On the limits of experimental knowledge.

To demarcate the limits of experimental knowledge, we probe the limits of what might be called an experiment. By appeal to examples of scientific practice from astrophysics and analogue gravity, we demonstrate that the reliability of knowledge regarding certain phenomena gained from an experiment is not circumscribed by the manipulability or accessibility of the target phenomena. Rather, the limits of experimental knowledge are set by the extent to which strategies for what we call 'inductive triangulation' are available: that is, the validation of the mode of inductive reasoning involved in the source-target inference via appeal to one or more distinct and independent modes of inductive reasoning. When such strategies are able to partially mitigate reasonable doubt, we can take a theory regarding the phenomena to be well supported by experiment. When such strategies are able to fully mitigate reasonable doubt, we can take a theory regarding the phenomena to be established by experiment. There are good reasons to expect the next generation of analogue experiments to provide genuine knowledge of unmanipulable and inaccessible phenomena such that the relevant theories can be understood as well supported. This article is part of a discussion meeting issue 'The next generation of analogue gravity experiments'.

A free parking trial to increase visitation and improve extremely low birth weight infant outcomes.

OBJECTIVE: Frequent parental visits are likely to benefit infants in a neonatal intensive care unit (NICU), particularly extremely low birth weight (ELBW; ⩽1000 g) survivors. Parking costs (⩾$10 per visit in our center) may deter visitation, especially for low-income parents. We assessed whether free parking (FP) decreased survivors' length of stay (LOS). STUDY DESIGN: Parents (N=138) of ELBW infants (7 to 14 days old) were randomized to usual care (UC; n=66) or FP (n=72). The primary outcome was LOS. RESULTS: Among survivors (n=116), LOS was not significantly less with FP than UC (means: FP=89, UC=102 days, P=0.22; medians: FP=82, UC=84 days, P=0.30). Groups did not differ significantly on proportion of visit days (FP=0.69, UC=0.72, P=0.47), parental involvement, knowledge/skills and satisfaction. Post hoc analyses found that parents with a greater income, a car and fewer children visited more. CONCLUSION: More potent interventions than FP are needed to increase parental visits and reduce LOS for ELBW infants in disadvantaged urban populations.

Biochemical studies of human placental microvillous plasma membrane proteins.

Isolated human syncytiotrophoblast microvillous plasma membranes (StMPM) have been examined by electron microscopy, SDS-polyacrylamide gel electrophoresis (SDS-PAGE), two-dimensional PAGE (2D-PAGE), and immunoblots. Electron microscopy of StMPM pellets revealed populations of membrane-bounded vesicles that disrupted after treatment with the chaotrope 3M KCl for 16 hr; with increasing molarity of another chaotrope (NH4SCN), the vesicles became smaller and more homogeneous. NH4SCN treatment resulted in significant reduction on SDS and 2D-PAGE analysis of only one protein at 80kd, shown by immunoblotting to be transferrin; 3M KCl had little effect and appeared to be a poor chaotrope. Chromogenic silver staining of SDS-PAGE gels demonstrated over 50 StMPM-associated discrete protein components. Immunoblotting revealed transferrin (80kd), albumin (65kd), IgG heavy chain (56kd), and Gc protein (56kd). Alpha-2-macroglobulin (alpha 2M) was identified at 180kd and 95kd; the smaller component may be a proteolytic derivative indicating alpha 2M binding to a trophoblast surface protease. Numerous discrete protein dots, and groups of dots characteristic of charge heterogeneity of individual proteins, were observed on high resolution 2D-PAGE. The most intensely stained proteins were transferrin (80kd), albumin (65kd), placental-type alkaline phosphatase (66kd), and actin (46kd). This 2D-PAGE technique is a superior method for analyzing the trophoblast membrane proteins, and the system described will enable systematic mapping of these components.

Variation in detection of VEGF in maternal serum by immunoassay and the possible influence of binding proteins.

Using radioimmunoassay (RIA) and a polyclonal antibody we have shown that maternal serum vascular endothelial growth factor (VEGF) is elevated during pregnancy. In contrast, a commercial VEGF ELISA utilizing a sandwich two-site immunoassay was unable to detect VEGF in 19 of the 20 maternal serum samples analysed. In addition, the recovery of exogenous VEGF added to the pregnancy samples was low or not recordable with the ELISA. Using RIA, 82-101% of the added VEGF was recovered. These differing results could be explained by the formation of VEGF-protein complexes that are detectable using RIA but undetectable with the ELISA. Our data imply that there is a substantial increase in circulating VEGF binding proteins during pregnancy. The increase in VEGF and its binding proteins during pregnancy may reflect important physiological events in the mother and feto-placental unit.

Preliminary experience with controlled-release aminophylline in asthmatic children: salivary levels and peak flow following a single dose.

Preliminary experience of a controlled-release aminophylline tablet in twenty-five asthmatic children has been gained by measuring salivary theophylline levels and peak flow after a single dose (11 mg/kg). The results were compared with an oral theophylline preparation. Mean salivary levels remained elevated at eight hours following ingestion of controlled-release aminophylline, at which time 58% of the children continued to show an improvement in peak flow. Individual children showed a wide variation in salivary levels and respiratory response. It is recommended that theophylline levels should be monitored in the saliva to ensure maximum benefit from the drug.

Predictors of neurodevelopmental outcomes in preterm infants with intraparenchymal hemorrhage.

OBJECTIVE: To determine which neuroimaging, clinical and sociodemographic factors predict neurodevelopment at 18-22 months age among extremely preterm infants with intraparenchymal hemorrhage (IPH). STUDY DESIGN: Cranial ultrasounds performed before 42 days of age and cranial ultrasounds/magnetic resonance images of the brain performed near discharge were reviewed for hemorrhage location and other abnormalities. Clinical and sociodemographic factors were extracted from existing databases. The primary outcome was presence of cerebral palsy (CP) and the secondary outcome was cognitive development (Bayley Scales of Infant Development). RESULT: Of 1168 infants (<1000 g or <27 weeks), 141 infants had an IPH and 48 infants were seen in follow-up. All infants with extensive hemorrhages (involving three or more lobes) developed CP. In early imaging (before 42 days of age), ventriculomegaly, intraventricular hemorrhage (IVH) and extensive hemorrhage were predictors of CP. In imaging performed near discharge, ventriculomegaly, intraventricular echodensity and having a ventricular shunt were predictors of CP. Clinical, imaging and sociodemographic factors were not associated with low cognitive score. CONCLUSION: In preterm infants surviving with IPH, extensive hemorrhage, ventriculomegaly, IVH and having a shunt increased the risk of developing CP.

Role of diffusion tensor imaging as an independent predictor of cognitive and language development in extremely low-birth-weight infants.

BACKGROUND AND PURPOSE: Diffusion tensor imaging at term can predict later development of cerebral palsy. Less is known about its ability to independently predict cognitive and language development in extremely preterm infants. The goals of the study were to investigate the following: 1) whether regional DTI measures at term-equivalent age in extremely low-birth-weight infants (birth weight, ≤1000 g) are predictive of Bayley III developmental scores at 18- to 22-months' corrected age, and 2) to compare white matter microstructural development at term and neurodevelopmental outcomes of extremely low-birth-weight infants with healthy term controls. MATERIALS AND METHODS: Fractional anisotropy and mean diffusivity in 7 vulnerable cerebral regions were measured in 42 extremely low-birth-weight and 16 term infants with high-quality DTI scans. The Bayley mental scale score (average of cognitive and language scale scores) was the primary outcome of interest with individual scores serving as secondary outcomes. Multiple linear regression modeling was used to identify the incremental ability of DTI measures to predict Bayley scores over known predictors. RESULTS: Compared with healthy term infants, extremely low-birth-weight infants exhibited significantly higher mean diffusivity and lower fractional anisotropy in 6 of 7 regions. At 18- to 22-months' corrected age, 39 extremely low-birth-weight infants (93%) and 14 term infants (88%) had undergone neurodevelopmental assessments. Although not statistically significant, extremely low-birth-weight infants averaged 7-9 points lower on Bayley subtests than term controls. In multivariable analyses, centrum semiovale mean diffusivity was a significant predictor of mental and language scale scores, and subventricular zone fractional anisotropy was a significant predictor of cognitive scale scores. A 10% increase in centrum semiovale mean diffusivity was associated with a 4.6 (95% CI, 1.6-7.6) point lower mental scale score (adjusted R(2) = 0.341, P = .001). CONCLUSIONS: In our extremely low-birth-weight cohort, DTI was an independent predictor of later cognitive and language development.

A longitudinal study of maternal serum vascular endothelial growth factor in early pregnancy.

Using a competitive radioimmunoassay to measure total immunoreactive vascular endothelial growth factor (VEGF), we describe for the first time longitudinal changes in serum VEGF in early pregnancy. The measurements were obtained from 26 women following the transfer of cryopreserved embryos; 18 singleton and eight twin pregnancies were identified by ultrasound at 6 weeks gestation and subsequently delivered as live births. Subjects did not have corpora lutea and exogenous hormone support was provided for the first 70 days of pregnancy. Serum VEGF increased approximately 30 days after embryo transfer and thereafter continued to rise in both singleton and twin pregnancies over a period of 20-40 days after which concentrations remained elevated. The longitudinal profile of serum VEGF concentrations was characterized by a logistic curve for singleton and twin pregnancies; the profile of VEGF concentrations in the twin pregnancies was significantly higher than in the singleton pregnancies (P < 0.0001). Profiles of the longitudinal concentrations of serum human chorionic gonadotrophin (HCG), oestradiol and progesterone were created by polynomial regression for singleton and twin pregnancies. The VEGF profiles were positively correlated with the profiles of HCG (r = 0.44, P = 0.02) and oestradiol (r = 0.36, P = 0.07) but not progesterone (r = 0.16, P = 0.42). Serum VEGF concentrations in the singleton thawed embryo pregnancies were compared with gestation-matched normal singleton pregnancies with corpora lutea. Concentrations of VEGF were significantly (P = 0.004) greater in the pregnancies with corpora lutea although this difference became less marked with advancing gestation. In addition to its important role in angiogenesis, we speculate that VEGF is involved in mechanisms which control the maternal cardiovascular adaptation to pregnancy.

Oxalosis in infancy.

We describe 3 infants with nephrocalcinosis and terminal renal failure. In all 3 there was widespread oxalate deposition: biochemical evidence of primary hyperoxaluria was sought but the presence of severe renal failure and the lack of established normal values for urinary and plasma oxalate and glycollate in infants made this diagnosis difficult to establish.

Relationship between maternal serum vascular endothelial growth factor concentration in early pregnancy and fetal and placental growth.

Vascular endothelial growth factor (VEGF) has important effects on endothelial cells increasing cell proliferation, permeability and nitric oxide production; concentrations of VEGF in the maternal serum increase during the first 10 weeks of pregnancy. In this study, the relationship of maternal serum VEGF with maternal health during pregnancy and with fetal and placental size at mid-pregnancy and at term was investigated. Serum was obtained from 539 Caucasian women with singleton pregnancies between 8 and 20 weeks of pregnancy (mean 14 weeks). Total serum VEGF concentrations were measured by direct competitive radioimmunoassay. Fetal size and placental volume were measured by ultrasound between 16 and 20 weeks gestation. Birthweight, placental weight and anthropometric measurements of the baby were obtained after delivery. Serum VEGF concentrations were found to be higher in women with a lower weight before pregnancy (P = 0.01) and in those carrying a female fetus (P = 0.002). VEGF concentrations were positively correlated with placental volume (r = 0.17, P = 0.0001) but not with fetal size between 16 and 20 weeks gestation. Serum VEGF concentrations were positively correlated with both birthweight (r = 0.10, P = 0.02) and placental weight at delivery (r = 0.13, P = 0.003). The data presented support the view that VEGF may be one of the factors involved in mediating the maternal cardiovascular adaptation to pregnancy.