The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury

BACKGROUND: Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. METHODS: Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS). RESULTS: 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. CONCLUSION: This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial provides no reliable evidence of benefit or harm and a larger trial would be needed to establish safety and effectiveness. TRIAL REGISTRATION: This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN23625128

Rh-POP Pincer Xantphos Complexes for C-S and C-H Activation. Implications for Carbothiolation Catalysis

The neutral Rh­(I)–Xantphos complex [Rh­(κ³-_P,O,P-Xantphos)­Cl]_<i>n</i>, <b>4</b>, and cationic Rh­(III) [Rh­(κ³-_P,O,P-Xantphos)­(H)₂]­[BAr^F₄], <b>2a</b>, and [Rh­(κ³-_P,O,P-Xantphos-3,5-C₆H₃(CF₃)₂)­(H)₂]­[BAr^F₄], <b>2b</b>, are described [Ar^F = 3,5-(CF₃)₂C₆H₃; Xantphos = 4,5-bis­(diphenylphosphino)-9,9-dimethylxanthene; Xantphos-3,5-C₆H₃(CF₃)₂ = 9,9-dimethylxanthene-4,5-bis­(bis­(3,5-bis­(trifluoromethyl)­phenyl)­phosphine]. A solid-state structure of <b>2b</b> isolated from C₆H₅Cl solution shows a κ¹-chlorobenzene adduct, [Rh­(κ³-_P,O,P-Xantphos-3,5-C₆H₃(CF₃)₂)­(H)₂(κ¹-ClC₆H₅)]­[BAr^F₄], <b>3</b>. Addition of H₂ to <b>4</b> affords, crystallographically characterized, [Rh­(κ³-_P,O,P-Xantphos)­(H)₂Cl], <b>5</b>. Addition of diphenyl acetylene to <b>2a</b> results in the formation of the C–H activated metallacyclopentadiene [Rh­(κ³-_P,O,P-Xantphos)­(ClCH₂Cl)­(σ,σ-(C₆H₄)­C­(H)CPh)]­[BAr^F₄], <b>7</b>, a rare example of a crystallographically characterized Rh–dichloromethane complex, alongside the Rh­(I) complex <i>mer</i>-[Rh­(κ³-_P,O,P-Xantphos)­(η²-PhCCPh)]­[BAr^F₄], <b>6</b>. Halide abstraction from [Rh­(κ³-_P,O,P-Xantphos)­Cl]_<i>n</i> in the presence of diphenylacetylene affords <b>6</b> as the only product, which in the solid state shows that the alkyne binds perpendicular to the κ³-POP Xantphos ligand plane. This complex acts as a latent source of the [Rh­(κ³-_P,O,P-Xantphos)]⁺ fragment and facilitates <i>ortho</i>-directed C–S activation in a number of 2-arylsulfides to give <i>mer</i>-[Rh­(κ³-_P,O,P-Xantphos)­(σ,κ¹-Ar)­(SMe)]­[BAr^F₄] (Ar = C₆H₄COMe, <b>8</b>; C₆H₄(CO)­OMe, <b>9</b>; C₆H₄NO₂, <b>10</b>; C₆H₄CNCH₂CH₂O, <b>11</b>; C₆H₄C₅H₄N, <b>12</b>). Similar C–S bond cleavage is observed with allyl sulfide, to give <i>fac</i>-[Rh­(κ³-_P,O,P-Xantphos)­(η³-C₃H₅)­(SPh)]­[BAr^F₄], <b>13</b>. These products of C–S activation have been crystallographically characterized. For <b>8</b> in situ monitoring of the reaction by NMR spectroscopy reveals the initial formation of <i>fac</i>-κ³-<b>8</b>, which then proceeds to isomerize to the <i>mer</i>-isomer. With the <i>para</i>-ketone aryl sulfide, 4-SMeC ₆H₄COMe, C–H activation <i>ortho</i> to the ketone occurs to give <i>mer</i>-[Rh­(κ³-_P,O,P-Xantphos)­(σ,κ¹-4-(COMe)­C₆H₃SMe)­(H)]­[BAr^F₄], <b>14</b>. The temporal evolution of carbothiolation catalysis using <i>mer</i>-κ³-<b>8</b>, and phenyl acetylene and 2-(methylthio)­acetophenone substrates shows initial fast catalysis and then a considerably slower evolution of the product. We suggest that the initially formed <i>fac</i>-isomer of the C–S activation product is considerably more active than the <i>mer</i>-isomer (i.e., <i>mer</i>-<b>8</b>), the latter of which is formed rapidly by isomerization, and this accounts for the observed difference in rates. A likely mechanism is proposed based upon these data

A strong limit on the very-high-energy emission from GRB 150323A

On 2015 March 23, VERITAS responded to a $Swift$-BAT detection of a gamma-ray burst, with observations beginning 270 seconds after the onset of BAT emission, and only 135 seconds after the main BAT emission peak. No statistically significant signal is detected above 140 GeV. The VERITAS upper limit on the fluence in a 40 minute integration corresponds to about 1% of the prompt fluence. Our limit is particularly significant since the very-high-energy (VHE) observation started only $\sim$2 minutes after the prompt emission peaked, and $Fermi$-LAT observations of numerous other bursts have revealed that the high-energy emission is typically delayed relative to the prompt radiation and lasts significantly longer. Also, the proximity of GRB~150323A ($z=0.593$) limits the attenuation by the extragalactic background light to $\sim 50$ % at 100-200 GeV. We conclude that GRB 150323A had an intrinsically very weak high-energy afterglow, or that the GeV spectrum had a turnover below $\sim100$ GeV. If the GRB exploded into the stellar wind of a massive progenitor, the VHE non-detection constrains the wind density parameter to be $A\gtrsim 3\times 10^{11}$ g cm$^{-1}$, consistent with a standard Wolf-Rayet progenitor. Alternatively, the VHE emission from the blast wave would be weak in a very tenuous medium such as the ISM, which therefore cannot be ruled out as the environment of GRB 150323A.Comment: 6 pages, 1 figure. Accepted for publication in The Astrophysical Journa

Tree diversity and species identity effects on soil fungi, protists and animals are context dependent

Plant species richness and the presence of certain influential species (sampling effect) drive the stability and functionality of ecosystems as well as primary production and biomass of consumers. However, little is known about these floristic effects on richness and community composition of soil biota in forest habitats owing to methodological constraints. We developed a DNA metabarcoding approach to identify the major eukaryote groups directly from soil with roughly species-level resolution. Using this method, we examined the effects of tree diversity and individual tree species on soil microbial biomass and taxonomic richness of soil biota in two experimental study systems in Finland and Estonia and accounted for edaphic variables and spatial autocorrelation. Our analyses revealed that the effects of tree diversity and individual species on soil biota are largely context dependent. Multiple regression and structural equation modelling suggested that biomass, soil pH, nutrients and tree species directly affect richness of different taxonomic groups. The community composition of most soil organisms was strongly correlated due to similar response to environmental predictors rather than causal relationships. On a local scale, soil resources and tree species have stronger effect on diversity of soil biota than tree species richness per se

The spectrum of singly ionized potassium, KII

Using 10.7 m and 3 m normal-incidence vacuum ultraviolet spectrographs, we investigated the spectrum of singly ionized potassium in the regions 495 - 612 angstrom and 1247 - 2150 angstrom. More than 120 new K II lines were identified. The previous study on this spectrum was revised and extended. All levels of the 3p(5)4f and 5f configurations as well as the levels of 3p(5)6f based on the 3p(5) P-2(3/2) core state have now been located. Several new levels of 3p(5)3d were also located. The ionization limit was determined from the 3p(5)nf 1.5[4.5](5) ( n = 4 - 6) series as 255072.8 +/- 1.5 cm(-1)(31.6250 +/- 0.0002 eV)

Long-term dynamics of breeding birds in broad-leaved deciduous forest on Hanikatsi Island in the West-Estonian archipelago

The temporal dynamics (1974-2004) of the breeding bird community in broad-leaved de- ciduous forest on Hanikatsi Island on the eastern side of the Baltic Sea was studied. Alto- gether 33 bird species of seven orders were recorded. The year-to-year variation in the number of species (CV = 10.99%) and in the total numbers (CV = 15.17%) were relatively small. No significant trends in the number of bird species and in their abundances were detected, though an abrupt change in community structure took place at the beginning of the 1990s. No significant relationships between abundance of single bird species were de- tected, except for Turdus merula and Turdus philomelos

Cs 3d absorption and resonant photoemission study of caesium halogenides

The highly localized 4f electrons play an important role in forming of the electronic structure and properties of compounds. The 3d photoabsorption and resonant decay spectra of Cs halides represent an interesting case showing both the localized and spatially extended f wave function features. We present and discuss the Cs 3d X-ray absorption and resonant photoelectron emission spectra of the Cs halides. The Cs 3d absorption spectra exhibit a strong atom-like shape resonance behavior, solid-state effects play a minor role. The appearance of the spectral features, which are intrinsic to a localized state, in the decay spectra show that the Cs 3d photoelectron, temporally and spatially trapped in the Cs 3d shape resonance due to the potential barrier for epsilon f electrons near threshold, has substantially localized nature

Potential barrier effects in Cs 3d resonance photoemission of CsF

We present and discuss the Cs 3d X-ray absorption spectra and resonant photoelectron emission spectra of CsF. The resonant photoelectron spectra excited at the Cs 3d absorption maxima, exhibit a strong resonance behavior. The different behaviour of participator and spectator channels and interference effects of the 4d partial photoionisation cross-section at the 3d resonances are discussed. The experimental evidence of the phenomenon of spin-orbit activated interchannel coupling in the 3d photoionization of Cs is presented. (C) 2004 Elsevier B.V. All rights reserved