Multisite neural tube closure in humans

We present evidence for multisite NT closure in humans with representative examples of types of NTDs that would be expected if NT closure in humans is similar to experimental mice models. We determine that the majority of NTDs can be classified by the multisite closure model. Further evidence for multisite closure of the NT is apparent in previous epidemiological studies, recognized monogenic disorders, and environmental and teratogenic exposures. Previous reliance on the single-site closure model has resulted in grouping of anomalies, obscuring evidence for multisite NT closure, etiological heterogeneity, varying recurrence risks, and site-specific effects of environmental factors. The NTDs have been previously referred to as being multifactorial, due to multiple genes and environmental factors. Etiological heterogeneity has been demonstrated previously as well. Classification of NTDs by closure site will be beneficial in better defining etiologies and environmental susceptibilities. Similarly, it is apparent to us that genetic variations in closure sequence, rate, and location are most likely monogenic and result in affected embryos being more susceptible to specific environmental factors, such as the effect of folic acid deficiency. Individual closure sites are most likely under the control of specific embryonically expressed genes, whose monogenic nature may not be apparent postnatally. For the disorders such as Meckel-Gruber syndrome and Walker-Warburg syndrome, the monogenic etiology for NTDs in affected individuals is apparent because of associated malformations. There are three important implications of this study: The first is that monogenic mouse models will be helpful in investigating the pathogenesis of NTDs in humans. The homologies between the mouse and human genome may allow linkage studies to be done in some families who have recurrence of NTDs. Second, in order to have useful results from studies of NTDs, NT anomalies need to be accurately described, either by the classical nomenclature (eg, meroacranium) or by referring to the corresponding closure site involvement (eg, closure 2 defect). Special attention needs to be addressed to those NTDs that do not appear to fit into a discrete closure site (eg, midthoracic spina bifida cystica) or laterally displaced NTDs, since they may be due to other etiologies. With improved nutrition, particularly folic acid treatment, specific etiologies for the remaining NTDs may become more apparent. Finally, recurrence risks for NTDs may vary between families based on the closure site affected, and whether or not associated anomalies are present.     

Malignant teratoid medulloepithelioma: a case report

We report the histopathological findings of the anterior cornea from a patient with skin biopsy-proven epidermolysis bullosa simplex. As seen with light microscopy, the cornea had a fibrocellular pannus deep to a thickened epithelial basement membrane. Transmission electron microscopy of the anterior cornea demonstrated a nonhomogeneous basal epithelial layer with abnormal attachment complexes to an irregular, multilaminar basement membrane. The findings of transmission electron microscopy of the bulbar conjunctiva were normal.     

Maternal serum screening for Down syndrome and neural tube defects

OBJECTIVE: Evaluation of maternal serum screening for Down's syndrome (DS) and neural tube defects (NTDs). DESIGN: Longitudinal study. SETTING: Department of Obstetrics and Gynaecology, University Hospital Utrecht, the Netherlands. METHOD: 6362 pregnant women underwent serum screening for DS and (or) NTD between the 15th and 21st weeks of pregnancy between March 1991 and March 1996. Screening was performed using alpha-foetoprotein, unconjugated oestriol, human chorionic gonadotrophin and maternal age. The result of each individual test was a calculated risk for delivering a child with DS and (or) NTD. RESULTS: Nine out of 12 singleton pregnancies of a foetus with DS were detected. To this purpose, 573 women who, according to the serum screening had an increased risk of a child with the abnormality, were offered amniocentesis, which was performed in 471 of them. Two twin pregnancies with a total of 3 DS affected foetuses were also detected; one twin pregnancy of a DS foetus was screen-negative. The one case of spina bifida was screen-positive. The proportion of women eligible for invasive prenatal diagnosis because of maternal age increased from 9% to 25% in the course of the study. Of 1118 women aged > or = 36 years 913 (82%) declined invasive investigation compared with 40% in the general population. CONCLUSION: The results of the maternal serum screening program in Utrecht were comparable with other studies. Maternal serum screening is accepted as an alternative by women above 36 years, and allows to decrease the need for amniocentesis without a significant loss in detection rate.     

Socioeconomic status, neighborhood social conditions, and neural tube defects

OBJECTIVES: This study evaluated the contributions of lower socioeconomic status (SES) and neighborhood socioeconomic characteristics to neural tube defect etiology. The influence of additional factors, including periconceptional multivitamin use and race/ethnicity, was also explored. METHODS: Data derived from a case-control study of California pregnancies from 1989 to 1991. Mothers of 538 (87.8% of eligible) case infants/fetuses with neural tube defects and mothers of 539 (88.2%) nonmalformed infants were interviewed about their SES. Reported addresses were linked to 1990 US census information to characterize neighborhoods. RESULTS: Twofold elevated risks were observed for several SES indicators. Risks were somewhat confounded by vitamin use, race/ethnicity, age, body mass index, and fever but remained elevated after adjustment. A risk gradient was seen with increasing number of lower SES indicators. Women with 1 to 3 and 4 to 6 lower SES indicators had adjusted odds ratios of 1.6 (1.1-2.2) and 3.2 (1.9-5.4), respectively, compared with women with no lower SES indicators. CONCLUSIONS: Both lower SES and residence in a SES-lower neighborhood increased the risk of an neural tube defect-affected pregnancy, with risks increasing across a gradient of SES indicators.     

Maternal smoking, body mass index, and neural tube defects

The Swedish health registries were used to investigate a possible effect on the incidence of neural tube defects (NTDs) of maternal smoking and maternal body mass index (BMI) (kg/m2). Among 1,199,701 infants born in 1983-1993 with known smoking exposure in early pregnancy, 621 infants with NTDs were selected. After controlling for year of birth, maternal age, parity, education level, BMI, and immigrant status (yes/no), a highly significant, protective effect of maternal smoking on the incidence of NTDs was found. The adjusted odds ratios (OR) and (95% confidence intervals (CI)) for maternal smoking among infants with NTDs (total), anencephaly, and spina bifida were 0.75 (0.61-0.91), 0.49 (0.28-0.85), and 0.76 (0.61-0.95), respectively. A protective dose-response effect of smoking was indicated but was not statistically significant. The association between NTDs and maternal BMI found in earlier studies was supported. Women with BMI >26.0 were found to be at higher risk of having an infant with NTD compared with women in other BMI classes (adjusted OR=1.35, 95% CI 1.00-1.83). For women with BMI > or =29, the corresponding odds ratio was 1.29 (0.81-2.05). No obvious explanation was found, either for the detected association between NTDs and BMI, or for the protective effect of maternal smoking.     

Prepregnant weight in relation to risk of neural tube defects

OBJECTIVE: To examine the relation between prepregnant weight and the risk of neural tube defects (NTDs). DESIGN: Data were collected from 1988 to 1994 in a case-control surveillance program of birth defects. SETTING: Study subjects were ascertained at tertiary care centers and birth hospitals in the greater metropolitan areas of Boston, Mass, and Philadelphia, Pa, and in southeastern Ontario. PARTICIPANTS: Cases were 604 fetuses or infants with an NTD identified within 6 months of delivery. Controls were 1658 fetuses or infants with other major malformations identified within 6 months of delivery. For 1992 to 1994, there were 93 control infants without major malformations. MAIN OUTCOME MEASURE: Relative risk of NTDs in infants or fetuses for different maternal weights. RESULTS: Relative to women who weighed 50 to 59 kg, risk of NTDs increased from 1.9 (95% confidence interval [CI], 1.2 to 2.9) for women weighing 80 to 89 kg to 4.0 (95% CI, 1.6 to 9.9) for women weighing 110 kg or more. When women were classified according to daily intake above or below the recommended level of 400 micrograms of folate, approximate threefold increases in risk were estimated for the heaviest weights in both groups. Intakes of 400 micrograms of folate or more reduced risk of NTDs by 40% among women weighing less than 70 kg, but no risk reduction was observed among heavier women. CONCLUSION: The risk of NTDs increased with increasing prepregnant weight, independent of the effects of folate intake.     

Ventrally emigrating neural tube cells differentiate into heart muscle

A population of ventrally emigrating neural tube cells has been shown to migrate along the vagus nerve and contribute to the development of the gastrointestinal tract. Since the vagus also goes to the heart, we sought to determine if these cells migrated into the heart. Neural tube cells were tagged with replication-deficient retroviral vectors containing the LacZ gene, to permanently label their progeny. The virus was microinjected into the lumen of the caudal hindbrain of chick embryos on day 2. Embryos were later processed for the detection of LacZ positive cells. Labeled cells were initially confined to the neural tube. Later, they migrated in association with the vagus nerve into the heart, where they were located in the myocardium. Labeled cells were identified as cardiac muscle cells of non-neural crest origin, with specific markers. It is concluded that some cardiac muscle cells differentiate from the neural tube cells.     

Incidence of neural tube defects in the Magdeburg administrative district

The Magdeburg Register of birth defects includes information on the incidence rate of neural tube defects (NTD) in the city of Magdeburg since 1980, and in the Regierungsbezirk (administrational district) since 1987. The average prevalence of NTD was 16.4 per 10,000 births in the city of Magdeburg, and 12 per 10,000 births in the surrounding counties. Besides of this significant difference between the city and counties, there are conspicuous variations from one year to the next. In 1987 the prevalence of NTD was about 27 per 10,000 births in the city of Magdeburg whereas the observed prevalence in the countryside was about 19 per 10,000 births. Different eating habits and/or increased teratogenic influences in the city may be considered as causes. In 1997 there was also a high rate of incidence of NTD in the city of Magdeburg--16.4 per 10,000 births. The incidence rate of NTD in the counties (about 10 per 10,000) births) is again lower than in the city. Because of these incidence rates, we may assume that the examined population is insufficiently protected by folic acid in the preconceptional stage.     

A role for rhoB in the delamination of neural crest cells from the dorsal neural tube

The differentiation of neural crest cells from progenitors located in the dorsal neural tube appears to involve three sequential steps: the specification of premigratory neural crest cell fate, the delamination of these cells from the neural epithelium and the migration of neural crest cells in the periphery. BMP signaling has been implicated in the specification of neural crest cell fate but the mechanisms that control the emergence of neural crest cells from the neural tube remain poorly understood. To identify molecules that might function at early steps of neural crest differentiation, we performed a PCR-based screen for genes induced by BMPs in chick neural plate cells. We describe the cloning and characterization of one gene obtained from this screen, rhoB, a member of the rho family GTP-binding proteins. rhoB is expressed in the dorsal neural tube and its expression persists transiently in migrating neural crest cells. BMPs induce the neural expression of rhoB but not the more widely expressed rho family member, rhoA. Inhibition of rho activity by C3 exotoxin prevents the delamination of neural crest cells from neural tube explants but has little effect on the initial specification of premigratory neural crest cell fate or on the later migration of neural crest cells. These results suggest that rhoB has a role in the delamination of neural crest cells from the dorsal neural tube.     

Absorption of pteroylpolyglutamates in mothers of infants with neural tube defects

The ability to hydrolyse and absorb pteroylpolyglutamates (PteGlun) included in a standard meal in mothers who had given birth to an infant with a neural tube defect was tested by comparing them with mothers who had not had any infants with this defect. When compared with control mothers working in the research unit in which the study was performed, case mothers had significantly lower baseline serum and erythrocyte folate levels, and smaller increases in serum folate following the meal containing PteGlun. However, all estimates of folate were similar when case mothers were compared with a group of mothers who were friends of the case mothers. The results show that the higher the baseline levels of serum and erythrocyte folate the greater the increase in serum folate after the test meal. Fitting a model for the serum folate response curve resulted in coefficients which differed significantly between case mothers and all control mothers. We conclude that intestinal hydrolysis of PteGlun taken orally is not impaired in mothers who have had infants with neural tube defects when compared with control mothers with similar baseline folate levels, although the curves describing the response to the meal for the two groups do differ significantly. Further investigation is required to determine the mechanism underlying this difference.     

Amniotic fluid B12 and folate levels associated with neural tube defects

Abnormal marrow signal and marrow enhancement have not been described in association with benign avulsive cortical irregularity. We present the case of an 11-year-old gymnast with such findings that partially resolved over time. The marrow MR abnormalities are believed to represent an extension or spectrum of findings associated with avulsive cortical irregularity, and should not instantly suggest infection or malignancy, as has been previously indicated. Careful and close clinical and radiological follow-up is required to confirm its benign course.     

Immunohistochemistry diagnosis of fungal infections

BACKGROUND: A potential beneficial outcome of treatment with certain of the atypical neuroleptics is the reduced risk of cognitive impairment, stemming from purported low affinity for cholinergic receptors. In vitro experiments have shown that clozapine is highly anticholinergic and risperidone is minimally so. In vivo tests of the anticholinergic burden imposed by these medications and its potential cognitive consequences are needed. This study examines anticholinergic burden in schizophrenia patients taking clozapine and risperidone and tests whether this burden is associated with cognitive deficits. METHOD: Serum anticholinergic levels were determined in a sample of 22 chronic schizophrenia patients using the radioreceptor assay method of Tune and Coyle (1980). Fifteen patients received clozapine; 7 received risperidone. Mean +/- SD age of the sample, comprising 12 men and 10 women (68% white), was 44.7 +/- 8.4 years. Mean +/- SD age at onset of schizophrenia illness was 23.5 +/- 7.4 years. Two anticholinergic assays based on blood samples collected 1 week apart were available on each patient. RESULTS: Data indicated that clozapine patients had significantly (p < .001) higher anticholinergic levels at both collection points, and levels for both drugs remained stable over time. The clozapine and risperidone patients had essentially equivalent scores on the cognitive measure. CONCLUSION: These data suggest that anticholinergicity distinguishes clozapine and risperidone in vivo but that this effect is not associated with differences in global cognitive functioning. Results suggest that clozapine, despite producing moderately high in vivo serum anticholinergic levels, still holds clinical advantage over standard neuroleptics in terms of cognitive side effects. Reasons for this lowered risk of cognitive impairment are discussed.