Effects of methylazoxymethanol-induced micrencephaly on parvalbumin-positive GABAergic interneurons in the rat rostral basolateral amygdala.

The amygdala plays a crucial role in anxiety-related behavior and various neuropsychiatric disorders. The offspring of dams, administered methylazoxymethanol acetate (MAM) intraperitoneally at gestational day 15, exhibit micrencephaly and anxiety-related behavior, such as hyperactivity in rearing and crossing behavior, alongside a distinct Fos expression profile in the basolateral (BLA) and central amygdala. However, the histochemical underpinnings of these changes remain to be elucidated. To determine the histochemical alterations in MAM-induced model rats, we performed Nissl staining, immunohistochemistry for parvalbumin (PV) or calbindin (Calb), and immunohistochemistry for PV in conjunction with in situ hybridization for glutamate decarboxylase (GAD). We compared immunoreactivity in the BLA between normal and MAM-induced model rats and observed a significant decrease in the number of PV-positive neurons in MAM-induced model rats; however, no significant differences in the number of Nissl- and Calb-positive neurons were observed. We did not detect any significant between-group differences with regards to the effects of environmental enrichment on the number of PV-positive neurons in the BLA. Double-labeling for GAD and PV revealed that many PV-positive neurons colocalized with digoxigenin-GAD65/67 signals. In addition, GAD/PV double-positive neurons and the total number of GAD-positive neurons in the BLA were lower in the MAM-induced model rats. These results indicate that histochemical alterations observed in the BLA of the MAM-induced model rats may attribute to an aberrant GABAergic inhibitory system.

Ocular measurements in fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and neurologic deficits in individuals exposed to alcohol prenatally. Reduced palpebral fissure length is one of the cardinal facial features of FASD. However, other ocular measurements have not been studied extensively in FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how inner canthal distance (ICD), interpupillary distance (IPD), and outer canthal distance (OCD) centiles differed between FASD and non-FASD individuals. We compared ocular measurement centiles in children with FASD to non-FASD individuals and observed reductions in all three centiles for ICD, IPD, and OCD. However, when our non-FASD children who had various forms of growth deficiency (microcephaly, short-stature, or underweight) were compared to controls, we did not observe a similar reduction in ocular measurements. This suggests that reductions in ocular measurements are a direct effect of alcohol on ocular development independent of its effect on growth parameters, which is consistent with animal models showing a negative effect of alcohol on developing neural crest cells. Interpupillary distance centile appeared to be the most significantly reduced ocular measure we evaluated, suggesting it may be a useful measure to be considered in the diagnosis of FASD.

El recién nacido expuesto a cocaína antenatal: una propuesta de intervención médica y psicosocial integrada / The newborn exposed to antenatal cocaine: a proposal for integrated medical and psychosocial intervention

Introducción: El consumo de cocaína durante la gestación gatilla isquemia, muerte y licuefacción celular en el cerebro fetal, consolidando en la infancia grados variables de retraso mental. El presente estudio busca identificar mediante test de drogas en orina los recién nacidos (RN) expuestos a cocaína en el embarazo y describir el procedimiento clínico y social a seguir. Metodología: Estudio de cohorte prospectivo enero 2016 y enero 2018 en RN con exposición antenatal a cocaína, Unidad de Neonatología del Hospital Clínico San Borja Arriarán. Resultados: Se estudió a 64 RN con test en orina positivo a cocaína. El 42% fue pequeño para la edad gestacional, 33% tenía microcefalia. Se encontraron malformaciones en sistema nervioso y vías urinarias, trastornos del ritmo cardíaco e hipoacusia. Solo 32,8% de las madres controló su embarazo y 52% rechazó la rehabilitación. Servicio Social interpuso medidas de protección a los RN e instó a las madres a programas de rehabilitación. El 12,5% de los RN no tenía familia de apoyo y debió ser derivado a instituciones gubernamentales. Conclusiones: Las consecuencias de la exposición a cocaína antenatal en el RN son devastadoras. Este trabajo permite orientar la pesquisa, estudio y pasos legales a seguir con los RN afectados y sus madres.

Introduction: The consumption of cocaine during pregnancy triggers events such as ischemia, death and cell liquefaction in the fetal brain, consolidating varying degrees of intellectual disability. This study proposed to identify by urine drug test the newborns (NB) with antenatal exposure to and describe the clinical and social procedure to follow with them and their mothers until neonatal discharge. Methodology: Prospective cohort study, conducted in RN who met criteria for risk of antenatal exposure to cocaine, Neonatology Unit of the San Borja Arriaran Clinical Hospital between January 2016 -2018. Results: Antenatal exposure to cocaine was confirmed on 64 NB. Forty-two percent of them were small for gestational age and 33% had microcephaly. Malformations were found in the nervous system urinary tract, as well as disorders in the rhythm of the heart and loss of hearing. Only 32% of mothers controlled her pregnancy, none of them was derived to the secondary. Social Services implemented all the NB protective measures in place and urged mothers to participate in rehabilitation programs. Fifty-two percent rejected rehabilitation and 12.5% of the NB have not family support and had to be referred to government institutions. Conclusions: The consequences of exposure to antenatal cocaine in the NB are devastating. This work allows orienting the research with the NB and showing the legal steps should be taken with the RN and their mothers.

A systems biology approach to predictive developmental neurotoxicity of a larvicide used in the prevention of Zika virus transmission.

The need to prevent developmental brain disorders has led to an increased interest in efficient neurotoxicity testing. When an epidemic of microcephaly occurred in Brazil, Zika virus infection was soon identified as the likely culprit. However, the pathogenesis appeared to be complex, and a larvicide used to control mosquitoes responsible for transmission of the virus was soon suggested as an important causative factor. Yet, it is challenging to identify relevant and efficient tests that are also in line with ethical research defined by the 3Rs rule (Replacement, Reduction and Refinement). Especially in an acute situation like the microcephaly epidemic, where little toxicity documentation is available, new and innovative alternative methods, whether in vitro or in silico, must be considered. We have developed a network-based model using an integrative systems biology approach to explore the potential developmental neurotoxicity, and we applied this method to examine the larvicide pyriproxyfen widely used in the prevention of Zika virus transmission. Our computational model covered a wide range of possible pathways providing mechanistic hypotheses between pyriproxyfen and neurological disorders via protein complexes, thus adding to the plausibility of pyriproxyfen neurotoxicity. Although providing only tentative evidence and comparisons with retinoic acid, our computational systems biology approach is rapid and inexpensive. The case study of pyriproxyfen illustrates its usefulness as an initial or screening step in the assessment of toxicity potentials of chemicals with incompletely known toxic properties.

Effects of environmental enrichment on the activity of the amygdala in micrencephalic rats exposed to a novel open field.

Environmental enrichment (EE) mediates recovery from sensory, motor, and cognitive deficits and emotional abnormalities. In the present study, we examined the effects of EE on locomotor activity and neuronal activity in the amygdala in control and methylazoxymethanol acetate (MAM)-induced micrencephalic rats after challenge in a novel open field. Control rats housed in EE (CR) showed reduced locomotor activity compared to rats housed in a conventional cage (CC), whereas hyperactivity was seen in MAM rats housed in a conventional cage (MC) and in MAM rats housed in EE (MR). Novel open field exposure in both CC and MC resulted in a marked increase in Fos expression in the anterior and posterior parts of the basolateral amygdaloid nucleus, basomedial nucleus, and medial nucleus, whereas these increases in expression were not observed in CR. The effect of EE on Fos expression in the amygdala was different in MR exposed to a novel open field compared to CR. Furthermore, we observed a quite different pattern of Fos expression in the central nucleus of the amygdala between control and MAM rats. The present results suggest that neuronal activity in the amygdala that responds to anxiety is altered in MAM rats, especially when the rats are reared in EE. These alterations may cause behavioral differences between control and MAM rats.

The larvicide pyriproxyfen blamed during the Zika virus outbreak does not cause microcephaly in zebrafish embryos.

Although the zika virus (ZIKV) has now been strongly correlated with emerging cases of microcephaly in the Americas, suspicions have been raised regarding the use of pyriproxyfen, a larvicide that prevents mosquito development, in drinking water. The effects of this compound on neurodevelopment have not yet been addressed specifically in vertebrates. As a result, we aimed at addressing the effects, if any, of pyriproxyfen on neurodevelopment in the zebrafish embryo as a vertebrate model. Using zebrafish transgenic lines expressing GFP in different cell populations (elavl3 in newborn neurons, gfap and nestin in neural stem cells), we focused on the analysis of whole embryonic brain volume after confocal 3D-reconstruction and the quantification of purified neural stem cells during early neurodevelopment by FACS-cell sorting from whole in vivo embryos. Interestingly, though lethal at very high doses, pyriproxyfen did not cause brain malformation nor any significant changes in the number of observed stem cells in the developing central nervous system. Our data indicate that pyriproxyfen does not affect central nervous system development in zebrafish, suggesting that this larvicide on its own, may not be correlated with the increase in microcephaly cases reported recently.

Pyriproxyfen and the microcephaly epidemic in Brazil - an ecological approach to explore the hypothesis of their association.

The microcephaly epidemic in Brazil generated intense debate regarding its causality, and one hypothesised cause of this epidemic, now recognised as congenital Zika virus syndrome, was the treatment of drinking water tanks with pyriproxyfen to control Aedes aegypti larvae. We present the results of a geographical analysis of the association between the prevalence of microcephaly confirmed by Fenton growth charts and the type of larvicide used in the municipalities that were home to the mothers of the affected newborns in the metropolitan region of Recife in Pernambuco, the state in Brazil where the epidemic was first detected. The overall prevalence of microcephaly was 82 per 10,000 live births in the three municipalities that used the larvicide Bti (Bacillus thuringiensis israelensis) instead of pyriproxyfen, and 69 per 10,000 live births in the eleven municipalities that used pyriproxyfen. The difference was not statistically significant. Our results show that the prevalence of microcephaly was not higher in the areas in which pyriproxyfen was used. In this ecological approach, there was no evidence of a correlation between the use of pyriproxyfen in the municipalities and the microcephaly epidemic.

Nota técnica sobre microcefalia e doenças vetoriais relacionadas ao Aedes aegypti: os perigos das abordagens com larvicidas e nebulizações químicas – fumacê

Notícia sobre nota técnica produzida pela Abrasco sobre causa de microcefalia devido à nebulização utilizada no combate ao mosquito Aedes Aegypt. O documento pretende aprofundar reflexões, questionamentos e fazer proposições que possam orientar as políticas públicas na intervenção preventiva frente ao surto de infecções por vírus zika e microcefalia.

Fetal Growth Outcomes in a Cohort of Polydrug- and Opioid-Dependent Patients.

OBJECTIVES: To evaluate the effects of prenatal polydrug and exclusive opioid use on fetal growth outcomes. METHODS: This analysis relied on the data obtained from two prospective cohorts at the University of New Mexico. For both cohorts, pregnant women were recruited during one of their prenatal care visits and followed up to delivery. The merged sample included 59 polydrug users, 22 exclusive opioid users, and 278 abstinent controls. Continuous growth measures (birth weight, height, occipital frontal circumference [OFC], and corresponding sex-specific percentiles) were compared by ANOVA and ANCOVA in bivariate and multivariable analyses, respectively. Categorical outcomes (prevalence of small-for-gestational age [SGA] for weight, length, and OFC) were compared among groups by Chi-square and multivariable logistic regression analyses.. RESULTS: The sample included a large proportion of ethnic minorities (78.8% Hispanic) and patients with low educational attainment (68% ≤ high school). The risk of microcephaly (OFC<10th percentile) was significantly greater in the polydrug (OR=4.7; 95% CI: 2.0; 10.8) and exclusive opioid (OR=2.8; 95% CI: 1.0; 8.1) groups compared to abstinent controls. CONCLUSION: Given that microcephaly is often associated with serious neurocognitive and behavioral deficits later in life, our finding of 49.2% incidence of microcephaly among polydrug users is alarming and requires further investigation.

ENU mutagenesis identifies mice modeling Warburg Micro Syndrome with sensory axon degeneration caused by a deletion in Rab18.

Mutations in the gene of RAB18, a member of Ras superfamily of small G-proteins, cause Warburg Micro Syndrome (WARBM) which is characterized by defective neurodevelopmental and ophthalmological phenotypes. Despite loss of Rab18 had been reported to induce disruption of the endoplasmic reticulum structure and neuronal cytoskeleton organization, parts of the pathogenic mechanism caused by RAB18 mutation remain unclear. From the N-ethyl-N-nitrosourea (ENU)-induced mutagenesis library, we identified a mouse line whose Rab18 was knocked out. This Rab18(-/-) mouse exhibited stomping gait, smaller testis and eyes, mimicking several features of WARBM. Rab18(-/-) mice were obviously less sensitive to pain and touch than WT mice. Histological examinations on Rab18(-/-) mice revealed progressive axonal degeneration in the optic nerves, dorsal column of the spinal cord and sensory roots of the spinal nerves while the motor roots were spared. All the behavioral and pathological changes that resulted from abnormalities in the sensory axons were prevented by introducing an extra copy of Rab18 transgene in Rab18(-/-) mice. Our results reveal that sensory axonal degeneration is the primary cause of stomping gait and progressive weakness of the hind limbs in Rab18(-/-) mice, and optic nerve degeneration should be the major pathology of progressive optic atrophy in children with WARBM. Our results indicate that the sensory nervous system is more vulnerable to Rab18 deficiency and WARBM is not only a neurodevelopmental but also neurodegenerative disease.

Maternal single injection of N-methyl-N-nitrosourea to cause microcephaly in offspring induces transient aberration of hippocampal neurogenesis in mice.

N-Methyl-N-nitrosourea (MNU) is an alkylating agent having antiproliferative cytotoxity targeting the neural stem/progenitor cells to cause microcephaly by maternal exposure. This study investigated the effect of transient exposure to MNU on the process of hippocampal neurogenesis in later life using mice. Pregnant mice received a single injection of MNU at 0, 5 and 10 mg/kg body weight, intraperitoneally on gestational day 14, and their offspring were examined on postnatal day (PND) 21 and PND 77. On PND 21, offspring displayed microcephaly and hippocampal formation hypoplasia at 10 mg/kg, decrease of doublecortin (Dcx)(+) cells in the dentate subgranular zone from 5mg/kg, and decrease of TUNEL(+) apoptotic cells and increase of transcript expression of anti-apoptotic Bcl-2 at 10 mg/kg in the dentate gyrus. In the dentate hilus, numbers of reelin(+) or parvalbumin (Pvalb)(+) interneurons or neuron-specific nuclear protein(+) neurons increased at 10 mg/kg. Microcephaly and hippocampal formation hypoplasia continued through PND 77 at 10 mg/kg. Thus, apart from the massive cell killing at the migratory stream causing microcephaly, MNU may decrease Dcx(+) cells reflecting disruption of the differentiation process of late-stage neuronal progenitors and immature granule cells through defective molecular functions by gene mutations. Increase of reelin(+) and Pvalb(+) cells may reflect the disruption of neurogenesis and following neuronal migration. All of the granule cell lineage and interneuron changes disappeared at the adult stage on PND 77 suggesting that MNU mainly targets transient populations of highly proliferative progenitor cells but hardly affects their stem cells having self-renewal ability.

Toxicity of endosulfan on embryo-larval development of the South American toad Rhinella arenarum.

Endosulfan is a widely used pesticide despite its extreme toxicity to a variety of taxa and its worldwide ban. The aim of the present study was to evaluate the acute and chronic toxicity of endosulfan on the embryonic-larval development of the common South American toad Rhinella arenarum. The results showed that lethal and sublethal effects increased with concentration and exposure time. The sensitivity to endosulfan increased during the larval period, the complete operculum stage (S.25) being the most sensitive (504-h median lethal concentration [LC50] = 0.01 mg endosulfan/L; 10% lethal concentration [LC10] = 0.004 mg endosulfan/L). Endosulfan exposure caused morphological abnormalities such as general underdevelopment, edema, gill malformations, and cellular dissociation as well as neurotoxicity. Our results also showed that larvae exposed to concentrations of 0.005 mg endosulfan/L and 0.01 mg endosulfan/L completed metamorphosis earlier than controls, but with underdevelopment. The 240-h teratogenic index was 6.13, implying a high risk for embryos to be malformed in the absence of significant embryonic lethality. Because the hazard quotients for chronic exposure were over 1, the level of concern value and toxicity endpoints obtained in the present study for R. arenarum occurred at concentrations lower than the levels of endosulfan reported in the environment, this pesticide should be considered a potential risk for this species.

Differential effects of antiepileptic drugs on neonatal outcomes.

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.

Prenatal alcohol exposure patterns and alcohol-related birth defects and growth deficiencies: a prospective study.

BACKGROUND: The physical features of fetal alcohol syndrome include smooth philtrum, thin vermillion border, short palpebral fissures, microcephaly, and growth deficiencies on weight and height. However, little is known about the specific quantities of alcohol exposure, pattern of drinking, timing of exposure, and magnitude of risk for each of these features. METHODS: Using data on 992 subjects collected prospectively in California between 1978 and 2005, we examined the patterns and timing of alcohol exposure in relation to these features. Structural features were assessed by a dysmorphologist who performed a blinded physical examination of all infants. Patterns of drinking were evaluated by drinks per day, number of binge episodes, and maximum number of drinks. Timing of exposure was evaluated 0 to 6 weeks postconception, 6 to 12 weeks postconception, first trimester, second trimester, and third trimester. RESULTS: Higher prenatal alcohol exposure in every pattern was significantly associated with the incidence of smooth philtrum but not with short palpebral fissures. The strongest associations were with timing of exposure in the second half of the first trimester (RR 1.25, 95% CI 1.14 to 1.36 for average number of drinks per day; RR 1.17, 95% CI 1.09 to 1.26 for maximum number of drinks in 1 episode). Similarly, thin vermillion border was most strongly associated with exposure in the second half of the first trimester. Findings with respect to timing of exposure were similar for microcephaly and reduced birth weight. However, reduced birth length was increased with exposure in any trimester. These associations were linear, and there was no evidence of a threshold. CONCLUSIONS: Reduced birth length and weight, microcephaly, smooth philtrum, and thin vermillion border are associated with specific gestational timing of prenatal alcohol exposure and are dose-related without evidence of a threshold. Women should continue to be advised to abstain from alcohol consumption from conception throughout pregnancy.

Valproate-induced teratogenesis in Japanese rice fish (Oryzias latipes) embryogenesis.

Fertilized eggs of Japanese rice fish (medaka) at three developmental stages (Iwamatsu stages 4-30) were exposed to waterborne valproic acid (VPA) (0-80 mM) in hatching solution for 48 h. The amount of valproate to cause 50% mortality (IC(50)) is found to be developmental stage-specific. The embryos were more sensitive to valproate at early stages of development (Iwamatsu stages 4-10) than in the embryos in late stages (Iwamatsu stages 17-30). Valproate exposed embryos have microcephaly and disrupted cardiovasculature with delayed vessel circulation, thrombus formation, and slow heart rate. The hatching efficiency is also reduced by valproate exposure due to developmental delay. The mRNA analysis of nine genes belong to oxidative stress (catalase, gsr, gst), neurogenesis (iro3, wnt1, shh, otx2, nlgn3b) and cell cycle regulation (ccna2) have been done. It was observed that the genes belong to oxidative stress remained unaltered after valproate exposure. However, some of the genes belong to neurogenesis (wnt1,shh, otx2 and nlgn3b) and cell cycle (ccna2) showed developmental stage-specific alteration after valproate exposure. This study indicates that valproate is able to induce some of the phenotypic features which are analogous to human fetal valproate syndrome (FVS). Modulation of genes expressed in neural tissues indicates that this fish can be used to analyze the mechanisms of many neurobehavioral disorders like Autism spectrum disorder (ASD) in human.

Prevention of retinoic acid-induced early craniofacial abnormalities by vitamin B12 in mice.

OBJECTIVE: The purpose of the present study was to identify the potential effect of prenatal vitamin B12 administration on retinoic acid (RA)-induced early craniofacial abnormalities in mice and to investigate the possible mechanisms by which vitamin B12 reduces malformations. DESIGN: In our study, whole embryo culture was used to explore the effect of vitamin B12 on mouse embryos during the critical period of organogenesis. All embryos were exposed to 0.4 µM RA and different concentrations of vitamin B12 and scored for their growth in the branchial region at the end of a 48-hour culture period. The endothelin-1 (ET-1)/dHAND protein expression levels in the first branchial arch were investigated using an immunohistochemical method. RESULTS: In the whole embryo culture, 100 and 10 µM vitamin B12 dose-dependently prevented branchial region malformations and decreased craniofacial defects by 90.5% and 77.3%, respectively. ET-1 and dHAND protein levels were significantly increased in vitamin B12-supplemented embryos compared to the RA-exposed group in embryonic branchial region. CONCLUSIONS: These results suggest that vitamin B12 may prevent RA-induced craniofacial abnormalities via prevention of an RA-induced decrease of ET-1 and dHAND protein levels in the branchial region during the organogenic period. This study may shed new light on preventing craniofacial abnormalities.

Methylnitrosourea induces neural progenitor cell apoptosis and microcephaly in mouse embryos.

BACKGROUND: Prenatal exposure to methylnitrosourea (MNU), an alkylating agent, induces microcephaly in mice. However, its pathogenetic mechanism has not been clarified, especially that in the development of the cerebral cortex. METHODS: ICR mice were treated with MNU at 10 mg/kg intraperitoneally on day 13.5 or 15.5 of gestation, and the embryos were observed histologically 24 hr after treatment with MNU or at term. To clarify the pathogenesis of microcephaly and histological changes, especially apoptosis, neurogenesis, and neural migration/positioning, we performed histological analysis employing a cell-specific labeling experiment using thymidine-like substances (BrdU, CldU, and IdU) and markers of neurons/neural stem cells. RESULTS: Histological abnormalities of the dorsal telencephalon, and the excessive cell death of proliferative neural progenitor/stem cells were noted in the MNU-treated embryos. The highest frequencies of cell death occurred at 36 hr after MNU treatment, and little or no neurogenesis was observed in the ventricular zone of the dorsal telencephalon. Abnormality of the radial migration was caused by the reduction of radial fibers in the radial glias. Birth-date analysis revealed the abnormal positioning of neurons and aberrant lamination of the cerebral cortex. CONCLUSIONS: Our data suggest that prenatal exposure to MNU induces the excessive cell death of neural precursor/stem cells, and the defective development of the cerebral cortex, resulting in microcephalic abnormalities.

Improved learning in microencephalic rats.

ABSTRACT Environmental enrichment (EE) facilitates recovery from behavioral abnormalities and spatial memory disabilities in several neurological disease models. Exposure to EE improves spatial memory acquisition and enhances the survival of newly generated cells in the dentate gyri of adult rodents. However, the effects of EE on spatial learning and neurogenesis in the methylazoxymethanol acetate-induced microencephalic rat have not been investigated. Depletion of serotonin in the rat hippocampus is known to influence spatial memory and adult neurogenesis, suggesting a role for serotonin in these processes. To confirm this hypothesis, male methylazoxymethanol acetate-induced microencephalic rats were exposed to EE or conventional housing after weaning; half of these rats further received intracisternal 5,7-dihydroxytryptamine on postnatal day 3, to induce long-lasting depletion of serotonin. As adults, these microencephalic rats were observed using the Morris water maze test and examined for hippocampal neurogenesis. EE alleviated the impairment of spatial memory acquisition and enhanced neurogenesis in the dentate gyri of adult microencephalic rats. Injection of 5,7-dihydroxytryptamine during the neonatal period caused pronounced reductions in hippocampal serotonin levels in these rats. Long-lasting depletion of serotonin eliminated the EE-induced alleviation of spatial memory acquisition and neurogenesis impairment in microencephalic rats. The present results suggest that EE alleviates spatial memory performance deficits in microencephalic rats and further indicate that serotonin might be involved in the underlying mechanisms through increased hippocampal neurogenesis. These data provide new insights into therapeutic interventions for individuals with human migration disorders associated with learning disabilities.

Unexpected neurological sequelae following propofol anesthesia in infants: Three case reports.

UNLABELLED: Propofol is a widely used hypnotic agent for induction and maintenance of pediatric anesthesia with a well known safety profile. Experimental in vitro studies suggest that propofol may be toxic to developing neurons. We report the cases of three infants who underwent surgery before 2 months of age for different benign pathologies. Propofol was used for induction and maintenance of anesthesia in all cases. The three patients developed convulsions with similar clinical characteristics (cluster of recurrent clinical and subclinical seizures) between the 23th and 30th hours following anesthesia. Clinical and electroencephalographic improvement was obtained between the third and fourth day of management in pediatric intensive care unit. The seizures never recurred, and the three patients underwent further uneventful general anesthesia without propofol. Follow-up of the three patients disclosed unexpected neurological dysfunction: progressive microcephaly (head circumferences were normal at birth), developmental impairment with cognitive and behavioural disturbances in two cases, and bilateral symmetrical white-matter abnormalities on cerebral magnetic resonance imaging. CONCLUSION: The causal relationship between propofol anesthesia and the neurological symptoms of our patients remains difficult to ascertain, but we believe that pediatricians, anesthetists and intensive care-givers should be aware of this possible adverse reaction that has never been described before.