Interplay of Hypoxia-Inducible Factors and Oxygen Therapy in Cardiovascular Medicine

Mammals have evolved to adapt to differences in oxygen availability. Although systemic oxygen homeostasis relies on respiratory and circulatory responses, cellular adaptation to hypoxia involves the transcription factor hypoxia-inducible factor (HIF). Given that many cardiovascular diseases involve some degree of systemic or local tissue hypoxia, oxygen therapy has been used liberally over many decades for the treatment of cardiovascular disorders. However, preclinical research has revealed the detrimental effects of excessive use of oxygen therapy, including the generation of toxic oxygen radicals or attenuation of endogenous protection by HIFs. In addition, investigators in clinical trials conducted in the past decade have questioned the excessive use of oxygen therapy and have identified specific cardiovascular diseases in which a more conservative approach to oxygen therapy could be beneficial compared with a more liberal approach. In this Review, we provide numerous perspectives on systemic and molecular oxygen homeostasis and the pathophysiological consequences of excessive oxygen use. In addition, we provide an overview of findings from clinical studies on oxygen therapy for myocardial ischaemia, cardiac arrest, heart failure and cardiac surgery. These clinical studies have prompted a shift from liberal oxygen supplementation to a more conservative and vigilant approach to oxygen therapy. Furthermore, we discuss the alternative therapeutic strategies that target oxygen-sensing pathways, including various preconditioning approaches and pharmacological HIF activators, that can be used regardless of the level of oxygen therapy that a patient is already receiving

Etiology and Clinical Characteristics of Influenza-Like Illness (ILI) in Outpatients in Beijing, June 2010 to May 2011

BACKGROUND: Since May 2009, exposure of the population of Beijing, China to pH1N1 has resulted in an increase in respiratory illnesses. Limited information is available on the etiology and clinical characteristics of the influenza-like illness (ILI) that ensued in adults following the pH1N1 pandemic. METHODS: Clinical and epidemiological data of ILI in adults was collected. A total of 279 throat swabs were tested for twelve respiratory viruses using multiplex RT-PCR. Clinical characteristics of influenza A in outpatients versus test-negative patients were compared using Pearson's χ2 and the Mann-Whitney U test. 190 swabs were tested for pH1N1 by virus isolation. Consultation rates for ILI were compared between 2009 and 2010. RESULTS: One or two virus were detected in 29% of the samples. Influenza A virus (FLU-A) accounted for 22.9% (64/279). Other viruses were present at a frequency less than 3.0%. Cough was significantly associated with Influenza A virus infection (χ2, p<0.001). The positive rate of FLU-A was consistent with changes in the ILI rate during the same period and there was a significant reduction in the incidence of ILI in 2010 when compared to 2009. During the 2010-2011 influenza season, the incidence peaked in January 2011 in Beijing and north China. CONCLUSIONS: Exposure to pH1N1 had no impact on typical influenza seasonal peaks, although FLU-A remained the predominant virus for 2010 in Beijing. Symptomatically, cough was associated with FLU-A infection. The positive rate of influenza virus was consistent with changes in the ILI rate during the same period and there was a significant reduction in the incidence of ILI in 2010 when compared to that of 2009

Targeting Myocardial Equilibrative Nucleoside Transporter ENT1 Provides Cardioprotection by Enhancing Myeloid Adora2b Signaling.

Previous studies implicate extracellular adenosine signaling in attenuating myocardial ischemia and reperfusion injury (IRI). This extracellular adenosine signaling is terminated by its uptake into cells by equilibrative nucleoside transporters (ENTs). Thus, we hypothesized that targeting ENTs would function to increase cardiac adenosine signaling and concomitant cardioprotection against IRI. Mice were exposed to myocardial ischemia and reperfusion injury. Myocardial injury was attenuated in mice treated with the nonspecific ENT inhibitor dipyridamole. A comparison of mice with global Ent1 or Ent2 deletion showed cardioprotection only in Ent1-/- mice. Moreover, studies with tissue-specific Ent deletion revealed that mice with myocyte-specific Ent1 deletion (Ent1loxP/loxP Myosin Cre+ mice) experienced smaller infarct sizes. Measurements of cardiac adenosine levels demonstrated that postischemic elevations of adenosine persisted during reperfusion after targeting ENTs. Finally, studies in mice with global or myeloid-specific deletion of the Adora2b adenosine receptor (Adora2bloxP/loxP LysM Cre+ mice) implied that Adora2b signaling on myeloid-inflammatory cells in cardioprotection provided by ENT inhibition. These studies reveal a previously unrecognized role for myocyte-specific ENT1 in cardioprotection by enhancing myeloid-dependent Adora2b signaling during reperfusion. Extension of these findings implicates adenosine transporter inhibitors in cardioprotection against ischemia and reperfusion injury

Antitumor Effects of Berberine on Gliomas via Inactivation of Caspase-1-Mediated IL-1β and IL-18 Release

Gliomas arise in the glial cells of the brain or spine and are the most prevalent and devastating type of brain tumors. Studies of tumor immunology have established the importance of the tumor micro-environment as a driver of oncogenesis. Inflammatory mediators such as IL-1β and IL-18 released by monocytes regulate transcriptional networks that are required for malignant cell growth. Berberine is a natural botanical alkaloid that is widely found in the Berberis species. Although it has been widely used as an anti-diarrheal treatment in North America for several decades, our study is the first to investigate berberine as an anti-tumor agent in glioma cells. In this study, we demonstrate that berberine significantly inhibits inflammatory cytokine Caspase-1 activation via ERK1/2 signaling and subsequent production of IL-1β and IL-18 by glioma cells. Moreover, we found that berberine treatment led to decreased motility and subsequently cell death in U251 and U87 cells. In addition, our study is the first to indicate that berberine can reverse the process of epithelial-mesenchymal transition, a marker of tumor invasion. Taken together, our work supports berberine as a putative anti-tumor agent targeting glioma cells

Pore Scale Thermal Hydraulics Investigations of Molten Salt Cooled Pebble Bed High Temperature Reactor with BCC and FCC Configurations

The present paper systematically investigated pore scale thermal hydraulics characteristics of molten salt cooled high temperature pebble bed reactor. By using computational fluid dynamics (CFD) methods and employing simplified body center cubic (BCC) and face center cubic (FCC) model, pressure drop and local mean Nusselt number are calculated. The simulation result shows that the high Prandtl number molten salt in packed bed has unique fluid-dynamics and thermodynamic properties. There are divergences between CFD results and empirical correlations’ predictions of pressure drop and local Nusselt numbers. Local pebble surface temperature distributions in several default conditions are investigated. Thermal removal capacities of molten salt are confirmed in the case of nominal condition; the pebble surface temperature under the condition of local power distortion shows the tolerance of pebble in extreme neutron dose exposure. The numerical experiments of local pebble insufficient cooling indicate that in the molten salt cooled pebble bed reactor, the pebble surface temperature is not very sensitive to loss of partial coolant. The methods and results of this paper would be useful for optimum designs and safety analysis of molten salt cooled pebble bed reactors

Preventing type flaw attacks on security protocols with a simplified tagging scheme

abstract. A type flaw attack on a security protocol is an attack where a field in a message that was originally intended to have one type is subsequently interpreted as having another type. Heather et al. proves that type flaw attacks can be prevented with the technique of tagging each field with the information that indicates its intended type. We simplify Heather et al.’s tagging scheme by combining all the tags inside each encrypted component into a single tag and by omitting the tags on the outmost level. The simplification reduces the sizes of messages in the security protocol. We also formally prove our simplified tagging scheme is as secure as Heather et al.’s with the strand space method. Note that Heather et al.’s tagging scheme and our simplified tagging are applicable to, not just one protocol, but a variety of security protocols

Forested Land Use Efficiency in China: Spatiotemporal Patterns and Influencing Factors from 1999 to 2010

More attention needs to be paid to efficiency in the use of forested land. This article is devoted to the study of forested land use efficiency (FLUE) and its spatiotemporal differences in China during the period from 1999 to 2010. The global generalized directional distance function (GGDDF) and global Malmquist–Luenberger (GML) index models are used to measure and analyze forested land use efficiency. The empirical results showed that forested land use efficiency continued to increase during the study period. The FLUE of Shanghai was always highest, whereas Tibet, Inner Mongolia, and Qinghai suffered the most inefficiency in forested land use. There were obvious spatial differences in forested land use efficiency among the 31 provinces. Urbanization, economic development context, and population density were the main factors influencing spatial differences in forested land use efficiency. The growth in the non-radial Malmquist forested land performance index (NMPFI) in the east was driven mainly by technological change, whereas the growth in the central region was mostly derived from progress in efficiency change. For the western region, the change in the productivity of forested land was the result of the interactive effect between technological change and effect change, and only in the western region did an absolute β-convergence exist