Plasma vasopressin levels are closely associated with fetal hypotension and neuronal injury after hypoxia-ischemia in near-term fetal sheep.

BACKGROUND: Sensitive biomarkers are needed to rapidly identify high-risk infants after hypoxia-ischemia for neuroprotective treatment. Hypotension is a key determinant of hypoxic-ischemic neural injury, and a potent stimulus of humoral pressors including angiotensin-II and arginine vasopressin. We therefore aimed to quantify the relationship between vasopressin and angiotensin-II levels in the latent phase after hypoxia-ischemia induced by umbilical cord occlusion (UCO) with both the severity of preceding hypotension and subsequent neuronal injury. METHODS: Chronically instrumented near-term fetal sheep underwent sham-UCO or UCO for either 15 min or until mean arterial pressure was <8 mmHg. Neuronal injury was assessed after 72 h recovery. RESULTS: Umbilical cord occlusion was associated with severe hypotension that recovered after UCO; two fetuses developed profound secondary hypotension within 6 h and died. Vasopressin levels but not angiotensin-II were significantly elevated 1-3 h after UCO and were closely associated with the severity of hypotension during UCO and the subsequent severity of neuronal loss in the parasagittal and lateral cortex, caudate nucleus and putamen. The Youden cut-point for vasopressin at 1 h was 180.0 pmol/L, with sensitivity 100% and specificity 92.3% for severe neuronal injury or death. CONCLUSION: Vasopressin levels shortly after moderate-severe hypoxia-ischemia may be a useful early biomarker to guide the timely implementation of neuroprotective treatment. IMPACT: It can be difficuIt to rapidly identify infants who might benefit from therapeutic hypothermia. We investigated whether increases in plasma pressor hormones early after hypoxia-ischemia were biomarkers for neonatal hypoxic-ischemic encephalopathy using near-term fetal sheep. Arginine vasopressin levels were elevated at 1-3 h after hypoxia-ischemia and were predictive of the severity of preceding hypotension and subsequent risk of severe neuronal injury or death after hypoxia-ischemia. Arginine vasopressin may help identify neonates at high risk of hypoxic-ischemic encephalopathy early within the therapeutic window for hypothermia.

Endocrine-Disrupting Chemicals in Human Fetal Growth.

Fetal growth is regulated by a complex interaction of maternal, placental, and fetal factors. The effects and outcomes that chemicals, widely distributed in the environment, may have on the health status of both the mother and the fetus are not yet well defined. Mainly mixtures of chemical substances are found in the mothers and placenta. Exposure to endocrine-disrupting chemicals (EDCs) can be associated with fetal growth retardation, thyroid dysfunction, and neurological disorders. EDCs mostly interfere with insulin, glucocorticoid, estrogenic, and thyroid pathways, with subsequent effects on normal endocrine and metabolic functions, which cause changes in the epigenome and state of inflammation with life-long effects and consequences. International scientific societies recommend the implementation of research and of all possible preventive measures. This review briefly summarizes all these aspects.

Chromatin accessibility dynamics in a model of human forebrain development.

Forebrain development is characterized by highly synchronized cellular processes, which, if perturbed, can cause disease. To chart the regulatory activity underlying these events, we generated a map of accessible chromatin in human three-dimensional forebrain organoids. To capture corticogenesis, we sampled glial and neuronal lineages from dorsal or ventral forebrain organoids over 20 months in vitro. Active chromatin regions identified in human primary brain tissue were observed in organoids at different developmental stages. We used this resource to map genetic risk for disease and to explore evolutionary conservation. Moreover, we integrated chromatin accessibility with transcriptomics to identify putative enhancer-gene linkages and transcription factors that regulate human corticogenesis. Overall, this platform brings insights into gene-regulatory dynamics at previously inaccessible stages of human forebrain development, including signatures of neuropsychiatric disorders.

Effect of comorbidities on direct cost among type 2 diabetes mellitus (T2DM) patients in tertiary care government hospital in Uttarakhand, India: A primary data analysis of out of pocket expenditure.

BACKGROUND AND AIMS: The objective of present study was to estimate and compare the direct cost between diabetics and age and gender matched non-diabetics. It also aimed to estimate and compare the effect of various comorbidities on direct cost between cases and controls, while simultaneously trying to determine the predictors of direct cost among T2DM patients. METHODS: A hospital-based pair matched case-control study was conducted in a tertiary care hospital in Garhwal division of Uttarakhand, India to accomplish the objectives of study. Regression analysis was applied to determine the predictors of direct cost among diabetics. RESULTS: Mean annual direct cost among diabetics was estimated to be US$ 104.6 (Indian Rupees (INR) 7338.9)) in comparison to US$ 27.8 (INR 1905.8) among non-diabetics. The total cost among cases was significantly higher than controls, if they had comorbidities from CVS, nervous, ophthalmic, respiratory and musculoskeletal system. Gender, education, duration of diabetes and number of comorbidities were significant predictors in estimating the direct cost among cases. For each one-year increase in duration of diabetes, direct cost increased by 13.1 unit. CONCLUSIONS: The study provides us conclusive evidence of significantly higher expenditure among diabetics in comparison to non-diabetics. An effect on direct cost among diabetics was observed with types and increasing number of comorbidities.

An embryonic 100µg/L lead exposure results in sex-specific expression changes in genes associated with the neurological system in female or cancer in male adult zebrafish brains.

Developmental lead (Pb) exposure is linked to neurological health issues. Results from non-human primate and rodent studies suggest detrimental effects of an early life Pb exposure, showing transcriptional disturbances and pathological evidence of Alzheimer's disease in the adult animal brain. To elucidate the impacts of an embryonic Pb exposure on the adult brain, transcriptomic analysis was completed on the brain of zebrafish aged 12months exposed to a control treatment or to an embryonic 100µg/L Pb exposure by sex. In the adult female zebrafish brain, significant changes in expression profiles occurred in a number of genes involved in neurological disease and nervous system development and function. On the other hand, in adult males, a number of genes with significant expression alterations were found to be associated with cancer and tumors. p38 mitogen-activated protein kinase (p38 MAPK) was also indicated as an upstream regulator of observed gene expression changes. Western blot analysis confirmed activation of p38 MAPK in the form of phosphorylated p38 MAPK in the male zebrafish brain. In addition, we compared transcriptomic changes observed in this study to a previous study with an embryonic exposure of 10µg/L Pb by sex, showing unique sets of genes dependent on Pb concentration. Overall, these results show sex-specific and concentration-dependent disturbances of global gene expression patterns in the brain of adult zebrafish exposed to Pb during embryogenesis.

Development of cortical interneurons.

Inhibitory local circuit neurons (LCNs), often called interneurons, have vital roles in the development and function of cortical networks. Their inhibitory influences regulate both the excitability of cortical projection neurons on the level of individual cells, and the synchronous activity of projection neuron ensembles that appear to be a neural basis for major aspects of cognitive processing. Dysfunction of LCNs has been associated with neurological and psychiatric diseases, such as epilepsy, schizophrenia, and autism. Here we review progress in understanding LCN fate determination, their nonradial migration to the cortex, their maturation within the cortex, and the contribution of LCN dysfunction to neuropsychiatric disorders.

Modalities of fetal evaluation to detect fetal compromise prior to the development of significant neurological damage.

AIMS: The aim of this study was to clarify the developmental mechanism underlying fetal heart rate (FHR) long-term variability (LTV) and acceleration with respect to fetal brain damage. MATERIAL AND METHODS: The fetal state was deduced from the developmental mechanism of FHR variability analyzed by actocardiogram, animal experiments, and simulations. RESULTS: LTV develops due to minor fetal movements in the fetal midbrain, moderate LTV by fetal periodic movements and triangular accelerations by large fetal movement bursts. Stimulation of the fetal midbrain by sound and light produces fetal movements that lead to FHR acceleration. Severe hypoxia can result in the loss of LTV and neuronal necrosis that may damage the fetal brain. Therefore, a cesarean section is recommended prior to the loss of LTV, rather than after its loss. The vagal center of the fetal medulla oblongata is excited by hypoxia and produces FHR bradycardia. The heart rate of hypoxic rabbits was found to be closely correlated with the PaO2, thus the impact of hypoxia could be estimated by the hypoxia index, which is calculated from the reciprocal of nadir FHR and bradycardia duration. CONCLUSIONS: Analyzing the development of FHR signs could help to diagnose fetal state. An early cesarean section is recommended before the loss of LTV as indicated by the hypoxia index, which will contribute to prevent fetal brain damage and neurological sequels.

Remote control of gene function by local translation.

The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function.

Neurodevelopmental outcome in children with congenital heart disease.

Children with congenital heart disease (CHD) have multiple factors contributing toward their risk of later neurodevelopmental difficulties. With earlier diagnosis and improved survival rates, the management of CHD now includes the recognition of neurodevelopmental risks and optimisation of neurodevelopmental outcomes is emphasised. Neuroimaging studies have shown early differences in brain development for children with CHD, who then are vulnerable to additional brain injury in the perinatal period. For some children, complications and co-morbidities may further increase the risk of brain injury. Synthesis of multiple factors is necessary to estimate neurodevelopmental prognosis for an individual child. Long-term neurodevelopmental follow-up of children with CHD is warranted for early identification of and intervention for difficulties.

The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis.

The caudal serotonergic (5-HT) system is a critical component of a medullary "homeostatic network" that regulates protective responses to metabolic stressors such as hypoxia, hypercapnia, and hyperthermia. We define anatomically the caudal 5-HT system in the human medulla as 5-HT neuronal cell bodies located in the raphé (raphé obscurus, raphé magnus, and raphé pallidus), extra-raphé (gigantocellularis, paragigantocellularis lateralis, intermediate reticular zone, lateral reticular nucleus, and nucleus subtrigeminalis), and ventral surface (arcuate nucleus). These 5-HT neurons are adjacent to all of the respiratory- and autonomic-related nuclei in the medulla where they are positioned to modulate directly the responses of these effector nuclei. In the following review, we highlight the topography and development of the caudal 5-HT system in the human fetus and infant, and its inter-relationships with nicotinic, GABAergic, and cytokine receptors. We also summarize pediatric disorders in early life which we term "developmental serotonopathies" of the caudal (as well as rostral) 5-HT domain and which are associated with homeostatic imbalances. The delineation of the development and organization of the human caudal 5-HT system provides the critical foundation for the neuropathologic elucidation of its disorders directly in the human brain.

Focusing forward genetics: a tripartite ENU screen for neurodevelopmental mutations in the mouse.

The control of growth, patterning, and differentiation of the mammalian forebrain has a large genetic component, and many human disease loci associated with cortical malformations have been identified. To further understand the genes involved in controlling neural development, we have performed a forward genetic screen in the mouse (Mus musculus) using ENU mutagenesis. We report the results from our ENU screen in which we biased our ascertainment toward mutations affecting neurodevelopment. Our screen had three components: a careful morphological and histological examination of forebrain structure, the inclusion of a retinoic acid response element-lacZ reporter transgene to highlight patterning of the brain, and the use of a genetically sensitizing locus, Lis1/Pafah1b1, to predispose animals to neurodevelopmental defects. We recovered and mapped eight monogenic mutations, seven of which affect neurodevelopment. We have evidence for a causal gene in four of the eight mutations. We describe in detail two of these: a mutation in the planar cell polarity gene scribbled homolog (Drosophila) (Scrib) and a mutation in caspase-3 (Casp3). We find that refining ENU mutagenesis in these ways is an efficient experimental approach and that investigation of the developing mammalian nervous system using forward genetic experiments is highly productive.

Mercury is a direct and potent γ-secretase inhibitor affecting Notch processing and development in Drosophila.

Prenatal exposure to mercury causes neurodevelopmental disorders and neurological pathologies in infants, such as microcephaly and mental retardation. Despite critical importance, the molecular interactions leading to mercury toxicity are yet to be elucidated. We first used a cell-free assay to investigate mercury effects on purified γ-secretase activity. Next, we treated adult Drosophila melanogaster with mercury and collected control and mercury-treated embryos, which were subjected to mild hypotonic protein extraction, or immunostained to reveal nervous system morphology. Embryos left to develop into adults were examined for wing phenotypes. Relative to control metals, we found that mercury strongly inhibits in vitro γ-secretase processing of both amyloid-ß precursor protein (APP) and Notch. Mercury inhibited APP and Notch cleavage in a dose-dependent manner, with IC(50) values of 50-125 nM, and is therefore comparable in potency to benchmark γ-secretase inhibitors. Immunoblot analysis of embryonic protein extracts showed that mercury inhibits Notch cleavage by γ-secretase in vivo. This is accompanied by severe neurodevelopmental abnormalities in embryos and adult wing-notching phenotypes. Our findings provide first evidence that mercury is a direct and potent γ-secretase inhibitor and suggest that inhibition of γ-secretase and disruption of the Notch developmental pathway potentially contribute to mercury-induced toxicity in the nervous system.

Parvovirus B19 infection in pregnancy: new insights and management.

In this article, we review the virology, pathology, epidemiology and clinical spectrum of intrauterine human parvovirus B19 (B19V) infection, including intrauterine fetal death, non-immune hydrops fetalis, thrombocytopenia and neurological manifestations such as pediatric stroke and perivascular calcifications. In addition, we discuss the new insights into the neurodevelopmental outcome of intrauterine B19V infection. Current diagnosis and management of B19V infection is summarized, including a diagnostic and follow-up flowchart for practical clinical use.

Developmental neurotoxicity study of dietary bisphenol A in Sprague-Dawley rats.

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F(1) offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day 0 through lactation day 21. F(1) offspring were evaluated using the following tests: detailed clinical observations (postnatal days [PNDs] 4, 11, 21, 35, 45, and 60), auditory startle (PNDs 20 and 60), motor activity (PNDs 13, 17, 21, and 61), learning and memory using the Biel water maze (PNDs 22 and 62), and brain and nervous system neuropathology and brain morphometry (PNDs 21 and 72). For F(1) offspring, there were no treatment-related neurobehavioral effects, nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 and 13.1 mg/kg/day during gestation and lactation, respectively), with no treatment-related effects at lower doses or nonmonotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats, and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 and 410 mg/kg/day during gestation and lactation, respectively).

In utero domoic acid toxicity: a fetal basis to adult disease in the California sea lion (Zalophus californianus).

California sea lions have been a repeated subject of investigation for early life toxicity, which has been documented to occur with increasing frequency from late February through mid-May in association with organochlorine (PCB and DDT) poisoning and infectious disease in the 1970's and domoic acid poisoning in the last decade. The mass early life mortality events result from the concentrated breeding grounds and synchronization of reproduction over a 28 day post partum estrus cycle and 11 month in utero phase. This physiological synchronization is triggered by a decreasing photoperiod of 11.48 h/day that occurs approximately 90 days after conception at the major California breeding grounds. The photoperiod trigger activates implantation of embryos to proceed with development for the next 242 days until birth. Embryonic diapause is a selectable trait thought to optimize timing for food utilization and male migratory patterns; yet from the toxicological perspective presented here also serves to synchronize developmental toxicity of pulsed environmental events such as domoic acid poisoning. Research studies in laboratory animals have defined age-dependent neurotoxic effects during development and windows of susceptibility to domoic acid exposure. This review will evaluate experimental domoic acid neurotoxicity in developing rodents and, aided by comparative allometric projections, will analyze potential prenatal toxicity and exposure susceptibility in the California sea lion. This analysis should provide a useful tool to forecast fetal toxicity and understand the impact of fetal toxicity on adult disease of the California sea lion.

Congenital anomalies and early functional impairments in a prospective birth cohort: risk of schizophrenia-spectrum disorder in adulthood.

BACKGROUND: Adversities operating over intrauterine life have been associated with risk of schizophrenia, but the biology of resultant developmental perturbation is poorly understood. AIMS: To examine the relationship of congenital anomalies and related functional impairments in infancy to risk of schizophrenia. METHOD: Using the Congenital Anomalies data-set from the Prenatal Determinants of Schizophrenia birth cohort, congenital anomalies and related functional impairments were categorised and related to subsequent risk of schizophrenia-spectrum disorder. RESULTS: The presence of any hypothesis-based congenital anomaly or related functional impairment was associated with a doubling of risk of schizophrenia-spectrum disorder. In contrast, having any other congenital anomaly or related functional impairment was not associated with risk of schizophrenia-spectrum disorder. CONCLUSIONS: These findings constitute evidence for early events, which may result from both genetic predisposition and environmental insults, in the pathogenesis of schizophrenia.

Determining normal variability in a developmental neurotoxicity test: a report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints.

With the implementation of the Food Quality Protection Act in 1996, more detailed evaluations of possible health effects of pesticides on developing organisms have been required. As a result, considerable developmental neurotoxicity (DNT) data have been generated on a variety of endpoints, including developmental changes in motor activity, auditory startle habituation, and various learning and memory parameters. One issue in interpreting these data is the level of variability for the measures used in these studies: excessive variability can obscure treatment-related effects, or conversely, small but statistically significant changes could be viewed as treatment related, when they might in fact be within the normal range. To aid laboratories in designing useful DNT studies for regulatory consideration, an operational framework for evaluating observed variability in study data has been developed. Elements of the framework suggest how an investigator might approach characterization of variability in the dataset; identification of appropriate datasets for comparison; evaluation of similarities and differences in variability between these datasets, and of possible sources of the variability, including those related to test conduct and test design. A case study using auditory startle habituation data is then presented, employing the elements of this proposed approach.

Statistical issues and techniques appropriate for developmental neurotoxicity testing: a report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints.

The data from developmental neurotoxicity (DNT) guideline studies present a number of challenges for statistical design and analysis. The importance of specifying the planned statistical analyses a priori cannot be overestimated. A review of datasets submitted to the US Environmental Protection Agency revealed several inadequate approaches, including issues of Type I error control, power considerations, and ignoring gender, time, and litter allocation as factors in the analyses. Since DNT studies include numerous experimental procedures conducted on the dam and offspring at several ages, it is not unusual to have hundreds of significance tests if each was analyzed separately. Two general approaches to control experiment-wise Type I inflation are: 1) statistical/design considerations that reduce the number of p-values, including factorial designs, multivariate techniques, and repeated-measures analyses; and 2) adjustments to the alpha level, including newer approaches that are less conservative than, for example, Bonferroni corrections. The design of the DNT study includes testing of both sexes, and gender must be included in the statistical analysis for the determination of sex-related differences, and, indeed, including both sexes may increase power. The influence of litter must be taken into account in the allocation of test animals as well as the statistical analyses. This manuscript reviews many key considerations in the analysis of DNT studies with recommendations for statistical approaches and reporting of the data.

Vasoactive intestinal peptide in neurodevelopmental disorders: therapeutic potential.

Vasoactive intestinal peptide (VIP) mediates important events during the development of the nervous system. VIP can stimulate neuronogenesis as well as differentiation and neurite outgrowth; it can promote the survival of neurons and assist in neuronal repair; it is also anti-inflammatory and can modulate immune responses. In addition, VIP is necessary for the normal growth and development of the early postimplantation mouse embryo during the period when the major embryonic events are neural tube formation, neuronogenesis and expansion of the vascular system. Receptors for VIP appear during early postimplantation embryogenesis in the rodent and exhibit changing localization patterns throughout the development of the brain. During embryogenesis, unregulated VIP may have major and permanent consequences on the formation of the brain and may be a participating factor in disorders of neurodevelopment. VIP has been linked to autism, Down syndrome and fetal alcohol syndrome. This paper will review the role of VIP in neurodevelopment, its known involvement in neurodevelopmental disorders and propose ways in which VIP might be of therapeutic value.