Cultural Border Crossing: An Exploration of Power, Positionality, and Pedagogy in Context

This paper explores literature drawn from interdisciplinary scholarship that speaks to positionality as it applies to the complex dynamics of intercultural border crossing through the lens of two distinctly different institutional contexts – an adult service learning partnership at a private, Northeastern college and an indigenous adult cohort university program

A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection

Nipah virus is a broadly tropic and highly pathogenic zoonotic paramyxovirus in the genus Henipavirus whose natural reservoirs are several species of Pteropus fruit bats. Nipah virus has repeatedly caused outbreaks over the past decade associated with a severe and often fatal disease in humans and animals. Here, a new ferret model of Nipah virus pathogenesis is described where both respiratory and neurological disease are present in infected animals. Severe disease occurs with viral doses as low as 500 TCID50 within 6 to 10 days following infection. The underlying pathology seen in the ferret closely resembles that seen in Nipah virus infected humans, characterized as a widespread multisystemic vasculitis, with virus replicating in highly vascular tissues including lung, spleen and brain, with recoverable virus from a variety of tissues. Using this ferret model a cross-reactive neutralizing human monoclonal antibody, m102.4, targeting the henipavirus G glycoprotein was evaluated in vivo as a potential therapeutic agent. All ferrets that received m102.4 ten hours following a high dose oral-nasal Nipah virus challenge were protected from disease while all controls died. This study is the first successful post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody

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

Substrate Reduction Augments the Efficacy of Enzyme Therapy in a Mouse Model of Fabry Disease

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease

Promoting Community Conversations About Research to End Suicide: learning and behavioural outcomes of a training-of-trainers model to facilitate grassroots community health education to address Indigenous youth suicide prevention

Alaska Native (AN) youth suicide remains a substantial and recalcitrant health disparity, especially in rural/remote communities. Promoting Community Conversations About Research to End Suicide (PC CARES) is a community health intervention that responds to the need for culturally responsive and evidence-supported prevention practice, using a grassroots approach to spark multilevel and community-based efforts for suicide prevention. This paper describes theoretical and practical considerations of the approach, and assesses the feasibility and preliminary learning and behavioural outcomes of the training-of-trainers model. It details the training of a first cohort of intervention facilitators in Northwest Alaska (NWA). Thirty-two people from 11 NWA village communities completed the PC CARES facilitator training, preparing them to implement the intervention in their home communities. Facilitator pre-post surveys focused on readiness to facilitate, a group quiz assessed participants’ understanding of relevant research evidence, and practice facilitation exercises demonstrated competency. Curriculum fidelity and accuracy scores were calculated using audio recordings from learning circles conducted by facilitators in their home communities. Facilitator reflections describe the successes of the model and identify several areas for improvement. As of March 2017, 20 of the 32 trained facilitators in 10 of the 11 participating villages have hosted 54 LCs, with a total of 309 unique community members. Coding of these LCs by 2 independent raters indicate acceptable levels of fidelity and accurate dissemination of research evidence by facilitators. Facilitator reflections were positive overall, suggesting PC CARES is feasible, acceptable and potentially impactful as a way to translate research to practice in under-resourced, rural AN communities. PC CARES represents a practical community education and mobilisation approach to Indigenous youth suicide prevention that displays preliminary success in learning and behavioural outcomes of local facilitators

Creating a Community of Practice to Prevent Suicide Through Multiple Channels: Describing the Theoretical Foundations and Structured Learning of PC CARES

It is critical to develop practical, effective, ecological, and decolonizing approaches to indigenous suicide prevention and health promotion for the North American communities. The youth suicide rates in predominantly indigenous small, rural, and remote Northern communities are unacceptably high. This health disparity, however, is fairly recent, occurring over the last 50 to 100 years as communities experienced forced social, economic, and political change and intergenerational trauma. These conditions increase suicide risk and can reduce people’s access to shared protective factors and processes. In this context, it is imperative that suicide prevention includes—at its heart— decolonization, while also utilizing the “best practices” from research to effectively address the issue from multiple levels. This article describes such an approach: Promoting Community Conversations About Research to End Suicide (PC CARES). PC CARES uses popular education strategies to build a “community of practice” among local and regional service providers, friends, and families that fosters personal and collective learning about suicide prevention in order to spur practical action on multiple levels to prevent suicide and promote health. This article will discuss the theoretical underpinnings of the community intervention and describe the form that PC CARES takes to structure ongoing dialogue, learning, solidarity, and multilevel mobilization for suicide prevention

Letsemot, “Togetherness”: Exploring How Connection to Land, Water, and Territory Influences Health and Wellness with First Nations Knowledge Keepers and Youth in the Fraser Salish Region of British Columbia

Connection to land has been identified as a central determinant of the health and well-being of First Nations in Canada. The wholistic, interconnected, spiritual, and sacred relationship that many Indigenous Peoples have with the land is an integral part of strengthening physical, spiritual, mental, and emotional health and well-being. However, there has been little empirical evidence on how to assess, measure, and report on connection to land for First Nations Peoples. Using a Two- Eyed Seeing approach, this study explores what connection to land, water, and territory means for health and wellness for First Nations in the Fraser Salish region in the province of British Columbia (BC), Canada. Data were collected through a sharing circle with five First Nations Knowledge Keepers and five youth from Stó:lō communities as part of a land-based gathering in Stó:lō territory. Three themes were identified: (a) “the spirits of the land, water, and territory are within us”: the intersection of cultural identity, spirituality, ancestral knowledge, and health and well-being; (b) letsemot, “togetherness”: relationality; and (c) disruptions and new ways of living. For Stó:lō Peoples, connection to the land is an integral component of health and well-being. Connection to land was found to strongly influence physical, spiritual, mental, and emotional aspects of health while also intersecting with Stó:lō cultural identity, spirituality, ancestral knowledge, and ways of living. The findings can be used to inform the development of an indicator for connection to land, water, and territory as a measurement of ecological wellness for the First Nations Population Health and Wellness Agenda in BC

A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease

An approach to treating Gaucher disease is substrate inhibition therapy which seeks to abate the aberrant lysosomal accumulation of glucosylceramide. We have identified a novel inhibitor of glucosylceramide synthase (Genz-112638) and assessed its activity in a murine model of Gaucher disease (D409V/null). Biochemical characterization of Genz-112638 showed good potency (IC(50) approximately 24nM) and specificity against the target enzyme. Mice that received drug prior to significant accumulation of substrate (10 weeks of age) showed reduced levels of glucosylceramide and number of Gaucher cells in the spleen, lung and liver when compared to age-matched control animals. Treatment of older mice that already displayed significant amounts of tissue glucosylceramide (7 months old) resulted in arrest of further accumulation of the substrate and appearance of additional Gaucher cells in affected organs. These data indicate that substrate inhibition therapy with Genz-112638 represents a viable alternate approach to enzyme therapy to treat the visceral pathology in Gaucher diseas

Feline Model of Acute Nipah Virus Infection and Protection with a Soluble Glycoprotein-Based Subunit Vaccine

Nipah virus (NiV) and Hendra virus (HeV) are paramyxoviruses capable of causing considerable morbidity and mortality in a number of mammalian species, including humans. Case reports from outbreaks and previous challenge experiments have suggested that cats were highly susceptible to NiV infection, responding with a severe respiratory disease and systemic infection. Here we have assessed the cat as a model of experimental NiV infection and use it in the evaluation of a subunit vaccine comprised of soluble G glycoprotein (sG). Two groups of two adult cats each were inoculated subcutaneously with either 500 or 5,000 50% tissue culture infective dose(s) (TCID(50)) of NiV. Animals were monitored closely for disease onset, and extensive analysis was conducted on samples and tissues taken during infection and at necropsy to determine viral load and tissue tropism. All animals developed clinical disease 6 to 9 days postinfection, a finding consistent with previous observations. In a subsequent experiment, two cats were immunized with HeV sG and two were immunized with NiV sG. Homologous serum neutralizing titers were greater than 1:20,000, and heterologous titers were greater than 1:20,000 to 16-fold lower. Immunized animals and two additional naive controls were then challenged subcutaneously with 500 TCID(50) of NiV. Naive animals developed clinical disease 6 to 13 days postinfection, whereas none of the immunized animals showed any sign of disease. TaqMan PCR analysis of samples from naive animals revealed considerable levels of NiV genome in a wide range of tissues, whereas the genome was evident in only two immunized cats in only four samples and well below the limit of accurate detection. These results indicate that the cat provides a consistent model for acute NiV infection and associated pathogenesis and an effective subunit vaccine strategy appears achievable

Combined enzyme-replacement therapy and substrate reduction therapy is most effective at reducing uromodulin levels in the urine of Fabry-Rag mouse.

<p>Urine was collected from 10-month old Fabry-Rag mice. Mice receiving no treatment were used to standardize urine volume and uromodulin levels for those treated with ERT every two months (ERT2), ERT every two months+eliglustat tartrate (ERT2+SRT), ERT every four months+eliglustat tartrate (ERT4+SRT) and eliglustat tartrate alone (SRT). Relative urine uromodulin levels from the Fabry-Rag mice were determined using a sandwich ELISA. Data are presented as % of uromodulin concentration relative to an age-matched untreated control Fabry-Rag mouse. Data are shown as mean ± SEM (n = 10 mice/time point). Statistical comparisons are to the ERT2 treatment group and were determined using the Graphpad Prism software t test (* = p<0.05; ** = p<0.01; *** = p<0.001).</p