Neuroinflammation is a well-characterized pathophysiology occurring in association with the progression of Parkinson’s disease. Characterizing the cellular and molecular basis of neuroinflammation is critical to understanding its impact on the incidence and progression of PD and other neurologic disorders. Inflammasomes are intracellular pro-inflammatory pattern-recognition receptors capable of initiating and propagating inflammation. These cellular complexes are well characterized in the innate immune system and activity of the NLRP3 inflammasome has been reported in microglia. NLRP3 inflammasome activity has been associated with Alzheimer’s disease, and recent reports, from our laboratory and others, indicate that Nlrp3 is required for neuroinflammation and nigral cell loss in animal models of PD. NLRP3 has not yet been characterized in PD patients. Here we characterize NLRP3 in PD using immunohistologic and genetic approaches. Histologic studies revealed elevated NLRP3 expression in mesencephalic neurons of PD patients. Analysis of exome sequencing data for genetic variation of NLRP3 identified multiple single-nucleotide polymorphisms (SNPs) including rs7525979 that was associated with a significantly reduced risk of developing PD. Mechanistic studies conducted in HEK293 cells indicated that the synonymous SNP, NLRP3 rs7525979, alters the efficiency of NLRP3 translation impacting NLRP3 protein stability, ubiquitination state, and solubility. These data provide evidence that dopaminergic neurons are a cell-of-origin for inflammasome activity in PD and are consistent with recent animal studies, suggesting that inflammasome activity may impact the progression of PD.
Introduction: Direct observation assessments that provide both formative feedback and data for summative decisions can be difficult to achieve. The mini-clinical evaluation exercise (mini-CEX) is a widely used tool of direct observation that provides opportunities for feedback. We introduced a direct observation system with frequent mini-CEXs to increase clerkship student learning opportunities and to improve competency-based summative decisions. However, students may express resistance to assessments for learning with any summative impact as they may perceive the assessments as purely a series of summative evaluations. Aims:We explored how frequent low-stakes mini-CEXs affect clerkship students' perception of learning and to understand student perceptions of these assessments supporting their end-of-rotation summative clinical performance evaluations.Methods: This qualitative study used a purposive sampling strategy of focus groups with students who completed multiple mini-CEXs during their four-week neurology clerkship at one of three sites. All eleven students chose to participate. Eight students completed eight mini-CEXs, two students completed seven, and one student completed four. Investigator triangulation was used with interpretation comparisons that included independent content analysis. The emerging themes were discussed and final theme consensus was reached.Results: Three major themes arose: perceived effects of frequent mini-CEXs for clerkship student learning by facilitating multiple opportunities for guided practice under low assessment anxiety; the importance of consistent, effective faculty feedback and engagement to maximize mini-CEXs for learning; and support for summative impact of frequent, mainly formative, low stakes mini-CEXs.
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