Monochloroacetic acid and 60% salicylic acid as a treatment for simple plantar warts:effectiveness and mode of action

Monochloroacetic acid crystals and 60% salicylic acid ointment was found to be more effective than placebo as a treatment for simple plantar warts in a double blind study on 57 patients. Nineteen (66%) patients in the active treatment group compared with five (18%) patients in the placebo group were cured after 6 weeks (P = 0.002). The active treatment was associated with a significantly higher cure rate 6 months after entry (P = 0.04). Treatments were well tolerated. IgG or IgM antibodies or both to human papilloma virus (HPV) types 1 or 2 or both were detected significantly more frequently in the actively treated group 6 weeks after entry (P = 0.0005). Twelve (50%) patients considered to be cured had no detectable secondary immune response. Our results suggest that cure does not depend primarily on the humoral system but rather on mechanical destruction of wart tissue, or occurs as a result of cell mediated immunity.

Electrochemical promotion of a platinum catalyst supported on the high-temperature proton conductor La0.99Sr0.01NbO4-δ

The recently discovered, high-temperature proton conductor, La_0.99Sr_0.01NbO_4-δ, was used as a support for the electrochemical promotion of a platinum catalyst. Ethylene oxidation was used as a probe reaction in the temperature range 350-450 °C. Moderate non-Faradaic rate modification, attributable to a protonic promoting species, occurred under negative polarisation; some permanent promotion was also observed. In oxidative atmospheres, both the p_O2 of the reaction mixture and the temperature influenced the type and magnitude of the observed rate modification. Rate-enhancement values of up to ρ = 1.4 and Faradaic-efficiency values approaching Λ = -100 were obtained. Promotion was observed under positive polarisation and relatively dry, oxygen-rich atmospheres suggesting that some oxygen ion conductivity may occur under these conditions. Impedance spectroscopy performed in atmospheres of 4 kPa O₂/N₂ and of 5 kPa H₂/N₂ under dry and slightly humidified (0.3 kPa H₂O) conditions indicated that the electrical resistivity is heavily dominated by the grain-boundary response in the temperature range of the EPOC studies; much lower grain-boundary impedances in the wetter conditions are likely to be attributable to proton transport. © 2009 Elsevier B.V. All rights reserved.

The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

Although recent decades have seen an improved cure rate for newly diagnosed paediatric acute lymphoplastic leukaemia (ALL), the treatment options for adult ALL, T-cell ALL (T-ALL) and relapsed disease remain poor. We have developed a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds and established their anticancer efficacy in a variety of human tumour cell types. Here, we demonstrate that PBOX-15 inhibits cell growth, and induces G2/M cell cycle arrest and apoptosis in both T-ALL and B-cell ALL (B-ALL) cells. In addition, prior to PBOX-15-induced apoptosis, PBOX-15 decreases ALL cell adhesion, spreading and migration. Concurrently, PBOX-15 differentially down-regulates β1-, β2- and α4-integrin expression in ALL cells and significantly decreases integrin-mediated cell attachment. PBOX-15 interferes with the lateral mobility and clustering of integrins in both B-ALL and T-ALL cells. These data suggest that PBOX-15 is not only effective in inducing apoptosis in ALL cells, but also has the potential to disrupt integrin-mediated adhesion of malignant lymphocytes, which represents a novel avenue for regulating leukaemic cell homing and migration.

Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial

BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia.

METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535.

FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group.

INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.

The Conditional Phase-type distribution: Graphical Models for Continuous Non-Normal Data:The Conditional Phase-type (C-Ph) distribution:

Conditional Gaussian (CG) distributions allow the inclusion of both discrete and continuous variables in a model assuming that the continuous variable is normally distributed. However, the CG distributions have proved to be unsuitable for survival data which tends to be highly skewed. A new method of analysis is required to take into account continuous variables which are not normally distributed. The aim of this paper is to introduce the more appropriate conditional phase-type (C-Ph) distribution for representing a continuous non-normal variable while also incorporating the causal information in the form of a Bayesian network.

Dose, dose-rate and field size effects on cell survival following exposure to non-uniform radiation fields

For the delivery of intensity-modulated radiation therapy (IMRT), highly modulated fields are used to achieve dose conformity across a target tumour volume. Recent in vitro evidence has demonstrated significant alterations in cell survival occurring out-of-field which cannot be accounted for on the basis of scattered dose. The radiobiological effect of area, dose and dose-rate on out-of-field cell survival responses following exposure to intensity-modulated radiation fields is presented in this study. Cell survival was determined by clonogenic assay in human prostate cancer (DU-145) and primary fibroblast (AG0-1522) cells following exposure to different modulated field configurations delivered using a X-Rad 225 kVp x-ray source. Uniform survival responses were compared to in- and out-of-field responses in which 25-99% of the cell population was shielded. Dose delivered to the out-of-field region was varied from 1.6-37.2% of that delivered to the in-field region using different levels of brass shielding. Dose rate effects were determined for 0.2-4 Gy min⁻¹ for uniform and modulated exposures with no effect seen in- or out-of-field. Survival responses showed little dependence on dose rate and area in- and out-of-field with a trend towards increased survival with decreased in-field area. Out-of-field survival responses were shown to scale in proportion to dose delivered to the in-field region and also local dose delivered out-of-field. Mathematical modelling of these findings has shown survival response to be highly dependent on dose delivered in- and out-of-field but not on area or dose rate. These data provide further insight into the radiobiological parameters impacting on cell survival following exposure to modulated irradiation fields highlighting the need for refinement of existing radiobiological models to incorporate non-targeted effects and modulated dose distributions.

Aging in personal and social immunity: do immune traits senesce at the same rate?

How much should an individual invest in immunity as it grows older? Immunity is costly and its value is likely to change across an organism's lifespan. A limited number of studies have focused on how personal immune investment changes with age in insects, but we do not know how social immunity, immune responses that protect kin, changes across lifespan, or how resources are divided between these two arms of the immune response. In this study, both personal and social immune functions are considered in the burying beetle, Nicrophorus vespilloides. We show that personal immune function declines (phenoloxidase levels) or is maintained (defensin expression) across lifespan in nonbreeding beetles but is maintained (phenoloxidase levels) or even upregulated (defensin expression) in breeding individuals. In contrast, social immunity increases in breeding burying beetles up to middle age, before decreasing in old age. Social immunity is not affected by a wounding challenge across lifespan, whereas personal immunity, through PO, is upregulated following wounding to a similar extent across lifespan. Personal immune function may be prioritized in younger individuals in order to ensure survival until reproductive maturity. If not breeding, this may then drop off in later life as state declines. As burying beetles are ephemeral breeders, breeding opportunities in later life may be rare. When allowed to breed, beetles may therefore invest heavily in "staying alive" in order to complete what could potentially be their final reproductive opportunity. As parental care is important for the survival and growth of offspring in this genus, staying alive to provide care behaviors will clearly have fitness payoffs. This study shows that all immune traits do not senesce at the same rate. In fact, the patterns observed depend upon the immune traits measured and the breeding status of the individual.

The ejected mass distribution of Type Ia supernovae: a significant rate of non-Chandrasekhar-mass progenitors

The ejected mass distribution of Type Ia supernovae (SNe Ia) directly probes progenitor evolutionary history and explosion mechanisms, with implications for their use as cosmological probes. Although the Chandrasekhar mass is a natural mass scale for the explosion of white dwarfs as SNe Ia, models allowing SNe Ia to explode at other masses have attracted much recent attention. Using an empirical relation between the ejected mass and the light-curve width, we derive ejected masses Mej and 56Ni masses MNi for a sample of 337 SNe Ia with redshifts z <0.7 used in recent cosmological analyses. We use hierarchical Bayesian inference to reconstruct the joint Mej-MNi distribution, accounting for measurement errors. The inferred marginal distribution of Mej has a long tail towards sub-Chandrasekhar masses, but cuts off sharply above 1.4 M⊙. Our results imply that 25-50 per cent of normal SNe Ia are inconsistent with Chandrasekhar-mass explosions, with almost all of these being sub-Chandrasekhar mass; super-Chandrasekhar-mass explosions make up no more than 1 per cent of all spectroscopically normal SNe Ia. We interpret the SN Ia width-luminosity relation as an underlying relation between Mej and MNi, and show that the inferred relation is not naturally explained by the predictions of any single known explosion mechanism.

Fundamentals of steady state, non-Newtonian rimming flow

Rimming flow on the inner surface of a horizontal rotating cylinder is investigated. Using a scale analysis, a theoretical description is obtained for steady-state non-Newtonian flow. Simple lubrication theory is applied since the Reynolds number is small and the liquid film is thin. Since the Deborah number is very small the flow is viscometric. The shear-thinning number, which characterizes the shear-thinning effect, may be small or large. A general constitutive law for this kind of flow requires only a single function relating shear stress and shear rate that corresponds to a generalized Newtonian liquid. For this case the run-off condition for rimming flow is derived. Provided the run-off condition is satisfied, the existence of a continuous steady-state solution is proved. The rheological models, which show Newtonian behavior at low shear rates with transition to power-law shear thinning at moderate shear rates, are considered. Numerical results are carried out for the Carreau and Ellis models, which exhibit Newtonian behavior near the free surface and power-law behavior near the wall of the rotating cylinder.

Contingent screening for down syndrome is an efficient alternative to non-disclosure sequential screening

Objective To present a first and second trimester Down syndrome screening strategy, whereby second-trimester marker determination is contingent on the first-trimester results. Unlike non-disclosure sequential screening (the Integrated test), which requires all women to have markers in both trimesters, this allows a large proportion of the women to complete screening in the first trimester. Methods Two first-trimester risk cut-offs defined three types of results: positive and referred for early diagnosis; negative with screening complete; and intermediate, needing second-trimester markers. Multivariate Gaussian modelling with Monte Carlo simulation was used to estimate the false-positive rate for a fixed 85% detection rate. The false-positive rate was evaluated for various early detection rates and early test completion rates. Model parameters were taken from the SURUSS trial. Results Completion of screening in the first trimester for 75% of women resulted in a 30% early detection rate and a 55% second trimester detected rate (net 85%) with a false-positive rate only 0.1% above that achievable by the Integrated test. The screen-positive rate was 0.1% in the first trimester and 4.7% for those continuing to be tested in the second trimester. If the early detection rate were to be increased to 45% or the early completion rate were to be increased to 80%, there would be a further 0.1% increase in the false-positive rate. Conclusion Contingent screening can achieve results comparable with the Integrated test but with earlier completion of screening for most women. Both strategies need to be evaluated in large-scale prospective studies particularly in relation to psychological impact and practicability.

Excitation rate coefficients for transitions from the ground level of Gd XXXVII

Excitation rate coefficients, for transitions from the ground level to excited levels of Gd XXXVII, have been calculated over the temperature range 5002500 eV using the R-matrix method. It is observed that the contribution of resonances enhances the rates by up to an order of magnitude over the available (non- resonant) results of Hagelstein.

Beyond Ehrenfest: correlated non-adiabatic molecular dynamics

A method for introducing correlations between electrons and ions that is computationally affordable is described. The central assumption is that the ionic wavefunctions are narrow, which makes possible a moment expansion for the full density matrix. To make the problem tractable we reduce the remaining many-electron problem to a single-electron problem by performing a trace over all electronic degrees of freedom except one. This introduces both one- and two-electron quantities into the equations of motion. Quantities depending on more than one electron are removed by making a Hartree-Fock approximation. Using the first-moment approximation, we perform a number of tight binding simulations of the effect of an electric current on a mobile atom. The classical contribution to the ionic kinetic energy exhibits cooling and is independent of the bias. The quantum contribution exhibits strong heating, with the heating rate proportional to the bias. However, increased scattering of electrons with increasing ionic kinetic energy is not observed. This effect requires the introduction of the second moment.