Impaired Brain Development Research Articles

Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.

Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in patients with moderate AOP, these treatments are beneficial or deleterious.

Intellectual disability in Indigenous Australians: issues and challenges.

Literature on Indigenous Australians (Aboriginal and Torres Strait Islander people) and intellectual disability (ID) is summarized in order to identify current state of knowledge, gaps, and areas for further research. A selective review of psychiatric literature using relevant medical databases was undertaken. Key articles were identified and their findings described. ID is reported to be more prevalent in Indigenous Australians. Sociocultural constructs and a lack of validated psychometric measures affect what is considered to be ID in Indigenous communities. Prenatal, perinatal, and postnatal factors impair brain development and contribute to ID in Indigenous communities. Comorbid physical and psychiatric disorders need to be assessed and managed. ID is an emerging area of health concern for general and mental health professionals working with Indigenous Australians. This important area requires further research, appropriate training, and resourcing.

Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions.

IntroductionSulf1 and Sulf2 are cell surface sulfatases, which remove specific 6-O-sulfate groups from heparan sulfate (HS) proteoglycans, resulting in modulation of various HS-dependent signaling pathways. Both Sulf1 and Sulf2 knockout mice show impairments in brain development and neurite outgrowth deficits in neurons.Methodology and Main FindingsTo analyze the molecular mechanisms behind these impairments we focused on the postnatal cerebellum, whose development is mainly characterized by proliferation, migration, and neurite outgrowth processes of precursor neurons. Primary cerebellar granule cells isolated from Sulf1 or Sulf2 deficient newborns are characterized by a reduction in neurite length and cell survival. Furthermore, Sulf1 deficiency leads to a reduced migration capacity. The observed impairments in cell survival and neurite outgrowth could be correlated to Sulf-specific interference with signaling pathways, as shown for FGF2, GDNF and NGF. In contrast, signaling of Shh, which determines the laminar organization of the cerebellar cortex, was not influenced in either Sulf1 or Sulf2 knockouts. Biochemical analysis of cerebellar HS demonstrated, for the first time in vivo, Sulf-specific changes of 6-O-, 2-O- and N-sulfation in the knockouts. Changes of a particular HS epitope were found on the surface of Sulf2-deficient cerebellar neurons. This epitope showed a restricted localization to the inner half of the external granular layer of the postnatal cerebellum, where precursor cells undergo final maturation to form synaptic contacts.ConclusionSulfs introduce dynamic changes in HS proteoglycan sulfation patterns of the postnatal cerebellum, thereby orchestrating fundamental mechanisms underlying brain development.

Timing of therapies for Down syndrome: the sooner, the better.

Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Accumulating evidence shows that DS is characterized by numerous neurodevelopmental alterations among which the reduction of neurogenesis, dendritic hypotrophy and connectivity alterations appear to play a particularly prominent role. Although the mechanisms whereby gene triplication impairs brain development in DS have not been fully clarified, it is theoretically possible to correct trisomy-dependent defects with targeted pharmacotherapies. This review summarizes what we know about the effects of pharmacotherapies during different life stages in mouse models of DS. Since brain alterations in DS start to be present prenatally, the prenatal period represents an optimum window of opportunity for therapeutic interventions. Importantly, recent studies clearly show that treatment during the prenatal period can rescue overall brain development and behavior and that this effect outlasts treatment cessation. Although late therapies are unlikely to exert drastic changes in the brain, they may have an impact on the hippocampus, a brain region where neurogenesis continues throughout life. Indeed, treatment at adult life stages improves or even rescues hippocampal neurogenesis and connectivity and hippocampal-dependent learning and memory, although the duration of these effects still remains, in the majority of cases, a matter of investigation. The exciting discovery that trisomy-linked brain abnormalities can be prevented with early interventions gives us reason to believe that treatments during pregnancy may rescue brain development in fetuses with DS. For this reason we deem it extremely important to expedite the discovery of additional therapies practicable in humans in order to identify the best treatment/s in terms of efficacy and paucity of side effects. Prompt achievement of this goal is the big challenge for the scientific community of researchers interested in DS.

White and Gray Matter Abnormalities After Cranial Radiation in Children and Mice

Pediatric patients treated with cranial radiation are at high risk of developing lasting cognitive impairments. We sought to identify anatomical changes in both gray matter (GM) and white matter (WM) in radiation-treated patients and in mice, in which the effect of radiation can be isolated from other factors, the time course of anatomical change can be established, and the effect of treatment age can be more fully characterized. Anatomical results were compared between species. Patients were imaged with T1-weighted magnetic resonance imaging (MRI) after radiation treatment. Nineteen radiation-treated patients were divided into groups of 7 years of age and younger (7-) and 8 years and older (8+) and were compared to 41 controls. C57BL6 mice were treated with radiation (n=52) or sham treated (n=52) between postnatal days 16 and 36 and then assessed with in vivo and/or ex vivo MRI. In both cases, measurements of WM and GM volume, cortical thickness, area and volume, and hippocampal volume were compared between groups. WM volume was significantly decreased following treatment in 7- and 8+ treatment groups. GM volume was unchanged overall, but cortical thickness was slightly increased in the 7- group. Results in mice mostly mirrored these changes and provided a time course of change, showing early volume loss and normal growth. Hippocampal volume showed a decreasing trend with age in patients, an effect not observed in the mouse hippocampus but present in the olfactory bulb. Changes in mice treated with cranial radiation are similar to those in humans, including significant WM and GM alterations. Because mice did not receive any other treatment, the similarity across species supports the expectation that radiation is causative and suggests mice provide a representative model for studying impaired brain development after cranial radiation and testing novel treatments.

Wolfram syndrome 1: from ER stress to impaired mitochondrial dynamics and neuronal development

Wolfram syndrome 1 (WFS1) is a genetic disorder which has been associated both with impaired early brain development and neurodegeneration. Recent studies have suggested regulation of Ca2+ homeostasis by wolframin (Wfs1) and have demonstrated the involvement of endoplasmatic reticulum (ER) stress in Wfs1 deficiency. Despite the ER dysfunction WFS1 shows several characteristics of pathologies related to mitochondrial dynamics. Therefore our aim was to examine the hypothesis that Wfs1 deficiency could disturb mitochondrial dynamics contributing to impaired neuronal functioning. First we show that Wfs1 deficiency induces mild ER stress leading to Inositol 1,4,5-Trisphosphate Receptor (IP3R) dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn alters mitochondrial trafficking, inhibits mitochondrial fusion and augments mitophagy. The overexpression of the active IP3R fragment restores IP3R-mediated Ca2+ release and corrects all perturbations in mitochondrial dynamics suggesting that these events are causally linked. We further demonstrate that suppressing the expression of two Parkinson disease-related proteins, Pink1 and Parkin, leads to reduced Wfs1 deficiency-induced mitophagy and also to the correction of the fusion-fission dynamics and mitochondrial motility. These data suggest that Wfs1 deficiency may over-activate Pink1 and Parkin pathways. Our most important discovery is that Wfs1 deficiency delays neuronal development and axonal growth in primary rat cortical neurons. According to our data, the link between Wfs1 deficiency and delayed neuronal development appears to be mediated by impaired mitochondrial dynamics because suppression of the Pink1-Parkin pathway corrected also the developmental delay. Our data shed light on the mechanisms of neuronal abnormalities in WFS1 and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.

Automatic segmentation of MR brain images of preterm infants using supervised classification

Preterm birth is often associated with impaired brain development. The state and expected progression of preterm brain development can be evaluated using quantitative assessment of MR images. Such measurements require accurate segmentation of different tissue types in those images.This paper presents an algorithm for the automatic segmentation of unmyelinated white matter (WM), cortical grey matter (GM), and cerebrospinal fluid in the extracerebral space (CSF). The algorithm uses supervised voxel classification in three subsequent stages. In the first stage, voxels that can easily be assigned to one of the three tissue types are labelled. In the second stage, dedicated analysis of the remaining voxels is performed. The first and the second stages both use two-class classification for each tissue type separately. Possible inconsistencies that could result from these tissue-specific segmentation stages are resolved in the third stage, which performs multi-class classification. A set of T1- and T2-weighted images was analysed, but the optimised system performs automatic segmentation using a T2-weighted image only.We have investigated the performance of the algorithm when using training data randomly selected from completely annotated images as well as when using training data from only partially annotated images. The method was evaluated on images of preterm infants acquired at 30 and 40weeks postmenstrual age (PMA). When the method was trained using random selection from the completely annotated images, the average Dice coefficients were 0.95 for WM, 0.81 for GM, and 0.89 for CSF on an independent set of images acquired at 30weeks PMA. When the method was trained using only the partially annotated images, the average Dice coefficients were 0.95 for WM, 0.78 for GM and 0.87 for CSF for the images acquired at 30weeks PMA, and 0.92 for WM, 0.80 for GM and 0.85 for CSF for the images acquired at 40weeks PMA. Even though the segmentations obtained using training data from the partially annotated images resulted in slightly lower Dice coefficients, the performance in all experiments was close to that of a second human expert (0.93 for WM, 0.79 for GM and 0.86 for CSF for the images acquired at 30weeks, and 0.94 for WM, 0.76 for GM and 0.87 for CSF for the images acquired at 40weeks).These results show that the presented method is robust to age and acquisition protocol and that it performs accurate segmentation of WM, GM, and CSF when the training data is extracted from complete annotations as well as when the training data is extracted from partial annotations only. This extends the applicability of the method by reducing the time and effort necessary to create training data in a population with different characteristics.

The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice.

Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)–placental ACTH–fetal LIF signaling relay pathway (maternal–fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal–fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal–fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis.

A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly

We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.

Nicotine and the Developing Human: A Neglected Element in the Electronic Cigarette Debate.

The elimination of cigarettes and other combusted tobacco products in the U.S. would prevent tens of millions of tobacco-related deaths. It has been suggested that the introduction of less harmful nicotine delivery devices, such as electronic cigarettes or other electronic nicotine delivery systems, will accelerate progress toward ending combustible cigarette use. However, careful consideration of the potential adverse health effects from nicotine itself is often absent from public health debates. Human and animal data support that nicotine exposure during periods of developmental vulnerability (fetal through adolescent stages) has multiple adverse health consequences, including impaired fetal brain and lung development, and altered development of cerebral cortex and hippocampus in adolescents. Measures to protect the health of pregnant women and children are needed and could include (1) strong prohibitions on marketing that increase youth uptake; (2) youth access laws similar to those in effect for other tobacco products; (3) appropriate health warnings for vulnerable populations; (4) packaging to prevent accidental poisonings; (5) protection of non-users from exposure to secondhand electronic cigarette aerosol; (6) pricing that helps minimize youth initiation and use; (7) regulations to reduce product addiction potential and appeal for youth; and (8) the age of legal sale.

Zinc: indications in brain disorders

Zinc is the authoritative metal which is present in our body, and reactive zinc metal is crucial for neuronal signaling and is largely distributed within presynaptic vesicles. Zinc also plays an important role in synaptic function. At cellular level, zinc is a modulator of synaptic activity and neuronal plasticity in both development and adulthood. Different importers and transporters are involved in zinc homeostasis. ZnT-3 is a main transporter involved in zinc homeostasis in the brain. It has been found that alterations in brain zinc status have been implicated in a wide range of neurological disorders including impaired brain development and many neurodegenerative disorders such as Alzheimer's disease, and mood disorders including depression, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Furthermore, zinc has also been implicated in neuronal damage associated with traumatic brain injury, stroke, and seizure. Understanding the mechanisms that control brain zinc homeostasis is thus critical to the development of preventive and treatment strategies for these and other neurological disorders.

Perinatal exposure to chlordecone, thyroid hormone status and neurodevelopment in infants: The Timoun cohort study in Guadeloupe (French West Indies)

BackgroundPerinatal exposure to endocrine-disrupting chemicals may affect thyroid hormones homeostasis and impair brain development. Chlordecone, an organochlorine insecticide widely used in the French West Indies has known estrogenic and progestin properties, but no data is available, human or animal, on its action on thyroid hormone system. ObjectivesOur aim was to evaluate the impact of perinatal exposure to chlordecone on the thyroid hormone system of a sample of infants from the Timoun mother–child cohort in Guadeloupe and their further neurodevelopment. MethodsChlordecone was measured in cord blood and breast milk samples. Thyroid stimulating hormone (TSH), free tri-iodothyronine (FT3), free thyroxine (FT4) were determined in child blood at 3 months (n=111). Toddlers were further assessed at 18 months using an adapted version of the Ages and Stages Questionnaire (ASQ). ResultsCord chlordecone was associated with an increase in TSH in boys, whereas postnatal exposure was associated with a decrease in FT3 overall, and in FT4 among girls. Higher TSH level at 3 months was positively associated with the ASQ score of fine motor development at 18 months among boys, but TSH did not modify the association between prenatal chlordecone exposure and poorer ASQ fine motor score. ConclusionsPerinatal exposure to chlordecone may affect TSH and thyroid hormone levels at 3 months, differently according to the sex of the infant. This disruption however did not appear to intervene in the pathway between prenatal chlordecone exposure and fine motor child development.

Association of brain metabolism with sulcation and corpus callosum development assessed by MRI in late-onset small fetuses

We sought to determine the relationship between fetal brain metabolism and microstructure expressed by brain sulcation, and corpus callosum (CC) development assessed by fetal brain magnetic resonance (MR) imaging and proton MR spectroscopy ((1)H-MRS). A total of 119 fetuses, 64 that were small for gestational age (estimated fetal weight <10th centile and normal umbilical artery Doppler) and 55 controls underwent a 3T MR imaging/(1)H-MRS exam at 37 weeks. Anatomical T2-weighted images were obtained in the 3 orthogonal planes and long echo time (TE) (1)H-MRS acquired from the frontal lobe. Head biometrics, cortical fissure depths (insula, Sylvian, parietooccipital, cingulate, and calcarine), and CC area and biometries were blindly performed by manual and semiautomated delineation using Analyze software and corrected creating ratios for biparietal diameter and frontooccipital diameter, respectively, for group comparison. Spectroscopic data were processed using LCModel software and analyzed as metabolic ratios of N-acetylaspartate (NAA) to choline (Cho), Cho to creatine (Cr), and myo-inositol (Ino) to Cho. Differences between cases and controls were assessed. To test for the association between metabolic ratios and microstructural parameters, bivariate correlation analyses were performed. Spectroscopic findings showed decreased NAA/Cho and increased Cho/Cr ratios in small fetuses. They also presented smaller head biometrics, shorter and smaller CC, and greater insular and cingulate depths. Frontal lobe NAA/Cho significantly correlated with biparietal diameter (r = 0.268; P = .021), head circumference (r = 0.259; P = .026), CC length (r = 0.265; P = .026), CC area (r = 0.317; P = .007), and the area of 6 from the 7 CC subdivisions. It did not correlate with any of the cortical sulcation parameters evaluated. None of the other metabolic ratios presented significant correlations with cortical development or CC parameters. Frontal lobe NAA/Cho levels-which are considered a surrogate marker of neuronal activity-show a strong association with CC development. These results suggest that both metabolic and callosal alterations may be part of the same process of impaired brain development associated with intrauterine growth restriction.

Intellectual disability and indigenous Australians: an overview.

The review summarizes important literature in the emerging field of intellectual disability (ID) in indigenous Australians. Search of various electronic databases revealed 19 papers that provide information regarding prevalence, sociodemographic factors, and issues in assessment and management. Overall, there is limited information regarding ID in indigenous Australians, which is reported to be more prevalent compared with nonindigenous Australians. Sociocultural constructs affect what is considered to be ID in indigenous communities and this may be at odds with western notions. Other difficulties include lack of validated psychometric instruments to effectively measure cognitive functioning in indigenous Australians. Prenatal, perinatal, and postnatal factors are significant factors that impair brain development and contribute to ID in indigenous communities. Comorbid physical and psychiatric disorders need to be assessed and managed. This paper provides an overview of current knowledge regarding this important area that requires further research, appropriate training, and resourcing.

Improving lifetime trajectories for vulnerable young children and families living with significant stress and social disadvantage: the early years education program randomised controlled trial.

BackgroundChildren who experience neglect and abuse are likely to have impaired brain development and entrenched learning deficiencies. Early years interventions such as intensive education and care for these children are known to have the potential to increase their human capital. The Early Years Education Program (EYEP) is a new program offered by the Children’s Protection Society (CPS) in Melbourne, Australia. EYEP is targeted at the needs of children who have been or are at risk of being abused or neglected. It has the dual focus of seeking to address the consequences of abuse and neglect on children’s brain development and redressing their learning deficiencies. Our objective is to determine whether EYEP can improve school readiness by conducting a randomised controlled trial (RCT) of its impacts.Methods/DesignThe RCT is being conducted with 90 participants (45 intervention and 45 control). Eligible children must be aged under three years and assessed as having two or more risk factors as defined in the Department of Human Services Best Interest Case Practice Model. The intervention group participate for three years (or until school entry) in EYEP. The trial does not provide any early years education or care to the control group. Data are being collected on outcome measures for participants in EYEP and the control group at the baseline, at yearly intervals for three years, and six months after commencing the first year of school. Outcome measures encompass children’s health and development, academic ability and emotional and behavioural regulation; and quality of parenting practices. The study will evaluate the impact of EYEP on these outcomes, and undertake a benefit-cost analysis of the program.DiscussionFindings from the study have the potential to influence the quality of care and education for the large population of children in Australia who are at risk of abuse and neglect, as well as for children in mainstream childcare. The study will provide up-to-date evidence on the impact of an early years intervention relevant to an urban population in Australia; as well as (to our knowledge) being the first RCT of an early years education and care intervention in Australia.Trial registrationACTRN 12611000768998. Date 22nd July 2011.

Neurological Structure Variations in Individuals with Autism Spectrum Disorder: a Review

Autism spectrum disorder is a neurodevelopmental disorder that is characterized by impairments in social communication and social interactions along with repetitive, stereotyped behaviors and interests. The spectrum is quite broad, and the pathophysiology appears to be related to a number of factors. A common theme is that the disorder is one of impaired brain development. Neuroimaging studies offer a way to investigate impaired brain development by considering structural differences between those with autism and those without. Areas of focus include neuroanatomical regions that correlate with the clinically recognizable features of autism. In this review of structural studies, volumetric variation in terms of grey and white matter and total brain volume and in terms of neurological structures (e.g. frontal lobe, parietal cortex, amygdala, etc.) is discussed. Although a few trends have been noted, much of the literature demonstrates heterogeneity in the reported findings, which likely reflects the heterogeneity of the clinical presentation of this disorder. Further studies will need to correlate these structural findings with functional data and look to better understand the underlying molecular and genetic processes.

General anaesthesia for nonobstetric surgery during pregnancy

Nonobstetric surgery may be required in up to 1% of pregnancies. Most common procedures are urgent abdominal surgeries requiring general anaesthesia. Maintaining normal maternal physiology during anaesthesia is vital. Left lateral tilt position prevents aortocaval compression and preserves normal venous return. Preparation for a difficult airway is required in all obstetric patients due to the known anatomical and physiological changes. Aspiration prophylaxis and a rapid sequence induction are traditionally recommended to avoid the (probably overestimated) risk of aspiration. Although the minimum alveolar concentration (MAC) of volatile anaesthetic agents is reduced by 30 to 40%, awareness occurs more frequently in the obstetric population. Maternal outcomes from surgery are comparable with those of nonpregnant women, but increased incidences of foetal loss, preterm delivery, low birth weight and caesarean section have been reported. Although animal studies have observed impaired foetal brain development after antenatal exposure to anaesthesia, the translational value of these studies remain controversial. Clinical evidence is nearly absent. Withholding urgent/essential procedures is certainly more threatening than proceeding with the surgery. To increase the safety of mother and foetus, nonurgent or nonessential procedures should be postponed until after delivery, and if procedures cannot wait, locoregional anaesthesia should be used if possible. Where general anaesthesia cannot be avoided, the duration of exposure should be kept to a minimum. This narrative review summarises the literature of the past 20 years concerning the anaesthetic management and outcomes of nonobstetric surgery under general anaesthesia during pregnancy.

Influenza vaccination during early pregnancy contributes to neurogenesis and behavioral function in offspring

Prenatal influenza virus infection has been associated with an increased risk of schizophrenia. Thus, inactivated flu vaccines are widely recommended for pregnant women. In a mouse model of pregnancy, immune activation via exposure to viruses or lipopolysaccharide (LPS) impaired brain development and behavioral function in offspring. The objective of our study was to determine if flu vaccination as an immune activation could affect postnatal neurogenesis and behavior. Female C57BL/6J mice were administered A(H1N1) influenza vaccine (AIV) or seasonal influenza vaccine (SIV) early in pregnancy. We found that the offspring of vaccinated mice, especially AIV group, presented superior performance in terms of exploratory behavior and spatial ability compared with controls at postnatal day 28 (P28), but at P56, there was no significance differences among these pups. Quantification of BrdU(+)/DCX(+) and BrdU(+)/NeuN(+) cells in the dentate gyrus (DG) indicated an increase in the hippocampal neurogenesis of the pups born to both vaccinated mothers. The cytokine levels in both the serum and hippocampus changed to varying degrees. Furthermore, administration of the A(H1N1) vaccine blocked LPS-induced cognitive impairment in the progeny. Altogether, the results suggest that maternal influenza vaccination promotes neurogenesis and behavioral function, as well as protection from LPS insults in the developing offspring.

Impaired brain development and reduced cognitive function in phospholipase D-deficient mice

The phospholipases D (PLD1 and 2) are signaling enzymes that catalyze the hydrolysis of phosphatidylcholine to phosphatidic acid, a lipid second messenger involved in cell proliferation, and choline, a precursor of acetylcholine (ACh). In the present study, we investigated development and cognitive function in mice that were deficient for PLD1, or PLD2, or both. We found that PLD-deficient mice had reduced brain growth at 14–27 days post partum when compared to wild-type mice. In adult PLD-deficient mice, cognitive function was impaired in social and object recognition tasks. Using brain microdialysis, we found that wild-type mice responded with a 4-fold increase of hippocampal ACh release upon behavioral stimulation in the open field, while PLD-deficient mice released significantly less ACh. These results may be relevant for cognitive dysfunctions observed in fetal alcohol syndrome and in Alzheimer’ disease.