Abstract
Blazars exhibit stochastic flux variability across the electromagnetic spectrum, often exhibiting heavy-tailed flux distributions, commonly modeled as lognormal. However, Tavecchio et al. ...and Adams et al. found that the high-energy gamma-ray flux distributions of several of the brightest flaring Fermi-LAT flat-spectrum radio quasars (FSRQs) are well modeled by an even heavier-tailed distribution, which we show is the inverse gamma distribution. We propose an autoregressive inverse gamma variability model in which an inverse gamma flux distribution arises as a consequence of a shot-noise process. In this model, discrete bursts are individually unresolved and averaged over within time bins, as in the analysis of Fermi-LAT data. Stochastic variability on timescales longer than the time-bin duration is modeled using first-order autoregressive structure. The flux distribution becomes approximately lognormal in the limiting case of many weak bursts. The fractional variability is predicted to decrease as the time-bin duration increases. Using simulated light curves, we show that the proposed model is consistent with the typical gamma-ray variability properties of FSRQs and BL Lac objects. The model parameters can be physically interpreted as the average burst rate, the burst fluence, and the timescale of long-term stochastic fluctuations.
Background
Sleep disorders are highly prevalent in the general population and may be linked in a bidirectional fashion to stroke, which is one of the leading causes of morbidity and mortality.
Aim
...Four major scientific societies established a task force of experts in neurology, stroke, respiratory medicine, sleep medicine and methodology to critically evaluate the evidence regarding potential links and the impact of therapy.
Materials and methods
Thirteen research questions were evaluated in a systematic literature search using a stepwise hierarchical approach: first, systematic reviews and meta‐analyses; second, primary studies post‐dating the systematic reviews/meta‐analyses. A total of 445 studies were evaluated and 88 were included. Statements were generated regarding current evidence and clinical practice.
Results
Severe obstructive sleep apnoea (OSA) doubles the risk for incident stroke, especially in young to middle‐aged patients. Continuous positive airway pressure (CPAP) may reduce stroke risk, especially in treatment‐compliant patients. The prevalence of OSA is high in stroke patients and can be assessed by polygraphy. Severe OSA is a risk factor for recurrence of stroke and may be associated with stroke mortality, whilst CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, whilst the pharmacotherapy of insomnia may increase it. Periodic limb movements in sleep (PLMS), but not restless limb syndrome (RLS), may be associated with an increased risk of stroke. Preliminary data suggest a high frequency of post‐stroke insomnia and RLS and their association with a less favourable stroke outcome, whilst treatment data are scarce.
Discussion/Conclusion
Overall, the evidence base is best for OSA relationship with stroke and supports active diagnosis and therapy. Research gaps remain especially regarding insomnia and RLS/PLMS relationships with stroke.
In internal radionuclide therapy, a growing interest in voxel-level estimates of tissue-absorbed dose has been driven by the desire to report radiobiologic quantities that account for the biologic ...consequences of both spatial and temporal nonuniformities in these dose estimates. This report presents an overview of 3-dimensional SPECT methods and requirements for internal dosimetry at both regional and voxel levels. Combined SPECT/CT image-based methods are emphasized, because the CT-derived anatomic information allows one to address multiple technical factors that affect SPECT quantification while facilitating the patient-specific voxel-level dosimetry calculation itself. SPECT imaging and reconstruction techniques for quantification in radionuclide therapy are not necessarily the same as those designed to optimize diagnostic imaging quality. The current overview is intended as an introduction to an upcoming series of MIRD pamphlets with detailed radionuclide-specific recommendations intended to provide best-practice SPECT quantification-based guidance for radionuclide dosimetry.
The lipid phosphatase Sac1 was identified more than 25 years ago in a yeast genetic screen. Since then, investigators have learned much about its roles in the cell. In this review, we present our ...current understanding of Sac1 structure, regulation and function, and we describe how Sac1—as a phosphatidylinositol 4‐phosphatase—plays multifaceted roles in membrane homeostasis, vesicular and nonvesicular transport, cell signaling, development and disease.
The lipid phosphatase Sac1 dephosphorylates phosphatidylinositol 4‐phosphate (PI4P), thereby holding levels of this crucial membrane signaling molecule in check. Sac1 regulates multiple cellular processes, including cytoskeletal organization, membrane trafficking and cell signaling. Here, we review the structure and regulation of Sac1, its roles in cell signaling and development and its links to health and disease. Remarkably, many of the diverse roles attributed to Sac1 can be explained by the recent discovery of its requirement at membrane contact sites, where its consumption of PI4P is proposed to drive interorganelle transfer of other cellular lipids, thereby promoting normal lipid homeostasis within cells.
Summary
Background
The risk of thrombotic complications such as deep vein thrombosis (DVT) during tumor development is well known. Tumors release into the circulation procoagulant microparticles ...(MPs) that can participate in thrombus formation following vessel injury. The importance of this MP tissue factor (TF) in the initiation of cancer‐associated DVT remains uncertain.
Objective
To investigate how pancreatic cancer MPs promote DVT in vivo.
Methods
We combined a DVT mouse model in which thrombosis is induced by flow restriction in the inferior vena cava with one of subcutaneous pancreatic cancer in C57BL/6J mice. We infused high‐TF and low‐TF tumor MPs to determine the importance of TF in experimental cancer‐associated DVT.
Results
Both tumor‐bearing mice and mice infused with tumor MPs subjected to 3 h of partial flow restriction developed an occlusive thrombus; fewer than one‐third of the control mice did. We observed that MPs adhered to neutrophil extracellular traps (NETs), which are functionally important players during DVT, whereas neither P‐selectin nor glycoprotein Ib were required for MP recruitment in DVT. The thrombotic phenotype induced by MP infusion was suppressed by hirudin, suggesting the importance of thrombin generation. TF carried by tumor MPs was essential to promote DVT, as mice infused with low‐TF tumor MPs had less thrombosis than mice infused with high‐TF tumor MPs.
Conclusions
TF expressed on tumor MPs contributes to the increased incidence of cancer‐associated venous thrombosis in mice in vivo. These MPs may adhere to NETs formed at the site of thrombosis.
ABSTRACTJuly 1, 2019, JAMA Internal Medicine released online an article authored by Kitahara et al entitled “Association of radioactive iodine treatment with cancer mortality in patients with ...hyperthyroidism.” The Altmetric Attention Score, a global indicator of interest from lay public and colleagues, skyrocketed to 223 by July 7, placing the article in the top 5% of all scored reports. The overall perception of death from cancer risk associated with I is inflated and not supported by evidence. As co-authors of this article, we offer previously unpublished data and analysis that (1) disputes clinical significance of the associated risk from I and (2) shows, again, that antithyroid drugs carry a statistically significant and a much more obvious cancer death risk.
The potential of alpha-particle emitters to treat cancer has been recognized since the early 1900s. Advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the ...increased availability of alpha-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with alpha-particle emitters. Although alpha-emitters have been studied for many decades, their current use in humans for targeted therapy is an important milestone. The objective of this work is to review those aspects of the field that are pertinent to targeted alpha-particle emitter therapy and to provide guidance and recommendations for human alpha-particle emitter dosimetry.
In systems as diverse as yeast, slime mold and animal cells, the levels and distribution of phosphatidylinositol phosphates (PIPs) must be strictly regulated for successful cell cleavage. The precise ...mechanism by which PIPs function in this process remains unknown. Recent experiments are beginning to shed light on the cellular pathways in which PIPs make key contributions during cytokinesis. In particular, PIPs promote proper actin cytoskeletal organization and direct membrane trafficking in dividing cells. Future research will uncover temporal and spatial regulation of the different PIPs, thus elucidating their role in cytoskeletal and membrane events that drive cell cleavage.
Background: Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular ...chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT). Objective: To explore the source and role of extracellular chromatin in DVT. Methods: We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC). Results: We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham‐operated mice. Immunohistochemical staining revealed the presence of Gr‐1‐positive neutrophils in both red (RBC‐rich) and white (platelet‐rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs’ structure, was present only in the red part of thrombi and was frequently associated with the Gr‐1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application. Conclusions: Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.
The accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of ...the imaging time points. MIRD Pamphlet no. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on (177)Lu (lutetium) and its application in radiopharmaceutical therapy.
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