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Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of Parkinson's disease (PD). The LRRK2 PD-associated mutations LRRK2G2019S and LRRK2R1441C, located in the kinase domain and in the ROC-COR domain, respectively, have been demonstrated to impair mitochondrial function. Here, we sought to further our understanding of mitochondrial health and mitophagy by integrating data from LRRK2R1441C rat primary cortical and human induced pluripotent stem cell-derived dopamine (iPSC-DA) neuronal cultures as models of PD. We found that LRRK2R1441C neurons exhibit decreased mitochondrial membrane potential, impaired mitochondrial function and decreased basal mitophagy levels. Mitochondrial morphology was altered in LRRK2R1441C iPSC-DA but not in cortical neuronal cultures or aged striatal tissue, indicating a cell-type-specific phenotype. Additionally, LRRK2R1441C but not LRRK2G2019S neurons demonstrated decreased levels of the mitophagy marker pS65Ub in response to mitochondrial damage, which could disrupt degradation of damaged mitochondria. This impaired mitophagy activation and mitochondrial function were not corrected by the LRRK2 inhibitor MLi-2 in LRRK2R1441C iPSC-DA neuronal cultures. Furthermore, we demonstrate LRRK2 interaction with MIRO1, a protein necessary to stabilize and to anchor mitochondria for transport, occurs at mitochondria, in a genotype-independent manner. Despite this, we found that degradation of MIRO1 was impaired in LRRK2R1441C cultures upon induced mitochondrial damage, suggesting a divergent mechanism from the LRRK2G2019S mutation., (© The Author(s) 2023. Published by Oxford University Press.)

Copy number variant (CNV) syndromes are often associated with both neurocognitive deficits (NCDs) and congenital heart defects (CHDs). Children and adults with cardiac developmental defects likely to have NCDs leading to increased risk of hospitalisation and reduced level of independence. To date, the association between these two phenotypes have not been explored in relation to CNV syndromes. In order to address this question, we systematically reviewed the prevalence of CHDs in a range of CNV syndromes associated with NCDs. A meta-analysis showed a relationship with the size of CNV and its association with both NCDs and CHDs, and also inheritance pattern. To our knowledge, this is the first review to establish association between NCD and CHDs in CNV patients, specifically in relation to the severity of NCD. Importantly, we also found specific types of CHDs were associated with severe neurocognitive deficits. Finally, we discuss the implications of these results for patients in the clinical setting which warrants further exploration of this association in order to lead an improvement in the quality of patient's life., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Passive motions at the subtalar joint, talonavicular joint and calcaneocuboid joint were measured in eight ankle specimens, using an ultrasonic motion analysis system. Arthrodeses of the three joints were performed in all feasible combinations and the resulting motion change at the unfused joints was determined. Motion at the subtalar joint was not significantly affected by fusion of the calcaneocuboid joint, reduced to one quarter by fusion of the talonavicular and calcaneocuboid joints (double arthrodesis) and almost completely eliminated with all other fusions. Motion at the talonavicular joint was not significantly affected by calcaneocuboid fusion and reduced to approximately one third with the subtalar and the double arthrodesis. Motion at the calcaneocuboid joint was not significantly reduced by subtalar fusion but almost completely eliminated in all fusions involving the talonavicular joint. It is concluded that the talonavicular joint is the key articulation for hindfoot motion. Double arthrodesis preserved significant motion at the subtalar joint. Fusion of the calcaneocuboid joint had no significant influence on remaining hindfoot motion.

In this article, a protocol for the evaluation of new materials for small joint prostheses is introduced. The testing methods employed in the protocol were developed by reviewing reported clinical failure modes and conditions found in vivo. The methods developed quantitatively evaluates the fatigue, fatigue crack propagation, and wear resistance properties of materials. For this study, a silicone elastomer similar to Dow Corning Silastic HP100, a radiation stable polypropylene, and a copolymer of polypropylene and ethylene propylene-diene monomer (EPDM) are evaluated. None of the materials tested demonstrated the ideal properties that are sought in a self-hinging joint prostheses. The silicone elastomer had excellent wear properties; however, cracks quickly propagated, causing catastrophic failure when fatigued. Conversely, the copolymer showed excellent fatigue crack propagation resistance and less than favorable wear properties. The polypropylene did not perform well in any evaluation.