Paternal Preconception Chronic Variable Stress Confers Attenuated Ethanol Drinking Behavior Selectively to Male Offspring in a Pre-Stress Environment Dependent Manner

Stress-related psychiatric disorders such as major depression are strongly associated with alcohol abuse and alcohol use disorder. Recently, many epidemiological and preclinical studies suggest that chronic stress prior to conception has cross-generational effects on the behavior and physiological response to stress in subsequent generations. Thus, we hypothesized that chronic stress may also affect ethanol drinking behaviors in the next generation. In the first cohort of mice, we found that paternal preconception chronic variable stress significantly reduced both two-bottle choice and binge-like ethanol drinking selectively in male offspring. However, these results were not replicated in a second cohort that were tested under experimental conditions that were nearly identical, except for one notable difference. Cohort 1 offspring were derived from in-house C57BL/6J sires that were born in the animal vivarium at the University of Pittsburgh whereas cohort 2 offspring were derived from C57BL/6J sires shipped directly from the vendor. Therefore, a third cohort that included both in-house and vendor born sires was analyzed. Consistent with the first two cohorts, we observed a significant interaction between chronic stress and sire-source with only stressed sires that were born in-house able to impart reduced ethanol drinking behaviors to male offspring. Overall, these results demonstrate that paternal preconception stress can impact ethanol drinking behavior in males of the next generation. These studies provide additional support for a recently recognized role of the paternal preconception environment in shaping ethanol drinking behavior

Comparison of treatment effect sizes from pivotal and postapproval trials of novel therapeutics approved by the FDA based on surrogate markers of disease: a meta-epidemiological study

Background: The U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product’s actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication. Methods: We searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials. Results: Between 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01–2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95% CI -0.15–0.16). Conclusions: Many postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection. Although treatment effects from pivotal trials supporting FDA approval of novel therapeutics based on non-continuous surrogate markers of disease are often larger than those observed among postapproval trials using surrogate markers as trial endpoints, there is no evidence of difference between pivotal and postapproval trials using continuous surrogate markers

Defining and unpacking the core concepts of pharmacology education

Pharmacology education currently lacks a research-based consensus on which core concepts all graduates should know and understand, as well as a valid and reliable means to assess core conceptual learning. The Core Concepts in Pharmacology Expert Group (CC-PEG) from Australia and New Zealand recently identified a set of core concepts of pharmacology education as a first step toward developing a concept inventory—a valid and reliable tool to assess learner attainment of concepts. In the current study, CC-PEG used established methodologies to define each concept and then unpack its key components. Expert working groups of three to seven educators were formed to unpack concepts within specific conceptual groupings: what the body does to the drug (pharmacokinetics); what the drug does to the body (pharmacodynamics); and system integration and modification of drug–response. First, a one-sentence definition was developed for each core concept. Next, sub-concepts were established for each core concept. These twenty core concepts, along with their respective definitions and sub-concepts, can provide pharmacology educators with a resource to guide the development of new curricula and the evaluation of existing curricula. The unpacking and articulation of these core concepts will also inform the development of a pharmacology concept inventory. We anticipate that these resources will advance further collaboration across the international pharmacology education community to improve curricula, teaching, assessment, and learning.Marina Santiago, Elizabeth A. Davis, Tina Hinton, Thomas A. Angelo, Alison Shield, Anna-Marie Babey, Barbara Kemp-Harper, Gregg Maynard, Hesham S. Al-Sallami, Ian F. Musgrave, Lynette B. Fernandes, Suong N. T. Ngo, Arthur Christopoulos, Paul J. Whit

Greed, recklessness and/or dishonesty? An investigation into the micro-regulation and culture of five UK banks between 2004-2009

The author uses a multiple case study approach to examine five UK banks in her paper. The banks are Northern Rock, the Royal Bank of Scotland, Barclays, Lloyds Banking Group and HSBC. The author feels that it is appropriate to use a multiple case study here because it will be interesting to study the micro aspects of regulation and corporate governance of five UK banks. The banks have to comply with the same regulations and laws on a macro level, so it is essential to examine the differences between these banks on a micro level through reviewing annual reports and financial ratios. The case study is longitudinal, spanning across 2004-2009. In accordance to the aims of a case study, the author will describe, understand and explain the effects of the financial crisis 2007 on five UK banks. This case study provides an opportunity to examine the weaknesses and failures of corporate governance of five UK banks at a micro level. The author has two hypotheses at the beginning of the study. First, banks moved from a customer driven culture to sales driven one. Secondly, the banking culture during between 2004-2009 is one of greed, recklessness and dishonesty. With the caveat that one should not make generalisations, there is evidence from the case study that both hypotheses are correct to a certain extent

Subaqueous basaltic magmatic explosions trigger phreatomagmatism: a case study from Askja, Iceland

Sequences of basaltic pillow lavas that transition upwards with systematic gradation from pillow fragment breccias to fluidal bomb-bearing breccia to bomb-bearing lapilli tuffs are common at Askja volcano, Iceland. Based on the detailed textural investigation of three of these sequences, we argue that they record temporally continuous transition from effusive to explosive products that were erupted from and deposited at or near a single subaqueous vent. The recognition of such sequences is important as they provide evidence for controls on the onset of explosive activity in subaqueous environments. Such investigations are complicated by the interplay of magmatic gas expansion, phreatomagmatic and mechanical granulation fragmentation mechanisms in the subaqueous eruptive environment. All of the sequences studied at Askja have textural, componentry and sedimentological characteristics suggestive of a close genetic and spatial relationship between the pillow lavas and all of the overlying glassy clastic deposits. The identification of magma fragmentation signatures in pyroclasts was accomplished through detailed textural studies of pyroclasts within the full range of grain sizes of a given deposit i.e. bomb/blocks, lapilli and fine ash. These textural characteristics were compared and evaluated as discriminators of fragmentation in pyroclastic deposits. The presence of angular vitric clasts within the breccia and lapilli tuff displaying fragile glassy projections indicates little or no postdepositional textural modification. A shift in vesicle and clast textures between the pillow lavas and the large concentration of fluidal bombs in the breccia indicate that the phreatomagmatic explosions were initially triggered by magmatic vesiculation. The initial magmatic gas expansion may have been triggered by depressurization caused by the drainage of the ice-confined lake surrounding Askja. The Fuel Coolant Interactions (FCI) of the more efficient phreatomagmatic explosion was enabled by the increase in the surface area to volume ratio of the fluidal bombs in the water, producing a premix of magma and water. The onset and increasing influence of phreatomagmatic fragmentation is preserved in the presence of very fine blocky ash particles and diminished presence of larger particles such as fluidal bombs. The textural, sedimentological and environmental characteristics of these deposits suggest that phreatomagmatic explosions can be triggered by initial magmatic gas expansion, but that it is likely one of many mechanisms for triggering such explosions

Future research directions on the "elusive" white shark

White sharks, Carcharodon carcharias, are often described as elusive, with little information available due to the logistical difficulties of studying large marine predators that make long-distance migrations across ocean basins. Increased understanding of aggregation patterns, combined with recent advances in technology have, however, facilitated a new breadth of studies revealing fresh insights into the biology and ecology of white sharks. Although we may no longer be able to refer to the white shark as a little-known, elusive species, there remain numerous key questions that warrant investigation and research focus. Although white sharks have separate populations, they seemingly share similar biological and ecological traits across their global distribution. Yet, white shark’s behavior and migratory patterns can widely differ, which makes formalizing similarities across its distribution challenging. Prioritization of research questions is important to maximize limited resources because white sharks are naturally low in abundance and play important regulatory roles in the ecosystem. Here, we consulted 43 white shark experts to identify these issues. The questions listed and developed here provide a global road map for future research on white sharks to advance progress toward key goals that are informed by the needs of the research community and resource managers

In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS

Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer’s disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer’s disease (AD). Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ) peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis

Submarine Fernandina : magmatism at the leading edge of the Galapagos hot spot

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 7 (2006): Q12007, doi:10.1029/2006GC001290.New multibeam and side-scan sonar surveys of Fernandina volcano and the geochemistry of lavas provide clues to the structural and magmatic development of Galápagos volcanoes. Submarine Fernandina has three well-developed rift zones, whereas the subaerial edifice has circumferential fissures associated with a large summit caldera and diffuse radial fissures on the lower slopes. Rift zone development is controlled by changes in deviatoric stresses with increasing distance from the caldera. Large lava flows are present on the gently sloping and deep seafloor west of Fernandina. Fernandina's submarine lavas are petrographically more diverse than the subaerial suite and include picrites. Most submarine glasses are similar in composition to aphyric subaerially erupted lavas, however. These rocks are termed the “normal” series and are believed to result from cooling and crystallization in the subcaldera magma system, which buffers the magmas both thermally and chemically. These normal-series magmas are extruded laterally through the flanks of the volcano, where they scavenge and disaggregate olivine-gabbro mush to produce picritic lavas. A suite of lavas recovered from the terminus of the SW submarine rift and terraces to the south comprises evolved basalts and icelandites with MgO = 3.1 to 5.0 wt.%. This “evolved series” is believed to form by fractional crystallization at 3 to 5 kb, involving extensive crystallization of clinopyroxene and titanomagnetite in addition to plagioclase. “High-K” lavas were recovered from the southwest rift and are attributed to hybridization between normal-series basalt and evolved-series magma. The geochemical and structural findings are used to develop an evolutionary model for the construction of the Galápagos Platform and better understand the petrogenesis of the erupted lavas. The earliest stage is represented by the deep-water lava flows, which over time construct a broad submarine platform. The deep-water lavas originate from the subcaldera plumbing system of the adjacent volcano. After construction of the platform, eruptions focus to a point source, building an island with rift zones extending away from the adjacent, buttressing volcanoes. Most rift zone magmas intrude laterally from the subcaldera magma chamber, although a few evolve by crystallization in the upper mantle and deep crust.This work was supported by the National Science Foundation grants OCE0002818 and EAR0207605 (D.G.), OCE0002461 (D.J.F. and M.K.), OCE9811504 (D.J.F. and M.R.P.), and EAR0207425 (K.H.) and WHOI postdoctoral support for Soule

Functioning of Coastal River-Dominated Ecosystems and Implications for Oil Spill Response: From Observations to Mechanisms and Models

Coastal river-dominated oceans are physically complex, biologically productive, and intimately connected to human socioeconomic activity. The Deepwater Horizon blowout and subsequent advection of oil into coastal waters of the northern Gulf of Mexico (nGOM) highlighted the complex linkages among oceanographic processes within this river-dominated system and knowledge gaps about it that resulted in imprecise information on both oil transport and ecosystem consequences. The interdisciplinary research program implemented through the CONsortium for oil exposure pathways in COastal River-Dominated Ecosystems (CONCORDE) is designed to identify and quantitatively assess key physical, biological, and geochemical processes acting in the nGOM, in order to provide the foundation for implementation of a synthesis model (coupled circulation and biogeochemistry) of the nGOM shelf system that can ultimately aid in prediction of oil spill transport and impacts. CONCORDE field and modeling efforts in 2015–2016 focused on defining the influence of freshwater input from river plumes in the nGOM. In situ observations, combined with field-deployed and simulated drifters, show considerable variability in the spatial extent of freshwater influence that is related to wind direction and strength. Increased primary production and particle abundance (a proxy for secondary production) was observed during the spring when nGOM shelf waters were becoming stratified. Zooplankton and marine snow displayed intense vertical and horizontal patchiness during all seasons, often aggregating near the halocline. Simulations of a neutrally buoyant tracer released offshore of the Mississippi Bight showed surface advection of low tracer concentrations onto the inner shelf under high river discharge, high stratification, and variable wind conditions compared to almost no advection onto the inner shelf under low discharge, negligible stratification, and generally northeasterly winds. The interconnectedness of environmental variables and biological activity indicate that multiple factors can affect the transport of oil and the resulting ecological impacts. The process-oriented understanding provided by CONCORDE is necessary to predict ecosystem-level impacts of oil spills, and these results are applicable to other river-dominated coastal systems worldwide that often support oil extraction activities