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

Effect of Conditioning Regimen Intensity on Acute Myeloid Leukemia Outcomes after Umbilical Cord Blood Transplantation

Reduced-intensity conditioning (RIC) umbilical cord blood (UCB) transplantation is increasingly used in hematopoietic stem cell transplantation (HCT) for older and medically unfit patients. Data on the efficacy of HCT after RIC relative to myeloablative conditioning (MAC) are limited. We compared the outcomes of acute myeloid leukemia (AML) patients >18 yrs who received UCB grafts after either RIC or MAC. One hundred nineteen adult patients with AML in complete remission (CR) underwent an UCB transplant after RIC (n =74, 62%) or MAC (n = 45, 38%) between January 2001 and December 2009. Conditioning was either reduced intensity and consisted of cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2, and total-body irradiation (TBI) 200 cGy or myelablative and consisted for cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2, and TBI 1200-1320 cGy. All patients received cyclosporine (day −3 to day +180) and mycophenolate mofetil (day −3 to day +45) post-HCT immunosuppression and hematopoietic growth factor. Use of RIC was reserved for patients >45 years (n = 66, 89%) or preexisting severe comorbidities (n = 8, 11%). The 2 groups were similar except for preceding myelodysplastic syndrome (RIC = 28% versus MAC = 4%, P < .01) and age that was dictated by the treatment protocols (median, RIC = 55 years versus MAC = 33years; P < .01). The incidence of neutrophil recovery at day +42 was higher with RIC (94% versus MAC = 82%, P < .1), whereas platelet recovery at the sixth month was similar (RIC = 68% versus MAC = 67%, P = .30). Incidence of grade II-IV acute graft-versus-host disease (aGVHD) (RIC = 47% versus MAC = 67%, P < .01) was decreased with similar incidence of chronic GVHD (cGVHD) (RIC = 30% versus MAC = 34%, P = .43). Median follow-up for survivors was 3.8 and 4.5 years for RIC and MAC, respectively (P = .4). Using RIC, 3-year leukemia-free survival (LFS) was decreased (31% versus MAC = 55%, P = .02) and 3-year relapse incidence was increased (43% versus MAC = 9%, P < .01). Two-year transplant-related mortality (TRM) was similar (RIC = 19% versus MAC = 27%; P = .55). In multivariate analysis, RIC recipients and those in CR2 with CR1 duration <1 year had higher risk of relapse and poorer LFS with no independent predictors of TRM. UCB with RIC extends the use of allogeneic HCT for older and frail patients without excessive TRM with greater benefit for patients in CR1 and CR2 with longer CR1

Persönliche Anliegen in Alltagssituationen

Brunstein JC, Ganserer J, Maier GW, Heckhausen H. Persönliche Anliegen in Alltagssituationen. Memorandum. Vol 82. Erlangen: Friedrich-Alexander-Universität Erlangen-Nürnberg; Draft.In einer Feldstudie, an der 42 Hausfrauen teilnahmen, wurden charakteristische Merkmale von persönlichen Anliegen untersucht, und es wurde überprüft, welchen Einfluß persönliche Anliegen auf die Erfahrung und Beurteilung von Alltagssituationen ausüben. In einem Interview beschrieben die Teilnehmerinnen zunächst ihre Anliegen und schätzten sie anschießend nach einer Reihe von Anliegenparametern ein (z.B. nach der Höhe ihrer Bereitschaft, sich für die Verwirklichung eines Anliegens einzusetzen; oder nach der Verfügbarkeit von günstigen Gelegenheiten, bei denen ein Anliegen verfolgt werden kann). Außerdem zeichneten sie eine Woche lang ihre täglichen Aktivitäten, Stimmungen und Bedürfnisse auf. Die Ergebnisse zeigten, (a) daß persönliche Anliegen nach dem Ausmaß an Entschlossenheit, ein anliegenrelevantes Ziel zu realisieren, sowie nach der Qualität vorteilhafter versus nachteiliger Realisierungsbedingungen beurteilt wurden; (b) daß die Intensität, mit der sich die Teilnehmerinnen mit ihre persönlichen Anliegen beschäftigten, eng mit dem Ausmaß ihrer Entschlossenheit zusammenhing, während ihre diesbezügliche Erfolgserwartung von der Beurteilung der vorliegenden Realisierungsbedingungen bestimmt wurde; (c) daß sich Fortschritte bei der Realisierung von Anliegen ebenso wie positive und negative Stimmungslagen im Alltag in bedeutsamem Umfang auf Unterschiede in der persönlichen Einsatzbereitschaft und in der Verfügbarkeit von günstigen Gelegenheiten zurückführen ließen; sowie (d) daß die Teilnehmerinnen anliegenrelevante Situationen im Alltag als Herausforderung erlebten, bei der sie ihre Fähigkeiten demonstrieren und ihr Selbstwertgefühl stärken konnten.42 housewives participated in a field study in which characteristic dimensions of current concerns were explored, and influences current concerns exerted upon subjects' experience of and judgements about everyday situations were examined. A preceding interview required participants to describe their current concerns and to assess them through a series of concern attributes (e.g., subjects' readiness to invest effort in order to attain a concern-related goal; or availability of favorable opportunities to pursue current concerns). Subjects also recorded their daily activities, moods, and needs over a one-week period. Results demonstrated (a) that current concerns were construed along two dimensions indicating subjects' commitment to attain a concern-related goal and reflecting their judgement of facilitating versus debilitating environmental conditions; (b) that intensity of concern-related preoccupations was closely linked to commitment-related variables, whereas judgements about environmental conditions determined the subjective pro- bability of success; (c) that readiness to invest effort and availability of favorable opportunities accounted both for significant variations in progress toward goal attainment and for individual differences in positive versus negative mood in daily life situations; and (d) that participants perceived concern-related everyday situations as challenges, allowing them to demonstrate their abilities and to increase their sense of self-esteem

Exploring alternative symmetry breaking mechanisms at the LHC with 7, 8 and 10 TeV total energy

In view of the annnouncement that in 2012 the LHC will run at 8 TeV, we study the possibility of detecting signals of alternative mechanisms of ElectroWeak Symmetry Breaking, described phenomenologically by unitarized models, at energies lower than 14 TeV. A complete calculation with six fermions in the final state is performed using the PHANTOM event generator. Our results indicate that at 8 TeV some of the scenarios with TeV scale resonances are likely to be identified while models with no resonances or with very heavy ones will be inaccessible, unless the available luminosity will be much higher than expected

Corrections to Scaling for the Two-dimensional Dynamic XY Model

With large-scale Monte Carlo simulations, we confirm that for the two-dimensional XY model, there is a logarithmic correction to scaling in the dynamic relaxation starting from a completely disordered state, while only an inverse power law correction in the case of starting from an ordered state. The dynamic exponent $z$ is $z=2.04(1)$.Comment: to appear as a Rapid commu. in Phys. Rev.

Low-Energy Constraints on New Physics Revisited

It is possible to place constraints on non-Standard-Model gauge-boson self-couplings and other new physics by studying their one-loop contributions to precisely measured observables. We extend previous analyses which constrain such nonstandard couplings, and we present the results in a compact and transparent form. Particular attention is given to comparing results for the light-Higgs scenario, where nonstandard effects are parameterized by an effective Lagrangian with a linear realization of the electroweak symmetry breaking sector, and the heavy-Higgs/strongly interacting scenario, described by the electroweak chiral Lagrangian. The constraints on nonstandard gauge-boson self-couplings which are obtained from a global analysis of low-energy data and LEP/SLC measurements on the Z pole are updated and improved from previous studies. Replaced version: tables and figures of Section VIb recalculated. There were roundoff problems, especially in Fig. 8. Text unchanged.Comment: \documentstyle[preprint,aps,floats,psfig]{revtex}, 10 figures, postscript version available from ftp://ftp.kek.jp/kek/preprints/TH/TH-51

Atmospheric drying as the main driver of dramatic glacier wastage in the southern Indian Ocean

This study was funded by IPEV-1048 GLACIOCLIM-KESAACO and LEFE-INSU KCRuMBLE programs, and the Agence Nationale de la Recherche through contract ANR-14-CE01-0001-01 (ASUMA).The ongoing retreat of glaciers at southern sub-polar latitudes is particularly rapid and widespread. Akin to northern sub-polar latitudes, this retreat is generally assumed to be linked to warming. However, no long-term and well-constrained glacier modeling has ever been performed to confirm this hypothesis. Here, we model the Cook Ice Cap mass balance on the Kerguelen Islands (Southern Indian Ocean, 49°S) since the 1850s. We show that glacier wastage during the 2000s in the Kerguelen was among the most dramatic on Earth. We attribute 77% of the increasingly negative mass balance since the 1960s to atmospheric drying associated with a poleward shift of the mid-latitude storm track. Because precipitation modeling is very challenging for the current generation of climate models over the study area, models incorrectly simulate the climate drivers behind the recent glacier wastage in the Kerguelen. This suggests that future glacier wastage projections should be considered cautiously where changes in atmospheric circulation are expected.Publisher PDFPeer reviewe