Expression of Dystrophin Dp71 Splice Variants Is Temporally Regulated During Rodent Brain Development.

Dystrophin Dp71 is the major product of the Duchenne muscular dystrophy (DMD) gene in the brain, and its loss in DMD patients and mouse models leads to cognitive impairments. Dp71 is expressed as a range of proteins generated by alternative splicing of exons 71 to 74 and 78, classified in the main Dp71d and Dp71f groups that contain specific C-terminal ends. However, it is unknown whether each isoform has a specific role in distinct cell types, brain regions, and/or stages of brain development. In the present study, we characterized the expression of Dp71 isoforms during fetal (E10.5, E15.5) and postnatal (P1, P7, P14, P21 and P60) mouse and rat brain development. We finely quantified the expression of several Dp71 transcripts by RT-PCR and cloning assays in samples from whole-brain and distinct brain structures. The following Dp71 transcripts were detected: Dp71d, Dp71d∆71, Dp71d∆74, Dp71d∆71,74, Dp71d∆71-74, Dp71f, Dp71f∆71, Dp71f∆74, Dp71f∆71,74, and Dp71fΔ71-74. We found that the Dp71f isoform is the main transcript expressed at E10.5 (> 80%), while its expression is then progressively reduced and replaced by the expression of isoforms of the Dp71d group from E15.5 to postnatal and adult ages. This major finding was confirmed by third-generation nanopore sequencing. In addition, we found that the level of expression of specific Dp71 isoforms varies as a function of postnatal stages and brain structure. Our results suggest that Dp71 isoforms have different and complementary roles during embryonic and postnatal brain development, likely taking part in a variety of maturation processes in distinct cell types.

Neuroimaging Findings in Fetal Hemimegalencephaly: Case Study and Review.

BACKGROUND: Limited information exists in the prenatal literature regarding the neuroimaging features of fetal hemimegalencephaly. SUMMARY: This report describes ultrasound and magnetic resonance imaging (MRI) findings in a second-trimester fetus with an isolated, severe form of hemimegalencephaly. The most prominent imaging findings included unilateral enlarged cerebral hemisphere and ipsilateral ventriculomegaly causing cerebral asymmetry, midline shift, and macrocephaly. Abnormal cortical development imaging signs were also evident. A literature review encompassing 23 reports describing 36 cases, including ours, is presented. KEY MESSAGES: Characteristic ultrasound findings for the diagnosis of hemimegalencephaly are not always apparent prenatally. Asymmetric ventriculomegaly emerges as the most common but nonspecific presenting feature during routine second- or third-trimester ultrasound scans. Subsequent high-resolution prenatal neurosonography and fetal MRI facilitate definitive prenatal diagnosis, showcasting associated features primarily related to cortical migration, differentiation, and maturation. Postnatally, the prognosis is poor due to intractable seizures, hemiplegia, and progressive neurodevelopmental delay.

Fetal neurosurgery.

Among fetal surgical procedures, neurosurgery stands out due to the number of cases and the possibility of developing new procedures that can be performed in the fetal period. To perform fetal neurosurgical procedures, there is a need for specialized centers that have experts in the diagnosis of fetal pathologies and a highly complex obstetrics service with specialized maternal-fetal teams associated with a pediatric neurosurgery center with expertise in the diverse pathologies of the fetus and the central nervous system that offers multidisciplinary follow-up during postnatal life. Services that do not have these characteristics should refer their patients to these centers to obtain better treatment results. It is essential that the fetal neurosurgical procedure be performed by a pediatric neurosurgeon with extensive experience, as he will be responsible for monitoring these patients in the postnatal period and for several years. The objective of this manuscript is to demonstrate the diagnostic and treatment possibilities, in the fetal period, of some neurosurgical diseases such as hydrocephalus, tumors, occipital encephalocele, and myelomeningocele.

First-trimester ventriculomegaly in fetuses with callosal agenesis: Cause or association?

The sonographic findings in four fetuses presenting with ventriculomegaly at first-trimester ultrasound that were subsequently diagnosed as having agenesis of the corpus callosum (ACC) are described. The diagnosis of early ventriculomegaly was suspected subjectively by identification of increased cerebrospinal fluid within the lateral ventricles and confirmed by measuring choroid plexus-to-lateral ventricle length and area ratios. Subsequent scans revealed complete ACC in two cases and partial ACC in the other two. This report adds to the increasing evidence suggesting that first-trimester ventriculomegaly is a strong sonographic marker of underlying brain anomalies, including less evident malformations such as ACC. Detailed second-trimester fetal neurosonography in those women continuing their pregnancies should be performed.

Basic sonographic examination of the fetal brain at 11-13 weeks' gestation: Rationale for a simple and reliable four-step technique.

The widespread incorporation of first-trimester scanning between 11 and 13 weeks' gestation has shifted from the screening of chromosomal abnormalities, mainly by measuring nuchal translucency thickness and visualization of the nasal bone, to a more detailed study of the fetal anatomy leading to early detection of several structural congenital anomalies. This goal can be improved by the routine and focused sonographic assessment of specific anatomic planes and the identification of distinctive landmarks that can help disclosing a particular, non-evident condition. In this article we present the basis for a basic, early examination of the fetal brain during screening using a four-step technique, which can be readily incorporated during the first-trimester scan. The technique includes the focused visualization of the cranial contour, choroid plexuses of the lateral ventricles and midline, aqueduct of Sylvius, brainstem, fourth ventricle, and the choroid plexus of the fourth ventricle. The rationale for this approach is presented and discussed.

¿Podría contribuir la resonancia magnética a detectar la ventriculomegalia fetal aislada aparte de otras anormalidades?

Objetivo. Determinar el papel de la resonancia magnética (RM) cerebral en fetos que presentan ventriculomegalia aislada (VMA) en la evaluación ecográfica del cerebro fetal. Métodos. Se evaluaron retrospectivamente los hallazgos por ecografía y RM de 197 fetos diagnosticados con VMA entre noviembre de 2018 y noviembre de 2020. Se excluyeron los fetos con cariotipos anormales, anomalías adicionales o etiologías relacionadas a ventriculomegalia. Se comparó los resultados de ecografía y RM tanto en términos de medidas ventriculares medias como de grado de VMA. Resultados. Las mediciones de la RM fueron significativamente mayores en la VMA leve (10,33±0,38 mm frente a 11,11±0,51 mm, p<0,001) en comparación con la ecografía. En la VMA leve, la RM midió los ventrículos más anchos que la ecografía, con una diferencia media de 0,78 mm. No hubo diferencias significativas en las mediciones por ecografía y RM en cuanto a los valores medios de la VMA moderada y grave. Hubo buena concordancia entre la ecografía y la RM en la detección de la gravedad de la VMA derecha, izquierda y la media (Κ=0,265, Κ=0,324 y Κ=0,261, respectivamente). Los análisis de regresión lineal revelaron una relación estadísticamente significativa entre las mediciones de ecografía y RM de la VMA derecha, izquierda y la media (p<0,001, p<0,001 y p<0,001, respectivamente). La RM mostró una concordancia perfecta con la ecografía en detectar la lateralidad de la VMA (Κ=1,0, p<0,001). Conclusiones. En fetos con VMA leve detectada por ecografía se debe considerar la evaluación por RM del cerebro fetal para un diagnóstico preciso. Este enfoque puede proporcionar una estrategia eficaz en el manejo prenatal y el asesoramiento de estos embarazos.

Objective: To assess the role of brain magnetic resonance imaging (MRI) in fetuses presenting with isolated ventriculomegaly (IVM) in the ultrasound (US) evaluation of the fetal brain. Methods: US and MRI findings of 197 fetuses diagnosed with IVM between November 2018 and November 2020 were retrospectively evaluated. Fetuses with abnormal karyotypes, additional anomalies, or known etiologies for ventriculomegaly were excluded. US and MRI findings were compared both in terms of mean ventricular measurements and IVM grade. Results: MRI measurements were significantly higher in mild IMV (10.33 ± 0.38 mm vs. 11.11 ± 0.51 mm, p< 0.001) compared to US. In mild IVM, MRI measured ventricles larger than US with a mean difference of 0.78 mm. There was no significant difference in US and MRI measurements in terms of mean values in moderate and severe IVM. There was good agreement between US and MRI in detecting right, left and mean IVM severity (Κ=0.265, Κ=0.324, and Κ=0.261, respectively). Linear regression analyses revealed a statistically significant relationship between US and MRI measurements of the right, left, and mean IVM (p<0.001, p<0.001, and p<0.001, respectively). MRI showed perfect agreement with US in detecting IVM laterality (Κ=1.0, p<0.001). Conclusions: In fetuses with mild IVM detected by US, fetal brain MRI evaluation should be considered for accurate diagnosis. This approach may provide effective strategies in the antenatal management and counseling of these pregnancies.

Sex differences in gene regulatory networks during mid-gestational brain development.

Neurodevelopmental disorders differ considerably between males and females, and fetal brain development is one of the most critical periods to determine risk for these disorders. Transcriptomic studies comparing male and female fetal brain have demonstrated that the highest difference in gene expression occurs in sex chromosomes, but several autossomal genes also demonstrate a slight difference that has not been yet explored. In order to investigate biological pathways underlying fetal brain sex differences, we applied medicine network principles using integrative methods such as co-expression networks (CEMiTool) and regulatory networks (netZoo). The pattern of gene expression from genes in the same pathway tend to reflect biologically relevant phenomena. In this study, network analysis of fetal brain expression reveals regulatory differences between males and females. Integrating two different bioinformatics tools, our results suggest that biological processes such as cell cycle, cell differentiation, energy metabolism and extracellular matrix organization are consistently sex-biased. MSET analysis demonstrates that these differences are relevant to neurodevelopmental disorders, including autism.

Prenatal intracranial hypotension syndrome: new insights into the mechanisms of fenestration of septi pellucidi and ventriculomegaly in fetuses with open spinal dysraphism.

OBJECTIVE: To study the prevalence of abnormalities of the septi pellucidi (SP) in a cohort of fetuses with open spinal dysraphism (OSD) and to determine whether this condition is secondary to obstructive ventriculomegaly and, therefore, part of the natural history of prenatal intracranial hypotension (PICH) syndrome. METHODS: Magnetic resonance imaging (MRI) studies from fetuses with OSD were analyzed. The SP were assessed using axial and coronal T2-weighted images of the fetal brain and classified as intact, partially absent, or completely absent. Additionally, the correlation between the presence or absence of the SP and the size of the lateral ventricles, degree of cerebellar tonsillar herniation, collapse of the fourth ventricle, and interpeduncular angle was investigated. RESULTS: A total of 32 fetuses with OSD were studied. Mean gestational age at the time of the fetal MRI was 25.5 ± 3.9 weeks (range, 19-35) and mean ventricular size was 16.2 ± 4.2 mm (range, 8-26). Twenty-three (71.9%) fetuses had cerebellar tonsillar herniation. The IPA was completely collapsed in 23 cases (71.9%), reduced in seven (21.9%), and unreadable in two (6.3%). Twenty (62.5%) fetuses presented with intact SP, 10 (31.3%) with partially absent SP (incomplete fenestration), and two (6.3%) with completely absent SP (complete fenestration). Fenestration of the SP correlated significantly with the degree of ventriculomegaly (Pearson's correlation coefficient =0.459; p = .01). However, there was no correlation with the IPA, collapse of the fourth ventricle, and cerebellar tonsillar herniation. CONCLUSIONS: More than one-third of the fetuses with OSD had fenestration of the SP. The most probable etiology is increased intraventricular pressure leading to local necrosis of the SP. As fenestration of the SP is a secondary event associated with PICH syndrome, this condition should not be considered a contraindication for intrauterine repair of the spinal defect. Instead, it should be seen as an indicator of the severity of the intraventricular pressure.

Sex differences in gene regulatory networks during mid-gestational brain development

Neurodevelopmental disorders differ considerably between males and females, and fetal brain development is one of the most critical periods to determine risk for these disorders. Transcriptomic studies comparing male and female fetal brain have demonstrated that the highest difference in gene expression occurs in sex chromosomes, but several autossomal genes also demonstrate a slight difference that has not been yet explored. In order to investigate biological pathways underlying fetal brain sex differences, we applied medicine network principles using integrative methods such as co-expression networks (CEMiTool) and regulatory networks (netZoo). The pattern of gene expression from genes in the same pathway tend to reflect biologically relevant phenomena. In this study, network analysis of fetal brain expression reveals regulatory differences between males and females. Integrating two different bioinformatics tools, our results suggest that biological processes such as cell cycle, cell differentiation, energy metabolism and extracellular matrix organization are consistently sex-biased. MSET analysis demonstrates that these differences are relevant to neurodevelopmental disorders, including autism.

Everolimus as a possible prenatal treatment of in utero diagnosed subependymal lesions in tuberous sclerosis complex: a case report.

INTRODUCTION: The association between cardiac rhabdomyoma and intraventricular tumors and/or subcortical nodules is characteristic of tuberous sclerosis complex (TSC). Patients with TSC may have refractory seizures, autistic behavior, and cognitive decline. CASE REPORT: The patient received the fetal diagnosis of TSC at the age of 19 weeks of gestations, where presented at prenatal ultrasound cardiac and brain tumors. Fetal MRI showed a lesion in the right and left lateral ventricles near the foramen of Monro associated with subependymal lesions along the entire ependyma of the lateral ventricles and several subcortical tubercles, and the fetal Doppler echocardiogram revealed three cardiac lesions. The fetus underwent intrauterine treatment with everolimus and presented regression and subsequent stabilization of the cardiac and brain lesions; additionally, the patient did not develop seizures or autism and presented good neuropsychomotor development. CONCLUSION: It is the first evidence that mTOR inhibitors may help to prevent neurological complications associated with TSC.

Fetal cerebellar growth and Sylvian fissure maturation: international standards from Fetal Growth Longitudinal Study of INTERGROWTH-21st Project.

OBJECTIVE: To construct international ultrasound-based standards for fetal cerebellar growth and Sylvian fissure maturation. METHODS: Healthy, well nourished pregnant women, enrolled at < 14 weeks' gestation in the Fetal Growth Longitudinal Study (FGLS) of INTERGROWTH-21st , an international multicenter, population-based project, underwent serial three-dimensional (3D) fetal ultrasound scans every 5 ± 1 weeks until delivery in study sites located in Brazil, India, Italy, Kenya and the UK. In the present analysis, only those fetuses that underwent developmental assessment at 2 years of age were included. We measured the transcerebellar diameter and assessed Sylvian fissure maturation using two-dimensional ultrasound images extracted from available 3D fetal head volumes. The appropriateness of pooling data from the five sites was assessed using variance component analysis and standardized site differences. For each Sylvian fissure maturation score (left or right side), mean gestational age and 95% CI were calculated. Transcerebellar diameter was modeled using fractional polynomial regression, and goodness of fit was assessed. RESULTS: Of those children in the original FGLS cohort who had developmental assessment at 2 years of age, 1130 also had an available 3D ultrasound fetal head volume. The sociodemographic characteristics and pregnancy/perinatal outcomes of the study sample confirmed the health and low-risk status of the population studied. In addition, the fetuses had low morbidity and adequate growth and development at 2 years of age. In total, 3016 and 2359 individual volumes were available for transcerebellar-diameter and Sylvian-fissure analysis, respectively. Variance component analysis and standardized site differences showed that the five study populations were sufficiently similar on the basis of predefined criteria for the data to be pooled to produce international standards. A second-degree fractional polynomial provided the best fit for modeling transcerebellar diameter; we then estimated gestational-age-specific 3rd , 50th and 97th smoothed centiles. Goodness-of-fit analysis comparing empirical centiles with smoothed centile curves showed good agreement. The Sylvian fissure increased in maturation with advancing gestation, with complete overlap of the mean gestational age and 95% CIs between the sexes for each development score. No differences in Sylvian fissure maturation between the right and left hemispheres were observed. CONCLUSION: We present, for the first time, international standards for fetal cerebellar growth and Sylvian fissure maturation throughout pregnancy based on a healthy fetal population that exhibited adequate growth and development at 2 years of age. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal Ethanol Exposure Misregulates Genes Involved in Iron Homeostasis Promoting a Maladaptation of Iron Dependent Hippocampal Synaptic Transmission and Plasticity.

Prenatal ethanol exposure (PAE) induces behavioral maladptations in offspring, including a deficit in memory formation which is part of the umbrella sign of fetal alcohol spectrum disorder. Clinical and preclinical studies have shown that iron depletion exacerbates cognitive problems in offspring exposed to ethanol in utero and that PAE promotes dysregulation in brain iron homeostasis. However, the mechanisms underlying brain iron dysregulation and neuronal activity defects in adolescent offspring of PAE are unclear and poorly understand. Here, we used a PAE rat model to analyze messenger RNA (mRNA) and protein expression of iron homeostasis genes such as transferrin receptor (TfR), divalent metal transporter (DMT1), ferroportin (FPN1), and ferritin (FT) in brain areas associated with memory formation such as the prefrontal cortex (PFC), ventral tegmental area, and hippocampus. Interestingly, we found that 21 day old PAE rats have higher mRNA expression of DMT1 in the PFC, and TfR in the hippocampus, compared to control animals. In contrast FPN has lower mRNA expression in the PFC, and FT and FPN1 have lower expression in the hippocampus. In agreement with these results, we found a 1.5-2 fold increase of TfR and DMT1 protein levels both in the hippocampus and the PFC. Additionally, using an electrophysiological approach, we found that in hippocampal slices from PAE rats, iron treatment decreased long-term potentiation (LTP), but not AMPAR basal transmission (AMPAR fEPSP). In contrast, in control slices Fe-NTA did not affect LTP but decreased significantly the AMPAR fEPSP. Meanwhile, iron chelation with deferiprone decreased AMPAR transmission in PAE and control slices and decreased LTP only in controls slices. These results suggest that PAE affects iron homeostasis of specific brain areas-PFC and hippocampus-which could be involved in maladaptive cognition observed in this animal model.

Congenital Zika syndrome phenotype in a child born in Brazil in December 2011.

We report a case of a Brazilian child born in 2011 with congenital Zika syndrome phenotype. Zika virus (ZIKV) may have been circulating in Brazil more than 4 years before the outbreak. ZIKV infection might be considered in children with this phenotype even without known circulation of ZIKV.

Clinical assessment and brain findings in a cohort of mothers, fetuses and infants infected with ZIKA virus.

BACKGROUND: Congenital Zika virus (ZIKV) infection can be detected in both the presence and absence of microcephaly and manifests as a number of signs and symptoms that are detected clinically and by neuroimaging. However, to date, qualitative and quantitative measures for the purpose of diagnosis and prognosis are limited. OBJECTIVES: Main objectives of this study conducted on fetuses and infants with confirmed congenital Zika virus infection and detected brain abnormalities were (1) to assess the prevalence of microcephaly and the frequency of the anomalies that include a detailed description based on ultrasound and magnetic resonance imaging in fetuses and ultrasound, magnetic resonance imaging, and computed tomography imaging postnatally, (2) to provide quantitative measures of fetal and infant brain findings by magnetic resonance imaging with the use of volumetric analyses and diffusion-weighted imaging, and (3) to obtain additional information from placental and fetal histopathologic assessments and postnatal clinical evaluations. STUDY DESIGN: This is a longitudinal cohort study of Zika virus-infected pregnancies from a single institution in Colombia. Clinical and imaging findings of patients with laboratory-confirmed Zika virus infection and fetal brain anomalies were the focus of this study. Patients underwent monthly fetal ultrasound scans, neurosonography, and a fetal magnetic resonance imaging. Postnatally, infant brain assessment was offered by the use of ultrasound imaging, magnetic resonance imaging, and/or computed tomography. Fetal head circumference measurements were compared with different reference ranges with <2 or <3 standard deviations below the mean for the diagnosis of microcephaly. Fetal and infant magnetic resonance imaging images were processed to obtain a quantitative brain volumetric assessment. Diffusion weighted imaging sequences were processed to assess brain microstructure. Anthropometric, neurologic, auditory, and visual assessments were performed postnatally. Histopathologic assessment was included if patients opted for pregnancy termination. RESULTS: All women (n=214) had been referred for Zika virus symptoms during pregnancy that affected themselves or their partners or if fetal anomalies that are compatible with congenital Zika virus syndrome were detected. A total of 12 pregnant patients with laboratory confirmation of Zika virus infection were diagnosed with fetal brain malformations. Most common findings that were assessed by prenatal and postnatal imaging were brain volume loss (92%), calcifications (92%), callosal anomalies (100%), cortical malformations (89%), and ventriculomegaly (92%). Results from fetal brain volumetric assessment by magnetic resonance imaging showed that 1 of the most common findings associated with microcephaly was reduced supratentorial brain parenchyma and increased subarachnoid cerebrospinal fluid. Diffusion weighted imaging analyses of apparent diffusion coefficient values showed microstructural changes. Microcephaly was present in 33.3-58.3% of the cases at referral and was present at delivery in 55.6-77.8% of cases. At birth, most of the affected neonates (55.6-77.8%) had head circumference measurements >3 standard deviations below the mean. Postnatal imaging studies confirmed brain malformations that were detected prenatally. Auditory screening results were normal in 2 cases that were assessed. Visual screening showed different anomalies in 2 of the 3 cases that were examined. Pathologic results that were obtained from 2 of the 3 cases who opted for termination showed similar signs of abnormalities in the central nervous system and placental analyses, including brain microcalcifications. CONCLUSION: Congenital microcephaly is not an optimal screening method for congenital Zika virus syndrome, because it may not accompany other evident and preceding brain findings; microcephaly could be an endpoint of the disease that results from progressive changes that are related to brain volume loss. Long-term studies are needed to understand the clinical and developmental relevance of these findings.

Spatial Compounding of 3-D Fetal Brain Ultrasound Using Probabilistic Maps.

A new method to address the problem of shadowing in fetal brain ultrasound volumes is presented. The proposed approach is based on the spatial composition of multiple 3-D fetal head projections using the weighted Euclidean norm as an operator. A support vector machine, which is trained with optimal textural features, was used to assign weighting according to the posterior probabilities of brain tissue and shadows. Both phantom and real fetal head ultrasound volumes were compounded using previously reported operators and compared with the proposed composition method to validate it. The quantitative evaluations revealed increases in signal-to-noise ratio ≤35% and in contrast-to-noise ratio ≤135% using real data. Qualitative comparisons made by obstetricians indicated that this novel method adequately recovers brain tissue and improves the visibility of the main cerebral structures. This may prove useful both for fetal monitoring and in the diagnosis of brain defects. Overall this new approach outperforms spatial composition methods previously reported.

Maternal administration of melatonin exerts short- and long-term neuroprotective effects on the offspring from lipopolysaccharide-treated mice.

Preterm birth is a major contributor to early and delayed physical and cognitive impairment. Epidemiological and experimental data indicate that maternal infections are a significant and preventable cause of preterm birth. Recently, melatonin has been suggested to exert neuroprotective effects in several models of brain injury. Here, we sought to investigate whether the administration of melatonin is able to prevent lipopolysaccharide (LPS)-induced fetal brain damage in a model of LPS-induced preterm labor. For this purpose, 15-day pregnant BALB/c mice received intraperitoneally 2 doses of LPS or vehicle: the first one at 10:00 hours (0.26 mg/kg) and the second at 13:00 hours (0.52 mg/kg). On day 14 of pregnancy, a group of mice was subcutaneously implanted with a pellet of 25 mg melatonin. This experimental protocol resulted in 100% of preterm birth and pup death in the LPS group and a 50% of term birth and pup survival in the melatonin + LPS group. In the absence of melatonin, fetuses from LPS-treated mothers showed histological signs of brain damage, microglial/macrophage activation, and higher levels of IL-1ß, inducible nitric oxide synthase (NOS), and neuronal NOS mRNAs as well as increased histone acetyltransferase activity and histone H3 hyperacetylation. In contrast, antenatal administration of melatonin prevented LPS-induced fetal brain damage. Moreover, when behavioral traits were analyzed in the offspring from control, melatonin, and melatonin + LPS, no significant differences were found, suggesting that melatonin prevented LPS-induced long-term neurodevelopmental impairments. Collectively, our results suggest that melatonin could be a new therapeutic tool to prevent fetal brain damage and its long-term consequences induced by maternal inflammation.

Induction of ABCG2/BCRP restricts the distribution of zidovudine to the fetal brain in rats.

Safety concerns for fetus development of zidovudine (AZT) administration as prophylaxis of vertical transmission of HIV persist. We evaluated the participation of the ATP-binding cassette efflux transporter ABCG2 in the penetration of AZT into the fetal brain and the relevance for drug safety. Oral daily doses of AZT (60mg/kg body weight) or its vehicle were administered between post gestational days 11 (E11) and 20 (E20) to Sprague-Dawley pregnant rats. At E21, animals received an intravenous bolus of 60mg AZT/kg body weight in the presence or absence of the ABCG2 inhibitor gefitinib (20mg/kg body weight, ip) and AZT in maternal plasma and fetal brain were measured by HPLC-UV. ABCG2 protein expression in placenta and fetal brain, as well as mitochondrial function and ultrastructure in fetal brain were also analyzed. In utero chronic exposure to AZT markedly induced ABCG2 expression in placenta and fetal brain whereas did not significantly alter mitochondrial functionality in the fetal brain. The area-under-the-concentration-time-curve of AZT significantly decreased in fetal brains isolated from AZT-exposed fetuses compared to control group, but this effect was abolished by ABCG2 inhibition. Our results suggest that the absence of mitochondrial toxicity in the fetal brain after chronic in utero administration of AZT could be attributed to its low accumulation in the tissue caused, at least in part, by ABCG2 overexpression. We propose that any interference with ABCG2 activity due to genetic, pathological or iatrogenic factors would increase the amount of AZT reaching the fetal brain, which could increase the risk of toxicity of this drug on the tissue.

The phenotypic spectrum of congenital Zika syndrome.

In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM-ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM-ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV.

Central Nervous System and Vertebrae Development in Horses: a Chronological Study with Differential Temporal Expression of Nestin and GFAP.

The neural system is one of the earliest systems to develop and the last to be fully developed after birth. This study presents a detailed description of organogenesis of the central nervous system (CNS) at equine embryonic/fetal development between 19 and 115 days of pregnancy. The expression of two important biomarkers in the main structure of the nervous system responsible for neurogenesis in the adult individual, and in the choroid plexus, was demonstrated by Nestin and glial fibrillary acid protein (GFAP) co-labeling. In the 29th day of pregnancy in the undifferentiated lateral ventricle wall, the presence of many cells expressing Nestin and few expressing GFAP was observed. After the differentiation of the lateral ventricle wall zones at 60 days of pregnancy, the subventricular zone, which initially had greater number of Nestin+ cells, began to show higher numbers of GFAP+ cells at 90 days of pregnancy. A similar pattern was observed for Nestin+ and GFAP+ cells during development of the choroid plexus. This study demonstrates, for the first time, detailed chronological aspects of the equine central nervous system organogenesis associated with downregulation of Nestin and upregulation of GFAP expression.

Biometría del cráneo y sistema ventricular cerebral fetal: tablas de normalidad a través de pruebas no paramétricas

Objetivos: Realizar tablas de referencia a través de estadística no paramétrica para definir en percentiles los rangos de normalidad del diámetro biparietal, la circunferencia cefálica, el atrio ventricular cerebral, la cisterna magna, el cavum septum pellucidum y los ventrículos laterales, según recomendaciones de la International Society of Ultrasound in Obstetrics and Gynecology de evaluación y medida. Métodos: Estudio transversal realizado desde enero 2014 a enero 2016. Se evaluaron 1004 embarazadas normales, en diferentes edades gestacionales, y de manera previamente estandarizada se midieron las estructuras mencionadas. El análisis estadístico se realizó con el software libre PAST 3.04 para la organización de los datos de cada edad gestacional en percentiles. Se presentaron en gráficos tipo nomogramas y en modelo de regresión polinómica de primer orden. Cada gráfico fue evaluado con significancia estadística con P<0,05. Resultados: Las estructuras intracraneales pudieron medirse en su totalidad en 864 casos (86 % de los exámenes). Los diámetros biparietal y las circunferencias cefálica pudieron obtenerse en todos los casos, se observó un crecimiento directamente proporcional a la edad gestacional (P< 0,05). La medida del atrio ventricular resultó estable lo largo del embarazo. Se presentan las medidas de la cisterna magna, del cavum septum pellucidum y de los ventrículos laterales. Conclusiones: Los rangos de normalidad se representaron en tablas para correcto uso clínico y de investigación, no difieren de investigaciones previas realizadas en otros países. Se presentan valores de referencia utilizables en la consulta prenatal, a través de estadística no gaussiana.

Objectives: To carry out reference tables through non-parametric statistics to define in percentile ranges of normality of the biparietal diameter, head circumference, the cerebral ventricular atrium, the cisterna magna, cavum septum pellucidum, and the lateral ventricles, according to the recommendations of the International Society of Ultrasound in Obstetrics and Gynecology of evaluation and measurement. Methods: A cross-sectional study was carried out from January 2014 to January 2016; 1004 normal pregnant women, in different gestational ages, were evaluated, and the mentioned structures, previously standardized, were measured. The statistical analysis was performed with the FOSS PAST 3.04 for the organization of the data at each gestational age, in percentiles. They arose in graphic type nomograms and first-order polynomial regression model. Each graphic was evaluated with statistics significance with P < 0.05. Results: The intracranial structures could be measured entirely in 864 cases (86% of the tests). Biparietal diameter and head circumferences were obtained in all cases; it was observed a directly proportional growth to gestational age (P < 0.05). The measurement of the ventricular Atrium was stable throughout the pregnancy. Measures of the cisterna magna, cavum septum pellucidum and of the lateral ventricles are represented. Conclusions: Normal ranges are represented in tables for correct clinical use and research, the results are not different from previous research conducted in other countries. Usable reference values, in the prenatal consultation, through non-Gaussian statistics are presented.