Neurodevelopmental outcomes among extremely premature infants with linear growth restriction.

OBJECTIVE: To compare neurodevelopmental outcomes in linear growth-restricted (LGR) infants born <29 weeks with and without weight gain out of proportion to linear growth. STUDY DESIGN: We compared 2-year neurodevelopmental outcomes between infants with and without LGR and between LGR infants with and without weight gain out of proportion to linear growth. The outcomes were Bayley-III cognitive, motor, and language scores, cerebral palsy, Gross Motor Function Classification System (GMFCS) level ≥ 2, and neurodevelopmental impairment. RESULT: In total, 1227 infants were analyzed. LGR infants were smaller and less mature at birth, had higher BMI, and had lower Bayley-III language scores (82.3 vs. 85.0, p < 0.05). Among infants with LGR, infants with high BMI had lower language scores compared with those with low-to-normal BMI (80.8 vs. 83.3, p < 0.05), and were more likely to have GMFCS level ≥2 and neurodevelopmental impairment. CONCLUSION: Among infants with LGR, weight gain out of proportion to linear growth was associated with poorer neurodevelopmental outcomes.

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

Neurodevelopmental outcomes in postnatal growth-restricted preterm infants with postnatal head-sparing.

OBJECTIVE: To compare neurodevelopmental outcomes in postnatal growth-restricted infants born <29 weeks with and without postnatal head-sparing (PHS). STUDY DESIGN: We analyzed developmental outcomes at 2 years of age among postnatally growth-restricted infants with and without head-sparing. The primary outcome was Bayley III cognitive composite score; secondary outcomes included Bayley III motor composite score, moderate/severe cerebral palsy, gross motor functional classification scale level⩾2, and presence or absence of neurodevelopmental impairment (NDI). RESULTS: Of 1098 infants evaluated at 18 to 22 months, 658 were postnatally growth restricted, of whom 301 had head-sparing. In the multivariate model including independent risk factors for poor growth and poor developmental outcome, infants with head-sparing had higher adjusted motor composite scores (mean difference 4.65, P<0.01), but no differences in other neurodevelopmental outcomes. CONCLUSION: PHS is associated with improved neurodevelopmental outcome in extremely preterm infants, specifically Bayley III motor scores, but whether beneficial effects of PHS persist later in life is unknown.

Do currently recommended Bayley-III cutoffs overestimate motor impairment in infants born <27 weeks gestation?

OBJECTIVE: To determine whether a Bayley-III motor composite score of 85 may overestimate moderate-severe motor impairment by analyzing Bayley-III motor components and developing cut-point scores for each. STUDY DESIGN: Retrospective study of 1183 children born <27 weeks gestation at NICHD Neonatal Research Network centers and evaluated at 18-22 months corrected age. Gross Motor Function Classification System determined gross motor impairment. Statistical analyses included linear and logistic regression and sensitivity/specificity. RESULTS: Bayley-III motor composite scores were strong indicators of gross/fine motor impairment. A motor composite cut-point of 73 markedly improved the specificity for identifying gross and/or fine motor impairment (94% compared with a specificity of 76% for the proposed new cut-point of 85). A Fine Motor Scaled Score <3 differentiated mild from moderate-severe fine motor impairment. CONCLUSIONS: This study indicates that a Bayley-III motor composite score of 85 may overestimate impairment. Further studies are needed employing term controls and longer follow-up.

Regional cerebral blood flow in children from 3 to 5 months of age.

BACKGROUND AND PURPOSE: Understanding the relationship between brain and behavior in early childhood requires a probe of functional brain development. We report the first large study of regional CBF by use of arterial spin-labeling in young children. MATERIALS AND METHODS: Cerebral blood flow by use of arterial spin-labeling was measured in 61 healthy children between the ages of 3 and 5 months. Blood flow maps were parcellated into 8 broadly defined anatomic regions of each cerebral hemisphere. RESULTS: There was no sex effect; however, group analysis demonstrated significantly greater CBF in the sensorimotor and occipital regions compared with dorsolateral prefrontal, subgenual, and orbitofrontal areas (P < .0001). A significant age effect was also identified, with the largest increase in blood flow between 3 and 5 months occurring in the following regions: orbitofrontal (P < .009), subgenual (P < .002), and inferior occipital lobe (P = .001). CONCLUSIONS: These results are consistent with prior histologic studies demonstrating regional variation in brain maturation and suggest that arterial spin-labeling is sensitive to regional as well as age-related differences in CBF in young children.

Immunomodulatory cytokines suppress epithelial nitric oxide production in inflammatory bowel disease by acting on mononuclear cells.

Inducible nitric oxide synthase (iNOS) activity in colonic epithelial HT-29 cells is modulated by the T-cell-derived cytokines IL-4 and IL-13, but is not affected by IL-10 despite its effect in models of colitis. We studied the effects of these cytokines on nitric oxide (NO) production by colonic tissue. IL-10 and IL-4 but not IL-13 suppressed the NO production and iNOS expression by inflamed tissue and cytokine-stimulated noninflamed tissue from patients with ulcerative colitis, whereas the three cytokines suppressed NO production in cytokine-stimulated biopsies from controls. To examine why colonic biopsies and HT-29 cells respond differently to immunomodulatory cytokines, a coculture of mixed mononuclear monocytes (MMC) and HT-29 cells was studied. Treatment of HT-29 cells with conditioned medium from IFN-gamma/LPS-stimulated MMC produced significant amounts of NO, which suggested the presence of an MMC-derived soluble factor modifying epithelial NO production. Pretreatment of IFN-gamma/LPS-stimulated MMC with IL-10 and IL-4 but not IL-13 suppressed NO production by HT-29 cells. Interestingly, pretreatment of HT-29 cells with IL-1 receptor antagonist suppressed the IFN-gamma/LPS-stimulated MMC-induced NO production. These results suggest that immunomodulatory cytokines might exert an inhibitory effect on NO up-regulation by colonic epithelium via the inhibition of MMC-derived soluble mediators, such as IL-1.

Prediction of upper airway closure in inhalational injury.

Inhalational injury is an imprecise term used to refer to a wide range of airway and pulmonary problems in the context of thermal injury. It markedly increases the mortality and morbidity of a given degree of cutaneous thermal injury. The incidence of proximal airway edema on the modern battlefield is likely to increase with the advent of enhanced blast and thermobaric weapons systems. Current military medical doctrine suggests that soldiers who are at risk of airway closure from edema should have a surgical airway provided. This in turn is likely to lead to complications in the hands of inexperienced nonsurgeons far-forward and a choking of the medical evacuation chain more rearward. This article examines the pathophysiology of inhalational injury and ways in which prediction of airway closure might be effected to prevent unnecessary surgical airway operations.

Effect of corticosteroids on nitric oxide production in inflammatory bowel disease: are leukocytes the site of action?

Nitric oxide (NO) production is increased in the human colonic mucosa in intestinal inflammation. We examined the effect of corticosteroids and the role of mononuclear cells in this production. Colonic biopsies from patients with ulcerative colitis and normal controls were cultured with either budesonide or prednisolone in the presence of proinflammatory cytokines. Human mixed mononuclear cells (MMCs) were cocultured with HT-29 cells stimulated with IFN-gamma and LPS in the presence or absence of corticosteroids. Nitrite production was measured in supernatants by a modification of the Griess reaction, and inducible NO synthase (iNOS) mRNA expression was studied in colonic tissue by RT-PCR. Both steroids significantly suppressed the nitrite production and iNOS mRNA expression in inflamed colonic biopsies from ulcerative colitis patients and in cytokine-stimulated normal colonic biopsies but not in cytokine-stimulated HT-29 cells. Nitrite production by HT-29 cells was significantly increased (P < 0.01) in cocultures with MMCs stimulated with IFN-gamma and LPS. The presence of either prednisolone or budesonide significantly (P < 0.01) suppressed nitrite production from cocultures of HT-29 cells and MMCs but not from cultures of HT-29 cells stimulated with conditioned media from activated MMCs. Interestingly, stimulation of HT-29 with conditioned media from MMCs pretreated with steroids before stimulation with LPS and IFN-gamma induced a significantly (P < 0.01) lower nitrite production. These results suggest that the inhibitory effect of corticosteroids on the NO production in the intestinal inflammation might be via the inhibition of MMC-produced mediators responsible for NO production by colonic epithelial cells.

Differential regulation of prostaglandin E biosynthesis by interferon-gamma in colonic epithelial cells.

1. Cyclooxygenase (COX)-2 expression and activity in response to pro-inflammatory cytokines TNF alpha and IFN gamma was evaluated in the colonic epithelial cell line HT29 and the airway epithelial cell line A549. 2. TNF alpha induced concentration- and time-dependent upregulation of COX-2 mRNA, protein and prostaglandin (PG)E(2) synthesis. 3. Co-stimulation of TNF alpha with IFN gamma resulted in reduced COX-2 mRNA and protein expression. 4. IFN gamma had no effect on the stability of TNF alpha-induced COX-2 mRNA. 5. TNF alpha-induced PGE(2) biosynthesis was significantly enhanced by the simultaneous addition of IFN gamma and was COX-2 dependent. 6. The combination of IFN gamma and TNF alpha induced the microsomal prostaglandin E synthase (mPGES), comensurate with the enhanced PGE(2) synthesis. 7. These results suggest that, in terms of PGE(2) biosynthesis, IFN gamma plays a negative regulatory role at the level of COX-2 expression and a positive regulatory role at the level of mPGES expression. This may have important implications for the clinical use of IFN gamma in inflammatory diseases.