7 research outputs found
Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy
Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid Ă²â glucosidase), with consequent cellular accumulation of glucosylceramide (GLâ 1). The disease is managed by intravenous administrations of recombinant glucocerebrosidase (imiglucerase), although symptomatic patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy (ERT) is not an option may also be treated by substrate reduction therapy (SRT) with miglustat. To determine whether the sequential use of both ERT and SRT may provide additional benefits, we compared the relative pharmacodynamic efficacies of separate and sequential therapies in a murine model of Gaucher disease (D409V/null). As expected, ERT with recombinant glucocerebrosidase was effective in reducing the burden of GLâ 1 storage in the liver, spleen, and lung of 3â monthâ old Gaucher mice. SRT using a novel inhibitor of glucosylceramide synthase (Genzâ 112638) was also effective, albeit to a lesser degree than ERT. Animals administered recombinant glucocerebrosidase and then Genzâ 112638 showed the lowest levels of GLâ 1 in all the visceral organs and a reduced number of Gaucher cells in the liver. This was likely because the additional deployment of SRT following enzyme therapy slowed the rate of reaccumulation of GLâ 1 in the affected organs. Hence, in patients whose disease has been stabilized by intravenously administered recombinant glucocerebrosidase, orally administered SRT with Genzâ 112638 could potentially be used as a convenient maintenance therapy. In patients naĂÂŻve to treatment, ERT followed by SRT could potentially accelerate clearance of the offending substrate.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147062/1/jimd0281.pd
Comparison of measures of marker informativeness for ancestry and admixture mapping
<p>Abstract</p> <p>Background</p> <p>Admixture mapping is a powerful gene mapping approach for an admixed population formed from ancestral populations with different allele frequencies. The power of this method relies on the ability of ancestry informative markers (AIMs) to infer ancestry along the chromosomes of admixed individuals. In this study, more than one million SNPs from HapMap databases and simulated data have been interrogated in admixed populations using various measures of ancestry informativeness: Fisher Information Content (FIC), Shannon Information Content (SIC), F statistics (F<sub>ST</sub>), Informativeness for Assignment Measure (I<sub>n</sub>), and the Absolute Allele Frequency Differences (delta, δ). The objectives are to compare these measures of informativeness to select SNP markers for ancestry inference, and to determine the accuracy of AIM panels selected by each measure in estimating the contributions of the ancestors to the admixed population.</p> <p>Results</p> <p>F<sub>ST </sub>and I<sub>n </sub>had the highest Spearman correlation and the best agreement as measured by Kappa statistics based on deciles. Although the different measures of marker informativeness performed comparably well, analyses based on the top 1 to 10% ranked informative markers of simulated data showed that I<sub>n </sub>was better in estimating ancestry for an admixed population.</p> <p>Conclusions</p> <p>Although millions of SNPs have been identified, only a small subset needs to be genotyped in order to accurately predict ancestry with a minimal error rate in a cost-effective manner. In this article, we compared various methods for selecting ancestry informative SNPs using simulations as well as SNP genotype data from samples of admixed populations and showed that the I<sub>n </sub>measure estimates ancestry proportion (in an admixed population) with lower bias and mean square error.</p
Influence of Herbicides and Tillage on Weed Control, Yield, and Quality of Cabbage ( Brassica oleracea
Proceedings from an International Virtual Townhall: Reflecting on the COVID-19 Pandemic: Themes from Long-Term Care
Residents of long-term care (LTC) homes have suffered disproportionately during the COVID-19 pandemic, from the virus itself and often from the imposition of lockdown measures. Provincial Geriatrics Leadership Ontario, in collaboration with interRAI and the International Federation on Aging, hosted a virtual Town Hall on September 25, 2020. The purpose of this event was to bring together international perspectives from researchers, clinicians, and policy experts to address important themes potentially amenable to timely policy interventions. This article summarizes these themes and the ensuing discussions among 130 attendees from 5 continents. The disproportionate impact of the COVID-19 pandemic on frail residents of LTC homes reflects a systematic lack of equitable prioritization by health system decision makers around the world. The primary risk factors for an outbreak in an LTC home were outbreaks in the surrounding community, high staff and visitor traffic in large facilities, and crowding of residents in ageing buildings. Infection control measures must be prioritized in LTC homes, though care must be taken to protect frail and vulnerable residents from their overly blunt application that deprives residents from appropriate physical and psychosocial support. Staffing, in terms of overall numbers, training, and leadership skills, was inadequate. The built environment of LTC homes can be configured for both optimal resident well-being and infection control. Infection control and resident wellness need not be mutually exclusive. Improving outcomes for LTC residents requires more staffing with proper training and interprofessional leadership. All these initiatives must be underpinned by an effective quality assurance system based on standardized, comprehensive, accessible, and clinically relevant data, and which can support broad communities of practice capable of effecting real and meaningful change for frail older persons, wherever they chose to reside