Environmentally persistent free radicals decrease cardiac function before and after ischemia/reperfusion injury in vivo

Exposure to airborne particles is associated with increased cardiovascular morbidity and mortality. During the combustion of chlorine-containing hazardous materials and fuels, chlorinated hydrocarbons chemisorb to the surface of transition metal-oxide-containing particles, reduce the metal, and form an organic free radical. These radical-particle systems can survive in the environment for days and are called environmentally persistent free radicals (EPFRs). This study determined whether EPFRs could decrease left ventricular function before and after ischemia and reperfusion (I/R) in vivo. Male Brown-Norway rats were dosed (8mg/kg, intratracheal) 24h prior to testing with particles containing the EPFR of 1, 2-dichlorobenzene (DCB230). DCB230 treatment decreased systolic and diastolic function. DCB230 also produced pulmonary and cardiac inflammation. After ischemia, systolic, but not diastolic function was significantly decreased in DCB230-treated rats. Ventricular function was not affected by I/R in control rats. There was greater oxidative stress in the heart and increased 8-isoprostane (biomarker of oxidative stress) in the plasma of treated vs. control rats after I/R. These data demonstrate for the first time that DCB230 can produce inflammation and significantly decrease cardiac function at baseline and after I/R in vivo. Furthermore, these data suggest that EPFRs may be a risk factor for cardiac toxicity in healthy individuals and individuals with ischemic heart disease. Potential mechanisms involving cytokines/chemokines and/or oxidative stress are discussed. © 2011 Informa Healthcare USA, Inc

Model combustion-generated particulate matter containing persistent free radicals redox cycle to produce reactive oxygen species

Particulate matter (PM) is emitted during thermal decomposition of waste. During this process, aromatic compounds chemisorb to the surface of metal-oxide-containing PM, forming a surface-stabilized environmentally persistent free radical (EPFR). We hypothesized that EPFR-containing PM redox cycle to produce ROS and that this redox cycle is maintained in biological environments. To test our hypothesis, we incubated model EPFRs with the fluorescent probe dihydrorhodamine (DHR). Marked increases in DHR fluorescence were observed. Using a more specific assay, hydroxyl radicals ( •OH) were also detected, and their level was further increased by cotreatment with thiols or ascorbic acid (AA), known components of epithelial lining fluid. Next, we incubated our model EPFR in bronchoalveolar lavage fluid (BALF) or serum. Detection of EPFRs and •OH verified that PM generate ROS in biological fluids. Moreover, incubation of pulmonary epithelial cells with EPFR-containing PM increased •OH levels compared to those in PM lacking EPFRs. Finally, measurements of oxidant injury in neonatal rats exposed to EPFRs by inhalation suggested that EPFRs induce an oxidant injury within the lung lining fluid and that the lung responds by increasing antioxidant levels. In summary, our EPFR-containing PM redox cycle to produce ROS, and these ROS are maintained in biological fluids and environments. Moreover, these ROS may modulate toxic responses of PM in biological tissues such as the lung. © 2013 American Chemical Society

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively.Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling.These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Angiotensin-converting enzyme 2 over-expression in the central nervous system reduces angiotensin-II-mediated cardiac hypertrophy.

Angiotensin-converting enzyme type 2 (ACE2) has been shown to be an important member of the renin angiotensin system. Previously, we observed that central ACE2 reduces the development of hypertension following chronic angiotensin II (Ang-II) infusion in syn-hACE2 transgenic (SA) mice, in which the human ACE2 transgene is selectively targeted to neurons. To study the physiological consequences of central ACE2 over-expression on cardiac function and cardiac hypertrophy, SA and non-transgenic (NT) mice were infused with Ang-II (600 ng/kg/min, sc) for 14 days, and cardiac function was assessed by echocardiography. Blood pressure (BP), hemodynamic parameters, left ventricle (LV) mass/tibia length, relative ventricle wall thickness (2PW/LVD), cardiomyocyte diameters and collagen deposition were similar (P>0.05) between NT and SA mice during saline infusion. After a 2-week infusion, BP was elevated in NT but not in SA mice. Although ejection fraction and fractional shortening were not altered, Ang-II infusion increased 2PW/LVD compared to saline infusion in NT mice. Interestingly, the 2PW/LVD and LV mass/tibia ratios were significantly lower in SA compared to NT mice at the end of infusion. Moreover, Ang-II infusion significantly increased arterial collagen deposition and cardiomyocytes diameter in NT mice but not in transgenic animals (P<0.05). More importantly, ACE2 over expression significantly reduced the Ang-II-mediated increase in urine norepinephrine levels in SA compared to NT mice. The protective effect of ACE2 appears to involve reductions in Ang-II-mediated hypertension and sympathetic nerve activity

Cardiac hemodynamic parameters for NT and SA mice.

<p>The data is expressed as mean ± SEM (n = 6). All measurements were performed on 3 different cardiac cycles and the values averaged. BP: blood pressure; HR: heart rate; IVS: interventricular septum; LVID: left ventricle internal diameter; LVPW: left ventricle posterior wall thickness; LV Vol: left ventricle end volume; %EF: ejection fraction; %FS: <i>P</i> value (<0.05).</p>*<p>compared to NT in the same treatment and</p>#<p>compared to saline in the same genotype.</p