"Random" gentamicin concentrations do not predict trough levels in neonates receiving once daily fixed dose regimens

BACKGROUND: Monitoring plasma gentamicin concentrations in neonates 24 hours after a once daily dose (4 mg/kg) often necessitates additional blood sampling. In adults a nomogram has been developed enabling evaluation of gentamicin doses by sampling concentrations with other blood tests, 4 – 16 hours after administration. We attempted to develop a similar nomogram for neonates. METHODS: In addition to standard 24 hour sampling to monitor trough concentrations, one additional "random" gentamicin concentration was measured in each of 50 neonates <4 days of age (median gestation 33 weeks [28–41]), when other blood samples were clinically necessary, 4 – 20 hours after gentamicin administration. 24 hour concentrations of >1 mg/L were considered high, and an indication to extend the dosing interval. RESULTS: Highest correlation (r(2 )= 0.51) of plasma gentamicin concentration against time (4 to 20 hours) was with logarithmic regression. A line drawn 0.5 mg/L below the true regression line resulted in all babies with 24 hr gentamicin concentrations >1 mg/L having the additional "random" test result above that line, i.e. 100% sensitivity for 24 hour concentrations>1 mg/L, though only 58% specificity. Having created the nomogram, 39 further babies (median gestation 34 weeks [28–41]), were studied and results tested against the nomogram. In this validation group, sensitivity of the nomogram for 24 hr concentrations >1 mg/L was 92%; specificity 14%, positive predictive value 66%, and negative predictive value 50%. Prematurity (≤ 37 weeks) was a more sensitive (94%) and specific (61%) indicator of high 24-hour concentrations. 62 (87%) of 71 preterm babies had high 24-hour concentrations. CONCLUSION: It was not possible to construct a nomogram to predict gentamicin concentrations at 24 hours in neonates with a variety of gestational ages. Dosage tailored to gestation with monitoring of trough concentrations remains management of choice

The bispectrum and 21-cm foregrounds during the Epoch of Reionization

Numerous studies have established the theoretical potential of the 21-cm bispectrum to boost our understanding of the Epoch of Reionization (EoR). We take a first look at the impact of foregrounds (FGs) and instrumental effects on the 21-cm bispectrum and our ability to measure it. Unlike the power spectrum for which (in the absence of instrumental effects) there is a window clear of smooth-spectrum FGs in which it may be detectable, there is no such 'EoR window' for the bispectrum. For the triangle configurations and scales we consider, the EoR structures are completely swamped by those of the FGs, and the EoR + FG bispectrum is entirely dominated by that of the FGs. By applying a rectangular window function on the sky combined with a Blackman-Nuttall filter along the frequency axis, we find that spectral, or in our case scale, leakage (caused by FFTing non-periodic data) suppresses the FG contribution so that cross-terms of the EoR and FGs dominate. While difficult to interpret, these findings motivate future studies to investigate whether filtering can be used to extract information about the EoR from the 21-cm bispectrum. We also find that there is potential for instrumental effects to seriously corrupt the bispectrum. FG removal using GMCA (generalized morphological component analysis) is found to recover the EoR bispectrum to a reasonable level of accuracy for many configurations. Further studies are necessary to understand the error and/or bias associated with FG removal before the 21-cm bispectrum can be practically applied in analysis of future data

Developments in the Chemical Synthesis of Heparin and Heparan Sulfate.

Heparin and heparan sulfate represent key members of the glycosaminoglycan family of carbohydrates and underpin considerable repertoires of biological importance. As such, their efficiency of synthesis represents a key requirement, to further understand and exploit the H/HS structure-to-biological function axis. In this review we focus on chemical approaches to and methodology improvements for the synthesis of these essential sugars (from 2015 onwards). We first consider advances in accessing the heparin-derived pentasaccharide anticoagulant fondaparinux. This is followed by heparan sulfate targets, including key building block synthesis, oligosaccharide construction and chemical sulfation techniques. We end with a consideration of technological improvements to traditional, solution-phase synthesis approaches that are increasingly being utilised

Social media use in the research workflow

The paper reports on a major international survey, covering 2,000 researchers, which investigated the use of social media in the research workflow. The topic is the second to emerge from the Charleston Observatory, the research adjunct of the popular annual Charleston Conference (http://www.katina.info/conference/). The study shows that social media have found serious application at all points of the research lifecycle, from identifying research opportunities to disseminating findings at the end. The three most popular social media tools in a research setting were those for collaborative authoring, conferencing, and scheduling meetings. The most popular brands used tend to be mainstream anchor technologies or ‘household brands‘, such as Twitter. Age is a poor predictor of social media use in a research context, and humanities and social science scholars avail themselves most of social media. Journals, conference proceedings, and edited books remain the core traditional means of disseminating research, with institutional repositories highly valued as well, but social media have become important complementary channels for disseminating and discovering research

Stable Coexistence of an Invasive Plant and Biocontrol Agent: A Parameterized Coupled Plant-Herbivore Model

1. Coupled plant-herbivore models, allowing feedback from plant to herbivore populations and vice versa, enable us to predict the impact of biocontrol agents on their target weed populations; however, they are rarely used in biocontrol studies. We describe the population biology of the invasive plant Echium plantagineum and the weevil Mogulones larvatus, a biocontrol agent, in Australia. In order to understand the dynamics of this plant-herbivore system, a series of coupled models of increasing complexity was developed. 2. A simple model was extended to include a seed bank, density-dependent plant fecundity, competition between weevil larvae and plant tolerance of herbivory, where below a threshold plants could compensate for larval feeding. Parameters and functional forms were estimated from experimental and field data. 3. The plant model, in the absence of the weevil, exhibited stable dynamics and provided a good quantitative description of field densities before the weevil was introduced. 4. In the coupled plant-herbivore model, density dependence in both plant fecundity and weevil larval competition stabilized the dynamics. Without larval competition the model was unstable, and plant tolerance of herbivory exacerbated this instability. This was a result of a time delay in plant response to herbivore densities. 5. Synthesis and applications. The coupled plant-herbivore model allowed us to predict whether stable coexistence of target plant and biocontrol agents was achievable at an acceptable level. We found this to be the case for the Echium-Mogulones system and believe that similar models would be of use when assessing new agents in this and other invasive plant biocontrol systems. Density dependence in new biocontrol agents should be assessed in order to determine whether it is likely to result in the aims of classical biocontrol: low, stable and sustainable populations of plant and herbivore. Further work should be done to characterize the strength of density dependence according to the niche occupied by the biocontrol agent, for example the strength and functional form of density dependence in stem borers may be quite different to that of defoliators

The effect of gold nanoparticles on the impedance of microcapsules visualized by scanning photo-induced impedance microscopy

Polyelectrolyte microcapsules have attracted great interest in drug delivery applications, and microcapsules modified with gold nanoparticles have been used in this way with triggered release when a laser can be used to remotely open shells through light-induced local heating. The electrical impedance of unmodified microcapsules has been studied due to its implications for their permeability, however, the impedance of functionalised microcapsules has not yet been investigated. Herein, the impedance of microcapsules modified with gold nanoparticles was studied for the first time. It was shown that the modification of microcapsules with gold nanoparticles leads to a much greater impedance than would be expected from the increase in the thickness caused by the presence of a layer of gold nanoparticles alone. The impedance of gold nanoparticle modified capsules was measured using scanning photo-induced impedance microscopy (SPIM), which is based on photocurrent measurements at an electrolyte-insulator-semiconductor (EIS) field-effect structure. High resolution and good sensitivity were achieved using a two-photon effect for charge carrier excitation and organic monolayer modified silicon-on-sapphire (SOS) as the SPIM substrate. SPIM allowed impedance imaging of collapsed microcapsules with unprecedented detail. SPIM images of capsules labelled with gold nanoparticles (AuNPs) showed a good agreement with the corresponding optical images, including the creases resulting from the collapse of the hollow shells. The significant increase in impedance caused by the impregnation with AuNPs was also verified by conductive Atomic Force Microscopy (C-AFM) measurements in the dry state

Population overlap and habitat segregation in wintering Black-tailed Godwits Limosa limosa

Distinct breeding populations of migratory species may overlap both spatially and temporally, but differ in patterns of habitat use. This has important implications for population monitoring and conservation. To quantify the extent to which two distinct breeding populations of a migratory shorebird, the Black-tailed Godwit Limosa limosa, overlap spatially, temporally and in their use of different habitats during winter. We use mid-winter counts between 1990 and 2001 to identify the most important sites in Iberia for Black-tailed Godwits. Monthly surveys of estuarine mudflats and rice-fields at one major site, the Tejo estuary in Portugal in 2005-2007, together with detailed tracking of colour-ringed individuals, are used to explore patterns of habitat use and segregation of the Icelandic subspecies L. l. islandica and the nominate continental subspecies L. l. limosa. In the period 1990-2001, over 66 000 Black-tailed Godwits were counted on average in Iberia during mid-winter (January), of which 80% occurred at just four sites: Tejo and Sado lower basins in Portugal, and Coto Dontildeana and Ebro Delta in Spain. Icelandic Black-tailed Godwits are present throughout the winter and forage primarily in estuarine habitats. Continental Black-tailed Godwits are present from December to March and primarily use rice-fields. Iberia supports about 30% of the Icelandic population in winter and most of the continental population during spring passage. While the Icelandic population is currently increasing, the continental population is declining rapidly. Although the estuarine habitats used by Icelandic godwits are largely protected as Natura 2000 sites, the habitat segregation means that conservation actions for the decreasing numbers of continental godwits should focus on protection of rice-fields and re-establishment of freshwater wetlands

Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment

Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized protooncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake

The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells

The PTTG1-Binding Factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a proto-oncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear. Here, we present extensive evidence demonstrating that PBF is a novel regulator of p53, a tumor suppressor protein with a key role in maintaining genetic stability, which is infrequently mutated in differentiated thyroid cancer. By coimmunoprecipitation and proximity ligation assays, we show that PBF binds specifically to p53 in thyroid cells, and significantly represses transactivation of responsive promoters. Further, we identify that PBF decreases p53 stability by enhancing ubiquitination, which appears dependent on the E3 ligase activity of Mdm2. Impaired p53 function was evident in a transgenic mouse model with thyroid-specific PBF over-expression (PBF-Tg), which had significantly increased genetic instability as indicated by FISSR-PCR analysis. Consistent with this, ~40% of all DNA repair genes examined were repressed in PBF-Tg primary cultures, including genes with critical roles in maintaining genomic integrity such as Mgmt, Rad51 and Xrcc3. Our data also revealed that PBF induction resulted in upregulation of the E2 enzyme Rad6 in murine thyrocytes, and was associated with Rad6 expression in human thyroid tumors. Overall, this work provides novel insights into the role of the proto-oncogene PBF as a negative regulator of p53 function in thyroid tumorigenesis, where PBF is generally over-expressed and p53 mutations are rare compared to other tumor types