State Agency Promising Practice: Washington - Promoting public sector jobs for people with intellectual and developmental disabilities

King County’s program to employ people with disabilities in county jobs is an example of Washington’s commitment to the use of innovative approaches to increase integrated employment. In 1989, a training resource funded by Washington State and the county Division of Developmental Disabilities, O’Neill and Associates, submitted a grant application to the Rehabilitation Services Administration to develop public sector jobs for people with developmental disabilities within the state. These jobs were to be concentrated in King County (Seattle area) government because of the availability of high-paying jobs with benefits. With the political assistance of a King County councilor, the County approved a resolution to encourage county departments to hire people with developmental disabilities in 1990 (Mank, O’Neill, & Jenson, 1998). Over the past 15 years, this project has experienced tremendous expansion and replication

Patients' ratings of genetic conditions validate a taxonomy to simplify decisions about preconception carrier screening via genome sequencing

Advances in genome sequencing and gene discovery have created opportunities to efficiently assess more genetic conditions than ever before. Given the large number of conditions that can be screened, the implementation of expanded carrier screening using genome sequencing will require practical methods of simplifying decisions about the conditions for which patients want to be screened. One method to simplify decision making is to generate a taxonomy based on expert judgment. However, expert perceptions of condition attributes used to classify these conditions may differ from those used by patients. To understand whether expert and patient perceptions differ, we asked women who had received preconception genetic carrier screening in the last 3 years to fill out a survey to rate the attributes (predictability, controllability, visibility, and severity) of several autosomal recessive or X-linked genetic conditions. These conditions were classified into one of five taxonomy categories developed by subject experts (significantly shortened lifespan, serious medical problems, mild medical problems, unpredictable medical outcomes, and adult-onset conditions). A total of 193 women provided 739 usable ratings across 20 conditions. The mean ratings and correlations demonstrated that participants made distinctions across both attributes and categories. Aggregated mean attribute ratings across categories demonstrated logical consistency between the key features of each attribute and category, although participants perceived little difference between the mild and serious categories. This study provides empirical evidence for the validity of our proposed taxonomy, which will simplify patient decisions for results they would like to receive from preconception carrier screening via genome sequencing

Generating a taxonomy for genetic conditions relevant to reproductive planning

As genome or exome sequencing (hereafter genome-scale sequencing) becomes more integrated into standard care, carrier testing is an important possible application. Carrier testing using genome-scale sequencing can identify a large number of conditions, but choosing which conditions/genes to evaluate as well as which results to disclose can be complicated. Carrier testing generally occurs in the context of reproductive decision-making and involves patient values in a way that other types of genetic testing may not. The Kaiser Permanente Clinical Sequencing Exploratory Research program is conducting a randomized clinical trial of preconception carrier testing that allows participants to select their preferences for results from among broad descriptive categories rather than selecting individual conditions. This paper describes 1) the criteria developed by the research team, the return of results committee (RORC), and stakeholders for defining the categories; 2) the process of refining the categories based on input from patient focus groups and validation through a patient survey; and, 3) how the RORC then assigned specific gene-condition pairs to taxonomy categories being piloted in the trial. The development of four categories (serious, moderate/mild, unpredictable, late onset) for sharing results allows patients to select results based on their values without separately deciding their interest in knowing their carrier status for hundreds of conditions. A fifth category, lifespan limiting, was always shared. The lessons learned may be applicable in other results disclosure situations, such as incidental findings

Genome sequencing and carrier testing: decisions on categorization and whether to disclose results of carrier testing

We are investigating the use of genome sequencing for preconception carrier testing. Genome sequencing could identify one or more of thousands of X-linked or autosomal recessive conditions that could be disclosed during preconception or prenatal counseling. Therefore, a framework that helps both clinicians and patients understand the possible range of findings is needed to respect patient preferences by ensuring that information about only the desired types of genetic conditions are provided to a given patient

Clinical correlates of grey matter pathology in multiple sclerosis

Traditionally, multiple sclerosis has been viewed as a disease predominantly affecting white matter. However, this view has lately been subject to numerous changes, as new evidence of anatomical and histological changes as well as of molecular targets within the grey matter has arisen. This advance was driven mainly by novel imaging techniques, however, these have not yet been implemented in routine clinical practice. The changes in the grey matter are related to physical and cognitive disability seen in individuals with multiple sclerosis. Furthermore, damage to several grey matter structures can be associated with impairment of specific functions. Therefore, we conclude that grey matter damage - global and regional - has the potential to become a marker of disease activity, complementary to the currently used magnetic resonance markers (global brain atrophy and T2 hyperintense lesions). Furthermore, it may improve the prediction of the future disease course and response to therapy in individual patients and may also become a reliable additional surrogate marker of treatment effect

State Agency Promising Practice: Washington - Promoting public sector jobs for people with intellectual and developmental disabilities

King County’s program to employ people with disabilities in county jobs is an example of Washington’s commitment to the use of innovative approaches to increase integrated employment. In 1989, a training resource funded by Washington State and the county Division of Developmental Disabilities, O’Neill and Associates, submitted a grant application to the Rehabilitation Services Administration to develop public sector jobs for people with developmental disabilities within the state. These jobs were to be concentrated in King County (Seattle area) government because of the availability of high-paying jobs with benefits. With the political assistance of a King County councilor, the County approved a resolution to encourage county departments to hire people with developmental disabilities in 1990 (Mank, O’Neill, & Jenson, 1998). Over the past 15 years, this project has experienced tremendous expansion and replication

State Agency Promising Practice: Washington - Promoting public sector jobs for people with intellectual and developmental disabilities

King County’s program to employ people with disabilities in county jobs is an example of Washington’s commitment to the use of innovative approaches to increase integrated employment. In 1989, a training resource funded by Washington State and the county Division of Developmental Disabilities, O’Neill and Associates, submitted a grant application to the Rehabilitation Services Administration to develop public sector jobs for people with developmental disabilities within the state. These jobs were to be concentrated in King County (Seattle area) government because of the availability of high-paying jobs with benefits. With the political assistance of a King County councilor, the County approved a resolution to encourage county departments to hire people with developmental disabilities in 1990 (Mank, O’Neill, & Jenson, 1998). Over the past 15 years, this project has experienced tremendous expansion and replication

State Agency Promising Practice: Washington - Promoting public sector jobs for people with intellectual and developmental disabilities

King County’s program to employ people with disabilities in county jobs is an example of Washington’s commitment to the use of innovative approaches to increase integrated employment. In 1989, a training resource funded by Washington State and the county Division of Developmental Disabilities, O’Neill and Associates, submitted a grant application to the Rehabilitation Services Administration to develop public sector jobs for people with developmental disabilities within the state. These jobs were to be concentrated in King County (Seattle area) government because of the availability of high-paying jobs with benefits. With the political assistance of a King County councilor, the County approved a resolution to encourage county departments to hire people with developmental disabilities in 1990 (Mank, O’Neill, & Jenson, 1998). Over the past 15 years, this project has experienced tremendous expansion and replication

Lufaxin, a novel factor Xa inhibitor from the salivary gland of the sand fly Lutzomyia longipalpis blocks protease-activated receptor 2 activation and inhibits inflammation and thrombosis in vivo.

OBJECTIVE: Blood-sucking arthropods' salivary glands contain a remarkable diversity of antihemostatics. The aim of the present study was to identify the unique salivary anticoagulant of the sand fly Lutzomyia longipalpis, which remained elusive for decades. METHODS AND RESULTS: Several L. longipalpis salivary proteins were expressed in human embryonic kidney 293 cells and screened for inhibition of blood coagulation. A novel 32.4-kDa molecule, named Lufaxin, was identified as a slow, tight, noncompetitive, and reversible inhibitor of factor Xa (FXa). Notably, Lufaxin's primary sequence does not share similarity to any physiological or salivary inhibitors of coagulation reported to date. Lufaxin is specific for FXa and does not interact with FX, Dansyl-Glu-Gly-Arg-FXa, or 15 other enzymes. In addition, Lufaxin blocks prothrombinase and increases both prothrombin time and activated partial thromboplastin time. Surface plasmon resonance experiments revealed that FXa binds Lufaxin with an equilibrium constant ≈3 nM, and isothermal titration calorimetry determined a stoichiometry of 1:1. Lufaxin also prevents protease-activated receptor 2 activation by FXa in the MDA-MB-231 cell line and abrogates edema formation triggered by injection of FXa in the paw of mice. Moreover, Lufaxin prevents FeCl(3)-induced carotid artery thrombus formation and prolongs activated partial thromboplastin time ex vivo, implying that it works as an anticoagulant in vivo. Finally, salivary gland of sand flies was found to inhibit FXa and to interact with the enzyme. CONCLUSIONS: Lufaxin belongs to a novel family of slow-tight FXa inhibitors, which display antithrombotic and anti-inflammatory activities. It is a useful tool to understand FXa structural features and its role in prohemostatic and proinflammatory events

Characterization of the early inflammatory infiltrate at the feeding site of infected sand flies in mice protected from vector-transmitted Leishmania major by exposure to uninfected bites.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-06-03T18:08:48Z No. of bitstreams: 1 Teixeira C Characterization of the early....pdf: 895063 bytes, checksum: dbe0f9f7b434254bd5a6f08ee52a46f8 (MD5)Made available in DSpace on 2014-06-03T18:08:48Z (GMT). No. of bitstreams: 1 Teixeira C Characterization of the early....pdf: 895063 bytes, checksum: dbe0f9f7b434254bd5a6f08ee52a46f8 (MD5) Previous issue date: 2014Vector Molecular Biology Section. Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, Maryland, USA / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilVector Molecular Biology Section. Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, Maryland, USA / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilVector Molecular Biology Section. Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, Maryland, USAVector Molecular Biology Section. Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, Maryland, USAVector Molecular Biology Section. Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, Maryland, USADepartment of Zoology. University of Maryland Eastern Shore. Princess Anne. Maryland, USAVector Molecular Biology Section. Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, Maryland, USAVector Molecular Biology Section. Laboratory of Malaria and Vector Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Rockville, Maryland, USABACKGROUND: Mice exposed to sand fly saliva are protected against vector-transmitted Leishmania major. Although protection has been related to IFN-γ producing T cells, the early inflammatory response orchestrating this outcome has not been defined. METHODOLOGY/PRINCIPAL FINDINGS: Mice exposed to uninfected P. duboscqi bites and naïve mice were challenged with L. major-infected flies to characterize their early immune response at the bite site. Mostly, chemokine and cytokine transcript expression post-infected bites was amplified in exposed compared to naïve mice. In exposed mice, induced chemokines were mostly involved in leukocyte recruitment and T cell and NK cell activation; IL-4 was expressed at 6 h followed by IFN-γ and iNOS2 as well as IL-5 and IL-10 expression. In naïve animals, the transcript expression following Leishmania-infected sand fly bites was suppressed. Expression profiles translated to an earlier and significantly larger recruitment of leukocytes including neutrophils, macrophages, Gr+ monocytes, NK cells and CD4+ T cells to the bite site of exposed compared to naïve mice post-infected bites. Additionally, up to 48 hours post-infected bites the number of IFN-γ-producing CD4+ T cells and NK cells arriving at the bite site was significantly higher in exposed compared to naïve mice. Thereafter, NK cells become cytolytic and persist at the bite site up to a week post-bite. CONCLUSION/SIGNIFICANCE: The quiet environment induced by a Leishmania-infected sand fly bite in naïve mice was significantly altered in animals previously exposed to saliva of uninfected flies. We propose that the enhanced recruitment of Gr+ monocytes, NK cells and CD4 Th1 cells observed at the bite site of exposed mice creates an inhospitable environment that counters the establishment of L. major infectio