Dissecting α-synuclein inclusion pathology diversity in multiple system atrophy: implications for the prion-like transmission hypothesis.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of insoluble, aggregated α-synuclein (αS) pathological inclusions. Multiple system atrophy (MSA) presents with extensive oligodendroglial αS pathology and additional more limited neuronal inclusions while most of the other synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies (DLB), develop αS pathology primarily in neuronal cell populations. αS biochemical alterations specific to MSA have been described but thorough examination of these unique and disease-specific protein deposits is further warranted especially given recent findings implicating the prion-like nature of synucleinopathies perhaps with distinct strain-like properties. Taking advantage of an extensive panel of antibodies that target a wide range of epitopes within αS, we investigated the distinct properties of the various types of αS inclusion present in MSA brains with comparison to DLB. Brain biochemical fractionation followed by immunoblotting revealed that the immunoreactive profiles were significantly more consistent for DLB than for MSA. Furthermore, epitope-specific immunohistochemistry varied greatly between different types of MSA αS inclusions and even within different brain regions of individual MSA brains. These studies highlight the importance of using a battery of antibodies for adequate appreciation of the various pathology in this distinct synucleinopathy. In addition, it can be posited that if the spread of pathology in MSA undergoes prion-like mechanisms, "strains" of αS aggregated conformers must be inherently unstable and readily mutable, perhaps resulting in a more stochastic progression process.

Tissue-based multigene expression tests for pretreatment prostate cancer risk assessment: current status and future perspectives.

Prostate cancer is a highly prevalent disease with ample spectrum of aggressiveness and treatment options. Low-risk disease can be safely managed by nonintervention strategies, such as active surveillance; however, accurate risk assessment is warranted. Molecular tests have been developed and validated to complement standard clinicopathological parameters and help to improve risk stratification in prostate cancer. Herein, we review selected tissue-based assays, including genomic prostate score, cell cycle progression score and genomic classifier, with particular emphasis on their role in patient risk assessment in a pretreatment setting, in view of their current or potential utilization in active surveillance.

Semaglutide-associated kidney injury.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are multipurpose agents effective in improving glycemic control in patients with type 2 diabetes while also achieving weight loss and risk reduction of major cardiovascular (CV) events and chronic kidney disease progression. With their increased utility in diabetes, obesity, CV health and renal protection, the use of GLP-1RAs has increased. However, with this increased use, there have also been increased reports of associated kidney adverse events, including case reports of acute interstitial nephritis (AIN) associated with GLP-1RA use. We report the data from the Food and Drug Administration adverse event reporting system (FAERS) in relation to GLP-1RA use and adverse kidney events, with acute kidney injury being the most common. In addition, we report two cases of semaglutide-associated biopsy-proven AIN and one with associated podocytopathy. To our knowledge, this is the first case of biopsy-proven AIN with podocytopathy associated with semaglutide use. Both patients experienced complete remission shortly after discontinuing semaglutide and undergoing immunosuppressive therapy. Further analysis of the FAERS database revealed 17 cases of proteinuria and 1 case of glomerulonephritis associated with semaglutide in the FAERS database, however no further information was available. While further research is needed to establish causality, this case series adds to the growing body of literature that semaglutide is associated with AIN and adds a new association, semaglutide with AIN and podocytopathies. While the overall clinical and mortality benefits of GLP-1RAs may outweigh the rarer risks, prescribers need to be aware of these associations, particularly as the use of GLP-1RAs continues to expand.