Neonatology

Self-destructive behavior in current society promotes a search for psychobiological factors underlying this epidemic. Perinatal brain plasticity increases the vulnerability to early adverse experiences, thus leading to abnormal development and behavior. Although several epidemiological investigations have correlated perinatal and neonatal complications with abnormal adult behavior, our understanding of the underlying mechanisms remains rudimentary. Models of early experience, such as repetitive pain, sepsis, or maternal separation in rodents and other species have noted multiple alterations in the adult brain, correlated with specific behavioral phenotypes depending on the timing and nature of the insult. The mechanisms mediating such changes in the neonatal brain have remained largely unexplored. We propose that lack of N-methyl-<i>D</i>-aspartate (NMDA) receptor activity from maternal separation and sensory isolation leads to increased apoptosis in multiple areas of the immature brain. On the other hand, exposure to repetitive pain may cause excessive NMDA/excitatory amino acid activation resulting in excitotoxic damage to developing neurons. These changes promote two distinct behavioral phenotypes characterized by increased anxiety, altered pain sensitivity, stress disorders, hyperactivity/attention deficit disorder, leading to impaired social skills and patterns of self-destructive behavior. The clinical important of these mechanisms lies in the prevention of early insults, effective treatment of neonatal pain and stress, and perhaps the discovery of novel therapeutic approaches that limit neuronal excitotoxicity or apoptosis.

Clinical and laboratory investigations of neonatal pain suggest that preterm neonates have an increased sensitivity to pain and that acute painful stimuli lead to the development of prolonged periods of hyperalgesia. Non-noxious stimuli during these periods of hyperalgesia may expose preterm neonates to established or chronic pain. Acute physiologic changes caused by painful or stressful stimuli can be implicated as important factors in the causation or subsequent extension of early intraventricular hemorrhage (IVH) or the ischemic changes leading to periventricular leukomalacia (PVL). Therapeutic interventions that provide comfort/analgesia in preterm neonates were correlated with a decreased incidence of severe IVH. Long-term follow-up studies of preterm neonates may substantiate the preliminary data associating repetitive painful experiences with some of the neurobehavioral and developmental sequelae resulting from neonatal intensive care.

Histological development of the epidermis was studied on skin samples from 169 infants (gestation 24–40 weeks, age up to 1 year). Gestation markedly influenced epidermal development. Before 30 weeks, the epidermis is thin, has few cell layers and a poorly formed stratum corneum, but by 34 weeks it has largely matured. Postnatal influence on epidermal development is marked in the preterm infant, so that histologically the epidermis of the most immature infant resembles that of a term infant by 2 weeks of age. These changes in histology exactly parallel the development of the barrier properties of newborn skin.

This review summarizes published as well as preliminary data on the biology of erythropoietin (Epo) in the developing and mature human central nervous system (CNS). Both Epo receptor (Epo-R) and Epo gene expression underlie developmental changes and a brain-specific regulation. These features suggest a different role of Epo in normal brain development than in neuroprotection and neuronal tissue repair after brain injury. Epo concentrations in the cerebrospinal fluid may have primary paracrine effects. While the transport of Epo across the intact blood brain barrier (BBB) is generally limited in humans, systemically produced or administrated Epo may cross during BBB dysfunction. Summarized data of the in vivo and in vitro effects of Epo in the CNS show significant neuroprotective and neurotrophic effects of this molecule. These effects are mediated by several mechanisms, including the activation of a variety of genes and their consecutive protein production. Therapeutic strategies involving activation of the CNS Epo-R are discussed, including the potential use of Epo mimetic peptides.

<i>Background:</i> As preterm and term infants in the neonatal intensive care unit (NICU) undergo multiple stressful/painful procedures, research is required that addresses chronic stress. <i>Objectives:</i> To determine whether (a) hair cortisol levels differed between term and preterm infants exposed to stress in the NICU and (b) an association exists between hair cortisol levels and severity of illness or indicators of acute stress. <i>Methods:</i> Hair cortisol levels were determined using the ELISA method (solid-phase enzyme-linked immunoassay, Alpco Diagnostics, Windham, N.H., USA) in 60 infants >25 weeks gestational age at birth. <i>Results:</i> No significant differences were found between the hair cortisol levels of term infants compared to preterm infants in the NICU. When compared to a group of healthy term infants, hospitalized infants had significantly higher hair cortisol levels (t (76) = 2.755, p = 0.004). A subgroup analysis of the term NICU infants showed a statistically significant association between total number of ventilator days and hair cortisol levels. For every extra day on the ventilator, hair cortisol levels increased on average by 0.2 nmol/g (p = 0.03). 21% of the variance in hair cortisol levels was explained by the total number of days on the ventilator. <i>Conclusions:</i> Hair cortisol is influenced by days of ventilation in NICU term infants. This is a potentially valid outcome for chronic neonatal stress in these infants and warrants further investigation.

<i>Background:</i> Physicians and parents face significant uncertainties when making care decisions for extremely low birth weight (ELBW) infants. Many published estimates of death and developmental outcome are from well-funded university programs and may not reflect outcomes of infants from a variety of settings. The best estimates of the probabilities of death and severe disability combine local experience and published data. <i>Objective:</i> To describe the neurodevelopmental outcome of ELBW infants from centers of the ELBW Infant Follow-Up Group of the Vermont Oxford Network (VON) and to identify characteristics associated with severe disability. <i>Methods:</i> Predefined measures of living situation, health and developmental outcome were collected at 18–24 months’ corrected age for infants born from July 1, 1998 to December 31, 2003 with birth weights of 401–1,000 g at 33 North American VON centers. Logistic regression was used to identify characteristics associated with severe disability. <i>Results:</i> 6,198 ELBW infants were born and survived until hospital discharge; by the time of follow-up, 88 infants (1.4%) had died. Of the remaining 6,110 infants, 3,567 (58.4%) were evaluated. Severe disability occurred in 34% of the assessed infants. Multivariate logistic regression suggested cystic periventricular leukomalacia, congenital malformation and severe intraventricular hemorrhage were the characteristics most highly associated with severe disability. There were marked variations among the follow-up clinics in the attrition rate. <i>Conclusion:</i> ELBW infants completing evaluation were at a high risk for severe disability. There are considerable differences among participating centers in attrition at follow-up. Further resources will be needed to study the effect of follow-up care for this group of infants.

Inflammatory mediators are multifunctional cytokines that play important roles both in normal central nervous system (CNS) development and in the response of the brain to diverse forms of injury. Interleukin (IL)-1β, tumor necrosis factor-α and IL-6 are among the best-characterized early-response cytokines. Recent data suggest that they may be synthesized and secreted by several CNS cell types, including microglia, astrocytes and neurons. Biological effects of these cytokines that could influence the progression of injury in the brain include stimulating the synthesis of other cytokines and neuronal injury mediators such as nitric oxide synthase, inducing leukocyte infiltration and the expression of adhesion molecules, influencing glial gene expression and damaging oligodendrocytes. In the immature brain, proinflammatory cytokines might lead to white matter damage during prenatal intrauterine infection and contribute to progressive neuronal damage in acute brain injury evoked by cerebral hypoxia-ischemia. Interrupting the proinflammatory cascade might limit the extent of irreversible injury.

In a model of perinatal hypoxic-ischemic brain damage, we examined the neuroprotective efficacy of posttreatment with the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist NBQX. Unilateral brain damage developed in 95% of rat pups subjected to hypoxia-ischemia with a 27.8 ± 1.2% weight deficit of the damaged hemisphere. MK-801 in doses of 0.3 and 0.5 mg/kg i.p. reduced the brain damage by 61% (p < 0.001) and 43% (p < 0.001), respectively. A higher dose of MK-801 (0.75 mg/kg) did not offer neuroprotection. Treatment with NBQX (40 mg/kg) reduced the hemispheric lesion by 28% (p < 0.05). In conclusion, posttreatment with both NBQX and low doses of MK-801 reduced perinatal brain damage. The NMDA receptor antagonist offered stronger neuroprotection which is in agreement with a proposed NMDA receptor hyperactivity around postnatal day 7 in rats.

Erythropoietin (Epo) decreases neuronal injury and cell death in vitro and in vivo. To lay the groundwork for use of Epo as a potential therapy for brain injury, we tested the hypothesis that systemic dosing of high-dose recombinant Epo (rEpo) would result in neuroprotective rEpo concentrations in the spinal fluid of adult and developing animals. This report characterizes the pharmacokinetics of high-dose rEpo in the blood and spinal fluid of juvenile and adult nonhuman primates (n = 7) and fetal sheep (n = 37) following a single injection. Timed blood and spinal fluid samples were collected following rEpo injection. Epo accumulation in spinal fluid was dependent on peak serum concentration and time following injection. We demonstrate that high-dose rEpo was well tolerated and results in neuroprotective concentrations in spinal fluid of adult and developing animal models by 2–2.5 h after injection.

Chúng tôi đã nghiên cứu tác động của áp lực dương liên tục (CPAP) đến cơ chế phổi và thể tích khí trong lồng ngực ở 15 lần quan sát trên 12 trẻ sơ sinh khỏe mạnh. Như dự đoán, thể tích khí trong lồng ngực tăng lên và tổng kháng trở phổi giảm. Độ co giãn động giảm xuống trong tất cả các lần quan sát. 43% áp lực được áp dụng đã được truyền qua các cấu trúc trung thất.