Placental contribution to neonatal encephalopathy.

Placental assessment, although currently underused, can inform our understanding of the etiology and timing of Neonatal Encephalopathy (NE). We review our current understanding of the links between placental dysfunction and NE and how this information may inform clinical decisions, now and in the future, emphasizing the four major placental lesions associated with NE. In addition, we discuss maternal and fetal factors that are hypothesized to contribute to specific placental pathologies, especially innate or acquired thrombophilias. We outline the importance of assessing placenta across trimesters and after delivery. As this field continues to evolve, currently available placental histopathological examination methods may need to be combined with advanced prenatal molecular and imaging assessments of placenta and be applied in well-designed studies in large representative populations to better define the links between placental dysfunction and NE.

Effect of magnesium sulfate exposure on term neonates.

OBJECTIVE: To compare neonatal intensive care unit and special care unit (NICU) admission rates between term neonates exposed to antenatal magnesium sulfate (MS) and those unexposed. STUDY DESIGN: We performed a retrospective cohort study of all singleton neonates ≥37 weeks born to women with pre-eclampsia from August 2006 to July 2008. Cases were defined by antenatal exposure to MS and controls by absence of MS exposure. The primary outcome was NICU admission. Data were analyzed via univariable and multivariable regression analyses. RESULT: In all, 28 (14.7%) out of 190 MS-exposed neonates ≥37 weeks were admitted to the NICU, compared with 4 (5.4%) of 74 non-exposed neonates (P=0.04). This association persisted after controlling for potential confounding variables including severe pre-eclampsia and cesarean delivery (AOR 3.69, 1.13 to 11.99). NICU admission was associated in a dose-dependent relationship with total hours and mean dose of MS exposure. Number needed to harm with MS was 11 per NICU admission. Among neonates admitted to the NICU, MS-exposed were more likely to require fluid and nutritional support than unexposed neonates (60.7 vs 0%, P=0.04), and trended toward more frequent requirement for respiratory support and greater length of stay. CONCLUSION: In term neonates, MS exposure may be associated independently with NICU admission in a dose-dependent relationship. Requirements for fluid and nutritional support are common in this group, likely due to feeding difficulties in exposed neonates. Assessment of acute care needs among all neonates exposed to MS for maternal eclampsia prophylaxis should be considered.

Global hormone profiling of murine placenta reveals Secretin expression.

OBJECTIVE: To elucidate and categorize the murine placental hormones expressed across gestation, including the expression of hormones with previously undescribed roles. STUDY DESIGN: Expression levels of all genes with known or predicted hormone activity expressed in two separate tissues, the placenta and maternal decidua, were assessed across a timecourse spanning the full lifetime of the placenta. Novel expression patterns were confirmed by in situ hybridization and protein level measurements. RESULTS: A combination of temporal and spatial information defines five groups that can accurately predict the patterns of uncharacterized hormones. Our analysis identified Secretin, a novel placental hormone that is expressed specifically by the trophoblast at levels many times greater than in any other tissue. CONCLUSIONS: The characteristics of Secretin fit the paradigm of known placental hormones and suggest that it may play an important role during pregnancy.

Perspectives of recent trainees on career choices in neonatology.

A major goal for neonatology training programs is to produce neonatologists who will pursue careers that combine clinical and research responsibilities. However, there appears to be a continuing decline in the number of trainees who choose academic, as opposed to private sector, jobs. The reason for this decline is perhaps best addressed by the people making career choices now, the recent trainees. Although many factors influence any individual's career choice, information from recent fellows indicates that several major factors play a strong role: finances; time demands; adequacy of research training; and academic institutions' attitudes toward recent trainees. Whereas the first two factors have been addressed by prior studies, the latter two factors have been less explored. The responses of a few recent trainees to an informal survey will be used to guide a discussion that focuses on the factors of research training and academic status. Ways to improve the success of training programs in producing academic neonatologists will be suggested, including the proposal of a research training curriculum, changes in the structure of post-fellowship academic status and increased encouragement of collaborative research efforts. A future survey of a broad group of recent trainees about their career choices and about proposals for training changes, such as those considered here, is needed to evaluate programs aimed at increasing the number of neonatologists engaged in research. Journal of Perinatology (2006) 26, S53-S56. doi:10.1038/sj.jp.7211527.

Early brain wiring: activity-dependent processes.

One of the leading theories of the neuropathology of schizophrenia is that it is a developmental disorder of "neural connectivity." To assess this theory, it is first necessary to understand how precise neural connections normally are established. Sensory-driven neural activity has been widely recognized as crucial for this process. Recent studies have revealed a similar requirement for endogenous neural activity generated by the nervous system itself, long before there is any sensory input. These patterns of sensory-driven and endogenously generated neural activity sculpt the precise circuits that are crucial to the many complex functions of the adult brain. This article summarizes the principles of activity-dependent neural development as determined from basic neuroscience experiments, particularly those done using the mammalian visual system, to illustrate the role of patterned activity, neuronal competition, and critical periods in shaping neural circuitry. The potential molecular mechanisms involved in these features of activity-dependent neurodevelopment are discussed and possible links to the etiology of schizophrenia are briefly explored.

Brain waves and brain wiring: the role of endogenous and sensory-driven neural activity in development.

Neural activity is critical for sculpting the intricate circuits of the nervous system from initially imprecise neuronal connections. Disrupting the formation of these precise circuits may underlie many common neurodevelopmental disorders, ranging from subtle learning disorders to pervasive developmental delay. The necessity for sensory-driven activity has been widely recognized as crucial for infant brain development. Recent experiments in neurobiology now point to a similar requirement for endogenous neural activity generated by the nervous system itself before sensory input is available. Here we use the formation of precise neural circuits in the visual system to illustrate the principles of activity-dependent development. Competition between the projections from lateral geniculate nucleus neurons that receive sensory input from the two eyes shapes eye-specific connections from an initially diffuse projection into ocular dominance columns. When the competition is altered during a critical period for these changes, by depriving one eye of vision, the normal ocular dominance column pattern is disrupted. Before ocular dominance column formation, the highly ordered projection from retina to lateral geniculate nucleus develops. These connections form before the retina can respond to light, but at a time when retinal ganglion cells spontaneously generate highly correlated bursts of action potentials. Blockade of this endogenous activity, or biasing the competition in favor of one eye, results in a severe disruption of the pattern of retinogeniculate connections. Similar spontaneous, correlated activity has been identified in many locations in the developing central nervous system and is likely to be used during the formation of precise connections in many other neural systems. Understanding the processes of activity-dependent development could revolutionize our ability to identify, prevent, and treat developmental disorders resulting from disruptions of neural activity that interfere with the formation of precise neural circuits.

Competition in retinogeniculate patterning driven by spontaneous activity.

When contacts are first forming in the developing nervous system, many neurons generate spontaneous activity that has been hypothesized to shape appropriately patterned connections. In Mustela putorius furo, monocular intraocular blockade of spontaneous retinal waves of action potentials by cholinergic agents altered the subsequent eye-specific lamination pattern of the lateral geniculate nucleus (LGN). The projection from the active retina was greatly expanded into territory normally belonging to the other eye, and the projection from the inactive retina was substantially reduced. Thus, interocular competition driven by endogenous retinal activity determines the pattern of eye-specific connections from retina to LGN, demonstrating that spontaneous activity can produce highly stereotyped patterns of connections before the onset of visual experience.

Thalamic relay of spontaneous retinal activity prior to vision.

Before vision, retinal ganglion cells produce spontaneous waves of action potentials. A crucial question is whether this spontaneous activity is transmitted to lateral geniculate nucleus (LGN) neurons. Using a novel in vitro preparation, we report that LGN neurons receive periodic barrages of postsynaptic currents from the retina that drive them to fire bursts of action potentials. Groups of LGN neurons are highly correlated in their firing. Experiments in wild-type and NMDAR1 knockout mice show that NMDA receptor activation is not necessary for firing. The transmission of the highly correlated retinal activity to the LGN supports the hypothesis that retinal waves drive retinogeniculate synaptic remodeling. Because LGN neurons are driven to fire action potentials, this spontaneous activity could also act more centrally to influence synaptic modification within the developing visual cortex.

Imaging studies of cerebral hyperperfusion after carotid endarterectomy. Case report.

A case is reported of severe unilateral hemispheric edema and localized hemorrhage associated with seizures following endarterectomy of an ipsilateral high-grade carotid stenosis. Imaging studies including angiography, computerized tomography (CT), magnetic resonance imaging/angiography, and xenon-CT, suggested postoperative ipsilateral cerebral hyperperfusion. Cerebral hyperperfusion syndromes caused by a probable failure of vascular autoregulation are rare but potentially serious complications after endarterectomy. The literature on this type of complication is briefly reviewed, and the role of various imaging modalities in identification of the syndrome and in guiding management decisions is emphasized.

Neuronal coupling in the developing mammalian retina.

During the first 3 weeks of postnatal development in the ferret retina, cells in the ganglion cell layer spontaneously generate waves of electrical activity that travel across the retina in the absence of mature photoreceptors (Meister et al., 1991; Wong et al., 1993). Since few chemical synapses are present at the earliest stages when waves are present, we have explored whether gap junctions could act to correlate the activity of cells in the immature ganglion cell layer. Retinal ganglion cells in a living in vitro preparation from postnatal day 1 (P1) to P45 were intracellularly injected with the tracer Neurobiotin and the fluorescent dye Lucifer yellow, molecules that are known to pass through gap junctions. Lucifer yellow consistently filled only the injected cell, whereas Neurobiotin filled not only the injected cell but also passed to a constellation of neighboring cells. Coupling revealed by Neurobiotin is seen as early as P1, but, at this stage, it was not possible to identify the various morphological types of cells that were coupled. Thereafter, alpha ganglion cells showed homologous coupling to other alpha cells and to both conventionally placed and displaced amacrine cells. Likewise, gamma ganglion cells appeared coupled to other gamma cells and to amacrine cells. However, beta ganglion cells never showed tracer coupling in the neonatal or in adult retinas. The percentage of alpha and gamma cells that were coupled to other cells increased progressively with age. By the end of the third postnatal week, the pattern of Neurobiotin coupling in the ferret retina was adult-like, with virtually every injected alpha cell showing tracer coupling. Our observations suggest that intercellular junctions able to pass Neurobiotin are present in the inner plexiform layer during the period when the firing of retinal ganglion cells is highly correlated. Such junctions could contribute to synchronization of the activity of subsets of neighboring ganglion cells during development, but it cannot be the sole mediator of this activity because beta cells, which also participate in the correlated activity, showed no coupling at any stage. In addition, the continued presence of coupling in the adult retina implies that other changes in retinal circuitry are likely to contribute to the disappearance of the waves.