Wayne A. Price

Neurodevelopmental Outcome of Infants With Unilateral or Bilateral Periventricular Hemorrhagic Infarction

OBJECTIVE: Periventricular hemorrhagic infarction (PVHI) is a major contributing factor to poor neurodevelopmental outcomes in preterm infants. We hypothesized that surviving infants with unilateral PVHI would have more favorable outcomes than those with bilateral PVHI. METHODS: This was a multicenter, retrospective study of infants who were admitted to 3 NICUs in North Carolina from 1998 to 2004. The clinical course and late neuroimaging studies and neurodevelopmental outcomes of 69 infants who weighed <1500 g and had confirmed PVHI on early cranial ultrasonography were reviewed. A predictive model for Bayley Scales of Infant Development, Second Edition, Mental Developmental Index (MDI) <70 was constructed by using radiologic and clinical variables. RESULTS: Infants with unilateral PVHI had higher median MDI (82 vs 49) and Psychomotor Developmental Index (53 vs 49) than infants with bilateral PVHI. Infants with unilateral PVHI were less likely to have severe cerebral palsy (adjusted odds ratio: 0.15 [95% confidence interval (CI): 0.05–0.45]) than infants with bilateral PVHI. Infants who had unilateral PVHI and developed periventricular leukomalacia and retinopathy of prematurity that required surgery had an increased probability of having MDI <70 compared with those without these complications (probability of MDI <70: 89% [95% CI: 0.64–1.00] vs 11% [95% CI: 0.01–0.28]). CONCLUSIONS: Infants with unilateral PVHI had better motor and cognitive outcomes than infants with bilateral PVHI. By combining laterality of PVHI, periventricular leukomalacia, and retinopathy of prematurity it is possible to estimate the probability of having an MDI <70, which will assist clinicians when counseling families.

Administration of granulocyte colony-stimulating factor to neutropenic low birth weight infants of mothers with preeclampsia

Nine low birth weight infants with neutropenia born to mothers with preeclampsia were treated with granulocyte-colony stimulating factor, 10 micrograms/kg intravenously, within 24 hours of birth and at 24-hour intervals for a maximum of three doses if neutropenia persisted. The absolute neutrophil count increased significantly in eight of the nine infants within 6 hours, and neutrophilia was sustained for at least 72 hours after administration of a single dose of granulocyte-colony stimulating factor.

Tumor necrosis factor-α regulation of insulin-like growth factor-I, type 1 IGF receptor, and IGF binding protein expression in cerebellum of transgenic mice

Tumor necrosis factor‐α (TNF‐α), a proinflammatory cytokine, has been implicated in the pathogenesis of several disorders and injuries in the central nervous system (CNS). Unlike IGF‐I, which promotes CNS growth, TNF‐α causes brain growth retardation and neural damage. Recently TNF‐α has been shown to inhibit IGF‐I signaling and actions in non‐neural tissue. To investigate whether TNF‐α deleteriously influences brain growth by altering the IGF‐I system in vivo, we examined the expression of IGF‐I, the type 1 IGF receptor (IGF1R) and IGF binding proteins (IGFBPs) in the brain of transgenic (Tg) mice with murine TNF‐α overexpression. We show that overexpression of TNF‐α reduces the weights of whole brain and all brain regions examined during development. In adult TNF‐α Tg mice, cerebellum (CB) exhibited the greatest reduction in weight among the five brain regions examined, being ∼77% of that in wild‐type (WT) mice. IGF‐I abundance was decreased in the CB, as well as in cerebral cortex and diencephalon, of TNF‐α Tg mice. When compared to those in WT mice, CB IGF‐I abundance in Tg mice was reduced by ∼35%, ∼45%, and ∼40% at 2, 6, and 9 weeks of age, respectively. Of the IGFBPs studied the abundance of IGFBP‐3 and IGFBP‐4 was increased by 2–3.7‐fold, and the abundance of IGFBP‐5 was decreased by ∼3‐fold (as judged by Western immunoblot analysis). Histological analysis and immunocytochemical staining confirmed that TNF‐α specifically increases IGFBP‐3 and IGFBP‐4 immunoreactivity, as well as that of the IGF1R, in radial glial and Purkinje cells. In addition, TNF‐α alters CB cytoarchitecture, apparently by influencing granule cell migration. Our data indicate that TNF‐α alters the expression of IGF‐I system proteins in vivo, and suggest that altered expression of IGF‐I system proteins may in part explain TNF‐α deleterious actions on brain growth.

Relation between serum insulinlike growth factor-1, insulinlike growth factor binding protein-2, and insulinlike growth factor binding protein-3 and nutritional intake in premature infants with bronchopulmonary dysplasia.

Background The usefulness of serum insulinlike growth factor (IGF)-system–peptide measurement to assess the adequacy of nutritional intake in premature infants with chronic lung disease bronchopulmonary dysplasia (BPD) was assessed. Methods Twenty-nine premature infants had serial measurements taken of their serum IGF-1, insulinlike growth factor binding protein (IGFBP)-2, and IGFBP-3 concentrations between 2 and 6 weeks of age. Regression analyses were used to examine the relation between nutritional parameters and IGF-1, IGFBP-2, and IGFBP-3 concentrations in premature infants with and without BPD. Results The group of infants with BPD (n = 12) did not differ from infants without BPD (n = 17) in gestational age or weight at entry, but gained less weight during the study period. In infants without BPD, IGF-1 correlated positively with protein intake (r = 0.50) and caloric intake (r = 0.41) over the 3 days before sample collection and with weight change over the previous week (r = 0.46). In contrast, infants with BPD showed a significant correlation between IGF-1 and weight change (r = 0.54) only. There was a significant negative correlation between IGFBP-2 and protein intake in infants without BPD (r = −0.50) and in infants with BPD (r = −0.41). Negative correlations between IGFBP-2 and both weight change (r = −0.64) and caloric intake (r = −0.43) over the previous week were found only in the group of infants without BPD. IGFBP-3 correlated positively with weight changes and protein intake in both groups but correlated with caloric intake only in the group without BPD. Multiple regression analyses were used to determine significant independent variables associated with IGF-1, IGFBP-2, and IGFBP-3. In infants without BPD, significant independent predictors of IGFBP-2 were 7-day weight change and 2-day protein intake; 3-day caloric intake was the only significant independent predictor for IGFBP-3. For infants with BPD, 3-day weight gain was the only independent variable associated with serum IGF-1. Protein intake in the week before sample collection was an independent predictor of IGFBP-2 and 3-day weight change and 2-day protein intake were independent predictors of IGFBP-3. Conclusions These results confirm that changes in serum IGF-1, IGFBP-2, and IGFBP-3 reflect the nutritional status of premature infants and demonstrate that the relation between these proteins and nutritional intake differs in premature infants with and without BPD. Refinement of these observations by future studies may permit a more accurate determination of the protein and caloric intake sufficient for growth and repair after injury in premature infants with lung disease.

New insights into lung growth and development

Lung development requires a complex series of developmentally controlled interactions that involve mechanical forces, genetic and endocrine influences, and cell-cell communication. At each step, cell-matrix or cell-cell signaling mediated by peptide growth factors and extracellular matrix components is crucial in directing cell proliferation, differentiation, and migration. Although a comprehensive understanding of how these components interact to guide lung organogenesis has been elusive, the action and control of peptide growth factors in autocrine and paracrine signaling, mesenchymal-epithelial interactions in controlling branching morphogenesis, cell-cell communication in the regulation of cellular differentiation, and factors regulating pattern formation are being clarified.

Dexamethasone changes the composition of insulin-like growth factor binding proteins in the newborn mouse ileum.

Background Early postnatal glucocorticoid exposure accelerates the maturation of the bowel mucosa but results in bowel wall thinning in the newborn mouse ileum and increases the risk of focal ileal perforation in extremely premature infants. We have previously demonstrated a redistribution of insulin-like growth factor-I (IGF-I) from the submucosa in control animals to the distal villi of those treated with early postnatal dexamethasone, implicating IGF-I as an important mediator of dexamethasones capacity to alter tissue growth. To investigate the possibility that IGF binding proteins (IGFBPs) might contribute to this process, we characterized the localization and abundance of IGFBP peptides and mRNAs in the same model. Methods Newborn mice received daily intraperitoneal injections of dexamethasone (l &mgr;g/g) or phosphate-buffered saline and then were euthanized on day 3 of life. Their ileums were harvested and prepared for microscopy. Tissue sections of ileum from both treatment conditions were processed in parallel for immunolocalization of each of the six IGFBP peptides and for in situ hybridization of each of the six IGFBP transcripts. Results Transcripts for IGFBP-1, -2, and -3 were highly abundant and ubiquitous the ileal mucosa, whereas transcripts for IGFBP-4, -5, and -6 were less abundant in epithelial cells. There were no differences in abundance between control and dexamethasone-treated ileum with regard to mRNA localization or abundance for IGFBP-1, -2, -3, and -6. In contrast, mRNA transcripts for IGFBP-4 and -5 were modestly increased with dexamethasone treatment (although only IGFBP-4 was significant). Strikingly different patterns of IGFBP immunolocalization were observed between control and dexamethasone-treated animals. IGFBP-1, -2, -3, and -5 were not detected in control ileum, whereas IGFBP-4 and -6 were both present in the mucosa. In contrast, dexamethasone treatment resulted in dramatic mucosal increases in IGFBP-2, -3, -4, and -5, paralleling the changing distribution of IGF-I that we previously reported. Conclusion Taken together, these findings further implicate the IGF system as an important participant in dexamethasone-induced maturation in the newborn mouse ileum.

Comparison of noninvasive and central arterial blood pressure measurements in ELBW infants

Objective:The objective of this study was to evaluate the difference between noninvasive and central arterial blood pressure measurements in extremely low-birth-weight (ELBW) infants.Study Design:We conducted a retrospective cohort study of infants with birth weight ⩽1000 g and who were admitted to a single center in 2005. Paired noninvasive and umbilical arterial blood pressure measurements obtained in the first 72 h were compared. The primary outcome was the differential between the paired measurements. Noninvasive blood pressure (NBP) measurements were defined as clinically acceptable if the differential between the pairs was 15% or lower.Result:We obtained 146 pairs of measurements from 38 infants. The median absolute differences between noninvasive and arterial systolic, mean and diastolic blood pressure measurements were +18.5, +12 and +10 mm Hg, respectively (percentage differential of 43, 39 and 41%, respectively). In total 75% of the noninvasive measurements of mean blood pressure were clinically unacceptable. No patient or measurement characteristic was significantly associated with clinically unacceptable noninvasive measurements.Conclusion:In ELBW infants, NBP measurements substantially overestimate systolic, mean and diastolic blood pressures compared with central arterial measurements.

Expression of the Insulin-Like Growth Factor System in Postpneumonectomy Lung Growth

The insulin-like growth factors (IGF-I and IGF-II) may play an important role in postpneumonectomy compensatory lung growth by translating hormonal inputs and mechanical forces into cellular proliferation signals. We examined the mRNA abundance of IGF-I, IGF-II, and IGF binding proteins (IGFBPs) in lungs of rats on postoperative days 1, 2, 3, 5, and 7 following left pneumonectomy (PNX) or shamoperation (SC) and in normal animals (CON). There was no difference in the abundance of lung IGF-I mRNA (measured by Northern analysis) or serum IGF-I (measured by radioimmunoassay (RIA)) between SC and PNX animals. IGF-II mRNA abundance was initially decreased following PNX (73% decrease compared to SC animals on day 1, p < .05) and then rose to approach SC group values on subsequent days. Transcripts for IGFBP-2, -3, -4, -5, and -6 were decreased in both the SC and PNX groups compared to CON animals on the day following pneumonectomy, then rose back to baseline by postoperative day 2-3. Tissue IGFBPs, measured by ligand blot analyses, were not different in either the SC or PNX groups. In contrast, all serum IGFBP bands were increased on postoperative day 1 following either sham or PNX surgery. In addition, serum IGFBP-4 was increased in PNX animals compared to the SC group on days 1 and 2 (increase of 38% and 78%, respectively, p < .05). We conclude that the changes observed in lung IGF and IGFBP expression following pneumonectomy do not represent major.

Practice variation in late-preterm deliveries: a physician survey.

Objective:Late-preterm (LPT) neonates account for over 70% of all preterm births in the US. Approximately 60% of LPT births are the result of non-spontaneous deliveries. The optimal timing of delivery for many obstetric conditions at LPT gestations is unclear, likely resulting in obstetric practice variation. The purpose of this study is to identify variation in the obstetrical management of LPT pregnancies.Study Design:We surveyed obstetrical providers in North Carolina identified from North Carolina Medical Board and North Carolina Obstetrical and Gynecological Society membership lists. Participants answered demographic questions and six multiple-choice vignettes on management of LPT pregnancies.Result:We obtained 215/859 (29%) completed surveys which are as follows: 167 (78%) from obstetrics/gynecology, 27 (13%) from maternal–fetal medicine, and 21 (10%) from family medicine physicians. Overall, we found more agreement on respondents’ management of chorioamnionitis (97% would proceed with delivery), mild pre-eclampsia (84% would delay delivery/expectantly manage) and fetal growth restriction (FGR) (80% would delay delivery/expectantly manage). We found less agreement on the management of severe preeclampsia (71% would proceed with delivery), premature preterm rupture of membranes (69% would proceed with delivery) and placenta previa (67% would delay delivery/expectantly manage). Management of LPT pregnancies complicated by preterm premature rupture of membranes, FGR and placenta previa vary by specialty.Conclusion:Obstetrical providers report practice variation in the management of LPT pregnancies. Variation might be influenced by provider specialty. The absence of widespread agreement on best practice might be a source of modifiable LPT birth.

The Insulin-like Growth Factor System and Lung

The insulin-like growth factor (IGF) system is composed of two peptide growth factors, IGF-I and IGF-II, two cell-surface receptors, the type 1 and type 2 IGF receptors, and at least six binding proteins, IGFBP-1 to -6. The development of a comprehensive model of IGF system actions has been hampered by our incomplete understanding of the complex interactions both within the IGF system and with other hormones, growth factors, matrix components, and cytokines. However, there is strong evidence that the IGF system participates in lung development and various aspects of lung injury and repair.