High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT

Metal–silicate partitioning of W and Mo and the role of carbon in controlling their abundances in the bulk silicate earth

The liquid metal–liquid silicate partitioning of molybdenum and tungsten during core formation must be well-constrained in order to understand the evolution of Earth and other planetary bodies, in particular because the Hf–W isotopic system is used to date early planetary evolution. The partition coefficients DMo and DW have been suggested to depend on pressure, temperature, silicate and metal compositions, although previous studies have produced varying and inconsistent models. Additionally, the high cationic charges of W and Mo in silicate melts make their partition coefficients particularly sensitive to oxygen fugacity. We combine 48 new high pressure and temperature experimental results with a comprehensive database of previous experiments to re-examine the systematics of Mo and W partitioning, and produce revised partitioning models from the large combined dataset. W partitioning is particularly sensitive to silicate and metallic melt compositions and becomes more siderophile with increasing temperature. We show that W has a 6+ oxidation state in silicate melts over the full experimental fO2 range of ΔIW −1.5 to −3.5. Mo has a 4+ oxidation state, and its partitioning is less sensitive to silicate melt composition but also depends on metallic melt composition. DMo stays approximately constant with increasing depth in Earth. Both W and Mo become more siderophile with increasing C content of the metal: we therefore performed experiments with varying C concentrations and fit epsilon interaction parameters:  = −7.03 ± 0.30 and  = −7.38 ± 0.57. W and Mo along with C are incorporated into a combined N-body accretion and core–mantle differentiation model, which already includes the major rock-forming elements as well as S, and moderately and highly siderophile elements. In this model, oxidation and volatility gradients extend through the protoplanetary disk so that Earth accretes heterogeneously. These gradients, as well as the metal–silicate equilibration pressure, are fitted using a least squares optimisation so that the model Earth-like planet reproduces the composition of the bulk silicate Earth (BSE) in terms of 17 simulated element concentrations (Mg, Fe, Si, Ni, Co, Nb, Ta, V, Cr, S, Pt, Pd, Ru, Ir, W, Mo, and C). The effects of the interaction of W and Mo with Si, S, O, and C in metal are included. Using this model with six separate terrestrial planet accretion simulations, we show that W and Mo require the early accreting Earth to be sulfur-depleted and carbon-enriched so that W and Mo are efficiently partitioned into Earth’s core and do not accumulate in the mantle. When this is the case, the produced Earth-like planets possess mantle compositions matching the BSE for all simulated elements. However, there are two distinct groups of estimates of the bulk mantle’s C abundance in the literature: low (∼100 ppm) and high (∼800 ppm), and all six models are consistent with the higher estimated carbon abundance. The low BSE C abundance would be achievable when the effects of the segregation of dispersed metal droplets produced in deep magma oceans by the disproportionation of Fe2+ to Fe3+ plus metallic Fe is included

Evaluation of a blocking ELISA for the detection of antibodies against Lawsonia intracellularis in pig sera

<p>Abstract</p> <p>Background</p> <p><it>Lawsonia intracellularis </it>is a common cause of chronic diarrhoea and poor performance in young growing pigs. Diagnosis of this obligate intracellular bacterium is based on the demonstration of the microbe or microbial DNA in tissue specimens or faecal samples, or the demonstration of <it>L. intracellularis</it>-specific antibodies in sera. The aim of the present study was to evaluate a blocking ELISA in the detection of serum antibodies to <it>L. intracellularis</it>, by comparison to the previously widely used immunofluorescent antibody test (IFAT).</p> <p>Methods</p> <p>Sera were collected from 176 pigs aged 8-12 weeks originating from 24 herds with or without problems with diarrhoea and poor performance in young growing pigs. Sera were analyzed by the blocking ELISA and by IFAT. Bayesian modelling techniques were used to account for the absence of a gold standard test and the results of the blocking ELISA was modelled against the IFAT test with a "2 dependent tests, 2 populations, no gold standard" model.</p> <p>Results</p> <p>At the finally selected cut-off value of percent inhibition (PI) 35, the diagnostic sensitivity of the blocking ELISA was 72% and the diagnostic specificity was 93%. The positive predictive value was 0.82 and the negative predictive value was 0.89, at the observed prevalence of 33.5%.</p> <p>Conclusion</p> <p>The sensitivity and specificity as evaluated by Bayesian statistic techniques differed from that previously reported. Properties of diagnostic tests may well vary between countries, laboratories and among populations of animals. In the absence of a true gold standard, the importance of validating new methods by appropriate statistical methods and with respect to the target population must be emphasized.</p

Neurospora from natural populations: Population genomics insights into the Life history of a model microbial Eukaryote

The ascomycete filamentous fungus Neurospora crassa played a historic role in experimental biology and became a model system for genetic research. Stimulated by a systematic effort to collect wild strains initiated by Stanford geneticist David Perkins, the genus Neurospora has also become a basic model for the study of evolutionary processes, speciation, and population biology. In this chapter, we will first trace the history that brought Neurospora into the era of population genomics. We will then cover the major contributions of population genomic investigations using Neurospora to our understanding of microbial biogeography and speciation, and review recent work using population genomics and genome-wide association mapping that illustrates the unique potential of Neurospora as a model for identifying the genetic basis of (potentially adaptive) phenotypes in filamentous fungi. The advent of population genomics has contributed to firmly establish Neurospora as a complete model system and we hope our review will entice biologists to include Neurospora in their research

Open Problems on Central Simple Algebras

We provide a survey of past research and a list of open problems regarding central simple algebras and the Brauer group over a field, intended both for experts and for beginners.Comment: v2 has some small revisions to the text. Some items are re-numbered, compared to v

Imaging Mitochondrial Calcium Fluxes with Fluorescent Probes and Single- or Two-Photon Confocal Microscopy

The concentration of calcium ions in the mitochondria has been shown to affect its function, modulating respiratory activity at low levels and causing lethal damage at high concentrations. The rhodamine series of dyes can be used to measure mitochondrial calcium concentration, but the reliability of measurements depends upon correct partitioning of the dye within to the mitochondria. Methods are described to aid verification and quantification of the mitochondrial calcium concentration using single- or two-photon confocal microscopy. The method of linear unmixing to separate fluorescent signals based on either differing excitation or emission spectra is outlined and for the purposes of illustration is applied to the separation of rhod-2 signals originating from the dye within the mitochondria and nucleoli

Association between free testosterone levels and anal human papillomavirus Types 16/18 infections in a cohort of men who have sex with men

Background Human papillomavirus (HPV) types 16 and 18 cause invasive cervical cancer and most invasive anal cancers (IACs). Overall, IAC rates are highest among men who have sex with men (MSM), especially MSM with HIV infection. Testosterone is prescribed for men showing hypogonadism and HIV-related wasting. While there are direct and indirect physiological effects of testosterone in males, its role in anal HPV16/18 infections in men is unknown. Methods Free testosterone (FT) was measured in serum from 340 Multicenter AIDS Cohort Study (MACS) participants who were tested for anal HPV16/18-DNA approximately 36 months later. The effect of log10-transformed current FT level on anal HPV16/18 prevalence was modeled using Poisson regression with robust error variance. Multivariate models controlled for other HPV types, cumulative years of exogenous testosterone use, race, age, lifetime number of receptive anal intercourse partnerships, body mass index, tobacco smoking, HIV-infection and CD4+ T-cell counts among HIV-infected, and blood draw timing. Results Participants were, on average, 60 (+5.4) years of age, White (86%), and HIV-uninfected (56%); Twenty-four percent tested positive for anal HPV16 and/or 18-DNA (HPV16 prevalence= 17.1%, HPV18=9.1%). In adjusted analysis, each half-log10 increase of FT was associated with a 1.9-fold (95% Confidence Interval: 1.11, 3.24) higher HPV16/18 prevalence. Additionally, other Group 1 high-risk HPVs were associated with a 1.56-fold (1.03, 2.37) higher HPV16/18 prevalence. Traditional risk factors for HPV16/18 infection (age, tobacco smoking; lifetime number of sexual partners, including the number of receptive anal intercourse partnerships within 24 months preceding HPV testing) were poorly correlated with one another and not statistically significantly associated with higher prevalence of HPV16/ 18 infection in unadjusted and adjusted analyses. Conclusions Higher free testosterone was associated with increased HPV16/18 prevalence measured approximately three years later, independent of sexual behavior and other potential confounders. The mechanisms underlying this association remain unclear and warrant further study

Perturbative quantum gravity with the Immirzi parameter

We study perturbative quantum gravity in the first-order tetrad formalism. The lowest order action corresponds to Einstein-Cartan plus a parity-odd term, and is known in the literature as the Holst action. The coupling constant of the parity-odd term can be identified with the Immirzi parameter of loop quantum gravity. We compute the quantum effective action in the one-loop expansion. As in the metric second-order formulation, we find that in the case of pure gravity the theory is on-shell finite, and the running of Newton's constant and the Immirzi parameter is inessential. In the presence of fermions, the situation changes in two fundamental aspects. First, non-renormalizable logarithmic divergences appear, as usual. Second, the Immirzi parameter becomes a priori observable, and we find that it is renormalized by a four-fermion interaction generated by radiative corrections. We compute its beta function and discuss possible implications. The sign of the beta function depends on whether the Immirzi parameter is larger or smaller than one in absolute value, and the values plus or minus one are UV fixed-points (we work in Euclidean signature). Finally, we find that the Holst action is stable with respect to radiative corrections in the case of minimal coupling, up to higher order non-renormalizable interactions.Comment: v2 minor amendment

The combined diabetes and renal control trial (C-DIRECT) - a feasibility randomised controlled trial to evaluate outcomes in multi-morbid patients with diabetes and on dialysis using a mixed methods approach

Background: This cluster randomised controlled trial set out to investigate the feasibility and acceptability of the “Combined Diabetes and Renal Control Trial” (C-DIRECT) intervention, a nurse-led intervention based on motivational interviewing and self-management in patients with coexisting end stage renal diseases and diabetes mellitus (DM ESRD). Its efficacy to improve glycaemic control, as well as psychosocial and self-care outcomes were also evaluated as secondary outcomes. Methods: An assessor-blinded, clustered randomised-controlled trial was conducted with 44 haemodialysis patients with DM ESRD and ≥ 8% glycated haemoglobin (HbA1c), in dialysis centres across Singapore. Patients were randomised according to dialysis shifts. 20 patients were assigned to intervention and 24 were in usual care. The C-DIRECT intervention consisted of three weekly chair-side sessions delivered by diabetes specialist nurses. Data on recruitment, randomisation, and retention, and secondary outcomes such as clinical endpoints, emotional distress, adherence, and self-management skills measures were obtained at baseline and at 12 weeks follow-up. A qualitative evaluation using interviews was conducted at the end of the trial. Results: Of the 44 recruited at baseline, 42 patients were evaluated at follow-up. One patient died, and one discontinued the study due to deteriorating health. Recruitment, retention, and acceptability rates of C-DIRECT were generally satisfactory HbA1c levels decreased in both groups, but C-DIRECT had more participants with HbA1c < 8% at follow up compared to usual care. Significant improvements in role limitations due to physical health were noted for C-DIRECT whereas levels remained stable in usual care. No statistically significant differences between groups were observed for other clinical markers and other patient-reported outcomes. There were no adverse effects. Conclusions: The trial demonstrated satisfactory feasibility. A brief intervention delivered on bedside as part of routine dialysis care showed some benefits in glycaemic control and on QOL domain compared with usual care, although no effect was observed in other secondary outcomes. Further research is needed to design and assess interventions to promote diabetes self-management in socially vulnerable patients