Regional myocardial blood flow, function and metabolism using phosphorus-31 nuclear magnetic resonance spectroscopy during ischemia and reperfusion in dogs

Postreperfusion regional myocardial dysfunction may be associated with depletion of high energy phosphate compounds during ischemia and with their relatively slow repletion during reperfusion. However, few studies have correlated relatively rapid changes in regional myocardial function (sonomicrometers) and blood flow (microspheres) with high energy phosphate concentrations measured using phosphorus-31 nuclear magnetic resonance spectroscopy in intact large animal models of regional myocardial ischemia. The left anterior descending coronary artery of mongrel dogs was abruptly occluded for 17.1 ± 1.9 minutes and then completely released; measurements were made for an additional 22 minutes. Transmural blood flow decreased from 1.07 ± 0.25 to 0.25 ± 0.10 ml/(min × g) and holosystolic expansion was observed in all dogs (segmental systolic shortening decreased from 9.3 ± 3.7 to −6.3 ± 6.0%). Phosphocreatine (PCr) measured during 4.4 minute sampling intervals decreased to steady state within the first sampling period after occlusion and was 45.9 ± 17.0% of control at the end of the occlusion, whereas beta-adenosine triphosphate (beta-ATP) reached its lowest level early after reperfusion (72.7 ± 13.3% of control). The ratio of PCr to inorganic phosphate (Pi) decreased during the occlusion (3.34 ± 0.75 versus 1.01 ± 0.61) but returned to control level early during reperfusion. The ratio of PCr to beta-ATP also decreased during coronary occlusion (2.16 ± 0.39 versus 1.29 ± 0.39) but did not return to control level during reperfusion.Significant correlations were observed between the intensity of ischemia (reduced blood flow) and reductions in regional contractile function, PCr, beta-ATP, myocardial pH and the increase in Pi during the coronary occlusion. Also during ischemia, there were significant correlations between regional contractile function and both myocardial pH and Pi. PCr returned to control level rapidly after reperfusion (95.9 ± 13.2% of control in less than 5 minutes of reperfusion) whereas beta-ATP recovered only partially after 22 minutes (80.0 ± 17.5% of control). The correlation between the fraction of control beta-ATP and the fraction of control regional function at this time was r = 0.84 (p = 0.017).These results demonstrate metabolic correlates to regional myocardial ischemia in an intact dog model using phosphorus-31 spectroscopy. Additionally during reperfusion, beta-ATP, but not PCr, could be associated with the recovery of regional segmental contractile function

Imprints of Short Distance Physics On Inflationary Cosmology

We analyze the impact of certain modifications to short distance physics on the inflationary perturbation spectrum. For the specific case of power-law inflation, we find distinctive -- and possibly observable -- effects on the spectrum of density perturbations.Comment: Revtex 4, 3 eps figs, 4 page

Drug safety Africa: An overview of safety pharmacology & toxicology in South Africa.

This meeting report is based on presentations given at the first Drug Safety Africa Meeting in Potchefstroom, South Africa from November 20-22, 2018 at the North-West University campus. There were 134 attendees (including 26 speakers and 34 students) from the pharmaceutical industry, academia, regulatory agencies as well as 6 exhibitors. These meeting proceedings are designed to inform the content that was presented in terms of Safety Pharmacology (SP) and Toxicology methods and models that are used by the pharmaceutical industry to characterize the safety profile of novel small chemical or biological molecules. The first part of this report includes an overview of the core battery studies defined by cardiovascular, central nervous system (CNS) and respiratory studies. Approaches to evaluating drug effects on the renal and gastrointestinal systems and murine phenotyping were also discussed. Subsequently, toxicological approaches were presented including standard strategies and options for early identification and characterization of risks associated with a novel therapeutic, the types of toxicology studies conducted and relevance to risk assessment supporting first-in-human (FIH) clinical trials and target organ toxicity. Biopharmaceutical development and principles of immunotoxicology were discussed as well as emerging technologies. An additional poster session was held that included 18 posters on advanced studies and topics by South African researchers, postgraduate students and postdoctoral fellows

Structural discordance between neogene detachments and frontal Sevier thrusts, central Mormon Mountains, southern Nevada

Detailed geologic mapping in the Mormon Mountains of southern Nevada provides significant insight into processes of extensional tectonics developed within older compressional orogens. A newly discovered, WSW-directed low-angle normal fault, the Mormon Peak detachment, juxtaposes the highest levels of the frontal most part of the east-vergent, Mesozoic Sevier thrust belt with autochthonous crystalline basement. Palinspastic analysis suggests that the detachment initially dipped 20–25° to the west and cut discordantly across thrust faults. Nearly complete lateral removal of the hanging wall from the area has exposed a 5 km thick longitudinal cross-section through the thrust belt in the footwall, while highly attenuated remnants of the hanging wall (nowhere more than a few hundred meters thick) structurally veneer the range. The present arched configuration of the detachment resulted in part from progressive “domino-style” rotation of a few degrees while it was active, but is largely due to rotation on younger, structurally lower, basement-penetrating normal faults that initiated at high-angle. The geometry and kinematics of normal faulting in the Mormon Mountains suggest that pre-existing thrust planes are not required for the initiation of low-angle normal faults, and even where closely overlapped by extensional tectonism, need not function as a primary control of detachment geometry. Caution must thus be exercised in interpreting low-angle normal faults of uncertain tectonic heritage such as those seen in the COCORP west-central Utah and BIRP's MOIST deep-reflection profiles. Although thrust fault reactivation has reasonably been shown to be the origin of a very few low-angle normal faults, our results indicate that it may not be as fundamental a component of orogenic architecture as it is now widely perceived to be. We conclude that while in many instances thrust fault reactivation may be both a plausible and attractive hypothesis, it may never be assumed