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1

Neural Tube Defects  

MedlinePLUS

... NICHD Research Information Clinical Trials Resources and Publications Neural Tube Defects (NTDs): Overview Skip sharing on social media links Share this: Page Content Neural tube defects are birth defects that can occur ...

2

A search for environmental and genetic background for neural tube defects: twenty-five years of experience.  

PubMed

The present paper illustrates the author's 25-year experience in a step by step approach to the definition of environmental and genetic background of neural tube defects. Based on the birth defects registry, a complete ascertainment of all deliveries was performed in Southern Poland during two periods: 1970-1972, and 1979-1981. The birth prevalence of neural tube defects (NTD), as well as other CNS malformations was determined. The empiric recurrence risk was calculated as 3.2% +/- 1.6. Based on this figure, the relative risk (RR = 37.6 p < 0.001) and heritability (h2 = 74.7 +/- 6.7) were estimated. Our own modification of Morton's complex segregation analysis was applied. Three Mendelian (dominant, additive and recessive) and one multifactorial model were tested. The results did not provide a clear cut discrimination between different models; however the lowest x2 value was obtained for additive inheritance with 61% of penetrance and the frequency of sporadic cases equaled 55%. A search for genetic markers did not support the hypothesis that HLA-A,B,C loci are equivalents of T/t like locus in mice. The results of the study on transcobalamine levels in amniotic fluid may suggests that different transcobalamine metabolism reflects phenotypic expression of genetic susceptibility to NTD development. Current research status and future perspectives on genetic and environmental background of NTD are also presented. PMID:9208165

Pietrzyk, J J

1997-06-01

3

What Are Neural Tube Defects?  

MedlinePLUS

... NICHD Research Information Clinical Trials Resources and Publications Neural Tube Defects (NTDs): Condition Information Skip sharing on ... media links Share this: Page Content What are neural tube defects? Neural (pronounced NOOR-uhl ) tube defects ...

4

Neural tube defects.  

PubMed

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

Greene, Nicholas D E; Copp, Andrew J

2014-07-01

5

Neural Tube Defects  

MedlinePLUS

... The two most common neural tube defects are spina bifida and anencephaly. In spina bifida, the fetal spinal column doesn't close completely. There is usually nerve damage that causes at least some paralysis of the legs. In anencephaly, ... National Institute of Child Health and Human Development

6

Abnormal skull findings in neural tube defects  

PubMed Central

The human neural tube develops and closes during the third and fourth week after conception and is normally completed by 28 days post-conception. Malformations, knows as neural tube defects, occure, when the normal closure process fails. Several clinical types of neural tube defects are recognized, anencefaly and spina bifida being the most common. Such malformations are generally associated with cranial abnormlities

Imbruglia, Laura; Cacciatore, Alessandra; Carrara, Sabina; Recupero, Stefania; La Galia, Tindara; Pappalardo, Elisa Maria; Chiara Accardi, Manuela; Pedata, Rosa; Rapisarda, Giusi; Mammaro, Alessia

2009-01-01

7

Pediatric neuroanesthesia. Neural tube defects.  

PubMed

Neural tube defects of the brain and spinal cord, among the most common birth defects in the United States, cause neurologic morbidity from the lesions themselves and from associated hydrocephalus and Arnold-Chiari malformation. Because the myelomeningoceles, and encephaloceles are repaired surgically within hours of birth, neonatal anesthetic management with attention to fluids, body temperature, intravenous access, and monitoring is important. Anesthesia for treatment of hydrocephalus and Arnold-Chiari malformation takes into consideration the presence of intracranial hypertension and the need for manipulation of vital structures in the posterior fossa. PMID:11469061

Hamid, R K; Newfield, P

2001-06-01

8

Opioid Use and Neural Tube Defects  

MedlinePLUS

... For Questions About This Page Contact Us Key Findings: Opioid Use and Neural Tube Defects The journal ... a summary of findings from this article. Main Findings from this Study Mothers with pregnancies affected by ...

9

Folic Acid Helps Prevent Neural Tube Defects  

MedlinePLUS

... Submit What's this? Submit Button CDC Features Folic Acid Helps Prevent Neural Tube Defects Language: English Español ( ... day before and during pregnancy. What Is Folic Acid? Folic acid is a B vitamin. Our bodies ...

10

Preconceptional Vitamin Use and Neural Tube Defects.  

National Technical Information Service (NTIS)

This study sought to establish the potential benefit of preconceptional vitamin supplementation in reducing the incidence of neural tube defects (NTDs), and examine some of the potential hazards of excessive preconceptional vitamin supplementation. The pr...

A. A. Mitchell

1992-01-01

11

Dynamic Imaging of Mammalian Neural Tube Closure  

PubMed Central

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.

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

2013-01-01

12

Are There Disorders or Conditions Associated with Neural Tube Defects?  

MedlinePLUS

... Publications Are there disorders or conditions associated with neural tube defects? Skip sharing on social media links Share this: Page Content Infants born with neural tube defects that are not immediately fatal may ...

13

Nodal signaling is required for closure of the anterior neural tube in zebrafish  

Microsoft Academic Search

BACKGROUND: Nodals are secreted signaling proteins with many roles in vertebrate development. Here, we identify a new role for Nodal signaling in regulating closure of the rostral neural tube of zebrafish. RESULTS: We find that the neural tube in the presumptive forebrain fails to close in zebrafish Nodal signaling mutants. For instance, the cells that will give rise to the

Allisan Aquilina-Beck; Kristine Ilagan; Qin Liu; Jennifer O Liang

2007-01-01

14

Neural tube defects and folate: case far from closed  

PubMed Central

Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents ~50–75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.

Blom, Henk J.; Shaw, Gary M.; Heijer, Martin den; Finnell, Richard H.

2010-01-01

15

Neural Tube Defects, Folic Acid and Methylation  

PubMed Central

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.

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

2013-01-01

16

Shroom Induces Apical Constriction and Is Required for Hingepoint Formation during Neural Tube Closure  

Microsoft Academic Search

Background: The morphogenetic events of early vertebrate development generally involve the combined actions of several populations of cells, each engaged in a distinct behavior. Neural tube closure, for instance, involves apicobasal cell heightening, apical constriction at hingepoints, convergent extension of the midline, and pushing by the epidermis. Although a large number of genes are known to be required for neural

John B. Wallingford; Jeffrey D. Hildebrand; Richard M. Harland

2003-01-01

17

Nodal signaling is required for closure of the anterior neural tube in zebrafish  

PubMed Central

Background Nodals are secreted signaling proteins with many roles in vertebrate development. Here, we identify a new role for Nodal signaling in regulating closure of the rostral neural tube of zebrafish. Results We find that the neural tube in the presumptive forebrain fails to close in zebrafish Nodal signaling mutants. For instance, the cells that will give rise to the pineal organ fail to move from the lateral edges of the neural plate to the midline of the diencephalon. The open neural tube in Nodal signaling mutants may be due in part to reduced function of N-cadherin, a cell adhesion molecule expressed in the neural tube and required for neural tube closure. N-cadherin expression and localization to the membrane are reduced in fish that lack Nodal signaling. Further, N-cadherin mutants and morphants have a pineal phenotype similar to that of mutants with deficiencies in the Nodal pathway. Overexpression of an activated form of the TGF? Type I receptor Taram-A (Taram-A*) cell autonomously rescues mesendoderm formation in fish with a severe decrease in Nodal signaling. We find that overexpression of Taram-A* also corrects their open neural tube defect. This suggests that, as in mammals, the mesoderm and endoderm have an important role in regulating closure of the anterior neural tube of zebrafish. Conclusion This work helps establish a role for Nodal signals in neurulation, and suggests that defects in Nodal signaling could underlie human neural tube defects such as exencephaly, a fatal condition characterized by an open neural tube in the anterior brain.

Aquilina-Beck, Allisan; Ilagan, Kristine; Liu, Qin; Liang, Jennifer O

2007-01-01

18

Neural Tube Defects, Folate, and Immune Modulation  

PubMed Central

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.

Fathe, Kristin; Finnell, Richard H.; Taylor, Stephen M.; Woodruff, Trent M.

2014-01-01

19

Neural tube defects, folate, and immune modulation.  

PubMed

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

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

2013-09-01

20

Apparent prevention of neural tube defects by periconceptional vitamin supplementation.  

PubMed Central

An earlier preliminary paper is expanded. Women who had given birth to one or more infants with a neural tube defect were recruited into a trial of per conceptional vitamin supplementation. Two hundred mothers attending five centres were fully supplemented (FS), 50 were partially supplemented (PS), and 300 were unsupplemented (US). Neural tube defect recurrences in the study pregnancies were 1 (0.5%), in FS, none in PS, and 13 (4%) in US mothers. The difference in outcome between FS and US mothers is significant. The most likely explanation is that supplementation has prevented some neural tube defects, but further studies are needed.

Smithells, R W; Sheppard, S; Schorah, C J; Seller, M J; Nevin, N C; Harris, R; Read, A P; Fielding, D W

1981-01-01

21

Images in Clinical Medicine Congenital Neural Malformations Related to Their Embryological Background  

PubMed Central

Congenital neural malformations are complex anomalies, which stem from an abnormality in the embryological development of the nervous system. The development of the nervous system begins by the formation of the neural tube and its subsequent closure. The failure of closure results in neural tube defects (NTD). Defect in the formation of prosencehalon or rhombencephalon will result in holoprosencephaly or Dandy walker complex respectively. The formation of neuroblasts and their migration to cerebral cortex may be altered by many neuronal migration disorders. Lissencephaly, schizencephaly, and heterotopic gray matter are the most prominent. Conclusion: The objective of the study is relating congenital neural malformations to their corresponding embryological background, and so helping in better understanding the time and the way of the occurrence of such anomalies.

Bahnassy, Ahmed A.; Aly, Nehal N.

2008-01-01

22

Neural tissue continues its maturation at the site of neural tube closure defects: implications for prenatal intervention in human samples  

Microsoft Academic Search

Objective Our objective was to investigate the relation between the embryological development and neural tissue maturation at the site where the neural plate failed to form a neural tube. Material and methods Samples from 15 aborted human fetuses with neural tube defects (NTD). All of the fetuses were between 20 and 25 gestational weeks old. Indicators of neural tissue maturation,

Mehmet Selçuki; Seda Vatansever; Sevinç Inan; Muzaffer Sanc?; Sevil Sayhan; Celal Ba?dato?lu

2004-01-01

23

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

PubMed

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

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

2013-08-01

24

Risk Factors of Neural Tube Defects in Northern Iran  

PubMed Central

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.

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

2014-01-01

25

Homocysteine metabolism in pregnancies complicated by neural-tube defects  

Microsoft Academic Search

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

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

1995-01-01

26

What are those cilia doing in the neural tube?  

PubMed Central

Primary cilia are present on almost all vertebrate cells, and they have diverse functions in distinct tissues. Cilia are important for sensation in multiple capacities in contexts as different as the retina, kidney, and inner ear. In addition to these roles, cilia play a critical part in various developmental processes. Of particular importance is the development of the neural tube, where cilia are essential for the transduction of the Sonic Hedgehog (Shh) signaling pathway that specifies neuronal cell fates. This relationship is well established and is the most recognizable function for cilia in the neural tube, but it may be part of a larger picture. Here, we discuss the links between cilia and Shh signaling, as well as suggesting additional roles for cilia, and mechanisms for their placement, in the neural tube.

2012-01-01

27

Screening for fetal aneuploidy and neural tube defects  

PubMed Central

Maternal serum screening for neural tube defects and fetal aneuploidy in the second trimester has been incorporated into obstetrical practice over the past two decades. Now, as a result of several multicenter trials, first trimester screening between 11 and 14 weeks has been shown to be an effective and reliable screening test for Down syndrome and trisomy 18. This policy updates the American College of Medical Genetics policy statement entitled Second Trimester Maternal Serum Screening for Fetal Open Neural Tube Defects and Aneuploidy (2004), incorporates First trimester diagnosis and screening for fetal aneuploidy (2008) and complements the sections of American College of Medical Genetic’s Standards and Guidelines for Clinical Genetics Laboratories entitled Prenatal Screening for Down syndrome (2005) and Prenatal Screening for Open Neural Tube Defects (2005).

Driscoll, Deborah A.; Gross, Susan J.

2009-01-01

28

Prenatal ultrasound diagnosis of neural tube defects. Pictorial essay.  

PubMed

Neural tube defects (NTD) are a heterogeneous group of malformations resulting from failure of normal neural tube closure before the fourth and fifth week of embryologic development. The three most common forms of NTD are: anencephaly, encephalocele and spinal dysraphism. Less common forms of neural tube defects include iniencephaly, amniotic bands and other types of spinal abnormalities including scoliosis/cyphosis, sacral agenesis, limb-body wall complex, diastematomyelia. The most part of these abnormalities are accessible to the ultrasound diagnosis in the midtrimester and sometimes even in the late first trimester of the pregnancy. This kind of abnormalities can occur in isolation or in association with other anomalies, which can also be characterized with ultrasound. In this pictorial essay the ultrasonographic aspects of the NTD will be discussed. PMID:22675716

R?dulescu, Micaela; Ulmeanu, Emil Coriolan; Nedelea, Mihaela; Oncescu, Andrei

2012-06-01

29

Periconceptional folate deficiency and implications in neural tube defects.  

PubMed

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

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

2012-01-01

30

Prevention of neural tube defects in an urban health district.  

PubMed Central

An evaluation of voluntary prenatal screening for neural tube defects with serum alphafetoprotein (s-AFP) is presented. During a three year period, there were 52 fetuses with neural lesions. Of 46 mothers who bore a fetus with an open neural lesion, 25 were detected, of whom 23 agreed to the termination of their pregnancies. An unscreened group of 2331 mothers (17% of all deliveries) produced 14 fetuses with neural tube defects, an incidence of 6.0 per 1000, 1.8 times the incidence (3.3 per 1000) in the screened group. Pitfalls occurring in the assessment of hyper-alphafetoproteinemia included inaccurate gestational dating and allowance for excessive body weight. The results of a robust AFP-NTD screening programme supported in selected cases by ultrasonar visualisation of the spine argue for its continuance in this district.

Watson, D; Pow, M; Ellam, A; Costeloe, K

1983-01-01

31

21 CFR 101.79 - Health claims: Folate and neural tube defects.  

Code of Federal Regulations, 2011 CFR

...with a neural tube defect, those with insulin-dependent diabetes mellitus, and women with seizure disorders who are being...with a neural tube defect; those with insulin-dependent diabetes mellitus; those with seizure disorders who are being...

2011-04-01

32

LRP2 mediates folate uptake in the developing neural tube.  

PubMed

The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2) is a multifunctional cell-surface receptor expressed in the embryonic neuroepithelium. Loss of LRP2 in the developing murine central nervous system (CNS) causes impaired closure of the rostral neural tube at embryonic stage (E) 9.0. Similar neural tube defects (NTDs) have previously been attributed to impaired folate metabolism in mice. We therefore asked whether LRP2 might be required for the delivery of folate to neuroepithelial cells during neurulation. Uptake assays in whole-embryo cultures showed that LRP2-deficient neuroepithelial cells are unable to mediate the uptake of folate bound to soluble folate receptor 1 (sFOLR1). Consequently, folate concentrations are significantly reduced in Lrp2(-/-) embryos compared with control littermates. Moreover, the folic-acid-dependent gene Alx3 is significantly downregulated in Lrp2 mutants. In conclusion, we show that LRP2 is essential for cellular folate uptake in the developing neural tube, a crucial step for proper neural tube closure. PMID:24639464

Kur, Esther; Mecklenburg, Nora; Cabrera, Robert M; Willnow, Thomas E; Hammes, Annette

2014-05-15

33

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

ERIC Educational Resources Information Center

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…

Arc, Arlington, TX.

34

Neural tube defects - recent advances, unsolved questions and controversies  

PubMed Central

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.

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

2014-01-01

35

High dose zolpidem induced fetal neural tube defects.  

PubMed

Use of zolpidem, a short-acting imidazopyridine hypnotic, has not been associated with teratogenic effects in usual clinical doses. We report a case of fetal neural tube defects occurring in a female dependent on zolpidem and consuming high doses in the first trimester of pregnancy. Possible mechanisms by which high dose zolpidem may lead to teratogenicity are discussed. Clinicians are advised to be aware of the risks of high-dose zolpidem abuse in early pregnancy. PMID:21385155

Sharma, Avinash; Sayeed, Neha; Khees, Christoday R J; Akhtar, Sayeed

2011-04-01

36

BMP2 is Required for Cephalic Neural Tube Closure in the Mouse  

PubMed Central

Summary BMPs have been shown to play a role in neural tube development particularly as dorsalizing factors. To explore the possibility that BMP2 could play a role in the developing neural tube (NT) beyond the lethality of Bmp2 null embryos we created Bmp2 chimeras from Bmp2 null ES cells and WT blastocysts. Analysis of Bmp2 chimeras reveals NT defects at day 9.5 (E9.5). We found that exclusion of Bmp2 null ES cells from the dorsal NT did not always prevent defects. For further comparison, we used a Bmp2 mutant line in a mixed background. Phenotypes observed were similar to chimeras including open NT defects, postneurulation defects and abnormal neural ectoderm in heterozygous and homozygous null embryos demonstrating a pattern of dose dependent signaling. Our data exposes BMP2 as a unique player in the developing NT for dorsal patterning and identity and normal cephalic neural tube closure in a dose dependent manner.

Castranio, Trisha; Mishina, Yuji

2011-01-01

37

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

Microsoft Academic Search

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

Dhara B. Dhaulakhandi; Seema Rohilla; Kamal Nain Rattan

2010-01-01

38

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

PubMed Central

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.

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

2014-01-01

39

Grainyhead-like 2 regulates neural tube closure and adhesion molecule expression during neural fold fusion  

PubMed Central

Summary Defects in closure of embryonic tissues such as the neural tube, body wall, face and eye lead to severe birth defects. Cell adhesion is hypothesized to contribute to closure of the neural tube and body wall, however potential molecular regulators of this process have not been identified. Here we identify an ENU-induced mutation in mice that reveals a molecular pathway of embryonic closure. Line2F homozygous mutant embryos fail to close the neural tube, body wall, face, and optic fissure, and they also display defects in lung and heart development. Using a new technology of genomic sequence capture and high-throughput sequencing of a 2.5 Mb region of the mouse genome, we discovered a mutation in the grainyhead-like 2 gene (Grhl2). Microarray analysis revealed Grhl2 affects the expression of a battery of genes involved in cell adhesion and E-cadherin protein is drastically reduced in tissues that require Grhl2 function. The tissue closure defects in Grhl2 mutants are similar to that of AP-2? null mutants and AP-2? has been shown to bind to the promoter of E-cadherin. Therefore, we tested for a possible interaction between these genes. However, we find that Grhl2 and AP-2? do not regulate each other’s expression, E-cadherin expression is normal in AP-2? mutants during neural tube closure, and Grhl2;AP-2? trans-heterozygous embryos are morphologically normal. Taken together, our studies point to a complex regulation of neural tube fusion and highlight the importance of comparisons between these two models to understand more fully the molecular pathways of embryonic tissue closure.

Pyrgaki, Christina; Liu, Aimin; Niswander, Lee

2011-01-01

40

An increase in MECP2 dosage impairs neural tube formation.  

PubMed

Epigenetic mechanisms are fundamental for shaping the activity of the central nervous system (CNS). Methyl-CpG binding protein 2 (MECP2) acts as a bridge between methylated DNA and transcriptional effectors responsible for differentiation programs in neurons. The importance of MECP2 dosage in CNS is evident in Rett Syndrome and MECP2 duplication syndrome, which are neurodevelopmental diseases caused by loss-of-function mutations or duplication of the MECP2 gene, respectively. Although many studies have been performed on Rett syndrome models, little is known about the effects of an increase in MECP2 dosage. Herein, we demonstrate that MECP2 overexpression affects neural tube formation, leading to a decrease in neuroblast proliferation in the neural tube ventricular zone. Furthermore, an increase in MECP2 dose provokes premature differentiation of neural precursors accompanied by greater cell death, resulting in a loss of neuronal populations. Overall, our data indicate that correct MECP2 expression levels are required for proper nervous system development. PMID:24657916

Petazzi, Paolo; Akizu, Naiara; García, Alejandra; Estarás, Conchi; Martínez de Paz, Alexia; Rodríguez-Paredes, Manuel; Martínez-Balbás, Marian A; Huertas, Dori; Esteller, Manel

2014-07-01

41

Recurrence risk after neural tube defects in a genetic counselling clinic.  

PubMed Central

The recurrence of isolated neural tube defects in a population of women from a genetic counselling clinic was found to be 3.4%. After one baby with a neural tube defect the recurrence was 2.3%. Of the 15 pregnancies of women who had two previous babies with neural tube defects, there were three further recurrences. These findings show that the Hungarian recurrence risk of isolated neural tube defects has not changed with a declining birth prevalence, and that the rate in genetic counselling clinic patients is the same as in a previous population based epidemiological study.

Czeizel, A; Metneki, J

1984-01-01

42

Further evidence for an intermittent pattern of neural tube closure in humans.  

PubMed Central

Evidence is presented to support the recent suggestion that human neural tube closure is similar to that observed in mice, and comprises several regionally distinct closure sites rather than being a simple zipping up process. Seven subjects, each with more than one neural tube defect (NTD), are described. Comparative studies of the location of the lesions in relation to the closed parts of the neural tube imply that such NTD could only have come about if there were intermittent closure of the neural tube. Images

Seller, M J

1995-01-01

43

Amniotic fluid test for the diagnosis of neural tube defects.  

PubMed

Alpha-fetoprotein and acetylcholinesterase were assayed in 374 amniotic fluids from normal pregnancies, at 9-15 weeks of gestation. We have investigated the correlations with the gestational age and have established our cutoff levels for these biochemical markers. We also report the values, that we have obtained in two cases of neural tube defects (NTD) and in several chromosomal aberrations. For early prenatal diagnosis of NTD, we wide to point out the importance of the contemporary determination of the two analytes and of the ultrasonographic investigation and biometry. PMID:2480426

Lituania, M; Canini, S; Cordone, M; Lenzi, A

1989-01-01

44

Contribution of VANGL2 mutations to isolated neural tube defects  

PubMed Central

Vangl2 was identified as the gene defective in the Looptail mouse model for neural tube defects (NTDs). This gene forms part of the planar cell polarity 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 7 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.

Kibar, Zoha; Salem, Sandra; Bosoi, Ciprian M.; Pauwels, Elodie; De Marco, Patrizia; Merello, Elisa; Bassuk, Alexander G; Capra, Valeria; Gros, Philippe

2010-01-01

45

Prenatal diagnosis of neural tube defects using the cholinesterases.  

PubMed

The usefulness of a cholinesterase assay and electrophoresis in the prenatal diagnosis of neural tube defects was investigated in amniotic fluids from 1,512 women. The assay used a alpha-naphthyl acetate as substrate and measured the combined activity of the enzymes acetylcholinesterase (AChE, E.C. 3.1.1.7) and cholinesterase (ChE, E.C. 3.1.1.8); the activity of both enzymes was raised in amniotic fluid from women carrying open NTDs. The alpha-naphthyl acetate assay distinguished fetuses with neural tube defects from normal fetuses more effectively than assays using acetylthiocholine as substate. A perfect score could be obtained on the sample tested when both enzyme assay and electrophoresis were done on those samples with activity greater than or equal to 4 mU. There was no correlation between gestational age between 13-21 weeks and activity of AChE + ChE (r = 0.03). The electrophoretic band of AChE activity proved to be a valuable diagnostic adjunct to both AFP or the AChE + ChE assay. A similar band or AChE activity was seen in adult brain and intestine but not in kidney, heart, liver, or lung, or in sera from women carrying normal or NTD fetuses. PMID:6642992

Simpson, N E

1983-01-01

46

Multigeneration maternal transmission in Italian families with neural tube defects.  

PubMed

Periconceptional vitamin supplementation with folate prevents about three-quarters of expected cases of neural tube defects (NTDs) in clinical trials. However, vitamin action may be regulated at the level of the gene, and individual susceptibility to environmental agents, including dietary components, also may be under genetic control. We investigated the presence of familial factors in a retrospective case control study of neural tube defects in Genoa, Italy. Cases included all patients treated at a single pediatric neurosurgical service. Controls matched on age and sex came from the same hospital. We found strong evidence for the contribution of genetic factors in this study. There was an excess risk of 14 for the occurrence of NTDs in first-degree relatives compared to controls (P < .0005). There was no difference in sex ratio in any group of relatives, but maternal grandparents of children with a high spinal lesion had 14% fewer off-spring than paternal grandparents (P < .005), possibly because of excess miscarriages. Our study is the first to show complex patterns of inheritance in spina bifida families affecting three generation in one clinical subgroup and preferentially on the mother's side. These results support a role for genomic imprinting and highlight the value of multidisciplinary epidemiologic and clinical studies that include multiple generations. New studies incorporating dietary and genetic approaches will help clarify and extend these findings. PMID:8985492

Byrne, J; Cama, A; Reilly, M; Vigliarolo, M; Levato, L; Boni, L; Lavia, N; Andreussi, L

1996-12-18

47

Neural tube defects - disorders of neurulation and related embryonic processes  

PubMed Central

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.

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

2014-01-01

48

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

Microsoft Academic Search

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

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

2000-01-01

49

Isolation and culture of neural crest cells from embryonic murine neural tube.  

PubMed

The embryonic neural crest (NC) is a multipotent progenitor population that originates at the dorsal aspect of the neural tube, undergoes an epithelial to mesenchymal transition (EMT) and migrates throughout the embryo, giving rise to diverse cell types. NC also has the unique ability to influence the differentiation and maturation of target organs. When explanted in vitro, NC progenitors undergo self-renewal, migrate and differentiate into a variety of tissue types including neurons, glia, smooth muscle cells, cartilage and bone. NC multipotency was first described from explants of the avian neural tube. In vitro isolation of NC cells facilitates the study of NC dynamics including proliferation, migration, and multipotency. Further work in the avian and rat systems demonstrated that explanted NC cells retain their NC potential when transplanted back into the embryo. Because these inherent cellular properties are preserved in explanted NC progenitors, the neural tube explant assay provides an attractive option for studying the NC in vitro. To attain a better understanding of the mammalian NC, many methods have been employed to isolate NC populations. NC-derived progenitors can be cultured from post-migratory locations in both the embryo and adult to study the dynamics of post-migratory NC progenitors, however isolation of NC progenitors as they emigrate from the neural tube provides optimal preservation of NC cell potential and migratory properties. Some protocols employ fluorescence activated cell sorting (FACS) to isolate a NC population enriched for particular progenitors. However, when starting with early stage embryos, cell numbers adequate for analyses are difficult to obtain with FACS, complicating the isolation of early NC populations from individual embryos. Here, we describe an approach that does not rely on FACS and results in an approximately 96% pure NC population based on a Wnt1-Cre activated lineage reporter. The method presented here is adapted from protocols optimized for the culture of rat NC. The advantages of this protocol compared to previous methods are that 1) the cells are not grown on a feeder layer, 2) FACS is not required to obtain a relatively pure NC population, 3) premigratory NC cells are isolated and 4) results are easily quantified. Furthermore, this protocol can be used for isolation of NC from any mutant mouse model, facilitating the study of NC characteristics with different genetic manipulations. The limitation of this approach is that the NC is removed from the context of the embryo, which is known to influence the survival, migration and differentiation of the NC. PMID:22688801

Pfaltzgraff, Elise R; Mundell, Nathan A; Labosky, Patricia A

2012-01-01

50

Isolation and Culture of Neural Crest Cells from Embryonic Murine Neural Tube  

PubMed Central

The embryonic neural crest (NC) is a multipotent progenitor population that originates at the dorsal aspect of the neural tube, undergoes an epithelial to mesenchymal transition (EMT) and migrates throughout the embryo, giving rise to diverse cell types 1-3. NC also has the unique ability to influence the differentiation and maturation of target organs4-6. When explanted in vitro, NC progenitors undergo self-renewal, migrate and differentiate into a variety of tissue types including neurons, glia, smooth muscle cells, cartilage and bone. NC multipotency was first described from explants of the avian neural tube7-9. In vitro isolation of NC cells facilitates the study of NC dynamics including proliferation, migration, and multipotency. Further work in the avian and rat systems demonstrated that explanted NC cells retain their NC potential when transplanted back into the embryo10-13. Because these inherent cellular properties are preserved in explanted NC progenitors, the neural tube explant assay provides an attractive option for studying the NC in vitro. To attain a better understanding of the mammalian NC, many methods have been employed to isolate NC populations. NC-derived progenitors can be cultured from post-migratory locations in both the embryo and adult to study the dynamics of post-migratory NC progenitors11,14-20, however isolation of NC progenitors as they emigrate from the neural tube provides optimal preservation of NC cell potential and migratory properties13,21,22. Some protocols employ fluorescence activated cell sorting (FACS) to isolate a NC population enriched for particular progenitors11,13,14,17. However, when starting with early stage embryos, cell numbers adequate for analyses are difficult to obtain with FACS, complicating the isolation of early NC populations from individual embryos. Here, we describe an approach that does not rely on FACS and results in an approximately 96% pure NC population based on a Wnt1-Cre activated lineage reporter23. The method presented here is adapted from protocols optimized for the culture of rat NC11,13. The advantages of this protocol compared to previous methods are that 1) the cells are not grown on a feeder layer, 2) FACS is not required to obtain a relatively pure NC population, 3) premigratory NC cells are isolated and 4) results are easily quantified. Furthermore, this protocol can be used for isolation of NC from any mutant mouse model, facilitating the study of NC characteristics with different genetic manipulations. The limitation of this approach is that the NC is removed from the context of the embryo, which is known to influence the survival, migration and differentiation of the NC2,24-28.

Pfaltzgraff, Elise R.; Mundell, Nathan A.; Labosky, Patricia A.

2012-01-01

51

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

PubMed

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

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

2013-09-01

52

Prenatal screening and diagnosis of neural tube defects.  

PubMed

This review article discusses prenatal screening and diagnosis of neural tube defects (NTD). High detection rates occur in countries operating ultrasound screening programmes because classical two-dimensional ultrasound cranial signs (lemon shaped head, banana cerebellum, ventriculomegaly) are important diagnostic clues to the presence of spina bifida. Careful evaluation of both the spine and a search for other abnormalities is warranted. Important prognostic information for spina bifida relates to the lesion level, with a "watershed" between L3 and L4 marking a very high chance of being wheelchair bound with the higher lesions. Three-dimensional ultrasound using multiplanar views can achieve diagnostic accuracy within one vertebral body in around 80% of patients. There are high rates of pregnancy termination for spina bifida in many European countries, but the use of new imagining techniques allow better prediction of outcome, and consequently a refinement of prenatal counselling. PMID:19301349

Cameron, Martin; Moran, Paul

2009-04-01

53

The relationship of ceruloplasmin and neural tube defects  

PubMed Central

Objective To compare the levels of ceruloplasmin (cp) in the amniotic fluids and maternal bloods of second trimester fetuses with and without neural tube defects (NTD). Materials and Methods 66 pregnant women were included in the study. Amniocentesis was performed in 32 women in a patient group diagnosed as NTD or anencephaly and 34 pregnants in a control group with positive Down Syndrome screening test. Maternal bloods were also taken. Cp was measured with Erel’s ceruloplasmin measurement method. Results The cp levels of the amniotic fluid of patients and controls were not statistically different (p>0.05). The cp levels of the maternal bloods were not different in two groups (p>0.05). Conclusion As an antioxidant, no relation was found between cp and NTD.

Yaz?c?oglu, Caglar; Cebesoy, Fatma Bahar; Balat, Ozcan; Dikensoy, Ebru; Celik, Hakim; Erel, Ozcan

2010-01-01

54

Requirement of a neural tube signal for the differentiation of neural crest cells into dorsal root ganglia.  

PubMed

The influence of the neural tube on early development of neural crest cells into sensory ganglia was studied in the chick embryo. Silastic membranes were implanted between the neural tube and the somites in 30-somite-stage embryos at the level of somites 21-24, thus separating the early migrated population of neural crest cells from the neural tube. Neural crest cells and peripheral ganglia were visualized by immunofluorescence using the HNK-1 monoclonal antibody and several histochemical techniques. Separation of crest cells from the neural tube caused the selective death of the neural crest cells from which dorsal root ganglia (DRG) would have developed. Complete disappearance of HNK-1 positive cells was evident already 10 hr after silastic implantation, before early differentiation sensory neurons could have reached their peripheral targets. In older embryos, DRG were absent at the level of implantation. In contrast, the development of ventral roots, sympathetic ganglia and adrenal gland was normal, and so was somitic differentiation into cartilage and muscle, while morphogenesis of the vertebrae was perturbed. To overcome the experimentally induced crest cell death, the silastic membranes were impregnated with a 3-day-old embryonic chick neural tube extract. Under these conditions, crest cells which were separated from the tube survived for a period of 30 hr after operation, compared to less than 10 hr in respective controls. The extract of another tissue, the liver, did not protract survival of DRG progenitor cells. Among the cells which survived with neural tube extract, some even succeeded in extending neurites; nevertheless, in absence of normal connections with the central nervous system (CNS) they finally died. Treatment of silastic implanted embryos with nerve growth factor (NGF) did not prevent the experimentally induced crest cell death. These results demonstrate that DRG develop from a population of neural crest cells which depends for its survival and probably for its differentiation upon a signal arising from the CNS, needed as early as the first hours after initiation of migration. Recovery experiments suggest that the subpopulation of crest cells which will develop along the sensory pathway probably depends for its survival and/or differentiation upon a factor contained in the neural tube, which is different from NGF. PMID:3525281

Kalcheim, C; Le Douarin, N M

1986-08-01

55

[Neural tube defects (NTD)--assessment from the perspective of 25 years of studies].  

PubMed

The present paper illustrates the authors 25-year experience in step by step approach to the definition of environmental and genetic background of neural tube defects. Based on the birth defects registry, a complete ascertainment of all deliveries was performed in Southern Poland during two period: 1970-1972, and 1979-1981. The birth prevalence of neural tube defects (NTD), as well as other CNS malformations was determined. The empiric recurrence risk was calculated as 3.2% +/- 1.6. Based on this figure, the relative risk (RR = 37.6 p < 0.001) and heritability (h2 = 74.7 +/- 6.7) were estimated. Our own modification of Morton's complex segregation analysis was applied. Three Mendelian (dominant, additive and recessive) and one multifactorial model were tested. The results did not provide a clear cut discrimination between different models; however the lowest 2 value was obtained for additive inheritance with 61% of penetrance and the frequency of sporadic cases equaled 55%. A search for genetic markers did not support the hypothesis that HLA-A,B,C loci are equivalents of T/t like locus in mice. The results of the study on transcobalamine levels in amniotic fluid may suggests that different transcobalamine metabolism reflects phenotypic expression of genetic susceptibility to NTD development. Current research and future perspectives on genetic and environmental background of NTD are also presented. PMID:9656740

Pietrzyk, J J

1998-01-01

56

21 CFR 101.79 - Health claims: Folate and neural tube defects.  

...2014-04-01 2014-04-01 false Health claims: Folate and neural tube defects...AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD...FOOD LABELING Specific Requirements for Health Claims § 101.79 Health...

2014-04-01

57

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

PubMed Central

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.

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

2008-01-01

58

Dieting behaviors and risk of neural tube defects.  

PubMed

The authors examined whether maternal dieting behaviors were associated with increased neural tube defect (NTD) risk among offspring, using population-based, case-control data. The analysis included 538 cases and 539 nonmalformed controls delivered from 1989 to 1991 in selected California counties, and exposures were assessed by in-person maternal interview. Among four reported dieting behaviors involving restricted food intake, diets to lose weight (odds ratio=2.1, 95% confidence interval: 1.1, 4.1), fasting diets (odds ratio=5.8, 95% confidence interval: 1.7, 20.0), and eating disorders (odds ratio=1.7, 95% confidence interval: 0.8, 3.6) were associated with increased NTD risk during the first trimester of pregnancy. Risk estimates for these behaviors during the 3 months before conception tended to be closer to 1. The fourth behavior, "other special diets," was not associated with increased NTD risk during either period. Women also reported whether they took diet pills, laxatives, or diuretics, engaged in binge eating, induced vomiting, or exercised excessively from the first 3 months before conception through the end of pregnancy. Only the intake of diuretics was associated with substantially increased NTD risk (odds ratio=2.7, 95% confidence interval: 0.7, 10.2). This study suggests that maternal dieting behaviors involving restricted food intake during the first trimester may be associated with increased NTD risk. PMID:14652296

Carmichael, Suzan L; Shaw, Gary M; Schaffer, Donna M; Laurent, Cecile; Selvin, Steve

2003-12-15

59

Diagnostic ultrasound: early detection of fetal neural tube defects.  

PubMed

In a series of 366 patients identified as at risk for a fetal neural tube defect (NTD) before the 24th week of pregnancy, 64 had an abnormal fetus. The abnormalities included anencephaly (39), open spinal defect (17), closed spinal defect (2), encephalocele (1), and a miscellany of other abnormalities (5). An ultrasound examinaton prior to diagnostic anmiocentesis positively identified all anencephalic fetuses, the fetus with the encephalocele, and 15 of the 19 fetuses with spina bifida. The spinal defects in 3 of the remaining 4 fetuses were demonstrated at a second examination. Since both amniotic fluid alpha-fetoprotein (AFP) assays and ultrasound examination have been shown to give false results in the diagnosis of NTDs, the importance of using 2 independent diagnostic techniques is stressed. In patients with elevated levels of maternal serum AFP, a careful ultrasound examination, in addition to identifying the majority of cases associated with an abnormal fetus, provided a good explanation for the elevation in over half of the remainder. In this series more than half the patients (40/69) who underwent amniocentesis because of raised maternal serum AFP levels were shown to have an abnormal fetus. PMID:6160439

Robinson, H P; Hood, V D; Adam, A H; Gibson, A A; Ferguson-Smith, M A

1980-12-01

60

Associated malformations among infants with neural tube defects.  

PubMed

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

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

2011-03-01

61

Antenatal diagnosis of neural tube defects in Canada: extension of a collaborative study.  

PubMed Central

Experience with the diagnosis of neural tube defects from alpha1-fetoprotein (AFP) concentrations in amniotic fluid is reported from a prospective study of five laboratories testing for 13 Canadian genetic centres. The results of the study indicate that antenatal diagnosis of open neural tube defects is being carried out effectively in Canada (in 99.2% of cases the AFP measurements were interpreted correctly). Amniocentesis should be recommended to women at high risk for having a child with a neural tube defect (i.e., those who have a child, a parent or a sibling with a neural tube defect). The rate of neural tube defects in 182 high-risk pregnancies was 2.2% for an open defect and 1.1% for a closed defect, whereas the rate in 673 pregnancies in which amniocentesis was being performed for other reasons was 0.3%. This suggests that the AFP concentration should be measured in any sample of amniotic fluid collected for other reasons (usually fetal karyotyping). There were three instances of false-negative results, for a rate of 0.4%. Two closed neural tube defects were not detected; this limitation of the test has also been found by others. One of the six fetuses with an open neural tube defect, who died in utero, had a large myelocele in the neck that was not recognized. There were also four instances of false-positive results, for a rate of 0.5%. The findings suggest that AFP values that are more than 2 but less than 7 standard deviations (SDs) above the mean may indicate a neural tube defect, and that values 7 or more SDs above the mean very likely indicate such a defect, although other reasons for such high values (e.g., fetal erythrocytes in the amniotic fluid, intrauterine death and mistaken gestational age) must be ruled out by other methods.

Simpson, N. E.; Dallaire, L.; Miller, J. R.; Siminovitch, L.; Miller, J.; Hamerton, J. L.

1979-01-01

62

The role of retinoic acid in the morphogenesis of the neural tube.  

PubMed

We have examined the role of the signalling molecule, retinoic acid, in the process of neurulation and the subsequent growth and differentiation of the central nervous system using quail embryos that have developed in the absence of retinoic acid. Such retinoic acid-free embryos undergo abnormal neural tube formation in terms of its shape and structure, but the embryos do not display spina bifida or exencephaly. The neural tubes have a wider floor plate, a thicker roof plate and a different dorsoventral shape. Phalloidin staining and electron microscopy revealed alterations in the actin filaments and the junctional complexes of the cell layer lining the lumen. Initially the neural tubes proliferated at the same rate as normal, but later the proliferation rate declined drastically and neuronal differentiation was highly deficient. There were very few motoneurons extending neurites into the periphery, and within the neural tube axon trajectories were chaotic. These results reveal several functions for retinoic acid in the morphogenesis and growth of the neural tube, many of which can be explained by defective notochord signalling, but they do not suggest that this molecule plays a role in neural tube closure. PMID:14620376

Wilson, L; Gale, E; Maden, M

2003-10-01

63

Regional differences in the expression of laminin isoforms during mouse neural tube development  

PubMed Central

Many significant human birth defects originate around the time of neural tube closure or early during post-closure nervous system development. For example, failure of the neural tube to close generates anencephaly and spina bifida, faulty cell cycle progression is implicated in primary microcephaly, while defective migration of neuroblasts can lead to neuronal migration disorders such as lissencephaly. At the stage of neural tube closure, basement membranes are becoming organised around the neuroepithelium, and beneath the adjacent non-neural surface ectoderm. While there is circumstantial evidence to implicate basement membrane dynamics in neural tube and surface ectodermal development, we have an incomplete understanding of the molecular composition of basement membranes at this stage. In the present study, we examined the developing basement membranes of the mouse embryo at mid-gestation (embryonic day 9.5), with particular reference to laminin composition. We performed in situ hybridization to detect the mRNAs of all eleven individual laminin chains, and immunohistochemistry to identify which laminin chains are present in the basement membranes. From this information, we inferred the likely laminin variants and their tissues of origin: that is, whether a given basement membrane laminin is contributed by epithelium, mesenchyme, or both. Our findings reveal major differences in basement composition along the body axis, with the rostral neural tube (at mandibular arch and heart levels) exhibiting many distinct laminin variants, while the lumbar level where the neural tube is just closing shows a much simpler laminin profile. Moreover, there appears to be a marked difference in the extent to which the mesenchyme contributes laminin variants to the basement membrane, with potential contribution of several laminins rostrally, but no contribution caudally. This information paves the way towards a mechanistic analysis of basement membrane laminin function during early neural tube development in mammals.

Copp, Andrew J.; Carvalho, Rita; Wallace, Adam; Sorokin, Lydia; Sasaki, Takako; Greene, Nicholas D.E.; Ybot-Gonzalez, Patricia

2013-01-01

64

Disruption of the MacMARCKS gene prevents cranial neural tube closure and results in anencephaly.  

PubMed Central

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 and the PKC signal transduction pathway in the folding of the anterior neural plate during the early phases of brain formation, and supports the hypothesis that actin-based motility directs cranial neural tube closure. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4

Chen, J; Chang, S; Duncan, S A; Okano, H J; Fishell, G; Aderem, A

1996-01-01

65

Early pregnancy screening for neural tube defects in Israel.  

PubMed

A pilot project to detect neural tube defects (NTD) of the fetus by maternal serum alpha-fetoprotein (MSAFP) screening of women in early pregnancy was initiated in Tel Aviv in 1982 at the instigation of the Israel Ministry of Health. The program was designed to be an extension of routine pregnancy care, which in this city is provided in municipal family clinics that are attended by about 50% of pregnant women before the 20th week of pregnancy. Of these women, 89% complied with the program. Women with a MSAFP level above a cutoff point of 2.4 multiples of the median (MOM) were invited for an ultrasound examination of the fetus, without having to repeat the MSAFP test, thereby reducing maternal anxiety. This deviation from the usual test system protocol did not impair sensitivity (87%), or specificity of the test on its own (95.6%), or in combination with ultrasound examination of the fetus and alpha-fetoprotein and acetylcholinesterase testing of the amniotic fluid (99.9%). The program detected 13 fetuses with an NTD; there were two false-negative results and one false-positive. The predictive value of a positive test was 93%. Its effectiveness as a preventive measure was impaired by the fact that 50% of pregnant women did not attend the family clinic before the 20th gestational week. An educational program for professionals and for the public is contemplated in order to reduce this proportion. Only 50% of normal twin pregnancies had an elevated MSAFP. A check on compliance with other screening systems during the interview for MSAFP screening led to the detection and elective abortion of two fetuses with Tay-Sachs disease. MSAFP screening in Israel is cost-effective rather than cost-beneficial. PMID:2427475

Legum, C; Shomrat, R; Yedwab, G; Jaffa, A J; Rudick, A

1986-01-01

66

The dorsal neural tube: a dynamic setting for cell fate decisions.  

PubMed

The dorsal neural tube first generates neural crest cells that exit the neural primordium following an epithelial-to-mesenchymal conversion to become sympathetic ganglia, Schwann cells, dorsal root sensory ganglia, and melanocytes of the skin. Following the end of crest emigration, the dorsal midline of the neural tube becomes the roof plate, a signaling center for the organization of dorsal neuronal cell types. Recent lineage analysis performed before the onset of crest delamination revealed that the dorsal tube is a highly dynamic region sequentially traversed by fate-restricted crest progenitors. Furthermore, prospective roof plate cells were shown to originate ventral to presumptive crest and to progressively relocate dorsalward to occupy their definitive midline position following crest delamination. These data raise important questions regarding the mechanisms of cell emigration in relation to fate acquisition, and suggest the possibility that spatial and/or temporal information in the dorsal neural tube determines initial segregation of neural crest cells into their derivatives. In addition, they emphasize the need to address what controls the end of neural crest production and consequent roof plate formation, a fundamental issue for understanding the separation between central and peripheral lineages during development of the nervous system. PMID:20683859

Krispin, Shlomo; Nitzan, Erez; Kalcheim, Chaya

2010-10-01

67

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

PubMed Central

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.

Kerosuo, Laura; Bronner, Marianne E.

2014-01-01

68

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

PubMed

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

Amarin, Zouhair O; Obeidat, Ahmed Z

2010-07-01

69

Prevalence of neural tube defects in South Australia, 1966-91: effectiveness and impact of prenatal diagnosis  

Microsoft Academic Search

OBJECTIVE--To determine trends in total prevalence of neural tube defects in South Australia during 1966-91, the impact of prenatal diagnosis on birth prevalence, and the effectiveness of prenatal screening for neural tube defects in 1986-91. DESIGN--All births and terminations of pregnancy affected by neural tube defects and information on prenatal screening were ascertained from multiple sources including the South Australian

A Chan; E F Robertson; E A Haan; R J Keane; E Ranieri; A Carney

1993-01-01

70

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

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

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

2003-01-01

71

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

PubMed

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

Kappen, Claudia

2013-11-01

72

Is LMNB1 a Susceptibility Gene for Neural Tube Defects in Humans?  

PubMed Central

BACKGROUND Lamins are intermediate filament proteins that form a major component of the nuclear lamina, a protein complex at the surface of the inner nuclear membrane. Numerous clinically diverse conditions, termed laminopathies, have been found to result from mutation of LMNA. In contrast, coding or loss of function mutations of LMNB1, encoding lamin B1, have not been identified in human disease. In mice, polymorphism in Lmnb1 has been shown to modify risk of neural tube defects (NTDs), malformations of the central nervous system that result from incomplete closure of the neural folds. METHODS Mutation analysis by DNA sequencing was performed on all exons of LMNB1 in 239 samples from patients with NTDs from the United Kingdom, Sweden, and United States. Possible functional effects of missense variants were analyzed by bioinformatics prediction and fluorescence in photobleaching. RESULTS In NTD patients, we identified two unique missense variants that were predicted to disrupt protein structure/function and represent putative contributory mutations. Fluorescence loss in photobleaching analysis showed that the A436T variant compromised stability of lamin B1 interaction within the lamina. CONCLUSION The genetic basis of human NTDs appears highly heterogenous with possible involvement of multiple predisposing genes. We hypothesize that rare variants of LMNB1 may contribute to susceptibility to NTDs. Birth Defects Research (Part A) 97:398–402, 2013. © 2013 Wiley Periodicals, Inc.

Robinson, Alexis; Partridge, Darren; Malhas, Ashraf; De Castro, Sandra CP; Gustavsson, Peter; Thompson, Dominic N; Vaux, David J; Copp, Andrew J; Stanier, Philip; Bassuk, Alexander G; Greene, Nicholas DE

2013-01-01

73

Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients  

SciTech Connect

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, methionine, myoinositol, thiamine, thymidine, and {alpha}-tocopherol) was determined with respect to the incidence of NTDs. In order to explore how different exposure parameters (time, dose, and route of compound administration) modulate the beneficial effects of micronutrient supplementation, female mice received either short- or long-term nutrient supplements via enteral or parenteral routes. Embryos were collected on E12.5 and examined for the presence of anterior or posterior NTDs. Additionally, whole mount in situ hybridization studies were conducted in order to reveal/confirm normal expression patterns of the Pax3 gene during neurulation in the wild-type and Sp/Sp homozygous mutant mouse embryos utilized in this study. A strong Pax3 signal was demonstrated in CXL-Sp embryos during neural tube closure (E9.5 to E10.5). The intensity and spatial pattern of expression were similar to other Splotch mutant mice. Of all the micronutrients tested, only supplementation with folic acid or 5-methyltetrahydrofolate rescued the normal phenotype in Sp/Sp embryos. When the folate supplementation dose was increased to 200 mg/kg in the diet, the incidence of rescued splotch homozygotes reached 30%; however, this was accompanied by six-fold increased resorption rate.

Wlodarczyk, Bogdan J. [Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, TX 77030 (United States)]. E-mail: bwlodarczyk@ibt.tamhsc.edu; Tang, Louisa S. [Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, TX 77030 (United States); Triplett, Aleata [Center for Human Molecular Genetics, Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198-5455 (United States); Aleman, Frank [Center for Human Molecular Genetics, Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198-5455 (United States); Finnell, Richard H. [Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, TX 77030 (United States); Center for Human Molecular Genetics, Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198-5455 (United States)

2006-05-15

74

Review of neural tube defects: risk factors in parental occupation and the environment.  

PubMed Central

We conducted a study of published work to evaluate the evidence for the hypothesis that environmental exposure and parental occupation are risk factors for neural tube defects. As other risk factors such as maternal illnesses, medication, and dietary factors have been reviewed before, this review only summarizes this information. In studies concerning environmental pollution, only a few weak associations were found. It appears that specific studies on the topic of parental occupation and neural tube defects are scarce. Therefore, studies on broader malformation categories, such as central nervous system defects, were also taken into account. Both maternal and paternal occupation seem to be associated with the occurrence of neural tube defects. However, results are not always consistent with each other, and relevant recommendations concerning prevention thus cannot be given before more studies with larger populations are conducted to confirm or refute the findings reviewed. Images p140-a

Blatter, B M; van der Star, M; Roeleveld, N

1994-01-01

75

Role of Rab11 in planar cell polarity and apical constriction during vertebrate neural tube closure.  

PubMed

Epithelial folding is a critical process underlying many morphogenetic events including vertebrate neural tube closure, however, its spatial regulation is largely unknown. Here we show that during neural tube formation Rab11-positive recycling endosomes acquire bilaterally symmetric distribution in the Xenopus neural plate, being enriched at medial apical cell junctions. This mediolateral polarization was under the control of planar cell polarity (PCP) signalling, was necessary for neural plate folding and was accompanied by the polarization of the exocyst component Sec15. Our further experiments demonstrate that similar PCP-dependent polarization of Rab11 is essential for ectopic apical constriction driven by the actin-binding protein Shroom and during embryonic wound repair. We propose that anisotropic membrane trafficking has key roles in diverse morphogenetic behaviours of individual cells and propagates in a tissue by a common mechanism that involves PCP. PMID:24818582

Ossipova, Olga; Kim, Kyeongmi; Lake, Blue B; Itoh, Keiji; Ioannou, Andriani; Sokol, Sergei Y

2014-01-01

76

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

PubMed Central

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.

Escobedo, Noelia; Contreras, Osvaldo; Munoz, Rosana; Farias, Marjorie; Carrasco, Hector; Hill, Charlotte; Tran, Uyen; Pryor, Sophie E.; Wessely, Oliver; Copp, Andrew J.; Larrain, Juan

2013-01-01

77

Disruption of palladin results in neural tube closure defects in mice  

Microsoft Academic Search

Palladin is a newly identified actin-associated protein which was proposed to be involved in actin cytoskeleton organization and nervous system development. Here, we show that inactivation of palladin leads to embryonic lethality due to severe defects of cranial neural tube closure and herniation of liver and intestine. It was found that palladin?\\/? embryos died around E15.5 and developed cranial neural

Huijun Luo; Xuesong Liu; Fang Wang; Qiuhua Huang; Shuhong Shen; Long Wang; Guojiang Xu; Xia Sun; Hui Kong; Mingmin Gu; Saijuan Chen; Zhu Chen; Zhugang Wang

2005-01-01

78

Prevention of neural tube malformation by genetic counselling, and prenatal diagnostic surveillance.  

PubMed

The aetiology and genetics of the spectrum of dysraphic neural tube malformations from anencephaly through encephalocele, myelocele and meningocele to complicated spina bifida occulta, is outlined. The risk of recurrence, the methods and problems of genetic counselling are discussed. All women known to be at risk for neural tube malformation should be counselled carefully and offered prenatal diagnostic surveillance for any future pregnancy. There is no longer any need for a couple able to accept termination, to go through with a pregnancy in fear of recurrence. PMID:95483

Laurence, K M

1979-12-01

79

Klippel-Feil syndrome, iniencephalus, anencephalus, hindbrain hernia and mirror movements: overdistention of the neural tube.  

PubMed

Bony anomalies encountered in the 'no neck' form of Klippel-Feil syndrome (KFS) are a wide, short, fused, bifid, retroflexed spinal canal; craniolacunia, cranium bifidum, and acrania. The only symptom may be mirror movement (MM). The CNS anomalies are hindbrain hernia, hydrocephalus, hydromyelia, syringomyelia, meningocele, myelocele, encephalocele, and anencephalus. In severe KFS, i.e. iniencephalus (IN) and in anencephalus (AN), the inion is in contact with the back. In both there is hindbrain hernia and the left thorax may contain the stomach tethered to an anterior spina bifida. KFS results from distortion of somites by an overdistended neural tube. A neural tube that fails to close cannot overdistend. PMID:456110

Gardner, W J

1979-01-01

80

Regulation of the onset of neural crest migration by coordinated activity of BMP4 and Noggin in the dorsal neural tube.  

PubMed

For neural crest cells to engage in migration, it is necessary that epithelial premigratory crest cells convert into mesenchyme. The mechanisms that trigger cell delamination from the dorsal neural tube remain poorly understood. We find that, in 15- to 40-somite-stage avian embryos, BMP4 mRNA is homogeneously distributed along the longitudinal extent of the dorsal neural tube, whereas its specific inhibitor noggin exists in a gradient of expression that decreases caudorostrally. This rostralward reduction in signal intensity coincides with the onset of emigration of neural crest cells. Hence, we hypothesized that an interplay between Noggin and BMP4 in the dorsal tube generates graded concentrations of the latter that in turn triggers the delamination of neural crest progenitors. Consistent with this suggestion, disruption of the gradient by grafting Noggin-producing cells dorsal to the neural tube at levels opposite the segmental plate or newly formed somites, inhibited emigration of HNK-1-positive crest cells, which instead accumulated within the dorsal tube. Similar results were obtained with explanted neural tubes from the same somitic levels exposed to Noggin. Exposure to Follistatin, however, had no effect. The Noggin-dependent inhibition was overcome by concomitant treatment with BMP4, which when added alone, also accelerated cell emigration compared to untreated controls. Furthermore, the observed inhibition of neural crest emigration in vivo was preceded by a partial or total reduction in the expression of cadherin-6B and rhoB but not in the expression of slug mRNA or protein. Altogether, these results suggest that a coordinated activity of Noggin and BMP4 in the dorsal neural tube triggers delamination of specified, slug-expressing neural crest cells. Thus, BMPs play multiple and discernible roles at sequential stages of neural crest ontogeny, from specification through delamination and later differentiation of specific neural crest derivatives. PMID:10518492

Sela-Donenfeld, D; Kalcheim, C

1999-11-01

81

Neural tube defects in Western Australia 1966-81 and a review of Australian data 1942-81  

Microsoft Academic Search

Cases of neural tube defects born in Western Australia during the years 1966-81 were identified from hospital records and death certificates. The overall rate for the 16 year period was 1.81 cases of neural tube defects per 1000 births. The rate rose and then fell over the 16 years. The initial lower rate may have been due to underascertainment, but

C Bower; M Hobbs; A Carney; D Simpson

1984-01-01

82

Neural Tube Defects and Maternal Residential Proximity to Agricultural Pesticide Applications  

Microsoft Academic Search

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

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

2006-01-01

83

The role of maternal reproductive history in the aetiology of neural tube defects  

Microsoft Academic Search

The contribution of environmental factors to the aetiology of neural tube defects (NTD) has been stressed over recent years and many different risk factors have been proposed. We evaluated the reproductive history of 113 NTD cases to investigate the possible role of maternal age, gestational age, sex, parity and previous pregnancy. Our results show that parity and previous spontaneous abortion

S. Bianca; M. Bianca; F. Bonaffini; G. Ettore

2002-01-01

84

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

Microsoft Academic Search

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

Pornswan Wasant

85

Looking for causes of neural tube defects: where does the environment fit in?  

PubMed

The neural tube defects anencephaly and spina bifida are important causes of infant mortality and morbidity. Recent studies suggest that many of these defects can be prevented by the periconceptional use of folic acid. At the same time, we do not know what causes most cases of neural tube defects and there is evidence to suggest that they are etiologically heterogeneous. Additional research needs to be directed toward the role of occupational and environmental exposures in the etiology of these defects. Importantly, studies need to examine embryologically and anatomically specific types of defects and develop accurate information on biologically relevant exposures. Exposures toward which attention needs to be directed include organic solvents; agricultural chemicals, including pesticides; water nitrates; heavy metals such as mercury; ionizing radiation; and water disinfection by products. We also recommend that additional attention be paid to mechanisms of neural tube closure and to the potential role of genetic heterogeneity in the absorption and metabolism of xenobiotics and in their effects on the neural tube. PMID:8549468

Sever, L E

1995-09-01

86

Looking for causes of neural tube defects: where does the environment fit in?  

PubMed Central

The neural tube defects anencephaly and spina bifida are important causes of infant mortality and morbidity. Recent studies suggest that many of these defects can be prevented by the periconceptional use of folic acid. At the same time, we do not know what causes most cases of neural tube defects and there is evidence to suggest that they are etiologically heterogeneous. Additional research needs to be directed toward the role of occupational and environmental exposures in the etiology of these defects. Importantly, studies need to examine embryologically and anatomically specific types of defects and develop accurate information on biologically relevant exposures. Exposures toward which attention needs to be directed include organic solvents; agricultural chemicals, including pesticides; water nitrates; heavy metals such as mercury; ionizing radiation; and water disinfection by products. We also recommend that additional attention be paid to mechanisms of neural tube closure and to the potential role of genetic heterogeneity in the absorption and metabolism of xenobiotics and in their effects on the neural tube.

Sever, L E

1995-01-01

87

Knowledge about folic acid and the prevention of neural tube defects in two general practice populations.  

PubMed Central

Knowledge about the link between folic acid supplementation in pregnancy and the prevention of neural tube defects was assessed in women from two contrasting general practices using a questionnaire. The persisting lack of awareness, particularly in the more at-risk group from the inner city area, lends support to the argument in favour of the fortification of flour.

Krischer, J

1997-01-01

88

Crushing behavior of laterally compressed composite elliptical tubes: Experiments and predictions using artificial neural networks  

Microsoft Academic Search

Composite materials have been increasingly used in the automobile industry for weight saving and part integration purposes. In this regard, composite elliptical tubes have been effectively employed as energy absorber devices. This increases the need for accurate and simple prediction techniques to optimize these structures.The present work deals with the implementation of artificial neural networks (ANN) technique in the prediction

El-Sadig Mahdi; Hany El Kadi

2008-01-01

89

Neurotrophin 3 stimulates the differentiation of motoneurons from avian neural tube progenitor cells.  

PubMed

Neurotrophin 3 (NT-3) promotes differentiation of neural tube progenitors into motoneurons expressing the BEN/SC1 and islet-1 epitopes. A 1.75- to 6.7-fold increase in BEN-positive motoneurons was obtained when quail neural tube cells were cultured with NT-3 at 0.1-10 ng/ml, respectively. In contrast, the overall number of cells, as well as the proportion of motoneurons that developed from cycling precursors, did not change. Addition of NT-3 at 1 ng/ml to cells obtained from ventral half-neural tubes promoted a 2.5-fold stimulation in motoneuron number, confirming the specificity of the effect. Moreover, NT-3 had no significant effect on survival of differentiated avian motoneurons. The distribution of trkC mRNA, which encodes the high-affinity receptor for NT-3, is consistent with these findings. trkC expression is homogeneous in the embryonic day 2 (E2) neural tube, becomes restricted to the mantle layer on E3, where differentiation occurs, and disappears from the ventral third of the E4-E5 spinal cord right before the onset of normal motoneuron death. These results suggest that NT-3 and trkC regulate early neurogenesis in the avian central nervous system. PMID:8159733

Averbuch-Heller, L; Pruginin, M; Kahane, N; Tsoulfas, P; Parada, L; Rosenthal, A; Kalcheim, C

1994-04-12

90

Neurotrophin 3 stimulates the differentiation of motoneurons from avian neural tube progenitor cells.  

PubMed Central

Neurotrophin 3 (NT-3) promotes differentiation of neural tube progenitors into motoneurons expressing the BEN/SC1 and islet-1 epitopes. A 1.75- to 6.7-fold increase in BEN-positive motoneurons was obtained when quail neural tube cells were cultured with NT-3 at 0.1-10 ng/ml, respectively. In contrast, the overall number of cells, as well as the proportion of motoneurons that developed from cycling precursors, did not change. Addition of NT-3 at 1 ng/ml to cells obtained from ventral half-neural tubes promoted a 2.5-fold stimulation in motoneuron number, confirming the specificity of the effect. Moreover, NT-3 had no significant effect on survival of differentiated avian motoneurons. The distribution of trkC mRNA, which encodes the high-affinity receptor for NT-3, is consistent with these findings. trkC expression is homogeneous in the embryonic day 2 (E2) neural tube, becomes restricted to the mantle layer on E3, where differentiation occurs, and disappears from the ventral third of the E4-E5 spinal cord right before the onset of normal motoneuron death. These results suggest that NT-3 and trkC regulate early neurogenesis in the avian central nervous system. Images

Averbuch-Heller, L; Pruginin, M; Kahane, N; Tsoulfas, P; Parada, L; Rosenthal, A; Kalcheim, C

1994-01-01

91

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

Microsoft Academic Search

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

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

92

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice.  

PubMed

Maternal supplementation with folic acid is known to reduce the incidence of neural tube defects (NTDs) by as much as 70%. Despite the strong clinical link between folate and NTDs, the biochemical mechanisms through which folic acid acts during neural tube development remain undefined. The Mthfd1l gene encodes a mitochondrial monofunctional 10-formyl-tetrahydrofolate synthetase, termed MTHFD1L. This gene is expressed in adults and at all stages of mammalian embryogenesis with localized regions of higher expression along the neural tube, developing brain, craniofacial structures, limb buds, and tail bud. In both embryos and adults, MTHFD1L catalyzes the last step in the flow of one-carbon units from mitochondria to cytoplasm, producing formate from 10-formyl-THF. To investigate the role of mitochondrial formate production during embryonic development, we have analyzed Mthfd1l knockout mice. All embryos lacking Mthfd1l exhibit aberrant neural tube closure including craniorachischisis and exencephaly and/or a wavy neural tube. This fully penetrant folate-pathway mouse model does not require feeding a folate-deficient diet to cause this phenotype. Maternal supplementation with sodium formate decreases the incidence of NTDs and partially rescues the growth defect in embryos lacking Mthfd1l. These results reveal the critical role of mitochondrially derived formate in mammalian development, providing a mechanistic link between folic acid and NTDs. In light of previous studies linking a common splice variant in the human MTHFD1L gene with increased risk for NTDs, this mouse model provides a powerful system to help elucidate the specific metabolic mechanisms that underlie folate-associated birth defects, including NTDs. PMID:23267094

Momb, Jessica; Lewandowski, Jordan P; Bryant, Joshua D; Fitch, Rebecca; Surman, Deborah R; Vokes, Steven A; Appling, Dean R

2013-01-01

93

The actin depolymerizing factor n-cofilin is essential for neural tube morphogenesis and neural crest cell migration.  

PubMed

Cofilin/ADF proteins are a ubiquitously expressed family of F-actin depolymerizing factors found in eukaryotic cells including plants. In vitro, cofilin/ADF activity has been shown to be essential for actin driven motility, by accelerating actin filament turnover. Three actin depolymerizing factors (n-cofilin, m-cofilin, ADF) can be found in mouse and human. Here we show that in mouse the non-muscle-specific gene-n-cofilin-is essential for migration of neural crest cells as well as other cell types in the paraxial mesoderm. The main defects observed in n-cofilin mutant embryos are an impaired delamination and migration of neural crest cells, affecting the development of neural crest derived tissues. Neural crest cells lacking n-cofilin do not polarize, and F-actin bundles or fibers are not detectable. In addition, n-cofilin is required for neuronal precursor cell proliferation and scattering. These defects result in a complete lack of neural tube closure in n-cofilin mutant embryos. Although ADF is overexpressed in mutant embryos, this cannot compensate the lack of n-cofilin, suggesting that they might have a different function in embryonic development. Our data suggest that in mammalian development, regulation of the actin cytoskeleton by the F-actin depolymerizing factor n-cofilin is critical for epithelial-mesenchymal type of cell shape changes as well as cell proliferation. PMID:15649475

Gurniak, Christine B; Perlas, Emerald; Witke, Walter

2005-02-01

94

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

PubMed Central

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 neural cell adhesion molecule 1 (NCAM1) in risk of human NTDs, we screened for novel single-nucleotide polymorphisms (SNPs) within the gene. Eleven SNPs across NCAM1 were genotyped using TaqMan. We utilized a family-based approach to evaluate evidence for association and/or linkage disequilibrium. We evaluated American Caucasian simplex lumbosacral myelomeningocele families (n=132 families) using the family based association test (FBAT) and the pedigree disequilibrium test (PDT). Association analysis revealed a significant association between risk for NTDs and intronic SNP rs2298526 using both the FBAT test (P=0.0018) and the PDT (P=0.0025). Using the HBAT version of the FBAT to look for haplotype association, all pairwise comparisons with SNP rs2298526 were also significant. A replication study set, consisting of 72 additional families showed no significant association; however, the overall trend for overtransmission of the less common allele of SNP rs2298526 remained significant in the combined sample set. In addition, we analyzed the expression pattern of the NCAM1 protein in human embryos, and while NCAM1 is not expressed within the neural tube at the time of closure, it is expressed in the surrounding and later in differentiated neurons of the CNS. These results suggest variations in NCAM1 may influence risk for human NTDs.

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

2011-01-01

95

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

PubMed

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 neural cell adhesion molecule 1 (NCAM1) in risk of human NTDs, we screened for novel single-nucleotide polymorphisms (SNPs) within the gene. Eleven SNPs across NCAM1 were genotyped using TaqMan. We utilized a family-based approach to evaluate evidence for association and/or linkage disequilibrium. We evaluated American Caucasian simplex lumbosacral myelomeningocele families (n=132 families) using the family based association test (FBAT) and the pedigree disequilibrium test (PDT). Association analysis revealed a significant association between risk for NTDs and intronic SNP rs2298526 using both the FBAT test (P=0.0018) and the PDT (P=0.0025). Using the HBAT version of the FBAT to look for haplotype association, all pairwise comparisons with SNP rs2298526 were also significant. A replication study set, consisting of 72 additional families showed no significant association; however, the overall trend for overtransmission of the less common allele of SNP rs2298526 remained significant in the combined sample set. In addition, we analyzed the expression pattern of the NCAM1 protein in human embryos, and while NCAM1 is not expressed within the neural tube at the time of closure, it is expressed in the surrounding and later in differentiated neurons of the CNS. These results suggest variations in NCAM1 may influence risk for human NTDs. PMID:15883837

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

2005-07-01

96

Neural tube defects in mice with reduced levels of inositol 1,3,4-trisphosphate 5/6-kinase  

PubMed Central

Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a key regulatory enzyme at the branch point for the synthesis of inositol hexakisphosphate (IP6), an intracellular signaling molecule implicated in the regulation of ion channels, endocytosis, exocytosis, transcription, DNA repair, and RNA export from the nucleus. IP6 also has been shown to be an integral structural component of several proteins. We have generated a mouse strain harboring a ?-galactosidase (?gal) gene trap cassette in the second intron of the Itpk1 gene. Animals homozygous for this gene trap are viable, fertile, and produce less ITPK1 protein than wild-type and heterozygous animals. Thus, the gene trap represents a hypomorphic rather than a null allele. Using a combination of immunohistochemistry, in situ hybridization, and ?gal staining of mice heterozygous for the hypomorphic allele, we found high expression of Itpk1 in the developing central and peripheral nervous systems and in the paraxial mesoderm. Examination of embryos resulting from homozygous matings uncovered neural tube defects (NTDs) in some animals and axial skeletal defects or growth retardation in others. On a C57BL/6 × 129(P2)Ola background, 12% of mid-gestation embryos had spina bifida and/or exencephaly, whereas wild-type animals of the same genetic background had no NTDs. We conclude that ITPK1 is required for proper development of the neural tube and axial mesoderm.

Wilson, Monita P.; Hugge, Christopher; Bielinska, Malgorzata; Nicholas, Peter; Majerus, Philip W.; Wilson, David B.

2009-01-01

97

Power and Phase Properties of Oscillatory Neural Responses in the Presence of Background Activity  

PubMed Central

Natural sensory inputs, such as speech and music, are often rhythmic. Recent studies have consistently demonstrated that these rhythmic stimuli cause the phase of oscillatory, i.e. rhythmic, neural activity, recorded as local field potential (LFP), electroencephalography (EEG) or magnetoencephalography (MEG), to synchronize with the stimulus. This phase synchronization, when not accompanied by any increase of response power, has been hypothesized to be the result of phase resetting of ongoing, spontaneous, neural oscillations measurable by LFP, EEG, or MEG. In this article, however, we argue that this same phenomenon can be easily explained without any phase resetting, and where the stimulus-synchronized activity is generated independently of background neural oscillations. It is demonstrated with a simple (but general) stochastic model that, purely due to statistical properties, phase synchronization, as measured by ‘inter-trial phase coherence’, is much more sensitive to stimulus-synchronized neural activity than is power. These results question the usefulness of analyzing the power and phase of stimulus-synchronized activity as separate and complementary measures; particularly in the case of attempting to demonstrate whether stimulus-phase-locked neural activity is generated by phase resetting of ongoing neural oscillations.

Ding, Nai; Simon, Jonathan Z.

2012-01-01

98

Distinct regulatory mechanisms act to establish and maintain Pax3 expression in the developing neural tube.  

PubMed

Pattern formation in developing tissues is driven by the interaction of extrinsic signals with intrinsic transcriptional networks that together establish spatially and temporally restricted profiles of gene expression. How this process is orchestrated at the molecular level by genomic cis-regulatory modules is one of the central questions in developmental biology. Here we have addressed this by analysing the regulation of Pax3 expression in the context of the developing spinal cord. Pax3 is induced early during neural development in progenitors of the dorsal spinal cord and is maintained as pattern is subsequently elaborated, resulting in the segregation of the tissue into dorsal and ventral subdivisions. We used a combination of comparative genomics and transgenic assays to define and dissect several functional cis-regulatory modules associated with the Pax3 locus. We provide evidence that the coordinated activity of two modules establishes and refines Pax3 expression during neural tube development. Mutational analyses of the initiating element revealed that in addition to Wnt signaling, Nkx family homeodomain repressors restrict Pax3 transcription to the presumptive dorsal neural tube. Subsequently, a second module mediates direct positive autoregulation and feedback to maintain Pax3 expression. Together, these data indicate a mechanism by which transient external signals are converted into a sustained expression domain by the activities of distinct regulatory elements. This transcriptional logic differs from the cross-repression that is responsible for the spatiotemporal patterns of gene expression in the ventral neural tube, suggesting that a variety of circuits are deployed within the neural tube regulatory network to establish and elaborate pattern formation. PMID:24098141

Moore, Steven; Ribes, Vanessa; Terriente, Javier; Wilkinson, David; Relaix, Frédéric; Briscoe, James

2013-01-01

99

Inhibition of noggin expression in the dorsal neural tube by somitogenesis: a mechanism for coordinating the timing of neural crest emigration.  

PubMed

We have previously shown that axial-dependent delamination of specified neural crest cells is triggered by BMP4 and negatively regulated by noggin. Increasing activity of BMP4 towards the rostral part of the axis is achieved by graded expression of noggin in the dorsal neural tube, the latter being high opposite unsegmented mesoderm, and progressively downregulated facing epithelial and dissociating somites, coinciding in time and axial level with initial delamination of neural crest cells (Sela-Donenfeld, D. and Kalcheim, C. (1999) Development 126, 4749-4762). Here we report that this gradient-like expression of noggin in the neuroepithelium is controlled by the paraxial mesoderm. Deletion of epithelial somites prevented normal downregulation of noggin in the neural tube. Furthermore, partial ablation of either the dorsal half or only the dorsomedial portion of epithelial somites was sufficient to maintain high noggin expression. In contrast, deletion of the segmental plate had no effect. These data suggest that the dorsomedial region of developing somites produces an inhibitor of noggin transcription in the dorsal neural tube. Consistent with this notion, grafting dissociating somites in the place of the unsegmented mesoderm precociously downregulated the expression of noggin and triggered premature emigration of neural crest progenitors from the caudal neural tube. Thus, opposite the unsegmented mesoderm, where noggin expression is high in the neural tube, BMP4 is inactive and neural crest cells fail to delaminate. Upon somitogenesis and further dissociation, the dorsomedial portion of the somite inhibits noggin transcription. Progressive loss of noggin activity releases BMP4 from inhibition, resulting in crest cell emigration. We propose that this inhibitory crosstalk between paraxial mesoderm and neural primordium controls the timing of neural crest delamination to match the development of a suitable mesodermal substrate for subsequent crest migration. PMID:11044399

Sela-Donenfeld, D; Kalcheim, C

2000-11-01

100

Applying Bayesian neural networks to separate neutrino events from backgrounds in reactor neutrino experiments  

NASA Astrophysics Data System (ADS)

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 8He/9Li 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.

Xu, Y.; Meng, Y. X.; Xu, W. W.

2008-08-01

101

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

PubMed Central

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 NTD (to 15 to 20%) in the offspring, while total litter size is unaffected. All these substances are inhibitors of DNA synthesis, yet are apparently beneficial to subjects predisposed to NTD. As a consequence, it is suggested that the underlying mechanism causing NTD in the mice, and also in man, is a basic metabolic defect in DNA synthesis which affects cell replication and results in abnormal morphogenesis of the neuraxis.

Seller, M J

1983-01-01

102

Importance of accurate diagnosis in counseling for neural tube defects diagnosed prenatally.  

PubMed

In cases of fetal neural tube defects (NTD), termination of pregnancy without ascertainment of specific etiology may lead to provision of incorrect recurrence risks and erroneous diagnosis in future pregnancies. Four patients are presented who illustrate the etiologic diversity of neural tube defects. The patients were referred for prenatal diagnosis because of elevated maternal serum alphafetoprotein (AFP). All four chose pregnancy termination. Diagnostic methods included fetal ultrasound, amniocentesis for fetal karyotyping and amniotic fluid AFP/acetylcholinesterase (AChE) and/or fetal karyotyping after delivery, and dysmorphology evaluation of the fetus after intact delivery. These cases highlight the benefits of fetal karyotype analysis and of an intact delivery and thorough clinical examination of the fetus when patients choose to terminate pregnancies with fetal anomalies. PMID:1713538

Steinhaus, K A; Bernstein, R; Bocian, M E

1991-05-01

103

Folic acid for prevention of neural tube defects: Pediatric anticipatory guidance  

Microsoft Academic Search

The incidence of neural tube defects including myelomeningocele, which is one of the most common causes of infant and childhood disability, can be substantially reduced by folic acid supplementation to the diet of women before and during the early stages of pregnancy. All females of childbearing age should be taking folic acid supplements of 0.4 mg\\/day (400 ?g\\/day) and consuming

Judy D Morrow; Kristine Kelsey

1998-01-01

104

Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro  

Microsoft Academic Search

ABSTRACT Arole for choline during early stages of mammalian embryogenesis has not been established, although recent studies show that inhibitors of choline uptake and metabolism, 2- dimethylaminoethanol (DMAE), and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3), produce neural tube defects in mouse embryos grown in vitro. To determine potential mechanismsresponsible for these abnormalities, choline metabolismin the presence or absence of these inhibitors was evaluated in

Melanie C. Fisher; Steven H. Zeisel; Mei-heng Mar; Thomas W. sadler

2002-01-01

105

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

Microsoft Academic Search

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

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

1996-01-01

106

The present status of prenatal detection of neural tube defects.  

PubMed

In experimentally induced myelocele in rats, efforts to find neural cells in amniotic fluid (AF) were unsuccessful. Creatine phosphokinase (CPK) and aldolase concentrations studied in serum of 118 and cerebrospinal fluid (CSF) in 9 patients with myelomeningocele showed serum CPK to be significantly elevated and more responsive to additional muscle injury than aldolase, but both enzymes appeared in lower concentrations in patients with myelomeningocele than those with infantile atrophy or cerebral palsy. In CSF, CPK, and aldolase concentrations averaged 4.2 I.U. and 2.7 S.L.U. per milliliter, respectively. Significant CPK elevation (p less than 0.001) was also found in AF from myeloschitic fetuses and maternal rat serum. Although these findings suggest that increased CPK concentration is an indicator of myelocele in rats, the technique is impractical for prenatal detection of human fetus occurs too late in gestation. This does not, however, preclude the value of CPK for detecting onset of paraparesis. In all myeloschitic human fetuses, the CSF communicates directly with AF for at least 3 to 4 weeks. This implies that CSF is probably the principal source of increased alpha-fetoprotein concentration encountered in AF of all pregnancies with NTD. When biological variables are recognized, it is evident that increased concentration of amniotic fluid alpha fetoprotein is a reliable indicator of fetuses with open myelocele and/or anenciphalus. PMID:1090171

Chaube, S; Swinyard, C A

1975-02-01

107

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

Microsoft Academic Search

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

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

1981-01-01

108

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

Microsoft Academic Search

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

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

2007-01-01

109

Amniotic fluid alpha-fetoprotein as a marker in prenatal diagnosis of neural tube defects.  

PubMed

The prenatal diagnosis of anencephaly and spina bifida (neural tube defect, NTD) through amniotic fluid analysis for alpha-fetoprotein (AFP) is gradually gaining clinical recognition. AFP concentrations were determined in 237 amniotic fluids from normal pregnancies ranging between 7 and 42 weeks of gestation. A steady decline in AFP from 26 mug/ml at 7-9 weeks to 155 ng/ml at term is observed. AFP concentration was determined in 35 amniotic fluids from 33 confirmed neural tube defective pregnancies. In 14 cases where amniotic fluid was examined prior to the 26th week of gestation. AFP was markedly elevated when compared with the normal range of the same gestational period. In 21 amniotic fluids past the 26th week, 17 cases (85-) had markedly elevated AFP levels; however, 2 cases of anencephaly, 1 of spina bifida, and 1 of hydrocephaly gave levels within the normal range. It is concluded that elevated AFP in the amniotic fluid is a reliable but nonspecific marker for open neural tube defects prior to the 26th week of pregnancy, but may become normal after the 26th week in a small percentage of patients. PMID:55990

Weiss, R R; Macri, J N; Elligers, K; Princler, G L; McIntire, R; Waldman, T A

1976-02-01

110

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

PubMed

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

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

2014-06-01

111

The mouse Ovol2 gene is required for cranial neural tube development.  

PubMed

The Ovo gene family encodes a group of evolutionarily conserved transcription factors and includes members that reside downstream of key developmental signaling pathways such as Wg/Wnt and BMP/TGF-beta. In the current study, we explore the function of Ovol2, one of three Ovo paralogues in mice. We report that Ovol2 is expressed during early-mid embryogenesis, particularly in the inner cell mass at E3.5, in epiblast at E6.5, and at later stages in ectodermally derived tissues such as the rostral surface (epidermal) ectoderm. Embryos in which Ovol2 is ablated exhibit lethality by E10.5, prior to which they display severe defects including an open cranial neural tube. The neural defects are associated with improper Shh expression in the underlying rostral axial mesoderm and localized changes of neural marker expression along the dorsoventral axis, as well as with expanded cranial neural tissue and reduced cranial surface ectoderm culminating in a lateral shift of the neuroectoderm/surface ectoderm border. We propose that these defects reflect the involvement of Ovol2 in independent processes such as regionalized gene expression and neural/non-neural ectodermal patterning. Additionally, we present evidence that Ovol2 is required for efficient migration and survival of neural crest cells that arise at the neuroectoderm/surface ectoderm border, but not for their initial formation. Collectively, our studies indicate that Ovol2 is a key regulator of neural development and reveal a previously unexplored role for Ovo genes in mammalian embryogenesis. PMID:16423343

Mackay, Douglas R; Hu, Ming; Li, Baoan; Rhéaume, Catherine; Dai, Xing

2006-03-01

112

Shroom, a PDZ Domain–Containing Actin-Binding Protein, Is Required for Neural Tube Morphogenesis in Mice  

Microsoft Academic Search

Using gene trap mutagenesis, we have identified a mutation in mice that causes exencephaly, acrania, facial clefting, and spina bifida, all of which can be attributed to failed neural tube closure. This mutation is designated shroom (shrm) because the neural folds “mushroom” outward and do not converge at the dorsal midline. shrm encodes a PDZ domain protein that is involved

Jeffrey D. Hildebrand; Philippe Soriano

1999-01-01

113

Discontinuity of primary and secondary neural tube in spina bifida induced by retinoic acid in mice.  

PubMed

This report shows by light microscopy the appearance of secondary neurulation separated from primary neurulation and its developmental fate in the spinal cord of mice exposed to retinoic acid in utero. The embryos and fetuses were derived from pregnant mice (ICR strain) given 60, 40, or 0 mg/kg of retinoic acid in olive oil on day 8 of gestation orally and killed 1, 2, or 10 days later. Separation of the primary neural fold from the secondary neural tube was seen in 9- and 10-day-old embryos: the caudal part of the neuroepithelium of the primary neural fold was disarranged with non-closed posterior neuropore, and underneath it the secondary neural tissue extended caudally with abnormal notochord. At term, fetuses showed spina bifida, including myeloschisis, myelocele, and diplomyelia (diastematomyelia) with abnormal distribution of ganglionic cells. These cord lesions were located between the third lumbar and second coccygeal levels. The former two cord anomalies were associated with diplomyelia and split the dorsal and ventral portions of the spinal cord with an overlapping zone between the third lumbar and third sacral levels. These findings suggest that the separation from primary neurulation is due to the lesions in both primary neural folds and notochord induced by retinoic acid and that the spinal cord caudal to the third lumbar level originates from both neuroectoderm and mesenchyme-like cells while that caudal to the third sacral level originates from mesenchyme-like cells only. PMID:2183387

Yasuda, Y; Konishi, H; Kihara, T; Tanimura, T

1990-03-01

114

Estimating the burden of neural tube defects in low- and middle-income countries  

PubMed Central

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.

Lo, Annie; Polsek, Dora; Sidhu, Simrita

2014-01-01

115

Natural history of hydrocephalus in children with spinal open neural tube defect  

PubMed Central

Background: The long-term prognosis of patients with Spinal Open Neural Tube Defect (SONTD)-associated hydrocephalus is not well known. This study was conducted to ascertain the incidence and natural history of hydrocephalus in patients with SONTD. Methods: All 82 patients with SONTD referred to Neurosurgery/Spina Bifida Clinics at King Khalid University Hospital, Riyadh, Saudi Arabia (January 1995 - July 2010) were studied and followed for a period of 1-16 years. Patients were divided into three groups: Group “A” with active hydrocephalus treated with ventriculoperitoneal shunt (VPS), or endoscopic third ventriculostomy (ETV); Group “B” with compensated hydrocephalus; and Group “C” with no hydrocephalus. Timing of shunt insertion, complications of treatment and status of hydrocephalus were analyzed. Results: The mean age of the 82 patients was 7.4 years (range 1-16 years). Group “A” included 59 (72%) patients, Group “B” 7 (8.5%) patients, and Group “C” 16 (19.5%) patients. Chiari malformation type II was found in 71 (86.6%) patients, 57 of whom (80%) were in Group “A” with active hydrocephalus. They were treated by VPS (51 patients) and ETV (8 patients). The shunts were revised or replaced in 10 (19.6%) patients due to obstruction or infection. Primary ETV failed in 3/8 patients, and treated by VPS. None of those in Groups “B” or “C” required treatment for hydrocephalus during the follow up. Conclusion: Hydrocephalus affects the majority of patients with SONTD who have Myelomeningocele (MMC) and CM II and requires close surveillance and prompt management. Children with SONTD should routinely undergo MRI examination of brain and craniocervical junction to clarify ventricular size, and the presence of CM II.

Elgamal, Essam A.

2012-01-01

116

ARSENATE-INDUCED MATERNAL GLUCOSE INTOLERANCE AND NEURAL TUBE DEFECTS IN A MOUSE MODEL  

PubMed Central

Background Epidemiological 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. Objectives We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic’s teratogenicity in early neurodevelopment. Methods We evaluated maternal intraperitoneal (I.P.) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selected compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), L-methionine (L-Met), N-tert-Butyl-?-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate’s effects. Results Arsenate caused significant glucose elevation during an I.P. glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p=0.0260). Arsenate caused NTDs (100%, p<0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%. Conclusions IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin’s success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.

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

2009-01-01

117

Maternal vitamin levels in pregnancies affected by congenital malformations other than neural tube defects  

PubMed Central

Background Periconceptional use of folic acid prevents most neural tube defects (NTDs). Whether folic acid and/or multivitamins can prevent other congenital anomalies is not clear. This study tested whether maternal blood levels of folate and vitamin B12 in pregnancies affected by congenital malformations excluding NTDs are lower when compared to non-affected pregnancies. Methods We measured pregnancy red cell folate (RCF), vitamin B12, and homocysteine (tHcy) concentrations in blood samples taken at the first antenatal clinic in Dublin maternity hospitals in 1986–1990 when vitamin supplementation was rare. The cases were mothers who delivered a baby with a congenital malformation other than NTD identified by the Dublin EUROCAT Registry; controls were a systematic sample of mothers of offspring without congenital malformations from the same hospitals in the same time period. Results The median maternal levels of RCF and tHcy did not differ significantly between cases and controls for any of the congenital malformation groups examined (RCF: all malformations 275.9 ug/L v controls 271.2; p=0.77; tHcy: all malformations 7.5 umol/L v controls 7.6; p=0.57). In an unadjusted analysis vitamin B12 was significantly higher in case-mothers whose babies had cleft palate only (p=0.006), musculoskeletal malformations (p=0.034) and midline defects (p=0.039) but not after adjustment for multiple testing. Conclusions Our data suggest that low maternal folate and B12 levels or high tHcy levels in early pregnancy are not associated with all congenital malformations excluding NTDs. Fortification with folic acid or B12 may not have a beneficial effect in the prevention of these anomalies.

Sutton, Marie; Mills, James L.; Molloy, Anne M.; Troendle, James F.; Brody, Lawrence C.; Conley, Mary; Mc Donnell, Robert; Scott, John M.; Kirke, Peadar N.

2012-01-01

118

The association between weight gain during pregnancy and neural tube defects and gastroschisis in offspring  

PubMed Central

Background Limited information is available about the association of maternal weight gain during pregnancy and birth defects. The objective of this study was to investigate the association of maternal weight gain with neural tube defects and gastroschisis among offspring. Methods We used data from the National Birth Defects Prevention Study, an ongoing multi-center, population-based case-control study. Mothers of cases and controls were interviewed by phone. Analyses included 255 anencephaly, 577 spina bifida, and 648 gastroschisis cases and 5,587 controls with deliveries from 1999–2005. After subtracting birth weight, the associations of total and average weekly weight gain(kg) with each phenotype were estimated, stratified by gestational age (<37vs.?37 weeks) and adjusted for relevant covariates Results Among deliveries <37 weeks gestation, mothers of anencephaly and spina bifida cases had lower weight gains compared to control mothers; no association between weight gains and gastroschisis was observed. Among deliveries ?37 weeks, mothers of anencephaly cases had lower weight gains during pregnancy; a similar association was not observed for spina bifida; mothers of gastroschisis cases were twice as likely to have weight gains in the highest quartile. Stratification by maternal age (gastroschisis) or BMI or race/ethnicity (all phenotypes) did not alter odds ratio estimates. Conclusion Altered weight gain during pregnancy may be a consequence of carrying a NTD/gastroschisis affected fetus or a marker for underlying factors common to the etiology of these birth defects. It is possible that whatever mechanisms influence weight gain may also influence the development of NTDs and gastroschisis, but in opposite directions.

Yang, Wei; Carmichael, Suzan L.; Tinker, Sarah; Shaw, Gary M.

2012-01-01

119

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

SciTech Connect

Background: Epidemiological 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. Objectives: We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic's teratogenicity in early neurodevelopment. Methods: We evaluated maternal intraperitoneal (IP) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selected compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), L-methionine (L-Met), N-tert-Butyl-{alpha}-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate's effects. Results: Arsenate caused significant glucose elevation during an IP glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p = 0.0260). Arsenate caused NTDs (100%, p < 0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%. Conclusions: IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin's success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.

Hill, Denise S.; Wlodarczyk, Bogdan J. [Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, TX 77030 (United States); Mitchell, Laura E. [Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, TX 77030 (United States); Center for Environmental and Rural Health Texas A and M University, College Station, TX 77843 (United States); Finnell, Richard H. [Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, TX 77030 (United States); Interdisciplinary Faculty of Toxicology, Texas A and M University, College Station, TX 77843 (United States); Center for Environmental and Rural Health Texas A and M University, College Station, TX 77843 (United States)], E-mail: rfinnell@ibt.tamhsc.edu

2009-08-15

120

Uncoupling Protein 2 Polymorphisms as Risk Factors for Neural Tube Defects  

PubMed Central

BACKGROUND: Both environmental and genetic factors are involved in the etiology of neural tube defects (NTDs). Inadequate folate intake and obesity are important environmental risk factors. Several folate-related genetic variants have been identified as risk factors; however, little is known about how genetic variants relate to the increased risk seen in obese women. Uncoupling Protein 2 (UCP2) is an attractive candidate to screen for NTD risk because of its possible role in obesity as well as energy metabolism, type-2 diabetes, and the regulation of reactive oxygen species. Interestingly, a previous study found that a common UCP2 compound homozygous genotype was associated with a threefold increase in NTD risk. METHODS: We evaluated three polymorphisms, ?866G>A, A55V, and the 3?UTR 45bp insertion/deletion, as risk factors for NTDs in Irish NTD cases (N=169), their mothers (N=163), their fathers (N=167) and normal control subjects (N=332). RESULTS: Allele and genotype frequencies were not significantly different when comparing NTD mothers, NTD fathers, or affected children to controls. Additionally, the previously reported risk genotype (combined homozygosity of 55VV and 3?UTR 45bp deletion/deletion) was not present at a higher frequency in any NTD group when compared to controls. CONCLUSIONS: In our Irish study population, UCP2 polymorphisms do not influence NTD risk. Moreover, the prevalence of this allele in other populations was similar to the Irish prevalence but far lower than reported in the previous NTD study, suggesting that this previous finding of an association with NTDs might have been due to an unrepresentative study sample.

Mitchell, Adam; Pangilinan, Faith; VanderMeer, Julie; Molloy, Anne M.; Troendle, James; Conley, Mary; Kirke, Peadar N.; Scott, John M.; Brody, Lawrence C.; Mills, James L.

2008-01-01

121

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

PubMed

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

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

2013-09-01

122

The amniotic fluid as a source of neural stem cells in the setting of experimental neural tube defects.  

PubMed

We sought to determine whether neural stem cells (NSCs) can be isolated from the amniotic fluid in the setting of neural tube defects (NTDs), as a prerequisite for eventual autologous perinatal therapies. Pregnant Sprague-Dawley dams (n=62) were divided into experimental (n=42) and control (n=20) groups, depending on prenatal exposure to retinoic acid for the induction of fetal NTDs. Animals were killed before term for analysis (n=685 fetuses). Amniotic fluid samples from both groups underwent epigenetic selection for NSCs, followed by exposure to neural differentiation media. Representative cell samples underwent multiple morphological and phenotypical analyses at different time points. No control fetus (n=267) had any structural abnormality, whereas at least one type of NTD developed in 52% (217/418) of the experimental fetuses (namely, isolated spina bifida, n=144; isolated exencephaly, n=24; or a combination of the two, n=49). Only amniotic samples from fetuses with a NTD yielded cells with typical neural progenitor morphology and robust expression of both Nestin and Sox-2, primary markers of NSCs. These cells responded to differentiation media by displaying typical morphological changes, along with expression of beta-tubulin III, glial fibrillary acidic protein, and/or O4, markers for immature neurons, astrocytes, and oligodendrocytes, respectively. This was concurrent with downregulation of Nestin and Sox-2. We conclude that the amniotic fluid can harbor disease-specific stem cells, for example, NSCs in the setting of experimental NTDs. The amniotic fluid may be a practical source of autologous NSCs applicable to novel forms of therapies for spina bifida. PMID:22957979

Turner, Christopher G; Klein, Justin D; Wang, Junmei; Thakor, Devang; Benedict, Darcy; Ahmed, Azra; Teng, Yang D; Fauza, Dario O

2013-02-15

123

Maternal hyperglycemia activates an ASK1-FoxO3a-caspase 8 pathway that leads to embryonic neural tube defects.  

PubMed

Neural tube defects result from failure to completely close neural tubes during development. Maternal diabetes is a substantial risk factor for neural tube defects, and available evidence suggests that the mechanism that links hyperglycemia to neural tube defects involves oxidative stress and apoptosis. We demonstrated that maternal hyperglycemia correlated with activation of the apoptosis signal-regulating kinase 1 (ASK1) in the developing neural tube, and Ask1 gene deletion was associated with reduced neuroepithelial cell apoptosis and development of neural tube defects. ASK1 activation stimulated the activity of the transcription factor FoxO3a, which increased the abundance of the apoptosis-promoting adaptor protein TRADD, leading to activation of caspase 8. Hyperglycemia-induced apoptosis and the development of neural tube defects were reduced with genetic ablation of either FoxO3a or Casp8 or inhibition of ASK1 by thioredoxin. Examination of human neural tissues affected by neural tube defects revealed increased activation or abundance of ASK1, FoxO3a, TRADD, and caspase 8. Thus, activation of an ASK1-FoxO3a-TRADD-caspase 8 pathway participates in the development of neural tube defects, which could be prevented by inhibiting intermediates in this cascade. PMID:23982205

Yang, Peixin; Li, Xuezheng; Xu, Cheng; Eckert, Richard L; Reece, E Albert; Zielke, Horst Ronald; Wang, Fang

2013-08-27

124

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

PubMed

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

Yamaguchi, Yoshifumi; Miura, Masayuki

2013-09-01

125

Neurotrophin-3 affects proliferation and differentiation of distinct neural crest cells and is present in the early neural tube of avian embryos.  

PubMed

Neurotrophin-3 is mitogenic for cultured quail neural crest cells (Kalcheim et al., 1992, Proc. Natl. Acad. Sci. USA 89:1661-1665). We now report that neurotrophin-3 also influences the survival and/or differentiation of a subset of postmitotic neural crest precursors into neurons, provided these progenitors are grown on a cellular substrate. When cultured for 1 day on monolayers of NT-3-producing, chinese hamster ovary cells, 59% of the neural crest clusters growing on the transfected line revealed the presence of intense neuronal outgrowth, compared to 25% of that in controls. Moreover, dissociated neural crest cells grown for 20 h on top of mesodermal cells in the presence of various concentrations of purified recombinant neurotrophin-3 displayed a dose-dependent increase in neuronal number. Localization experiments using specific polyclonal antibodies, revealed that neurotrophin-3 is confined to neuroepithelial cells of quail neural tubes in situ on E2 and E3, and to E2 neural tubes grown in culture for 24 h. At this stage, neural crest cells and somites were negative. At later stages, staining was likewise apparent in peripheral nerves and dorsal root ganglia. We, therefore, propose that NT-3, a factor that is expressed in the early avian central nervous system, has multiple effects both on the proliferation and differentiation of distinct neural crest cells, which depend on the state of commitment of the responsive progenitors. PMID:8301270

Pinco, O; Carmeli, C; Rosenthal, A; Kalcheim, C

1993-12-01

126

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

PubMed Central

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.

Ragunath, PK; Abhinand, PA

2013-01-01

127

Nitrosatable Drug Exposure During Early Pregnancy and Neural Tube Defects in Offspring  

PubMed Central

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.

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.

2011-01-01

128

Neural tube malformations: complex segregation analysis and calculation of recurrence risks.  

PubMed Central

Familial data on neural tube malformations in Great Britain were submitted to segregation analysis under the mixed model. Maternal and fetal factors cannot be discriminated in the absence of substantial bodies of data on spina bifida survivors who reproduce or on half-sibs. Early abortion studies would allow differential mortality in utero to be taken into account. After fitting the mixed and generalised single locus models, it is concluded that the multifactorial model can provisionally be used for calculation of recurrence risks. Pathogenic hypotheses implicating twinning seem to rest on little evidence.

Lalouel, J M; Morton, N E; Jackson, J

1979-01-01

129

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

PubMed

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

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

2013-02-01

130

Determination of maternal serum acetylcholinesterase in pregnancies with fetal neural tube defects.  

PubMed

We have investigated the occurrence of acetylcholinesterase (AChE) (E.C. 3.1.1.7) in fetal serum, amniotic fluid and maternal serum using an immuno-chemical assay-technique employing both polyclonal and monoclonal antibodies. Fetal serum had increased amounts of AChE, which is due to an increase in the 10.5S form of the enzyme. This form was also found in amniotic fluids of pregnancies with a fetal neural tube defect (NTD), but not in normal amniotic fluid. The increase in amniotic fluid AChE was however, not reflected in the maternal serum. PMID:3575265

Sorensen, K; Brodbeck, U; Rasmussen, A G; Norgaard-Pedersen, B

1987-02-01

131

Amniotic fluid fibrinogen degradation products in the prenatal diagnosis of neural tube defects.  

PubMed

Elevated levels of fibrin(ogen) degradation products (FDP) have been detected in second-trimester amniotic fluid in association with open neural tube defects (NTD'S) in the fetus. The FDP assay has been proposed for the prenatal diagnosis of NTD's and in this paper is compared with the established use of the alpha-fetoprotein (AFP) assay. FDP and AFP levels were measured in 132 amniotic fluid samples, including 20 NTD cases. The false negative and false positive rates for the FDP assay are high compared with the AFP assay, but it may be of value as an adjunct assay to reduce the over-all false positive rate. PMID:67808

Kimball, M E; Milunsky, A; Giannusa, P; Carvalho, A C

1977-06-01

132

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

NASA Astrophysics Data System (ADS)

The Double Chooz is a reactor neutrino experiment which measures the last unknown neutrino mixing angle ?13. 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 and characterize the PMTs and to tune operation parameter, we developed two types of PMT test system and evaluated 400 PMTs before installation. Those PMTs fulfilled our requirements and half of them were installed in the far detector in 2009 and physics data have been successfully taken since 2011.

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

2012-01-01

133

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

PubMed

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

Zohn, Irene E

2012-06-01

134

Severity of abnormality influences decision to terminate pregnancies affected with fetal neural tube defects.  

PubMed

We examined parental decision concerning pregnancy management in women having fetuses with neural tube defects (NTDs) to determine whether severity of defect or method of detection has an impact on the decision making process. Analysis of decisions by 50 women, whose pregnancies were affected by an isolated neural tube defect (NTD) and characterized by a singleton gestation at 24 gestational weeks or less with normal chromosomal complement (46,XX or 46,XY), were assessed. All 23 women carrying fetuses with anencephaly elected to terminate their pregnancies. Of the 27 women carrying fetuses with spina bifida, 21 (77.8%) elected to terminate their pregnancies and 6 (22.2%) elected to continue their pregnancies. Of the 6 pregnancies that were continued, 4 were initially detected by ultrasonography and 2 were ascertained by maternal serum alpha-fetoprotein screening; defects ranged from 2 to 14 vertebral bodies, and none of the defects were craniad to the T9 level. This is in comparison to 5 of the 21 spina bifida cases that were elective pregnancy terminations, which were characterized by fetal lesions craniad to the T9 level. Severity of NTD thus appears to influence the decision to continue or terminate an affected pregnancy. PMID:7524525

Grevengood, C; Shulman, L P; Dungan, J S; Martens, P; Phillips, O P; Emerson, D S; Felker, R E; Simpson, J L; Elias, S

1994-01-01

135

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects  

PubMed Central

Background Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs. Methods The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined. Results Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24–5.87). Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27–8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways. Conclusions Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.

Gao, Yonghui; Zhao, Huizhi; Sheng, Xiaoming; Zou, Jizhen; Lip, Va; Xie, Hua; Guo, Jin; Shao, Hong; Bao, Yihua; Shen, Jianliang; Niu, Bo; Gusella, James F.; Wu, Bai-Lin; Zhang, Ting

2013-01-01

136

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

PubMed

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

Copp, Andrew J; Greene, Nicholas D E

2013-01-01

137

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

Microsoft Academic Search

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

Liang Yang; Chun-Lu Zhang

2009-01-01

138

Integration of Signals along Orthogonal Axes of the Vertebrate Neural Tube Controls Progenitor Competence and Increases Cell Diversity.  

PubMed

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

Sasai, Noriaki; Kutejova, Eva; Briscoe, James

2014-07-01

139

Integration of Signals along Orthogonal Axes of the Vertebrate Neural Tube Controls Progenitor Competence and Increases Cell Diversity  

PubMed Central

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.

Sasai, Noriaki; Kutejova, Eva; Briscoe, James

2014-01-01

140

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

PubMed

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

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

2000-01-01

141

DNA methyltransferase3A as a molecular switch mediating the neural tube-to-neural crest fate transition  

PubMed Central

Here, we explore whether silencing via promoter DNA methylation plays a role in neural versus neural crest cell lineage decisions. We show that DNA methyltransferase3A (DNMT3A) promotes neural crest specification by directly mediating repression of neural genes like Sox2 and Sox3. DNMT3A is expressed in the neural plate border, and its knockdown causes ectopic Sox2 and Sox3 expression at the expense of neural crest markers. In vivo chromatin immunoprecipitation of neural folds demonstrates that DNMT3A specifically associates with CpG islands in the Sox2 and Sox3 promoter regions, resulting in their repression by methylation. Thus, DNMT3A functions as a molecular switch, repressing neural to favor neural crest cell fate.

Hu, Na; Strobl-Mazzulla, Pablo; Sauka-Spengler, Tatjana; Bronner, Marianne E.

2012-01-01

142

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

PubMed

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

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

2013-01-01

143

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

ERIC Educational Resources Information Center

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…

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

2011-01-01

144

Gel electrophoresis of maternal and fetal serum cholinesterases from normal pregnancies and of those affected by neural tube defects.  

PubMed

The cholinesterase isozymes of maternal and fetal sera from normal pregnancies and those in which the fetus had a neural tube defect were studied using flat-bed vertical polyacrylamide gel electrophoresis. Normal maternal and fetal sera had multiple bands of cholinesterase activity, including the two bands in the position of those found in amniotic fluid from NTD pregnancies. The one difference between maternal and fetal sera was that the faster of these two "amniotic fluid bands" was acetylcholinesterase in fetal serum, as in the neural tube defect amniotic fluids, but non-specific cholinesterase in maternal serum. In artificial mixtures this difference could be used to differentiate between maternal and fetal blood-contamination of amniotic fluids, but in samples naturally contaminated at amniocentesis this test did not always agree with the Kleihauer findings. Both maternal and fetal sera had additional weak acetylcholinesterase activity in the most anodally migrating enzyme bands, but all other enzyme activity was non-specific cholinesterase. No difference was observed in the isozymes of fetal serum from normal fetuses and those with neural tube defects, or of maternal serum from normal and neural tube defect pregnancies. PMID:7060269

Cole, K J; Seller, M J

1982-02-26

145

Epithelial-mesenchymal conversion of dermatome progenitors requires neural tube-derived signals: characterization of the role of Neurotrophin-3.  

PubMed

Development of the somite-derived dermatome involves conversion of the epithelial dermatome progenitors into mesenchymal cells of the dermis. In chick embryos, neural tube-derived signals are required for this conversion, as the interposition of a membrane between neural tube and somites results in a failure of the dermatome to lose its epithelial arrangement. However, dermis formation can be completely rescued by coating the membranes with Neurotrophin-3, but not with the related molecule Nerve growth factor. Neurotrophin-3 was also found to be necessary for dermatome dissociation using in vitro explants or partially dissociated dermomyotomes. The functional relevance of these observations was investigated by neutralizing endogenous Neurotrophin-3 using a specific blocking antibody. Antibody-treated embryos revealed the presence of tightly aggregated cells between myotome and ectoderm instead of the loose dermal mesenchyme observed in embryos treated with control antibodies. As previous studies have demonstrated the presence of Neurotrophin-3 in the neural tube, these results suggest that it may be a necessary neural tube-derived signal required for early stages of dermis formation. PMID:7671821

Brill, G; Kahane, N; Carmeli, C; von Schack, D; Barde, Y A; Kalcheim, C

1995-08-01

146

Syndromes, disorders and maternal risk factors associated with neural tube defects (III).  

PubMed

Fetuses with neural tube defects (NTDs) may be associated with syndromes, disorders, and maternal and fetal risk factors. This article provides a comprehensive review of syndromes, disorders, and maternal and fetal risk factors associated with NTDs, such as omphalocele, OEIS (omphalocele-exstrophy-imperforate anus-spinal defects) complex, pentalogy of Cantrell, amniotic band sequence, limb-body wall complex, Meckel syndrome, Joubert syndrome, skeletal dysplasia, diabetic embryopathy, and single nucleotide polymorphisms in genes of glucose metabolism. NTDs associated with syndromes, disorders, and maternal and fetal risk factors are a rare but important cause of NTDs. The recurrence risk and the preventive effect of maternal folic acid intake in NTDs associated with syndromes, disorders and maternal risk factors may be different from those of nonsyndromic multifactorial NTDs. Perinatal identification of NTDs should alert the clinician to the syndromes, disorders, and maternal and fetal risk factors associated with NTDs, and prompt a thorough etiologic investigation and genetic counseling. PMID:18603496

Chen, Chih-Ping

2008-06-01

147

Gene Regulatory Logic for Reading the Sonic Hedgehog Signaling Gradient in the Vertebrate Neural Tube  

PubMed Central

Summary Secreted signals, known as morphogens, provide the positional information that organizes gene expression and cellular differentiation in many developing tissues. In the vertebrate neural tube, Sonic Hedgehog (Shh) acts as a morphogen to control the pattern of neuronal subtype specification. Using an in vivo reporter of Shh signaling, mouse genetics, and systems modeling, we show that a spatially and temporally changing gradient of Shh signaling is interpreted by the regulatory logic of a downstream transcriptional network. The design of the network, which links three transcription factors to Shh signaling, is responsible for differential spatial and temporal gene expression. In addition, the network renders cells insensitive to fluctuations in signaling and confers hysteresis—memory of the signal. Our findings reveal that morphogen interpretation is an emergent property of the architecture of a transcriptional network that provides robustness and reliability to tissue patterning.

Balaskas, Nikolaos; Ribeiro, Ana; Panovska, Jasmina; Dessaud, Eric; Sasai, Noriaki; Page, Karen M.; Briscoe, James; Ribes, Vanessa

2012-01-01

148

Neural-tube defect risk assessment for individual pregnancies using alphafetoprotein and acetylcholinesterase test results.  

PubMed Central

Pregnancies at risk of being associated with (open) neural tube defects can be identified by maternal serum and amniotic-fluid alphafetoprotein (AFP) concentrations in excess of established screening cut-off valves in conjunction with the results of an amniotic fluid electrophoretic acetylcholinesterase screening test. The risk associated with the AFP cut-off values are formulated in terms of a population screening programme. These "population risks" are of little value in the assessment of test results from individual "at-risk" pregnancies, especially when the observed AFP concentrations are in proximity to the "cut-off" values. A complete risk assessment procedure for individual pregnancies is described and presented in graphical form to permit immediate access by clinical staff.

Strike, P W; Smith, J

1982-01-01

149

Neural tube defects: a survey of lesion descriptions made by different European pathologists.  

PubMed Central

Recent epidemiological interest has focused on separation of neural tube defects (NTD) into subgroups which may differ pathogenetically and aetiologically, for example, 'upper' and 'lower' spina bifida. In order to validate the use of pathologists' lesion descriptions by epidemiologists and others, a postal survey of 18 European perinatal pathologists, identified by EUROCAT registries, was conducted. Pathologists were asked, anonymously, to describe and identify the lesions in 15 photographs of midtrimester termination fetuses. There was a 50% response rate. Even taking into consideration the limitations of dealing with photographs rather than the fetuses themselves, there was often marked variation in the descriptions. Standardisation of terminology and international consensus about the type of detail recorded for NTD are urgently needed. Images

Dolk, H; Seller, M J

1993-01-01

150

Nutrient levels in amniotic fluid from women with normal and neural tube defect pregnancies.  

PubMed

We analyzed nutrient levels in amniotic fluid obtained during the second trimester of normal, uncomplicated pregnancies from 221 women who delivered apparently healthy infants and from 8 with neural tube defect (NTD) pregnancies. Folate was measured by microbiological assay, vitamin B12 by a radiobinding method, and zinc, copper and iron by atomic absorption spectrophotometry. We found that the mean amniotic fluid nutrient levels of normal pregnancies were 24.7 nmol/l for folate, 600 pmol/l for vitamin B12, and 1.7, 1.9, and 9.0 mumol/l for zinc, copper and iron, respectively. Amniotic fluid folate, zinc, copper and iron levels of NTD pregnancies were similar to those found during normal pregnancy, however, vitamin B12 levels were markedly lower than those of normal pregnancies. PMID:1610951

Weekes, E W; Tamura, T; Davis, R O; Birch, R; Vaughn, W H; Franklin, J C; Barganier, C; Cosper, P; Finley, S C; Finley, W H

1992-01-01

151

Amniotic fluid cholinesterase measurement as a rapid method for the exclusion of fetal neural tube defects.  

PubMed

Amniotic fluid total cholinesterase (ChE) and acetylcholinesterase (AChE) activities have been measured in 404 pregnancies without fetal malformation and 79 pregnancies associated with open neural-tube defects (NTDs). Neither measurement, either alone or in combination, gave complete separation of the two groups. However, measurement of ChE can be used to assess the probability that a woman is carrying a fetus with an open NTD. Since ChE can be measured within 15 minutes and shows at least 70% of women selected for amniocentesis by serum alpha-fetoprotein screening to have a less than 1 in 100 chance of carrying a fetus with an open NTD, we suggest that this test may be used in an amniocentesis clinic both to reassure women with normal pregnancies and to select probable abnormalities for immediate further investigation. PMID:6115109

Hullin, D A; Elder, G H; Laurence, K M; Roberts, A; Newcombe, R G

1981-08-15

152

Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro.  

PubMed

A role for choline during early stages of mammalian embryogenesis has not been established, although recent studies show that inhibitors of choline uptake and metabolism, 2-dimethylaminoethanol (DMAE), and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3), produce neural tube defects in mouse embryos grown in vitro. To determine potential mechanisms responsible for these abnormalities, choline metabolism in the presence or absence of these inhibitors was evaluated in cultured, neurulating mouse embryos by using chromatographic techniques. Results showed that 90%-95% of 14C-choline was incorporated into phosphocholine and phosphatidylcholine (PtdCho), which was metabolized to sphingomyelin. Choline was oxidized to betaine, and betaine homocysteine methyltransferase was expressed. Acetylcholine was synthesized in yolk sacs, but 70 kDa choline acetyltransferase was undetectable by immunoblot. DMAE reduced embryonic choline uptake and inhibited phosphocholine, PtdCho, phosphatidylethanolamine (PtdEtn), and sphingomyelin synthesis. ET-18-OCH3 also inhibited PtdCho synthesis. In embryos and yolk sacs incubated with 3H-ethanolamine, 95% of recovered label was PtdEtn, but PtdEtn was not converted to PtdCho, which suggested that phosphatidylethanolamine methyltransferase (PeMT) activity was absent. In ET-18-OCH3 treated yolk sacs, PtdEtn was increased, but PtdCho was still not generated through PeMT. Results suggest that endogenous PtdCho synthesis is important during neurulation and that perturbed choline metabolism contributes to neural tube defects produced by DMAE and ET-18-OCH3. PMID:11919173

Fisher, Melanie C; Zeisel, Steven H; Mar, Mei-Heng; Sadler, Thomas W

2002-04-01

153

Methanol-induced neural tube defects in mice: Characterization of lesions, target and teratogen  

SciTech Connect

The present studies investigated the hypothesis that methanol induces neural tube defects (e.g., exenephaly) through the cytotoxic action of its metabolite, formate, upon embryonic neuroepithelium during neurulation. Methanol was tested because of concerns raised by the proposed heavier use of this alcohol in automobile fuels, which could result in increased exposure of the general public. Neurulation (gestational days [GD] 7-9 in mice) was shown to be the period of greatest vulnerability. Pregnant mice inhaled methanol (5,000 to 15,000 ppm) for 6 hr/day either during GD 7-9 or during a encephaly was observed only if exposure to [>=] 10,000 ppm encompassed GD 7 and/or GD 8. Aberrant neural tube closure was confirmed as the pathogensis by demonstrating persistent patency of the anterior neuropore in embryos. Peak concentrations of 431 mmol methanol/kg and 14 mmol formate/kg were measured in embryos following maternal methanol inhalation at a teratogenic level (15,000 ppm for 6 hr on GD 8). Autoradiography of pregnant mice after intravenous injection with 0.06 or 6 mmol [sup 14]C-formate/kg on GD 8 revealed selective localization of radioactivity to the neuroepithelium within 10 minutes after administration, with at least a two fold greater level in each tissue of formate-exposed embryos. Exposure in vitro to either 187 mM methanol or [>=]12 mM formate for 12 hr delayed closure of the anterior neuropore in neurulating mouse embryos. In addition, in vitro exposure to formate resulted in lower reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bormide (MTT) and decreased levels of ATP in cephalic tissues of embryos. Formate also reduced MTT staining in neuroepithelium and mesoderm, suggesting these embryonic tissues as potential targets.

Bolon, B.N.

1993-01-01

154

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

PubMed

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

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

155

Maternal exposure to nitrate from drinking water and diet and risk for neural tube defects.  

PubMed

In this population-based case-control study conducted in California between June 1989 and May 1991, the authors investigated the association between maternal periconceptional exposure to nitrate from drinking water and diet and risk for neural tube defects. The mothers of 538 cases and 539 nonmalformed controls were interviewed regarding residential history, consumption of tap water at home, and dietary intake during the periconceptional period. Dietary nitrate exposure was not associated with increased risk for neural tube defects. Exposure to nitrate in drinking water at concentrations above the 45 mg/liter maximum contaminant level was associated with increased risk for anencephaly (odds ratio (OR) = 4.0, 95% confidence interval (CI): 1.0, 15.4), but not for spina bifida. Increased risks for anencephaly were observed at nitrate levels below the maximum contaminant level among groundwater drinkers only (OR = 2.1, 95% CI: 1.1,4.1 for 5-15 mg/liter; OR = 2.3, 95% CI: 1.1, 4.5 for 16-35 mg/liter; and OR = 6.9, 95% CI: 1.9, 24.9 for 36-67 mg/liter compared with <5 mg/liter). Adjustment for identified risk factors for anencephaly did not substantially alter these associations, nor did control for maternal dietary nitrate, total vitamin C intake, and quantity of tap water consumed. The lack of an observed elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater may indicate that something other than nitrate accounts for these findings. PMID:11207149

Croen, L A; Todoroff, K; Shaw, G M

2001-02-15

156

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?  

PubMed

Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of >200 ?g. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs. PMID:23482308

Obeid, Rima; Holzgreve, Wolfgang; Pietrzik, Klaus

2013-09-01

157

ATLAS monitored drift tube chambers in E = 11 MeV neutron background  

Microsoft Academic Search

The influence of fast neutrons on the occupancy and the single tube resolution of ATLAS muon drift detectors was investigated by exposing a chamber built out of 3 layers of 3 short standard drift tubes to neutron flux-densities of up to 16 kHz\\/cm2 at a neutron energy of E=11 MeV. Pulse shape capable NE213 scintillaton detectors and a calibrated BF3

T. Muller; A. Mlynek; O. Biebel; R. Hertenberger; T. Nunnemann; D. Merkl; F. Rauscher; D. Schaile; R. Strohmer

2008-01-01

158

ATLAS Monitored Drift Tube Chambers in E = 11 MeV Neutron Background  

Microsoft Academic Search

The influence of fast neutrons on the occupancy and the single tube resolution of ATLAS muon drift detectors was investigated by exposing a chamber built out of 3 layers of 3 short standard drift tubes to neutron flux-densities of up to 16 kHz\\/cm2 at a neutron energy of E=11 MeV. Pulse shape capable NE213 scintillaton detectors and a calibrated BF3

T. Mueller; A. Mlynek; O. Biebel; R. Hertenberger; T. Nunnemann; D. Merkl; F. Rauscher; D. Schaile; R. Stroehmer

2009-01-01

159

Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3- dependent development and tumorigenesis  

PubMed Central

Pax-3 is a transcription factor that is expressed in the neural tube, neural crest, and dermomyotome. We previously showed that apoptosis is associated with neural tube defects (NTDs) in Pax-3-deficient Splotch (Sp/Sp) embryos. Here we show that p53 deficiency, caused by germ-line mutation or by pifithrin-?, an inhibitor of p53-dependent apoptosis, rescues not only apoptosis, but also NTDs, in Sp/Sp embryos. Pax-3 deficiency had no effect on p53 mRNA, but increased p53 protein levels. These results suggest that Pax-3 regulates neural tube closure by inhibiting p53-dependent apoptosis, rather than by inducing neural tube-specific gene expression.

Pani, Lydie; Horal, Melissa; Loeken, Mary R.

2002-01-01

160

Sulf1 influences the Shh morphogen gradient during the dorsal ventral patterning of the neural tube in Xenopus tropicalis.  

PubMed

Genetic studies have established that heparan sulphate proteoglycans (HSPGs) are required for signalling by key developmental regulators, including Hedgehog, Wnt/Wg, FGF, and BMP/Dpp. Post-synthetic remodelling of heparan sulphate (HS) by Sulf1 has been shown to modulate these same signalling pathways. Sulf1 codes for an N-acetylglucosamine 6-O-endosulfatase, an enzyme that specifically removes the 6-O sulphate group from glucosamine in highly sulfated regions of HS chains. One striking aspect of Sulf1 expression in all vertebrates is its co-localisation with that of Sonic hedgehog in the floor plate of the neural tube. We show here that Sulf1 is required for normal specification of neural progenitors in the ventral neural tube, a process known to require a gradient of Shh activity. We use single-cell injection of mRNA coding for GFP-tagged Shh in early Xenopus embryos and find that Sulf1 restricts ligand diffusion. Moreover, we find that the endogenous distribution of Shh protein in Sulf1 knockdown embryos is altered, where a less steep ventral to dorsal gradient forms in the absence of Sulf1, resulting in more a diffuse distribution of Shh. These data point to an important role for Sulf1 in the ventral neural tube, and suggests a mechanism whereby Sulf1 activity shapes the Shh morphogen gradient by promoting ventral accumulation of high levels of Shh protein. PMID:24768893

Ramsbottom, Simon A; Maguire, Richard J; Fellgett, Simon W; Pownall, Mary Elizabeth

2014-07-15

161

Transcriptome Profiling of Genes Involved in Neural Tube Closure During Human Embryonic Development Using Long Serial Analysis of Gene Expression (Long-SAGE)  

PubMed Central

Background Neural tube defects (NTDs) are common human birth defects with a complex etiology. To develop a comprehensive knowledge of the genes expressed during normal neurulation, we established transcriptomes from human neural tube fragments during and after neurulation using long Serial Analysis of Gene Expression (long-SAGE). Methods Rostral and caudal neural tubes were dissected from normal human embryos aged between 26 and 32 days of gestation. Tissues from the same region and Carnegie stage were pooled (n>=4) and total RNA extracted to construct four long-SAGE libraries. Tags were mapped using the UniGene Homo sapiens 17 bp tag-to-gene best mapping set. Differentially expressed genes were identified by chi-square or Fisher’s exact test and validation was performed for a subset of those transcripts using in situ hybridization. In silico analyses were performed with BinGO and EXPANDER. Results We observed most genes to be similarly regulated in rostral and caudal regions, but expression profiles differed during and after closure. In silico analysis found similar enrichments in both regions for biological process terms, transcription factor binding and miRNA target motifs. Twelve genes potentially expressing alternate isoforms by region or developmental stage, and the miRNAs miR-339-5p, miR-141/200a, miR-23ab, and miR-129/129-5p, are among several potential candidates identified here for future research. Conclusions Time appears to influence gene expression in the developing central nervous system more than location. These data provide a novel complement to traditional strategies of identifying genes associated with human NTDs, and offer unique insight into the genes associated with normal human neurulation.

Krupp, D. R.; Xu, P-T.; Thomas, S.; Dellinger, A.; Etchevers, H. C.; Vekemans, M.; Gilbert, J. R.; Speer, M.C.; Ashley-Koch, A. E.; Gregory, S. G.

2012-01-01

162

Temporal deletion of Arl13b reveals that a mispatterned neural tube corrects cell fate over time  

PubMed Central

Cilia are necessary for sonic hedgehog (Shh) signaling, which is required to pattern the neural tube. We know that ventral neural cell fates are defined by a specific cohort of transcription factors that are induced by distinct thresholds of Shh activity mediated by opposing gradients of Gli activator (GliA) and Gli repressor (GliR). Despite this understanding, the role of Shh as an instructive morphogen is viewed as increasingly complex, with current models integrating positive inputs in terms of ligand concentration and time, along with negative feedback via the downstream gene regulatory network. To investigate the relative contributions of the positive and negative inputs from Shh signaling in neural patterning, we took advantage of a protein that uncouples the regulation of GliA and GliR: the cilia protein ADP-ribosylation factor-like 13b (Arl13b). By deleting Arl13b in mouse, we induced low-level constitutive GliA function at specific developmental stages and defined a crucial period prior to E10.5 when shifts in the level of GliA cause cells to change their fate. Strikingly, we found that improperly patterned cells in these mice converted to the wild-type pattern by E12.5. We further showed that the recovery of patterning did not occur when we also deleted Gli3, the primary GliR in the neural tube, revealing a crucial role of Gli3 in the maintenance of neural patterning.

Su, Chen-Ying; Bay, Sarah N.; Mariani, Laura E.; Hillman, Michael J.; Caspary, Tamara

2012-01-01

163

The impact of maternal serum alpha fetoprotein screening on open neural tube defect births in north-east Scotland.  

PubMed

Over the three years period 1980-1982, 18 256 pregnancies in the Grampian Region of N-E Scotland including the islands of Orkney and Shetland were screened for raised levels of maternal serum alpha fetoprotein (MSAFP) in the second trimester. Thirty six cases of fetal open neural tube defect in singletons were detected (18 anencephaly and 18 spina bifida). Four additional cases of open spina bifida were associated with normal MSAFP levels although two of these were detected by amniotic fluid AFP measurement when amniocentesis was carried out because of previous NTD history. A further three cases of open spina bifida and two of anencephaly occurred in unscreened pregnancies. The MSAFP screening programme alone was thus instrumental in reducing the birth incidence of open neural tube defects by 36 out of 45 cases (80 per cent) in singletons. PMID:2579374

Thom, H; Campbell, A G; Farr, V; Fisher, P M; Hall, M H; Swapp, G H; Gray, E S

1985-01-01

164

Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects  

PubMed Central

The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure and has been implicated in the pathogenesis of neural tube defects (NTDs) in animal models and human cohorts. In this study, we analyzed the role of one core PCP gene PRICKLE1 in these malformations. We screened this gene in 810 unrelated NTD patients and identified 7 rare missense heterozygous mutations that were absent in all controls analyzed and predicted to be functionally deleterious using bioinformatics. Functional validation of 5 PRICKLE1 variants in a zebrafish model demonstrated that one variant, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a in a dominant fashion. Our study demonstrates that PRICKLE1 could act as a predisposing factor to human NTDs and further expands our knowledge of the role of PCP genes in the pathogenesis of these malformations.

Bosoi, Ciprian M.; Capra, Valeria; Allache, Redouane; Trinh, Vincent Quoc-Huy; De Marco, Patrizia; Merello, Elisa; Drapeau, Pierre; Bassuk, Alexander G.; Kibar, Zoha

2011-01-01

165

Congenital hydrocephalus in two pregnancies following the birth of a child with a neural tube defect: aetiology and management.  

PubMed

A family is described with congenital hydrocephalus occurring in two pregnancies following the birth of a child with a neural tube defect (NTD). Prenatal diagnosis of hydrocephalus at mid-gestation was achieved by ultrasonography. The increased frequency of hydrocephalus among sibs of probands with a NTD and vice versa suggests that, following the birth of a child with either malformations, subsequent pregnancies should be monitored at mid-gestation by amniotic fluid AFP and serial ultrasound examination. PMID:7241527

Robertson, R D; Sarti, D A; Brown, W J; Crandall, B F

1981-04-01

166

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

Microsoft Academic Search

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

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

167

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

PubMed

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

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

2014-06-01

168

Neural tube defects and maternal residential proximity to agricultural pesticide applications.  

PubMed

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 physicochemical groups of pesticides during early gestation increases the risk of these malformations. Maternal residential proximity within 1,000 m of pesticide applications was ascertained by linking mothers' addresses with agricultural pesticide use reports and crop maps. Odds ratios were computed by using conventional single- and multiple-pesticide and hierarchical multiple-pesticide logistic regression. In single-pesticide models, several pesticides were associated with NTDs after adjustment for study population, maternal ethnicity, educational level, cigarette smoking, and vitamin use. In a hierarchical multiple-pesticide model, effect estimates for only benomyl and methomyl suggested a possible association. Elevated risks of NTDs and anencephaly or spina bifida subtypes were also associated with exposures to chemicals classified as amide, benzimidazole, methyl carbamate, or organophosphorus pesticides and with increasing numbers of pesticides. These results suggest that ambient exposure to certain categories of agricultural pesticides may increase the risk of NTDs. PMID:16495467

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

2006-04-15

169

Periconceptional glycaemic load and intake of sugars and their association with neural tube defects in offspring.  

PubMed

In a California population, we previously observed increased neural tube defect (NTD) risks associated with maternal intakes of periconceptional diets predicting higher glycaemic responses and higher sucrose. Our objective here was to replicate these results in a larger study of multiple regions within the United States. This population-based case-control study included deliveries from 1997 to 2003 from the National Birth Defects Prevention Study. NTD cases were infants or fetuses born with spina bifida or anencephaly. Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. There were 720 NTD case and 4699 control mothers with completed interviews included in analyses. Diet was assessed using a 58-item food frequency questionnaire focusing on the year before conception, whereas cereals, beverages and supplement use was assessed periconceptionally. We found no increased risks of NTD-affected pregnancies with increased intakes (adjusted for kcal/day) of sucrose, glucose, fructose or with maternal diets with a higher glycaemic load. The reasons for current findings to be inconsistent with previous findings are unknown. PMID:19000288

Shaw, Gary M; Carmichael, Suzan L; Laurent, Cecile; Siega-Riz, Anna M

2008-11-01

170

[Analysis on 2158 neural tube defects diagnosed prenatally by ultrasound examination].  

PubMed

A retrospective survey was made to study the prenatal diagnosis on neural tube defects(NTD) by ultrasound examination from 1990 to 1993 in China. A total of 2158 livebirths and stillbirths affected by NTD with 28 weeks or more of gestation were investigated in 233 hospitals of 28 provinces, municipalities and autonomous regions all over the country. The results showed that 61.8% of the NTD were diagnosed prenatally, and 56.5% of the NTD were diagnosed by ultrasound examination. The ratios of anencephaly, myelocele and meningocele diagnosed prenatally by ultrasound examination were 66.7%, 62.5% and 52.5% respectively. Thoracic(46.4%) and lumbar (43.4%) spina bifida were diagnosed more frequently than cervical(35.5%) and sacral(31.7%) spina bifida. The ratios of prenatal diagnosis on NTD by ultrasound examination in provincial, municipal, county, and factory hospital units were 55.7%, 59.4%, 49.0% and 57.2% respectively. The ratios of prenatal diagnosis of NTD by ultrasound examination from 1990 to 1993 were 53.5%, 55.8%, 60.7% and 54.7% respectively. There was an increase in the prenatal diagnosis of NTD by ultrasound examination from 1990 to 1993. The ratios of prenatal diagnosis of NTD in county hospitals by ultrasound examination were relatively low. Anencephaly, myelocele and meningocele were more frequently diagnosed by prenatal ultrasound examination. PMID:12515142

Wang, Y; Liang, J; Zhou, G; Miao, L; Zhu, J; Wu, Y

2000-06-01

171

Prevalence and Correlates of Neural Tube Defect in South West Iran  

PubMed Central

Objective: In view of the large number of pregnancies complicated by neural tube defect (NTD) in Khuzestan, south west Iran, this study assesses the prevalence of NTD and its ecological and social factors. Methods: This is a retrospective study, based on medical documents using an analytic assessment of NTDs in pregnant women attending the Jundi Shapur University hospitals in Ahvaz from 21 March 2002 to 20 March 2004. Results: The total number of pregnant women was 13,262 and 56 pregnancies were complicated with NTD. A large number of the infants with NTDs were female (70%) and the most common anomaly was anencephaly. The prevalence was 4.2 in 1,000 births. The percentage in primigravida was 42.6% and in multigravida 57.4%. The main risk factor for NTD was age of the mother, those between 21 and 30 being the most affected. Consanguinity is the second risk factor with 31% of couples who were close relatives. Other socio-demographic factors were also significant. Conclusion: This retrospective study confirms clinical observation that pregnancies complicated by NTD in Khuzestan are common. There are various ecological and social factors that correlate with the prevalence of NTD.

Behrooz, Ahmad; Gorjizadeh, Mohammad H

2007-01-01

172

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

PubMed

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

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

173

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

PubMed

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

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

174

Neural tube defects in Malaysia: data from the Malaysian National Neonatal Registry.  

PubMed

This study aimed to determine the prevalence and early outcome of neural tube defects (NTDs) in Malaysia. This prospective study included all neonates with NTDs (spina bifida, anencephaly, encephalocoele) born in 2009 in 32 Malaysian hospitals in the Malaysian National Neonatal Network. The prevalence of NTDs was 0.42 per 1000 live births, being highest among the indigenous people of Sarawak (1.09 per 1000 live births) and lowest among Malaysians of Chinese descent (0.09 per 1000 live births). The most common type of NTDs was anencephaly (0.19 per 1000 live births), followed by spina bifida (0.11 per 1000 live births) and encephalocoele (0.07 per 1000 live births). Majority of the infants with anencephaly (94.5%, n = 51), 45.8% (n = 11) with encephalocoele and 9.5% (n = 4) with spina bifida died. The median duration of hospital stay was 4 (range: 0-161) days. Conclusion: NTDs were common in Malaysia. Mortality was high. Long-term monitoring of NTD prevalence following folic fortification of food is recommended. PMID:23583959

Boo, Nem-Yun; Cheah, Irene G S; Thong, Meow-Keong

2013-10-01

175

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

PubMed

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

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

2012-07-01

176

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

SciTech Connect

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.

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

1996-10-01

177

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

PubMed Central

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.

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

2012-01-01

178

Amniotic fluid B12 and folate levels associated with neural tube defects.  

PubMed

Amniotic fluid levels of B12 and folate in neural tube defect (NTD) affected pregnancies were compared with the weekly group mean +/-SD changes in amniotic fluid B12 and folate levels of 10 unaffected pregnancies each week between 15 and 20 weeks' gestation age. Comparison was by analysis of variance (ANOVA) and Pearson's correlation to B12 and folate levels and to the NTD samples of corresponding gestation age. Amniotic fluid B12 and folate decreased 67 and 62%, respectively, between 15 and 20 weeks' gestation in the unaffected pregnancies, associated with an increase in amniotic fluid volume. The mean +/-SD B12 and folate of the NTD affected pregnancies (308+/-156 pg/mL and 3.1+/-1.6 ng/mL) were below the mean +/-SD B12 and folate of the total population of unaffected pregnancies (453+/-155 pg/mL and 3.9+/-1.2 ng/mL). The correlation between gestation age and amniotic fluid B12 was -0.9914 (p< or =.0001) and -0.9599 (p< or =.002) for amniotic fluid folate. The B12 levels of the affected pregnancies were below the range of unaffected pregnancies in four of the nine affected pregnancies, and folate levels in two of the nine affected pregnancies. PMID:9890246

Dawson, E B; Evans, D R; Van Hook, J W

1998-01-01

179

Maternal plasma alpha-fetoprotein screening for fetal neural tube defects.  

PubMed

Maternal plasma alpha-fetoprotein (AFP) screening for fetal neural tube defects (NTD) was used as a part of routine antenatal care in three hospitals over a 26 month period. Blood samples were obtained for plasma AFP measurement at 15 to 20 weeks gestation from 6377 women, representing 79 per cent of antenatal bookings. The outcome of pregnancy was ascertained in 96 per cent of patients: 13 cases of anencephaly and 7 of open spina bifida were detected by plasma screening and a further 3 cases of open NTD through the mother's previous medical history and amniotic fluid determination. Four fetuses with open NTDs and four with closed NTDS were not detected by plasma AFP measurement and the detection efficiency for open NTDs was thus 83 per cent. Integration of screening into the existing pattern of antenatal care required only minor alterations in clinic schedules. Some extra time was needed for explanation of the objectives of the study, for ultrasound examination and for amniocentesis. Eight patients declined the offer of a plasma test, while only one refused an amniocentesis. PMID:80224

Brock, D J; Scrimgeour, J B; Steven, J; Barron, L; Watt, M

1978-08-01

180

Should women at high risk of neural tube defect have an amniocentesis?  

PubMed Central

As part of an investigation into the practical problems of a maternal serum alphafetoprotein (AFP) neural tube defect (NTD) screening programme carried out in Mid Glamorgan, South Wales, between 1977 and 1979, obstetricians were recommended to refer women with high risk pregnancies directly for counselling, high resolution ultrasonography, and amniocentesis without first carrying out serum screening. Out of 15 687 pregnant women one-third attended too late to be screened. A total of 637 was classed as high risk, mostly at greater risk than 1 in 50 because of a previously affected pregnancy or an affected close relative. Compliance with recommended procedure was relatively low as many were screened. There were 10 pregnancies with a recurrence of NTD, of which one was not tested at all, two were not detected (one closed meningocele and one closed iniencephalic), and seven were detected and the pregnancies terminated. All the latter, as well as the iniencephalic, would have been detected from a serum AFP determination and a high resolution ultrasound scan alone. It is concluded that these investigations are sufficient for high risk pregnancies and that amniocentesis is not really cost effective or necessary unless either of these investigations is abnormal. As numbers in this study were small it is suggested that these conclusions should be tested in a larger study.

Laurence, K M; Elder, G; Evans, K T; Hibbard, B M; Hoole, M; Roberts, C J

1985-01-01

181

Methylmalonic acid in amniotic fluid and maternal urine as a marker for neural tube defects.  

PubMed

To evaluate the implication of methymalonic acid (MMA) in the early diagnosis of neural tube defects (NTD), a quantitative assay for MMA was established by using gas chromatography-mass spectrometry with stable isotope of MMA as an internal standard. Amniotic fluid and maternal urine MMA concentration, maternal serum folate, red blood cell folate and vitamin B12 levels were measured in the middle term of NTD-affected and normal pregnancies. Amniotic fluid and maternal urine MMA concentrations in the middle term of NTD affected pregnancies (1.4 +/- 0.9 micromol/L, and 22.1 +/- 12.6 nmol/micromol creatinine) were significantly higher than that of normal pregnancies (1.0 +/- 0. 4 micromol/L, and 2.5 +/- 1.1 nmol/micromol creatinine). There was no significant difference between normal and NTD pregnancies for serum folate, red blood cell folate and vitamin B12 levels. The results suggested that MMAs in amniotic fluid and maternal urine are sensitive markers for early diagnosis of NTD. Vitamin B12 is an active cofactor involved in the remethylation of homocycteine and its deficiency is an independent risk factor for NTD. MMA is a specific and sensitive marker for intracellular vitamin B12 deficiency. This study suggests that it is necessary to monitor the vitamin B12 deficiency and advocates vitamin B12 supplementation with folate prevention program. PMID:15315171

Luo, Xiaoping; Zhang, Lian; Wei, Hong; Liu, Wanjun; Wang, Muti; Ning, Qin

2004-01-01

182

Detecting neural tube defects by amniocentesis between 11 and 15 weeks' gestation.  

PubMed

Forty-two open neural tube defects (NTDs) were identified in our series of 7440 amniocenteses tested between 11 and 15 weeks of gestation. Using a cut-off of > or = 2.0 MOM, the detection rate for open NTDs was 95 per cent; 100 per cent each for anencephaly and spina bifida; and 78 per cent for encephalocele. Two encephaloceles had AFP levels less than 2.0 MOM and negative AChEs. Thirty-four (81 per cent) of these NTDs were tested between 13 and 15 weeks and 8 (19 per cent) before 13 weeks. There were 0.6 per cent false positives by AFP (excluding serious abnormalities and fetal death) and 0.1 per cent after AChE. The likelihood of an open NTD after an elevated AFP (> or = 2.0 MOM) was 24 and 77 per cent for any serious abnormality. These results, when combined with an earlier study, indicate that amniotic fluid AFP appears to be as sensitive a test for open NTDs between 13 and 15 weeks as between 16 and 20 weeks. Additional experience is necessary to determine this before 13 weeks. PMID:7542382

Crandall, B F; Chua, C

1995-04-01

183

Diagnosis of neural tube defects by estimation of amniotic fluid acetylcholinesterase.  

PubMed

Acetylcholinesterase (AChE) activity in amniotic fluid was assayed directly by a reaction rate method at 30 degrees C using acetylthiocholine iodide as substrate and ethopropazine as a safe 'pseudo' cholinesterase inhibitor. Fresh samples from 101 normal pregnancies of 14-24 weeks gestation had a mean AChE activity of 2.56 u/l (SD 1.10). Elevated levels of AChE were found in association with open spina bifida (5.5-20.4 u/l), anencephaly (10.2-19.5 u/l), exomphalos (2.7-15.6 u/l), intrauterine death (30.2-59.3 u/l) and Turner's syndrome (36.4 u/l) but not with closed spina bifida or rhesus isoimmunisation. When AChE activity was expressed as a percentage of the total cholinesterase activity ('percentage AChE'), there was a good correlation between AChE activity and 'percentage AChE' in normal pregnancies and the values associated with the 37 pregnancies affected by open neural tube defects (NTD) fell outside the 99.9 per cent confidence limits of the normal group. Qualitative differences in cholinesterase activity could be demonstrated between the groups with exomphalos and open NTD. It is suggested that the assay might be used satisfactorily to demonstrate the presence of open NTD in affected pregnancies. PMID:7459300

Dale, G; Archibald, A; Bonham, J R; Lowdon, P

1981-02-01

184

Amniotic fluid folate, vitamin B12 and transcobalamins in neural tube defects.  

PubMed

Levels of folate, vitamin B12, the vitamin B12 binding proteins, apotranscobalamin I, II and III (TC I, II and III) and the unsaturated vitamin B12 binding capacity (UBBC) were measured in mid-trimester amniotic fluids from normal pregnancies, and from those where the fetus had open spina bifida, anencephaly or omphalocoele, and where the fetus was normal but the mother had had a previous neural tube defect pregnancy. At 15-19 weeks' gestation, vitamin B12 levels were low in the fluids of all the types of abnormal fetuses, and also of normal fetuses where there had been a previous NTD sib. In contradistinction, TC I, II and III and UBBC levels were generally abnormally high in all these groups. Low vitamin B12 levels in the face of high carrier protein levels suggest deranged vitamin B12 production or transport. Since these abnormalities are present in fluids from normal sibs of NTD individuals as well as from those with midline lesions, an inherited defect is implied. We propose that at least part of the genetic predisposition to NTD, and possibly other midline defects, could reside in an abnormality connected with vitamin B12 production, transport or metabolism, and a mechanism is suggested. PMID:3048802

Gardiki-Kouidou, P; Seller, M J

1988-06-01

185

Antenatal detection of neural tube defects: comparison of biochemical and immunofluorescence methods.  

PubMed

The aim of this study was to determine whether identification of glial cells in amniotic fluid samples could form a useful supplementary test in the antenatal diagnosis of neural tube defects (NTDs). In a 5-year study, 1452 samples of middle trimester amniotic fluid were examined blind to the results of other antenatal diagnostic tests and to the outcome of pregnancy. Reason of amniocentesis included raised serum alpha-fetoprotein (329), previous NTD (73), and a family history of NTDs (71). Duplicate cytospin preparations were stained with Giemsa and an antibody to glial fibrillary acidic protein (GFAP), and on this basis a prediction of fetal NTD status was made which was not communicated to clinicians. Subsequent management of pregnancies was influenced only by the results of routine antenatal testing for NTDs. Twenty cases of NTDs occurred among the 1406 cases in which the outcome was subsequently known. Of these 20 cases, only five (four anencephalic, one spina bifida) were correctly predicated by immunofluorescent identification of GFAP-positive cells in the amniotic fluid. The remaining 15 cases (two anencephalic, 13 spina bifida) were not so identified. In a further 18 cases, apparently GFAP-positive cells were identified in the absence of NTDs. We conclude that GFAP immunofluorescence examination of routine amniocentesis samples of amniotic fluid is not a useful predictive test for NTDs. PMID:7526368

Bell, J E; Barron, L; Raab, G

1994-07-01

186

Sonography, a complementary examination to alpha-fetoprotein testing for fetal neural tube defects.  

PubMed

Neural tube defects (NTDs) are among the most common congenital anomalies in the United States, with an estimated prevalence of 16 per 10,000 births. The measurement of amniotic fluid alpha-fetoprotein (AF-AFP) concentration has been used to detect NTDs since the early 1970s. When the AF-AFP concentration is elevated, ultrasonography is commonly used to confirm the presence of a NTD. In this study, patient charts, amniocentesis records, and ultrasound reports from a three-year period were reviewed. The 97 fetuses identified as being at high risk for NTDs were divided into four groups: those with high AF-AFP concentrations (Groups 1 and 2, with from 3 to 5 standard deviations (SD) above the mean and with more than 5 SD above the mean, respectively): those referred from other institutions because of suspicious sonographic results (Group 3); and those at risk because of a previous sibling with a NTD (Group 4). Ultrasonography was 100 per cent sensitive and 100 per cent specific in diagnosing NTDs. Thus, in pregnancies with an elevated AF-AFP concentration, ultrasonography can reliably identify normal fetuses as well as differentiate between those with NTDs and those with other congenital anomalies. Also, since AF-AFP concentrations decline after 20 weeks' gestation, ultrasonography may be a better test than a repeat amniocentesis in equivocal cases of AF-AFP elevation. PMID:2409295

Hashimoto, B E; Mahony, B S; Filly, R A; Golbus, M S; Anderson, R L; Callen, P W

1985-06-01

187

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

PubMed

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

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

188

Association of folic acid receptor ? in maternal serum with neural tube defects.  

PubMed

Abstract Objective: To evaluate whether serum folic receptor ? levels are changed in women whose previous pregnancies were complicated with neural tube defects (NTDs). Methods: This was a case-control study that included 41 women as the control group who had previously had at least one healthy pregnancy and 37 women as the study group who had a previous pregnancy complicated with NTDs. Blood samples were obtained from all of the participants six weeks after the termination of pregnancy or delivery of a baby. Serum folate receptor ? concentrations were analyzed using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. Results: The mean concentrations of serum folate receptor ? were significantly lower in the NTD cases compared to those in the control group (p?=?0.02). There was no significant difference in mean serum folate titers between the NTD cases and the control group (p?=?0.07). Conclusion: Low serum folic acid receptor ? levels in the current study did not appear to be a regulatory marker of maternal folate homeostasis per se but rather a factor that contributed to the development of NTDs. PMID:24094304

Celik, Ebru; Karaer, Abdullah; Turkcuoglu, Ilgin; Turhan, Ugur; Gungoren, Arif; Taskapan, Cagatay; Ozyalin, Fatma; Berker, Bulent

2014-07-01

189

FZD6 is a novel gene for human neural tube defects  

PubMed Central

Abstract Neural tube defects (NTDs) are severe malformations of the central nervous system, affecting 1 of 1,000 live births. Mouse models were instrumental in defining the signaling pathways defective in NTDs, including the planar cell polarity (PCP), also called noncanonical Frizzled/Disheveled pathway. Based on the highly penetrant occurrence of NTDs in double Fzd3/Fzd6?/? mutant mice, we investigated the role of the human orthologues, FZD3 and FZD6, by resequencing a cohort of 473 NTDs patients and 639 ethnically matched controls. While we could not demonstrate a significant contribution of FZD3 gene, we identified five rare FZD6 variants that were absent in all controls and predicted to have a functional effect by computational analysis: one de novo frameshift mutation (c.1843_1844insA), three missense changes (p.Arg405Gln, p.Arg511Cys p.Arg511His), and one substitution (c.*20C>T) affecting the 3?-untranslated region (UTR) of the gene. The overall rate of predicted deleterious variants of FZD6 was 5.1-fold higher in cases compared to controls, resulting in a significantly increased NTDs mutation burden. This study demonstrates that rare nonsynonymous variants in FZD6 may contribute to NTDs in humans and enlarges the spectrum of mutations that link PCP pathway to NTDs. Hum Mutat 33:384–390, 2012. © 2011 Wiley Periodicals, Inc.

De Marco, Patrizia; Merello, Elisa; Rossi, Andrea; Piatelli, Gianluca; Cama, Armando; Kibar, Zoha; Capra, Valeria

2011-01-01

190

Long Term Maintenance of Neural Tube Defects Prevention in a High Prevalence State  

PubMed Central

Objective To assess the efficacy of folic acid (FA) supplementation and fortification in preventing neural tube defects (NTDs) in a high prevalence region of the US. Study design Active and passive surveillance methods were used to identify all fetuses/infants affected by an NTD in South Carolina. Prevalence rates were compared with FA intake to determine the effects of increased intake on NTD occurrence and recurrence. Results From 1992–2009, 916 NTD cases occurred in South Carolina with isolated defects comprising 79% of cases. The NTD rate decreased 58% during this period. There was one NTD-affected pregnancy among 418 subsequent pregnancies (0.2%) in mothers with previous NTD-affected pregnancies who consumed periconceptional FA supplements and four NTDs among 66 pregnancies (6.1%) in which the mother did not take FA supplements. Folic acid supplementation increased from 8% to 35% from 1992–2007 and knowledge of the protective benefits of FA increased from 8% to 65% in women of childbearing age. Conclusions Increased periconceptional intake of FA appeared to reduce NTDs in a high prevalence region. The rate of spina bifida and anencephaly in South Carolina is now essentially the same (0.69 cases per 1000 live births and fetal deaths) as the 1998–2005 US rate (0.69).

Collins, Julianne S.; Atkinson, Kristy K.; Dean, Jane H.; Best, Robert G.; Stevenson, Roger E.

2011-01-01

191

Maternal serum AGEs levels in pregnancies associated with neural tube defects.  

PubMed

Advanced glycation end products (AGEs) plays an important role in diabetic embryopathy. AGE-mediated DNA damage could be a significant factor in the teratogenicity. The aim of the present study was to evaluate the association between the AGEs level and neural tube defects (NTDs) occurrence risk. Forty-eight mothers with NTD-affected pregnancies and 50 normal mothers were selected in this study. Blood were collected from the mothers and were assayed for serum AGEs, malondiadehyde (MDA) and hemoglobin A1c (HbA1c). Data were analyzed by logistic regression method. The study indicated that there were significant but modest lower prevalence for cases mothers on age, BMI and glucose levels compared with controls. NTD-affected mothers were significantly more likely to have higher AGEs levels (5.6±0.48 AU vs. 4.6±0.68 AU ?<0.01) than controls. The AGEs levels were not correlated with MDA and HbA1c in NTDs mothers (r(2)=0.0006 p=0.8691 and r(2)=0.001 p=0.8172, respectively). The conclusion is that AGEs might be associated with NTDs occurrence. PMID:24345611

Li, Rulin; Yang, Peiyao; Chen, Xuyang; Wang, Li

2014-04-01

192

In ovo electroporation of miRNA-based-plasmids to investigate gene function in the developing neural tube.  

PubMed

When studying gene function in vivo during development, gene expression has to be controlled in a precise temporal and spatial manner. Technologies based on RNA interference (RNAi) are well suited for such studies, as they allow for the efficient silencing of a gene of interest. In contrast to challenging and laborious approaches in mammalian systems, the use of RNAi in combination with oviparous animal models allows temporal control of gene silencing in a fast and precise manner. We have developed approaches using RNAi in the chicken embryo to analyze gene function during neural tube development. Here we describe the construction of plasmids that direct the expression of one or two artificial microRNAs (miRNAs) to knock down expression of endogenous protein/s of interest upon electroporation into the spinal cord. The miRNA cassette is directly linked to a fluorescent protein reporter, for the direct visualization of transfected cells. The transcripts are under the control of different promoters/enhancers which drive expression in genetically defined cell subpopulations in the neural tube. Mixing multiple RNAi vectors allows combinatorial knockdowns of two or more genes in different cell types of the spinal cord, thus permitting the analysis of complex cellular and molecular interactions in a fast and precise manner. The technique that we describe can easily be applied to other cell types in the neural tube, or even adapted to other organisms in developmental studies. PMID:24233790

Andermatt, Irwin; Wilson, Nicole; Stoeckli, Esther T

2014-01-01

193

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

PubMed

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

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

2014-06-01

194

Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite.  

PubMed

Embryonic patterning in vertebrates is dependent upon the balance of inductive signals and their specific antagonists. We show that Noggin, which encodes a bone morphogenetic protein (BMP) antagonist expressed in the node, notochord, and dorsal somite, is required for normal mouse development. Although Noggin has been implicated in neural induction, examination of null mutants in the mouse indicates that Noggin is not essential for this process. However, Noggin is required for subsequent growth and patterning of the neural tube. Early BMP-dependent dorsal cell fates, the roof plate and neural crest, form in the absence of Noggin. However, there is a progressive loss of early, Sonic hedgehog (Shh)-dependent ventral cell fates despite the normal expression of Shh in the notochord. Further, somite differentiation is deficient in both muscle and sclerotomal precursors. Addition of BMP2 or BMP4 to paraxial mesoderm explants blocks Shh-mediated induction of Pax-1, a sclerotomal marker, whereas addition of Noggin is sufficient to induce Pax-1. Noggin and Shh induce Pax-1 synergistically. Use of protein kinase A stimulators blocks Shh-mediated induction of Pax-1, but not induction by Noggin, suggesting that induction is mediated by different pathways. Together these data demonstrate that inhibition of BMP signaling by axially secreted Noggin is an important requirement for normal patterning of the vertebrate neural tube and somite. PMID:9585504

McMahon, J A; Takada, S; Zimmerman, L B; Fan, C M; Harland, R M; McMahon, A P

1998-05-15

195

[Neural tube defects and vitamin B12: a report of three cases].  

PubMed

Periconceptional folic acid supplementation reduces the frequency of embryological neural tube defects (NTD). This fact led the USA to fortify grain products with folic acid (140 microg/100 g) starting in January 1998, with a resultant decrease in the incidence of NTD. Folate deficiency is thus confirmed to be a risk factor for NTD. However, in a prospective study, we investigated three women who conceived a fetus with NTD; no folate deficiency was found in these women but all three had decreased vitamin B12 levels (cobalamin), which can be an other risk factor. Samples were obtained from two women in Algeria, 2 days after interruption of pregnancy, and from a vegetarian woman, in France, one month after interruption of pregnancy. Red cell folate and plasma folate, vitamin B12, B6 and homocysteine were assayed and the mutations C677T (in metylenetetrahydrofolate reductase gene), A2756G (in methionine synthase gene) and A66G (in methionine synthase reductase gene) were sought. Elevated plasma folate levels were found in both Algerian women. Vitamin B 12 levels in all three women were decreased or in the lowest quartile of normal values. One woman presented simultaneously a vitamin B 12 deficiency, and heterozygous mutations in the three genes. The second woman presented a A66G homozygous mutation and the third heterozygous C677T and A66G mutations. Acquired and inborn factors are intricated in some cases of pregnancies with NTD and B 12 deficiency can be responsible for intracellular folate cycle failure. It would therefore be advisable to consider fortifying grain products with both folic acid and vitamin B12. PMID:15047478

Candito, M; Houcher, B; Boisson, C; Abellard, J; Demarcq, M-J; Guéant, J-L; Benhacine, K; Gérard, P; Van Obberghen, E

2004-01-01

196

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

PubMed

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

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

2013-10-01

197

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

SciTech Connect

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{mu}g/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.

Brender, Jean D. [Department of Epidemiology and Biostatistics, Texas A and M School of Rural Public Health, Texas A and M University System Health Science Center, Bryan, TX 77802 (United States)]. E-mail: jdbrender@aol.com; Suarez, Lucina [Division of Prevention and Preparedness, Texas Department of State Health Services, Austin, TX (United States); Felkner, Marilyn [Division of Prevention and Preparedness, Texas Department of State Health Services, Austin, TX (United States); Gilani, Zunera [Division of Prevention and Preparedness, Texas Department of State Health Services, Austin, TX (United States); Stinchcomb, David [Center for Health Statistics, Texas Department of State Health Services, Austin, TX (United States); Moody, Karen [Department of Health Services Research, Texas State University, San Marcos, TX (United States); Henry, Judy [Division of Prevention and Preparedness, Texas Department of State Health Services, Austin, TX (United States); Hendricks, Katherine [Medical Institute, Austin, TX (United States)

2006-05-15

198

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

PubMed

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

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

2012-08-01

199

An increase in neural tube defect notifications, South Australia, 2009-2010  

PubMed Central

Introduction In South Australia, reporting of live births, stillbirths of at least 20 weeks or 400 g birth weight, termination of pregnancies and congenital anomalies is mandated. We describe the investigation of an increase in notifications of neural tube defects (NTDs) in South Australia in 2009 and 2010 using data from several surveillance systems. Methods NTD trend data from 1966 to 2010 were reviewed. Comparisons of pregnancies affected by an NTD in 2009 and 2010 were made with pregnancies affected by an NTD in the period 2003–2008 and with all pregnancies in 2009 and 2010. Statistical analysis was undertaken using Poisson regression, ?2 or Fisher’s exact tests. Results The prevalence of NTD-affected pregnancies was 1.95 per 1000 births (39 cases) in 2010 and 1.91 per 1000 births in 2009 (38 cases), the highest annual rates since 1991. Case series comparisons indicated women with NTD-affected pregnancies in 2009 and 2010 were less likely to be Caucasian compared with women who had NTD-affected pregnancies in the period 2003–2008. Women born in the Middle East and African region (n = 7) were significantly more likely to have NTD-affected pregnancies in the years 2009 and 2010 (relative risk: 3.03; 95% confidence interval: 1.39–6.62) compared with women born in the Oceania region. Discussion The increased notifications of NTDs can only be partially explained by the increase in numbers of women from the Middle East and African region, with no other contributory causes revealed. This analysis highlighted areas where prevention efforts should be strengthened and surveillance data improved.

Scheil, Wendy; Nguyen, Anh-Minh; Sage, Leonie; Scott, Joan

2013-01-01

200

[Amniotic and serum alphafetoprotein in the chick embryo with neural tube defect].  

PubMed

Although alpha-feto-protein (AFP) is a widely used marker for human neural tube defects (NTD) little is known about the mechanisms for its increase in the amniotic fluid in this condition. For investigating this issue we developed a chick embryo AFP assay and tested it in a NTD experimental model. AFP obtained by electroelution on PAGE/SDS gels from the plasma of 12-day-old embryos was used to produce rabbit polyclonal and mouse monoclonal antibodies. A specific sandwich-type enzyme-immune-assay was developed using both reagents. Sterile aspiration of 5 ml. of albumen from 602 fertile hen eggs on the 27th hour of incubation (Hamburger stages 8 to 11) led to the appearance of NTD in 36 out of the 270 survivors (13%). Amniotic and seric AFP levels were measured on the 15th day of incubation in NTD chicks (n = 11) and in control ones (n = 9) and the results were compared by non-parametric tests. Serum AFP was five times higher in NTD chicks than in controls (119.2 +/- 32.6 vs 523.3 +/- 173.62 micrograms/ml., p < 0.001) and amniotic AFP was absent in control and very increased in NTD animals (0.15 +/- 0.02 vs 87.14 +/- 84 micrograms/ml., p < 0.001). It is concluded that: 1) serum AFP is intriguingly increased in the chick with NTD; 2) since urine is not diversed into the amniotic sac in the avian embryo, the only source of AFP in its fluid is exudation through an open defect. This conclusion is further supported by the absence of amniotic AFP in a chick with a large closed NTD. PMID:7692911

Uriarte, S; Barrena, M J; López de Torre, B; Aldazábal, P; Cuadrado, E; Tovar, J A

1993-07-01

201

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

PubMed Central

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.

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

2011-01-01

202

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

PubMed Central

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.

Liu, Zhenjiang; Yuan, Zhengwei; Zhao, Qun

2014-01-01

203

Transcobalamin II Receptor Polymorphisms Are Associated with Increased Risk for Neural Tube Defects  

PubMed Central

Objective: Women who have low cobalamin (vitamin B12) levels are at increased risk for having children with neural tube defects (NTDs). The transcobalamin II receptor (TCblR) mediates uptake of cobalamin into cells. We evaluated inherited variants in the TCblR gene as NTD risk factors. Methods: Case-control and family-based tests of association were used to screen common variation in TCblR as genetic risk factors for NTDs in a large Irish group. A confirmatory group of NTD triads was used to test positive findings. Results: We found two tightly linked variants associated with NTDs in a recessive model: TCblR rs2336573 (G220R) (pcorr=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (pcorr =0. 0279). These variants were also associated with NTDs in a family-based test prior to multiple test correction (log-linear analysis of a recessive model: rs2336573 (G220R) (RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). We describe a copy number variant (CNV) distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms. Conclusions: TCblR rs2336573 (G220R) and TCblR rs9426 represent a significant risk factor in NTD cases in the Irish population. The homozygous risk genotype was not detected in nearly one thousand controls, indicating this NTD risk factor may be of low frequency and high penetrance. Nine other variants are in perfect LD with the associated SNPs. Additional work is required to identify the disease-causing variant. Our data suggest that variation in TCblR plays a role in NTD risk and that these variants may modulate cobalamin metabolism.

Pangilinan, Faith; Mitchell, Adam; VanderMeer, Julie; Molloy, Anne M.; Troendle, James; Conley, Mary; Kirke, Peadar N.; Sutton, Marie; Sequeira, Jeffrey M.; Quadros, Edward V.; Scott, John M.; Mills, James L.; Brody, Lawrence C.

2014-01-01

204

Analysis of the MTHFD1 promoter and risk of neural tube defects  

PubMed Central

Genetic variants in MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase/ 5,10-methenyltetrahydrofolate cyclohydrolase/ 10-formyltetrahydrofolate synthetase), an important folate metabolic enzyme, are associated with a number of common diseases, including neural tube defects (NTDs). This study investigates the promoter of the human MTHFD1 gene in a bid to understand how this gene is controlled and regulated. Following a combination of in silico and molecular approaches, we report that MTHFD1 expression is controlled by a TATA-less, Initiator-less promoter and transcription is initiated at multiple start sites over a 126bp region. We confirmed the presence of three database polymorphisms (dbSNP) by direct sequencing of the upstream region (rs1076991 C>T, rs8010584 G>A, rs4243628 G>T), with a fourth (dbSNP rs746488 A>T) not found to be polymorphic in our population and no novel polymorphisms identified. We demonstrate that a common SNP rs1076991 C>T within the window of transcriptional initiation exerts a significant effect on promoter activity in vitro. We investigated this SNP as a potential risk factor for NTDs in a large homogenous Irish population and determined that it is not an independent risk factor, but, it does increase both case (?2 = 11.06, P = 0.001) and maternal (?2 = 6.68, P = 0.01) risk when allele frequencies were analysed in combination with the previously identified disease-associated p.R653Q (c.1958 G>A; dbSNP rs2236225) polymorphism. These results provide the first insight into how MTHFD1 is regulated and further emphasise its importance during embryonic development.

Carroll, Nicola; Pangilinan, Faith; Molloy, Anne M.; Troendle, James; Mills, James L.; Kirke, Peadar N.; Brody, Lawrence C.; Scott, John M.; Parle-McDermott, Anne

2009-01-01

205

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

PubMed Central

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.

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

2011-01-01

206

Frontiers in research on maternal diabetes-induced neural tube defects: Past, present and future  

PubMed Central

Diabetes mellitus rightly regarded as a silent-epidemic is continually on the rise and estimated to have a global prevalence of 6.4 % as of 2010. Diabetes during pregnancy is a well known risk factor for congenital anomalies in various organ systems that contribute to neonatal mortality, including cardiovascular, gastrointestinal, genitourinary and neurological systems, among which the neural tube defects are frequently reported. Over the last two to three decades, several groups around the world have focussed on identifying the molecular cues and cellular changes resulting in altered gene expression and the morphological defects and in diabetic pregnancy. In recent years, the focus has gradually shifted to looking at pre-programmed changes and activation of epigenetic mechanisms that cause altered gene expression. While several theories such as oxidative stress, hypoxia, and apoptosis triggered due to hyperglycemic conditions have been proposed and proven for being the cause for these defects, the exact mechanism or the link between how high glucose can alter gene expression/transcriptome and activate epigenetic mechanisms is largely unknown. Although preconceptual control of diabetes, (i.e., managing glucose levels during pregnancy), and in utero therapies has been proposed as an effective solution for managing diabetes during pregnancy, the impact that a fluctuating glycemic index can have on foetal development has not been evaluated in detail. A tight glycemic control started before pregnancy has shown to reduce the incidence of congenital abnormalities in diabetic mothers. On the other hand, a tight glycemic control after organogenesis and embryogenesis have begun may prove insufficient to prevent or reverse the onset of congenital defects. The importance of determining the extent to which glycemic levels in diabetic mothers should be regulated is critical as foetal hypoglycemia has also been shown to be teratogenic. Finally, the major question remaining is if this whole issue is negligible and not worthy of investigation as the efficient management of diabetes during pregnancy is well in place in many countries.

Sukanya, Shyamasundar; Bay, Boon Huat; Tay, Samuel Sam Wah; Dheen, S Thameem

2012-01-01

207

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

PubMed Central

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

Clark, B J; Scothorne, R J

1990-01-01

208

Eddy Current Signature Classification of Steam Generator Tube Defects Using A Learning Vector Quantization Neural Network  

SciTech Connect

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.

Gabe V. Garcia

2005-01-03

209

Integrated models of signals and background for an HMM\\/neural net ocean acoustic event classifier  

Microsoft Academic Search

The authors investigate the use of hidden Markov models (HMMs) for the classification and detection of ocean acoustic events in a nonstationary ocean background. A statistical formalism is described for integrating models for dynamic acoustic events and ocean background into a unified statistical framework. In this framework, both signal processes and background processes are modeled as HMMs, and signal classification

W. Y. Huang; Richard C. Rose

1991-01-01

210

Epigenetic Profiles in Children with a Neural Tube Defect; A Case-Control Study in Two Populations  

PubMed Central

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.

Stolk, Lisette; Bouwland-Both, Marieke I.; van Mill, Nina H.; Verbiest, Michael M. P. J.; Eilers, Paul H. C.; Zhu, Huiping; Suarez, Lucina; Uitterlinden, Andre G.; Steegers-Theunissen, Regine P. M.

2013-01-01

211

Neural network analysis of fin-tube refrigerating heat exchanger with limited experimental data  

Microsoft Academic Search

We consider the problem of accuracy in heat rate estimations from artificial neural network (ANN) models of heat exchangers used for refrigeration applications. Limited experimental measurements from a manufacturer are used to show the capability of the neural network technique in modeling the heat transfer phenomena in these systems. A well-trained network correlates the data with errors of the same

Arturo Pacheco-Vega; Mihir Sen; K. T. Yang; Rodney L. McClain

2001-01-01

212

Maternal-fetal metabolic gene-gene interactions and risk of neural tube defects.  

PubMed

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

Lupo, Philip J; Mitchell, Laura E; Canfield, Mark A; Shaw, Gary M; Olshan, Andrew F; Finnell, Richard H; Zhu, Huiping

2014-01-01

213

Distinct Sonic Hedgehog signaling dynamics specify floor plate and ventral neuronal progenitors in the vertebrate neural tube  

PubMed Central

The secreted ligand Sonic Hedgehog (Shh) organizes the pattern of cellular differentiation in the ventral neural tube. For the five neuronal subtypes, increasing levels and durations of Shh signaling direct progenitors to progressively more ventral identities. Here we demonstrate that this mode of action is not applicable to the generation of the most ventral cell type, the nonneuronal floor plate (FP). In chick and mouse embryos, FP specification involves a biphasic response to Shh signaling that controls the dynamic expression of key transcription factors. During gastrulation and early somitogenesis, FP induction depends on high levels of Shh signaling. Subsequently, however, prospective FP cells become refractory to Shh signaling, and this is a prerequisite for the elaboration of their identity. This prompts a revision to the model of graded Shh signaling in the neural tube, and provides insight into how the dynamics of morphogen signaling are deployed to extend the patterning capacity of a single ligand. In addition, we provide evidence supporting a common scheme for FP specification by Shh signaling that reconciles mechanisms of FP development in teleosts and amniotes.

Ribes, Vanessa; Balaskas, Nikolaos; Sasai, Noriaki; Cruz, Catarina; Dessaud, Eric; Cayuso, Jordi; Tozer, Samuel; Yang, Lin Lin; Novitch, Ben; Marti, Elisa; Briscoe, James

2010-01-01

214

Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis.  

PubMed

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

Robinson, Alexis; Escuin, Sarah; Doudney, Kit; Vekemans, Michel; Stevenson, Roger E; Greene, Nicholas D E; Copp, Andrew J; Stanier, Philip

2012-02-01

215

Sonic hedgehog and retinoic acid are not sufficient to induce motoneuron generation in the avian caudal neural tube.  

PubMed

The caudal neural tube (CNT) of the avian embryo is devoid of both dorsal and ventral roots. We show that the lack of ventral roots in the CNT, from somite 48 caudalwards, is due to an absence of post-mitotic motoneurons (MNs). The absence of MNs is not due to a defective notochordal induction since Sonic Hedgehog (SHH) signaling is intact and the caudal notochord is able to induce ectopic MNs when grafted laterally to a host neural tube. The transcription factors involved in MN specification (Pax6, Nkx6.1, and Olig2) are all expressed in the CNT, despite the lower expression level of Pax6, but an overlap between Olig2 and the ventrally expressed transcription factor Nkx2.2 is observed in the CNT. Grafting a quail CNT into the cervical level of a chick host rescues MN generation, demonstrating both the CNT potential for MN generation and the key role of the caudal environment in the MN differentiation blockade. The transplantation of the CNT-flanking somites into the cervical level does not inhibit MN generation. Furthermore, implantation of a retinoic-acid-soaked bead laterally to the CNT does not rescue MN generation. Together, these data indicate that the rostral environment contains a signal different from both SHH and Retinoic Acid that acts on MN differentiation. PMID:15733664

Afonso, Nuno D; Catala, Martin

2005-03-15

216

Neural-tube defects are associated with low concentrations of cobalamin (vitamin B12) in amniotic fluid.  

PubMed

While folate supplementation reduces the risk of recurrent neural-tube defects (NTD), both folate and cobalamin deficiencies may be independent risk-factors for neural-tube defects. Folate-dependence and impaired remethylation of homocysteine are implicated as mechanisms for NTD. There are few references reported for folate, cobalamin, homocysteine and methionine in the fetal compartment. This case-controlled pilot study of amniotic fluid (AF) samples derived from 16 NTD pregnancies and 64 age-matched controls quantities total homocysteine (tHcy), total cysteine (tCys), folate, cobalamin (B12), and methionine. Only decreased AF B12 concentrations were found (150 pg/ml versus 540 pg/ml, P < 0.02). Since cobalamin, folate and homocysteine participate in the remethylation of homocysteine, via methyl transfer from 5-methyltetrahydrofolate to B12, to methionine, we compared ratios of these methionine synthase (EC 2.1.1.13)-related intermediates. The ratio of B12/folate for NTD versus controls was 48 (34-90) versus 126 (123-182), P < 0.001. The ratio of methionine/(folate x tHcy) was 1.4 (1.2-2.2) versus 2.7 (2.4-3.3), P < 0.001. We conclude that AF from pregnancies with NTD have lower B12 concentrations, and that ratios of product to substrate(s) of homocysteine remethylation suggest impaired methionine synthase in the fetal compartment through the early second trimester. PMID:9664599

Steen, M T; Boddie, A M; Fisher, A J; Macmahon, W; Saxe, D; Sullivan, K M; Dembure, P P; Elsas, L J

1998-06-01

217

Evidence for increased SOX3 dosage as a risk factor for X-linked hypopituitarism and neural tube defects.  

PubMed

Genomic duplications of varying lengths at Xq26-q27 involving SOX3 have been described in families with X-linked hypopituitarism. Using array-CGH we detected a 1.1?Mb microduplication at Xq27 in a large family with three males suffering from X-linked hypopituitarism. The duplication was mapped from 138.7 to 139.8?Mb, harboring only two annotated genes, SOX3 and ATP11C, and was shown to be a direct tandem copy number gain. Unexpectedly, the microduplication did not fully segregate with the disease in this family suggesting that SOX3 duplications have variable penetrance for X-linked hypopituitarism. In the same family, a female fetus presenting with a neural tube defect was also shown to carry the SOX3 copy number gain. Since we also demonstrated increased SOX3 mRNA levels in amnion cells derived from an unrelated t(X;22)(q27;q11) female fetus with spina bifida, we propose that increased levels of SOX3 could be a risk factor for neural tube defects. © 2014 Wiley Periodicals, Inc. PMID:24737742

Bauters, Marijke; Frints, Suzanna G; Van Esch, Hilde; Spruijt, Liesbeth; Baldewijns, Marcella M; Die-Smulders, Christine E M de; Fryns, Jean-Pierre; Marynen, Peter; Froyen, Guy

2014-08-01

218

Crashworthiness Design for Cylindrical Tube using Neural Network and Genetic Algorithm  

Microsoft Academic Search

In this article, the multi-objective optimization of cylindrical aluminum tubes under axial impact load is presented. Absorbed energy and specific absorbed energy are considered as objective functions while the mean crush load should not exceed allowable limit. The geometric dimensions of tubes including diameter, length and thickness are chosen as design variables. The Non-dominated Sorting Genetic Algorithm –II (NSGAII) is

M. Mirzaei; M. Shakeri; M. Sadighi; H. Akbarshahi

2011-01-01

219

Maternal and Neonatal Serum Zinc Level and Its Relationship with Neural Tube Defects  

PubMed Central

Neural tube defect (NTD) is a multi-factorial disorder in which nutritional, genetic and environmental factors are involved. Among the nutritional factors, low level of serum zinc has been reported from different parts of the world. This hospital-based case-control study was conducted with the objective of finding the relationship between serum zinc level in newborns and their mothers and NTDs in a Bangladeshi population. The study was conducted during August 2006–July 2007 at the Bangabandhu Sheikh Mujib Medical University (BSMMU) in Dhaka. In total, 32 mothers and their newborns with NTDs were included as cases and another 32 mothers with their normal babies were included as controls. Concentration of serum zinc was determined by pyro-coated graphite furnace atomic absorption spectrophotometer (GF-AAS). The mean age of the case and control mothers was 25.28 years and 24.34 years respectively. The mean gestational age of the case newborns was 36.59 weeks and that of the control newborns was 37.75 weeks. The mean serum zinc level of the case and control mothers was 610.2 ?g/L and 883.0 ?g/L respectively (p<0.01). The mean serum zinc level of the case and control newborns was 723 ?g/L and 1,046 ?g/L respectively (p<0.01). In both case and control groups, the serum zinc level of the newborns positively correlated with that of the mothers. The serum zinc levels of the mothers and newborns negatively correlated with NTDs. Mothers with serum zinc level lower than normal were 7.66 [95% confidence interval (CI) 2.5-23.28] times more likely to have NTDs compared to the normal zinc level of mothers. After adjusting for the zinc level of the newborns, parity, and age of the mothers, this risk reduced 1.61 times [confidence interval (CI) 95% 0.24-8.77]. On the other hand, the low serum zinc level of the newborns was 7.22 times more associated with NTDs compared to the newborns with the normal serum zinc level, which was statistically significant (p=0.001). After adjusting for other factors, such as maternal age and parity, newborns with the low serum zinc level was found to be 9.186 times more likely to be associated with NTDs compared to newborns with normal serum zinc level. Based on the findings, it may be concluded that the low serum zinc levels of newborns may be associated with NTDs. To confirm these findings, a further study with a larger sample-size is recommended. Moreover, a follow-up study with zinc supplementation to pregnant women and its impact on NTDs is also recommended.

Shahidullah, Mohammod; Mannan, Mohammad Abdul; Noor, Mohammad Khaled; Saha, Laxmi; Rahman, Shahana A.

2010-01-01

220

Combined analysis of acetylcholinesterase and alpha-fetoprotein improves the accuracy of antenatal diagnosis of neural-tube defects.  

PubMed

Acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and alpha-fetoprotein (AFP) were measured in 293 amniotic fluids from the second and third trimesters of pregnancy in a prospective study of their diagnostic value in the detection of neural-tube defects (NTD). In normal samples, the mean AChE and BChE concentrations were 3.0 u/L (SEM = 9.1 u/L) and 15.2 u/L (SEM = 1.2 u/L) in the second trimester, and 1.6 u/L (SEM = 0.1 u/L) and 7.8 u/L (SEM = 0.6 u/L) in the third trimester. AFP levels fell throughout the second trimester to unmeasurable levels in the third. AChE levels were markedly elevated in samples from NTD pregnancies at all gestational ages, and a cut-off level of the mean + 3 SD optimally separated normal from abnormal samples. This cut-off correctly predicted 10 of 11 fetuses with neural lesions; there were three false positive results. A similar cut-off for AFP predicted nine of 11 cases of neural lesion with two false positive results. For BChE, a cut off of 50 u/L predicted eight of 11 neural lesions with two false positive results. The specificity, sensitivity, and predictive value positive (PVP) were calculated for each test. The assays of AFP and AChE were useful when used individually (PVP congruent to 80%), but a Bayesian combination of these two tests produced a superior PVP (98%). Because the cost of AChE assay is low, and the test is so simple, it is suggested that an AChE analysis should be performed whenever an amniocentesis is requested for the diagnosis of NTD. PMID:6166840

Hodgson, A J; Pilowsky, P M; Robertson, E F; Pollard, A C; Chubb, I W

1981-05-01

221

Modeling of the effects of length to diameter ratio and nozzle number on the performance of counterflow Ranque–Hilsch vortex tubes using artificial neural networks  

Microsoft Academic Search

In this study, the effect of length to diameter ratio and nozzle number on the performance of a counterflow Ranque–Hilsch vortex tube has been modeled with artificial neural networks (ANN), by using experimental data. In the modeling, experimental data, which were obtained from experimental studies in a laboratory environment have been used. ANN has been designed by MATLAB 6.5 NN

K. Dincer; S. Tasdemir; S. Baskaya; B. Z. Uysal

2008-01-01

222

Neural tube defects in Mexican-Americans living on the US-Mexico border: The effects of folic acid and dietary folate  

Microsoft Academic Search

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

Lucina Suarez; Katherine A. Hendricks; Sharon P. Cooper; Anne M. Sweeney; Robert J. Hardy; Russell D. Larsen

1998-01-01

223

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

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

Jennifer N. Murdoch; Kit Doudney; Caroline Paternotte; Andrew J. Copp; Philip Stanier

2001-01-01

224

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

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

Fassiatou Tairou; Philippe De Wals

2006-01-01

225

Prenatal diagnosis of neural tube defects. I. Problems and pitfalls: analysis of 2495 cases using the alpha-fetoprotein assay.  

PubMed

The alpha-fetoprotein (AFP) assay is now an established tool for the prenatal diagnosis of neural tube defects (NTDs). About 90% of these defects are diagnosable prenatally early in the second trimester, the other 10% consisting of closed lesions that are not amenable to this approach. From the analysis of our 2495 consecutive cases, 49 NTDs were diagnosed with AFP levels 3 SD above the mean. One closed NTD sample, as expected, did not have an elevated AFP level. Various other fetal disorders or conditions were also associated with elevated AFP levels. AFP assays on amniotic fluids from 1858 patients without a family history of NTD and studied primarily for fetal karyotyping yielded a frequency of 1 NTD in 310 cases. Any amniotic fluid study in the second trimester of pregnancy should include an assay for AFP. PMID:59327

Milunsky, A; Alpert, E

1976-07-01

226

Maternal Folate and Vitamin B12 Status and Neural Tube Defects in Northern Iran: A Case Control Study  

PubMed Central

Objective This study was conducted to determine the serum level of folic acid and vitamin B12 in neural tube defects pregnancies (NTD) and healthy controls in Northern Iran. Methods This case-control study was performed on women with neural tube defects pregnancies and controls with unaffected pregnancies in Northern Iran during 2006. Twenty three pregnant women whose pregnancies were diagnosed as NTD by a second-trimester ultrasonographic examination were recruited as cases. The control group (n=23) consisted of women who were selected among socio-economic status (SES) matched women who had a normal targeted ultrasound during the second trimester with documented normal fet al outcome. Fetal NTD was suspected with targeted second-trimester ultrasound during the 16th week of gestation and confirmed with high maternal serum ?-fetoprotein levels. Folate, vitamin B12, homocysteine and alpha fetoprotein were evaluated after target ultrasonography. Findings Serum alpha fetoprotein level (mean±SD) in cases and controls was 120.2±64.1 and 50±33.5 iu/ml, respectively (P<0.05). The mean±SD folate in cases and controls was 8.4±4.2 versus 9.3±4.2 ng/ml, respectively. This difference was not significant. Folate deficiency was found in 30.4% of the cases and 13% of the controls (OR=2.9, 95%: 0.54–19.8). Vitamin B12 deficiency was found in 13% of cases and 17.7% of the controls (OR=0.7, 95%: 0.1-4.9). Conclusion This study showed that the probability of having a newborn with NTDs in maternal folate deficiency is three times higher than with normal folate in Northern Iran.

Mobasheri, Elahm; Keshtkar, Abbasali; Golalipour, Mohammad-Jafar

2010-01-01

227

Analyses of copy number variation reveal putative susceptibility loci in MTX-induced mouse neural tube defects.  

PubMed

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. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 877-893, 2014. PMID:24515751

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

228

Histone modification mapping in human brain reveals aberrant expression of histone H3 lysine 79 dimethylation in neural tube defects.  

PubMed

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

Zhang, Qin; Xue, Peng; Li, Huili; Bao, Yihua; Wu, Lihua; Chang, Shaoyan; Niu, Bo; Yang, Fuquan; Zhang, Ting

2013-06-01

229

Artificial neural networks to correlate in-tube turbulent forced convection of binary gas mixtures  

Microsoft Academic Search

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

Gerardo Diaz; Antonio Campo

2009-01-01

230

Human amniotic fluid-derived mesenchymal cells from fetuses with a neural tube defect do not deposit collagen type i protein after TGF-?1 stimulation in vitro.  

PubMed

In spina bifida, the neural tube fails to close during the embryonic period. Exposure of the neural tube to the amniotic fluid during pregnancy causes additional neural damage. Intrauterine tissue engineering using a biomaterial seeded with stem cells might prevent this additional damage. For this purpose, autologous cells from the amniotic fluid are an attractive source. To close the defect, it is important that these cells deposit an extracellular matrix. However, it is not known if amniotic fluid mesenchymal cells (AFMCs) from a fetus with a neural tube defect (NTD) share the same characteristics as AFMCs from a healthy fetus. We found that cells derived from fetuses with a NTD, in contrast to healthy human amniotic fluid cells, did not deposit collagen type I. Furthermore, the NTD cells showed, compared with both healthy amniotic fluid cells and fetal fibroblasts, much lower mRNA expression levels of genes that are involved in collagen biosynthesis [procollagen C-endopeptidase enhancer proteins (PCOLCE), PCOLCE2, ADAM metallopeptidase with thrombospondin type 1 motif, 2 (ADAMTS2), ADAMTS14]. This indicates that NTD-AFMCs have different characteristics compared with healthy AFMCs and might not be suitable for fetal therapy to close the defect in spina bifida patients. PMID:24171700

Hosper, Nynke A; Bank, Ruud A; van den Berg, Paul P

2014-03-01

231

Ectopic expression of lunatic Fringe leads to downregulation of Serrate1 in the developing chick neural tube; analysis using in ovo electroporation transfection technique  

Microsoft Academic Search

Lunatic Fringe (l-Fng) is one of the vertebrate homologues of Drosophila Fringe, which interacts with the Notch signal pathway and regulates activation of the Notch ligands, Delta and Serrate. To elucidate the roles of l-Fng in vertebrate neurogenesis, we transfected chick l-Fng (C-l-Fng) to chick neural tube using the in ovo electroporation technique and examined the subsequent changes in expression

Kei Sakamoto; Harukazu Nakamura; Minoru Takagi; Shin'ichi Takeda; Ken-ichi Katsube

1998-01-01

232

[The alpha-fetoprotein level analysis in open neural tube defects and chromosomal aberrations in the fetus].  

PubMed

During the last 12 years 4258 amniocenteses were performed between the 12th and 20th week of gestation (including 323 early amniocenteses carried out before 15th week). In every case, cytogenetical examination was performed and concentration of AFP was determined. In cases with elevated AFP level electrophoresis of AchE izoenzymes was performed. The results of the tests enabled us to calculate laboratory standard values of AFP in the amniotic fluid for 12th to 20th weeks of gestation. In 22 of 44 pregnancies with Down's syndrome the value of AFP concentration was below the 25th percentile of the laboratory normal value. In 5 of 10 pregnancies with Edward's syndrome AFP level exceeded significantly the 75th percentile of the laboratory norm. In two cases it was due to coexisting spina bifida and in one case due to omphalocele. In 28 amniotic fluid samples AFP concentration exceeded normal level and electrophoresis of AchE revealed additional band. In 26 cases increased values of AFP were due to open neural tube defect in the fetus: 13 cases of anencephaly and 13 cases of spina bifida; in the remaining two other cases omphalocele was found. PMID:8657351

Ilnicka, A; Paw?owska, B; Czyzewska, J; G?ogowska, I; Korlak, J; Rodo, M; Bieganowska, K; Szirkowiec, W; Zdzienicka, E; Zaremba, J

1996-01-01

233

Program Specificity for Ptf1a in Pancreas versus Neural Tube Development Correlates with Distinct Collaborating Cofactors and Chromatin Accessibility  

PubMed Central

The lineage-specific basic helix-loop-helix transcription factor Ptf1a is a critical driver for development of both the pancreas and nervous system. How one transcription factor controls diverse programs of gene expression is a fundamental question in developmental biology. To uncover molecular strategies for the program-specific functions of Ptf1a, we identified bound genomic regions in vivo during development of both tissues. Most regions bound by Ptf1a are specific to each tissue, lie near genes needed for proper formation of each tissue, and coincide with regions of open chromatin. The specificity of Ptf1a binding is encoded in the DNA surrounding the Ptf1a-bound sites, because these regions are sufficient to direct tissue-restricted reporter expression in transgenic mice. Fox and Sox factors were identified as potential lineage-specific modifiers of Ptf1a binding, since binding motifs for these factors are enriched in Ptf1a-bound regions in pancreas and neural tube, respectively. Of the Fox factors expressed during pancreatic development, Foxa2 plays a major role. Indeed, Ptf1a and Foxa2 colocalize in embryonic pancreatic chromatin and can act synergistically in cell transfection assays. Together, these findings indicate that lineage-specific chromatin landscapes likely constrain the DNA binding of Ptf1a, and they identify Fox and Sox gene families as part of this process.

Meredith, David M.; Borromeo, Mark D.; Deering, Tye G.; Casey, Bradford H.; Savage, Trisha K.; Mayer, Paul R.; Hoang, Chinh; Tung, Kuang-Chi; Kumar, Manonmani; Shen, Chengcheng; Swift, Galvin H.

2013-01-01

234

Periconceptional vitamin supplementation and the prevention of neural tube defects in south-east England and Northern Ireland.  

PubMed Central

A comparison has been made of the effectiveness of periconceptional vitamin supplementation for the prevention of recurrence of neural tube defects (NTD) in south-east England and Northern Ireland. These areas represent the extremes of birth prevalence of NTD (low and high respectively) within the United Kingdom. Vitamin therapy resulted in a slightly less than two-fold reduction in the recurrence risk in south-east England and a greater than three-fold reduction in Northern Ireland, when compared with unsupplemented women at the same risk from the two areas. It is probable that one of the recurrences in each area did not involve the multifactorial form of NTD and, if these are excluded, then the reduction in recurrence risk with vitamin supplementation is 2.4 times in south-east England and 5.4 times in Northern Ireland. Either way, beneficial effects of supplementation are apparent in both areas but are more marked in the high prevalence area. The implications of this for the future are discussed. Two other important findings were that all but one of the recurrences of NTD with full supplementation occurred in male fetuses, and there was a higher than expected occurrence of isolated hydrocephalus in infants or fetuses following full supplementation.

Seller, M J; Nevin, N C

1984-01-01

235

Neural tube defects in Beijing-Tianjin area of China. Urban-rural distribution and some other epidemiological characteristics.  

PubMed Central

Records in the obstetric wards and nurseries of 18 hospitals were reviewed and studied epidemiologically, covering about 210,000 deliveries and 1000 cases of neural tube defects (NTD). All live and still births occurred in the period 1970-84. Following the NTD classification used by Koch (1984), our case series consisted of anencephalus 50.3%, spina bifida 44.2%, and NTD with other system defects 5.5%. Overall NTD prevalence rate at birth was 4 per thousand, obviously higher than those in most other countries. Marked urban-rural differences in NTD prevalence rate at birth were observed. The rate in rural areas after correction for selection bias was still as high as 7.25 per thousand. As compared with cities and suburbs, the relative risk of NTD born to mothers in rural regions was 2.4. The male-to-female ratios were much less than 1 for various kinds of NTD. Looking at the effect of maternal age and birth order simultaneously in 12 different settings, it can be seen that prevalence of NTD was moderately higher among second and third births to women aged less than or equal to 24 and those greater than or equal to 35 years of age.

Lian, Z H; Yang, H Y; Li, Z

1987-01-01

236

Promoter haplotype combinations of the platelet-derived growth factor alpha-receptor gene predispose to human neural tube defects.  

PubMed

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

Joosten, P H; Toepoel, M; Mariman, E C; Van Zoelen, E J

2001-02-01

237

Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population.  

PubMed

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

Jin, Lei; Zhang, Le; Li, Zhiwen; Liu, Jian-meng; Ye, Rrongwei; Ren, Aiguo

2013-01-01

238

Notes from the field: investigation of a cluster of neural tube defects - central Washington, 2010-2013.  

PubMed

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

2013-09-01

239

When does mass screening for open neural tube defects in low-risk pregnancies result in cost savings?  

PubMed Central

Using a decision analysis model, we estimated the savings that might be derived from a mass prenatal screening program aimed at detecting open neural tube defects (NTDs) in low-risk pregnancies. Our baseline analysis showed that screening v. no screening could be expected to save approximately $8 per pregnancy given a cost of $7.50 for the maternal serum alpha-feto-protein (MSAFP) test and a cost of $42,507 for hospital and rehabilitation services for the first 10 years of life for a child with spina bifida. When a more liberal estimate of the costs of caring for such a child was used, the savings with the screening program were more substantial. We performed extensive sensitivity analyses, which showed that the savings were somewhat sensitive to the cost of the MSAFP test and highly sensitive to the specificity (but not the sensitivity) of the test. A screening program for NTDs in low-risk pregnancies may result in substantial savings in direct health care costs if the screening protocol is followed rigorously and efficiently.

Tosi, L L; Detsky, A S; Roye, D P; Morden, M L

1987-01-01

240

Prenatal diagnosis of neural tube defects. II. Analysis of false positive and false negative alpha-fetoprotein results.  

PubMed

Certain problems and pitfalls attend the use of the alpha-fetoprotein (AFP) assay for the prenatal diagnosis of neural tube defects (NTDs). Analysis of 2495 consecutive cases revealed 57 (2.3%) with amniotic fluid AFP levels greater than 3 SD above the mean. Fetal deaths (9), various fetal abnormalities, (7) and spontaneous abortions (4) occurred among this group. In addition, there were 30 cases with AFP levels greater than + 3 SD above the mean in which a normal child was delivered--a true false positive rate of 1.2%. To determine if the false positive rate could be diminished, 40 amniotic fluid samples with AFP greater than + 2 SD were subjected to further detailed analysis for fetal hemoglobin, total protein, and IgM concentrations. Even with this battery of tests, we estimate that between 1 and 2% of normal amniotic fluids have elevated AFP levels and either fall as expected outside the + 3 SD range, or have elevated AFP levels due to unknown causes. PMID:59328

Milunsky, A; Alpert, E

1976-07-01

241

Neural tube defect-specific acetylcholinesterase: its properties and quantitation in the detection of anencephaly and spina bifida.  

PubMed

Amniotic fluid from neural tube defect-affected pregnancies (NTD) contains three forms of acetylcholinesterase (AChE), the major species of which is present only in trace amounts in normal pregnancies or those associated with a non-NTD fetal malformation. The activity of this 'specific' AChE is increased 62-fold in the presence of NTD and its measurement provides a sensitive and specific test for the biochemical detection of this disorder. The sedimentation coefficient of 'NTD specific' AChE (10.3S) indicates that it is a tetrameric species, and that the two additional forms present, (4.0S and 5.5S) are monomer and dimer, respectively. Gel filtration studies also support these findings. Combining these data, the molecular masses of monomer, dimer and tetramer are shown to be 78, 126 and 256 kDa (+/- 10%). 'NTD-Specific' AChE does not react with the detergent Triton X-100, indicating that it is a soluble, and probably secreted, species without membrane associating properties. PMID:2449304

Bonham, J R; Dale, G; Atack, J R

1987-11-30

242

Similarities in the epidemiology of neural tube defects and coronary heart disease: is homocysteine the missing link?  

PubMed Central

It is hypothesised that a single aetiological pathway could explain both the strong ecological association between the birth prevalence of neural tube defects (NTD) and coronary heart disease (CHD) mortality and the potential efficacy of dietary measures, especially increased folic acid intake, in their prevention. The epidemiological similarities between NTD and CHD are strong and consistent suggesting that the relation is real rather than artefactual. It is suggested that this epidemiological association reflects a shared aetiology arising from the role of disturbed homocysteine metabolism in the pathogenesis of both conditions. Current public health measures designed to increase the intake of periconceptional folic acid in women, reinforced by a broadening of this policy to target both sexes throughout life, will (if successful) result in a reduction in both the birth prevalence of NTD and the incidence of CHD, although not necessarily contemporaneously. If disordered homocysteine metabolism is the cause of both NTD and CHD, this has implications for future research and preventive strategies for these serious and often lethal diseases.  

Stone, D. H.; McCarron, P.; Smith, G. D.

1999-01-01

243

Food Fortification and Decline in the Prevalence of Neural Tube Defects: Does Public Intervention Reduce the Socioeconomic Gap in Prevalence?  

PubMed Central

Objective: A significant decline in the prevalence of neural tube defects (NTD) through food fortification has been reported. Questions remain, however, about the effectiveness of this intervention in reducing the gap in prevalence across socioeconomic status (SES). Study Design: Using health number and through record linkage, children born in Ontario hospitals between 1994 and 2009 were followed for the diagnosis of congenital anomalies. SES quintiles were assigned to each child using census information at the time of birth. Adjusted rates and multivariate models were used to compare trends among children born in different SES groups. Results: Children born in low SES areas had significantly higher rates of NTDs (RR = 1.25, CI: 1.14–1.37). Prevalence of NTDs among children born in low and high SES areas declined since food fortification began in 1999 although has started rising again since 2006. While the crude decline was greater in low SES areas, after adjustment for maternal age, the slope of decline and SES gap in prevalence rates remained unchanged overtime. Conclusions: While food fortification is successful in reducing the prevalence of NTDs, it was not associated with removing the gap between high and low SES groups.

Agha, Mohammad M.; Glazier, Richard H.; Moineddin, Rahim; Moore, Aideen M.; Guttmann, Astrid

2013-01-01

244

Genetic diversity of stem cells and their functional impact on the development of neural tube defects in Eastern population of India.  

PubMed

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

Saxena, A K; Pandey, S; Pandey, L K

2013-01-01

245

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

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.

Peake, Jordana N; Copp, Andrew J; Shawe, Jill

2013-01-01

246

Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies  

PubMed Central

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.

Zou, Peng; Ji, Guixiang; Gu, Aihua; Zhao, Peng

2012-01-01

247

Neural Tube Defects and Folate Pathway Genes: Family-Based Association Tests of Gene-Gene and Gene-Environment Interactions  

PubMed Central

Background Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results. Objectives Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation. Methods In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase. Results Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission. Conclusions BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene–gene interactions in large data sets.

Boyles, Abee L.; Billups, Ashley V.; Deak, Kristen L.; Siegel, Deborah G.; Mehltretter, Lorraine; Slifer, Susan H.; Bassuk, Alexander G.; Kessler, John A.; Reed, Michael C.; Nijhout, H. Frederik; George, Timothy M.; Enterline, David S.; Gilbert, John R.; Speer, Marcy C.

2006-01-01

248

Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature  

PubMed Central

Background Neural Tube Defects (NTDs) are among the most prevalent and most severe congenital malformations worldwide. Polymorphisms in key genes involving the folate pathway have been reported to be associated with the risk of NTDs. However, the results from these published studies are conflicting. We surveyed the literature (1996–2011) and performed a comprehensive meta-analysis to provide empirical evidence on the association. Methods and Findings We investigated the effects of 5 genetic variants from 47 study populations, for a total of 85 case-control comparisons MTHFR C677T (42 studies; 4374 cases, 7232 controls), MTHFR A1298C (22 studies; 2602 cases, 4070 controls), MTR A2756G (9 studies; 843 cases, 1006 controls), MTRR A66G (8 studies; 703 cases, 1572 controls), and RFC-1 A80G (4 studies; 1107 cases, 1585 controls). We found a convincing evidence of dominant effects of MTHFR C677T (OR 1.23; 95%CI 1.07–1.42) and suggestive evidence of RFC-1 A80G (OR 1.55; 95%CI 1.24–1.92). However, we found no significant effects of MTHFR A1298C, MTR A2756G, MTRR A66G in risk of NTDs in dominant, recessive or in allelic models. Conclusions Our meta-analysis strongly suggested a significant association of the variant MTHFR C677T and a suggestive association of RFC-1 A80G with increased risk of NTDs. However, other variants involved in folate pathway do not demonstrate any evidence for a significant marginal association on susceptibility to NTDs.

Zhang, Ti; Lou, Jiao; Zhong, Rong; Wu, Jing; Zou, Li; Sun, Yu; Lu, Xuzai; Liu, Li; Miao, Xiaoping; Xiong, Guanglian

2013-01-01

249

Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects  

PubMed Central

Background Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors. Methods We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes and recurrence risks to relatives of various types. Results Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, two of the five monozygotic twins and only three of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04 0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (P = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (P = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies in the maternal aunts and uncles (P = < 0.0001) and of first cousins (P = 0.04). Conclusions Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.

Deak, Kristen L.; Siegel, Deborah G.; George, Timothy M.; Gregory, Simon; Ashley-Koch, Allison; Speer, Marcy C.

2010-01-01

250

Association between MTHFD1 G1958A Polymorphism and Neural Tube Defects Susceptibility: A Meta-Analysis  

PubMed Central

Objectives The methylenetetrahydrofolate dehydrogenase (MTHFD1) gene, as one of the key genes involved in the folate pathway, has been reported to play a critical role in the pathogenesis of neural tube defects (NTDs). However, the results of published studies are contradictory and inconclusive. Thus, this meta-analysis aimed to evaluate the effect of the common polymorphism in the MTHFD1 gene, the G1958A (R653Q, dbSNP ID: rs2236225) variant, on the risk of NTDs in all eligible studies. Methods Relevant literature published before January 3, 2014 was retrieved from the MEDLINE, EMBASE, Cochrane Library, and CBM databases. Pooled crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between the MTHFD1 G1958A polymorphism and NTDs risk. Results We performed a meta-analysis of nine studies with a total of 4,302 NTDs patients and 4,238 healthy controls. Our results demonstrated a significant correlation between the MTHFD1 G1958A polymorphism and NTDs in an overall meta-analysis. For family-based studies, the study subjects were classified as NTD cases, mothers with NTDs offspring, and fathers with NTDs offspring. We found no association between any of the fathers’ genotypes and NTDs, whereas there was a clear excess of the 1958A allele in the mothers of children with NTDs compared with controls individuals. Conclusions In summary, our meta-analysis strongly suggests that the MTHFD1 G1958A polymorphism might be associated with maternal risk for NTDs in Caucasian populations. However, the evidence of this association should be interpreted with caution due to the selective nature of publication of genetic association studies.

Jiang, Jianxin; Zhang, Yanfei; Wei, Liang; Sun, Zhiyang; Liu, Zhongmin

2014-01-01

251

Dieting to lose weight and occurrence of neural tube defects in offspring of Mexican-American women.  

PubMed

Lowered maternal weight gain and reduction in early pregnancy have been associated with risk of neural tube defects (NTDs) in offspring. We examined the association of self-reported maternal dieting behaviors on the occurrence of NTDs. We conducted a population based case-control study among Mexican-American women who were residents of the 14 Texas counties bordering Mexico. Case women had an NTD-affected pregnancy identified at birth or prenatally and had deliveries during the years 1995-2000. Control women were those who delivered live born infants without an apparent congenital malformation, randomly selected and frequency-matched to cases by year and facility. One hundred eighty-four case women and 225 control women were asked in person about the use of nutritional supplements, dieting to lose weight, and type of weight reduction supplements used during the 3 months before conception. Women who reported being on a diet to lose weight during the 3 months before conception had an NTD odds ratio (OR) of 1.9 (95% confidence interval (CI) = 1.1, 3.3) compared with those not reporting being on a diet. Neither consuming vitamin drinks (OR = 1.2) nor using diet pills (OR = 1.6) during the 3 months before conception had ORs that were different from the null, when compared to women not reporting those behaviors. The risk effect for dieting did not differ markedly among normal or underweight (OR = 2.0, 95% CI = 0.7, 5.6), overweight (OR = 1.9, 95% CI = 0.7, 5.0), or obese women (OR = 1.5, 95% CI = 0.6, 4.0). No effect was seen among dieting women who were consuming at least 1.0 mg/day of folate (OR = 1.1, CI = 0.3, 4.5). Maternal dieting prior to conception may increase the risk of NTDs in offspring. PMID:21512779

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

2012-05-01

252

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?  

PubMed Central

Recently, we showed that homozygosity for the common 677(C-->T) 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(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs.

van der Put, N M; Gabreels, F; Stevens, E M; Smeitink, J A; Trijbels, F J; Eskes, T K; van den Heuvel, L P; Blom, H J

1998-01-01

253

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

PubMed Central

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 patients from the Dutch population. Sequence variation was studied by SSC analysis of the paired domain regions of the PAX1, PAX7, and PAX9 genes and of the complete PAX3 gene. In one patient with spina bifida, a mutation in the PAX1 gene was detected changing the conserved amino acid Gln to His at position 42 in the paired domain of the protein. The mutation was inherited through the maternal line from the unaffected grandmother and was not detected in 300 controls. In the PAX3 gene, variation was detected at several sites including a Thr/Lys amino acid substitution in exon 6. All alleles were present among patients and controls in about the same frequencies. However, an increased frequency of the rare allele of a silent polymorphism in exon 2 was found in NTD patients, but no significant association was observed (p = 0.06). No sequence variation was observed in the paired domain of the PAX7 and PAX9 genes. Our findings so far do not support a major role of the PAX genes examined in the aetiology of NTD. However, the detection of a mutation in PAX1 suggests that, in principle, this gene can act as a risk factor for human NTD. Images

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

1996-01-01

254

A GCH1 Haplotype and Risk of Neural Tube Defects in the National Birth Defects Prevention Study  

PubMed Central

Tetrahydrobiopterin (BH4) is an essential cofactor and an important cellular antioxidant. BH4 deficiency has been associated with diseases whose etiologies stem from excessive oxidative stress. GTP cyclohydrolase I (GCH1) catalyzes the first and rate-limiting step of de novo BH4 synthesis. A 3-SNP haplotype in GCH1 (rs8007267, rs3783641, and rs10483639) is known to modulate GCH1 gene expression levels and has been suggested as a major determinant of plasma BH4 bioavailability. As plasma BH4 bioavailability has been suggested as a mechanism of neural tube defect (NTD) teratogenesis, we evaluated the association between this GCH1 haplotype and the risk of NTDs. Samples were obtained from 760 NTD case-parent triads included in the National Birth Defects Prevention Study (NBDPS). The three SNPs were genotyped using TaqMan® SNP assays. An extension of the log-linear model was used to assess the association between NTDs and both offspring and maternal haplotypes. Offspring carrying two copies of haplotype C-T-C had a significantly increased NTD risk (risk ratio [RR] = 3.40, 95% confidence interval [CI]: 1.02–11.50), after adjusting for the effect of the maternal haplotype. Additionally, mothers carrying two copies of haplotype C-T-C had a significantly increased risk of having an NTD-affected offspring (RR = 3.46, 95% CI: 1.05–11.00), after adjusting for the effect of the offspring haplotype. These results suggest offspring and maternal variation in the GCH1 gene and altered BH4 biosynthesis may contribute to NTD risk.

Lupo, Philip J.; Chapa, Claudia; Nousome, Darryl; Duhon, Cody; Canfield, Mark A.; Shaw, Gary M.; Finnell, Richard H.; Zhu, Huiping

2012-01-01

255

Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10  

PubMed Central

Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world. Periconceptional maternal folate supplementation reduces NTD risk by 50–70%; however, studies of folate related and other developmental genes in humans have failed to definitively identify a major causal gene for NTD. The aetiology of NTDs remains unknown and both genetic and environmental factors are implicated. We present findings from a microsatellite based screen of 44 multiplex pedigrees ascertained through the NTD Collaborative Group. For the linkage analysis, we defined our phenotype narrowly by considering individuals with a lumbosacral level myelomeningocele as affected, then we expanded the phenotype to include all types of NTDs. Two point parametric analyses were performed using VITESSE and HOMOG. Multipoint parametric and nonparametric analyses were performed using ALLEGRO. Initial results identified chromosomes 7 and 10, both with maximum parametric multipoint lod scores (Mlod) >2.0. Chromosome 7 produced the highest score in the 24 cM interval between D7S3056 and D7S3051 (parametric Mlod 2.45; nonparametric Mlod 1.89). Further investigation demonstrated that results on chromosome 7 were being primarily driven by a single large pedigree (parametric Mlod 2.40). When this family was removed from analysis, chromosome 10 was the most interesting region, with a peak Mlod of 2.25 at D10S1731. Based on mouse human synteny, two candidate genes (Meox2, Twist1) were identified on chromosome 7. A review of public databases revealed three biologically plausible candidates (FGFR2, GFRA1, Pax2) on chromosome 10. The results from this screen provide valuable positional data for prioritisation of candidate gene assessment in future studies of NTDs.

Rampersaud, E; Bassuk, A; Enterline, D; George, T; Siegel, D; Melvin, E; Aben, J; Allen, J; Aylsworth, A; Brei, T; Bodurtha, J; Buran, C; Floyd, L; Hammock, P; Iskandar, B; Ito, J; Kessler, J; Lasarsky, N; Mack, P; Mackey, J; McLone, D; Meeropol, E; Mehltretter, L; Mitchell, L; Oakes, W; Nye, J; Powell, C; Sawin, K; Stevenson, R; Walker, M; West, S; Worley, G; Gilbert, J; Speer, M

2005-01-01

256

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

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.

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

257

A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects.  

PubMed

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

Juriloff, Diana M; Harris, Muriel J

2012-10-01

258

Health needs assessment for congenital anomalies in middle-income countries: Examining the case for neural tube defects in Brazil.  

PubMed

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

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

259

Female predisposition to cranial neural tube defects is not because of a difference between the sexes in the rate of embryonic growth or development during neurulation.  

PubMed Central

The susceptibility of females to anencephaly is well established and has been suggested to result from a slower rate of growth and development of female embryos during cranial neurulation. We have tested this hypothesis by measuring the rates of growth and development, both in utero and in vitro, of male and female embryos of the curly tail (ct) mutant mouse strain, in which cranial neural tube defects occur primarily in females. Embryonic growth was assessed by increase in protein content, while development progression was judged from increase in somite number and morphological score. Embryos were sexed by use of the polymerase chain reaction to amplify a DNA sequence specific to the Y chromosome, and by sex chromatin analysis. We find that, during neurulation (between 8.5 and 10.5 days of gestation), males are advanced in growth and development relative to their female litter mates, but that the rates of growth and development do not differ between the sexes during this period. We conclude that rate of embryonic growth and development is unlikely to determine susceptibility to cranial neural tube defects. It seems more likely that male and female embryos differ in some specific aspect(s) of the neurulation process that increases the susceptibility of females to development of anencephaly. Images

Brook, F A; Estibeiro, J P; Copp, A J

1994-01-01

260

Regulation of cell surface protease matriptase by HAI2 is essential for placental development, neural tube closure and embryonic survival in mice  

PubMed Central

Summary Hypomorphic mutations in the human SPINT2 gene cause a broad spectrum of abnormalities in organogenesis, including organ and digit duplications, atresia, fistulas, hypertelorism, cleft palate and hamartoma. SPINT2 encodes the transmembrane serine protease inhibitor HAI2 (placental bikunin), and the severe developmental effects of decreased HAI2 activity can be hypothesized to be a consequence of excess pericellular proteolytic activity. Indeed, we show here that HAI2 is a potent regulator of protease-guided cellular responses, including motogenic activity and transepithelial resistance of epithelial monolayers. Furthermore, we show that inhibition of the transmembrane serine protease matriptase (encoded by St14) is an essential function of HAI2 during tissue morphogenesis. Genetic inactivation of the mouse Spint2 gene led to defects in neural tube closure, abnormal placental labyrinth development associated with loss of epithelial cell polarity, and embryonic demise. Developmental defects observed in HAI2-deficient mice were caused by unregulated matriptase activity, as both placental development and embryonic survival in HAI2-deficient embryos were completely restored by the simultaneous genetic inactivation of matriptase. However, neural tube defects were detected in HAI2-deficient mice even in the absence of matriptase, although at lower frequency, indicating that the inhibition of additional serine protease(s) by HAI2 is required to complete neural development. Finally, by genetic complementation analysis, we uncovered a unique and complex functional interaction between HAI2 and the related HAI1 in the regulation of matriptase activity during development. This study indicates that unregulated matriptase-dependent cell surface proteolysis can cause a diverse array of abnormalities in mammalian development.

Szabo, Roman; Hobson, John P.; Christoph, Kristina; Kosa, Peter; List, Karin; Bugge, Thomas H.

2009-01-01

261

Differences in the neural mechanisms of selective attention in children from different socioeconomic backgrounds: An event-related brain potential study  

PubMed Central

Previous research indicates that children from lower socioeconomic backgrounds show deficits in aspects of attention, including a reduced ability to filter irrelevant information and to suppress prepotent responses. However, less is known about the neural mechanisms of group differences in attention, which could reveal the stages of processing at which attention deficits arise. The present study examined this question using an event-related brain potential (ERP) measure of selective auditory attention. Thirty-two children aged 3- to 8-years participated in the study. Children were cued to attend selectively to one of two simultaneously presented narrative stories. The stories differed in location (left/right speaker), narration voice (male/female), and content. ERPs were recorded to linguistic and non-linguistic probe stimuli embedded in the attended and unattended stories. Children whose mothers had lower levels of educational attainment (no college experience) showed reduced effects of selective attention on neural processing relative to children whose mothers had higher levels of educational attainment (at least some college). These differences occurred by 100 msec after probe onset. Furthermore, the differences were related specifically to a reduced ability to filter irrelevant information (i.e., to suppress the response to sounds in the unattended channel) among children whose mothers had lower levels of education. These data provide direct evidence for differences in the earliest stages of processing within neural systems mediating selective attention in children from different socioeconomic backgrounds. Results are discussed in the context of intervention programs aimed at improving attention and self-regulation abilities in children at-risk for school failure.

Stevens, Courtney; Lauinger, Brittni; Neville, Helen

2009-01-01

262

Single-Tube Multiplexed Molecular Detection of Endemic Porcine Viruses in Combination with Background Screening for Transboundary Diseases  

PubMed Central

Detection of several pathogens with multiplexed real-time quantitative PCR (qPCR) assays in a one-step setup allows the simultaneous detection of two endemic porcine and four different selected transboundary viruses. Reverse transcription (RT)-qPCR systems for the detection of porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2), two of the most economically important pathogens of swine worldwide, were combined with a screening system for diseases notifiable to the World Organization of Animal Health, namely, classical and African swine fever, foot-and-mouth disease, and Aujeszky's disease. Background screening was implemented using the identical fluorophore for all four different RT-qPCR assays. The novel multiplex RT-qPCR system was validated with a large panel of different body fluids and tissues from pigs and other animal species. Both reference samples and clinical specimens were used for a complete evaluation. It could be demonstrated that a highly sensitive and specific parallel detection of the different viruses was possible. The assays for the notifiable diseases were even not affected by the simultaneous amplification of very high loads of PRRSV- and PCV2-specific sequences. The novel broad-spectrum multiplex assay allows in a unique form the routine investigation for endemic porcine pathogens with exclusion diagnostics of the most important transboundary diseases in samples from pigs with unspecific clinical signs, such as fever or hemorrhages. The new system could significantly improve early detection of the most important notifiable diseases of swine and could lead to a new approach in syndromic surveillance.

Wernike, Kerstin; Hoffmann, Bernd

2013-01-01

263

Rare and private variations in neural crest, apoptosis and sarcomere genes define the polygenic background of isolated Tetralogy of Fallot.  

PubMed

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Its genetic basis is demonstrated by an increased recurrence risk in siblings and familial cases. However, the majority of TOF are sporadic, isolated cases of undefined origin and it had been postulated that rare and private autosomal variations in concert define its genetic basis. To elucidate this hypothesis, we performed a multilevel study using targeted re-sequencing and whole-transcriptome profiling. We developed a novel concept based on a gene's mutation frequency to unravel the polygenic origin of TOF. We show that isolated TOF is caused by a combination of deleterious private and rare mutations in genes essential for apoptosis and cell growth, the assembly of the sarcomere as well as for the neural crest and secondary heart field, the cellular basis of the right ventricle and its outflow tract. Affected genes coincide in an interaction network with significant disturbances in expression shared by cases with a mutually affected TOF gene. The majority of genes show continuous expression during adulthood, which opens a new route to understand the diversity in the long-term clinical outcome of TOF cases. Our findings demonstrate that TOF has a polygenic origin and that understanding the genetic basis can lead to novel diagnostic and therapeutic routes. Moreover, the novel concept of the gene mutation frequency is a versatile measure and can be applied to other open genetic disorders. PMID:24459294

Grunert, Marcel; Dorn, Cornelia; Schueler, Markus; Dunkel, Ilona; Schlesinger, Jenny; Mebus, Siegrun; Alexi-Meskishvili, Vladimir; Perrot, Andreas; Wassilew, Katharina; Timmermann, Bernd; Hetzer, Roland; Berger, Felix; Sperling, Silke R

2014-06-15

264

Primary prevention of neural-tube defects and some other congenital abnormalities by folic acid and multivitamins: history, missed opportunity and tasks  

PubMed Central

The history of intervention trials of periconception folic acid with multivitamin and folic acid supplementation in women has shown a recent breakthrough in the primary prevention of structural birth defects, namely neural-tube defects and some other congenital abnormalities. Recently, some studies have demonstrated the efficacy of this new method in reducing congenital abnormalities with specific origin; for example, in the offspring of diabetic and epileptic mothers, and in pregnancy with high fever. The benefits and drawbacks of four possible uses of periconception folate/folic acid and multivitamin supplementation are discussed: we believe there has been a missed opportunity to implement this preventive approach in medical practice. The four methods are as follows: (i) dietary intake of folate and other vitamins, (ii) periconception folic acid/multivitamin supplementation, (iii) food fortification with folic acid, and (iv) the combination of oral contraceptives with 6S-5-methytetrahydrofolate (‘folate’).

Bartfai, Zoltan; Banhidy, Ferenc

2011-01-01

265

Amniotic fluid alpha-fetoprotein levels and the prenatal diagnosis of neural tube defects: a collaborative study of 2180 pregnancies in the Netherlands.  

PubMed

Amniotic fluid alpha-fetoprotein (AFP) concentrations were measured in 2180 patients at risk of fetal abnormality because of previous history, family history, advanced maternal age, suspected fetal growth retardation and hydramnios. In 12 patients investigated before 20 weeks gestation, pregnancy was terminated because of a raised amniotic fluid AFP-level: 11 fetuses had neural tube defects (NTDs) and one had a congenital nephrosis. There were no false negative results in the 1927 patients tested before 20 weeks and with a pregnancy of known outcome. In patients tested after 20 weeks, the amniotic fluid AFP concentration was raised in 20 cases of anencephaly, in 9 fetuses with severe congenital malformations without NTD and in one apparently normal fetus. Of 428 patients with a previous offspring who had a NTD, only 8(1.9 per cent) again had a fetus with a NTD. PMID:79418

Kleijer, W J; De Bruijn, H W; Leschot, N J

1978-07-01

266

Construction of a High Resolution Linkage Disequilibrium Map to Evaluate Common Genetic Variation in TP53 and Neural Tube Defect Risk in an Irish Population  

PubMed Central

Genetic and environmental factors contribute to the etiology of neural tube defects (NTDs). While periconceptional folic acid supplementation is known to significantly reduce the risk of NTDs, folate metabolic pathway related factors do not account for all NTDs. Evidence from mouse models indicates that the tumor protein p53 (TP53) is involved in implantation and normal neural tube development. To determine whether genetic variation in the TP53 might contribute to NTD risk in humans, we constructed a high resolution linkage disequilibrium (LD) map of the TP53 genomic region based on genotyping 21 markers in an Irish population. We found that nine of these variants can be used to capture the majority of common variation in the TP53 genomic region. In contrast, the 3-marker haplotype commonly reported in the TP53 literature offers limited coverage of the variation in the gene. We used the expanded set of polymorphisms to measure the influence of TP53 on NTDs using both case-control and family-based tests of association. We also assayed a functional variant in the p53 regulator MDM2 (rs2279744). Alleles of three noncoding TP53 markers were associated with NTD risk. A case effect was seen with the GG genotype of rs1625895 in intron 6 (OR = 1.37 [1.04-1.79], p=0.02). A maternal effect was seen with the 135/135 genotype of the intron 1 VNTR (OR = 1.86 [1.16-2.96], p=0.01) and the TT genotype of rs1614984 (RR = 0.58 [0.37-0.91], p=0.02). As multiple comparisons were made, these cannot be considered definitive positive findings and additional investigation is required.

Pangilinan, Faith; Geiler, Kerry; Dolle, Jessica; Troendle, James; Swanson, Deborah A.; Molloy, Anne M.; Sutton, Marie; Conley, Mary; Kirke, Peadar N.; Scott, John M.; Mills, James L.; Brody, Lawrence C.

2010-01-01

267

Maternal PCMT1 gene polymorphisms and the risk of neural tube defects in a Chinese population of Lvliang high-risk area.  

PubMed

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

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

268

Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube.  

PubMed

Protein kinase A (PKA) is an evolutionarily conserved negative regulator of the hedgehog (Hh) signal transduction pathway. PKA is known to be required for the proteolytic processing event that generates the repressor forms of the Ci and Gli transcription factors that keep target genes off in the absence of Hh. Here, we show that complete loss of PKA activity in the mouse leads to midgestation lethality and a completely ventralized neural tube, demonstrating that PKA is as strong a negative regulator of the sonic hedgehog (Shh) pathway as patched 1 (Ptch1) or suppressor of fused (Sufu). Genetic analysis shows that although PKA is important for production of the repressor form of Gli3, the principal function of PKA in the Shh pathway in neural development is to restrain activation of Gli2. Activation of the Hh pathway in PKA mutants depends on cilia, and the catalytic and regulatory subunits of PKA are localized to a compartment at the base of the primary cilia, just proximal to the basal body. The data show that PKA does not affect cilia length or trafficking of smoothened (Smo) in the cilium. Instead, we find that there is a significant increase in the level of Gli2 at the tips of cilia of PKA-null cells. The data suggest a model in which PKA acts at the base of the cilium after Gli proteins have transited the primary cilium; in this model the sequential movement of Gli proteins between compartments in the cilium and at its base controls accessibility of Gli proteins to PKA, which determines the fates of Gli proteins and the activity of the Shh pathway. PMID:22007132

Tuson, Miquel; He, Mu; Anderson, Kathryn V

2011-11-01

269

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case-control study in a population with relatively low folate intake.  

PubMed

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

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

270

Periodic health examination, 1994 update: 3. Primary and secondary prevention of neural tube defects. Canadian Task Force on the Periodic Health Examination.  

PubMed Central

OBJECTIVE: To make recommendations on nutritional interventions and screening manoeuvres to prevent the birth of infants with neural tube defects (NTDs). OPTIONS: Folic acid consumption through diet or supplementation in women at low risk and at high risk of having a fetus with an NTD, and maternal serum alpha-fetoprotein (MSAFP) screening in low-risk pregnancies. OUTCOMES: A reduction in the incidence rate of NTDs and potentially harmful effects of false-positive results of screening tests (i.e., abortion of a normal fetus). EVIDENCE: A MEDLINE search with the use of medical subject headings "neural tube defects," "prenatal diagnosis" and "prevention and control" identified 103 original articles published between January 1979 and March 1993. Two reviewers extracted the data by applying the rules of evidence developed by the Canadian Task Force on the Periodic Health Examination. VALUES: The task force's evidence-based methods and values were used; high value was placed on prevention of NTDs and on limitation of the harmful effects of a pregnancy involving a fetus with an NTD. BENEFITS, HARMS AND COSTS: Evidence suggests that folic acid supplementation can decrease the incidence rate of NTDs in low-risk pregnancies by 40% to 60% with no adverse effects. MSAFP screening between the 16th and 18th weeks of gestation can reach a sensitivity of 83% and a specificity of 98% when it is used as part of an organized program. The effect of screening on the incidence rate of NTDs depends on whether affected fetuses are aborted. RECOMMENDATIONS: All women of childbearing age should be advised to increase their consumption of folic acid through diet or supplementation to 0.4 mg/d beginning 1 month before pregnancy and ending at the start of the second trimester. MSAFP screening is recommended in low-risk pregnancies only when it is part of a screening program that includes access to all necessary diagnostic services. High-risk women should be referred to genetic counselling before they plan a pregnancy. VALIDATION: These recommendations are comparable to the current recommendations of the US Centers for Disease Control and Prevention, the Society of Obstetricians and Gynaecologists of Canada, the Canadian Laboratory Centre for Disease Control and the Canadian College of Medical Geneticists, and they were validated through external review. SPONSOR: These guidelines were developed and endorsed by the Canadian task force, which funded by Health Canada.

1994-01-01

271

Levels of PAH-DNA Adducts in Placental Tissue and the Risk of Fetal Neural Tube Defects in a Chinese Population  

PubMed Central

We examined the relationship between PAH-DNA adduct levels in the placental tissue, measured by a highly sensitive 32P-postlabeling assay, and the risk of fetal neural tube defects (NTDs). We further explored the interaction between PAH-DNA adducts and placental PAHs with respect to NTD risk. Placental tissues from 80 NTD-affected pregnancies and 50 uncomplicated normal pregnancies were included in this case-control study. Levels of PAH-DNA adducts were lower in the NTD group (8.12 per 108 nucleotides) compared to controls (9.92 per 108 nucleotides). PAH-DNA adduct concentrations below the median was associated with a 3-fold increased NTD risk. Women with a low PAH-DNA adduct level in concert with a high placental PAH level resulted in a 10-fold elevated risk of having an NTD-complicated pregnancy. A low level of placental PAH-DNA adducts was associated with an increased risk of NTDs; this risk increased dramatically when a low adduct level was coupled with a high placental PAH concentration.

Yuan, Yue; Jin, Lei; Wang, Linlin; Li, Zhiwen; Zhang, Le; Zhu, Huiping; Finnell, Richard H; Zhou, Guodong; Ren, Aiguo

2014-01-01

272

A prospective study of amniotic fluid cholinesterases: comparison of quantitative and qualitative methods for the detection of open neural tube defects.  

PubMed

The value of quantitative and qualitative methods of cholinesterase (ChE) analysis in the detection of open neural tube defect (NTD) has been assessed in a prospective survey of 1495 mid-trimester amniotic fluids. Using a quantitative method the mean ChE values were much lower in fluids from pregnancies of normal outcome but it was not possible to discriminate these fluids completely from those associated with NTD pregnancies, particularly when the specimens were contaminated with blood. Similarly, measurement of acetylcholinesterase (AChE) activity alone by three different methods also failed to eliminate the overlap between the two groups. In contrast, polyacrylamide gel electrophoresis revealed only a single band of ChE activity in 1408 out of 1410 fluids from pregnancies with a normal outcome whilst amniotic fluids from all 60 cases of open NTD, 6 out of 7 cases of exomphalos and 3 out of 4 cases of intra-uterine death gave the characteristic second faster-running AChE band. A qualitative gel method which requires the same amount of ChE activity to be loaded from each amniotic fluid is an effective method for pre-natal diagnosis of NTDs. PMID:6209697

Wyvill, P C; Hullin, D A; Elder, G H; Laurence, K M

1984-01-01

273

Concanavalin A reactivity pattern of human amniotic fluid AFP examined by crossed affino-immunoelectrophoresis. A definite test for neural tube defect?  

PubMed

The percentage of alpha-fetoprotein (AFP) not reacting with concanavalin A (con A) was determined by crossed line affino-immunoelectrophoresis in amniotic fluid from 25 pregnancies with neural tube defects (NTD) and other fetal abnormalities giving rise to elevated AFP levels, and from 128 pregnancies with normal outcome. The percentage of con A non-reactive AFP is significantly lower in the presence of fetal abnormalities (mean 3.4%, range: 0.0-6.3, n = 25), compared to the percentage found in normal pregnancies (mean 17.2%, range: 6.6-35.8%, n = 128). In amniotic fluid samples from normal pregnancies, the percentage of con A non-reactive AFP in 84 cases with total AFP levels lying within the 95% reference interval was not significantly different from the percentage found in 44 cases with levels above the 95% reference interval. The percentage of non-reactive AFP in fetal serum and cerebrospinal fluid was of the same magnitude as found in amniotic fluids of pregnancies with fetal abnormalities. It is concluded that analysis of the percentage of con A non-reactive AFP by crossed line affino-immunoelectrophoresis is a simple, reliable and apparently diagnostic test for NTD and other abnormalities with leakage of fetal serum or cerebrospinal fluid into the amniotic fluid. The test should therefore be used in all cases with only marginally elevated AFP levels, so false positives may be avoided. PMID:6159997

Nørgaard-Pedersen, B; Toftager-Larsen, K; Philip, J; Hindersson, P

1980-05-01

274

Increased levels of apo-transcobalamins I and II in amniotic fluid from pregnant women with previous neural tube defect offspring.  

PubMed

In an attempt to identify biochemical components of the genetic predisposition to neural tube defects (NTDs), levels of folate, cobalamin, apo-transcobalamins I and II and alpha-fetoprotein were studied in midtrimester amniotic fluid from 24 pregnant women who had previously had a child with NTD. The control group consisted of 76 mothers, subjected to amniocentesis for reasons other than risk of NTD in offspring. Only pregnancies with normal outcome were included. No differences were found between groups for levels of folate, cobalamin or alpha-fetoprotein. Folate intake or metabolism did not appear to differ between groups. In contrast, the level of apo-transcobalamin I was doubled and the level of apo-transcobalamin II tripled in amniotic fluid from women who had had a child with NTD compared with the control group. Since the variation in apo-transcobalamin II in adults is to a high degree genetically determined, the present results may suggest that the genetic predisposition to NTD is associated with variation in this protein. Further studies are needed to substantiate or reject this possibility. PMID:2430743

Magnus, P; Magnus, E M; Berg, K

1986-09-01

275

Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia  

PubMed Central

The objectives of this study were to identify tissue-specific differentially methylated regions (T-DMR’s) in the folate transport genes in placental tissue compared with leukocytes, and from placental tissues obtained from normal infants or with neural tube defects (NTDs). Using pyrosequencing, we developed methylation assays for the CpG islands (CGIs) and the CGI shore regions of the folate receptor ? (FOLR1), proton-coupled folate transporter (PCFT) and reduced folate carrier 1 (RFC1) genes. The T-DMRs differed in location for each gene and the difference in methylation ranged between 2 and 54%. A higher T-DMR methylated fraction was associated with a lower mRNA level of the FOLR1 and RFC1 genes. Methylation fractions differed according to RFC1 80G > A genotype in the NTD cases and in leukocytes from subjects with high total plasma homocysteine (tHcy). There were no differences in methylated fraction of folate transporter genes between NTD cases and controls. We suggest that T-DMRs participate in the regulation of expression of the FOLR1 and RFC1 genes, that the RFC1 80G > A polymorphism exerts a gene-nutrition interaction on DNA methylation in the RFC1 gene, and that this interaction appears to be most prominent in NTD-affected births and in subjects with high tHcy concentrations.

Farkas, Sanja A.; Bottiger, Anna K.; Isaksson, Helena S.; Finnell, Richard H.; Ren, Aiguo; Nilsson, Torbjorn K.; Nilsson, Torbjorn K.

2013-01-01

276

Mesoderm is required for coordinated cell movements within zebrafish neural plate in vivo  

PubMed Central

Background Morphogenesis of the zebrafish neural tube requires the coordinated movement of many cells in both time and space. A good example of this is the movement of the cells in the zebrafish neural plate as they converge towards the dorsal midline before internalizing to form a neural keel. How these cells are regulated to ensure that they move together as a coherent tissue is unknown. Previous work in other systems has suggested that the underlying mesoderm may play a role in this process but this has not been shown directly in vivo. Results Here we analyze the roles of subjacent mesoderm in the coordination of neural cell movements during convergence of the zebrafish neural plate and neural keel formation. Live imaging demonstrates that the normal highly coordinated movements of neural plate cells are lost in the absence of underlying mesoderm and the movements of internalization and neural tube formation are severely disrupted. Despite this, neuroepithelial polarity develops in the abnormal neural primordium but the resulting tissue architecture is very disorganized. Conclusions We show that the movements of cells in the zebrafish neural plate are highly coordinated during the convergence and internalization movements of neurulation. Our results demonstrate that the underlying mesoderm is required for these coordinated cell movements in the zebrafish neural plate in vivo.

2014-01-01

277

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

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.

2013-01-01

278

Neural induction and factors that stabilize a neural fate  

PubMed Central

The neural ectoderm of vertebrates forms when the BMP signaling pathway is suppressed. Herein we review the molecules that directly antagonize extracellular BMP and the signaling pathways that further contribute to reduce BMP activity in the neural ectoderm. Downstream of neural induction, a large number of “neural fate stabilizing” (NFS) transcription factors are expressed in the presumptive neural ectoderm, developing neural tube, and ultimately in neural stem cells. Herein we review what is known about their activities during normal development to maintain a neural fate and regulate neural differentiation. Further elucidation of how the NFS genes interact to regulate neural specification and differentiation should ultimately prove useful for regulating the expansion and differentiation of neural stem and progenitor cells.

Rogers, Crystal; Moody, Sally A.; Casey, Elena

2009-01-01

279

Massive-training artificial neural network (MTANN) for reduction of false positives in computer-aided detection of polyps: Suppression of rectal tubes  

SciTech Connect

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.

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

280

Peptidergic Agonists of Activity-Dependent Neurotrophic Factor Protect Against Prenatal Alcohol-Induced Neural Tube Defects and Serotonin Neuron Loss  

PubMed Central

Introduction Prenatal alcohol exposure via maternal liquid diet consumption by C57BL/6 (B6) mice causes conspicuous midline neural tube deficit (dysraphia) and disruption of genesis and development of serotonin (5-HT) neurons in the raphe nuclei, together with brain growth retardation. The current study tested the hypothesis that concurrent treatment with either an activity-dependent neurotrophic factor (ADNF) agonist peptide [SALLRSIPA, (SAL)] or an activity-dependent neurotrophic protein (ADNP) agonist peptide [NAPVSIPQ, (NAP)] would protect against these alcohol-induced deficits in brain development. Methods Timed-pregnant B6 dams consumed alcohol from embryonic day 7 (E7, before the onset of neurulation) until E15. Fetuses were obtained on E15 and brain sections processed for 5-HT immunocytochemistry, for evaluation of morphologic development of the brainstem raphe and its 5-HT neurons. Additional groups were treated either with SAL or NAP daily from E7 to E15 to assess the potential protective effects of these peptides. Measures of incomplete occlusion of the ventral canal and the frequency and extent of the openings in the rhombencephalon were obtained to assess fetal dysraphia. Counts of 5-HT-immunostained neurons were also obtained in the rostral and caudal raphe. Results Prenatal alcohol exposure resulted in abnormal openings along the midline and delayed closure of ventral canal in the brainstem. This dysraphia was associated with reductions in the number of 5-HT neurons both in the rostral raphe nuclei (that gives rise to ascending 5-HT projections) and in the caudal raphe (that gives rise to the descending 5-HT projections). Concurrent treatment of the alcohol-consuming dams with SAL prevented dysraphia and protected against the alcohol-induced reductions in 5-HT neurons in both the rostral and caudal raphe. NAP was less effective in protecting against dysraphia and did not protect against 5-HT loss in the rostral raphe, but did protect against loss in the caudal raphe. Conclusions These findings further support the potential usefulness of these peptides for therapeutic interventions in pregnancies at risk for alcohol-induced developmental deficits. Notably, the ascending 5-HT projections of the rostral raphe have profound effects in regulating forebrain development and function, and the descending 5-HT projections of the caudal raphe are critical for regulating respiration. Protection of the rostral 5-HT-system may help prevent structural and functional deficits linked to abnormal forebrain development, and protection of the caudal systems may also reduce the increased risk for sudden infant death syndrome associated with prenatal alcohol exposure.

Zhou, Feng C.; Fang, Yuan; Goodlett, Charles

2009-01-01

281

Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects. Clinical Teratology Committee, Canadian College of Medical Geneticists.  

PubMed Central

OBJECTIVE: To prevent the recurrence of neural tube defects (NTDs) in families at increased risk of having offspring with NTDs with the use of periconceptional folic acid supplementation. OPTIONS: Genetic counselling and prenatal diagnosis of NTDs. OUTCOMES: NTDs cause stillbirth, neonatal death and severe disabilities. The cost for medical care and rehabilitation in the first 10 years of life of a child with spina bifida cystica was estimated to be $42,507 in 1987. EVIDENCE: The authors reviewed the medical literature, communicated with investigators from key studies, reviewed policy recommendations from other organizations and drew on their own expertise. A recent multicentre randomized controlled trial showed that among women at high risk of having a child with an NTD those who received 4 mg/d of folic acid had 72% fewer cases of NTD-affected offspring than nonsupplemented women. Two previous intervention studies also demonstrated that folic acid supplementation was effective in reducing the rate of NTD recurrence. Several retrospective studies support this conclusion. VALUES: Recommendations are the consensus of the Clinical Teratology Committee of the Canadian College of Medical Geneticists (CCMG) and have been approved by the CCMG Board. The committee believes that primary prevention of NTDs is preferable to treatment or to prenatal detection and abortion. BENEFITS, HARMS AND COSTS: Folic acid supplementation should result in fewer NTDs among infants in Canada and ancillary savings in medical costs. The recommended dosage of folic acid is not known to be associated with adverse effects. Higher dosages of folic acid may make vitamin B12 deficiency difficult to diagnose and may alter seizure frequency in patients with epilepsy due to drug interactions with anticonvulsants. RECOMMENDATIONS: A minimum dosage of folic acid of 0.8 mg/d, not to exceed 5.0 mg/d, is recommended along with a well-balanced, nutritious diet for all women who are at increased risk of having offspring with NTDs and who are planning a pregnancy or may become pregnant. Supplementation should begin before conception and continue for at least 10 to 12 weeks of pregnancy. VALIDATION: These guidelines are similar to those of the Society of Obstetricians and Gynaecologists of Canada, the US Centers for Disease Control and Prevention and the Department of Health in Britain. SPONSORS: These guidelines were developed by the CCMG Clinical Teratology Committee and endorsed by the Board of the CCMG. No funding for the development of these guidelines was obtained from any other sources.

Van Allen, M I; Fraser, F C; Dallaire, L; Allanson, J; McLeod, D R; Andermann, E; Friedman, J M

1993-01-01

282

Tube support  

DOEpatents

A tube support for supporting horizontal tubes from an inclined vertical support tube passing between the horizontal tubes. A support button is welded to the vertical support tube. Two clamping bars or plates, the lower edges of one bearing on the support button, are removably bolted to the inclined vertical tube. The clamping bars provide upper and lower surface support for the horizontal tubes.

Mullinax, Jerry L. (Green Township, Summit County, OH)

1988-01-01

283

Analysis of the critical heat flux in round vertical tubes under low pressure and flow oscillation conditions. Applications of artificial neural network  

Microsoft Academic Search

Artificial neural networks (ANNs) for predicting critical heat flux (CHF) under low pressure and oscillation conditions have been trained successfully for either natural circulation or forced circulation (FC) in the present study. The input parameters of the ANN are pressure, mean mass flow rate, relative amplitude, inlet subcooling, oscillation period and the ratio of the heated length to the diameter

Su Guanghui; K Morita; K Fukuda; Mark Pidduck; Jia Dounan; Jaakko Miettinen

2003-01-01

284

Slits Affect the Timely Migration of Neural Crest Cells via Robo Receptor  

PubMed Central

SUMMARY Background Neural crest cells emerge by delamination from the dorsal neural tube and give rise to various components of the peripheral nervous system in vertebrate embryos. These cells change from non-motile into highly motile cells migrating to distant areas before further differentiation. Mechanisms controlling delamination and subsequent migration of neural crest cells are not fully understood. Slit2, a chemorepellant for axonal guidance that repels and stimulates motility of trunk neural crest cells away from the gut has recently been suggested to be a tumor suppressor molecule. The goal of this study was to further investigate the role of Slit2 in trunk neural crest cell migration by constitutive expression in neural crest cells. Results We found that Slit gain-of-function significantly impaired neural crest cell migration while Slit loss-of-function favored migration. In addition, we observed that the distribution of key cytoskeletal markers was disrupted in both gain and loss of function instances. Conclusions These findings suggest that Slit molecules might be involved in the processes that allow neural crest cells to begin migration and transitioning to a mesenchymal type.

Giovannone, Dion; Reyes, Michelle; Reyes, Rachel; Correa, Lisa; Martinez, Darwin; Ra, Hannah; Gomez, Gustavo; Kaiser, Josh; Ma, Le; Stein, Mary-Pat; de Bellard, Maria Elena

2013-01-01

285

Tube of Tubes  

NSDL National Science Digital Library

In this activity related to bone structures and Haversian systems, learners discover how a circle of straws becomes a circle of strength. Learners fill a stiff paper tube with drinking straws to represent a "bone." When they stand the "bone" upright on a table, learners discover it can withstand the weight of a book or the pressure of their hand. Learners are encouraged to improve the design to make it stronger and have more structural integrity. This activity is featured on p. 20 of the "Bones: More Than They Appear" unit of study for 4th, 5th, and 6th grade learners.

Indianapolis, The C.; Creative Street, Inc.

2012-06-26

286

The genesis of avian neural crest cells: a classic embryonic induction.  

PubMed Central

Neural crest cells arise from the ectoderm and are first recognizable as discrete cells in the chicken embryo when they emerge from the neural tube. Despite the classical view that neural crest precursors are a distinct population lying between epidermis and neuroepithelium, our results demonstrate that they are not a segregated population. Cell lineage analyses have demonstrated that individual precursor cells within the neural folds can give rise to epidermal, neural crest, and neural tube derivatives. Interactions between the neural plate and epidermis can generate neural crest cells, since juxtaposition of these tissues at early stages results in the formation of neural crest cells at the interface. Inductive interactions between the epidermis and neural plate can also result in "dorsalization" of the neural plate, as assayed by the expression of the Wnt transcripts characteristic of the dorsal neural tube. The competence of the neural plate changes with time, however, such that interaction of early neural plate with epidermis generates only neural crest cells, whereas interaction of slightly older neural plate with epidermis generates neural crest cells and Wnt-expressing cells. At cranial levels, neuroepithelial cells can regulate to generate neural crest cells when the endogenous neural folds are removed, probably via interaction of the remaining neural tube with the epidermis. Taken together, these experiments demonstrate that: (i) progenitor cells in the neural folds are multipotent, having the ability to form multiple ectodermal derivatives, including epidermal, neural crest, and neural tube cells; (ii) the neural crest is an induced population that arises by interactions between the neural plate and the epidermis; and (iii) the competence of the neural plate to respond to inductive interactions changes as a function of embryonic age. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4

Selleck, M A; Bronner-Fraser, M

1996-01-01

287

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 Central

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.

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.

2004-01-01

288

Wind Tubes  

NSDL National Science Digital Library

In this activity, learners create and experiment with wind tubes. These tubes are a playful and inventive way to explore the effect that moving air has on objects. Construction uses everyday materials such as a fan and embroidery hoops. Itâs fun to make things fly out of or float in the tubes, and to adjust the tubes to change the way the objects fly. The activity requires a significant amount of time and resources to build and may require adult help in construction. Experimentation with the wind tubes is engaging for a wide age range of learners.

Exploratorium

2012-12-14

289

Tracheostomy tubes.  

PubMed

Tracheostomy tubes are used to administer positive-pressure ventilation, to provide a patent airway, and to provide access to the lower respiratory tract for airway clearance. They are available in a variety of sizes and styles from several manufacturers. The dimensions of tracheostomy tubes are given by their inner diameter, outer diameter, length, and curvature. Differences in dimensions between tubes with the same inner diameter from different manufacturers are not commonly appreciated but may have important clinical implications. Tracheostomy tubes can be cuffed or uncuffed and may be fenestrated. Some tracheostomy tubes are designed with an inner cannula. It is important for clinicians caring for patients with a tracheostomy tube to appreciate the nuances of various tracheostomy tube designs and to select a tube that appropriately fits the patient. The optimal frequency of changing a chronic tracheostomy tube is controversial. Specialized teams may be useful in managing patients with a tracheostomy. Speech can be facilitated with a speaking valve in patients with a tracheostomy tube who are breathing spontaneously. In mechanically ventilated patients with a tracheostomy, a talking tracheostomy tube, a deflated cuff technique with a speaking valve, or a deflated cuff technique without a speaking valve can be used to facilitate speech. PMID:24891201

Hess, Dean R; Altobelli, Neila P

2014-06-01

290

Emergence and migration of trunk neural crest cells in a snake, the California Kingsnake (Lampropeltis getula californiae)  

PubMed Central

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.

2010-01-01

291

Workshop on neural networks  

Microsoft Academic Search

The topics covered in this report are: Learning, Memory, and Artificial Neural Systems; Emerging Neural Network Technology; Neural Networks; Digital Signal Processing and Neural Networks; Application of Neural Networks to In-Core Fuel Management; Neural Networks in Process Control; Neural Network Applications in Image Processing; Neural Networks for Multi-Sensor Information Fusion; Neural Network Research in Instruments Controls Division; Neural Networks Research

R. E. Uhrig; M. L. Emrich

1990-01-01

292

Neural network analysis for ?? -> ?+?-?0 at Daphne  

NASA Astrophysics Data System (ADS)

We consider the possibility of using neural networks in experimental data analysis in Daphne. We analyze the process ?? -> ?+?-?0 and its backgrounds using neural networks and we compare their performances with traditional methods of applying cuts on several kinematical variables. We find that the neural networks are more efficient and can be of great help for processes with small number of produced events.

Ametller, Ll.; Garrido, Ll.; Talavera, P.

1997-02-01

293

Workshop on neural networks.  

National Technical Information Service (NTIS)

The topics covered in this report are: Learning, Memory, and Artificial Neural Systems; Emerging Neural Network Technology; Neural Networks; Digital Signal Processing and Neural Networks; Application of Neural Networks to In-Core Fuel Management; Neural N...

R. E. Uhrig M. L. Emrich

1990-01-01

294

Neural Crest Cell Migration  

NSDL National Science Digital Library

This simple FlashTM animation depicts migration of neural crest cells throughout the mesoderm of the neurulating germ disc. For context it opens with a cross section of the germ disc showing the neural crests at the dorsal end of the neural tube. It then turns to a lateral view, which allows users to observe neural crest cells separating from the crests and migrating into the mesoderm along the neural tube or epidermis. A back button allows users to jump to previous scenes, a rate button allows them to toggle between fast and slow modes, and a text button allows them to toggle explanatory text on and off. Instructions for opening animation with Windows system. 1. Double click the icon for the SWF. 2. A dialog box may pop up that begins with the statement "Windows cannot open this file:" If this box does not appear proceed to step 4. If it does choose "Select the program from a list," then click OK. 3. Another dialog box will pop up that lists different programs. Make sure " Internet Explorer" is selected, then click OK. 4. A Window for Internet Explorer will pop up. Beneath the toolbars at the top of the window a yellow bar will appear that reads "To help protect your security, Internet Explorer has restricted this webpage from running scripts or Active X controls that could access your computer. Click here for options..." Pass the cursor over this yellow bar and click the right mouse button. 5. A dialog box will pop up. Left click the option "Allow Blocked Content." 6. Another dialog box will appear labeled "Security Warning" asking you to confirm that you want to run the content. Click "Yes." 7. The Flash animation will appear in the Internet Explorer Window. 8. Left click anywhere in the animation to advance the display. 9. Read instructions provided by the animation for additional controls such as navigation buttons.

PhD Jack D Thatcher (West Virginia School of Osteopathic Medicine Structural Biology)

2010-11-29

295

Regional differences in neural crest morphogenesis  

PubMed Central

Neural crest cells are pluripotent cells that emerge from the neural epithelium, migrate extensively and differentiate into numerous derivatives, including neurons, glial cells, pigment cells and connective tissue. Major questions concerning their morphogenesis include: (1) what establishes the pathways of migration? And (2), what controls the final destination and differentiation of various neural crest subpopulations? These questions will be addressed in this Review. Neural crest cells from the trunk level have been explored most extensively. Studies show that melanoblasts are specified shortly after they depart from the neural tube and this specification directs their migration into the dorsolateral pathway. We also consider other reports that present strong evidence for ventrally migrating neural crest cells being similarly fate restricted. Cranial neural crest cells have been less analyzed in this regard but the preponderance of evidence indicates that either the cranial neural crest cells are not fate-restricted or are extremely plastic in their developmental capability and that specification does not control pathfinding. Thus, the guidance mechanisms that control cranial neural crest migration and their behavior vary significantly from the trunk. The vagal neural crest arises at the axial level between the cranial and trunk neural crest and represents a transitional cell population between the head and trunk neural crest. We summarize new data to support this claim. In particular, we show that: (1) the vagal-level neural crest cells exhibit modest developmental bias; (2) there are differences in the migratory behavior between the anterior and the posterior vagal neural crest cells reminiscent of the cranial and the trunk neural crest, respectively and (3) the vagal neural crest cells take the dorsolateral pathway to the pharyngeal arches and the heart, but take the ventral pathway to the peripheral nervous system and the gut. However, these pathways are not rigidly specified because of prior fate restriction. Understanding the molecular, cellular and behavioral differences between these three populations of neural crest cells will be of enormous assistance when trying to understand the evolution of the neck.

Kuo, Bryan R

2010-01-01

296

Amniotic-fluid alpha-fetoprotein measurement in antenatal diagnosis of anencephaly and open spina bifida in early pregnancy. Second report of the U.K. Collaborative Study on Alpha-fetoprotein in Relation to Neural-tube Defects.  

PubMed

Results of a collaborative study performed in the United Kingdom of the correlation between amniotic fluid alpha fetoprotein (AFP) levels and occurrence of open neural tube defects (NTDs) are presented. AFP measurement between 13 and 24 weeks of pregnancy was investigated as a tool for diagnosing NTDs early in pregnancy. Data on 13,105 singleton pregnancies without fetal NTDs and on 385 with fetal NTDs (222 with anencephaly and 152 with spina bifida) were collected. The percentage of unaffected pregnancies with amniotic fluid AFP values equal to or greater than a given cut-off level (expressed as a multiple of the normal median) increased with gestational age, but similar percentages could be obtained by using different cut-off levels at different gestational ages such as 2.5 times median at 13-15 weeks, 3 times at 16-18, 3.5 at 19-21, and 4 at 22-24 weeks. Using these cut-off levels, 98% (120/123) of spnia bifida cases and 98% (218/222) of anencephalics gave positive results; .48% (61/12,804) of unaffected singleton pregnancies not associated with miscarriage also gave positive results (excluding 7 positive results relating to cases of serious fetal malformations). Where amniotic fluid samples were blood-free, detection rates were the same (98% and 98%), but the false positive rate was much lower (.27%, i.e., 31/11,625). In the study area as a whole, the estimated approximate odds of having a fetus with open spina bifida, given 1 amniocentesis sample for AFP measurement, are 18:1 among women with AFP equal to or greater than 2.5 times the median at 16-18 weeks, 5:1 among women who have previously had an infant with an NTD, and 1:2 among other women. The corresponding odds for all open NTDs are approximately 35:1, 9:1, and 1:1, respectively. Raising the cut-off levels by .5 times the median at every gestational period reduced the detection en spina bifida to 93% and reduced the false positive rate to .24%. PMID:90757

1979-09-29

297

Fetal surgery for neural tube defects.  

PubMed

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

Sutton, Leslie N

2008-02-01

298

Fetal surgery for neural tube defects  

PubMed Central

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.

Sutton, Leslie N.

2008-01-01

299

Vitamin dificiencies and neural tube defects  

Microsoft Academic Search

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

R. W. Smithells; S Sheppard; C J Schorah

1976-01-01

300

Electron Tubes  

NSDL National Science Digital Library

All About Circuits is a website that âÂÂprovides a series of online textbooks covering electricity and electronics.â Written by Tony R. Kuphaldt, the textbooks available here are wonderful resources for students, teachers, and anyone who is interested in learning more about electronics. This specific section, Electron Tubes, is the thirteenth chapter in Volume II âÂÂAlternating Current. A few of the topics covered in this chapter include: Early tube history; The Triode; The Tetrode; The Pentode; Tube parameters; and Display tubes. Diagrams and detailed descriptions of concepts are included throughout the chapter to provide users with a comprehensive lesson. Visitors to the site are also encouraged to discuss concepts and topics using the All About Circuits discussion forums (registration with the site is required to post materials).

Kuphaldt, Tony R.

2008-07-18

301

Mechanisms of Neural Blockade  

Microsoft Academic Search

Originally, regional anesthesia was performed by compressing peripheral nerves over an extended period of time to cause profound long lasting anesthe- sia, distal to the site of compression. This could also produce long lasting nerve damage as well. This method of nerve compression was described in the 16 th Background: Neural blockade remains a key diagnostic and treatment modality for

Andreas Grabinsky

2005-01-01

302

Multiple tube premixing device  

DOEpatents

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.

Uhm, Jong Ho; Varatharajan, Balachandar; Ziminsky, Willy Steve; Kraemer, Gilbert Otto; Yilmaz, Ertan; Lacy, Benjamin; Stevenson, Christian; Felling, David

2012-12-11

303

Multiple tube premixing device  

DOEpatents

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.

Uhm, Jong Ho; Naidu, Balachandar; Ziminksy, Willy Steve; Kraemer, Gilbert Otto; Yilmaz, Ertan; Lacy, Benjamin; Stevenson, Christian; Felling, David

2013-08-13

304

Division of labor during trunk neural crest development  

PubMed Central

Neural crest cells, the migratory precursors of numerous cell types including the vertebrate peripheral nervous system, arise in the dorsal neural tube and follow prescribed routes into the embryonic periphery. While the timing and location of neural crest migratory pathways has been well documented in the trunk, a comprehensive collection of signals that guides neural crest migration along these paths has only recently been established. In this review, we outline the molecular cascade of events during trunk neural crest development. After describing the sequential routes taken by trunk neural crest cells, we consider the guidance cues that pattern these neural crest trajectories. We pay particular attention to segmental neural crest development and the steps and signals that generate a metameric peripheral nervous system, attempting to reconcile conflicting observations in chick and mouse. Finally, we compare cranial and trunk neural crest development in order to highlight common themes.

Gammill, Laura S.; Roffers-Agarwal, Julaine

2010-01-01

305

Mystery Tubes  

NSDL National Science Digital Library

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.

Paleontology, University O.

2010-01-01

306

Tube Zither  

NSDL National Science Digital Library

In this activity, learners explore sound by constructing tube zithers, stringed instruments from Southeast Asia and the South Pacific. Use this activity to demonstrate principles of sound including vibration, pitch, tone, frequency, and volume. Note: this activity requires the use of a drill, not included in the cost of materials.

Centers, Oakland D.

2012-01-01

307

An easier method for percutaneous endoscopic gastrojejunostomy tube placement  

Microsoft Academic Search

Background: The current procedures for percutaneous endoscopic gastrojejunostomy (PEG-J) tube placement require fluoroscopy and are time consuming. We describe a new, simple method. Methods: Ten patients had a PEG-J tube placed by the new method. After placement of a percutaneous endoscopic gastrostomy (PEG) tube using standard technique, the PEG tube was pushed up to the pylorus to make it easier

Alain Sibille; Denis Glorieux; Jean-Philippe Fauville; Philippe Warzée

1998-01-01

308

Neutron tubes  

DOEpatents

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.

Leung, Ka-Ngo (Hercules, CA); Lou, Tak Pui (Berkeley, CA); Reijonen, Jani (Oakland, CA)

2008-03-11

309

Electron tube  

DOEpatents

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.

Suyama, Motohiro (Hamamatsu, JP); Fukasawa, Atsuhito (Hamamatsu, JP); Arisaka, Katsushi (Los Angeles, CA); Wang, Hanguo (North Hills, CA)

2011-12-20

310

Fallopian Tube Cancer  

MedlinePLUS

... Cancer.Net Guide Fallopian Tube Cancer Overview Statistics Medical Illustrations Risk Factors and Prevention Symptoms and Signs Diagnosis ... section. Fallopian Tube Cancer - Statistics Fallopian Tube Cancer - Medical Illustrations Fallopian Tube Cancer - Risk Factors and Prevention Fallopian ...

311

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 ...

312

Evolvable synthetic neural system  

NASA Technical Reports Server (NTRS)

An evolvable synthetic neural system includes an evolvable neural interface operably coupled to at least one neural basis function. Each neural basis function includes an evolvable neural interface operably coupled to a heuristic neural system to perform high-level functions and an autonomic neural system to perform low-level functions. In some embodiments, the evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy.

Curtis, Steven A. (Inventor)

2009-01-01

313

Method of processing tubing  

Microsoft Academic Search

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

Prizzi

1987-01-01

314

The neural crest and neural crest cells: discovery and significance for theories of embryonic organization.  

PubMed

The neural crest has long fascinated developmental biologists,and,increasingly over the past decades,evolutionary and evolutionary developmental biologists.The neural crest is the name given to the fold of ectoderm at the junction between neural and epidermal ectoderm in neurula-stage vertebrate embryos.In this sense,the neural crest is a morphological term akin to head fold or limb bud.This region of the dorsal neural tube consists of neural crest cells,a special population(s)of cell,that give rise to an astonishing number of cell types and to an equally astonishing number of tissues and organs.Neural crest cell contributions may be direct - providing cells - or indirect - providing a necessary, often inductive, environment in which other cells develop.The enormous range of cell types produced provides an important source of evidence of the neural crest as a germ layer, bringing the number of germ layers to four - ectoderm,endoderm,mesoderm,and neural crest. In this paper I provide a brief overview of the major phases of investigation into the neural crest and the major players involved,discuss how the origin of the neural crest relates to the origin of the nervous system in vertebrate embryos,discuss the impact on the germ-layer theory of the discovery of the neural crest and of secondary neurulation,and present evidence of the neural crest as the fourth germ layer.A companion paper (Hall, Evol. Biol.2008) deals with the evolutionary origins of the neural crest and neural crest cells. PMID:19179766

Hall, Brian K

2008-12-01

315

Tapered pulse tube for pulse tube refrigerators  

DOEpatents

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.

Swift, Gregory W. (Sante Fe, NM); Olson, Jeffrey R. (San Mateo, CA)

1999-01-01

316

Collapse Tubes  

NASA Technical Reports Server (NTRS)

[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.

2006-01-01

317

Working with neural networks  

Microsoft Academic Search

As explanation of how neural networks operate is given. Programming of neural networks and regular computers is compared. Matching a neural network to an application is discussed. Designing and training a neural network is examined

D. Hammerstrom

1993-01-01

318

Tube-in-tube thermophotovoltaic generator  

DOEpatents

A thermophotovoltaic device includes at least one thermal radiator tube, a cooling tube concentrically disposed within each thermal radiator tube and an array of thermophotovoltaic cells disposed on the exterior surface of the cooling tube. A shell having a first end and a second end surrounds the thermal radiator tube. Inner and outer tubesheets, each having an aperture corresponding to each cooling tube, are located at each end of the shell. The thermal radiator tube extends within the shell between the inner tubesheets. The cooling tube extends within the shell through the corresponding apertures of the two inner tubesheets to the corresponding apertures of the two outer tubesheets. A plurality of the thermal radiator tubes can be arranged in a staggered or an in-line configuration within the shell.

Ashcroft, John (Scotia, NY); Campbell, Brian (Scotia, NY); DePoy, David (Clifton Park, NY)

1998-01-01

319

Tube-in-tube thermophotovoltaic generator  

DOEpatents

A thermophotovoltaic device includes at least one thermal radiator tube, a cooling tube concentrically disposed within each thermal radiator tube and an array of thermophotovoltaic cells disposed on the exterior surface of the cooling tube. A shell having a first end and a second end surrounds the thermal radiator tube. Inner and outer tubesheets, each having an aperture corresponding to each cooling tube, are located at each end of the shell. The thermal radiator tube extends within the shell between the inner tubesheets. The cooling tube extends within the shell through the corresponding apertures of the two inner tubesheets to the corresponding apertures of the two outer tubesheets. A plurality of the thermal radiator tubes can be arranged in a staggered or an in-line configuration within the shell. 8 figs.

Ashcroft, J.; Campbell, B.; DePoy, D.

1998-06-30

320

Concentric insulated tubing string  

SciTech Connect

An improved insulated tubing string with insulated coupling formed of concentric tubing members insulated from each other to prevent heat from the inner tubing from being conducted to and through the outer tubing. The coupling joins the outer tubing of successive tubing assemblies to provide additional strength to the string and the inner tubing is insulated within the coupling to prevent heat loss at the coupling. The inner tubing is elongated during fabrication and joined to the outer tubing when elongated to reduce heat stress on the string when in use.

Hutchison, S. O.

1984-10-16

321

Emission Tube Apparatus  

NSDL National Science Digital Library

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.

Ward, Charles

2003-01-16

322

Feeding tube (image)  

MedlinePLUS

A feeding tube is a small, soft, plastic tube placed through the nose or mouth into the stomach. A feeding tube is used to provide food and medicine into the stomach until a person can take food by mouth.

323

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) ...

324

Magnetic merging in colliding flux tubes  

NASA Technical Reports Server (NTRS)

We develop an analytical theory of reconnection between colliding, twisted magnetic flux tubes. Our analysis is restricted to direct collisions between parallel tubes and is based on the collision dynamics worked out by Bogdan (1984). We show that there is a range of collision velocities for which neutral point reconnection of the Parker-Sweet type can occur, and a smaller range for which reconnection leads to coalescence. Mean velocities within the solar convection zone are probably significantly greater than the upper limit for coalescence. This suggests that the majority of flux tube collisions do not result in merging, unless the frictional coupling of the tubes to the background flow is extremely strong.

Zweibel, Ellen G.; Rhoads, James E.

1995-01-01

325

Hanford Site background: Part 3, Groundwater background.  

National Technical Information Service (NTIS)

This report presents and interprets groundwater background data collected from the unconfined aquifer beneath the Hanford Site, a U.S. Department of Energy complex located near Richland, Washington. Characterization of background composition is an importa...

1997-01-01

326

Neural regeneration.  

PubMed

Regeneration of the nervous system requires either the repair or replacement of nerve cells that have been damaged by injury or disease. While lower organisms possess extensive capacity for neural regeneration, evolutionarily higher organisms including humans are limited in their ability to regenerate nerve cells, posing significant issues for the treatment of injury and disease of the nervous system. This chapter focuses on current approaches for neural regeneration, with a discussion of traditional methods to enhance neural regeneration as well as emerging concepts within the field such as stem cells and cellular reprogramming. Stem cells are defined by their ability to self-renew as well as their ability to differentiate into multiple cell types, and hence can serve as a source for cell replacement of damaged neurons. Traditionally, adult stem cells isolated from the hippocampus and subventricular zone have served as a source of neural stem cells for replacement purposes. With the advancement of pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs), new and exciting approaches for neural cell replacement are being developed. Furthermore, with increased understanding of the human genome and epigenetics, scientists have been successful in the direct genetic reprogramming of somatic cells to a neuronal fate, bypassing the intermediary pluripotent stage. Such breakthroughs have accelerated the timing of production of mature neuronal cell types from a patient-specific somatic cell source such as skin fibroblasts or mononuclear blood cells. While extensive hurdles remain to the translational application of such stem cell and reprogramming strategies, these approaches have revolutionized the field of regenerative biology and have provided innovative approaches for the potential regeneration of the nervous system. PMID:23292211

Steward, Melissa M; Sridhar, Akshayalakshmi; Meyer, Jason S

2013-01-01

327

Real-Time Decision Fusion for Multimodal Neural Prosthetic Devices  

Microsoft Academic Search

BackgroundThe field of neural prosthetics aims to develop prosthetic limbs with a brain-computer interface (BCI) through which neural activity is decoded into movements. A natural extension of current research is the incorporation of neural activity from multiple modalities to more accurately estimate the user's intent. The challenge remains how to appropriately combine this information in real-time for a neural prosthetic

James Robert White; Todd Levy; William Bishop; James D. Beaty; Joel M. Schnur

2010-01-01

328

Limitations and uses of gastrojejunal feeding tubes  

PubMed Central

Background: Gastrostomy feeding is a well established alternative method to long term nasogastric tube feeding. Many such patients have gastro-oesophageal reflux (GOR) and require a fundoplication. A transgastric jejunal tube is an alternative when antireflux surgery fails, or is hazardous or inappropriate. Aims: To review experience of gastrojejunal (G-J) feeding over six years in two regional centres in the UK. Methods: Retrospective review of all children who underwent insertion of a G-J feeding tube. Results: There were 18 children, 12 of whom were neurologically impaired. G-J tubes were inserted at a median age of 3.1 years (range 0.6–14.7) because of persistent symptoms after Nissen fundoplication (n = 8) or symptomatic GOR where fundoplication was inappropriate. Four underwent primary endoscopic insertion of the G-J tube; the remainder had the tube inserted via a previous gastrostomy track. Seventeen showed good weight gain. There was one insertion related complication. During a median follow up of 10 months (range 1–60), four experienced recurrent aspiration, bilious aspirates, and/or diarrhoea. There were 65 tube related complications in 14 patients, necessitating change of the tube at a median of 74 days. Jejunal tube migration was the commonest problem. Five died from complications of their underlying disease. Conclusions: Although G-J feeding tubes were inserted safely and improved nutritional status, their use was associated with a high rate of morbidity. Surgical alternatives such as an Roux-en-Y jejunostomy may be preferable.

Godbole, P; Margabanthu, G; Crabbe, D; Thomas, A; Puntis, J; Abel, G; Arthur, R; Stringer, M

2002-01-01

329

Neural Communication  

NSDL National Science Digital Library

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 ...

Johnson, Mrs.

2010-06-22

330

New laser tracheal tube  

NASA Astrophysics Data System (ADS)

The complication of a laser induced tube fire during surgery was first published in 1979. The protection of tracheal tubes against ignition is necessary to enable a safe laser surgery of the upper airway. in an experimental study a new compound tube was tested: this tube had a higher laser resistance than a pure metal tube. The damage threshold of this tube was tested against the emission of various lasers as CO2. The metal tube was damaged within seconds at CO2 laser power densities of 103 W/cm2 whereas the damage threshold of the compound tube was 3.106 W/cm2. We compared the compound laser tube to the so far used metal tube in a prospective clinical trial in our department of ENT in patients undergoing CO2-laser surgery of the upper airway. 66 patients were included into the study: 33 received the compound tube, 33 the metal tube. During endotracheal intubation the handling of the compound tube was better. During laser surgery high airway pressures occured more often with the metal tube. Whereas kinking was the problem of the compound tubes. Destruction of cuffs occured in both groups but did not cause any complications. No tube or cuff fire was noticed.

Ungemach, Josef; Foth, Hans-Jochen; Hoermann, Karl; Preponis, E.

1996-09-01

331

Bender/Coiler for Tubing  

NASA Technical Reports Server (NTRS)

Easy-to-use tool makes coils of tubing. Tubing to be bend clamped with stop post. Die positioned snugly against tubing. Operator turns handle to slide die along tubing, pushing tubing into spiral groove on mandrel.

Stoltzfus, J. M.

1983-01-01

332

Neural Network Real Time Video Processor for early aircraft detection  

Microsoft Academic Search

Detecting an aircraft solely by its infrared (IR) signature in real time can be extremely challenging task depending on the image background clutter. Neural networks offer a reliable method of detecting targets (aircraft) against a multitude of background scenes and a variety of environmental conditions. Neural networks can rapidly \\

Gregory Hauser; Milos Manic

2009-01-01

333

Torsion tests of tubes  

NASA Technical Reports Server (NTRS)

This report presents the results of tests of 63 chromium-molybdenum steel tubes and 102 17st aluminum-alloy tubes of various sizes and lengths made to study the dependence of the torsional strength on both the dimensions of the tube and the physical properties of the tube material. Three types of failure are found to be important for sizes of tubes frequently used in aircraft construction: (1) failure by plastic shear, in which the tube material reached its yield strength before the critical torque was reached; (2) failure by elastic two-lobe buckling, which depended only on the elastic properties of the tube material and the dimensions of the tube; and (3) failure by a combination of (1) and (2) that is, by buckling taking place after some yielding of the tube material.

Stang, Ambrose H; Ramberg, Walter; Back, Goldie

1937-01-01

334

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

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

Godfrey P. Oakley; Karen N. Bell; Mary Beth Weber

2004-01-01

335

Condenser tube repairs using tube inserts  

SciTech Connect

It is common knowledge that many heat exchanger (HX) tube failures occur within the first 6 in. (150 mm) of the bundle. Inlet-end erosion, stress corrosion cracking, and crevice corrosion are different types of failure mechanisms that are common in shell-and-tube HX.

Tallman, P.M.

2000-05-01

336

Annular-Tube Reinforcer  

NASA Technical Reports Server (NTRS)

Cylindrical tool inserts support sleeves into annular space between coaxial tubes to provide local reinforcement. Tool particularly useful when space between outer ends of coaxial tubes is narrow, requiring thin sleeve.

Pessin, R.

1985-01-01

337

Glass tube splitting tool  

NASA Technical Reports Server (NTRS)

Tool accurately splits glass tubing so cuts are aligned 180 deg apart and reassembled tube forms low pressure, gastight enclosure. Device should interest industries using cylindrical closed glass containers.

Klein, J. A.; Murray, C. D.; Stein, J. A.

1971-01-01

338

Tracheostomy tube - speaking  

MedlinePLUS

... part of communicating with people. Having a tracheostomy tube can change your ability to talk and interact ... re-learn how to speak with a tracheostomy tube. It just takespractice. There are even speaking devices ...

339

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 ...

340

Nonlinear neural field filters  

Microsoft Academic Search

Design, stability and implementation of nonlinear neural field filters are examined. The input and output of the neural field filters are vector fields. A neural transform is used to represent the input, output signals and the transfer function of the neural field filter. It is concluded that the Lyapunov conditions for such fields are taken care of by a novel

H. T. Sherief; H. A. Fatmi

1991-01-01

341

A Neural Network Approach for Video Object Segmentation in Traffic Surveillance  

Microsoft Academic Search

This paper presents a neural background modeling based on subtraction approach for video object segmentation. A competitive\\u000a neural network is proposed to form a background model for traffic surveillance. The unsupervised neural classifier handles\\u000a the segmentation in natural traffic sequences with changes in illumination. The segmentation performance of the proposed neural\\u000a network is qualitatively examined and compared to mixture of

Rafael Marcos Luque; Enrique Domínguez; Esteban J. Palomo; José Muñoz

2008-01-01

342

Torpedo Tube Slide Valve.  

National Technical Information Service (NTIS)

A torpedo tube and slide valve assembly includes a torpedo tube having a plurality of circumferentially spaced slots therein and an impulse tank surrounding the torpedo tube wherein the slots provide a flow path between the impulse tank and the interior o...

P. E. Moody

1994-01-01

343

True color tube bore inspection system  

NASA Astrophysics Data System (ADS)

A True Color Tube Bore Inspection System (TCTBIS) has been developed to aid in the visual nondestructive examination of the inside surfaces of small bore stainless steel tubes. The instrument was developed to inspect for the presence of contaminants and oxidation on the inner surfaces of these 1.5 to 1.7 millimeter inside diameter tubes. Previously a parameter called the color factor, which can be calculated from the images collected by the TCTBIS, was found to be a good measure of the surface quality in these tubes. The color factor is a global number in the sense that it is calculated for the entire inspection region. Additional algorithms have also been developed to evaluate the tube based on surface inhomogeneities that are indicative of the presence of foreign matter, local chemical attack or other undesirable but localized conditions. These algorithms have been incorporated into an up-to-date apparatus which is described in detail. We have also investigated the feasibility of using artificial intelligence techniques to aid in the interpretation of these defects. Promising results were obtained with a feed forward, back propagation artificial neural network.

Pechersky, Martin J.; Harpring, Larry J.

2000-03-01

344

A True Color Tube Bore Inspection System  

SciTech Connect

A True Color Tube Bore Inspection System (TCTBIS) has been developed to aid in the visual nondestructive examination of the inside surfaces of small bore stainless steel tubes. The instrument was developed to inspect for the presence of contaminants and oxidation on the inner surfaces of these 1.5 to 1.7 millimeter inside diameter tubes. Previously a parameter called the color factor, which can be calculated from the images collected by the TCTBIS, was found to be a good measure of the surface quality in these tubes. The color factor is a global number in the sense that it is calculated for the entire inspection region. Additional algorithms have also been developed to evaluate the tube based on surface inhomogeneities that are indicative of the presence of foreign matter, local chemical attack or other undesirable but localized conditions. These algorithms have been incorporated into an up-to-date apparatus which is described in detail. The author has also investigated the feasibility of using artificial intelligence techniques to aid in the interpretation of these defects. Promising results were obtained with a feed forward, back propagation artificial neural network.

Pechersky, M.J.

1999-12-08

345

The tight junction scaffolding protein cingulin regulates neural crest cell migration  

PubMed Central

Neural crest cells give rise to a diverse range of structures during vertebrate development. These cells initially exist in the dorsal neuroepithelium and subsequently acquire the capacity to migrate. Although studies have documented the importance of adherens junctions in regulating neural crest cell migration, little attention has been paid to tight junctions during this process. We now identify the tight junction protein cingulin as a key regulator of neural crest migration. Cingulin knock-down increases the migratory neural crest cell domain, which is correlated with a disruption of the neural tube basal lamina. Overexpression of cingulin also augments neural crest cell migration and is associated with similar basal lamina changes and an expansion of the premigratory neural crest population. Cingulin overexpression causes aberrant ventrolateral neuroepithelial cell delamination, which is linked to laminin loss and a decrease in RhoA. Together, our results highlight a novel function for cingulin in the neural crest.

Wu, Chyong-Yi; Jhingory, Sharon; Taneyhill, Lisa A.

2011-01-01

346

Immunophenotypic characterisation of enteric neural crest cells in the developing avian colorectum  

PubMed Central

Background The enteric nervous system (ENS) develops from neural crest-derived cells that migrate along the intestine to form two plexuses of neurons and glia. While the major features of ENS development are conserved across species, minor differences exist, especially in the colorectum. Given the embryologic and disease-related importance of the distal ENS, the aim of this study was to characterize the migration and differentiation of enteric neural crest cells (ENCCs) in the colorectum of avian embryos. Results Using normal chick embryos and vagal neural tube transplants from GFP-transgenic chick embryos, we find ENCCs entering the colon at embryonic day (E) 6.5, with colonization complete by E8. Undifferentiated ENCCs at the wavefront express HNK-1, N-cadherin, Sox10, p75, and L1CAM. By E7, differentiation begins in the proximal colon, with L1CAM and Sox10 becoming restricted to neuronal and glial lineages, respectively. By E8, multiple markers of differentiation are expressed along the entire colorectum. Conclusions Our results establish the pattern of ENCC migration and differentiation in the chick colorectum, demonstrate the conservation of marker expression across species, highlight a range of markers, including neuronal cell adhesion molecules, which label cells at the wavefront, and provide a framework for future studies in avian ENS development.

Nagy, Nandor; Burns, Alan J.; Goldstein, Allan M.

2012-01-01

347

The Cosmological Background Radiation  

Microsoft Academic Search

This book provides an introduction to the physics, astrophysics and cosmology of the cosmic microwave background radiation. Adopting the Standard Big Bang model of the universe, the authors cover topics including the origin of the background, intrinsic fluctuations, and the universe and background radiation after recombination. Finally they present measurement of the radiation and its anisotropies, along with a review

Marc Lachièze-Rey; Edgard Gunzig

1999-01-01

348

Terminal Attractors In Neural Networks  

NASA Technical Reports Server (NTRS)

Neural networks made to "learn" faster. Report presents theoretical study of terminal attractors in neural networks. Includes systematic analysis of applications to activation dynamics of neural networks.

Zak, Michail A.

1991-01-01

349

Plasticity in mouse neural crest cells reveals a new patterning role for cranial mesoderm  

Microsoft Academic Search

The anteroposterior identity of cranial neural crest cells is thought to be preprogrammed before these cells emigrate from the neural tube. Here we test this assumption by developing techniques for transposing cells in the hindbrain of mouse embryos, using small numbers of cells in combination with genetic and lineage markers. This technique has uncovered a surprising degree of plasticity with

Paul Trainor; Robb Krumlauf

2000-01-01

350

Heat tube device  

NASA Technical Reports Server (NTRS)

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.

Khattar, Mukesh K. (inventor)

1990-01-01

351

Notch Signaling Maintains Neural Rosette Polarity  

PubMed Central

Formation of the metazoan body plan requires a complex interplay of morphological changes and patterning, and central to these processes is the establishment of apical/basal cell polarity. In the developing nervous system, apical/basal cell polarity is essential for neural tube closure and maintenance of the neural stem cell population. In this report we explore how a signaling pathway important for nervous system development, Notch signaling, impacts on apical/basal cell polarity in neural differentiation. CSL?/? mouse embryos, which are devoid of canonical Notch signaling, demonstrated a neural tube phenotype consistent with cell polarity and convergent extension defects, including deficiencies in the restricted expression of apical polarity markers in the neuroepithelium. CSL?/? mouse embryonic stem (ES) cells, cultured at low density, behaved as wild-type in the establishment of neural progenitors and apical specification, though progression through rosette formation, an in vitro correlate of neurulation, required CSL for correct maintenance of rosette structure and regulation of neuronal differentiation. Similarly, acute pharmacological inhibition of Notch signaling led to the breakdown of neural rosettes and accelerated neuronal differentiation. In addition to functional Notch signaling, rosette integrity was found to require actin polymerization and Rho kinase (ROCK) activity. Disruption of rosettes through inhibition of actin polymerization or ROCK activity, however, had no effect on neuronal differentiation, indicating that rosette maintenance is not a prerequisite for normal neuronal differentiation. In conclusion, our data indicate that Notch signaling plays a role not only in differentiation, but also in organization and maintenance of polarity during development of the early nervous system.

Main, Heather; Radenkovic, Jelena; Jin, Shao-bo; Lendahl, Urban; Andersson, Emma R.

2013-01-01

352

iBioSeminar: Role of the Neural Crest in Vertebrate Development and Evolution  

NSDL National Science Digital Library

The neural crest (NC) is a transitory structure of the Vertebrate embryo. It forms when the neural tube closes through the epithelio- mesenchymal transition of the cells in the joining neural folds. Its constitutive cells are endowed of migratory capacities and are highly pluripotent. NC cells migrate in the developing embryo along definite pathways, at precise periods of time during embryogenesis and settle in elected sites in the body where they develop into a large of cell types.

Nicole Le Douarin (CNRS and Collège de France, Paris;)

2008-03-01

353

Pediatric cuffed endotracheal tubes  

PubMed Central

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.

Bhardwaj, Neerja

2013-01-01

354

Neural edelmanism.  

PubMed

The recent book Neural Darwinism (ND) by Gerald Edelman, claims to put forward 'a radically new view of the function of the brain and nervous system'. Its main focus is on the understanding of the biological basis of perception. This new view is based on what Edelman calls 'The Theory of Neuronal Group Selection', the subtitle of his book. In spite of Edelman's lengthy and spirited account of this new theory, most readers appear to have had some difficulty in grasping his ideas and many have complained that the book is not easy to read. It has been particularly difficult to relate Edelman's ideas to those already current and well-known, especially as Edelman himself says rather little on this topic. In this critique I aim to set out Edelman's central ideas, as they appear to me, in a clearer and more digestible form. I examine both his general exposition of these ideas and the simulations he has presented to support them, giving page references so that the concerned reader can check my statements against the text. I have considered also Edelman's original papers, upon which the book is based, but I have not considered more recent papers which deal with matters (such as Darwin III) that are not covered in the book. PMID:2475933

Crick, F

1989-07-01

355

The Cosmic Background Explorer.  

ERIC Educational Resources Information Center

Outlines the Cosmic Background Explorer (COBE) mission to measure celestial radiation. Describes the instruments used and experiments involving differential microwave radiometers, and a far infrared absolute spectrophotometer. (YP)

Gulkis, Samuel; And Others

1990-01-01

356

Kaumana lava tube  

NASA Technical Reports Server (NTRS)

The entrance to Kaumana Lava Tube is in a picnic ground next to Highway 20 (Kaumana Drive) about 6.5 km southwest of Hilo. The area is passed on the way to the Kona Coast via the Saddle Road and is identified by a Hawaii Visitors Bureau sign. Although it is not the largest lava tube in the islands, Kaumana Lava Tube is an interesting geological formation, displaying many of the features typical of lava tube interiors. It is accessible, relatively easy to walk through, and is in an excellent state of preservation. The tube developed in a historic lava flow (1881, from Mauna Loa), and many aspects of lava tube activity are observed.

Greeley, R.

1974-01-01

357

Reconnection of vortex tubes  

Microsoft Academic Search

The mechanism of vortex reconnection is investigated by solving the Navier-Stokes equation numerically starting with a trefoiled closed knotted vortex tube. A new type of vortex reconnection mechanism-bridging-is observed. Small regions of high-vorticity burst out of the vortex tube. grow up and bridge different portions of the tube. A relation between the change of the helicity and the mechanism of

S. Kida; M. Takaoka

1988-01-01

358

Conduction cooled tube supports  

DOEpatents

In boilers, process tubes are suspended by means of support studs that are in thermal contact with and attached to the metal roof casing of the boiler and the upper bend portions of the process tubes. The support studs are sufficiently short that when the boiler is in use, the support studs are cooled by conduction of heat to the process tubes and the roof casing thereby maintaining the temperature of the stud so that it does not exceed 1400.degree. F.

Worley, Arthur C. (Mt. Tabor, NJ) [Mt. Tabor, NJ; Becht, IV, Charles (Morristown, NJ)

1984-01-01

359

Ruggedized electronographic tube development  

NASA Technical Reports Server (NTRS)

Because of their glass components and lack of far ultraviolet sensitivity, currently available Spectracons are not suited for rocket launch. Technology developed for second generation image tubes and for magnetically focused image tubes can be applied to improve the optical and mechanical properties of these magnetically focused electronographic tubes whose 40 kilovolt signal electrons exit a 4-micrometer thick mica window and penetrate a photographic recording emulsion.

Nevin, S.

1981-01-01

360

Correlators in nontrivial backgrounds  

SciTech Connect

Operators in N=4 super Yang-Mills theory with an R-charge of O(N{sup 2}) are dual to backgrounds which are asymtotically AdS{sub 5}xS{sup 5}. In this article we develop efficient techniques that allow the computation of correlation functions in these backgrounds. We find that (i) contractions between fields in the string words and fields in the operator creating the background are the field theory accounting of the new geometry, (ii) correlation functions of probes in these backgrounds are given by the free field theory contractions but with rescaled propagators and (iii) in these backgrounds there are no open string excitations with their special end point interactions; we have only closed string excitations.

Mello Koch, Robert de [National Institute for Theoretical Physics, Department of Physics and Centre for Theoretical Physics, University of the Witwatersrand, Wits, 2050 (South Africa); Stellenbosch Institute for Advanced Studies, Stellenbosch (South Africa); Ives, Norman; Stephanou, Michael [National Institute for Theoretical Physics, Department of Physics and Centre for Theoretical Physics, University of the Witwatersrand, Wits, 2050 (South Africa)

2009-01-15

361

Sapphire tube pressure vessel  

DOEpatents

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.

Outwater, John O. (Cambridge, MA)

2000-01-01

362

Wound tube heat exchanger  

DOEpatents

What is disclosed is a wound tube heat exchanger in which a plurality of tubes having flattened areas are held contiguous adjacent flattened areas of tubes by a plurality of windings to give a double walled heat exchanger. The plurality of windings serve as a plurality of effective force vectors holding the conduits contiguous heat conducting walls of another conduit and result in highly efficient heat transfer. The resulting heat exchange bundle is economical and can be coiled into the desired shape. Also disclosed are specific embodiments such as the one in which the tubes are expanded against their windings after being coiled to insure highly efficient heat transfer.

Ecker, Amir L. (Duncanville, TX)

1983-01-01

363

Composite Pulse Tube  

NASA Technical Reports Server (NTRS)

A modification of the design of the pulse tube in a pulse-tube cryocooler reduces axial thermal conductance while preserving radial thermal conductance. It is desirable to minimize axial thermal conductance in the pulse-tube wall to minimize leakage of heat between the warm and cold ends of the pulse tube. At the same time, it is desirable to maximize radial thermal conductance at the cold end of the pulse tube to ensure adequate thermal contact between (1) a heat exchanger in the form of a stack of copper screens inside the pulse tube at the cold end and (2) the remainder of the cold tip, which is the object to which the heat load is applied and from which heat must be removed. The modified design yields a low-heat-leak pulse tube that can be easily integrated with a cold tip. A typical pulse tube of prior design is either a thin-walled metal tube or a metal tube with a nonmetallic lining. It is desirable that the outer surface of a pulse tube be cylindrical (in contradistinction to tapered) to simplify the design of a regenerator that is also part of the cryocooler. Under some conditions, it is desirable to taper the inner surface of the pulse tube to reduce acoustic streaming. The combination of a cylindrical outer surface and a tapered inner surface can lead to unacceptably large axial conduction if the pulse tube is made entirely of metal. Making the pulse-tube wall of a nonmetallic, lowthermal- conductivity material would not solve the problem because the wall would not afford the needed thermal contact for the stack of screens in the cold end. The modified design calls for fabricating the pulse tube in two parts: a longer, nonmetallic part that is tapered on the inside and cylindrical on the outside and a shorter, metallic part that is cylindrical on both the inside and the outside. The nonmetallic part can be made from G-10 fiberglass-reinforced epoxy or other low-thermal-conductivity, cryogenically compatible material. The metallic part must have high thermal conductivity in the cryogenic temperature range and would typically be made of pure copper to satisfy this requirement. The metallic part is bonded to the nonmetallic part with epoxy. Copper screens are inserted in the metallic part to form the cold-end heat exchanger, then the assembled pulse tube is inserted in the cold tip.

Martin, Jerry L.; Cloyd, Jason H.

2007-01-01

364

Parallel Consensual Neural Networks  

NASA Technical Reports Server (NTRS)

A new neural network architecture is proposed and applied in classification of remote sensing/geographic data from multiple sources. The new architecture is called the parallel consensual neural network and its relation to hierarchical and ensemble neural networks is discussed. The parallel consensual neural network architecture is based on statistical consensus theory. The input data are transformed several times and the different transformed data are applied as if they were independent inputs and are classified using stage neural networks. Finally, the outputs from the stage networks are then weighted and combined to make a decision. Experimental results based on remote sensing data and geographic data are given. The performance of the consensual neural network architecture is compared to that of a two-layer (one hidden layer) conjugate-gradient backpropagation neural network. The results with the proposed neural network architecture compare favorably in terms of classification accuracy to the backpropagation method.

Benediktsson, J. A.; Sveinsson, J. R.; Ersoy, O. K.; Swain, P. H.

1993-01-01

365

Artificial-neural-network-based failure detection and isolation  

NASA Astrophysics Data System (ADS)

This paper presents the design of a systematic failure detection and isolation system that uses the concept of failure sensitive variables (FSV) and artificial neural networks (ANN). The proposed approach was applied to tube leak detection in a utility boiler system. Results of the experimental testing are presented in the paper.

Sadok, M.; Gharsalli, I.; Alouani, Ali T.

1998-03-01

366

Acoustic streaming in pulse tube refrigerators: tapered pulse tubes  

Microsoft Academic Search

Acoustic streaming is investigated in tapered tubes with axially varying temperature, in the boundary layer limit. By appropriately shaping the tube, the streaming can be eliminated. Experimental data demonstrate that an orifice pulse tube refrigerator with a conical pulse tube whose cone angle eliminates streaming has more cooling power than one with either a cylindrical pulse tube or a conical

J. R. Olson; G. W. Swift

1997-01-01

367

Optical neural interfaces.  

PubMed

Genetically encoded optical actuators and indicators have changed the landscape of neuroscience, enabling targetable control and readout of specific components of intact neural circuits in behaving animals. Here, we review the development of optical neural interfaces, focusing on hardware designed for optical control of neural activity, integrated optical control and electrical readout, and optical readout of population and single-cell neural activity in freely moving mammals. PMID:25014785

Warden, Melissa R; Cardin, Jessica A; Deisseroth, Karl

2014-07-11

368

Background stratospheric aerosol layer  

SciTech Connect

Balloonborne aerosol particle counter measurements are used in studying the stratospheric sulfate layer at Laramie, Wyoming, during 1978 and 1979, a 2-year volcanically quiescent period in which the layer appears to have been in a near equilibrium background state. Subtracting the background aerosol concentration from data obtained during an earlier volcanically active period indicates that the actual decay rate of volcanic aerosol is over 30% faster than one would obtain without this correction. At background, the aerosol size distribution is found to remain remarkably constant between the tropopause and an altitude of approx.25 km, with a sudden transition to a distribution dominated by smaller particles above this altitude. The observations, in some respects, compare favorably with equilibrium one-dimensional stratospheric aerosol models and thus to some extent support the concept of relatively inert tropospheric sulfurous gases, such as carbonyl sulfide and carbon disulfide, as the main background stratospheric aerosol sulfur source. Models which incorporate sulfur chemistry are apparently not able to predict the observed variation of particle size with altitude. The 2-year background period is not long enough in itself to establish long-term trends. The eruption of Mt. St. Helens in May 1980 has considerably disrupted the background stratospheric aerosol which will probably not recover for several years. A comparison of the 1978--79 observations with Junge's original measurements made some 20 years earlier, also during a period void of volcanic perturbations, does not preclude a long-term increase in the background stratospheric aerosol level.

Hofmann, D.J.; Rosen, J.M.

1981-01-01

369

Adaptive background model  

NASA Astrophysics Data System (ADS)

An adaptive background model aiming at outdoor vehicle detection is presented in this paper. This model is an improved model of PICA (pixel intensity classification algorithm), it classifies pixels into K-distributions by color similarity, and then a hypothesis that the background pixel color appears in image sequence with a high frequency is used to evaluate all the distributions to determine which presents the current background color. As experiments show, the model presented in this paper is a robust, adaptive and flexible model, which can deal with situations like camera motions, lighting changes and so on.

Lu, Xiaochun; Xiao, Yijun; Chai, Zhi; Wang, Bangping

2007-11-01

370

The cosmic neutrino background  

NASA Technical Reports Server (NTRS)

The cosmic neutrino background is expected to consist of relic neutrinos from the big bang, of neutrinos produced during nuclear burning in stars, of neutrinos released by gravitational stellar collapse, and of neutrinos produced by cosmic ray interactions with matter and radiation in the interstellar and intergalactic medium. Formation of baryonic dark matter in the early universe, matter-antimatter annihilation in a baryonic symmetric universe, and dark matter annihilation could have also contributed significantly to the cosmic neutrino background. The purpose of this paper is to review the properties of these cosmic neutrino backgrounds, the indirect evidence for their existence, and the prospects for their detection.

Dar, Arnon

1991-01-01

371

Neural Differentiation of Embryonic Stem Cells In Vitro: A Road Map to Neurogenesis in the Embryo  

Microsoft Academic Search

BackgroundThe in vitro generation of neurons from embryonic stem (ES) cells is a promising approach to produce cells suitable for neural tissue repair and cell-based replacement therapies of the nervous system. Available methods to promote ES cell differentiation towards neural lineages attempt to replicate, in different ways, the multistep process of embryonic neural development. However, to achieve this aim in

Elsa Abranches; Margarida Silva; Laurent Pradier; Herbert Schulz; Oliver Hummel; Domingos Henrique; Evguenia Bekman; Gianni Parise

2009-01-01

372

Amphioxus and lamprey AP-2 genes: implications for neural crest evolution and migration patterns.  

PubMed

The neural crest is a uniquely vertebrate cell type present in the most basal vertebrates, but not in cephalochordates. We have studied differences in regulation of the neural crest marker AP-2 across two evolutionary transitions: invertebrate to vertebrate, and agnathan to gnathostome. Isolation and comparison of amphioxus, lamprey and axolotl AP-2 reveals its extensive expansion in the vertebrate dorsal neural tube and pharyngeal arches, implying co-option of AP-2 genes by neural crest cells early in vertebrate evolution. Expression in non-neural ectoderm is a conserved feature in amphioxus and vertebrates, suggesting an ancient role for AP-2 genes in this tissue. There is also common expression in subsets of ventrolateral neurons in the anterior neural tube, consistent with a primitive role in brain development. Comparison of AP-2 expression in axolotl and lamprey suggests an elaboration of cranial neural crest patterning in gnathostomes. However, migration of AP-2-expressing neural crest cells medial to the pharyngeal arch mesoderm appears to be a primitive feature retained in all vertebrates. Because AP-2 has essential roles in cranial neural crest differentiation and proliferation, the co-option of AP-2 by neural crest cells in the vertebrate lineage was a potentially crucial event in vertebrate evolution. PMID:12397104

Meulemans, Daniel; Bronner-Fraser, Marianne

2002-11-01

373

Developmental Outcomes after Early or Delayed Insertion of Tympanostomy Tubes  

Microsoft Academic Search

background To prevent later developmental impairments, myringotomy with the insertion of tympa- nostomy tubes has often been undertaken in young children who have persistent otitis media with effusion. We previously reported that prompt as compared with delayed in- sertion of tympanostomy tubes in children with persistent effusion who were younger than three years of age did not result in improved

Jack L. Paradise; Thomas F. Campbell; Christine A. Dollaghan; Heidi M. Feldman; Beverly S. Bernard; D. Kathleen Colborn; Howard E. Rockette; Janine E. Janosky; Dayna L. Pitcairn; Marcia Kurs-Lasky; Diane L. Sabo; Clyde G. Smith

2010-01-01

374

Boussignac Continuous Positive Airway Pressure for Weaning with Tracheostomy Tubes  

Microsoft Academic Search

Background: In patients who are weaned with a tracheostomy tube (TT), continuous positive airway pressure (CPAP) is frequently used. Dedicated CPAP systems or ventilators with bulky tubing are usually applied. However, CPAP can also be effective without a ventilator by the disposable Boussignac CPAP (BCPAP) system that is normally used with face masks. Objective:It was the aim of this audit

Willem Dieperink; Leon P. H. J. Aarts; Michael G. G. Rodgers; Hans Delwig; Maarten W. N. Nijsten

2008-01-01

375

Building Background Knowledge  

NSDL National Science Digital Library

Too often, students enter our classrooms with insufficient knowledge of physical science. As a result, they have a difficult time understanding content in texts, lectures, and laboratory activities. This lack of background knowledge can have an impact on

Ross, Donna; Fisher, Douglas; Grant, Maria

2010-01-01

376

Background and Statistics  

MedlinePLUS

Background & Statistics FAQ About Homeless Veterans Homeless Veterans Facts Demographics of Homeless Veterans Incarcerated Veterans Research Briefs Sources FAQ ... VETERANS In May 2007, the Bureau of Justice Statistics released a special report on incarcerated veterans. The ...

377

Background Oriented Schlieren Demonstrations.  

National Technical Information Service (NTIS)

In this project report we present the application of a novel schlieren technique for two different tests. The optical method is referred to as 'Background Oriented Schlieren' (BOS) in the following. Additionally the differences between BOS and an extensio...

H. Richard M. Raffel

2000-01-01

378

Vortex tube optimization theory  

Microsoft Academic Search

The Ranque–Hilsch vortex tube splits a single high pressure stream of gas into cold and warm streams. Simple models for the vortex tube combined with regenerative precooling are given from which an optimization can be undertaken. Two such optimizations are needed: the first shows that at any given cut or fraction of the cold stream, the best refrigerative load, allowing

Jeffery Lewins; Adrian Bejan

1999-01-01

379

Tube plug inspection system  

Microsoft Academic Search

This patent describes a system for inspecting a tube plug defining a chamber therein and having an open end in communication with the chamber, the chamber having disposed therein an expander element having a bore therethrough. It comprises: probe means having a sensor probe connected thereto for inspecting the tube plug, the probe means capable of being connected to the

W. E. Pirl; E. A. Ray; A. M. Costlow; C. H. Jr. Roth; F. X. Gradich; D. A. Chizmar

1992-01-01

380

Steam generator tube failures  

Microsoft Academic Search

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

P. E. MacDonald; V. N. Shah; L. W. Ward; P. G. Ellison

1996-01-01

381

Memory Tube Diffusion Studies.  

National Technical Information Service (NTIS)

Memory tubes were devised to sample the gas composition in the Space Shuttle Main Engine (SSME) duct at many locations (33-100) using only a few mass spectrometers. The feasibility of this technique was evaluated by examining the capability of long tubes ...

L. R. Martin R. A. Hertz R. B. Cohen R. N. Abernathy

1988-01-01

382

Tracheostomy tube - eating  

MedlinePLUS

Most people with a tracheostomy tube will be able to eat normally. However, swallowing food or liquid may feel differently. ... When you get your tracheostomy tube, or trach, you will not be able ... Instead, you will get nutrients through an IV (a intravenous ...

383

Photoelectric Electron Tubes  

Microsoft Academic Search

Three electrode tubes containing alkali vapor metals or vapor of alloys of alkali metals possessing low ionizing potentials and the characteristics of a photoelectric cell give remarkable results as detectors both in the plain and the oscillating condition with 10 volts on the plate, these detectors are extremely sensitive, at least three times that of the gas content tube. The

H. A. Brown; C. T. Knipp

1922-01-01

384

Pyrotechnic Tubing Connector  

NASA Technical Reports Server (NTRS)

Tool forms mechanical seal at joint without levers or hydraulic apparatus. Proposed tool intended for use in outer space used on Earth by heavily garbed workers to join tubing in difficult environments. Called Pyrotool, used with Lokring (or equivalent) fittings. Piston slides in cylinder when pushed by gas from detonating pyrotechnic charge. Impulse of piston compresses fittings, sealing around butting ends of tubes.

Graves, Thomas J.; Yang, Robert A.

1988-01-01

385

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

386

NEI You Tube Videos: Amblyopia  

MedlinePLUS

Home » NEI YouTube Videos » Amblyopia NEI YouTube Videos: Amblyopia NEI YouTube Home | Age-Related Macular Degeneration | Amblyopia | Animations | Blindness | Cataracts | Convergence Insufficiency | Diabetic Eye Disease | Dilated Eye Exam | Dry Eye | For ...

387

Unitarity and singular backgrounds  

NASA Astrophysics Data System (ADS)

We compute the graviton Kaluza-Klein spectrum on a gravity-dilaton background with a naked singularity for all possible boundary conditions at the singularity which are consistent with unitary evolution. We apply methods from nonrelativistic quantum mechanics with singular Schrödinger potentials. In general, the spectrum contains a tachyon, a sign of instability. Only for a particular boundary condition at the singularity is the spectrum free of tachyons. In this case, the lowest-lying graviton mode is massless. We argue that this result will also hold for other backgrounds with similar geometry near the curvature singularity. We complete our study with a brief discussion on radion perturbations and the Higgs mechanism on this singular background.

Brouzakis, Nikolaos; Quiros, Mariano

2013-11-01

388

High voltage capacitors for low background experiments  

NASA Astrophysics Data System (ADS)

Low background experiments place stringent constraints on amount of radioactive impurities in the materials used for their assembly. Often these are in conflict with the constraints placed on the materials by their roles in the experiment. This is especially true for certain electronic components. A high value, high voltage capacitor for use in low background experiments has been developed from specially selected radiopure materials. Electroformed copper foils are separated by polyethylene napthalate (PEN) foils and supported within a PTFE teflon spiral coil tube. The electrical performance as well as radiopurity are scrutinized here. With some minor modifications to tune the performance for the application, this capacitor can be well suited for a variety of applications in low background experiments. Here the use of the capacitor for high voltage (HV) decoupling in the operation of high purity germanium (HPGe) detectors is demonstrated.

O'Shaughnessy, C.; Andreotti, E.; Budjáš, D.; Caldwell, A.; Gangapshev, A.; Gusev, K.; Hult, M.; Lubashevskiy, A.; Majorovits, B.; Schönert, S.; Smolnikov, A.

2013-05-01

389

The Cosmic Background Explorer  

NASA Technical Reports Server (NTRS)

The Cosmic Background Explorer (CBE), NASA's cosmological satellite which will observe a radiative relic of the big bang, is discussed. The major questions connected to the big bang theory which may be clarified using the CBE are reviewed. The satellite instruments and experiments are described, including the Differential Microwave Radiometer, which measures the difference between microwave radiation emitted from two points on the sky, the Far-Infrared Absolute Spectrophotometer, which compares the spectrum of radiation from the sky at wavelengths from 100 microns to one cm with that from an internal blackbody, and the Diffuse Infrared Background Experiment, which searches for the radiation from the earliest generation of stars.

Gulkis, Samuel; Lubin, Philip M.; Meyer, Stephan S.; Silverberg, Robert F.

1990-01-01

390

Cosmic Microwave Background  

NSDL National Science Digital Library

In this lesson, students explore the cosmic microwave background to understand why it permeates the universe and why it peaks as microwave radiation. Students should be able to explain that the origin of the background radiation is the uniform thermal radiation of the big bang and that the radiation produced was evenly distributed around the small early universe, causing it to permeate today's universe. This activity is part of the Cosmic Times teachers guide and is intended to be used in conjunction with the 1965 Cosmic Times Poster.

391

What Are the Treatments for Neural Tube Defects?  

MedlinePLUS

... abnormalities in the skull and face. Treatment for spina bifida depends on the severity of the condition and ... depending on the severity or complications. 1 Open spina bifida. An infant with myelomeningocele, in which the spinal ...

392

Alexia and the Neural Basis of Reading.  

ERIC Educational Resources Information Center

The historical background of alexia (loss or impairment of the ability to comprehend written or printed language based on damage to the brain) is reviewed, classification and symptomatology considered, theories on the involvement of right hemisphere reading are noted, and the neural basis of reading is postulated. (CL)

Benson, D. Frank

1984-01-01

393

Image intensifier tube  

US Patent & Trademark Office Database

An image intensifier tube includes a photocathode (20) with an active layer (52) providing an electrical spectral response to photons of light. The photocathode (20) also includes integral spacer structure (42) which extends toward and physically touches a microchannel plate (22) of the image intensifier tube in order to establish and maintain a desirably precise and fine-dimension spacing distance "G" between the photocathode and the microchannel plate. A method of making the photocathode and a method of making the image intensifier tube are described also.

2002-10-15

394

Targets, backgrounds, and discrimination  

Microsoft Academic Search

The present volume discusses a model-based aircraft identification technique, target intensity and angle scintillations, spatiotemporal nonstationary scene generation, an overview of the Strategic Scene Generation Model (SSGM), nuclear backgrounds for SSGM, and an atmospheric and transmittance code for 50-300 km altitudes. Also discussed are a data base for airborne target signatures, the auroral module of the Strategic High Altitude Radiance

J. S. Accetta; G. H. Kelley

1992-01-01

395

Cosmic microwave background radiation  

Microsoft Academic Search

The cosmic microwave background radiation (CMBR) is widely interpreted as the thermal afterglow of a hot big bang. Measurements of the CMBR intensity as a function of frequency constrain the history of cosmic energetics. Measurements of the anisotropy in the CMBR temperature provide a snapshot of the distribution of fluctuations in the gravitational potential at the earliest stages of cosmic

Lyman Page; David Wilkinson

1999-01-01

396

The Cosmic Background Radiation  

Microsoft Academic Search

We review the current status of experimental data for spectral distortions and angular anisotropies of the cosmic microwave background, as well as discussing the relevant physical processes. This is one of a number of new articles in astrophysics and cosmology which will appear in the 1996 Review of Particle Properties (Phys. Rev. D. in press). Other relevant reviews include: \\

G. F. Smoot; D. Scott

1996-01-01

397

The other backgrounds  

Microsoft Academic Search

The significance of the cosmic microwave background or CMB (3K, ther- mal, relict, black body, isotropic, etc) radiation in confirming a hot big bang model of the early Universe and in setting precise values of many of the parameters of that model is widely known and has recently been enhanced by the results of three years of operation of the

Virginia Trimble

2006-01-01

398

Iran: The Background.  

National Technical Information Service (NTIS)

The set is composed of three reports which are also available individually from NTIS. The set was assembled to provide scholars and other interested persons with historical background to the U.S.-Iran crisis of 1979-80. ;Titles included in the set are: IR...

1979-01-01

399

Genes, lineages and the neural crest: a speculative review.  

PubMed Central

Sensory and sympathetic neurons are generated from the trunk neural crest. The prevailing view has been that these two classes of neurons are derived from a common neural crest-derived progenitor that chooses between neuronal fates only after migrating to sites of peripheral ganglion formation. Here I reconsider this view in the light of new molecular and genetic data on the differentiation of sensory and autonomic neurons. These data raise several paradoxes when taken in the context of classical studies of the timing and spatial patterning of sensory and autonomic ganglion formation. These paradoxes can be most easily resolved by assuming that the restriction of neural crest cells to either sensory or autonomic lineages occurs at a very early stage, either before and/or shortly after they exit the neural tube.

Anderson, D J

2000-01-01

400

Evolvable Neural Software System  

NASA Technical Reports Server (NTRS)

The Evolvable Neural Software System (ENSS) is composed of sets of Neural Basis Functions (NBFs), which can be totally autonomously created and removed according to the changing needs and requirements of the software system. The resulting structure is both hierarchical and self-similar in that a given set of NBFs may have a ruler NBF, which in turn communicates with other sets of NBFs. These sets of NBFs may function as nodes to a ruler node, which are also NBF constructs. In this manner, the synthetic neural system can exhibit the complexity, three-dimensional connectivity, and adaptability of biological neural systems. An added advantage of ENSS over a natural neural system is its ability to modify its core genetic code in response to environmental changes as reflected in needs and requirements. The neural system is fully adaptive and evolvable and is trainable before release. It continues to rewire itself while on the job. The NBF is a unique, bilevel intelligence neural system composed of a higher-level heuristic neural system (HNS) and a lower-level, autonomic neural system (ANS). Taken together, the HNS and the ANS give each NBF the complete capabilities of a biological neural system to match sensory inputs to actions. Another feature of the NBF is the Evolvable Neural Interface (ENI), which links the HNS and ANS. The ENI solves the interface problem between these two systems by actively adapting and evolving from a primitive initial state (a Neural Thread) to a complicated, operational ENI and successfully adapting to a training sequence of sensory input. This simulates the adaptation of a biological neural system in a developmental phase. Within the greater multi-NBF and multi-node ENSS, self-similar ENI s provide the basis for inter-NBF and inter-node connectivity.

Curtis, Steven A.

2009-01-01

401

Sip1 mediates an E-cadherin-to-N-cadherin switch during cranial neural crest EMT  

PubMed Central

The neural crest, an embryonic stem cell population, initially resides within the dorsal neural tube but subsequently undergoes an epithelial-to-mesenchymal transition (EMT) to commence migration. Although neural crest and cancer EMTs are morphologically similar, little is known regarding conservation of their underlying molecular mechanisms. We report that Sip1, which is involved in cancer EMT, plays a critical role in promoting the neural crest cell transition to a mesenchymal state. Sip1 transcripts are expressed in premigratory/migrating crest cells. After Sip1 loss, the neural crest specifier gene FoxD3 was abnormally retained in the dorsal neuroepithelium, whereas Sox10, which is normally required for emigration, was diminished. Subsequently, clumps of adherent neural crest cells remained adjacent to the neural tube and aberrantly expressed E-cadherin while lacking N-cadherin. These findings demonstrate two distinct phases of neural crest EMT, detachment and mesenchymalization, with the latter involving a novel requirement for Sip1 in regulation of cadherin expression during completion of neural crest EMT.

Rogers, Crystal D.; Saxena, Ankur

2013-01-01

402

PE on YouTube--Investigating Participation in Physical Education Practice  

ERIC Educational Resources Information Center

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…

Quennerstedt, Mikael

2013-01-01

403

Steam Generator Tube Failures.  

National Technical Information Service (NTIS)

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) react...

L. W. Ward P. E. MacDonald P. G. Ellison V. N. Shah

1996-01-01

404

Integrated structure vacuum tube  

NASA Technical Reports Server (NTRS)

High efficiency, multi-dimensional thin film vacuum tubes suitable for use in high temperature, high radiation environments are described. The tubes are fabricated by placing thin film electrode members in selected arrays on facing in