How Well Do We Know the Neutron-Matter Equation of State at the Densities Inside Neutron Stars? A Bayesian Approach with Correlated Uncertainties.

We introduce a new framework for quantifying correlated uncertainties of the infinite-matter equation of state derived from chiral effective field theory (χEFT). Bayesian machine learning via Gaussian processes with physics-based hyperparameters allows us to efficiently quantify and propagate theoretical uncertainties of the equation of state, such as χEFT truncation errors, to derived quantities. We apply this framework to state-of-the-art many-body perturbation theory calculations with nucleon-nucleon and three-nucleon interactions up to fourth order in the χEFT expansion. This produces the first statistically robust uncertainty estimates for key quantities of neutron stars. We give results up to twice nuclear saturation density for the energy per particle, pressure, and speed of sound of neutron matter, as well as for the nuclear symmetry energy and its derivative. At nuclear saturation density, the predicted symmetry energy and its slope are consistent with experimental constraints.

Power counting of contact-range currents in effective field theory.

We analyze the power counting of two-body currents in nuclear effective field theories (EFTs). We find that the existence of nonperturbative physics at low energies, which is manifest in the existence of the deuteron and the ^{1}S_{0} NN virtual bound state, combined with the appearance of singular potentials in versions of nuclear EFT that incorporate chiral symmetry, modifies the renormalization-group flow of the couplings associated with contact operators that involve nucleon-nucleon pairs and external fields. The order of these couplings is thereby enhanced with respect to the naive-dimensional-analysis estimate. Consequently, short-range currents enter at a lower order in the chiral EFT than has been appreciated up until now, and their impact on low-energy observables is concomitantly larger. We illustrate the changes in the power counting with a few low-energy processes involving external probes and few-nucleon systems, including electron-deuteron elastic scattering and radiative neutron capture by protons.

Measurement of Compton scattering from the deuteron and an improved extraction of the neutron electromagnetic polarizabilities.

The electromagnetic polarizabilities of the nucleon are fundamental properties that describe its response to external electric and magnetic fields. They can be extracted from Compton-scattering data-and have been, with good accuracy, in the case of the proton. In contradistinction, information for the neutron requires the use of Compton scattering from nuclear targets. Here, we report a new measurement of elastic photon scattering from deuterium using quasimonoenergetic tagged photons at the MAX IV Laboratory in Lund, Sweden. These first new data in more than a decade effectively double the world data set. Their energy range overlaps with previous experiments and extends it by 20 MeV to higher energies. An analysis using chiral effective field theory with dynamical Δ(1232) degrees of freedom shows the data are consistent with and within the world data set. After demonstrating that the fit is consistent with the Baldin sum rule, extracting values for the isoscalar nucleon polarizabilities, and combining them with a recent result for the proton, we obtain the neutron polarizabilities as αn=[11.55±1.25(stat)±0.2(BSR)±0.8(th)]×10(-4) fm(3) and ßn=[3.65∓1.25(stat)±0.2(BSR)∓0.8(th)]×10(-4) fm(3), with χ(2)=45.2 for 44 degrees of freedom.

Radioarsenic from a portable (72)Se/(72)As generator: a current perspective.

Positron emission tomography (PET) of slower biological processes calls for the use of longer lived positron emitting radioisotopes. Beyond radionuclide production considerations, practicality and rapidity of subsequent labeling chemistry further limits the selection of radioisotopes with potentially favorable nuclear properties. One additional limitation is the availability of PET radiotracers at the point-of-care with appropriate on-site production methodologies or robust radionuclide generator systems. The positron emitter (72)As (half-life 26 h) is generated via decay of (72)Se (half-life 8.5 d); this pair comprises and excellent generator system for clinical availability of a longer lived PET isotope. Many (72)Se/As generator systems have been introduced utilizing the rich interplay of Se(IV)/Se(VI) and As(III) /As(V) chemical behavior. This paper describes available generator concepts, and briefly outlines some current arsenic labeling methodologies for the introduction of radioarsenic into biomolecules.

Processing of anthracycline-DNA adducts via DNA replication and interstrand crosslink repair pathways.

Anthracycline chemotherapeutics are well characterised as poisons of topoisomerase II, however many anthracyclines, including doxorubicin, are also capable of forming drug-DNA adducts. Anthracycline-DNA adducts present an unusual obstacle for cells as they are covalently attached to one DNA strand and stabilised by hydrogen bonding to the other strand. We now show that in cycling cells processing of anthracycline adducts through DNA replication appears dominant compared to processing via transcription-coupled pathways, and that the processing of these adducts into DNA breaks is independent of topoisomerase II. It has previously been shown that cells deficient in homologous recombination (HR) are hypersensitive to adduct forming treatments. Given that anthracycline-DNA adducts, whilst not true crosslinks, are associated with both DNA strands, the role of ICL repair pathways was investigated. Mus81 is a structure specific nuclease implicated in Holliday junction resolution and the resolution of branched DNA formed by stalled replication forks. We now show that ICL repair deficient cells (Mus81(-/-)) are hypersensitive to anthracycline-DNA adducts and ET-743, a compound which causes a chemically similar type of DNA damage. Further analysis of this mechanism showed that Mus81 does not appear to cause DNA breaks resulting from either anthracycline- or ET743-DNA adducts. This suggests Mus81 processes these novel forms of DNA damage in a fundamentally different way compared to the processing of classical covalent crosslinks. Improved understanding of the role of DNA repair in response to such adducts may lead to more effective chemotherapy for patients with BRCA1/2 mutations and other HR deficiencies.

Barminomycin, a model for the development of new anthracyclines.

Barminomycin is a member of the anthracycline class of anticancer agents and was originally discovered as a pink/red complex with DNA and RNA and named SN-07. The chromophore was subsequently separated from the nucleic acids by nuclease digestion and contained the four-membered anthraquinone ring system characteristic of anthracyclines, but with an unusual eight membered ring that contained a carbinolamine which readily interconverted to an imine. The imine form is analogous to the formaldehyde-activated form of other anthracyclines such as doxorubicin. The imine form confers exceptional activity to barminomycin which is 1,000-fold more cytotoxic than doxorubicin. Barminomycin rapidly forms adducts with DNA, reacting with the exocyclic amino group of guanine residues and with high selectivity for 5'-GC-3' sequences. The coupling to DNA appears to be identical to the N-C-N aminal linkage formed between doxorubicin and DNA where the carbon derives from formaldehyde for doxorubicin-DNA adducts, whereas this "activated carbon" is an inherent component of the imine group in the eight membered ring of barminomycin. Although the linkage of both drugs to DNA appears to be identical, barminomycin-DNA complexes are essentially irreversible compared to the labile doxorubicin-DNA adducts which have an in vitro (purified DNA) half-life of 25 h at 37 degrees C. A 3D model of the barminomycin-DNA complex has been defined from 307 NOE distance constraints. The enhanced stability of barminomycin-DNA adducts appears to be due primarily to protection of the aminal linkage from hydrolysis and this has provided insight into the design of new anthracycline derivatives with enhanced stability and activity. Strategies for harnessing the extreme reactivity and activity of barminomycin are also presented.

First UK report of successful treatment of Mycobacterium simiae and immune reconstitution inflammatory syndrome in an HIV-seropositive patient.

Non-tuberculous mycobacteria (NTM) such as Mycobacterium avium intracellulare are commonly encountered by HIV physicians and management strategies are well established. Experience of other NTM is, however, limited. As HIV epidemiology in the United Kingdom changes, we may expect the emergence of these lesser known mycobacterial infections. We present the first UK report of an AIDS patient who has survived infection with disseminated Mycobacterium simiae despite cerebrospinal fluid involvement, an extremely high level of baseline HIV viraemia and treatment complicated by severe immune reconstitution inflammatory syndrome.

Polymyxin E production by P. amylolyticus.

AIMS: To investigate antibiotic production by bacteria isolated from the hindgut of Tipula abdominalis, the aquatic crane fly. METHODS AND RESULTS: A group of five isolates with 99.1% 16S rRNA sequence similarity to Paenibacillus amylolyticus were identified as antibacterial producers using the cross-streak method against both Gram-positive and Gram-negative bacteria. For one isolate, P. amylolyticus C27, biochemical tests were performed to confirm 16S rRNA identification and the antibacterials were purified using chromatographic methods. Postsource decay (PSD) mass spectroscopy (MS) was used to identify the antimicrobials, which were found to be polymyxins E(1) and E(2). Investigation of the remaining four isolates using PSD MS revealed they all produce polymyxins E(1) and E(2) as well. CONCLUSIONS, SIGNIFICANCE AND IMPACT OF THE STUDY: Although variants of the polymyxin antibiotics are known to be produced by several species within the Paenibacillus genus, this first investigation of antibacterial production by bacteria isolated from the hindgut of T. abdominalis describes a novel source for polymyxin E production as well as the first report of antibiotic production by P. amylolyticus.

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity.

Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (DeltaPsim) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation.

How low-energy weak reactions can constrain three-nucleon forces and the neutron-neutron scattering length.

We show that chiral symmetry and gauge invariance enforce relations between the short-distance physics that occurs in a number of electroweak and pionic reactions on light nuclei. Within chiral perturbation theory, this is manifested via the appearance of the same axial isovector two-body contact term in pi(-)d --> nngamma, p-wave pion production in NN collisions, tritium beta decay, pp fusion, nud scattering, and the hep reaction. Using a Gamow-Teller matrix element obtained from calculations of pp fusion as input, we compute the neutron spectrum obtained in pi(-)d --> nngamma. With the short-distance physics in this process controlled from pp --> de(=)nu(e), the theoretical uncertainty in the nn scattering length extracted from pi(-)d --> nngamma is reduced by a factor larger than 3, to approximately < or = 0.05 fm.

Recent advances in understanding and exploiting the activation of anthracyclines by formaldehyde.

The anthracycline group of compounds are amongst the most effective chemotherapy agents currently in use for cancer treatment. They are generally classified as topoisomerase II inhibitors but also have a variety of other targets in cells. It has been known for some years that the anthracyclines are capable of forming DNA adducts, but the relevance and extent of these DNA adducts in cells and their role in causing cell death has remained obscure. When the adduct structure was solved, it became clear that formaldehyde was an absolute requirement for adduct formation. This led to a renewed interest in the capacity of anthracyclines to form DNA adducts, and there are now several ways in which adduct formation can be facilitated in cells. These involve strategies to provide the requisite formaldehyde in the form of anthracycline-formaldehyde conjugates, and the use of formaldehyde-releasing drugs in combination with anthracyclines. Of particular interest is the new therapeutic compound AN-9 that releases both butyric acid and formaldehyde, leading to efficient anthracycline-DNA adduct formation, and synergy between the two compounds. Targeted formation of adducts using anthracycline-formaldehyde conjugates tethered to cell surface targeted molecules is now also possible. Some of the cellular consequences of these adducts have now been studied, and it appears that their formation can overcome anthracycline-resistance mechanisms, and that they are more efficient at inducing apoptosis than when functioning primarily through impairment of topoisomerase II. The clinical application of the use of anthracyclines as DNA adduct forming agents is now being explored.

Dynamic instability in intergranular fracture.

A molecular-dynamics model for crack propagation under steady-state conditions is used to study dynamic instabilities along a grain boundary in aluminum that occur when the crack speed approaches 1/3 of the material's Rayleigh wave speed. Instead of crack branching, as is characteristic for a crack propagating in a homogeneous environment, the instability of an intergranular crack results in a periodic series of dislocation bursts. These bursts limit the crack speed and produce velocity oscillations with a large increase in energy dissipation that increases the grain boundary toughness.

Therapeutic approaches in arterial thrombosis.

The current standard of care for the treatment of arterial thrombosis includes anticoagulants and three classes of antiplatelet agents--aspirin, thienopyridines and glycoprotein IIb-IIIa antagonists. Although these drugs have had a significant impact on morbidity and mortality in several patient populations, up to 15% of the high risk patients with acute coronary syndrome continue to suffer from ischemic events. This problem may occur, in part, because the platelets in many patients are non-responsive to aspirin and clopidogrel. Murine models now indicate that platelets are not only responsible for arterial occlusion, they are also involved in the progression of atherosclerotic disease. New opportunities have emerged identifying potential targets and strategies for drug discovery suited to address these deficiencies by more effectively modulating platelet adhesion, thrombus growth, thrombus stability and the pro-inflammatory activity of platelets. In addition, a growing need has emerged for the development of bedside devices capable of bringing personalized medicine to patients being treated with antithrombotic drugs in order to measure the pharmacodynamic activities of new therapies, to assess the activities achieved by combined antithrombotic therapy, and to identify patients that fail to respond.

Effectiveness of manipulative physiotherapy for the treatment of a neurogenic cervicobrachial pain syndrome: a single case study -- experimental design.

A single case study ABC design was used to evaluate the effectiveness of manipulative physiotherapy in a 44-year-old woman with an 8-month history of neurogenic cervicobrachial pain. Clinical examination demonstrated significant signs of upper quadrant neural tissue mechanosensitivity indicating that neural tissue was the dominant tissue of origin for the subject's complaint of pain. Magnetic resonance imaging revealed correlating discal pathology at the C5/6 intersegmental level. The study involved a 4-week pre-assessment phase, a 4-week treatment phase and a 2-week home exercise phase. Functional disability was measured using the Northwick Park Neck Pain Questionnaire and pain was assessed using the McGill Short Form Pain Questionnaire. Cervical motion was measured by a cervical range of motion device (CROM) and the range of shoulder abduction with a mediclino inclinometer. Manipulative physiotherapy treatment involved a cervical lateral glide mobilization technique. Following treatment, visual analysis revealed beneficial effects on pain, functional disability as well as cervical and shoulder mobility. These improvements were maintained over the home exercise phase and at 1-month follow-up. The single case limits generalization of the findings, but the results support previous studies in this area and gives further impetus to controlled clinical trials.

Atopic eczema and the home environment.

BACKGROUND: There is strong evidence to suggest that the prevalence of atopic eczema is increasing in developed countries. Environmental factors have been implicated in the disease. OBJECTIVES: This descriptive case-control study sheds light on the possible association between atopic eczema in school children and various home environmental factors, and generates hypotheses for further studies. METHODS: The study uses data on reported atopic eczema symptoms collected via a cross-sectional parental postal survey (n = 1350) in Nottingham, U.K. Estimates of the risk of reported eczema associated with various home environmental factors were calculated by means of odds ratios (OR), along with population attributable risk percentages. RESULTS: The study showed statistically significant associations between atopic eczema symptoms and dampness in the home [OR 1.40; 95% confidence interval (CI) 1.00-1.97], the use of a radiator to heat the child's bedroom (OR 1.50; 95% CI 1.05-2.16) and the use of synthetic pillows (OR 1.51; 95% CI 1.01-2.28). Frequent vacuuming in the home was associated with a decreased prevalence of atopic eczema (OR 0.74; 95% CI 0.58-0.94). The associations with dampness in the home, synthetic pillows and frequency of vacuuming were not altered significantly after adjustment for age, sex and socio-economic status. Population attributable risk percentages for the use of a radiator and synthetic pillows indicate that although the relative risk estimates for these factors may be small, the population impact of these factors is considerable (26% and 28%, respectively), owing to the high prevalence of exposure to these factors among this group of school children. CONCLUSIONS: Further research is needed to confirm these associations and additional research is needed to see whether they might be causative. Practical public health advice about the importance of controlling the home environment may then be targeted at families with atopic eczema.

Differential effects of citrate versus PPACK anticoagulation on measured platelet inhibition by abciximab, eptifibatide and tirofiban.

BACKGROUND: High levels of glycoprotein (GP) IIb/IIIa receptor inhibition are required to prevent arterial thrombosis following percutaneous coronary intervention. Ex-vivo turbidometric platelet aggregation in citrate anticoagulated blood samples has been the primary method previously utilized to derive dose regimens for administering platelet GP IIb/IIIa inhibitors. Enhanced GP IIb/IIIa binding and inhibition of platelet aggregation for eptifibatide secondary to citrate induced reduction of ionized plasma calcium concentrations has been reported. METHODS/RESULTS: We evaluated the differential effects of citrate versus PPACK anticoagulation on turbidometric platelet inhibition in normal volunteers by eptifibatide, tirofiban or abciximab. The decrease in ionized calcium afforded by citrate was associated with enhanced in vitro platelet inhibition for all three GP IIb/IIIa inhibitors, including abciximab. The magnitude of citrate effect was greatest for eptifibatide. Both tirofiban and abciximab have similar citrate calcium chelation associated enhancement of measured platelet inhibition. CONCLUSION: Accurate assessment and comparison of platelet inhibition by GP IIb/IIIa inhibitors may require avoidance of calcium chelating anticoagulants.

Molecular basis for the synergistic interaction of adriamycin with the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate (AN-9).

The interaction of Adriamycin and pivaloyloxymethyl butyrate (AN-9) was investigated in IMR-32 neuroblastoma and MCF-7 breast adenocarcinoma cells. Adriamycin is a widely used anticancer drug, whereas AN-9 is an anticancer agent presently undergoing Phase II clinical trials. The anticancer activity of AN-9 has been attributed to its ability to act as a butyric acid prodrug, although it also releases formaldehyde and pivalic acid. Adriamycin and AN-9 in combination display synergy when exposed simultaneously to cells or when AN-9 treatment is up to 18 h after Adriamycin administration. However, the reverse order of addition results in antagonism. These interactions have been established using cell viability assays and classical isobologram analysis. To understand the molecular basis of this synergy, the relative levels of Adriamycin-DNA adducts were determined using various treatment combinations. Levels of Adriamycin-DNA adducts were enhanced when treatment combinations known to be synergistic were used and were diminished using those treatments known to be antagonistic. The relative timing of the addition of Adriamycin and AN-9 was critical, with a 20-fold enhancement of Adriamycin-DNA adducts occurring when AN-9 was administered 2 h after the exposure of cells to Adriamycin. The enhanced levels of these adducts and the accompanying decreased cell viability were directly related to the esterase-dependent release of formaldehyde from AN-9, providing evidence for the formaldehyde-mediated activation of Adriamycin.

Barminomycin functions as a potent pre-activated analogue of Adriamycin.

The anthracycline Adriamycin is known to form adducts with DNA, but requires prior activation by formaldehyde. In contrast, the anthracycline barminomycin is also able to form adducts with DNA, but does not require activation by formaldehyde. Barminomycin, therefore, appears to function as a pre-activated form of Adriamycin. The DNA adducts formed by both anthracyclines are bound covalently to only one strand of DNA, but both also stabilise duplex DNA sufficiently that they can be detected as virtual interstrand crosslinks in heat denaturation electrophoretic crosslinking assays. The barminomycin-DNA adducts form extremely rapidly with DNA, and at exceedingly low concentrations (approximately 50-fold lower than with Adriamycin in the presence of excess formaldehyde), both characteristics consistent with barminomycin being in a pre-activated state, hence, undergoing a bimolecular reaction with DNA compared with the trimolecular reaction (drug, formaldehyde and DNA) required with Adriamycin. Surprisingly, barminomycin-DNA adducts are substantially more stable (essentially irreversible) than Adriamycin-DNA adducts (half life of approximately 25 h at 37 degrees C). Due to this understanding of the reactivity of barminomycin and its exceptional cytotoxicity (1000-fold more cytotoxic than Adriamycin), detailed structural studies of barminomycin-DNA adducts are now warranted, both in vitro and in tumour cells.

Integrin tyrosine phosphorylation in platelet signaling.

The beta 3 integrin cytoplasmic tyrosine (ICY) motif of alpha IIb beta 3 becomes tyrosine phosphorylated during platelet aggregation, causing Shc and myosin to interact with the beta-integrin cytoplasmic domain. Platelets from mice lacking beta 3 ICY motif tyrosines formed defective aggregates and poorly retracted clots, establishing integrin tyrosine phosphorylation as a key mediator of beta 3-integrin signals.