Casein kinase iδ mutations in familial migraine and advanced sleep phase.

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine

Copyright ownership of teaching materials

In 1998, JISC commissioned a Senior Management Briefing Paper on Copyright (JISC, 1998, p.4), which recommended that “all members of HEIs [Higher Education Institutions], whether staff or students should be educated about the basics of copyright and what is acceptable practice”. A later study, also in relation to copyright in HEIs, stated that “there would seem to be a considerable gap between the legal position and what academic staff believe are their rights” (Weedon, 2000, p.16). Although this is not a recent study, the difference between the actual situation and the perceived situation amongst academics in terms of the ownership of their teaching materials is still unclear. Project RoMEO (2003), which focused on author attitudes associated with research outputs, surveyed participants and investigated who owned the copyright of journal papers that these authors had produced. Under one third (32%) of participants did not know this, which is concerning. It is no surprise then that Cornish (2004, p.12) believes the “ownership of copyright is complex”

Magnetism and Mössbauer study of formation of multi-core γ-Fe2O3 nanoparticles

A systematic investigation of magnetic nanoparticles and the formation of a core-shell structure, consisting of multiple maghemite (γ-Fe2O3) nanoparticles as the core and silica as the shell, has been performed using various techniques. High-resolution transmission electron microscopy clearly shows isolated maghemite nanoparticles with an average diameter of 13?nm and the formation of a core-shell structure. Low temperature Mössbauer spectroscopy reveals the presence of pure maghemite nanoparticles with all vacancies at the B-sites. Isothermal magnetization and zero-field-cooled and field-cooled measurements are used for investigating the magnetic properties of the nanoparticles. The magnetization results are in good accordance with the contents of the magnetic core and the non-magnetic shell. The multiple-core γ-Fe2O3 nanoparticles show similar behavior to isolated particles of the same size.We thank the assistance by Dr. Peter Klavins at the Department of Physics, the University of California Davis, in performing the magnetization measurements. This research was partially supported by the Department of Energy, Office of Nuclear Energy, Nuclear Energy Program, under Grant No. DE-NE000070

Water Banks in the West

1 v. (in various pagings) : ill, maps. ; 28 cmhttps://scholar.law.colorado.edu/books_reports_studies/1059/thumbnail.jp

Water Banks in the West

1 v. (in various pagings) : ill, maps. ; 28 cmhttps://scholar.law.colorado.edu/books_reports_studies/1059/thumbnail.jp

Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency

Patients who have common variable immunodeficiency (CVID) and granulomatous/lymphocytic interstitial lung disease (GLILD) are at high risk for early mortality and B cell lymphomas. Infection with human herpes virus type 8 (HHV8), a B cell lymphotrophic virus, is linked to lymphoproliferative disorders in people who have secondary immunodeficiencies. Therefore, we determined the prevalence of HHV8 infection in CVID patients with GLILD. Genomic DNA isolated from peripheral blood mononuclear cells was screened by nested- and real time-quantitative PCR (QRT-PCR) for the presence of HHV8 genome. It was positive in 6/9 CVID patients with GLILD (CVID-GLILD), 1/21 CVID patients without GLILD (CVID-control), and no patients receiving intravenous gamma globulin (n = 13) or normal blood donors (n = 20). Immunohistochemistry (IHC) demonstrated expression of the latency-associated nuclear antigen-1 (LANA-1) in the biopsies of the lung, liver, and bone marrow of four patients with CVID-GLILD. One CVID-GLILD patient developed a B cell lymphoma during the course of the study. QRT-PCR demonstrated high copy number of HHV8 genome and IHC showed diffuse staining for LANA-1 in the malignant lymph node. HHV8 infection may be an important factor in the pathogenesis of the interstitial lung disease and lymphoproliferative disorders in patients with CVID

Differential regulation of blood flow induced neovascularisation and mural cell recruitment by VEGF and angiopoietin signaling

Signalling through VEGF receptors and the Tie2 receptor by angiopoietins is required in combination with blood flow for the formation of a functional vascular network. We tested the hypothesis that VEGF and Ang1 contribute differentially to neovascularization induced by nitric oxide (NO) mediated vasodilatation, by comparing the phenotype of new microvessels in the mesentery during induction of vascular remodeling by over-expression of endothelial nitric oxide synthase (eNOS) in the fat pad of the adult rat mesentery during inhibition of Angiopoietin signalling with soluble Tie2 and VEGF signalling with sFlt1. We find that NO mediated angiogenesis was blocked by inhibition of VEGF with sFlt1 (from 881±98% increase in functional vessel area (FVA) to 279±72%) and by inhibition of angiopoietin with soluble Tie2 (to 337±67%). Exogenous angiopoietin-1 was required to induce arteriolargenesis (8.6±1.3% of vessels with recruitment of vascular smooth muscle cells, VSMC) in the presence of enhanced flow. Soluble Tie2 and sFlt1 both inhibited VSMC recruitment (both 0%), and VEGF inhibition increased pericyte recruitment to newly formed vessels (from 27±2 to 54±3% pericyte ensheathment). We demonstrate that a fine balance of VEGF and Angiopoietin signaling is required for the formation of a functional vascular network. Endogenous VEGF signaling prevents excess neovessel pericyte coverage, and is required for VSMC recruitment during increased nitric oxide mediated vasodilatation and angiopoietin signalling (NO-Tie mediated arteriogenesis). Therapeutic vascular remodeling paradigms may therefore require treatments that modulate blood flow to utilise endogenous VEGF, in combination with exogenous Ang1, for effective neovascularisation

Living in the hinterland: Survey and excavations at Lohari Ragho 2015–2017

Living in the hinterland: Survey and excavations at Lohari Ragho 2015–201

Designing an automated clinical decision support system to match clinical practice guidelines for opioid therapy for chronic pain

Abstract Background Opioid prescribing for chronic pain is common and controversial, but recommended clinical practices are followed inconsistently in many clinical settings. Strategies for increasing adherence to clinical practice guideline recommendations are needed to increase effectiveness and reduce negative consequences of opioid prescribing in chronic pain patients. Methods Here we describe the process and outcomes of a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS) to encourage good opioid prescribing practices during primary care visits. We based the DSS on the existing ATHENA-DSS. We used an iterative process of design, testing, and revision of the DSS by a diverse team including guideline authors, medical informatics experts, clinical content experts, and end-users to convert the written clinical practice guideline into a computable algorithm to generate patient-specific recommendations for care based upon existing information in the electronic medical record (EMR), and a set of clinical tools. Results The iterative revision process identified numerous and varied problems with the initially designed system despite diverse expert participation in the design process. The process of operationalizing the guideline identified areas in which the guideline was vague, left decisions to clinical judgment, or required clarification of detail to insure safe clinical implementation. The revisions led to workable solutions to problems, defined the limits of the DSS and its utility in clinical practice, improved integration into clinical workflow, and improved the clarity and accuracy of system recommendations and tools. Conclusions Use of this iterative process led to development of a multifunctional DSS that met the approval of the clinical practice guideline authors, content experts, and clinicians involved in testing. The process and experiences described provide a model for development of other DSSs that translate written guidelines into actionable, real-time clinical recommendations.http://deepblue.lib.umich.edu/bitstream/2027.42/78267/1/1748-5908-5-26.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/2/1748-5908-5-26.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/3/1748-5908-5-26-S3.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/4/1748-5908-5-26-S2.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/5/1748-5908-5-26-S1.TIFFPeer Reviewe

New approaches to measuring anthelminthic drug efficacy: parasitological responses of childhood schistosome infections to treatment with praziquantel

By 2020, the global health community aims to control and eliminate human helminthiases, including schistosomiasis in selected African countries, principally by preventive chemotherapy (PCT) through mass drug administration (MDA) of anthelminthics. Quantitative monitoring of anthelminthic responses is crucial for promptly detecting changes in efficacy, potentially indicative of emerging drug resistance. Statistical models offer a powerful means to delineate and compare efficacy among individuals, among groups of individuals and among populations.; We illustrate a variety of statistical frameworks that offer different levels of inference by analysing data from nine previous studies on egg counts collected from African children before and after administration of praziquantel.; We quantify responses to praziquantel as egg reduction rates (ERRs), using different frameworks to estimate ERRs among population strata, as average responses, and within strata, as individual responses. We compare our model-based average ERRs to corresponding model-free estimates, using as reference the World Health Organization (WHO) 90 % threshold of optimal efficacy. We estimate distributions of individual responses and summarize the variation among these responses as the fraction of ERRs falling below the WHO threshold.; Generic models for evaluating responses to anthelminthics deepen our understanding of variation among populations, sub-populations and individuals. We discuss the future application of statistical modelling approaches for monitoring and evaluation of PCT programmes targeting human helminthiases in the context of the WHO 2020 control and elimination goals