Resonant X-ray photoelectron spectroscopy: identification of atomic contributions to valence states.

Valence electronic structure is crucial for understanding and predicting reactivity. Valence non-resonant X-ray photoelectron spectroscopy (NRXPS) provides a direct method for probing the overall valence electronic structure. However, it is often difficult to separate the varying contributions to NRXPS; for example, contributions of solutes in solvents or functional groups in complex molecules. In this work we show that valence resonant X-ray photoelectron spectroscopy (RXPS) is a vital tool for obtaining atomic contributions to valence states. We combine RXPS with NRXPS and density functional theory calculations to demonstrate the validity of using RXPS to identify atomic contributions for a range of solutes (both neutral and ionic) and solvents (both molecular solvents and ionic liquids). Furthermore, the one-electron picture of RXPS holds for all of the closed shell molecules/ions studied, although the situation for an open-shell metal complex is more complicated. The factors needed to obtain a strong RXPS signal are investigated in order to predict the types of systems RXPS will work best for; a balance of element electronegativity and bonding type is found to be important. Additionally, the dependence of RXPS spectra on both varying solvation environment and varying local-covalent bonding is probed. We find that RXPS is a promising fingerprint method for identifying species in solution, due to the spectral shape having a strong dependence on local-covalency but a weak dependence on the solvation environment.

The outcome of patients in traumatic cardiac arrest presenting to deployed military medical treatment facilities: data from the UK Joint Theatre Trauma Registry.

BACKGROUND: The UK military was continuously engaged in armed conflict in Iraq and Afghanistan between 2003 and 2014, resulting in 629 UK fatalities. Traumatic cardiac arrest (TCA) is a precursor to traumatic death, but data on military outcomes are limited. In order to better inform military treatment protocols, the aim of this study was to define the epidemiology of TCA in the military population with a particular focus on survival rates and injury patterns. METHODS: A retrospective database analysis of the UK Joint Theatre Trauma Registry was undertaken. Patients who were transported to a UK deployed hospital between 2003 and 2014 and suffered TCA were included. Those patients injured by asphyxiation, electrocution, burns without other significant trauma and drowning were excluded. Data included mechanism of injury, Injury Severity Score (ISS), Abbreviated Injury Scale (AIS) for each body region and survival to deployed (Role 3) field hospital discharge. RESULTS: 424 TCA patients were identified during the study period; median age was 23 years, with a median ISS of 45. The most common mechanism of injury was explosive (55.7%), followed by gunshot wound (38.9%), road traffic collision (3.5%), crush (1.7%) and fall (0.2%). 45 patients (10.6% (95% CI 8.0% to 13.9%)) survived to deployed (Role 3) hospital discharge. The most prevalent body region with a severe to maximum AIS injury was the head, followed by the lower limbs, thorax and abdomen. Haemorrhage secondary to abdominal and lower limb injury was associated with survival; traumatic brain injury was associated with death. CONCLUSIONS: This study has shown that short-term survival from TCA in a military population is 10.6%. With appropriate and aggressive early management, although unlikely, survival is still potentially possible in military patients who suffer traumatic cardiac arrest.

Solubility of alkali metal halides in the ionic liquid [C4C1im][OTf].

The solubilities of the metal halides LiF, LiCl, LiBr, LiI, NaF, NaCl, NaBr, NaI, KF, KCl, KBr, KI, RbCl, CsCl, CsI, were measured at temperatures ranging from 298.15 to 378.15 K in the ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate ([C4C1im][OTf]). Li(+), Na(+) and K(+) salts with anions matching the ionic liquid have also been investigated to determine how well these cations dissolve in [C4C1im][OTf]. This study compares the influence of metal cation and halide anion on the solubility of salts within this ionic liquid. The highest solubility found was for iodide salts, and the lowest solubility for the three fluoride salts. There is no outstanding difference in the solubility of salts with matching anions in comparison to halide salts. The experimental data were correlated employing several phase equilibria models, including ideal mixtures, van't Hoff, the λh (Buchowski) equation, the modified Apelblat equation, and the non-random two-liquid model (NRTL). It was found that the van't Hoff model gave the best correlation results. On the basis of the experimental data the thermodynamic dissolution parameters (ΔH, ΔS, and ΔG) were determined for the studied systems together with computed gas phase metathesis parameters. Dissolution depends on the energy difference between enthalpies of fusion and dissolution of the solute salt. This demonstrates that overcoming the lattice energy of the solid matrix is the key to the solubility of inorganic salts in ionic liquids.

Challenging the dogma of traumatic cardiac arrest management: a military perspective.

Attempts to resuscitate patients in traumatic cardiac arrest (TCA) have, in the past, been viewed as futile. However, reported outcomes from TCA in the past five years, particularly from military series, are improving. The pathophysiology of TCA is different to medical causes of cardiac arrest, and therefore, treatment priorities may also need to be different. This article reviews recent literature describing the pathophysiology of TCA and describes how the military has challenged the assumption that outcome is universally poor in these patients.

Hydrogen abstraction from n-butanol by the methyl radical: high level ab initio study of abstraction pathways and the importance of low energy rotational conformers.

Hydrogen abstraction reactions by the methyl radical from n-butanol have been investigated at the ROCBS-QB3 level of theory. Reaction energies and product geometries for the most stable conformer of n-butanol (ROH) have been computed, the reaction energies order α < γ < ß < δ < OH. The preference for n-butane to favour H-abstraction at C(ß) and C(γ) while, in contrast, n-butanol favours radical reactions at the C(α) carbon is rationalised. Transition state (TS) barriers and geometries for the most stable conformer of n-butanol are presented, and discussed with respect to the Hammond postulate. The reaction barriers order as α < OH < γ < ß < δ. This relative ordering is not consistent with product radical stability, C-H bond dissociation energies or previous studies using O[combining dot above]H and HO[combining dot above](2) radicals. We provide a molecular orbital based rationalisation for this ordering and answer two related questions: Why is the γ-channel more stable than the ß-channel? Why do the two C(γ)-H H-abstraction TS differ in energy? The method and basis set dependence of the TS barriers is investigated. The Boltzmann probability distribution for the n-butanol conformers suggests that low energy conformers are present in approximately equal proportions to the most stable conformer at combustion temperatures where CH(3) radicals are present. Thus, the relative significance of the various H-abstraction channels has been assessed for a selection of higher energy conformers (ROH'). Key results include finding that higher energy n-butanol conformers (E(ROH') > E(ROH)) can generate lower energy product radicals, E(ROH') < E(ROH). Moreover, higher energy conformers can also have a globally competitive TS energy for H-abstraction.

Understanding the polarity of ionic liquids.

The polarities of a wide range of ionic liquids have been determined using the Kamlet-Taft empirical polarity scales α, ß and π*, with the dye set Reichardt's Dye, N,N-diethyl-4-nitroaniline and 4-nitroaniline. These have been compared to measurements of these parameters with different dye sets and to different polarity scales. The results emphasise the importance of recognising the role that the nature of the solute plays in determining these scales. It is particularly noted that polarity scales based upon charged solutes can give very different values for the polarity of ionic liquids compared to those based upon neutral probes. Finally, the effects of commonplace impurities in ionic liquids are reported.

Lack of checkpoint control at the metaphase/anaphase transition: a mechanism of meiotic nondisjunction in mammalian females.

A checkpoint mechanism operates at the metaphase/anaphase transition to ensure that a bipolar spindle is formed and that all the chromosomes are aligned at the spindle equator before anaphase is initiated. Since mistakes in the segregation of chromosomes during meiosis have particularly disastrous consequences, it seems likely that the meiotic cell division would be characterized by a stringent metaphase/ anaphase checkpoint. To determine if the presence of an unaligned chromosome activates the checkpoint and delays anaphase onset during mammalian female meiosis, we investigated meiotic cell cycle progression in murine oocytes from XO females and control siblings. Despite the fact that the X chromosome failed to align at metaphase in a significant proportion of cells, we were unable to detect a delay in anaphase onset. Based on studies of cell cycle kinetics, the behavior and segregation of the X chromosome, and the aberrant behavior and segregation of autosomal chromosomes in oocytes from XO females, we conclude that mammalian female meiosis lacks chromosome-mediated checkpoint control. The lack of this control mechanism provides a biological explanation for the high incidence of meiotic nondisjunction in the human female. Furthermore, since available evidence suggests that a stringent checkpoint mechanism operates during male meiosis, the lack of a comparable checkpoint in females provides a reason for the difference in the error rate between oogenesis and spermatogenesis.

Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlh1 mutant mice.

In mouse oocytes, the first meiotic spindle is formed through the action of multiple microtubule organizing centers rather than a pair of centrosomes. Although the chromosomes are thought to play a major role in organizing the meiotic spindle, it remains unclear how a stable bipolar spindle is established. We have studied the formation of the first meiotic spindle in murine oocytes from mice homozygous for a targeted disruption of the DNA mismatch repair gene, Mlh1. In the absence of the MLH1 protein meiotic recombination is dramatically reduced and, as a result, the vast majority of chromosomes are present as unpaired univalents at the first meiotic division. The orientation of these univalent chromosomes at prometaphase suggests that they are unable to establish stable bipolar spindle attachments, presumably due to the inability to differentiate functional kinetochore domains on individual sister chromatids. In the presence of this aberrant chromosome behavior a stable first meiotic spindle is not formed, the spindle poles continue to elongate, and the vast majority of cells never initiate anaphase. These results suggest that, in female meiotic systems in which spindle formation is based on the action of multiple microtubule organizing centers, the chromosomes not only promote microtubule polymerization and organization but their attachment to opposite spindle poles acts to stabilize the forming spindle poles.

Self assessment exercises in Intensive Care Medicine.

Intensive Care Medicine (ICM) is no longer the exclusive preserve of anaesthetists as both emergency medicine and general medicine trainees now also train in this increasingly important speciality. This edition of the JRAMC self assessment question series serves to cover some of the current 'hot topics' in ICM and enables readers with experience of ICM to test their knowledge as well as educating junior trainees in relevant subjects that they may be unfamiliar with. Similarly, the Focus On .... series of papers elsewhere in this journal demonstrate the increasing importance of ICM in the deployed Field Hospital setting.

Trisomy in humans: incidence, origin and etiology.

Molecular studies conducted over the past year have demonstrated the importance of aberrant genetic recombination in the etiology of several human trisomies, and have begun to shed light on the basis of the association between advancing maternal age and trisomy. Preliminary studies of gametes using fluorescence in situ hybridization indicate that this will be a useful approach in the analysis of human non-disjunction.

Why are ionic liquid ions mainly associated in water? A Car-Parrinello study of 1-ethyl-3-methyl-imidazolium chloride water mixture.

In this study we present the results of a first principles molecular dynamics simulation of a single 1-ethyl-3-methyl-imidazolium chloride [C(2)C(1)im][Cl] ion pair dissolved in 60 water molecules. We observe a preference of the in plane chloride coordination with respect to the cation ring plane as compared to the energetic slightly more demanding on top coordination. Evaluation of the different radial distribution functions demonstrates that the structure of the hydration shell around the ion pair differs significantly from bulk water and that no true ion pair dissociation in terms of completely autonomous solvation shells takes place on the timescale of the simulation. In addition, dipole moment distributions of the solvent in distinct solvation shells around different functional parts of the [C(2)C(1)im][Cl] ion pair are calculated from maximally localized Wannier functions. The analysis of these distributions gives evidence for a depolarization of water molecules close to the hydrophobic parts of the cation as well as close to the anion. Examination of the angular distribution of different OH(H(2)O)-X angles in turn shows a linear coordination of chloride accompanied by a tangential orientation of water molecules around the hydrophobic groups, being a typical feature of hydrophobic hydration. Based on these orientational aspects, a structural model for the obvious preference of ion pair association is developed, which justifies the associating behavior of solvated [C(2)C(1)im][Cl] ions in terms of an energetically favorable interface between the solvation shells of the anion and the hydrophobic parts of the cation.

The impact of ionic liquids on the coordination of anions with solvatochromic copper complexes.

Solvatochromic transition metal (TM)-complexes with weakly associating counter-anions are often used to evaluate traditional neutral solvent and anion coordination ability. However, when employed in ionic liquids (IL) many of the common assumptions made are no longer reliable. This study investigates the coordinating ability of weakly coordinating IL anions in traditional solvents and within IL solvents employing a range of solvatochromic copper complexes. Complexes of the form [Cu(acac)(tmen)][X] (acac = acetylacetonate, tmen = tetramethylethylenediamine) where [X]- = [ClO4]-, Cl-, [NO3]-, [SCN]-, [OTf]-, [NTf2]- and [PF6]- have been synthesised and characterised both experimentally and computationally. ILs based on these anions and imidazolium and pyrrolidinium cations, some of which are functionalised with hydroxyl and nitrile groups, have been examined. IL-anion coordination has been investigated and compared to typical weakly coordinating anions. We have found there is potential for competition at the Cu-centre and cases of anions traditionally assigned as weakly associating that demonstrate a stronger than expected level of coordinating ability within ILs. [Cu(acac)(tmen)][PF6] is shown to contain the least coordinating anion and is established as the most sensitive probe studied here. Using this probe, the donor numbers (DNs) of ILs have been determined. Relative donor ability is further confirmed based on the UV-Vis of a neutral complex, [Cu(sacsac)2] (sacsac = dithioacetylacetone), and DNs evaluated via23Na NMR spectroscopy. We demonstrate that ILs can span a wide donor range, similar in breadth to conventional solvents.

Nonrandom segregation of the mouse univalent X chromosome: evidence of spindle-mediated meiotic drive.

A fundamental principle of Mendelian inheritance is random segregation of alleles to progeny; however, examples of distorted transmission either of specific alleles or of whole chromosomes have been described in a variety of species. In humans and mice, a distortion in chromosome transmission is often associated with a chromosome abnormality. One such example is the fertile XO female mouse. A transmission distortion effect that results in an excess of XX over XO daughters among the progeny of XO females has been recognized for nearly four decades. Utilizing contemporary methodology that combines immunofluorescence, FISH, and three-dimensional confocal microscopy, we have readdressed the meiotic segregation behavior of the single X chromosome in oocytes from XO females produced on two different inbred backgrounds. Our studies demonstrate that segregation of the univalent X chromosome at the first meiotic division is nonrandom, with preferential retention of the X chromosome in the oocyte in approximately 60% of cells. We propose that this deviation from Mendelian expectations is facilitated by a spindle-mediated mechanism. This mechanism, which appears to be a general feature of the female meiotic process, has implications for the frequency of nondisjunction in our species.

Alzheimer's disease and Down syndrome: leukocyte membrane fluidity alterations.

Down Syndrome (DS) patients over the age of 40 have brain lesions identical to those of patients with Alzheimer's Disease (AD). We have earlier shown that with some membrane probes, the plasma membranes of circulating leukocytes had increased fluidity in AD compared to the normally more rigid membranes in similarly aged subjects. We next questioned whether the occurrence of AD-like pathological lesions in older DS subjects would be associated with a similar increase in membrane fluidity. Fluidity was assessed by measurements of steady-state fluorescence anisotropy using TMA-DPH, which anchors at the plasma membrane surface, and a series of 9-anthroyloxy fatty acids substituted with the fluorescent moiety at different positions on the fatty acid, which permit measurement of fluidity at different depths of the plasma membrane. This was done simultaneously in neutrophils, lymphocytes, and monocytes utilizing flow cytometry. In older DS subjects (average age 52.6), plasma membrane fluidity was indeed increased, a finding similar to that with AD leukocytes. Membrane fluidity of leukocytes of young DS subjects (average age 23.6 years) was less than that seen in older subjects. Membrane changes may result from lipophilic substances released from the central nervous system, or may reflect intrinsic differences in membrane structure unique in DS.

Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor.

The design, synthesis, and biological evaluation of a novel series of 3-[2-(pyrrolidin-1-yl)ethyl]indoles with excellent selectivity for h5-HT1D (formerly 5-HT1Dalpha) receptors over h5-HT1B (formerly 5-HT1Dbeta) receptors are described. Clinically effective antimigraine drugs such as Sumatriptan show little selectivity between h5-HT1D and h5-HT1B receptors. The differential expression of h5-HT1D and h5-HT1B receptors in neural and vascular tissue prompted an investigation of whether a compound selective for the h5-HT1D subtype would have the same clinical efficacy but with reduced side effects. The pyrrolidine 3b was initially identified as having 9-fold selectivity for h5-HT1D over h5-HT1B receptors. Substitution of the pyrrolidine ring of 3b with methylbenzylamine groups gave compounds with nanomolar affinity for the h5-HT1D receptor and 100-fold selectivity with respect to h5-HT1B receptors. Modification of the indole 5-substituent led to the oxazolidinones 24a,b with up to 163-fold selectivity for the h5-HT1D subtype and improved selectivity over other serotonin receptors. The compounds were shown to be full agonists by measurement of agonist-induced [35S]GTPgammaS binding in CHO cells expressed with h5-HT receptors. This study suggests that the h5-HT1D and h5-HT1B receptors can be differentiated by appropriate substitution of the ligand in the region which binds to the aspartate residue and reveals a large binding pocket in the h5-HT1D receptor domain which is absent for the h5-HT1B receptor. The compounds described herein will be important tools to delineate the role of h5-HT1D receptors in migraine.

Intellectual deficits after transient tyrosinemia in the term neonate.

In order to determine if prolonged, significant transient neonatal tyrosinemia (TNT) is injurious to the developing central nervous system, 15 term infants who had suffered from this disorder for a mean duration of 50 days underwent comprehensive psychometric evaluations at a mean (+/- 1 SD) age of 56.5 +/- 7.8 months. Their mean maximum detected tyrosine level had been 25.8 mg/dl (range, 13.6 to 42.0) and their defect was considered secondary to a combination of a high protein formula intake and a lack of supplemental vitamin C. Compared to a control group, significantly lower mean scores were obtained by the TNT group on the McCarthy Scale of Children's Abilities (77.1 vs. 92, P = .008) and the Illinois Test of Psycholinguistic Ability (92.3 vs. 109.9, P = .002). Performance scores varied inversely with the duration of TNT. Although these children are not classifiable as "mentally retarded," TNT may cause specific learning disabilities. There is, therefore, a need to determine the frequency of TNT in infants fed evaporated milk and other high-protein milk formulas and to develop ways to prevent its occurrence.

The use of cells doubly labelled with [14C]inositol and [3H]inositol to search for a hormone-sensitive inositol lipid pool with atypically rapid metabolic turnover.

Some, though not all, previous studies have suggested that the inositol lipid which is hydrolysed during transmembrane signalling in response to receptor activation might be drawn from a metabolically discrete and relatively small hormone-sensitive lipid pool that turns over more rapidly than the bulk of membrane inositol lipid. In order to seek evidence for the existence of this putative hormone-sensitive lipid pool, we have double-labelled cells by growing them for 3 days in a medium containing [14C]inositol and then supplying them with [3H]inositol for the final 2 h before stimulation. We anticipated that stimulation of these doubly labelled cells might provoke the formation, from the postulated hormone-sensitive pool, of small quantities of relatively 3H-enriched inositol phosphates, and that these could be harvested from cells (provided that the cytosolic inositol monophosphatase and inositol 1,4-bisphosphate/inositol 1,3,4-trisphosphate 1-phosphatase activities are first inhibited by Li+). Experiments of this type, using both vasopressin-stimulated WRK1 rat mammary tumour cells and 3T3 mouse fibroblasts stimulated by prostaglandin F2 alpha, have largely failed to demonstrate the formation of relatively 3H-enriched inositol phosphates. There was a tendency for phosphatidyl-inositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate to have slightly higher 3H: 14C ratios than phosphatidylinositol, but the 3H: 14C ratios of the inositol phosphates formed in stimulated cells were not substantially greater than the 3H: 14C ratios of the inositol lipids. We therefore conclude, at least for the two cell lines that we studied, that hormone-stimulated inositol lipid hydrolysis can call, either directly or indirectly, upon the majority of the inositol lipid complement of the stimulated cell.

A decade of modern epilepsy therapy in institutionalized mentally retarded patients.

OBJECTIVE: To evaluate epilepsy therapy in an institutionalized mentally retarded (MR) population involved in a long-term program to reduce anti-epilepsy drugs. DESIGN: An open 10-year study in 244 epileptic MR patients. An interim evaluation was performed in 1987 and a final evaluation in 1991. PATIENTS: MR patients, with a history of symptomatic generalized and partial seizures, at Southside Virginia Training Center (SVTC), Virginia Department of Mental Health, Mental Retardation and Substance Abuse Services. METHODS: In 1981, an evaluation was made of the clinical condition and anti-epilepsy drug (AED) therapy for each patient. AED therapy was tapered for patients who were seizure-free, performance-impairing agents were discontinued for patients receiving polytherapy, and therapy was re-evaluated for patients with poor seizure control. Adverse drug reactions were quantitatively assessed and sedative agents reduced. The staff was educated regarding identification of seizures and adverse drug reactions. RESULTS: A 19% reduction in polytherapy was accomplished. AEDs were discontinued in 12.7% of patients, however, nearly half required reinitiation of therapy. The percentage of patients receiving monotherapy increased from 36.5% to 58.1% with no observed loss in seizure control. Administration of barbiturates was reduced and a decrease in sedation was observed. Some patients required an increase in drug dosage. The drug reductions remained successful for up to 10 years. CONCLUSIONS: Anti-epilepsy drugs for many institutionalized MR patients can be simplified from polytherapy to monotherapy without loss of seizure control and resulting in improved quality of life. A reduction in drug-related toxicities may be accomplished by removal or reduction in barbiturate use.

Preparing for the MFAEM examination.

The MFAEM may take over as the primary membership examination for progression to higher professional training in Emergency Medicine. As a relatively young examination it still suffers from a lack of associated study material and a formal syllabus. The emergence of a specific membership examination such as MFAEM represents the growth in stature of A&E as a speciality in its own right. As the examination becomes more popular and growing numbers of doctors apply there will be a similar expansion of study material and available resources. MRCSEd(A&E) remains a solid alternative and eligibility for this examination is similar to MFAEM part B. However, success at a relevant part one is required before sitting this. The MFAEM part A is more balanced and relevant primary examination for A&E trainees but if one is interested in dual accreditation or has a specific interest in another speciality then sitting the MRCP, MRCS or FRCA may be more appropriate before approaching the MFAEM part B or MRCSEd(A&E).

New experimental density data and soft-SAFT models of alkylimidazolium ([C(n)C1im]⁺) chloride (Cl⁻), methylsulfate ([MeSO4]⁻), and dimethylphosphate ([Me2PO4]⁻) based ionic liquids.

Ionic liquids have been shown to have application in several areas of importance in the context of sustainable industrial activity. One application of particular interest is the ability of certain ionic liquids to dissolve biomass. This clearly marks them as useful materials with application within biorefineries. In this contribution, we present new coarse-grained soft-SAFT models and experimental density data of chloride (Cl(-)), methylsulfate ([MeSO4](-)), and dimethylphosphate ([Me2PO4](-)) based ionic liquids which are relevant for biomass deconstruction processes. Model parameters were obtained by fitting to pure component temperature density data, and the models were subsequently tested by assessing their ability to accurately calculate viscosity and interfacial surface tension. We also developed models of mixtures of the ionic liquids with water and short-chain linear alcohols. We decomposed the contributions to the excess Gibbs energy of mixing to chemical and structural contributions, and used this to provide some insight into the driving forces for solubility of molecular species in these ionic liquids.