Once-daily treatment of ADHD with guanfacine: patient implications

The standard of care for treating ADHD is to use a psychostimulant as the first line agent. Recent medical literature reports that approximately 70%–90% of patients with ADHD received some benefit from a stimulant medication. Even though psychostimulants have a high rate of efficacy, an estimated 30%–50% of children and adults may discontinue psychostimulants secondary to adverse effects or inadequate response. Guanfacine has been used for a number of years as an off label alternative to psychostimulants. This article reviews the current literature on the effectiveness of guanfacine in treating ADHD. It also introduces the preliminary data for guanfacine extended release and its effectiveness in decreasing the symptoms of ADHD

Perturbation of the Developmental Potential of Preimplantation Mouse Embryos by Hydroxyurea

Women are advised not to attempt pregnancy while on hydroxyurea (HU) due to the teratogenic effects of this agent, based on results obtained from animal studies. Several case reports suggest that HU may have minimal or no teratogenic effects on the developing human fetus. Fourteen cases of HU therapy in pregnant patients diagnosed with acute or chronic myelogenous leukemia, primary thrombocythemia, or sickle cell disease (SCD) have been reported. Three pregnancies were terminated by elective abortion; 1 woman developed eclampsia and delivered a phenotypically normal stillborn infant. All other patients delivered live, healthy infants without congenital anomalies. We contend that case studies such as these have too few patients and cannot effectively address the adverse effect of HU on preimplantation embryo or fetuses. The objective of this study was to assess the risks associated with a clinically relevant dose of HU used for the treatment of SCD, on ovulation rate and embryo development, using adult C57BL/6J female mice as a model. In Experiment 1, adult female mice were randomly assigned to a treatment or a control group (N = 20/group). Treatment consisted of oral HU (30 mg/kg) for 28 days; while control mice received saline (HU vehicle). Five days to the cessation of HU dosing, all mice were subjected to folliculogenesis induction with pregnant mare serum gonadotropin (PMSG). Five mice/group were anesthetized at 48 hours post PMSG to facilitate blood collection via cardiac puncture for estradiol-17β (E2) measurement by RIA. Ovulation was induced in the remaining mice at 48 hours post PMSG with human chorionic gonadotropin (hCG) and immediately caged with adult males for mating. Five plugged female mice/group were sacrificed for the determination of ovulation rate. The remaining mated mice were sacrificed about 26 hours post hCG, ovaries excised and weighed and embryos harvested and cultured in Whitten’s medium (WM) supplemented with CZBt. In Experiments 2 and 3, (N = 10/Experiment) folliculogenesis and ovulation were induced in untreated mice followed by mating. Recovered embryos were either exposed continuously (Experiment 2) or intermittently (Experiment 3) to bioavailable HU (18 μg HU/mL of WM + CZBt) or WM + CZBt only (control). Treated mice sustained decreased ovarian wt, ovulation rate and circulating E2 compared with controls (P < 0.05). Fewer embryos retrieved from HU-treated mice developed to blastocyst stage (32%) compared with those from controls (60%; P < 0.05). Furthermore, continuous or intermittent in vitro exposures of embryos to HU also resulted in reduced development to blastocyst stage (continuous HU, 9 vs. control, 63%; P < 0.05; intermittent HU, 20 vs. control, 62%; P < 0.05) with embryos exposed continuously to HU in vitro fairing worse. Even though HU is well tolerated, our data suggest that it compromises folliculogenesis and the ability of generated embryos to develop. Therefore, designed studies with larger numbers of patients receiving HU during pregnancy, with longer follow-up of exposed children and more careful assessment of embryo/fetotoxic effects, are required before this agent can be promoted as safe in pregnancy

An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis

FUNDING Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. ACKNOWLEDGEMENTS The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank Akira Sawa and Koko Ishzuki for advice on the PAK7–DISC1 interaction experiment and Jan Korbel for discussions on mechanism of structural variation.Peer reviewedPublisher PD

So what do we really mean when we say that systems biology is holistic?

Background: An old debate has undergone a resurgence in systems biology: that of reductionism versus holism. At least 35 articles in the systems biology literature since 2003 have touched on this issue. The histories of holism and reductionism in the philosophy of biology are reviewed, and the current debate in systems biology is placed in context. Results: Inter-theoretic reductionism in the strict sense envisaged by its creators from the 1930s to the 1960s is largely impractical in biology, and was effectively abandoned by the early 1970s in favour of a more piecemeal approach using individual reductive explanations. Classical holism was a stillborn theory of the 1920s, but the term survived in several fields as a loose umbrella designation for various kinds of anti-reductionism which often differ markedly. Several of these different anti-reductionisms are on display in the holistic rhetoric of the recent systems biology literature. This debate also coincides with a time when interesting arguments are being proposed within the philosophy of biology for a new kind of reductionism. Conclusions: Engaging more deeply with these issues should sharpen our ideas concerning the philosophy of systems biology and its future best methodology. As with previous decisive moments in the history of biology, only those theories that immediately suggest relatively easy experiments will be winners

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

The Influence of Seasonal Precipitation on Ponderosa Pine Carbon and Water Cycling in the Southwestern U.S.

Water is becoming increasingly scarce in the Southwestern U.S. Projections of precipitation are uncertain, but generally suggest that arid ecosystems will become more arid. As such, understanding how ecosystems in the arid Southwest are influenced by different seasonal precipitation aids our understanding of how these ecosystems may be impacted by future conditions. This dissertation incorporates a variety of approaches using tree rings and stable isotopes to investigate how cool-season precipitation, the North American Monsoon, and less frequent precipitation from tropical cyclone remnants, impact carbon and water cycling across the region. Appendix A is focused on leveraging two different metrics of forest water-use efficiency to investigate the role of the North American Monsoon on insulating forests from heightened drought stress during the ongoing megadrought. This research illustrates that the North American Monsoon has mediated the drought response of forests across the Southwestern U.S. Appendix B of this dissertation uses high-resolution measurements of 13C from tree rings to reconstruct three periods of growing season gross primary productivity in a Madrean sky island to determine the relative influences of cool-season, North American Monsoon, and tropical cyclone remnant precipitation on season gross primary productivity. In the third and final Appendix of this dissertation, I explicitly examine how cool-season moisture influences late-season growth and carbon dynamics in Ponderosa pine forests across the region. Taken in conjunction, these chapters provide robust and thorough insights into how the three predominant precipitation sources in the Southwest U.S. influence carbon and water cycling and provide information on how they may respond to perturbations in precipitation and aridity across the region.Release after 12/23/202

Impact of Sr-Containing Secondary Phases on Oxide Conductivity in Solid-Oxide Electrolyzer Cells

Solid-oxide electrolyzer cells (SOECs) based on yttria-stabilized zirconia (YSZ) oxide electrolytes are devices capable of producing hydrogen with excess thermal energy. However, beginning with initial materials sintering and extending through electrochemical aging, Sr diffusion within the Gd-doped CeO2 (GDC) barrier layer has been observed to lead to the formation of unwanted secondary phases such as SrO and SrZrO3. To establish the impact of these phases on SOEC performance, we perform firstprinciples calculations to determine secondary phase bulk oxide conductivities and compared them to that of the YSZ electrolyte. We find that SrO has a low conductivity arising from poor mobility and a low concentration of oxygen vacancies (V_O^2+), and its presence in SOECs should therefore be avoided as much as possible. SrZrO3 also has a lower oxide conductivity than YSZ; however, this discrepancy is primarily due to lower V_O^2+ concentrations, not V_O^2+ mobility. We find Y-doping to be a viable strategy to increase V_O^2+ concentrations in SrZrO3, with 16% substitution of Y on the Zr site leading to an ionic conductivity on par with that of YSZ. Energy dispersive x-ray spectroscopy obtained using scanning transmission electron microscropy on cross-sections of SOECs indicates that Y is the most common minority element present in SrZrO3 forming near the GDC—YSZ interface. Thus, we expect SrZrO3 to be rich in V_O^2+ and not to hinder long-term device performance. These results from our combined computational–experimental analysis can inform future materials engineering strategies designed to limit the detrimental effects of Sr-induced secondary phase formation on SOEC performance

Sampling density and date along with species selection influence spatial representation of tree-ring reconstructions

Our understanding of the natural variability of hydroclimate before the instrumental period (ca. 1900 CE in the United States) is largely dependent on tree-ring-based reconstructions. Large-scale soil moisture reconstructions from a network of tree-ring chronologies have greatly improved our understanding of the spatial and temporal variability in hydroclimate conditions, particularly extremes of both drought and pluvial (wet) events. However, certain regions within these large-scale network reconstructions in the US are modeled by few tree-ring chronologies. Further, many of the chronologies currently publicly available on the International Tree-Ring Data Bank (ITRDB) were collected in the 1980s and 1990s, and thus our understanding of the sensitivity of radial growth to soil moisture in the US is based on a period that experienced multiple extremely severe droughts and neglects the impacts of recent, rapid global change. In this study, we expanded the tree-ring network of the Ohio River valley in the US, a region with sparse coverage. We used a total of 72 chronologies across 15 species to examine how increasing the density of the tree-ring network influences the representation of reconstructing the Palmer Meteorological Drought Index (PMDI). Further, we tested how the sampling date and therefore the calibration period influenced the reconstruction models by creating reconstructions that ended in the year 1980 and compared them to reconstructions ending in 2010 from the same chronologies. We found that in- creasing the density of the tree-ring network resulted in reconstructed values that better matched the spatial variability of instrumentally recorded droughts and, to a lesser extent, pluvials. By extending the calibration period to 2010 compared to 1980, the sensitivity of tree rings to PMDI decreased in the southern portion of our region where severe drought conditions have been absent over recent decades. We emphasize the need of building a high-density tree-ring network to better represent the spatial variability of past droughts and pluvials. Further, chronologies on the ITRDB need updating regularly to better understand how the sensitivity of tree rings to climate may vary through time.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]