Gonadectomy increases neurogenesis in the male adolescent rhesus macaque hippocampus.

New neurons are continuously produced in the subgranular zone of the adult hippocampus and can modulate hippocampal plasticity across life. Adolescence is characterized by dramatic changes in sex hormone levels, and social and emotional behaviors. It is also an age for increased risk of psychiatric disorders, including schizophrenia, which may involve altered hippocampal neurogenesis. The extent to which testosterone and other testicular hormones modulate hippocampal neurogenesis and adolescent behavioral development is unclear. This study aimed to determine if removal of testicular hormones during adolescence alters neurogenesis in the male rhesus macaque hippocampus. We used stereology to examine levels of cell proliferation, cell survival and neuronal differentiation in late adolescent male rhesus macaques (4.6-yrs old) that had previously been gonadectomized or sham operated prior to puberty (2.4-yrs old). While the absence of adolescent testicular hormones had no effect on cell proliferation, cell survival was increased by 65% and indices of immature neuronal differentiation were increased by 56% in gonadectomized monkeys compared to intact monkeys. We show for the first time that presence of circulating testicular hormones, including testosterone, may decrease neuronal survival in the primate hippocampus during adolescence. Our findings are in contrast to existing studies in adults where testosterone tends to be a pro-survival factor and demonstrate that testicular hormones may reduce hippocampal neurogenesis during the age typical of schizophrenia onset.

Maternal serum S100 protein in normal and Down syndrome pregnancies.

Protein S100 is a low molecular weight (10-12 kD) calcium-binding protein the beta subunit of which is coded for at the 22.2-22.3 region of the long arm of chromosome 21. This region has also been shown to be responsible for the phenotypic expression of Down syndrome. Previous studies demonstrated increased immunoreactivity to protein S100 in brain tissue from adults with Down syndrome. We have previously observed a higher concentration of S100 protein in the fetal blood of trisomy 21 fetuses compared with normal subjects. The aim of this study was therefore to investigate the use of measuring S100 protein concentration in maternal blood for Down syndrome screening. Maternal blood was taken at the time of chorionic villus sampling or cordocentesis (11-38 weeks' gestation) for fetal karyotyping. Protein S100 was measured by a two-site immunoradiometric assay (S-100 IRMA, Sangtec). There was no significant difference in the concentration of maternal S100 protein between normal and trisomy 21 pregnancies (p<0.10). Moreover, there was no significant association between maternal serum S100 protein concentration and gestational age (r(s)=0.27, p=0.07), maternal age (r(s)=-0.17, p=0.7) or maternal weight (r(s)=-0.013, p=0.9). This study shows that measurement of maternal serum S100 protein concentration does not appear to have a value in Down syndrome screening.

Maternal serum alpha-fetoprotein in fetal neural tube and abdominal wall defects at 10 to 14 weeks of gestation.

Maternal serum alpha-fetoprotein concentration was determined in nine pregnancies with fetal anencephaly, seven with exomphalos containing liver, two with spina bifida and 100 normal controls at 10 to 14 weeks of gestation. The median alpha-fetoprotein in the group with fetal anencephaly and exomphalos was significantly higher than in normal fetuses but the sensitivity of this test is likely to be only about 30% for a false positive rate of 5%.

Maternal serum free beta-hCG at 10 to 14 weeks of gestation in trisomic twin pregnancies.

Maternal serum free beta-hCG was measured at 10 to 14 weeks of gestation in 136 normal twin pregnancies and in 12 twin pregnancies where one or both fetuses had trisomy 21. The values were compared with a normal range from 4181 singleton pregnancies. In the normal twins the median free beta-hCG (65 ng/mL) was about twice as high as in singletons (34 ng/mL z = -12.1, P < 0.0001). In the trisomy 21 group the median free beta-hCG (95 ng/mL) was significantly higher than in normal twins (z = 2.1, P < 0.05). However, only one of the trisomic pregnancies had a level above the 95th centile. In twin pregnancies maternal serum free beta-hCG at 10 to 14 weeks of gestation is unlikely to be useful in the prediction of fetal trisomy 21.

Maternal serum inhibin-A and free beta-hCG concentrations in trisomy 21 pregnancies at 10 to 14 weeks of gestation.

OBJECTIVE: To determine the relation between maternal serum inhibin-A and free beta-hCG concentrations in chromosomally normal pregnancies and to compare the two biochemical markers for their sensitivity in identifying trisomy 21 pregnancies. SAMPLE: Inhibin-A and free beta-hCG were measured in maternal serum samples from 800 chromosomally normal singleton pregnancies at 10 to 14 weeks of gestation and 76 singleton pregnancies with fetal trisomy 21. RESULTS: In the normal group maternal serum inhibin-A was significantly associated with both maternal weight and gestational age (F = 11.2, P < 0.0001). In pregnancies with trisomy 21 the maternal serum inhibin-A and free beta-hCG concentrations were significantly increased (mean difference inhibin = 0.51 SD, F = 18, P < 0.0001 and mean difference free beta-hCG = 1.13 SD, F = 80, P < 0.0001). For a 5% false positive rate, the sensitivity of maternal serum free beta-hCG in identifying pregnancies with trisomy 21 was 28.9% compared with 12.8% for maternal serum inhibin-A. Delta inhibin-A was significantly associated with delta-free beta-hCG (r = 0.345, P < 0.01) and the deviation from the normal mean for free beta-hCG was significantly greater than the deviation for inhibin-A (t = 4.0, P < 0.0001). For a 5% false positive rate, the sensitivity achieved by combining information from delta inhibin-A and delta free beta-hCG was similar to the sensitivity of free beta-hCG alone (30.3% compared with 28.9%). CONCLUSION: At 10 to 14 weeks of gestation fetal trisomy 21 is associated with increased maternal serum inhibin-A and free beta-hCG levels. However, the degree of elevation of inhibin-A is less than that of free beta-hCG, and there is a significant association between levels of the two proteins. The sensitivity for trisomy 21 achieved with the combination of maternal serum inhibin-A and free beta-hCG is not significantly different from that achieved with maternal serum free beta-hCG alone.

Presence of the 'lemon' sign in fetuses with spina bifida at the 10-14-week scan.

In three cases of lumbosacral spina bifida diagnosed at 12, 13 and 14 weeks of gestation there was an associated lemon sign, or scalloping of the frontal bones, and in one case the fetal nuchal translucency was increased. In a multicenter ultrasound screening study at 10-14 weeks there were 61,972 singleton pregnancies including 29 cases of spina bifida, none of which was diagnosed at the routine first-trimester scan, but 28 of the 29 cases were detected by ultrasonography at 16-22 weeks; in one case the diagnosis was missed at the 20-week scan and the defect was identified at 32 weeks during a scan for localization of the placenta. The fetal nuchal translucency was above the 95th centile in only one of the cases (3.4%). It is possible that the majority of fetuses with spina bifida have a lemon sign in the first trimester, but the sensitivity of the 10-14-week scan in the diagnosis of spina bifida and the prevalence of the lemon sign at this gestation will only be established by further studies incorporating early systematic examination of the head and spine.

Fetal karyotyping in twin pregnancies: selection of technique by measurement of fetal nuchal translucency.

OBJECTIVE: To examine the usefulness of selecting the appropriate technique for fetal karyotyping in twin pregnancies by using maternal age and fetal nuchal translucency thickness to determine risk for chromosomal defects in each fetus. SETTING: Fetal Medicine Centre, London, United Kingdom. SUBJECTS: Sixty-seven twin pregnancies identified at the time of an ultrasound scan for determination of fetal nuchal translucency thickness, where the parents requested karyotyping. INTERVENTION: The risk for chromosomal defects in each fetus was calculated from the maternal age and fetal nuchal translucency thickness at 10 to 14 weeks of gestation. If the estimated risk for either fetus was 1 in 50 or greater, chorion villus sampling was the method of choice, whereas if the risk was less than 1 in 50 second trimester amniocentesis was performed. RESULTS: The estimated risk for trisomies was more than 1 in 50 in 34 pregnancies and 23.5% of these fetuses were found to be chromosomally abnormal. In contrast, in the 33 low risk pregnancies chromosomal abnormalities were found in only 1.5% of the fetuses. CONCLUSIONS: In twin pregnancies the technique for fetal karyotyping may by selected by calculating the risk for chromosomal abnormality based on maternal age and fetal nuchal translucency thickness.

Fetal heart rate in trisomy 21 and other chromosomal abnormalities at 10-14 weeks of gestation.

Fetal heart rate was measured routinely as part of a prospective study examining the efficacy of screening for trisomy 21 by fetal nuchal translucency thickness and maternal age. In 6903 normal singleton pregnancies the fetal heart rate decreased from a mean of 171 bpm at 10 weeks of gestation to 156 bpm at 14 weeks (r = 0.413, p < 0.0001). In 85 trisomy 21 pregnancies, the mean heart rate was significantly higher than in the normal group (mean difference 0.67 SD, 95% confidence interval 0.42-0.92, t = 5.3, p < 0.001). The fetal heart rate in trisomy 18 and triploid fetuses was significantly lower and in trisomy 13 and Turner syndrome was higher than normal. There was no significant association between delta fetal heart rate and delta nuchal translucency thickness in either the normal (r = -0.018) or the trisomy 21 (r = -0.031) pregnancies. Consequently, the risk for chromosomal defects can be derived by combining data from maternal age, fetal nuchal translucency and fetal heart rate. The effectiveness of screening by this method was examined in a self-selected population with completed pregnancies that had undergone first-trimester scanning. This population contained 6903 normal and 29 trisomy 21 fetuses. For a false-positive rate of about 5%, the sensitivity for trisomy 21 was 48% by maternal age, 26% by fetal heart rate, 72% by nuchal translucency thickness, 59% by maternal age and fetal heart rate, 76% by maternal age and nuchal translucency thickness and 83% by a combination of maternal age, nuchal translucency thickness and fetal heart rate.

Single uterine entry for genetic amniocentesis in twin pregnancies.

In 176 diamniotic twin pregnancies at 10-20 weeks of gestation, amniotic fluid for cytogenetic studies was successfully obtained from both sacs by the use of a single uterine entry. There were no cases of discordancy between sex at amniocentesis and birth. There were six pregnancies with fetal unbalanced chromosomal defects; in one pregnancy both fetuses were abnormal and in five pregnancies only one fetus was abnormal. The total fetal loss rate was 5.7% (20 of 352 fetuses), including six (1.7%) terminations or selective fetocides and 14 (4.0%) spontaneous deaths. In the 176 pregnancies there were five (2.8%) with no survivors, including one termination and four (2.3%) spontaneous miscarriages or intrauterine deaths. There are only two (1.1%) pregnancies in which amniocentesis could have contributed directly to the losses and therefore the procedure-related rate of fetal loss may be similar to that in singleton pregnancies. The median gestation at delivery was 37 (range 16-40) weeks and delivery before 32 weeks occurred in 9% of the pregnancies. The birth weight distribution was similar to that reported in singleton pregnancies. This study demonstrates that in twin pregnancies amniotic fluid for cytogenetic studies can be obtained successfully from both sacs by use of a single uterine entry. The risk of fetal loss from this procedure appears to be similar to that in singleton pregnancies.

Screening for fetal trisomy 21 in the first trimester of pregnancy: maternal serum free beta-hCG and fetal nuchal translucency thickness.

The aim of this prospective study was to measure the contribution of maternal serum free beta-human chorionic gonadotropin (beta-hCG) in a screening program for fetal trisomy 21 based on fetal nuchal translucency in the first trimester of pregnancy. The maternal serum was collected at the time of the ultrasound scan and assayed without knowledge of the nuchal translucency measurement or karyotype. A total of 2529 pregnancies were examined (normal group, n = 2427; trisomy 21 group, n = 102). Maternal serum free beta-hCG was significantly associated with gestational age and maternal weight. In the trisomy 21 group the free beta-hCG was significantly higher than in the normals, being above the 95th centile in 29% of the cases. There was no significant association between the deviation from the mean for free beta-hCG and nuchal translucency thickness in either the normal or the trisomy 21 groups. When maternal serum free beta-hCG was added to a model based on maternal age and fetal nuchal translucency thickness, the detection rate for trisomy 21 was increased from 80% to 85%.