Evaluation of Dopamine D3 Receptor Antagonists PG01037, PG01042, and VK4-116 Against D1R-induced Dyskinesia

Parkinson’s Disease (PD) results in motor deficits that can be relieved with L-DOPA, a dopamine (DA) replacement therapy. Unfortunately, chronic treatment often leads to L-DOPA-induced dyskinesia (LID), a debilitating side effect characterized by abnormal involuntary movements (AIMs). Overactivity of the direct striatonigral pathway is seen in LID and is characterized by potent changes in D1 and D3 receptors (D1R, D3R). Further, D1R and D3R may physically and functionally interact to form D1R-D3R heteromer thereby potentiating LID. This D1R-D3R heteromer uniquely switches from G-protein dependent to G-protein independent signaling, allowing for an avenue to manage LID. To uncover the role of these pathways in LID, Sprague-Dawley rats were rendered hemi-parkinsonian and treated daily for 2 weeks with L-DOPA (6 mg/kg; s.c.) to induce stable LID. In a within subjects, counterbalanced design, they were then split into treatment groups that received D3R antagonists: PG01037 (10, 30 mg/kg; i.p.), PG01042 (5, 10 mg/kg; i.p.), or VK4-116 (10, 20 mg/kg; i.p.). PG01037 (PG1) is a mixed D3R antagonist, acting at both the G-protein dependent and independent pathways. PG01042 (PG2) acts as an antagonist on G-protein independent signaling and VK4-116 acts as a G-protein dependent antagonist. All drugs were tested against D1R agonist-induced dyskinesia with SKF38393 (2mg/kg; s.c.). The only effects found were with PG2 which implicates promotion of the D1R G-protein dependent pathway as contributing to D1R-induced dyskinesia. Future studies with these drugs and L-DOPA treatment should unveil the importance of D1R, D3R, and D1R-D3R influences in the presence of the natural ligand DA.https://orb.binghamton.edu/research_days_posters_2021/1038/thumbnail.jp

Voices Raised, Spring 2022

Director\u27s column; workforce diversification; women\u27s leadership immersion; staff spotlight on Leah Ward; focus on equity, education, and research (UD Men for Gender Equity; Gender Equity Research Colloquium); diversity and inclusion; Women of UD; student organization spotlight; Voice of Black Women; staff summaries.https://ecommons.udayton.edu/wc_newsletter/1057/thumbnail.jp

Guidelines for Developing Area-of-Origin Compensation: A Research Report Prepared for the Colorado Water Resources Research Institute

i, 60 p. ; 28 cmhttps://scholar.law.colorado.edu/books_reports_studies/1126/thumbnail.jp

Guidelines for Developing Area-of-Origin Compensation: A Research Report Prepared for the Colorado Water Resources Research Institute

i, 60 p. ; 28 cmhttps://scholar.law.colorado.edu/books_reports_studies/1126/thumbnail.jp

Policy Feedback and the Politics of the Affordable Care Act

There is a large body of literature devoted to how “policies create politics” and how feedback effects from existing policy legacies shape potential reforms in a particular area. Although much of this literature focuses on self‐reinforcing feedback effects that increase support for existing policies over time, Kent Weaver and his colleagues have recently drawn our attention to self‐undermining effects that can gradually weaken support for such policies. The following contribution explores both self‐reinforcing and self‐undermining policy feedback in relationship to the Affordable Care Act, the most important health‐care reform enacted in the United States since the mid‐1960s. More specifically, the paper draws on the concept of policy feedback to reflect on the political fate of the ACA since its adoption in 2010. We argue that, due in part to its sheer complexity and fragmentation, the ACA generates both self‐reinforcing and self‐undermining feedback effects that, depending of the aspect of the legislation at hand, can either facilitate or impede conservative retrenchment and restructuring. Simultaneously, through a discussion of partisan effects that shape Republican behavior in Congress, we acknowledge the limits of policy feedback in the explanation of policy stability and change

The State of the Region: Hampton Roads 2021

[From the introductory material] This is Old Dominion University’s 22nd annual State of the Region Report. While it represents the work of many people connected in various ways to the university, the report does not constitute an official viewpoint of Old Dominion, its president, Brian O. Hemphill, Ph.D., the Board of Visitors, the Strome College of Business or the generous donors who support the activities of the Dragas Center for Economic Analysis and Policy. Over the past year, we have endured the depths of the COVID-19 pandemic, the introduction of vaccines and a return to a semblance of normality in Hampton Roads. Even as the economy recovers in the region, Virginia and the nation, we cannot forget that some have been left behind. Invigorating growth that raises the fortunes of all is the challenge that lies before us. This task will involve difficult discussions about how to diversify our economy in the coming years. Hampton Roads plays a significant role in national security, provides college education to thousands of Virginians and is culturally diverse. Given these realities and the fact that many residents live in one community and work in another, solutions to our regional challenges will require conversations and policies that span jurisdictional boundaries. If there is an overarching lesson to be learned from the pandemic, it is simply that we are all in this together

The State of the Region: Hampton Roads 2022

[From the introductory material] This is Old Dominion University’s 23rd annual State of the Region Report. While it represents the work of many people connected in various ways to the university, the report does not constitute an official viewpoint of Old Dominion, its president, Brian O. Hemphill, Ph.D., the Board of Visitors, the Strome College of Business or the generous donors who support the activities of the Dragas Center for Economic Analysis and Policy. Over the past year, we have experienced the continued uncertainty of the COVID-19 pandemic, the rise of inflation, and geopolitical shocks that have affected our daily lives. We live, for better or worse, in uncertain times, and our resilience is likely to be tested in the coming years. The question before us remains the same as in many previous reports: How can we invigorate economic growth as a region that raises the fortunes of all, not just the most fortunate? We only need to look at neighboring metropolitan areas for examples of how setting aside parochial differences and working together can yield a sum that is greater than its parts. Hampton Roads faces two generational challenges: sea-level rise and the revolution in military affairs due to the transformative impact of unmanned weapons on the modern battlefield. If challenge and opportunity are two sides of the same coin, we must move beyond talk and into action, else we may be left behind. Our work seeks to inform without minimizing the challenges facing the region or downplaying the opportunities to emerge stronger and more resilient from the experiences of the past

Congenital myasthenic syndrome caused by a frameshift insertion mutation in

Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families. Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed. Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the GFPT1 gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology. Conclusions: These results expand on the spectrum of known loss-of-function GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD

Neighborhood disparities in stroke and myocardial infarction mortality: a GIS and spatial scan statistics approach

<p>Abstract</p> <p>Background</p> <p>Stroke and myocardial infarction (MI) are serious public health burdens in the US. These burdens vary by geographic location with the highest mortality risks reported in the southeastern US. While these disparities have been investigated at state and county levels, little is known regarding disparities in risk at lower levels of geography, such as neighborhoods. Therefore, the objective of this study was to investigate spatial patterns of stroke and MI mortality risks in the East Tennessee Appalachian Region so as to identify neighborhoods with the highest risks.</p> <p>Methods</p> <p>Stroke and MI mortality data for the period 1999-2007, obtained free of charge upon request from the Tennessee Department of Health, were aggregated to the census tract (neighborhood) level. Mortality risks were age-standardized by the direct method. To adjust for spatial autocorrelation, population heterogeneity, and variance instability, standardized risks were smoothed using Spatial Empirical Bayesian technique. Spatial clusters of high risks were identified using spatial scan statistics, with a discrete Poisson model adjusted for age and using a 5% scanning window. Significance testing was performed using 999 Monte Carlo permutations. Logistic models were used to investigate neighborhood level socioeconomic and demographic predictors of the identified spatial clusters.</p> <p>Results</p> <p>There were 3,824 stroke deaths and 5,018 MI deaths. Neighborhoods with significantly high mortality risks were identified. Annual stroke mortality risks ranged from 0 to 182 per 100,000 population (median: 55.6), while annual MI mortality risks ranged from 0 to 243 per 100,000 population (median: 65.5). Stroke and MI mortality risks exceeded the state risks of 67.5 and 85.5 in 28% and 32% of the neighborhoods, respectively. Six and ten significant (p < 0.001) spatial clusters of high risk of stroke and MI mortality were identified, respectively. Neighborhoods belonging to high risk clusters of stroke and MI mortality tended to have high proportions of the population with low education attainment.</p> <p>Conclusions</p> <p>These methods for identifying disparities in mortality risks across neighborhoods are useful for identifying high risk communities and for guiding population health programs aimed at addressing health disparities and improving population health.</p