Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to ...allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.
Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive ...agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m(2) orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy.
PSR J1903+0327, a millisecond pulsar in an eccentric (e= 0.44) 95-d orbit with an ∼1 M⊙ companion poses a challenge to our understanding of stellar evolution in binary and multiple-star systems. Here ...we describe optical and radio observations which rule out most of the scenarios proposed to explain formation of this system. Radio timing measurements of three post-Keplerian effects yield the most precise measurement of the mass of a millisecond pulsar to date: 1.667 ± 0.021 solar masses (99.7 per cent confidence limit). This rules out some equations of state for superdense matter; furthermore, it is consistent with the spin-up of the pulsar by mass accretion, as suggested by its short spin period and low magnetic field. Optical spectroscopy of a proposed main-sequence counterpart shows that its orbital motion mirrors the pulsar's 95-d orbit; being therefore its binary companion. This finding rules out a previously suggested scenario which proposes that the system is presently a hierarchical triple. Conventional binary evolution scenarios predict that, after recycling a neutron star into a millisecond pulsar, the binary companion should become a white dwarf and its orbit should be nearly circular. This suggests that if PSR J1903+0327 was recycled, its present companion was not responsible for it. The optical detection also provides a measurement of the systemic radial velocity of the binary; this and the proper motion measured from pulsar timing allow the determination of the systemic 3D velocity in the Galaxy. We find that the system is always within 270 pc of the plane of the Galaxy, but always more than 3 kpc away from the Galactic Centre. Thus an exchange interaction in a dense stellar environment (like a globular cluster or the Galactic Centre) is not likely to be the origin of this system. We suggest that after the supernova that formed it, the neutron star was in a tight orbit with a main-sequence star and the present companion was a tertiary farther out. The neutron star then accreted matter from its evolving inner companion, forming a millisecond pulsar. The inner companion then disappeared, either due to a chaotic three-body interaction with the outer star (caused by the expansion of the inner orbit that necessarily results from mass transfer), or in the case of a very compact inner system, due to ablation/accretion by the newly formed millisecond pulsar. We discuss in detail the possible evolution of such a system before the supernova.
A repeating fast radio burst Spitler, L G; Scholz, P; Hessels, J W T ...
Nature,
03/2016, Letnik:
531, Številka:
7593
Journal Article
Recenzirano
Odprti dostop
Fast radio bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow-up observations have failed to find ...additional bursts at the same dispersion measure (that is, the integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non-repeating nature of these bursts has led to the suggestion that they originate in cataclysmic events. Here we report observations of ten additional bursts from the direction of the fast radio burst FRB 121102. These bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB 121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB 121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and which vary on timescales of minutes or less. Although there may be multiple physical origins for the population of fast radio bursts, these repeat bursts with high dispersion measure and variable spectra specifically seen from the direction of FRB 121102 support an origin in a young, highly magnetized, extragalactic neutron star.
In mammalian neocortex, the delicate balance of neural circuits is regulated by a rich repertoire of inhibitory control mechanisms mediated by diverse classes of GABAergic interneurons. A key step ...common to all GABAergic neurons is the synthesis of GABA, catalyzed by 2 isoforms of glutamic acid decarboxylases (GAD). Among these, GAD67 is the rate-limiting enzyme. GAD67 level is regulated by neural activity and is altered in multiple neuropsychiatric disorders. The significance of altered GAD67 levels on inhibitory transmission, however, remains unclear. The presence of GAD65, postsynaptic GABA receptor regulation, and the diversity of cortical interneurons make the link from GAD67 levels to GABA transmission less than straightforward. Here, we selectively removed one allele of the GAD67 gene, Gad1, in PV interneurons in juvenile mice. We found substantial deficits in transmission from PV to pyramidal neurons in prefrontal cortex, along with increases of pyramidal cell excitability and excitation/inhibition balance in PV cells. Synaptic deficits recovered in adult mice, suggesting engagement of homeostatic and compensatory mechanisms. These results demonstrate that GAD67 levels directly influence synaptic inhibition. Thus, GAD67 deficiency in PV cells likely contributes to cortical dysfunction in disease states; the reversibility of synaptic deficits suggests nonpermanent damage to inhibitory circuitry.
We report the discovery and initial follow-up of a double neutron star (DNS) system, PSR J1946+2052, with the Arecibo L-Band Feed Array pulsar (PALFA) survey. PSR J1946+2052 is a 17 ms pulsar in a ...1.88 hr, eccentric (e = 0.06) orbit with a 1.2 M companion. We have used the Jansky Very Large Array to localize PSR J1946+2052 to a precision of 0 09 using a new phase binning mode. We have searched multiwavelength catalogs for coincident sources but did not find any counterparts. The improved position enabled a measurement of the spin period derivative of the pulsar ( P ˙ = 9 2 × 10 − 19 ); the small inferred magnetic field strength at the surface (BS = 4 × 109 G) indicates that this pulsar has been recycled. This and the orbital eccentricity lead to the conclusion that PSR J1946+2052 is in a DNS system. Among all known radio pulsars in DNS systems, PSR J1946+2052 has the shortest orbital period and the shortest estimated merger timescale, 46 Myr; at that time it will display the largest spin effects on gravitational-wave waveforms of any such system discovered to date. We have measured the advance of periastron passage for this system, ˙ = 25.6 0.3 deg yr − 1 , implying a total system mass of only 2.50 0.04 M , so it is among the lowest-mass DNS systems. This total mass measurement combined with the minimum companion mass constrains the pulsar mass to 1.3 M .
In this paper, we present the results of timing observations of PSRs J1949+3106 and J1950+2414, two binary millisecond pulsars (MSPs) discovered in data from the Arecibo ALFA pulsar survey (PALFA). ...The timing parameters include precise measurements of the proper motions of both pulsars, which show that PSR J1949+3106 has a transversal motion very similar to that of an object in the local standard of rest. The timing also includes measurements of the Shapiro delay and the rate of advance of periastron for both systems. Assuming general relativity, these allow estimates of the masses of the components of the two systems; for PSR J1949+3106, the pulsar mass is and the companion mass for PSR J1950+2414 and (all values have 68.3% confidence limits). We use these masses and proper motions to investigate the evolutionary history of both systems: PSR J1949+3106 is likely the product of a low-kick supernova; PSR J1950+2414 is a member of a new class of eccentric MSP binaries with an unknown formation mechanism. We discuss the proposed hypotheses for the formations of these systems in light of our new mass measurements.
Several studies reported that patients with acute myeloid leukemia (AML) who remain in long-term remission after allogeneic or autologous transplant have a shorter life expectancy, compared to the ...general population. However, little is known about the life expectancy of adult long-term survivors of AML who were treated with chemotherapy alone without a transplant and there have been no comparisons with survival among the general population. The current study indicates that the life expectancy of AML patients who achieved and maintained CR for at least 3 years is shorter than expected for age in the US population. This was observed also in patients who did not undergo a transplant including those who have not relapsed during the entire long follow-up period. Thus, late relapse does not explain why patients without transplants have a shortened life expectancy. Taken together, these data strongly suggest that prior chemotherapy for the underlying AML is at least a major contributing factor for the known shortened life expectancy post-transplant.
Australian and New Zealand universities commenced a new academic year in February/March 2020 largely with “business as usual.” The subsequent Covid‐19 pandemic imposed unexpected disruptions to ...anatomical educational practice. Rapid change occurred due to government‐imposed physical distancing regulations from March 2020 that increasingly restricted anatomy laboratory teaching practices. Anatomy educators in both these countries were mobilized to adjust their teaching approaches. This study on anatomy education disruption at pandemic onset within Australia and New Zealand adopts a social constructivist lens. The research question was “What are the perceived disruptions and changes made to anatomy education in Australia and New Zealand during the initial period of the Covid‐19 pandemic, as reflected on by anatomy educators?.” Thematic analysis to elucidate “the what and why” of anatomy education was applied to these reflections. About 18 anatomy academics from ten institutions participated in this exercise. The analysis revealed loss of integrated “hands‐on” experiences, and impacts on workload, traditional roles, students, pedagogy, and anatomists' personal educational philosophies. The key opportunities recognized for anatomy education included: enabling synchronous teaching across remote sites, expanding offerings into the remote learning space, and embracing new pedagogies. In managing anatomy education's transition in response to the pandemic, six critical elements were identified: community care, clear communications, clarified expectations, constructive alignment, community of practice, ability to compromise, and adapt and continuity planning. There is no doubt that anatomy education has stepped into a yet unknown future in the island countries of Australia and New Zealand.
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