Sample records for background neural tube

  1. Recent perspectives on the genetic background of neural tube defects with special regard to iniencephaly.

    PubMed

    Joó, József Gábor

    2009-04-01

    Iniencephaly is a rare and mostly lethal type of neural tube defect. The pattern of inheritance of this group of malformations is multifactorial, rendering the identification of the underlying causes. Numerous studies have been conducted to elucidate the genetic basis of human neurulation. Essential signaling pathways of the development of the CNS include the planar cell polarity pathway, which is important for the initiation of neural tube closure, as well as the sonic hedgehog pathway, which regulates the neural plate bending. Genes influencing the different stages of neurulation have been investigated for their eventual role in the development of these malformations. Among the environmental factors, folic acid seems to be the most important modifier of the risk of human neural tube defects. Genes of the folate metabolism pathways have also been investigated to identify mutations resulting in increased risk of neural tube defects. In this review we have attempted to summarize the knowledge on iniencephaly and neural tube defects, with special regard to genetic factors of the etiology. PMID:19379086

  2. Neural Tube Defects

    MedlinePLUS

    ... greater risk of having an infant with a neural tube defect if you Are obese Have poorly controlled diabetes Take certain antiseizure medicines Getting enough folic acid, a type of B vitamin, before and during ...

  3. Neural tube defects.

    PubMed

    Greene, Nicholas D E; Copp, Andrew J

    2014-01-01

    Neural tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying neural tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies. PMID:25032496

  4. Neural Tube Defects

    PubMed Central

    Greene, Nicholas D.E.; Copp, Andrew J.

    2015-01-01

    Neural tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying neural tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies. PMID:25032496

  5. Screening for neural tube defects.

    PubMed

    Drugan, A; Weissman, A; Evans, M I

    2001-06-01

    Neural tube defects are separated into two main categories: (1) abnormalities of the skull and brain (anencephaly, acrania, and encephalocele) and (2) malformations of the spine (meningomyelocele or spina bifida). The cause of neural tube defects is not always clear, and include chromosomal abnormalities, single gene mutations, maternal disease, or maternal exposure to teratogens. Mostly the disorder emerges as a multifactorial trait. Routine screening for neural tube defects was introduced in the United Kingdom in the mid-1970s and the United States in the mid-1980s. The use of screening has resulted in a marked decline in the frequency of neural tube defects diagnosed at birth. PMID:11499052

  6. Are Encephaloceles Neural Tube Defects?

    Microsoft Academic Search

    Courtney A. Rowland; Adolfo Correa; Janet D. Cragan; Clinton J. Alverson

    2010-01-01

    OBJECTIVE.Encephalocele is classified as a neural tube defect, but questions have been raised regarding whether its epidemiological characteristics are similar to those of other neural tube defects. DESIGN.We compared characteristics of temporal trends in, and the impact of folic acid grain fortification on, the prevalence of encephalocele, spina bifida, and anencephaly using data from the Metropolitan Atlanta Congenital Defects Pro-

  7. Neural tube defects in pondicherry

    Microsoft Academic Search

    B. Mahadevan; B. Vishnu Bhat

    2005-01-01

    Objective: This study was carried out to identify the trend and the frequency of neural tube defects from July 1998 to June 2004.Methods; A total of 310 babies were born with neural tube defects with the overall frequency of 5.7\\/1000 births compared to 2.3\\/1000\\u000a births observed earlier in our hospital.Results : The most common defect was spina bifida (54.8%) followed

  8. Epidemiology of neural tube defects.

    PubMed

    Frey, Lauren; Hauser, W Allen

    2003-01-01

    Neural tube defects (NTDs)-malformations secondary to abnormal neural tube closure between the third and fourth weeks of gestational age-have a complex and imperfectly understood etiology in which both genetic and environmental factors appear to be involved. A number of specific chromosomal or single-gene disorders, presumably not affected by environmental influences, are associated with the development of NTDs, but such syndromal cases account for a small proportion of NTDs in live-born infants. Analysis of recurrence patterns within families and of twin-concordance data provides evidence of a genetic influence in nonsyndromal cases, but factors such as socioeconomic status and geographic area (independent of race or ethnicity) are also associated with variations in the incidence of NTDs. The prevalence at birth of both anencephaly and spina bifida has decreased, but the advent of antenatal diagnosis and elective termination of affected pregnancies has undermined the reliability of birth prevalence rate as an estimate of incidence. Some occupational and other exposures, including maternal use of antiepileptic drugs (AEDs), are associated with increased risk for NTDs. Among women who have had an NTD-affected pregnancy, recurrence risk is markedly higher than the risk for a first NTD-affected pregnancy in the general population. There is strong evidence, overall, for a protective effect of adequate folate consumption. In some high-risk groups, however, such as women taking AEDs, folate supplementation has not been proven to reduce NTD risk. PMID:12790881

  9. Brain tissue aspiration neural tube defect

    Microsoft Academic Search

    Luiz Cesar Peres; Gustavo Henrique T. de Sales Barbosa

    2005-01-01

    The study aimed to find out how frequent is brain tissue aspiration and if brain tissue hetero- topia could be found in the lung of human neural tube defect cases. Histological sections of each lobe of both lungs of 22 fetuses and newborn with neural tube defect were immunostained for glial fibrillary acidic protein (GFAP). There were 15 (68.2%) females

  10. Non-multifactorial neural tube defects.

    PubMed

    Lynch, Sally Ann

    2005-05-15

    Although most neural tube defects (anencephaly, spina bifida) occur as isolated malformations, a substantial proportion are attributable to chromosome anomalies, known teratogens, or component manifestations of multiple anomaly syndromes. This review describes known chromosome alterations and the candidate genes residing in the altered region, as well as syndromes associated with neural tube defects and causative genes, if known. PMID:15800854

  11. Epidemiology of neural tube defects.

    PubMed

    Mitchell, Laura E

    2005-05-15

    The epidemiological investigation of the common open neural tube defects (NTDs), anencephaly, and spina bifida, has a long history. The most significant finding from these past studies of NTDs was the identification of the protective effect of maternal, periconceptional supplementation with folic acid. Fortuitously, the association between folic acid and NTDs became widely accepted in the early 1990s, at a time when genetic association studies of complex traits were becoming increasingly feasible. The confluence of these events has had a major impact on the direction of epidemiological, NTD research. Association studies to evaluate genes that may influence the risk of NTDs through their role in folate-related processes, or through other metabolic or developmental pathways are now commonplace. Moreover, the study of genetic as well as non-genetic, factors that may influence NTD risk through effects on the nutrient status of the mother or embryo has emerged as a major research focus. Research efforts over the past decade indicate that gene-gene, gene-environment, and higher-order interactions, as well as maternal genetic effects influence NTD risk, highlighting the complexity of the factors that underlie these conditions. The challenge for the future is to design studies that address these complexities, and are adequately powered to detect the factors or combination of factors that influence the development of NTDs. PMID:15800877

  12. Further characterization of the genetic defect of the Bent tail mouse, a mouse model for human neural tube defects

    Microsoft Academic Search

    E. D. Klootwijk; Mascha M. V. A. P. Schijvenaars; Edwin C. M. Mariman; Barbara Franke

    2004-01-01

    BACKGROUND: Neural tube defects (NTDs) are congenital malformations arising mostly from incomplete neural tube closure during early embryogenesis. Most NTDs in humans have a complex etiology, with involvement of both genetic and environmental factors. More than 100 mouse models for human neural tube defects exist; Bent tail is one of them. The mouse mutant is caused by a submicroscopic deletion

  13. Dynamic Imaging of Mammalian Neural Tube Closure

    PubMed Central

    Pyrgaki, Christina; Trainor, Paul; Hadjantonakis, Anna-Katerina; Niswander, Lee

    2013-01-01

    Neurulation, the process of neural tube formation, is a complex morphogenetic event. In the mammalian embryo, an understanding of the dynamic nature of neurulation has been hampered due to its in utero development. Here we use laser point scanning confocal microscopy of a membrane expressed fluorescent protein to visualize the dynamic cell behaviors comprising neural tube closure in the cultured mouse embryo. In particular, we have focused on the final step wherein the neural folds approach one another and seal to form the closed neural tube. Our unexpected findings reveal a mechanism of closure in the midbrain different from the zipper-like process thought to occur more generally. Individual non-neural ectoderm cells on opposing sides of the neural folds undergo a dramatic change in shape to protrude from the epithelial layer and then form intermediate closure points to “button-up” the folds. Cells from the juxtaposed neural folds extend long and short flexible extensions and form bridges across the physical gap of the closing folds. Thus, the combination of live embryo culture with dynamic imaging provides intriguing insight into the cell biological processes that mold embryonic tissues in mammals. PMID:20558153

  14. Morphogenetic movements in the neural plate and neural tube: mouse.

    PubMed

    Massarwa, R'ada; Ray, Heather J; Niswander, Lee

    2014-01-01

    The neural tube (NT), the embryonic precursor of the vertebrate brain and spinal cord, is generated by a complex and highly dynamic morphological process. In mammals, the initially flat neural plate bends and lifts bilaterally to generate the neural folds followed by fusion of the folds at the midline during the process of neural tube closure (NTC). Failures in any step of this process can lead to neural tube defects (NTDs), a common class of birth defects that occur in approximately 1 in 1000 live births. These severe birth abnormalities include spina bifida, a failure of closure at the spinal level; craniorachischisis, a failure of NTC along the entire body axis; and exencephaly, a failure of the cranial neural folds to close which leads to degeneration of the exposed brain tissue termed anencephaly. The mouse embryo presents excellent opportunities to explore the genetic basis of NTC in mammals; however, its in utero development has also presented great challenges in generating a deeper understanding of how gene function regulates the cell and tissue behaviors that drive this highly dynamic process. Recent technological advances are now allowing researchers to address these questions through visualization of NTC dynamics in the mouse embryo in real time, thus offering new insights into the morphogenesis of mammalian NTC. PMID:24902834

  15. Preventing neural tube defects in Europe: A missed opportunity

    Microsoft Academic Search

    Araceli Busby; Ben Armstrong; Helen Dolk; Nicola Armstrong; Martin Haeusler; Andrea Berghold; Yves Gillerot; Andre Baguette; Romana Gjergja; Ingeborg Barisic; Marianne Christiansen; Janine Goujard; Volker Steinbicker; Christine Rösch; Robert McDonnell; Gioacchino Scarano; Elisa Calzolari; Amanda Neville; Guido Cocchi; Sebastiano Bianca; Miriam Gatt; Hermien De Walle; Paula Braz; Anna Latos-Bielenska; Blance Gener; Isabel Portillo; Marie-Claude Addor; Lenore Abramsky; Annukka Ritvanen; Elisabeth Robert-Gnansia; Anne Kjersti Daltveit; Goran Aneren; Birgitta Olars; Grace Edwards

    2005-01-01

    Each year, more than 4500 pregnancies in the European Union are affected by neural tube defects (NTD). Unambiguous evidence of the effectiveness of periconceptional folic acid in preventing the majority of neural tube defects has been available since 1991. We report on trends in the total prevalence of neural tube defects up to 2002, in the context of a survey

  16. Genetic Studies in Neural Tube Defects

    Microsoft Academic Search

    Elizabeth C. Melvin; Timothy M. George; Gordon Worley; Amy Franklin; Joanne Mackey; Kristi Viles; Nishu Shah; Courtney R. Drake; David S. Enterline; David McLone; Jeffrey Nye; W. Jerry Oakes; Colleen McLaughlin; Marion L. Walker; Paula Peterson; Timothy Brei; Connie Buran; Joanna Aben; Bonnie Ohm; Iskandar Bermans; Mazin Qumsiyeh; Jeffrey Vance; Margaret A. Pericak-Vance; Marcy C. Speer

    2000-01-01

    Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed

  17. Genetics and development of neural tube defects.

    PubMed

    Copp, Andrew J; Greene, Nicholas D E

    2010-01-01

    Congenital defects of neural tube closure (neural tube defects; NTDs) are among the commonest and most severe disorders of the fetus and newborn. Disturbance of any of the sequential events of embryonic neurulation produce NTDs, with the phenotype (eg anencephaly, spina bifida) varying depending on the region of neural tube that remains open. While mutation of > 200 genes is known to cause NTDs in mice, the pattern of occurrence in humans suggests a multifactorial polygenic or oligogenic aetiology. This emphasizes the importance of gene-gene and gene-environment interactions in the origins of these defects. A number of cell biological functions are essential for neural tube closure, with defects of the cytoskeleton, cell cycle and molecular regulation of cell viability prominent among the mouse NTD mutants. Many transcriptional regulators and proteins that affect chromatin structure are also required for neural tube closure, although the downstream molecular pathways regulated by these proteins is unknown. Some key signalling pathways for NTDs have been identified: over-activation of sonic hedgehog signalling and loss of function in the planar cell polarity (non-canonical Wnt) pathway are potent causes of NTD, with requirements also for retinoid and inositol signalling. Folic acid supplementation is an effective method for primary prevention of a proportion of NTDs in both humans and mice, although the embryonic mechanism of folate action remains unclear. Folic acid-resistant cases can be prevented by inositol supplementation in mice, raising the possibility that this could lead to an additional preventive strategy for human NTDs in future. PMID:19918803

  18. Genetics and development of neural tube defects

    PubMed Central

    Copp, Andrew J.; Greene, Nicholas D. E.

    2014-01-01

    Congenital defects of neural tube closure (neural tube defects; NTDs) are among the commonest and most severe disorders of the fetus and newborn. Disturbance of any of the sequential events of embryonic neurulation produce NTDs, with the phenotype (e.g. anencephaly, spina bifida) varying depending on the region of neural tube that remains open. While mutation of more than 200 genes is known to cause NTDs in mice, the pattern of occurrence in humans suggests a multifactorial polygenic or oligogenic aetiology. This emphasises the importance of gene-gene and gene-environment interactions in the origin of these defects. A number of cell biological functions are essential for neural tube closure, with defects of the cytoskeleton, cell cycle and molecular regulation of cell viability prominent among the mouse NTD mutants. Many transcriptional regulators and proteins that affect chromatin structure are also required for neural tube closure, although the downstream molecular pathways regulated by these proteins is unknown. Some key signalling pathways for NTDs have been identified: over-activation of sonic hedgehog signalling and loss of function in the planar cell polarity (non-canonical Wnt) pathway are potent causes of NTD, with requirements also for retinoid and inositol signalling. Folic acid supplementation is an effective method for primary prevention of a proportion of NTDs, in both humans and mice, although the embryonic mechanism of folate action remains unclear. Folic acid-resistant cases can be prevented by inositol supplementation in mice, raising the possibility that this could lead to an additional preventive strategy for human NTDs in future. PMID:19918803

  19. Neural tube defects: prevalence, etiology and prevention.

    PubMed

    Kondo, Atsuo; Kamihira, Osamu; Ozawa, Hideo

    2009-01-01

    Spina bifida and anencephaly, the common form of neural tube defects, affect approximately 300 000 newborns each year worldwide. The effectiveness of folic acid supplementation in preventing their occurrence or recurrence has been unambiguous since 1991. In general, the prevalence of these abnormalities has decreased in the past 20 to 30 years because of periconceptional folate supplementation, food fortification in several countries, avoiding exposure to environmental factors, and increased accuracy of prenatal screening for fetal anomalies. Women who are planning to conceive should be informed about the importance of folic acid in fetal development and advised to take 400 microg/day of folic acid supplements. Food fortification with folic acid will ultimately be necessary to reduce the number of patients. Primary prevention of neural tube defects by the periconceptional intake of folic acid is a major public health opportunity and has wide implications in reducing the mortality and morbidity of offspring. PMID:19120526

  20. Neural tube defects, folic acid and methylation.

    PubMed

    Imbard, Apolline; Benoist, Jean-François; Blom, Henk J

    2013-09-01

    Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects. PMID:24048206

  1. Neural Tube Defects, Folic Acid and Methylation

    PubMed Central

    Imbard, Apolline; Benoist, Jean-François; Blom, Henk J.

    2013-01-01

    Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects. PMID:24048206

  2. Introduction Anteroposterior (AP) patterning of the developing neural tube

    E-print Network

    Blumberg, Bruce

    2653 Introduction Anteroposterior (AP) patterning of the developing neural tube is a crucial early in Spemann's Organizer such as noggin, follistatin or chordin become neuralized in the absence of mesoderm., 1995; Xu et al., 1995) that normally acts to repress neural fate. Organizer-expressed neural inducing

  3. Folic acid in the prevention of neural tube defects

    Microsoft Academic Search

    J. M. Scott; P. N. Kirke; D. G. Weir

    1992-01-01

    Failure of the embryonal neural tube to close gives rise to a group of severe congenital malformations known as neural tube defects (NTD). These anomalies include spina bifida, anenceph~us, encephalocoele and inencephaly. The prevalence rate at birth* of NTD in the Eastern Health Board area was 2.3 per 1,000 births in 19871 . The neural tube closes between 24 and

  4. What Are the Treatments for Neural Tube Defects?

    MedlinePLUS

    ... and Publications What are the treatments for neural tube defects? Skip sharing on social media links Share ... surgeon can implant a shunt—a small hollow tube to drain fluid—to relieve pressure on the ...

  5. Mouse models for neural tube closure defects.

    PubMed

    Juriloff, D M; Harris, M J

    2000-04-12

    Neural tube closure defects (NTDs), in particular anencephaly and spina bifida, are common human birth defects (1 in 1000), their genetics is complex and their risk is reduced by periconceptional maternal folic acid supplementation. There are > 60 mouse mutants and strains with NTDs, many reported within the past 2 years. Not only are NTD mutations at loci widely heterogeneous in function, but also most of the mutants demonstrate variable low penetrance and some show complex inheritance patterns (e.g. SELH/Bc, Abl / Arg, Mena / Profilin1 ). In most of these mouse models, the NTDs are exencephaly (equivalent to anencephaly) or spina bifida or both, reflecting failure of neural fold elevation in well defined, mechanistically distinct elevation zones. NTD risk is reduced in various models by different maternal nutrient supplements, including folic acid ( Pax3, Cart1, Cd mutants), inositol ( ct ) and methionine ( Axd ). Lack of de novo methylation in embryos ( Dnmt3b -null) leads to NTD risk, and we suggest a potential link between methylation and the observed female excess among cranial NTDs in several models. Some surprising NTD mutants ( Gadd45a, Terc, Trp53 ) suggest that genes with a basic mitotic function also have a function specific to neural fold elevation. The genes mutated in several mouse NTD models involve actin regulation ( Abl/Arg, Macs, Mena/Profilin1, Mlp, Shrm, Vcl ), support the postulated key role of actin in neural fold elevation, and may be a good candidate pathway to search for human NTD genes. PMID:10767323

  6. Neural tube defects, folate, and immune modulation.

    PubMed

    Denny, Kerina J; Jeanes, Angela; Fathe, Kristin; Finnell, Richard H; Taylor, Stephen M; Woodruff, Trent M

    2013-09-01

    Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored. PMID:24078477

  7. Neural tube defects: pathogenesis and folate metabolism.

    PubMed

    Pulikkunnel, Scaria T; Thomas, S V

    2005-02-01

    Neural tube defects (NTDs) are a group of congenital malformations with worldwide distribution and complex aetio-pathogenesis. Animal studies indicate that there may be four sites of initiation of neural tube closure (NTC). Selective involvement of these sites may lead to defects varying from anencephaly to spina bifida. The NTC involves formation of medial and dorsolateral hinge points, convergent extension and a zipper release process. Proliferation and migration of neuroectodermal cells and its morphological changes brought about by microfilaments and other cytoskeletal proteins mediate NTC. Genetic, nutritional and teratogenic mechanisms have been implicated in the pathogenesis of NTDs. Folate is an important component in one carbon metabolism that provides active moieties for synthesis of nucleic acids and proteins. Several gene defects affecting enzymes and proteins involved in transport and metabolism of folate have been associated with NTDs. It may be possible in future, to identify individuals at higher risk of NTDs by genetic studies. Epidemiological and clinical studies have shown that dietary supplementation or food fortification with folic acid would reduce the incidence of NTDs. The protective effect of folic acid may be by overcoming these metabolic blocks through unidentified mechanisms. Genetic and biochemical studies on foetal cells may supplement currently available prenatal tests to diagnose NTDs. Antiepileptic drugs (AEDs), particularly valproate and carbamazepine have been shown to increase the risk of NTDs by possibly increasing the oxidative stress and deranging the folate metabolism. Accordingly, it is recommended that all women taking AEDs may use 1-5 mg folic acid daily in the pre conception period and through pregnancy. PMID:15847033

  8. Risk Factors of Neural Tube Defects in Northern Iran

    PubMed Central

    Golalipour, Mohammad Jafar; Qorbani, Mostafa; Mirfazeli, Arezo; Mobasheri, Elham

    2014-01-01

    Background: Neural tube defects (NTDs) including spina bifida and anencephaly are the second most common birth defects with 2.8 per 1000 births in northern Iran. Objectives: This study was conducted to determine the risk factors of neural tube defects in Gorgan, north of Iran. Patients and Methods: This hospital-based, case-control study was carried out on all NTD-affected pregnancies (n = 59) during February 2007 - August 2010, and 160 healthy pregnancies were selected via convenient sampling method in three hospitals in Gorgan, north of Iran. Risk factors including maternal body mass index (BMI), season of birth, gender of the newborn, mother’s age, ethnicity, consanguineous marriage, folic acid consumption, nutrition, habitat, and education, were assessed through interviews with mothers. Univariate and multivariate logistic regression analyses were used to estimate the risks by odds ratios (ORs) and 95% confidence intervals. Results: The multivariate analysis showed that maternal BMI (normal/underweight OR: 0.23, overweight/underweight OR: 0.15, obese/underweight OR: 0.13) and maternal ethnicity (Fars/Sistani OR: 3.49) and maternal nutrition (good/poor OR: 0.46) were significantly correlated with NTDs in the newborns. Conclusions: This study showed that maternal ethnicity, insufficient nutrition, and BMI, were the main risk factors of NTDs in northern Iran. PMID:25068063

  9. Neural tube defects: recent advances, unsolved questions, and controversies.

    PubMed

    Copp, Andrew J; Stanier, Philip; Greene, Nicholas D E

    2013-08-01

    Neural tube defects are severe congenital malformations affecting around one in every 1000 pregnancies. An innovation in clinical management has come from the finding that closure of open spina bifida lesions in utero can diminish neurological dysfunction in children. Primary prevention with folic acid has been enhanced through introduction of mandatory food fortification in some countries, although not yet in the UK. Genetic predisposition accounts for most of the risk of neural tube defects, and genes that regulate folate one-carbon metabolism and planar cell polarity have been strongly implicated. The sequence of human neural tube closure events remains controversial, but studies of mouse models of neural tube defects show that anencephaly, open spina bifida, and craniorachischisis result from failure of primary neurulation, whereas skin-covered spinal dysraphism results from defective secondary neurulation. Other malformations, such as encephalocele, are likely to be postneurulation disorders. PMID:23790957

  10. How Do Health Care Providers Diagnose Neural Tube Defects?

    MedlinePLUS

    ... Information Clinical Trials Resources and Publications How do health care providers diagnose neural tube defects? Skip sharing on ... AFP, as well as high levels of acetylcholinesterase; health care providers might conduct this test to confirm high ...

  11. Homocysteine metabolism in pregnancies complicated by neural-tube defects

    Microsoft Academic Search

    J. L. Mills; Y. J. Lee; M. R. Conley; P. N. Kirke; J. M. McPartlin; D. G. Weir; J. M. Scott

    1995-01-01

    Folic acid taken around the time of conception can prevent many neural-tube defects. Women with low-normal vitamin B12 values may also be at increased risk. We considered whether homocysteine metabolism via the enzyme methionine synthase, which requires both folate and B12, could be the critical defect in folate-related neural tube defects. Blood was obtained during pregnancies that produced 81 infants

  12. Aneuploidy among prenatally detected neural tube defects

    SciTech Connect

    Hume, R.F. Jr.; Lampinen, J.; Martin, L.S.; Johnson, M.P.; Evans, M.I. [Wayne State Univ., Detroit, MI (United States)] [and others] [Wayne State Univ., Detroit, MI (United States); and others

    1996-01-11

    We have reported previously a 10% aneuploidy detection rate among 39 cases of fetal neural tube defects (NTD). Subsequently we amassed an additional experience of over 17,000 prenatal diagnosis cases over a 5-year period. During this period 106 cases of NTDs were identified; 44 with anencephaly, 62 with open spina bifida. The average maternal age of this population with NTDs was 29 years (15-40); 6 patients declined amniocentesis. Six of 100 cytogenetic studies were aneuploid; on anencephalic fetus had inherited a maternal marker chromosome, and 5 NTD cases had trisomy 18. The average maternal age of the aneuploid cases was 21 (19-40); 3 were 35 years or older. Four of 5 trisomy 18 cases had multiple congenital anomalies (MCA). The overall aneuploidy detection rate in our cohort was 5-6, while aneuploidy occurred in 2% of the isolated NTD cases, and 24% of the MCA cases. Combining the earlier experience, 4/39 aneuploidy (2 trisomy 18, 4p+, del 13q) yields an aneuploidy detection frequency of 10/145 (7%), of which most (7/10) had trisomy 18. These data support fetal karyotyping for accurate diagnosis, prognosis, and recurrence-risk counseling. 5 refs., 2 tabs.

  13. Incidence of open neural tube defects in Nova Scotia after folic acid fortification

    Microsoft Academic Search

    Vidia L. Persad; Michiel C. Van den Hof; Johanne M. Dubé; Pamela Zimmer

    2002-01-01

    Background: With the goal of preventing open neural tube defects (NTDs), recom- mendations for folic acid supplementation before conception were introduced in Canada in 1994, and by November 1998 Canadian grain products were being fortified with folic acid. We wished to determine whether the annual incidence of open NTDs in Nova Scotia, including those in stillbirths and terminated preg- nancies,

  14. Identifying environmental risk factors for human neural tube defects before and after folic acid supplementation

    Microsoft Academic Search

    Yilan Liao; Jinfeng Wang; Xinhu Li; Yaoqin Guo; Xiaoying Zheng

    2009-01-01

    BACKGROUND: Birth defects are a major cause of infant mortality and disability in many parts of the world. Neural tube defects (NTDs) are one of the most common types of birth defects. In 2001, the Chinese population and family planning commission initiated a national intervention program for the prevention of birth defects. A key step in the program was the

  15. Lowered weight gain during pregnancy and risk of neural tube defects among offspring

    Microsoft Academic Search

    Gary M Shaw; Karen Todoroff; Suzan L Carmichael; Donna M Schafferb; Steve Selvinc

    2001-01-01

    Background Maternal nutritional factors have been implicated in the complex aetiology of neural tube defects (NTD). We investigated whether the amount of weight a woman gained during pregnancy was associated with her risk of delivering an infant with an NTD. Methods We conducted a population-based case-control study within the cohort of 708 129 live births and fetal deaths occurring in

  16. Arsenate-induced maternal glucose intolerance and neural tube defects in a mouse model

    Microsoft Academic Search

    Denise S. Hill; Bogdan J. Wlodarczyk; Laura E. Mitchell; Richard H. Finnell

    2009-01-01

    BackgroundEpidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals.

  17. Genetics of human neural tube defects

    PubMed Central

    Greene, Nicholas D.E.; Stanier, Philip; Copp, Andrew J.

    2009-01-01

    Neural tube defects (NTDs) are common, severe congenital malformations whose causation involves multiple genes and environmental factors. Although more than 200 genes are known to cause NTDs in mice, there has been rather limited progress in delineating the molecular basis underlying most human NTDs. Numerous genetic studies have been carried out to investigate candidate genes in cohorts of patients, with particular reference to those that participate in folate one-carbon metabolism. Although the homocysteine remethylation gene MTHFR has emerged as a risk factor in some human populations, few other consistent findings have resulted from this approach. Similarly, attention focused on the human homologues of mouse NTD genes has contributed only limited positive findings to date, although an emerging association between genes of the non-canonical Wnt (planar cell polarity) pathway and NTDs provides candidates for future studies. Priorities for the next phase of this research include: (i) larger studies that are sufficiently powered to detect significant associations with relatively minor risk factors; (ii) analysis of multiple candidate genes in groups of well-genotyped individuals to detect possible gene–gene interactions; (iii) use of high throughput genomic technology to evaluate the role of copy number variants and to detect ‘private’ and regulatory mutations, neither of which have been studied to date; (iv) detailed analysis of patient samples stratified by phenotype to enable, for example, hypothesis-driven testing of candidates genes in groups of NTDs with specific defects of folate metabolism, or in groups of fetuses with well-defined phenotypes such as craniorachischisis. PMID:19808787

  18. Signaling by Sonic hedgehog (Shh) controls important developmental processes, including dorsoventral neural tube

    E-print Network

    Quake, Stephen R.

    dorsoventral neural tube patterning, neural stem cell proliferation, and neuronal and glial cell survival. Shh and cyclopia due to a failure of separation of the lobes of the forebrain [1,2]. In the neural tube, Shh of the Shh and Hh signal transduction mechanisms. The graded activity of Shh in patterning the neural tube

  19. Cellular mechanisms of posterior neural tube morphogenesis in the zebrafish.

    PubMed

    Harrington, Michael J; Chalasani, Kavita; Brewster, Rachel

    2010-03-01

    The zebrafish is a well established model system for studying neural development, yet neurulation remains poorly understood in this organism. In particular, the morphogenetic movements that shape the posterior neural tube (PNT) have not been described. Using tools for imaging neural tissue and tracking the behavior of cells in real time, we provide the first comprehensive analysis of the cellular events shaping the PNT. We observe that this tissue is formed in a stepwise manner, beginning with merging of presumptive neural domains in the tailbud (Stage 1); followed by neural convergence and infolding to shape the neural rod (Stage 2); and continued elongation of the PNT, in absence of further convergence (Stage 3). We further demonstrate that cell proliferation plays only a minimal role in PNT elongation. Overall, these mechanisms resemble those previously described in anterior regions, suggesting that, in contrast to amniotes, neurulation is a fairly uniform process in zebrafish. PMID:20077475

  20. Periconceptional Folate Deficiency and Implications in Neural Tube Defects

    PubMed Central

    Safi, J.; Joyeux, L.; Chalouhi, G. E.

    2012-01-01

    Nutritional deficiencies are preventable etiological and epigenetic factors causing congenital abnormalities, first cause of infant mortality. Folate deficiency has a well-established teratogenic effect, leading to an increasing risk of neural tube defects. This paper highlights the most recent medical literature about folate deficiency, be it maternal or paternal. It then focuses on associated deficiencies as nutritional deficiencies are multiple and interrelated. Observational and interventional studies have all been consistent with a 50–70% protective effect of adequate women consumption of folates on neural tube defects. Since strategies to modify women's dietary habits and vitamin use have achieved little progress, scientific as well as political effort is mandatory in order to implement global preventive public health strategies aimed at improving the alimentation of women in reproductive age, especially folic acid supplementation. Even with the recent breakthrough of fetal surgery for myelomeningocele, the emphasis should still be on prevention as the best practice rather than treatment of neural tube defects. PMID:22900183

  1. Gene expression profiling within the developing neural tube.

    PubMed

    Finnell, Richard H; Junker, Wade M; Wadman, Lisa Kvist; Cabrera, Robert M

    2002-10-01

    The developing mammalian nervous system is subject to devastating congenital malformations with clinical significance that extends into the billions of health care dollars annually worldwide. Neural tube defects (NTDs) are among the most common of all human congenital defects, yet their etiology remains poorly understood. This is largely due to the complexity of the genetic factors regulating the intricate events involved in neurulation. Using mouse model systems and the application of modern molecular biological technologies, we have recently gained a greater appreciation for the factors that not only regulate normal neural tube closure (NTC), but those genetic factors that predispose an embryo to significant birth defects such as anencephaly or spina bifida. We have selected prominent murine mutants, both spontaneous and genetically modified, as well as the use of teratogenic agents, to examine the impact of altering the normal pattern of gene expression in the developing neural tube. PMID:12462415

  2. Human neural tube defects: developmental biology, epidemiology, and genetics.

    PubMed

    Detrait, Eric R; George, Timothy M; Etchevers, Heather C; Gilbert, John R; Vekemans, Michel; Speer, Marcy C

    2005-01-01

    Birth defects (congenital anomalies) are the leading cause of death in babies under 1 year of age. Neural tube defects (NTD), with a birth incidence of approximately 1/1000 in American Caucasians, are the second most common type of birth defect after congenital heart defects. The most common presentations of NTD are spina bifida and anencephaly. The etiologies of NTDs are complex, with both genetic and environmental factors implicated. In this manuscript, we review the evidence for genetic etiology and for environmental influences, and we present current views on the developmental processes involved in human neural tube closure. PMID:15939212

  3. Mutations in VANGL1 associated with neural-tube defects.

    PubMed

    Kibar, Zoha; Torban, Elena; McDearmid, Jonathan R; Reynolds, Annie; Berghout, Joanne; Mathieu, Melissa; Kirillova, Irena; De Marco, Patrizia; Merello, Elisa; Hayes, Julie M; Wallingford, John B; Drapeau, Pierre; Capra, Valeria; Gros, Philippe

    2007-04-01

    Neural-tube defects such as anencephaly and spina bifida constitute a group of common congenital malformations caused by complex genetic and environmental factors. We have identified three mutations in the VANGL1 gene in patients with familial types (V239I and R274Q) and a sporadic type (M328T) of the disease, including a spontaneous mutation (V239I) appearing in a familial setting. In a protein-protein interaction assay V239I abolished interaction of VANGL1 protein with its binding partners, disheveled-1, -2, and -3. These findings implicate VANGL1 as a risk factor in human neural-tube defects. PMID:17409324

  4. Prevention of Neural Tube Defects. ARC Q&A #101-45.

    ERIC Educational Resources Information Center

    Arc, Arlington, TX.

    This fact sheet uses a question-and-answer format to summarize issues related to the prevention of neural tube defects. Questions and answers address the following topics: what neural tube defects are and the most common types (spina bifida and anencephaly); occurrence of neural tube defects during the first month of pregnancy; the frequency of…

  5. Birth order and neural tube defects: a reappraisal

    Microsoft Academic Search

    Alexandre R Vieira

    2004-01-01

    There is evidence that late birth order is associated with some complex disorders. For neural tube defects (NTDs) there is no consensus as to whether first or increased birth order is associated or not. A meta-analysis of published data on NTDs was carried out to ascertain whether there is an increased risk for children first born or of high birth

  6. Social networks and risk of neural tube defects

    Microsoft Academic Search

    Suzan L. Carmichael; Gary M. Shaw; Eric Neri; Donna M. Schaffer; Steve Selvin

    2003-01-01

    The contribution of social support and social networks to risk of neural tube defects (NTDs) has not been explored, despite evidence that various aspects of the social environment contribute to their etiology. Using data from a population-based case–control study of deliveries occurring in California from 1989 to 1991, this study investigates whether social networks, as measured by the presence and

  7. East Ireland 1980-1994: epidemiology of neural tube defects

    Microsoft Academic Search

    R. J. McDonnell; Z. Johnson; V. Delaney; P. Dack

    1999-01-01

    STUDY OBJECTIVE: The objective of the study was to describe the epidemiology of neural tube defects (NTD) in the eastern region of Ireland using the EUROCAT register of congenital malformations. DESIGN, SETTING AND PATIENTS: EUROCAT registries monitor the prevalence of congenital anomalies in defined populations using multiple sources for case ascertainment. All cases of NTD on the Dublin EUROCAT register

  8. Gene Expression Profiling Within the Developing Neural Tube

    Microsoft Academic Search

    Richard H. Finnell; Wade M. Junker; Lisa Kvist Wadman; Robert M. Cabrera

    2002-01-01

    The developing mammalian nervous system is subject to devastating congenital malformations with clinical significance that extends into the billions of health care dollars annually worldwide. Neural tube defects (NTDs) are among the most common of all human congenital defects, yet their etiology remains poorly understood. This is largely due to the complexity of the genetic factors regulating the intricate events

  9. Chapter 1 Modeling Neural Tube Defects in the Mouse

    Microsoft Academic Search

    Irene E. Zohn; Anjali A. Sarkar

    2008-01-01

    Neural tube defects (NTDs) are among the most common structural birth defects observed in humans. Mouse models provide an excellent experimental system to study the underlying causes of NTDs. These models not only allow for identification of the genes required for neurulation, they provide tractable systems for uncovering the developmental, pathological and molecular mechanisms underlying NTDs. In addition, mouse models

  10. Transcription factor TEAD2 is involved in neural tube closure.

    PubMed

    Kaneko, Kotaro J; Kohn, Matthew J; Liu, Chengyu; DePamphilis, Melvin L

    2007-09-01

    TEAD2, one of the first transcription factors expressed at the beginning of mammalian development, appears to be required during neural development. For example, Tead2 expression is greatest in the dorsal neural crest where it appears to regulate expression of Pax3, a gene essential for brain development. Consistent with this hypothesis, we found that inactivation of the Tead2 gene in mice significantly increased the risk of exencephaly (a defect in neural tube closure). However, none of the embryos exhibited spina bifida, the major phenotype of Pax3 nullizygous embryos, and expression of Pax3 in E11.5 Tead2 nullizygous embryos was normal. Thus, Tead2 plays a role in neural tube closure that is independent of its putative role in Pax3 regulation. In addition, the risk of exencephaly was greatest with Tead2 nullizygous females, and could be suppressed either by folic acid or pifithrin-alpha. These results reveal a maternal genetic contribution to neural tube closure, and suggest that Tead2-deficient mice provide a model for anencephaly, a common human birth defect that can be prevented by folic acid. PMID:17868131

  11. Neural Tube Defect Genes and Maternal Diabetes during Pregnancy

    PubMed Central

    Salbaum, J. Michael; Kappen, Claudia

    2012-01-01

    BACKGROUND Maternal diabetes during pregnancy is a well-known teratogen that increases the risk for birth defects, such as neural tube defects (NTDs). We have previously shown that maternal diabetes profoundly affects gene expression in the developing embryo, in particular a suite of known NTD genes. In rodent experimental systems, NTDs present as phenotypes of incomplete penetrance in diabetic pregnancies. This property is difficult to reconcile with observations of consistently altered gene expression in exposed embryos. We here show that maternal diabetes increases the overall variability of gene expression levels in embryos. RESULTS Altered gene expression and increased variability of gene expression together may constitute the molecular correlates for incomplete phenotype penetrance. DISCUSSION Based on this model, we suggest that maternal diabetes reduces the precision of gene regulation in exposed individuals. Loss of precision in embryonic gene regulation may include changes to the epigenome via deregulated expression of chromatin-modifying factors. Unraveling the mechanisms underlying such epigenetic modifications in diabetic pregnancies will help to understand how teratogenic insults compromise embryonic development and possibly provide avenues for therapeutic intervention. PMID:20564432

  12. Prevention of Neural-Tube Defects with Periconceptional Folic Acid, Methylfolate, or Multivitamins?

    Microsoft Academic Search

    Andrew E. Czeizel; István Dudás; László Paput; Ferenc Bánhidy

    2011-01-01

    Background\\/Aims: To review the main results of intervention trials which showed the efficacy of periconceptional folic acid-containing multivitamin and folic acid supplementation in the prevention of neural-tube defects (NTD). Methods and Results: The main findings of 5 intervention trials are known: (i) the efficacy of a multivitamin containing 0.36 mg folic acid in a UK nonrandomized controlled trial resulted in

  13. Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients

    Microsoft Academic Search

    Bogdan J.. Wlodarczyk; Louisa S. Tang; Aleata Triplett; Frank Aleman; Richard H. Finnell

    2006-01-01

    Splotch (Sp\\/Sp) mice homozygous for a mutation in the Pax3 gene inevitably present with neural tube defects (NTDs), along with other associated congenital anomalies. The affected mutant embryos usually die by gestation days (E) 12–13. In the present study, the effect of modifier genes from a new genetic background (CXL-Sp) and periconceptional supplementation with selected micronutrients (folic acid, 5-formyltetrahydrofolate, 5-methyltetrahydrofolate,

  14. Adaptive Control Using Combined Online and Background Learning Neural Network

    E-print Network

    Johnson, Eric N.

    Adaptive Control Using Combined Online and Background Learning Neural Network Eric N. Johnson of stability properties. The NN learns the plant dynamics with online training, and then combines set [1], [2], and that the neural networks have an online learning adaptation capability that does

  15. Cats, frogs, and snakes: early concepts of neural tube defects.

    PubMed

    Obladen, Michael

    2011-11-01

    Disturbed neurulation fascinated scientists of all times. In Egypt, anencephalic infants were venerated as animal-headed gods. Roman law required them to be killed. The medieval world held the mother responsible, either because of assumed imagination or "miswatching," or because of suspected intercourse with animals or devils. Modern embryology and teratology began with the use of the microscope by Malpighi in 1672. Details of neural tube closure were described by Koelliker in 1861 and by His in 1874. From 1822, genetic disease and familial recurrence due to insufficient nutrition were discerned and lower social class identified as a risk factor. It took a century to define the malnutrition as insufficient folate intake. The mandatory supplementation of folate in staple foods successfully reduced the incidence of neural tube defects in the United States, Australia, Canada, and Chile, but it was not adopted by most European countries. PMID:21730342

  16. Neural tube defects – recent advances, unsolved questions and controversies

    PubMed Central

    Copp, Andrew J.; Stanier, Philip; Greene, Nicholas D. E.

    2014-01-01

    Neural tube defects (NTDs) are severe congenital malformations affecting around 1 in every 1000 pregnancies. Here we review recent advances and currently unsolved issues in the NTD field. An innovation in clinical management has come from the demonstration that closure of open spina bifida lesions in utero can diminish neurological dysfunction in children. Primary prevention by folic acid has been enhanced through introduction of mandatory food fortification in some countries, although not yet in UK. Genetic predisposition comprises the majority of NTD risk, and genes that regulate folate one-carbon metabolism and planar cell polarity have been strongly implicated. The sequence of human neural tube closure events remains controversial, but study of mouse NTD models shows that anencephaly, open spina bifida and craniorachischisis result from failure of primary neurulation, while skin-covered spinal dysraphism results from defective secondary neurulation. Other ‘NTD’ malformations, such as encephalocele, are likely to be post-neurulation disorders. PMID:23790957

  17. Novel Mutations in VANGL1 in Neural Tube Defects

    PubMed Central

    Kibar, Zoha; Bosoi, Ciprian M.; Kooistra, Megan; Salem, Sandra; Finnell, Richard H.; Marco, Patrizia De; Merello, Elisa; Bassuk, Alexander G.; Capra, Valeria; Gros, Philippe

    2010-01-01

    Neural tube defects (NTDs) are severe congenital malformations caused by failure of the neural tube to close during neurulation. Their etiology is complex involving both environmental and genetic factors. We have recently reported three mutations in the planar cell polarity gene VANGL1 associated with NTDs. The aim of the present study was to define the role of VANGL1 genetic variants in the development of NTDs in a large cohort of various ethnic origins. We identified five novel missense variants in VANGL1, p.Ser83Leu, p.Phe153Ser, p.Arg181Gln, p.Leu202Phe and p.Ala404Ser, occurring in sporadic and familial cases of spinal dysraphisms. All five variants affect evolutionary conserved residues and are absent from all controls analyzed. This study provides further evidence supporting the role of VANGL1 as a risk factor in the development of spinal NTDs. PMID:19319979

  18. Etiology, pathogenesis and prevention of neural tube defects.

    PubMed

    Padmanabhan, Rengasamy

    2006-06-01

    Spina bifida, anencephaly, and encephalocele are commonly grouped together and termed neural tube defects (NTD). Failure of closure of the neural tube during development results in anencephaly or spina bifida aperta but encephaloceles are possibly post-closure defects. NTD are associated with a number of other central nervous system (CNS) and non-neural malformations. Racial, geographic and seasonal variations seem to affect their incidence. Etiology of NTD is unknown. Most of the non-syndromic NTD are of multifactorial origin. Recent in vitro and in vivo studies have highlighted the molecular mechanisms of neurulation in vertebrates but the morphologic development of human neural tube is poorly understood. A multisite closure theory, extrapolated directly from mouse experiments highlighted the clinical relevance of closure mechanisms to human NTD. Animal models, such as circle tail, curly tail, loop tail, shrm and numerous knockouts provide some insight into the mechanisms of NTD. Also available in the literature are a plethora of chemically induced preclosure and a few post-closure models of NTD, which highlight the fact that CNS malformations are of hetergeneitic nature. No Mendelian pattern of inheritance has been reported. Association with single gene defects, enhanced recurrence risk among siblings, and a higher frequency in twins than in singletons indicate the presence of a strong genetic contribution to the etiology of NTD. Non-availability of families with a significant number of NTD cases makes research into genetic causation of NTD difficult. Case reports and epidemiologic studies have implicated a number of chemicals, widely differing therapeutic drugs, environmental contaminants, pollutants, infectious agents, and solvents. Maternal hyperthermia, use of valproate by epileptic women during pregnancy, deficiency and excess of certain nutrients and chronic maternal diseases (e.g. diabetes mellitus) are reported to cause a manifold increase in the incidence of NTD. A host of suspected teratogens are also available in the literature. The UK and Hungarian studies showed that periconceptional supplementation of women with folate (FA) reduces significantly both the first occurrence and recurrence of NTD in the offspring. This led to mandatory periconceptional FA supplementation in a number of countries. Encouraged by the results of clinical studies, numerous laboratory investigations focused on the genes involved in the FA, vitamin B12 and homocysteine metabolism during neural tube development. As of today no clinical or experimental study has provided unequivocal evidence for a definitive role for any of these genes in the causation of NTD suggesting that a multitude of genes, growth factors and receptors interact in controlling neural tube development by yet unknown mechanisms. Future studies must address issues of gene-gene, gene-nutrient and gene-environment interactions in the pathogenesis of NTD. PMID:16732763

  19. Folate receptor gene variants and neural tube defect occurrence

    Microsoft Academic Search

    R. Finnell; K. Greer; E. Lammer

    1994-01-01

    Recent epidemiological evidence shows that periconceptional use of folic acid supplements may prevent 40-50% of neural tube defects (NTDs). The FDA has subsequently recommended folic acid supplementation of all women of childbearing potential, even though the mechanism by which folic acid prevents NTDs is unknown. We investigated genetic variation of a candidate gene, the 5-methyltetrahydrofolate (5-MeTHF) receptor, that may mediate

  20. Neural tube defects : Prevention by folic acid and other vitamins

    Microsoft Academic Search

    Andrew J. Copp; Nicholas D. E. Greene

    2000-01-01

    Folic acid has been demonstrated in clinical trials to reduce significantly the recurrence (and probably occurrence) of neural\\u000a tube defects (NTD). In the U.K., there has been no decline in prevalence of NTD since the publication of the findings with\\u000a folic acid. This article examines a series of questions relating to the action of folic acid, with emphasis on the

  1. Physical Activity and Risk of Neural Tube Defects

    Microsoft Academic Search

    Suzan L. Carmichael; Gary M. Shaw; Eric Neri; Donna M. Schaffer; Steve Selvin

    2002-01-01

    Objective: Owing to its association with known risk factors for neural tube defects (NTDs) and its impact on physiologic processes relevant to fetal development, physical activity was identified as a potential risk factor for NTD-affected pregnancy. Methods: Using data from a population-based case-control study of deliveries occurring in California from 1989 to 1991, we estimated the potential risk of having

  2. Neurofibromin Deficiency in Mice Causes Exencephaly and Is a Modifier for Splotch Neural Tube Defects

    Microsoft Academic Search

    Maha M. Lakkis; Jeffrey A. Golden; K. Sue O'Shea; Jonathan A. Epstein

    1999-01-01

    Neural tube defects are common and serious human congenital anomalies. These malformations have a multifactorial etiology and can be reproduced in mouse models by mutations of numerous individual genes and by perturbation of multiple environmental factors. The identification of specific genetic interactions affecting neural tube closure will facilitate our understanding of molecular pathways regulating normal neural development and will enhance

  3. Neural Tube Defects: Review of Experimental Evidence on Stem Cell Therapy and Newer Treatment Options

    Microsoft Academic Search

    Dhara B. Dhaulakhandi; Seema Rohilla; Kamal Nain Rattan

    2010-01-01

    The failure of closure of the neural tube during development leads to malformations called neural tube defects (NTDs). The most common neural malformations in humans include anencephaly, encephalocele, exencephaly, craniorachischisis spina bifida with or without myelomeningocele, lipomyeloschisis, lipomyelomeningocele, meningocele and myelocystocele. Current preventive strategies are mainly based on pharmacologic\\/folic acid supplementation. However, stem cell-based and other combination approaches may emerge

  4. Histological Evaluation of Acute Covering of an Experimental Neural Tube Defect with Biomatrices in Fetal Sheep

    Microsoft Academic Search

    A. J. Eggink; L. A. J. Roelofs; M. M. Y. Lammens; W. F. J. Feitz; R. M. H. Wijnen; R. A. Mullaart; H. T. B. van Moerkerk; T. H. van Kuppevelt; A. J. Crevels; A. Hanssen; F. K. Lotgering; P. P. van den Berg

    2006-01-01

    Objective: The aim of the study was to determine the histological effect on the neural tissue of in utero covering of an experimental neural tube defect in fetal lambs, with the use of two different biomatrices. Materials and Methods: In 23 fetal sheep, surgery was performed at 79 days’ gestation. In 19 of these, a neural tube defect was created,

  5. Population red blood cell folate concentrations for prevention of neural tube defects: bayesian model

    PubMed Central

    Devine, Owen; Hao, Ling; Dowling, Nicole F; Li, Song; Molloy, Anne M; Li, Zhu; Zhu, Jianghui; Berry, Robert J

    2014-01-01

    Objective To determine an optimal population red blood cell (RBC) folate concentration for the prevention of neural tube birth defects. Design Bayesian model. Setting Data from two population based studies in China. Participants 247?831 participants in a prospective community intervention project in China (1993-95) to prevent neural tube defects with 400 ?g/day folic acid supplementation and 1194 participants in a population based randomized trial (2003-05) to evaluate the effect of folic acid supplementation on blood folate concentration among Chinese women of reproductive age. Intervention Folic acid supplementation (400 ?g/day). Main outcome measures Estimated RBC folate concentration at time of neural tube closure (day 28 of gestation) and risk of neural tube defects. Results Risk of neural tube defects was high at the lowest estimated RBC folate concentrations (for example, 25.4 (95% uncertainty interval 20.8 to 31.2) neural tube defects per 10?000 births at 500 nmol/L) and decreased as estimated RBC folate concentration increased. Risk of neural tube defects was substantially attenuated at estimated RBC folate concentrations above about 1000 nmol/L (for example, 6 neural tube defects per 10?000 births at 1180 (1050 to 1340) nmol/L). The modeled dose-response relation was consistent with the existing literature. In addition, neural tube defect risk estimates developed using the proposed model and population level RBC information were consistent with the prevalence of neural tube defects in the US population before and after food fortification with folic acid. Conclusions A threshold for “optimal” population RBC folate concentration for the prevention of neural tube defects could be defined (for example, approximately 1000 nmol/L). Population based RBC folate concentrations, as a biomarker for risk of neural tube defects, can be used to facilitate evaluation of prevention programs as well as to identify subpopulations at elevated risk for a neural tube defect affected pregnancy due to folate insufficiency. PMID:25073783

  6. D-chiro-inositol is more effective than myo-inositol in preventing folate-resistant mouse neural tube defects

    Microsoft Academic Search

    Patricia Cogram; Sheila Tesh; John Tesh; Angie Wade; Geoffrey Allan; Nicholas D. E. Greene; Andrew J. Copp

    BACKGROUND: Among mouse genetic mutants that develop neural tube defects (NTDs), some respond to folic acid administration during early pregnancy, whereas NTDs in other mutants are not prevented. This parallels human NTDs, in which up to 30% of cases may be resistant to folic acid. Most spina bifida cases in the folic acid- resistant 'curly tail' mouse can be prevented

  7. A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects

    Microsoft Academic Search

    Shiliang Liu; Roy West; Edward Randell; Linda Longerich; Kathleen Steel O'Connor; Helen Scott; Marian Crowley; Angeline Lam; Victor Prabhakaran; Catherine McCourt

    2004-01-01

    BACKGROUND: Periconceptional use of vitamin supplements containing folic acid reduces the risk of a neural tube defect (NTD). In November 1998, food fortification with folic acid was mandated in Canada, as a public health strategy to increase the folic acid intake of all women of childbearing age. We undertook a comprehensive population based study in Newfoundland to assess the benefits

  8. Recent studies on neural tube defects in embryos of diabetic pregnancy: an overview.

    PubMed

    Dheen, S Thameem; Tay, Samuel S W; Boran, Jiang; Ting, Loh Wan; Kumar, S Dinesh; Fu, Jiang; Ling, Eng-Ang

    2009-01-01

    Maternal diabetes develops in 2-6% of total pregnancies, depending on geographical and ethnic background. About 10% of fetuses from diabetic pregnancy display congenital malformations in various organ systems including cardiovascular, gastrointestinal, genitourinary and neurological systems, among which the neural tube defects (NTDs) such as anencephaly, holoprosencephaly and syntelencephaly were more frequently demonstrated. Recent studies by the Diabetes Control and Complications Trial Research Group show that tight glycemic control early in pregnancy decreases the progression of a number of diabetic complications. However, it appears that the pre-existing tissue damage cannot be reversed even after normoglycemic levels are achieved during pregnancy. In recent years, considerable efforts have been made to investigate the etiology of birth defects among infants of diabetic mothers. It has been shown that diabetes-induced fetal abnormalities are accompanied by some metabolic disturbances including elevated superoxide dismutase (SOD) activity, reduced levels of myoinositol and arachidonic acid and inhibition of the pentose phosphate shunt pathway. Moreover, the frequency of fetal malformations in diabetic pregnancy has been reported to be markedly reduced by dietary supplements of antioxidants such as vitamin E, vitamin C and butylated hy- droxytoluene, suggesting that oxidative stress is involved in the etiology of fetal dysmorphogenesis. Furthermore, several experimental studies have shown that NTDs in embryos of diabetic mice are associated with altered expression of genes, which control development of the neural tube. In this review, recent findings of possible molecular mechanisms which cause morphological changes during neural tube development in embryos of diabetic pregnancy are discussed. PMID:19519395

  9. Polymorphisms of 5,10-Methylenetetrahydrofolate Reductase and Cystathionine ?-Synthase Genes as a Risk Factor for Neural Tube Defects in Sétif, Algeria

    Microsoft Academic Search

    Bakhouche Houcher; Romyla Bourouba; Farida Djabi; Erkan Yilmaz; Nejat Akar

    2009-01-01

    Background: Neural tube defects (NTD) are severe congenital malformations due to a failure in neural tube formation at the beginning of pregnancy. The etiology of NTD is multifactorial, with environmental and genetic determinants. We suggest a study of gene-gene interactions regarding the possible association of NTD with specific mutations of 5,10-methylenetetrahydrofolate reductase (MTHFR) and cystathionine ?-synthase (CBS) genes. Patients and

  10. Global Burden of Neural Tube Defects, Risk Factors, and Prevention

    PubMed Central

    Flores, AL; Vellozzi, C; Valencia, D; Sniezek, J

    2015-01-01

    Neural tube defects (NTDs), serious birth defects of the brain and spine usually resulting in death or paralysis, affect an estimated 300,000 births each year worldwide. Although the majority of NTDs are preventable with adequate folic acid consumption during the preconception period and throughout the first few weeks of gestation, many populations, in particular those in low and middle resource settings, do not have access to fortified foods or vitamin supplements containing folic acid. Further, accurate birth defects surveillance data, which could help inform mandatory fortification and other NTD prevention initiatives, are lacking in many of these settings. The burden of birth defects in South East Asia is among the highest in the world. Expanding global neural tube defects prevention initiatives can support the achievement of the United Nations Millennium Development Goal 4 to reduce child mortality, a goal which many countries in South East Asia are currently not poised to reach, and the 63rd World Health Assembly Resolution on birth defects. More work is needed to develop and implement mandatory folic acid fortification policies, as well as supplementation programs in countries where the reach of fortification is limited.

  11. Epidemiology of neural tube defects in Saudi Arabia

    PubMed Central

    AlShail, Essam; De Vol, Edward; Yassen, Ahsan; Elgamal, Essam A.

    2014-01-01

    Objective: To evaluate the distribution and pattern of neural tube defects in Saudi Arabia by creating a hospital based registry. Methods: All cases registered in the King Faisal Specialist Hospital and Research Center (KFSH&RC) neural tube defect (NTD) registry since it was established in October 2000 until December 2012 were studied through active surveillance comprising a registrar who collects NTD information by reviewing the patient’s medical records, and interviewing patient’s families. Results: The total number of patients registered from October 2000 to December 2012 was 718 patients. There were more females (417, 58%) than males (301, 42%). Of 620 mothers who underwent antenatal ultrasonography; 392 (63%) were diagnosed at birth, and 204 (33%) were diagnosed with antenatal hydrocephalus. In our registry sample, most mothers (95%) did not take folic acid 3 months prior to pregnancy, and 76% did not take folic acid during the 3 months after conception with the affected child. Only 5% received folic acid prior to conception. Conclusions: The KFSH&RC-NTD registry has met its objectives as a source of data that may significantly contribute to the prevention of NTDs, and improving quality of care for NTD patients through active publication of registry findings and management approaches. PMID:25551116

  12. Contribution of VANGL2 mutations to isolated neural tube defects.

    PubMed

    Kibar, Z; Salem, S; Bosoi, C M; Pauwels, E; De Marco, P; Merello, E; Bassuk, A G; Capra, V; Gros, P

    2011-07-01

    Vangl2 was identified as the gene defective in the Looptail (Lp) mouse model for neural tube defects (NTDs). This gene forms part of the planar cell polarity (PCP) pathway, also called the non-canonical Frizzled/Dishevelled pathway, which mediates the morphogenetic process of convergent extension essential for proper gastrulation and neural tube formation in vertebrates. Genetic defects in PCP signaling have strongly been associated with NTDs in mouse models. To assess the role of VANGL2 in the complex etiology of NTDs in humans, we resequenced this gene in a large multi-ethnic cohort of 673 familial and sporadic NTD patients, including 453 open spina bifida and 202 closed spinal NTD cases. Six novel rare missense mutations were identified in seven patients, five of which were affected with closed spinal NTDs. This suggests that VANGL2 mutations may predispose to NTDs in approximately 2.5% of closed spinal NTDs (5 in 202), at a frequency that is significantly different from that of 0.4% (2 in 453) detected in open spina bifida patients (p = 0.027). Our findings strongly implicate VANGL2 in the genetic causation of spinal NTDs in a subset of patients and provide additional evidence for a pathogenic role of PCP signaling in these malformations. PMID:20738329

  13. Three generations of matrilineal excess of birth defects in Irish families with neural tube defects

    Microsoft Academic Search

    J. Byrne

    2011-01-01

    Background  Neural tube defects (NTDs) and birth defects overall are more likely to occur among maternal compared to paternal relatives\\u000a in two generations (uncles\\/aunts and first cousins) of Irish families where an individual has been born with an NTD.\\u000a \\u000a \\u000a \\u000a \\u000a Aims  The aim of this study was to determine if the matrilineal excess persisted into the third generation.\\u000a \\u000a \\u000a \\u000a Methods  First cousins were interviewed about

  14. Periconceptional folic acid prevents miscarriage in Irish families with neural tube defects

    Microsoft Academic Search

    J. Byrne

    2011-01-01

    Background  Miscarriages occur to excess in sibships with neural tube defects (NTDs) and among maternal versus paternal relatives in NTD\\u000a families. Folic acid prevents most NTDs. Its potential to prevent miscarriages has been controversial.\\u000a \\u000a \\u000a \\u000a \\u000a Aim  We evaluated the relationship of maternal line and periconceptional folic acid with miscarriage.\\u000a \\u000a \\u000a \\u000a Methods  First cousins in Irish families with NTDs were interviewed about pregnancy outcomes and the

  15. Birth Prevalence of Neural Tube Defects and Orofacial Clefts in India: A Systematic Review and Meta-Analysis

    PubMed Central

    Allagh, Komal Preet; Shamanna, B. R.; Murthy, Gudlavalleti V. S.; Ness, Andy R.; Doyle, Pat; Neogi, Sutapa B.; Pant, Hira B.

    2015-01-01

    Background In the last two decades, India has witnessed a substantial decrease in infant mortality attributed to infectious disease and malnutrition. However, the mortality attributed to birth defects remains constant. Studies on the prevalence of birth defects such as neural tube defects and orofacial clefts in India have reported inconsistent results. Therefore, we conducted a systematic review of observational studies to document the birth prevalence of neural tube defects and orofacial clefts. Methods A comprehensive literature search for observational studies was conducted in MEDLINE and EMBASE databases using key MeSH terms (neural tube defects OR cleft lip OR cleft palate AND Prevalence AND India). Two reviewers independently reviewed the retrieved studies, and studies satisfying the eligibility were included. The quality of included studies was assessed using selected criteria from STROBE statement. Results The overall pooled birth prevalence (random effect) of neural tube defects in India is 4.5 per 1000 total births (95% CI 4.2 to 4.9). The overall pooled birth prevalence (random effect) of orofacial clefts is 1.3 per 1000 total births (95% CI 1.1 to 1.5). Subgroup analyses were performed by region, time period, consanguinity, and gender of newborn. Conclusion The overall prevalence of neural tube defects from India is high compared to other regions of the world, while that of orofacial clefts is similar to other countries. The majority of studies included in the review were hospital based. The quality of these studies ranged from low to moderate. Further well-designed, high quality community-based observational studies are needed to accurately estimate the burden of neural tube defects and orofacial clefts in India. PMID:25768737

  16. Neural tube defects – disorders of neurulation and related embryonic processes

    PubMed Central

    Copp, Andrew J.; Greene, Nicholas D. E.

    2014-01-01

    Neural tube defects (NTDs) are severe congenital malformations affecting 1 in every 1000 pregnancies. ‘Open’ NTDs result from failure of primary neurulation as seen in anencephaly, myelomeningocele (open spina bifida) and craniorachischisis. Degeneration of the persistently open neural tube in utero leads to loss of neurological function below the lesion level. ‘Closed’ NTDs are skin-covered disorders of spinal cord structure, ranging from asymptomatic spina bifida occulta to severe spinal cord tethering, and usually traceable to disruption of secondary neurulation. ‘Herniation’ NTDs are those in which meninges, with or without brain or spinal cord tissue, become exteriorised through a pathological opening in the skull or vertebral column (e.g. encephalocele and meningocele). NTDs have multifactorial etiology, with genes and environmental factors interacting to determine individual risk of malformation. While over 200 mutant genes cause open NTDs in mice, much less is known about the genetic causation of human NTDs. Recent evidence has implicated genes of the planar cell polarity signalling pathway in a proportion of cases. The embryonic development of NTDs is complex, with diverse cellular and molecular mechanisms operating at different levels of the body axis. Molecular regulatory events include the BMP and Sonic hedgehog pathways which have been implicated in control of neural plate bending. Primary prevention of NTDs has been implemented clinically following the demonstration that folic acid, when taken as a peri-conceptional supplement, can prevent many cases. Not all NTDs respond to folic acid, however, and adjunct therapies are required for prevention of this folic acid-resistant category. PMID:24009034

  17. Folic Acid Supplementation of Pregnant Mice Suppresses Heat Induced Neural Tube Defects in the

    Microsoft Academic Search

    Jae-Ho Shin; Kohei Shiota

    Neural tube defects (NTD) are a group of mal- formations that result from the failure of the neural tube to close early in embryonic development and among the most common congenital malformations in humans. It has been reported that a substantial proportion of NTD in humans can be prevented by folic acid (FA) supplementation prior to conception and during the

  18. Awareness of the use of folic acid to prevent neural tube defects in a Mediterranean area

    Microsoft Academic Search

    Oriol Coll; Sonia Pisa; Montserrat Palacio; Llorenç Quintó; Vicenç Cararach

    2004-01-01

    Objectives: The risk of neural tube defects (NTDs) is decreased in women who take folic acid during the periconceptional period. The main objective of our study was to evaluate the awareness of the need for folic acid supplementation and also the actual intake during the periconceptional period to prevent neural tube defects in a Mediterranean area. Study design: A retrospective

  19. Promoter haplotype combinations for the human PDGFRA gene are associated with risk of neural tube defects

    Microsoft Academic Search

    Huiping Zhu; Ned J Wicker; Kelly Volcik; Jing Zhang; Gary M Shaw; Edward J Lammer; Lucina Suarez; Mark Canfield; Richard H Finnell

    2004-01-01

    Recent animal studies suggested that deregulated expression of the platelet-derived growth factor receptor alpha (PDGFR?) may contribute to the failure of normal neural tube closure (NTC). There is also suggestive evidence that the promoter haplotype of the PDGFRA is associated with genetic susceptibility in human neural tube defects (NTDs). The purpose of our study was to investigate the association between

  20. Lead levels in domestic water supplies and neural tube defects in Glasgow

    Microsoft Academic Search

    J E Macdonell; H Campbell; D H Stone

    2000-01-01

    OBJECTIVETo study the association between “pregnancy” prevalence (affected births and terminations) of neural tube defects in postcode districts of Glasgow and lead concentrations in domestic water.SETTINGPostcode districts of Glasgow supplied by water from the Loch Katrine reservoir.DESIGNAn ecological study. Lead concentrations from 1911 randomly selected domestic water samples were obtained from the Glasgow 93 lead study. Neural tube defects (affected

  1. Weekly Administration of Folic Acid and Epidemiology of Neural Tube Defects

    Microsoft Academic Search

    Laura E. Martínez de Villarreal; Patricia Arredondo; Ricardo Hernández; Jesús Z. Villarreal

    2006-01-01

    Objective: In 1999, a folic acid campaign for prevention of neural tube defects was started in Nuevo León, México, with the recommendation of taking a 5000 -mcg tablet of folic acid per week. The purpose of this study was to compare the epidemiology of neural tube defects after four years of the campaign. Methods: Cases of anencephaly, spina bifida, and

  2. Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans

    Microsoft Academic Search

    R. M. Guéant-Rodriguez; C. Rendeli; B. Namour; L. Venuti; A. Romano; G. Anello; P. Bosco; R. Debard; P. Gérard; M. Viola; E. Salvaggio; J. L. Guéant

    2003-01-01

    The pathogenic mechanism of neural tube defects may involve genetic polymorphisms and nutritional factors related to homocysteine metabolism. We evaluated the association of polymorphisms of three genes affecting vitamin B12-dependent remethylation of homocysteine, transcobalamin (TC), methioninesynthase (MTR) and MTRreductase (MTRR), combined or not with methylenetetrahydrofolatereductase (MTHFR), with the risk of having neural tube defect in 40 children with spina bifida

  3. Cell polarity pathways converge and extend to regulate neural tube closure.

    PubMed

    Zohn, Irene E; Chesnutt, Catherine R; Niswander, Lee

    2003-09-01

    Neural tube defects, such as spinabifida, craniorachischisis and anencephaly, are some of the most common birth defects in humans. Recent studies in mouse model systems suggest that craniorachischisis is associated with mutations in genes that regulate cell polarity. Using Xenopus as a model system, Wallingford and Harland have now shed light on the mechanism by which these pathways affect neural tube closure. PMID:12946622

  4. The cause of neural tube defects: some experiments and a hypothesis

    Microsoft Academic Search

    M J Seller

    1983-01-01

    The mouse mutant curly-tail is an animal model for human neural tube defects (NTD). Around 60% spontaneously have NTD. It has been found that maternal administration of hydroxyurea, mitomycin C, or 5-fluorouracil on day 9 of pregnancy, that is, when the fetal neural tube is in the final stages of closure, leads to a significant reduction in the proportion of

  5. Effect of hyaluronic acid on the emergence of neural crest cells from the neural tube of the quail, Coturnix coturnix japonica

    Microsoft Academic Search

    Louise Luckenbill-Edds; Jill L. Carrington

    1988-01-01

    Hyaluronic acid (HA) added to the medium of quail neural tubes explanted in vitro influences the number of migratory neural crest cells that emerge, compared with controls. Neural crest cells were counted with an ocular grid after 20 h of migration into 0.1 mm wide areas or ‘bins’ lying parallel to the neural tube, and the results were analyzed by

  6. A Homeodomain Protein Code Specifies Progenitor Cell Identity and Neuronal Fate in the Ventral Neural Tube

    Microsoft Academic Search

    James Briscoe; Alessandra Pierani; Thomas M. Jessell; Johan Ericson

    2000-01-01

    Distinct classes of neurons are generated at defined positions in the ventral neural tube in response to a gradient of Sonic Hedgehog (Shh) activity. A set of homeodomain transcription factors expressed by neural progenitors act as intermediaries in Shh-dependent neural patterning. These homeodomain factors fall into two classes: class I proteins are repressed by Shh and class II proteins require

  7. Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse.

    PubMed

    Leung, Kit-Yi; De Castro, Sandra C P; Savery, Dawn; Copp, Andrew J; Greene, Nicholas D E

    2013-09-01

    Closure of the neural tube during embryogenesis is a crucial step in development of the central nervous system. Failure of this process results in neural tube defects, including spina bifida and anencephaly, which are among the most common birth defects worldwide. Maternal use of folic acid supplements reduces risk of neural tube defects but a proportion of cases are not preventable. Folic acid is thought to act through folate one-carbon metabolism, which transfers one-carbon units for methylation reactions and nucleotide biosynthesis. Hence suboptimal performance of the intervening reactions could limit the efficacy of folic acid. We hypothesized that direct supplementation with nucleotides, downstream of folate metabolism, has the potential to support neural tube closure. Therefore, in a mouse model that exhibits folic acid-resistant neural tube defects, we tested the effect of specific combinations of pyrimidine and purine nucleotide precursors and observed a significant protective effect. Labelling in whole embryo culture showed that nucleotides are taken up by the neurulating embryo and incorporated into genomic DNA. Furthermore, the mitotic index was elevated in neural folds and hindgut of treated embryos, consistent with a proposed mechanism of neural tube defect prevention through stimulation of cellular proliferation. These findings may provide an impetus for future investigations of supplemental nucleotides as a means to prevent a greater proportion of human neural tube defects than can be achieved by folic acid alone. PMID:23935126

  8. Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse

    PubMed Central

    Leung, Kit-Yi; De Castro, Sandra C.P.; Savery, Dawn; Copp, Andrew J.

    2013-01-01

    Closure of the neural tube during embryogenesis is a crucial step in development of the central nervous system. Failure of this process results in neural tube defects, including spina bifida and anencephaly, which are among the most common birth defects worldwide. Maternal use of folic acid supplements reduces risk of neural tube defects but a proportion of cases are not preventable. Folic acid is thought to act through folate one-carbon metabolism, which transfers one-carbon units for methylation reactions and nucleotide biosynthesis. Hence suboptimal performance of the intervening reactions could limit the efficacy of folic acid. We hypothesized that direct supplementation with nucleotides, downstream of folate metabolism, has the potential to support neural tube closure. Therefore, in a mouse model that exhibits folic acid-resistant neural tube defects, we tested the effect of specific combinations of pyrimidine and purine nucleotide precursors and observed a significant protective effect. Labelling in whole embryo culture showed that nucleotides are taken up by the neurulating embryo and incorporated into genomic DNA. Furthermore, the mitotic index was elevated in neural folds and hindgut of treated embryos, consistent with a proposed mechanism of neural tube defect prevention through stimulation of cellular proliferation. These findings may provide an impetus for future investigations of supplemental nucleotides as a means to prevent a greater proportion of human neural tube defects than can be achieved by folic acid alone. PMID:23935126

  9. Analysis of the embryonic phenotype of Bent tail, a mouse model for X-linked neural tube defects

    Microsoft Academic Search

    Barbara Franke; Riko Klootwijk; Johan W. M. Hekking; Roelie T. de Boer; Hans J. ten Donkelaar; Edwin C. M. Mariman; Henny W. M. van Straaten

    2003-01-01

    Neural tube defects, mostly believed to result from closure defects of the neural tube during embryonic development, are frequently observed congenital malformations in humans. Since the etiology of these defects is not well understood yet, many animal models for neural tube defects, either arising from spontaneous mutations or generated by gene targeting, are being studied. The Bent tail mouse is

  10. USE OF A MURINE EMBRYONIC STEM CELL LINE THAT IS SENSITIVE TO HIGH GLUCOSE ENVIRONMENT TO MODEL NEURAL TUBE DEVELOPMENT IN DIABETIC PREGNANCY

    PubMed Central

    Sanders, Kaitlyn; Jung, Jin Hyuk; Loeken, Mary R.

    2014-01-01

    Background Neural tube defects (NTDs) are significantly increased by maternal diabetes. Embryonic stem cells (ESC) that can differentiate into neuroepithelium and can sense supraphysiological glucose concentrations would be very valuable to simulate the effects of maternal diabetes on molecular and cellular processes during neural tube formation. Methods LG-ESC, a recently established ESC line that expresses the glucose transporter, Scl2a2, and is sensitive to elevated glucose concentrations, were grown for up to 8 days in a 3-dimensional culture to form neural cysts (NC). We tested whether high glucose media inhibits expression of Pax3, a gene that is required for neural tube closure and whose expression is inhibited in embryos of diabetic mice, and inhibits formation of NC. Results Pax3 expression was detected after 4 days of culture and increased with time. Pax3 expression was inhibited by high glucose media, but not if cells had been cultured in low glucose media for the first 4 days of culture. Pax7, which is also expressed in dorsal neural tube, was not detected. Pax6, which is expressed in the ventral neural tube, was detected only after 8 days of culture, but was not inhibited by high glucose. High glucose media did not inhibit formation of NC. Conclusions LG-ESC can be used as a model of embryonic exposure to a diabetic environment during neural tube development. While high glucose exposure inhibits expression of a gene required for neural tube closure, it may not inhibit all of the processes involved in formation of a neural tube-like structure. PMID:25124397

  11. SNPs in the neural cell adhesion molecule 1 gene ( NCAM1 ) may be associated with human neural tube defects

    Microsoft Academic Search

    Kristen L. Deak; Abee L. Boyles; Heather C. Etchevers; Elizabeth C. Melvin; Deborah G. Siegel; Felicia L. Graham; Susan H. Slifer; David S. Enterline; Timothy M. George; Michel Vekemans; David McClay; Alexander G. Bassuk; John A. Kessler; Elwood Linney; John R. Gilbert; Marcy C. Speer

    2005-01-01

    Neural tube defects (NTDs) are common birth defects, occurring in approximately 1\\/1,000 births; both genetic and environmental factors are implicated. To date, no major genetic risk factors have been identified. Throughout development, cell adhesion molecules are strongly implicated in cell–cell interactions, and may play a role in the formation and closure of the neural tube. To evaluate the role of

  12. Epidemiology, prenatal management, and prevention of neural tube defects

    PubMed Central

    Salih, Mustafa A.; Murshid, Waleed R.; Seidahmed, Mohammed Z.

    2014-01-01

    This review article discusses the epidemiology, risk factors, prenatal screening, diagnosis, prevention potentials, and epidemiologic impact of neural tube defects (NTDs). The average incidence of NTDs is 1/1000 births, with a marked geographic variation. In the developed countries, the incidence of NTDs has fallen over recent decades. However, it still remains high in the less-developed countries in Latin America, Africa, the Middle East, Asia, and the Far East (>1 to 11/1000 births). Recognized NTDs risks include maternal diabetes, obesity, lower socioeconomic status, hyperthermia, and exposure to certain teratogens during the periconceptional period. Periconceptional folic acid supplementation decreased the prevalence of NTDs by 50-70%, and an obligatory folic acid fortification of food was adopted in several countries to reach women with unplanned pregnancies and those facing social deprivation. Prevention of NTDs can be accelerated if more, especially low income countries, adopted fortification of the staple food in their communities. PMID:25551106

  13. Strategies of vertebrate neurulation and a re-evaluation of teleost neural tube formation

    E-print Network

    Lowery, Laura Anne

    Review Strategies of vertebrate neurulation and a re-evaluation of teleost neural tube formation tube develops by two distinct mechanisms. Anteriorly, in the brain and future trunk (cervicothoracic) region, `primary neurulation' occurs, where an epithelial sheet rolls or bends into a tube. Posteriorly

  14. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects

    Microsoft Academic Search

    G. J Cuskelly; H McNulty; J. M Scott

    1996-01-01

    SummaryBackground Recommendations by the UK Department of Health suggest that protection from neural tube defects (NTD) can be achieved through intakes of an extra 400 ?g daily of folate\\/folic acid as natural food, foods fortified with folic acid, or supplements. The assumption is that all three routes of intervention would have equal effects on folate status.Methods We assessed the effectiveness

  15. Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects

    Microsoft Academic Search

    Ron Korstanje; Jigar Desai; Gloria Lazar; Benjamin King; Jarod Rollins; Melissa Spurr; Jamie Joseph; Sindhuja Kadambi; Yang Li; Allison Cherry; Paul G. Matteson; Beverly Paigen; James H. Millonig

    2008-01-01

    The vacuolated lens (vl) mouse mutant arose spontaneously on the C3H\\/HeSn background and exhibits neural tube defects (NTDs), congenital cataract, and occasionally a white belly spot. We previously reported that 1) the vl phenotypes are due to a mutation in an orphan G protein-coupled receptor (GPCR), Gpr161; 2) the penetrance of the vl NTD and cataract phenotypes are affected by

  16. The relationship between Sonic hedgehog signalling, cilia and neural tube defects

    PubMed Central

    Murdoch, Jennifer N.; Copp, Andrew J.

    2013-01-01

    The Hedgehog signalling pathway is essential for many aspects of normal embryonic development, including formation and patterning of the neural tube. Absence of Shh ligand is associated with the midline defect holoprosencephaly, while increased Shh signalling is associated with exencephaly and spina bifida. To complicate this apparently simple relationship, mutation of proteins required for function of cilia often leads to impaired Shh signalling and to disruption of neural tube closure. In this manuscript, we review the literature on Shh pathway mutants and discuss the relationship between Shh signalling, cilia and neural tube defects. PMID:20544799

  17. Sall1, Sall2, and Sall4 Are Required for Neural Tube Closure in Mice

    PubMed Central

    Böhm, Johann; Buck, Anja; Borozdin, Wiktor; Mannan, Ashraf U.; Matysiak-Scholze, Uta; Adham, Ibrahim; Schulz-Schaeffer, Walter; Floss, Thomas; Wurst, Wolfgang; Kohlhase, Jürgen; Barrionuevo, Francisco

    2008-01-01

    Four homologs to the Drosophila homeotic gene spalt (sal) exist in both humans and mice (SALL1 to SALL4/Sall1 to Sall4, respectively). Mutations in both SALL1 and SALL4 result in the autosomal-dominant developmental disorders Townes-Brocks and Okihiro syndrome, respectively. In contrast, no human diseases have been associated with SALL2 to date, and Sall2-deficient mice have shown no apparent abnormal phenotype. We generated mice deficient in Sall2 and, contrary to previous reports, 11% of our Sall2-deficient mice showed background-specific neural tube defects, suggesting that Sall2 has a role in neurogenesis. To investigate whether Sall4 may compensate for the absence of Sall2, we generated compound Sall2 knockout/Sall4 genetrap mutant mice. In these mutants, the incidence of neural tube defects was significantly increased. Furthermore, we found a similar phenotype in compound Sall1/4 mutant mice, and in vitro studies showed that SALL1, SALL2, and SALL4 all co-localized in the nucleus. We therefore suggest a fundamental and redundant function of the Sall proteins in murine neurulation, with the heterozygous loss of a particular SALL protein also possibly compensated in humans during development. PMID:18818376

  18. Insights into metabolic mechanisms underlying folate-responsive neural tube defects: a minireview.

    PubMed

    Beaudin, Anna E; Stover, Patrick J

    2009-04-01

    Neural tube defects (NTDs), including anencephaly and spina bifida, arise from the failure of neurulation during early embryonic development. Neural tube defects are common birth defects with a heterogenous and multifactorial etiology with interacting genetic and environmental risk factors. Although the mechanisms resulting in failure of neural tube closure are unknown, up to 70% of NTDs can be prevented by maternal folic acid supplementation. However, the metabolic mechanisms underlying the association between folic acid and NTD pathogenesis have not been identified. This review summarizes our current understanding of the mechanisms by which impairments in folate metabolism might ultimately lead to failure of neural tube closure, with an emphasis on untangling the relative contributions of nutritional deficiency and genetic risk factors to NTD pathogenesis. PMID:19180567

  19. Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy

    PubMed Central

    Kappen, Claudia; Kruger, Claudia; MacGowan, Jacalyn; Salbaum, J. Michael

    2010-01-01

    Pregnancies complicated by maternal diabetes have long been known to carry a higher risk for congenital malformations, such as neural tube defects. Using the FVB inbred mouse strain and the Streptozotocin-induced diabetes model, we tested whether the incidence of neural tube defects in diabetic pregnancies can be modulated by maternal diet. In a comparison of two commercial mouse diets, which are considered nutritionally replete, we found that maternal consumption of the unfavorable diet was associated with a more than three-fold higher rate of neural tube defects. Our results demonstrate that maternal diet can act as a modifier of the risk for abnormal development in high-risk pregnancies, and provide support for the possibility that neural tube defects in human diabetic pregnancies might be preventable by optimized maternal nutrition. PMID:20868740

  20. Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy.

    PubMed

    Kappen, Claudia; Kruger, Claudia; MacGowan, Jacalyn; Salbaum, J Michael

    2011-01-01

    Pregnancies complicated by maternal diabetes have long been known to carry a higher risk for congenital malformations, such as neural tube defects. Using the FVB inbred mouse strain and the Streptozotocin-induced diabetes model, we tested whether the incidence of neural tube defects in diabetic pregnancies can be modulated by maternal diet. In a comparison of two commercial mouse diets, which are considered nutritionally replete, we found that maternal consumption of the unfavorable diet was associated with a more than 3-fold higher rate of neural tube defects. Our results demonstrate that maternal diet can act as a modifier of the risk for abnormal development in high-risk pregnancies, and provide support for the possibility that neural tube defects in human diabetic pregnancies might be preventable by optimized maternal nutrition. PMID:20868740

  1. Preventing neural tube defects: The importance of periconceptional folic acid supplements

    Microsoft Academic Search

    GregoryJ Locksmith; Patrick Duff

    1998-01-01

    Objective: To inform the obstetrician-gynecologist of recent scientific evidence regarding the use of supplemental folic acid for prevention of neural tube defects (NTDs).Data Sources: We selected English language articles via MEDLINE published from January 1990 through February 1997, using the search terms “folic acid” and “neural tube defect.” Additional sources were identified through cross-referencing and through searching selected journals published

  2. Reduction in Neural-Tube Defects after Folic Acid Fortification in Canada

    Microsoft Academic Search

    Fassiatou Tairou; Margot I. Van Allen; Soo-Hong Uh; R. Brian Lowry; Barbara Sibbald; Jane A. Evans; Michiel C. Van den Hof; Pamela Zimmer; Marian Crowley; Bridget Fernandez; Nora S. Lee; Theophile Niyonsenga

    2010-01-01

    Results A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each

  3. Genetic, chromosomal, and syndromic causes of neural tube defects

    PubMed Central

    Seidahmed, Mohammed Z.; Abdelbasit, Omer B.; Shaheed, Meeralebbae M.; Alhussein, Khalid A.; Miqdad, Abeer M.; Samadi, Abdulmohsen S.; Khalil, Mohammed I.; Al-Mardawi, Elham; Salih, Mustafa A.

    2014-01-01

    Objective: To ascertain the incidence, and describe the various forms of neural tube defects (NTDs) due to genetic, chromosomal, and syndromic causes. Methods: We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years (1996-2009) at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. Results: Out of 103 infants with NTDs admitted during this period, 20 (19.4%) were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. Conclusions: There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions. PMID:25551112

  4. Folate receptor gene variants and neural tube defect occurrence

    SciTech Connect

    Finnell, R.; Greer, K. [Texas A& M Univ., College Station, TX (United States); Lammer, E. [Stanford Univ., Palo Alto, CA (United States)] [and others

    1994-09-01

    Recent epidemiological evidence shows that periconceptional use of folic acid supplements may prevent 40-50% of neural tube defects (NTDs). The FDA has subsequently recommended folic acid supplementation of all women of childbearing potential, even though the mechanism by which folic acid prevents NTDs is unknown. We investigated genetic variation of a candidate gene, the 5-methyltetrahydrofolate (5-MeTHF) receptor, that may mediate this preventive effect. The receptor concentrates folate within cells and we have localized its mRNA to neuroepithelial cells during neurulation. Our hypothesis is that dysfunctional 5-MeTHF receptors inadequately concentrate folate intracellularly, predisposing infants to NTDs. We have completed SSCP analysis on 3 of the 4 coding exons of the 5-MeTHF receptor gene of 474 infants participating in a large population-based epidemiological case-control study of NTDs in California; genotyping of another 500 infants is ongoing. Genomic DNA was extracted from residual blood spots from newborn screening samples of cases and controls. Genotyping was done blinded to case status. Polymorphisms have been detected for exons 4 and 5; fourteen percent of the infants have exon 5 polymorphisms. Data will be presented on the prevalence of 5-MeTHF receptor polymorphisms among cases and controls. Relationships among the polymorphisms and NTD occurrence may shed light on how folic acid supplementation prevents NTDs.

  5. Associated malformations among infants with neural tube defects.

    PubMed

    Stoll, Claude; Dott, Beatrice; Alembik, Yves; Roth, Marie-Paule

    2011-03-01

    Infants with neural tube defects (NTDs) often have associated congenital anomalies. The reported frequency and types of associated malformations vary between different studies. The purpose of this investigation was to assess the frequency and types of associated malformations among infants with NTDs in a geographically well-defined population from 1979 to 2008 of 402,532 consecutive births. Of the 441 infants with NTDs born during this period, 20.4% had associated malformations. Infants with associated malformations were divided into those with recognizable conditions [11 (2.5%) infants with chromosomal and 23 (5.2%) with non-chromosomal conditions], and those without recognizable conditions [56 (12.7%) infants with multiple malformations]. Associated malformations were more frequent among infants with encephalocele (36.8%) than those with anencephaly (11.5%) or spina bifida (23.8%). Oral clefts and malformations in the musculoskeletal, renal and cardiovascular systems were the most commonly observed associated anomalies. The frequency of associated malformations in infants with NTDs emphasizes the need for a thorough investigation of these infants. Routine screening for other malformations, especially facial clefts and musculoskeletal, renal and cardiac anomalies, may need to be considered in infants with NTDs, and referral of these infants for genetics evaluation and counseling seems warranted. PMID:21337695

  6. Abnormal folate metabolism in foetuses affected by neural tube defects.

    PubMed

    Dunlevy, Louisa P E; Chitty, Lyn S; Burren, Katie A; Doudney, Kit; Stojilkovic-Mikic, Taita; Stanier, Philip; Scott, Rosemary; Copp, Andrew J; Greene, Nicholas D E

    2007-04-01

    Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs. PMID:17438019

  7. RFX7 is required for the formation of cilia in the neural tube

    PubMed Central

    Manojlovic, Zarko; Earwood, Ryan; Kato, Akiko; Stefanovic, Branko; Kato, Yoichi

    2014-01-01

    Regulatory Factor X (RFX) transcription factors are important for development and are likely involved in the pathogenesis of serious human diseases including ciliopathies. While seven RFX genes have been identified in vertebrates and several RFX transcription factors have been reported to be regulators of ciliogenesis, the role of RFX7 in development including ciliogenesis is not known. Here we show that RFX7 in Xenopus laevis is expressed in the neural tube, eye, otic vesicles, and somites. Knockdown of RFX7 in Xenopus embryos resulted in a defect of ciliogenesis in the neural tube and failure of neural tube closure. RFX7 controlled the formation of cilia by regulating the expression of RFX4 gene, which has been reported to be required for ciliogenesis in the neural tube. Moreover, ectopic expression of Foxj1, which is a master regulator of motile cilia formation, suppressed the expression of RFX4 but not RFX7. Taken together, RFX7 plays an important role in the process of neural tube closure at the top of the molecular cascade which controls ciliogenesis in the neural tube. PMID:24530844

  8. Cell polarity pathways converge and extend to regulate neural tube closure

    Microsoft Academic Search

    Irene E. Zohn; Catherine R. Chesnutt; Lee Niswander

    2003-01-01

    Neural tube defects, such as spinabifida, craniorachischisis and anencephaly, are some of the most common birth defects in humans. Recent studies in mouse model systems suggest that craniorachischisis is associated with mutations in genes that regulate cell polarity. Using Xenopus as a model system, Wallingford and Harland have now shed light on the mechanism by which these pathways affect neural

  9. Neural tube defects: review of experimental evidence on stem cell therapy and newer treatment options.

    PubMed

    Dhaulakhandi, Dhara B; Rohilla, Seema; Rattan, Kamal Nain

    2010-01-01

    The failure of closure of the neural tube during development leads to malformations called neural tube defects (NTDs). The most common neural malformations in humans include anencephaly, encephalocele, exencephaly, craniorachischisis spina bifida with or without myelomeningocele, lipomyeloschisis, lipomyelomeningocele, meningocele and myelocystocele. Current preventive strategies are mainly based on pharmacologic/folic acid supplementation. However, stem cell-based and other combination approaches may emerge as potential treatment options for NTDs. This review provides an account of experimental evidence on stem cell therapy and newer treatment options for NTDs which have become available in recent years. PMID:20689263

  10. Phenotype of the neural tube defect mouse model bent tail is not sensitive to maternal folinic acid,myo-inositol, or zinc supplementation

    Microsoft Academic Search

    Barbara Franke; Riko Klootwijk; Bianca Lemmers; Carolien G. F. De Kovel; Regine P. M. Steegers-Theunissen; Edwin C. M. Mariman

    2003-01-01

    BACKGROUND: Bent tail is a mouse model for X-linked neural tube defects (NTDs) that is characterized by the presence of exencephaly, a delayed posterior neuropore closure, and a tail phenotype. In addition, Bent tail shows laterality defects and increased prenatal mortality. The congenital malformations of this mouse are caused by a submicroscopic deletion that completely encompasses the gene coding for

  11. Misexpression of BRE gene in the developing chick neural tube affects neurulation and somitogenesis

    PubMed Central

    Wang, Guang; Li, Yan; Wang, Xiao-Yu; Chuai, Manli; Yeuk-Hon Chan, John; Lei, Jian; Münsterberg, Andrea; Lee, Kenneth Ka Ho; Yang, Xuesong

    2015-01-01

    The brain and reproductive expression (BRE) gene is expressed in numerous adult tissues and especially in the nervous and reproductive systems. However, little is known about BRE expression in the developing embryo or about its role in embryonic development. In this study, we used in situ hybridization to reveal the spatiotemporal expression pattern for BRE in chick embryo during development. To determine the importance of BRE in neurogenesis, we overexpressed BRE and also silenced BRE expression specifically in the neural tube. We established that overexpressing BRE in the neural tube indirectly accelerated Pax7+ somite development and directly increased HNK-1+ neural crest cell (NCC) migration and TuJ-1+ neurite outgrowth. These altered morphogenetic processes were associated with changes in the cell cycle of NCCs and neural tube cells. The inverse effect was obtained when BRE expression was silenced in the neural tube. We also determined that BMP4 and Shh expression in the neural tube was affected by misexpression of BRE. This provides a possible mechanism for how altering BRE expression was able to affect somitogenesis, neurogenesis, and NCC migration. In summary, our results demonstrate that BRE plays an important role in regulating neurogenesis and indirectly somite differentiation during early chick embryo development. PMID:25568339

  12. Effect of folic acid fortification on the incidence of neural tube defects.

    PubMed

    Amarin, Zouhair O; Obeidat, Ahmed Z

    2010-07-01

    In a few countries enriched cereal grains have been fortified with folic acid to reduce the incidence of neural tube defects. The objective of this study was to analyse the effect of folic acid fortified foods on the incidence of neural tube defects in live newborns at Princess Badea Teaching Hospital, in the north of Jordan, before and after the national food fortification with folic acid was implemented. For the 7-year period from 1 January 2000 to 31 December 2006, we retrospectively extracted the total number of births at Princess Badea Hospital, as well as the number of pregnancies affected by spina bifida and anencephaly, per 1000 births during the periods before (2000-01), during (2002-04) and after (2005-06) folic acid fortification of grain products, was implemented. Neural tube defects were defined in accordance with the International Classification of Diseases, 10th revision (ICD-10): anencephaly, encephalocele and spina bifida. A total of 78 subjects with neural tube defects were recorded among 61 447 births during the study period. The incidence of neural tube defects decreased from 1.85 per 1000 births before fortification [95% confidence interval (CI) 1.2, 2.4] to 1.07 per 1000 births during the fortification period [95% CI 0.7, 1.5], and 0.95 after full fortification [95% CI 0.5, 1.5], a 49% reduction. The difference between incidence of neural tube defects in the periods before and after food fortification with folic acid was statistically significant. We conclude that food fortification with folic acid was associated with a significant reduction in the rate of neural tube defects in north Jordan. PMID:20618724

  13. Biphasic influence of Miz1 on neural crest development by regulating cell survival and apical adhesion complex formation in the developing neural tube.

    PubMed

    Kerosuo, Laura; Bronner, Marianne E

    2014-02-01

    Myc interacting zinc finger protein-1 (Miz1) is a transcription factor known to regulate cell cycle- and cell adhesion-related genes in cancer. Here we show that Miz1 also plays a critical role in neural crest development. In the chick, Miz1 is expressed throughout the neural plate and closing neural tube. Its morpholino-mediated knockdown affects neural crest precursor survival, leading to reduction of neural plate border and neural crest specifier genes Msx-1, Pax7, FoxD3, and Sox10. Of interest, Miz1 loss also causes marked reduction of adhesion molecules (N-cadherin, cadherin6B, and ?1-catenin) with a concomitant increase of E-cadherin in the neural folds, likely leading to delayed and decreased neural crest emigration. Conversely, Miz1 overexpression results in up-regulation of cadherin6B and FoxD3 expression in the neural folds/neural tube, leading to premature neural crest emigration and increased number of migratory crest cells. Although Miz1 loss effects cell survival and proliferation throughout the neural plate, the neural progenitor marker Sox2 was unaffected, suggesting a neural crest-selective effect. The results suggest that Miz1 is important not only for survival of neural crest precursors, but also for maintenance of integrity of the neural folds and tube, via correct formation of the apical adhesion complex therein. PMID:24307680

  14. Serum zinc, selenium, copper, and lead levels in women with second-trimester induced abortion resulting from neural tube defects

    Microsoft Academic Search

    Bora Cengiz; Feride Söylemez; Ebru Öztürk; Ayhan O. Çavdar

    2004-01-01

    Neural tube defects are important causes of infant mortality and childhood morbidity. We investigated the relationship between\\u000a zinc, selenium, copper, and lead concentrations and neural-tube-defect occurrence in women with a second-trimester termination\\u000a due to fetal-neural-tube defects (NTDs) in this case-control study. Fourteen pregnant women whose pregnancies were terminated\\u000a as a result of second-trimester ultrasonographic diagnosis of neural tube defects were

  15. Modeling anterior development in mice: diet as modulator of risk for neural tube defects.

    PubMed

    Kappen, Claudia

    2013-11-01

    Head morphogenesis is a complex process that is controlled by multiple signaling centers. The most common defects of cranial development are craniofacial defects, such as cleft lip and cleft palate, and neural tube defects, such as anencephaly and encephalocoele in humans. More than 400 genes that contribute to proper neural tube closure have been identified in experimental animals, but only very few causative gene mutations have been identified in humans, supporting the notion that environmental influences are critical. The intrauterine environment is influenced by maternal nutrition, and hence, maternal diet can modulate the risk for cranial and neural tube defects. This article reviews recent progress toward a better understanding of nutrients during pregnancy, with particular focus on mouse models for defective neural tube closure. At least four major patterns of nutrient responses are apparent, suggesting that multiple pathways are involved in the response, and likely in the underlying pathogenesis of the defects. Folic acid has been the most widely studied nutrient, and the diverse responses of the mouse models to folic acid supplementation indicate that folic acid is not universally beneficial, but that the effect is dependent on genetic configuration. If this is the case for other nutrients as well, efforts to prevent neural tube defects with nutritional supplementation may need to become more specifically targeted than previously appreciated. Mouse models are indispensable for a better understanding of nutrient-gene interactions in normal pregnancies, as well as in those affected by metabolic diseases, such as diabetes and obesity. PMID:24124024

  16. Modeling Anterior Development in Mice: Diet as Modulator of Risk for Neural Tube Defects

    PubMed Central

    Kappen, Claudia

    2014-01-01

    Head morphogenesis is a complex process that is controlled by multiple signaling centers. The most common defects of cranial development are craniofacial defects, such as cleft lip and cleft palate, and neural tube defects, such as anencephaly and encephalocoele in humans. More than 400 genes that contribute to proper neural tube closure have been identified in experimental animals, but only very few causative gene mutations have been identified in humans, supporting the notion that environmental influences are critical. The intrauterine environment is influenced by maternal nutrition, and hence, maternal diet can modulate the risk for cranial and neural tube defects. This article reviews recent progress toward a better understanding of nutrients during pregnancy, with particular focus on mouse models for defective neural tube closure. At least four major patterns of nutrient responses are apparent, suggesting that multiple pathways are involved in the response, and likely in the underlying pathogenesis of the defects. Folic acid has been the most widely studied nutrient, and the diverse responses of the mouse models to folic acid supplementation indicate that folic acid is not universally beneficial, but that the effect is dependent on genetic configuration. If this is the case for other nutrients as well, efforts to prevent neural tube defects with nutritional supplementation may need to become more specifically targeted than previously appreciated. Mouse models are indispensable for a better understanding of nutrient–gene interactions in normal pregnancies, as well as in those affected by metabolic diseases, such as diabetes and obesity. PMID:24124024

  17. The role of primary cilia in the pathophysiology of neural tube defects.

    PubMed

    Vogel, Timothy W; Carter, Calvin S; Abode-Iyamah, Kingsley; Zhang, Qihong; Robinson, Shenandoah

    2012-10-01

    Neural tube defects (NTDs) are a set of disorders that occur from perturbation of normal neural development. They occur in open or closed forms anywhere along the craniospinal axis and often result from a complex interaction between environmental and genetic factors. One burgeoning area of genetics research is the effect of cilia signaling on the developing neural tube and how the disruption of primary cilia leads to the development of NTDs. Recent progress has implicated the hedgehog (Hh), wingless-type integration site family (Wnt), and planar cell polarity (PCP) pathways in primary cilia as involved in normal neural tube patterning. A set of disorders involving cilia function, known as ciliopathies, offers insight into abnormal neural development. In this article, the authors discuss the common ciliopathies, such as Meckel-Gruber and Joubert syndromes, that are associated with NTDs, and review cilia-related signaling cascades responsible for mammalian neural tube development. Understanding the contribution of cilia in the formation of NTDs may provide greater insight into this common set of pediatric neurological disorders. PMID:23025443

  18. An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure.

    PubMed

    Harris, Muriel J; Juriloff, Diana M

    2010-08-01

    The number of mouse mutants and strains with neural tube defects (NTDs) now exceeds 240, including 205 representing specific genes, 30 for unidentified genes, and 9 multifactorial strains. These mutants identify genes needed for embryonic neural tube closure. Reports of 50 new NTD mutants since our 2007 review (Harris and Juriloff, 2007) were considered in relation to the previously reviewed mutants to obtain new insights into mechanisms of NTD etiology. In addition to null mutations, some are hypomorphs or conditional mutants. Some mutations do not cause NTDs on their own, but do so in digenic, trigenic, and oligogenic combinations, an etiology that likely parallels the nature of genetic etiology of human NTDs. Mutants that have only exencephaly are fourfold more frequent than those that have spina bifida aperta with or without exencephaly. Many diverse cellular functions and biochemical pathways are involved; the NTD mutants draw new attention to chromatin modification (epigenetics), the protease-activated receptor cascade, and the ciliopathies. Few mutants directly involve folate metabolism. Prevention of NTDs by maternal folate supplementation has been tested in 13 mutants and reduces NTD frequency in six diverse mutants. Inositol reduces spina bifida aperta frequency in the curly tail mutant, and three new mutants involve inositol metabolism. The many NTD mutants are the foundation for a future complete genetic understanding of the processes of neural fold elevation and fusion along mechanistically distinct cranial-caudal segments of the neural tube, and they point to several candidate processes for study in human NTD etiology. PMID:20740593

  19. Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice

    PubMed Central

    Murdoch, Jennifer N.; Damrau, Christine; Paudyal, Anju; Bogani, Debora; Wells, Sara; Greene, Nicholas D. E.; Stanier, Philip; Copp, Andrew J.

    2014-01-01

    Neural tube defects (NTDs) are among the commonest and most severe forms of developmental defect, characterized by disruption of the early embryonic events of central nervous system formation. NTDs have long been known to exhibit a strong genetic dependence, yet the identity of the genetic determinants remains largely undiscovered. Initiation of neural tube closure is disrupted in mice homozygous for mutations in planar cell polarity (PCP) pathway genes, providing a strong link between NTDs and PCP signaling. Recently, missense gene variants have been identified in PCP genes in humans with NTDs, although the range of phenotypes is greater than in the mouse mutants. In addition, the sequence variants detected in affected humans are heterozygous, and can often be detected in unaffected individuals. It has been suggested that interactions between multiple heterozygous gene mutations cause the NTDs in humans. To determine the phenotypes produced in double heterozygotes, we bred mice with all three pairwise combinations of Vangl2Lp, ScribCrc and Celsr1Crsh mutations, the most intensively studied PCP mutants. The majority of double-mutant embryos had open NTDs, with the range of phenotypes including anencephaly and spina bifida, therefore reflecting the defects observed in humans. Strikingly, even on a uniform genetic background, variability in the penetrance and severity of the mutant phenotypes was observed between the different double-heterozygote combinations. Phenotypically, Celsr1Crsh;Vangl2Lp;ScribCrc triply heterozygous mutants were no more severe than doubly heterozygous or singly homozygous mutants. We propose that some of the variation between double-mutant phenotypes could be attributed to the nature of the protein disruption in each allele: whereas ScribCrc is a null mutant and produces no Scrib protein, Celsr1Crsh and Vangl2Lp homozygotes both express mutant proteins, consistent with dominant effects. The variable outcomes of these genetic interactions are of direct relevance to human patients and emphasize the importance of performing comprehensive genetic screens in humans. PMID:25128525

  20. Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity.

    PubMed

    Escobedo, Noelia; Contreras, Osvaldo; Muñoz, Rosana; Farías, Marjorie; Carrasco, Héctor; Hill, Charlotte; Tran, Uyen; Pryor, Sophie E; Wessely, Oliver; Copp, Andrew J; Larraín, Juan

    2013-07-01

    Syndecan 4 (Sdc4) is a cell-surface heparan sulfate proteoglycan (HSPG) that regulates gastrulation, neural tube closure and directed neural crest migration in Xenopus development. To determine whether Sdc4 participates in Wnt/PCP signaling during mouse development, we evaluated a possible interaction between a null mutation of Sdc4 and the loop-tail allele of Vangl2. Sdc4 is expressed in multiple tissues, but particularly in the non-neural ectoderm, hindgut and otic vesicles. Sdc4;Vangl2(Lp) compound mutant mice have defective spinal neural tube closure, disrupted orientation of the stereocilia bundles in the cochlea and delayed wound healing, demonstrating a strong genetic interaction. In Xenopus, co-injection of suboptimal amounts of Sdc4 and Vangl2 morpholinos resulted in a significantly greater proportion of embryos with defective neural tube closure than each individual morpholino alone. To probe the mechanism of this interaction, we overexpressed or knocked down Vangl2 function in HEK293 cells. The Sdc4 and Vangl2 proteins colocalize, and Vangl2, particularly the Vangl2(Lp) mutant form, diminishes Sdc4 protein levels. Conversely, Vangl2 knockdown enhances Sdc4 protein levels. Overall HSPG steady-state levels were regulated by Vangl2, suggesting a molecular mechanism for the genetic interaction in which Vangl2(Lp/+) enhances the Sdc4-null phenotype. This could be mediated via heparan sulfate residues, as Vangl2(Lp/+) embryos fail to initiate neural tube closure and develop craniorachischisis (usually seen only in Vangl2(Lp/Lp)) when cultured in the presence of chlorate, a sulfation inhibitor. These results demonstrate that Sdc4 can participate in the Wnt/PCP pathway, unveiling its importance during neural tube closure in mammalian embryos. PMID:23760952

  1. Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity

    PubMed Central

    Escobedo, Noelia; Contreras, Osvaldo; Muñoz, Rosana; Farías, Marjorie; Carrasco, Héctor; Hill, Charlotte; Tran, Uyen; Pryor, Sophie E.; Wessely, Oliver; Copp, Andrew J.; Larraín, Juan

    2013-01-01

    Syndecan 4 (Sdc4) is a cell-surface heparan sulfate proteoglycan (HSPG) that regulates gastrulation, neural tube closure and directed neural crest migration in Xenopus development. To determine whether Sdc4 participates in Wnt/PCP signaling during mouse development, we evaluated a possible interaction between a null mutation of Sdc4 and the loop-tail allele of Vangl2. Sdc4 is expressed in multiple tissues, but particularly in the non-neural ectoderm, hindgut and otic vesicles. Sdc4;Vangl2Lp compound mutant mice have defective spinal neural tube closure, disrupted orientation of the stereocilia bundles in the cochlea and delayed wound healing, demonstrating a strong genetic interaction. In Xenopus, co-injection of suboptimal amounts of Sdc4 and Vangl2 morpholinos resulted in a significantly greater proportion of embryos with defective neural tube closure than each individual morpholino alone. To probe the mechanism of this interaction, we overexpressed or knocked down Vangl2 function in HEK293 cells. The Sdc4 and Vangl2 proteins colocalize, and Vangl2, particularly the Vangl2Lp mutant form, diminishes Sdc4 protein levels. Conversely, Vangl2 knockdown enhances Sdc4 protein levels. Overall HSPG steady-state levels were regulated by Vangl2, suggesting a molecular mechanism for the genetic interaction in which Vangl2Lp/+ enhances the Sdc4-null phenotype. This could be mediated via heparan sulfate residues, as Vangl2Lp/+ embryos fail to initiate neural tube closure and develop craniorachischisis (usually seen only in Vangl2Lp/Lp) when cultured in the presence of chlorate, a sulfation inhibitor. These results demonstrate that Sdc4 can participate in the Wnt/PCP pathway, unveiling its importance during neural tube closure in mammalian embryos. PMID:23760952

  2. Folic acid knowledge and use among relatives in Irish families with neural tube defects: An intervention study

    Microsoft Academic Search

    J Byrne

    2003-01-01

    Background Relatives in families where a child has a neural tube defect (NTD) may be at higher risk of having an affected child. Little\\u000a is known of their level of knowledge and use of folic acid.\\u000a \\u000a \\u000a Aim To carry out an intervention study intended to increase knowledge and use of folic acid among relatives.\\u000a \\u000a \\u000a \\u000a \\u000a Methods One hundred aunts and female

  3. Effect of maternal exposure to homocystine on sodium valproate-induced neural tube defects in the mouse embryos

    Microsoft Academic Search

    R. Padmanabhan; M. Shafiullah; S. Benedict; N. Nagelkerke

    2006-01-01

    Summary\\u000a Background  Neural tube defects (NTD) are mainly of multifactorial origin. Maternal treatment with valproic acid (VPA) during pregnancy\\u000a induces NTD in susceptible fetuses. Elevated levels of homocysteine are observed in pregnancies with NTD. The mechanism by\\u000a which homocysteine might cause NTD is unknown.\\u000a \\u000a \\u000a \\u000a Aim of the Study  The aim of this study was to determine if homocystine would augment VPA-induced exencephaly

  4. The murine homeobox gene Msx-3 shows highly restricted expression in the developing neural tube

    Microsoft Academic Search

    Sebastian M. Shimeld; Ian J. McKay; Paul T. Sharpe

    1996-01-01

    The mouse homeobox-genes Msx-1 and Msx-2 are expressed in several areas of the developing embryo, including the neural tube, neural crest, facial processes and limb buds. Here we report the characterisation of a third mouse Msx gene, which we designate Msx-3. The embryonic expression of Msx-3 was found to differ from that of Msx-1 and -2 in that it was

  5. An amphioxus Msx gene expressed predominantly in the dorsal neural tube

    Microsoft Academic Search

    Anna C. Sharman; Sebastian M. Shimeld; Peter W. H. Holland

    1999-01-01

    Genomic and cDNA clones of an Msx class homeobox gene were isolated from amphioxus (Branchiostoma floridae). The gene, AmphiMsx, is expressed in the neural plate from late gastrulation; in later embryos it is expressed in dorsal cells of the neural\\u000a tube, excluding anterior and posterior regions, in an irregular reiterated pattern. There is transient expression in dorsal\\u000a cells within somites,

  6. Convergent extension, planar cell polarity signalling and initiation of mouse neural tube closure

    PubMed Central

    Ybot-Gonzalez, Patricia; Savery, Dawn; Gerrelli, Dianne; Signore, Massimo; Mitchell, Claire E.; Faux, Clare H.; Greene, Nicholas D. E.; Copp, Andrew J.

    2007-01-01

    SUMMARY Planar cell polarity (PCP) signalling is necessary for initiation of neural tube closure in higher vertebrates. In mice with PCP gene mutations, a broad embryonic midline prevents the onset of neurulation through wide spacing of the neural folds. In order to evaluate the role of convergent extension in this defect, we vitally labelled the midline of loop-tail (Lp) embryos mutant for the PCP gene, Vangl2. Injection of DiI into the node, and electroporation of a GFP expression vector into the midline neural plate, reveal defective convergent extension in both axial mesoderm and neuroepithelium, prior to the onset of neurulation. Chimeras containing both wild type and Lp mutant cells exhibit mainly wild type cells in the midline neural plate and notochordal plate, consistent with a cell autonomous disturbance of convergent extension. Inhibitor studies in whole embryo culture demonstrate a requirement for signalling via RhoA/Rho kinase, but not jun N-terminal kinase, in convergent extension and the onset of neural tube closure. These findings identify a cell autonomous defect of convergent extension, requiring PCP signalling via RhoA/Rho kinase, during development of severe mouse neural tube defects. PMID:17229766

  7. Levels of alpha-fetoprotein in amniotic fluids of mice (curly-tail) with neural tube defects

    Microsoft Academic Search

    M Adinolfi; S Beck; S Embury; P E Polani; M J Seller

    1976-01-01

    Mutant curly-tail mice are genetically predisposed to produce offspring with neural tube defects. Estimation of alpha-fetoprotein in the amniotic fluid of fetuses of these mutants has shown that the levels are raised in fetuses with exencephaly and open spina bifida. This suggests that these mice are a valid model for studies of the aetiology and genesis of neural tube defects

  8. Methionine Synthase: High-Resolution Mapping of the Human Gene and Evaluation as a Candidate Locus for Neural Tube Defects

    Microsoft Academic Search

    Lawrence C. Brody; Priscilla J. Baker; Peter S. Chines; Anjene Musick; Anne M. Molloy; Deborah A. Swanson; Peadar N. Kirke; Soumitra Ghosh; John M. Scott; James L. Mills

    1999-01-01

    Periconceptual folate supplementation has been found to prevent the occurrence of many neural tube defects (NTDs). Consequently, genetic variation in folate metabolism genes is expected to contribute to the risk for neural tube defects. Methionine synthase catalyzes the vitamin B12-dependent conversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. The observation that homocysteine and vitamin B12 levels are independent predictors

  9. Rescue of the neural tube defect of loop-tail mice by a BAC clone containing the Ltap gene

    Microsoft Academic Search

    Zoha Kibar; Susan Gauthier; Seung-Hwan Lee; Silvia Vidal; Philippe Gros

    2003-01-01

    The mouse mutant loop-tail (Lp) is an accepted model for the study of neural tube defects (NTDs) in humans. Whereas Lp\\/+ heterozygotes show a mild tail defect (looped), homozygous Lp\\/Lp embryos show a very severe form of NTD, with a completely open neural tube from the hindbrain region to the caudal portion of the spinal cord (craniorachischisis). We have recently

  10. In toto live imaging of mouse morphogenesis and new insights into neural tube closure

    PubMed Central

    Massarwa, R’ada; Niswander, Lee

    2013-01-01

    In the field of developmental biology, live imaging is a powerful tool for studying, in real time, the dynamic behaviors of tissues and cells during organ formation. Mammals, which develop in utero, have presented a challenge for live imaging. Here, we offer a novel, prolonged and robust live imaging system for visualizing the development of a variety of embryonic tissues in the midgestation mouse embryo. We demonstrate the advantages of this imaging system by following the dynamics of neural tube closure during mouse embryogenesis and reveal extensive movements of the cranial neural tissue that are independent of neural fold zipping. PMID:23175632

  11. ?-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

    PubMed Central

    Zhao, Tianyu; Gan, Qini; Stokes, Arjun; Lassiter, Rhonda N. T.; Wang, Yongping; Chan, Jason; Han, Jane X.; Pleasure, David E.; Epstein, Jonathan A.; Zhou, Chengji J.

    2014-01-01

    Non-canonical Wnt/planar cell polarity (PCP) signaling plays a primary role in the convergent extension that drives neural tube closure and body axis elongation. PCP signaling gene mutations cause severe neural tube defects (NTDs). However, the role of canonical Wnt/?-catenin signaling in neural tube closure and NTDs remains poorly understood. This study shows that conditional gene targeting of ?-catenin in the dorsal neural folds of mouse embryos represses the expression of the homeobox-containing genes Pax3 and Cdx2 at the dorsal posterior neuropore (PNP), and subsequently diminishes the expression of the Wnt/?-catenin signaling target genes T, Tbx6 and Fgf8 at the tail bud, leading to spina bifida aperta, caudal axis bending and tail truncation. We demonstrate that Pax3 and Cdx2 are novel downstream targets of Wnt/?-catenin signaling. Transgenic activation of Pax3 cDNA can rescue the closure defect in the ?-catenin mutants, suggesting that Pax3 is a key downstream effector of ?-catenin signaling in the PNP closure process. Cdx2 is known to be crucial in posterior axis elongation and in neural tube closure. We found that Cdx2 expression is also repressed in the dorsal PNPs of Pax3-null embryos. However, the ectopically activated Pax3 in the ?-catenin mutants cannot restore Cdx2 mRNA in the dorsal PNP, suggesting that the presence of both ?-catenin and Pax3 is required for regional Cdx2 expression. Thus, ?-catenin signaling is required for caudal neural tube closure and elongation, acting through the transcriptional regulation of key target genes in the PNP. PMID:24284205

  12. Failure of neural tube closure in the loop-tail ( Lp) mutant mouse: analysis of the embryonic mechanism

    Microsoft Academic Search

    Dianne Gerrelli; Andrew J Copp

    1997-01-01

    Loop-tail (Lp) is unique among mouse mutants in failing to initiate neural tube closure at the cervical\\/hindbrain boundary (so-called `Closure 1'), at the 5–7 somite stage. Lp\\/Lp embryos go on to develop a malformation that closely resembles cranio-rachischisis, the most severe neural tube defect found in humans. We investigated several possible embryological mechanisms that may underlie this failure of neural

  13. U-tube steam generator empirical model development and validation using neural networks

    Microsoft Academic Search

    A. G. Parlos; K. T. Chong; A. Atiya

    1992-01-01

    Empirical modeling techniques that use model structures motivated from neural networks research have proven effective in identifying complex process dynamics. A recurrent multilayer perception (RMLP) network was developed as a nonlinear state-space model structure along with a static learning algorithm for estimating the parameter associated with it. The methods developed were demonstrated by identifying two submodels of a U-tube steam

  14. The Role of Folic Acid Fortification in Neural Tube Defects: A Review

    Microsoft Academic Search

    Anja Osterhues; Nyima S. Ali; Karin B. Michels

    2012-01-01

    The worldwide prevalence of neural tube defects (NTDs) has fallen noticeably during the past thirty years but the specific etiology and causative mechanism of NTDs remain unknown. Since introduction of mandatory fortification of grains with folic acid, a further decrease in NTD prevalence has been reported in North America and other countries with large variations among ethnic subgroups. However, a

  15. Survival of Infants With Neural Tube Defects in the Presence of Folic Acid Fortification

    Microsoft Academic Search

    Kirk A. Bol; Julianne S. Collins; Russell S. Kirby

    2010-01-01

    OBJECTIVE.Neural tube defects (NTDs) are preventable through preconceptional and periconceptional folic acid intake. Although decreases in the prevalence of NTDs have been reported since folic acid fortification of United States grain products began, it is not known whether folic acid plays a role in reducing the severity of occurring NTDs. Our aim was to determine whether survival among infants born

  16. Folic acid fortification, maternal obesity and neural tube defects: Policy implications

    Microsoft Academic Search

    Parisa Assassi

    2008-01-01

    In 1996, the Food and Drug Administration (FDA) mandated that beginning in January 1998, flour and other enriched grain products be fortified with 140 ?g of folic acid per 100 g of grain to prevent neural tube defects (NTDs) that occur in approximately 1 in 1,000 pregnancies in the United States (U.S.). Although this program has demonstrated important public health

  17. Neural Tube Defects at Siriraj Hospital, Bangkok, Thailand10 Years Review (1990-1999)

    Microsoft Academic Search

    Pornswan Wasant

    Objectives: Neural tube defects (NTDs), (including anencephaly, meningomyelocele and encephalocele), are among the most common birth defects, with high associated mortality and morbidity. NTDs occur in 1-5 per 1,000 births, with marked geographic and ethnic variations. However, there are few data concerning the incidence, associated anomalies, treatment and outcome of NTDs in Thailand. The objective of this study is to

  18. Neural Tube Defects: Knowledge and Preconceptional Prevention Practices in Minority Young Women

    Microsoft Academic Search

    Janice L. Grover; Peggy B. Smith

    ABSTRACT. Objective. To assess 1) knowledge of neural tube defect (NTD) prevention by folic acid, 2) frequency of intake of multivitamins and folate- and folic acid–fortified food, and 3) factors associated with knowledge and prevention practices among sexually ac- tive minority adolescent and young adult women. Methods. Young minority women were enrolled in a folic acid program at 3 urban

  19. Are the recommendations on the prevention of neural tube defects working?

    Microsoft Academic Search

    C. Stoll; Y. Alembik; B. Dott

    2006-01-01

    Many studies showed that reduction by an estimated 80% or more of neural tube defects (NTD) by consumption of folic acid from before conception is achievable. The objectives of this study were to evaluate the effectiveness of recommendations on folic acid aimed at reducing the occurrence of NTD in our region. Cases of NTD were ascertained among liveborn infants, stillbirths,

  20. Involvement of deprivation and environmental lead in neural tube defects: a matched case-control study

    Microsoft Academic Search

    John P Bound; Peter W Harvey; Brian J Francis; Fuad Awwad; Anthony C Gatrell

    1997-01-01

    OBJECTIVETo analyse the prevalence of neural tube defects in small geographical areas and seek to explain any spatial variations with reference to environmental lead and deprivation.SETTINGThe Fylde of Lancashire in the north west of England.DESIGNCases were ascertained as part of a prospective survey of major congenital malformations in babies born in the Fylde to residents there between 1957 and 1981.

  1. Neural Tube Defects and Maternal Residential Proximity to Agricultural Pesticide Applications

    Microsoft Academic Search

    Rudolph P. Rull; Beate Ritz; Gary M. Shaw

    2006-01-01

    Residential proximity to applications of agricultural pesticides may be an important source of exposure to agents that have been classified as developmental toxins. Data on two case-control study populations of infants with neural tube defects (NTDs) and nonmalformed controls delivered in California between 1987 and 1991 were pooled to investigate whether maternal residential proximity to applications of specific pesticides or

  2. How Many People Are Affected By or Are at Risk for Neural Tube Defects?

    MedlinePLUS

    ... it diagnosed? Is there a cure? Are there associated conditions? What are the treatments? Other FAQs NICHD Research Information Clinical Trials Resources and Publications How many people are affected by or are at risk for neural tube defects? Skip sharing on social media links Share this: ...

  3. Improving the health and well-being of women at risk for neural tube defect recurrence

    Microsoft Academic Search

    Tasneem Husain

    2009-01-01

    There is growing interest in providing women with internatal care, a package of healthcare and ancillary services that can improve their health during the period after the termination of one pregnancy but before the conception of the next pregnancy. Women who have had a pregnancy affected by a neural tube defect can especially benefit from internatal care because they are

  4. Demonstration of astrocytes in cultured amniotic fluid cells of three cases with neural-tube defect

    Microsoft Academic Search

    Marion Cremer; Melitta Schachner; Thomas Cremer; Werner Schmidt; Theda Voigtlfinder

    1981-01-01

    We have investigated the origin of rapidly adhering (RA) cells in three cases of neural tube defects (two anencephali, one encephalocele). We were able to demonstrate the presence of glial fibrillary acidic (GFA) protein in variable percentages (4–80%) of RA cells cultured for 4–6 days by use of indirect immunofluorescence with GFA antiserum. Cells cultured from amniotic fluids of normal

  5. Time trends in neural tube defects prevalence in relation to preventive strategies: an international study

    Microsoft Academic Search

    A. Rosano; D. Smithells; L. Cacciani; B. Botting; E. Castilla; M. Cornel; D. Erickson; J. Goujard; L. Irgens; P. Merlob; E. Robert; C. Siffel; C. Stoll; Y. Sumiyoshi

    1999-01-01

    OBJECTIVE: To examine time trends in neural tube defects (NTD) prevalence from 1987 to 1996 in relation to the primary prevention policies for folic acid supplementation strategies in different countries. DESIGN: Retrospective time trends analysis of NTD prevalence. SETTING: 11 birth defect registries of congenital malformations participating in the International Clearinghouse for Birth Defects Monitoring System, in the period from

  6. Fgf8Related Secondary Organizers Exert Different Polarizing Planar Instructions along the Mouse Anterior Neural Tube

    Microsoft Academic Search

    Ivan Crespo-Enriquez; Juha Partanen; Salvador Martinez; Diego Echevarria

    2012-01-01

    Early brain patterning depends on proper arrangement of positional information. This information is given by gradients of secreted signaling molecules (morphogens) detected by individual cells within the responding tissue, leading to specific fate decisions. Here we report that the morphogen FGF8 exerts initially a differential signal activity along the E9.5 mouse neural tube. We demonstrate that this polarizing activity codes

  7. Lipid mediators link cells progression with placental and neural tube defects after maternal fumonisin exposure

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of maize. Increased risk for neural tube defects (NTDs) is observed in populations that rely on maize as a dietary staple. FB1 inhibits ceramide synthase, resulting in altered pools of biologically active sphingolipids. FB1...

  8. Identification of sensitivity genes involved in teratogen-induced neural tube defects

    E-print Network

    Hayes, Blaine G

    2013-02-22

    Neural tube defects (NTDs) are common human congenital anomalies affecting 1 per 1000 live-born infants in the United States. NTDs are medical conditions that result from improper formation of the brain and spinal cord. There is evidence to suggest...

  9. Genetic interaction between members of the Vangl family causes neural tube defects in mice

    PubMed Central

    Torban, Elena; Patenaude, Anne-Marie; Leclerc, Severine; Rakowiecki, Staci; Gauthier, Susan; Andelfinger, Gregor; Epstein, Douglas J.; Gros, Philippe

    2008-01-01

    Neural tube defects (NTDs) are very frequent congenital abnormalities in humans. Recently, we have documented independent association of Vangl1 and Vangl2 gene mutations with NTDs. In the Looptail mouse, homozygosity (but not heterozygosity) for loss-of-function alleles at Vangl2 causes the severe NTD craniorachischisis, whereas heterozygosity for mutant variants of VANGL1 is associated with NTDs in a human cohort of sporadic and familial cases. To understand the role of Vangl1 in normal development, we created a mouse mutant with an inactivating mutation at Vangl1 (Vangl1gt). Vangl1 shows a dynamic pattern of expression in the developing neural tube and notochord at the time of neural tube closure. Vangl1gt/+ heterozygotes and Vangl1gt/gt homozygotes are viable and fertile, although Vangl1gt/gt display subtle alterations in polarity of inner hair cells of the cochlea. Remarkably, and as opposed to healthy Vangl1gt/+ and Vangl2lp/+ heterozygotes, Vangl1gt/+;Vangl2lp/+ double heterozygotes show profound developmental defects that include severe craniorachischisis, inner ear defects (disorganization of the stereociliary bundles of hair cells of the organ of Corti), and cardiac abnormality (aberrant right subclavian artery). These results show that genetic interaction between Vangl1 and Vangl2 genes causes neural tube defects and raise the possibility that interaction between individual Vangl genes and other genetic loci and/or environmental factors may additionally contribute to the etiology of NTDs. PMID:18296642

  10. Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects

    Microsoft Academic Search

    Huiping Zhu; Ned J Wicker; Gary M Shaw; Edward J Lammer; Kate Hendricks; Lucina Suarez; Mark Canfield; Richard H Finnell

    2003-01-01

    Folic acid supplementation can effectively reduce the risk of neural tube defects (NTDs); however, the mechanism underlying this beneficial effect remains unclear. Recent evidence suggests that certain folate pathway genes, as well as those related to homocysteine metabolism might be contributing to this effect. The purpose of this study is to investigate whether gene polymorphisms of methionine synthase (MTR) and

  11. Role of ZIP14 (SLC39A14) gene histidine rich regions in neural tube defects

    Microsoft Academic Search

    Didem Torun; Erkan Y?lmaz; Ece Akar; Nejat Akar

    Neural tube defects (NTDs) comprise a group of congenital malformations that includes spina bifida, anencephaly, meningomyelocele and encephalocele. Reports have implicated zinc deficiency as one of the causative factors of NTDs. Both environmental and genetic factors are involved in the etiology of NTDs. Inadequate folate intake and nutritional deficiency are important environmental risk factors. The aim of this study was

  12. The Detection System for Oil Tube Defect Based on Multisensor Data Fusion by Wavelet Neural Network

    Microsoft Academic Search

    Jingwen Tian; Meijuan Gao; Hao Zhou; Kai Li

    2007-01-01

    A detection system of oil tube defect based on wavelet neural network is presented, it got the original information by multigroup vortex sensors and leakage magnetic sensors. We made multiscale wavelet transform and frequency analysis to multichannels original data and extracted multi-attribute parameters from time domain and frequency domain, then we selected the key attribute parameters that have bigger correlativity

  13. Prevention of spinal neural tube defects in the mouse embryo by growth retardation during neurulation

    Microsoft Academic Search

    ANDREW J. COPP; JOHN A. CROLLA; FRANCES A. BROOK

    Summary Homozygous mutant curly tail mouse embryos devel- oping spinal neural tube defects (NTD) exhibit a cell- type-specific abnormality of cell proliferation that affects the gut endoderm and notochord but not the neuroepithelium. We suggested that spinal NTD in these embryos may result from the imbalance of cell proliferation rates between affected and unaffected cell types. In order to test

  14. Exclusion mapping of the gene for X-linked neural tube defects in an Icelandic family

    Microsoft Academic Search

    F. A. Hol; M. P. A. Geurds; O. Jensson; B. C. J. Hamel; G. E. Moore; R. Newton; E. C. M. Mariman

    1994-01-01

    Various polymorphic markers with a random distribution along the X chromosome were used in a linkage analysis performed on a family with apparently Xlinked recessive inheritance of neural tube defects (NTD). The lod score values were used to generate an exclusion map of the X chromosome; this showed that the responsible gene was probably not located in the middle part

  15. A study on the possible involvement of the PAX3 gene in human neural tube defects

    Microsoft Academic Search

    F. A. Hol; B. C. J. Hamel; M. P. A. Geurds

    1994-01-01

    Neural tube defects (NTD) are congenital malformations of the central nervous system which are generally attributed to a combination of environmental and genetic factors. Recently, the molecular defect responsible for the phenotype of the Splotch mouse, a monogenic model system for NTD, was determined. A mutation disrupts the homeodomain of the gene for Pax3. In humans, mutations in the cognate

  16. derived growth factor ? -receptor gene predispose to human neural tube defects

    Microsoft Academic Search

    Paul H. L. J. Joosten; Mascha Toepoel; Edwin C. M. Mariman; J. J. Van Zoelen

    Neural tube defects (NTDs), including anencephaly and spina bifida, are multifactorial diseases that occur with an incidence of 1 in 300 births in the United Kingdom 1 . Mouse models have indicated that deregulated expression of the gene encoding the platelet-derived growth factor ? -receptor (Pdgfra) causes congenital NTDs (refs. 2-4), whereas mutant forms of Pax-1 that have been associated

  17. Arsenic-induced gene expression changes in the neural tube of folate transport defective mouse embryos

    Microsoft Academic Search

    Bogdan J. Wlodarczyk; Robert M. Cabrera; Denise S. Hill; Daniel Bozinov; Huiping Zhu; Richard H. Finnell

    2006-01-01

    Arsenic injected intraperitoneally (i.p.) during early organogenesis to small pregnant laboratory rodents (mouse, rat, and hamster) induces several congenital defects in the progeny. Among those abnormalities consistently and predominantly observed are exencephaly and encephalocele. These severe defects of the central nervous system originate from a corrupted process of neurulation and are better known as neural tube defects (NTDs). In order

  18. Homocysteine is embryotoxic but does not cause neural tube defects in mouse embryos

    Microsoft Academic Search

    Nicholas D. E. Greene; Louisa P. Dunlevy; Andrew J. Copp

    2003-01-01

    The observation of elevated maternal plasma homocysteine concentration in pregnancies affected by neural tube defects (NTD) suggests that folate metabolism may be disturbed in NTD cases. In addition, studies on the chick embryo suggest that hyperhomocysteinaemia may contribute directly to the development of NTD. In order to test the hypothesis that homocysteine may cause NTD, we cultured mouse embryos in

  19. Fetotoxicity and neural tube defects in CD1 mice exposed to the mycotoxin Fumonisin B1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisins are mycotoxins that are produced by Fusarium verticillioides and that occur in corn and corn-based foods. Their effects on human health are unclear, however, epidemiological and experimental evidence suggests that they increase the risk of neural tube defects (NTDs) in populations routine...

  20. Heat Transfer Coefficient and Friction Factor Prediction of Corrugated Tubes Combined With Twisted Tape Inserts Using Artificial Neural Network

    Microsoft Academic Search

    Mohammad Reza Jafari Nasr; Ali Habibi Khalaj

    2010-01-01

    In the research described here, artificial neural network (ANN) approach has been utilized to characterize the thermohydraulic behavior of corrugated tubes combined with twisted tape inserts in a turbulent flow regime. The experimental data sets were extracted from 57 tubes, 9 and 3 spirally corrugated tubes with varying geometries combined with 5 and 4 twisted tapes with different pitches. The

  1. Cellular basis of neuroepithelial bending during mouse spinal neural tube closure.

    PubMed

    McShane, Suzanne G; Molè, Matteo A; Savery, Dawn; Greene, Nicholas D E; Tam, Patrick P L; Copp, Andrew J

    2015-08-15

    Bending of the neural plate at paired dorsolateral hinge points (DLHPs) is required for neural tube closure in the spinal region of the mouse embryo. As a step towards understanding the morphogenetic mechanism of DLHP development, we examined variations in neural plate cellular architecture and proliferation during closure. Neuroepithelial cells within the median hinge point (MHP) contain nuclei that are mainly basally located and undergo relatively slow proliferation, with a 7h cell cycle length. In contrast, cells in the dorsolateral neuroepithelium, including the DLHP, exhibit nuclei distributed throughout the apico-basal axis and undergo rapid proliferation, with a 4h cell cycle length. As the neural folds elevate, cell numbers increase to a greater extent in the dorsolateral neural plate that contacts the surface ectoderm, compared with the more ventromedial neural plate where cells contact paraxial mesoderm and notochord. This marked increase in dorsolateral cell number cannot be accounted for solely on the basis of enhanced cell proliferation in this region. We hypothesised that neuroepithelial cells may translocate in a ventral-to-dorsal direction as DLHP formation occurs, and this was confirmed by vital cell labelling in cultured embryos. The translocation of cells into the neural fold, together with its more rapid cell proliferation, leads to an increase in cell density dorsolaterally compared with the more ventromedial neural plate. These findings suggest a model in which DLHP formation may proceed through 'buckling' of the neuroepithelium at a dorso-ventral boundary marked by a change in cell-packing density. PMID:26079577

  2. International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?

    PubMed Central

    Botto, Lorenzo D; Lisi, Alessandra; Robert-Gnansia, Elisabeth; Erickson, J David; Vollset, Stein Emil; Mastroiacovo, Pierpaolo; Botting, Beverley; Cocchi, Guido; de Vigan, Catherine; de Walle, Hermien; Feijoo, Maria; Irgens, Lorentz M; McDonnell, Bob; Merlob, Paul; Ritvanen, Annukka; Scarano, Gioacchino; Siffel, Csaba; Metneki, Julia; Stoll, Claude; Smithells, Richard; Goujard, Janine

    2005-01-01

    Objectives To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects. Design Retrospective cohort study of births monitored by birth defect registries. Setting 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review. Main outcome measures Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable). Results The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects. Conclusions Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements. PMID:15722368

  3. The essential role of protein kinase C? in diabetes-induced neural tube defects

    PubMed Central

    Cao, Yuanning; Zhao, Zhiyong; Eckert, Richard L.; Reece, E. Albert

    2015-01-01

    Background Maternal diabetes causes neural tube defects (NTDs) in the embryos via activating protein kinase Cs (PKCs), which regulate programmed cell death (apoptosis). The aims of this study are to investigate the role of proapoptotic PKC? in NTD formation and the underlying mechanisms. Methods PKC? heterozygous (pkc?+/?) female mice were diabetic (DM) induced by intravenous injection of streptozotocin. Occurrence of NTDs was evaluated at embryonic day 11.5 and compared between wild type (WT) and PKC? homozygous (pkc??/?) embryos. Changes in oxidative and endoplasmic reticulum (ER) stress-associated factors and stress-response c-Jun N-terminal kinases (JNKs) were assessed using Western blot assay. Results Compared to DM/WT, the DM/PKC??/? embryos had significantly lower NTD rate and lower levels of oxidative and ER stress factors and JNK activation. These values were similar to those in the non-diabetic control group. Conclusion PKC? plays a critical role in diabetes-induced NTDs, potentially through increasing oxidative and ER stress and JNK-associated stress-response pathways. PMID:22463764

  4. Exposure to polychlorinated biphenyls and risk of neural-tube defects in a Mexican American population.

    PubMed

    Suarez, Lucina; Gilani, Zunera; Felkner, Marilyn; Brender, Jean; Henry, Judy; Hendricks, Kate

    2005-01-01

    The authors examined the association between maternal polychlorinated biphenyl (PCB) levels and risk of neural tube defects (NTDs) in Mexican American women with NTD-affected pregnancies who resided in the 14 Texas-Mexico border counties during 1995-2000 (cases). Controls were randomly selected from study area women delivering normal live births. For PCB congeners with sufficient numbers of detectable values (PCB 99, 101, 110, 118, 138, 153, 180), there was little association between the proportions with detectable PCB levels in cases and controls. Odds ratios were <1 or compatible with the null, but power was low for some congeners. An index of seven PCB congeners (105, 118, 138, 153, 170, 180, 194) was also not associated with NTD risk. The maternal serum PCB levels in this study population (median PCB 153 level: 18 ng/g) were comparable to those with background exposure and do not appear to have contributed to the high prevalence of NTDs in this population. PMID:16130963

  5. An adverse outcome pathway framework for neural tube and axial defects mediated by modulation of retinoic acid homeostasis.

    PubMed

    Tonk, Elisa C M; Pennings, Jeroen L A; Piersma, Aldert H

    2015-08-01

    Developmental toxicity can be caused through a multitude of mechanisms and can therefore not be captured through a single simple mechanistic paradigm. However, it may be possible to define a selected group of overarching mechanisms that might allow detection of the vast majority of developmental toxicants. Against this background, we have explored the usefulness of retinoic acid mediated regulation of neural tube and axial patterning as a general mechanism that, when perturbed, may result in manifestations of developmental toxicity that may cover a large part of malformations known to occur in experimental animals and in man. Through a literature survey, we have identified key genes in the regulation of retinoic acid homeostasis, as well as marker genes of neural tube and axial patterning, that may be used to detect developmental toxicants in in vitro systems. A retinoic acid-neural tube/axial patterning adverse outcome pathway (RA-NTA AOP) framework was designed. The framework was tested against existing data of flusilazole exposure in the rat whole embryo culture, the zebrafish embryotoxicity test, and the embryonic stem cell test. Flusilazole is known to interact with retinoic acid homeostasis, and induced common and unique NTA marker gene changes in the three test systems. Flusilazole-induced changes were similar in directionality to gene expression responses after retinoic acid exposure. It is suggested that the RA-NTA framework may provide a general tool to define mechanistic pathways and biomarkers of developmental toxicity that may be used in alternative in vitro assays for the detection of embryotoxic compounds. PMID:25461899

  6. Reassessing folic acid consumption patterns in the United States (1999-2004): potential effect on neural tube defects and overexposure to folate1-3

    Microsoft Academic Search

    Eoin P Quinlivan; Jesse F Gregory

    Background: In the United States, folic acid fortification of cereal- grainfoodshassignificantlyincreasedfolatestatus.However,blood folate concentrations have decreased from their postfortification high as a result, in part, of decreasing food fortification concentra- tions and the popularity of low-carbohydrate weight-loss diets. Objectives:The objectives of the study were to quantify changes in folateintakeafterfolicacidfortificationandtoestimatetheeffecton neural tube defect (NTD) occurrence. Design: Expanding on an earlier model, we

  7. Molecular mechanisms of cell shape changes that contribute to vertebrate neural tube closure.

    PubMed

    Suzuki, Makoto; Morita, Hitoshi; Ueno, Naoto

    2012-04-01

    During early development of the central nervous system, the neuroepithelial cells undergo dynamic changes in shape, cumulative action of which cause the neural plate to bend mediolaterally to form the neural tube. The apicobasal elongation changes the cuboidal cells into columnar ones, whereas apical constriction minimizes the cell apices, causing them to adopt wedge-like shapes. To achieve the morphological changes required for the formation of a hollow structure, these cellular changes must be controlled in time and space. To date, it is widely accepted that spatial and temporal changes of the cytoskeletal organization are fundamental to epithelial cell shape changes, and that noncetrosomal microtubules assembled along apicobasal axis and actin filaments and non-muscle myosin II at the apical side are central machineries of cell elongation and apical constriction, respectively. Hence, especially in the last decade, intracellular mechanisms regulating these cytoskeletons have been extensively investigated at the molecular level. As a result, several actin-binding proteins, Rho/ROCK pathway, and cell-cell adhesion molecules have been proven to be the central regulators of apical constriction, while the regulatory mechanisms of cell elongation remain obscure. In this review, we first describe the distribution and role of cytoskeleton in cell shape changes during neural tube closure, and then summarize the current knowledge about the intracellular proteins that directly modulate the cytoskeletal organization and thus the neural tube closure. PMID:22524600

  8. CDC Grand Rounds: additional opportunities to prevent neural tube defects with folic acid fortification.

    PubMed

    2010-08-13

    Neural tube defects (NTDs) are serious birth defects that result from the failure of the neural tube to close in the cranial region (anencephaly) or more caudally along the spine (spina bifida) by the 28th day of gestation. Infants born with anencephaly usually die within a few days of birth, and those with spina bifida have life-long disabilities with varying degrees of paralysis. Currently, identified risk factors for NTDs include a mother who previously had an NTD-affected pregnancy, maternal diabetes, obesity, hyperthermia, certain antiseizure medications, genetic variants, race/ethnicity, and nutrition (particularly folic acid insufficiency). In the United States, during 1995-1996, approximately 4,000 pregnancies were affected by an NTD. This number declined to 3,000 pregnancies in 1999-2000 after fortification of enriched cereal grain products with folic acid was mandated. Worldwide, in 1998, approximately 300,000 births were affected by an NTD. PMID:20703205

  9. Disruption of the MacMARCKS Gene Prevents Cranial Neural Tube Closure and Results in Anencephaly

    Microsoft Academic Search

    Jianmin Chen; Sandy Chang; Stephen A. Duncan; Hirotaka J. Okano; Gord Fishell; Alan Aderem

    1996-01-01

    MacMARCKS is a member of the MARCKS family of protein kinase C (PKC) substrates. Biochemical evidence demonstrates that these proteins integrate calcium and PKC-dependent signals to regulate actin structure at the membrane. We report here that deletion of the MacMARCKS gene prevents cranial neural tube closure in the developing brain, resulting in anencephaly. This suggests a central role for MacMARCKS

  10. Economic burden of neural tube defects and impact of prevention with folic acid: a literature review

    Microsoft Academic Search

    Yunni Yi; Marion Lindemann; Antje Colligs; Claire Snowball

    Neural tube defects (NTDs) are the second most common group of serious birth defects. Although folic acid has been shown to\\u000a reduce effectively the risk of NTDs and measures have been taken to increase the awareness, knowledge, and consumption of\\u000a folic acid, the full potential of folic acid to reduce the risk of NTDs has not been realized in most

  11. Neural Tube Defects in Relation to Use of Folic Acid Antagonists during Pregnancy

    Microsoft Academic Search

    Sonia Hernández-Díaz; Martha M. Werler; Alexander M. Walker; Allen A. Mitchell

    Periconceptional folic acid supplementation reduces the risk of neural tube defects (NTDs). To determine whether periconceptional exposure to folic acid antagonists (FAAs) might therefore increase the risk of NTDs, the authors examined data from an ongoing case-control study of birth defects (1979-1998) in the United States and Canada. They compared data on 1,242 infants with NTDs (spina bifida, anencephaly, and

  12. Periconceptional folic acid use and the prevalence of neural tube defects in The Netherlands

    Microsoft Academic Search

    Karin M. van der Pal-de Bruin; Simone E. Buitendijk; A. Lya den Ouden

    2003-01-01

    Objective: To study the effect of increased folic acid intake on the prevalence of neural tube defects (NTD) in The Netherlands. Study design: Using the capture–recapture method, the prevalence of NTD was estimated on the basis of five different registries on births affected by NTD. Results: Total prevalence over the 1988–1998 period varied between 1.43 and 1.96 per 1000 live

  13. Urban–rural residence and the occurrence of neural tube defects in Texas, 1999–2003

    Microsoft Academic Search

    T. J. Luben; L. C. Messer; P. Mendola; S. E. Carozza; S. A. Horel; P. H. Langlois

    2009-01-01

    Neural tube birth defects (NTDs) affect more than 4000 pregnancies in the US annually. The etiology of NTDs is believed to be multifactorial, but much remains unknown. We examined the pattern and magnitude of urban–rural variation in anencephaly, spina bifida without anencephaly, and encephalocele in Texas in relation with urban–rural residence for the period 1999–2003. There was no evidence that

  14. Maternal Supplemental and Dietary Zinc Intake and the Occurrence of Neural Tube Defects in California

    Microsoft Academic Search

    Ellen M. Velie; Gladys Block; Gary M. Shaw; Steven J. Samuels; Donna M Schaffer; Martin Kulldorff

    The authors investigated the association between maternal preconceptional supplemental and dietary zinc intake and risk of neural tube defects (NTDs) in a population-based case-control study conducted between 1989 and 1991 in California. Cases were 430 NTD-affected fetuses\\/infants, and controls were 429 randomly selected non-malformed infants. Mothers reported their preconceptional use of vitamin, mineral, and food supplements, and completed a 98-item

  15. Genetic interaction between members of the Vangl family causes neural tube defects in mice

    Microsoft Academic Search

    Elena Torban; Anne-Marie Patenaude; Severine Leclerc; Staci Rakowiecki; Susan Gauthier; Gregor Andelfinger; Douglas J. Epstein; Philippe Gros

    2008-01-01

    Neural tube defects (NTDs) are very frequent congenital abnormalities in humans. Recently, we have documented independent association of Vangl1 and Vangl2 gene mutations with NTDs. In the Looptail mouse, homozygosity (but not heterozygosity) for loss-of-function alleles at Vangl2 causes the severe NTD craniorachischisis, whereas heterozygosity for mutant variants of VANGL1 is associated with NTDs in a human cohort of sporadic

  16. Reduction in valproic acid-induced neural tube defects by maternal immune stimulation: role of apoptosis.

    PubMed

    Mallela, Mural; Hrubec, Theresa

    2012-08-01

    Teratogenic deregulation of apoptosis during development is a possible mechanism for birth defects. Administration of valproic acid (VA) during first trimester of pregnancy causes neural tube defects (NTDs). Nonspecific stimulation of the mother's immune system has been shown to reduce various teratogen-induced fetal malformations including NTDs in rodents. This present study investigated the role of reduced apoptosis by maternal immune stimulation in prevention of VA-induced NTDs in CD-1 mice. Prevention of VA-induced NTDs by nonspecific maternal immune stimulation using IFN? was employed to evaluate the role of reduced apoptosis by IFN? in this protective mechanism. Apoptosis was quantified using flow cytometry. Terminal Transferase dUTP Nick End Labeling assay was used to localize the apoptosis. 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 levels in embryos with closed neural tubes from IFN? + VA dams were similar to controls indicating resistance to VA-induced apoptosis and protection against teratogenicity of VA. In IFN? + VA exposed embryos with open neural tubes, maternal immune stimulation failed to regulate apoptosis resulting in an NTD. Overall, these results suggest that VA alters several biological processes including apoptosis in the developing embryos to induce fetal malformations. Resistance to VA-induced apoptosis in embryos resulting from maternal immune stimulation may be involved in protective mechanism. PMID:22767483

  17. Absence of linkage between familial neural tube defects and PAX3 gene

    Microsoft Academic Search

    S. Chatkupt; F. A. Hol; Y. Y. Shugart; M. P. A. Geurds; E. S. Stenroos; M. R. Koenigsberger; B. C. J. Hamel; W. G. Johnson; E. C. M. Mariman

    1995-01-01

    Neural tube defects (NTD) are among the most common and disabling birth defects. The aetiology of NTD is unknown and their genetics are complex. The majority of NTD cases are sporadic, isolated, nonsyndromic, and generally considered to be multifactorial in origin. Recently, PAX3 (formerly HuP2, the human homologue of mouse Pax-3), on chromosome 2q35-37, was suggested as a candidate gene

  18. Excess methionine suppresses the methylation cycle and inhibits neural tube closure in mouse embryos

    Microsoft Academic Search

    Louisa P. E. Dunlevy; Katie A. Burren; Lyn S. Chitty; Andrew J. Copp; Nicholas D. E. Greene

    2006-01-01

    Suppression of one-carbon metabolism or insufficient methionine intake are suggested to increase risk of neural tube defects (NTD). Here, exogenous methionine unexpectedly caused frequent NTD in cultured mouse embryos. NTD were associated with reduced cranial mesenchyme cell density, which may result from a preceding reduction in proliferation. The abundance ratio of S-adenosylmethionine to S-adenosylhomocysteine was also decreased in treated embryos,

  19. Antisense modulation of 5,10-methylenetetrahydrofolate reductase expression produces neural tube defects in mouse embryos

    Microsoft Academic Search

    Deborah K. Hansen; Scott A. Barbee; Thomas F. Grafton; Yan Gu; Randal D. Streck

    2000-01-01

    The role of folate metabolism in producing neural tube defects (NTDs) in humans is unknown. In the current study, antisense oligodeoxyribonucleotide technology was utilized to disrupt normal expression of the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) in organogenesis-stage mouse embryos. Two different antisense probes were microinjected into the amniotic sac of gestation day (GD) 8 mouse embryos with PBS or scrambled

  20. Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk

    Microsoft Academic Search

    Patrizia De Marco; Elisa Merello; Maria Grazia Calevo; Samantha Mascelli; Alessandro Raso; Armando Cama; Valeria Capra

    2006-01-01

    Genetic variants of enzymes involved in the folate pathway might be expected to have an impact on neural tube defect (NTD) risk. Given its key role in folate metabolism, the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene could represent an attractive candidate in NTD aetiology. In this study, the impact of the MTHFD1 1958G>A polymorphism on NTD risk in the Italian population

  1. Induction of Neural Tube Defects and Skeletal Malformations in Mice following Brief Hyperthermia in utero

    Microsoft Academic Search

    Kohei Shiota

    1988-01-01

    Hyperthermia was induced in ICR mice on day 8.5 of gestation by immersing them in hot water. Control mice were immersed in water at 38°C for 15 min. In dams exposed to 42°C for 12.5–15 min or to 43°C for 7.5–10 min, externally malformed fetuses increased significantly and in a dose-related manner. Anterior neural tube defects (exencephaly, anencephaly, encephalocele, and

  2. Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects

    Microsoft Academic Search

    K. M. LAURENCE; NANSI JAMES; MARY H. MILLER; G. B. TENNANT; H. CAMPBELL

    1981-01-01

    A randomized controlled double-blind trial was undertaken in south Wales to prevent the recurrence of neural-tube defects in women who had had one child with a neural-tube defect. Sixty women were allocated before conception to take 4 mg of folic acid a day before and during early pregnancy and 44 complied with these instructions. Fifty-one women were allocated to placebo

  3. Expression of p53\\/hgf\\/c-met\\/STAT3 signal in fetuses with neural tube defects

    Microsoft Academic Search

    Maria Trovato; Maria D’Armiento; Luca Lavra; Alessandra Ulivieri; Roberto Dominici; Enrica Vitarelli; Maddalena Grosso; Raffaella Vecchione; Gaetano Barresi; Salvatore Sciacchitano

    2007-01-01

    Neural tube defects (NTD) are morphogenetic alterations due to a defective closure of neural tube. Hepatocyte growth factor\\u000a (HGF)\\/c-met system plays a role in morphogenesis of nervous system, lung, and kidney. HGF\\/c-met morphogenetic effects are\\u000a mediated by signal transducers and activators of transcription (STAT)3 and both HGF and c-met genes are regulated from p53.\\u000a The aim of our study was

  4. Folate and cobalamin uptake by human placenta in complicated pregnancies: Prematurity, preeclampsia and fetal neural tube defects

    Microsoft Academic Search

    Gláucia J. O. Melo; Nadia M. F. Trugo

    2000-01-01

    The purpose of the present study was to evaluate whether folate and cobalamin uptakes by microvillous membrane vesicles (MMV) from human placenta are affected in pregnancy complications such as prematurity, preeclampsia, and fetal neural tube defects. MMVs were obtained from pooled placental samples from adult women with uncomplicated full-term gestations (n=4), premature delivery (n=3), preeclampsia (n=3), and fetal neural tube

  5. An association study between SUFU gene polymorphisms and neural tube defects.

    PubMed

    Lu, Xiaolin; Wang, Zhen; Wang, Jianhua; Shangguan, Shaofang; Bao, Yihua; Lu, Ping; Wang, Li

    2014-06-01

    Neural tube defects (NTDs) in mammals are rooted in aberrant neural tube closure during early embryogenesis, which is caused by multiple environmental and genetic factors. The Sonic Hedgehog pathway is involved in the induction of the floor plate and participates in formation of the neural tube. Mutation of the suppressor of fused gene (SUFU), an essential repressor of Sonic Hedgehog signaling pathway, can result in NTDs. A case-control study was designed to compare the frequencies of the polymorphism at four sites in the SUFU gene in control and NTDs group, as well as in subtype groups, including anencephaly, spina bifida and encephalocele. We also explored the association between polymorphism and NTDs risk in a high prevalence population in China. Rs10786691, but not the other three SNPs, had an association between polymorphisms and NTDs. The heterozygous AG allele of rs10786691 was significantly related with NTDs and encephalocele (OR = 1.60, 95% CI: 1.04-2.48, p = 0.034; OR = 2.83, 95% CI: 1.07-7.47, p = 0.036). In female but not male fetuses, the AG genotype of rs10786691 increased the risk of NTDs (OR = 1.88, 95% CI: 1.03-3.41, p = 0.040). The SUFU rs10786691 A>G polymorphism may be a potential risk factor for NTDs and encephalocele in this high-risk population, but the association between the polymorphism and NTDs was probably influenced by gender. PMID:24070372

  6. Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism.

    PubMed

    Wang, Xiuwei; Guan, Zhen; Chen, Yan; Dong, Yanting; Niu, Yuhu; Wang, Jianhua; Zhang, Ting; Niu, Bo

    2015-01-01

    DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005), 5-formyltetrahydrofolate (5-FoTHF, P = 0.040), S-adenosylmethionine (SAM, P = 0.004) and higher concentrations of folic acid (P = 0.041), homocysteine (Hcy, P = 0.006) and S-adenosylhomocysteine (SAH, P = 0.045) compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions) were selected by microarray. Two genes (Siah1b, Prkx) in Wnt signal pathway demonstrated lower methylated regions (peak) and higher expression in NTDs (P<0.05; P<0.05). Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs. PMID:25822193

  7. Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure

    PubMed Central

    Merte, Janna; Jensen, Devon; Wright, Kevin; Sarsfield, Sarah; Wang, Yanshu; Schekman, Randy; Ginty, David D.

    2010-01-01

    Craniorachischisis is a rare but severe birth defect that results in a completely open neural tube. Mouse mutants in planar cell polarity (PCP) signaling components have deficits in the morphological movements of convergent extension (CE) that result in craniorachischisis. Using a forward-genetic screen in mice, we have identified Sec24b, a cargo-sorting member of the core complex of the COPII endoplasmic reticulum (ER)-Golgi transport vesicle, as critical for neural tube closure. Sec24bY613 mutants exhibit craniorachischisis, deficiencies in CE, and other PCP-related phenotypes. Vangl2, a key component of the PCP-signaling pathway critical for CE, is selectively sorted into COPII vesicles by Sec24b. Moreover, Sec24bY613 genetically interacts with a loss-of-function Vangl2 allele (Vangl2LP) causing a marked increase in the prevalence of spina bifida. Interestingly, the Vangl2 looptail point mutants D255E and S464N, known to cause defects in CE, fail to sort into COPII vesicles and are trapped in the ER. Thus, during COPII vesicle formation, Sec24b exhibits cargo specificity for a core PCP component, Vangl2, the proper ER to Golgi transport of which is essential for the establishment of PCP, convergent extension, and closure of the neural tube. PMID:19966784

  8. The Chromatin Targeting Protein Brd2 is Required for Neural Tube Closure and Embryogenesis

    PubMed Central

    Gyuris, Aron; Donovan, Diana J.; Seymour, Kimberly A.; Lovasco, Lindsay A.; Smilowitz, Nathaniel R.; Halperin, Anthony L. P.; Klysik, Jan E.; Freiman, Richard N.

    2009-01-01

    Chromatin modifications are essential for directing transcription during embryonic development. Bromodomain-containing protein 2 (Brd2; also called RING3 and Fsrg1) is one of four BET (bromodomain and extra terminal domain) family members known to selectively bind acetylated histones H3 and H4. Brd2 associates with multiple subunits of the transcriptional apparatus including the mediator, TFIID and Swi/Snf multi-protein complexes. While molecular interactions of Brd2 are known, the functions of Brd2 in mammalian embryogenesis remain unknown. In developing a mouse model deficient in Brd2, we find that Brd2 is required for the completion of embryogenesis and proper neural tube closure during development. Embryos lacking Brd2 expression survive up to embryonic day 13.5, soon after mid-gestation, and display fully penetrant neurulation defects that largely result in exencephaly of the developing hindbrain. In this study, we find that highest expression of Brd2 is detected in the developing neural tube, correlating with the neural tube defects found in Brd2-null embryos. Additionally, embryos lacking Brd2 expression display altered gene expression programs, including the mis-expression of multiple genes known to guide neuronal development. Together these results implicate essential roles for Brd2 as a critical integrator of chromatin structure and transcription during mammalian embryogenesis and neurogenesis. PMID:19362612

  9. Mini-review: toward understanding mechanisms of genetic neural tube defects in mice.

    PubMed

    Harris, M J; Juriloff, D M

    1999-11-01

    We review the data from studies of mouse mutants that lend insight to the mechanisms that lead to neural tube defects (NTDs). Most of the 50 single-gene mutations that cause neural tube defects (NTDs) in mice also cause severe embryonic-lethal syndromes, in which exencephaly is a nonspecific feature. In a few mutants (e.g., Trp53, Macs, Mlp or Sp), other defects may be present, but affected fetuses can survive to birth. Multifactorial genetic causes, as are present in the curly tail stock (15-20% spina bifida), or the SELH/Bc strain (15-20% exencephaly), lead to nonsyndromic NTDs. The mutations indicate that "spina bifida occulta," a dorsal gap in the vertebral arches over an intact neural tube, is usually genetically and developmentally unrelated to exencephaly or "spina bifida" (aperta). Almost all exencephaly or spina bifida aperta of genetic origin is caused by failure of neural fold elevation. The developmental mechanisms in genetic NTDs are considered in terms of distinct rostro-caudal zones along the neural folds that likely differ in mechanism of elevation. Failure of elevation leads to: split face (zone A), exencephaly (zone B), rachischisis (all of zone D), or spina bifida (caudal zone D). The developmental mechanisms leading to these genetic NTDs are heterogeneous, even within one zone. At the tissue level, the mutants show that the mechanism of failure of elevation can involve, e.g., (1) slow growth of adjacent tethered tissue (curly tail), (2) defective forebrain mesenchyme (Cart1 or twist), (3) defective basal lamina in surface ectoderm (Lama5), (4) excessive breadth of floorplate and notochord (Lp), (5) abnormal neuroepithelium (Apob, Sp, Tcfap2a), (6) morphological deformation of neural folds (jmj), (7) abnormal neuroepithelial and neural crest cell gap-junction communication (Gja1), or (8) incomplete compensation for a defective step in the elevation sequence (SELH/Bc). At the biochemical level, mutants suggest involvement of: (1) faulty regulation of apoptosis (Trp53 or p300), (2) premature differentiation (Hes1), (3) disruption of actin function (Macs or Mlp), (4) abnormal telomerase complex (Terc), or (5) faulty pyrimidine synthesis (Sp). The NTD preventative effect of maternal dietary supplementation is also heterogeneous, as demonstrated by: (1) methionine (Axd), (2) folic acid or thymidine (Sp), or (3) inositol (curly tail). The heterogeneity of mechanism of mouse NTDs suggests that human NTDs, including the common nonsyndromic anencephaly or spina bifida, may also reflect a variety of genetically caused defects in developmental mechanisms normally responsible for elevation of the neural folds. PMID:10525207

  10. Evaluation of 400 low background 10-in. photo-multiplier tubes for the Double Chooz experiment

    Microsoft Academic Search

    T. Matsubara; T. Haruna; T. Konno; Y. Endo; M. Bongrand; H. Furuta; T. Hara; M. Ishitsuka; T. Kawasaki; M. Kuze; J. Maeda; Y. Mishina; Y. Miyamoto; H. Miyata; Y. Nagasaka; Y. Sakamoto; F. Sato; A. Shigemori; F. Suekane; T. Sumiyoshi; H. Tabata; N. Tamura

    2012-01-01

    The Double Chooz is a reactor neutrino experiment which measures the last unknown neutrino mixing angle theta13. The Double Chooz experiment uses two identical detectors placed at sites far and near from Chooz reactor cores. The detector uses 390 low-background and high performance 10-in. Photo-Multiplier Tubes (PMTs) to detect scintillation light from gadolinium loaded liquid scintillator. In order to test

  11. Sonic hedgehog induces the differentiation of ventral forebrain neurons: A common signal for ventral patterning within the neural tube

    Microsoft Academic Search

    J Ericson; J Muhr; M Placzek; T Lints; T. M Jessel; T Edlund

    1995-01-01

    The vertebrate hedgehog-related gene Sonic hedge-hog (Shh) is expressed in ventral domains along the entire rostrocaudal length of the neural tube, including the forebrain. We show here that SHH induces the differentiation of ventral neuronal cell types in explants derived from prospective forebrain regions of the neural plate. Neurons induced in explants derived from both diencephalic and telencephalic levels of

  12. Neural Tube Defects and Maternal Biomarkers of Folate, Homocysteine, and Glutathione Metabolism

    PubMed Central

    Zhao, Weizhi; Mosley, Bridget S.; Cleves, Mario A.; Melnyk, Stepan; James, S. Jill; Hobbs, Charlotte A.

    2010-01-01

    Background Alterations in maternal folate and homocysteine metabolism are associated with neural tube defects (NTDs). The role that specific micronutrients and metabolites play in the causal pathway leading to NTDs is not fully understood. Methods We conducted a case-control study to investigate the association between NTDs and maternal alterations in plasma micronutrients and metabolites in two metabolic pathways, the methionine remethylation and glutathione transsulfuration. Biomarkers were measured in a population-based sample of women who had NTD-affected pregnancies (n = 43) and a control group of women who had a pregnancy unaffected by a birth defect (n = 160). Plasma concentrations of folate, Vitamin B12, Vitamin B6, methionine, S-adenosylmethionine (SAM), s- adenosylhomocysteine (SAH), adenosine, homocysteine, cysteine, and reduced and oxidized glutathione were compared between cases and controls after adjusting for lifestyle and sociodemographic factors. Results Women with NTD-affected pregnancies had significantly higher plasma concentrations of SAH (29.12 vs. 23.13 nmol/L, P = 0.0011), adenosine (0.323 vs. 0.255 ?mol/L, P = 0.0269), homocysteine (9.40 vs. 7.56 ?mol/L, P < 0.001), and oxidized glutathione (0.379 vs. 0.262?mol/L, P = 0.0001), but lower plasma SAM concentration (78.99 vs. 83.16 nmol/L, P = 0.0172) than controls. This metabolic profile is consistent with reduced methylation capacity and increased oxidative stress in women with affected pregnancies. Conclusions Increased maternal oxidative stress and decreased methylation capacity may contribute to the occurrence of NTDs. Further analysis of relevant genetic and environmental factors is required to define the basis for these observed alterations. PMID:16575882

  13. IS LOW IRON STATUS A RISK FACTOR FOR NEURAL TUBE DEFECTS?

    PubMed Central

    Molloy, Anne M; Einri, Caitriona Nic; Jain, Divyanshu; Laird, Eamon; Fan, Ruzong; Wang, Yifan; Shane, Barry; Brody, Lawrence C; Kirke, Peadar N; Mills, James L

    2014-01-01

    Background Folic acid supplements can protect against neural tube defects (NTDs). Low folate and low vitamin B12 status may be maternal risk factors for having an NTD affected pregnancy. However, not all NTDs are preventable by having an adequate folate/ B12 status and other potentially modifiable factors may be involved. Folate and vitamin B12 status have important links to iron metabolism. Animal studies support an association between poor iron status and NTDs but human data are scarce. We examined the relevance of low iron status in a nested NTD case-control study of women within a pregnant population-based cohort. Methods Pregnant women were recruited between 1986 and 1990, when vitamin or iron supplementation in early pregnancy was rare. Blood samples, taken at an average of 14 weeks gestation, were used to measure ferritin and hemoglobin in 64 women during an NTD affected pregnancy and 207 women with unaffected pregnancies. Results No significant differences in maternal ferritin or hemoglobin concentrations were observed between NTD affected and non-affected pregnancies (case median ferritin 16.8?g/L and hemoglobin 12.4g/dL versus 15.4?g/L and 12.3g/dL in controls). As reported previously, red cell folate and vitamin B12 concentrations were significantly lower in cases. Furthermore, there was no significant association of iron status with type of NTD lesion (anencephaly or spina bifida) Conclusions We conclude that low maternal iron status during early pregnancy is not an independent risk factor for NTDs. Adding iron to folic acid for periconceptional use may improve iron status but is not likely to prevent NTDs. PMID:24535840

  14. Estimating the burden of neural tube defects in low– and middle–income countries

    PubMed Central

    Lo, Annie; Polšek, Dora; Sidhu, Simrita

    2014-01-01

    Background To provide an estimate for the burden of neural tube defects (NTD) in low– and middle–income countries (LMIC) and explore potential public health policies that may be implemented. Although effective interventions are available to prevent NTD, there is still considerable childhood morbidity and mortality present in LMIC. Methods A search of Medline, EMBASE, Global Health Library and PubMed identified 37 relevant studies that provided estimates of the burden of NTD in LMIC. Information on burden of total NTD and specific NTD types was separated according to the denominator into two groups: (i) estimates based on the number of live births only; and (ii) live births, stillbirths and terminations. The data was then extracted and analysed. Results The search retrieved NTD burden from 18 countries in 6 WHO regions. The overall burden calculated using the median from studies based on livebirths was 1.67/1000 (IQR?=?0.98–3.49) for total NTD burden, 1.13/1000 (IQR?=?0.75–1.73) for spina bifida, 0.25/1000 (IQR?=?0.08–1.07) for anencephaly and 0.15/1000 (IQR?=?0.08–0.23) for encephalocele. Corresponding estimates based on all pregnancies resulting in live births, still births and terminations were 2.55/1000 (IQR?=?1.56–3.91) for total NTD burden, 1.04/1000 (IQR?=?0.67–2.48) for spina bifida, 1.03/1000 (IQR?=?0.67–1.60) for anencephaly and 0.21 (IQR?=?0.16–0.28) for encephalocele. This translates into about 190?000neonates who are born each year with NTD in LMIC. Conclusion Limited available data on NTD in LMIC indicates the need for additional research that would improve the estimated burden of NTD and recommend suitable aid policies through maternal education on folic acid supplementation or food fortification. PMID:24976961

  15. A spatial model to predict the incidence of neural tube defects

    PubMed Central

    2012-01-01

    Background Environmental exposure may play an important role in the incidences of neural tube defects (NTD) of birth defects. Their influence on NTD may likely be non-linear; few studies have considered spatial autocorrelation of residuals in the estimation of NTD risk. We aimed to develop a spatial model based on generalized additive model (GAM) plus cokriging to examine and model the expected incidences of NTD and make the inference of the incidence risk. Methods We developed a spatial model to predict the expected incidences of NTD at village level in Heshun County, Shanxi Province, China, a region with high NTD cases. GAM was used to establish linear and non-linear relationships between local covariates and the expected NTD incidences. We examined the following village-level covariates in the model: projected coordinates, soil types, lithodological classes, distance to watershed, rivers, faults and major roads, annual average fertilizer uses, fruit and vegetable production, gross domestic product, and the number of doctors. The residuals from GAM were assumed to be spatially auto-correlative and cokriged with regional residuals to improve the prediction. Our approach was compared with three other models, universal kriging, generalized linear regression and GAM. Cross validation was conducted for validation. Results Our model predicted the expected incidences of NTD well, with a good CV R2 of 0.80. Important predictive factors included the fertilizer uses, locations of the centroid of each village, the shortest distance to rivers and faults and lithological classes with significant spatial autocorrelation of residuals. Our model out-performed the other three methods by 16% or more in term of R2. Conclusions The variance explained by our model was approximately 80%. This modeling approach is useful for NTD epidemiological studies and intervention planning. PMID:23134640

  16. Experimental modeling of a cavitation vortex in the draft tube of a Francis turbine using artificial neural networks

    Microsoft Academic Search

    Marko Ho? Evar; Brane Širok; Bogdan Blagojevi?; Igor Grabec

    2007-01-01

    Experimental modeling of a cavitation vortex structure in a Francis turbine draft tube is presented. Pressure in the draft tube and images of vortex structure were acquired simultaneously for the experiment. Non-parametric radial basis neural networks were used for the experimental modeling. Two variables were modeled: average image intensities in the selected region, and entire images of the cavitation vortex.

  17. Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis.

    PubMed

    Xu, Cheng; Li, Xuezheng; Wang, Fang; Weng, Hongbo; Yang, Peixin

    2013-09-01

    Preexisting maternal diabetes increases the risk of neural tube defects (NTDs). The mechanism underlying maternal diabetes-induced NTDs is not totally defined, and its prevention remains a challenge. Autophagy, an intracellular process to degrade dysfunction protein and damaged cellular organelles, regulates cell proliferation, differentiation, and apoptosis. Because autophagy impairment causes NTDs reminiscent of those observed in diabetic pregnancies, we hypothesize that maternal diabetes-induced autophagy impairment causes NTD formation by disrupting cellular homeostasis, leading to endoplasmic reticulum (ER) stress and apoptosis, and that restoration of autophagy by trehalose, a natural disaccharide, prevents diabetes-induced NTDs. Embryos from nondiabetic and type 1 diabetic mice fed with or without 2 or 5% trehalose water were used to assess markers of autophagy, ER stress, and neurogenesis, numbers of autophagosomes, gene expression that regulates autophagy, NTD rates, indices of mitochondrial dysfunction, and neuroepithelial cell apoptosis. Maternal diabetes suppressed autophagy by significantly reducing LC3-II expression, autophagosome numbers, and GFP-LC3 punctate foci in neuroepithelial cells and by altering autophagy-related gene expression. Maternal diabetes delayed neurogenesis by blocking Sox1 neural progenitor differentiation. Trehalose treatment reversed autophagy impairment and prevented NTDs in diabetic pregnancies. Trehalose resolved homeostatic imbalance by correcting mitochondrial defects, dysfunctional proteins, ER stress, apoptosis, and delayed neurogenesis in the neural tubes exposed to hyperglycemia. Our study demonstrates for the first time that maternal diabetes suppresses autophagy in neuroepithelial cells of the developing neural tube, leading to NTD formation, and provides evidence for the potential efficacy of trehalose as an intervention against hyperglycemia-induced NTDs. PMID:23880312

  18. How to form and close the brain: insight into the mechanism of cranial neural tube closure in mammals.

    PubMed

    Yamaguchi, Yoshifumi; Miura, Masayuki

    2013-09-01

    The development of the embryonic brain critically depends on successfully completing cranial neural tube closure (NTC). Failure to properly close the neural tube results in significant and potentially lethal neural tube defects (NTDs). We believe these malformations are caused by disruptions in normal developmental programs such as those involved in neural plate morphogenesis and patterning, tissue fusion, and coordinated cell behaviors. Cranial NTDs include anencephaly and craniorachischisis, both lethal human birth defects. Newly emerging methods for molecular and cellular analysis offer a deeper understanding of not only the developmental NTC program itself but also mechanical and kinetic aspects of closure that may contribute to cranial NTDs. Clarifying the underlying mechanisms involved in NTC and how they relate to the onset of specific NTDs in various experimental models may help us develop novel intervention strategies to prevent NTDs. PMID:23242429

  19. Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis

    PubMed Central

    Žigman, Mihaela; Laumann-Lipp, Nico; Titus, Tom; Postlethwait, John; Moens, Cecilia B.

    2014-01-01

    Hox genes are classically ascribed to function in patterning the anterior-posterior axis of bilaterian animals; however, their role in directing molecular mechanisms underlying morphogenesis at the cellular level remains largely unstudied. We unveil a non-classical role for the zebrafish hoxb1b gene, which shares ancestral functions with mammalian Hoxa1, in controlling progenitor cell shape and oriented cell division during zebrafish anterior hindbrain neural tube morphogenesis. This is likely distinct from its role in cell fate acquisition and segment boundary formation. We show that, without affecting major components of apico-basal or planar cell polarity, Hoxb1b regulates mitotic spindle rotation during the oriented neural keel symmetric mitoses that are required for normal neural tube lumen formation in the zebrafish. This function correlates with a non-cell-autonomous requirement for Hoxb1b in regulating microtubule plus-end dynamics in progenitor cells in interphase. We propose that Hox genes can influence global tissue morphogenesis by control of microtubule dynamics in individual cells in vivo. PMID:24449840

  20. Temporal control of BMP signalling determines neuronal subtype identity in the dorsal neural tube

    PubMed Central

    Tozer, Samuel; Le Dréau, Gwenvael; Marti, Elisa; Briscoe, James

    2013-01-01

    The conventional explanation for how a morphogen patterns a tissue holds that cells interpret different concentrations of an extrinsic ligand by producing corresponding levels of intracellular signalling activity, which in turn regulate differential gene expression. However, this view has been challenged, raising the possibility that distinct mechanisms are used to interpret different morphogens. Here, we investigate graded BMP signalling in the vertebrate neural tube. We show that defined exposure times to Bmp4 generate distinct levels of signalling and induce specific dorsal identities. Moreover, we provide evidence that a dynamic gradient of BMP activity confers progressively more dorsal neural identities in vivo. These results highlight a strategy for morphogen interpretation in which the tight temporal control of signalling is important for the spatial pattern of cellular differentiation. PMID:23462473

  1. Temporal control of BMP signalling determines neuronal subtype identity in the dorsal neural tube.

    PubMed

    Tozer, Samuel; Le Dréau, Gwenvael; Marti, Elisa; Briscoe, James

    2013-04-01

    The conventional explanation for how a morphogen patterns a tissue holds that cells interpret different concentrations of an extrinsic ligand by producing corresponding levels of intracellular signalling activity, which in turn regulate differential gene expression. However, this view has been challenged, raising the possibility that distinct mechanisms are used to interpret different morphogens. Here, we investigate graded BMP signalling in the vertebrate neural tube. We show that defined exposure times to Bmp4 generate distinct levels of signalling and induce specific dorsal identities. Moreover, we provide evidence that a dynamic gradient of BMP activity confers progressively more dorsal neural identities in vivo. These results highlight a strategy for morphogen interpretation in which the tight temporal control of signalling is important for the spatial pattern of cellular differentiation. PMID:23462473

  2. Systems biological approach to investigate the lack of familial link between Down's Syndrome & Neural Tube Disorders

    PubMed Central

    Ragunath, PK; Abhinand, PA

    2013-01-01

    Systems Biology involves the study of the interactions of biological systems and ultimately their functions. Down's syndrome (DS) is one of the most common genetic disorders which are caused by complete, or occasionally partial, triplication of chromosome 21, characterized by cognitive and language dysfunction coupled with sensory and neuromotor deficits. Neural Tube Disorders (NTDs) are a group of congenital malformations of the central nervous system and neighboring structures related to defective neural tube closure during the first trimester of pregnancy usually occurring between days 18-29 of gestation. Several studies in the past have provided considerable evidence that abnormal folate and methyl metabolism are associated with onset of DS & NTDs. There is a possible common etiological pathway for both NTDs and Down's syndrome. But, various research studies over the years have indicated very little evidence for familial link between the two disorders. Our research aimed at the gene expression profiling of microarray datasets pertaining to the two disorders to identify genes whose expression levels are significantly altered in these conditions. The genes which were 1.5 fold unregulated and having a p-value <0.05 were filtered out and gene interaction network were constructed for both NTDs and DS. The top ranked dense clique for both the disorders were recognized and over representation analysis was carried out for each of the constituent genes. The comprehensive manual analysis of these genes yields a hypothetical understanding of the lack of familial link between DS and NTDs. There were no genes involved with folic acid present in the dense cliques. Only – CBL, EGFR genes were commonly present, which makes the allelic variants of these genes – good candidates for future studies regarding the familial link between DS and NTDs. Abbreviations NTD - Neural Tube Disorders, DS - Down's Syndrome, MTHFR - Methylenetetrahydrofolate reductase, MTRR– 5 - methyltetrahydrofolate-homocysteine methyltransferase reductase. PMID:23904737

  3. Neural tube defects and their significance in clinical dentistry: a mini review.

    PubMed

    Garg, Anuradha; Utreja, Ashok; Singh, Satinder P; Angurana, Suresh K

    2013-02-01

    Neural tube defects are common congenital malformations that could be apparent at birth or manifested in later stages of life. Morbidity is high in anencephaly, whereas in spina bifida, there are neurological and motor disorders. These defects deserve paramount importance in clinical dentistry. Latex allergy, dental caries, difficulty in mouth opening, and sitting in a dental chair are common problems. There is a high risk of anaphylactic response during anaesthesia. There could be associated craniosynostosis causing maxillary deficiency, and malformed sella turcica might be seen. An association of the defects has been linked with orofacial clefts and Down syndrome. PMID:23255477

  4. MicroRNA GENE EXPRESSION SIGNATURES IN THE DEVELOPING NEURAL TUBE

    PubMed Central

    Mukhopadhyay, Partha; Brock, Guy; Appana, Savitri; Webb, Cynthia; Greene, Robert M.; Pisano, M. Michele

    2011-01-01

    BACKGROUND Neurulation requires precise, spatio-temporal expression of numerous genes and coordinated interaction of signal transduction and gene regulatory networks, disruption of which may contribute to the etiology of neural tube (NT) defects. MicroRNAs are key modulators of cell and tissue differentiation. In order to define potential roles of miRNAs in development of the murine NT, miRNA microarray analysis was conducted to establish expression profiles, and identify miRNA target genes and functional gene networks. METHODS miRNA expression profiles in murine embryonic NTs derived from gestational days 8.5, 9.0 and 9.5 were defined and compared utilizing miRXplore™ microarrays from Miltenyi Biotech GmbH. Gene expression changes were verified by TaqMan™ quantitative Real-Time PCR. clValid R package and the UPGMA (hierarchical) clustering method were utilized for cluster analysis of the microarray data. Functional associations among selected miRNAs were examined via Ingenuity Pathway Analysis. RESULTS miRXplore™ chips enabled examination of 609 murine miRNAs. Expression of approximately 12% of these was detected in murine embryonic NTs. Clustering analysis revealed several developmentally regulated expression clusters among these expressed genes. Target analysis of differentially expressed miRNAs enabled identification of numerous target genes associated with cellular processes essential for normal NT development. Utilization of Ingenuity Pathway Analysis revealed interactive biological networks which connected differentially expressed miRNAs with their target genes, and highlighted functional relationships. CONCLUSIONS The present study defined unique gene expression signatures of a range of miRNAs in the developing NT during the critical period of NT morphogenesis. Analysis of miRNA target genes and gene interaction pathways revealed that specific miRNAs may direct expression of numerous genes encoding proteins which have been shown to be indispensable for normal neurulation. This study is the first to identify miRNA expression profiles and their potential regulatory networks in the developing mammalian NT. PMID:21770019

  5. Primary cilium and sonic hedgehog signaling during neural tube patterning: role of GPCRs and second messengers.

    PubMed

    Pal, Kasturi; Mukhopadhyay, Saikat

    2015-04-01

    The ventral neural tube in vertebrates is patterned by a gradient of sonic hedgehog (Shh) secreted from the notochord and floor plate. Forward genetic screens first pointed to the role of the primary cilium in ventral neural tube patterning. Further research has shown that most components of the Shh pathway localize to or shuttle through the primary cilium. In the absence of Shh, the bifunctional Gli transcription factors are proteolytically processed into repressor forms in a protein kinase A (PKA)- and cilium-dependent manner. Recent work suggests that the orphan G-protein-coupled receptor (GPCR) Gpr161 localizes to cilia, and functions as a negative regulator of Shh signaling by determining Gli processing via cAMP signaling. The primary cilium also functions as a signaling compartment for calcium in the Shh pathway. A better understanding of the role of the cilium as a signaling compartment, and the interplay of second messenger systems that regulate PKA activation and Gli amplification during signaling is critical for deciphering the role of Shh during development, neuronal differentiation, and tumorigenesis. PMID:24863049

  6. Variants in MTHFR gene and neural tube defects susceptibility in China.

    PubMed

    Wang, Yongxin; Liu, Yuan; Ji, Wenyu; Qin, Hu; Wu, Hao; Xu, Danshu; Turtuohut, Tukebai; Wang, Zengliang

    2015-08-01

    Neural tube defect (NTD) is a severe congenital birth abnormalities involving incomplete neural tube closure. 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene plays key role in folate cycle and methylation cycle, which could affect the DNA synthesis, repair and methylation. In this study, we aim to investigate the correlation between MTHFR polymorphisms and NTD-affected pregnancy. There were 444 participants involved in our study. Tag-SNPs were identified in HapMap Databases. Blood samples were collected from all subjects to further extract the genomic DNAs by TaqMan Blood DNA kits. We also carried out a meta-analysis based on previous published studies to further examine the association between MTHFR polymorphisms and NTD. In case-control study analysis, two SNPs were identified to be associated with NTD risk. The 677 C > T genetic variant was correlated with increased risk of NTD-affected pregnancy. However, the 1298 A > C polymorphism was shown to lower the risk of NTD-affected pregnancy. The protective role of 1298 A > C polymorphisms was further supported by the result of meta-analysis. Our study revealed that the SNPs of 677C > T and 1298A > C in MTHFR were associated with NTD-affected pregnancy, in which 677C > T was a risk factor and in contrast 1298A > C was protective factor against NTD. Our results of meta-analysis also revealed the 1298A > C MTHFR polymorphism play protective role in NTD. PMID:25855017

  7. Mouse as a model for multifactorial inheritance of neural tube defects.

    PubMed

    Zohn, Irene E

    2012-06-01

    Neural tube defects (NTDs) such as spina bifida and anencephaly are some of the most common structural birth defects found in humans. These defects occur due to failures of neurulation, a process where the flat neural plate rolls into a tube. In spite of their prevalence, the causes of NTDs are poorly understood. The multifactorial threshold model best describes the pattern of inheritance of NTDs where multiple undefined gene variants interact with environmental factors to cause an NTD. To date, mouse models have implicated a multitude of genes as required for neurulation, providing a mechanistic understanding of the cellular and molecular pathways that control neurulation. However, the majority of these mouse models exhibit NTDs with a Mendelian pattern of inheritance. Still, many examples of multifactorial inheritance have been demonstrated in mouse models of NTDs. These include null and hypomorphic alleles of neurulation genes that interact in a complex fashion with other genetic mutations or environmental factors to cause NTDs. These models have implicated several genes and pathways for testing as candidates for the genetic basis of NTDs in humans, resulting in identification of putative pathogenic mutations in some patients. Mouse models also provide an experimental paradigm to gain a mechanistic understanding of the environmental factors that influence NTD occurrence, such as folic acid and maternal diabetes, and have led to the discovery of additional preventative nutritional supplements such as inositol. This review provides examples of how multifactorial inheritance of NTDs can be modeled in the mouse. PMID:22692891

  8. Folic acid supplementation can adversely affect murine neural tube closure and embryonic survival.

    PubMed

    Marean, Amber; Graf, Amanda; Zhang, Ying; Niswander, Lee

    2011-09-15

    Neural tube defects (NTDs), a common birth defect in humans, result from the failure of the embryonic neural tube (NT) to close properly. NT closure is a complex, poorly understood morphogenetic process influenced by genes and environment. The most effective environmental influence in decreasing the risk for NTDs is folic acid (FA) fortification and supplementation, and these findings led to the recommendation of periconceptual FA intake and mandatory fortification of the US grain supply in 1998. To explore the relationship between genetics and responsiveness to FA supplementation, we used five mouse NTDs models-Zic2, Shroom3, Frem2, Grhl2 (Grainyhead-like 2) and L3P (Line3P)-and a long-term generational FA supplementation scheme. Contrary to expectations, we find that three genetic mutants respond adversely to FA supplementation with increased incidence of NTDs in homozygous mutants, occurrence of NTDs in heterozygous embryos and embryonic lethality prior to NT closure. Because of these unexpected responses, we examined NTD risk after short-term FA supplementation. Our results indicate that, for the same genetic allele, NTD risk can depend on the length of FA exposure. Our data indicate that, depending on the gene mutation, FA supplementation may adversely influence embryonic development and NT closure. PMID:21693562

  9. Wnt Signaling Inhibitors Regulate the Transcriptional Response to Morphogenetic Shh-Gli Signaling in the Neural Tube

    Microsoft Academic Search

    Qiubo Lei; Yongsu Jeong; Kamana Misra; Shike Li; Alice K. Zelman; Douglas J. Epstein; Michael P. Matise

    2006-01-01

    Summary Shh-Gli signaling controls cell fates in the developing ventral neural tube by regulating the patterned expres- sion of transcription factors in neural progenitors. However, the molecular mechanisms that limit tar- get gene responses to specific domains are unclear. Here, we show that Wnt pathway inhibitors regulate the threshold response of a ventral Shh target gene, Nkx2.2, to establish its

  10. Molecular Genetics and Pathogenic Mechanisms for the Severe Ciliopathies: Insights into Neurodevelopment and Pathogenesis of Neural Tube Defects

    Microsoft Academic Search

    Clare V. Logan; Zakia Abdel-Hamed; Colin A. Johnson

    2011-01-01

    Meckel–Gruber syndrome (MKS) is a severe autosomal recessively inherited disorder characterized by developmental defects of\\u000a the central nervous system that comprise neural tube defects that most commonly present as occipital encephalocele. MKS is\\u000a considered to be the most common syndromic form of neural tube defect. MKS is genetically heterogeneous with six known disease\\u000a genes: MKS1, MKS2\\/TMEM216, MKS3\\/TMEM67, RPGRIP1L, CEP290, and

  11. Different Epigenetic Alterations Are Associated with Abnormal IGF2/Igf2 Upregulation in Neural Tube Defects

    PubMed Central

    Bai, Baoling; Zhang, Qin; Liu, Xiaozhen; Miao, Chunyue; Shangguan, Shaofang; Bao, Yihua; Guo, Jin; Wang, Li; Zhang, Ting; Li, Huili

    2014-01-01

    The methylation status of DNA methylation regions (DMRs) of the imprinted gene IGF2/Igf2 is associated with neural tube defects (NTDs), which are caused by a failure of the neural tube to fold and close and are the second-most common birth defect; however, the characterization of the expression level of IGF2/Igf2 in neural tissue from human fetuses affected with NTDs remains elusive. More importantly, whether abnormal chromatin structure also influences IGF2/Igf2 expression in NTDs is unclear. Here, we investigated the transcriptional activity of IGF2/Igf2 in normal and NTD spinal cord tissues, the methylation status of different DMRs, and the chromatin structure of the promoter. Our data indicated that in NTD samples from both human fetuses and retinoic acid (RA)-treated mouse fetuses, the expression level of IGF2/Igf2 was upregulated 6.41-fold and 1.84-fold, respectively, compared to controls. H19 DMR1, but not IGF2 DMR0, was hypermethylated in human NTD samples. In NTD mice, h19 DMR1 was stable, whereas the chromatin structure around the promoter of Igf2 might be loosened, which was displayed by higher H3K4 acetylation and lower H3K27 trimethylation. Therefore, the data revealed that IGF2/Igf2 expression can be ectopically up-regulated by dual epigenetic factors in NTDs. In detail, the upregulation of IGF2/Igf2 is likely controlled by hypermethylation of H19 DMR1 in human NTDs, however, in acute external RA-induced NTD mice it is potentially determined by more open chromatin structure. PMID:25423083

  12. Neural tube defects--disorders of neurulation and related embryonic processes.

    PubMed

    Copp, Andrew J; Greene, Nicholas D E

    2013-01-01

    Neural tube defects (NTDs) are severe congenital malformations affecting 1 in every 1000 pregnancies. 'Open' NTDs result from failure of primary neurulation as seen in anencephaly, myelomeningocele (open spina bifida), and craniorachischisis. Degeneration of the persistently open neural tube in utero leads to loss of neurological function below the lesion level. 'Closed' NTDs are skin-covered disorders of spinal cord structure, ranging from asymptomatic spina bifida occulta to severe spinal cord tethering, and usually traceable to disruption of secondary neurulation. 'Herniation' NTDs are those in which meninges, with or without brain or spinal cord tissue, become exteriorized through a pathological opening in the skull or vertebral column (e.g., encephalocele and meningocele). NTDs have multifactorial etiology, with genes and environmental factors interacting to determine individual risk of malformation. While over 200 mutant genes cause open NTDs in mice, much less is known about the genetic causation of human NTDs. Recent evidence has implicated genes of the planar cell polarity signaling pathway in a proportion of cases. The embryonic development of NTDs is complex, with diverse cellular and molecular mechanisms operating at different levels of the body axis. Molecular regulatory events include the bone morphogenetic protein and Sonic hedgehog pathways which have been implicated in control of neural plate bending. Primary prevention of NTDs has been implemented clinically following the demonstration that folic acid (FA), when taken as a periconceptional supplement, can prevent many cases. Not all NTDs respond to FA, however, and adjunct therapies are required for prevention of this FA-resistant category. PMID:24009034

  13. Different epigenetic alterations are associated with abnormal IGF2/Igf2 upregulation in neural tube defects.

    PubMed

    Bai, Baoling; Zhang, Qin; Liu, Xiaozhen; Miao, Chunyue; Shangguan, Shaofang; Bao, Yihua; Guo, Jin; Wang, Li; Zhang, Ting; Li, Huili

    2014-01-01

    The methylation status of DNA methylation regions (DMRs) of the imprinted gene IGF2/Igf2 is associated with neural tube defects (NTDs), which are caused by a failure of the neural tube to fold and close and are the second-most common birth defect; however, the characterization of the expression level of IGF2/Igf2 in neural tissue from human fetuses affected with NTDs remains elusive. More importantly, whether abnormal chromatin structure also influences IGF2/Igf2 expression in NTDs is unclear. Here, we investigated the transcriptional activity of IGF2/Igf2 in normal and NTD spinal cord tissues, the methylation status of different DMRs, and the chromatin structure of the promoter. Our data indicated that in NTD samples from both human fetuses and retinoic acid (RA)-treated mouse fetuses, the expression level of IGF2/Igf2 was upregulated 6.41-fold and 1.84-fold, respectively, compared to controls. H19 DMR1, but not IGF2 DMR0, was hypermethylated in human NTD samples. In NTD mice, h19 DMR1 was stable, whereas the chromatin structure around the promoter of Igf2 might be loosened, which was displayed by higher H3K4 acetylation and lower H3K27 trimethylation. Therefore, the data revealed that IGF2/Igf2 expression can be ectopically up-regulated by dual epigenetic factors in NTDs. In detail, the upregulation of IGF2/Igf2 is likely controlled by hypermethylation of H19 DMR1 in human NTDs, however, in acute external RA-induced NTD mice it is potentially determined by more open chromatin structure. PMID:25423083

  14. Applying Bayesian Neural Networks to Separate Neutrino Events from Backgrounds in Reactor Neutrino Experiments

    E-print Network

    Ye Xu; Yixiong Meng; Weiwei Xu

    2008-08-02

    A toy detector has been designed to simulate central detectors in reactor neutrino experiments in the paper. The samples of neutrino events and three major backgrounds from the Monte-Carlo simulation of the toy detector are generated in the signal region. The Bayesian Neural Networks(BNN) are applied to separate neutrino events from backgrounds in reactor neutrino experiments. As a result, the most neutrino events and uncorrelated background events in the signal region can be identified with BNN, and the part events each of the fast neutron and $^{8}$He/$^{9}$Li backgrounds in the signal region can be identified with BNN. Then, the signal to noise ratio in the signal region is enhanced with BNN. The neutrino discrimination increases with the increase of the neutrino rate in the training sample. However, the background discriminations decrease with the decrease of the background rate in the training sample.

  15. Genetic variants in ZIC1, ZIC2, and ZIC3 are not major risk factors for neural tube defects in humans

    Microsoft Academic Search

    E. D. Klootwijk; Pascal Groenen; M. M. V. A. P. Schijvenaars; Frans Hol; B. C. J. Hamel; H. M. P. M. Straatman; Edwin Mariman; Barbara Franke

    2004-01-01

    Neural tube defects (NTD) are congenital malformations arising from incomplete neural tube closure during early embryogenesis. Most NTD in humans show complex inheritance patterns, with both genetic and environmental factors involved in the etiology of this malformation. More than 120 mouse models for human NTD exist. NTD have been observed in mice deficient for the Zic family genes, Zic1, Zic2,

  16. Differences in axial curvature correlate with species-specific rate of neural tube closure in embryos of chick, rabbit, mouse, rat and human

    Microsoft Academic Search

    M. C. E. Peeters; Johan W. M. Hekking; Kohei Shiota; J. Drukker; Henny W. M. Van Straaten

    1998-01-01

    Studies on the mouse strain curly tail, a mutant for neural tube defects, have indicated that axial curvature is an important factor in neural tube closure. Previously reported results from experimental interventions in both mouse and chick embryos indicated that curvature along the craniocaudal axis and closure of the posterior neuropore (PNP) are inversely related, a correlation that is also

  17. Modified neural network correlation of refrigerant mass flow rates through adiabatic capillary and short tubes: Extension to CO 2 transcritical flow

    Microsoft Academic Search

    Liang Yang; Chun-Lu Zhang

    2009-01-01

    This paper presents a modified dimensionless neural network correlation of refrigerant mass flow rates through adiabatic capillary tubes and short tube orifices. In particular, CO2 transcritical flow is taken into account. The definition of neural network input and output dimensionless parameters is grounded on the homogeneous equilibrium model and extended to supercritical inlet conditions. 2000 sets of experimental mass flow-rate

  18. Twist Function Is Required for the Morphogenesis of the Cephalic Neural Tube and the Differentiation of the Cranial Neural Crest Cells in the Mouse Embryo

    Microsoft Academic Search

    Kenneth Soo; Meredith P. O'Rourke; Poh-Lynn Khoo; Kirsten A. Steiner; Nicole Wong; Richard R. Behringer; Patrick P. L. Tam

    2002-01-01

    Loss of Twist function in the cranial mesenchyme of the mouse embryo causes failure of closure of the cephalic neural tube and malformation of the branchial arches. In the Twist?\\/? embryo, the expression of molecular markers that signify dorsal forebrain tissues is either absent or reduced, but those associated with ventral tissues display expanded domains of expression. Dorsoventral organization of

  19. Lack of serologic evidence for an association between Cache Valley Virus infection and anencephaly and other neural tube defects in Texas.

    PubMed

    Edwards, J F; Hendricks, K

    1997-01-01

    We tested the hypothesis that Cache Valley Virus (CVV), an endemic North American bunyavirus, may be involved in the pathogenesis of human neural tube defects. This investigation followed a 1990 and 1991 south Texas outbreak of neural tube defects with a high prevalence of anencephaly and the demonstration in 1987 that in utero infection by CVV was the cause of outbreaks of central nervous system and musculoskeletal defects in North American ruminants. Sera from 74 women who gave birth to infants with neural tube defects in south Texas from 1993 through early 1995 were tested for CVV neutralizing antibody. All tested sera did not neutralize CVV. These data suggest that CVV is not involved in the induction of human neural tube defects during nonepidemic periods but do not preclude CVV involvement during epidemics. Other endemic bunyaviruses may still be involved in the pathogenesis of neural tube defects or other congenital central nervous system or musculoskeletal malformations. PMID:9204303

  20. Integration of signals along orthogonal axes of the vertebrate neural tube controls progenitor competence and increases cell diversity.

    PubMed

    Sasai, Noriaki; Kutejova, Eva; Briscoe, James

    2014-07-01

    A relatively small number of signals are responsible for the variety and pattern of cell types generated in developing embryos. In part this is achieved by exploiting differences in the concentration or duration of signaling to increase cellular diversity. In addition, however, changes in cellular competence-temporal shifts in the response of cells to a signal-contribute to the array of cell types generated. Here we investigate how these two mechanisms are combined in the vertebrate neural tube to increase the range of cell types and deliver spatial control over their location. We provide evidence that FGF signaling emanating from the posterior of the embryo controls a change in competence of neural progenitors to Shh and BMP, the two morphogens that are responsible for patterning the ventral and dorsal regions of the neural tube, respectively. Newly generated neural progenitors are exposed to FGF signaling, and this maintains the expression of the Nk1-class transcription factor Nkx1.2. Ventrally, this acts in combination with the Shh-induced transcription factor FoxA2 to specify floor plate cells and dorsally in combination with BMP signaling to induce neural crest cells. As development progresses, the intersection of FGF with BMP and Shh signals is interrupted by axis elongation, resulting in the loss of Nkx1.2 expression and allowing the induction of ventral and dorsal interneuron progenitors by Shh and BMP signaling to supervene. Hence a similar mechanism increases cell type diversity at both dorsal and ventral poles of the neural tube. Together these data reveal that tissue morphogenesis produces changes in the coincidence of signals acting along orthogonal axes of the neural tube and this is used to define spatial and temporal transitions in the competence of cells to interpret morphogen signaling. PMID:25026549

  1. Amniotic fluid homocysteine levels, 5,10-methylenetetrahydrafolate reductase genotypes, and neural tube closure sites.

    PubMed

    Wenstrom, K D; Johanning, G L; Owen, J; Johnston, K E; Acton, S; Cliver, S; Tamura, T

    2000-01-01

    A specific gene mutation leading to altered homocysteine metabolism has been identified in parents and fetuses with neural tube defects (NTDs). In addition, current animal and human data indicate that spine closure occurs simultaneously in five separate sites that then fuse. We sought to determine whether either this mutation or abnormal amniotic fluid homocysteine levels are associated with all five neural tube closure sites. We retrieved stored amniotic fluid from cases of isolated fetal neural tube defect diagnosed from 1988 to 1998 (n = 80) and from normal controls matched for race, month and year of amniocentesis, and maternal age. Cases were categorized according to defect site by using all available medical records. The presence or absence of the 677C-->T mutation of 5, 10-methylenetetrahydrafolate reductase (MTHFR) gene was determined, and homocysteine levels were measured; case and controls were compared. Significantly more cases than controls were heterozygous or homozygous for the 677C-->T MTHFR mutation (44% vs. 17%, P < or = 0. 001). Likewise, cases were significantly more likely than controls to have amniotic fluid homocysteine levels >90th centile (>1.85 micromol/L), 27% vs. 10%, P = 0.02. Most (83%) of control cases had both normal MTHFR alleles and normal amniotic fluid homocysteine levels (normal/normal), whereas only 56% of NTD case were normal/normal (P = 0.001). When evaluated by defect site, only defects involving the cervical-lumbar spine, lumbosacral spine, and occipital encephalocele were significantly less likely to be normal/normal than controls (P = 0.007, 0.0003, and 0.007, respectively), suggesting a strong association with the 677C-->T allele. In contrast, anencephaly, exencephaly, and defects confined to the sacrum included many cases that had both normal MTHFR alleles and normal homocysteine and were not significantly different from controls. The 677C-->T MTHFR mutation and elevated homocysteine levels appear to be disproportionately associated with defects spanning the cervical-lumbar spine, lumbosacral spine, and occipital encephalocele. In contrast, anencephaly, exencephaly, and defects confined to the sacrum may not be related to altered homocysteine metabolism. PMID:10602110

  2. Optimal Combination of Neural Temporal Envelope and Fine Structure Cues to Explain Speech Identification in Background Noise

    PubMed Central

    Moon, Il Joon; Won, Jong Ho; Ives, D. Timothy; Nie, Kaibao; Heinz, Michael G.; Lorenzi, Christian; Rubinstein, Jay T.

    2014-01-01

    The dichotomy between acoustic temporal envelope (ENV) and fine structure (TFS) cues has stimulated numerous studies over the past decade to understand the relative role of acoustic ENV and TFS in human speech perception. Such acoustic temporal speech cues produce distinct neural discharge patterns at the level of the auditory nerve, yet little is known about the central neural mechanisms underlying the dichotomy in speech perception between neural ENV and TFS cues. We explored the question of how the peripheral auditory system encodes neural ENV and TFS cues in steady or fluctuating background noise, and how the central auditory system combines these forms of neural information for speech identification. We sought to address this question by (1) measuring sentence identification in background noise for human subjects as a function of the degree of available acoustic TFS information and (2) examining the optimal combination of neural ENV and TFS cues to explain human speech perception performance using computational models of the peripheral auditory system and central neural observers. Speech-identification performance by human subjects decreased as the acoustic TFS information was degraded in the speech signals. The model predictions best matched human performance when a greater emphasis was placed on neural ENV coding rather than neural TFS. However, neural TFS cues were necessary to account for the full effect of background-noise modulations on human speech-identification performance. PMID:25186758

  3. The use of the computerized and revised vital record in conducting etiologic studies on neural tube defects

    Microsoft Academic Search

    Mark A Canfield

    1993-01-01

    The purpose of this study was to evaluate the adequacy of computerized vital records in Texas for conducting etiologic studies on neural tube defects (NTDs), using the revised and expanded National Centers for Health Statistics vital record forms introduced in Texas in 1989.^ Cases of NTDs (anencephaly and spina bifida) among Harris County (Houston) residents were identified from the computerized

  4. Hydrolyzed fumonisin B1 (HFB1) did not induce neural tube defects in LM/Bc mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisins are mycotoxins produced by Fusarium verticillioides. They are found in corn-based foods and are toxic and carcinogenic to rodents. There is evidence suggesting that consumption of corn tortillas containing fumonisins contributed to an enigmatic cluster of neural tube defects (NTDs) in s...

  5. Major derivatives of the ectoderm germ layer Primary neurulation: neural tube formation in the chick embryo (Part 1)

    E-print Network

    in the chick embryo (Part 1) #12;Primary neurulation: neural tube formation in the chick embryo (Part 2) #12;Neurulation in an amphibian embryo, showing early, middle, and late neurulae in each case (Part 1) #12;Neurulation in an amphibian embryo, showing early, middle, and late neurulae in each case (Part 2) #12

  6. An integrated signal processing and neural networks system for steam generator tubing diagnostics using eddy current inspection

    Microsoft Academic Search

    Wu Yan; Belle R. Upadhyaya

    1996-01-01

    The primary purpose of this research was to develop an integrated approach by combining information compression methods and artificial neural networks for the monitoring of plant components using nondestructive evaluation (NDE) data. Specifically, data from eddy current inspection of steam generator tubing were utilized to evaluate this technology. The focus of the research was to develop and test various data

  7. A randomised trial of low dose folic acid to prevent neural tube defects. The Irish Vitamin Study Group

    Microsoft Academic Search

    P N Kirke; L E Daly; J H Elwood

    1992-01-01

    A randomised trial was initiated in Ireland in 1981 to determine if periconceptional supplementation with either folic acid alone or a multivitamin preparation alone could reduce the recurrence risk of neural tube defects (NTDs) in women with a previously affected pregnancy from 5.0% to 1.0% or less. The trial was concluded before the initial target number of study subjects was

  8. Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD1 mice

    Microsoft Academic Search

    Jennifer E. Dawson; Angela M. Raymond; Louise M.. Winn

    2006-01-01

    In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of

  9. Determining associations and assessing methodological issues in a case-control study of hazardous air pollutants and neural tube defects

    Microsoft Academic Search

    Philip Joseph Lupo

    2009-01-01

    Recent studies have reported positive associations between maternal exposures to air pollutants and several adverse birth outcomes. However, there have been no assessments of the association between environmental hazardous air pollutants (HAPs) such as benzene, toluene, ethylbenzene, and xylene (BTEX) and neural tube defects (NTDs) a common and serious group of congenital malformations. Before examining this association, two important methodological

  10. Association of maternal sphinganine:sphingosine ratio and folate levels with neural tube defects along the South Texas border

    Microsoft Academic Search

    John J Cotton

    2010-01-01

    Neural tube defects (NTDs) remain elevated in Hispanic women along the South Texas Border, despite folate supplementation and folate fortification of cereal products. Missmer et al. examined the relationships between fumonisins, a class of corn mycotoxin, and NTDs in Hispanic women who ate corn tortillas and found increased odds ratios with increasing exposure, as measured by serum sphinganine:sphingosine (sa:so) ratios.

  11. [Prevalence and spatial distribution of neural tube defects in São Paulo State, Brazil, before and after folic acid flour fortification].

    PubMed

    Fujimori, Elizabeth; Baldino, Camila Florido; Sato, Ana Paula Sayuri; Borges, Ana Luiza Vilela; Gomes, Murilo Novaes

    2013-01-01

    This cross-sectional study analyzed the prevalence and spatial distribution of neural tube defects before and after folic acid flour fortification. The study used the Information System on Live Births (SINASC) and presented prevalence rates according to maternal characteristics with odds ratios (OR) and 95% confidence intervals (95%CI). Polynomial regression was used in time trend analysis and empirical Bayesian smoothed maps for spatial analysis. Total prevalence of neural tube defects decreased by 35%, from 0.57/1,000 to 0.37/1,000 live births after fortification (OR = 0.65; 95%CI: 0.59-0.72). There was a reduction among newborns of mothers with the following characteristics: all age groups (except < 15 years), more than three years of schooling, and seven or more prenatal visits. There was a reduction over time and in most of São Paulo State, except in a few municipalities (counties) located in the western region of the State. Other factors may have contributed to the observed decline, but the results corroborate flour fortification as an important measure to prevent neural tube defects. Further research is needed to elucidate the lack of a decline in neural tube defects in the western part of São Paulo State. PMID:23370034

  12. The involvement of cell death and survival in neural tube defects: a distinct role for apoptosis and autophagy?

    Microsoft Academic Search

    F Cecconi; M Piacentini; G M Fimia

    2008-01-01

    Neural tube defects (NTDs), such as spina bifida (SB) or exencephaly, are common congenital malformations leading to infant mortality or severe disability. The etiology of NTDs is multifactorial with a strong genetic component. More than 70 NTD mouse models have been reported, suggesting the involvement of distinct pathogenetic mechanisms, including faulty cell death regulation. In this review, we focus on

  13. Evaluation of BMP4 and its specific inhibitor NOG as candidates in human neural tube defects (NTDs)

    Microsoft Academic Search

    Bärbel Felder; Karolin Stegmann; Almut Schultealbert; Frank Geller; Elisabeth Strehl; August Ermert; Manuela C Koch

    2002-01-01

    Neural tube defects (NTD) are among the most common congenital malformations in humans. The current view is that there are no major genes causing NTDs, but combinations of sequence variants in different genes have additive effects on determining the malformation. Therefore it is important to identify such sequence variants to get a better understanding of NTD pathogenesis. Studies on animal

  14. Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Ingestion of FB1-contaminated food is associated with increased risk for neural tube defects (NTDs). FB1 induces NTDs in inbred LM/Bc mice. FB1 inhibits ceramide synthase in de novo sphingolipid biosynthesis, resultin...

  15. Neural Tube Defect Induction by Fumonisin B1 in LM/Bc Mice Fed Folate Deficient or Folate Replete Diets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides and F. proliferatum. FB1 is found in corn-based foods and evidence suggests that it is a risk factor for neural tube defects (NTD). The mechanism(s) underlying NTD induction by FB1 in the sensitive LM/Bc mouse model is not well...

  16. Malformations of the axial skeleton in cranioschisis aperta and exencephaly in rat fetuses induced after neural tube closure

    Microsoft Academic Search

    Rengasamy Padmanabhan; Mohamed Shahul Hameed

    1985-01-01

    Single doses of cyclophosphamide were administered (IP) to groups of Wistar rats, on different days of gestation after neural tube closure (days 12–15) and fetuses were collected on day 20. A very large number of the fetuses treated during days 12–14 exhibited cranioschisis and exencephaly. Ethanol fixed, alizarin red stained specimens were observed for axial skeletal abnormalities. The exencephalic ones

  17. GENE-NUTRIENT-ENVIRONMENT INTERACTIONS AS RISK FACTORS FOR BIRTH DEFECTS: FUMONISIN, FOLATE, GENETIC VARIATION AND NEURAL TUBE DEFECTS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The second most common birth defect is neural tube defects (NTDs). In Guatemala, parts of China and Africa, NTD risk is estimated to be higher than that observed in the USA. The etiology of NTD in these areas is complex. Increased risk has been associated with genetic predisposition, dietary expo...

  18. Fumonisin B1 induced neural tube defects were not increased in LM/Bc mice fed folate-deficient diet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides that is found in corn-based foods and is possibly a risk factor for neural tube defects (NTD). The mechanism(s) underlying NTD induction by FB1 in the sensitive LM/Bc mouse model is not well understood, however, there is evidenc...

  19. Use of Family History Information for Neural Tube Defect Prevention: Integration into State-Based Recurrence Prevention Programs

    ERIC Educational Resources Information Center

    Green, Ridgely Fisk; Ehrhardt, Joan; Ruttenber, Margaret F.; Olney, Richard S.

    2011-01-01

    A family history of neural tube defects (NTDs) can increase the risk of a pregnancy affected by an NTD. Periconceptional folic acid use decreases this risk. Purpose: Our objective was to determine whether second-degree relatives of NTD-affected children showed differences in folic acid use compared with the general population and to provide them…

  20. Fumonisin as a possible contributing factor to neural tube defects in populations consuming large amounts of maize

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisin B1 (FB) is an inhibitor of sphingolipid (SL) biosynthesis and folate transport and can induce neural tube defects (NTD) in mice. NTD incidence is high in countries where maize is a dietary staple and FB exposure is likely. In Guatemala the incidence of FB in maize has been well documented ...

  1. Will Increasing Folic Acid in Fortified Grain Products Further Reduce Neural Tube Defects without Causing Harm?: Consideration of the Evidence

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Will Increasing Folic Acid in Fortified Grain Products Further Reduce Neural Tube Defects without Causing Harm?: Consideration of the Evidence. In the January issue of this journal, Johnston (1) includes our group’s recent analysis of data from the 1999-2002 National Health and Nutrition Examination...

  2. Relationship between altered axial curvature and neural tube closure in normal and mutant ( curly tail ) mouse embryos

    Microsoft Academic Search

    Marian C. E. Peeters; Johan W. M. Hekking; Henny W. M. Straaten; Alisa S. W. Shum; Andrew J. Copp

    1996-01-01

    Neural tube defects, including spina bifida, develop in the curly tail mutant mouse as a result of delayed closure of the posterior neuropore at 10.5 days of gestation. Affected embryos are characterized by increased ventral curvature of the caudal region. To determine whether closure of the neuropore could be affected by this angle of curvature, we experimentally enhanced the curvature

  3. Multifactorial inheritance of neural tube defects: localization of the major gene and recognition of modifiers in ct mutant mice

    Microsoft Academic Search

    Paul E. Neumann; Wayne N. Frankel; Verity A. Letts; John M. Coffin; Andrew J. Copp; Merton Bernfield

    1994-01-01

    Neural tube defects (NTD) in humans have been considered to have a multifactorial aetiology, however the participating genes have not been identified. The curly-tail (ct) mutant mouse develops NTD that resemble the human malformations in location, pathology and associated abnormalities. Moreover, there appears to be multifactorial influence on the incidence of NTD in offspring of curly-tail mice. We now describe

  4. PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida

    Microsoft Academic Search

    F. A. Hol; M. P. A. Geurds; S. Chatkupt; Y. Y. Shugart; R. Balling; C. T. R. M. Schrander-Stumpel; W. G. Johnson; B. C. J. Hamel; E. C. M. Mariman

    1996-01-01

    From studies in the mouse and from the clinical and molecular analysis of patients with type 1 Waardenburg syndrome, particular members of the PAX gene family are suspected factors in the aetiology of human neural tube defects (NTD). To investigate the role of PAX1, PAX3, PAX7, and PAX9, allelic association studies were performed in 79 sporadic and 38 familial NTD

  5. Inositol and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3

    Microsoft Academic Search

    Stephen B Ting; Tomasz Wilanowski; Alana Auden; Mark Hall; Anne K Voss; Tim Thomas; Vishwas Parekh; John M Cunningham; Stephen M Jane

    2003-01-01

    The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct\\/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene,

  6. Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects.

    PubMed

    Yaliwal, Laxmi V; Desai, Rathnamala M

    2012-01-01

    Methylenetetrahydrofolate reductase (MTHFR) gene mutations have been implicated as risk factors for neural tube defects (NTDs). The best-characterized MTHFR genetic mutation 677C?T is associated with a 2-4 fold increased risk of NTD if patient is homozygous for this mutation. This risk factor is modulated by folate levels in the body. A second mutation in the MTHFR gene is an A?C transition at position 1298. The 1298A?C mutation is also a risk factor for NTD, but with a smaller relative risk than 677C?T mutation. Under conditions of low folate intake or high folate requirements, such as pregnancy, this mutation could become of clinical importance. We present a case report with MTHFR genetic mutation, who presented with recurrent familial pregnancy losses due to anencephaly/NTDs. PMID:22754237

  7. Potential relationship between dengue fever and neural tube defects in a northern district of India.

    PubMed

    Sharma, J B; Gulati, N

    1992-12-01

    A sudden increase in number of births of newborns with neural tube defects (NTD) was observed from June, 1989 to September, 1989 in Medical College and Hospital, Rohtak and various other government and private hospitals of the district of Rohtak. Out of a total 4785 deliveries whose records were collected, there were 87 newborns with NTD with an incidence of 18.18/1000 births which was three times higher than the previous incidence of 6.8/1000 births in the preceding 4 years. There was an epidemic of dengue fever in this area from September, 1988 to December, 1988 affecting almost one member from each family. This coincided with the period of their first trimester. Of these, 18 patients suffered clinically from dengue fever, 21 patients had positive dengue fever history in their family members, 21 patients had positive history in their neighbors. The cluster of NTD appears to be due to dengue virus infection. PMID:1361462

  8. Recurrence risks for neural tube defects in a genetic counseling clinic population.

    PubMed Central

    Seller, M J

    1981-01-01

    The recurrence of neural tube defects (NTD) in the sib following the index case of all patients who consulted the South-East Thames Regional Health Authority Genetics Centre in the period 1972 to mid-1979 was calculated. A total of 1037 consecutive patients was studied, of whom 958 (93%) were traced. The overall recurrence was 3.44% (1 in 29). However, if the index case was the first affected child in the family, the recurrence in the next sib was 3.15% (1 in 32), and if it was the second affected child, the recurrence was 11.76% (1 in 9). These figures give an indication of the actual recurrence among the 'selected' population who consult a genetic advice centre, and are somewhat, but not significantly, different from figures for the general NTD population, which have been derived from studies of whole families. PMID:7277415

  9. Genetic association analyses of nitric oxide synthase genes and neural tube defects vary by phenotype.

    PubMed

    Soldano, Karen L; Garrett, Melanie E; Cope, Heidi L; Rusnak, J Michael; Ellis, Nathen J; Dunlap, Kaitlyn L; Speer, Marcy C; Gregory, Simon G; Ashley-Koch, Allison E

    2013-10-01

    Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes. PMID:24323870

  10. Experience of a tertiary care center on 100 newborns with neural tube defects.

    PubMed

    Aygün, Canan; Kurucu, Sevgi; Çakmak-Çelik, Fatma; Da?ç?nar, Adnan; Tanyeri, Bilge; Küçüködük, ?ükrü

    2013-01-01

    The aim of this study was to analyze the sociodemographic features, postoperative complications, long-term problems, and cost of care of patients followed in the neonatal intensive care unit (NICU) with a diagnosis of neural tube defects (NTDs). Babies with NTD followed in the Neonatology Unit of Ondokuz May?s University Faculty of Medicine between January 2003 and December 2011 were analyzed retrospectively. One hundred (1.2%) of 8408 babies admitted to the NICU were diagnosed as NTD during the study period. Of the cases with NTD, 74% of mothers were graduates of primary school/illiterate, and none had used folic acid (FA) preconceptionally. Prenatal diagnosis was made in 72%, but parents had chosen not to terminate the pregnancy. The most frequent type and site of NTD was meningomyelocele (82%) of the lumbosacral region (36%). In 80% of the babies, the NTD sac was closed with in the first 72 hours of life. The most frequently observed postoperative complications were wound infection and septicemia. The mortality rate of babies with NTD during the follow-up period was 7%, and all deaths occurred in the first year of life. Sixty-two percent of the patients had neurologic deficits on follow-up. Patients were rehospitalized during the follow-up for an average of 2.9 times. Neural tube defect (NTD) is a disabling problem, with operations, rehospitalizations and other costly treatments. Maternal education regarding preconceptional FA use/fortification of food with FA and appropriate guidance to the family with prenatal diagnosis will decrease the incidence and burden of the disease. PMID:24292027

  11. Promoter haplotype combinations for the human PDGFRA gene are associated with risk of neural tube defects.

    PubMed

    Zhu, Huiping; Wicker, Ned J; Volcik, Kelly; Zhang, Jing; Shaw, Gary M; Lammer, Edward J; Suarez, Lucina; Canfield, Mark; Finnell, Richard H

    2004-02-01

    Recent animal studies suggested that deregulated expression of the platelet-derived growth factor receptor alpha (PDGFRalpha) may contribute to the failure of normal neural tube closure (NTC). There is also suggestive evidence that the promoter haplotype of the PDGFRA is associated with genetic susceptibility in human neural tube defects (NTDs). The purpose of our study was to investigate the association between promoter haplotype combinations of the human PDGFRA gene and risk for NTDs in a Hispanic population from the Texas-Mexico border region. This population has a considerably higher prevalence of NTDs (16/10,000 live births) than that generally reported in the United States (8-10/10,000 live births). In the present study, NTDs were defined as spina bifida or anencephaly. The haplotype of PDGFRA gene promoter was determined by direct DNA sequence analysis. Two novel haplotypes, H2epsilon and H1beta, were found. We observed significant differences among variable haplotype groups from in vitro transient transfection studies in U2-OS osteosarcoma cell and two other cell lines (HeLa cell and MCF7 cell). Result from our case-control study demonstrated that the frequencies of haplotypes with low transcription activity were significantly higher in NTD mothers than that observed in control mothers (odds ratio=2.2, 95% CI=1.0-4.6). Infants with at least one low activity allele showed slightly higher risk (odds ratio=1.5, 95%=0.8-3.1). Our study suggests that the reduced transcriptional activity of PDGFRA gene could increase the risk of having an NTD-affected pregnancy. PMID:14741194

  12. Genetic Association Analyses of Nitric Oxide Synthase Genes and Neural Tube Defects Vary by Phenotype

    PubMed Central

    Soldano, Karen L.; Garrett, Melanie E.; Cope, Heidi L.; Rusnak, J. Michael; Ellis, Nathen J.; Dunlap, Kaitlyn L.; Speer, Marcy C.; Gregory, Simon G.; Ashley-Koch, Allison E.

    2014-01-01

    Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes. PMID:24323870

  13. Prediction of Mechanical Properties of 25CrMo48V Seamless Tube Using Neural Network Model

    NASA Astrophysics Data System (ADS)

    Sun, Laibo; Zhang, Chuanyou; Wang, Qingfeng; Wang, Mingzhi; Yan, Zesheng

    In this investigation, a neural network model was established to predict mechanical properties of 25CrMo48V seamless tubes. The sensitivity analysis was also performed to estimate the relative significance of each chemical composition in mechanical behavior of steel tubes. The results of this investigation show that there is a good agreement between experimental and predicted values indicating desirable validity of the model. Among those alloying elements, the elements of carbon, silicon and chromium tended to play a more important role in controlling both the yielding strength and the Charpy-V-Notch transverse impact toughness. In comparison, the impurities such as O, N, S and P have a relatively weak impact. More detailed dependences of mechanical properties on each chemical composition in isolation can be revealed using the established model. The well-trained neural network has a great potential in designing tough and ultrahigh-strength seamless tubes and modeling the on-line production parameters.

  14. Neural tube defects in Costa Rica, 1987-2012: origins and development of birth defect surveillance and folic acid fortification.

    PubMed

    Barboza-Argüello, María de la Paz; Umaña-Solís, Lila M; Azofeifa, Alejandro; Valencia, Diana; Flores, Alina L; Rodríguez-Aguilar, Sara; Alfaro-Calvo, Thelma; Mulinare, Joseph

    2015-03-01

    Our aim was to provide a descriptive overview of how the birth defects surveillance and folic acid fortification programs were implemented in Costa Rica-through the establishment of the Registry Center for Congenital Anomalies (Centro de Registro de Enfermedades Congénitas-CREC), and fortification legislation mandates. We estimated the overall prevalence of neural tube defects (i.e., spina bifida, anencephaly and encephalocele) before and after fortification captured by CREC. Prevalence was calculated by dividing the total number of infants born with neural tube defects by the total number of live births in the country (1987-2012).A total of 1,170 newborns with neural tube defects were identified from 1987 to 2012 (1992-1995 data excluded); 628 were identified during the baseline pre-fortification period (1987-1991; 1996-1998); 191 during the fortification period (1999-2002); and 351 during the post-fortification time period (2003-2012). The overall prevalence of neural tube defects decreased from 9.8 per 10,000 live-births (95 % CI 9.1-10.5) for the pre-fortification period to 4.8 per 10,000 live births (95 % CI 4.3-5.3) for the post-fortification period. Results indicate a statistically significant (P < 0.05) decrease of 51 % in the prevalence of neural tube defects from the pre-fortification period to the post-fortification period. Folic acid fortification via several basic food sources has shown to be a successful public health intervention for Costa Rica. Costa Rica's experience can serve as an example for other countries seeking to develop and strengthen both their birth defects surveillance and fortification programs. PMID:24952876

  15. Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure

    PubMed Central

    Zwerts, Femke; Lupu, Florea; De Vriese, Astrid; Pollefeyt, Saskia; Moons, Lieve; Altura, Rachel A.; Jiang, Yuying; Maxwell, Patrick H.; Hill, Peter; Oh, Hideyasu; Rieker, Claus; Collen, Désiré; Conway, Simon J.

    2007-01-01

    We explored the physiologic role of endothelial cell apoptosis during development by generating mouse embryos lacking the inhibitor of apoptosis protein (IAP) survivin in endothelium. This was accomplished by intercrossing survivinlox/lox mice with mice expressing cre recombinase under the control of the endothelial cell specific tie1 promoter (tie1-cre mice). Lack of endothelial cell survivin resulted in embryonic lethality. Mutant embryos had prominent and diffuse hemorrhages from embryonic day 9.5 (E9.5) and died before E13.5. Heart development was strikingly abnormal. Survivin-null endocardial lineage cells could not support normal epithelial-mesenchymal transformation (EMT), resulting in hypoplastic endocardial cushions and in utero heart failure. In addition, 30% of mutant embryos had neural tube closure defects (NTDs) that were not caused by bleeding or growth retardation, but were likely due to alterations in the release of soluble factors from endothelial cells that otherwise support neural stem cell proliferation and neurulation. Thus, regulation of endothelial cell survival, and maintenance of vascular integrity by survivin are crucial for normal embryonic angiogenesis, cardiogenesis, and neurogenesis. PMID:17299096

  16. A unique missense allele of BAF155, a core BAF chromatin remodeling complex protein, causes neural tube closure defects in mice.

    PubMed

    Harmacek, Laura; Watkins-Chow, Dawn E; Chen, Jianfu; Jones, Kenneth L; Pavan, William J; Salbaum, J Michael; Niswander, Lee

    2014-05-01

    Failure of embryonic neural tube closure results in the second most common class of birth defects known as neural tube defects (NTDs). While NTDs are likely the result of complex multigenic dysfunction, it is not known whether polymorphisms in epigenetic regulators may be risk factors for NTDs. Here we characterized Baf155(msp3) , a unique ENU-induced allele in mice. Homozygous Baf155(mps3) embryos exhibit highly penetrant exencephaly, allowing us to investigate the roles of an assembled, but malfunctional BAF chromatin remodeling complex in vivo at the time of neural tube closure. Evidence of defects in proliferation and apoptosis were found within the neural tube. RNA-Seq analysis revealed that surprisingly few genes showed altered expression in Baf155 mutant neural tissue, given the broad epigenetic role of the BAF complex, but included genes involved in neural development and cell survival. Moreover, gene expression changes between individual mutants were variable even though the NTD was consistently observed. This suggests that inconsistent gene regulation contributes to failed neural tube closure. These results shed light on the role of the BAF complex in the process of neural tube closure and highlight the importance of studying missense alleles to understand epigenetic regulation during critical phases of development. PMID:24170322

  17. Improving Application of Bayesian Neural Networks to Discriminate Neutrino Events from Backgrounds in Reactor Neutrino Experiments

    E-print Network

    Ye Xu; WeiWei Xu; YiXiong Meng; Bin Wu

    2009-01-12

    The application of Bayesian Neural Networks(BNN) to discriminate neutrino events from backgrounds in reactor neutrino experiments has been described in Ref.\\cite{key-1}. In the paper, BNN are also used to identify neutrino events in reactor neutrino experiments, but the numbers of photoelectrons received by PMTs are used as inputs to BNN in the paper, not the reconstructed energy and position of events. The samples of neutrino events and three major backgrounds from the Monte-Carlo simulation of a toy detector are generated in the signal region. Compared to the BNN method in Ref.\\cite{key-1}, more $^{8}$He/$^{9}$Li background and uncorrelated background in the signal region can be rejected by the BNN method in the paper, but more fast neutron background events in the signal region are unidentified using the BNN method in the paper. The uncorrelated background to signal ratio and the $^{8}$He/$^{9}$Li background to signal ratio are significantly improved using the BNN method in the paper in comparison with the BNN method in Ref.\\cite{key-1}. But the fast neutron background to signal ratio in the signal region is a bit larger than the one in Ref.\\cite{key-1}.

  18. Modifying a sealed tube zinc reduction method for preparation of AMS graphite targets: Reducing background and attaining high precision

    Microsoft Academic Search

    Xiaomei Xu; Susan E. Trumbore; Shuhui Zheng; John R. Southon; Kelsey E. McDuffee; Madelyn Luttgen; Julia C. Liu

    2007-01-01

    The sealed tube zinc reduction method for converting CO2 to graphite for AMS 14C measurements was originally developed for rapid production of graphite in biomedical tracer experiments. The method was usually thought to have low precision and a high background. We have modified the zinc reduction method originally outlined in Vogel [J.S. Vogel, Radiocarbon 34 (3) (1992) 344] by carefully

  19. Migration of Schwann cells and axons into developing chick forelimb muscles following removal of either the neural tube or the neural crest.

    PubMed

    Noakes, P G; Bennett, M R; Stratford, J

    1988-11-01

    A study has been made of the effects of neural crest and neural tube removal at the brachial level on the migration of Schwann cells and axons into the flexor digitorum profundus (fdp) and flexor carpi ulnaris (fcu) muscles of the avian forelimb. The identification of Schwann cells was based on the assumption that antibody HNK-1 uniquely labels these cells at the growing end of limb nerves. Myotubes and nerves were identified by using antibodies to myosin and to neurofilament protein, respectively. The removal of neural crest cells at stage 13 gave a complete Schwann cell-free embryo at the brachial level. Motor axons only grew to the base of the forelimb, forming a rudimentary plexus by stage 27, and failed to penetrate the limb. Removal of the neural tube at stage 13 did not prevent sensory axons from forming a plexus at the base of the limb; these axons subsequently developed into the brachialis longus inferior (bli n) and superior (bls n) nerves. By stage 27 the bli n had branched into the interosseus nerve (in n) and the medial-ulnar nerve (m-u n) trunks. However, unlike the result in control embryos, no nerves were detected amongst the developing fdp and fcu muscles, thus indicating that sensory axons do not grow into the muscles in the absence of motor axons. In contrast, Schwann cells were observed amongst the myotubes at the level of the in n and m-u nerve trunks. The present observations show that motor axons do not enter the limb bud and innervate limb muscles in the absence of Schwann cells. Furthermore, in the absence of motor axons (neural-tube-removed embryos) sensory axons still enter the limb (behind migrating Schwann cells) but fail to innervate developing muscles even though Schwann cells are present among the developing myotubes. PMID:3068263

  20. LRP6 exerts non-canonical effects on Wnt signaling during neural tube closure

    PubMed Central

    Gray, Jason D.; Kholmanskikh, Stanislav; Castaldo, Bozena S.; Hansler, Alex; Chung, Heekyung; Klotz, Brian; Singh, Shawn; Brown, Anthony M. C.; Ross, M. Elizabeth

    2013-01-01

    Low-density lipoprotein receptor related protein 6 (Lrp6) mutational effects on neurulation were examined using gain (Crooked tail, Lrp6Cd) and loss (Lrp6?) of function mouse lines. Two features often associated with canonical Wnt signaling, dorsal–ventral patterning and proliferation, were no different from wild-type (WT) in the Lrp6Cd/Cd neural tube. Lrp6?/? embryos showed reduced proliferation and subtle patterning changes in the neural folds. Cell polarity defects in both Lrp6Cd/Cd and Lrp6?/? cranial folds were indicated by cell shape, centrosome displacement and failure of F-actin and GTP-RhoA accumulation at the apical surface. Mouse embryonic fibroblasts (MEFs) derived from Lrp6Cd/Cd or Lrp6?/? embryos exhibited elevated and decreased RhoA basal activity levels, respectively. While ligand-independent activation of canonical Wnt signaling, bypassing Lrp-Frizzled receptors, did not activate RhoA, non-canonical Wnt5a stimulation of RhoA activity was impaired in Lrp6?/? MEFs. RhoA inhibition exacerbated NTDs in cultured Lrp6 knockout embryos compared with WT littermates. In contrast, a ROCK inhibitor rescued Lrp6Cd/Cd embryos from NTDs. Lrp6 co-immunoprecipitated with Disheveled-associated activator of morphogenesis 1 (DAAM1), a formin promoting GEF activity in Wnt signaling. Biochemical and cell biological data revealed intracellular accumulation of Lrp6Cd protein where interaction with DAAM1 could account for observed elevated RhoA activity. Conversely, null mutation that eliminates Lrp6 interaction with DAAM1 led to lower basal RhoA activity in Lrp6?/? embryos. These results indicate that Lrp6 mediates not only canonical Wnt signaling, but can also modulate non-canonical pathways involving RhoA-dependent mechanisms to impact neurulation, possibly through intracellular complexes with DAAM1. PMID:23773994

  1. Supplemental figure 1. PCR analysis of BMPRII expression and western blotting of ADF/cofilin in Xenopus neural tube tissues. (A). Expression of the long form of BMPRII

    E-print Network

    and western blotting of ADF/cofilin in Xenopus neural tube tissues. (A). Expression of the long form of BMPRII stages of developing Xenopus embryos and their correlations with the specific stage of commissural axon

  2. Folate Deficiency and Folic Acid Supplementation: The Prevention of Neural-Tube Defects and Congenital Heart Defects

    PubMed Central

    Czeizel, Andrew E.; Dudás, Istvan; Vereczkey, Attila; Bánhidy, Ferenc

    2013-01-01

    Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in their origin. The findings of the Hungarian intervention (randomized double-blind and cohort controlled) trials indicated that periconceptional folic acid (FA)-containing multivitamin supplementation prevented the major proportion (about 90%) of neural-tube defects (NTD) as well as a certain proportion (about 40%) of congenital heart defects. Finally the benefits and drawbacks of three main practical applications of folic acid/multivitamin treatment such as (i) dietary intake; (ii) periconceptional supplementation; and (iii) flour fortification are discussed. The conclusion arrived at is indeed confirmation of Benjamin Franklin’s statement: “An ounce of prevention is better than a pound of care”. PMID:24284617

  3. Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects.

    PubMed

    Czeizel, Andrew E; Dudás, Istvan; Vereczkey, Attila; Bánhidy, Ferenc

    2013-11-01

    Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in their origin. The findings of the Hungarian intervention (randomized double-blind and cohort controlled) trials indicated that periconceptional folic acid (FA)-containing multivitamin supplementation prevented the major proportion (about 90%) of neural-tube defects (NTD) as well as a certain proportion (about 40%) of congenital heart defects. Finally the benefits and drawbacks of three main practical applications of folic acid/multivitamin treatment such as (i) dietary intake; (ii) periconceptional supplementation; and (iii) flour fortification are discussed. The conclusion arrived at is indeed confirmation of Benjamin Franklin's statement: "An ounce of prevention is better than a pound of care". PMID:24284617

  4. The thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) is not a major risk factor for neural tube defect in American Caucasians

    Microsoft Academic Search

    Marcy C. Speer; Gordon Worley; Joanne F. Mackey; Elizabeth Melvin; W. Jerry Oakes; Timothy M. George

    1997-01-01

    Mutations in the gene for methylenetetrahydrofolate reductase (MTHFR) have been implicated as a risk factor in the formation\\u000a of neural tube defects. We investigated this gene in a series of 65 sporadic American Caucasians patients with lumbosacral\\u000a NTD and their unaffected parents, using both case-control design and assessment of linkage disequilibrium. We found no evidence\\u000a to support mutations in MTHFR

  5. A Second Common Mutation in the Methylenetetrahydrofolate Reductase Gene: An Additional Risk Factor for Neural-Tube Defects?

    Microsoft Academic Search

    Fons Gabreëls; Erik M. B. Stevens; Jan A. M. Smeitink; Frans J. M. Trijbels; Tom K. A. B. Eskes; Lambert P. van den Heuvel; Henk J. Blom

    1998-01-01

    Summary Recently, we showed that homozygosity for the common 677(CrT) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(ArC) mutation, which changes a glutamate into an alanine residue. This mutation destroys anMboII recognition site and has an

  6. Periconceptional Multivitamin Folic Acid Use, Dietary Folate, Total Folate and Risk of Neural Tube Defects in South Carolina

    Microsoft Academic Search

    Shirley J Thompson; Myriam E Torres; Roger E Stevenson; Jane H Dean; Robert G Best

    2003-01-01

    PURPOSE: To investigate whether dietary folate or multivitamin folic acid taken 3 months before conception and during the first 3 months of pregnancy reduces the risk of isolated occurrent neural tube defect (NTD)-affected pregnancies.METHODS: This population-based case control study conducted between 1992 and 1997 included 179 women with NTD-affected pregnancies and 288 randomly selected controls. Women completed a food frequency

  7. The impact of prenatal diagnosis on neural tube defect (NTD) pregnancy versus birth incidence in British Columbia

    Microsoft Academic Search

    Margot I. Van Allen; Erin Boyle; Paul Thiessen; Deborah McFadden; Douglas Cochrane; G. Keith Chambers; Sylvie Langlois; Patricia Stathers; Beverly Irwin; Elizabeth Cairns; Patrick MacLeod; Marie-France Delisle; Soo-Hong Uh

    2006-01-01

    The birth incidence of neural tube defect (NTD) cases in British Columbia (B.C.), and elsewhere in North America, is reported\\u000a to be declining. This decline is being attributed to folic acid (FA) supplementation and food fortification, but 2nd trimester\\u000a prenatal screening of pregnancies for NTDs and other congenital anomalies has increased during this timeframe, as well. This\\u000a descriptive, population-based study

  8. Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population

    Microsoft Academic Search

    Bärbel Richter; Karolin Stegmann; Britta Röper; Inke Böddeker; Ernestine T K M Ngo; Manuela C Koch

    2001-01-01

    Neural tube defects (NTD) are likely to result from an interaction of several genes and environmental factors. Because periconceptional\\u000a folate intake reduces the NTD risk in the fetus, and because mothers of children with NTD showed elevated plasma homocysteine\\u000a levels, gene polymorphisms of the folate and homocysteine pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C?T, MTHFR 1298A?C and cystathionine ?-synthase (CBS)

  9. Folic acid and the prevention of neural tube defects: A position paper of the national society of genetic counselors

    Microsoft Academic Search

    Bonnie Jeanne Baty; Leslie Cohen; Lorna Phelps; Marcy C. Speer; Pamela Stengel; Lori Williamson-Kruse

    1996-01-01

    Considerable scientific evidence demonstrates the reduction in risk for neural tube defects (NTDs) associated with maternal preconceptional folic acid supplementation. The National Society of Genetic Counselors (NSGC) endorses the U.S. Public Health Service recommendations for folic acid supplementation at the 0.4 mg level for women in the general population and at the 4.0 mg level for women at high or

  10. Awareness and Intake of Folic Acid for the Prevention of Neural Tube Defects Among Lebanese Women of Childbearing Age

    Microsoft Academic Search

    Claudine Nasr Hage; Maya Jalloul; Mohamad Sabbah; Salim M. Adib

    Since the early 1990s, international recommendations have promoted folic acid supplementation during the periconception period\\u000a as an effective way of preventing neural tube defects (NTDs). However, the adoption of this recommendation remains insufficient.\\u000a To assess the awareness and actual intake of folic acid among married Lebanese women aged 18–45 years, a cross-sectional study\\u000a was conducted among 600 women selected from all

  11. Awareness of folic acid for prevention of neural tube defects in a community with high prevalence of consanguineous marriages

    Microsoft Academic Search

    Lutfi Jaber; Igbaria A. Karim; Abu Moch Jawdat; Mawasi Fausi; Paul Merlob

    2004-01-01

    Neural tube defects (NTDs) are severe congenital malformations and can be fatal. Intake of 0.4 mg folic in the periconceptional period reduces the risk of NTD by 50–70%. Consanguinity in the Arab population in Israel is a prevalent custom. The aim of this study was to assess the level of awareness regarding folic acid and its effect in the prevention of

  12. Folate supplementation, MTHFR gene polymorphism and neural tube defects: a community based case control study in North India

    Microsoft Academic Search

    Roumi Deb; Jyoti Arora; Sanjenbam Yaiphaba Meitei; Sangeeta Gupta; Vanita Verma; Kallur Nava Saraswathy; Sunil Saran; Aloke Kumar Kalla

    The present study analyses the potential role of MTHFR gene polymorphism, folate supplementation and dietary pattern among\\u000a the mothers of NTD neonates and controls in heterogeneous populations of North India, with the special focus on their ethnic\\u000a labels. Results indicated significant increased risk for neural tube defects with respect to low folic acid supplementation\\u000a and vegetarian diet in univariate and

  13. Angiogenesis within the developing mouse neural tube is dependent on sonic hedgehog signaling: possible roles of motor neurons

    Microsoft Academic Search

    Takashi Nagase; Miki Nagase; Kotaro Yoshimura; Toshiro Fujita; Isao Koshima

    2005-01-01

    Embryonic morphogenesis of vascular and nervous systems is tightly coordinated, and recent studies revealed that some neurogenetic factors such as Sonic hedgehog (Shh) also exhibit angio- genetic potential. Vascularization within the developing mouse neural tube depends on vessel sprouting from the surrounding vascular plexus. Previous studies implicated possible roles of VEGF\\/Flk-1 and Angiopoietin-1(Ang-1)\\/Tie-2 signaling as candidate molecules functioning in this

  14. Pax1\\/E2a Double-Mutant Mice Develop Non-Lethal Neural Tube Defects that Resemble Human Malformations

    Microsoft Academic Search

    Paulus H. L. J. Joosten; Everardus J. J. van Zoelen; Cornelis Murre

    2005-01-01

    Many mouse models exist for neural tube defects (NTDs), but only few of them are relevant for human patients that are born\\u000a alive with spina bifida aperta. NTDs in humans show a complex inheritance, which most likely result from the involvement of\\u000a a variety of predisposing genetic and environmental factors. Hints toward the identity of predisposing genetic factors for\\u000a human

  15. Altered cell proliferation in the spinal cord of mouse neural tube mutants curly tail and Pax3 splotch-delayed

    Microsoft Academic Search

    Cynthia R Keller-Peck; Richard J Mullen

    1997-01-01

    The mutant mouse strains splotch-delayed (Pax3Sp-d) and curly tail (ct) develop neural tube defects (NTDs) in the lumbosacral region of the neuraxis. Some research has focused on cell proliferation around the time of posterior neuropore closure in these mutants; however, there are little data on the effects of NTDs on cell birth at later stages of development. To investigate the

  16. Dieting to Lose Weight and Occurrence of Neural Tube Defects in Offspring of Mexican–American Women

    Microsoft Academic Search

    Lucina Suarez; Marilyn Felkner; Jean D. Brender; Mark A. Canfield

    Lowered maternal weight gain and reduction in early pregnancy have been associated with risk of neural tube defects (NTDs)\\u000a in offspring. We examined the association of self-reported maternal dieting behaviors on the occurrence of NTDs. We conducted\\u000a a population based case–control study among Mexican–American women who were residents of the 14 Texas counties bordering Mexico.\\u000a Case women had an NTD-affected

  17. Enhancement of re-closure capacity by the intra-amniotic injection of human embryonic stem cells in surgically induced spinal open neural tube defects in chick embryos

    Microsoft Academic Search

    Do-Hun Lee; Eun Young Kim; Seung-Ki Kim; You-Nam Chung; Byung-Kyu Cho; Young Jae Lee; Jinho Lim; Kyu-Chang Wang

    2004-01-01

    To evaluate the re-closure promoting capacity of human embryonic stem (hES) cells injected into the amniotic cavity on spinal open neural tube defects (ONTDs) of chick embryos, neural tubes were opened at Hamburger and Hamilton stage 18 or 19 and the embryos were divided into three groups: a control group (no injection), a vehicle group, and a hES cell group

  18. Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development

    Microsoft Academic Search

    Hongbo Chi; Matthew R. Sarkisian; Pasko Rakic; Richard A. Flavell

    2005-01-01

    Neural tube defects (NTDs) are prevalent human birth defects. Mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK), are implicated in facilitating neural tube closure, yet upstream regulators remain to be identified. Here, we show that MAP kinase kinase kinase 4 (MEKK4) is strongly expressed in the developing neuroepithelium. Mice deficient in MEKK4 develop highly penetrant NTDs that cannot

  19. Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans.

    PubMed

    Narisawa, Ayumi; Komatsuzaki, Shoko; Kikuchi, Atsuo; Niihori, Tetsuya; Aoki, Yoko; Fujiwara, Kazuko; Tanemura, Mitsuyo; Hata, Akira; Suzuki, Yoichi; Relton, Caroline L; Grinham, James; Leung, Kit-Yi; Partridge, Darren; Robinson, Alexis; Stone, Victoria; Gustavsson, Peter; Stanier, Philip; Copp, Andrew J; Greene, Nicholas D E; Tominaga, Teiji; Matsubara, Yoichi; Kure, Shigeo

    2012-04-01

    Neural tube defects (NTDs), including spina bifida and anencephaly, are common birth defects of the central nervous system. The complex multigenic causation of human NTDs, together with the large number of possible candidate genes, has hampered efforts to delineate their molecular basis. Function of folate one-carbon metabolism (FOCM) has been implicated as a key determinant of susceptibility to NTDs. The glycine cleavage system (GCS) is a multi-enzyme component of mitochondrial folate metabolism, and GCS-encoding genes therefore represent candidates for involvement in NTDs. To investigate this possibility, we sequenced the coding regions of the GCS genes: AMT, GCSH and GLDC in NTD patients and controls. Two unique non-synonymous changes were identified in the AMT gene that were absent from controls. We also identified a splice acceptor site mutation and five different non-synonymous variants in GLDC, which were found to significantly impair enzymatic activity and represent putative causative mutations. In order to functionally test the requirement for GCS activity in neural tube closure, we generated mice that lack GCS activity, through mutation of AMT. Homozygous Amt(-/-) mice developed NTDs at high frequency. Although these NTDs were not preventable by supplemental folic acid, there was a partial rescue by methionine. Overall, our findings suggest that loss-of-function mutations in GCS genes predispose to NTDs in mice and humans. These data highlight the importance of adequate function of mitochondrial folate metabolism in neural tube closure. PMID:22171071

  20. GEF-H1 functions in apical constriction and cell intercalations and is essential for vertebrate neural tube closure.

    PubMed

    Itoh, Keiji; Ossipova, Olga; Sokol, Sergei Y

    2014-06-01

    Rho family GTPases regulate many morphogenetic processes during vertebrate development including neural tube closure. Here we report a function for GEF-H1/Lfc/ArhGEF2, a RhoA-specific guanine nucleotide exchange factor that functions in neurulation in Xenopus embryos. Morpholino-mediated depletion of GEF-H1 resulted in severe neural tube defects, which were rescued by GEF-H1 RNA. Lineage tracing of GEF-H1 morphants at different developmental stages revealed abnormal cell intercalation and apical constriction, suggesting that GEF-H1 regulates these cell behaviors. Molecular marker analysis documented defects in myosin II light chain (MLC) phosphorylation, Rab11 and F-actin accumulation in GEF-H1-depleted cells. In gain-of-function studies, overexpressed GEF-H1 induced Rho-associated kinase-dependent ectopic apical constriction - marked by apical accumulation of phosphorylated MLC, ?-tubulin and F-actin in superficial ectoderm - and stimulated apical protrusive activity of deep ectoderm cells. Taken together, our observations newly identify functions of GEF-H1 in morphogenetic movements that lead to neural tube closure. PMID:24681784

  1. The interaction between Shroom3 and Rho-kinase is required for neural tube morphogenesis in mice.

    PubMed

    Das, Debamitra; Zalewski, Jenna K; Mohan, Swarna; Plageman, Timothy F; VanDemark, Andrew P; Hildebrand, Jeffrey D

    2014-01-01

    Shroom3 is an actin-associated regulator of cell morphology that is required for neural tube closure, formation of the lens placode, and gut morphogenesis in mice and has been linked to chronic kidney disease and directional heart looping in humans. Numerous studies have shown that Shroom3 likely regulates these developmental processes by directly binding to Rho-kinase and facilitating the assembly of apically positioned contractile actomyosin networks. We have characterized the molecular basis for the neural tube defects caused by an ENU-induced mutation that results in an arginine-to-cysteine amino acid substitution at position 1838 of mouse Shroom3. We show that this substitution has no effect on Shroom3 expression or localization but ablates Rock binding and renders Shroom3 non-functional for the ability to regulate cell morphology. Our results indicate that Rock is the major downstream effector of Shroom3 in the process of neural tube morphogenesis. Based on sequence conservation and biochemical analysis, we predict that the Shroom-Rock interaction is highly conserved across animal evolution and represents a signaling module that is utilized in a variety of biological processes. PMID:25171888

  2. Registries of cases with neural tube defects in Denizli, Turkey, 2004-2010.

    PubMed

    Tomatir, A G; Kiray Vural, B; Acikbas, I; Akdag, B

    2014-01-01

    Neural tube defects (NTD) are among the most common congenital abnormalities, with an incidence of 3 per 1000 live births in Turkey. In a study of major congenital abnormalities in the city of Denizli, Turkey, abnormalities of the central nervous system are particularly common (31.1%). The objective of this study was to develop a registry of cases with NTDs in Denizli. Cases that had been diagnosed with NTD between January 2004 and September 2010 in State Hospitals of Central Denizli were retrospectively examined. The diagnoses were established based on the ICD-10 criteria. A total of 250 subjects with NTD were identified, including 123 (49.2%) females and 127 (50.8%) males with a mean age of 13.72 ± 15.62 years (age range 1-81 years). Interestingly, spina bifida constituted a significant percentage of the cases (149 cases; 59.6%). In addition, 10 (4.0%) cases had hydrocephalus plus spina bifida. The second most common diagnosis was microcephaly, which included 70 cases (28.0%). Encephalocele was observed in only 2 cases (0.8%). Development of NTD is influenced by nutrition, socioeconomic factors, and the use of folic acid during the peri-conceptional period. Studies examining the effect of these factors on NTD in Turkey and a review of primary prevention measures are necessary. PMID:25366748

  3. The role of folic acid fortification in neural tube defects: a review.

    PubMed

    Osterhues, Anja; Ali, Nyima S; Michels, Karin B

    2013-01-01

    The worldwide prevalence of neural tube defects (NTDs) has fallen noticeably during the past 30 years, but the specific etiology and causative mechanism of NTDs remain unknown. Since introduction of mandatory fortification of grains with folic acid, a further decrease in NTD prevalence has been reported in North America and other countries with large variations among ethnic subgroups. However, a significant portion of NTDs still persists. Population data suggest that women of childbearing age may not yet be adequately targeted, while the general population may be overfortified with folic acid. While an excessive folate intake may be associated with adverse effects, there remains uncertainty about the minimum effective folate intake and status required for NTD prevention, and the safe upper folate level. Besides folate, several other lifestyle and environmental factors as well as genetic variations may influence NTD development, possibly by affecting one-carbon metabolism and thus epigenetic events. In conclusion, mandatory folic acid fortification plays a significant part in the reduction of NTD prevalence, but possibly at a cost and with a portion of NTDs remaining. More effective preventive strategies require better understanding of the etiology of this group of birth defects. PMID:24007422

  4. [Knowledge of physicians and obstetric nurses about the prevention of neural tube defects].

    PubMed

    Conceição, Ricardo Campelo da; Barbosa, Marcella Amaral Horta; Dornela, Leonardo Lima; Ramos, Plínio Santos; Castellano Filho, Didier Silveira; Ricardo, Djalma Rabelo; Calado, Adriano Almeida; Netto, José Murillo Bastos

    2012-10-01

    The scope of this study was to evaluate the knowledge of obstetricians and obstetric nurses about folic acid in the prevention of neural tube defects (NTD). A cross-sectional study was conducted in which 118 volunteers (95 physicians and 23 nurses) answered a questionnaire with 21 questions about prevention of NTD. The data were analyzed according to the reported knowledge, the recommendations made by the Brazilian Ministry of Health (MOH) and the scientific evidence (SE) available in the literature on the topic. The knowledge based on the SE and recommendations of MOH was different (4.64 ± 0.20 vs. 5.55 ± 0.15, p <0.001, Mean ± SEM). There was no difference between the knowledge of respondents compared to their training, the time spent in prenatal care and between the two classes of professionals evaluated. There were differences between the reported knowledge and that based on SE (6.76 ± 0.18 vs. 4.64 ± 0.15, p <0.001) and based on the MOH recommendations (6.76 ± 0.18 vs. 5.55 ± 0.20, p <0.001). Thus, the conclusion reached was that 94.1% of those evaluated reported knowing the importance of folic acid in preventing NTD, though 64.2% reported that they did not know when to begin administration of the supplement. PMID:23099765

  5. Agenesis of the corpus callosum associated with spinal open neural tube defect

    PubMed Central

    Elgamal, Essam A.; Elwatidy, Sherif M.; Alhabib, Amro F.; Jamjoom, Zain B.; Murshid, Waleed R.; Hassan, Hamdy H.; Salih, Mustafa A.

    2014-01-01

    Objective: To ascertain the incidence and clinical implications of agenesis of the corpus callosum (ACC) in spinal open neural tube defects (SONTD). Methods: All cases of SONTD registered at the Spina Bifida Clinic in King Khalid University Hospital, Riyadh, Saudi Arabia between 1995 and 2010 were retrospectively reviewed, and mid-sagittal MRI of the corpus callosum (CC) area was analyzed in each case. Neurodevelopmental outcome was classified as poor in children with seizures, severe neurodevelopmental impairment, or death. Results: Thirty-eight patients (45.8%) with ACC were identified among 83 cases with SONTD. Patients’ age ranged between one and 16 years. Total ACC was found in 10 patients, partial ACC in 25, and in 3 patients, the CC was hypoplastic. Active hydrocephalus was an associated finding in 9 out of 10 patients with total ACC, 22 out of 25 with partial ACC, and in all patients with hypoplasia of the CC. Thirteen patients (34.2%) had normal intellectual function, whereas 24 patients presented with learning disability, epilepsy, or poor intellectual function; and one patient died of respiratory failure. Conclusion: Agenesis of the corpus callosum is found in a significant portion of patients with SONTD. When associated with hydrocephalus, its presence affects neuro-developmental outcome. PMID:25551114

  6. Orally administered melatonin prevents lipopolysaccharide-induced neural tube defects in mice.

    PubMed

    Fu, Lin; Yu, Zhen; Chen, Yuan-Hua; Xia, Mi-Zhen; Wang, Hua; Zhang, Cheng; Tao, Fang-Biao; Xu, De-Xiang

    2014-01-01

    Lipopolysaccharide (LPS) has been associated with adverse pregnant outcomes, including fetal demise, intra-uterine growth restriction (IUGR), neural tube defects (NTDs) and preterm delivery in rodent animals. Previous studies demonstrated that melatonin protected against LPS-induced fetal demise, IUGR and preterm delivery. The aim of the present study was to investigate the effects of melatonin on LPS-induced NTDs. All pregnant mice except controls were intraperitoneally injected with LPS (25 µg/kg) daily from gestational day (GD)8 to GD12. Some pregnant mice were orally administered with melatonin (MT, 50 mg/kg) before each LPS injection. A five-day LPS injection resulted in 27.5% of fetuses with anencephaly, exencephaly or encephalomeningocele. Additional experiment showed that maternal LPS exposure significantly down-regulated placental proton-coupled folate transporter (pcft) and disturbed folate transport from maternal circulation through the placentas into the fetus. Interestingly, melatonin significantly attenuated LPS-induced down-regulation of placental pcft. Moreover, melatonin markedly improved the transport of folate from maternal circulation through the placentas into the fetus. Correspondingly, orally administered melatonin reduced the incidence of LPS-induced anencephaly, exencephaly or encephalomeningocele. Taken together, these results suggest that orally administered melatonin prevents LPS-induced NTDs through alleviating LPS-induced disturbance of folate transport from maternal circulation through the placenta into the fetus. PMID:25420102

  7. Orally Administered Melatonin Prevents Lipopolysaccharide-Induced Neural Tube Defects in Mice

    PubMed Central

    Chen, Yuan-Hua; Xia, Mi-Zhen; Wang, Hua; Zhang, Cheng; Tao, Fang-Biao; Xu, De-Xiang

    2014-01-01

    Lipopolysaccharide (LPS) has been associated with adverse pregnant outcomes, including fetal demise, intra-uterine growth restriction (IUGR), neural tube defects (NTDs) and preterm delivery in rodent animals. Previous studies demonstrated that melatonin protected against LPS-induced fetal demise, IUGR and preterm delivery. The aim of the present study was to investigate the effects of melatonin on LPS-induced NTDs. All pregnant mice except controls were intraperitoneally injected with LPS (25 µg/kg) daily from gestational day (GD)8 to GD12. Some pregnant mice were orally administered with melatonin (MT, 50 mg/kg) before each LPS injection. A five-day LPS injection resulted in 27.5% of fetuses with anencephaly, exencephaly or encephalomeningocele. Additional experiment showed that maternal LPS exposure significantly down-regulated placental proton-coupled folate transporter (pcft) and disturbed folate transport from maternal circulation through the placentas into the fetus. Interestingly, melatonin significantly attenuated LPS-induced down-regulation of placental pcft. Moreover, melatonin markedly improved the transport of folate from maternal circulation through the placentas into the fetus. Correspondingly, orally administered melatonin reduced the incidence of LPS-induced anencephaly, exencephaly or encephalomeningocele. Taken together, these results suggest that orally administered melatonin prevents LPS-induced NTDs through alleviating LPS-induced disturbance of folate transport from maternal circulation through the placenta into the fetus. PMID:25420102

  8. Association study of PARD3 gene polymorphisms with neural tube defects in a Chinese Han population.

    PubMed

    Gao, Yonghui; Chen, Xiaoli; Shangguan, Shaofang; Bao, Yihua; Lu, Xiaoli; Zou, Jizhen; Guo, Jin; Dai, Yaohua; Zhang, Ting

    2012-07-01

    Partitioning defective 3 homolog (PARD3) is an attractive candidate gene for screening neural tube defect (NTD) risk. To investigate the role of genetic variants in PARD3 on NTD risk, a case-control study was performed in a region of China with a high prevalence of NTDs. Total 53 single-nucleotide polymorphisms (SNPs) in PARD3 were genotyped in 224 fetuses with NTDs and in 253 normal fetuses. We found that 6 SNPs (rs2496720, rs2252655, rs3851068, rs118153230, rs10827337, and rs12218196) were statistically associated with NTDs (P < .05). After stratifying participants by NTD phenotypes, the significant association only existed in cases with anencephaly rather than spina bifida. Further haplotype analysis confirmed the association between PARD3 polymorphisms and NTD risk (global test P = 3.41e-008). Our results suggested that genetic variants in PARD3 were associated with susceptibility to NTDs in a Chinese Han population, and this association was affected by NTD phenotypes. PMID:22447895

  9. Metabonomic profiling of human placentas reveals different metabolic patterns among subtypes of neural tube defects.

    PubMed

    Chi, Yi; Pei, Lijun; Chen, Gong; Song, Xinming; Zhao, Aihua; Chen, Tianlu; Su, Mingming; Zhang, Yinan; Liu, Jianmeng; Ren, Aiguo; Zheng, Xiaoying; Xie, Guoxiang; Jia, Wei

    2014-02-01

    Neural tube defects (NTDs) are one of the most common types of birth defects with a complex etiology. We have previously profiled serum metabolites of pregnant women in Lvliang prefecture, Shanxi Province of China, which revealed distinct metabolic changes in pregnant women with NTDs outcome. Here we present a metabonomics study of human placentas of 144 pregnant women with normal pregnancy outcome and 115 pregnant women affected with NTDs recruited from four rural counties (Pingding, Xiyang, Taigu, and Zezhou) of Shanxi Province, the area with the highest prevalence worldwide. A panel of 19 metabolites related to one-carbon metabolism was also quantitatively determined. We observed obvious differences in global metabolic profiles and one-carbon metabolism among three subtypes of NTDs, anencephaly (Ane), spina bifida (SB), and Ane complicated with SB (Ane & SB) via mass-spectrometry-based metabonomics approach. Disturbed carbohydrate, amino acid, lipid, and nucleic acid metabolism were identified. Placental transport of amino acids might be depressed in Ane and Ane & SB group. Deficiency of choline contributes to Ane and Ane & SB pathogenesis via different metabolic pathways. The formation of NTDs seemed to be weakly related to folates. The metabonomic analysis reveals that the physiological and biochemical processes of the three subtypes of NTDs might be different and the subtype condition should be considered for the future investigation of NTDs. PMID:24397701

  10. Novel VANGL1 Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects

    PubMed Central

    Bartsch, O.; Kirmes, I.; Thiede, A.; Lechno, S.; Gocan, H.; Florian, I.S.; Haaf, T.; Zechner, U.; Sabova, L.; Horn, F.

    2012-01-01

    Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system occurring at an average rate of 1 per 1,000 human pregnancies worldwide. Numerous genetic and environmental factors are discussed to be relevant in their etiology. In mice, mutants in >200 genes including the planar cell polarity (PCP) pathway are known to cause NTDs, and recently, heterozygous mutations in the human VANGL1 gene have been described in a small subset of patients with NTDs. We performed a VANGL1 mutation analysis in 144 unrelated individuals with NTDs from Slovakia, Romania and Germany and identified 3 heterozygous missense mutations: c.613G>A (p.Gly205Arg) with an open spina bifida (lumbosacral meningomyelocele), c.557G>A (p.Arg186His) with a closed spina bifida (tethered cord and spinal lipoma) and c.518G>A (p.Arg173His) with an unknown NTD. The c.613G>A mutation was also found in a healthy sibling. None of the mutations were described previously. Findings support that heterozygous VANGL1 mutations represent hypomorphs or conditional mutants predisposing to NTDs and occur at a frequency of approximately 2.1% of open and closed spinal NTDs. The mutations (p.Arg173His, p.Arg186His, p.Gly205Arg) modified conserved regions of the VANGL1 protein and shared similarities with previously described mutants, providing further evidence for the presence of mutational hot spots in these patients. PMID:23326252

  11. Role of arsenic as a reproductive toxin with particular attention to neural tube defects

    SciTech Connect

    Shalat, S.L.; Walker, D.B.; Finnell, R.H. [Texas A& M Univ., College Station, TX (United States)

    1996-10-01

    Arsenic has been recognized as a human toxicant for over 2000 years. More recently it has been readily accepted as a human carcinogen. Animal research has demonstrated arsenic`s ability to have profound detrimental effects on the developing embryo in avian and mamalian species. This article comprehensively reviews the human and animal literature on the subject of the reproductive toxicity of arsenic. A variety of endpoints are considered, including spontaneous abortion, cardiovascular defects, and arsenic`s role in the causation of neural tube defects (NTDs). A summary of the literature that has examined the various postulated mechanisms by which arsenic may produce NTDs is also considered. In addition, a discussion of literature relative to the presence of arsenic in the general environment and in the workplace presented. This article reaches the conclusion that while further research is clearly needed, particularly on the potential toxicity of organic arsenical compounds, the current literature suggests it may be prudent and appropriate to treat inorganic arsenic as a probable human reproductive toxin. 132 refs.

  12. Drinking water treatment is not associated with an observed increase in neural tube defects in mice.

    PubMed

    Melin, Vanessa E; Johnstone, David W; Etzkorn, Felicia A; Hrubec, Terry C

    2014-06-01

    Disinfection by-products (DBPs) arise when natural organic matter in source water reacts with disinfectants used in the water treatment process. Studies have suggested an association between DBPs and birth defects. Neural tube defects (NTDs) in embryos of untreated control mice were first observed in-house in May 2006 and have continued to date. The source of the NTD-inducing agent was previously determined to be a component of drinking water. Tap water samples from a variety of sources were analyzed for trihalomethanes (THMs) to determine if they were causing the malformations. NTDs were observed in CD-1 mice provided with treated and untreated surface water. Occurrence of NTDs varied by water source and treatment regimens. THMs were detected in tap water derived from surface water but not detected in tap water derived from a groundwater source. THMs were absent in untreated river water and laboratory purified waters, yet the percentage of NTDs in untreated river water were similar to the treated water counterpart. These findings indicate that THMs were not the primary cause of NTDs in the mice since the occurrence of NTDs was unrelated to drinking water disinfection. PMID:24497082

  13. Novel VANGL1 Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects.

    PubMed

    Bartsch, O; Kirmes, I; Thiede, A; Lechno, S; Gocan, H; Florian, I S; Haaf, T; Zechner, U; Sabova, L; Horn, F

    2012-08-01

    Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system occurring at an average rate of 1 per 1,000 human pregnancies worldwide. Numerous genetic and environmental factors are discussed to be relevant in their etiology. In mice, mutants in >200 genes including the planar cell polarity (PCP) pathway are known to cause NTDs, and recently, heterozygous mutations in the human VANGL1 gene have been described in a small subset of patients with NTDs. We performed a VANGL1 mutation analysis in 144 unrelated individuals with NTDs from Slovakia, Romania and Germany and identified 3 heterozygous missense mutations: c.613G>A (p.Gly205Arg) with an open spina bifida (lumbosacral meningomyelocele), c.557G>A (p.Arg186His) with a closed spina bifida (tethered cord and spinal lipoma) and c.518G>A (p.Arg173His) with an unknown NTD. The c.613G>A mutation was also found in a healthy sibling. None of the mutations were described previously. Findings support that heterozygous VANGL1 mutations represent hypomorphs or conditional mutants predisposing to NTDs and occur at a frequency of approximately 2.1% of open and closed spinal NTDs. The mutations (p.Arg173His, p.Arg186His, p.Gly205Arg) modified conserved regions of the VANGL1 protein and shared similarities with previously described mutants, providing further evidence for the presence of mutational hot spots in these patients. PMID:23326252

  14. Metabolic signature of pregnant women with neural tube defects in offspring.

    PubMed

    Zheng, Xiaoying; Su, Mingming; Pei, Lijun; Zhang, Ting; Ma, Xu; Qiu, Yunping; Xia, Hongfei; Wang, Fang; Zheng, Xiaojiao; Gu, Xue; Song, Xinming; Li, Xin; Qi, Xin; Chen, Gong; Bao, Yihua; Chen, Tianlu; Chi, Yi; Zhao, Aihua; Jia, Wei

    2011-10-01

    Neural tube defects (NTDs) are one of the most common types of birth defects, affecting approximately 1 of every 1000 pregnancies in the United States and an estimated 300?000 newborns worldwide each year. The metabolic signature of pregnant women with NTDs in offspring has not previously been characterized. In this paper, we report a profiling study that characterized the serum metabolome of 101 pregnant women affected with NTDs in offspring in comparison with 143 pregnant women with normal pregnancy outcomes in Lvliang prefecture, the area with the highest birth prevalence of NTDs in China. A serum metabonomic study was also conducted to identify significantly altered metabolites associated with di-n-butyl phthalate (DBP)-induced teratogenesis in mice. The metabolic signature of NTD in pregnant women is characterized by the impaired mitochondrial respiration, neurotransmitter ?-aminobutyric acid, and methionine cycle. Of interest, consistent findings from DBP-induced teratogenesis in mice demonstrated increased succinate and decreased fumarate, suggesting an inhibited succinic dehydrogenase implicated in the defective mitochondria. The characteristic disruption of maternal metabolism offers important insights into metabolic mechanisms underlying human NTDs as well as potential preventive strategies. PMID:21902205

  15. Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice

    PubMed Central

    Pai, Yun Jin; Leung, Kit-Yi; Savery, Dawn; Hutchin, Tim; Prunty, Helen; Heales, Simon; Brosnan, Margaret E.; Brosnan, John T.; Copp, Andrew J.; Greene, Nicholas D.E.

    2015-01-01

    Glycine decarboxylase (GLDC) acts in the glycine cleavage system to decarboxylate glycine and transfer a one-carbon unit into folate one-carbon metabolism. GLDC mutations cause a rare recessive disease non-ketotic hyperglycinemia (NKH). Mutations have also been identified in patients with neural tube defects (NTDs); however, the relationship between NKH and NTDs is unclear. We show that reduced expression of Gldc in mice suppresses glycine cleavage system activity and causes two distinct disease phenotypes. Mutant embryos develop partially penetrant NTDs while surviving mice exhibit post-natal features of NKH including glycine accumulation, early lethality and hydrocephalus. In addition to elevated glycine, Gldc disruption also results in abnormal tissue folate profiles, with depletion of one-carbon-carrying folates, as well as growth retardation and reduced cellular proliferation. Formate treatment normalizes the folate profile, restores embryonic growth and prevents NTDs, suggesting that Gldc deficiency causes NTDs through limiting supply of one-carbon units from mitochondrial folate metabolism. PMID:25736695

  16. Kif11 dependent cell cycle progression in radial glial cells is required for proper neurogenesis in the zebrafish neural tube

    PubMed Central

    Johnson, Kimberly; Moriarty, Chelsea; Tania, Nessy; Ortman, Alissa; DiPietrantonio, Kristina; Edens, Brittany; Eisenman, Jean; Ok, Deborah; Krikorian, Sarah; Barragan, Jessica; Gole, Christophe; Barresi, Michael J.F.

    2014-01-01

    Radial glia serve as the resident neural stem cells in the embryonic vertebrate nervous system, and their proliferation must be tightly regulated to generate the correct number of neuronal and glial cell progeny in the neural tube. During a forward genetic screen, we recently identified a zebrafish mutant in the kif11 loci that displayed a significant increase in radial glial cell bodies at the ventricular zone of the spinal cord. Kif11, also known as Eg5, is a kinesin-related, plus-end directed motor protein responsible for stabilizing and separating the bipolar mitotic spindle. We show here that Gfap+ radial glial cells express kif11 in the ventricular zone and floor plate. Loss of Kif11 by mutation or pharmacological inhibition with S-trityl-L-cysteine (STLC) results in monoastral spindle formation in radial glial cells, which is characteristic of mitotic arrest. We show that M-phase radial glia accumulate over time at the ventricular zone in kif11 mutants and STLC treated embryos. Mathematical modeling of the radial glial accumulation in kif11 mutants not only confirmed an ~226x delay in mitotic exit (likely a mitotic arrest), but also predicted two modes of increased cell death. These modeling predictions were supported by an increase in the apoptosis marker, anti-activated Caspase-3, which was also found to be inversely proportional to a decrease in cell proliferation. In addition, treatment with STLC at different stages of neural development uncovered two critical periods that most significantly require Kif11 function for stem cell progression through mitosis. We also show that loss of Kif11 function causes specific reductions in oligodendroglia and secondary interneurons and motorneurons, suggesting these later born populations require proper radial glia division. Despite these alterations to cell cycle dynamics, survival, and neurogenesis, we document unchanged cell densities within the neural tube in kif11 mutants, suggesting that a mechanism of compensatory regulation may exist to maintain overall proportions in the neural tube. We propose a model in which Kif11 normally functions during mitotic spindle formation to facilitate the progression of radial glia through mitosis, which leads to the maturation of progeny into specific secondary neuronal and glial lineages in the developing neural tube. PMID:24370453

  17. Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?

    PubMed Central

    2014-01-01

    Background Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is not understood. In addition, many cases remain resistant to the beneficial effects of folic acid supplementation. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation. Results We examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apob tm1Unc and Vangl2 Lp mice, hereafter referred to as Apob and Lp respectively. The FA supplemented diet did not reduce the incidence or severity of NTDs in Apob or Lp mutant homozygotes or the loop-tail phenotype in Lp mutant heterozygotes, suggesting that mice with these mutant alleles are resistant to FA supplementation. Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles. Conclusion Similar genotypic biases have been reported for several NTD models, but were interpreted as diet-induced increases in the incidence and severity of NTDs that led to increased embryonic lethality. Absence of differences in resorption rates and litter sizes argue against induced embryonic lethality. We suggest an alternative interpretation, namely that FA supplementation led to strongly skewed allelic inheritance, perhaps from disturbances in polyamine metabolism that biases fertilization in favor of wild-type gametes. PMID:25154628

  18. Lamin b1 polymorphism influences morphology of the nuclear envelope, cell cycle progression, and risk of neural tube defects in mice.

    PubMed

    De Castro, Sandra C P; Malhas, Ashraf; Leung, Kit-Yi; Gustavsson, Peter; Vaux, David J; Copp, Andrew J; Greene, Nicholas D E

    2012-01-01

    Neural tube defects (NTDs), including spina bifida and anencephaly, are common birth defects whose complex multigenic causation has hampered efforts to delineate their molecular basis. The effect of putative modifier genes in determining NTD susceptibility may be investigated in mouse models, particularly those that display partial penetrance such as curly tail, a strain in which NTDs result from a hypomorphic allele of the grainyhead-like-3 gene. Through proteomic analysis, we found that the curly tail genetic background harbours a polymorphic variant of lamin B1, lacking one of a series of nine glutamic acid residues. Lamins are intermediate filament proteins of the nuclear lamina with multiple functions that influence nuclear structure, cell cycle properties, and transcriptional regulation. Fluorescence loss in photobleaching showed that the variant lamin B1 exhibited reduced stability in the nuclear lamina. Genetic analysis demonstrated that the variant also affects neural tube closure: the frequency of spina bifida and anencephaly was reduced three-fold when wild-type lamin B1 was bred into the curly tail strain background. Cultured fibroblasts expressing variant lamin B1 show significantly increased nuclear dysmorphology and diminished proliferative capacity, as well as premature senescence, associated with reduced expression of cyclins and Smc2, and increased expression of p16. The cellular basis of spinal NTDs in curly tail embryos involves a proliferation defect localised to the hindgut epithelium, and S-phase progression was diminished in the hindgut of embryos expressing variant lamin B1. These observations indicate a mechanistic link between altered lamin B1 function, exacerbation of the Grhl3-mediated cell proliferation defect, and enhanced susceptibility to NTDs. We conclude that lamin B1 is a modifier gene of major effect for NTDs resulting from loss of Grhl3 function, a role that is likely mediated via the key function of lamin B1 in maintaining integrity of the nuclear envelope and ensuring normal cell cycle progression. PMID:23166514

  19. Variation in the response of chick embryos to incision of the roof plate of the neural tube at different developmental stages.

    PubMed Central

    Clark, B J; Scothorne, R J

    1990-01-01

    The effects of microsurgical reopening of the neural tube were examined in chick embryos of Stages 12-18. The roof plate of the thoracic neural tube was incised for a length equivalent to 7 somites. The site of incision was studied histologically and by SEM and TEM at intervals up to 48 hours. 48 hours after operation, persistent neural tube defects were more frequent and longer in embryos of more advanced stages at operation. Exposure of embryos to Streptomyces hyaluronidase, which inhibits neurulation in normal embryos, has no effect on the healing of the incised neural tube in the young embryos. Healing of the lesion in younger embryos appeared to occur in two stages: initially, by repair of the surface ectoderm, by a cephalo-caudal zipper-like mechanism, followed by a reconstitution of the roof plate by migration of neurectodermal cells on the deep surface of the ectoderm. Neural tubes of older embryos splay open more widely on incision of the roof plate, apparently making healing mechanically more difficult. This wider splaying may be related to the decline of forces which maintain occlusion of the neural canal in younger embryos. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 Fig. 16 PMID:2323991

  20. Field emission characteristics of carbon nano tubes under varying background pressure conditions

    Microsoft Academic Search

    Shaomao Li; Hulya Kirkici

    2009-01-01

    In general, for plasma switches, the initiation of the plasma is critical and this is usually achieved by a ¿trigger¿ scheme. The seed electrons needed to initiate a breakdown can be generated by several means such as thermionic, field or optical emission. While the thermionic emission has been used mainly in vacuum tubes and is a mature technology, field emission

  1. Maternal exposure to arsenic, cadmium, lead, and mercury and neural tube defects in offspring.

    PubMed

    Brender, Jean D; Suarez, Lucina; Felkner, Marilyn; Gilani, Zunera; Stinchcomb, David; Moody, Karen; Henry, Judy; Hendricks, Katherine

    2006-05-01

    Arsenic, cadmium, lead, and mercury are neurotoxins, and some studies suggest that these elements might also be teratogens. Using a case-control study design, we investigated the relation between exposure to these heavy metals and neural tube defects (NTDs) in offspring of Mexican-American women living in 1 of the 14 Texas counties bordering Mexico. A total of 184 case-women with NTD-affected pregnancies and 225 control-women with normal live births were interviewed about their environmental and occupational exposures during the periconceptional period. Biologic samples for blood lead and urinary arsenic, cadmium, and mercury were also obtained for a subset of these women. Overall, the median levels of these biomarkers for heavy metal exposure did not differ significantly (P > 0.05) between case- and control-women. However, among women in the highest income group, case-women were nine times more likely (95% confidence interval (CI) 1.4-57) than control-women to have a urinary mercury 5.62 microg/L. Case-women were 4.2 times more likely (95% CI 1.1-16) to report burning treated wood during the periconceptional period than control-women. Elevated odds ratios (ORs) were observed for maternal and paternal occupational exposures to arsenic and mercury, but the 95% CIs were consistent with unity. The 95% CIs of the ORs were also consistent with unity for higher levels of arsenic, cadmium, lead, and mercury in drinking water and among women who lived within 2 miles at the time of conception to industrial facilities with reported emissions of any of these heavy metals. Our findings suggest that maternal exposures to arsenic, cadmium, or lead are probably not significant risk factors for NTDs in offspring. However, the elevated urinary mercury levels found in this population and exposures to the combustion of treated wood may warrant further investigation. PMID:16171797

  2. Markers of macromolecular oxidative damage in maternal serum and risk of neural tube defects in offspring.

    PubMed

    Yuan, Yue; Zhang, Le; Jin, Lei; Liu, Jufen; Li, Zhiwen; Wang, Linlin; Ren, Aiguo

    2015-03-01

    Neural tube defects (NTDs) are among the most common and severe congenital malformations. To examine the association between markers of macromolecular oxidative damage and risk of NTDs, we measured levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), protein carbonyl (PC), and 8-iso-prostaglandin F2? (8-iso-PGF2?) in maternal serum samples of 117 women with NTD-affected pregnancies and 121 women with healthy term newborns. We found higher levels of 8-OHdG and PC in the NTD group than in the control group; however, we did not observe a statistically significant difference in 8-iso-PGF2? levels between the NTD and the control groups. NTD risk increased with increasing quartiles of 8-OHdG [odds ratio (OR)=1.17; 95% confidence interval (CI) 0.39-3.51; OR=2.19; 95% CI, 0.68-7.01; OR=3.70; 95% CI, 1.30-10.51, for the second, third, and fourth quartile relative to the lowest quartile, respectively; P=0.009], and with increasing quartiles of PC (OR=2.26; 95% CI, 0.66-7.69; OR=3.86; 95% CI, 1.17-12.80; OR=5.98; 95% CI, 1.82-19.66, for the second, third, and fourth quartile relative to the lowest quartile, respectively; P=0.002]. Serum levels of 8-OHdG were higher in women who did not take folic acid supplements during the periconceptional period. These results suggest that oxidative stress is present in women carrying pregnancies affected by NTDs. PMID:25542138

  3. Absence of linkage between familial neural tube defects and PAX3 gene.

    PubMed

    Chatkupt, S; Hol, F A; Shugart, Y Y; Geurds, M P; Stenroos, E S; Koenigsberger, M R; Hamel, B C; Johnson, W G; Mariman, E C

    1995-03-01

    Neural tube defects (NTD) are among the most common and disabling birth defects. The aetiology of NTD is unknown and their genetics are complex. The majority of NTD cases are sporadic, isolated, nonsyndromic, and generally considered to be multifactorial in origin. Recently, PAX3 (formerly HuP2, the human homologue of mouse Pax-3), on chromosome 2q35-37, was suggested as a candidate gene for NTD because mutations of Pax-3 cause the mouse mutant Splotch (Sp), an animal model for human NTD. Mutations in PAX3 were also identified in patients with Waardenburg syndrome type 1 (WS1). At least eight patients with both WS1 and NTD have been described suggesting pleiotropy or a contiguous gene syndrome. Seventeen US families and 14 Dutch families with more than one affected person with NTD were collected and 194 people (50 affected) from both data sets were genotyped using the PAX3 polymorphic marker. The data were analysed using affecteds only linkage analysis. The lod scores were -7.30 (US), -3.74 (Dutch), and -11.04 (combined) at theta = 0.0, under the assumption of the autosomal dominant model. For the recessive model, the lod scores were -3.30 (US), -1.46 (Dutch), and -4.76 (combined) at theta = 0.0. Linkage between PAX3 and familial NTD was excluded to 9.9 cM on either side of the gene for the dominant model and to 3.63 cM on either side of the gene for the recessive model in the families studied. No evidence of heterogeneity was detected using the HOMOG program. Our data indicate that PAX3 is not a major gene for NTD. PMID:7783169

  4. Higher diet quality reduces risks of neural tube defects and orofacial clefts

    PubMed Central

    Carmichael, SL; Yang, W; Feldkamp, ML; Munger, RG; Siega-Riz, AM; Botto, LD; Shaw, GM

    2014-01-01

    Objective To examine whether better maternal diet quality was associated with reduced risk for selected birth defects. Design A multi-center, population-based case-control study, the National Birth Defects Prevention Study. Setting Ten participating centers in the United States. Patients/Participants Eligible subjects’ estimated due dates were from October, 1997 through December, 2005. Telephone interviews were conducted with 72% of case and 67% of control mothers. Analyses included 936 cases with neural tube defects (NTDs), 2,475 with orofacial clefts, and 6,147 non-malformed controls. Main exposures Food-frequency data were used to calculate the Mediterranean Diet Score (MDS) and Diet Quality Index (DQI), modeled after existing indices. Main outcome measures Adjusted odds ratios. Results After covariate adjustment, increasing diet quality based on either index was associated with reduced risks for the birth defects studied. The strongest association was between anencephaly and DQI; the odds ratio (OR) for highest versus lowest quartile was 0.49 (95% CI 0.31, 0.75). ORs for cleft lip+/?cleft palate and cleft palate and DQI were also notable, with ORs = 0.66 (0.54, 0.81) and 0.74 (0.56, 0.96), respectively. Conclusions Healthier maternal dietary patterns, as measured by diet quality scores, were associated with reduced risks of NTDs and clefts. These results suggest that dietary approaches could lead to further reduction in risks of major birth defects and complement existing efforts to fortify foods and encourage periconceptional multivitamin use. PMID:21969361

  5. Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects

    PubMed Central

    Ren, Aiguo; Qiu, Xinghua; Jin, Lei; Ma, Jin; Li, Zhiwen; Zhang, Le; Zhu, Huiping; Finnell, Richard H.; Zhu, Tong

    2011-01-01

    Persistent organic pollutants (POPs) have been associated with a wide range of adverse health effects. Our case–control study was performed to explore the association between placental levels of selected POPs and risks for neural tube defects (NTDs) in a Chinese population with a high prevalence of NTDs. Cases included 80 fetuses or newborns with NTDs, whereas the controls were 50 healthy, nonmalformed newborn infants. Placental concentrations of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers were analyzed by gas chromatography–mass spectrometry. The medians of PAHs, o,p?-isomers of dichlorodiphenyltrichloroethane (DDT) and metabolites, ?- and ?-hexachlorocyclohexane (HCH), and ?-endosulfan were significantly higher in case placentas than in controls. PAH concentrations above the median were associated with a 4.52-fold [95% confidence interval (CI), 2.10–9.74) increased risk for any NTDs, and 5.84- (95% CI, 2.28–14.96) and 3.71-fold (95% CI, 1.57–8.79) increased risks for anencephaly and spina bifida, respectively. A dose–response relationship was observed between PAH levels and the risk of NTDs, with odds ratios for the second, third, and fourth quartiles, compared with the first, of 1.77- (95% CI, 0.66–4.76), 3.83- (95% CI, 1.37–10.75), and 11.67-fold (95% CI, 3.28–41.49), respectively. A dose–response relationship was observed for anencephaly and spina bifida subtypes. Similar results were observed for o,p?-DDT and metabolites, ?-HCH, ?-HCH, and ?-endosulfan, whereas no dose–response relationship was observed for the last two pollutants. Elevated placental concentrations of PAHs, o,p?-DDT and metabolites, and ?-HCH were associated with increased risks of NTDs in this population. PMID:21768370

  6. Quantitative assessment of maternal biomarkers related to one-carbon metabolism and neural tube defects.

    PubMed

    Tang, Ke-Fu; Li, Yao-Long; Wang, Hong-Yan

    2015-01-01

    Periconceptional supplementation with folic acid reduces the occurrence of neural tube defects (NTDs). The association between maternal abnormalities in homocysteine metabolism (e.g., hyperhomocysteinaemia, folate deficiency and low vitamin B12) and the risk of NTDs-affected pregnancies has been widely evaluated in recent years, although the results are conflicting. To investigate this inconsistency, we performed a meta-analysis of 32 studies, involving 1,890 NTD-affected mothers and 3,995 control mothers, to develop an understanding of the relationship between maternal biomarkers related to one-carbon metabolism and NTD. A random-effects model was used to calculate the ratio of means (RoM) between the cases and controls, along with the 95% confidence intervals (CIs). A significant increase in homocysteine levels was observed in NTD-affected mothers compared with controls (RoM: 1.16, 95% CI: 1.09-1.23, P = 1.8 × 10(-6)). The pooled analysis also revealed that NTD-affected mothers had significantly lower levels of folate (RoM: 0.93, 95% CI: 0.88-0.97, P = 0.002), vitamin B12 (RoM: 0.91, 95% CI: 0.87-0.95, P = 3.6 × 10(-5)) and red blood cell folate (RoM: 0.92, 95% CI: 0.86-0.98, P = 0.01). Therefore, altered plasma levels of biomarkers related to one-carbon metabolism are associated with NTD-affected pregnancies. PMID:25728980

  7. Maternal dietary patterns are associated with risk of neural tube and congenital heart defects.

    PubMed

    Sotres-Alvarez, Daniela; Siega-Riz, Anna Maria; Herring, Amy H; Carmichael, Suzan L; Feldkamp, Marcia L; Hobbs, Charlotte A; Olshan, Andrew F

    2013-06-01

    Studying empirically derived dietary patterns is useful in understanding dietary practice. We classified women by their dietary patterns using latent class analysis of 66 foods and studied the association of these patterns with neural tube defects (NTDs) and congenital heart defects (CHDs) in the U.S. National Birth Defects Prevention Study (1997-2005). Logistic regression models used data from 1,047 with an NTD, 6,641 with a CHD, and 6,123 controls that were adjusted for maternal characteristics and tested the effect modification of multivitamin supplement use. Four latent dietary patterns were identified: prudent, Western, low-calorie Western, and Mexican. Among participants who did not use supplements, those in the Mexican, Western, and low-calorie Western classes were significantly more likely (odds ratios of 1.6, 1.5, and 1.4, respectively) to have offspring born with NTDs than were those in the prudent class after adjustment of for dietary folic acid intake. In contrast, among supplement users, there was no difference in the incidence of NTDs between classes. Associations between dietary class and CHD subgroups were not modified by supplement use except for tetralogy of Fallot; among supplement users, those in the Western class were twice as likely (95% confidence interval: 1.4, 2.8) as the prudent class to have offspring with tetralogy of Fallot. Women who adhered to a Western diet were 1.2 (95% confidence interval: 1.03, 1.35) times more likely to have an infant with septal heart defect than were women who adhered to a prudent diet. A prudent dietary pattern, even with folate fortification, may decrease the risk of NTDs and some heart defects. PMID:23639938

  8. Wheat flour fortification with folic acid: changes in neural tube defects rates in Chile.

    PubMed

    Cortés, Fanny; Mellado, C; Pardo, R A; Villarroel, L A; Hertrampf, E

    2012-08-01

    In January 2000, Chilean Ministry of Health mandated the addition of folic acid (FA) to wheat flour in order to reduce the risk of neural tube defects (NTDs). This policy resulted in significant increases in serum and red cell folate in women of fertile age 1 year after fortification. To evaluate the effect of wheat flour fortification on the prevalence of NTDs in Chile we designed a prospective hospital-based surveillance program to monitor the frequency of NTDs in all births (live and stillbirths) with birth weight?500?g at the nine public maternity hospitals of Santiago, Chile from 1999 to 2009. During the pre-fortification period (1999-2000) the NTD rate was 17.1/10,000 births in a total of 120,566 newborns. During the post-fortification period (2001-2009) the NTD rate decreased to 8.6/10,000 births in a total of 489,915 newborns, which translates into a rate reduction of 50% (RR: 0.5; 95% CI: 0.42-0.59) for all NTDs. The rate reduction by type of NTD studied was: 50% in anencephaly (RR: 0.5; 95% CI: 0.38-0.67), 42% in cephalocele (RR: 0.58; 95% CI: 0.37-0.89), and 52% in spina bifida (RR: 0.48; 95% CI: 0.38-0.6). Rates showed significant reduction both in stillbirths and live births: 510.3 to 183.6/10,000 (RR=0.36; 95% CI: 0.25-0.53) and 13.3 to 7.5/10,000 (RR=0.56; 95% CI: 0.47-0.68), respectively. In Chile, fortification of wheat flour with FA has proven to be an effective strategy for the primary prevention of NTDs. PMID:22711368

  9. Placental concentrations of manganese and the risk of fetal neural tube defects.

    PubMed

    Liu, Jufen; Jin, Lei; Zhang, Le; Li, Zhiwen; Wang, Linlin; Ye, Rongwei; Zhang, Yali; Ren, Aiguo

    2013-10-01

    Manganese (Mn) is an essential trace element required for normal growth, development, and cellular homeostasis, but excess Mn is toxic to the central nervous system. The present pilot study examined whether the level of Mn in the placenta was associated with the risk of fetal neural tube defects (NTDs). A case-control study was conducted. Cases were 80 fetuses or newborns with NTDs, and controls were 50 healthy, nonmalformed newborns. Placental Mn, zinc, copper, iron, and selenium were determined with inductively coupled plasma-mass spectrometry. The median Mn concentration was significantly higher in case placentas than in controls: cases, 131.60 ng/g (95% confidence interval [CI], 99.25-166.76); controls, 101.54 ng/g (95% CI, 80.14-119.79). Mn concentrations above the median were associated with a 4-fold (95% CI, 1.23-14.79) increased risk for any NTDs and a 7-fold (95% CI, 1.52-39.64) increased risk for spina bifida after other confounding factors were controlled. Elevated Mn levels were associated with an increased risk of anencephaly, although the adjusted odds ratio did not reach statistical significance. The association between higher Mn concentrations and risk of NTDs showed a clear dose-response relationship. Risk of NTDs increased to 1.51 (95% CI, 0.65-3.52) and 5.03 (95% CI, 1.89-13.33) for those whose placental Mn level was in the second and third tertiles, respectively, compared with the lowest tertile. Elevated placental concentrations of Mn may be associated with increased risks of NTDs in this population. PMID:23664920

  10. SELDI-TOF-MS Proteomic Profiling of Serum, Urine, and Amniotic Fluid in Neural Tube Defects

    PubMed Central

    Liu, Zhenjiang; Yuan, Zhengwei; Zhao, Qun

    2014-01-01

    Neural tube defects (NTDs) are common birth defects, whose specific biomarkers are needed. The purpose of this pilot study is to determine whether protein profiling in NTD-mothers differ from normal controls using SELDI-TOF-MS. ProteinChip Biomarker System was used to evaluate 82 maternal serum samples, 78 urine samples and 76 amniotic fluid samples. The validity of classification tree was then challenged with a blind test set including another 20 NTD-mothers and 18 controls in serum samples, and another 19 NTD-mothers and 17 controls in urine samples, and another 20 NTD-mothers and 17 controls in amniotic fluid samples. Eight proteins detected in serum samples were up-regulated and four proteins were down-regulated in the NTD group. Four proteins detected in urine samples were up-regulated and one protein was down-regulated in the NTD group. Six proteins detected in amniotic fluid samples were up-regulated and one protein was down-regulated in the NTD group. The classification tree for serum samples separated NTDs from healthy individuals, achieving a sensitivity of 91% and a specificity of 97% in the training set, and achieving a sensitivity of 90% and a specificity of 97% and a positive predictive value of 95% in the test set. The classification tree for urine samples separated NTDs from controls, achieving a sensitivity of 95% and a specificity of 94% in the training set, and achieving a sensitivity of 89% and a specificity of 82% and a positive predictive value of 85% in the test set. The classification tree for amniotic fluid samples separated NTDs from controls, achieving a sensitivity of 93% and a specificity of 89% in the training set, and achieving a sensitivity of 90% and a specificity of 88% and a positive predictive value of 90% in the test set. These suggest that SELDI-TOF-MS is an additional method for NTDs pregnancies detection. PMID:25054433

  11. Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects.

    PubMed

    Ren, Aiguo; Qiu, Xinghua; Jin, Lei; Ma, Jin; Li, Zhiwen; Zhang, Le; Zhu, Huiping; Finnell, Richard H; Zhu, Tong

    2011-08-01

    Persistent organic pollutants (POPs) have been associated with a wide range of adverse health effects. Our case-control study was performed to explore the association between placental levels of selected POPs and risks for neural tube defects (NTDs) in a Chinese population with a high prevalence of NTDs. Cases included 80 fetuses or newborns with NTDs, whereas the controls were 50 healthy, nonmalformed newborn infants. Placental concentrations of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers were analyzed by gas chromatography-mass spectrometry. The medians of PAHs, o,p'-isomers of dichlorodiphenyltrichloroethane (DDT) and metabolites, ?- and ?-hexachlorocyclohexane (HCH), and ?-endosulfan were significantly higher in case placentas than in controls. PAH concentrations above the median were associated with a 4.52-fold [95% confidence interval (CI), 2.10-9.74) increased risk for any NTDs, and 5.84- (95% CI, 2.28-14.96) and 3.71-fold (95% CI, 1.57-8.79) increased risks for anencephaly and spina bifida, respectively. A dose-response relationship was observed between PAH levels and the risk of NTDs, with odds ratios for the second, third, and fourth quartiles, compared with the first, of 1.77- (95% CI, 0.66-4.76), 3.83- (95% CI, 1.37-10.75), and 11.67-fold (95% CI, 3.28-41.49), respectively. A dose-response relationship was observed for anencephaly and spina bifida subtypes. Similar results were observed for o,p'-DDT and metabolites, ?-HCH, ?-HCH, and ?-endosulfan, whereas no dose-response relationship was observed for the last two pollutants. Elevated placental concentrations of PAHs, o,p'-DDT and metabolites, and ?-HCH were associated with increased risks of NTDs in this population. PMID:21768370

  12. Epidemiologic and genetic aspects of spina bifida and other neural tube defects.

    PubMed

    Au, Kit Sing; Ashley-Koch, Allison; Northrup, Hope

    2010-01-01

    The worldwide incidence of neural tube defects (NTDs) ranges from 1.0 to 10.0 per 1,000 births with almost equal frequencies between two major categories: anencephaly and spina bifida (SB). Epidemiological studies have provided valuable insight for (a) researchers to identify nongenetic and genetic factors contributing to etiology, (b) public health officials to design and implement policies to prevent NTD pregnancies, and (c) individuals to take precautions to reduce the chance of having an NTD-affected pregnancy. Despite extensive research, our knowledge of the genetic etiology of human NTDs is limited. Although more than 200 small animal models with NTDs exist, most of these models do not replicate the human disease phenotype. Over a hundred candidate genes have been examined for risk association to human SB. The candidate genes studied include those important in folic acid metabolism, glucose metabolism, retinoid metabolism, and apoptosis. Many genes that regulate transcription in early embryogenesis and maintain planar cell polarity have also been tested as candidates. Additionally, genes identified through mouse models of NTDs have been explored as candidates. We do not know how many genes in the human genome may confer risk for NTDs in human. Less than 20% of the studied candidate genes have been determined to confer even a minor effect on risk association. Many studies have provided conflicting conclusions due to limitations in study design that potentially affect the power of statistical analysis. Future directions such as genomewide association studies (GWAS) and whole exome or even whole genome sequencing are discussed as possible avenues to identify genes that affect risk for human NTDs. PMID:20419766

  13. MTHFD1 polymorphism as maternal risk for neural tube defects: a meta-analysis.

    PubMed

    Zheng, Jinyu; Lu, Xiaocheng; Liu, Hao; Zhao, Penglai; Li, Kai; Li, Lixin

    2015-04-01

    Recently, the association between methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) G1958A polymorphism and neural tube defects (NTD) susceptibility has been widely investigated; however, the results remained inconclusive. Hence, we conducted a meta-analysis to evaluate the effect of MTHFD1 G1958A polymorphism on NTD. The relative literatures were identified by search of the electronic databases PubMed, MEDLINE, and EMBASE. The extracted data were statistically analyzed, and pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to estimate the association strength using Stata version 11.0 software. Finally, ten studies met our inclusion criteria, including 2,132/4,082 in NTD infants and controls; 1,402/3,136 in mothers with NTD offspring and controls; and 993/2,879 in fathers with NTD offspring and controls. This meta-analysis showed that, compared with the mothers with GG genotype, the women with AA genotype had an increased risk of NTD in their offspring, with OR values and 95 % CI at 1.39 (1.16-1.68), p < 0.001. Interestingly, fathers with AG genotype had a significant decreased risk of NTD offspring (OR = 0.79, 95 % CI = 0.66-0.94, p = 0.009). However, there was no significant association between the MTHFD1 G1958A polymorphism in NTD patients and the risk of NTD. In conclusion, the present meta-analysis provided evidence of the association between maternal MTHFD1 G1958A polymorphism and NTD susceptibility. PMID:25502174

  14. VANGL1 rare variants associated with neural tube defects affect convergent extension in zebrafish

    PubMed Central

    Reynolds, Annie; McDearmid, Jonathan R.; Lachance, Stephanie; De Marco, Patrizia; Merello, Elisa; Capra, Valeria; Gros, Philippe; Drapeau, Pierre; Kibar, Zoha

    2010-01-01

    In humans, rare non-synonymous variants in the planar cell polarity gene VANGL1 are associated with neural tube defects (NTDs). These variants were hypothesized to be pathogenic based mainly on genetic studies in a large cohort of NTD patients. In this study, we validate the potential pathogenic effect of these mutations in vivo by investigating their effect on convergent extension in zebrafish. Knocking down the expression of tri, the ortholog of Vangl2, using an antisense morpholino (MO), as shown previously, led to a defective convergent extension (CE) manifested by a shortened body axis and widened somites. Co-injection of the human VANGL1 with the tri-MO was able to partially rescue the tri-MO induced phenotype in zebrafish. In contrast, co-injection of two human VANGL1 variants, p.Val239Ile and p.Met328Thr, failed to rescue this phenotype. We next carried out overexpression studies where we measured the ability of the human VANGL1 alleles to induce a CE phenotype when injected at high doses in zebrafish embryos. While overexpressing the wild-type allele led to a severely defective CE, overexpression of either p.Val239Ile or p.Met328Thr variant failed to do so. Results from both tri-MO knockdown/rescue results and overexpression assays suggest that these two variants most likely represent “loss-of-function” alleles that affect protein function during embryonic development. Our study demonstrates a high degree of functional conservation of VANGL genes across evolution and provides a model system for studying potential variants identified in human NTDs. PMID:20043994

  15. Epidemiologic and genetic aspects of spina bifida and other neural tube defects

    PubMed Central

    Au, Kit Sing; Ashley-Koch, Allison; Northrup, Hope

    2011-01-01

    The worldwide incidence of neural tube defects (NTDs) ranges from 1.0 to 10.0 per 1,000 births with almost equal frequencies between two major categories: anencephaly and spina bifida (SB). Epidemiological studies have provided valuable insight for (a) researchers to identify nongenetic and genetic factors contributing to etiology, (b) public health officials to design and implement policies to prevent NTD pregnancies, and (c) individuals to take precautions to reduce the chance of having an NTD-affected pregnancy. Despite extensive research, our knowledge of the genetic etiology of human NTDs is limited. Although more than 200 small animal models with NTDs exist, most of these models do not replicate the human disease phenotype. Over a hundred candidate genes have been examined for risk association to human SB. The candidate genes studied include those important in folic acid metabolism, glucose metabolism, retinoid metabolism, and apoptosis. Many genes that regulate transcription in early embryogenesis and maintain planar cell polarity have also been tested as candidates. Additionally, genes identified through mouse models of NTDs have been explored as candidates. We do not know how many genes in the human genome may confer risk for NTDs in human. Less than 20% of the studied candidate genes have been determined to confer even a minor effect on risk association. Many studies have provided conflicting conclusions due to limitations in study design that potentially affect the power of statistical analysis. Future directions such as genomewide association studies (GWAS) and whole exome or even whole genome sequencing are discussed as possible avenues to identify genes that affect risk for human NTDs. PMID:20419766

  16. Maternal Dietary Patterns are Associated With Risk of Neural Tube and Congenital Heart Defects

    PubMed Central

    Sotres-Alvarez, Daniela; Siega-Riz, Anna Maria; Herring, Amy H.; Carmichael, Suzan L.; Feldkamp, Marcia L.; Hobbs, Charlotte A.; Olshan, Andrew F.

    2013-01-01

    Studying empirically derived dietary patterns is useful in understanding dietary practice. We classified women by their dietary patterns using latent class analysis of 66 foods and studied the association of these patterns with neural tube defects (NTDs) and congenital heart defects (CHDs) in the US National Birth Defects Prevention Study (1997–2005). Logistic regression models used data from 1,047 with an NTD, 6,641 with a CHD, and 6,123 controls that were adjusted for maternal characteristics and tested the effect modification of multivitamin supplement use. Four latent dietary patterns were identified: prudent, Western, low-calorie Western, and Mexican. Among participants who did not use supplements, those in the Mexican, Western, and low-calorie Western classes were significantly more likely (odds ratios of 1.6, 1.5, and 1.4, respectively) to have offspring born with NTDs than were those in the prudent class after adjustment of for dietary folic acid intake. In contrast, among supplement users, there was no difference in the incidence of NTDs between classes. Associations between dietary class and CHD subgroups were not modified by supplement use except for tetralogy of Fallot; among supplement users, those in the Western class were twice as likely (95% confidence interval: 1.4, 2.8) as the prudent class to have offspring with tetralogy of Fallot. Women who adhered to a Western diet were 1.2 (95% confidence interval: 1.03, 1.35) times more likely to have an infant with septal heart defect than were women who adhered to a prudent diet. A prudent dietary pattern, even with folate fortification, may decrease the risk of NTDs and some heart defects. PMID:23639938

  17. Neural tube defects in Latin America and the impact of fortification: a literature review

    PubMed Central

    Rosenthal, Jorge; Casas, Jessica; Taren, Douglas; Alverson, Clinton J; Flores, Alina; Frias, Jaime

    2015-01-01

    Objective Data on the prevalence of birth defects and neural tube defects (NTD) in Latin America are limited. The present review summarizes NTD prevalence and time trends in Latin American countries and compares pre- and post-fortification periods to assess the impact of folic acid fortification in these countries. Design We carried out a literature review of studies and institutional reports published between 1990 and 2010 that contained information on NTD prevalence in Latin America. Results NTD prevalence in Latin American countries varied from 0.2 to 9.6 per 1000 live births and was influenced by methods of ascertainment. Time trends from Bogota, Costa Rica, Dominican Republic, Guatemala City, México and Puerto Rico showed average annual declines of 2.5% to 21.8%. Pre- and post-fortification comparisons were available for Argentina, Brazil, Chile, Costa Rica, Puerto Rico and México. The aggregate percentage decline in NTD prevalence ranged from 33% to 59%. Conclusions The present publication is the first to review data on time trends and the impact of folic acid fortification on NTD prevalence in Latin America. Reported NTD prevalence varied markedly by geographic region and in some areas of Latin America was among the lowest in the world, while in other areas it was among the highest. For countries with available information, time trends showed significant declines in NTD prevalence and these declines were greater in countries where folic acid fortification of staples reached the majority of the population at risk, such as Chile and Costa Rica. PMID:23464652

  18. Genetic susceptibility to neural tube defect pregnancy varies with offspring phenotype.

    PubMed

    Relton, C L; Wilding, C S; Jonas, P A; Lynch, S A; Tawn, E J; Burn, J

    2003-11-01

    Neural tube defects (NTDs) have a well-established genetic basis, although no single genetic factor has been identified as a major risk factor in NTD susceptibility. A large number of association studies have been conducted to investigate the possibility that NTD susceptibility is linked to polymorphic variation in genes involved in early embryonic development or in the absorption or metabolism of folate, a nutrient that has been clearly associated with a reduction in the risk of NTD pregnancy. A study of three candidate gene polymorphisms at loci implicated in folate absorption and metabolism has been conducted on a population of 211 mothers of a heterogeneous mix of NTD phenotypes: 59% spina bifida aperta (SBA), 20.3% spina bifida occulta (SBO), 17% anencephaly, and 3.7% other NTD. Allele and genotype frequencies were stratified according to offspring NTD phenotype, and variation in the level of NTD risk was associated with different phenotypes. All the three variants (MTHFR 677C > T, GCPII 1561C > T, and RFC-1 80G > A) were shown to significantly influence the risk of anencephalic pregnancy. In addition, the MTHFR 677C > T variant conferred a modest protective effect in SBO mothers and the total NTD mother group, but not in SBA mothers. The RFC-1 80G > A variant elevated the risk of SBO and anencephalic pregnancy. The findings of this study suggest that NTD phenotypic heterogeneity may help explain the mixed findings of previous association studies and that different polymorphisms may hold differing degrees of significance for the various NTD phenotypes. PMID:14616766

  19. A study on the possible involvement of the PAX3 gene in human neural tube defects

    SciTech Connect

    Hol, F.A.; Hamel, B.C.J.; Geurds, M.P.A. [University Hospital Nijmegen (Netherlands)] [and others

    1994-09-01

    Neural tube defects (NTD) are congenital malformations of the central nervous system which are generally attributed to a combination of environmental and genetic factors. Recently, the molecular defect responsible for the phenotype of the Splotch mouse, a monogenic model system for NTD, was determined. A mutation disrupts the homeodomain of the gene for Pax3. In humans, mutations in the cognate gene for PAX3 can cause Waardenburg syndrome (WS), which is associated with NTD. Based on these findings, PAX3 can be regarded as a candidate gene for human NTD. To test this hypothesis we have screened the DNA of 39 familial and 70 sporadic NTD patients for mutations in the coding exons and flanking intron sequences of the PAX3 gene. SSC analysis revealed abnormal bands in exon 2, exon 5, exon 6 and exon 7 in different patients. A missense mutation was identified in exon 6 downstream from the homeodomain in several patients resulting in an amino acid substitution (Thr315Lys) in the protein. However, the same substitution was detected in unaffected controls suggesting no biological significance. Above shifts most likely represent polymorphisms that are irrelevant for NTD. A conspicuous SSC-band shift was observed in exon 5 of one familial patient with spina bifida. Sequencing revealed that the patient was heterozygous for a 5 bp deletion upstream of the homeodomain. The deletion causes a frameshift, which leads to premature termination of translation. Mild characteristics of WS were detected in several members of the family including the index patient. DNA analysis showed co-segregation of the mutation with these symptoms. Although PAX3 mutations can increase the penetrance of NTD in families with WS, our results show that their presence is not sufficient to cause NTD.

  20. VANGL1 rare variants associated with neural tube defects affect convergent extension in zebrafish.

    PubMed

    Reynolds, Annie; McDearmid, Jonathan R; Lachance, Stephanie; De Marco, Patrizia; Merello, Elisa; Capra, Valeria; Gros, Philippe; Drapeau, Pierre; Kibar, Zoha

    2010-01-01

    In humans, rare non-synonymous variants in the planar cell polarity gene VANGL1 are associated with neural tube defects (NTDs). These variants were hypothesized to be pathogenic based mainly on genetic studies in a large cohort of NTD patients. In this study, we validate the potential pathogenic effect of these mutations in vivo by investigating their effect on convergent extension in zebrafish. Knocking down the expression of tri, the ortholog of Vangl2, using an antisense morpholino (MO), as shown previously, led to a defective convergent extension (CE) manifested by a shortened body axis and widened somites. Co-injection of the human VANGL1 with the tri-MO was able to partially rescue the tri-MO induced phenotype in zebrafish. In contrast, co-injection of two human VANGL1 variants, p.Val239Ile and p.Met328Thr, failed to rescue this phenotype. We next carried out overexpression studies where we measured the ability of the human VANGL1 alleles to induce a CE phenotype when injected at high doses in zebrafish embryos. While overexpressing the wild-type allele led to a severely defective CE, overexpression of either p.Val239Ile or p.Met328Thr variant failed to do so. Results from both tri-MO knockdown/rescue results and overexpression assays suggest that these two variants most likely represent "loss-of-function" alleles that affect protein function during embryonic development. Our study demonstrates a high degree of functional conservation of VANGL genes across evolution and provides a model system for studying potential variants identified in human NTDs. PMID:20043994

  1. Exposure to Fumonisins and the Occurrence of Neural Tube Defects along the Texas–Mexico Border

    PubMed Central

    Missmer, Stacey A.; Suarez, Lucina; Felkner, Marilyn; Wang, Elaine; Merrill, Alfred H.; Rothman, Kenneth J.; Hendricks, Katherine A.

    2006-01-01

    Along the Texas–Mexico border, the prevalence of neural tube defects (NTDs) among Mexican-American women doubled during 1990–1991. The human outbreak began during the same crop year as epizootics attributed to exposure to fumonisin, a mycotoxin that often contaminates corn. Because Mexican Americans in Texas consume large quantities of corn, primarily in the form of tortillas, they may be exposed to high levels of fumonisins. We examined whether or not maternal exposure to fumonisins increases the risk of NTDs in offspring using a population-based case–control study. We estimated fumonisin exposure from a postpartum sphinganine:sphingosine (sa:so) ratio, a biomarker for fumonisin exposure measured in maternal serum, and from maternal recall of periconceptional corn tortilla intake. After adjusting for confounders, moderate (301–400) compared with low (? 100) consumption of tortillas during the first trimester was associated with increased odds ratios (ORs) of having an NTD-affected pregnancy (OR = 2.4; 95% confidence interval, 1.1–5.3). No increased risks were observed at intakes higher than 400 tortillas (OR = 0.8 for 401–800, OR = 1.0 for > 800). Based on the postpartum sa:so ratio, increasing levels of fumonisin exposure were associated with increasing ORs for NTD occurrences, except for the highest exposure category (sa:so > 0.35). Our findings suggest that fumonisin exposure increases the risk of NTD, proportionate to dose, up to a threshold level, at which point fetal death may be more likely to occur. These results also call for population studies that can more directly measure individual fumonisin intakes and assess effects on the developing embryo. PMID:16451860

  2. 59 FR- Food Labeling: Health Claims and Label Statements; Folate and Neural Tube Defects

    Federal Register 2010, 2011, 2012, 2013, 2014

    1994-01-04

    ...tube defect-affected pregnancy is a personal or family history of a pregnancy affected with a such a...of conception, race, nutrition, and maternal health...tube defect-affected pregnancies in the United...

  3. Eddy Current Signature Classification of Steam Generator Tube Defects Using A Learning Vector Quantization Neural Network

    SciTech Connect

    Gabe V. Garcia

    2005-01-03

    A major cause of failure in nuclear steam generators is degradation of their tubes. Although seven primary defect categories exist, one of the principal causes of tube failure is intergranular attack/stress corrosion cracking (IGA/SCC). This type of defect usually begins on the secondary side surface of the tubes and propagates both inwards and laterally. In many cases this defect is found at or near the tube support plates.

  4. Nitrosatable drug exposure during early pregnancy and neural tube defects in offspring: National Birth Defects Prevention Study.

    PubMed

    Brender, Jean D; Werler, Martha M; Kelley, Katherine E; Vuong, Ann M; Shinde, Mayura U; Zheng, Qi; Huber, John C; Sharkey, Joseph R; Griesenbeck, John S; Romitti, Paul A; Langlois, Peter H; Suarez, Lucina; Canfield, Mark A; The National Birth Defects Prevention Study

    2011-12-01

    Nitrosatable drugs, such as secondary or tertiary amines and amides, form N-nitroso compounds in the presence of nitrite. Various N-nitroso compounds have been associated with neural tube defects in animal models. Using data from the National Birth Defects Prevention Study, the authors examined nitrosatable drug exposure 1 month before and 1 month after conception in 1,223 case mothers with neural tube defect-affected pregnancies and 6,807 control mothers who delivered babies without major congenital anomalies from 1997 to 2005. Nitrite intakes were estimated from mothers' responses to a food frequency questionnaire. After adjustment for maternal race/ethnicity, educational level, and folic acid supplementation, case women were more likely than were control women to have taken tertiary amines (odds ratio = 1.60, 95% confidence interval (CI): 1.31, 1.95). This association was strongest with anencephalic births (odds ratio = 1.96, 95% CI: 1.40, 2.73); odds ratios associated with tertiary amines from the lowest tertile of nitrite intake to the highest tertile were 1.16 (95% CI: 0.59, 2.29), 2.19 (95% CI: 1.25, 3.86), and 2.51 (95% CI: 1.45, 4.37), respectively. Odds ratios for anencephaly with nitrosatable drug exposure were reduced among women who also took daily vitamin supplements that contained vitamin C. Prenatal exposure to nitrosatable drugs may increase the risk of neural tube defects, especially in conjunction with a mother's higher dietary intake of nitrites, but vitamin C might modulate this association. PMID:22047825

  5. Hypothesis: the female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating X chromosome on the molecular mechanisms of neural fold elevation.

    PubMed

    Juriloff, Diana M; Harris, Muriel J

    2012-10-01

    Females have long been known to be in excess among cranial neural tube defect (NTD) cases. Up to two thirds of human anencephalics and mouse exencephalics from various genetic causes are female, but the cause of this female excess is unknown. It appears not to be attributable to gonadal hormones, developmental delay in females, or preferential death of affected males. Recent studies of the Trp53 mouse mutant showed that exencephaly susceptibility depends on the presence of two X chromosomes, not the absence of the Y. Over a decade ago, we hypothesized that the relevant difference between female and male mammalian embryos at the time of cranial neural tube closure is the fact that females methylate most of the DNA in the large inactive X chromosome after every cell division, reducing the methylation available for other needs in female cells. Recently, the Whitelaw laboratory identified several proteins in mice (Momme D genes) involved in epigenetic silencing and methylation and shared in the silencing of transgenes, retrotransposons, and the inactive-X, and suggested that the inactive-X acts as a "sink" for epigenetic silencing proteins. The "inactive-X sink" hypothesis can be used to suggest expected changes in sex ratio in cranial NTDs in response to various genetic or environmental alterations. We recommend that observation of sex ratio become a standard component of all NTD studies. We suggest that the female excess among cranial NTDs is an epigenetic phenomenon whose molecular investigation will produce insight into the mechanisms underlying NTDs. PMID:22753363

  6. Epigenetic Profiles in Children with a Neural Tube Defect; A Case-Control Study in Two Populations

    PubMed Central

    Stolk, Lisette; Bouwland-Both, Marieke I.; van Mill, Nina H.; Verbiest, Michael M. P. J.; Eilers, Paul H. C.; Zhu, Huiping; Suarez, Lucina; Uitterlinden, André G.; Steegers-Theunissen, Régine P. M.

    2013-01-01

    Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (IGF2-DMR, H19, KCNQ1OT1) and non-imprinted genes (the LEKR/CCNL gene region associated with birth weight, and MTHFR and VANGL1 associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of MTHFR (absolute decrease in methylation of ?0.33% in cases, P-value?=?0.001), and LEKR/CCNL (absolute increase in methylation: 1.36% in cases, P-value?=?0.048), and a borderline significant association for VANGL (absolute increase in methylation: 0.17% in cases, P-value?=?0.063). Only the association between MTHFR and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the MTHFR gene, and maybe VANGL and LEKKR/CNNL, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively. PMID:24223810

  7. Epigenetic profiles in children with a neural tube defect; a case-control study in two populations.

    PubMed

    Stolk, Lisette; Bouwland-Both, Marieke I; van Mil, Nina H; van Mill, Nina H; Verbiest, Michael M P J; Eilers, Paul H C; Zhu, Huiping; Suarez, Lucina; Uitterlinden, André G; Steegers-Theunissen, Régine P M

    2013-01-01

    Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (IGF2-DMR, H19, KCNQ1OT1) and non-imprinted genes (the LEKR/CCNL gene region associated with birth weight, and MTHFR and VANGL1 associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of MTHFR (absolute decrease in methylation of -0.33% in cases, P-value?=?0.001), and LEKR/CCNL (absolute increase in methylation: 1.36% in cases, P-value?=?0.048), and a borderline significant association for VANGL (absolute increase in methylation: 0.17% in cases, P-value?=?0.063). Only the association between MTHFR and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the MTHFR gene, and maybe VANGL and LEKKR/CNNL, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively. PMID:24223810

  8. A population-based case-control study of risk factors for neural tube defects in Shenyang, China

    Microsoft Academic Search

    Zhihua Yin; Wei Xu; Changying Xu; Shiqi Zhang; Yajun Zheng; Wei Wang; Baosen Zhou

    2011-01-01

    Purpose  To explore the risk factors for neural tube defects (NTD) in Shenyang, we carried out a population-based case-control study.\\u000a \\u000a \\u000a \\u000a Methods  We used chi-square test or Fisher’s exact test to evaluate variations in the prevalence by selected covariates. Adjusted odds\\u000a ratios and 95% confidence intervals were derived from univariate and multivariable conditional logistic models.\\u000a \\u000a \\u000a \\u000a \\u000a Results  A history of maternal previous birth defect-affected pregnancy

  9. Dual Labeling of Neural Crest Cells and Blood Vessels Within Chicken Embryos Using ChickGFP Neural Tube Grafting and Carbocyanine Dye DiI Injection.

    PubMed

    Delalande, Jean-Marie; Thapar, Nikhil; Burns, Alan J

    2015-01-01

    All developing organs need to be connected to both the nervous system (for sensory and motor control) as well as the vascular system (for gas exchange, fluid and nutrient supply). Consequently both the nervous and vascular systems develop alongside each other and share striking similarities in their branching architecture. Here we report embryonic manipulations that allow us to study the simultaneous development of neural crest-derived nervous tissue (in this case the enteric nervous system), and the vascular system. This is achieved by generating chicken chimeras via transplantation of discrete segments of the neural tube, and associated neural crest, combined with vascular DiI injection in the same embryo. Our method uses transgenic chick(GFP) embryos for intraspecies grafting, making the transplant technique more powerful than the classical quail-chick interspecies grafting protocol used with great effect since the 1970s. Chick(GFP)-chick intraspecies grafting facilitates imaging of transplanted cells and their projections in intact tissues, and eliminates any potential bias in cell development linked to species differences. This method takes full advantage of the ease of access of the avian embryo (compared with other vertebrate embryos) to study the co-development of the enteric nervous system and the vascular system. PMID:26065540

  10. Maternal and infant gene-folate interactions and the risk of neural tube defects.

    PubMed

    Etheredge, Analee J; Finnell, Richard H; Carmichael, Suzan L; Lammer, Edward J; Zhu, Huiping; Mitchell, Laura E; Shaw, Gary M

    2012-10-01

    Neural tube defects (NTDs) are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. The authors evaluated maternal or offspring folate-related gene variants and interactions between the gene variants and maternal intake of folates on the risk of NTDs in their offspring. A case-control study was conducted on mothers and/or their fetuses and infants who were born in California from 1999 to 2003 with an NTD (cases n = 222, including 24 mother-infant pairs) or without a major malformation (controls n = 454, including 186 mother-infant pairs). Maternal intake of folates was assessed by food frequency questionnaire and genotyping was performed on samples from mothers and infants. For mothers in the lowest folate-intake group, risk of NTDs in offspring was significantly decreased for maternal MTHFR SNPs rs1476413, rs1801131, and rs1801133 (odds ratio [OR] = 0.55, 80% confidence interval [CI]: 0.20, 1.48; OR = 0.58, 80% CI: 0.24, 1.43; OR = 0.69, 80% CI: 0.41, 1.17, respectively), and TYMS SNPs rs502396 and rs699517 (OR = 0.91, 80% CI: 0.53, 1.56; OR = 0.70, 80% CI: 0.38, 1.29). A gene-only effect was observed for maternal SHMT1 SNP rs669340 (OR?=?0.69, 95% CI: 0.49, 0.96). When there was low maternal folate intake, risk of NTDs was significantly increased for infant MTHFD1 SNPs rs2236224, rs2236225, and rs11627387 (OR = 1.58, 80% CI: 0.99, 2.51; OR = 1.53, 80% CI: 0.95, 2.47; OR = 4.25, 80% CI: 2.33, 7.75, respectively) and SHMT1 SNP rs12939757 (OR = 2.01, 80% CI: 1.20, 3.37), but decreased for TYMS SNP rs2847153 (OR = 0.73, 80% CI: 0.37, 1.45). Although power to detect interaction effects was low for this birth defects association study, the gene-folate interactions observed in this study represent preliminary findings that will be useful for informing future studies on the complex etiology of NTDs. PMID:22903727

  11. Maternal-Fetal Metabolic Gene-Gene Interactions and Risk of Neural Tube Defects

    PubMed Central

    Lupo, Philip J.; Mitchell, Laura E.; Canfield, Mark A.; Shaw, Gary M.; Olshan, Andrew F.; Finnell, Richard H.; Zhu, Huiping

    2013-01-01

    Single-gene analyses indicate that maternal genes associated with metabolic conditions (e.g., obesity) may influence the risk of neural tube defects (NTDs). However, to our knowledge, there have been no assessments of maternal-fetal metabolic gene-gene interactions and NTDs. We investigated 23 single nucleotide polymorphisms among 7 maternal metabolic genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, and TCF7L2) and 2 fetal metabolic genes (SLC2A2 and UCP2). Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study for birth years 1999–2007. We used a 2-step approach to evaluate maternal-fetal gene-gene interactions. First, a case-only approach was applied to screen all potential maternal and fetal interactions (n=76), as this design provides greater power in the assessment of gene-gene interactions compared to other approaches. Specifically, ordinal logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each maternal-fetal gene-gene interaction, assuming a log-additive model of inheritance. Due to the number of comparisons, we calculated a corrected p-value (q-value) using the false discovery rate. Second, we confirmed all statistically significant interactions (q<0.05) using a log-linear approach among case-parent triads. In step 1, there were 5 maternal-fetal gene-gene interactions with q<0.05. The “top hit” was an interaction between maternal ENPP1 rs1044498 and fetal SLC2A2 rs6785233 (interaction OR=3.65, 95% CI: 2.32–5.74, p=2.09×10?8, q=0.001), which was confirmed in step 2 (p=0.00004). Our findings suggest that maternal metabolic genes associated with hyperglycemia and insulin resistance and fetal metabolic genes involved in glucose homeostasis may interact to increase the risk of NTDs. PMID:24332798

  12. Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States, 1995-2011.

    PubMed

    Williams, Jennifer; Mai, Cara T; Mulinare, Joe; Isenburg, Jennifer; Flood, Timothy J; Ethen, Mary; Frohnert, Barbara; Kirby, Russell S

    2015-01-16

    In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 µg of folic acid daily to prevent neural tube defects (NTDs). NTDs are major birth defects of the brain and spine that occur early in pregnancy as a result of improper closure of the embryonic neural tube, which can lead to death or varying degrees of disability. The two most common NTDs are anencephaly and spina bifida. Beginning in 1998, the United States mandated fortification of enriched cereal grain products with 140 µg of folic acid per 100 g. Immediately after mandatory fortification, the birth prevalence of NTD cases declined. Fortification was estimated to avert approximately 1,000 NTD-affected pregnancies annually. To provide updated estimates of the birth prevalence of NTDs in the period after introduction of mandatory folic acid fortification (i.e., the post-fortification period), data from 19 population-based birth defects surveillance programs in the United States, covering the years 1999-2011, were examined. After the initial decrease, NTD birth prevalence during the post-fortification period has remained relatively stable. The number of births occurring annually without NTDs that would otherwise have been affected is approximately 1,326 (95% confidence interval = 1,122-1,531). Mandatory folic acid fortification remains an effective public health intervention. There remain opportunities for prevention among women with lower folic acid intakes, especially among Hispanic women, to further reduce the prevalence of NTDs in the United States. PMID:25590678

  13. Rho-kinase-dependent actin turnover and actomyosin disassembly are necessary for mouse spinal neural tube closure.

    PubMed

    Escuin, Sarah; Vernay, Bertrand; Savery, Dawn; Gurniak, Christine B; Witke, Walter; Greene, Nicholas D E; Copp, Andrew J

    2015-07-15

    The cytoskeleton is widely considered essential for neurulation, yet the mouse spinal neural tube can close despite genetic and non-genetic disruption of the cytoskeleton. To investigate this apparent contradiction, we applied cytoskeletal inhibitors to mouse embryos in culture. Preventing actomyosin cross-linking, F-actin assembly or myosin II contractile activity did not disrupt spinal closure. In contrast, inhibiting Rho kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) or blocking F-actin disassembly prevented closure, with apical F-actin accumulation and adherens junction disturbance in the neuroepithelium. Cofilin-1-null embryos yielded a similar phenotype, supporting the hypothesis that there is a key role for actin turnover. Co-exposure to Blebbistatin rescued the neurulation defects caused by RhoA inhibition, whereas an inhibitor of myosin light chain kinase, ML-7, had no such effect. We conclude that regulation of RhoA, Rho kinase, LIM kinase and cofilin signalling is necessary for spinal neural tube closure through precise control of neuroepithelial actin turnover and actomyosin disassembly. In contrast, actomyosin assembly and myosin ATPase activity are not limiting for closure. PMID:26040287

  14. Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis.

    PubMed

    Robinson, Alexis; Escuin, Sarah; Doudney, Kit; Vekemans, Michel; Stevenson, Roger E; Greene, Nicholas D E; Copp, Andrew J; Stanier, Philip

    2012-02-01

    Craniorachischisis (CRN) is a severe neural tube defect (NTD) resulting from failure to initiate closure, leaving the hindbrain and spinal neural tube entirely open. Clues to the genetic basis of this condition come from several mouse models, which harbor mutations in core members of the planar cell polarity (PCP) signaling pathway. Previous studies of humans with CRN failed to identify mutations in the core PCP genes, VANGL1 and VANGL2. Here, we analyzed other key PCP genes: CELSR1, PRICKLE1, PTK7, and SCRIB, with the finding of eight potentially causative mutations in both CELSR1 and SCRIB. Functional effects of these unique or rare human variants were evaluated using known protein-protein interactions as well as subcellular protein localization. While protein interactions were not affected, variants from five of the 36 patients exhibited a profound alteration in subcellular protein localization, with diminution or abolition of trafficking to the plasma membrane. Comparable effects were seen in the crash and spin cycle mouse Celsr1 mutants, and the line-90 mouse Scrib mutant. We conclude that missense variants in CELSR1 and SCRIB may represent a cause of CRN in humans, as in mice, with defective PCP protein trafficking to the plasma membrane a likely pathogenic mechanism. PMID:22095531

  15. Noggin and basic FGF were implicated in forebrain fate and caudal fate, respectively, of the neural tube-like structures emerging in mouse ES cell culture

    Microsoft Academic Search

    Shunmei Chiba; Manae S. Kurokawa; Hideshi Yoshikawa; Ritsuko Ikeda; Mitsuhiro Takeno; Mamoru Tadokoro; Hiroaki Sekino; Takuo Hashimoto; Noboru Suzuki

    2005-01-01

    We developed neural tube-like structures accompanying neural crest-like cells by treating embryonic stem (ES) cells with retinoic acid. The structures contained pseudostratified Nestin+Vimentin+ neuroepithelial cells surrounded by Masson staining+ basement membrane. ßIIItubulin+Synaptophysin+ mature neurons and glial fibrillary acidic protein (GFAP)+ glial cells dispersed outside of the membrane. Addition of Noggin to the culture induced prominent proliferation of the neuroepithelial cells,

  16. The use of mouse models to elucidate the genetic and environmental components of neural tube defects

    E-print Network

    Gefrides, Lisa Anne

    1998-01-01

    Neural tub defects (NTDs) rank among the most common phics. congenital anomalies affecting human infants worldwide. Unfortunately, the: etiology is poorly understood accuse the genetic and environmental components contributing to their expression...

  17. Neural tube, skeletal and body wall defects in mice lacking transcription factor AP2

    Microsoft Academic Search

    Jian Zhang; Stephanie Hagopian-Donaldson; George Serbedzija; Jennifer Elsemore; Debora Plehn-Dujowich; Andrew P. McMahon; Richard A. Flavell; Trevor Williams

    1996-01-01

    THE retinoic acid-inducible transcription factor AP-2 is expressed in epithelial and neural crest cell lineages during murine development1-5. AP-2 can regulate neural and epithelial gene transcription, and is associated with overexpression of c-erbB-2 in human breast-cancer cell lines4-6. To ascertain the importance of AP-2 for normal development, we have derived mice containing a homozygous disruption of the AP-2 gene. These

  18. Modifying a sealed tube zinc reduction method for preparation of AMS graphite targets: Reducing background and attaining high precision

    NASA Astrophysics Data System (ADS)

    Xu, Xiaomei; Trumbore, Susan E.; Zheng, Shuhui; Southon, John R.; McDuffee, Kelsey E.; Luttgen, Madelyn; Liu, Julia C.

    2007-06-01

    The sealed tube zinc reduction method for converting CO 2 to graphite for AMS 14C measurements was originally developed for rapid production of graphite in biomedical tracer experiments. The method was usually thought to have low precision and a high background. We have modified the zinc reduction method originally outlined in Vogel [J.S. Vogel, Radiocarbon 34 (3) (1992) 344] by carefully controlling the amounts of reagents (zinc, titanium hydride and Co or Fe catalyst) and now routinely obtain a precision of 2-3‰ and a relatively low background of ˜50,000 14C years when analyzing for 14C at the Keck Carbon Cycle AMS facility at UC Irvine. Fractionation of carbon isotopes does occur during graphitization and depends on the graphitization yield, which can be affected by the amounts of reagents used and other conditions. The ?13C of our zinc-reduced graphite is usually lighter by 2-3‰ than the CO 2 from which it is made, but this is corrected for in our system by simultaneous measurement of 13C/ 12C along with 14C/ 12C by the spectrometer. This method is suitable for 14C enriched samples, as well as natural abundance 14C samples, especially those with modern 14C contents. With improved precision and background, we believe that many disciplines can benefit from this technique because of its low cost and rapid production of graphite.

  19. A functional study of miR-124 in the developing neural tube

    PubMed Central

    Cao, Xinwei; Pfaff, Samuel L.; Gage, Fred H.

    2007-01-01

    Neural development is a highly orchestrated process that entails precise control of gene expression. Although microRNAs (miRNAs) have been implicated in fine-tuning gene networks, the roles of individual miRNAs in vertebrate neural development have not been studied in vivo. We investigated the function of the most abundant neuronal miRNA, miR-124, during spinal cord development. Neither inhibition nor overexpression of miR-124 significantly altered the acquisition of neuronal fate, suggesting that miR-124 is unlikely to act as a primary determinant of neuronal differentiation. Two endogenous targets of miR-124, laminin ?1 and integrin ?1, were identified, both of which are highly expressed by neural progenitors but repressed upon neuronal differentiation. Thus miR-124 appears to ensure that progenitor genes are post-transcriptionally inhibited in neurons. PMID:17344415

  20. A new approach for the prediction of the heat transfer rate of the wire-on-tube type heat exchanger––use of an artificial neural network model

    Microsoft Academic Search

    Yasar Islamoglu

    2003-01-01

    This study presents an application of artificial neural networks (ANNs) to predict the heat transfer rate of the wire-on-tube type heat exchanger. A back propagation algorithm, the most common learning method for ANNs, is used in the training and testing of the network. To solve this algorithm, a computer program was developed by using C++ programming language. The consistence between

  1. Folic Acid and the Prevention of Neural Tube Defects: A Survey of Awareness Among Latina Women of Childbearing Age Residing in Southeast Michigan

    Microsoft Academic Search

    Srimathi Kannan; Elaine Menotti; Holly K. Scherer; Jennifer Dickinson; Kimberly Larson

    2007-01-01

    Periconceptional intake of folic acid is known to reduce the risk for neural tube defects (NTDs). To inform southeast Michigan Latina women of childbearing age about the benefits of food and supplemental sources of the micronutrient in the prevention of NTDs, Spanish-English bilingual health educators carried out 20 education events in supermarkets and community organizations serving Latina women. One hundred

  2. Neural tube defects in Mexican-Americans living on the US-Mexico border: The effects of folic acid and dietary folate

    Microsoft Academic Search

    Lucina Suarez; Katherine A. Hendricks; Sharon P. Cooper; Anne M. Sweeney; Robert J. Hardy; Russell D. Larsen

    1998-01-01

    Neural tube defects (NTDs) are malformations of the developing brain and spinal cord; the most common are anencephaly and spina bifida. Evidence from many populations suggests that 50% of NTDs can be prevented through daily consumption of folic acid. A recent study has reported that folic acid may not protect populations of Mexican descent. This finding has serious implications for

  3. Effects of Folic Acid Public Education on Awareness, Knowledge and Behavior Change in Women of Childbearing Age in Preventing Neural Tube Defects

    Microsoft Academic Search

    M. A. McFarland; C. B. Johnson; J. M. Moore; C. D. Pierce; K. T. Robinson; K. M. Smith; W. B. Boone; K. N. Broome

    1999-01-01

    One goal of Healthy People 2000 is to reduce incidence of spina bifida and other neural tube defects to 3\\/10,000 live births. The US Public Health Service confirms the role of folate hi preventing NTDs by recommending that all women of childbearing age consume at least 400 micrograms of folate per day. NTDs occur before most women realize they are

  4. Investigation, using rat embryo culture, of the role of methionine supply in folic acid-mediated prevention of neural tube defects

    Microsoft Academic Search

    L. A. G. J. M. Vanaerts

    1995-01-01

    Peri-conceptional folic acid supplementation has become a well established way to prevent neural tube defects (NTDs) and such supplementation reduces the prevalence of these defects by approximately 70%. However, the mechanism of the preventive effect of folic acid is not clear. This overview focuses on the biochemical basis of folic acid-preventable NTDs and on the results obtained with whole embryo

  5. Electron-Microscopic Studies on the Pathogenesis of Exencephaly and Cranioschisis Induced in the Rat after Neural Tube Closure: Role of the Neuroepithelium and Choroid Plexus

    Microsoft Academic Search

    R. Padmanabhan

    1990-01-01

    Exencephaly was induced in Wistar rat fetuses by the administration of a single dose of cyclophosphamide (15 mg\\/kg) in saline after neural tube closure. The neuroepithelium (NE) and the choroid plexus were studied electron-microscopically in sections taken from a few hours after treatment to day 19 of gestation. The reduction in polyribosomes and condensation of the nucleus and cytoplasm were

  6. Mouse Fkbp8 activity is required to inhibit cell death and establish dorso-ventral patterning in the posterior neural tube

    Microsoft Academic Search

    Rebecca Lee; Yean Wong; Bogdan J. Wlodarczyk; Kyung Soo Min; Melissa L. Scott; Susan Kartiko; Wei Yu; Michelle Y. Merriweather; Peter Vogel; Brian P. Zambrowicz; Richard H. Finnell

    2008-01-01

    Neural tube defects (NTDs) are birth defects that can be disabling or lethal and are second in their prevalence after cardiac defects among major human congenital malformations. Spina bifida is a NTD where the spinal cord is dysplastic, and the overlying spinal column is absent. At present, the molecular mechanisms under- lying the spinal bifida development are largely unknown. In

  7. Consumption of folate deficient diet did not increase neural tube defects in LM/Bc mice exposed to fumonisin B1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides and F. proliferatum. It is found in corn and evidence suggests it is a possible risk factor for neural tube defects (NTD) in populations consuming large amounts of contaminated corn-based foods. The mechanism(s) underlying NTD i...

  8. Genetic basis of neural tube defects: the mouse gene loop-tail maps to a region of chromosome 1 syntenic with human 1q21–q23

    Microsoft Academic Search

    Philip Stanier; Jennifer N. Henson; Jane Eddleston; Gudrun E. Moore; Andrew J. Copp

    1995-01-01

    A genetic basis for neural tube defects (NTD) is rarely doubted, but the genes involved have not yet been identified. This is partly due to a lack of suitable families on which to perform linkage analysis. An alternative approach is to use the many mouse genes that cause NTD as a means of isolating their human homologues. Loop-tail (Lp) is

  9. Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification

    Microsoft Academic Search

    Jennifer N. Murdoch; Kit Doudney; Caroline Paternotte; Andrew J. Copp; Philip Stanier

    2001-01-01

    Neural tube defects (NTD) are clinically important congenital malformations whose molecular mecha- nisms are poorly understood. The loop-tail ( Lp) mutant mouse provides a model for the most severe NTD, craniorachischisis, in which the brain and spinal cord remain open. During a positional cloning approach, we have identified a mutation in a novel gene, Lpp1, in the Lp mouse, providing

  10. Validity of death and stillbirth certifi cates and hospital discharge summaries for the identifi cation of neural tube defects in Quebec City

    Microsoft Academic Search

    Fassiatou Tairou; Philippe De Wals

    2006-01-01

    The objectives of this study were 1) to assess the validity of different databases which identify neural tube defect (NTD) cases in the population, and 2) to examine the tempo- ral trends in NTD rates and the impact of prenatal diagnoses among pregnancies referred to a tertiary care hospital in Quebec City, Canada, from 1993 to 2002. Infant death and

  11. High Prevalence of the Thermolabile Methylenetetrahydrofolate Reductase Variant in Mexico: A Country with a Very High Prevalence of Neural Tube Defects

    Microsoft Academic Search

    Osvaldo M. Mutchinick; Mar??a A. López; Leonora Luna; Jonathan Waxman; Victoria E. Babinsky

    1999-01-01

    Neural tube defects (NTD) are highly prevalent in the Mexican population. According to data from the Registry and Epidemiological Surveillance of External Congenital Malformations (RYVEMCE), at least 1 in 250 conceptions that reach 20 weeks of pregnancy or more has a NTD. This number is three to four times higher than that observed in other related ethnic groups. A common

  12. Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail.

    PubMed

    Kibar, Z; Vogan, K J; Groulx, N; Justice, M J; Underhill, D A; Gros, P

    2001-07-01

    Neural tube defects (NTDs) such as spina bifida and anencephaly are common congenital malformations in humans (1/1,000 births) that result from failure of the neural tube to close during embryogenesis. The etiology of NTDs is complex, with both genetic and environmental contributions; the genetic component has been extensively studied with mouse models. Loop-tail (Lp) is a semidominant mutation on mouse chromosome 1 (ref. 4). In the two known Lp alleles (Lp, Lpm1Jus), heterozygous mice exhibit a characteristic looped tail, and homozygous embryos show a completely open neural tube in the hindbrain and spinal region, a condition similar to the severe craniorachischisis defect in humans. Morphological and neural patterning studies indicate a role for the Lp gene product in controlling early morphogenesis and patterning of both axial midline structures and the developing neural plate. The 0.6-cM/0.7-megabase (Mb) Lp interval is delineated proximally by D1Mit113/Apoa2/Fcer1g and distally by Fcer1a/D1Mit149/Spna1 and contains a minimum of 17 transcription units. One of these genes, Ltap, encodes a homolog of Drosophila Strabismus/Van Gogh (Stbm/Vang), a component of the frizzled/dishevelled tissue polarity pathway. Ltap is expressed broadly in the neuroectoderm throughout early neurogenesis and is altered in two independent Lp alleles, identifying this gene as a strong candidate for Lp. PMID:11431695

  13. Developmental basis of severe neural tube defects in the loop-tail (Lp) mutant mouse: use of microsatellite DNA markers to identify embryonic genotype.

    PubMed

    Copp, A J; Checiu, I; Henson, J N

    1994-09-01

    Mouse embryos homozygous for the mutation loop-tail (Lp) develop lethal defects in which the neural tube remains open from the hindbrain to the caudal extremity, a condition that closely resembles the human malformation craniorachischisis. Heterozygotes develop tail defects and occasional spina bifida, but are generally viable. In order to study the early development of these defects, it is necessary to determine the genotype of embryos at stages prior to the first appearance of the morphological abnormalities. We used a microsatellite DNA sequence, Crp, that is closely linked to the Lp locus and which segregates polymorphic variants in matings between Lp/+ mice, thus permitting identification of embryos of Lp/Lp, Lp/+ and +/+ genotypes. We found that the severe phenotype craniorachischisis is present at 9.5 and 10.5 days of gestation only in Lp/Lp embryos in utero, whereas Lp/+ and +/+ littermates show neural tube closure throughout most of the body axis. The open neural tube phenotype also develops in Lp/Lp embryos growing in whole embryo culture. A small proportion of Lp/+ embryos were found to develop this phenotype in vitro, but only when culture conditions were suboptimal. Analysis of 8.5-day embryos revealed that the initial defect in Lp/Lp embryos is failure to initiate neural tube closure at the cervical/hindbrain boundary when the embryo has 6-7 somites. Thereafter, the neural tube remains open throughout the body axis, with the exception of the midbrain and forebrain where neural tube closure is initiated independently. Closure at the midbrain/forebrain boundary does not appear to be defective in Lp/Lp embryos. Heterozygous Lp/+ embryos initiate neural tube closure at the cervical/hindbrain boundary with a slight delay compared with +/+ littermates. Moreover, at 10.5 days of gestation, Lp/+ embryos undergo delayed closure of the posterior neuropore. Thus, Lp/+ embryos are defective in several aspects of the neurulation process. The pattern of delayed neuropore closure in Lp/+ embryos resembles that caused by the ct and Sp mutations and is likely to be responsible for the development of tail defects (i.e., looped tails) and spina bifida in Lp/+ mice. The use of microsatellite markers to determine the genotype of mutant embryos has general application: microsatellites are widespread throughout the mouse genome, so that informative sequences are likely to be available with close linkage to the majority of mutant genes. Moreover, polymorphisms can be detected using the polymerase chain reaction, making it possible to determine the genotype of very early embryos when only small amounts of material are available. PMID:8088438

  14. Association between the methionine synthase A2756G polymorphism and neural tube defect risk: a meta-analysis.

    PubMed

    Yang, Mei; Yang, Liping; Qi, Ling; Guo, Yiyang; Lin, Xiaofang; Zhang, Yu; Du, Yukai

    2013-05-10

    Many studies have accessed the association between methionine synthase (MTR) A2756G polymorphism and neural tube defect (NTD). However, the conclusions are inconsistent. Our study aimed to clarify the nature of the genetic risks contributed by this polymorphism for NTD using meta-analysis. We searched electronic literature from the PubMed, EMBASE, and Medline databases, from which 10 articles were selected according to the inclusion criteria. The meta-analysis was conducted in 3 groups, namely, NTD patients, mothers with NTD offspring and fathers with NTD offspring. Pooled odds ratios (ORs) and 95% confidence intervals were used to evaluate the strength of the association and the result was corrected by multiple testing. To sum up, no associations between the MTR A2756G polymorphism and NTD risk were found among the 3 groups in all genetic models. However, as their sample size is not large enough, this result needs further research. PMID:23438943

  15. Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice

    SciTech Connect

    Dawson, Jennifer E. [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Kingston, Ontario, K7L 3N6 (Canada); Raymond, Angela M. [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Kingston, Ontario, K7L 3N6 (Canada); Winn, Louise M. [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Kingston, Ontario, K7L 3N6 (Canada)]. E-mail: winnl@biology.queensu.ca

    2006-03-01

    In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of p53, NF-{kappa}B, Pim-1, c-Myb, Bax, and Bcl-2 in the CD-1 mouse. We also evaluated the protective effects of folic acid and pantothenic acid on VPA-induced NTDs and VPA-induced embryonic protein changes in this model. Pregnant CD-1 mice were administered a teratogenic dose of VPA prior to neural tube closure and embryonic protein levels were analyzed. In our study, VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with an NTD showed a 2-fold increase in p53, and 4-fold decreases in NF-{kappa}B, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P < 0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P < 0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P < 0.05). Folic acid also reduced VPA-induced alterations in p53, NF-{kappa}B, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-{kappa}B, Pim-1, and c-Myb. We hypothesize that folic acid and pantothenic acid protect CD-1 embryos from VPA-induced NTDs by independent, but not mutually exclusive mechanisms, both of which may be mediated by the prevention of VPA-induced alterations in proteins involved in neurulation.

  16. Raltitrexed's effect on the development of neural tube defects in mice is associated with DNA damage, apoptosis, and proliferation.

    PubMed

    Dong, Yanting; Wang, Xiuwei; Zhang, Jianlin; Guan, Zhen; Xu, Lin; Wang, Jianhua; Zhang, Ting; Niu, Bo

    2015-01-01

    The causal metabolic pathway and the underlying mechanism between folate deficiency and neural tube defects (NTDs) remain obscure. Thymidylate (dTMP) is catalyzed by thymidylate synthase (TS) using the folate-derived one-carbon unit as the sole methyl donor. This study aims to examine the role of dTMP biosynthesis in the development of neural tube in mice by inhibition of TS via a specific inhibitor, raltitrexed (RTX). Pregnant mice were intraperitoneally injected with various doses of RTX on gestational day 7.5, and embryos were examined for the presence of NTDs on gestational day 11.5. TS activity and changes of dUMP and dTMP levels were measured following RTX treatment at the optimal dose. DNA damage was determined by detection of phosphorylated replication protein A2 (RPA2) and ?-H2AX in embryos with NTDs induced by RTX. Besides, apoptosis and proliferation were also analyzed in RTX-treated embryos with NTDs. We found that NTDs were highly occurred by the treatment of RTX at the optimal dose of 11.5 mg/kg b/w. RTX treatment significantly inhibited TS activity. Meanwhile, dTMP was decreased associated with the accumulation of dUMP in RTX-treated embryos. Phosphorylated RPA2 and ?-H2AX were significantly increased in RTX-treated embryos with NTDs compared to control. More apoptosis and decreased proliferation were also found in embryos with NTDs induced by RTX. These results indicate that impairment of dTMP biosynthesis caused by RTX led to the development of NTDs in mice. DNA damage and imbalance between apoptosis and proliferation may be potential mechanisms. PMID:25245820

  17. Vinyl chloride monomer (VCM) induces high occurrence of neural tube defects in embryonic mouse brain during neurulation.

    PubMed

    Quan, Hongyu; Ma, Teng; Zhao, Xianxian; Zhao, Baixiong; Liu, Yunlai; Li, Hongli

    2014-05-01

    The aim of this study was to explore the direct embryonic teratogenicity of vinyl chloride monomer (VCM), especially the toxic effects on the early development of the nervous system and its underlying mechanisms. Pregnant mice at embryonic day 6.5 (E6.5) were injected with different doses of VCM (200, 400 and 600 mg/kg) and embryos were harvested at E10.5. Our results showed that doses higher than 400 mg/kg of VCM increased the incidence of malformed embryos, especially the neural tube defects (NTDs). In addition, high-dose of VCM decreased mitotic figure counts in the neuroepithelium and enhanced the percentage of cells in G0/G1 phase, while they were reduced in S phase. The more VCM was injected into mice, the fewer positive PCNA cells were seen and the more positive TUNEL cells were observed in the neuroepithelium. Moreover, significant increases in the levels of caspase-3 protein were observed in NTD embryos. Our results demonstrate that during early pregnancy, exposure to doses higher than 400 mg/kg of VCM increases the incidence of malformations and particularly the rate of NTDs. High-dose of VCM inhibits the proliferation of neural cells and induces cell apoptosis, leading to an imbalance in the ratio of proliferation and apoptosis. Meanwhile, the apoptosis of neuroepithelial cells might be accelerated by the activation of the caspase-3 pathway, and it might be a reason for NTDs. PMID:24664314

  18. Analyses of copy number variation reveal putative susceptibility loci in MTX-induced mouse neural tube defects.

    PubMed

    Wang, Jianhua; Wang, Xiuwei; Guan, Tao; Xiang, Qian; Wang, Mingsheng; Zhang, Zhi; Guan, Zhen; Wang, Guoliang; Zhu, Zhiqiang; Xie, Qiu; Li, Guannan; Guo, Jin; Wang, Fang; Zhang, Zhengguo; Niu, Bo; Zhang, Ting

    2014-09-01

    Copy number variations (CNVs) are thought to act as an important genetic mechanism underlying phenotypic heterogeneity. Impaired folate metabolism can result in neural tube defects (NTDs). However, the precise nature of the relationship between low folate status and NTDs remains unclear. Using an array-comparative genomic hybridization (aCGH) assay, we investigated whether CNVs could be detected in the NTD embryonic neural tissues of methotrexate (MTX)-induced folate dysmetabolism pregnant C57BL/6 mice and confirmed the findings with quantitative real-time PCR (qPCR). The CNVs were then comprehensively investigated using bioinformatics methods to prioritize candidate genes. We measured dihydrofolate reductase (DHFR) activity and concentrations of folate and relevant metabolites in maternal serum using enzymologic method and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Three high confidence CNVs on XqA1.1, XqA1.1-qA2, and XqE3 were found in the NTD embryonic neural tissues. Twelve putative genes and three microRNAs were identified as potential susceptibility candidates in MTX-induced NTDs and possible roles in NTD pathogenesis. DHFR activity and 5-methyltetrahydrofolate (5-MeTHF), 5-formyltetrahydrofolate (5-FoTHF), and S-adenosylmethionine (SAM) concentrations of maternal serum decreased significantly after MTX injection. These findings suggest that CNVs caused by defects in folate metabolism lead to NTD, and further support the hypothesis that folate dysmetabolism is a direct cause for CNVs in MTX-induced NTDs. PMID:24515751

  19. 3D Reconstitution of the Patterned Neural Tube from Embryonic Stem Cells

    PubMed Central

    Meinhardt, Andrea; Eberle, Dominic; Tazaki, Akira; Ranga, Adrian; Niesche, Marco; Wilsch-Bräuninger, Michaela; Stec, Agnieszka; Schackert, Gabriele; Lutolf, Matthias; Tanaka, Elly M.

    2014-01-01

    Summary Inducing organogenesis in 3D culture is an important aspect of stem cell research. Anterior neural structures have been produced from large embryonic stem cell (ESC) aggregates, but the steps involved in patterning such complex structures have been ill defined, as embryoid bodies typically contained many cell types. Here we show that single mouse ESCs directly embedded in Matrigel or defined synthetic matrices under neural induction conditions can clonally form neuroepithelial cysts containing a single lumen in 3D. Untreated cysts were uniformly dorsal and could be ventralized to floor plate (FP). Retinoic acid posteriorized cysts to cervical levels and induced localize FP formation yielding full patterning along the dorsal/ventral (DV) axis. Correct spatial organization of motor neurons, interneurons, and dorsal interneurons along the DV axis was observed. This system serves as a valuable tool for studying morphogen action in 3D and as a source of patterned spinal cord tissue. PMID:25454634

  20. Histone modification mapping in human brain reveals aberrant expression of histone H3 lysine 79 dimethylation in neural tube defects.

    PubMed

    Zhang, Qin; Xue, Peng; Li, Huili; Bao, Yihua; Wu, Lihua; Chang, Shaoyan; Niu, Bo; Yang, Fuquan; Zhang, Ting

    2013-06-01

    Neural tube defects (NTDs) are severe, common birth defects that result from failure of neural tube closure, but their pathological mechanisms are not yet fully understood. Histone modifications have an important role in gene regulation during fetal development. We therefore hypothesized that the human NTDs may be partly caused by an imbalance in metabolism, perhaps caused by nutritional deficiencies, that leads to aberrant histone modifications. Here, we report a screen of fetal brain histone modifications using 2D nano-LC strong cation exchange reverse phase (SCX/RP) MS/MS and the identification of 61 unique post-translational modification sites on histones H1, H2a, H2b, H3, and H4. Of these, 38 sites are novel (not already found in the Uniprot database). Furthermore, we compared the histone modification patterns between normal brains and NTD brains special of which maternal folate levels were lower than of normal control. The results showed that histone H3 lysine 79 dimethylation (H3K79me2) and a novel identified site, H2bK5 monomethylation (H2bK5me1), were completely absent in individuals with NTDs. Follow-up Western blotting validated the decreased H3K79me2 expression in brains with NTDs, but the amplified samples experiments displayed that decreased H3K79me2 expression was not suitable for all samples with NTDs. Furthermore, folate-free treated mouse embryonic stem cells induced the decreased H3K79me2 level. Subsequently, our ChIP results in normal fetal brain tissues showed that H3K79me2 binds to SUFU, RARA and ITGA3 which induce NTDs phenotype after knockout in mice, and in NTDs brain tissues the bindings of H3K79me2 to these three genes were significantly altered. Taken together, our study indicated that low folate treatment might attenuate H3K79 dimethylation, further affect its regulate activation on target genes, some of which are NTDs-resulting associated, lastly interrupt early embryo developing. Our study increases the understanding of normal fetal brain histone modifications and provides a platform for investigating histone modifications in neural disease and also has an insight into a potential role of aberrant histone modification in etiology of NTDs. PMID:23376398

  1. Prevention of Neural Tube Defects: A Cross-Sectional Study of the Uptake of Folic Acid Supplementation in Nearly Half a Million Women

    PubMed Central

    Bestwick, Jonathan P.; Huttly, Wayne J.; Morris, Joan K.; Wald, Nicholas J.

    2014-01-01

    Background Taking folic acid supplements before pregnancy to reduce the risk of a neural tube defect (NTD) is especially important in countries without universal folic acid fortification. The extent of folic acid supplementation among women who had antenatal screening for Down’s syndrome and NTDs at the Wolfson Institute of Preventive Medicine, London between 1999 and 2012 was assessed. Methods and Findings 466,860 women screened provided details on folic acid supplementation. The proportion of women who took folic acid supplements before pregnancy was determined according to year and characteristics of the women. The proportion of women taking folic acid supplements before pregnancy declined from 35% (95% CI 34%–35%) in 1999–2001 to 31% (30%–31%) in 2011–2012. 6% (5%–6%) of women aged under 20 took folic acid supplements before pregnancy compared with 40% of women aged between 35 and 39. Non-Caucasian women were less likely to take folic acid supplements before pregnancy than Caucasian women; Afro-Caribbean 17% (16%–17%), Oriental 25% (24%–25%) and South Asian 20% (20%–21%) compared with 35% (35%–35%) for Caucasian women. 51% (48%–55%) of women who previously had an NTD pregnancy took folic acid supplements before the current pregnancy. Conclusions The policy of folic acid supplementation is failing and has led to health inequalities. This study demonstrates the need to fortify flour and other cereal grain with folic acid in all countries of the world. PMID:24586711

  2. No association of the polyhistidine tract polymorphism of the ZIC2 gene with neural tube defects in a South American (ECLAMC) population.

    PubMed

    Costa-Lima, Marcelo A; Meneses, Heloisa N M; El-Jaick, Kenia B; Amorim, Márcia R; Castilla, Eduardo E; Orioli, Iêda M

    2008-01-01

    The ZIC genes comprise a family of transcriptional factors associated with neural tube defects (NTDs) in mice and with holoprosencephaly in humans. An allelic variant of ZIC2, a CAC repeat within the first exon, was reported in association with an increased risk of non-syndromic NTDs in patients with a Hispanic ethnic background. We investigated whether this 10-residue histidine tract polymorphism of the ZIC2 gene (c.718_720dupCAC) was associated with the risk of NTDs in a sample of 138 patients and their parents from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) hospital network. Analysis with log-linear models of 138 family triads of mother, father and affected child did not provide evidence to support the notion that case (or maternal) 10H/10H or -/10H genotypes were associated with NTDs in this South American population sample, where the 10H variant occurred in 5% of newborns affected with NTDs. We also described the first example of the homozygous state of the 10H allele in a patient with cephalocele, holoprosencephaly and microphthalmia, but did not ascertain whether this polymorphism is associated with the increased risk of a specific subgroup of NTDs, as a normal father of a patient with anencephaly presented the same genotype. PMID:21479430

  3. Artificial neural networks to correlate in-tube turbulent forced convection of binary gas mixtures

    Microsoft Academic Search

    Gerardo Diaz; Antonio Campo

    2009-01-01

    Turbulent forced convection correlations are documented in the literature for air, gases and vapors (Pr?0.7), for common liquids (Pr>1) and for liquid metals (Pr0.03). In spite of this, there is a small gap in the Pr sub-interval between 0.1 and 1.0, which is occupied by binary gas mixtures. In this paper, data for turbulent forced convection for the in-tube flow

  4. The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear

    PubMed Central

    2010-01-01

    Background The planar cell polarity (PCP) signalling pathway is fundamental to a number of key developmental events, including initiation of neural tube closure. Disruption of the PCP pathway causes the severe neural tube defect of craniorachischisis, in which almost the entire brain and spinal cord fails to close. Identification of mouse mutants with craniorachischisis has proven a powerful way of identifying molecules that are components or regulators of the PCP pathway. In addition, identification of an allelic series of mutants, including hypomorphs and neomorphs in addition to complete nulls, can provide novel genetic tools to help elucidate the function of the PCP proteins. Results We report the identification of a new N-ethyl-N-nitrosourea (ENU)-induced mutant with craniorachischisis, which we have named chuzhoi (chz). We demonstrate that chuzhoi mutant embryos fail to undergo initiation of neural tube closure, and have characteristics consistent with defective convergent extension. These characteristics include a broadened midline and reduced rate of increase of their length-to-width ratio. In addition, we demonstrate disruption in the orientation of outer hair cells in the inner ear, and defects in heart and lung development in chuzhoi mutants. We demonstrate a genetic interaction between chuzhoi mutants and both Vangl2Lp and Celsr1Crsh mutants, strengthening the hypothesis that chuzhoi is involved in regulating the PCP pathway. We demonstrate that chuzhoi maps to Chromosome 17 and carries a splice site mutation in Ptk7. This mutation results in the insertion of three amino acids into the Ptk7 protein and causes disruption of Ptk7 protein expression in chuzhoi mutants. Conclusions The chuzhoi mutant provides an additional genetic resource to help investigate the developmental basis of several congenital abnormalities including neural tube, heart and lung defects and their relationship to disruption of PCP. The chuzhoi mutation differentially affects the expression levels of the two Ptk7 protein isoforms and, while some Ptk7 protein can still be detected at the membrane, chuzhoi mutants demonstrate a significant reduction in membrane localization of Ptk7 protein. This mutant provides a useful tool to allow future studies aimed at understanding the molecular function of Ptk7. PMID:20704721

  5. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines.

    PubMed

    Cordero, Amy M; Crider, Krista S; Rogers, Lisa M; Cannon, Michael J; Berry, R J

    2015-04-24

    Neural tube defects (NTDs) such as spina bifida, anencephaly, and encephalocele are serious birth defects of the brain and spine that occur during the first month of pregnancy when the neural tube fails to close completely. Randomized controlled trials and observational studies have shown that adequate daily consumption of folic acid before and during early pregnancy considerably reduces the risk for NTDs. The U.S. Public Health Service recommends that women capable of becoming pregnant consume 400 µg of folic acid daily for NTD prevention. Furthermore, fortification of staple foods (e.g., wheat flour) with folic acid has decreased folate-sensitive NTD prevalence in multiple settings and is a highly cost-effective intervention. PMID:25905896

  6. Detection of Foreign Matter in Transfusion Solution Based on Gaussian Background Modeling and an Optimized BP Neural Network

    PubMed Central

    Zhou, Fuqiang; Su, Zhen; Chai, Xinghua; Chen, Lipeng

    2014-01-01

    This paper proposes a new method to detect and identify foreign matter mixed in a plastic bottle filled with transfusion solution. A spin-stop mechanism and mixed illumination style are applied to obtain high contrast images between moving foreign matter and a static transfusion background. The Gaussian mixture model is used to model the complex background of the transfusion image and to extract moving objects. A set of features of moving objects are extracted and selected by the ReliefF algorithm, and optimal feature vectors are fed into the back propagation (BP) neural network to distinguish between foreign matter and bubbles. The mind evolutionary algorithm (MEA) is applied to optimize the connection weights and thresholds of the BP neural network to obtain a higher classification accuracy and faster convergence rate. Experimental results show that the proposed method can effectively detect visible foreign matter in 250-mL transfusion bottles. The misdetection rate and false alarm rate are low, and the detection accuracy and detection speed are satisfactory. PMID:25347581

  7. Impact of Prenatal Diagnosis and Elective Termination on Prevalence and Risk Estimates of Neural Tube Defects in California, 1989-1991

    Microsoft Academic Search

    Ellen M. Velie; Gary M. Shaw

    The authors examined the impact of prenatal diagnosis and elective termination of neural tube defect (NTD)-affected pregnancies on NTD prevalence and risk estimates. Prevalence data were actively ascertained and were derived from a population-based 1989-1991 cohort of California births. Included were 664 singleton infants\\/fetuses with an NTD. The birth prevalence (livebirths and stillbirths only) was 48.4% of the total prevalence

  8. Folate-Regulated Changes in Gene Expression in the Anterior Neural Tube of Folate Binding Protein1 (Folbp1)Deficient Murine Embryos

    Microsoft Academic Search

    Ofer Spiegelstein; Robert M. Cabrera; Daniel Bozinov; Bogdan Wlodarczyk; Richard H. Finnell

    2004-01-01

    Inactivation of the murine folate binding protein-1 (Folbp1) has been shown to play a vital role in embryonic development. Nullizygous embryos (Folbp1-\\/-) have significant malformations of the neural tube, craniofacies, and conotruncus, and invariably die in utero by gestational day(E) 10. Administration of 25 mg·kg-1·day-1 folinic acid to dams prior to and throughout gestation rescues the majority of embryos from

  9. Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

    Microsoft Academic Search

    Y. Sugimura; T. Murase; K. Oyama; A. Uchida; N. Sato; S. Hayasaka; Y. Kano; Y. Takagishi; Y. Hayashi; Y. Oiso; Y. Murata

    2009-01-01

    Aims\\/hypothesis  Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although\\u000a the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated\\u000a in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital\\u000a malformations and that

  10. Neural tube defect in a 4000-year-old Egyptian infant mummy: A case of meningocele from the museum of anthropology and ethnography of Turin (Italy)

    Microsoft Academic Search

    Rosa Boano; Ezio Fulcheri; Maria Cristina Martina; Andrea Ferraris; Renato Grilletto; Rossana Cremo; Federico Cesarani; Giovanni Gandini; Emma Rabino Massa

    2009-01-01

    This paper reports a paleopathological study of a severe neural tube defect in an ancient mummy, more specifically, a meningocele in an Egyptian infant from the XI dynasty (2100–1955B.C.). This is one of the most ancient cases of meningocele in mummified human remains described in paleopathological literature.Prehistoric and early historic examples of severe congenital defects of the vertebral column and

  11. Assessing the prevalence of spina bifida and encephalocele in a Kenyan hospital from 2005–2010: implications for a neural tube defects surveillance system

    PubMed Central

    Githuku, Jane N; Azofeifa, Alejandro; Valencia, Diana; Ao, Trong; Hamner, Heather; Amwayi, Samuel; Gura, Zeinab; Omolo, Jared; Albright, Leland; Guo, Jing; Arvelo, Wences

    2014-01-01

    Introduction Neural tube defects such as anencephaly, spina bifida, and encephalocele are congenital anomalies of the central nervous system. Data on the prevalence of neural tube defects in Kenya are limited. This study characterizes and estimates the prevalence of spina bifida and encephalocele reported in a referral hospital in Kenya from 2005-2010. Methods Cases were defined as a diagnosis of spina bifida or encephalocele. Prevalence was calculated as the number of cases by year and province of residence divided by the total number of live-births per province. Results From a total of 6,041 surgical records; 1,184 (93%) had reported diagnosis of spina bifida and 88 (7%) of encephalocele. Estimated prevalence of spina bifida and encephalocele from 2005-2010 was 3.3 [95% Confidence Interval (CI): 3.1-3.5] cases per 10,000 live-births. The highest prevalence of cases were reported in 2007 with 4.4 (95% CI: 3.9-5.0) cases per 10,000 live-births. Rift Valley province had the highest prevalence of spina bifida and encephalocele at 6.9 (95% CI: 6.3-7.5) cases per 10,000 live-births from 2005-2010. Conclusion Prevalence of spina bifida and encephalocele is likely underestimated, as only patients seeking care at the hospital were included. Variations in regional prevalence could be due to referral patterns and healthcare access. Implementation of a neural tube defects surveillance system would provide a more thorough assessment of the burden of neural tube defects in Kenya.

  12. Amniotic fluid cholinesterase of valproate-induced exencephaly in the mouse: an animal model for prenatal diagnosis of neural tube defects

    Microsoft Academic Search

    Mohamed M. A. Elmazar; Richard Vogel; Horst Spielmann

    1988-01-01

    After a single administration of the antiepileptic drug valproic acid (VPA; i.p.: 600 mg\\/kg) on day 8 of gestation in the mouse embryotoxicity and amniotic fluid (AF) cholinesterase (ChE) were evaluated on day 16 of gestation. VPA treatment induced an increase in embryolethality, neural tube defects (exencephaly), cleft palate, deformed vertebrae, open eyes, and a reduction in fetal weight. In

  13. Physical and Transcriptional Map of a 3Mb Region of Mouse Chromosome 1 Containing the Gene for the Neural Tube Defect Mutant loop-tail( Lp)

    Microsoft Academic Search

    Jane Eddleston; Jennifer N. Murdoch; Andrew J. Copp; Philip Stanier

    1999-01-01

    TheLpmouse mutant provides a model for the severe human neural tube defect (NTD), cranio-rachischisis. To identify theLpgene, a positional cloning approach has been adopted. Previously, linkage analysis in a large intraspecific backcross was used to map theLplocus to distal mouse chromosome 1. Here we report a detailed physical map of this region. The interval surroundingLphas been cloned in a yeast

  14. Amniotic fluid concentrations of alpha-fetoprotein (AFP) in early normal pregnancy, and pregnancy complicated by neural tube defects. A review of 18 months experience.

    PubMed

    Coltart, R M; Seller, M J; Singer, J D; Campbell, S

    1974-01-01

    Amniotic fluid concentrations of alpha-fetoprotein (AFP) in early normal pregnancy and pregnancy complicated by neural tube defects were investigated. The normal range of AFP values was determined from 163 samples obtained at 14-20 weeks of pregnancy. The relationship between AFP level and gestational age was represented by a linear regression (p less than .001). Regression lines for males and females differed significantly in position (p less than .01) but not in slope, the line for males 2.7 mcg/ml higher than that for females. No correlation was seen between maternal age and AFP level. 50 ''at risk'' cases, in whom there has been a history of previous anencephaly or spina bifida, were included in the noraml values. 6 of these patients had amniotic fluid AFP values outside the normal range and in 5 of the 6 cases, ultrasound examination of the fetus confirmed the diagnosis of an anencephalic type lesion and so termination was undertaken, All 5 fetuses had severe neural tube defects. The 6th fetus revealed an intact neural tube but clear-cut evidence of growth retardation and the placenta was small and infarcted. PMID:4143202

  15. 61 FR 49964 - Food Labeling: Health Claims and Label Statements; Folate and Neural Tube Defects; Revocation

    Federal Register 2010, 2011, 2012, 2013, 2014

    1996-09-24

    ...for Food Safety and Applied Nutrition (HFS-175), Food and Drug...INFORMATION: I. Background The Nutrition Labeling and Education Act...reducing their risk of having a pregnancy affected with spina bifida...CFR Part 101 Food labeling, Nutrition, Reporting and...

  16. Awareness and intake of folic acid for the prevention of neural tube defects among Lebanese women of childbearing age.

    PubMed

    Nasr Hage, Claudine; Jalloul, Maya; Sabbah, Mohamad; Adib, Salim M

    2012-01-01

    Since the early 1990s, international recommendations have promoted folic acid supplementation during the periconception period as an effective way of preventing neural tube defects (NTDs). However, the adoption of this recommendation remains insufficient. To assess the awareness and actual intake of folic acid among married Lebanese women aged 18-45 years, a cross-sectional study was conducted among 600 women selected from all five administrative districts in Lebanon, using a multistage cluster sampling procedure. An anonymous questionnaire was completed which covered measures of knowledge and use of folate supplements, as well as demographic, socioeconomic and obstetrical factors. Sixty percent of surveyed women (60%; n = 360) had heard about folic acid. Doctors were the most frequent source of information (61.1%) but only 24.7% of women have been told of the correct period during which folic acid supplementation was useful. Overall, only 6.2% had taken folic acid tablets during the adequate period. Younger age, higher education level and stability/sufficiency of income appeared to be significant predictors of awareness among Lebanese women. Actual folic acid intake was significantly associated with younger age, higher number of pregnancies, planning the last pregnancy and having had that last one after 1990. In Lebanon, the level of folic acid awareness and adequate intake remain relatively low. Several approaches should be used to promote folic acid intake including awareness campaigns, and routine counseling by primary health care physicians on folic acid during preconception visits. PMID:21210201

  17. Notes from the field: investigation of a cluster of neural tube defects - central Washington, 2010-2013.

    PubMed

    2013-09-01

    During August 2012, a health-care provider in central Washington alerted the Washington State Department of Health (DOH) about an excessive number of anencephaly births at a local hospital. After examining referral patterns for high-risk pregnancies in central Washington, DOH identified pregnancies affected by a severe neural tube defect (NTD) in a three-county area. Case findings included a review of area hospital discharge records for International Classification of Diseases, Ninth Revision codes 740, 741, 742, or 655.0; vital statistics reports; and perinatology office records. From these sources, 27 confirmed NTD-affected pregnancies occurring during January 2010-January 2013 were identified among women residing in the three-county area. Twenty-three pregnancies were affected by anencephaly, three with spina bifida, and one with encephalocele. The anencephaly rate was 8.4 per 10,000 live births (95% confidence interval [CI] = 4.5-12.0), compared with a national estimate of 2.1 per 10,000 live births (CI = 1.9-2.2). In contrast, the rate of spina bifida was 1.3 per 10,000 live births (CI = 0.3-3.8), compared with 3.5 per 10,000 live births nationally (CI = 3.3-3.7). PMID:24005228

  18. Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population.

    PubMed

    Jin, Lei; Zhang, Le; Li, Zhiwen; Liu, Jian-meng; Ye, Rrongwei; Ren, Aiguo

    2013-01-01

    To examine whether in utero exposure to mercury (Hg), cadmium (Cd), lead (Pb) and arsenic (As) is associated with an elevated neural tube defects (NTDs) risk, placental concentrations of total Hg, Cd, Pb and As were measured with an inductively coupled plasma mass spectrometer (ICP-MS) in 36 anencephaly and 44 spina bifida cases as well as in 50 healthy controls. The median Hg concentration in the NTD cases (2.25 ng/g) was higher than that of the controls (1.16 ng/g). The odds ratio (OR) for an Hg concentration above the median was 8.80 (95% CI 3.80-20.36) for the NTD cases. NTD risks increased for the second and third high levels of the concentrations, with ORs of 2.70 (95% CI 1.13-6.43) and 18.20 (95% CI 5.45-60.73), respectively. Therefore, higher placental levels of Hg are associated with an elevated risk of NTDs. PMID:23164984

  19. Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid.

    PubMed

    Heseker, Helmut B; Mason, Joel B; Selhub, Jacob; Rosenberg, Irwin H; Jacques, Paul F

    2009-07-01

    Some countries have introduced mandatory folic acid fortification, whereas others support periconceptional supplementation of women in childbearing age. Several European countries are considering whether to adopt a fortification policy. Projections of the possible beneficial effects of increased folic acid intake assume that the measure will result in a considerable reduction in neural-tube defects (NTD) in the target population. Therefore, the objective of the present study is to evaluate the beneficial effects of different levels of folic acid administration on the prevalence of NTD. Countries with mandatory fortification achieved a significant increase in folate intake and a significant decline in the prevalence of NTD. This was also true for supplementation trials. However, the prevalence of NTD at birth declined to approximately five cases at birth per 10 000 births and seven to eight cases at birth or abortion per 10 000 births. This decline was independent of the amount of folic acid administered and apparently reveals a 'floor effect' for folic acid-preventable NTD. This clearly shows that not all cases of NTD are preventable by increasing the folate intake. The relative decline depends on the initial NTD rate. Countries with NTD prevalence close to the observed floor may have much smaller reductions in NTD rates with folic acid fortification. Additionally, potential adverse effects of fortification on other vulnerable population groups have to be seriously considered. Policy decisions concerning national mandatory fortification programmes must take into account realistically projected benefits as well as the evidence of risks to all vulnerable groups. PMID:19079944

  20. Supplementation with vitamin d3 during pregnancy protects against lipopolysaccharide-induced neural tube defects through improving placental folate transportation.

    PubMed

    Chen, Yuan-Hua; Yu, Zhen; Fu, Lin; Xia, Mi-Zhen; Zhao, Mei; Wang, Hua; Zhang, Cheng; Hu, Yong-Fang; Tao, Fang-Biao; Xu, De-Xiang

    2015-05-01

    Several reports demonstrated that maternal lipopolysaccharide (LPS) exposure at middle gestational stage caused neural tube defects (NTDs). This study investigated the effects of supplementation with vitamin D3 (VitD3) during pregnancy on LPS-induced NTDs. Pregnant mice except controls were ip injected with LPS (25??g/kg) daily from gestational day (GD)8 to GD12. In LPS+VitD3 group, pregnant mice were orally administered with VitD3 (25??g/kg) before LPS injection. As expected, a 5-day LPS injection resulted in 62.5% (10/16) of dams and 20.3% of fetuses with NTDs. Additional experiment showed that a 5-day LPS injection downregulated placental proton-coupled folate transporter (pcft) and reduced folate carrier 1 (rfc1), 2 major folate transporters in placentas. Consistent with downregulation of placental folate transporters, folate transport from maternal circulation into embryos was disturbed in LPS-treated mice. Interestingly, VitD3 not only inhibited placental inflammation but also attenuated LPS-induced downregulation of placental folate transporters. Correspondingly, VitD3 markedly improved folate transport from maternal circulation into the embryos. Importantly, supplementation with VitD3 during pregnancy protected mice from LPS-induced NTDs. Taken together, these results suggest that supplementation with VitD3 during pregnancy prevents LPS-induced NTDs through inhibiting placental inflammation and improving folate transport from maternal circulation into the embryos. PMID:25673501

  1. Promoter haplotype combinations of the platelet-derived growth factor alpha-receptor gene predispose to human neural tube defects.

    PubMed

    Joosten, P H; Toepoel, M; Mariman, E C; Van Zoelen, E J

    2001-02-01

    Neural tube defects (NTDs), including anencephaly and spina bifida, are multifactorial diseases that occur with an incidence of 1 in 300 births in the United Kingdom. Mouse models have indicated that deregulated expression of the gene encoding the platelet-derived growth factor alpha-receptor (Pdgfra) causes congenital NTDs (refs. 2-4), whereas mutant forms of Pax-1 that have been associated with NTDs cause deregulated activation of the human PDGFRA promoter. There is an increasing awareness that genetic polymorphisms may have an important role in the susceptibility for NTDs (ref. 6). Here we identify five different haplotypes in the human PDGFRA promoter, of which the two most abundant ones, designated H1 and H2 alpha, differ in at least six polymorphic sites. In a transient transfection assay in human bone cells, the five haplotypes differ strongly in their ability to enhance reporter gene activity. In a group of patients with sporadic spina bifida, haplotypes with low transcriptional activity, including H1, were under-represented, whereas those with high transcriptional activity, including H2 alpha, were over-represented. When testing for haplotype combinations, H1 homozygotes were fully absent from the group of sporadic patients, whereas H1/H2 alpha heterozygotes were over-represented in the groups of both sporadic and familial spina bifida patients, but strongly under-represented in unrelated controls. Our data indicate that specific combinations of naturally occurring PDGFRA promoter haplotypes strongly affect NTD genesis. PMID:11175793

  2. Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3.

    PubMed

    Ting, Stephen B; Wilanowski, Tomasz; Auden, Alana; Hall, Mark; Voss, Anne K; Thomas, Tim; Parekh, Vishwas; Cunningham, John M; Jane, Stephen M

    2003-12-01

    The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene, grainyhead-like-3 (Grhl3), is a compelling candidate for the gene underlying the curly tail phenotype. The NTDs in Grhl3-null mice are more severe than those in the curly tail strain, as the Grhl3 alleles in ct/ct mice are hypomorphic. Spina bifida in ct/ct mice is folate resistant, but its incidence can be markedly reduced by maternal inositol supplementation periconceptually. The NTDs in Grhl3-/- embryos are also folate resistant, but unlike those in ct/ct mice, they are resistant to inositol. These findings suggest that residual Grhl3 expression in ct/ct mice may be required for inositol rescue of folate-resistant NTDs. PMID:14608380

  3. Mutations in the COPII vesicle component gene SEC24B are associated with human neural tube defects.

    PubMed

    Yang, Xue-Yan; Zhou, Xiang-Yu; Wang, Qing Qing; Li, Hong; Chen, Ying; Lei, Yun-Ping; Ma, Xiao-Hang; Kong, Pan; Shi, Yan; Jin, Li; Zhang, Ting; Wang, Hong-Yan

    2013-08-01

    Neural tube defects (NTDs) are severe birth malformations that affect one in 1,000 live births. Recently, mutations in the planar cell polarity (PCP) pathway genes had been implicated in the pathogenesis of NTDs in both the mouse model and in human cohorts. Mouse models indicate that the homozygous disruption of Sec24b, which mediates the ER-to-Golgi transportation of the core PCP gene Vangl2 as a component of the COPII vesicle, will result in craniorachischisis. In this study, we found four rare missense heterozygous SEC24B mutations (p.Phe227Ser, p.Phe682Leu, p.Arg1248Gln, and p.Ala1251Gly) in NTDs cases that were absent in all controls. Among them, p.Phe227Ser and p.Phe682Leu affected its protein stability and physical interaction with VANGL2. Three variants (p.Phe227Ser, p.Arg1248Gln, and p.Ala1251Gly) were demonstrated to affect VANGL2 subcellular localization in cultured cells. Further functional analysis in the zebrafish including overexpression and dosage-dependent rescue study suggested that these four mutations all displayed loss-of-function effects compared with wild-type SEC24B. Our study demonstrated that functional mutations in SEC24B might contribute to the etiology of a subset of human NTDs and further expanded our knowledge of the role of PCP pathway-related genes in the pathogenesis of human NTDs. PMID:23592378

  4. Genetic diversity of stem cells and their functional impact on the development of neural tube defects in Eastern population of India.

    PubMed

    Saxena, A K; Pandey, S; Pandey, L K

    2013-01-01

    Anencephaly and myelomeningocele are the 2 most common forms of neural tube defects (NTDs). During embryogenesis large numbers of extrinsic and intrinsic factors are responsible for the closing of the neural tube. "Stem cells" maintain the pluripotency during differentiation of 3 germ layers, including the neural ectoderm. We examined the role of Oct4, Nanog3, and Sox2 genes in the etiopathology of NTDs in an eastern Indian population using PCR-based DNA analysis. The highest frequency (16%) of complete loss of the Sox2 gene was found in NTDs. The highest frequency (48%) of overexpression (upregulation) was found for Nanog3, while 40% was observed for Oct4 and Sox2. The odds ratio for cases versus controls was from 0.132 at 95% confidence interval = 0.005-1.298 for Nanog3 to 2.316 (0.424-13.812) for Oct4. The highest frequency (77%) of overexpression for Nanog3 and Sox2 was observed in encephalocele and anencephalic patients, while in the comparison of regional variation, i.e., cephalic to caudal regions of NTDs, the highest frequency of downregulation (regression) of Nanog3 and Sox2 was found in lumbosacral myelomeningocele patients. However, cervical myelomeningocele patients had the highest frequency of overexpression in all 3 genes, suggesting that the mutational spectra of stem cells influence the cells of the neural crest in NTDs. PMID:23979878

  5. Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

    PubMed Central

    Zou, Peng; Ji, Guixiang; Gu, Aihua; Zhao, Peng

    2012-01-01

    Background Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs. Methods An electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis. Results A significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR ?=?2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR ?=?1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR ?=?1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR ?=?1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls. Conclusion The results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted. PMID:23056169

  6. Knowledge and periconceptional use of folic acid for the prevention of neural tube defects in ethnic communities in the United Kingdom: Systematic review and meta-analysis

    PubMed Central

    Peake, Jordana N; Copp, Andrew J; Shawe, Jill

    2013-01-01

    BACKGROUND: It is widely accepted that periconceptional supplementation with folic acid can prevent a significant proportion of neural tube defects (NTDs). The present study evaluated how folic acid knowledge and periconceptional use for NTD prevention varies by ethnicity in the United Kingdom (U.K.). METHODS: A literature search was conducted to identify studies that included assessment of folic acid knowledge or use in U.K. women of different ethnicities. Only research and referenced sources published after 1991, the year of the landmark Medical Research Council’s Vitamin Study, were included. A meta-analysis was performed of studies that assessed preconceptional folic acid use in Caucasians and non-Caucasians. RESULTS: Five studies met the inclusion criteria for assessment of knowledge and/or use of folic acid supplements in U.K. women including non-Caucasians. The available evidence indicates that South Asians specifically have less knowledge and lower periconceptional use of folic acid than Caucasians; one study found that West Indian and African women also had lower folic acid uptake. A synthesis of results from three of the studies, in a meta-analysis, shows that Caucasians are almost three times more likely to take folic acid before conception than non-Caucasians. CONCLUSION: From the limited evidence available, U.K. women of non-Caucasian ethnicity appear to have less knowledge and a lower uptake of folic acid supplementation than Caucasians during the periconceptional period. Implementing targeted, innovative education campaigns together with a mandatory fortification policy, including the fortification of ethnic minority foods, will be required for maximum prevention of folic acid–preventable NTDs across different ethnic groups. Birth Defects Research (Part A) 97:444–451, 2013. © 2013 Wiley Periodicals, Inc. PMID:23873812

  7. Cloning of zebrafish nkx6.2 and a comprehensive analysis of the conserved transcriptional response to Hedgehog/Gli signaling in the zebrafish neural tube

    PubMed Central

    Guner, Burcu; Karlstrom, Rolf O.

    2007-01-01

    Sonic Hedgehog (Shh) signaling helps pattern the vertebrate neural tube, in part by regulating the dorsal/ventral expression of a number of homeodomain containing transcription factors. These Hh responsive genes have been divided into two classes, with Class II genes being activated by Hh signaling and Class I genes being repressed by Hh signaling. While the transcriptional response to varying Hh levels is well defined in chick and mouse, it is only partially described in zebrafish, despite the fact that zebrafish has emerged as a powerful genetic system for the study of neural patterning. To better characterize the Hh response in the zebrafish neural tube, we cloned the zebrafish Class II Hh target genes nkx2.9 and nkx6.2. We then analyzed the expression of a number of Class I and Class II Hh responsive genes in wild type, Hh mutant, and Hh over-expressing zebrafish embryos. We show that expression of Class I and Class II genes is highly conserved in the vertebrate neural tube. Further, ventral-most Class II gene expression was completely lost in all Hh pathway mutants analyzed, indicating high levels of Hh signaling are blocked in all of these mutants. In contrast, more dorsally expressed genes were variably affected in different Hh pathway mutants, indicating mid-levels of Hh signaling are differentially affected. This comprehensive expression study provides an important tool for the characterization of Hh signaling in zebrafish and provides a sensitive assay for determining the degree to which newly identified zebrafish mutants affect Hh signaling. PMID:17307034

  8. Nausea and Vomiting in Early Pregnancy and the Risk of Neural Tube Defects: a Case-Control Study

    PubMed Central

    Lu, Qing-Bin; Wang, Zhi-Ping; Gao, Li-Jie; Gong, Rui; Sun, Xi-Hong; Wang, Meng; Zhao, Zhong-Tang

    2015-01-01

    There has been considerable professional debate on the association between nausea and vomiting in early pregnancy (NVP) and neural tube defects (NTDs) risk. This study explored the association between NVP and NTDs risk, and the effect of folic acid supplements on the association. A 1:1 matched case-control study was conducted and conditional logistic regression model was used to analyze the associations. The result showed the odds ratio (OR) of severe NVP for NTDs was 2.403 (95%CI 1.437,4.017; P<0.001) and that of moderate NVP was 1.469 (95%CI 1.063,2.031; P = 0.020) compared with light NVP when adjusted by the potential confounders. Stratified by intake of folic acid supplements, the ORs for severe and moderate NVP turned to 2.147 (95%CI 1.140, 4.043; P = 0.018) and 2.055 (95%CI 1.320, 3.199; P = 0.001) in the stratum of non-intake of folic acid supplements while ORs reduced to 1.851 (95%CI 0.729, 4.699; P = 0.195) and 1.003 (95%CI 0.594, 1.694; P = 0.992) in the stratum of intake of folic acid supplements, respectively. We conclude that severe/moderate NVP has an association with the risk of NTDs, which was not found in the group with intake of folic acid supplements. Folic acid supplements should be recommended to use for the prevention of NTDs. PMID:25567703

  9. A population-based case-control study of risk factors for neural tube defects in Shenyang, China.

    PubMed

    Yin, Zhihua; Xu, Wei; Xu, Changying; Zhang, Shiqi; Zheng, Yajun; Wang, Wei; Zhou, Baosen

    2010-07-01

    PURPOSE: To explore the risk factors for neural tube defects (NTD) in Shenyang, we carried out a population-based case-control study. METHODS: We used chi-square test or Fisher's exact test to evaluate variations in the prevalence by selected covariates. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were derived from univariate and multivariable conditional logistic models. RESULTS: A total of 360,990 births from 2000 to 2007 were screened in Shenyang. Using conditional logistic regression model, 246 mothers of NTD-affected pregnancy were compared with 246 control mothers. A history of maternal previous birth defect-affected pregnancy was a risk factor for NTDs (adjusted OR = 4.00, 95% CI = 1.29-12.45). Risks for NTDs were significantly associated with exposure to maternal factors during the periconceptional period such as a history of fever or cold (adjusted OR = 6.36, 95% CI = 3.24-12.52), use of analgesic and antipyretic drugs (adjusted OR = 4.94, 95% CI = 1.79-13.63), oral contraceptive use (adjusted OR = 2.06, 95% CI = 1.16, 3.68), and passive smoking (adjusted OR = 2.24, 95% CI = 1.04-4.81). Folic acid tablets use and fresh vegetable or fruit consumption >/=6 meals a week in periconception appeared to be protective factors (adjusted OR = 0.33, 0.55, and 0.40 and 95% CI = 0.13-0.44, 0.30-1.01, and 0.21-0.74, respectively). Differences in risk were found between the two most common phenotypes of NTD, anencephaly and spina bifida. CONCLUSIONS: This study suggests that a history of previous birth defect-affected pregnancy, a history of maternal fever or cold, use of analgesics, antipyretics, and oral contraceptives, exposure to passive smoking, folic acid use, and consumption of fresh vegetable and fruit may be associated with NTD risk. PMID:20607247

  10. Maternal consumption of non-staple food in the first trimester and risk of neural tube defects in offspring.

    PubMed

    Wang, Meng; Wang, Zhi-Ping; Gao, Li-Jie; Yang, Hui; Zhao, Zhong-Tang

    2015-01-01

    To study the associations between maternal consumption of non-staple food in the first trimester and risk of neural tube defects (NTDs) in offspring. Data collected from a hospital-based case-control study conducted between 2006 and 2008 in Shandong/Shanxi provinces including 459 mothers with NTDs-affected births and 459 mothers without NTDs-affected births. Logistic regression models were used to examine the associations between maternal consumption of non-staple food in the first trimester and risk of NTDs in offspring. The effects were evaluated by odds ratio (OR) and 95% confidence intervals (95% CIs) with SAS9.1.3.software. Maternal consumption of milk, fresh fruits and nuts in the first trimester were protective factors for total NTDs. Compared with consumption frequency of ?1 meal/week, the ORs for milk consumption frequency of 1-2, 3-6, ?7 meals/week were 0.50 (95% CI: 0.28-0.88), 0.56 (0.32-0.99), and 0.59 (0.38-0.90), respectively; the ORs for fresh fruits consumption frequency of 1-2, 3-6, ?7 meals/week were 0.29 (95% CI: 0.12-0.72), 0.22 (0.09-0.53), and 0.32 (0.14-0.71), respectively; the ORs for nuts consumption frequency of 1-2, 3-6, ?7 meals/week were 0.60 (95% CI: 0.38-0.94), 0.49 (0.31-0.79), and 0.63 (0.36-1.08), respectively. Different effects of above factors on NTDs were found for subtypes of anencephaly and spina bifida. Maternal non-staple food consumption of milk, fresh fruits and nuts in the first trimester was associated with reducing NTDs risk in offspring. PMID:25919306

  11. "Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis".

    PubMed

    Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil Kumar; Mishra, Om Prakash; Rai, Vandana

    2015-02-01

    Epidemiological studies have evaluated the association between maternal methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms and risk of neural tube defects (NTDs) in offspring. However, the results from the published studies on the association between these three polymorphisms and NTD risk are conflicting. To derive a clearer picture of association between these three maternal polymorphisms and risk of NTD, we performed meta-analysis. A comprehensive search was conducted to identify all case-control studies of maternal MTHFR and MTRR polymorphisms and NTD risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, we found that maternal MTHFR C677T polymorphism (OR(TvsC) =1.20; 95% CI = 1.13-1.28) and MTRR A66G polymorphism (OR(GvsA) = 1.21; 95% CI = 0.98-1.49) were risk factors for producing offspring with NTD but maternal MTHFR A1298C polymorphism (OR(CvsA) = 0.91; 95% CI = 0.78-1.07) was not associated with NTD risk. However, in stratified analysis by geographical regions, we found that the maternal C677T polymorphism was significantly associated with the risk of NTD in Asian (OR(TvsC)?= 1.43; 95% CI: 1.05-1.94), European (OR(TvsC)?= 1.13; 95% CI: 1.04-1.24) and American (OR(TvsC)?= 1.26; 95% CI: 1.13-1.41) populations. In conclusion, present meta-analysis supports that the maternal MTHFR C677T and MTRR A66G are polymorphisms contributory to risk for NTD. PMID:25005003

  12. Maternal Consumption of Non-Staple Food in the First Trimester and Risk of Neural Tube Defects in Offspring

    PubMed Central

    Wang, Meng; Wang, Zhi-Ping; Gao, Li-Jie; Yang, Hui; Zhao, Zhong-Tang

    2015-01-01

    To study the associations between maternal consumption of non-staple food in the first trimester and risk of neural tube defects (NTDs) in offspring. Data collected from a hospital-based case-control study conducted between 2006 and 2008 in Shandong/Shanxi provinces including 459 mothers with NTDs-affected births and 459 mothers without NTDs-affected births. Logistic regression models were used to examine the associations between maternal consumption of non-staple food in the first trimester and risk of NTDs in offspring. The effects were evaluated by odds ratio (OR) and 95% confidence intervals (95% CIs) with SAS9.1.3.software. Maternal consumption of milk, fresh fruits and nuts in the first trimester were protective factors for total NTDs. Compared with consumption frequency of ?1 meal/week, the ORs for milk consumption frequency of 1–2, 3–6, ?7 meals/week were 0.50 (95% CI: 0.28–0.88), 0.56 (0.32–0.99), and 0.59 (0.38–0.90), respectively; the ORs for fresh fruits consumption frequency of 1–2, 3–6, ?7 meals/week were 0.29 (95% CI: 0.12–0.72), 0.22 (0.09–0.53), and 0.32 (0.14–0.71), respectively; the ORs for nuts consumption frequency of 1–2, 3–6, ?7 meals/week were 0.60 (95% CI: 0.38–0.94), 0.49 (0.31–0.79), and 0.63 (0.36–1.08), respectively. Different effects of above factors on NTDs were found for subtypes of anencephaly and spina bifida. Maternal non-staple food consumption of milk, fresh fruits and nuts in the first trimester was associated with reducing NTDs risk in offspring. PMID:25919306

  13. Genome-wide association mapping in dogs enables identification of the homeobox gene, NKX2-8, as a genetic component of neural tube defects in humans.

    PubMed

    Safra, Noa; Bassuk, Alexander G; Ferguson, Polly J; Aguilar, Miriam; Coulson, Rochelle L; Thomas, Nicholas; Hitchens, Peta L; Dickinson, Peter J; Vernau, Karen M; Wolf, Zena T; Bannasch, Danika L

    2013-01-01

    Neural tube defects (NTDs) is a general term for central nervous system malformations secondary to a failure of closure or development of the neural tube. The resulting pathologies may involve the brain, spinal cord and/or vertebral column, in addition to associated structures such as soft tissue or skin. The condition is reported among the more common birth defects in humans, leading to significant infant morbidity and mortality. The etiology remains poorly understood but genetic, nutritional, environmental factors, or a combination of these, are known to play a role in the development of NTDs. The variable conditions associated with NTDs occur naturally in dogs, and have been previously reported in the Weimaraner breed. Taking advantage of the strong linkage-disequilibrium within dog breeds we performed genome-wide association analysis and mapped a genomic region for spinal dysraphism, a presumed NTD, using 4 affected and 96 unaffected Weimaraners. The associated region on canine chromosome 8 (pgenome ?=3.0 × 10(-5)), after 100,000 permutations, encodes 18 genes, including NKX2-8, a homeobox gene which is expressed in the developing neural tube. Sequencing NKX2-8 in affected Weimaraners revealed a G to AA frameshift mutation within exon 2 of the gene, resulting in a premature stop codon that is predicted to produce a truncated protein. The exons of NKX2-8 were sequenced in human patients with spina bifida and rare variants (rs61755040 and rs10135525) were found to be significantly over-represented (p=0.036). This is the first documentation of a potential role for NKX2-8 in the etiology of NTDs, made possible by investigating the molecular basis of naturally occurring mutations in dogs. PMID:23874236

  14. Genome-Wide Association Mapping in Dogs Enables Identification of the Homeobox Gene, NKX2-8, as a Genetic Component of Neural Tube Defects in Humans

    PubMed Central

    Safra, Noa; Bassuk, Alexander G.; Ferguson, Polly J.; Aguilar, Miriam; Coulson, Rochelle L.; Thomas, Nicholas; Hitchens, Peta L.; Dickinson, Peter J.; Vernau, Karen M.; Wolf, Zena T.; Bannasch, Danika L.

    2013-01-01

    Neural tube defects (NTDs) is a general term for central nervous system malformations secondary to a failure of closure or development of the neural tube. The resulting pathologies may involve the brain, spinal cord and/or vertebral column, in addition to associated structures such as soft tissue or skin. The condition is reported among the more common birth defects in humans, leading to significant infant morbidity and mortality. The etiology remains poorly understood but genetic, nutritional, environmental factors, or a combination of these, are known to play a role in the development of NTDs. The variable conditions associated with NTDs occur naturally in dogs, and have been previously reported in the Weimaraner breed. Taking advantage of the strong linkage-disequilibrium within dog breeds we performed genome-wide association analysis and mapped a genomic region for spinal dysraphism, a presumed NTD, using 4 affected and 96 unaffected Weimaraners. The associated region on canine chromosome 8 (pgenome?=?3.0×10?5), after 100,000 permutations, encodes 18 genes, including NKX2-8, a homeobox gene which is expressed in the developing neural tube. Sequencing NKX2-8 in affected Weimaraners revealed a G to AA frameshift mutation within exon 2 of the gene, resulting in a premature stop codon that is predicted to produce a truncated protein. The exons of NKX2-8 were sequenced in human patients with spina bifida and rare variants (rs61755040 and rs10135525) were found to be significantly over-represented (p?=?0.036). This is the first documentation of a potential role for NKX2-8 in the etiology of NTDs, made possible by investigating the molecular basis of naturally occurring mutations in dogs. PMID:23874236

  15. A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects.

    PubMed

    Juriloff, Diana M; Harris, Muriel J

    2012-10-01

    A variety of human birth defects originate in failure of closure of the embryonic neural tube. The genetic cause of the most common nonsyndromic defects, spina bifida (SB) or anencephaly, is considered to be combinations of variants at multiple genes. The genes contributing to the etiology of neural tube closure defects (NTDs) are unknown. Mutations in planar cell polarity (PCP) genes in mice cause a variety of defects including the NTD, craniorachischisis, and sometimes SB or exencephaly (EX); they also demonstrate the role of digenic combinations of PCP mutants in NTDs. Recent studies have sought rare predicted-to-be-deleterious alterations (putative mutations) in coding sequence of PCP genes in human cases with various anomalies of the neural tube. This review summarizes the cumulative results of these studies according to a framework based on the embryopathogenesis of NTDs, and considers some of the insights from the approaches used and the limitations. Rare putative mutations in the PCP genes VANGL2, SCRIB, DACT1, and CELSR1 cumulatively contributed to over 20% of cases with craniorachischisis, a rare defect; no contributing variants were found for PRICKLE1 or PTK7. PCP rare putative mutations had a weaker role in myelomeningocele (SB), being found in approximately 6% of cases and cumulated across CELSR1, FUZ, FZD6, PRICKLE1, VANGL1, and VANGL2. These results demonstrate that PCP gene alterations contribute to the etiology of human NTDs. We recommend that future research should explore other types of PCP gene variant such as regulatory mutations and low frequency (1 to 5%) deleterious polymorphisms. PMID:23024041

  16. Health needs assessment for congenital anomalies in middle-income countries: Examining the case for neural tube defects in Brazil.

    PubMed

    Schuler-Faccini, Lavinia; Sanseverino, Maria Teresa V; de Rocha Azevedo, Lígia Marques; Moorthie, Sowmiya; Alberg, Corinna; Chowdhury, Susmita; Sagoo, Gurdeep S; Burton, Hilary; Nacul, Luis C

    2014-04-01

    Recent economic improvement in Brazil has been reflected in better maternal-child health indicators, with decreases in infant and perinatal mortality. However, under-five mortality due to congenital disorders remained unchanged, and congenital disorders have become the second leading cause of infant mortality. In the present study, we used the PHG Foundation Health Needs Assessment (HNA) Toolkit with the objective of first assessing the burden of disease caused by neural tube defects (NTDs) in Brazil and the impact of interventions already put in place to address the burden, and second to evaluate and prioritize further interventions and policies required for its prevention and treatment. The results from these two components of the HNA process are described in this paper. The published literature was reviewed to identify studies of NTDs (prevalence; morbidity; prenatal, perinatal, and postnatal mortality; treatment or prevention). Data on indicators of maternal and child health were obtained directly from the Brazilian Ministry of Health, through the online Live Births Information System (SINASC) and from the Mortality Information System (SIM). Descriptive analyses included reports of the rates of NTD in liveborns, fetal, and infant deaths. Differences between folic acid flour pre-fortification (2001-2004) and post-fortification (2006-2010) periods were expressed as prevalence rate ratios. Around 20 % of fetal deaths were related to congenital disorders with approximately 5 % of those being NTDs. For infant mortality, congenital disorders were notified in approximately 15 % of cases, with NTDs present in 10 % of the malformed children. Although statistically significant, the prevalence rate ratio (PRR) for spina bifida in live births was only 0.937 (95 % confidence interval (CI) 0.884-0.994), a decrease of 6.3 % when comparing the pre and post-fortification periods. The impact of fortification seemed to be more visible in fetal deaths due to anencephaly (PRR?=?0.727, 95 % CI 0.681-0.777) and for spina bifida (PRR?=?0.700, 95 % CI 0.507-0.967) with associated decreases of 27.3 and 30 %. The lower impact of folic acid fortification in Brazil, compared to other Latin-American countries, can be due to differences in dietary habits, concentration of folic acid in flour, as well as characteristic population ethnic composition. The HNA led to the identification of the needs to be addressed in Brazil, including the improvement of reporting congenital disorders within the nationwide birth certification system, and revision of the policy of flour folic acid fortification. PMID:23990401

  17. Neural Tube Defects

    MedlinePLUS

    ... Trying to get pregnant Folic acid During your pregnancy Your pregnant body Prenatal care Eating and nutrition Physical activity Emotional and life changes Staying safe Smoking, alcohol and drugs Dads To Be Giving birth ...

  18. Frizzled 1 and frizzled 2 genes function in palate, ventricular septum and neural tube closure: general implications for tissue fusion processes

    PubMed Central

    Yu, Huimin; Smallwood, Philip M.; Wang, Yanshu; Vidaltamayo, Roman; Reed, Randall; Nathans, Jeremy

    2010-01-01

    The closure of an open anatomical structure by the directed growth and fusion of two tissue masses is a recurrent theme in mammalian embryology, and this process plays an integral role in the development of the palate, ventricular septum, neural tube, urethra, diaphragm and eye. In mice, targeted mutations of the genes encoding frizzled 1 (Fz1) and frizzled 2 (Fz2) show that these highly homologous integral membrane receptors play an essential and partially redundant role in closure of the palate and ventricular septum, and in the correct positioning of the cardiac outflow tract. When combined with a mutant allele of the planar cell polarity gene Vangl2 (Vangl2Lp), Fz1 and/or Fz2 mutations also cause defects in neural tube closure and misorientation of inner ear sensory hair cells. These observations indicate that frizzled signaling is involved in diverse tissue closure processes, defects in which account for some of the most common congenital anomalies in humans. PMID:20940229

  19. Mutations in PTF1A are not a common cause for human VATER/VACTERL association or neural tube defects mirroring Danforth's short tail mouse.

    PubMed

    Gurung, Nirmala; Grosse, Greta; Draaken, Markus; Hilger, Alina C; Nauman, Nuzhat; Müller, Andreas; Gembruch, Ulrich; Merz, Waltraut M; Reutter, Heiko; Ludwig, Michael

    2015-07-01

    Danforth's short tail (Sd) mutant mice exhibit defects of the neural tube and other abnormalities, which are similar to the human vertebral anomalies, anal atresia, cardiac defects, tracheosophageal fistula and/or esophageal atresia, renal and radial abnormalities, and limb defects (VATER/VACTERL) association, including defects of the hindgut. Sd has been shown to underlie ectopic gene expression of murine Ptf1a, which encodes pancreas?specific transcription factor 1A, due to the insertion of a retrotansposon in its 5' regulatory domain. In order to investigate the possible involvement of this gene in human VATER/VACTERL association and human neural tube defects (NTDs), a sequence analysis was performed. DNA samples from 103 patients with VATER/VACTERL and VATER/VACTERL?like association, all presenting with anorectal malformations, and 72 fetuses with NTDs, where termination of pregnancy had been performed, were included in the current study. The complete PTF1A coding region, splice sites and 1.5 kb of the 5' flanking promotor region was sequenced. However, no pathogenic alterations were detected. The results of the present study do not support the hypothesis that high penetrant mutations in these regions of PTF1A are involved in the development of human VATER/VACTERL association or NTDs, although rare mutations may be detectable in larger patient samples. PMID:25775927

  20. Loop-tail phenotype in heterozygous mice and neural tube defects in homozygous mice result from a nonsense mutation in the Vangl2 gene.

    PubMed

    Chen, B; Mao, H H; Chen, L; Zhang, F L; Li, K; Xue, Z F

    2013-01-01

    N-ethyl-N-nitrosourea (ENU) is a powerful point mutagen that can generate random mutations. It has been used to generate mouse mutations to produce phenotypic models of human disease. Neural tube defects (NTD) are common birth defects in which the brain and/or spinal cord can be exposed; however, the mechanisms of these defects are poorly understood. Craniorachischisis is one type of NTD that bears a close resemblance to the phenotype of the loop-tail (Lp) mouse. Here we describe a C57BL/6J Lp mouse generated by ENU-induced mutagenesis. The mutation was mapped to the Vangl2 gene on chromosome 1, near markers D1Mit113 and D1Mit149. Sequence analysis of Vangl2 heterozygotes (Vangl2(m1Yzcm)/+) revealed a C/T transition mutation that resulted in substitution of a glutamine codon for a stop (nonsense) codon at position 449. The Vangl2 protein is involved in epithelium planar cell polarity. The predicted truncated protein would lack the PDZ-domain binding motif involved in protein-protein interaction; therefore, Vangl2(m1Yzcm) may be a loss-of-function mutant. Morphological and histological examination of homozygous mouse embryos revealed a neural tube closure defect that leads to craniorachischisis. This Vangl2(m1Yzcm) mouse represents a valuable model for the study of NTDs in humans. PMID:23359061

  1. NEWS & VIEWS NATURE|Vol 439|26 January 2006 consequence, the edges of the neural tube

    E-print Network

    Tabin, Cliff

    extend neural connections to specialized neurons called granule cells, and to the inferior olive nucleus the inferior olive nucleus5,9 . Additionally, the ratio of these precursor pools within the rhombic lip

  2. Qualitative and quantitative diagnosis of lethal cranial neural tube defects from the fetal and neonatal human skeleton, with a case study involving taphonomically altered remains.

    PubMed

    Dudar, J Christopher

    2010-07-01

    Cranial neural tube defect, or anencephaly, is the absence of normal brain development because of severe developmental defect in the fetus. While the current incidence of human anencephaly ranges between 1 to 5 per 1000 births, and was higher prior to folic acid supplementation, there is no discussion of anencephaly diagnosis in the forensic literature and only one published example from the archeological record. This article presents both qualitative observations of abnormal cranial elements and an osteometric method to quantitatively determine anencephaly from forensic recovery contexts where taphonomic variables may otherwise mask diagnostic characteristics. Evidence is presented for only the second case of anencephaly diagnosed from a burial context, and the first not involving soft tissue mummification. The initial recognition and accurate prediction of anencephaly is a significant contribution to investigators recovering found human fetal remains. PMID:20384923

  3. Neural tube defects on the Texas-Mexico border: what we've learned in the 20 years since the Brownsville cluster.

    PubMed

    Suarez, Lucina; Felkner, Marilyn; Brender, Jean D; Canfield, Mark; Zhu, Huiping; Hendricks, Katherine A

    2012-11-01

    We reviewed the published findings from the Texas Neural Tube Defect Project, a 6-year case-control study (1995-2000) of neural tube defects (NTDs) on the Texas-Mexico border. In this review, we highlight what was learned about environmental, genetic, and nutritional factors (i.e., those related to the folate and other metabolic pathways) and the novel putative risk factors that emerged from this study of Mexican American women living on the Texas-Mexico border. Our investigations of the micronutrients and metabolic pathways involved confirmed the findings of other researchers that increased folate intake has a protective effect and that low serum B(12) , high serum homocysteine levels, and obesity independently contribute to risk. Studies of this population also have implicated hyperinsulinemia and low ferritin, metabolic risk factors, which require additional study to elucidate their physiologic mechanism. Environmental contaminants such as heavy metals, pesticides, and polychlorinated biphenyls (PCBs), which were of community concern, did little to explain NTD risk. Studies in this folic acid deficit-population also revealed several novel risk factors, namely, diarrhea, stress, fumonisins, and the combination of nitrosatable drug exposure with high nitrate/nitrite intake. In conclusion, the 23 studies among the Mexican American women living along the Texas-Mexico border have demonstrated the multifactorial nature of NTDs and that a population deficient in folic acid will be vulnerable to a variety of insults whether brought on by individual behaviors (e.g., obesity) or through the surrounding environment (e.g., fumonisins). Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc. PMID:22945287

  4. Independent mutations at Arg181 and Arg274 of Vangl proteins that are associated with neural tube defects in humans decrease protein stability and impair membrane targeting.

    PubMed

    Iliescu, Alexandra; Gravel, Michel; Horth, Cynthia; Gros, Philippe

    2014-08-19

    In vertebrates, Vangl proteins play important roles during embryogenesis, including establishing planar polarity and coordinating convergent extension movements. In mice, homozygosity for mutations in the Vangl1 and Vangl2 genes or combined heterozygosity for Vangl1/Vangl2 mutations causes the very severe neural tube defect (NTD) craniorachischisis. Recently, a number of patient-specific VANGL1 and VANGL2 protein mutations have been identified in familial and sporadic cases of mild and severe forms of NTDs. The biochemical nature of pathological effects in these mutations remains unknown. Of interest are two arginine residues, R181 and R274, that are highly conserved in Vangl protein homologues and found to be independently mutated in VANGL1 (R181Q and R274Q) and VANGL2 (R177H and R270H) in human cases of NTDs. The cellular and biochemical properties of R181Q and R274Q were established in transfected MDCK kidney epithelial cells and compared to those of wild-type (WT) Vangl1. Compared to that of WT, these mutations displayed impaired targeting to the plasma membrane and were instead detected in an intracellular endomembrane compartment that was positive for the endoplasmic reticulum. R181Q and R274Q showed impaired stability with significant reductions in measured half-lives from >20 h for WT protein to 9 and 5 h, respectively. These mutations have a cellular and biochemical phenotype that is indistinguishable from that of Vangl mutations known to cause craniorachichisis in mice (Lp). These results strongly suggest that R181 and R274 play critical roles in Vangl protein function and that their mutations cause neural tube defects in humans. PMID:25068569

  5. Maternal PCMT1 gene polymorphisms and the risk of neural tube defects in a Chinese population of Lvliang high-risk area.

    PubMed

    Zhao, Huizhi; Wang, Fang; Wang, Jianhua; Xie, Hua; Guo, Jin; Liu, Chi; Wang, Li; Lu, Xiaolin; Bao, Yihua; Wang, Guoliang; Zhong, Rugang; Niu, Bo; Zhang, Ting

    2012-09-01

    Protein-L-isoaspartate (D-aspartate) O-methyltransferase 1 (PCMT1) gene encodes for the protein repair enzyme L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), which is known to protect certain neural cells from Bax-induced apoptosis. Previous study has shown that PCMT1 polymorphisms rs4552 and rs4816 of infant are associated with spina bifida in the Californian population. The association between maternal polymorphism and neural tube defects is still uncovered. A case-control study was conducted to investigate a possible association between maternal PCMT1 and NTDs in Lvliang high-risk area of Shanxi Province in China, using a high-resolution DNA melting analysis genotyping method. We found that increased risk for anencephaly in isolated NTDs compared with the normal control group was observed for the G (vs. A) allele (p=0.034, OR=1.896, 95% CI, 1.04-3.45) and genotypes GG+GA (p=0.025, OR=2.237, 95% CI, 1.09-4.57). Although the significance was lost after multiple comparison correction, the results implied that maternal polymorphisms in PCMT1 might be a potential genetic risk factor for isolated anencephaly in this Chinese population. PMID:22647835

  6. PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case-control study in a population with relatively low folate intake.

    PubMed

    Wang, Fang; Wang, Jianhua; Guo, Jin; Chen, Xiaoli; Guan, Zhen; Zhao, Huizhi; Xie, Hua; Liu, Chi; Bao, Yihua; Zou, Jizhen; Niu, Bo; Zhang, Ting

    2013-11-01

    The PCMT1 gene encodes the protein repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase, which is known to protect certain neural cells against Bax-induced apoptosis. Previous studies have produced inconsistent results regarding the effects of PCMT1 (rs4816 and rs4552) polymorphisms on neural tube defects (NTDs). Reduced maternal plasma folate levels and/or elevated homocysteine (Hcy) levels are considered to be risk factors for NTDs. In order to clarify the key factors contributing to the apparent discrepancy and investigate gene-environment interaction, we conducted a case-control study including 121 cases and 146 matched controls to investigate the association between the two PCMT1 polymorphisms in fetuses and the risk of NTDs in the Chinese population of Lvliang, which has low folate intake. Maternal plasma folate and Hcy levels were also measured, and the interaction between fetal PCMT1 gene status and maternal folate metabolites was assessed. Maternal plasma folate concentrations in the NTD group were lower than in controls (10.23 vs. 13.08 nmol/L, adjusted P = 0.059), and Hcy concentrations were significantly higher (14.46 vs. 11.65 ?mol/L, adjusted P = 0.026). Fetuses carrying the rs4816 AG + GG genotype, combined with higher maternal plasma Hcy, had a 6.46-fold (95 % CI 1.15-36.46) increased risk of anencephaly. The results of this study imply that the fetal PCMT1 rs4816 polymorphism may play only a weak role in NTD formation and that gene-environment interactions might be more significant. PMID:23918616

  7. Neurobiology and Neural Systems

    Microsoft Academic Search

    Tsuneya Ikezu; Howard E. Gendelman

    Neurobiology is the study and functional organization of the cells that make up the nervous system. The central nervous system\\u000a (CNS) begins as a simple neural plate that folds to form a groove and then a tube. Then stem cells within the neural tube\\u000a are directed toward glia and neurons under the influence of various neural developing signaling processes. It

  8. Selective screening for inborn errors of metabolism and secondary methylmalonic aciduria in pregnancy at high risk district of neural tube defects: A human metabolome study by GC-MS in China

    Microsoft Academic Search

    Yuan-Zong Song; Bing-Xiao Li; Hu Hao; Ruo-Lei Xin; Ting Zhang; Chun-Hua Zhang; Keiko Kobayashi; Zi-Neng Wang; Xiao-Ying Zheng

    2008-01-01

    ObjectiveUrease pretreatment-gas chromatography-mass spectrometry (UP-GC-MS) has become a valuable tool in the field of metabolome research, including analysis of inborn errors of metabolism (IEMs) and acquired metabolic disturbances secondary to nutrition or drugs. This research aims to screen IEMs in Chinese patients and to explore the cause of neural tube defects (NTDs), a congenital malformation very common in North China.

  9. Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa

    Microsoft Academic Search

    Abdul-Rauf Sayed; David Bourne; Robert Pattinson; Jo Nixon; Bertram Henderson

    2008-01-01

    BACKGROUND: In October 2003 South Africa embarked on a program of folic acid fortification of staple foods. We measured the change in prevalence of NTDs before and after fortification and assessed the cost benefit of this primary health care intervention. METHODS: Since the beginning of 2002 an ecological study was conducted among 12 public hospitals in four provinces of South

  10. Genetic effects on variation in red-blood-cell folate in adults: Implications for the familial aggregation of neural tube defects

    SciTech Connect

    Mitchell, L.E. [Children`s Hospital of Philadelphia, PA (United States); Duffy, P.; Bellingham, G. [Prince Charles Hospital, Brisbane (Australia)] [and others

    1997-02-01

    Recent studies have implicated folic acid as an important determinant of normal human growth, development, and function. Insufficient folate levels appear to be a risk factor for neural tube defects (NTD), as well as for several chronic diseases of adulthood. However, relatively little is known about the factors that influence folate status in the general population. To estimate the relative contribution of genetic and nongenetic factors to variation in folate, we have evaluated red blood cell (RBC) folate levels in 440 pairs of MZ twins and in 331 pairs of DZ twins. The data were best described by a model in which 46% of the variance in RBC folate was attributable to additive genetic effects, 16% of the variance was due to measured phenotypic covariates, and 38% of the variance was due to random environmental effects. Moreover, the correlations for RBC folate in MZ co-twins (r = .46) and in repeat measures from the same individual (r = .51) were very similar, indicating that virtually all repeatable variation in RBC folate is attributable to genetic factors. On the basis of these results, it would seem reasonable to initiate a search for the specific genes that influence RBC folate levels in the general population. Such genes ultimately may be used to identify individuals at increased risk for NTD and other folate-related diseases. 23 refs., 1 tab.

  11. SNPs in the CpG island of NAP1L2: a possible link between DNA methylation and neural tube defects?

    PubMed

    Rogner, Ute Christine; Danoy, Patrick; Matsuda, Fumihiko; Moore, Gudrun Elizabeth; Stanier, Philip; Avner, Philip

    2002-07-01

    Deletion of the murine X-linked Nap1l2 gene causes lethality from midgestation onwards. The affected embryos exhibit neural tube defects (NTDs) closely resembling spina bifida and anencephaly in humans. X-linked familial and spontaneous cases of NTD were analyzed for sequence alterations in the human NAP1L2. No differences were found in the familial cases. However, a number of single nucleotide polymorphisms (SNPs) within the 5' region of NAP1L2 were identified both in cases of spontaneous NTD and in normal controls. Most of these SNPs lead to the replacement of guanidines or cytosines within a CpG island that is conserved between the human and the mouse promoter regions. Demethylation in vitro activates Nap1l2 transcriptional activity, suggesting the importance of the CpG island in regulating the activity of the Nap1l2/NAP1L2 genes, and the potential importance of the polymorphisms in modifying their transcriptional activity. NAP1L2/Nap1l2 expression may therefore depend on the genetic-environmental factors that are frequently associated with NTDs. PMID:12116227

  12. Genetic basis of neural tube defects: The mouse gene loop-tail maps to a region of chromosome 1 syntenic with human 1q21-q23

    SciTech Connect

    Stanier, P.; Moore, G.E. [Institute of Obstetrics and Gynaecology, London (United Kingdom)] [Institute of Obstetrics and Gynaecology, London (United Kingdom); Henson, J.N. [Univ. of London (United Kingdom)] [and others] [Univ. of London (United Kingdom); and others

    1995-04-10

    A genetic basis for neural tube defects (NTD) is rarely doubted, but the genes involved have not yet been identified. This is partly due to a lack of suitable families on which to perform linkage analysis. An alternative approach is to use the many mouse genes that cause NTD as a means of isolating their human homologues. Loop-tail (Lp) is a semidominant mouse gene that, in homozygous mutants, causes the severe NTD phenotype cranio-rachischisis. As a first step toward cloning Lp, we have performed linkage analysis on an intraspecific backcross, using microsatellite and RFLP DNA markers. This study has localized Lp to a region of approximately 1.46 cM on mouse chromosome 1, flanked by the gene for the {alpha} chain of high-affinity Fc receptor for IgE (Fcer1{alpha}) and a microsatellite repeat D1Mit113. Physical mapping data in the region suggest that the interval is likely to be no more than 1.8 Mb in size. The localization is several centimorgans distal to that previously assigned by linkage studies with biochemical and visible markers and suggests that the human homologue of Lp is likely to reside in a region of conserved homology on 1q21-q23. 36 refs., 3 figs., 3 tabs.

  13. Geographic and urban–rural disparities in the total prevalence of neural tube defects and their subtypes during 2006–2008 in China: a study using the hospital-based birth defects surveillance system

    PubMed Central

    2013-01-01

    Background Previous reports on the prevalence of neural tube defects (NTDs) in China did not include cases of NTDs that were less than 28?weeks of gestational age (GA) and hence did not accurately reflect the total prevalence of NTDs or the geographic and urban–rural disparities in their prevalence. This article includes cases of NTDs that were less than 28?weeks of GA. Methods Data used in this study were collected from 2006 to 2008 using a nationwide hospital-based registry, the Chinese Birth Defects Monitoring Network. The total prevalence ratio (PR) of NTDs and their subtypes, the ratios of PR (PRR), and 95% confidence intervals (CI) were used to analyse geographic disparities at both the regional (north, south) and provincial levels and to analyse disparities between rural and urban areas. Results Overall, the total PR of NTDs was 14.0 per 10,000 births. The PRR of NTDs of rural women between the north and south region was 2.26 (95% CI: 2.04-2.52), which was much higher than that of urban women (PRR: 1.56, 95% CI: 1.41-1.72). The three subtypes of NTDs had different geographic distribution at the level of province. The urban–rural PRR of NTDs was 2.14 (95% CI: 1.94-2.34) in the north but only 1.47 (95% CI: 1.31-1.66) in the south. Conclusions There is a high total prevalence of NTDs, which remains one of the major public health concerns in China. Eliminating the geographic and urban–rural disparities in the disease burden is a priority for future intervention. PMID:23433029

  14. Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

    PubMed Central

    Allache, Redouane; Lachance, Stéphanie; Guyot, Marie Claude; De Marco, Patrizia; Merello, Elisa; Justice, Monica J.; Capra, Valeria; Kibar, Zoha

    2014-01-01

    Wnt signaling has been classified as canonical Wnt/?-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor–related protein Lrp6 is crucial for the activation of the Wnt/?-catenin pathway, but its function in Wnt/PCP signaling remains largely unknown. In this study, we investigate the role of Lrp6 as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of Lrp6 (Skax26m1Jus) and in human NTDs. We demonstrate that Skax26m1Jus represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6Skax26-Jus genetically interacts with a PCP mutant (Vangl2Lp) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells’ polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process. PMID:24203697

  15. Gender-dependent differences in the incidence of ochratoxin A-induced neural tube defects in the Pdn/Pdn mouse.

    PubMed

    Ueta, Etsuko; Kodama, Mami; Sumino, Yoshiki; Kurome, Maho; Ohta, Ken-ichi; Katagiri, Ryu-ichi; Naruse, Ichiro

    2010-03-01

    Genetic polydactyly/arhinencephaly mouse embryo, Pdn/Pdn, exhibits suppression of Gli3 gene expression. Ochratoxin A (OTA) is a teratogen that causes neural tube defects (NTD) in mice. We investigated gender-dependent differences in the incidence of NTD induced by OTA in the Pdn/Pdn mouse. After administering 2 mg/kg OTA to Pdn/+ female mice, mated with Pdn/+ males, on day 7.5 of gestation, we examined the genotypes, sex and NTD of fetuses on day 18. Non-treated Pdn/Pdn had a 15.8% risk of NTD, and all NTD fetuses were female. When Pdn/Pdn embryos were exposed to OTA, the incidence of NTD increased to 16 (51.6%) of 31 Pdn/Pdn fetuses, and 10 (71.4%) of 14 male Pdn/Pdn fetuses exhibited NTD. From these results, it was speculated that NTD in OTA-treated male Pdn/Pdn were due to the synergistic effect between depressed Gli3 and altered sex-correlated gene expression from OTA treatment. After treatment with OTA, the embryos were recovered on day 9 and gene expressions, which were correlated with Gli3, telencephalic morphogenesis, formation of gonadal anlage, and gender-dependent differentiation were investigated. From real-time polymerase chain reaction analysis results, it was suggested that the manifestation of NTD in the male OTA-treated Pdn/Pdn might be due to the complicated altered gene expressions among Gli3, Wnt7b, Wnt8b, Fez1, Barx1, Lim1, Dmrt1, Igf1, Fog2, Dax1 and Sox9, and in particular, upregulation and gender-dependent difference in Barx1 and gender-dependent difference in Sox9 gene expressions might be noteworthy findings. PMID:20201966

  16. The Maternal ITPK1 Gene Polymorphism Is Associated with Neural Tube Defects in a High-Risk Chinese Population

    PubMed Central

    Guo, Jin; Wang, Fang; Wang, Xiuwei; Li, Guannan; Xie, Qiu; Han, Xu; Niu, Bo; Zhang, Ting

    2014-01-01

    Background Epidemiological surveys and animal studies have revealed that inositol metabolism is associated with NTDs, but the mechanisms are not clear. Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a pivotal regulatory enzyme in inositol metabolic pathway. The objective was to assess the potential impact of the maternal ITPK1 genotypes on the inositol parameter and on the NTD risk in a NTD high-risk area in China. Methodology/Results A case-control study of pregnant women affected with NTDs (n?=?200) and controls (n?=?320) was carried out. 13 tag SNPs of ITPK1 were selected and genotyped by the Sequenom MassArray system. We found that 4 tag SNPs were statistically significant in spina bifida group (P<0.05). MACH was used to impute the un-genotyped SNPs in ITPK1 locus and showed that 3 meaningful SNPs in the non-coding regions were significant. We also predicted the binding capacity of transcription factors in the positive SNPs using the bioinformatics method and found that only rs3783903 was located in the conserved sequence of activator protein-1 (AP-1). To further study the association between biochemical values and genotypes, maternal plasma inositol hexakisphosphate (IP6) levels were also assessed using LC-MS. The maternal plasma IP6 concentrations in the spina bifida subgroup were 7.1% lower than control (136.67 vs. 147.05 ng mL?1, P<0.05), and significantly lower in rs3783903 GG genotype than others (P<0.05). EMSA showed a different allelic binding capacity of AP-1 in rs3783903, which was affected by an A?G exchange. The RT-PCR suggested the ITPK1 expression was decreased significantly in mutant-type of rs3783903 compared with wild-type in the 60 healthy pregnancies (P<0.05). Conclusions/Significance These results suggested that the maternal rs3783903 of ITPK1 might be associated with spina bifida, and the allele G of rs3783903 might affect the binding of AP-1 and the decrease of maternal plasma IP6 concentration in this Chinese population. PMID:24465924

  17. Artificial Neural Networks Single Layer Networks Multi Layer Networks Generalization Artificial Neural Networks

    E-print Network

    Kjellström, Hedvig

    Artificial Neural Networks Single Layer Networks Multi Layer Networks Generalization Artificial Neural Networks #12;Artificial Neural Networks Single Layer Networks Multi Layer Networks Generalization 1 Artificial Neural Networks Properties Applications Classical Examples Biological Background 2

  18. Artificial Neural Networks Single Layer Networks Multi Layer Networks Generalization Artificial Neural Networks

    E-print Network

    Kjellström, Hedvig

    Artificial Neural Networks Single Layer Networks Multi Layer Networks Generalization Artificial Neural Networks Artificial Neural Networks Single Layer Networks Multi Layer Networks Generalization 1 Artificial Neural Networks Properties Applications Classical Examples Biological Background 2 Single Layer

  19. Massive-training artificial neural network (MTANN) for reduction of false positives in computer-aided detection of polyps: Suppression of rectal tubes

    SciTech Connect

    Suzuki, Kenji; Yoshida, Hiroyuki; Naeppi, Janne; Dachman, Abraham H. [Department of Radiology, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637 (United States); Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 75 Blossom Court, Suite 220, Boston, Massachusetts 02114 (United States); Department of Radiology, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637 (United States)

    2006-10-15

    One of the limitations of the current computer-aided detection (CAD) of polyps in CT colonography (CTC) is a relatively large number of false-positive (FP) detections. Rectal tubes (RTs) are one of the typical sources of FPs because a portion of a RT, especially a portion of a bulbous tip, often exhibits a cap-like shape that closely mimics the appearance of a small polyp. Radiologists can easily recognize and dismiss RT-induced FPs; thus, they may lose their confidence in CAD as an effective tool if the CAD scheme generates such ''obvious'' FPs due to RTs consistently. In addition, RT-induced FPs may distract radiologists from less common true positives in the rectum. Therefore, removal RT-induced FPs as well as other types of FPs is desirable while maintaining a high sensitivity in the detection of polyps. We developed a three-dimensional (3D) massive-training artificial neural network (MTANN) for distinction between polyps and RTs in 3D CTC volumetric data. The 3D MTANN is a supervised volume-processing technique which is trained with input CTC volumes and the corresponding ''teaching'' volumes. The teaching volume for a polyp contains a 3D Gaussian distribution, and that for a RT contains zeros for enhancement of polyps and suppression of RTs, respectively. For distinction between polyps and nonpolyps including RTs, a 3D scoring method based on a 3D Gaussian weighting function is applied to the output of the trained 3D MTANN. Our database consisted of CTC examinations of 73 patients, scanned in both supine and prone positions (146 CTC data sets in total), with optical colonoscopy as a reference standard for the presence of polyps. Fifteen patients had 28 polyps, 15 of which were 5-9 mm and 13 were 10-25 mm in size. These CTC cases were subjected to our previously reported CAD scheme that included centerline-based segmentation of the colon, shape-based detection of polyps, and reduction of FPs by use of a Bayesian neural network based on geometric and texture features. Application of this CAD scheme yielded 96.4% (27/28) by-polyp sensitivity with 3.1 (224/73) FPs per patient, among which 20 FPs were caused by RTs. To eliminate the FPs due to RTs and possibly other normal structures, we trained a 3D MTANN with ten representative polyps and ten RTs, and applied the trained 3D MTANN to the above CAD true- and false-positive detections. In the output volumes of the 3D MTANN, polyps were represented by distributions of bright voxels, whereas RTs and other normal structures partly similar to RTs appeared as darker voxels, indicating the ability of the 3D MTANN to suppress RTs as well as other normal structures effectively. Application of the 3D MTANN to the CAD detections showed that the 3D MTANN eliminated all RT-induced 20 FPs, as well as 53 FPs due to other causes, without removal of any true positives. Overall, the 3D MTANN was able to reduce the FP rate of the CAD scheme from 3.1 to 2.1 FPs per patient (33% reduction), while the original by-polyp sensitivity of 96.4% was maintained.

  20. A population-based case-control study of risk factors for neural tube defects in four high-prevalence areas of Shanxi province, China.

    PubMed

    Li, Zhiwen; Ren, Aiguo; Zhang, Le; Guo, Zhanying; Li, Zhu

    2006-01-01

    Shanxi province in Northern China has one of the highest reported prevalence rates of neural tube defects (NTD) in the world. To explore the risk factors for NTDs in Shanxi province, we carried out a population-based case-control study in four selected counties with prevalence rates >10 per 1000 births during 2003. Using a multi-logistic regression model analysis (alpha = 0.10), 158 NTD cases were compared with 226 control mothers. Maternal factors significantly associated with increased risk for an NTD were a primary school education or lower (adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 1.09, 4.97); a history of a previous birth defect-affected pregnancy (adjusted OR 5.27, 95% CI 0.98, 28.37); history of a fever or 'cold' (adjusted OR 3.36, 95% CI 1.68, 6.72); use of analgesic and antipyretic drugs (adjusted OR 4.89, 95% CI 0.92, 25.97); daily passive exposure to cigarette smoke (adjusted OR 1.60, 95% CI 0.94, 2.73); poor ventilation during heating (adjusted OR 3.91, 95% CI 0.75, 20.81); and consumption of >or= six meals per week containing pickled vegetables (adjusted OR 3.86, 95% CI 1.11, 13.47) during pregnancy. Factors which appeared to be protective were meat consumption one to three times per week (adjusted OR 0.62, 95% CI 0.37, 1.06), or >or= four times per week (adjusted OR 0.28, 95% CI 0.11, 0.77); and legume consumption >or= six times per week (adjusted OR 0.39, 95% CI 0.17, 0.89). Differences in risk were found between the two most common phenotypes, anencephaly and spina bifida. Most of the environmental factors had stronger positive and negative associations with risk for anencephaly rather than spina bifida, whereas history of a previous birth defect-associated pregnancy, as well as legume consumption, were more strongly associated with the risk for spina bifida than for anencephaly. The findings suggest that aetiological heterogeneity may exist between anencephaly and spina bifida. PMID:16420340

  1. What Are Neural Tube Defects?

    MedlinePLUS

    ... are born with spina bifida will have normal intelligence, but some will have learning or intellectual disabilities . ... effects, some children with this condition have normal intelligence. 6 Iniencephaly Iniencephaly(pronounced in-ee-ehn-SEF- ...

  2. apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-I transport rates in heterozygotes.

    PubMed Central

    Huang, L S; Voyiaziakis, E; Markenson, D F; Sokol, K A; Hayek, T; Breslow, J L

    1995-01-01

    apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes. Images PMID:7593600

  3. The curly tail mouse model of human neural tube defects demonstrates normal spinal cord differentiation at the level of the meningomyelocele: implications for fetal surgery

    Microsoft Academic Search

    Mehmet Selçuki; Simon Manning; Merton Bernfield

    2001-01-01

    The paralysis associated with lumbosacral meningomyelocele has been attributed both to myelodysplasia and to degeneration\\u000a of the exposed neural tissue. Surgically created dysraphism shows that exposure of an intact spinal cord in a genetically\\u000a normal animal results in degeneration of the normal nervous tissue and subsequent paralysis. Our objective was to study neuronal\\u000a differentiation in the curly tail mouse mutant

  4. Null mutation of the Lmo4 gene or a combined null mutation of the Lmo1/Lmo3 genes causes perinatal lethality, and Lmo4 controls neural tube development in mice.

    PubMed

    Tse, E; Smith, A J H; Hunt, S; Lavenir, I; Forster, A; Warren, A J; Grutz, G; Foroni, L; Carlton, M B L; Colledge, W H; Boehm, T; Rabbitts, T H

    2004-03-01

    The LIM-only family of proteins comprises four members; two of these (LMO1 and LMO2) are involved in human T-cell leukemia via chromosomal translocations, and LMO2 is a master regulator of hematopoiesis. We have carried out gene targeting of the other members of the LIM-only family, viz., genes Lmo1, Lmo3 and Lmo4, to investigate their role in mouse development. None of these genes has an obligatory role in lymphopoiesis. In addition, while null mutations of Lmo1 or Lmo3 have no discernible phenotype, null mutation of Lmo4 alone causes perinatal lethality due to a severe neural tube defect which occurs in the form of anencephaly or exencephaly. Since the Lmo1 and Lmo3 gene sequences are highly related and have partly overlapping expression domains, we assessed the effect of compound Lmo1/Lmo3 null mutations. Although no anatomical defects were apparent in compound null pups, these animals also die within 24 h of birth, suggesting that a compensation between the related Lmo1 and 3 proteins can occur during embryogenesis to negate the individual loss of these genes. Our results complete the gene targeting of the LIM-only family in mice and suggest that all four members of this family are important in regulators of distinct developmental pathways. PMID:14966285

  5. Nasogastric feeding tube

    MedlinePLUS

    Feeding - nasogastric tube; NG tube; Bolus feeding; Continuous pump feeding; Gavage tube ... A nasogastric tube (NG tube) is a special tube that carries food and medicine to the stomach through the nose. It ...

  6. Feeding tube insertion - gastrostomy

    MedlinePLUS

    ... tube insertion; G-tube insertion; PEG tube insertion; Stomach tube insertion; Percutaneous endoscopic gastrostomy tube insertion ... and down the esophagus, which leads to the stomach. After the endoscopy tube is inserted, the skin ...

  7. Multiple tube premixing device

    DOEpatents

    Uhm, Jong Ho; Varatharajan, Balachandar; Ziminsky, Willy Steve; Kraemer, Gilbert Otto; Yilmaz, Ertan; Lacy, Benjamin; Stevenson, Christian; Felling, David

    2012-12-11

    The present application provides a premixer for a combustor. The premixer may include a fuel plenum with a number of fuel tubes and a burner tube with a number of air tubes. The fuel tubes extend about the air tubes.

  8. Emergence and migration of trunk neural crest cells in a snake, the California Kingsnake (Lampropeltis getula californiae)

    PubMed Central

    2010-01-01

    Background The neural crest is a group of multipotent cells that emerges after an epithelial-to-mesenchymal transition from the dorsal neural tube early during development. These cells then migrate throughout the embryo, giving rise to a wide variety derivatives including the peripheral nervous system, craniofacial skeleton, pigment cells, and endocrine organs. While much is known about neural crest cells in mammals, birds, amphibians and fish, relatively little is known about their development in non-avian reptiles like snakes and lizards. Results In this study, we show for the first time ever trunk neural crest migration in a snake by labeling it with DiI and immunofluorescence. As in birds and mammals, we find that early migrating trunk neural crest cells use both a ventromedial pathway and an inter-somitic pathway in the snake. However, unlike birds and mammals, we also observed large numbers of late migrating neural crest cells utilizing the inter-somitic pathway in snake. Conclusions We found that while trunk neural crest migration in snakes is very similar to that of other amniotes, the inter-somitic pathway is used more extensively by late-migrating trunk neural crest cells in snake. PMID:20482793

  9. Autophagic Tubes

    PubMed Central

    Müller, Oliver; Sattler, Tanja; Flötenmeyer, Matthias; Schwarz, Heinz; Plattner, Helmut; Mayer, Andreas

    2000-01-01

    Many intracellular compartments of eukaryotic cells do not adopt a spherical shape, which would be expected in the absence of mechanisms organizing their structure. However, little is known about the principles determining the shape of organelles. We have observed very defined structural changes of vacuoles, the lysosome equivalents of yeast. The vacuolar membrane can form a large tubular invagination from which vesicles bud off into the lumen of the organelle. Formation of the tube is regulated via the Apg/Aut pathway. Its lumen is continuous with the cytosol, making this inverse budding reaction equivalent to microautophagocytosis. The tube is highly dynamic, often branched, and defined by a sharp kink of the vacuolar membrane at the site of invagination. The tube is formed by vacuoles in an autonomous fashion. It persists after vacuole isolation and, therefore, is independent of surrounding cytoskeleton. There is a striking lateral heterogeneity along the tube, with a high density of transmembrane particles at the base and a smooth zone devoid of transmembrane particles at the tip where budding occurs. We postulate a lateral sorting mechanism along the tube that mediates a depletion of large transmembrane proteins at the tip and results in the inverse budding of lipid-rich vesicles into the lumen of the organelle. PMID:11062254

  10. Mystery Tubes

    NSDL National Science Digital Library

    2012-12-27

    Learners investigate a pre-constructed mystery tube to determine its interior mechanism. Working in small groups, learners pose explanations (hypotheses) for what they are observing and test their hypotheses. In a possible extension of this activity, learners build their own model to test their hypothesis. This lesson serves as a good introduction to the nature of scientific inquiry.

  11. Tube Feedings.

    ERIC Educational Resources Information Center

    Plummer, Nancy

    This module on tube feedings is intended for use in inservice or continuing education programs for persons who work in long-term care. Instructor information, including teaching suggestions and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then provided. A brief discussion follows…

  12. Samba, a Xenopus hnRNP expressed in neural and neural crest tissues.

    PubMed

    Yan, Chao Yun Irene; Skourides, Paris; Chang, Chenbei; Brivanlou, Ali

    2009-01-01

    RNA binding proteins regulate gene expression at the posttranscriptional level and play important roles in embryonic development. Here, we report the cloning and expression of Samba, a Xenopus hnRNP that is maternally expressed and persists at least until tail bud stages. During gastrula stages, Samba is enriched in the dorsal regions. Subsequently, its expression is elevated only in neural and neural crest tissues. In the latter, Samba expression overlaps with that of Slug in migratory neural crest cells. Thereafter, Samba is maintained in the neural crest derivatives, as well as other neural tissues, including the anterior and posterior neural tube and the eyes. Overexpression of Samba in the animal pole leads to defects in neural crest migration and cranial cartilage development. Thus, Samba encodes a Xenopus hnRNP that is expressed early in neural and neural crest derivatives and may regulate crest cells migratory behavior. PMID:19097051

  13. Neural crest cell formation and migration in the developing embryo

    Microsoft Academic Search

    MARIANNE BRONNER-FRASER

    1994-01-01

    Neural crest cells arise from the neural tube shortly after its closure and migrate extensively through prescribed regions of the embryos, where they differentiate into most of the peripheral nervous system as well as the facial skeleton and pigment cells. Along the embryonic axis, several distinct neural crest populations differ both in their migratory pathways and range of derivatives. Whereas

  14. Electron tube

    DOEpatents

    Suyama, Motohiro (Hamamatsu, JP); Fukasawa, Atsuhito (Hamamatsu, JP); Arisaka, Katsushi (Los Angeles, CA); Wang, Hanguo (North Hills, CA)

    2011-12-20

    An electron tube of the present invention includes: a vacuum vessel including a face plate portion made of synthetic silica and having a surface on which a photoelectric surface is provided, a stem portion arranged facing the photoelectric surface and made of synthetic silica, and a side tube portion having one end connected to the face plate portion and the other end connected to the stem portion and made of synthetic silica; a projection portion arranged in the vacuum vessel, extending from the stem portion toward the photoelectric surface, and made of synthetic silica; and an electron detector arranged on the projection portion, for detecting electrons from the photoelectric surface, and made of silicon.

  15. Neutron tubes

    DOEpatents

    Leung, Ka-Ngo (Hercules, CA); Lou, Tak Pui (Berkeley, CA); Reijonen, Jani (Oakland, CA)

    2008-03-11

    A neutron tube or generator is based on a RF driven plasma ion source having a quartz or other chamber surrounded by an external RF antenna. A deuterium or mixed deuterium/tritium (or even just a tritium) plasma is generated in the chamber and D or D/T (or T) ions are extracted from the plasma. A neutron generating target is positioned so that the ion beam is incident thereon and loads the target. Incident ions cause D-D or D-T (or T-T) reactions which generate neutrons. Various embodiments differ primarily in size of the chamber and position and shape of the neutron generating target. Some neutron generators are small enough for implantation in the body. The target may be at the end of a catheter-like drift tube. The target may have a tapered or conical surface to increase target surface area.

  16. Vitamin dificiencies and neural tube defects

    Microsoft Academic Search

    R. W. Smithells; S Sheppard; C J Schorah

    1976-01-01

    Serum folate, red cell folate, white blood cell vitamin C, riboflavin saturation index, and serum vitamin A were determined during the first trimester of pregnancy in over 900 cases. For each of these there was a social classes I + II showed the highest levels which differed significantly from other classes, except for serum folate. In 6 mothers who gave

  17. Embryology Applied to Neural Tube Defects (NTDs)

    Microsoft Academic Search

    Martin Catala

    Spina bifida is a frequent congenital malformation involving the spinal cord. It was first described by Nicolas Tulp in 1651\\u000a (Figs. 2.1 and 2.2). Nicolas Tulp is also famous for the portrait Rembrandt painted of him during his anatomical lessons.\\u000a The term spina bifida was suggested by Tulp and proposed solely to describe the vertebral anomaly that was considered a

  18. Fetal surgery for neural tube defects

    PubMed Central

    Sutton, Leslie N.

    2008-01-01

    Open spina bifida remains a major source of disability despite an overall decrease in incidence. It is frequently diagnosed prenatally and can thus -- potentially -- be treated by fetal surgery. Animal studies and preliminary human studies strongly suggest that at least a portion of the neurological abnormalities seen in these patients are secondary, and occur in mid-gestation. It is estimated that approximately 400 fetal operations have now been performed for myelomeningocele world wide. Despite this large experience, the technique remains of unproven benefit. Preliminary results suggest that fetal surgery results in reversal of hindbrain herniation (the Chiari II malformation), a decrease in shunt-dependent hydrocephalus, and possibly improvement in leg function, but these findings might be explained by selection bias and changing management indications. A randomized prospective trial (the MOMS trial) is currently being conducted by three centers in the United States, and is estimated to be completed in 2009. PMID:17714997

  19. Role of the Isthmus and FGFs in Resolving the Paradox of Neural Crest Plasticity and Prepatterning

    Microsoft Academic Search

    Paul A. Trainor; Linda Ariza-McNaughton; Robb Krumlauf

    2002-01-01

    Cranial neural crest cells generate the distinctive bone and connective tissues in the vertebrate head. Classical models of craniofacial development argue that the neural crest is prepatterned or preprogrammed to make specific head structures before its migration from the neural tube. In contrast, recent studies in several vertebrates have provided evidence for plasticity in patterning neural crest populations. Using tissue

  20. Chest tube insertion

    MedlinePLUS

    Chest drainage tube insertion; Insertion of tube into chest; Tube thoracostomy ... When your chest tube is inserted, you will lie on your side or sit partly upright, with one arm over your head. The ...

  1. Patterns of neural differentiation in melanomas

    PubMed Central

    2010-01-01

    Background Melanomas, highly malignant tumors arise from the melanocytes which originate as multipotent neural crest cells during neural tube genesis. The purpose of this study is to assess the pattern of neural differentiation in relation to angiogenesis in VGP melanomas using the tumor as a three dimensional system. Methods Tumor-vascular complexes [TVC] are formed at the tumor-stroma interphase, by tumor cells ensheathing angiogenic vessels to proliferate into a mantle of 5 to 6 layers [L1 to L5] forming a perivascular mantle zone [PMZ]. The pattern of neural differentiation is assessed by immunopositivity for HMB45, GFAP, NFP and synaptophysin has been compared in: [a] the general tumor [b] tumor-vascular complexes and [c] perimantle zone [PC] on serial frozen and paraffin sections. Statistical Analysis: ANOVA: Kruskal-Wallis One Way Analysis of Variance; All Pairwise Multiple Comparison Procedures [Tukey Test]. Results The cells abutting on the basement membrane acquire GFAP positivity and extend processes. New layers of tumor cells show a transition between L2 to L3 followed by NFP and Syn positivity in L4&L5. The level of GFAP+vity in L1&L2 directly proportionate to the percentage of NFP/Syn+vity in L4&L5, on comparing pigmented PMZ with poorly pigmented PMZ. Tumor cells in the perimantle zone show high NFP [65%] and Syn [35.4%] positivity with very low GFAP [6.9%] correlating with the positivity in the outer layers. Discussion From this study it is seen that melanoma cells revert to the embryonic pattern of differentiation, with radial glial like cells [GFAP+ve] which further differentiate into neuronal positive cells [NFP&Syn+ve] during angiogenic tumor-vascular interaction, as seen during neurogenesis, to populate the tumor substance. PMID:21080952

  2. Neural crest migration methods in the chicken embryo.

    PubMed

    Elena de Bellard, Maria; Bronner-Fraser, Marianne

    2005-01-01

    Neural crest cells emerge from the neural tube early in development. They migrate extensively throughout the embryo and form most of the head and peripheral nervous system, giving rise to sensory and sympathetic ganglia, heart regions, adrenal cells, head bones, teeth, muscle cells, sensory organs, melanocytes, and other cell types. The neural crest is interesting because of its unique origin, development and differentiation. These cells are initially part of the dorsal neural tube, with a clear epithelial character; later, they transform into actively motile mesenchymal cells. Little is known about the underlying mechanism directing this process. It remains unknown why neural crest cells target particular derivatives (neurons, heart muscle and glia) and body regions (peripheral nerves, heart, skin, head and gut). Neural crest migration can be divided into three stages: 1) emigration from the neural tube; 2) migration along defined pathways; and 3) cessation of migration. At the onset of migration, neural crest cells lose their epithelial nature within the neural tube and transform into a migratory, mesenchymal cell type. Neural crest development has been best studied in avian embryos, which are amenable to surgical manipulation, cell marking techniques, cell culture and transgenesis by electroporation and retrovirally mediate gene transfer. The methods outlined below are those typically used to study and understand the different factors and signals necessary for the neural crest development before and during their migration. PMID:15576917

  3. Method of processing tubing

    Microsoft Academic Search

    Prizzi

    1987-01-01

    This patent describes a process for manufacturing zirconium base alloy tubing having a substantially uniform metallic composition throughout the tubing, comprising the steps of: cold pilgering a starting tube to produce an as cold pilgered intermediate tube; intermediate surface annealing the as cold pilgered intermediate tube by rapidly scanning the tube with a rapid heating means to heat a first

  4. Making a Neural Tube: Neural Induction and Neurulation

    Microsoft Academic Search

    Raj Ladher; Gary C. Schoenwolf

    The future central nervous system is derived from an unspecified sheet of ectoderm, with fate being instructed by signals\\u000a emanating, in the main, from a specialized region of the early embryo, the organizer. The organizer secretes signals that\\u000a have the net effect of inhibiting the BMP pathway, be it by extra-cellular antagonism or by intracellular modulation of the\\u000a ability of

  5. Tube furnace

    DOEpatents

    Foster, Kenneth G. (Livermore, CA); Frohwein, Eugene J. (San Ramon, CA); Taylor, Robert W. (Livermore, CA); Bowen, David W. (Livermore, CA)

    1991-01-01

    A vermiculite insulated tube furnace is heated by a helically-wound resistance wire positioned within a helical groove on the surface of a ceramic cylinder, that in turn is surroundingly disposed about a doubly slotted stainless steel cylindrical liner. For uniform heating, the pitch of the helix is of shorter length over the two end portions of the ceramic cylinder. The furnace is of large volume, provides uniform temperature, offers an extremely precise programmed heating capability, features very rapid cool-down, and has a modest electrical power requirement.

  6. Collapse Tubes

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Context image for PIA02154 Collapse Tubes

    The discontinuous channels in this image are collapsed lava tubes.

    Image information: VIS instrument. Latitude -19.7N, Longitude 317.5E. 17 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  7. Tapered pulse tube for pulse tube refrigerators

    DOEpatents

    Swift, Gregory W. (Sante Fe, NM); Olson, Jeffrey R. (San Mateo, CA)

    1999-01-01

    Thermal insulation of the pulse tube in a pulse-tube refrigerator is maintained by optimally varying the radius of the pulse tube to suppress convective heat loss from mass flux streaming in the pulse tube. A simple cone with an optimum taper angle will often provide sufficient improvement. Alternatively, the pulse tube radius r as a function of axial position x can be shaped with r(x) such that streaming is optimally suppressed at each x.

  8. Eustachian Tube Dysfunction

    MedlinePLUS

    MENU Return to Web version Eustachian Tube Dysfunction Overview What is eustachian tube dysfunction? The eustachian tubes are small passageways that connect the upper part of your throat (pharynx) ...

  9. Emission Tube Apparatus

    NSDL National Science Digital Library

    Dr. Charles Ward

    This is an image of an emission tube apparatus with tube in place. When plugged in and turned on the gas in the tube will become excited and emit a specific color of light depending upon the type of gas.

  10. Data analysis for steam generator tubing samples

    SciTech Connect

    Dodd, C.V.

    1996-07-01

    The objective of the Improved Eddy-Current ISI for Steam Generators program is to upgrade and validate eddy-current inspections, including probes, instrumentation, and data processing techniques for inservice inspection of new, used, and repaired steam generator tubes; to improve defect detection, classification and characterization as affected by diameter and thickness variations, denting, probe wobble, tube sheet, tube supports, copper and sludge deposits, even when defect types and other variables occur in combination; to transfer this advanced technology to NRC`s mobile NDE laboratory and staff. This report provides a description of the application of advanced eddy-current neural network analysis methods for the detection and evaluation of common steam generator tubing flaws including axial and circumferential outer-diameter stress-corrosion cracking and intergranular attack. The report describes the training of the neural networks on tubing samples with known defects and the subsequent evaluation results for unknown samples. Evaluations were done in the presence of artifacts. Computer programs are given in the appendix.

  11. Neural crest contributions to the lamprey head

    NASA Technical Reports Server (NTRS)

    McCauley, David W.; Bronner-Fraser, Marianne

    2003-01-01

    The neural crest is a vertebrate-specific cell population that contributes to the facial skeleton and other derivatives. We have performed focal DiI injection into the cranial neural tube of the developing lamprey in order to follow the migratory pathways of discrete groups of cells from origin to destination and to compare neural crest migratory pathways in a basal vertebrate to those of gnathostomes. The results show that the general pathways of cranial neural crest migration are conserved throughout the vertebrates, with cells migrating in streams analogous to the mandibular and hyoid streams. Caudal branchial neural crest cells migrate ventrally as a sheet of cells from the hindbrain and super-pharyngeal region of the neural tube and form a cylinder surrounding a core of mesoderm in each pharyngeal arch, similar to that seen in zebrafish and axolotl. In addition to these similarities, we also uncovered important differences. Migration into the presumptive caudal branchial arches of the lamprey involves both rostral and caudal movements of neural crest cells that have not been described in gnathostomes, suggesting that barriers that constrain rostrocaudal movement of cranial neural crest cells may have arisen after the agnathan/gnathostome split. Accordingly, neural crest cells from a single axial level contributed to multiple arches and there was extensive mixing between populations. There was no apparent filling of neural crest derivatives in a ventral-to-dorsal order, as has been observed in higher vertebrates, nor did we find evidence of a neural crest contribution to cranial sensory ganglia. These results suggest that migratory constraints and additional neural crest derivatives arose later in gnathostome evolution.

  12. Efeito da fortificação com ácido fólico na redução dos defeitos do tubo neural

    Microsoft Academic Search

    Leonor Maria Pacheco Santos; Michelle Zanon Pereira

    2007-01-01

    Neural tube defects are congenital malforma- tions that occur during initial fetal develop- ment, leading to anencephaly and spina bifida; folic acid deficiency is the most important risk factor identified to date. Brazil has one of the world's highest neural tube defect rates. Food consumption surveys among pregnant Brazilian women showed a high rate of inadequate folic acid intake (<

  13. Solar energy collection tube

    Microsoft Academic Search

    P. E. Mather; S. T. Sherlock

    1979-01-01

    A cylindrical metal tube is provided with an outer transparent jacket, the jacket being spaced apart from the tube by bushings at each end and sealed therewith by means of o-ring type elastomeric seals positioned in grooves in the bushings. The intermediate space between the tube and the jacket is evacuated through a side tube on the jacket to reduce

  14. RDP Neural Network RDP Neural Network Construction Principle

    E-print Network

    Gorban, Alexander N.

    RDP Neural Network RDP Neural Network Construction Principle Linear Separability Methods for building RDP Neural Networks Geometrical Approaches for Artificial Neural Networks David Elizondo Centre Elizondo Geometrical Approaches for Artificial Neural Networks #12;RDP Neural Network RDP Neural Network

  15. Bourdon Tube Gauge

    NSDL National Science Digital Library

    A Bourdon tube gauge animation. The objective is to describe how a Bourdon Tube Gauge measures vacuum. This simulation is from Module 101 of the vacuum technology and gas control cluster of the MATEC Module Library (MML).

  16. Tracheostomy tube - speaking

    MedlinePLUS

    ... part of communicating with people. Having a tracheostomy tube can change your ability to talk and interact ... can learn how to speak with a tracheostomy tube. It just takes practice. There are even speaking ...

  17. Eustachian tube (image)

    MedlinePLUS

    ... are more common in children because their eustachian tubes are shorter, narrower, and more horizontal than in ... become trapped when the tissue of the eustachian tube becomes swollen from colds or allergies. Bacteria trapped ...

  18. Eye and neural defects associated with loss of GDF6

    Microsoft Academic Search

    Meredith L Hanel; Carmel Hensey

    2006-01-01

    BACKGROUND: In Xenopus the bone morphogenetic protein growth and differentiation factor 6 (GDF6) is expressed at the edge of the neural plate, and within the anterior neural plate including the eye fields. Here we address the role of GDF6 in neural and eye development by morpholino knockdown experiments. RESULTS: We show that depletion of GDF6 (BMP13) resulted in a reduction

  19. Microhole Tubing Bending Report

    DOE Data Explorer

    Oglesby, Ken

    A downhole tubing bending study was made and is reported herein. IT contains a report and 2 excel spreadsheets to calculate tubing bending and to estimate contact points of the tubing to the drilled hole wall (creating a new support point).

  20. Chest Tube Thoracostomy

    MedlinePLUS

    Why Do I Need a Chest Tube? Common reasons why a chest tube is needed include: ? Collapsed lung (pneumothorax)— This occurs when air has built up in ... make it easier for the patient to breathe. ? Chest Surgery— Sometimes a chest tube is left in ...

  1. Microhole Tubing Bending Report

    SciTech Connect

    Oglesby, Ken

    2012-01-01

    A downhole tubing bending study was made and is reported herein. IT contains a report and 2 excel spreadsheets to calculate tubing bending and to estimate contact points of the tubing to the drilled hole wall (creating a new support point).

  2. 21 CFR 868.5800 - Tracheostomy tube and tube cuff.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...2014-04-01 2014-04-01 false Tracheostomy tube and tube cuff. 868.5800 Section 868.5800 Food and Drugs...DEVICES Therapeutic Devices § 868.5800 Tracheostomy tube and tube cuff. (a) Identification. A...

  3. 21 CFR 868.5800 - Tracheostomy tube and tube cuff.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...2012-04-01 2012-04-01 false Tracheostomy tube and tube cuff. 868.5800 Section 868.5800 Food and Drugs...DEVICES Therapeutic Devices § 868.5800 Tracheostomy tube and tube cuff. (a) Identification. A...

  4. 21 CFR 868.5800 - Tracheostomy tube and tube cuff.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...2011-04-01 2011-04-01 false Tracheostomy tube and tube cuff. 868.5800 Section 868.5800 Food and Drugs...DEVICES Therapeutic Devices § 868.5800 Tracheostomy tube and tube cuff. (a) Identification. A...

  5. 21 CFR 868.5800 - Tracheostomy tube and tube cuff.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...2013-04-01 2013-04-01 false Tracheostomy tube and tube cuff. 868.5800 Section 868.5800 Food and Drugs...DEVICES Therapeutic Devices § 868.5800 Tracheostomy tube and tube cuff. (a) Identification. A...

  6. EFFECTS OF TOXICANTS ON NEURAL DIFFERENTIATION

    EPA Science Inventory

    This manuscript describes in vitro measures of neural differentiation. This overview provides the background and literature review for measures that could be employed in both screening assays and mechanistic studies. this chapter also reviews data from key endpoints like neurite ...

  7. Heat tube device

    NASA Technical Reports Server (NTRS)

    Khattar, Mukesh K. (inventor)

    1990-01-01

    The present invention discloses a heat tube device through which a working fluid can be circulated to transfer heat to air in a conventional air conditioning system. The heat tube device is disposable about a conventional cooling coil of the air conditioning system and includes a plurality of substantially U-shaped tubes connected to a support structure. The support structure includes members for allowing the heat tube device to be readily positioned about the cooling coil. An actuatable adjustment device is connected to the U-shaped tubes for allowing, upon actuation thereof, for the heat tubes to be simultaneously rotated relative to the cooling coil for allowing the heat transfer from the heat tube device to air in the air conditioning system to be selectively varied.

  8. Illuminated Emission Tubes and Emission Tube Apparatus

    NSDL National Science Digital Library

    Dr. Charles Ward

    This is an image of illuminated emission tubes with the high voltage apparatus that causes the gas to become excited. Elements represented include: hydrogen, nitrogen, chlorine, mercury, and neon. This image is not labeled.

  9. Neural Networks

    SciTech Connect

    Smith, Patrick I.

    2003-09-23

    Physicists use large detectors to measure particles created in high-energy collisions at particle accelerators. These detectors typically produce signals indicating either where ionization occurs along the path of the particle, or where energy is deposited by the particle. The data produced by these signals is fed into pattern recognition programs to try to identify what particles were produced, and to measure the energy and direction of these particles. Ideally, there are many techniques used in this pattern recognition software. One technique, neural networks, is particularly suitable for identifying what type of particle caused by a set of energy deposits. Neural networks can derive meaning from complicated or imprecise data, extract patterns, and detect trends that are too complex to be noticed by either humans or other computer related processes. To assist in the advancement of this technology, Physicists use a tool kit to experiment with several neural network techniques. The goal of this research is interface a neural network tool kit into Java Analysis Studio (JAS3), an application that allows data to be analyzed from any experiment. As the final result, a physicist will have the ability to train, test, and implement a neural network with the desired output while using JAS3 to analyze the results or output. Before an implementation of a neural network can take place, a firm understanding of what a neural network is and how it works is beneficial. A neural network is an artificial representation of the human brain that tries to simulate the learning process [5]. It is also important to think of the word artificial in that definition as computer programs that use calculations during the learning process. In short, a neural network learns by representative examples. Perhaps the easiest way to describe the way neural networks learn is to explain how the human brain functions. The human brain contains billions of neural cells that are responsible for processing information [2]. Each one of these cells acts as a simple processor. When individual cells interact with one another, the complex abilities of the brain are made possible. In neural networks, the input or data are processed by a propagation function that adds up the values of all the incoming data. The ending value is then compared with a threshold or specific value. The resulting value must exceed the activation function value in order to become output. The activation function is a mathematical function that a neuron uses to produce an output referring to its input value. [8] Figure 1 depicts this process. Neural networks usually have three components an input, a hidden, and an output. These layers create the end result of the neural network. A real world example is a child associating the word dog with a picture. The child says dog and simultaneously looks a picture of a dog. The input is the spoken word ''dog'', the hidden is the brain processing, and the output will be the category of the word dog based on the picture. This illustration describes how a neural network functions.

  10. [Neural crest and vertebrate evolution].

    PubMed

    Le Douarin, Nicole M; Creuzet, Sophie

    2011-01-01

    The neural crest (NC) is a remarkable structure of the Vertebrate embryo, which forms from the lateral borders of the neural plate (designated as neural folds) during neural tube closure. As soon as the NC is formed, its constitutive cells detach and migrate away from the neural primordium along definite pathways and at precise periods of time according to a rostro-caudal progression. The NC cells aggregate in definite places in the developing embryo, where they differentiate into a large variety of cell types including the neurons and glial cells of the peripheral nervous system, the pigment cells dispersed throughout the body and endocrine cells such as the adrenal medulla and the calcitonin producing cells. At the cephalic level only, in higher Vertebrates (but along the whole neural axis in Fishes and Amphibians), the NC is also at the origin of mesenchymal cells differentiating into connective tissue chondrogenic and osteogenic cells. Vertebrates belong to the larger group of Cordates which includes also the Protocordates (Cephalocordates and the Urocordates). All Cordates are characterized by the same body plan with a dorsal neural tube and a notochord which, in Vertebrates, exists only at embryonic stages. The main difference between Protocordates and Vertebrates is the very rudimentary development of cephalic structures in the former. As a result, the process of cephalization is one of the most obvious characteristics of Vertebrates. It was accompanied by the apparition of the NC which can therefore be considered as an innovation of Vertebrates during evolution. The application of a cell marking technique which consists in constructing chimeric embryos between two species of birds, the quail and the chicken, has led to show that the vertebrate head is mainly formed by cells originating from the NC, meaning that this structure was an important asset in Vertebrate evolution. Recent studies, described in this article, have strengthened this view by showing that the NC does not only provide the cells that build up the facial skeleton and most of the skull but plays a major role in early brain neurogenesis. It was shown that the cephalic NC cells produce signaling molecules able to regulate the activity of the two secondary organizing centers previously identified in the developing brain: the anterior neural ridge and the midbrain-hindbrain junction, which secrete Fgf8, a potent stimulator of early brain neurogenesis. PMID:21831339

  11. Pediatric cuffed endotracheal tubes

    PubMed Central

    Bhardwaj, Neerja

    2013-01-01

    Endotracheal intubation in children is usually performed utilizing uncuffed endotracheal tubes for conduct of anesthesia as well as for prolonged ventilation in critical care units. However, uncuffed tubes may require multiple changes to avoid excessive air leak, with subsequent environmental pollution making the technique uneconomical. In addition, monitoring of ventilatory parameters, exhaled volumes, and end-expiratory gases may be unreliable. All these problems can be avoided by use of cuffed endotracheal tubes. Besides, cuffed endotracheal tubes may be of advantage in special situations like laparoscopic surgery and in surgical conditions at risk of aspiration. Magnetic resonance imaging (MRI) scans in children have found the narrowest portion of larynx at rima glottides. Cuffed endotracheal tubes, therefore, will form a complete seal with low cuff pressure of <15 cm H2O without any increase in airway complications. Till recently, the use of cuffed endotracheal tubes was limited by variations in the tube design marketed by different manufacturers. The introduction of a new cuffed endotracheal tube in the market with improved tracheal sealing characteristics may encourage increased safe use of these tubes in clinical practice. A literature search using search words "cuffed endotracheal tube" and "children" from 1980 to January 2012 in PUBMED was conducted. Based on the search, the advantages and potential benefits of cuffed ETT are reviewed in this article. PMID:23492803

  12. Pulse Tube Refrigerator

    NASA Astrophysics Data System (ADS)

    Matsubara, Yoichi

    The pulse tube refrigerator is one of the regenerative cycle refrigerators such as Stirling cycle or Gifford-McMahon cycle which gives the cooling temperature below 150 K down to liquid helium temperature. In 1963, W. E. Gifford invented a simple refrigeration cycle which is composed of compressor, regenerator and simple tube named as pulse tube which gives a similar function of the expander in Stirling or Gifford-McMahon cycle. The thermodynamically performance of this pulse tube refrigerator is inferior to that of other regenerative cycles. In 1984, however, Mikulin and coworkers made a significant advance in pulse tube configuration called as orifice pulse tube. After this, several modifications of the pulse tube hot end configuration have been developed. With those modifications, the thermodynamic performance of the pulse tube refrigerator became the same order to that of Stirling and Gifford-McMahon refrigerator. This article reviews the brief history of the pulse tube refrigerator development in the view point of its thermodynamically efficiency. Simplified theories of the energy flow in the pulse tube have also been described.

  13. Recommendations for accelerating global action to prevent folic acid-preventable birth defects and other folate-deficiency diseases: Meeting of experts on preventing folic acid-preventable neural tube defects

    Microsoft Academic Search

    Godfrey P. Oakley; Karen N. Bell; Mary Beth Weber

    2004-01-01

    BACKGROUND: In April of 2003, The Micronutrient Initiative, in collaboration with several other organizations, convened a group of knowledgeable scientists and policy experts to discuss ways to accelerate the global pace at which countries implement effective and sustainable programs to prevent folic acid-preventable birth defects and other folate-deficiency diseases. Programs implemented to date by fewer than 40 countries have prevented

  14. Tube Thoracostomy: Complications and Its Management

    PubMed Central

    Kesieme, Emeka B.; Dongo, Andrew; Ezemba, Ndubueze; Irekpita, Eshiobo; Jebbin, Nze; Kesieme, Chinenye

    2012-01-01

    Background. Tube thoracostomy is widely used throughout the medical, surgical, and critical care specialities. It is generally used to drain pleural collections either as elective or emergency. Complications resulting from tube thoracostomy can occasionally be life threatening. Aim. To present an update on the complications and management of complications of tube thoracostomy. Methods. A review of the publications obtained from Medline search, medical libraries, and Google on tube thoracostomy and its complications was done. Results. Tube thoracostomy is a common surgical procedure which can be performed by either the blunt dissection technique or the trocar technique. Complication rates are increased by the trocar technique. These complications have been broadly classified as either technical or infective. Technical causes include tube malposition, blocked drain, chest drain dislodgement, reexpansion pulmonary edema, subcutaneous emphysema, nerve injuries, cardiac and vascular injuries, oesophageal injuries, residual/postextubation pneumothorax, fistulae, tumor recurrence at insertion site, herniation through the site of thoracostomy, chylothorax, and cardiac dysrhythmias. Infective complications include empyema and surgical site infection. Conclusion. Tube thoracostomy, though commonly performed is not without risk. Blunt dissection technique has lower risk of complications and is hence recommended. PMID:22028963

  15. Early Acquisition of Neural Crest Competence During hESCs Neuralization

    Microsoft Academic Search

    Carol Lynn Curchoe; Jochen Maurer; Sonja J. McKeown; Giulio Cattarossi; Flavio Cimadamore; Mats Nilbratt; Evan Y. Snyder; Marianne Bronner-Fraser; Alexey V. Terskikh; Joseph Najbauer

    2010-01-01

    BackgroundNeural crest stem cells (NCSCs) are a transient multipotent embryonic cell population that represents a defining characteristic of vertebrates. The neural crest (NC) gives rise to many derivatives including the neurons and glia of the sensory and autonomic ganglia of the peripheral nervous system, enteric neurons and glia, melanocytes, and the cartilaginous, bony and connective tissue of the craniofacial skeleton,

  16. Virtual Lava Tube

    NSDL National Science Digital Library

    Lava tubes are cave formations found where volcanoes generate surface flows in the western United States, Japan, Italy, Australia, and other areas. They vary in size and complexity, from short, straight formations to multi-leveled labyrinths that extend for miles. The largest and most extensive lava tubes discovered to date are in Hawaii, where lava flows can travel more than 80 kilometers (50 miles) from their source. This interactive feature offers a visual tour of lava tubes and various features formed by flowing, splashing, or dripping lava. Viewers can click on a cross-section of a lava tube and see photos and explanations for the formation of the features.

  17. Sapphire tube pressure vessel

    DOEpatents

    Outwater, John O. (Cambridge, MA)

    2000-01-01

    A pressure vessel is provided for observing corrosive fluids at high temperatures and pressures. A transparent Teflon bag contains the corrosive fluid and provides an inert barrier. The Teflon bag is placed within a sapphire tube, which forms a pressure boundary. The tube is received within a pipe including a viewing window. The combination of the Teflon bag, sapphire tube and pipe provides a strong and inert pressure vessel. In an alternative embodiment, tie rods connect together compression fittings at opposite ends of the sapphire tube.

  18. Alloy 690 for steam generator tubing applications

    Microsoft Academic Search

    R. E. Gold; D. L. Harrod; R. G. Aspden; A. J. Baum

    1990-01-01

    This report has been prepared to provide background information for Ni-Cr-Fe Alloy 690 which is currently the material of choice for steam generator heat transfer tubing applications. Activities directed toward the qualification of Alloy 690 for these applications are summarized; this includes efforts which focused on optimization of materials procurement specifications. Emphasis is placed on research accomplished primarily in the

  19. Looking Southeast Along Kilauea TEB Tube System

    USGS Multimedia Gallery

    View looking southeast along the fuming trace of the TEB tube system. The growing rootless shield field is in the background just above and to the left of center frame. The low, rounded shape of the shields--especially the shield in shadow to the left--are evident in this photo....

  20. Steam generator tube failures

    SciTech Connect

    MacDonald, P.E.; Shah, V.N.; Ward, L.W.; Ellison, P.G.

    1996-04-01

    A review and summary of the available information on steam generator tubing failures and the impact of these failures on plant safety is presented. The following topics are covered: pressurized water reactor (PWR), Canadian deuterium uranium (CANDU) reactor, and Russian water moderated, water cooled energy reactor (VVER) steam generator degradation, PWR steam generator tube ruptures, the thermal-hydraulic response of a PWR plant with a faulted steam generator, the risk significance of steam generator tube rupture accidents, tubing inspection requirements and fitness-for-service criteria in various countries, and defect detection reliability and sizing accuracy. A significant number of steam generator tubes are defective and are removed from service or repaired each year. This wide spread damage has been caused by many diverse degradation mechanisms, some of which are difficult to detect and predict. In addition, spontaneous tube ruptures have occurred at the rate of about one every 2 years over the last 20 years, and incipient tube ruptures (tube failures usually identified with leak detection monitors just before rupture) have been occurring at the rate of about one per year. These ruptures have caused complex plant transients which have not always been easy for the reactor operators to control. Our analysis shows that if more than 15 tubes rupture during a main steam line break, the system response could lead to core melting. Although spontaneous and induced steam generator tube ruptures are small contributors to the total core damage frequency calculated in probabilistic risk assessments, they are risk significant because the radionuclides are likely to bypass the reactor containment building. The frequency of steam generator tube ruptures can be significantly reduced through appropriate and timely inspections and repairs or removal from service.

  1. Introduction to Neural Computation Neural Computation

    E-print Network

    Bullinaria, John

    . Understand the relationship between real brains and simple artificial neural network models. 2. Describe and their History Biological Neurons and Neural Networks, Artificial Neurons 2 Networks of Artificial Neurons. 2. Investigate some common neural-based models and their applications. 3. Present neural network

  2. 56. INTERIOR VIEW OF TUBES OF UNCERTAIN USE BELOW THE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    56. INTERIOR VIEW OF TUBES OF UNCERTAIN USE BELOW THE LOWER WEST END OF THE AMALGAMATIONS PLATES. NOTE CUT STONE FOUNDATION WALLS ALONG THE BACKGROUND RIGHT. - Standard Gold Mill, East of Bodie Creek, Northeast of Bodie, Bodie, Mono County, CA

  3. Gastrostomy feeding tube - pump

    MedlinePLUS

    Feeding - gastrostomy tube - pump; G-tube - pump; Gastrostomy button - pump; Bard Button - pump; MIC-KEY - pump ... Gather supplies: Feeding pump (electronic or battery powered) Feeding set that matches the feeding pump (includes a feeding bag, drip chamber, roller clamp, ...

  4. Steam generator tube failures

    Microsoft Academic Search

    P. E. MacDonald; V. N. Shah; L. W. Ward; P. G. Ellison

    1996-01-01

    A review and summary of the available information on steam generator tubing failures and the impact of these failures on plant safety is presented. The following topics are covered: pressurized water reactor (PWR), Canadian deuterium uranium (CANDU) reactor, and Russian water moderated, water cooled energy reactor (VVER) steam generator degradation, PWR steam generator tube ruptures, the thermal-hydraulic response of a

  5. Some Notes on Vacuum Tubes

    Microsoft Academic Search

    J. H. Morecroft

    1920-01-01

    The value of the exponent connecting plate current and plate and grid potentials is experimentally investigated for a number of tubes. It is found to be markedly different for different tubes, and for the same tube at different plate voltages. Particularly is this the case for low plate voltage tubes. After discussing briefly distortion in amplifying tubes, the capacity and

  6. 2014 Tube -1 STANDING WAVES

    E-print Network

    Glashausser, Charles

    2014 Tube - 1 STANDING WAVES IN AN AIR COLUMN The objective of the experiment is: · To study, meterstick, sound tube apparatus, thermometer, microphone INTRODUCTION traveling wave of sinusoidal shape towards the open end of a tube. The other end of the tube is closed. When the sound wave enters the tube

  7. Neural Engineering

    Microsoft Academic Search

    Bin He

    2005-01-01

    About the Series: Bioelectric Engineering presents state-of-the-art discussions on modern biomedical engineering with respect to applications of electrical engineering and information technology in biomedicine. This focus affirms Springer's commitment to publishing important reviews of the broadest interest to biomedical engineers, bioengineers, and their colleagues in affiliated disciplines. Recent volumes have covered modeling and imaging of bioelectric activity, neural engineering, biosignal

  8. Chest tube insertion - series (image)

    MedlinePLUS

    ... lung can collapse, preventing adequate air exchange. Chest tubes are used to treat conditions that can cause ... Chest tubes are inserted to drain blood, fluid, or air and allow full expansion of the lungs. The tube ...

  9. Tube flare inspection tool

    NASA Technical Reports Server (NTRS)

    Meunier, G. E.

    1980-01-01

    Flare angle and symmetry of tube ends can be checked by simple tool that consists of two stainless steel pins bonded to rubber plug. Primary function of tool is to inspect tubes before they are installed, thereby eliminating expense and inconvenience of repairing leaks caused by imperfect flares. Measuring hole tapers, countersink angles, and bearing race angles are other possible uses. Tool is used with optical comparator. Axis of tool is alined with centerline of tube. Shadow of seated pins on comparator screen allows operator to verify flare angle is within tolerance.

  10. Differentiation state determines neural effects on microvascular endothelial cells

    SciTech Connect

    Muffley, Lara A., E-mail: muffley@u.washington.edu [University of Washington, Campus Box 359796, 300 9th Avenue, Seattle, WA 98104 (United States); Pan, Shin-Chen, E-mail: pansc@mail.ncku.edu.tw [University of Washington, Campus Box 359796, 300 9th Avenue, Seattle, WA 98104 (United States)] [University of Washington, Campus Box 359796, 300 9th Avenue, Seattle, WA 98104 (United States); Smith, Andria N., E-mail: gnaunderwater@gmail.com [University of Washington, Campus Box 359796, 300 9th Avenue, Seattle, WA 98104 (United States); Ga, Maricar, E-mail: marga16@uw.edu [University of Washington, Campus Box 359796, 300 9th Avenue, Seattle, WA 98104 (United States)] [University of Washington, Campus Box 359796, 300 9th Avenue, Seattle, WA 98104 (United States); Hocking, Anne M., E-mail: ahocking@u.washington.edu [University of Washington, Campus Box 359796, 300 9th Avenue, Seattle, WA 98104 (United States); Gibran, Nicole S., E-mail: nicoleg@u.washington.edu [University of Washington, Campus Box 359796, 300 9th Avenue, Seattle, WA 98104 (United States)

    2012-10-01

    Growing evidence indicates that nerves and capillaries interact paracrinely in uninjured skin and cutaneous wounds. Although mature neurons are the predominant neural cell in the skin, neural progenitor cells have also been detected in uninjured adult skin. The aim of this study was to characterize differential paracrine effects of neural progenitor cells and mature sensory neurons on dermal microvascular endothelial cells. Our results suggest that neural progenitor cells and mature sensory neurons have unique secretory profiles and distinct effects on dermal microvascular endothelial cell proliferation, migration, and nitric oxide production. Neural progenitor cells and dorsal root ganglion neurons secrete different proteins related to angiogenesis. Specific to neural progenitor cells were dipeptidyl peptidase-4, IGFBP-2, pentraxin-3, serpin f1, TIMP-1, TIMP-4 and VEGF. In contrast, endostatin, FGF-1, MCP-1 and thrombospondin-2 were specific to dorsal root ganglion neurons. Microvascular endothelial cell proliferation was inhibited by dorsal root ganglion neurons but unaffected by neural progenitor cells. In contrast, microvascular endothelial cell migration in a scratch wound assay was inhibited by neural progenitor cells and unaffected by dorsal root ganglion neurons. In addition, nitric oxide production by microvascular endothelial cells was increased by dorsal root ganglion neurons but unaffected by neural progenitor cells. -- Highlights: Black-Right-Pointing-Pointer Dorsal root ganglion neurons, not neural progenitor cells, regulate microvascular endothelial cell proliferation. Black-Right-Pointing-Pointer Neural progenitor cells, not dorsal root ganglion neurons, regulate microvascular endothelial cell migration. Black-Right-Pointing-Pointer Neural progenitor cells and dorsal root ganglion neurons do not effect microvascular endothelial tube formation. Black-Right-Pointing-Pointer Dorsal root ganglion neurons, not neural progenitor cells, regulate microvascular endothelial cell production of nitric oxide. Black-Right-Pointing-Pointer Neural progenitor cells and dorsal root ganglion neurons have different secretory profiles for angiogenic mediators.

  11. PE on YouTube--Investigating Participation in Physical Education Practice

    ERIC Educational Resources Information Center

    Quennerstedt, Mikael

    2013-01-01

    Background: In this article, students' diverse ways of participating in physical education (PE) practice shown in clips on YouTube were investigated. YouTube is the largest user-generated video-sharing website on the Internet, where different video content is presented. The clips on YouTube, as used in this paper, can be seen as a user-generated…

  12. Callose plug deposition patterns vary in pollen tubes of Arabidopsis thaliana ecotypes and in tomato species

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background The pollen grain contains the male gametophyte that extends a pollen tube that grows through female tissues in order to deliver sperm to the embryo sac for double fertilization. Growing pollen tubes form periodic callose plugs that are thought to block off the older parts of the tube and ...

  13. Neural Communication

    NSDL National Science Digital Library

    Mrs. Johnson

    2010-06-22

    First you will explore the neuron. Then how neurons communicate with each other by exploring action potentials and neural transmission. Let's start with the neuron. Explore the neuron and fill out the worksheet by labeling each part of the neuron and giving a brief description of what it does. Structure of the Neuron (Upon entering the site go through each link at the top of the page from intro to terminal buttons) Now take a look ...

  14. Tubing crimping pliers

    DOEpatents

    Lindholm, G.T.

    1981-02-27

    The disclosure relates to pliers and more particularly to pliers for crimping two or more pieces of copper tubing together prior to their being permanently joined by brazing, soldering or the like. A die containing spring-loaded pins rotates within a cammed ring in the head of the pliers. As the die rotates, the pins force a crimp on tubing held within the pliers.

  15. Nociceptive sensory neurons derive from contralaterally migrating, fate-restricted neural crest cells

    Microsoft Academic Search

    Lynn George; Marta Chaverra; Valerie Todd; Rusty Lansford; Frances Lefcort

    2007-01-01

    Neural crest cells (NCCs) are a transient population of multipotent progenitors that give rise to numerous cell types in the embryo. An unresolved issue is the degree to which the fate of NCCs is specified prior to their emigration from the neural tube. In chick embryos, we identified a subpopulation of NCCs that, upon delamination, crossed the dorsal midline to

  16. Early induction of neural crest cells: lessons learned from frog, fish and chick

    Microsoft Academic Search

    Manuel J Aybar; Roberto Mayor

    2002-01-01

    The identification of genes in Xenopus, chick and zebrafish expressed early in prospective neural crest (NC) cells has challenged the previous view that the NC is induced during the closure of the neural tube. We compare here the early inductive molecular mechanisms in different organisms and, despite observed differences, propose a general common model for NC induction.

  17. Does lumbosacral spina bifida arise by failure of neural folding or by defective canalisation?

    Microsoft Academic Search

    A J Copp; F A Brook

    1989-01-01

    The aim of this study was to determine whether open lumbosacral spina bifida results from an abnormality of neural folding (primary neurulation) or medullary cord canalisation (secondary neurulation). Homozygous curly tail (ct) mouse embryos were studied as a model system for human neural tube defects. The rostral end of the spina bifida was found to lie at the level of

  18. Nasogastric and Enteral Feeding Tubes GI/GU Nasogastric Tubes

    E-print Network

    Kay, Mark A.

    valve, allowing vent air into the tube but preventing gastric juice from exiting from the tube. Vygon reduces the risk of exposure to gastric contents. Anderson tube with Anti-Reflux Valve designed double lumen gastric sump tube: The principal green-colored channel is connected to a suction apparatus

  19. Aeronautical tubes and pipes

    NASA Astrophysics Data System (ADS)

    Beauclair, N.

    1984-12-01

    The main and subcomponent French suppliers of aircraft tubes and pipes are discussed, and the state of the industry is analyzed. Quality control is essential for tubes with regard to their i.d. and metallurgical compositions. French regulations do not allow welded seam tubes in hydraulic circuits unless no other form is available, and then rustproofed steel must be installed. The actual low level of orders for any run of tubes dictates that the product is only one of several among the manufacturers' line. Automation, both in NDT and quality control, assures that the tubes meet specifications. A total of 10 French companies participate in the industry, serving both civil and military needs, with some companies specializing only in titanium, steel, or aluminum materials. Concerns wishing to enter the market must upgrade their equipment to meet the higher aeronautical specifications and be prepared to furnish tubes and pipes that serve both functional and structural purposes simultaneously. Additionally, pipe-bending machines must also perform to tight specifications. Pipes can range from 0.2 mm exterior diameter to 40 mm, with wall thicknesses from 0.02 mm to 3 mm. A chart containing a list of manufacturers and their respective specifications and characteristics is presented, and a downtrend in production with reduction of personnel is noted.

  20. Dynamic tube/support interaction in heat exchanger tubes

    SciTech Connect

    Chen, S.S.

    1991-01-01

    The supports for heat exchanger tubes are usually plates with drilled holes; other types of supports also have been used. To facilitate manufacture and to allow for thermal expansion of the tubes, small clearances are used between tubes and tube supports. The dynamics of tube/support interaction in heat exchangers is fairly complicated. Understanding tube dynamics and its effects is important for heat exchangers. This paper summarizes the current state of the art on this subject and to identify future research needs. Specifically, the following topics are discussed: dynamics of loosely supported tubes, tube/support gap dynamics, tube response in flow, tube damage and wear, design considerations, and future research needs. 55 refs., 1 fig.