vendredi 29 janvier 2010

Minimum effective dose of folic acid for food fortification to prevent neural-tube defects

Although a daily supplement of 400 micrograms folic acid has been shown to prevent neural-tube defects (NTD), most women do not take the recommended supplement. Thus, food fortification is to be introduced in the USA and is being considered in the UK. Because of safety concerns, the USA has chosen a level of fortification that will increase the average woman's intake by only 100 micrograms. Such an increase, although safe, may be ineffective; but a trial to assess its efficacy would be unethical. Because women with red-cell folate concentrations above 400 micrograms/L have a very low risk of NTD, we undertook a randomised trial of several folic acid doses to find out how much is needed to reach this protective concentration.

We screened 323 women. 172 with red-cell folate between 150 micrograms/L and 400 micrograms/L were invited to take part in the trial. 121 women were randomly assigned placebo or 100 micrograms, 200 micrograms, or 400 micrograms daily of additional folic acid. Compliance was monitored by having the women sign a dated sheet when taking the tablet. 95 women completed the 6-month study.

There were significant increases in red-cell folate in all folic acid groups. The placebo group showed no significant change. The median incremental changes and median post-treatment concentrations were 67 micrograms/L (95% CI 43-120) and 375 micrograms/L (354-444) in the 100 micrograms/day group, 130 micrograms/L (108-184) and 475 micrograms/L (432-503) in the 200 micrograms/day group, and 200 micrograms/L (125-312) and 571 micrograms/L (481-654) in the 400 micrograms/day group.

A fortification programme that delivered 400 micrograms folic acid daily to women would protect against NTD, but at the expense of unnecessarily high exposure for many people. Delivery of 200 micrograms daily is also effective against NTD and safer for the general population. Based on projections from the positive folate balance in the group that received 100 micrograms daily, this dose taken continually, as it will be in fortified food, will also produce an important decrease in NTD.

Journal Reference:
Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM. 1997. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350:1666–1669.

mardi 26 janvier 2010

Pathobiology and genetics of Neural tube defects

Neural tube defects (NTDs), including spina bifida and anencephaly, are common congenital malformations that occur when the neural tube fails to achieve proper closure during early embryogenesis. Based on epidemiological and clinical data obtained over the last few decades, it is apparent that these multifactorial defects have a significant genetic component to theiretiology that interacts with specific environmental risk factors. The purpose of this review article is to synthesize the existing literature on the genetic factors contributing to NTD risk.

To date, there is evidence that closure of the mammalian neural tube initiates and fuses intermittently at four discrete locations. Disruption of this process at any of these four sites may lead to an NTD, possibly arising through closure site-specific genetic mechanisms. Candidate genes involved in neural tube closure include genes of the folate metabolic pathway, as well as those involved in folate transport.

Although extensive efforts have focused on elucidating the genetic risk factors contributing to the etiology of NTDs, the population burden for these malformations remains unknown. One group at high risk for having children with NTDs is epileptic women receiving antiepileptic medications during pregnancy. Efforts to better understand the genetic factors that may contribute to their heightened risk, as well as the pathogenesis of neural tube closure defects, are reviewed herein.

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Journal Reference:
FINNELL Richard H. et al. Pathobiology and genetics of Neural tube defects. Epilepsia 44 (Suppl. 3):14-23, 2003

Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States

In 1992, the United States Public Health Service recommended that all women of childbearing age consume 400 g of folic acid daily. The Food and Drug Administration authorized the addition of synthetic folic acid to grain products in March 1996 with mandatory compliance by January 1998. The impact of these public health policies on the prevalence of neural tube defects needs to be evaluated. We sought to determine the prevalences of spina bifida and anencephaly during the transition to mandatory folic acid fortification.

Twenty-four population-based surveillance systems were used to identify 5,630 cases of spina bifida and anencephaly from 1995-99. Cases were divided into three temporal categories depending on whether neural tube development occurred before folic acid fortification (January 1995 to December 1996), during optional fortification (January 1997 to September 1998), or during mandatory fortification (October 1998 to December 1999). Prevalences for each defect were calculated for each time period. Data were also stratified by programs that did and did not ascertain prenatally diagnosed cases.

The prevalence of spina bifida decreased 31% (prevalence ratio [PR] = 0.69, 95% confidence interval [CI] = 0.63-0.74) from the pre- to the mandatory fortification period and the prevalence of anencephaly decreased 16% (PR = 0.84, 95% CI = 0.75-0.95). Stratification by prenatal ascertainment did not alter results for spina bifida but did impact anencephaly trends.

The decline in the prevalence of spina bifida was temporally associated with folic acid fortification of US grain supplies. The temporal association between fortification and the prevalence of anencephaly is unclear.

Journal Reference:
L.J. Williams et al. Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Teratology 66:33-39, 2002

It is also possible that because these defects have multiple etiologies, and thus, may follow the multifactorial/threshold model (Fraser, ’98), the combination of factors that results in the development of spina bifida may differ from that for anencephaly. Given differing etiologies, two possible conclusions could be drawn about the relationship between folic acid consumption and these defects. First, the amount of folic acid needed to prevent anencephaly may be higher than the amount needed to prevent spina bifida. The MRC (’91) and Czeizel and Dudas studies (’92) administered 4,000 g and 800 g of folic acid to subjects, respectively. The current level of folic acid fortification mandated by the FDA may not be high enough to prevent cases of anencephaly. Second, there may be a smaller percentage of folic acid-preventable anencephaly cases compared to spina bifida and additional fortification would not contribute to the further prevention of this birth defect.

Anomalous Costochondral Cartilage in Fetal Anencephaly

Anencephaly is a human fetal malformation with absence of brain and calvarium superior to the orbits. The consequent absence of hypothalamus provides a unique model for studying human development, and therefore
skeletal growth, in the absence of hypothalamic hormones and their regulatory functions. To assess the influence of hypothalamic insufficiency on cartilage development, we studied costochondral cartilage sections from eight anencephalic fetuses (18–22 weeks old) and seven controls (16–22 weeks old) with pathologies not directly related to skeletal growth. We found a previously undescribed anomalous organization of the cartilage in the anencephalic. The proliferative chondrocytes showed a disordered appearance with an increased proliferative zonal length (156 6 28 mm in anencephalic fetuses vs. 103 6 14 mm in controls, p 5 0.006) and a concomitant decrease in the maturing portion, where
cells form ordered isogenic groups (58 6 13 mm in anencephalic fetuses vs. 93 6 19 mm in controls, p 5 0.003).
In addition, cell density was significantly decreased in the proliferating and maturing zones in the anencephalic cases (84 6 21 vs. 130 6 21 cells/40 mm2 in proliferating zone; 53 6 8 vs. 94 6 8 in maturing portion,
p , 0.005). These alterations in the developing cartilage of the anencephalic may contribute to the observed growth retardation in these fetuses and reflect modifications in pituitary hormones and growth factors resulting from reduction in hypothalamopituitary function.

Journal Reference:
Garcia-Ramirez M, Toran N, Carrascosa A, Audi L. Anomalous Costochondral Cartilage in Fetal Anencephaly. Pediatr Dev Pathol. 2000 May-Jun;3(3):256-63.

Epidemiology of Neural Tube Defects

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

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Journal Reference:
Frey, Lauren; Hauser, W. Allen. Epidemiology of Neural Tube Defects. Epilepsia, Volume 44, Supplement 3, June 2003 , pp. 4-13(10)

lundi 25 janvier 2010

Impact of Prenatal Diagnosis and Elective Termination on the Prevalence of Selected Birth Defects in Hawaii

This study examined the effect of prenatal diagnosis and elective termination on the prevalence of neural tube defects, oral clefts, abdominal wall defects, and chromosomal anomalies in Hawaii by using actively ascertained surveillance data collected between 1987 and 1996 by the Hawaii Birth Defects Program. Because the Program has nearly universal access to prenatal diagnostic information and to follow-up data on elective terminations, Hawaii is an ideal setting in which to study their effects on prevalence rates of birth defects.
Except for oral clefts, a large proportion of the defects studied were prenatally diagnosed: anencephaly (87%), spina bifida (62%), encephalocele (83%), cleft palate (0%), cleft lip with or without cleft palate (14%), omphalocele (60%), gastroschisis (76%), Down syndrome (43%), trisomy 18 (61%), and trisomy 13 (40%). The effect of elective terminations on the birth prevalence rates for most of these birth defects was significant. Including electively terminated cases in the calculations of birth prevalence rates increased the rates by more than 50% for five of the 10 birth defects studied.

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Journal Reference:
Forrester M.B. Impact of Prenatal Diagnosis and Elective Termination on the Prevalence of Selected Birth Defects in Hawaii. Am J Epidemiol Vol. 148, No. 12, 1998

Conflits d'intérêts entre jumeaux = Discordant anomaly in twin pregnancy

Le risque de perte fœtale spontanée est multiplié par 4 pour la grossesse monochoriale par rapport à la grossesse bichoriale. L'incidence du RCIU sélectif (sRCIU) varie de 12,5 à 25 % selon la définition du retard de croissance. Cette variation s'explique par le mélange entre des syndromes transfuseur-transfusé (STT) purs et des grossesses sans STT avec un sRCIU pur. La pertinence du diagnostic anténatal de sRCIU est faible, la VPP n'étant que de 37 % (NP4). Le Doppler ombilical avec flux diastolique nul (type II) ou avec flux intermittent (type III) est un facteur pronostique de risque de mortalité du fœtus hypotrophe et de lésions cérébrales du fœtus le plus gros (NP3). L'incidence observée des malformations des jumeaux est de 4,05 % versus 2,38 % pour les singletons (RR = 1,7 [IC 95 % 1,47-1,97]). De la même manière, le taux de malformations est supérieur dans les grossesses monochoriales par comparaison aux grossesses bichoriales, 6,33 % versus 3,43 % (RR = 1,8 [IC 95 % 1,3-2,5]) (NP3). Dans la majorité des cas, la malformation ne concerne que l'un des fœtus. Les malformations les plus fréquentes sont celles du système nerveux central (par comparaison aux singletons), du tractus urinaire et les malformations cardiaques (NP3). Les grossesses monozygotes ne sont pas nécessairement phénotypiquement et génétiquement identiques. Il faut proposer un prélèvement du fœtus porteur de la malformation, et secondairement du fœtus apparemment sain en cas d'anomalie chromosomique. Il faut discuter la recherche d'une disomie uniparentale en cas de discordance chromosomique (NP3). Dans le cadre du fœtus acardiaque, un suivi intensif de la taille du fœtus acardiaque, des Doppler et des signes d'insuffisance cardiaque du fœtus « pompe » est indispensable (avis d'expert). Lorsque la malformation met en péril la grossesse, pour les grossesses bichoriales avec anencéphalie de l'un des fœtus, un fœticide sélectif permet d'augmenter l'âge gestationnel à la naissance, au prix d'un taux de fausse couche de 8 % et d'un risque de prématurité de 12 %. Aussi pourrait-il être justifié d'attendre l'évolutivité ou le troisième trimestre pour la réalisation de ce geste (NP3). Dans la grossesse monochoriale, il faut privilégier l'occlusion funiculaire par coagulation à la pince bipolaire et attendre l'âge gestationnel d'au moins 18 semaines (NP4). Le principal risque est la rupture prématurée des membranes de 20 %. L'analyse actuelle de la littérature ne permet pas de dégager des indications formelles de geste fœticide hormis les rares situations de fœtus acardiaque avec décompensation du fœtus sain. La situation très particulière du sRCIU fait l'objet d'un essai randomisé. La participation active des patientes au choix thérapeutiques est indispensable (avis d'expert).

Source: Cat.Inist

Journal Reference:
FAVRE R. Conflits d'intérêts entre jumeaux. Journal de gynécologie obstétrique et biologie de la reproduction. 2009, vol. 38, no8, SUP, [Note(s): S90-S99] (51 ref.)

vendredi 22 janvier 2010

Zoonotic Ljungan Virus Associated with Central Nervous System Malformations in Terminated Pregnancy

The Ljungan virus (LV) has been shown to cause central nervous system malformations in laboratory mouse models. The LV has also been associated with intrauterine fetal death in humans. We investigated the presence of LV in a series of human hydrocephaly and anencephaly cases from elective abortions.

A series of elective abortions owing to hydrocephaly, anencephaly, and similarly aged trisomy 21 elective abortions as controls were examined for LV by immunohistochemistry and real time RTPCR. A second experiment involved newborn mice exposed to LV. RESULTS: LV was diagnosed in 9 of 10 cases with hydrocephalus and in 1 of 18 trisomy 21 controls by immunohistochemistry. Five of nine cases with anencephaly had a positive PCR result, whereas none of the 12 trisomy 21 available for PCR testing had a positive result. The 47 newborn mice exposed to LV all developed encephalitis, with eight having hydrocephalus. None of the 52 control animals had encephalitis or hydrocephalus.

The association between LV both hydrocephaly and anencephaly suggests that LV may be playing an important role in AQ3 central nervous system malformations in humans.

"The finding that LV causes anencephaly and hydrocephaly in infected laboratory mice stimulated our interest in studying possible associations between LV and CMS in humans (Samsioe et al., 2006). This small pilot study indicates that LV is associated with a substantial proportion of CMS. The present study demonstrated LV in the majority of hydrocephaly cases and in more than half of the anencephaly cases from elective abortions."

Journal Reference:
Bo Niklasson, et al. Zoonotic Ljungan Virus Associated with Central Nervous System Malformations in Terminated Pregnancy. Birth Defects Research (Part A) 00:000–000, 2009. 2009 Wiley-Liss, Inc.

Mutations in VANGL1 Associated with Neural-Tube Defects

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

Journal Reference:
Kibar Z. et al. Mutations in VANGL1 Associated with Neural-Tube Defects. N Engl J Med 2007;356:1432-7.

Toward understanding the genetic basis of NTDs

Neural tube defects (NTDs) represent a common group of severe congenital malformations that result from failure of neural tube closure during early development. Their etiology is quite complex involving environmental and genetic factors and their underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal studies have recently demonstrated an essential role for the planar cell polarity pathway (PCP) in mediating a morphogenetic process called convergent extension during neural tube formation. Alterations in members of this pathway lead to NTDs in vertebrate models, representing novel and exciting candidates for human NTDs. Genetic studies in NTDs have focused mainly on folate-related genes based on the finding that perinatal folic acid supplementation reduces the risk of NTDs by 60–70%. A few variants in these genes have been found to be significantly associated with an increased risk for NTDs. The candidate gene approach investigating genes involved in neurulation has failed to identify major causative genes in the etiology of NTDs. Despite this history of generally negative findings, we are achieving a rapid and impressive progress in understanding the genetic basis of NTDs, based mainly on the powerful tool of animal models.

Journal Reference:
Kibar Z, Capra V, Gros P. Toward understanding the genetic basis of neural tube defects. Clin Genet 2007: 71: 295–310.

Impact of Prenatal Diagnosis on the Birth Prevalence of NTDs

To determine the impact of prenatal diagnosis on the birth prevalence of neural tube defects (NTDs) in Atlanta during 1990 through 1991.
Methods. Live-born and stillborn infants with NTDs who were at least 20 weeks’ gestation were ascertained by the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based birth defects registry. Prenatally diagnosed NTh-affected pregnancies were ascertamed from the four perinatal centers and the three genetic laboratories operating in Atlanta during 1990 through 1991. Fetal death certificates were also reviewed for potential cases.

During 1990 through 1991, MACDP ascertamed 59 NTh cases, for a birth prevalence of 0.77/1000 live births. During this period, an additional 28 NTDaffected pregnancies were detected prenatally and terminated before 20 weeks’ gestation. The adjusted NTh rate
during 1990 through 1991, which includes prenatally diagnosed cases, was 1.13/1000 live births.

Prenatal diagnosis is making a substantial impact on the birth prevalence of NTDs in Atlanta.
However, since NTD rates in Atlanta were 2 to 2.5 per 1000 live births in 1970, prenatal diagnosis and termination of pregnancy does not completely account for the declining rate of NTDs.

Impact of Prenatal Diagnosis on the Birth Prevalence of Neural Tube Defects, Atlanta, 1990-4991. Helen E. Roberts et al. Pediatrics 1995;96:880-883;

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Children with anencephaly and their families

The project “Children with anencephaly” is leaded by Prof. Dr. Harald Goll, of the Division on Intellectual and Developmental Disabilities of the University of Erfurt / Germany. Since 2003 there has been an ongoing research cooperation with the professorship of theological ethics at the Theological Faculty of the University of Erfurt (Prof. Dr. Josef Römelt) and the integration of parents as experts. Several international conferences on the situation of children with anencephaly and their parents have been held. An interdisciplinary “anencephaly network” with participants from the fields of medicine, philosophy, psychology and law emerged from this activities.
One of the first results of the project was the publication of a book in Spring 2009. “Children with anencephaly and their families” has been published in German and contains articles from participants of the network from different disciplines.

Kinder mit Anenzephalie und ihre Familien

Anenzephalie bedeutet das Fehlen des Großhirns. Es gibt keine Heilung. Die Überlebensdauer der betroffenen Kinder beträgt nur wenige Tage. Die Diagnose wird meist pränatal gestellt. Zunehmend entscheiden sich Eltern, die Schwangerschaft fortsetzen. Sie wollen das Zusammensein mit ihrem Kind bereits vor der Geburt bewusst erleben und in Ruhe Abschied nehmen können. Angesichts der massiven Schädigung des Gehirns und der kurzen Lebenserwartung stellen sich anthropologisch-ethische Grundfragen des Menschseins sowie Fragen nach den Voraussetzungen für Bewusstsein, Wahrnehmung und Empfindung. Hinzu kommt die Entwicklung angemessener Angebote zur Begleitung von Eltern und Kind.

Seit vielen Jahren besteht eine Forschungskooperation der Herausgeber. Daraus entstand ein internationales „Netzwerk Anenzephalie“. Der kulturwissenschaftliche Zugang, die interdisziplinäre Zusammensetzung und die Einbindung betroffener Eltern als Experten in eigener Sache bilden ein zentrales Charakteristikum dieses Forschungsverbundes. Dies dürfte weltweit einzigartig sein.

Daher bietet das Buch Beiträge aus dem Bereich der Medizin, der Sonderpädagogik, der Psychologie sowie der philosophischen und theologischen Ethik. Und es bemüht sich um die Verknüpfung der wissenschaftlichen Diskussion mit den Erfahrungen von Eltern, die ein Kind mit Anenzephalie geboren haben.

Kinder mit Anenzephalie und ihre Familien
Harald Goll / Monika Jaquier / Josef Römelt (Hrsg.)
Bad Heilbrunn, Klinkhardt Verlag, Juli 2009
ISBN-13: 978-3-7815-1663-2

Neogenin and RGMa Control Neural Tube Closure and Neuroepithelial Morphology by Regulating Cell Polarity

In humans, neural tube closure defects occur in 1:1000 pregnancies. The design of new strategies for the prevention of such common defects would benefit from an improved understanding of the molecular events underlying neurulation. Neural fold elevation is a key morphological process that acts during neurulation to drive neural tube closure. However, to date, the molecular pathways underpinning neural fold elevation have not been elucidated. Here, we use morpholino knock-down technology to demonstrate that Repulsive Guidance Molecule (RGMa)-Neogenin interactions are essential for effective neural fold elevation during Xenopus neurulation and that loss of these molecules results in disrupted neural tube closure. We demonstrate that Neogenin and RGMa are required for establishing the morphology of deep layer cells in the neural plate throughout neurulation. We also show that loss of Neogenin severely disrupts the microtubule network within the deep layer cells suggesting that Neogenin-dependent microtubule organization within the deep cells is essential for radial intercalation with the overlying superficial cell layer, thereby driving neural fold elevation. In addition, we show that sustained Neogenin activity is also necessary for the establishment of the apicobasally polarized pseudostratified neuroepithelium of the neural tube. Therefore, our study identifies a novel

Journal Reference:
Nigel Kee et al. Neogenin and RGMa Control Neural Tube Closure and Neuroepithelial Morphology by Regulating Cell Polarity. The Journal of Neuroscience, November 26, 2008 • 28(48):12643–12653

Spontaneous pregnancy outcome after prenatal

Parents are usually told that many anencephalic offspring die in utero or soon after delivery, and many obstetricians offer electivetermination of the pregnancy. Following the personal experience of the first author, a personal website was created with the intentionof providing information and exchanging views with other parents confronted with a prenatal diagnosis of anencephaly. Data werecollected from 211 pregnancies where the parents opted not to terminate pregnancy.

These data revealed that polyhydramnios was a feature in 56 (26%) pregnancies, death in utero in 15 (7%) pregnancies, 72 (34%) babies were born prematurely (<37 weeksof gestation), 113 (53%) at term and 21 (10%) after 42 weeks. Stillbirth, presumably resulting from intrapartum death, occurred in 43 (20%) deliveries. One hundred and fifty-three (72%) ofanencephalic offspring were liveborn, of those, 103 (67%) died within 24 hours but 6/211 survived 6 or more days (maximum28 days). Continuation of pregnancy after a diagnosis of anencephaly is medically safe and should be considered as anoption. Free Fulltext

Journal Reference:
Jaquier M, Klein A, Boltshauser E., Spontaneous pregnancy outcome after prenatal diagnosis of anencephaly, BJOG 2006; 113:951-953

Consciousness without a cerebral cortex: A challenge for neuroscience and medicine

A broad range of evidence regarding the functional organization of the vertebrate brain – spanning from comparative neurology to experimental psychology and neurophysiology to clinical data – is reviewed for its bearing on conceptions of the neural organization of consciousness. A novel principle relating target selection, action selection, and motivation to one another, as a means to optimize integration for action in real time, is introduced. With its help, the principal macrosystems of the vertebrate brain can be seen to form a centralized functional design in which an upper brain stem system organized for conscious function performs a penultimate step in action control. This upper brain stem system retained a key role throughout the evolutionary process by which an expanding forebrain – culminating in the cerebral cortex of mammals – came to serve as a medium for the elaboration of conscious contents. This highly conserved upper brainstem system, which extends from the roof of the midbrain to the basal diencephalon, integrates the massively parallel and distributed information capacity of the cerebral hemispheres into the limited-capacity, sequential mode of operation required for coherent behavior. It maintains special connective relations with cortical territories implicated in attentional and conscious functions, but is not rendered nonfunctional in the absence of cortical input. This helps explain the purposive, goal-directed behavior exhibited by mammals after experimental decortication, as well as the evidence that children born without a cortex are conscious. Taken together these circumstances suggest that brainstem mechanisms are integral to the constitution of the conscious state, and that an adequate account of neural mechanisms of conscious function cannot be confined to the thalamocortical complex alone.

Journal Reference:
Bjorn Merker. Consciousness without a cerebral cortex: A challenge for neuroscience and medicine. BEHAVIORAL AND BRAIN SCIENCES (2007) 30, 63–134 DOI: 10.1017/S0140525X07000891

Proteins called protease-activated receptors (PARs) are required for neural tube closure

During normal embryonic development, a flat sheet of cells that is destined to give rise to the brain and spinal cord thickens and forms a groove with raised sides. Eventually, the sides of the groove fuse, almost like zipping a zipper, to form a hollow structure called the neural tube. If the neural tube does not "zip up" completely, it causes the brain and spinal cord to develop abnormally, resulting in defects that that range in severity from partial paralysis to death. These neural tube defects are relatively common, representing serious problems for 1/1000 live human births.

Details about what drives formation of the neural tube have remained elusive. But now, a study led by Drs. Eric Camerer and Shaun R. Coughlin from the Cardiovascular Research Institute at the University of California, San Francisco has shown that proteins called protease-activated receptors (PARs), which are best known for their role in tissue response to injury in adults, are required for neural tube closure. The researchers found that mice lacking specific PARs exhibited neural tube defects.

Interestingly, specific PARs and the protein that controls them were only active along the edges of the groove where and when the edges of the neural tube fused. These observations led the researchers to hypothesize that this PAR signaling system might sense the integrity of the tissue, as it does in the case of injuries, to regulate the closure of the tube. "Our discovery of molecular events that contribute to neural tube closure in mice might lead to insights into the complex mechanisms underlying human neural tube defects," concludes Dr. Coughlin.

Story Source: Science Daily

Journal Reference:
1.Camerer et al. Local Protease Signaling Contributes to Neural Tube Closure in the Mouse Embryo. Developmental Cell, 2010; 18 (1): 25-38 DOI: 10.1016/j.devcel.2009.11.014