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1.  Pharmacokinetics and Safety of a Single Intravenous Dose of myo-Inositol in Preterm Infants of 23 to 29 weeks 
Pediatric research  2013;74(6):721-729.
Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia (BPD) and reduced severe retinopathy of prematurity (ROP) in 2 randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed prior to efficacy trials.
Infants of 23–29 weeks gestation were randomized to a single intravenous (IV) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed effects approach. Safety outcomes were recorded.
A 1-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age (GA) strata and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance 0.0679 l/kg/h, endogenous production 2.67 mg/kg/h and the half life 5.22 h when modeled without the covariates. During the first 12 h renal inositol excretion quadrupled in the 120 mg/kg group, returning to near baseline after 48 h. There was no diuretic side-effect. No significant differences in adverse events occurred between the 3 groups (p > 0.05).
A single compartment model accounting for endogenous production satisfactorily described the PK of IV inositol.
PMCID: PMC3962781  PMID: 24067395
2.  Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial 
Pediatric research  2013;74(5):570-575.
Abnormal heart rate characteristics (HRC) wax and wane in early stages of culture-positive, late-onset septicemia (LOS) in patients in the neonatal intensive care unit (NICU). Continuously monitoring an HRC index leads to a reduction in mortality among very low birth weight (VLBW) infants. We hypothesized that the reduction in mortality was due to a decrease in septicemia-associated mortality.
This is a secondary analysis of clinical and HRC data from 2989 VLBW infants enrolled in a randomized controlled trial of HRC monitoring in 9 NICUs from 2004–2010.
LOS was diagnosed 974 times in 700 patients, and the incidence and distribution of organisms were similar in HRC display and non-display groups. Mortality within 30 days of LOS was lower in the HRC display compared to the non-display group (11.8% vs 19.6%, RR 0.61, 95% CI 0.43, 0.87, p<0.01), but mortality reduction was not statistically significant for patients without LOS. There were fewer large, abrupt increases in the HRC index in the days leading up to LOS diagnosis in infants whose HRC index was displayed.
Continuous HRC monitoring is associated with a lower septicemia-associated mortality in VLBW infants, possibly due to diagnosis earlier in the course of illness.
PMCID: PMC4026205  PMID: 23942558
3.  Adiposity in Adolescent Offspring Born Prematurely to Mothers with Preeclampsia 
The Journal of pediatrics  2012;162(5):912-7.e1.
To evaluate the relationship between maternal preeclampsia resulting in premature delivery and adiposity in the offspring during adolescence.
Study design
The 172 study participants were 14 years old and had very low birth weight. We compared height, weight, body mass index (BMI), percent fat, waist circumference, and triceps and subscapular skin fold thicknesses between those born prematurely secondary to preeclampsia (n = 51; 22 male) and those born prematurely after nor-motensive pregnancies (n = 121; 55 male). Multiple linear regression analysis was used to adjust for potential con-founders (maternal BMI, antenatal steroid exposure, and race) and to evaluate potential explanatory variables (fetal, infancy, and childhood weight gain, and caloric intake, level of fitness, and physical activity at 14 years).
When adjusted for potential prenatal confounders (antenatal steroid exposure and race), adolescent male offspring of preeclamptic pregnancies had higher BMI (4.0 kg/m2 [1.5, 6.6]) (mean difference [95% CI]), waist circumference (11.8 cm [3.8, 19.7]), triceps (4.6 mm [0.6, 8.6]) and subscapular skinfold thicknesses (6.2 mm [1.5, 10.9]), and percent body fat (4.1% [−0.1, 8.3]). Adjusting for infancy and childhood weight gain attenuated these group differences. There were no group differences among females.
Male adolescent offspring born prematurely of women with preeclampsia have higher measures of adiposity than those born prematurely of normotensive pregnancies. (J Pediatr 2012; ■:■-■).
PMCID: PMC3785107  PMID: 23211927
4.  Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants 
Brain, behavior, and immunity  2013;29:104-112.
Neonatal inflammation is associated with perinatal brain damage. We evaluated to what extent elevated blood levels of inflammation-related proteins supplement information about the risk of impaired early cognitive function provided by inflammation-related illnesses. From 800 infants born before the 28th week of gestation, we collected blood spots on days 1, 7 and 14, for analysis of 25 inflammation-related proteins, and data about culture-positive bacteremia, necrotizing enterocolitis (Bell stage IIIb), and isolated perforation of the intestine, during the first two weeks, and whether they were ventilated on postnatal day 14. We considered a protein to be persistently or recurrently elevated if its concentration was in the top quartile (for gestational age and day blood was collected) on two separate days one week apart. We assessed the children at 2 years of age with the Bayley Mental Development Index (MDI). The combinations of NEC and ventilation on day 14, and of bacteremia and ventilation on day 14 consistently provided information about elevated risk of MDI <55, regardless of whether or not a variable for an elevated protein concentration was included in the model. A variable for a persistently or recurrently elevated concentration of each of the following proteins provided additional information about an increased risk of MDI <55: CRP, SAA, IL-6, TNF-alpha, IL-8, MIP-1beta, ICAM-1, E-SEL, and IGFBP-1. We conclude that elevated blood concentrations of inflammation-related proteins provide information about the risk of impaired cognitive function at age 2 years that supplements information provided by inflammation-associated illnesses.
PMCID: PMC3582030  PMID: 23295265
cognitive impairment; necrotizing enterocolitis; extreme prematurity; systemic inflammatory response; neonatal chronic lung disease; neonatal sepsis
5.  Systemic inflammation associated with mechanical ventilation among extremely preterm infants 
Cytokine  2012;61(1):315-322.
Little evidence is available to document that mechanical ventilation is an antecedent of systemic inflammation in preterm humans. We obtained blood on postnatal day 14 from 726 infants born before the 28th week of gestation and measured the concentrations of 25 inflammation-related proteins. We created multivariable models to assess the relationship between duration of ventilation and protein concentrations in the top quartile. Compared to newborns ventilated for fewer than 7 days (N=247), those ventilated for 14 days (N=330) were more likely to have elevated blood concentrations of pro-inflammatory cytokines (IL-1β, TNF-α), chemokines (IL-8, MCP-1), an adhesion molecule (ICAM-1), and a matrix metalloprotease (MMP-9), and less likely to have elevated blood concentrations of two chemokines (RANTES, MIP-1β), a matrix metalloproteinase (MMP-1), and a growth factor (VEGF). Newborns ventilated for 7-13 days (N=149) had systemic inflammation that approximated the pattern of newborns ventilated for 14 days. These relationships were not confounded by chorioamnionitis or antenatal corticosteroid exposure, and were not altered appreciably among infants with and without bacteremia. These findings suggest that two weeks of ventilation are more likely than shorter durations of ventilation to be accompanied by high blood concentrations of pro-inflammatory proteins indicative of systemic inflammation, and by low concentrations of proteins that might protect from inflammation-mediated organ injury.
PMCID: PMC3518391  PMID: 23148992
inflammation; ventilation; preterm infant; cytokine; chemokine
6.  Brain damage in preterm newborns and maternal medication: The ELGAN Study 
To evaluate the association between maternal medication use during pregnancy and cerebral white matter damage and cerebral palsy (CP) among very preterm infants.
Study Design
This analysis of data from the ELGAN Study included 877 infants born <28 weeks gestation. Mothers were interviewed, charts reviewed, placentas were cultured and assessed histologically, and children evaluated at 24 months corrected age. A diagnostic algorithm classified neurologic findings as quadriparetic CP, diparetic CP, hemiparetic CP, or no CP.
After adjustment for the potential confounding of disorders for which medications might have been indicated, the risk of quadraparetic CP remained elevated among the infants of mothers who consumed aspirin (OR=3.0, 95% CI 1.3,6.9) and non-steroidal anti-inflammatory medications (NSAIDs) (OR=2.4, 95% CI 1.04,5.8). The risk of diparetic CP was also associated with maternal consumption of an NSAID, but only if the consumption was not approved by a physician (OR=3.5, 95% CI 1.1,11.0)
The possibility that aspirin and NSAID use in pregnancy could lead to perinatal brain damage cannot be excluded.
PMCID: PMC3432943  PMID: 22939723
Cerebral palsy; cerebral white matter damage; preterm
7.  Two-hit model of brain damage in the very preterm newborn: small for gestational age and postnatal systemic inflammation 
Pediatric research  2012;73(3):362-370.
We sought to disentangle the contributions of perinatal systemic inflammation and small for gestational age (SGA) to the occurrence of low Bayley Mental Development Indices (MDIs) at age 2 years.
We measured the concentration of 25 inflammation-related proteins in blood obtained during the first 2 postnatal weeks from 805 infants who were born before the 28th week of gestation and who had MDI measurements at age 2 years and were able to walk independently.
SGA newborns who did not have systemic inflammation (a concentration of an inflammation-related protein in the top quartile for gestational age on 2 days a week apart) were at greater risk of an MDI < 55, but not 55–69, than their peers who had neither SGA nor systemic inflammation. SGA infants who had elevated blood concentrations of IL-1beta, TNF-alpha, or IL-8 during the first two postnatal weeks were at even higher risk of an MDI < 55 than their SGA peers without systemic inflammation and of their non-SGA peers with systemic inflammation.
SGA appears to place very preterm newborns at increased risk of a very low MDI. Systemic inflammation adds considerably to the increased risk.
PMCID: PMC3642985  PMID: 23364171
8.  Birth weight- and fetal weight-growth restriction: impact on neurodevelopment 
Early human development  2012;88(9):765-771.
The newborn classified as growth-restricted on birth weight curves, but not on fetal weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA).
To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found.
Study design
Observational cohort of births before the 28 week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II.
B-SGA, but not F-SGA girls were at an increased risk of a PDI < 70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI < 70.
Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm.
PMCID: PMC3694609  PMID: 22732241
9.  Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis 
The Journal of Pediatrics  2012;161(2):264-269.e2.
To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants.
Study design
This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).
136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes.
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
10.  Intraventricular Hemorrhage and Developmental Outcomes at 24 months of age in Extremely Preterm Infants 
Journal of child neurology  2012;27(1):22-29.
Whether intraventricular hemorrhage increases the risk of adverse developmental outcome among premature infants is controversial. Using brain ultrasound, we identified IVH and white matter abnormalities among 1064 infants born before 28 weeks gestation. We identified adverse developmental outcomes at 24 months of age using a standardized neurological examination and the Bayley Scales of Infant Development Mental and Motor Scales. In logistic regression models that adjusted for gestational age, sex, and public insurance, isolated intraventricular hemorrhage was associated with visual fixation difficulty (odds ratio: 2.5 (95% confidence limits: 1.2, 5.1)) but no other adverse outcome. Infants who had a white matter lesion unaccompanied by intraventricular hemorrhage were at increased risk of cerebral palsy, low Mental and Motor Scores, and visual and hearing impairments. Except when accompanied or followed by a white matter lesion, intraventricular hemorrhage is associated with no more than a mild increase (and possibly no increase) in the risk of adverse developmental outcome during infancy.
PMCID: PMC3724508  PMID: 22232137
cerebral palsy; vision impairment; developmental delay; developmental disability; prematurity; Bayley Scales of Infant Development; neurodevelopmental outcome
11.  Cytokines and Perinatal Brain Damage 
Clinics in perinatology  2008;35(4):643-v.
PMCID: PMC3657129  PMID: 19026332
cyokines; developmental disability; cerebral palsy; mental retardation; periventricular leukomalacia; chorioamnionitis
12.  Agency Collaboration in the Care of Children with Complex Chronic Conditions 
Academic Pediatrics  2012;12(3):189-197.
To describe the network of collaboration among agencies that serve children with complex chronic conditions (CCC) and identify gaps in the network.
We surveyed representatives from agencies that serve children with CCC in Forsyth County, North Carolina about their agencies’ existing and desired collaborations with other agencies in the network. We used Social Network Analytical methods to describe gaps in the network. Mean out- and in-degree centrality (number of collaborative ties extending from or directed towards an agency) and density (ratio of extant ties to all possible ties) were measured.
In this network with 3,658 possible collaborative ties, care-coordination agencies and pediatric practices reported the highest existing collaborations with other agencies (out-degree centrality: 32 and 30 respectively). Pediatric practices reported strong ties with subspecialty clinics (density: 73%), but weak ties with family support services (density: 3%). Pediatric practices and subspecialty clinics (in-degree: 26) received the highest collaborative ties from other agencies. Support services and durable medical equipment companies reported low ties with other agencies (out-degree: 7 and 10 respectively). Nursing agencies reported the highest desired collaborations (out-degree: 18). Support services, pediatric practices and care-coordination programs had the highest in-degree centrality (7, 6 and 6 respectively) for desired collaborations. Nursing agencies and support services had the greatest gaps in collaboration.
Although collaboration exists among agencies serving children with CCC, there are many gaps in the network. Future studies should explore barriers and facilitators to inter-agency collaborations and whether increased collaboration in the network improves patient-level outcomes.
PMCID: PMC3354334  PMID: 22583632
children; special needs; collaboration; health services research
13.  Systemic responses of preterm newborns with presumed or documented bacteremia 
To compare the frequency of elevated concentrations of inflammation-related proteins in the blood of infants born before the 28th week of gestation who had documented bacteremia to those who had presumed (antibiotic-treated but culture-negative) bacteremia to those who neither.
The subjects of this study are the 868 infants born at 14 institutions for whom information about protein measurements on at least two of the three protocol days (days 1, 7, and 14) was available and who did not have Bell stage 3 necrotizing enterocolitis or isolated bowel perforation, which were strongly associated with bacteremia in this sample.
Newborns with presumed early (week 1) bacteremia had elevated concentrations of only a few inflammation-related proteins, while those who had presumed late (weeks 2–4) bacteremia did not have any elevations. In contrast, newborns who had documented early bacteremia had a moderately strong signal, while those who had documented late bacteremia had a stronger signal with more protein concentrations elevated on two separate occasions a week apart.
Culture-confirmed early and late bacteremia are accompanied/followed by systemic inflammatory responses not seen with presumed early and late bacteremia.
PMCID: PMC3294175  PMID: 22085230
bacteremia; infant; premature; blood proteins
14.  Elevated concentrations of inflammation-related proteins in postnatal blood predict severe developmental delay at two years in extremely premature infants 
The Journal of Pediatrics  2011;160(3):395-401.e4.
To evaluate the hypothesis that elevated levels of inflammation-related proteins in early postnatal blood predict impaired mental and motor development among extremely preterm infants.
Study design
We measured concentrations of 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14 from 939 infants born before 28 weeks gestation. An elevated level was defined as a concentration in the highest quartile for gestational age and day of blood collection. We identified impaired development at 24 months of age using the Bayley Scales of Infant Development. The primary outcomes were scores on the Mental or Motor Scale below 55 (more than 3 standard deviations below the mean).
For 17 of the 25 inflammation-related proteins, one or more statistically significant association (p < 0.01) was found between an elevated blood level of the protein and a developmental impairment. Elevations on multiple days were more often associated with developmental impairment than elevations present for only one day. The highest number of elevations was found in day-14 blood.
In extremely preterm infants, elevated levels of inflammation-related proteins in blood collected on postnatal days 7 and 14, especially when sustained, are associated with impaired mental and motor development at age two years.
PMCID: PMC3279610  PMID: 22000304
cytokines; developmental disability; prematurity; Bayley Scales of Infant Development; neurodevelopmental outcome
15.  Does Aggressive Phototherapy Increase Mortality while Decreasing Profound Impairment among the Smallest and Sickest Newborns? 
Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low birth weight (ELBW; (≤1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.
Study Design
ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12–36 hours. The effect of AgPT on outcomes (death; impairment; profound impairment; death or impairment [primary outcome], and death or profound impairment) at 18–22 months corrected age was related to BW stratum (501–750 g; 751–1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.
Baseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 hours age. Among mechanically ventilated infants ≤750 g BW (n =684), a reduction in impairment and in profound impairment was offset by higher mortality (p for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.
Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.
PMCID: PMC3558278  PMID: 22652561
Phototherapy; bilirubin; severity of illness; ELBW infant; impairment; randomized clinical trial; statistical interaction; Bayesian analysis
16.  Axonal trafficking of an antisense RNA transcribed from a pseudogene is regulated by classical conditioning 
Scientific Reports  2013;3:1027.
Natural antisense transcripts (NATs) are endogenous RNA molecules that are complementary to known RNA transcripts. The functional significance of NATs is poorly understood, but their prevalence in the CNS suggests a role in brain function. Here we investigated a long NAT (antiNOS-2 RNA) associated with the regulation of nitric oxide (NO) production in the CNS of Lymnaea, an established model for molecular analysis of learning and memory. We show the antiNOS-2 RNA is axonally trafficked and demonstrate that this is regulated by classical conditioning. Critically, a single conditioning trial changes the amount of antiNOS-2 RNA transported along the axon. This occurs within the critical time window when neurotransmitter NO is required for memory formation. Our data suggest a role for the antiNOS-2 RNA in establishing memories through the regulation of NO signaling at the synapse.
PMCID: PMC3537157  PMID: 23293742
17.  Extreme prematurity and attention deficit: epidemiology and prevention 
PMCID: PMC3776954  PMID: 24065904
extreme prematurity; neurodevelopmental impairment; attention; attention deficit hyperactivity disorder; neuroprotection
18.  Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2011;159(6):919-925.e3.
To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants.
Study design
Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants.
IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP.
CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
PMCID: PMC3215787  PMID: 21798559
19.  Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial 
The Journal of pediatrics  2011;159(6):900-906.e1.
To test the hypothesis that heart rate characteristics (HRC) monitoring improves neonatal outcomes.
Study design
Two-group, parallel, individually randomized controlled clinical trial of 3003 very low birth weight infants in 9 NICUs. In one group, HRC monitoring was displayed; in the other, it was masked. The primary outcome was number of days alive and ventilator-free in the 120 days after randomization. Secondary outcomes were mortality, number of ventilator days, NICU stay and antibiotic use.
Mortality was reduced in infants whose HRC monitoring was displayed, from 10.2% to 8.1% (HR = 0.78, 95% CI = 0.61 to 0.99, P = 0.04, number needed to monitor 48), and there was a trend toward increased days alive and ventilator-free (95.9 of 120 days compared to 93.6 in controls, P = 0.08). Mortality benefit was concentrated in infants with birth weight <1000g (HR=0.74, 95% CI 0.57 to 0.95, P=0.02, number needed to monitor 23). There were no significant differences in the other outcomes.
Heart rate characteristics monitoring can reduce mortality in very low birth weight infants.
PMCID: PMC3215822  PMID: 21864846
Neonatal sepsis; sample entropy; predictive monitoring; heart rate variability
20.  Patterns of blood protein concentrations of ELGANs classified by three patterns of respiratory disease in the first two postnatal weeks 
Pediatric research  2011;70(3):292-296.
We examined the association between elevated concentrations of 25 blood proteins in blood spots collected on postnatal days 1, 7, and 14 from infants < 28 weeks gestation who survived to 24 months and the risk of two patterns of early lung disease i.e., early and persistent pulmonary dysfunction (EPPD), and normal early pulmonary function followed by pulmonary deterioration (PD). 38% (N=347) of our cohort had PD, and 43% (N=383) had EPPD. On postnatal day 14, elevated concentrations of two proteins (RANTES and VEGF) were associated with reduced risk of PD. Similarly, the risk of EPPD was also reduced if three proteins had elevated concentrations on postnatal day 14 (RANTES, MMP-1, and VEGF). In contrast, the risk of EPPD was increased if on day 14 two proteins had elevated concentrations (IL-8 and ICAM-1). Inflammation might influence the risk of EPPD and PD, or be a consequence of lung damage or therapies to minimize lung dysfunction.
PMCID: PMC3152639  PMID: 21646942
21.  Multi-Neuronal Refractory Period Adapts Centrally Generated Behaviour to Reward 
PLoS ONE  2012;7(7):e42493.
Oscillating neuronal circuits, known as central pattern generators (CPGs), are responsible for generating rhythmic behaviours such as walking, breathing and chewing. The CPG model alone however does not account for the ability of animals to adapt their future behaviour to changes in the sensory environment that signal reward. Here, using multi-electrode array (MEA) recording in an established experimental model of centrally generated rhythmic behaviour we show that the feeding CPG of Lymnaea stagnalis is itself associated with another, and hitherto unidentified, oscillating neuronal population. This extra-CPG oscillator is characterised by high population-wide activity alternating with population-wide quiescence. During the quiescent periods the CPG is refractory to activation by food-associated stimuli. Furthermore, the duration of the refractory period predicts the timing of the next activation of the CPG, which may be minutes into the future. Rewarding food stimuli and dopamine accelerate the frequency of the extra-CPG oscillator and reduce the duration of its quiescent periods. These findings indicate that dopamine adapts future feeding behaviour to the availability of food by significantly reducing the refractory period of the brain's feeding circuitry.
PMCID: PMC3409166  PMID: 22860134
22.  Immunogenicity of Trivalent Influenza Vaccine in Extremely-Low-Birth-Weight, Premature versus Term Infants 
Influenza vaccine immunogenicity in premature infants is incompletely characterized.
To assess the immunogenicity of trivalent, inactivated influenza vaccine (TIV) in extremely low-birth-weight (ELBW, ≤1000 grams birth weight), premature (<30 weeks gestation) infants. We hypothesized that geometric mean titers (GMT) of influenza antibody would be lower in premature than in full-term (≥37 week) infants.
In this prospective, multicenter study, former premature and full-term infants ages, 6–17 months, received 2 doses of TIV during the 2006–7 or 2007–8 influenza seasons. Sera were drawn before dose 1 and 4–6 weeks after dose 2. Antibody was measured by hemagglutination inhibition.
Over two years, 41 premature and 42 full-term infants were enrolled; 36 and 33 of these infants, respectively, had post-vaccination titers available. Premature infants weighed less (mean 1.3 – 1.8 kg difference) at the time of immunization than full-term infants. Pre-vaccination titers did not differ between groups. Premature infants had higher post-vaccination antibody GMT than full-term infants to H1 (2006–7, 1:513 v. 1:91, P=0.03; 2007–8, 1:363 v. 1:189, P=0.02) and B/Victoria (2006–7, 1:51 v. 1:10, P=0.02). More premature than full-term infants had antibody titers ≥ 1:32 to B/Victoria (85% v. 60%, p=0.04) in 2007–8. Two (5%) premature and 8 (19%) full-term infants had adverse events, primarily fever, within 72 hours after vaccination. No child had medically-diagnosed influenza.
Former premature infants had antibody responses to two TIV doses greater than or equal to those of full-term children. Two TIV doses are immunogenic and well tolerated in ELBW, premature infants 6–17 months old.
PMCID: PMC3090695  PMID: 21273938
Premature infant; very low birth weight infant; influenza vaccines; immunization; vaccines
23.  Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation 
Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from 9 North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower GI series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child (matched odds ratio (OR)=3.6, 95% confidence interval (CI) 1.2, 11.2, 2-sided P=0.02), as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI 1.2, 14.4, P =0.02). Maternal history of lower GI series was also associated with increased risk (OR=7.6, 95% CI 2.8, 20.7, P <0.001) as was estimated total dose (OR for highest dose=3.0, 95% CI 1.4, 7.0, P =0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.
PMCID: PMC3124307  PMID: 20648557
germline mutation; ionizing radiation; retinoblastoma; case-control studies; pediatric cancer
24.  Blood protein concentrations in the first two postnatal weeks that predict bronchopulmonary dysplasia among infants born before the 28th week of gestation 
Pediatric research  2011;69(4):347-353.
Lung inflammation contributes to the pathogenesis of bronchopulmonary dysplasia (BPD) and may be accompanied by a systematic inflammatory response. The objective of this study was to investigate the role of systemic inflammation in the development of BPD in a cohort of extremely low gestational age newborns (ELGANs) by examining the relationships between inflammation-associated proteins in neonatal blood samples and pulmonary outcomes. Proteins were measured in blood specimens collected on postnatal days 1–3, 5–8 and 12–15 from 932 ELGANs. Increased risk of BPD was associated with elevated blood concentrations of a variety of pro-inflammatory cytokines, adhesion molecules and proteases. Reduced risk was prominently associated with increased concentrations of one chemokine, RANTES. Elevations of inflammatory proteins associated with BPD risk occurred during the first days following birth, and inflammation intensified thereafter. Therefore, exposures that promote inflammation after the first postnatal days may be more critical in the pathogenesis of BPD. Fetal growth restriction, a known BPD risk factor, was not accompanied by proteins elevations and therefore does not appear to be mediated by systemic inflammation. By contrast, mechanical ventilation altered protein levels and may be associated with systemic inflammation.
PMCID: PMC3083822  PMID: 21150694
25.  Clinical Seizures in Neonatal Hypoxic-Ischemic Encephalopathy Have No Independent Impact on Neurodevelopmental Outcome: Secondary Analyses of Data from the Neonatal Research Network Hypothermia Trial 
Journal of Child Neurology  2010;26(3):322-328.
It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.
PMCID: PMC3290332  PMID: 20921569
neonatal seizures; whole-body hypothermia; neurodevelopmental outcome; hypoxic-ischemic encephalopathy

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