Kimberly Dow

Elevated corticotropin releasing hormone/ corticotropin releasing hormone-R1 expression in postmortem brain obtained from children with generalized epilepsy

The corticotropin releasing hormone (CRH) system has been suggested to initiate seizure activity in the developing brain. However, human data to support this theory is lacking. In this study, we have demonstrated that the expression of CRH, CRH‐binding protein, and CRH‐R1 (a CRH membrane receptor) were significantly elevated in cortical tissue obtained from 6 children with generalized epilepsy (mean age 8.2 ± 1.5 years) relative to age‐matched controls (mean age 7.8 ± 1.4 years). In contrast, no significant difference in the expression of CRH‐R2 was observed. The advent of CRH‐R1 receptor antagonists may prove useful as novel anticonvulsants.

Modulation of neurite promoting proteoglycans by neuronal differentiation.

A human cell line committed to neuronal lineage was used to examine the influence of differentiation on proteoglycan synthesis and function. Where the LA-N-2 cells were stimulated to differentiate towards a phenotype of cholinergic neurons, proteoglycans of the heparan sulphate class increased relative to chondroitin sulphate proteoglycans and displayed more homogeneously shorter glycosaminoglycan chains with increasing degrees of sulphation. The changes were accompanied by increasing potency of the heparan sulphate proteoglycans in neurite growth-promoting activity when immobilized on a laminin substrate. These studies begin to address the role of activity-independent growth and differentiation on the synthesis and release by neurons of neurite growth-promoting proteoglycans. The observations have implications for understanding the role of proteoglycan overexpression and the production of dystrophic neurites in Alzheimer disease.

Percutaneously placed central venous catheter-related sepsis in Canadian neonatal intensive care units.

OBJECTIVES To estimate daily risk, variability between centers, and impact on outcomes of catheter-related sepsis (CRS) among preterm neonates. STUDY DESIGN Retrospective evaluation of data from centers in the Canadian Neonatal Network for neonates born at <29 weeks or <1000 g who had a percutaneously placed central venous catheter (PCVC) in place for ≥ 48 hours. RESULTS Of 2966 infants with a PCVC, 582 (19.6%) developed CRS (overall rate 11/1000 catheter days). The daily risk of CRS varied between 1% and 2% in the first 28 days, and rates of CRS varied between centers (0 to 37 infections/1000 catheter days). Birth weight and gestational age were lower, and Score for Neonatal Acute Physiology and day of life of insertion were higher among those with CRS. Average length of stay was 6.2 days longer for those with CRS. There was no difference in mortality or major morbidities between infants who had CRS and those without CRS. CONCLUSIONS No threshold length of catheter usage days within the first 28 days was identified at or after which the risk of CRS increased. Marked variability between centers was present. Patients with CRS had an increased length of stay, but no increased risk for mortality or major morbidities.

Inotrope use among extremely preterm infants in Canadian neonatal intensive care units: variation and outcomes.

OBJECTIVE To compare neonatal outcomes between infants who received inotropes and those who did not, and identify variation in inotrope use. STUDY DESIGN Retrospective review of data from neonates < 29 weeks gestation collected by the Canadian Neonatal Network during 2003 to 2010. After controlling for confounders and maternal/infant characteristics, rates of mortality and major morbidity were compared between those who received inotropes on days 1 and 3 of admission and those who did not. Rate of inotrope use was compared between sites. RESULTS Inotropes were administered to 772 (10%) of the 7,913 neonates. Infants who received inotropes had significantly higher illness severity, surfactant use, and need for mechanical ventilation. Inotrope use was also associated with significantly higher rates of mortality (adjusted odds ratio [AOR] = 2.05 [1.64, 2.57]), retinopathy of prematurity (AOR = 2.04 [1.54, 2.71]), intraventricular hemorrhage (AOR = 1.59 [1.29, 1.93]), bronchopulmonary dysplasia (AOR = 1.38 [1.11, 1.72]), and necrotizing enterocolitis (AOR = 2.06 [1.59, 2.67]). Rates of inotrope use varied significantly between participating sites (0-36%; AOR = 0 [0, 0.1]-7.7 [2.9, 21]). CONCLUSION Risk of mortality and major morbidities were significantly higher in neonates who received inotropes. Inotrope use varied significantly among Canadian neonatal intensive care units.

Corticotropin-releasing hormone potentiates neural injury induced by oxygen-glucose deprivation: a possible involvement of microglia.

While corticotropin-releasing hormone (CRH) has been implicated in a variety of brain disorders such as ischemic injury, the molecular mechanism by which CRH elicits its activities is largely unclear. In the present study, we have determined the effect of CRH on oxygen-glucose deprivation (OGD) induced apoptosis in fetal hippocampal neurons. CRH alone at concentrations of 10-200 nM had no effect on neuronal apoptosis. However, when neurons were co-cultured with microglia, CRH alone at concentrations greater than 100 nM induced neuronal apoptosis and CRH potentiated significant neuronal apoptosis following exposure to OGD. The effect of CRH on neuronal apoptosis was inhibited in the presence of the CRH antagonist astressin. Real-time RT-PCR revealed an increase in mRNA levels of Fas ligand (Fas-L), a membrane protein related to the TNF family, in cultured microglia following OGD exposure. In the presence of CRH, OGD-induced Fas-L expression was significantly increased. The effect of CRH on Fas-L expression was inhibited by specific inhibitors of the extracellular signal-regulated protein kinase (PD98059) and p38 mitogen-activated protein kinase (SB203580). These results suggest that CRH potentiates neuronal apoptosis induced by OGD in the presence of microglia and that this effect may be mediated through the induction of proinflammatory mediators in microglia.

Influence of N-linked oligosaccharides on the processing and neurite-promoting activity of proteoglycans released by neurons in vitro

SummaryInhibitors of enzymes involved in processing of N-linked oligosaccharides were used to examine biosynthesis and the neurite-promoting activity of proteoglycans produced by and released from dissociated chick embryo spinal cord neurons in vitro. In the cell compartment and in conditioned medium both castanospermine and swainsonine inhibited 3H-glucosamine incorporation into glycoprotein but only castanospermine reduced 3H-glucosamine incorporation into heparan sulphate and chondroitin sulphate proteoglycans. All of the neurite-promoting activity of neuron-conditioned medium that complexed to laminin was associated with heparan sulphate proteoglycans as determined by heparitinase digestion. Neuron-conditioned medium prepared in the presence of castanospermine displayed a 38±6% (mean±SD) reduction in 3H-glucosamine incorporation into heparan sulphate proteoglycans and a 30±5% reduction in substrate-attached neurite-promoting activity compared to control conditioned medium and to conditioned medium prepared in the presence of swainsonine. When neurons were coincubated with castanospermine, neurite growth on a laminin substrate was 50±10% of control growth or growth in the presence of swainsonine. However, when neuron-conditioned medium was used to pretreat the laminin substrate the inhibitory effect on neurite growth produced by castanospermine coincubation was reversed. Influences on neuronal processing of N-linked oligosaccharides alter neurite growth directly and also alter the neurite-promoting activity of neuron-conditioned medium by inhibiting the synthesis of heparan sulphate proteoglycans. These studies provide further evidence for an autocrine role for heparan sulphate proteoglycans in neurite growth.

Neurodevelopmental Outcomes of Infants Born at <29 Weeks of Gestation Admitted to Canadian Neonatal Intensive Care Units Based on Location of Birth

Objective To compare mortality and neurodevelopmental outcomes of outborn and inborn preterm infants born at <29 weeks of gestation admitted to Canadian neonatal intensive care units (NICUs). Study design Data were obtained from the Canadian Neonatal Network and Canadian Neonatal Follow‐up Network databases for infants born at <29 weeks of gestation admitted to NICUs from April 2009 to September 2011. Rates of death, severe neurodevelopmental impairment (NDI), and overall NDI were compared between outborn and inborn infants at 18‐21 months of age, corrected for prematurity. Results Of 2951 eligible infants, 473 (16%) were outborn. Mean birth weight (940 ± 278 g vs 897 + 237 g), rates of treatment with antenatal steroids (53.9% vs 92.9%), birth weight small for gestational age (5.3% vs 9.4%), and maternal college education (43.7% vs 53.9%) differed between outborn and inborn infants, respectively (all P values <.01). The median Score for Neonatal Acute Physiology‐II (P = .01) and Apgar score at 5 minutes (P < .01) were higher in inborn infants. Severe brain injury was more common among outborn infants (25.3% vs 14.7%, P < .01). Outborn infants had higher odds of death or severe NDI (aOR 1.7, 95% CI 1.3‐2.2), death or overall NDI (aOR 1.6, 95% CI 1.2‐2.2), death (aOR 2.1, 95% CI 1.5‐3.0), and cerebral palsy (aOR 1.9, 95% CI 1.1‐3.3). Conclusions The composite outcomes of death or neurodevelopmental impairment were significantly higher in outborn compared with inborn infants admitted to Canadian NICUs. Adverse outcomes were mainly attributed to increased mortality and cerebral palsy in outborn neonates.