Validation of a continuous infusion of low dose Iohexol to measure glomerular filtration rate: randomised clinical trial.

INTRODUCTION: There is currently no accurate method of measuring glomerular filtration rate (GFR) during acute kidney injury (AKI). Knowledge of how much GFR varies in stable subjects is necessary before changes in GFR can be attributed to AKI. We have designed a method of continuous measurement of GFR intended as a research tool to time effects of AKI. The aims of this crossover trial were to establish accuracy and precision of a continuous infusion of low dose Iohexol (CILDI) and variation in GFR in stable volunteers over a range of estimated GFR (23-138 mL/min/1.73 m(2)). METHODS: We randomised 17 volunteers to GFR measurement by plasma clearance (PC) and renal clearance (RC) of either a single bolus of Iohexol (SBI; routine method), or of a continuous infusion of low dose Iohexol (CILDI; experimental method) at 0.5 mL/h for 12 h. GFR was measured by the alternative method after a washout period (4-28 days). Iohexol concentration was measured by high performance liquid chromatography/electrospray tandem mass spectrometry and time to steady state concentration (Css) determined. RESULTS: Mean PC was 76.7 ± 28.5 mL/min/1.73 m(2) (SBI), and 78.9 ± 28.6 mL/min/1.73 m(2) (CILDI), p = 0.82. No crossover effects occurred (p = 0.85). Correlation (r) between the methods was 0.98 (p 10.3% depict evolving AKI. If this were applicable to AKI, this is less than the 50% change in serum creatinine currently required to define AKI. CILDI is now ready for testing in patients with AKI. TRIAL REGISTRATION: This trial was registered with the European Union Clinical Trials Register (https://www.clinicaltrialsregister.eu/), registration number: 2010-019933-89

The GuideLine Implementability Appraisal (GLIA): development of an instrument to identify obstacles to guideline implementation

BACKGROUND: Clinical practice guidelines are not uniformly successful in influencing clinicians' behaviour toward best practices. Implementability refers to a set of characteristics that predict ease of (and obstacles to) guideline implementation. Our objective is to develop and validate a tool for appraisal of implementability of clinical guidelines. METHODS: Indicators of implementability were identified from the literature and used to create items and dimensions of the GuideLine Implementability Appraisal (GLIA). GLIA consists of 31 items, arranged into 10 dimensions. Questions from 9 of the 10 dimensions are applied individually to each recommendation of the guideline. Decidability and Executability are critical dimensions. Other dimensions are Global, Presentation and Formatting, Measurable Outcomes, Apparent Validity, Flexibility, Effect on Process of Care, Novelty/Innovation, and Computability. We conducted a series of validation activities, including validation of the construct of implementability, expert review of content for clarity, relevance, and comprehensiveness, and assessment of construct validity of the instrument. Finally, GLIA was applied to a draft guideline under development by national professional societies. RESULTS: Evidence of content validity and preliminary support for construct validity were obtained. The GLIA proved to be useful in identifying barriers to implementation in the draft guideline and the guideline was revised accordingly. CONCLUSION: GLIA may be useful to guideline developers who can apply the results to remedy defects in their guidelines. Likewise, guideline implementers may use GLIA to select implementable recommendations and to devise implementation strategies that address identified barriers. By aiding the design and operationalization of highly implementable guidelines, our goal is that application of GLIA may help to improve health outcomes, but further evaluation will be required to support this potential benefit

Exoplanets and SETI

The discovery of exoplanets has both focused and expanded the search for extraterrestrial intelligence. The consideration of Earth as an exoplanet, the knowledge of the orbital parameters of individual exoplanets, and our new understanding of the prevalence of exoplanets throughout the galaxy have all altered the search strategies of communication SETI efforts, by inspiring new "Schelling points" (i.e. optimal search strategies for beacons). Future efforts to characterize individual planets photometrically and spectroscopically, with imaging and via transit, will also allow for searches for a variety of technosignatures on their surfaces, in their atmospheres, and in orbit around them. In the near-term, searches for new planetary systems might even turn up free-floating megastructures.Comment: 9 page invited review. v2 adds some references and v3 has other minor additions and modification

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Metabolic analysis of the interaction between plants and herbivores

Insect herbivores by necessity have to deal with a large arsenal of plant defence metabolites. The levels of defence compounds may be increased by insect damage. These induced plant responses may also affect the metabolism and performance of successive insect herbivores. As the chemical nature of induced responses is largely unknown, global metabolomic analyses are a valuable tool to gain more insight into the metabolites possibly involved in such interactions. This study analyzed the interaction between feral cabbage (Brassica oleracea) and small cabbage white caterpillars (Pieris rapae) and how previous attacks to the plant affect the caterpillar metabolism. Because plants may be induced by shoot and root herbivory, we compared shoot and root induction by treating the plants on either plant part with jasmonic acid. Extracts of the plants and the caterpillars were chemically analysed using Ultra Performance Liquid Chromatography/Time of Flight Mass Spectrometry (UPLCT/MS). The study revealed that the levels of three structurally related coumaroylquinic acids were elevated in plants treated on the shoot. The levels of these compounds in plants and caterpillars were highly correlated: these compounds were defined as the ‘metabolic interface’. The role of these metabolites could only be discovered using simultaneous analysis of the plant and caterpillar metabolomes. We conclude that a metabolomics approach is useful in discovering unexpected bioactive compounds involved in ecological interactions between plants and their herbivores and higher trophic levels.

Metabolomics demonstrates divergent responses of two Eucalyptus species to water stress

Past studies of water stress in Eucalyptus spp. generally highlighted the role of fewer than five “important” metabolites, whereas recent metabolomic studies on other genera have shown tens of compounds are affected. There are currently no metabolite profiling data for responses of stress-tolerant species to water stress. We used GC–MS metabolite profiling to examine the response of leaf metabolites to a long (2 month) and severe (Ψpredawn < −2 MPa) water stress in two species of the perennial tree genus Eucalyptus (the mesic Eucalyptus pauciflora and the semi-arid Eucalyptus dumosa). Polar metabolites in leaves were analysed by GC–MS and inorganic ions by capillary electrophoresis. Pressure–volume curves and metabolite measurements showed that water stress led to more negative osmotic potential and increased total osmotically active solutes in leaves of both species. Water stress affected around 30–40% of measured metabolites in E. dumosa and 10–15% in E. pauciflora. There were many metabolites that were affected in E. dumosa but not E. pauciflora, and some that had opposite responses in the two species. For example, in E. dumosa there were increases in five acyclic sugar alcohols and four low-abundance carbohydrates that were unaffected by water stress in E. pauciflora. Re-watering increased osmotic potential and decreased total osmotically active solutes in E. pauciflora, whereas in E. dumosa re-watering led to further decreases in osmotic potential and increases in total osmotically active solutes. This experiment has added several extra dimensions to previous targeted analyses of water stress responses in Eucalyptus, and highlights that even species that are closely related (e.g. congeners) may respond differently to water stress and re-waterin

Neutron Majorana mass from exotic instantons

We show how a Majorana mass for the Neutron could result from non-perturbative quantum gravity effects peculiar to string theory. In particular, "exotic instantons" in un-oriented string compactifications with D-branes extending the (supersymmetric) standard model could indirectly produce an effective operator delta{m} n^t n+h.c. In a specific model with an extra vector-like pair of `quarks', acquiring a large mass proportional to the string mass scale (exponentially suppressed by a function of the string moduli fields), delta{m} can turn out to be as low as 10^{-24}-10^{-25} eV. The induced neutron-antineutron oscillations could take place with a time scale tau_{n\bar{n}} > 10^8 s, that could be tested by the next generation of experiments. On the other hand, proton decay and FCNC's are automatically strongly suppressed and are compatible with the current experimental limits. Depending on the number of brane intersections, the model may also lead to the generation of Majorana masses for R-handed neutrini. Our proposal could also suggest neutron-neutralino or neutron-axino oscillations, with implications in UCN, Dark Matter Direct Detection, UHECR and Neutron-Antineutron oscillations. This suggests to improve the limits on neutron-antineutron oscillations, as a possible test of string theory and quantum gravity.Comment: 35 pages, 11 figures. More comments on neutron-neutralino mixin

Elephant (Loxodonta africana) Home Ranges in Sabi Sand Reserve and Kruger National Park: A Five-Year Satellite Tracking Study

During a five-year GPS satellite tracking study in Sabi Sand Reserve (SSR) and Kruger National Park (KNP) we monitored the daily movements of an elephant cow (Loxodonta africana) from September 2003 to August 2008. The study animal was confirmed to be part of a group of seven elephants therefore her position is representative of the matriarchal group. We found that the study animal did not use habitat randomly and confirmed strong seasonal fidelity to its summer and winter five-year home ranges. The cow's summer home range was in KNP in an area more than four times that of her SSR winter home range. She exhibited clear park habitation with up to three visits per year travelling via a well-defined northern or southern corridor. There was a positive correlation between the daily distance the elephant walked and minimum daily temperature and the elephant was significantly closer to rivers and artificial waterholes than would be expected if it were moving randomly in KNP and SSR. Transect lines established through the home ranges were surveyed to further understand the fine scale of the landscape and vegetation representative of the home ranges

Predictions for Higgs production at the Tevatron and the associated uncertainties

We update the theoretical predictions for the production cross sections of the Standard Model Higgs boson at the Fermilab Tevatron collider, focusing on the two main search channels, the gluon-gluon fusion mechanism $gg \to H$ and the Higgs-strahlung processes $q \bar q \to VH$ with $V=W/Z$, including all relevant higher order QCD and electroweak corrections in perturbation theory. We then estimate the various uncertainties affecting these predictions: the scale uncertainties which are viewed as a measure of the unknown higher order effects, the uncertainties from the parton distribution functions and the related errors on the strong coupling constant, as well as the uncertainties due to the use of an effective theory approach in the determination of the radiative corrections in the $gg \to H$ process at next-to-next-to-leading order. We find that while the cross sections are well under control in the Higgs--strahlung processes, the theoretical uncertainties are rather large in the case of the gluon-gluon fusion channel, possibly shifting the central values of the next-to-next-to-leading order cross sections by more than $\approx 40$. These uncertainties are thus significantly larger than the $\approx 10$ error assumed by the CDF and D0 experiments in their recent analysis that has excluded the Higgs mass range $M_H=$162-166 GeV at the 95% confidence level. These exclusion limits should be, therefore, reconsidered in the light of these large theoretical uncertainties.Comment: 40 pages, 12 figures. A few typos are corrected and some updated numbers are provide