In the United States, approximately 3% of infants are diagnosed with a major birth defect each year. Whereas prevention efforts have led to decreases in some birth defects, the cause of approximately 70% of birth defects remains unknown. More recently, there has been increasing concern regarding exposures to environmental agents, such as air pollution during pregnancy, and the risk of birth defects. Over the past decade, there has been an increase in research studies examining the association between air pollution and birth defects. The results have been inconsistent, with some studies reporting that higher levels of exposure from the same pollutant increase the risk of birth defects, whereas others report no risk or even a decrease in risk. These inconsistencies may arise from differences in exposure assessment methods across epidemiological studies. A comprehensive series of sensitivity analyses were conducted to evaluate the impact of different exposure estimation decisions on the adjusted measures of associations between ambient air pollution exposure and birth defects. For each of six decisions – spatial scale, spatial limit, temporal scale, temporal limit, data aggregation sequence, and weighting scheme – two alternative choices were considered, and maternal exposure to PM2.5 and benzene were estimated for each ‘sensitivity case' (unique combination of choices across all decisions). For each sensitivity case, adjusted prevalence ratios (aPRs) and 95% confidence intervals (CI) were estimated from multivariable regression models comparing each exposure quartile to the first quartile; each measure of association represented the associations between either benzene or PM2.5 and one of the birth defects under study. To then evaluate the impact of selecting alternative choices for each exposure assessment decision, three metrics were used: 1) the percent difference in the aPR point estimates between alternative choices for a specific decision (calculated for each sensitivity case pairing); 2) the percent of sensitivity cases in which the aPR 95% CIs for alternative choices for a specific decision overlapped (i.e., were not statistically significantly different); and 3) the percent of sensitivity cases in which there was agreement in the substantive conclusion of the association between exposure (pollutant) and outcome (defect), the conclusion being either statistically significant increased risk, statistically significant decreased risk, or no statistically significant difference in risk. Second, a retrospective cohort study was conducted to investigate the association between maternal exposure to ambient benzene and PM2.5 and the risk of musculoskeletal birth defects in offspring. For both analyses, data on singleton infants born from 2000 to 2013 were obtained from the Florida Birth Defects Registry and air pollution data were obtained from the Environmental Protection Agency Air Quality System database. Exposure estimates were calculated for all birth defect cases and non-affected births during etiologically relevant time windows and multivariable regression models were used to obtain aPRs and 99% CIs comparing each quartile of exposure to the first. For PM2.5, across all exposure-outcome pairs under study, the alternative choices for the decision of spatial scale resulted in the largest median percent difference in aPRs (e.g., between county and block group) when results were aggregated for all quartiles. This was followed by the temporal scale and spatial limit decisions. For benzene, spatial limit resulted in largest median percent difference in aPRs, followed by spatial scale and temporal scale. However, for both pollutants, when evaluating the agreement in aPRs between alternative choices on the direction and significance of the association (i.e., statistically significant increase, decrease, or no risk), the decision of spatial limit resulted in the lowest percent agreement (biggest impact). Temporal limit had the second lowest percent agreement for PM2.5, whereas spatial scale had the second lowest for benzene. Finally, the metric assessing the level of overlap in 95% CIs for the measures of association was inconsequential, suggesting little impact of any exposure assessment decision, and doing little to differentiate between the relative impacts of each decision. That is because, for all exposure-outcome pairs, when comparing alternative choices for each decision, there was 100% overlapping intervals (i.e., no aPRs were statistically significantly different from each other). Lastly, exposure assessment decisions impacted the analytic sample sizes, with some decisions resulting in a three-fold difference in the sample size alone. Mothers of singleton infants exposed to higher levels of ambient PM2.5 were more likely than mothers with lower exposure levels to give birth to an infant with isolated anomalies of the skull and face bones, any rib and sternum anomalies, any skull and face anomalies, any spine anomaly, and other congenital anomalies of lower limb including pelvic girdle. Higher PM2.5 exposure was also associated with an increased risk of non-isolated anomalies of skull and face bones, any skull and face anomalies, and reduction deformities of the upper limb. Exposure to higher levels of benzene was associated with an increased risk of isolated congenital hip dislocation and congenital valgus deformities of feet as well as multiple inverse associations. The findings presented here indicate that measures of association between maternal pollutant exposures (PM2.5 and benzene) and selected birth defect outcomes in offspring are sensitive to exposure assessment decisions, with some decisions more impactful than others. The findings can be used, not only to explain the lack of consistency in results across existing epidemiological studies, but to guide decision-making in future studies. This study also adds to the growing body of epidemiological studies suggesting an association between specific air pollutants and birth defects. In the current political climate, it is important that researchers continue to provide evidence of the detrimental health effects of air pollution in order to circumvent change in current policies established to regulate and reduce pollution emissions.

A long standing axiom in the field of teratology states that the teratogenic period, when most birth defects are produced, occurs during the third to eighth weeks of development post-fertilization. Any insults prior to this time are thought to result in a slowing of embryonic growth from which the conceptus recovers or death of the embryo followed by spontaneous abortion. However, new insights into embryonic development during the first two weeks, including formation of the anterior-posterior, dorsal-ventral, and left-right axes, suggests that signaling pathways regulating these processes are prime targets for genetic and toxic insults. Establishment of the left-right (laterality) axis is particularly sensitive to disruption at very early stages of development and these perturbations result in a wide variety of congenital malformations, especially heart defects. Thus, the time for teratogenic insults resulting in birth defects should be reset to include the first two weeks of development.

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<p>The tumor suppressor protein p53, encoded by Tp53 gene, is a transcription factor that regulates cell cycle arrest and apoptosis following cellular stresses that compromise DNA integrity and normal cellular function. Tp53 is mutated in approximately 50% of human cancers, thereby allowing cancer cells to replicate uncontrollably. In cancers in which Tp53 is not mutated, p53 is frequently functionally inactivated through other mechanisms. For example, Mdm2, a proximal negative regulator p53 is often overexpressed in cancers in which p53 is wild-type. Mdm2 is E3 ubiquitin ligase that binds to and targets p53 for proteasomal degradation and as well as inhibits p53 transcriptional activity. Pharmacological disruption of the Mdm2-p53 interaction in cancer cells with wild-type p53 is currently being explored as a strategy to enhance p53-mediated cell death in response to conventional chemotherapeutics. Nutlin-3, an Mdm2 inhibitor, promotes cell death in cultured cells from human medulloblastoma (MB), a common cerebellar pediatric cancer, suggesting that Mdm2 is a promising target to treat this tumor type. Consistent with this idea, studies in a mouse model of MB have shown that loss of Mdm2 limits the development of preneoplastic lesion in the cerebellum. The developing nature of the cerebellum in the youngest of MB patients is a major contributing factor to the side-effects resulting from current MB therapies. Studies in adult rodents suggest that nutlin-3 is non-genotoxic in normal homeostatic tissues; however the effects of nutlin-3 have not been evaluated in developing tissues. To gain insight into the potential side effects of p53 activation on the developing cerebellum, the pharmacological effects of Mdm2 inhibition in Granule Neuron Precursor cells (GNPs) was mimicked genetically using a mouse model in which Mdm2 could be selectively deleted in postnatal GNPs. My studies revealed that deletion of Mdm2 in GNPs led to a reduction in cerebellum size but did not negatively impact gross motor coordination. These results suggest that Mdm2 inhibitors may promote the killing of MB tumor cells of pediatric patients without minimal side effects on normal cerebellum development</p> <p>In addition to cancer, p53 has an important role guarding proliferating cells during development. Activation of p53 has been implicated in the pathology of several human congenital syndromes, and mice lacking Mdm2 die in utero due to p53-mediated apoptosis. These studies highlight the need for p53 function to be tightly regulated as even modest decreases or increases in p53 function can promote cancer or disrupt normal development, respectively. During the course of my studies on Mdm2 inhibition in MB, it was serendipitously discovered that in the absence of a wild-type level of Mdm2, the phenotypic consequences of p53 activation on the developing mouse embryo were strongly influenced by the genetic background. On a 129S6/B6 F1 hybrid genetic background, mice expressing ~30% the wild-type level of Mdm2 were viable, while mice on an inbred C57BL/6 genetic background died at birth and exhibited an array of craniofacial abnormalities including coloboma, exencephaly, and cleft palate. This is the first demonstration of a role for Mdm2 in craniofacial development. The genotype-dependence, further, indicates the presence of additional genes affecting craniofacial dysmorphology. In human pleiotropic malformation syndromes, there is often clinical variability amongst individuals with an identical underlying mutation at the major effect locus. Currently, the modifier genes that influence craniofacial dysmorphology are unknown. The allelic variants encoded by the divergent genetic backgrounds that increase the penetrance and expressivity of craniofacial malformations in the Mdm2 hypomorphic mice identify the gene and protein networks governing craniofacial development. In the future, it will be important to determine the genes that are differentially expressed between mice that express low levels of Mdm2 in C57BL/6 and 129S6/B6 F1 genetic backgrounds. The results from this comparison are predicted to lead to the identification of candidate genes that influence craniofacial development through the modulation of p53 function.</p>

The availability of online support communities creates new opportunities for caregivers of children affected by health conditions to manage their illness-related uncertainty. This dissertation includes two studies that examined the presence of uncertainty management behaviors in online interactions among parents (caregivers) of children with clubfeet, and empirically tested the applicability of the uncertainty management theory to online behaviors. The Uncertainty Management Theory provided the theoretical foundation for both studies. For the first study, a content analysis of messages exchanged in an online support community dedicated to parents of children with clubfeet was conducted. Most messages were authored by women. The majority of the emotions expressed in the messages were positive. The most frequent information-seeking behaviors were direct questioning and self-disclosure. Information exchanges as a strategy to manage uncertainty included names of health care professionals and medical information. Five major types of social support (informational, tangible, network, esteem, and emotional) were identified. Informational support was the most frequent type of support provided, followed by emotional and esteem support. A third of the messages included combinations of two or more types of social support. For the second study an online survey was distributed using a snow-balling technique. Based on the survey data structural equation modeling was used to empirically test the uncertainty management framework. Positive relationships were identified between knowledge and information seeking, information seeking and social support, social support and sense of virtual community, uncertainty and stress. The results suggested that the uncertainty management theory may need to be adapted for use in online contexts. Uncertainty seems to be an important part of the experience of parents caring for children with clubfoot. Online communities dedicated to these parents represent a promising setting for studying illness-related uncertainty and its potential causes. Such studies can be a critical source of information to inform priorities for research and practice. This dissertation is the first step in better understanding the audience and provides an initial exploration of uncertainty management and communication processes present in an online support community. As we learn more about the parent audience, the importance of communicating with them becomes increasingly clear.

While all women hope to deliver a healthy baby, approximately 3-5% babies are affected by birth defects. Birth defects can occur naturally or be induced by teratogens. Alcohol is a known teratogen that causes fetal alcohol spectrum disorder (FASD), the most commonly known cause of neurobehavioural and neurodevelopmental deficits. Individuals affected with FASD are likely to be involved with or require additional assistance from healthcare, education, social services, and justice sectors. Due to this immense burden, effective prevention of FASD can have a major public impact. Prevention of FASD can occur at different levels: primary prevention (preventing alcohol-induced birth defects from occurring in the first place); secondary prevention (preventing alcohol-induced birth defects from developing or progressing); tertiary prevention (improving the outcome of individuals affected with FASD); and quaternary prevention (preventing another child from being affected with FASD). The objective of this thesis was to explore a multilevel birth defect and FASD prevention strategy. Primary prevention by was investigated by maternal multivitamin supplementation to optimize fetal growing conditions, as alcoholics are commonly deficient in nutrients. A meta-analysis of maternal multivitamin supplementation demonstrated a decreased risk for certain congenital anomalies and pediatric cancers. Secondary prevention was investigated by a randomized double-blinded placebo-controlled evaluating the ability of high doses of antioxidants (vitamin C and vitamin E) to mitigate the effects of prenatal alcohol exposure. The study was ceased due to safety concerns regarding high doses of vitamin C and vitamin E in preeclamptic studies. Tertiary prevention was investigated by anonymous meconium screening of babies of Grey-Bruce, Ontario residents delivering at or transferred to St. Joseph’s Health Care in London, Ontario. A 30% prevalence of fatty acid ethyl esters (FAEE) positive meconium was observed at this high-risk unit. Meconium screening is also a means of quaternary prevention since positive screens also identify mothers who were unable to stop consuming alcohol after 13 weeks of pregnancy, and therefore are at risk of delivering another child who is prenatally exposed to alcohol. The identification and engagement of these mothers into treatment programs constitutes primary prevention of FASD in subsequent pregnancies.

Congenital heart disease affects tens of thousands of children and families throughout Iraq, where complex surgical treatment remains largely unavailable. Through participant-observation and in-depth interviews, I investigated the understandings of this disorder among families in two areas: Kurdish northern Iraq and Arab southern Iraq. I pay particular attention to families’ perspectives on causes and treatment of the disorder in relation to historical and current macrosocial forces. Among the families I spoke with, there is a strong connection between the recent history of violence in Iraq and congenital heart disease. This thesis is largely an attempt to understand the uses and implications of this connection between sickness and violence for Iraqi families pursuing treatment through an international non-governmental organization.

While all women hope to deliver a healthy baby, approximately 3-5% babies are affected by birth defects. Birth defects can occur naturally or be induced by teratogens. Alcohol is a known teratogen that causes fetal alcohol spectrum disorder (FASD), the most commonly known cause of neurobehavioural and neurodevelopmental deficits. Individuals affected with FASD are likely to be involved with or require additional assistance from healthcare, education, social services, and justice sectors. Due to this immense burden, effective prevention of FASD can have a major public impact. Prevention of FASD can occur at different levels: primary prevention (preventing alcohol-induced birth defects from occurring in the first place); secondary prevention (preventing alcohol-induced birth defects from developing or progressing); tertiary prevention (improving the outcome of individuals affected with FASD); and quaternary prevention (preventing another child from being affected with FASD). The objective of this thesis was to explore a multilevel birth defect and FASD prevention strategy. Primary prevention by was investigated by maternal multivitamin supplementation to optimize fetal growing conditions, as alcoholics are commonly deficient in nutrients. A meta-analysis of maternal multivitamin supplementation demonstrated a decreased risk for certain congenital anomalies and pediatric cancers. Secondary prevention was investigated by a randomized double-blinded placebo-controlled evaluating the ability of high doses of antioxidants (vitamin C and vitamin E) to mitigate the effects of prenatal alcohol exposure. The study was ceased due to safety concerns regarding high doses of vitamin C and vitamin E in preeclamptic studies. Tertiary prevention was investigated by anonymous meconium screening of babies of Grey-Bruce, Ontario residents delivering at or transferred to St. Joseph’s Health Care in London, Ontario. A 30% prevalence of fatty acid ethyl esters (FAEE) positive meconium was observed at this high-risk unit. Meconium screening is also a means of quaternary prevention since positive screens also identify mothers who were unable to stop consuming alcohol after 13 weeks of pregnancy, and therefore are at risk of delivering another child who is prenatally exposed to alcohol. The identification and engagement of these mothers into treatment programs constitutes primary prevention of FASD in subsequent pregnancies.

Congenital heart disease affects tens of thousands of children and families throughout Iraq, where complex surgical treatment remains largely unavailable. Through participant-observation and in-depth interviews, I investigated the understandings of this disorder among families in two areas: Kurdish northern Iraq and Arab southern Iraq. I pay particular attention to families’ perspectives on causes and treatment of the disorder in relation to historical and current macrosocial forces. Among the families I spoke with, there is a strong connection between the recent history of violence in Iraq and congenital heart disease. This thesis is largely an attempt to understand the uses and implications of this connection between sickness and violence for Iraqi families pursuing treatment through an international non-governmental organization.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13379号 / 論医博第2213号 / 新制||医||1047(附属図書館) / (主査)教授 川上 浩司, 教授 滝田 順子, 教授 古川 壽亮 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM