Over the course of most common neurodegenerative diseases the amygdala accumulates pathologically misfolded proteins. Misfolding of 1 protein in aged brains often is accompanied by the misfolding of other proteins, suggesting synergistic mechanisms. The multiplicity of pathogenic processes in human amygdalae has potentially important implications for the pathogenesis of Alzheimer disease, Lewy body diseases, chronic traumatic encephalopathy, primary age-related tauopathy, and hippocampal sclerosis, and for the biomarkers used to diagnose those diseases. Converging data indicate that the amygdala may represent a preferential locus for a pivotal transition from a relatively benign clinical condition to a more aggressive disease wherein multiple protein species are misfolded. Thus, understanding of amygdalar pathobiology may yield insights relevant to diagnoses and therapies; it is, however, a complex and imperfectly defined brain region. Here, we review aspects of amygdalar anatomy, connectivity, vasculature, and pathologic involvement in neurodegenerative diseases with supporting data from the University of Kentucky Alzheimer's Disease Center autopsy cohort. Immunohistochemical staining of amygdalae for Aβ, Tau, α-synuclein, and TDP-43 highlight the often-coexisting pathologies. We suggest that the amygdala may represent an "incubator" for misfolded proteins and that it is possible that misfolded amygdalar protein species are yet to be discovered.
TDP-43 proteinopathy is very common among the elderly (affecting at least 25% in individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n=136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p=0.051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p=0.025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in TDP-43 proteinopathy.
Background There are well‐documented racial and ethnic disparities in treatment and perioperative outcomes for patients with adolescent idiopathic scoliosis. Aims We hypothesize that the implementation of a coordinated care pathway for pediatric patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis may be associated with a reduction in racial and ethnic disparities in perioperative outcomes. Methods This is a retrospective pre‐ and post‐test cohort study of patients who underwent posterior spinal fusion for adolescent idiopathic scoliosis at our institution between July 1, 2013 and August 5, 2019. We implemented a coordinated care pathway in March 2015. Patient demographics included age, race, ethnicity, weight, gender, insurance status, ASA class, time between the date surgery was ordered and the date surgery occurred, degree of scoliosis, and the number of spinal levels fused. The primary outcome was length of stay. The secondary outcomes included transfusion rates, pain scores, and postoperative complications. Multivariable regression models compared outcome medians across race/ethnicity. Disparities were defined as the difference in adjusted outcomes by race/ethnicity. Results Four hundred twenty‐four patients underwent posterior spinal fusion for adolescent idiopathic scoliosis at our institution (116 prepathway and 308 postpathway). The median length of stay of Black patients was 1.0 day (95% CI: 0.4, 1.5; p = .006) longer than White patients prepathway. Prepathway patients who self‐identified as Other had a 1.2 (95% CI: 0.5, 1.9; p = .004) higher median average pain score on postoperative day 1 compared with White patients. On postoperative day 2, patients who identified as Other had 2.0 (95% CI: 0.8, 3.2; p = .005) higher pain score compared with White patients prepathway. Postpathway, there were no significant differences in outcomes by race/ethnicity. Conclusions Our study supports the hypothesis that use of a coordinated care pathway is associated with a reduction in racial and ethnic disparities in length of stay and pain scores in pediatric patients undergoing posterior spinal fusion.
Objectives: To determine whether primary arthrodesis (PA) or open reduction and internal fixation (ORIF) results in better functional outcomes through patient-reported outcome measures (PROMs). Reoperation rates and surgical characteristics among the 2 groups are evaluated as well. Design: A retrospective cohort study. Setting: Level 1 trauma center. Patients: Eighty-one patients treated using PA or ORIF for Lisfranc injuries between January 2010 and January 2019. Main Outcome Measurements: PROMs were collected using the validated Foot and Ankle Ability Measure questionnaire. Follow-up ranged from 1 to 10 years posttreatment. Results: Two hundred patients underwent ORIF, and 72 patients underwent PA. Eighty-one of 272 patients responded to the questionnaire. The Foot and Ankle Ability Measure revealed activities of daily living subscores for PA and ORIF of 69.78 ± 18.61 and 73.53 ± 25.60, respectively (P = 0.48). The Sports subscores for PA (45.81 ± 24.65) and ORIF (56.54 ± 31.13) were not significantly different (P = 0.11). Perceived levels of activities of daily living (P = 0.32) and Sports (P = 0.81) function, compared with preinjury levels, were also not significantly different between the 2 groups. Rates of reoperation were nearly identical for PA (28.1%) and ORIF (30.6%) (P = 1.00). Conclusion: Our results suggest that neither PA nor ORIF is superior regarding functional outcomes or rates of reoperation in the surgical treatment of Lisfranc injuries when appropriately triaged by the treating surgeon. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
For investigations into fate specification and cell rearrangements in live images of preimplantation embryos, automated and accurate 3D instance segmentation of nuclei is invaluable; however, the performance of segmentation methods is limited by the images' low signal-to-noise ratio and high voxel anisotropy and the nuclei's dense packing and variable shapes. Supervised machine learning approaches have the potential to radically improve segmentation accuracy but are hampered by a lack of fully annotated 3D data. In this work, we first establish a novel mouse line expressing near-infrared nuclear reporter H2B-miRFP720. H2B-miRFP720 is the longest wavelength nuclear reporter in mice and can be imaged simultaneously with other reporters with minimal overlap. We then generate a dataset, which we call BlastoSPIM, of 3D microscopy images of H2B-miRFP720-expressing embryos with ground truth for nuclear instance segmentation. Using BlastoSPIM, we benchmark the performance of five convolutional neural networks and identify Stardist-3D as the most accurate instance segmentation method across preimplantation development. Stardist-3D, trained on BlastoSPIM, performs robustly up to the end of preimplantation development (> 100 nuclei) and enables studies of fate patterning in the late blastocyst. We, then, demonstrate BlastoSPIM's usefulness as pre-train data for related problems. BlastoSPIM and its corresponding Stardist-3D models are available at: blastospim.flatironinstitute.org.
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