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 βâ 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 naïve 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_ST), Informativeness for Assignment Measure (I_n), 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_STand I_nhad 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_nwas 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_nmeasure estimates ancestry proportion (in an admixed population) with lower bias and mean square error.</p

Norwegian Scabies in the Immunocompromised Patient

Norwegian, or crusted, scabies can be defined as a generalized severe scabies (Sarcoptes scabiei var. hominis) infestation usually affecting the immunocompromised patient that is most commonly seen with the leukemia-lymphoma group of neoplasms. The diagnosis is commonly missed, which can lead to mismanagement. We describe a patient with Norwegian scabies involving the lower extremities. The patient circumstances and treatment, as well as a review of the literature, are presented. The diagnosis of scabies should always be considered in patients with advanced malignancies and associated pruritus. (J Am Podiatr Med Assoc 94(6): 583–586, 2004)</jats:p

Collaborative Technology Impacts in Distributed Learning Environments

Many studies have examined the impact of collaborative technology in distributed learning environments. Few of those studies involved new collaborative technologies such as mobile computing, and few were empirically tested. This chapter addresses the need to empirically examine the impacts of new collaborative technologies including mobile, wearable, embedded, and ubiquitous technologies, on distributed learners. The chapter introduces a technology-independent framework for considering collaborative technologies, including mobile technology; it relates expected technology impacts to user preferences using a generalizable research framework rooted in the social science, communication and technology acceptance literature. The framework is updated to include the lens of contextualization richness, and the results of an empirical test of the framework are presented. The results show user preferences for technologies with a high range of design features to support cognitive learning, while showing preference for technologies with a low range of design features to support perceived learning. Next steps and implications for future work conclude the chapter. </jats:p

A Prospective Multicenter Evaluation of the Value of the On-Call Orthopedic Resident

ABSTRACT Background  Funding for graduate medical education is at risk despite the services provided by residents. Objective  We quantified the potential monetary value of services provided by on-call orthopedic surgery residents. Methods  We conducted a prospective, cross-sectional, multicenter cohort study design. Over a 90-day period in 2014, we collected data on consults by on-call orthopedic surgery residents at 4 tertiary academic medical centers in the United States. All inpatient and emergency department consults evaluated by first-call residents during the study period were eligible for inclusion. Based on their current procedural terminology codes, procedures and evaluations for each consult were assigned a relative value unit and converted into a monetary value to determine the value of services provided by residents. The primary outcome measures were the total dollar value of each consult and the percentage of resident salaries that could be funded by the generated value of the resident consult services. Results  In total, 2644 consults seen by 33 residents from the 4 institutions were included for analysis. These yielded an average value of $81,868 per center for the 90-day study period, that is,$327,471 annually. With a median resident stipend of $53,992, the extrapolated average percentage of resident stipends that could be funded by these consult revenues was 73% of the stipends of the residents who took call or 36% of the stipends of the overall resident cohort. Conclusions  The potential monetary value generated by on-call orthopedic surgery residents is substantial. </jats:sec