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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
Maternal concentration of polychlorinated biphenyls and dichlorodiphenyl dichlorethylene and birth weight in Michigan fish eaters: a cohort study
BACKGROUND: Studies on maternal exposure to polychlorinated biphenyls (PCBs) reported inconsistent findings regarding birth weight: some studies showed no effect, some reported decreased birth weight, and one study found an increase in weights. These studies used different markers of exposure, such as measurement of PCBs in maternal serum or questionnaire data on fish consumption. Additionally maternal exposures, such as dichlorodiphenyl-dichloroethylene (DDE), which are related to PCB exposure and may interfere with the PCB effect, were rarely taken into account. METHODS: Between 1973 and 1991, the Michigan Department of Community Health conducted three surveys to assess PCB and DDE serum concentrations in Michigan anglers. Through telephone interviews with parents, we gathered information on the birth characteristics of their offspring, focusing on deliveries that occurred after 1968. We used the maternal organochlorine (OC) measurement closest to the date of delivery as the exposure. Although one mother may have contributed more than one child, serum concentrations derived from measurements in different surveys could vary for different children from the same mother. The maternal DDE and PCB serum concentrations were categorized as follows: 0 -< 5 microg / L, 5 -< 15 microg / L, 15 -< 25 microg / L, ≥25 microg / L. Using repeated measurement models (Generalized Estimation Equation), we estimated the adjusted mean birth weight controlling for gender, birth order, gestational age, date of delivery as well as maternal age, height, education, and smoking status. RESULTS: We identified 168 offspring who were born after 1968 and had maternal exposure information. We found a reduced birth weight for the offspring of mothers who had a PCB concentration ≥25 microg / L (adjusted birth weight = 2,958 g, p = 0.022). This group, however, was comprised of only seven observations. The association was not reduced when we excluded preterm deliveries. The birth weight of offspring was increased in women with higher DDE concentrations when controlling for PCBs; however, this association was not statistically significant. CONCLUSION: Our results contribute to the body of evidence that high maternal serum PCB concentration may reduce the birth weight in offspring. However, only a small proportion of mothers may actually be exposed to PCB concentrations ≥25 microg / L
Quantization of Midisuperspace Models
We give a comprehensive review of the quantization of midisuperspace models.
Though the main focus of the paper is on quantum aspects, we also provide an
introduction to several classical points related to the definition of these
models. We cover some important issues, in particular, the use of the principle
of symmetric criticality as a very useful tool to obtain the required
Hamiltonian formulations. Two main types of reductions are discussed: those
involving metrics with two Killing vector fields and spherically symmetric
models. We also review the more general models obtained by coupling matter
fields to these systems. Throughout the paper we give separate discussions for
standard quantizations using geometrodynamical variables and those relying on
loop quantum gravity inspired methods.Comment: To appear in Living Review in Relativit
Dropout in a longitudinal, cohort study of urologic disease in community men
BACKGROUND: Reasons for attrition in studies vary, but may be a major concern in long-term studies if those who drop out differ systematically from those who continue to participate. Factors associated with dropout were evaluated in a twelve-year community-based, prospective cohort study of urologic disease in men. METHODS: During 1989–1991, 2,115 randomly selected Caucasian men, ages 40–79 years from Olmsted County, Minnesota were enrolled and followed with questionnaires biennially; 332 men were added in follow-up. A random subset (~25%) received a urologic examination. Baseline characteristics including age, benign prostatic hyperplasia (BPH) symptoms, comorbidities, and socioeconomic factors were compared between subjects who did and did not participate after the twelfth year of follow-up. RESULTS: Of the 2,447 men, 195 died and were excluded; 682 did not participate in 2002. Compared with men in the 40–49 year age group, men ≥ 70 years of age at baseline had a greater relative odds of dropout, 2.65 (95% CI: 1.93, 3.63). In age-adjusted analyses, relative to men without stroke, men who had suffered a stroke had a higher odds of dropout, age-adjusted OR 3.07 (95% CI: 1.49, 6.33). Presence of at least one BPH symptom was not associated with dropout, (age-adjusted OR 1.12 (95% CI: 0.93, 1.36)). CONCLUSION: These results provide assurance that dropout was not related to primary study outcomes. However, factors associated with dropout should be taken into account in analyses where they may be potential confounders
Volumetric Magnetic Resonance Imaging Quantification of Longitudinal Brain Changes in Abstinent Alcoholics
Magnetic resonance imaging (MRI) of the brain was performed on a group of 24 recently detoxified, male alcoholics approximately 1 month after their date of last drink. The imaging was repeated 3 months later, at which point 9 subjects had resumed drinking and 15 had maintained abstinence. Contrasts between these two drinking groups revealed that, despite comparable baseline values, the Abstainers exhibited volumetric white matter increases and cerebrospinal fluid reductions over the follow-up interval, whereas the Drinkers did not show significant change on either of these MRI indices. These results provide the first evidence suggestive of significant volumetric white matter increase with abstinence
Effective Theory Approach to the Spontaneous Breakdown of Lorentz Invariance
We generalize the coset construction of Callan, Coleman, Wess and Zumino to
theories in which the Lorentz group is spontaneously broken down to one of its
subgroups. This allows us to write down the most general low-energy effective
Lagrangian in which Lorentz invariance is non-linearly realized, and to explore
the consequences of broken Lorentz symmetry without having to make any
assumptions about the mechanism that triggers the breaking. We carry out the
construction both in flat space, in which the Lorentz group is a global
spacetime symmetry, and in a generally covariant theory, in which the Lorentz
group can be treated as a local internal symmetry. As an illustration of this
formalism, we construct the most general effective field theory in which the
rotation group remains unbroken, and show that the latter is just the
Einstein-aether theory.Comment: 45 pages, no figures
Corner contributions to holographic entanglement entropy
The entanglement entropy of three-dimensional conformal field theories
contains a universal contribution coming from corners in the entangling
surface. We study these contributions in a holographic framework and, in
particular, we consider the effects of higher curvature interactions in the
bulk gravity theory. We find that for all of our holographic models, the corner
contribution is only modified by an overall factor but the functional
dependence on the opening angle is not modified by the new gravitational
interactions. We also compare the dependence of the corner term on the new
gravitational couplings to that for a number of other physical quantities, and
we show that the ratio of the corner contribution over the central charge
appearing in the two-point function of the stress tensor is a universal
function for all of the holographic theories studied here. Comparing this
holographic result to the analogous functions for free CFT's, we find fairly
good agreement across the full range of the opening angle. However, there is a
precise match in the limit where the entangling surface becomes smooth, i.e.,
the angle approaches , and we conjecture the corresponding ratio is a
universal constant for all three-dimensional conformal field theories. In this
paper, we expand on the holographic calculations in our previous letter
arXiv:1505.04804, where this conjecture was first introduced.Comment: 62 pages, 6 figures, 1 table; v2: minor modifications to match
published version, typos fixe
Rotating black holes with equal-magnitude angular momenta in d=5 Einstein-Gauss-Bonnet theory
We construct rotating black hole solutions in Einstein-Gauss-Bonnet theory in
five spacetime dimensions. These black holes are asymptotically flat, and
possess a regular horizon of spherical topology and two equal-magnitude angular
momenta associated with two distinct planes of rotation. The action and global
charges of the solutions are obtained by using the quasilocal formalism with
boundary counterterms generalized for the case of Einstein-Gauss-Bonnet theory.
We discuss the general properties of these black holes and study their
dependence on the Gauss-Bonnet coupling constant . We argue that most
of the properties of the configurations are not affected by the higher
derivative terms. For fixed the set of black hole solutions terminates
at an extremal black hole with a regular horizon, where the Hawking temperature
vanishes and the angular momenta attain their extremal values. The domain of
existence of regular black hole solutions is studied. The near horizon geometry
of the extremal solutions is determined by employing the entropy function
formalism.Comment: 25 pages, 7 figure
The holographic principle
There is strong evidence that the area of any surface limits the information
content of adjacent spacetime regions, at 10^(69) bits per square meter. We
review the developments that have led to the recognition of this entropy bound,
placing special emphasis on the quantum properties of black holes. The
construction of light-sheets, which associate relevant spacetime regions to any
given surface, is discussed in detail. We explain how the bound is tested and
demonstrate its validity in a wide range of examples.
A universal relation between geometry and information is thus uncovered. It
has yet to be explained. The holographic principle asserts that its origin must
lie in the number of fundamental degrees of freedom involved in a unified
description of spacetime and matter. It must be manifest in an underlying
quantum theory of gravity. We survey some successes and challenges in
implementing the holographic principle.Comment: 52 pages, 10 figures, invited review for Rev. Mod. Phys; v2:
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