The inclusion of human fetal skeletons in the archaeological record can reveal much about past cultures' perception of life and death. The preservation of fetal remains in the archaeological record is a rarity, and the discovery of pathological skeletons is even rarer. A fetal skeleton from a Roman period cemetery (c. 31BC - 303AD) in the Dakhleh Oasis, Egypt, displays what are thought to be classic skeletal indicators of the neural tube defect, anencephaly. The published literature concerning the skeletal diagnosis of anencephaly is scant so in order to diagnose this individual it is pertinent to create a diagnostic standard. The purpose of this thesis is twofold - first to create a quantitative standard from which researchers can determine the presence of anencephaly in the archaeological record, thus ruling out trauma or taphonomic processes as reasons for missing cranial elements. The second objective of this research is to conduct a qualitative comparison in order to diagnose the individual from the Dakhleh Oasis. A comparative analysis of nine documented anencephalic skeletal remains housed at the Smithsonian Institute was conducted to create a diagnostic standard for the skeletal characteristics of anencephaly. The comparative analysis of the Dakhleh specimen supports the diagnosis of anencephaly.

No description available.

Dysregulation of apoptosis during development is a possible mechanism for teratogen-induced birth defects. Neural tube defects (NTDs) are the second most common fetal malformations. Non-specific stimulation of maternal immune system prevents birth defects. This study investigated the role of dysregulated apoptosis in formation of NTDs from two teratogens: valproic acid (VA) and an unknown teratogen found in tap water. Interferon- γ (IFN γ) was used to stimulate maternal immunity to evaluate the role of altered apoptosis in this protective mechanism. Apoptosis was evaluated using flow cytometry, Terminal Transferase dUTP Nick End Labeling (TUNEL) assay and gene expression changes by RT2 Profiler PCR arrays. Additionally, changes in the expression of key signal transduction pathway genes that play a role in development were determined. Increased apoptosis, suggesting involvement in VA teratogenicity, was observed along the neural tube in both normal and abnormal embryos from VA-exposed dams. Increased apoptosis in normal VA-exposed embryos suggests that VA may alter other cellular processes such as cell proliferation and differentiation in addition to apoptosis. Apoptotic percentages in embryos with NTDs from IFNγ+VA dams were similar to controls, which indicated resistance to teratogen-induced apoptosis. In IFNγ+VA-exposed embryos with NTDs, immune stimulation failed to prevent apoptosis. VA initiated both death and survival signaling in the embryos; however, upregulation of the apoptotic genes and down regulation of anti-apoptotic genes of p53 and Bcl2 family tended to shift the balance towards death signaling. This change in gene expression patterns could result in increased apoptosis and NTDs in VA-exposed embryos. Immune stimulation normalized changes in the expression of pro-apoptotic signaling molecules. These results suggest immune stimulation protects embryos from teratogenicity of VA by preventing VA-induced apoptosis. VA altered the hedgehog, Wnt, retinoic acid and fibronectin signaling pathways in embryos with NTDs. These results suggest that VA also disrupted signaling pathways required for various morphogenic events during organogenesis. Immune stimulation normalized the expression of Fn1 and Hspb1 and thus may mediate protection through these signaling pathways. In tap water exposed embryos, no change in apoptotic pattern was observed by flow cytometry, TUNEL assay and RT-PCR. Also, none of the signal transduction pathway genes tested were significantly altered in tap water-exposed embryos. This suggests that apoptosis is not a mechanism for teratogenicity resulting from exposure to the contaminant in tap water. / Ph. D.

<p>Proper morphogenesis is essential for both form and function of mammalian craniofacial and neural tube development. Craniofacial deformities and neural tube defects are highly prevalent human birth defects. Although studies concerning craniofacial and neural tube development have revealed important genetic and/or environmental factors, understanding the mechanisms underlying proper development and the defects remain incomplete. </p><p>Among many genes that were cloned as the gastrula organizer genes in 1990s, Nog, a secreted BMP antagonist, is expressed in the relevant domains during craniofacial and neural tube development. Previous studies show that Nog null embryos exhibit fully penetrant spina bifida (open spine) and to the lesser extent exencephaly (open brain). Moreover, Nog null mice display deformities in skeletal structures including defects in craniofacial skeleton. As such, Nog is essential for proper neural tube and craniofacial development. However, it is still not clear that which domain(s) of Nog are responsible for proper craniofacial development or neural tube closure. In addition, it is also an important question when, and in what capacity Nog is necessary during development of craniofacial and neural tube.</p> / Dissertation

Neural tube defects (NTD) are among the most common birth defects and the leading cause of infant mortality. NTDs occur when the neural tube fails to close during early fetal development. The two most common types of NTD are spina bifida and anencephaly. NTDs result in lifelong complications like musculoskeletal deformities and loss of strength. The etiology of NTDs is complex and involves still unclear environmental and genetic factors. However, one of the well-established risk factors of NTDs is folic acid deficiency. The prevalence of NTDs can be lowered by an adequate intake of folic acid in the periconceptual period. In 1996, the Food and Drug Administration mandated that 140 micrograms of folic acid be added to 100 grams of bleached grain products with the goal of reducing the prevalence of NTDs. In the years following this fortification mandate, studies have shown that blood folate levels have more than doubled on average, that there are demographic and socioeconomic disparities in blood folate gains and that NTD rates have declined. However, no studies after the mandate have examined changes in blood folate distribution and differences in NTD prevalence by a wide range of theoretically and biologically relevant risk factors after the mandate. Using a nationally representative sample of non-institutionalized women of reproductive age, I investigated the relationship between the fortification mandate and blood folate levels. I also examined changes in the range/spread of blood folate distribution after the mandate. Using data on US live births from 45 states and the District of Colombia, the second study examined whether (1) the disparities in blood folate changes translate into differences in NTD prevalence and (2) NTD risk factors moderate the association between the mandate and NTD prevalence,. The final study explored potential unintended impacts of the mandate on birth weight, low birth weight, very low birth weight, high birth weight, and physician-diagnosed developmental delay, asthma and allergies. For this study, I employed samples from the Natality files and the National Survey for Children's Health. The cumulative results of my research suggested that the mandate was associated with increases in blood folate concentration, with greater increases in higher quantiles of the blood folate distribution and that the spread of blood folate distribution after the mandate widened. Additionally, the mandate was associated with a decrease in the prevalence of NTDs in the entire US population although the impact of the mandate was moderated by race/ethnicity, maternal educational attainment, acute illness during pregnancy and infant region of birth. Furthermore, the mandate was associated with other unintended infant and child health outcomes such as average birth weight increases in the population and increased risks of developmental delay among six year olds. This research is the first of its kind to examine changes in the spread of blood folate distribution after the mandate and whether NTD risk factors moderate the association between the mandate and NTD prevalence. It is also the first study to explore potential impacts of the actual mandate (not prenatal folic acid supplementation) on other unintended infant and child health outcomes. The results add significantly to our understanding of the effects of the mandate and have important implications for health care providers, women of reproductive age and policy makers because of the potentially increased risk of developmental delay among children and the increasing disparity in blood folate concentrations after the mandate.

No description available.

The development of the nervous system is a complex process. Cell divisions, cell differentiation and signalling interactions must be tightly regulated. To comprehend the mature nervous system, we have to understand its assembly during development. Two main questions were addressed in this thesis: (1) how is the caudal part of the central nervous system specified and (2) how is the early development of the olfactory placode regulated? By using tissue and whole embryo assays in the chick, we identified signalling molecules involved in these processes and propose possible mechanisms for their function. The central nervous system is regionalized along its rostrocaudal axis during development. However, the mechanisms by which cells in the caudal part of the neuraxis acquire rostrocaudal regional identity have been unresolved. We provide evidence that at gastrula stages cells in the caudal neural plate are specified as cells of caudal spinal cord character in response to Wnt and FGF signals and that cells of rostral spinal cord and caudal hindbrain character only emerge later at neurulation stages in response to retinoic acid signalling acting on previously caudalized cells. In the hindbrain and spinal cord distinct motor neuron subtypes differentiate at precise rostrocaudal positions from progenitor cells. We provide evidence that cells in the caudal neural plate have acquired sufficient positional information to differentiate into motor neurons of the correct rostrocaudal subtype. The olfactory placode gives rise to all the structures of the peripheral olfactory system, which, in the chick consists of the olfactory nerve, the sensory epithelium, where the olfactory sensory neurons (OSN) are located and the respiratory epithelium, that produces the mucus. Several studies have addressed the role of signalling cues in the specification of OSNs but much less is known about the regulation of sensory versus respiratory patterning and the events controlling early neurogenesis in the developing olfactory placode. We show that by stage 14 the olfactory placode is specified to give rise to both cells of sensory and respiratory epithelial character. Moreover, cells of respiratory epithelial character require BMP signalling, whereas cells of sensory epithelial character require FGF signalling. We suggest a mechanism in which FGF and BMP signals act in an opposing manner to regulate olfactory versus respiratory epithelial cell fate decision. BMP signalling has also been implicated in the regulation of neurogenesis in the sensory epithelium, and we show that BMP signals are required for the generation of OSNs, because in the absence of BMP signalling cells in the sensory epithelium do not mature. Independently, we also analyzed the role of Notch signalling during early olfactory development both in vitro and in vivo and provide evidence that active Notch signalling is required to prevent cells in the olfactory placode from premature differentiation.

Statement of problem: We have shown that the C677T 5,10 methylenetetrahydrofolate reductase (MTHFR) variant is associated with elevated maternal serum α-fetoprotein (MSAFP), the most common screening test for neural tube defects (NTD). Therefore, past contradictory studies of NTDs and C677T MTHFR may have been biased because of changes in case populations after prenatal diagnosis and termination of pregnancy. Further, an unexplained elevation of MSAFP is known to increase the risk for later pregnancy complications. Is the C677T MTHFR variant a predisposing genetic variant for both NTDs and later complications of pregnancy? Methods: A retrospective study of women with pregnancies resulting in NTD outcome and women with unexplained elevations of MSAFP was undertaken. Women and their partners were genotyped for the C677T MTHFR allele. Couples with a pregnancy resulting in a NTD outcome were compared to couples whose pregnancy outcome did not involve. Couples with unexplained elevations of MSAFP who did and did not have later complications of pregnancy were also compared. Allele frequencies for all groups were then compared against the previously established Manitoba population allele frequency (based on 977 consecutive newborn metabolic screening bloodspots). A review of all studies of NTDs and association with the C677T MTHFR variant was undertaken to determine if the association between the variant and MSAFP is a source of bias. NTD incidence was examined before and after folic acid food fortification introduced in Canada in 1999. Results: There is an increase in the allele frequency of the C677T MTHFR variant in parents with an unexplained elevated MSAFP followed by later complications of pregnancy. The C677T MTHFR variant is also a contributing genetic factor to NTDs worldwide. The incidence of NTDs in Manitoba has decreased by 37% since food fortification with folic acid was introduced. Conclusions: The C677T MTHFR variant is a contributing genetic factor to both later complications of pregnancy after an unexplained elevation of MSAFP and to NTDs. This variant is folate sensitive and folic acid fortification has reduced the incidence of NTDs. / February 2005

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 69-75).

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 133-156).