bluuebunny/crossref_metadata_2025 huggingface dataset:
The Nine Lives of Cosmic Rays in Galaxies
Authors: Grenier Isabelle A. , Black John H. , Strong Andrew W.
Published: June 2015

Cosmic-ray astrophysics has advanced rapidly in recent years, and its impact on other astronomical disciplines has broadened. Many new experiments measuring these particles, both directly in the atmosphere or space and indirectly via γ rays and synchrotron radiation, have widened the range and quality of the information available on their origin, propagation, and interactions. The impact of low-energy cosmic rays on interstellar chemistry is a fast-developing topic, including the propagation of these particles into the clouds in which the chemistry occurs. Cosmic rays, via their γ-ray production, also provide a powerful way to probe the gas content of the interstellar medium. Substantial advances have been made in the observations and modelling of the interplay between cosmic rays and the interstellar medium. Focusing on energies up to 1 TeV, these interrelating aspects are covered at various levels of detail, giving a guide to the state of the subject.
The Organellar Genomes of Chromera and Vitrella, the Phototrophic Relatives of Apicomplexan Parasites
Authors: Oborník Miroslav , Lukeš Julius
Published: June 2015

Apicomplexa are known to contain greatly reduced organellar genomes. Their mitochondrial genome carries only three protein-coding genes, and their plastid genome is reduced to a 35-kb-long circle. The discovery of coral-endosymbiotic algae Chromera velia and Vitrella brassicaformis, which share a common ancestry with Apicomplexa, provided an opportunity to study possibly ancestral forms of organellar genomes, a unique glimpse into the evolutionary history of apicomplexan parasites. The structurally similar mitochondrial genomes of Chromera and Vitrella differ in gene content, which is reflected in the composition of their respiratory chains. Thus, Chromera lacks respiratory complexes I and III, whereas Vitrella and apicomplexan parasites are missing only complex I. Plastid genomes differ substantially between these algae, particularly in structure: The Chromera plastid genome is a linear, 120-kb molecule with large and divergent genes, whereas the plastid genome of Vitrella is a highly compact circle that is only 85 kb long but nonetheless contains more genes than that of Chromera. It appears that organellar genomes have already been reduced in free-living phototrophic ancestors of apicomplexan parasites, and such reduction is not associated with parasitism.
Ground- and Space-Based Gamma-Ray Astronomy
Authors: Funk Stefan
Published: June 2015

In recent years, observational γ-ray astronomy has witnessed a remarkable range of exciting new results in the high-energy and very high-energy regimes. Coupled with extensive theoretical and phenomenological studies of nonthermal processes in the Universe, these observations have provided deep insights into a number of fundamental problems of high-energy astrophysics and astroparticle physics. Although the main motivations of γ-ray astronomy remain unchanged, recent observational results have contributed significantly toward our understanding of many related phenomena. This article aims to review the most important results in the young and rapidly developing field of γ-ray astrophysics.
Migration and Environment
Authors: Millock Katrin
Published: June 2015

The concept of environmental migrants occurs frequently in the policy debate, in particular with regard to climate change and the incidence of such migration in low-income countries. This article reviews the economic studies of environmentally induced migration. It includes recent empirical analyses that try to link environmental change to migration flows and the spatial distribution of population. A consensus seems to emerge that there is little likelihood of large increases in international migration flows due to climate variability. The evidence to date shows that regional migration will be affected, however, either on the African continent or internally, within country borders. Theoretically, environmentally induced migration can be analyzed using different frameworks: the classical Harris-Todaro model of rural-urban migration, new economic geography models, models grounded in environmental economics of pollution externalities with free factor mobility, and the new economics of labor migration. I review some of the latest attempts to analyze environmentally induced migration theoretically and the policy-relevant conclusions that can be drawn.
Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia
Authors: Devine Raymond D. , Bicer Sabahattin , Reiser Peter J. , Velten Markus , Wold Loren E.
Published: June 2015

Cardiac and skeletal muscle dysfunction is a recognized effect of cancer-induced cachexia, with alterations in heart function leading to heart failure and negatively impacting patient morbidity. Cachexia is a complex and multifaceted disease state with several potential contributors to cardiac and skeletal muscle dysfunction. Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading components of the extracellular matrix (ECM). Changes to the ECM cause disruption both in the connections between cells at the basement membrane and in cell-to-cell interactions. In the present study, we used a murine model of C26 adenocarcinoma-induced cancer cachexia to determine changes in MMP gene and protein expression in cardiac and skeletal muscle. We analyzed MMP-2, MMP-3, MMP-9, and MMP-14 as they have been shown to contribute to both cardiac and skeletal muscle ECM changes and, thereby, to pathology in models of heart failure and muscular dystrophy. In our model, cardiac and skeletal muscles showed a significant increase in RNA and protein levels of several MMPs and tissue inhibitors of metalloproteinases. Cardiac muscle showed significant protein increases in MMP-2, MMP-3, MMP-9, and MMP-14, whereas skeletal muscles showed increases in MMP-2, MMP-3, and MMP-14. Furthermore, collagen deposition was increased after C26 adenocarcinoma-induced cancer cachexia as indicated by an increased left ventricular picrosirius red-positive-stained area. Increases in serum hydroxyproline suggest increased collagen turnover, implicating skeletal muscle remodeling. Our findings demonstrate that cancer cachexia-associated matrix remodeling results in cardiac fibrosis and possible skeletal muscle remodeling. With these findings, MMPs represent a possible therapeutic target for the treatment of cancer-induced cachexia.
Autonomic cardiocirculatory control in mice with reduced expression of the vesicular acetylcholine transporter
Authors: Durand Marina T. , Becari Christiane , Tezini Geisa C. S. V. , Fazan Rubens , Oliveira Mauro , Guatimosim Silvia , Prado Vania F. , Prado Marco A. M. , Salgado Helio C.
Published: June 2015

In cardiovascular diseases, sympathetic tone has been comprehensively studied, whereas parasympathetic tone has received minor attention. The vesicular ACh transporter (VAChT) knockdown homozygous (VAChT KDHOM) mouse is a useful model for examining the cardiocirculatory sympathovagal balance. Therefore, we investigated whether cholinergic dysfunction caused by reduced VAChT expression could adversely impact hemodynamic parameter [arterial pressure (AP) and heart rate (HR)] daily oscillation, baroreflex sensitivity, hemodynamic variability, sympathovagal balance, and cardiovascular reactivity to restraint stress. Wild-type and VAChT KDHOM mice were anesthetized for telemetry transmitter implantation, and APs and HRs were recorded 10 days after surgical recovery. Changes in HR elicited by methylatropine and propranolol provided the indexes of sympathovagal tone. Cardiovascular reactivity in response to a restraint test was examined 24 h after continuous recordings of AP and HR. VAChT KDHOM mice exhibited reduced parasympathetic and elevated sympathetic tone. Daily oscillations of AP and HR as well as AP variability were similar between groups. Nevertheless, HR variability, patterns with two dissimilar variations from symbolic analysis, and baroreflex sensitivity were reduced in VAChT KDHOM mice. The change in mean AP due to restraint stress was greater in VAChT KDHOM mice, whereas the tachycardic response was not. These findings demonstrate that the cholinergic dysfunction present in the VAChT KDHOM mouse did not adversely impact basal hemodynamic parameters but promoted autonomic imbalance, an attenuation of baroreflex sensitivity, and a greater pressure response to restraint stress. These results provide a framework for understanding how autonomic imbalance impacts cardiovascular function.
The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity
Authors: Bordun Kimberly-Ann , Premecz Sheena , daSilva Megan , Mandal Soma , Goyal Vineet , Glavinovic Tamara , Cheung Matthew , Cheung David , White Christopher W. , Chaudhary Rakesh , Freed Darren H. , Villarraga Hector R. , Herrmann Joerg , Kohli Manish , Ravandi Amir , Thliveris James , Pitz Marshall , Singal Pawan K. , Mulvagh Sharon , Jassal Davinder S.
Published: June 2015

The recent introduction of novel anticancer therapies, including bevacizumab (BVZ) and sunitinib (SNT), is associated with an increased risk of cardiotoxicity. However, early identification of left ventricular (LV) systolic dysfunction may facilitate dose modification and avoid the development of advanced heart failure. Using a murine model of BVZ- and SNT-mediated cardiotoxicity, we investigated whether cardiac biomarkers and/or tissue velocity imaging (TVI) using echocardiography can detect early changes in cardiac function, before a decrease in LV ejection fraction is identified. A total of 75 wild-type C57Bl/6 male mice were treated with either 0.9% saline, BVZ, or SNT. Serial monitoring of blood pressure, high-sensitivity troponin I, and echocardiographic indexes were performed over a 14-day study period, after which the mice were euthanized for histological and biochemical analyses. Mice treated with either BVZ or SNT developed systemic hypertension as early as day 7, which increased by day 14. Cardiac biomarkers, specifically high-sensitivity troponin I, were not predictive of early LV systolic dysfunction. Although conventional LV ejection fraction values decreased at day 13 in mice treated with either BVZ or SNT, TVI confirmed early LV systolic dysfunction at day 8. Histological and biochemical analysis demonstrated loss of cellular integrity, increased oxidative stress, and increased cardiac apoptosis in mice treated with BVZ or SNT therapy at day 14. In a murine model of BVZ- or SNT-mediated cardiomyopathy, noninvasive assessment by TVI detected early LV systolic dysfunction before alterations in conventional echocardiographic indexes.
Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction
Authors: Julian Colleen Glyde , Gonzales Marcelino , Rodriguez Armando , Bellido Diva , Salmon Carlos Salinas , Ladenburger Anne , Reardon Lindsay , Vargas Enrique , Moore Lorna G.
Published: June 2015

Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects ∼10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600–4,100 m) residents aged 18–25 yr with excessive erythrocytosis (EE, Hb concentration ≥18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey ( n = 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio = 5.25, P = 0.05 and odds ratio = 6.44, P = 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension.
Ultrasound stimulates formation and release of vasoactive compounds in brain endothelial cells
Authors: Davis Catherine M. , Ammi Azzdine Y. , Alkayed Nabil J. , Kaul Sanjiv
Published: June 2015

Stroke outcome is improved by therapeutic ultrasound. This benefit is presumed to be principally from ultrasound-mediated thrombolysis. We hypothesized that the therapeutic benefit of ultrasound in stroke may, in part, be mediated by the release of beneficial vasoactive substances. Accordingly, we investigated the effect of ultrasound on levels of cytochrome P-450, lipoxygenase, and cyclooxygenase metabolites of arachidonic acid as well as adenosine release and endothelial nitric oxide synthase (eNOS) phosphorylation in primary brain endothelial cells in vitro. Brain endothelial cells were exposed to 1.05-MHz ultrasound at peak rarefactional acoustic pressure amplitudes of 0.35, 0.55, 0.90, and 1.30 MPa. Epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraenoic acids (HETEs), PGE2, adenosine, nitrate/nitrite, and eNOS phosphorylation were measured after ultrasound exposure. Levels of 8,9-EET, 11,12-EET, and 14,15-EET increased by 230 ± 28%, 240 ± 30%, and 246 ± 31% ( P < 0.05), respectively, whereas 5-HETE and 15-HETE levels were reduced to 24 ± 14% and 10 ± 3% ( P < 0.05), respectively, compared with cells not exposed to ultrasound. PGE2 levels were reduced to 56 ± 14% of control. Adenosine increased more than sixfold after ultrasound exposure compared with unstimulated cells (1.36 ± 0.22 vs. 0.37 ± 0.10 ng/ml, P < 0.05), nitrate/nitrite was below levels of quantification, and eNOS phosphorylation was not altered significantly. Our results suggest that ultrasound may enhance tissue perfusion during stroke by augmenting the generation of vasodilator compounds and inhibiting that of vasoconstrictors. Such regulation supports a beneficial role for therapeutic ultrasound in stroke independent of its effect on the occlusive thrombus.
Impairment of IKCachannels contributes to uteroplacental endothelial dysfunction in rat diabetic pregnancy
Authors: Gokina Natalia I. , Bonev Adrian D. , Phillips Julie , Gokin Alexander P. , Veilleux Kelsey , Oppenheimer Karen , Goloman Gabriela
Published: June 2015

Diabetes in rat pregnancy is associated with impaired vasodilation of the maternal uteroplacental vasculature. In the present study, we explored the role of endothelial cell (EC) Ca2+-activated K+channels of small conductance (SKCachannels) and intermediate conductance (IKCachannels) in diabetes-induced uterine vascular dysfunction. Diabetes was induced by injection of streptozotocin to second-day pregnant rats and confirmed by the development of maternal hyperglycemia. Control rats were injected with citrate buffer. Changes in smooth muscle cell intracellular Ca2+concentration, membrane potential, and vasodilation induced by SKCa/IKCachannel activators were studied in uteroplacental arteries of control and diabetic rats. The impact of diabetes on SKCa- and IKCa-mediated currents was explored in freshly dissociated ECs. NS309 evoked a potent vasodilation that was effectively inhibited by TRAM-34 but not by apamin. NS309-induced smooth muscle cell intracellular Ca2+concentration, membrane potential, and dilator responses were significantly diminished by diabetes; N-cyclohexyl- N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine (CyPPA)-evoked responses were not affected. Ca2+-activated ion currents in ECs were insensitive to paxilline, markedly inhibited by charybdotoxin (ChTX), and diminished by apamin. NS309-induced EC currents were generated mostly due to activation of ChTX-sensitive channels. Maternal diabetes resulted in a significant reduction in ChTX-sensitive currents with no effect on apamin-sensitive or CyPPA-induced currents. We concluded that IKCachannels play a prevalent role over SKCachannels in the generation of endothelial K+currents and vasodilation of uteroplacental arteries. Impaired function of IKCachannels importantly contributes to diabetes-induced uterine endothelial dysfunction. Therapeutic restoration of IKCachannel function may be a novel strategy for improvement of maternal uteroplacental blood flow in pregnancies complicated by diabetes.
15-Lipoxygenase and 15-hydroxyeicosatetraenoic acid regulate intravascular thrombosis in pulmonary hypertension
Authors: Shen Tingting , Shi Jiucheng , Wang Na , Yu Xiufeng , Zhang Chen , Li Jing , Wei Liuping , Ma Cui , Zhao Xijuan , Lian Mingming , Jiang Chun , Zhu Daling
Published: June 2015

Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1.
Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation
Authors: Romberger Debra J. , Heires Art J. , Nordgren Tara M. , Souder Chelsea P. , West William , Liu Xiang-de , Poole Jill A. , Toews Myron L. , Wyatt Todd A.
Published: June 2015

Workers exposed to aerosolized dust present in concentrated animal feeding operations (CAFOs) are susceptible to inflammatory lung diseases, such as chronic obstructive pulmonary disease. Extracts of dust collected from hog CAFOs [hog dust extract (HDE)] are potent stimulators of lung inflammatory responses in several model systems. The observation that HDE contains active proteases prompted the present study, which evaluated the role of CAFO dust proteases in lung inflammatory processes and tested whether protease-activated receptors (PARs) are involved in the signaling pathway for these events. We hypothesized that the damaging proinflammatory effect of HDE is due, in part, to the proteolytic activation of PARs, and inhibiting the proteases in HDE or disrupting PAR activation would attenuate HDE-mediated inflammatory indexes in bronchial epithelial cells (BECs), in mouse lung slices in vitro, and in a murine in vivo exposure model. Human BECs and mouse lung slice cultures stimulated with 5% HDE released significantly more of each of the cytokines measured (IL-6, IL-8, TNF-α, keratinocyte-derived chemokine/CXC chemokine ligand 1, and macrophage inflammatory protein-2/CXC chemokine ligand 2) than controls, and these effects were markedly diminished by protease inhibition. Inhibition of PARs also blunted the HDE-induced cytokine release from BECs. In addition, protease depletion inhibited HDE-induced BEC intracellular PKCα and PKCε activation. C57BL/6J mice administered 12.5% HDE intranasally, either once or daily for 3 wk, exhibited increased total cellular and neutrophil influx, bronchial alveolar fluid inflammatory cytokines, lung histopathology, and inflammatory scores compared with mice receiving protease-depleted HDE. These data suggest that proteases in dust from CAFOs are important mediators of lung inflammation, and these proteases and their receptors may provide novel targets for therapeutic intervention in CAFO dust-induced airways disease.
Multidimensional immunolabeling and 4D time-lapse imaging of vital ex vivo lung tissue
Authors: Burgstaller Gerald , Vierkotten Sarah , Lindner Michael , Königshoff Melanie , Eickelberg Oliver
Published: June 2015

During the last decades, the study of cell behavior was largely accomplished in uncoated or extracellular matrix (ECM)-coated plastic dishes. To date, considerable cell biological efforts have tried to model in vitro the natural microenvironment found in vivo. For the lung, explants cultured ex vivo as lung tissue cultures (LTCs) provide a three-dimensional (3D) tissue model containing all cells in their natural microenvironment. Techniques for assessing the dynamic live interaction between ECM and cellular tissue components, however, are still missing. Here, we describe specific multidimensional immunolabeling of living 3D-LTCs, derived from healthy and fibrotic mouse lungs, as well as patient-derived 3D-LTCs, and concomitant real-time four-dimensional multichannel imaging thereof. This approach allowed the evaluation of dynamic interactions between mesenchymal cells and macrophages with their ECM. Furthermore, fibroblasts transiently expressing focal adhesions markers incorporated into the 3D-LTCs, paving new ways for studying the dynamic interaction between cellular adhesions and their natural-derived ECM. A novel protein transfer technology (FuseIt/Ibidi) shuttled fluorescently labeled α-smooth muscle actin antibodies into the native cells of living 3D-LTCs, enabling live monitoring of α-smooth muscle actin-positive stress fibers in native tissue myofibroblasts residing in fibrotic lesions of 3D-LTCs. Finally, this technique can be applied to healthy and diseased human lung tissue, as well as to adherent cells in conventional two-dimensional cell culture. This novel method will provide valuable new insights into the dynamics of ECM (patho)biology, studying in detail the interaction between ECM and cellular tissue components in their natural microenvironment.
Scavenger receptor class B, type I-mediated uptake of A1AT by pulmonary endothelial cells
Authors: Lockett Angelia D. , Petrusca Daniela N. , Justice Matthew J. , Poirier Christophe , Serban Karina A. , Rush Natalia I. , Kamocka Malgorzata , Predescu Dan , Predescu Sanda , Petrache Irina
Published: June 2015

In addition to exerting a potent anti-elastase function, α-1 antitrypsin (A1AT) maintains the structural integrity of the lung by inhibiting endothelial inflammation and apoptosis. A main serpin secreted in circulation by hepatocytes, A1AT requires uptake by the endothelium to achieve vasculoprotective effects. This active uptake mechanism, which is inhibited by cigarette smoking (CS), involves primarily clathrin- but also caveola-mediated endocytosis and may require active binding to a receptor. Because circulating A1AT binds to high-density lipoprotein (HDL), we hypothesized that scavenging receptors are candidates for endothelial uptake of the serpin. Although the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) internalizes only elastase-bound A1AT, the scavenger receptor B type I (SR-BI), which binds and internalizes HDL and is modulated by CS, may be involved in A1AT uptake. Transmission electron microscopy imaging of colloidal gold-labeled A1AT confirmed A1AT endocytosis in both clathrin-coated vesicles and caveolae in endothelial cells. SR-BI immunoprecipitation identified binding to A1AT at the plasma membrane. Pretreatment of human lung microvascular endothelial cells with SR-B ligands (HDL or LDL), knockdown of SCARB1 expression, or neutralizing SR-BI antibodies significantly reduced A1AT uptake by 30–50%. Scarb1 null mice exhibited decreased A1AT lung content following systemic A1AT administration and reduced lung anti-inflammatory effects of A1AT supplementation during short-term CS exposure. In turn, A1AT supplementation increased lung SR-BI expression and modulated circulating lipoprotein levels in wild-type animals. These studies indicate that SR-BI is an important mediator of A1AT endocytosis in pulmonary endothelium and suggest a cross talk between A1AT and lipoprotein regulation of vascular functions.
Mass Cytometric Functional Profiling of Acute Myeloid Leukemia Defines Cell-Cycle and Immunophenotypic Properties That Correlate with Known Responses to Therapy
Authors: Behbehani Gregory K. , Samusik Nikolay , Bjornson Zach B. , Fantl Wendy J. , Medeiros Bruno C. , Nolan Garry P.
Published: June 2015

Acute myeloid leukemia (AML) is characterized by a high relapse rate that has been attributed to the quiescence of leukemia stem cells (LSC), which renders them resistant to chemotherapy. However, this hypothesis is largely supported by indirect evidence and fails to explain the large differences in relapse rates across AML subtypes. To address this, bone marrow aspirates from 41 AML patients and five healthy donors were analyzed by high-dimensional mass cytometry. All patients displayed immunophenotypic and intracellular signaling abnormalities within CD34+CD38lo populations, and several karyotype- and genotype-specific surface marker patterns were identified. The immunophenotypic stem and early progenitor cell populations from patients with clinically favorable core-binding factor AML demonstrated a 5-fold higher fraction of cells in S-phase compared with other AML samples. Conversely, LSCs in less clinically favorable FLT3-ITD AML exhibited dramatic reductions in S-phase fraction. Mass cytometry also allowed direct observation of the in vivo effects of cytotoxic chemotherapy.

Significance: The mechanisms underlying differences in relapse rates across AML subtypes are poorly understood. This study suggests that known chemotherapy sensitivities of common AML subsets are mediated by cell-cycle differences among LSCs and provides a basis for using in vivo functional characterization of AML cells to inform therapy selection. Cancer Discov; 5(9); 988–1003. ©2015 AACR.

See related commentary by Do and Byrd, p. 912.

This article is highlighted in the In This Issue feature, p. 893
APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity
Authors: Swanton Charles , McGranahan Nicholas , Starrett Gabriel J. , Harris Reuben S.
Published: June 2015

Deep sequencing technologies are revealing the complexities of cancer evolution, casting light on mutational processes fueling tumor adaptation, immune escape, and treatment resistance. Understanding mechanisms driving cancer diversity is a critical step toward developing strategies to attenuate tumor evolution and adaptation. One emerging mechanism fueling tumor diversity and subclonal evolution is genomic DNA cytosine deamination catalyzed by APOBEC3B and at least one other APOBEC family member. Deregulation of APOBEC3 enzymes causes a general mutator phenotype that manifests as diverse and heterogeneous tumor subclones. Here, we summarize knowledge of the APOBEC DNA deaminase family in cancer, and their role as driving forces for intratumor heterogeneity and a therapeutic target to limit tumor adaptation.

Significance: APOBEC mutational signatures may be enriched in tumor subclones, suggesting APOBEC cytosine deaminases fuel subclonal expansions and intratumor heterogeneity. APOBEC family members might represent a new class of drug target aimed at limiting tumor evolution, adaptation, and drug resistance. Cancer Discov; 5(7); 704–12. ©2015 AACR.
Use of Remote Monitoring Is Associated With Lower Risk of Adverse Outcomes Among Patients With Implanted Cardiac Defibrillators
Authors: Akar Joseph G. , Bao Haikun , Jones Paul W. , Wang Yongfei , Varosy Paul D. , Masoudi Frederick A. , Stein Kenneth M. , Saxon Leslie A. , Normand Sharon-Lise T. , Curtis Jeptha P.
Published: June 2015

Background—

We examined the association between the use of remote patient monitoring (RPM) of implantable cardioverter defibrillators (ICD) and all-cause mortality and rehospitalization among patients undergoing initial ICD implant.

Methods and Results—

A limited data set was constructed from Boston Scientific ALTITUDE Registry and National Cardiovascular Data Registry ICD Registry between January 2006 and March 2010. Vital status was determined using the Social Security Death Master File. All-cause mortality up to 3 years was compared in patients who used RPM with those who did not use RPM. Time-dependent frailty Cox models quantified the association between RPM use and all-cause mortality. Analyses were repeated in subgroups based on age, sex, race, ICD type, indication, and cardiomyopathy pathogenesis. Similar methodology examined the association between RPM use and all-cause rehospitalization in patients enrolled in Medicare fee-for-service patients ≥65 years. The study cohort (n=37 742, age 67±13, 72% male) had a 3-year mortality of 20.9% (median follow-up 832 days). In multivariable analyses, patients using RPM (n=22 023, 58%) had lower risk of mortality compared with those not using RPM (hazard ratio 0.67, 95% confidence interval 0.64–0.71,
P
<0.0001). The 3-year all-cause rehospitalization rate in the Medicare population (n=15 254) was 69.3% (median follow-up 922 days). Risk of rehospitalization of patients using RPM (n=9150, 60%) was lower than those not using RPM (hazard ratio 0.82, 95% confidence interval 0.80–0.84,
P
<0.0001). Findings were consistent across subgroups.

Conclusions—

Among patients undergoing initial ICD implant, RPM use is associated with significantly lower risk of adverse outcomes.
Elimination of the Negative Component of the Unipolar Atrial Electrogram as an In Vivo Marker of Transmural Lesion Creation
Authors: Bortone Agustín , Brault-Noble Guillaume , Appetiti Anthony , Marijon Eloi
Published: June 2015

Background—

It has been experimentally shown that elimination of the negative component of the unipolar atrial electrogram (R morphology completion) during radiofrequency applications reflects transmural lesions creation. Subsequently, it has been clinically suggested that such a transmurality can be either irreversible or reversible. The present study is aimed to determine, at the histological level, whether transmural lesions, assessed by R morphology completion, might indeed be reversible in some circumstances or not.

Methods and Results—

In 6 Mongrel hound dogs, superior and inferior vena cavae were isolated and individual lesions were created in the right atrium using radiofrequency energy (30 W/48°C/17 mL/min as presettings and 10
g
of force in average) under CARTO guidance. Five types of lesions were created; R
+
0: termination of ablation at the time of R morphology completion; R
+
5, R
+
10, or R
+
20: extension of ablation for 5, 10, or 20 seconds, respectively, after R morphology achievement; and conventional: radiofrequency applications lasting 30 seconds irrespective of the atrial electrogram modification. All conventional, R
+
5, R
+
10, and R
+
20 lesions were necrotic and transmural, whereas some R
+
0 lesions were not (comprising a part of necrosis and a part of reversible cell damage). Interestingly, surrounding organ injuries were observed after conventional, R
+
10, and R
+
20 radiofrequency applications but were not observed after R
+
0 and R
+
5 applications.

Conclusions—

Elimination of the negative component of the unipolar atrial electrogram reflects, in general, irreversible transmural necrosis creation. In some cases, however, it translates transmural lesion only (with potential reversibility) likely related to transient cell damage creation.
Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest
Authors: Deye Nicolas , Cariou Alain , Girardie Patrick , Pichon Nicolas , Megarbane Bruno , Midez Philippe , Tonnelier Jean-Marie , Boulain Thierry , Outin Hervé , Delahaye Arnaud , Cravoisy Aurélie , Mercat Alain , Blanc Pascal , Santré Charles , Quintard Hervé , Brivet François , Charpentier Julien , Garrigue Delphine , Francois Bruno , Quenot Jean-Pierre , Vincent François , Gueugniaud Pierre-Yves , Mira Jean-Paul , Carli Pierre , Vicaut Eric , Baud Frédéric J.
Published: June 2015

Background—

Targeted temperature management is recommended after out-of-hospital cardiac arrest. Whether advanced internal cooling is superior to basic external cooling remains unknown. The aim of this multicenter, controlled trial was to evaluate the benefit of endovascular versus basic surface cooling.

Methods and Results—

Inclusion criteria were the following: age of 18 to 79 years, out-of-hospital cardiac arrest related to a presumed cardiac cause, time to return of spontaneous circulation <60 minutes, delay between return of spontaneous circulation and inclusion <240 minutes, and unconscious patient after return of spontaneous circulation and before the start of cooling. Exclusion criteria were terminal disease, pregnancy, known coagulopathy, uncontrolled bleeding, temperature on admission <30°C, in-hospital cardiac arrest, immediate need for extracorporeal life support or hemodialysis. Patients were randomized between 2 cooling strategies: endovascular femoral devices (Icy catheter, Coolgard, Zoll, formerly Alsius; n=203) or basic external cooling using fans, a homemade tent, and ice packs (n=197). The primary end point, that is, favorable outcome evaluated by survival without major neurological damage (Cerebral Performance Categories 1–2) at day 28, was not significantly different between groups (odds ratio, 1.41; 95% confidence interval, 0.93–2.16;
P
=0.107). Improvement in favorable outcome at day 90 in favor of the endovascular group did not reach significance (odds ratio, 1.51; 95% confidence interval, 0.96–2.35;
P
=0.07). Time to target temperature (33°C) was significantly shorter and target hypothermia was more strictly maintained in the endovascular than in the surface group (
P
<0.001). Minor side effects directly related to the cooling method were observed more frequently in the endovascular group (
P
=0.009).

Conclusion—

Despite better hypothermia induction and maintenance, endovascular cooling was not significantly superior to basic external cooling in terms of favorable outcome.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00392639.
The “Arteries and Veins” of the Imperial Body: The Nature of the Relay and Post Station Systems in the Ming Dynasty, 1368–1644
Authors: Harris Lane J.
Published: June 2015

The “arteries and veins” of the Ming Empire were the relay (驛 yi) and post station (急遞鋪 jidipu) systems, two networks that worked together to circulate people, information, and goods throughout the realm. The relay system was an infrastructure of stations, horses, carts, and other facilities provided at government expense for the transportation, accommodation, and provision of a select group of imperial officials, tribute-bearing foreign envoys, and messengers from other government offices on their journeys to the capital. The express post station network with its foot posts and mail handling procedures was the communications system of the Ming Empire. Together, the two systems helped the state consolidate control over the empire, allowed the emperor to manage his officials, supported the conduct of diplomatic relations, and facilitated the movement of people, goods, and information across the empire.
Cannibals with Cannons: The Sino-Portuguese Clashes of 1521-1522 and the Early Chinese Adoption of Western Guns
Authors: Andrade Tonio
Published: June 2015

Did Europeans have a military advantage over other peoples of the world during the early modern period (1500-1800)? Scholars of the “military revolution” school have argued that European guns, tactics, fortification techniques, and ships conferred significant benefits on European forces, whereas other scholars suggest that the European military edge was slight at best. This article examines the first armed conflict in history between European and Chinese forces: the so-called Sino-Portuguese War of 1521 and 1522. Scholars on both sides of the military effectiveness argument have adduced this conflict to buttress their positions, but there are few studies of it in either western or East Asian languages. This article suggests that during the first set of engagements, which occurred in 1521, Portuguese artillery was markedly superior, but that in the second set of engagements, in 1522, Chinese artillery played a significant role, causing significant damage to the Portuguese. If there was still a gap in 1522, it was much smaller. Thus, the Sino-Portuguese conflict is less interesting for what it tells us about the “military balance” than for what it tells us about military change. When we discuss military balances, we tend to forget how swiftly they could shift, how rapidly adaptations could take hold. Indeed, historians should take a wider perspective on the military revolution: it was not a process that simply occurred in Europe and provided an edge to Europeans abroad. It was, rather, a global process of intermixture and adaptation. In the case of China, the rapid adoption of western artillery may have started around the time of the Sino-Portuguese Conflict, but it continued through the ensuing decades, as the Ming redesigned Portuguese-style guns and adapted them to their own needs until the only thing western about them was their name: Frankish guns.
Pacific Purgatory: Spanish Dominicans, Chinese Sangleys, and the Entanglement of Mission and Commerce in Manila, 1580-1620
Authors: Crewe Ryan Dominic
Published: June 2015

In late-sixteenth-century Manila, Spanish Dominican missionaries sought to convert Chinese merchants from Fujian Province known as Sangleys. The Dominican-Sangley encounter unfolded in a segregated Chinese quarter known as the Parián. This local encounter had outsize implications for an emerging early modern Pacific World: it enabled a lucrative transpacific trade that connected the histories of America and Asia, and it provided a foothold in Manila for both Dominicans and Sangleys to meet their respective spiritual and commercial goals. Dominicans offered protection to Sangleys with the intention of using their networks to reach China and evangelize there, while Sangleys understood that Dominicans were essential to their residency and prosperity in this Spanish colony. Sangley leverage in transpacific commerce, however, ultimately undermined missionary aspirations. Spanish Christian universalism, honed in prior New World conquests, lost ground to the religious pluralism of maritime Asia. Manila thus became a purgatory for the Dominicans, where Spanish Christian expansionism had to coexist with a burgeoning transpacific trade that required mutual accommodations.
Bacterial Laryngotracheitis and Associated Upper Airway Obstruction
Authors: Gross Jennifer H. , Giraldez-Rodriguez Laureano A. , Klein Adam M.
Published: June 2015

Background:

Iatrogenic laryngotracheal stenosis (LTS) continues to be a known complication of indwelling endotracheal tubes (ETTs). It is well established that secondary scar formation caused by inflammation and mucosal injury are the main mechanisms by which stenosis occurs. Additionally, there are reports of bacterial colonization of ETTs and its potential association with tracheal scar formation. We describe 4 cases of patients with history of intubation and/or tracheostomy and presumed LTS that improved with the management of concurrent bacterial laryngotracheitis.

Methods:

A retrospective case series of 4 subjects initially diagnosed at a tertiary care center with posterior glottic or subglottic stenosis and positive bacterial laryngotracheal cultures was performed.

Results:

All 4 patients with presumed LTS had culture-proven bacterial growth isolated from the laryngotrachea and were treated with adjunct antibiotics. In the first 3 cases, complete resolution of upper airway obstruction was achieved. The fourth patient had notable improvement in her airway status without the need for additional surgical intervention.

Conclusion:

This case series suggests that bacterial growth within the airway may play a larger role in adult postintubation airway injury. Those patients presenting with concern for LTS and symptoms suspicious for an ongoing bacterial infection may benefit from adjunct antibiotic therapy.
Acoustic Hearing After Murine Cochlear Implantation
Authors: Kopelovich Jonathan C. , Robinson Barbara K. , Soken Hakan , Verhoeven Kristien J. , Kirk Jonathon R. , Goodman Shawn S. , Hansen Marlan R.
Published: June 2015

Objectives:

To model the contribution of implant material and insertion trauma on loss of acoustic hearing after cochlear implantation in an appropriate animal model.

Methods:

Sixty-five C57Bl/6J mice underwent unilateral implantation with implant grade materials: 2 implant grade silicones and a third uncoated platinum wire. A sham surgery group was included as a control. Serial auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAEs) were used to discern effects on hearing over 22 weeks. Histologic measurements of damage to the organ of Corti and spiral ganglion were correlated with degree of hearing loss and material type.

Results:

Organ of Corti damage correlated with rate of hearing loss soon after implantation (0-2 weeks) but not subsequently (2-22 weeks). Organ of Corti damage did not depend on implant type and was present even in sham surgery subjects when hearing was severely damaged. Spiral ganglia appeared unaffected. There was no evidence of an inflammatory or toxic effect of the materials beyond the site of implant insertion.

Conclusions:

Hearing loss and cochlear damage appear to be related to insertion trauma, with minimal effect on delayed hearing loss caused by different materials. In the C57Bl/6J mouse model, the sensory epithelium appears to be the location of damage after cochlear implantation.
Changing Patterns in Reflux Care
Authors: Gooi Zhen , Ishman Stacey L. , Bock Jonathan M. , Blumin Joel H. , Akst Lee M.
Published: June 2015

Objectives:

To compare patterns of laryngopharyngeal reflux (LPR) diagnosis and management over time by American Broncho-Esophagological Association (ABEA) members.

Methods:

American Broncho-Esophagological Association members completed an online questionnaire focused on LPR evaluation and management in 2012; responses were compared to a 2002 survey.

Results:

Four hundred twenty-six members were emailed, of whom 63 (14.8%) responded. In both time periods, throat clearing, heartburn, globus, arytenoid edema, and erythema were considered highly related to LPR. Management in 2012 differed as respondents more commonly treated LPR empirically (82.6% vs 56.3%, P = .036). When adjunctive testing was ordered, dual pH probe were less frequently utilized in 2012 (61.5% vs 78.3%, P = .029). Either esophagogastroduodenoscopy (EGD) or transnasal esophagoscopy (TNE) was used more often in 2012 compared to EGD alone in 2002 (63.8% vs 42.4%, P = .020). Dual pH probe was regarded as the most sensitive and specific evaluation for LPR in both surveys, while the perceived sensitivity/specificity of EGD in 2012 was half that reported in 2002 (28.0% vs 56.3%, P = .003).

Conclusion:

Attitudes of ABEA members toward empiric treatment and adjunctive tests have changed between 2012 and 2002. While pH probe testing remains the test regarded as most sensitive/specific for evaluation of LPR, empiric management has become more common. Meanwhile, EGD use has increased despite a significant decrease in its perceived sensitivity/specificity.
Evaluation of the effect of clinical validation of out of hours critical laboratory results
Authors: Chandrajay Deepak , Narayanan Deepa , Barth Julian H
Published: June 2015

Aim

The aim of the study was to review the clinical validation process of out of hours critical biochemistry results by a clinical biochemist and its effect on primary care services.

Methods

A prospective study was conducted of all critical results for primary care patients who were analysed out of hours. The nine-month study period was conducted between June 2013 and February 2014. The data collected include patients’ age, clinical details, critical results and the urgency of result communicated. The patients’ subsequent attendance rate at the emergency department in the local hospital was reviewed.

Results

A total of 311 out of hours critical results were identified in the laboratory. After clinical validation, 110 (35.4%) results were telephoned urgently and 155 (49.8%) results were deferred to the next day. Forty-six (14.8%) results were not telephoned. Following the urgent result communication, 53/110 (48.2%) patients attended the hospital emergency department within 24 h and 17/110 (15.5%) had their repeat blood test by their general practitioner surgery within 48 h. When the result was telephoned during working hours the next day, only 15/155 (9.7%) attended the hospital acute services within 48 h and 16/155 (10.3%) had repeat blood test at their general practitioner surgery.

Conclusion

In our practice, the clinical validation of out of hours critical results by a clinical biochemist is associated with a reduction in the number of results telephoned when compared against the critical limits list recommended by the Royal College of Pathologists and may focus out of hours clinical activity on more suitable patients.
Returns to Apprenticeship Based on the 2006 Canadian Census
Authors: Gunderson Morley , Krashinsky Harry
Published: June 2015

To study the effect of apprenticeships in Canada, the authors use the 2006 Census, the first large-scale, representative Canadian data set to include information on apprenticeship certification. They find large returns for males with an apprenticeship certification when compared with no degree, a high school degree, or a trade certificate; these returns are almost as high as those to a community college diploma. By contrast, the returns for females who hold an apprenticeship certification are generally less than the returns to any other educational certification, except for no degree. For both genders, differences in observable characteristics account for little of the overall pay differences between apprentices and the alternative educational pathways, and the patterns tend to prevail across the quantiles of the pay distributions and for instrumental variable (IV) estimates.
Long Workweeks and Strange Hours
Authors: Hamermesh Daniel S. , Stancanelli Elena
Published: June 2015

U.S. workweeks are long compared to workweeks in other rich countries. Much less well-known is that Americans are more likely to work at night and on weekends. The authors examine the relationship between these two phenomena using the American Time Use Survey and time-diary data from France, Germany, the Netherlands, and the United Kingdom. Only small portions of the U.S.–European differences are attributable to observable characteristics. Adjusting for demographic and occupational differences, Americans’ incidence of night and weekend work would drop by no more than 10% if the average European workweek prevailed. Even if no Americans worked long hours, the incidence of unusual work times in the United States would far exceed those in continental Europe.