Despite improvements in mortality rates over the past several decades, cardiovascular (CV) disease remains the leading cause of death for African-Americans (AAs). Innovative approaches through mobile ...health (mHealth) interventions have the potential to support lifestyle change for CV disease prevention among AAs. We aimed to translate a behavioral theory-informed, evidence-based, face-to-face health education program into an mHealth lifestyle intervention for AAs. We describe the design and development of a culturally relevant, CV health and wellness digital application (app) and pilot testing using a community-based participatory research (CBPR) approach with AA churches.
This mixed methods study used a 4-phase iterative development process for intervention design with the AA community. Phase 1 included focus groups with AA community members and church partners (n = 23) to gain insight regarding potential app end user preferences. In Phase 2, the interdisciplinary research team synthesized Phase 1 input for preliminary app design and content development. Phase 3 consisted of a sequential 3-meeting series with church partners (n = 13) for iterative app prototyping (assessment, cultural tailoring, final review). Phase 4, a single group pilot study among AA church congregants (n = 50), assessed app acceptability, usability, and satisfaction.
Phase 1 focus groups indicated general and health-related apps preferences: multifunctional, high-quality graphics/visuals, evidence-based, yet simple health information and social networking capability. Phase 2 integrated these preferences into the preliminary app prototype. Phase 3 feedback was used to refine the app prototype for pilot testing. Phase 4 pilot testing indicated high app acceptability, usability, and satisfaction.
This study illustrates integration of formative and CBPR approaches to design a culturally relevant, mHealth lifestyle intervention to address CV health disparities among AAs. Given the positive app perceptions, our study supports the use of an iterative development process by others interested in implementing an mHealth lifestyle intervention for racial/ethnic minority communities.
Clinicaltrials.gov NCT03084822.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Huntington disease (HD) is a neurodegenerative disease caused by a trinucleotide repeat expansion in the HTT gene encoding an elongated polyglutamine tract in the huntingtin (HTT) protein. Expanded ...mutant HTT (mHTT) is toxic and leads to regional atrophy and neuronal cell loss in the brain, which occurs earliest in the striatum. Therapeutic lowering of mHTT in the central nervous system (CNS) has shown promise in preclinical studies, with multiple approaches currently in clinical development for HD. Quantitation of mHTT in the cerebrospinal fluid (CSF) is being used as a clinical pharmacodynamic biomarker of target engagement in the CNS. We have previously shown that the CNS is a major source of mHTT in the CSF. However, little is known about the specific brain regions and cell types that contribute to CSF mHTT. Therefore, a better understanding of the origins of CSF mHTT and whether therapies targeting mHTT in the striatum would be expected to be associated with significant lowering of mHTT in the CSF is needed. Here, we use complementary pharmacological and genetic-based approaches to either restrict expression of mHTT to the striatum or selectively deplete mHTT in the striatum to evaluate the contribution of this brain region to mHTT in the CSF. We show that viral expression of a mHTT fragment restricted to the striatum leads to detectable mHTT in the CSF. We demonstrate that targeted lowering of mHTT selectively in the striatum using an antisense oligonucleotide leads to a significant reduction of mHTT in the CSF of HD mice. Furthermore, using a transgenic mouse model of HD that expresses full length human mHTT and wild type HTT, we show that genetic inactivation of mHTT selectively in the striatum results in a significant reduction of mHTT in the CSF. Taken together, our data supports the conclusion that the striatum contributes sufficiently to the pool of mHTT in the CSF that therapeutic levels of mHTT lowering in the striatum can be detected by this measure in HD mice. This suggests that CSF mHTT may represent a pharmacodynamic biomarker for therapies that lower mHTT in the striatum.
•Striatal viral expression of mutant huntingtin (mHTT) is detectable in the CSF•Targeted striatal lowering of mHTT leads to a reduction of CSF mHTT in HD mice•Inactivation of mHTT in the striatum results in a reduction of CSF mHTT in HD mice•CSF mHTT is a pharmacodynamic biomarker for therapies lowering mHTT in the striatum
Abstract
Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. ...Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.
Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (
) gene. Therapeutics that lower HTT have shown preclinical promise and are ...being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons.
Changes in CSF mutant huntingtin (mHTT) are being used as an exploratory endpoint in HTT lowering clinical trials for the treatment of Huntington disease (HD). Recently, it was demonstrated that intrathecal administration of a HTT lowering agent leads to dose-dependent reduction of CSF mHTT in HD patients. However, little is known about how HTT, an intracellular protein, reaches the extracellular space and ultimately the CSF. Our findings that HTT enters CSF by both passive release and active secretion followed by glymphatic clearance may have significant implications for interpretation of treatment-induced changes of CSF mHTT in clinical trials for HD.
Quantitation of huntingtin protein in the brain is needed, both as a marker of Huntington disease (HD) progression and for use in clinical gene silencing trials. Measurement of huntingtin in ...cerebrospinal fluid could be a biomarker of brain huntingtin, but traditional protein quantitation methods have failed to detect huntingtin in cerebrospinal fluid. Using micro-bead based immunoprecipitation and flow cytometry (IP-FCM), we have developed a highly sensitive mutant huntingtin detection assay. The sensitivity of huntingtin IP-FCM enables accurate detection of mutant huntingtin protein in the cerebrospinal fluid of HD patients and model mice, demonstrating that mutant huntingtin levels in cerebrospinal fluid reflect brain levels, increasing with disease stage and decreasing following brain huntingtin suppression. This technique has potential applications as a research tool and as a clinical biomarker.
Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene (HTT). Heterozygous polymorphisms in cis with the mutation allow for ...allele-specific suppression of the pathogenic HTT transcript as a therapeutic strategy. To prioritize target selection, precise heterozygosity estimates are needed across diverse HD patient populations. Here we present the first comprehensive investigation of all common target alleles across the HTT gene, using 738 reference haplotypes from the 1000 Genomes Project and 2364 haplotypes from HD patients and relatives in Canada, Sweden, France, and Italy. The most common HD haplotypes (A1, A2, and A3a) define mutually exclusive sets of polymorphisms for allele-specific therapy in the greatest number of patients. Across all four populations, a maximum of 80% are treatable using these three target haplotypes. We identify a novel deletion found exclusively on the A1 haplotype, enabling potent and selective silencing of mutant HTT in approximately 40% of the patients. Antisense oligonucleotides complementary to the deletion reduce mutant A1 HTT mRNA by 78% in patient cells while sparing wild-type HTT expression. By suppressing specific haplotypes on which expanded CAG occurs, we demonstrate a rational approach to the development of allele-specific therapy for a monogenic disorder.
Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in huntingtin (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs ...in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and the brains of HD mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in neurons and mouse brains that have undergone accelerated aging, including selective increase in DNA damage. These findings suggest a role for aging in HD pathogenesis and interaction between biological age of HD neurons and sensitivity to exogenous stress.
Huntington disease (HD) is caused by the expression of mutant huntingtin (mHTT) bearing a polyglutamine expansion. In HD, mHTT accumulation is accompanied by a dysfunction in basal autophagy, which ...manifests as specific defects in cargo loading during selective autophagy. Here we show that the expression of mHTT resistant to proteolysis at the caspase cleavage site D586 (C6R mHTT) increases autophagy, which may be due to its increased binding to the autophagy adapter p62. This is accompanied by faster degradation of C6R mHTT in vitro and a lack of mHTT accumulation the C6R mouse model with age. These findings may explain the previously observed neuroprotective properties of C6R mHTT. As the C6R mutation cannot be easily translated into a therapeutic approach, we show that a scheduled feeding paradigm is sufficient to lower mHTT levels in YAC128 mice expressing cleavable mHTT. This is consistent with a previous model, where the presence of cleavable mHTT impairs basal autophagy, while fasting-induced autophagy remains functional. In HD, mHTT clearance and autophagy may become increasingly impaired as a function of age and disease stage, because of gradually increased activity of mHTT-processing enzymes. Our findings imply that mHTT clearance could be enhanced by a regulated dietary schedule that promotes autophagy.
General practitioner surgery: Anyone interested? Bacenas, Amber A.P., MD, CCFP; Ricketts, Chelsey A., MD, CCFP; Berkowitz, Jonathan, PhD ...
Canadian journal of rural medicine,
2015-Winter, Letnik:
20, Številka:
1
Journal Article
Recenzirano
Introduction We sought to assess awareness of, exposure to and interest in general practitioner (GP) surgery and enhanced surgical skills (ESS) among family practice residents in British Columbia, ...Alberta and Saskatchewan. Methods We distributed a survey to all family practice residents at 4 universities in BC, Alberta and Saskatchewan. The survey assessed demographic information, awareness of and exposure to GP surgery or ESS during training, and interest in pursuing formal ESS training. Results We received 174 responses (27.2% response rate). Numerous respondents were unaware of GP surgery (9.9% ± 4.5%) and ESS (17.9% ± 5.7%). Awareness was higher among respondents from rural hometowns (GP surgery and ESS awareness 100% and 94.1%, respectively), and with prior exposure to GP surgery (GP surgery and ESS awareness 96.9% and 95.4%, respectively). A minority (38.2%) had been exposed to GP surgery, with exposure higher in respondents from rural training sites and in their second postgraduate year (72.5% and 47.4%, respectively). A quarter (25.1%) of respondents were considering ESS training. Factors encouraging training included increased procedures, challenging medicine and impact on patient outcomes. The importance of ESS training opportunities and service was rated highly. Conclusion Many respondents were unaware of ESS as a career option. Exposure to GP surgery during training was associated with increased awareness. Furthermore, exposure fostered interest in this important field. These results may be helpful in the development of formal ESS training programs and in curricula for family practice residency programs.
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