périnatale de ce cancer et l’importance d’étudier les expositions survenant pendant la grossesse et les premières années de vie de l’enfant. Dans ce travail de recherche, nous avons analysé le lien entre certains facteurs périnataux et des expositions pendant la grossesse et le risque neuroblastome chez l’enfant. Matériel et méthodes : les données sont issues des enquêtes ESCALE (2003-2004) et ESTELLE (2010-2011) menées par notre équipe de recherche. Les mères de 357 cas de neuroblastome issus du Registre National des Cancers de l’Enfant (RNCE) ainsi que 1753 témoins recrutés en population générale ont répondu à un entretien qui portait sur les caractéristiques périnatales de l’enfant, les expositions maternelles pendant la grossesse, antécédents médicaux familiaux et personnels de l’enfant ainsi que sur des variables contextuelles et socioéconomiques. La taille de notre échantillon a permis de réaliser des analyses stratifiées sur l’âge au diagnostic et le statut du proto-oncogène MYCN. Résultats : une première analyse sur l’association entre les caractéristiques périnatales et le risque de neuroblastome chez l’enfant a mis en évidence des associations positives avec la présence de malformations congénitales (OR 3.6 [95% CI 1.3–8.9] parmi les enfants de moins de 18 mois) et des altérations de la croissance fœtale tels que le retard de croissance intra-utérine ou la surcroissance fœtale (OR 1.4 [95% CI 1.0-2.0]) et (OR 1.5 [95% CI 1.1–2.2], respectivement). Le fait d’être allaité était inversement associé au risque de neuroblastome (OR 0.7 [95% CI 0.5–1.0]). Des associations inverses ont été également observées avec la supplémentation maternelle préconceptionnelle en acide folique (OR 0.5 [95% CI 0.3–0.9]). La difficulté pour concevoir ou l’utilisation d’assistance médicale à la procréation n’ont pas été associé au risque de neuroblastome dans notre étude. Dans une deuxième partie de ce travail, nous avons analysé les expositions maternelles domestiques et professionnelles aux pesticides pendant la grossesse. Nos résultats suggèrent que l’utilisation domestique de pesticides pendant la grossesse pourrait augmenter le risque de neuroblastome chez l’enfant (OR 1.5 [95% CI 1.2–1.9]). Des associations positives ont été observées avec l’utilisation d’insecticides seulement (OR 1.4 [95% CI 1.1–1.9]), ou en combinaison avec d’autres pesticides (OR 2.0 [95% CI 1.1–3.4]). L’exposition professionnelle de la mère pendant la grossesse était également associée au risque de neuroblastome. La troisième partie de ce travail a porté sur l’analyse du tabagisme parental et la consommation maternelle d’alcool pendant la grossesse. La consommation maternelle de tabac était plus fréquente chez les mères des cas (24.1%) par rapport aux mères des témoins (19.7%) ; (OR 1.3 [95%CI 0.9–1.7]; OR à partir d’une méta-analyse 1.1 [95%CI 1.0–1.3]. Conclusion : nos résultats portant sur les associations entre neuroblastome, surcroissance fœtale et malformations congénitales supportent l’hypothèse d’un rôle des altérations de l’embryogénèse dans la survenue des neuroblastomes de l’enfant. Ce travail contribue à l’évidence en faveur des associations entre neuroblastome et certaines expositions pendant la grossesse, notamment l’utilisation domestique de pesticides et le tabagisme maternelle. Nos résultats soulignent l’importance des recommandations visant à réduire l’exposition aux pesticides et le tabagisme maternel pendant la grossesse. [...]
Background: Neuroblastoma is the most common extra-cranial tumor in children. Little is known about the etiology of neuroblastoma. The early age at onset and the embryonic nature suggest a role for perinatal exposures. In this work, we analyzed whether childhood neuroblastoma was associated with specific perinatal characteristics and environmental exposures around pregnancy. We assessed the following birth-related characteristics: gestational age, birth-weight and fetal growth, and the presence of congenital malformations. The maternal reproductive history before the index pregnancy and maternal intake of folic acid or vitamins/minerals before or during pregnancy was also assessed. With regards to environmental exposures related to parental habits, we focused on maternal use of household pesticides during pregnancy, parental smoking and maternal alcohol consumption. Methods: We conducted a pooled analysis of two French national-based case-control studies. The mothers of 357 neuroblastoma case and 1,783 control children younger than 6 years, frequency-matched by age and gender, completed a telephone interview that focused on sociodemographic and perinatal characteristics, childhood environment and parental lifestyle. Unconditional logistic regression was used to estimate pooled odds ratios (OR) and 95% confidence intervals (CIs), including matching variables, study of origin and potential confounders. A meta-analysis of our findings with those of previous studies was also conducted with regards to maternal smoking and alcohol consumption during pregnancy. We used random effects, precision-based weighting to calculate the summary OR including our results. Results: The first part of the thesis focused on perinatal characteristics. We observed that being born either small (OR 1.4 [95% CI 1.0-2.0]) or large (OR 1.5 [95% CI 1.1–2.2]) for gestational age and, among children younger than 18 months, having congenital malformations (OR 3.6 [95% CI 1.3–8.9]), were significantly associated with neuroblastoma. Inverse associations were observed with breastfeeding (OR 0.7 [95% CI 0.5–1.0]) and maternal use of any supplements containing folic acid, vitamins or minerals (OR 0.5 [95% CI 0.3–0.9]) during the preconception period. The second part of the thesis showed that maternal use of any type of household pesticide during pregnancy was associated with neuroblastoma (OR 1.5 [95% CI 1.2–1.9]). The most commonly used type of pesticides were insecticides and there was a positive association with their use alone (OR 1.4 [95% CI 1.1–1.9]) or with other pesticides (OR 2.0 [95% CI 1.1–3.4]). In the third part, our analyses showed that maternal smoking during pregnancy was slightly more often reported for the cases (24.1%) than for the controls (19.7%) (OR 1.3 [95% CI 0.9–1.7]; Paternal smoking in the year before child’s birth was not associated with neuroblastoma as independent exposure (OR 1.1 [95%CI 0.9–1.4] but the association was stronger when both parents reported having smoked during pregnancy (OR 1.5 [95% CI 1.1–2.1]. Finally, in a meta-analysis of maternal smoking and neuroblastoma the summary OR from meta-analysis was 1.1 [95% CI 1.0–1.3]. Conclusions: Our findings support the hypothesis of a defective embryogenesis in neuroblastoma since fetal growth anomalies and congenital malformations were associated with an increased risk of neuroblastoma. This work also adds to the evidence of an association between neuroblastoma and some exposures during pregnancy, such as maternal use of household pesticides and maternal smoking, which are additional reasons why to advise pregnant women to limit these exposures in this period. Further investigations are needed to clarify the role of folic acid supplementation and breastfeeding, given their potential importance in neuroblastoma prevention

Case-control study or prevalent parkinsonism and PD cases in Grampian and Easter Ross, Scotland. Cases were defined using United Kingdom Parkinson's Disease Society Brain Bank clinical diagnostic criteria. Dementia, cerebrovascular and drug-induced cases were excluded. Age and gender-balanced controls were drawn from hospital outpatients and the community. Trained interviewers administered a questionnaire regarding lifestyle and occupation including solvent, pesticide and metal exposure (iron, copper, manganese). An occupational hygienist estimated metal exposures blind to disease status using a job exposure matrix modified by subjective exposure estimation. Lifetime occupational histories were classified by occupational (Dictionary of Occupational Titles) and industry (modified International Standard Industrial Classification. A follow-up postal study in Grampian enquired about tea and coffee consumption, anxiolytic, anti-depressant and hypnotic use and head injury. 202 cases and 420 controls were recruited between June 2000 and July 2002 (responsive rate 46.2%). Multiple logistic regression analyses showed first-degree family history of PD (OR 4.12, 95%CI 1.92-8.83) and pesticides ('high' exposure OR 1.69, 95% CI 1.06-2.69) were risk factors. Smoking was protective (OR 0.26, 95%CI 0.18-0.29) with an exposure-response relationship. Both occupational and industry coding systems showed non-significantly increased risks for 'agriculture'. The follow-up study response rate was 93% (149 cases, 305 controls). Tea and coffee consumption were not associated with PD. A positive association of use of psychoactive medication with PD was probably explained by their use after disease onset. A non-significantly increased association of head injury and PD was not supported by the follow-up postal study. First-degree family history of PD was associated with PD. Pesticide use was a risk factor for PD, whereas smoking was associated with reduced risk. The increased risk for agriculture may reflect pesticide use.

The central scientific objective of this thesis was to take a broad multidisciplinary approach to make use of the full potential information to battle EDs, utilizing an interactive and translational approach running from basic science through to the clinic. In our studies we assessed a.) clinical factors and comorbidity [namely substance use in EDs (Studies 1 to 3)], b.) psychosocial, behavioural and environmental correlates of EDs (Studies 4 to 7) and c.) treatment effectiveness of specific forms of ED interventions (Studies 8 to 9).

Our first line of investigation comprised Studies 1 to 3 and assessed the comorbidity of substance use in EDs. The results of these studies suggest that compared to healthy controls, substance use was higher in individuals with EDs (Studies 1 and 3), that the presence of a family history of alcohol dependence was associated with the comorbidity of EDs and substance use (Study 2) that substance use was particularly prevalent in patients with bulimic characteristics (Studies 1 to 3) and that EDs and substance abuse may represent expressions of a fundamental predisposition to addictive behaviour possibly related to the genetically influenced traits such as novelty seeking (Study 2). Furthermore, we revealed some significant differences for the specific forms of drugs in people with EDs (Studies 1 and 3), which emphasize the significance of assessing various drug types in EDs. Finally we also observed cross-cultural differences across various European countries in the prevalence of substance use in EDs and healthy controls (Study 3).

The second research area was labelled psychological, behavioural and environmental correlates of EDs. In our animal study (Study 4) we found that contextual conditioning of eating response was more effective when high than low density caloric food was used. This result indicates that animal models are useful for analyzing and identifying human-animal links in feeding related behaviours.

Studies 5 and 6 assessed which early individual and family eating patterns play a role in the development of EDs. Our findings agree with the growing body of research indicating that a variety of environmental and social factors are associated with dysfunctional individual and family eating patterns (e.g. food used as individualization, control and rules about food) during the first years of life and which if not detected on time could lead to a subsequent ED. Conversely, healthy eating (including eating breakfast) was negatively linked to the development of a subsequent ED. Only a few differences across ED subtypes were observed. Finally some cross-cultural differences also emerged (Study 6).

In Study 7 we compared anger expressions in individuals with EDs and healthy controls and explored the relation among ED symptoms, comorbid psychopathology, personality traits and impulsive behaviours. The results indicated that individuals with EDs obtained significantly higher scores than controls on maladaptive anger expressions. When different purging methods were assessed independently, the frequency of laxative use was associated with anger suppression. ED symptoms and specific personality traits were also positively associated to different anger expressions. At last, we observed that inappropriate anger expressions were related to self-harming behaviours.

Finally our last research line assessed the effectiveness of various treatments for EDs. In Study 8 we compared full and subthreshold BN in terms of personality, clinical characteristics and short-term response to a psychoeducational therapy. The results showed that full-BN and sub-BN share common psychopathological symptoms and personality traits. Furthermore, no differences in therapy outcome were observed in terms of general ED symptomatology and psychopathology. In Study 9 we described and assessed a non-symptom oriented CBT treatment in a congenitally blind women. A dramatic reduction in ED symptoms was observed after the maintaining and triggering factors had been reduced.

To conclude, relatively little research has been performed towards understanding the aetiology of EDs. The findings from our investigations represent a major enhancement in the state of the art of EDs, and lead to the development of a new overall etiological model of EDs. The model we propose is a general understanding of how various ED predisposing and precipitating factors might eventually lead to EDs, and maintain the course of a disorder. Future work should address the effects of genes, environment and gene-environment interaction on the development and maintenance of EDs. Of specific interest is the query of which of these factors are non-specifically related to mental disorders and which factors may be more explicit factors that predispose an individual to EDs and related states, but not to mental disorders in general. The answers to these questions should hopefully become perceptible in the next couple of years.
El objetivo principal de esta tesis ha sido el abordar los Trastornos de la alimentación (TCA) desde una aproximación multidisciplinar, que nos ayude a combatir los TCA desde una perspectiva traslacional, en la que confluyan investigaciones básicas y aplicadas. En nuestros estudios hemos analizado en profundidad los siguientes aspectos: a.) Factores clínicos y comorbilidad [especialmente abuso de sustancias en TCA] (Estudios 1 a 3); b.) Correlatos psicosociales, conductuales y ambientales en TCA (Estudios 4 a 7); y c.) Eficacia de tratamientos específicos en TCA (Estudios 8 a 9).
Nuestra primera línea de investigación (Estudios 1-3), ha estudiado la comorbilidad de abuso de sustancias en TCA. Los resultados de estos estudios sugieren que: a) abuso de sustancias es más prevalente en TCA que en sujetos de control (Estudios 1 y 3); b) la presencia abuso de sustancias en pacientes con TCA, está asociada a historia familiar previa de dependencia de alcohol (Estudio 2); c) abuso de sustancias es especialmente prevalente en pacientes con características bulímicas (Estudios 1 a 3); y d) que presencia de abuso de sustancias en TCA puede ser expresión de una predisposición a conductas adictivas, cuya susceptibilidad viene determinada por rasgos de personalidad específicos (búsqueda de sensaciones) (Estudio 2). Asimismo, encontramos aspectos diferenciales en TCA, en base al tipo de droga que consumen (Estudio 1 y 3), hecho que enfatiza la importancia de evaluar los distintos tipos de drogas utilizados por estos pacientes. Finalmente, encontramos diferencias culturales entre distintos países europeos, respecto a la prevalencia de abuso de sustancias en TCA, al ser comparados con grupos de control (estudio 3).

Como segunda área de investigación, nos centramos en aspectos psicológicos, conductuales y ambientales en TCA. En un estudio, realizado siguiendo un modelo animal (estudio 4), encontramos que el condicionamiento contextual de respuesta alimentaria es más efectivo cuando es utilizado un alimento con alta densidad calórica, que cuando se utiliza un alimento con baja densidad calórica. Estos resultados sugieren qué modelos animales son útiles a la hora de analizar e identificar asociaciones entre comportamiento en humanos y animales, respecto a su conducta alimentaria.

En los estudios 5 y 6 se analizaron en qué medida conductas alimentarias tempranas y patrones alimentarios en la familia, influyen en la aparición posterior de un TCA. Los resultados de estos estudios sugieren, en concordancia con un creciente volumen estudios recientes, la influencia que poseen aspectos ambientales y sociales en el desarrollo posterior de una conducta alimentaria anormal (p.e., control y reglas entorno a la alimentación). Por contrario, patrones alimentarios regulares (p.e., desayunar antes de ir al colegio) se encontró negativamente asociado (factor protector) a subsecuente desarrollo de un TCA. Asimismo, fueron encontradas limitadas diferencias entre subtipos diagnósticos, aunque algunas hacían referencia al contexto cultural (estudio 6).

En el estudio 7 comparamos la expresión de ira en sujetos con un TCA y un grupo control, y analizamos su asociación con sintomatología alimentaria, psicopatología general comórbida, rasgos de personalidad y conductas impulsivas. Nuestros resultados indicaron que pacientes con TCA manifestaban sentimientos de ira de forma más inadecuada que grupos control. Al analizar los distintos procedimientos de purga, la frecuencia de abuso de laxantes iba asociada a supresión de sentimientos de ira.
La sintomatología alimentaria y algunos rasgos de personalidad se asociaban a determinadas formas inadecuadas de expresión de sentimientos. Asimismo, observamos que una inadecuada expresión de sentimientos en TCA se asociaba con una mayor frecuencia de conductas autoagresivas.

Finalmente, en nuestra última línea de investigación analizamos la eficacia de distintos tipos de tratamiento en TCA. En el estudio 8 comparamos casos totales y parciales de Bulimia nerviosa, en base rasgos de personalidad, sintomáticas alimentaria, psicopatología general y respuesta a un tratamiento de carácter psicoeducativo. Los resultados indicaron que los casos totales y parciales de BN comparten similitudes sintomáticas, psicopatológicas y de personalidad. Asimismo, no se obtuvieron diferencias respecto a la respuesta al tratamiento entre ambos grupos de pacientes. En el estudio 9, describimos y evaluamos un tratamiento cognitivo-conductual no centrado en los síntomas alimentarios, en una paciente ciega. En este caso, fue constatada una drástica reducción de los síntomas alimentarios tras este tipo de tratamiento.

En conclusión, hasta el momento, existen escasas referencias en la literatura que sirvan para esclarecer los aspectos etiopatológicos implicados en TCA. Los resultados obtenidos en nuestras investigaciones ayudan sobre el conocimiento actual de TCA, y contribuyen al desarrollo de un nuevo modelo multimodal de entendimiento de éstos. El modelo que proponemos combina la interacción de diversos factores (predisponentes, precipitantes y mantenedores). Trabajos futuros deberían prestar atención a la relevancia que tienen factores genéticos, ambientales e interacción genes-ambiente, en el desarrollo y mantenimiento de los TCA. Un especial interés presenta la pregunta de cuáles de estos factores son específicos para trastornos mentales y cuáles los son para TCA de forma específica.
RESUM:

L'objectiu principal d'aquesta tesi ha estat l'abordar els Trastorns de la conducta alimentària (TCA) des d'una aproximació multidisciplinar, que ens ajudi a combatre'ls des d'una perspectiva traslacional, en la que conflueixin investigacions bàsiques i aplicades. En els nostres estudis hem analitzat en profunditat els següents aspectes: a.) Factors clínics i comorbilitat [especialment abús de substàncies en TCA] (Estudis 1 a 3); b.) Correlats psicosocials, conductuals i ambientals en TCA (Estudis 4 a 7); i c.) Eficàcia de tractaments específics en TCA (Estudis 8 a 9).

La nostra primera línia d'investigació (Estudis 1 a 3), ha estudiat la comorbilitat d'abús de substàncies en TCA. Els resultats d'aquests estudis suggereixen que: a) l'abús de substàncies és més prevalent en TCA que en subjectes control (Estudis 1 i 3); b) la presència d'abús de substàncies en pacients amb TCA, està associada a història familiar prèvia de dependència d'alcohol (Estudi 2); c) l'abús de substàncies és especialment prevalent en pacients amb característiques bulímiques (Estudis 1 a 3); i d) que la presència d'abús de substàncies en TCA pot ser expressió d'una predisposició a conductes addictives, la susceptibilitat de les quals ve determinada per trets de personalitat específics (recerca percaça de sensacions) (Estudi 2). Així mateix, trobem aspectes diferencials en TCA, en base al tipus de droga que consumeixen (Estudis 1 i 3), fet que emfatitza la importància d'avaluar els diferents tipus de drogues utilitzats per aquests pacients. Finalment trobem diferències culturals entre distints països europeus, respecte a la prevalença d'abús de substàncies en TCA, al ser comparats amb grups control (Estudi 3).

Com a segona àrea d'investigació, ens centrem en aspectes psicològics, conductuals i ambientals en TCA. En un estudi realitzat seguint un model animal (Estudi 4), trobem que el condicionament contextual de resposta alimentària és més efectiu quan s'utilitza un aliment amb alta densitat calòrica, que quan se'n utilitza un amb baixa densitat calòrica. Aquests resultats suggereixen que els models animals són útils a l'hora d'analitzar i identificar associacions entre comportament en humans i animals, respecte la seva conducta alimentària.

En els estudis 5 i 6 es varen analitzar fins a quin punt conductes alimentàries primerenques i patrons alimentaris en la família influeixen en l'aparició posterior d'un TCA. Els resultats d'aquests estudis suggereixen, en concordància amb un volum creixent d'estudis recents, la influència que tenen aspectes ambientals i socials en el desenvolupament posterior d'una conducta alimentària anormal (per exemple, control i normes entorn a l'alimentació). Tanmateix, patrons alimentaris regulars (per exemple, esmorzar abans d'anar a l'escola) estaven negativament associats (factor protector) al subseqüent desenvolupament d'un TCA. Així mateix, es varen trobar diferències limitades entre subtipus diagnòstics. Finalment, es varen trobar algunes diferències en relació al context sociocultural. (Estudi 6).

En l'estudi 7 vàrem comparar expressió d'ira en subjectes amb un TCA i un grup control, i vàrem analitzar la seva associació amb simptomatologia alimentària, psicopatologia general comòrbida, trets de personalitat i conductes impulsives. Els nostres resultats varen indicar que pacients amb TCA manifestaven sentiments d'ira de forma més inadequada que grups control. A l'analitzar els diferents procediments de purga, la freqüència d'abús de laxants anava associada a la supressió de sentiments d'ira.
La simptomatologia alimentària i determinats trets de personalitat, s'associaven a determinades formes inadequades d'expressió de sentiments. Així mateix, vàrem observar que una expressió inadequada de sentiments en TCA anava associada a una freqüència major de conductes autoagressives.

Finalment, en la nostra darrera línia d'investigació vàrem analitzar l'eficàcia de diferents tipus de tractament en TCA. En l'estudi 8 vàrem comparar casos totals i parcials de Bulímia nerviosa (BN), en base a trets de personalitat, simptomatologia alimentària, psicopatologia general i resposta a un tractament de caràcter psicoeducatiu. Els resultats varen indicar que els casos totals i parcials de BN, comparteixen similituds simptomatològiques, psicopatològiques i de personalitat. Així mateix, no es varen obtenir diferències respecte a la resposta del tractament entre ambdós grups de pacients. En l'estudi 9, vàrem descriure i avaluar un tractament cognitiu-conductual no centrat en els símptomes alimentaris, en una pacient cega. En aquest cas es va constatar una reducció dràstica dels símptomes alimentaris després d'aquest tipus de tractament.
Fins el moment, existeixen escasses referències en la literatura que serveixin per aclarir els aspectes etiopatogènics implicats en els TCAs.

Els resultats obtinguts en les nostres investigacions ajuden en el coneixement actual dels TCA i contribueixen al desenvolupament d'un nou model multimodal per la comprensió de la seva etiologia. El model que proposem combina la interacció de diversos factors (predisponents, precipitants i mantenidors). Els treballs futurs haurien de incidir en la rellevància que tenen els factors genètics, ambientals i la interacció d'ambdós, en el desenvolupament i manteniment dels TCA. És d'especial interès la qüestió de quins d'aquests factors són específics per trastorns mentals i quins ho són per TCA.

Risk factors and diagnosis in young people have been little explored, despite brain tumours (BT) is one of the most frequent tumour type in children and adolescents. The purpose of this doctoral thesis is to study 1) the clinical characteristics and symptoms of BTs in young people, based on the international MOBI-Kids case-control study; 2) a systematic review (SR) of the literature on risk of BTs in young people in relation to environmental factors; 3) the BT risk in relation to chemicals present in drinking water and to heavy metals. The analyses of clinical characteristics revealed that the vast majority of tumours were neuroepithelial (mostly gliomas), followed by embryonal tumours and meningiomas. Overall, the most frequent symptoms were headache, followed by focal neurological signs and symptoms, nausea/ vomiting and visual signs and symptoms, being a 4% of the cases asymptomatic. The average time of diagnosis tended to be short (median 1.42 months), though this varied according to tumour type, age and type of symptom. I found many studies that showed an association between environmental factors (including tobacco smoke, pesticides and diet, among other exposures) and BT risk in the SR. Because of methodological limitations however, the evidence about the role of these factors in the aetiology of this disease is still uncertain. Our analyses in relation to water chemicals showed ORs below 1 for exposures to THMs, and ORs above 1 for nitrate exposure, for both pre- and postnatal exposure periods, some statistically significant so. Our analyses of heavy metals showed ORs below 1for exposures to chromium. However, literature is scarce about this association. Overall, this thesis served to fill a gap in knowledge concerning 1) the clinical characteristics of BT in young people, useful to both clinical practice and aetiological research; 2) causes of this disease; 3) the role of heavy metals and ubiquitous chemicals in water. Further research needs on the aetiology and prevention of BTs in young people are provided.
Los factores de riesgo y el diagnóstico en los jóvenes han sido poco explorados, a pesar de que los tumores cerebrales (TC) son uno de los tipos de tumores más frecuentes en los niños y jóvenes. El propósito de esta tesis doctoral es el estudio de 1) de las características clínicas y los síntomas de los TC en los jóvenes, basados en el estudio internacional de casos y controles MOBI-Kids; 2) una revisión sistemática de la literatura sobre el riesgo de TC en jóvenes en relación con factores ambientales; 3) el riesgo de TC en relación con los productos químicos presentes en el agua potable y con los metales pesados. Los análisis de las características clínicas revelaron que la gran mayoría de los tumores eran neuroepiteliales (principalmente gliomas), seguidos de tumores embrionarios y meningiomas. En general, los síntomas más frecuentes fueron dolor de cabeza, seguido de signos y síntomas neurológicos focales, náuseas/ vómitos y problemas en la visión, siendo un 4% de los casos asintomáticos. El tiempo promedio de diagnóstico tendió a ser corto (mediana 1,42 meses), aunque esto varió según el tipo de tumor, la edad y el tipo de síntoma. Encontré muchos estudios que encontraron asociación entre los factores ambientales (incluido el humo del tabaco, los pesticidas y la dieta, entre otras exposiciones) y el riesgo de TC en la revisión sistemática. Sin embargo, debido a limitaciones metodológicas, la evidencia sobre el papel de estos factores en la etiología de esta enfermedad aún es incierta. Nuestros análisis en relación con los productos químicos del agua mostraron unos OR por debajo de 1 para exposiciones a THMs, y OR por encima de 1 para exposición a nitrato, tanto en períodos de exposición prenatales como postnatales, algunos estadísticamente significativos. Nuestros análisis de metales pesados mostraron ORs por debajo de 1 para la exposición al cromo. Sin embargo, la literatura es escasa sobre esta asociación. En general, esta tesis sirvió para llenar un vacío en el conocimiento sobre 1) las características clínicas de la TC en los jóvenes, útiles tanto para la práctica clínica como para la investigación etiológica; 2) causas de esta enfermedad; 3) el papel de los metales pesados y los químicos ubicuos en el agua. Se ha identificado la necesidad de realizar más investigaciones sobre la etiología y la prevención de las TC en los jóvenes.

The negative effects of hazardous substances and possible measures that can be taken are evaluated in the environmental risk analysis process, consisting of risk assessment, risk communication and risk management. Uncertainty due to lack of knowledge and natural variability are always present in this process. The aim of this thesis is to evaluate some tools as well as discuss the management of uncertainty and variability, as it is necessary to treat them both in a reliable and transparent way to gain regulatory acceptance in decision making. The catalytic effects of various metals on the formation of chlorinated aromatic compounds during the heating of fly ash were investigated (paper I). Copper showed a positive catalytic effect, while cobalt, chromium and vanadium showed a catalytic effect for degradation. Knowledge of the catalytic effects may facilitate the choice and design of combustion processes to decrease emissions, but it also provides valuable information to identify and characterize the hazard. Exposure factors of importance in risk assessment (physiological parameters, time use factors and food consumption) were collected and evaluated (paper II). Interindividual variability was characterized by mean, standard deviation, skewness, kurtosis and multiple percentiles, while uncertainty in these parameters was estimated with confidence intervals. How these statistical parameters can be applied was shown in two exposure assessments (papers III and IV). Probability bounds analysis was used as a probabilistic approach, which enables separate propagation of uncertainty and variability even in cases where the availability of data is limited. In paper III it was determined that the exposure cannot be expected to cause any negative health effects for recreational users of a public bathing place. Paper IV concluded that the uncertainty interval in the estimated exposure increased when accounting for possible changes in climate-sensitive model variables. Risk managers often need to rely on precaution and an increased uncertainty may therefore have implications for risk management decisions. Paper V focuses on risk management and a questionnaire was sent to employees at all Swedish County Administrative Boards working with contaminated land. It was concluded that the gender, age and work experience of the employees, as well as the funding source of the risk assessment, all have an impact on the reviewing of risk assessments. Gender was the most significant factor, and it also affected the perception of knowledge.
Negativa effekter orsakade av skadliga ämnen och möjliga åtgärder bedöms och utvärderas i en miljöriskanalys, som kan delas i riskbedömning, riskkommunikation och riskhantering. Osäkerhet som beror på kunskapsbrist samt naturlig variabilitet finns alltid närvarande i denna process. Syftet med avhandlingen är att utvärdera några tillvägagångssätt samt diskutera hur osäkerhet och variabilitet hanteras då det är nödvändigt att båda hanteras trovärdigt och transparent för att riskbedömningen ska vara användbar för beslutsfattande. Metallers katalytiska effekt på bildning av klorerade aromatiska ämnen under upphettning av flygaska undersöktes (artikel I). Koppar visade en positiv katalytisk effekt medan kobolt, krom och vanadin istället katalyserade nedbrytningen. Kunskap om katalytisk potential för bildning av skadliga ämnen är viktigt vid val och design av förbränningsprocesser för att minska utsläppen, men det är också ett exempel på hur en fara kan identifieras och karaktäriseras. Information om exponeringsfaktorer som är viktiga i riskbedömning (fysiologiska parametrar, tidsanvändning och livsmedelskonsumtion) samlades in och analyserades (artikel II). Interindividuell variabilitet karaktäriserades av medel, standardavvikelse, skevhet, kurtosis (toppighet) och multipla percentiler medan osäkerhet i dessa parametrar skattades med konfidensintervall. Hur dessa statistiska parametrar kan tillämpas i exponeringsbedömningar visas i artikel III och IV. Probability bounds analysis användes som probabilistisk metod, vilket gör det möjligt att separera osäkerhet och variabilitet i bedömningen även när tillgången på data är begränsad. Exponeringsbedömningen i artikel III visade att vid nu rådande föroreningshalter i sediment i en badsjö så medför inte bad någon hälsofara. I artikel IV visades att osäkerhetsintervallet i den skattade exponeringen ökar när hänsyn tas till förändringar i klimatkänsliga modellvariabler. Riskhanterare måste ta hänsyn till försiktighetsprincipen och en ökad osäkerhet kan därmed få konsekvenser för riskhanteringsbesluten. Artikel V fokuserar på riskhantering och en enkät skickades till alla anställda som arbetar med förorenad mark på länsstyrelserna i Sverige. Det konstaterades att anställdas kön, ålder och erfarenhet har en inverkan på granskningsprocessen av riskbedömningar. Kön var den mest signifikanta variabeln, vilken också påverkade perceptionen av kunskap. Skillnader i de anställdas svar kunde också ses beroende på om riskbedömningen finansierades av statliga bidrag eller av en ansvarig verksamhetsutövare.

Post-transplant lymphoproliferative disorders (PTLDs) represent a serious complication in solid organ transplantation and are the first cause of cancer related mortality in this population. Furtehrmore, lymphomatous PTLD in this setting is frequently extranodal, can behave more aggressively and tends to have a worse prognosis. Previous work addressing risk factors for PTLD have been based on data from large registries, lacking the detail required to address the role of individual maintenance immunosuppressant drugs, taken over time. Studies looking at genetic risk factors for PTLD have focused on cytokine gene polymorphisms, but have been limited by small size, heterogeneous case/control populations, or both. Given a viral aetiology and a key role of the immune system, we hypothesise that a susceptibility to immunosuppression might favour lymphomagenesis. Moreover, we raise the question whether individual IS drugs have a role on lymphomagenesis additional to imuunosuppression. The effect of the calcineurin inhibitors on the transformation of peripheral blood mononuclear cells (PBMCs) was explored using two panels of 10 markers and flow cytometry: one panel to characterise the emerging lymphoblasts and the other to characterise the T cell response. Chronic administration was explored in a model of spontaneously occurring lymphoma model in transgenic mice expressing CD40/LMP1. We show that in the early steps of lymphomagenesis, chronic exposure to the CNIs does not appear to have a role outside of inhibiting the T response. In the CD40/LMP1 mouse model, there is evidence that chronic cyclosporine treatment enhances lymphomagenesis. A T response in this model cannot be ruled out, however the profile of T lymphocyte splenic infiltrates does not appear to be explained solely T cell inhibition by cyclosporine. Finally, we performed a case control study with the aim to study the pharmacogenetics of drug response and showed polymorphisms in IL10 and IL2 associate with PTLD, as well as azathioprine, whose use as an immunosuppressant in transplantation has fortunately largely been replaced by newer antimetabolite
Les lymphomes post-transplantation (PTLD) sont les complications malignes les plus fréquentes de l’immunosuppression (IS) après les cancers cutanés, et présentent la première cause de mortalité et de perte du greffon due aux cancers chez les transplantés. De plus, les lymphomes posttransplantation peuvent se comporter de manière plus agressive avec un plus mauvais pronostic. L’EBV joue un rôle clef dans la physiopathologie de la majorité des PTLDs. Chez l’hôte immunocompétent, les lymphocytes T cytotoxiques (LTC) spécifiques de l’EBV empêchent la croissance des lymphocytes B porteurs de l’EBV, mais cette immunovigilance est abaissée lors d’une immunosuppression, qu’elle soit thérapeutique ou pathologique. Les études s’intéressant aux facteurs de risque des PTLD ont été effectuées sur des données issues de larges registres de transplantation et qui sont par nature insuffisamment détaillées pour étudier l’influence du maintien d’un traitement IS au cours de temps sur le risque de PTLD. Les études s’intéressant aux risques génétiques des PTLDs ont été focalisées sur les polymorphismes des gènes des cytokines, mais elles étaient limitées par l’effectif réduit et/ou l’hétérogénéité des populations cas et témoins. Etant donnée l’étiologie virale des PTLDs et le rôle important du système immunologique, nous avons émis l’hypothèse qu’une hypoactivité spontanée des protéines cibles et des éléments de leurs voies de signalisation, ou une hypersensibilité de ces protéines en réponse à l’effet des IS seraient à l’origine d’une immunosuppression trop intense et par conséquent favoriseraient la lymphomagénèse. De plus, ce travail tente de répondre à la question suivante: est-ce que certains IS ont une influence particulière sur la survenue des PTLD, indépendamment de leur effet sur le système immunitaire? L'effet des inhibiteurs de la calcineurine (ICN) sur la transformation des cellules sanguines mononuclées (PBMC) par l’EBV a été exploré avec deux panels de 10 marquages par cytométrie en flux : l’un pour caractériser les lymphoblastes émergents et l’autre pour caractériser la réponse T. L’effet de l’administration chronique de la ciclosporine a été exploré sur un modèle de lymphome spontanée chez la souris, exprimant le transgène CD40/LMP1. Nous montrons que les ICN ne semblent pas avoir de rôle autre que l’inhibition des LTC. Chez les souris CD40/LMP1, la ciclosporine produit une augmentation des lymphocytes B activés dans la rate. Le profil des infiltrations des lymphocytes T dans la rate ne semble pas être expliqué seulement par une inhibition de LTC par la ciclosporine. Finalement, une étude pharmacogénétique clinique de type cas-témoins a été effectuée, et montre que des polymorphismes des gènes IL10 et IL2 sont associés à la pathologie, ainsi que l’administration d’azathioprine, un médicament immunosuppresseur heureusement aujourd’hui largement abandonné en transplantation

Asthma is a common chronic disorder in Western countries and is increasing in prevalence in both children and adults. Although genetic risk for atopy is an important factor for the development of asthma, it does not explain the tremendous increase in prevalence seen in recent decades. Environmental exposures in early life that affect immune maturation appear to be the key factors for the development of asthma. The indoor environment is a likely candidate since infants spend 90% of the time indoors at a time when immune deviation usually occurs. Exposure to indoor pollutants represents a potentially modifiable cause of allergic sensitization and asthma. In this context, it becomes important to establish which environmental factors might influence the development of asthma in predisposed individuals. Allergic reactions to certain environmental allergens such as house dust mites, cats, and cockroaches, have shown a high level of association with asthma prevalence, but in the last five years increasing attention is being paid to indoor environmental factors, other than allergens, that may be involved in the development of this disorder. The potential irritants include nitrogen dioxide, environmental tobacco smoke, formaldehyde, volatile organic compounds, and particulate matter (PM[subscript]2.5;10).The aim of the study was to examine the nature of the relationship between asthma and environmental exposure to indoor environmental irritants.A population based case-control study had been carried out in Perth, Western Australia. The study population consisted of young children (N = 192) aged between 6 months and 3 years old. Cases (n = 88) were asthmatic children who attended the Accident and Emergency Department at Princess Margaret Hospital for Children and were discharged with asthma as a primary diagnosis. Controls (n = 104) were children in the same age group as cases who had never been diagnosed with asthma, identified from birth records accessed through the Health Department of Western Australia. Information, regarding the respiratory conditions experienced by the study children and characteristics of the home, was collected using a standardised questionnaire. The questionnaire consists of questions about potential risk factors for asthma and these factors were grouped in three categories. The first category included information on personal and social factors such as age and gender of the child, and mother's and father's educational level. The second category was related to personal susceptibility factors such as child's allergy, parental and sibling's asthma, eczema and hay fever. The last category included environmental exposure in the house such as parental and visitors smoking inside the house, exposure to gas heating and cooking, kerosene space heaters, open fireplaces, and pets. Other questions related to environmental exposure were the presence of air conditioning, humidifiers, and type of floor covering in the child's bedroom and the living room. Measurements of indoor nitrogen dioxide (NO[subscript]2), formaldehyde (HCHO), volatile organic compounds (VOCs), particulate matter (PM[subscript]10), and house dust mite exposure were made on two occasions over one year, winter (middle June through September 1998) and summer (December 1998 through March 1999), Indoor temperature and relative humidity were also measured. The atopic status of the children was assessed by skin prick tests to common allergens.The study results indicated that age, gender, family history of asthma, atopy and domestic exposure to indoor environmental factors were significant predictors of asthma early in life. The study found that indoor exposure to formaldehyde, volatile organic compounds and house dust mite significantly increased the risk of having asthma. Presence of air conditioning appeared to be a protective factor for asthma.In conclusion, the study results confirmed the role of susceptibility factors in asthma and show that indoor environmental factors contribute as risk factors for asthma in early stage of fife. The observation that exposure to indoor air pollutants in early childhood is associated with asthma suggests the possibility that irritants in indoor air might be involved in the initiation phase of asthma. Since the quality of the indoor environment is potentially modifiable there might be opportunities for intervention to reduce asthma symptoms. In order to counteract the increasing prevalence in asthma, the significance of the indoor environment where children grow and spend most of their time need to be given greater attention.

La malaltia cardiovascular, que és primera causa de mortalitat al món, com a fenotip complex depèn tant dels factors ambientals com dels genètics. Les variants genètiques comunes expliquen un 15-20% de l’heretabilitat de la malaltia. La metilació de l’ADN, que regula l’expressió gènica sense alterar la seqüència genètica primària, ha estat proposada com a mecanisme per unificar els efectes de l’estil de vida, els factors ambientals i els genètics. Per estudiar les relacions entre metilació de l’ADN i estil de vida, factors ambientals i factors de risc cardiovascular hem utilitzat estudis d’associació d’epigenoma complet, randomització mendeliana i integració d’òmiques. Hem inclòs dades de 10 estudis diferents, però els resultats han estat basats sobretot en l’estudi REGICOR (REgistre Gironí del COR). Aquesta tesi demostra l’associació entre 63 llocs de metilació (CpGs) i l’exposició al tabaquisme. No troba associació entre contaminació ambiental i metilació de l’ADN. Identifica 94 CpGs associats a obesitat i 14 als nivells lipídics. Observa que els nivells de triglicèrids en sang poden ser modificats i al mateix temps afectar la metilació en els gens CPT1A i SLC7A11, evidenciant la complexitat de l’homeostasis dels lípids. A més, s’ha realitzat el primer estudi que mostra l’associació entre la metilació de l’ADN i la funcionalitat de la HDL. Com a conclusions d’aquesta recerca destaquen la forta associació del tabac a un patró de metilació específic i l’associació entre la metilació de l’ADN i diferents factors de risc cardiovascular amb una relació causal complexa.
Coronary artery disease is the first cause of death worldwide, and as a complex disease implies the interplay between genetic and environmental factors. Common genetic variants explain only 15-20% of its heritability. DNA methylation, which regulates the gene expression without altering the DNA sequence, has been proposed as a heritable signature to explain this missing heritability and as a mediator effect of lifestyle and environment on health. To study the relationship between DNA methylation and smoking, air pollution, and cardiovascular risk factors (obesity, lipid profile, and HDL functionality) we used epigenome-wide association studies, Mendelian randomization, and multi-stage omics integration approaches. We included data from ten studies, but the results were mainly based on the REGICOR (REgistre GIroní del COR) cohort. We report the association between smoking and 63 methylation sites (CpGs). We did not find association between air pollution and DNA methylation. We identified 94 CpGs associated with obesity and 14 with lipid profile. We observed that methylation at CPT1A and SLC7A11 can modify or be affected by the triglycerides levels, highlighting the complexity of the lipids homeostasis. Finally, we performed the first study showing an association between DNA methylation and HDL functionality. As conclusions of this research, smoking is strongly associated with a distinctive methylation pattern and there is a relationship between DNA methylation and several cardiovascular risk factors, although its causality is complex.

Alzheimer's disease (AD) is probably caused by both genetic and environmental risk factors. The major genetic risk factor is the E4 variant of apolipoprotein E gene called apoE4. Several risk factors for developing AD have been identified including lifestyle, such as dietary habits. The mechanisms behind the AD pathogenesis and the onset of cognitive decline in the AD brain are presently unknown. In this study we wanted to characterize the effects of the interaction between environmental risk factors and apoE genotype on neurodegeneration processes, with particular focus on behavioural studies and neurodegenerative processes at molecular level. Towards this aim, we used 6 months-old apoE4 and apoE3 Target Replacement (TR) mice fed on different diets (high intake of cholesterol and high intake of carbohydrates). These mice were evaluated for learning and memory deficits in spatial reference (Morris Water Maze (MWM)) and contextual learning (Passive Avoidance) tasks, which involve the hippocampus and the amygdala, respectively. From these behavioural studies we found that the initial cognitive impairments manifested as a retention deficit in apoE4 mice fed on high carbohydrate diet. Thus, the genetic risk factor apoE4 genotype associated with a high carbohydrate diet seems to affect cognitive functions in young mice, corroborating the theory that the combination of genetic and environmental risk factors greatly increases the risk of developing AD and leads to an earlier onset of cognitive deficits. The cellular and molecular bases of the cognitive decline in AD are largely unknown. In order to determine the molecular changes for the onset of the early cognitive impairment observed in the behavioural studies, we performed molecular studies, with particular focus on synaptic integrity and Tau phosphorylation. The most relevant finding of our molecular studies showed a significant decrease of Brain-derived Neurotrophic Factor (BDNF) in apoE4 mice fed on high carbohydrate diet. Our results may suggest that BDNF decrease found in apoE4 HS mice could be involved in the earliest impairment in long-term reference memory observed in behavioural studies. The second aim of this thesis was to study possible involvement of leptin in AD. There is growing evidence that leptin has neuroprotective properties in the Central Nervous System (CNS). Recent evidence has shown that leptin and its receptors are widespread in the CNS and may provide neuronal survival signals. However, there are still numerous questions, regarding the molecular mechanism by which leptin acts, that remain unanswered. Thus, given to the importance of the involvement of leptin in AD, we wanted to clarify the function of leptin in the pathogenesis of AD and to investigate if apoE genotype affect leptin levels through studies in vitro, in mice and in human. Our findings suggest that apoE4 TR mice showed an increase of leptin in the brain. Leptin levels are also increased in the cerebral spinal fluid of AD patients and apoE4 carriers with AD have higher levels of leptin than apoE3 carriers. Moreover, leptin seems to be expressed by reactive glial cells in AD brains. In vitro, ApoE4 together with Amyloid beta increases leptin production by microglia and astrocytes. Taken together, all these findings suggest that leptin replacement might not be a good strategy for AD therapy. Our results show that high leptin levels were found in AD brains. These findings suggest that, as high leptin levels do not promote satiety in obese individuals, it might be possible that they do not promote neuroprotection in AD patients. Therefore, we hypothesized that AD brain could suffer from leptin resistance. Further studies will be critical to determine whether or not the central leptin resistance in SNC could affect its potential neuroprotective effects.

Asthma is a common chronic disorder in Western countries and is increasing in prevalence in both children and adults. Although genetic risk for atopy is an important factor for the development of asthma, it does not explain the tremendous increase in prevalence seen in recent decades. Environmental exposures in early life that affect immune maturation appear to be the key factors for the development of asthma. The indoor environment is a likely candidate since infants spend 90% of the time indoors at a time when immune deviation usually occurs. Exposure to indoor pollutants represents a potentially modifiable cause of allergic sensitization and asthma. In this context, it becomes important to establish which environmental factors might influence the development of asthma in predisposed individuals. Allergic reactions to certain environmental allergens such as house dust mites, cats, and cockroaches, have shown a high level of association with asthma prevalence, but in the last five years increasing attention is being paid to indoor environmental factors, other than allergens, that may be involved in the development of this disorder. The potential irritants include nitrogen dioxide, environmental tobacco smoke, formaldehyde, volatile organic compounds, and particulate matter (PM[subscript]2.5;10).The aim of the study was to examine the nature of the relationship between asthma and environmental exposure to indoor environmental irritants.A population based case-control study had been carried out in Perth, Western Australia. The study population consisted of young children (N = 192) aged between 6 months and 3 years old. Cases (n = 88) were asthmatic children who attended the Accident and Emergency Department at Princess Margaret Hospital for Children and were discharged with asthma as a primary diagnosis. Controls (n = 104) were children in the same age group as cases ++
who had never been diagnosed with asthma, identified from birth records accessed through the Health Department of Western Australia. Information, regarding the respiratory conditions experienced by the study children and characteristics of the home, was collected using a standardised questionnaire. The questionnaire consists of questions about potential risk factors for asthma and these factors were grouped in three categories. The first category included information on personal and social factors such as age and gender of the child, and mother's and father's educational level. The second category was related to personal susceptibility factors such as child's allergy, parental and sibling's asthma, eczema and hay fever. The last category included environmental exposure in the house such as parental and visitors smoking inside the house, exposure to gas heating and cooking, kerosene space heaters, open fireplaces, and pets. Other questions related to environmental exposure were the presence of air conditioning, humidifiers, and type of floor covering in the child's bedroom and the living room. Measurements of indoor nitrogen dioxide (NO[subscript]2), formaldehyde (HCHO), volatile organic compounds (VOCs), particulate matter (PM[subscript]10), and house dust mite exposure were made on two occasions over one year, winter (middle June through September 1998) and summer (December 1998 through March 1999), Indoor temperature and relative humidity were also measured. The atopic status of the children was assessed by skin prick tests to common allergens.The study results indicated that age, gender, family history of asthma, atopy and domestic exposure to indoor environmental factors were significant predictors of asthma early in life. The study found that indoor exposure to formaldehyde, volatile organic compounds and house dust mite significantly increased the risk of ++
having asthma. Presence of air conditioning appeared to be a protective factor for asthma.In conclusion, the study results confirmed the role of susceptibility factors in asthma and show that indoor environmental factors contribute as risk factors for asthma in early stage of fife. The observation that exposure to indoor air pollutants in early childhood is associated with asthma suggests the possibility that irritants in indoor air might be involved in the initiation phase of asthma. Since the quality of the indoor environment is potentially modifiable there might be opportunities for intervention to reduce asthma symptoms. In order to counteract the increasing prevalence in asthma, the significance of the indoor environment where children grow and spend most of their time need to be given greater attention.

The overall objective of the research presented in this dissertation was to investigate molecular risk factors of susceptibility to estrogenic chemicals, polychlorinated biphenyls (PCBs), hormone replacement therapy, and oral contraceptives and how that leads to the development of pulmonary arterial hypertension (PAH). Environmental and molecular risk factors for PAH are not clearly understood. This is a major hurdle for the development of new therapy against PAH as well as understanding individual susceptibility to this disease. Gender has been shown to impact the prevalence of PAH. Although controversial, estrogens have been implicated to be a risk factor for PAH. Thus, we hypothesize that women exposed to estrogenic chemicals are at increased risk of developing PAH when endocrine disrupting chemicals interact with unopposed estrogen to worsen pulmonary arterial disease. In support of this hypothesis, we have accomplished the following: Microarray data on PAH were collected and subsequent meta-analysis was conducted using genome-wide association and environment-wide association approaches on published studies as well as GEO and NHANES data. All PCB geometric mean concentrations found higher levels in people at risk of PAH than people not at risk of PAH. The sum of non-dioxin-like PCBs and the sum of dioxin-like PCBs were significantly higher in people at risk of PAH than people not at risk of PAH. Also, different levels of LOD (including PCBs concentration >LOD, > 50th percentile, 50th-75th percentile, and ≥75th percentile) were significantly higher in people at risk of PAH than people not at risk of PAH. We reported that females used estrogen pills and oral contraceptive were associated with risk of PAH. However, females used progestin and estrogen/progestin pills were not at risk of PAH. Molecular risk factor analysis using machine learning approaches revealed that VAMP2, LAMA5, POLR2C, VEGFB, and PRKCH genes are causal genes of PAH pathogenesis. Gene ontology and pathway analysis of PAH showed that genes involved in the apoptosis pathway, p53 pathway, Ras Pathway, T-cell activation, TGF-beta pathway, VEGF pathway, and Wnt pathway appear to be significantly associated with PAH. Documenting the exposure to estrogenic chemicals among the general U.S. population, and identifying agents and molecular risk factors associated with PAH have the potential to fill research gaps and facilitate our understanding of the complex role environmental chemicals play in producing toxicity in the lungs.

Thesis (Dr. of Education)--University of Cincinnati, 2009.
Advisor: Nancy A. Evers. Title from electronic thesis title page (viewed Aug. 12, 2009). Includes abstract. Keywords: at-risk; urban; academic self-efficacy. Includes bibliographical references.

The overall aims of our studies were to identify risk factors for respiratory symptoms and asthma in indoor environment but even to look at some personal risk factors such as body mass index and gastroesophageal reflux. The study population is based on participants of the European Community Respiratory Health Survey I and II.

In the first study, water damage and visible moulds were reported in 7.4% and 17% of the homes respectively. The combination of water damage and visible moulds was independently associated with attacks of breathlessness when resting and after activity and also to long term cough. In the second study, the prevalence of nocturnal GER increased with higher BMI and the same pattern could be seen for habitual snoring. Reported onset of asthma, wheeze and night-time symptoms increased in prevalence along with the BMI gradient. In the multivariable analysis, obesity and nocturnal GER were independent risk factors for onset of asthma, wheeze and night-time symptoms. Habitual snoring was an independent risk factor for onset of wheeze and night-time symptoms, but not for onset of asthma. In the third study, a total of 18% of the subjects reported indoor dampness in the last 12 months and 27% of the subjects reported indoor dampness since the previous survey. Respiratory symptoms and asthma were significantly more prevalent in individuals exposed to indoor dampness and indoor dampness was a risk factor for respiratory symptoms and asthma after adjusting for possible confounders. Indoor dampness was an independent risk factor for onset of respiratory symptoms but not for asthma onset. Remission of respiratory symptoms was less likely to occur if subjects reported indoor dampness. In the fourth study, the lowest prevalence of atopy and the lowest levels of all indoor allergens, bacteria and moulds were found in Iceland. A positive association was found, between cat allergen exposure and asthma symptoms and between bronchial hyperresponsiveness and the amount of viable mould in indoor air.

The aim of this work was to study the environmental and genetic factors for Parkinson???s disease (PD) in Chinese and Australian. Using a case-control method, environmental factors for PD were studied in a Chinese population (n=528) in Hong Kong. Current smoking (OR=0.437; p=0.013) and infrequent tea drinking (OR=1.51; p=0.02) were found to be protective factors, whereas family history and pesticide exposure during farming in females were found to be risk factors in the univariate analysis. In the multivariate analysis, current smoking reached borderline significance at the 5% level and the variables, years exposed to pesticides and family history were significant at the 10% level. Similarly, a case-control study involving 534 subjects was conducted in Australia. A positive family history was the strongest risk factor (OR=3.4; p<0.001). In addition, rural residency was found to be another risk factor (OR=1.8; p<0.001). Hypertension, stroke and well water ingestion were inversely correlated with PD (OR=0.2; p<0.001, OR=0.2; p<0.001 and OR=0.7; p<0.03 respectively). When genetic factors were examined in the Chinese population, no association to PD were found for the polymorphisms of the following candidate genes: CYP-2D6 debrisoquine hydroxyalse gene, dopamine transporter gene and monamine oxidase B (MAOB) gene. Furthermore, the Ala53Thr and Ala30Pro mutations of the alpha-synuclein gene were not found amongst this large Chinese population, indicating that variations of this gene are probably rare in Chinese. When candidate genes were studied amongst Caucasian Australians, the poor metaboliser genotype of CYP-2D6 was found to be weaky associated with PD (OR=1.36) in a meta-analysis. The length of the GT repeat alleles of MAOB gene were found to be significantly associated with PD (>188 base pair and 186 base pair) while angiotensin converting enzyme gene polymorphism was not found to be associated with PD. A pilot study was then conducted in Randwick, New South Wales to find out the latest prevalence of PD as well as putative risk factors in a random population. A validation study was carried out for a screening tool (questionnaire) for PD, which was then used for the main study. A total of 730 subjects were involved (527 in the community and 203 in institutions). The survey found that PD prevalence was between 3.6% and 4.9% (higher in aged care facilities). The putative risk factors positively identified were ???family history???(p<0.01) and ???exposure to chemicals at work or in surrounding environment??? (p<0.05). The age adjusted prevalence rate of PD revealed at least 42.5 % increase in the disease compared to 1966. We conclude that there may be an increase in the disease in Australia due to aging and other risk factors.

Both environmental and inherited risk factors make significant contributions to coronary artery disease, however susceptibility and age of disease onset for individuals with similar risk profiles varies widely. Novel biomarkers may yet be found which could improve detection of high-risk individuals, and highlight new areas of research for treatment discovery. This thesis explores risk factors for coronary artery disease and cardiovascular mortality. The first study investigates one specific environmental variable—neighbourhood socioeconomic status—in a cohort of patients who underwent selective coronary angiography. In patients with coronary artery disease, neighbourhood-level disparities contributed to risk of non-cardiovascular mortality, particularly to deaths from cancer, but did not influence cardiovascular mortality risk. Although disparities in health and access to care may persist, these findings suggest other risk factors should be explored to improve cardiovascular patient risk assessment. Inflammation and oxidative stress contribute to all stages of atherosclerosis, and subsequent chapters focus on contributions of these pathways to cardiovascular risk. Interleukin-6 and C-reactive protein haplotypes were compared to plasma concentrations for prediction of coronary artery disease and cardiovascular mortality. Significant relationships observed between haplotypes, plasma concentrations, angiographic disease, and cardiovascular mortality did not demonstrate causality, which underscores the challenge of distinguishing causal from confounding pathways. Plasma oxidative stress biomarkers were measured to evaluate their utility for risk prediction, compared to conventional cardiovascular risk factors. Elevated plasma myeloperoxidase predicted coronary artery disease and cardiovascular mortality risk, independent of conventional risk factors and disease severity. Polymorphisms in candidate oxidative stress genes were also explored for associations with coronary artery disease, and effects on plasma biomarkers. A compound genotype of five polymorphisms predicted angiographic coronary artery disease and elevations in plasma myeloperoxidase. Following validation, these polymorphisms may be useful markers of lifetime oxidative stress burden and cardiovascular disease risk. Novel cardiovascular risk markers are explored in this thesis, and tested for association with angiographic coronary artery disease, conventional risk factors, and risk of mortality. New questions are raised regarding how disease susceptibility is influenced by environmental and inherited factors, and ideas for future research are discussed.

BACKGROUND: Asthma prevalence in African children is high and increasing, with more severe disease than that in high income countries. Specific factors driving the rising prevalence or disease severity are poorly understood. The aim of this study was to investigate environmental factors associated with asthma and severity in African children using data obtained from International Study of Asthma and Allergies in Childhood, (ISAAC) III. METHODS: A population based cross-sectional study of children aged 13-14 years from 10 African centres who participated in ISAAC III from randomly selected schools. The prevalence of asthma or severe asthma was calculated for each centre. Self-reported environmental exposures included engaging in physical exercise, television watching, biomass and ETS exposure, consumption of paracetamol, large family sizes and having pets in the home. Univariable and multivariable analyses were done adjusting for centre variations. Odds ratio and respective 95% confidence intervals (CI) were calculated. RESULTS: Amongst 28490 adolescents from 232 schools in 10 African centres (4 middle income and 6 low income), the prevalence of asthma was 12.8% (CI 12.4-13.2), while prevalence of severe disease was 8.7% (CI 8.4-8.0). Factors most strongly associated with asthma were maternal smoking (OR= 1.41; 95% CI: 1.23 - 1.64), exposure to open fire heating (OR=1.28; 95% CI: 1.08 - 1.51) and electric heating (OR=1.13; 95% CI: 1.01 - 1.28), engaging in strenuous exercise (OR= 1.29; 95% CI: 1.11 - 1.50 and monthly use of paracetamol (OR 1.23; 95% CI 1.13 - 1.33, while having an elder sibling was protective for asthma (OR=0.87; 95% CI 0.77 – 0.98). Factors strongly associated with severe asthma were maternal smoking (OR=1.61; 95% CI: 1.38 - 1.89), having a cat pet at home (OR=1.14; 95% CI: 1.04 - 1.25), engaging in≥3 weekly physical exercise (OR=1.42; 95% CI: 1.23 - 1.64) and monthly consumption of paracetamol (OR=1.20; 95% CI: 1.07 - 1.34). CONCLUSION: There was a high prevalence of severe asthma in African children. Several environmental exposures were associated with asthma or with severe disease. Strategies to reduce harmful environmental exposures must be strengthened to reduce the burden of childhood asthma in Africa.

Teenage pregnancy is both a social and a public health problem in the United States, with approximately 750,000 young women between the ages of 15 and 19 becoming pregnant each year. In addition, teen pregnancy is more prevalent in the African American (15%) and Hispanic (14%) communities than it is in White communities (5%). The purpose of this study was to identify risk factors contributing to teen pregnancy among racially diverse teenagers 15 to 19 years of age living in the rural south. This study, guided by social cognitive theory, used a quantitative, cross-sectional research design to determine whether living environment, educational resources, and access to healthcare impact risk of teenage pregnancy. A quantitative survey assessed factors such as sex-related attitudes, parent/peer communication, living environment, and educational attainment. Two primary research questions and 8 related hypotheses were formulated for investigation. Using binary logistic regression, the data in this study revealed that an increase in positive environmental factors (household income and parental education) and an increase in positive personal factors (parental/peer communication, teen's academic achievement, and attitudes toward sex) decreased negative behaviors (risks of teen pregnancy). This study may promote positive social change by providing information on relevant social and educational factors to those responsible for the design of comprehensive pregnancy prevention programs that target at-risk teenagers. Provision of comprehensive social and health services to teenage parents and their children may help to reduce rates of first-time and repeat teenage pregnancies and thus prevent the negative social consequences of these pregnancies.

Postpartum depression is a serious mental illness with onset of symptoms appearing anytime within the first four months after delivery (e.g. irritability, severe sadness, profound feelings of hopelessness, etc.). Environmental toxicants are synthetic (i.e. manufactured) or naturally found chemicals that are not produced by organisms as a result of cellular metabolism (e.g. tobacco smoke, pesticides, etc.). There is limited consideration for how exposure to environmental toxicants can create adverse psychological health effects, specifically postpartum depression. The purpose of this systematic review was to determine if the literature supports a link between exposure to environmental toxicants during the prenatal/perinatal period and postpartum depression and if so, to identify whether there are specific classes of toxicants that provide a higher risk for postpartum depression. Several databases were used to search the online literature, with the following inclusion criteria: articles published in English, publication years between 1995-2018, and with women of reproductive age (15-49 years old). The article selection process comprised of screening each article by title/abstract, followed by screening those articles based on full-text. Six categories of toxicants were identified among the thirty included articles. Active/passive smoke exposure was largely found to increase the risk of developing postpartum depression; dietary supplements provided mixed results; antidepressants demonstrated preventative effects; particulate air pollution was found to be associated with postpartum depression; oral contraceptives (DMPA) exhibited an increase in postpartum depressive symptoms; and organochlorine pesticides had no associative risk. Quality assessments were performed for all of the included articles, with the majority being assessed as satisfactory. This systematic review presents as a foundation for encouraging future research to investigate the link between environment and mental health, in order to attain a greater perspective.

This thesis examined associations between ecological indicators of residential radon and fine particulate matter air pollution (PM2.5) and lung cancer mortality using data from the American Cancer Society Cancer Prevention Study-II (CPS-II) prospective cohort. Nearly 1.2 million CPS-II participants were recruited in 1982. Mean county-level residential radon concentrations were linked to study participants according to ZIP code information at enrollment (mean (SD) = 53.5 (38.0) Bq/m3). Cox proportional hazards regression models were used to obtain adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer mortality associated with radon. After necessary exclusions, a total of 811,961 participants in 2,754 counties were retained for analysis. A significant positive linear trend was observed between categories of radon concentrations and lung cancer mortality (p = 0.02). A 15% (95% CI 1 - 31%) increase in the risk of lung cancer mortality was observed per each 100 Bq/m3 radon. Radon was also positively associated with chronic obstructive pulmonary disease mortality (HR per each 100 Bq/m3 = 1.13, 95% CI 1.05 - 1.21). No clear associations were observed between radon and non-respiratory mortality. In lifelong never smokers (n = 188,699), each 10 µg/m3 increase in mean metropolitan statistical area PM2.5 concentrations was associated with a 15-27% increase in the risk of lung cancer death which strengthened among individuals with a history of asthma or any prevalent chronic lung disease at enrollment (p for interaction < 0.05). There was no association between PM2.5 and mortality from non-malignant respiratory disease. In conclusion, this thesis observed significant positive associations between ecological indicators of residential radon and PM2.5 concentrations and lung cancer mortality. These findings further support efforts to reduce radon concentrations in homes to the lowest possible level and strengthens the evidence that ambient concentrations of PM2.5 measured in recent decades are associated with small but measurable increases in lung cancer mortality. Further research is needed to better understand possible complex inter-relationships between environmental risk factors, chronic lung disease, and lung cancer.

A survey of perceptions of health risk was conducted on 297 randomly selected residents of Akwesasne, a Mohawk community of approximately 13,000 citizens, straddling the border between Canada and the United States. The survey was conducted to understand how residents of Akwesasne perceive different types of health risks, and how attitudes about such risks are formed. Survey questions focused on association to the words risk and health, ranking of health hazards present in the community, sources of information on health risks, confidence in organizations and agencies responsible for health risk management, and a series of questions on risk related attitudes and behaviours. The survey demonstrated higher perceptions of risk among older as compared to younger respondents, and among women as compared to men. The media represented the primary source of information on risk, followed by traditional healers, although traditional healers were perceived as being more credible than the media.

AD is the most common age related neurodegenerative disease in the industrialized world. Clinically AD is defined as a progressing decline of cognitive functions. Neuropathologically, AD is characterized by the aggregation of b-amyloid (Ab) peptide in the form of extracellular senile plaques, and hyperphosphorlylated tau protein in the form of intracellular neurofibrillary tangles. These neuropathological hallmarks are often accompanied by abundant microvascular damage and pronounced inflammation of the affected brain regions. In this thesis we investigated several aspects of AD focusing on the genetic aspect. We confirmed that Alpha 1 antichymotrypsin (ACT), an acute phase protein, was associated to AD subjects, being plasma levels higher in AD cases than controls. In addition, in a GWA study we demonstrated that two different gene, Clusterin and CR1 were strongly associated to AD. A single gene association not explain such a complex disease like AD. The goal should be to created a network of genetic, phenotypic and clinical data associated to AD. We used a new algorithm, the ANNs, aimed to map variables and search for connectivity among variables. We found specific variables associated to AD like cholesterol levels, the presence of variation in HMGCR enzyme and the age. Other factors such as the BMI, the amount of HDL and blood folate levels were also associated with AD. Pathogen infections, above all viral infections, have been previously associated to AD. The hypothesis suggests that virus and in particular herpes virus could enter the brain when an individual becomes older, perhaps because of a decline in the immune system. Our new hypothesis is that the presence of SNPs in our GWA gene study results in a genetic signature that might affect individual brain susceptibility to infection by herpes virus family during aging.

This thesis reports research undertaken to better understand the factors that influence norovirus (NoV) contamination in shellfish production areas (SPAs). This knowledge is necessary to develop control measures for mitigating risk from NoV contamination in SPAs. Predictive models were developed for concentrations of NoV (as measured by the reverse transcription polymerase chain reaction method) and Escherichia coli (as measured by the culture method) in shellfish from 31 harvesting sites and climatic, hydrometric, demographic and pollution source-related characteristics of upstream river catchments. Concentrations of NoV in shellfish increased as water temperature decreased and volume of sewage discharges and river flows increased. Concentrations of E. coli increased as rainfall also increased. Field studies were conducted in an estuary and in a coastal embayment to inform risk management measures for these sites. Concentrations of NoV and E. coli and their removal efficiencies were quantified in effluents from primary, secondary and tertiary treatments at four sewage treatment works. Shellfish were placed at different distances downstream of sewage discharges and tested for NoV and E. coli. Dye tracing and drogue tracking studies were conducted to quantify the dispersion and dilution of sewage effluents. Significant NoV reductions were found as sewage treatment levels increased. Activated sludge was more effective in reducing NoV than trickling filters. Norovirus was frequently detected in sewage effluents and in shellfish. It was found that a NoV limit for shellfish established at 100 copies/g would have a high compliance impact on SPAs. The dispersive characteristics of the dye-tagged effluents were consistent with the variation of NoV contamination in the study sites. A buffer zone established at 1,000:1 dilution of estuarine water to treated effluent would afford a high level of public health protection while a buffer zone established at much lower dilution ratios (e.g. 300:1) would represent a much higher health risk.

La present tesi és una aportació a el coneixement de nous factors de risc per al tumor testicular de cèl·lules germinals (TTCG). El TTCG presenta una etiologia multifactorial, atribuïble a un retard en la diferenciació dels gonocitos fetals. El TTCG és més freqüent en homes amb una espermatogènesi alterada, suggerint una possible etiopatogènia comuna. El cromosoma I conté gens essencials per a una correcta espermatogènesi, les regions de l'factor d'azoospèrmia (AZF). La regió AZF més dinàmica és la regió AZFc que presenta punts fràgils que predisposa a reordenaments. El reordenament parcial més rellevant des del punt de vista clínic de la regió AZFc és la deleció gr / gr. S'ha relacionat la delació gr / gr amb un major risc de desenvolupar un TTCG, però la falta d'informació sobre els paràmetres seminals dels pacients no ha permès d'aclarir si l'associació observada està relacionada amb l'espermatogènesi alterada o si és un factor de risc independent. A més, encara queda per establir si altres tipus de delecions i duplicacions de la regió AZFc presenten relació amb el TTCG. La primera part d'aquesta tesi s'enfoca en l'estudi dels reordenaments parcials de la regió AZFc al TTCG. S'han analitzat 497 pacients amb TTCG i 2030 controls sense TTCG. Un 3.8% dels pacients amb TTCG presentaven algun tipus de deleció parcial de la regió AZFc respecte a l'2.5% de el grup control (p = 0.078). La deleció parcial més freqüent va ser la deleció gr / gr, mentre que els altres tipus de delecions parcials de la regió AZFc van resultar ser molt rares. Segons el fenotip seminal, es va observar un major risc de TTCG en pacients normozoospérmicos portadors de delecions parcials de la regió AZFc respecte als controls normozoospérmicos. No hi va haver diferències significatives entre pacients i controls segons les duplicacions parcials de la regió AZFc. Es va mostrar que les alteracions en la dosi de el gen DAZ confereixen un major risc de TTCG. Aquests resultats confirmen que un dèficit de l'contingut gènic de la regió AZFc juga un paper important en la etiopatogènesi de l'TTCG. En particular, la deleció gr / gr confereix un risc significatiu per al desenvolupament de l'TTCG independentment dels paràmetres seminals. Els factors ambientals també estan involucrats en la etiopatogènesi de l'TTCG, especialment si interfereixen en un període específic de el desenvolupament testicular, en el denominat ""masculinization programming window"" (MPW). Un desequilibri hormonal en aquest període compromet a la correcta funció de les cèl·lules fetals de Sertoli i Leydig, originant la síndrome de disgenèsia testicular (SDT). La distància anogenital (DAG) és considerada un biomarcador de l'acció dels andrògens durant el MPW. La DAG més curta ha estat relacionada amb tots els components de l'SDT, excepte amb el TTCG. La segona part d'aquesta tesi valora l'associació entre la DAG i el TTCG. A més avalua el paper de l'polimorfisme CAG de el gen AR en el desenvolupament de l'TTCG i la DAG. Es van analitzar a 156 pacients amb TTCG i 110 controls sans normozoospérmicos. Es va observar una distància anopeneana (DAGap) i una distància anoescrotal (dagues) significativament més curta en els TTCG respecte als controls. Es van definir uns punt de tall (DAGap: 130mm; dagues: 53mm) que indiquen un major risc de TTCG en aquells individus que es trobin per sota d'aquests valors. No s'ha trobat relació entre el polimorfisme CAG i el TTCG o la longitud de la DAG. En conclusió, les dades revelen que els pacients amb una DAG més curta presenten un major risc de TTCG, recolzant la teoria sobre la influència de l'desequilibri androgènic durant el desenvolupament fetal en l'etiopatogènia de l'TTCG.
La presente tesis es una aportación al conocimiento de nuevos factores de riesgo para el tumor testicular de células germinales (TTCG). El TTCG presenta una etiología multifactorial, atribuible a un retraso en la diferenciación de los gonocitos fetales. El TTCG es más frecuente en varones con una espermatogénesis alterada, sugiriendo una posible etiopatogenia común. El cromosoma Y contiene genes esenciales para una correcta espermatogénesis, las regiones del factor de azoospermia (AZF). La región AZF más dinámica es la región AZFc que presenta puntos frágiles que predispone a reordenamientos. El reordenamiento parcial más relevante desde el punto de vista clínico de la región AZFc es la deleción gr/gr. Se ha relacionado la delación gr/gr con un mayor riesgo de desarrollar un TTCG, pero la falta de información sobre los parámetros seminales de los pacientes no ha permitido de clarificar si la asociación observada está relacionada con la espermatogénesis alterada o si es un factor de riesgo independiente. Además, aún queda por establecer si otros tipos de deleciones y duplicaciones de la región AZFc presentan relación con el TTCG. La primera parte de esta tesis se enfoca en el estudio de los reordenamientos parciales de la región AZFc en el TTCG. Se han analizado 497 pacientes con TTCG y 2030 controles sin TTCG. Un 3.8% de los pacientes con TTCG presentaban algún tipo de deleción parcial de la región AZFc respecto al 2.5% del grupo control (p= 0.078). La deleción parcial más frecuente fue la deleción gr/gr, mientras que los otros tipos de deleciones parciales de la región AZFc resultaron ser muy raras. Según el fenotipo seminal, se observó un mayor riesgo de TTCG en pacientes normozoospérmicos portadores de deleciones parciales de la región AZFc respecto a los controles normozoospérmicos. No hubo diferencias significativas entre pacientes y controles según las duplicaciones parciales de la región AZFc. Se mostró que las alteraciones en la dosis del gen DAZ confieren un mayor riesgo de TTCG. Estos resultados confirman que un déficit del contenido génico de la región AZFc juega un papel importante en la etiopatogénesis del TTCG. En particular, la deleción gr/gr confiere un riesgo significativo para el desarrollo del TTCG independientemente de los parámetros seminales. Los factores ambientales también están involucrados en la etiopatogénesis del TTCG, especialmente si interfieren en un periodo específico del desarrollo testicular, en el denominado "masculinization programming window" (MPW). Un desequilibrio hormonal en este periodo compromete la correcta función de las células fetales de Sertoli y Leydig, originando el síndrome de disgenesia testicular (SDT). La distancia anogenital (DAG) es considerada un biomarcador de la acción de los andrógenos durante el MPW. La DAG más corta ha sido relacionada con todos los componentes del SDT, excepto con el TTCG. La segunda parte de esta tesis valora la asociación entre la DAG y el TTCG. Además evalúa el papel del polimorfismo CAG del gen AR en el desarrollo del TTCG y la DAG. Se analizaron a 156 pacientes con TTCG y 110 controles sanos normozoospérmicos. Se observó una distancia anopeneana (DAGap) y una distancia anoescrotal (DAGas) significativamente más corta en los TTCG respecto a los controles. Se definieron unos punto de corte (DAGap: 130mm ;DAGas: 53mm) que indican un mayor riesgo de TTCG en aquellos individuos que se encuentren por debajo de estos valores. No se encontró relación entre el polimorfismo CAG y el TTCG o la longitud de la DAG. En conclusión, los datos revelan que los pacientes con una DAG más corta presentan un mayor riesgo de TTCG, apoyando la teoría sobre la influencia del desequilibrio androgénico durante el desarrollo fetal en la etiopatogenia del TTCG.
This thesis is a contribution to the knowledge of new risk factors for testicular germ cell tumor (TTCG). TTCG has a multifactorial etiology, attributable to a delay in the differentiation of fetal gonocytes. TTCG is more frequent in men with altered spermatogenesis, suggesting a possible common etiopathogenesis. The Y chromosome contains essential genes for correct spermatogenesis, the azoospermia factor (AZF) regions. The most dynamic AZF region is the AZFc region that presents fragile points that predispose to rearrangements. The most clinically relevant partial rearrangement of the AZFc region is the gr / gr deletion. gr / gr cheating has been associated with an increased risk of developing TTCG, but the lack of information on the seminal parameters of the patients has not made it possible to clarify whether the observed association is related to altered spermatogenesis or if it is a factor of independent risk. Furthermore, it remains to be established whether other types of deletions and duplications of the AZFc region are related to TTCG. The first part of this thesis focuses on the study of partial rearrangements of the AZFc region in the TTCG. 497 patients with TTCG and 2030 controls without TTCG have been analyzed. 3.8% of the patients with TTCG presented some type of partial deletion of the AZFc region compared to 2.5% of the control group (p = 0.078). The most frequent partial deletion was the gr / gr deletion, while the other types of partial deletions of the AZFc region were found to be very rare. According to the seminal phenotype, a higher risk of TTCG was observed in normozoospermic patients carrying partial deletions of the AZFc region compared to normozoospermic controls. There were no significant differences between patients and controls according to the partial duplications of the AZFc region. Alterations in the dose of the DAZ gene were shown to confer an increased risk These results confirm that a deficit in the gene content of the AZFc region plays an important role in the etiopathogenesis of TTCG. In particular, the gr / gr deletion confers a significant risk for the development of TTCG regardless of seminal parameters. Environmental factors are also involved in the aetiopathogenesis of TTCG, especially if they interfere in a specific period of testicular development, in the so-called "masculinization programming window" (MPW). A hormonal imbalance in this period compromises the correct function of the fetal Sertoli and Leydig cells, causing the testicular dysgenesis syndrome (TDS). The anogenital distance (DAG) is considered a biomarker of the action of androgens during MPW. The shorter DAG has been related to all components of the SDT, except the TTCG. The second part of this thesis assesses the association between the DAG and the TTCG. It also evaluates the role of the CAG polymorphism of the AR gene in the development of TTCG and DAG. 156 patients with TTCG and 110 healthy normozoospermic controls were analyzed. A significantly shorter anopeneal distance (DAGap) and anoscrotal distance (DAGas) were observed in TTCG compared to controls. Cut-off points were defined (DAGap: 130mm; DAGas: 53mm) that indicate a greater risk of TTCG in those individuals who are below these values. No relationship was found between the CAG polymorphism and the TTCG or the length of the DAG. In conclusion, the data reveal that patients with a shorter DAG have a higher risk of TTCG, supporting the theory about the influence of androgen imbalance during fetal development on the etiopathogenesis of TTCG.

Patient falls are the most commonly reported "adverse events" in hospitals, according to studies conducted in the U.S. and elsewhere. The rate of falls is not high (2.3 to 7 falls per 1,000 patient days), but about a third of falls result in injuries or even death, and these preventable events drive up the cost of healthcare and, clearly, are harmful outcomes for the patients involved. This study of a private hospital, Dublin Methodist Hospital, in Dublin, Ohio analyzes data about patient falls and the facility's floor plans and design features and makes direct connections between hospital design and patient falls. This particular hospital, which was relatively recently constructed, offered particular advantages in investigating unit-layout-related environmental factors because of the very uniform configuration of its rooms, which greatly narrowed down the variables under study. This thesis investigated data about patients who had suffered falls as well as patients with similar characteristics (e.g., age, gender, and diagnosis) who did not suffer falls. This case-control study design helps limit differences between patients. Then patient data was correlated to the location of the fall and environmental characteristics of the locations, analyzed in terms of their layout and floor plan. A key part of this analysis was the development of tools to measure the visibility of the patient's head and body to nurses, the relative accessibility of the patient, the distance from the patient's room to the medication area, and the location of the bathroom in patient rooms (many falls apparently occur during travel to and from these areas). From the analysis of all this data there emerged a snapshot of the specific rooms in the hospital being analyzed where there was an elevated risk of a patient falling. While this finding is useful for the administrators of that particular facility, the study also developed a number of generally applicable conclusions. The most striking conclusion was that, for a number of reasons, patients whose heads were not visible from caregivers working from their seats in nurses' stations and/or from corridors had a higher risk of falling, in part because staff were unable to intervene in situations where a fall appeared likely to occur. This was also the case with accessibility; patients less accessible within a unit had a higher risk of falling. The implications for hospital design are clear: design inpatient floors to maximize a visible access to patients (especially their heads) from seats in nurses' stations and corridors.

Diarrheal diseases are a leading cause of childhood morbidity and mortality globally and in East Africa. Determining diarrheal disease risk factors and their strength of association to diarrheal disease in this region is necessary to identify and prioritize future research questions and interventions. Demographic and Health Surveys (DHS) Program Data on child health in Burundi, Rwanda, and Tanzania from 2010 were used and simple and multiple logistic regressions were completed to determine factors that predicted diarrheal disease. Diarrhea that occurred in the two weeks prior to data collection was reported for 24.80% of Burundian, 13.1% of Rwandan, and 13.91% of Tanzanian children under five. In Burundian children, increased risk of diarrhea was associated with unimproved sanitation, young mothers, and the mother’s education level (secondary school or less). In Rwandan children, increased risk of diarrhea was associated with more than 30-minute travel time to water source, rainy season, young mothers, mother’s lack of education, and low wealth index. In Tanzanian children, increased risk of diarrhea was associated with rainy season and young mothers. The impact of improved water source and sanitation facility on diarrheal disease is not consistent across the literature or results of this study. Future research should include information on hygiene practices, type of water storage container and types of household water treatment. Further, pathogen specific research, such as molecular fingerprinting, would assist to link the source to the disease. These additions would provide a more comprehensive understanding of risk factors for and sources of diarrheal disease globally and in East Africa.

[Truncated abstract] This thesis explores the risk factors and perinatal outcomes associated with prelabour rupture of membranes, with a particular focus on the environmental context. Prelabour rupture of membranes is defined as the rupture of fetal membranes before the onset of labour. It is a relatively common obstetric endpoint, occurring in approximately 8-10% of pregnant women at term (PROM) and in up to 40% of all preterm deliveries (pPROM). Despite the high prevalence of the condition, the biological mechanisms and risk factors, and in particular the role of environmental predictors, behind the development of PROM and pPROM remain largely unclear. A record-based prevalence design was used to analyse a population of 16,229 nulliparous, Caucasian women residing in Perth, Western Australia who gave birth to a single newborn during 2002-2004. Maternal age, socioeconomic status and threatened preterm labour during pregnancy were identified as risk factors for prelabour rupture of membranes. Term PROM was significantly associated with fetal distress (OR 1.19; 95%CI 1.00-1.43) and post-partum haemorrhage (OR 1.99; 95%CI 1.60-2.48). A number of perinatal complications were observed to be associated with the presentation of preterm PROM, including prolapsed cord (OR 13.95; 95%CI 4.57-42.61), ante-partum haemorrhage (OR 3.29; 95%CI 2.20-4.91), post-partum haemorrhage (OR 2.12; 95%CI 1.54-2.91), low birth weight (OR 17.79; 95%CI 13.87-22.82), very low birth weight (OR 20.01; 95%CI 14.12-28.35) and stillbirth (OR 5.42; 95%CI 2.87-10.21). However, the outcomes were similar between pPROM patients and other preterm deliveries, indicating that the complications arose due to the timing of the delivery. In contrast though, the risk factors between the two outcomes varied which may suggest that a different aetiological pathway exists between preterm PROM and other preterm deliveries. The frequency of complications decreased with increasing gestational age at delivery until the pregnancy reached full-term, whereupon an increase in gestational age at delivery resulted in an increased risk of fetal distress and post-partum haemorrhage. This finding is novel and may have important implications for the management of prelabour rupture of membranes, specifically with regard to the relative risks and benefits of expectant management (that is, the patient is admitted to an obstetric facility or hospital and closely monitored) versus planned delivery. ... This study represents the first attempt to investigate the potential associations between environmental risk factors and prelabour rupture of membranes. The results of the thesis provide a substantial contribution to our knowledge on prelabour rupture of membranes, including findings of direct relevance to clinical practice as well as a potentially contributing environmental exposure pathway. These original findings suggest a possible preventative approach to reducing the occurrence and associated morbidity of prelabour rupture of membranes may be feasible, and should be pursued if future research confirms the preliminary findings of this thesis.

Whilst the excess of psychosis among migrants is a well defined phenomenon in Northern Europe, it had not been demonstrated in Southern Europe. Moreover : 1) most studies focused on ethnic minorities and not on first generation migrants; 2) there are not studies conducted in contemporary times involving internal migrants; 3)published studies have mostly focused on risk factors in the post migration phase (such as ethnic fragmentation, unemployment, etc). My PhD project aimed to : 1) Verify whether there was an excess of psychosis among migrants in Italy 2) Understand the role of known environmental risk factors for psychosis (such as substance use, being single/living alone, being unemployed and low level of education) in the development and course of psychosis in migrants. I used data collected in Bologna West as an incidence of first-episode psychosis (Bo-FEP) study. All first episode psychosis patients (FEP) age 18 to 65 yrs old, presenting to the Bologna Mental Health Centres between January 2002 and December 2010, resident within defined catchment areas in Bologna, and without any previous contact with health services for psychosis, were identified and invited to take part in this project. I also used follow-up data collected 1 year after the first contact of FEP patients with services. My thesis contains 2 published papers and 1 accepted paper. (Tarricone et al., 2012; Tarricone et al., 2014; Tarricone et al, accepted with revisions), The overall Incidence Rare standardised for age and gender in the Bo-FEP study was 16.4 per 100,000 person-years (95% CI, 13.9- 18.9). The Incidence Rate Ratio was 1.93 (1.19-3.13, p=0.007) for internal migrants and 1.79 (1.06-3.02, p=0.03) for external migrants compared to natives. Substance users had a significantly higher rate of hospitalizations during the 12 months follow-up after adjusting for age, gender and other potential confounders (OR 5.84, 95% CI 2.44-13.97, p≤0.001).In addition I have reviewed the relevant literature, described the background and overall methodology of the study, discussed the limitations and written a conclusion.

Despite the efforts of food safety regulations and rules, food contamination remains a public health concern and prevalent vehicle of pathogens. This study identifies the predictors of food risk in different types of food establishments in Miami Dade County, Florida during the period November 2014 - November 2016. Guided by the epidemiologic triangle model, this correlational study analyzed the log number of risk factor violations and failure rates controlling for US Census sociodemographic data (2010 to 2014) for the food establishment neighborhoods by using linear and logistic regression. Results indicated that most of food entity types are significant predictors of risk violations. Among all the significant predictor food establishments, grocery stores (b = 2.877. p < 0.001) had a higher increase in violations. For the demographic variables, the only significant variable was the number of single parent households (B = .001, p = 0.022). The result reveals a significant association between food entity types and failing inspection (p < 0.005). Among all the entity types, convenience store with significant food service and/or packaged ice (22.2 %) have the highest percentage fail rate within inspection rate outcome. Findings indicate that a risk-based approach to food risk factor violations frequency could reduce the number of violations, particularly in convenience and grocery stores with the most violations and failing rate.

Considering the prominence of green supply chain management (GrSCM) research has developed expressively in this field. However, there is a dearth of studies from emerging economies comprised of modelling and empirical testing of hypotheses. Moreover, the literature is lacking the empirical evidence on the determinants of GrSCM practices by small and medium enterprises (SMEs) especially in the case of Pakistan. The literature has yet to determine what green practices are being adopted by SMEs in Pakistan, an elucidation why GrSCM practices are adhered, what construct is appropriate to evaluate adoption of GrSCM practices by SMEs in Pakistan, and whether mediation of internal factors exits between the relationship of GrSCM practices and external pressure. This dissertation uses Structural Equation Modelling (SEM) to investigate GrSCM practices adoption, the appropriate construct for evaluating green practices, and examining three potentially important determinants in Pakistani SMEs. With the data collected in two stages from the SMEs sector of Pakistan, exploratory factor analysis (EFA) revealed a three-dimension structure for measuring the GrSCM practices. Subsequently, the confirmatory factor analysis (CFA) was carried out on two measurement models (i.e. first and second order) of GrSCM adoption based on EFA. The empirically outcomes advocates that both models for GrSCM adoption are valid and reliable, however the second order model has better fit indices. The SEM testing shows significant results for mediation of internal factors in the hypothesized relationship among the GrSCM practices and external pressures. For academicians and supply chain mangers these results yield several exciting theoretical and practical implications.

Risk perception is the judgment people make about the characteristics and severity of a risk. Numerous theories and models exist which have identified the factors that influence risk perception. Among these factors, location, health status, and demographic characteristics are known to shape risk perception. To measure the influence of these factors on environmental perception, a series of surveys conducted in four Louisiana communities between 2004 and 2005 describe community perceptions about environmental issues and health status. The objective of the study was to characterize and compare environmental concerns relative to location, health status, and demographic characteristics. Results indicate that location has a strong influence in framing an individual’s concerns about environmental issues, particularly those living close to industry. Concern for general environmental and natural preservation issues were comparable among the communities indicating that concern for these issues is independent of residential location.