Radiation Injury After a Nuclear Detonation: Medical Consequences and the Need for Scarce Resources Allocation

A 10-kiloton (kT) nuclear detonation within a US city could expose hundreds of thousands of people to radiation. The Scarce Resources for a Nuclear Detonation Project was undertaken to guide community planning and response in the aftermath of a nuclear detonation, when demand will greatly exceed available resources. This article reviews the pertinent literature on radiation injuries from human exposures and animal models to provide a foundation for the triage and management approaches outlined in this special issue. Whole-body doses \u3e2 Gy can produce clinically significant acute radiation syndrome (ARS), which classically involves the hematologic, gastrointestinal, cutaneous, and cardiovascular/central nervous systems. The severity and presentation of ARS are affected by several factors, including radiation dose and dose rate, interindividual variability in radiation response, type of radiation (eg, gamma alone, gamma plus neutrons), partial-body shielding, and possibly age, sex, and certain preexisting medical conditions. The combination of radiation with trauma, burns, or both (ie, combined injury) confers a worse prognosis than the same dose of radiation alone. Supportive care measures, including fluid support, antibiotics, and possibly myeloid cytokines (eg, granulocyte colony-stimulating factor), can improve the prognosis for some irradiated casualties. Finally, expert guidance and surge capacity for casualties with ARS are available from the Radiation Emergency Medical Management Web site and the Radiation Injury Treatment Network

Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplantation: Subanalysis Data from an Open-Label, Phase III, Randomized Trial

Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of conditioning for hematopoietic stem cell transplantation (HSCT) and is associated with patient and transplant-related risk factors, such as prior therapies, underlying diagnoses, and conditioning regimen. Unpredictable in its occurrence and severity, VOD/SOS is clinically characterized by painful hepatomegaly, hyperbilirubinemia, ascites, and weight gain. Overall estimated prevalence is 14% post-HSCT, while rates in some high-risk populations (eg, osteopetrosis or prior gemtuzumab ozogamicin) are >60% (Wadleigh M et al. Blood . 2003;102:1578-82; Corbacioglu S et al. Bone Marrow Transplant . 2006;38:547-53). Evidence suggests that defibrotide stabilizes endothelial cells, with direct and endothelial-cell mediated restoration of the thrombo-fibrinolytic balance. Defibrotide is approved in the European Union for the treatment of severe hepatic VOD/SOS in patients receiving HSCT, and is available in the United States through an expanded-access study. In a previously reported randomized clinical trial, defibrotide prophylaxis for VOD/SOS in high-risk pediatric patients undergoing HSCT reduced the overall incidence of VOD/SOS by day +30 post-HSCT. Here we report novel subgroup analyses of VOD/SOS incidence from this trial in patients with specific VOD/SOS risk factors at baseline. Methods This was a phase 3, multicenter, open-label, randomized, controlled trial in patients aged 5% weight gain. Patients were randomized to standard care with or without defibrotide prophylaxis dosed at 25 mg/kg/day in 4 divided infusions of 6.25 mg/kg. Osteopetrosis was a stratification variable. Defibrotide began the same day as HSCT conditioning and continued for 30 days post-HSCT, or ≥14 days for patients discharged from hospital before day +30 post-HSCT. Control patients who developed VOD/SOS received defibrotide treatment. The primary endpoint was incidence of VOD/SOS at day +30 post-HSCT. Results The intent-to-treat population included 356 patients: 180 randomized to defibrotide prophylaxis and 176 in the control group. Mean (SD) age was 6.6 (5.3) years, and 40.7% of patients were female. Demographic and clinical characteristics, including VOD/SOS risk factors (Table), were well-matched in the defibrotide and control groups. The most common risk factors among all patients were conditioning with busulfan and melphalan (58%), preexisting liver disease (27%), and second myeloablative transplantation (13%). VOD/SOS occurred by day +30 post-HSCT in 22 (12%) patients in the defibrotide prophylaxis group vs 35 (20%) patients in the control group. For the stratification variable, osteopetrosis, rates of VOD/SOS were 14% in the defibrotide prophylaxis arm and 67% in the control arm (Table). Differences in rates of VOD/SOS were lowest for adrenoleukodystrophy (no cases) and prior abdominal irradiation (11% vs 13%, respectively) (Table). Conclusions Across risk-factor subgroups, the rate of VOD/SOS was lower in patients receiving defibrotide compared with controls (except adrenoleukodystrophy: no VOD/SOS in either group). In particular, rates of VOD/SOS by day +30 were reduced by ≥50% in the defibrotide arm vs the control arm among patients with osteopetrosis, hemophagocytic lymphohistiocytosis, second myeloablative transplantation, and prior gemtuzumab treatment. Although the total numbers of patients with these risk factors were small, these between-group differences are of clinical interest and should be further explored. | Risk Factor | Defibrotide (n=180) | Control (n=176) | | ------------------------------------ | ----------------------------------------------- | --------------- | ----------------------------------------------- | | Total n | VOD/SOS incidence (n=22; 12.2%) n (%*) | Total n | VOD/SOS incidence (n=35; 20.0%) n (%*) | | Adrenoleukodystrophy | 1 | 0 (0) | 1 | 0 (0) | | Osteopetrosis | 7 | 1 (14) | 6 | 4 (67) | | Prior abdominal irradiation | 9 | 1 (11) | 8 | 1 (13) | | Hemophagocytic lymphohistiocytosis | 10 | 0 (0) | 15 | 6 (40) | | Prior gemtuzumab | 11 | 2 (18) | 5 | 2 (40) | | Allogeneic HSCT for leukemia | 17 | 2 (12) | 11 | 2 (18) | | Second myeloablative transplantation | 25 | 2 (8) | 23 | 4 (17) | | Pre-existing liver disease | 41 | 6 (15) | 54 | 12 (22) | | Busulfan/melphalan conditioning | 106 | 15 (14) | 99 | 17 (17) | * *Percent of patients with VOD/SOS. Table. Support: Jazz Pharmaceuticals Disclosures Corbacioglu: Gentium S.p.A.: Consultancy, Honoraria. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Bader: Amgen: Consultancy; Medac: Other: Institutional grants; Neovii: Other: Institutional grants; Riemser: Other: Institutional grants; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy

Characteristics and anticancer properties of Sunitinib malate-loaded poly-lactic-co-glycolic acid nanoparticles against human colon cancer HT-29 cells lines

Purpose: To develop poly-lactic-co-glycolic acid (PLGA) -based nanoparticles (NPs) for the delivery of sunitinib malate (STM) to colon cancer cells.Methods: Three different formulations (F1 – F3) were developed by nano-precipitation technique using various concentrations of PLGA. The NPs were evaluated for particle size, polydispersity index, zeta potential, drug entrapment, and drug loading, using differential scanning calorimetry (DSC), Fouriertransform infrared spectroscopy (FTIR), x-ray diffraction (XRD), and scanning electron microscopy (SEM). Furthermore, in vitro drug release and anticancer studies were carried out on the formulations.Results: Among the three NPs, optimized NP (F3) of STM was chosen for in vitro anti-cancer study against H-29 human colon cancer cells lines based on its particle size (132.9 nm), PDI (0.115), zeta potential (-38.12 mV), entrapment efficiency (52.42 %), drug loading (5.24 %), and drug release (91.26 % in 48 h). A significant anti-cancer activity of the optimized NPs was observed, relative to free STM.Conclusion: These findings suggest that STM-loaded NPs possess significant anti-cancer activity against human colon cancer HT-29 cells lines.Keywords: Sunitinib malate, Poly-lactic-co-glycolic acid, Nanoparticles, Colon cance

Stability of Mine Car Motion in Curves of Invariable and Variable Radii

We discuss our experiences adapting three recent algorithms for maximum common (connected) subgraph problems to exploit multi-core parallelism. These algorithms do not easily lend themselves to parallel search, as the search trees are extremely irregular, making balanced work distribution hard, and runtimes are very sensitive to value-ordering heuristic behaviour. Nonetheless, our results show that each algorithm can be parallelised successfully, with the threaded algorithms we create being clearly better than the sequential ones. We then look in more detail at the results, and discuss how speedups should be measured for this kind of algorithm. Because of the difficulty in quantifying an average speedup when so-called anomalous speedups (superlinear and sublinear) are common, we propose a new measure called aggregate speedup

JDM treatment with rituximab Personal non-commercial use only

ABSTRACT. Objective. To evaluate the safety and efficacy of rituximab (RTX) in juvenile dermatomyositis (JDM) in off-trial patients. Methods. We conducted a multicenter prospective study of patients with JDM included in the French Autoimmunity and Rituximab (AIR) registry. Results. Nine patients with severe JDM were studied. The main indication for RTX treatment was severe and/or refractory muscle involvement (7 patients), severe calcinosis (1 patient), or severe chronic abdominal pain associated with abdominal lipomatosis (1 patient). RTX was associated with corticosteroids, immunosuppressive drugs, and plasma exchange therapy in 9/9, 5/9, and 2/9 patients, respectively. Mild infections of the calcinosis sites occurred in 2 patients and an infusion-related event in 1. Complete clinical response was achieved in 3/6 patients treated with RTX for muscle involvement. In these responders steroid therapy was stopped or tapered to < 15% of the baseline dosage, with no relapse, with a followup ranging from 1.3 to 3 years. Calcinosis did not improve in the 6 affected patients. Conclusion. This small series suggests that rituximab may be effective for treating muscle and skin involvement in a small subset of children with severe JDM, and that its safety profile was satisfactory. Further studies are needed to identify predictive factors of response to RTX in patients with sever

A Unifying Model of Genome Evolution Under Parsimony

We present a data structure called a history graph that offers a practical basis for the analysis of genome evolution. It conceptually simplifies the study of parsimonious evolutionary histories by representing both substitutions and double cut and join (DCJ) rearrangements in the presence of duplications. The problem of constructing parsimonious history graphs thus subsumes related maximum parsimony problems in the fields of phylogenetic reconstruction and genome rearrangement. We show that tractable functions can be used to define upper and lower bounds on the minimum number of substitutions and DCJ rearrangements needed to explain any history graph. These bounds become tight for a special type of unambiguous history graph called an ancestral variation graph (AVG), which constrains in its combinatorial structure the number of operations required. We finally demonstrate that for a given history graph $G$, a finite set of AVGs describe all parsimonious interpretations of $G$, and this set can be explored with a few sampling moves.Comment: 52 pages, 24 figure

Transition-metal dimers and physical limits on magnetic anisotropy

Recent advances in nanoscience have raised interest in the minimum bit size required for classical information storage, i.e. for bistability with suppressed quantum tunnelling and energy barriers that exceed ambient temperatures. In the case of magnetic information storage much attention has centred on molecular magnets[1] with bits consisting of ~ 100 atoms, magnetic uniaxial anisotropy energy barriers ~ 50 K, and very slow relaxation at low temperatures. In this article we draw attention to the remarkable magnetic properties of some transition metal dimers which have energy barriers approaching ~ 500 K with only two atoms. The spin dynamics of these ultra small nanomagnets is strongly affected by a Berry phase which arises from quasi-degeneracies at the electronic Highest Occupied Molecular Orbital (HOMO) energy. In a giant spin-approximation, this Berry phase makes the effective reversal barrier thicker. [1] Gatteschi, D., Sessoli, R. & Villain, J. Molecular Nanomagnets. (Oxford, New York 2006).Comment: 14 pages, 1 figur