Lesion environments direct transplanted neural progenitors towards a wound repair astroglial phenotype in mice.

Neural progenitor cells (NPC) represent potential cell transplantation therapies for CNS injuries. To understand how lesion environments influence transplanted NPC fate in vivo, we derived NPC expressing a ribosomal protein-hemagglutinin tag (RiboTag) for transcriptional profiling of transplanted NPC. Here, we show that NPC grafted into uninjured mouse CNS generate cells that are transcriptionally similar to healthy astrocytes and oligodendrocyte lineages. In striking contrast, NPC transplanted into subacute CNS lesions after stroke or spinal cord injury in mice generate cells that share transcriptional, morphological and functional features with newly proliferated host astroglia that restrict inflammation and fibrosis and isolate lesions from adjacent viable neural tissue. Our findings reveal overlapping differentiation potentials of grafted NPC and proliferating host astrocytes; and show that in the absence of other interventions, non-cell autonomous cues in subacute CNS lesions direct the differentiation of grafted NPC towards a naturally occurring wound repair astroglial phenotype.

Prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm: a prospective cohort.

OBJECTIVE: To determine the association between prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm (<28 weeks of gestation). DESIGN: The Extremely Low Gestational Age Newborn (ELGAN) Study, a prospective cohort. SETTING: Ten-year follow-up of extremely preterm infants born at 14 US hospitals between 2002 and 2004. METHODS: Prenatal tobacco smoke exposure was defined as a mother's report at enrolment of active (i.e. maternal) and passive smoking during pregnancy. Poisson regression with generalized estimating equations was used. Models adjusted for mother's age, race/ethnicity, education, insurance, pre-pregnancy body mass index, US region, multiple gestation and infant's sex; and in sensitivity analysis, gestational age at delivery and clinical subtype of preterm birth, given their classification as intermediate and non-confounding variables. MAIN OUTCOMES: Neurological impairment at 10 years, epilepsy, cerebral palsy and cognitive impairment. RESULTS: Of 1200 ELGAN study survivors, 856 were assessed at 10 years of age with neurological outcomes, of whom 14% (118/856) had active tobacco exposure during pregnancy and 24% (207/852) had passive tobacco exposure. Compared with children who were not exposed prenatally to tobacco, children exposed to active tobacco use during pregnancy had a higher risk of epilepsy (14% versus 5%; adjusted relative risk: 1.68, 95% CI 1.45-1.92). This risk remained after adjustment for gestational age at delivery and clinical subtype of preterm birth. Prenatal tobacco smoke exposure was not associated with other assessed neurological outcomes, including cerebral palsy and multiple measures of cognitive impairment. CONCLUSIONS: Among children born extremely preterm, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10 years of life. TWEETABLE ABSTRACT: Among infants born before 28 weeks of gestation, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10 years of life.

Injectable polypeptide hydrogels via methionine modification for neural stem cell delivery.

Injectable hydrogels with tunable physiochemical and biological properties are potential tools for improving neural stem/progenitor cell (NSPC) transplantation to treat central nervous system (CNS) injury and disease. Here, we developed injectable diblock copolypeptide hydrogels (DCH) for NSPC transplantation that contain hydrophilic segments of modified l-methionine (Met). Multiple Met-based DCH were fabricated by post-polymerization modification of Met to various functional derivatives, and incorporation of different amino acid comonomers into hydrophilic segments. Met-based DCH assembled into self-healing hydrogels with concentration and composition dependent mechanical properties. Mechanical properties of non-ionic Met-sulfoxide formulations (DCHMO) were stable across diverse aqueous media while cationic formulations showed salt ion dependent stiffness reduction. Murine NSPC survival in DCHMO was equivalent to that of standard culture conditions, and sulfoxide functionality imparted cell non-fouling character. Within serum rich environments in vitro, DCHMO was superior at preserving NSPC stemness and multipotency compared to cell adhesive materials. NSPC in DCHMO injected into uninjured forebrain remained local and, after 4 weeks, exhibited an immature astroglial phenotype that integrated with host neural tissue and acted as cellular substrates that supported growth of host-derived axons. These findings demonstrate that Met-based DCH are suitable vehicles for further study of NSPC transplantation in CNS injury and disease models.

Volume guarantee pressure support ventilation in extremely preterm infants and neurodevelopmental outcome at 18 months.

OBJECTIVE: Compared with pressure-controlled ventilation (PCV), volume-targeted ventilation is associated with decreased neonatal complications, including the combined outcome of death or bronchopulmonary dysplasia. However, little is known about its effect on neurodevelopmental outcome. We evaluated the hypothesis that as compared with PCV, volume-targeted ventilation reduces the risk of the combined outcome of neurodevelopmental impairment or death in very low birth weight infants. STUDY DESIGN: We studied a cohort of extremely preterm infants managed with either volume guarantee pressure support ventilation (VGPSV; n=135) or PCV (n=135). Infants were evaluated at 18 months adjusted age with a standardized neurological examination and the Bayley Scales of Infant and Toddler Development-third edition. Logistic regression models were used to evaluate the association of ventilation mode and neurodevelopmental outcome. RESULT: Rates of pulmonary interstitial emphysema (odds ratio 0.6; 95% confidence limits: 0.4, 0.8), hypotension (odds ratio: 0.7; 95% confidence limits: 0.5, 0.9) and mortality (odds ratio 0.45; 95% confidence limits: 0.22, 0.9) were lower among infants treated with VGPSV. The infants in the VGPSV group had a significantly shorter duration on mechanical ventilation compared with infants in the PCV group (log-rank test P<0.01). Seventy percent (155/221) of survivors were evaluated at 18 months adjusted age. A trend towards benefit for the combined outcome of death or neurodevelopmental impairment was seen in the VGPSV group but did not reach statistical significance (odds ratio: 0.59; 95% confidence limits: 0.32, 1.08). CONCLUSION: VGPSV was associated with a decreased risk of short-term complications but not long-term developmental impairment in this modest-sized cohort.

The ELGAN study of the brain and related disorders in extremely low gestational age newborns.

BACKGROUND: Extremely low gestational age newborns (ELGANs) are at increased risk for structural and functional brain abnormalities. AIM: To identify factors that contribute to brain damage in ELGANs. STUDY DESIGN: Multi-center cohort study. SUBJECTS: We enrolled 1506 ELGANs born before 28 weeks gestation at 14 sites; 1201 (80%) survived to 2 years corrected age. Information about exposures and characteristics was collected by maternal interview, from chart review, microbiologic and histological examination of placentas, and measurement of proteins in umbilical cord and early postnatal blood spots. OUTCOME MEASURES: Indicators of white matter damage, i.e. ventriculomegaly and echolucent lesions, on protocol cranial ultrasound scans; head circumference and developmental outcomes at 24 months adjusted age, i.e., cerebral palsy, mental and motor scales of the Bayley Scales of Infant Development, and a screen for autism spectrum disorders. RESULTS: ELGAN Study publications thus far provide evidence that the following are associated with ultrasongraphically detected white matter damage, cerebral palsy, or both: preterm delivery attributed to preterm labor, prelabor premature rupture of membranes, or cervical insufficiency; recovery of microorganisms in the placenta parenchyma, including species categorized as human skin microflora; histological evidence of placental inflammation; lower gestational age at delivery; greater neonatal illness severity; severe chronic lung disease; neonatal bacteremia; and necrotizing enterocolitis. CONCLUSIONS: In addition to supporting a potential role for many previously identified antecedents of brain damage in ELGANs, our study is the first to provide strong evidence that brain damage in extremely preterm infants is associated with microorganisms in placenta parenchyma.

Neonatal pulmonary hypertension treated with inhaled nitric oxide and high-frequency ventilation.

UNLABELLED: Term and near-term infants with pulmonary hypertension are frequently treated with inhaled nitric oxide. This therapy can be delivered with high-frequency ventilation, but there has been limited study of the relative effectiveness of high-frequency jet ventilation and high-frequency oscillatory ventilation. OBJECTIVE: To compare short-term clinical outcomes of neonates with pulmonary hypertension treated with inhaled nitric oxide plus either high-frequency jet ventilation or high-frequency oscillatory ventilation. STUDY DESIGN: Study infants met the following criteria: >or=35 weeks gestation, respiratory failure with pulmonary hypertension, no congenital malformations and treatment in the first week of life with inhaled nitric oxide plus either high-frequency jet ventilation (n=22) or high-frequency oscillatory ventilation (n=43). Data were collected from medical records. RESULT: The jet ventilation and oscillatory ventilation groups were similar in terms of gestational age, but the jet ventilation group had less severe respiratory illness (that is, lower oxygenation index) just prior to initiation of the combination of nitric oxide and high-frequency ventilation. The jet ventilation group spent more hours on inhaled nitric oxide (71.4 versus 40.8; P=0.004) but was less likely to require extracorporeal membrane oxygenation (2(9%) versus 19(44%); P=0.004). No difference was found in the ages at which oxygen and high-frequency ventilation were discontinued. CONCLUSION: Term and near-term neonates with pulmonary hypertension who require nitric oxide have similar short-term outcomes regardless of whether nitric oxide is delivered by high-frequency jet ventilation or high-frequency oscillatory ventilation.

Gastroesophageal reflux in very low birth weight infants: association with chronic lung disease and outcomes through 1 year of age.

OBJECTIVE: To analyze the association between chronic lung disease (CLD) and clinically diagnosed gastroesophageal reflux (GER) in very low birth weight (VLBW) infants, and between GER and outcomes at 1 year adjusted age. METHODS: A total of 375 consecutively born VLBW infants with CLD and 345 gestational age-matched controls were studied. Records were reviewed to ascertain which infants were diagnosed with GER (based on clinical suspicion or confirmatory tests) and which infants had delayed growth or development at 1 year adjusted age. RESULTS: Infants with CLD were treated for GER more frequently than controls (CLD: 27% versus controls: 9%; p < 0.0001). Among infants with CLD, those with and without GER were comparable in terms of the days on supplemental oxygen [124 (64 to 93) vs 121 (47 to 394)] and the proportion with cystic changes on chest radiograph (44% vs 47%). Comparing outcomes at 1 year for infants with and without GER, no differences were found in the rates of Bayley Mental Developmental and Psychomotor Developmental Indices of < 70, cerebral palsy, and measurements below the 10th percentile. CONCLUSION: Among VLBW infants, an association exists between CLD and GER, although this association might be due to greater diagnostic suspicion in infants with CLD. In VLBW infants, GER does not appear to increase the risk of delayed growth or development.

Randomized placebo-controlled trial of a 42-Day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants.

OBJECTIVE: To assess the effect on duration of ventilator dependency of a 42-day tapering course of dexamethasone in very low birth weight neonates. METHODS: Infants (N = 118) were assigned randomly, within birth weight/gender strata, to treatment with either a 42-day tapering course of dexamethasone or an equal volume of saline as placebo. Entry criteria were 1) birth weight <1501 g; 2) age between 15 and 25 days; 3) <10% decrease in ventilator settings for 24 hours and FIO2 >/=0.3; 4) absence of patent ductus arteriosus, sepsis, major congenital malformation, congenital heart disease; and 5) no evidence of maternal HIV or hepatitis B infection. The dosage schedule was 0.25 mg/kg bid for 3 days, then 0.15 mg/kg bid for 3 days, then a 10% reduction in the dose every 3 days until a dose of 0.1 mg/kg had been given for 3 days, from which time a dose of 0.1 mg/kg qod was continued until 42 days after entry. The primary endpoint was the number of days on assisted ventilation after study entry. Secondary outcomes of interest included days on supplemental oxygen, days of hospitalization, and potential adverse effects, such as infection, gastrointestinal bleeding, left ventricular hypertrophy, and severe retinopathy of prematurity. RESULTS: Infants in the dexamethasone- and placebo-treated groups were similar in terms of baseline attributes, including birth weight, gestational age, gender, race, and ventilator settings at entry. Infants treated with dexamethasone were on assisted ventilation and supplemental oxygen for fewer days after study entry (median days on ventilator, 5th and 95th percentiles, 13 [1-64] vs 25 [6-104]; days on oxygen, 59 [6-247] vs 100 [11-346]). No differences were found in risk of death, infection, or severe retinopathy. In subgroup analyses, the association of dexamethasone with more rapid weaning from the ventilator was weaker among infants enrolled before the 16th day of life, infants with chest radiographs showing cystic changes and/or hyperinflation, and infants requiring an FIO2 >/=0.7 or a peak inspiratory pressure >/=19 at study entry. CONCLUSIONS: A 42-day tapering course of dexamethasone decreases the duration of ventilator and oxygen dependency in very low birth weight infants and is not associated with an increased risk of short-term adverse effects.

Costs and benefits of respiratory syncytial virus immunoglobulin to prevent hospitalization for lower respiratory tract illness in very low birth weight infants.

BACKGROUND: Respiratory syncytial virus immunoglobulin intravenous (RSV-IGIV) has been shown to reduce the risk of lower respiratory illness (LRI) hospitalization in preterm infants and infants with bronchopulmonary dysplasia (BPD). The purpose of this analysis was to estimate the economic costs and benefits of prophylaxis with RSV-IGIV in these groups. METHODS: The analysis was performed from a payer's perspective and therefore included only costs and cost savings that would be realized by an insurer. Estimates of the direct costs of prophylaxis and the risk and cost of LRI hospitalization were based on data about preterm very low birth weight infants cared for at our medical center. Estimates of the reduction in risk of LRI hospitalization associated with RSV-IGIV were based on data from a randomized trial (the PREVENT Study). RESULTS: The range of cost for a five-dose course of RSV-IGIV was estimated to be $3280 to $8800 for infants weighing 1.2 to 10.0 kg at the time of the initial dose. Risks of LRI hospitalization were estimated to be 12, 17 and 28%, respectively, for preterm infants without BPD, with mild BPD and with moderate to severe BPD. Estimates of duration and per diem cost of LRI hospitalizations were, respectively, 5 days and $971. The estimated net cost of prophylaxis per infant ranged between $5415 for a 6-kg infant without BPD to $1689 for an infant with BPD and age < or =3 months. CONCLUSIONS: The cost of RSV-IGIV typically exceeds the cost of hospitalizations prevented by several thousand dollars. Cost minus benefit is lower for infants with BPD and infants 3 months of age or younger.

Response to dexamethasone in ventilated preterm infants: effect of radiographic subtype of chronic lung disease.

We compared the response to prolonged treatment with dexamethasone in two groups of ventilated preterm infants: one whose chest radiographs showed homogenous opacity, and one whose radiographs showed cystic changes and hyperinflation. Forty-nine infants were treated with dexamethasone for 42 days, beginning when they were 15 to 27 days old, had no evidence of sepsis or patent ductus arteriosus, and had experienced no decrease in ventilator support for 24 hours. Forty-nine controls were selected who met these criteria for dexamethasone treatment. All had birthweights of 500 to 1250 g. Two radiographs made between 14 and 28 days of age were reviewed. Among infants with homogeneous opacity (19 dexamethasone, 26 controls), dexamethasone was associated with fewer days on assisted ventilation (median [interquartile range]: 7 [3-11] versus 23 [9-40]; p = 0.001). Among those with cystic changes and hyperexpansion (30 dexamethasone, 23 controls), no difference was found between dexamethasone treated infants and controls (17 [7-34] versus 32 [16-47]; p = 0.9). Thus, the effect of dexamethasone on days of ventilation was attenuated in infants with cystic changes and hyperinflation.

Antibodies to tumor necrosis factor-alpha: use as adjunctive therapy in established group B streptococcal disease in newborn rats.

Group B Streptococcus (GBS) is the leading cause of neonatal sepsis. Adjunctive therapies are being sought to improve the outcome. Because increased blood levels of tumor necrosis factor (TNF)-alpha may play a role in the development of sepsis and an adverse outcome thereof, we evaluated the potential use of antibodies against TNF-alpha as adjunctive therapy of GBS sepsis. Using a neonatal rat model of GBS sepsis, we measured serum levels of TNF-alpha. Levels of TNF-alpha were significantly increased beginning 12 h after GBS inoculation and remained significantly increased at 30-36 h. We then examined the use of adjunctive therapy with antibody to TNF-alpha in animals with established GBS sepsis using polyclonal rabbit antirecombinant mouse TNF-alpha antiserum. Twelve hours after GBS inoculation, animals received a single dose of antibody to TNF-alpha or normal rabbit serum, and penicillin therapy (twice a day for 3 d) was begun. Animals receiving penicillin and antibody to TNF-alpha had a survival rate of 52% (13 of 25) versus 29% (7 of 24) for animals receiving penicillin and normal rabbit serum. Thus, the use of antibodies directed against TNF-alpha may have a role as adjunctive therapy of established GBS sepsis in the newborn infant.

Expectant management of preterm premature rupture of the membranes.

OBJECTIVES: Our purpose was to (1) evaluate expectant management of preterm premature rupture of the membranes between 20 and < 36 weeks' gestation and (2) compare outcomes in service and private populations. STUDY DESIGN: The study included only singleton pregnancies prospectively managed between 20 and < 36 weeks' gestation with proved preterm premature rupture of the membranes. None of the patients received prophylactic antibiotics, tocolytics, or steroids, and none of the neonates received surfactant or had lethal anomalies. Patients (n = 511) were divided into private (n = 194) and staff (n = 317) categories, but all were managed identically. RESULTS: Approximately 50% of patients were delivered within 48 hours. Infection is more likely with preterm premature rupture of membranes before 28 weeks' gestation (p = 0.001), as is fetal death associated with infection (p < 0.001). Other findings in this study were (1) no significant differences in evaluated outcomes between private and staff patients, except that significantly more vaginal deliveries occurred in staff patients, (2) a prolongation of pregnancy > or = 7 days in 12.9% of patients, (3) a significant increase in the rate of maternal infection if preterm rupture of membranes occurred before 28 weeks' gestation, (4) a significant increase in fetal and neonatal deaths if preterm premature rupture of membranes occurred before 28 weeks, and (5) an increased probability of survival whose rate of increase is dependent on the gestational age at which preterm premature rupture of membranes occurred. For babies weighing < 1500 gm at birth compared with controls, babies delivered of mothers not having preterm premature rupture of membranes, 1-year follow-up revealed (1) a significantly lower incidence of pulmonary interstitial emphysema and cerebral palsy in the study group delivered before 28 weeks' gestation, (2) a significantly lower incidence in bronchopulmonary dysplasia in the study group delivered after 28 weeks' gestation, and (3) no significant differences in the incidence of intraventricular hemorrhage, pneumothorax, or Bayley Mental Developmental Index < 68 between those delivered before or after 28 weeks' gestation. CONCLUSION: Over 47.8% of the patients continued their pregnancy beyond 48 hours, and in 12.9% of cases expectant management of preterm premature rupture of membranes prolonged the pregnancy by > or = 7 days. The maternal infection rate is greater before 28 weeks' gestation and is associated with higher fetal-neonatal mortality. Status has little impact on outcome. Expectant management is not detrimental to quality of survival. Survival probability increases at a more rapid rate with preterm premature rupture of membranes after 22 weeks of gestation.