Early Childhood Intervention. Rationale, Timing and Efficacy

This paper provides a brief review of the economic rationale for investing in early childhood. It discusses the optimal timing of intervention, with reference to recent work in developmental neuroscience, and asks how early is early? It motivates the need for early intervention by providing an overview of the impact of adverse factors during the antenatal and early childhood period on outcomes later in life. Early childhood interventions, even poorly designed ones, are costly to implement, therefore it is vital that interventions are well-designed if they are to yield high economic and social returns. The paper therefore presents a set of guiding principles for the effectiveness of early intervention. It concludes by presenting a case for a new study of the optimal timing of interventions.Early childhood intervention, brain development, optimal timing

β-adrenergic receptor activation in immortalized human urothelial cells stimulates inflammatory responses by PKA-independent mechanisms

BACKGROUND: Interstitial cystitis (IC) is a debilitating disease characterized by chronic inflammation of the urinary bladder, yet specific cellular mechanisms of inflammation in IC are largely unknown. Multiple lines of evidence suggest that β-adrenergic receptor (AR) signaling is increased in the inflamed urothelium, however the precise effects of these urothelial cell signals have not been studied. In order to better elucidate the AR signaling mechanisms of inflammation associated with IC, we have examined the effects of β-AR stimulation in an immortalized human urothelial cell line (UROtsa). For these studies, UROtsa cells were treated with effective concentrations of the selective β-AR agonist isoproterenol, in the absence or presence of selective inhibitors of protein kinase A (PKA). Cell lysates were analyzed by radioimmunoassay for generation of cAMP or by Western blotting for induction of protein products associated with inflammatory responses. RESULTS: Radioligand binding demonstrated the presence of β-ARs on human urothelial UROtsa cell membranes. Stimulating UROtsa cells with isoproterenol led to concentration-dependent increases of cAMP production that could be inhibited by pretreatment with a blocking concentration of the selective β-AR antagonist propranolol. In addition, isoproterenol activation of these same cells led to significant increases in the amount of phosphorylated extracellular signal-regulated kinase (pERK), inducible nitric oxide synthase (iNOS) and the induced form of cyclooxygenase (COX-2) when compared to control. Moreover, preincubation of UROtsa cells with the selective PKA inhibitors H-89 or Rp-cAMPs did not diminish this isoproterenol mediated phosphorylation of ERK or production of iNOS and COX-2. CONCLUSION: Functional β-ARs expressed on human urothelial UROtsa cell membranes increase the generation of cAMP and production of protein products associated with inflammation when activated by the selective β-AR agonist isoproterenol. However, the increased production of iNOS and COX-2 by isoproterenol is not blocked when UROtsa cells are preincubated with inhibitors of PKA. Therefore, UROtsa cell β-AR activation significantly increases the amount of iNOS and COX-2 produced by a PKA-independent mechanism. Consequently, this immortalized human urothelial cell line can be useful in characterizing potential AR signaling mechanisms associated with chronic inflammatory diseases of the bladder

Neurodevelopmental Outcomes at Two Years of Age for Premature Infants Diagnosed With Neonatal Obstructive Sleep Apnea

STUDY OBJECTIVES: Neurocognitive deficits have been shown in school-aged children with sleep apnea. The effect of obstructive sleep apnea (OSA) on the neurodevelopmental outcome of preterm infants is unknown. METHODS: A retrospective chart review was performed for all preterm infants ( 1 event/h. Regression analyses were performed to find a relationship between PSG parameters and cognitive, language, and motor scores. RESULTS: Fifteen patients (males: n = 10) were eligible for the study. Median postmenstrual age at the time of the PSG was 41 weeks (37-46). Median AHI for the cohort was 17.4 events/h (2.2-41.3). Median cognitive, language, and motor scores were 90 (65-125), 89 (65-121), and 91 (61-112), respectively. Mean end-tidal CO2 (median 47 mm Hg [25-60]) negatively correlated with cognitive scores (P = .01) but did not significantly correlate with language or motor scores. AHI was not associated with cognitive, language, or motor scores. CONCLUSIONS: The median score for cognitive, language, and motor scores for preterm infants with neonatal OSA were within one standard deviation of the published norm. Mean end-tidal CO2, independent of AHI, may serve as a biomarker for predicting poor cognitive outcome in preterm infants with neonatal OSA

Influence of Prolonged Serotonin and Ergovaline Pre-Exposure on Vasoconstriction Ex Vivo

Ergot alkaloid mycotoxins interfere in many functions associated with serotonergic neurotransmitters. Therefore, the objective was to evaluate whether the association of serotonin (5-hydroxytryptamine, 5-HT) and ergot alkaloids during a 24 h pre-incubation could affect the vascular contractile response to ergot alkaloids. To evaluate the effects of 24 h exposure to 5-HT and ergot alkaloids (ergovaline, ERV), two assays were conducted. The first assay determined the half-maximal inhibitory concentration (IC50)following the 24 h pre-exposure period, while the second assay evaluated the effect of IC50 concentrations of 5-HT and ERV either individually or in combination. There was an interaction between previous exposure to 5-HT and ERV. Previous exposure to 5-HT at the IC50 concentration of 7.57 × 10−7 M reduced the contractile response by more than 50% of control, while the exposure to ERV at IC50 dose of 1.57 × 10−10 M tended to decrease (p = 0.081) vessel contractility with a response higher than 50% of control. The 24 h previous exposure to both 5-HT and ERV did not potentiate the inhibitory response of blood vessels in comparison with incubation with each compound alone. These results suggest receptor competition between 5-HT and ERV. More studies are necessary to determine the potential of 5-HT to treat toxicosis caused by ergot alkaloids

Effect of Biochanin A on the Rumen Microbial Community of Holstein Steers Consuming a High Fiber Diet and Subjected to a Subacute Acidosis Challenge

Subacute rumen acidosis (SARA) occurs when highly fermentable carbohydrates are introduced into the diet, decreasing pH and disturbing the microbial ecology of the rumen. Rumen amylolytic bacteria rapidly catabolize starch, fermentation acids accumulate in the rumen and reduce environmental pH. Historically, antibiotics (e.g., monensin, MON) have been used in the prevention and treatment of SARA. Biochanin A (BCA), an isoflavone produced by red clover (Trifolium pratense), mitigates changes associated with starch fermentation ex vivo. The objective of the study was to determine the effect of BCA on amylolytic bacteria and rumen pH during a SARA challenge. Twelve rumen fistulated steers were assigned to 1 of 4 treatments: HF CON (high fiber control), SARA CON, MON (200 mg d-1), or BCA (6 g d-1). The basal diet consisted of corn silage and dried distiller’s grains ad libitum. The study consisted of a 2-wk adaptation, a 1-wk HF period, and an 8-d SARA challenge (d 1–4: 40% corn; d 5–8: 70% cracked corn). Samples for pH and enumeration were taken on the last day of each period (4 h). Amylolytic, cellulolytic, and amino acid/peptide-fermenting bacteria (APB) were enumerated. Enumeration data were normalized by log transformation and data were analyzed by repeated measures ANOVA using the MIXED procedure of SAS. The SARA challenge increased total amylolytics and APB, but decreased pH, cellulolytics, and in situ DMD of hay (P \u3c 0.05). BCA treatment counteracted the pH, microbiological, and fermentative changes associated with SARA challenge (P \u3c 0.05). Similar results were also observed with MON (P \u3c 0.05). These results indicate that BCA may be an effective alternative to antibiotics for mitigating SARA in cattle production systems

Gamma ray monitoring of a AGN and galactic black hole candidates by the Compton Gamma Ray Observatory

The Compton Gamma-Ray Observatory's Burst and Transient Source Experiment (BATSE) has a powerful capability to provide nearly uninterrupted monitoring in the 25 keV-10 MeV range of both active galactic nuclei (AGN) and galactic black hole candidates (GBHC) such as Cygnus X-1, using the occultation of cosmic sources by the Earth. Since the Crab is detected by the BATSE Large Area Detectors with roughly 25(sigma) significance in the 15-125 keV range in a single rise or set, a variation by a factor of two of a source having one-tenth the strength of Cygnus X-1 should be detectable within a day. Methods of modeling the background are discussed which will increase the accuracy, sensitivity, and reliability of the results beyond those obtainable from a linear background fit with a single rise or set discontinuity

Vasoactivity and Vasoconstriction Changes in Cattle Related to Time Off Toxic Endophyte-Infected Tall Fescue

Previous research has indicated that serotonergic and α-adrenergic receptors in peripheral vasculature are affected by exposure of cattle grazing toxic endophyte-infected (E+; Epichlöe coenophialia) tall fescue (Lolium arundinaceum). The objective of this experiment was to determine the period of time necessary for the vascular effects of ergot alkaloids to subside. Two experiments were conducted to investigate changes in vascular contractile response and vasoconstriction over time relative to removal from an ergot alkaloid-containing E+ tall fescue pasture. In Experiment 1, lateral saphenous vein biopsies were conducted on 21 predominantly Angus steers (357 ± 3 kg body weight) at 0 (n = 6), 7 (n = 6), 14 (n = 5), or 28 days (n = 4) after removal from grazing pasture (3.0 ha; endpoint ergovaline + ergovalinine = 1.35 mg/kg DM) for 126 days. In Experiment 2, lateral saphenous veins were biopsied from 24 Angus-cross steers (361 ± 4 kg body weight) at 0, 21, 42, and 63 days (n = 6 per time point) following removal from grazing tall fescue pastures (3.0 ha; first 88 days endpoint ergovaline + ergovalinine = 0.15 mg/kg DM; last 18 days endpoint ergovaline + ergovalinine = 0.57 mg/kg DM) for 106 total days. Six steers (370 ± 18 kg body weight) off of bermudagrass pasture for the same time interval were also biopsied on Day 0 and Day 63 (n = 3 per time point). Additionally, in Experiment 2, cross-sectional ultrasound scans of caudal artery at the fourth coccygeal vertebra were taken on Days 0, 8, 15, 21, 29, 36, 42, and 45 to determine mean artery luminal area to evaluate vasoconstriction. In both experiments, steers were removed from pasture and housed in a dry lot and fed a corn silage diet for the duration of biopsies and ultrasound scans. Biopsied vessels used to evaluate vasoactivity were cleaned, incubated in a multimyograph, and exposed to increasing concentrations of 4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide (TCB2; 5HT2A agonist), guanfacine (GF; α2A-adrenergic agonist), and (R)-(+)-m-nitrobiphenyline oxalate (NBP; α2C-adrenergic agonist) in both experiments and ergovaline (ERV) and ergotamine (ERT) in Experiments 1 and 2, respectively. In Experiment 1, days off pasture × agonist concentration was not significant (p \u3e 0.1) for all four compounds tested. In Experiment 2, GF, NBP, TCB2 and ERT were significant for days off pasture × agonist concentration interaction (p \u3c 0.02) and vasoactivity increased over time. Vasoactivity to agonists was reduced (p \u3c 0.05) when steers were initially removed from E+ tall fescue pasture compared to bermudagrass, but did not differ by Day 63 for any variable. Luminal areas of caudal arteries in steers grazed on E+ tall fescue relaxed and were similar to steers that had grazed bermudagrass for 36 days on non-toxic diet (p = 0.15). These data demonstrate changes in peripheral vasoactivity and recovery from vasoconstriction occur beyond five weeks off toxic pasture and 5HT2A receptors appear to be more dramatically affected in the lateral saphenous vein by grazing E+ tall fescue pasture than adrenergic receptors

Uncertainty analysis: an evaluation metric for synthesis science

The methods for conducting reductionist ecological science are well known and widely used. In contrast, those used in the synthesis of ecological science (i.e., synthesis science) are still being developed, vary widely, and often lack the rigor of reductionist approaches. This is unfortunate because the synthesis of ecological parts into a greater whole is critical to understanding many of the environmental challenges faced by society. To help address this imbalance in approaches, we examine how the rigor of ecological synthesis science might be increased by using uncertainty as an evaluation metric-as a parallel to methods used in reductionist science. To estimate and understand uncertainty we propose that it be divided into four general classes: (1) measurement uncertainty (i.e., experimental error) as defined by precision and accuracy, (2) sampling uncertainty that reflects natural variation in space and time as quantified by classical statistical moments (e.g., mean and variance), (3) model prediction uncertainty which relates to the transformation of measurements into other variables of interest (e.g., plant dimensions to biomass), and (4) model selection uncertainty which relates to uncertainty about the form of the relationships used in models. Of these sources of uncertainty, model selection is the least understood and potentially, the most important, because it is integral to how components of a system are combined and it reflects imperfect knowledge about these relationships. To demonstrate uncertainty in synthesis science, we examine each source of uncertainty in an analysis that estimates the live tree biomass of a forest and how knowledge of each source can improve future estimates. By quantifying sources of uncertainty in synthesis science, it should be possible to make rigorous comparisons among results, to judge whether they differ within the bounds of measurement and knowledge, and to assess the degree to which scientific progress is being made. However, to be accepted as a standard method, best practices analogous to those used in reductionist science need to be developed and implemented

Phylotastic! Making Tree-of-Life Knowledge Accessible, Reusable and Convenient

Scientists rarely reuse expert knowledge of phylogeny, in spite of years of effort to assemble a great "Tree of Life" (ToL). A notable exception involves the use of Phylomatic, which provides tools to generate custom phylogenies from a large, pre-computed, expert phylogeny of plant taxa. This suggests great potential for a more generalized system that, starting with a query consisting of a list of any known species, would rectify non-standard names, identify expert phylogenies containing the implicated taxa, prune away unneeded parts, and supply branch lengths and annotations, resulting in a custom phylogeny suited to the user's needs. Such a system could become a sustainable community resource if implemented as a distributed system of loosely coupled parts that interact through clearly defined interfaces. Results: With the aim of building such a "phylotastic" system, the NESCent Hackathons, Interoperability, Phylogenies (HIP) working group recruited 2 dozen scientist-programmers to a weeklong programming hackathon in June 2012. During the hackathon (and a three-month follow-up period), 5 teams produced designs, implementations, documentation, presentations, and tests including: (1) a generalized scheme for integrating components; (2) proof-of-concept pruners and controllers; (3) a meta-API for taxonomic name resolution services; (4) a system for storing, finding, and retrieving phylogenies using semantic web technologies for data exchange, storage, and querying; (5) an innovative new service, DateLife.org, which synthesizes pre-computed, time-calibrated phylogenies to assign ages to nodes; and (6) demonstration projects. These outcomes are accessible via a public code repository (GitHub.com), a website (www.phylotastic.org), and a server image. Conclusions: Approximately 9 person-months of effort (centered on a software development hackathon) resulted in the design and implementation of proof-of-concept software for 4 core phylotastic components, 3 controllers, and 3 end-user demonstration tools. While these products have substantial limitations, they suggest considerable potential for a distributed system that makes phylogenetic knowledge readily accessible in computable form. Widespread use of phylotastic systems will create an electronic marketplace for sharing phylogenetic knowledge that will spur innovation in other areas of the ToL enterprise, such as annotation of sources and methods and third-party methods of quality assessment.NESCent (the National Evolutionary Synthesis Center)NSF EF-0905606iPlant Collaborative (NSF) DBI-0735191Biodiversity Synthesis Center (BioSync) of the Encyclopedia of LifeComputer Science