In response to invading pathogens, Toll-like receptors (TLR) play a critical role in the initiation of the innate immune response, which can be either beneficial or detrimental to the host. In the present study, we demonstrated that central nervous system (CNS) glial cells are activated by Lymphocytic Choriomeningitis Virus (LCMV) in a TLR2-MyD88/Mal-dependent manner. Specifically, in response to LCMV, both astrocytes and microglial cells isolated from wild-type (WT) mice produced chemokines, such as MCP-1, RANTES and TNF-alpha. Similar responses occurred in TLR3 KO and TLR4 KO glial cells. In striking contrast, both astrocytes and microglial cells isolated from mice deficient in TLR2, MyD88, and Mal did not produce any of these chemokines. In addition, LCMV infection of glial cells induced up-regulation of TLR2, MHC class-I and II, CD40, CD86 in a MyD88-dependent manner. These results define a functional role for TLR signaling in viral infection-induced activation of CNS glial cells as well as for the immunopathology in the CNS.

Presenting physicians with previous test results reduced the ordering of those tests. The actual effect may have been greater than 13%, because there were reductions in study tests ordered for both intervention and control patients during the intervention period when compared with the pre-intervention period, and both tended to rise after the intervention, or display, was turned off.

Tricuspid valve endocarditis patients who undergo tricuspid valve excision, repair, and replacement have similar 30-day operative mortality, as defined by The Society of Thoracic Surgeons. Excision patients have significantly lower unplanned readmission rates at 1 year. Tricuspid valvectomy is an acceptable initial treatment in this high-risk group as part of a surgical strategy to identify patients who are candidates for eventual valve replacement. Further study of long-term outcomes and survival is warranted.

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ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age‐at‐onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age‐at‐onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non‐cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age‐at‐onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age‐at‐onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E‐08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co‐immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E‐07; age‐at‐onset top variant: p value = 9.3E‐07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age‐at‐onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82–94