Amyloid Mimicking Assemblies Formed by Glutamine, Glutamic Acid, and Aspartic Acid.

The aggregation of amino acids into amyloid-like structures is a critical phenomenon for understanding the pathophysiology of various diseases, including inborn errors of metabolism (IEMs) associated with amino acid imbalances. Previous studies have primarily focused on self-assembly of aromatic amino acids, leading to a limited understanding of nonaromatic, polar amino acids in this context. To bridge this gap, our study investigates the self-assembly and aggregation behavior of specific nonaromatic charged and uncharged polar amino acids l-glutamine (Gln), l-aspartic acid (Asp), and l-glutamic acid (Glu), which have not been reported widely in the context of amyloid aggregation. Upon aging these amino acids under controlled conditions, we observed the formation of uniform, distinct aggregates, with Gln forming fibrillar gel-like structures and Glu exhibiting fibrous globular morphologies. Computational simulations validated these findings, identifying Gln as the most potent in forming stable aggregates, followed by Glu and Asp. These simulations elucidated the driving forces behind the distinct morphologies and stabilities of the aggregates. Thioflavin T assays were employed to confirm the amyloid-like nature of these aggregates, suggesting their potential cytotoxic impact. To assess toxicity, we performed in vitro studies on neural cell lines and in vivo experiments in Caenorhabditis elegans (C. elegans), which demonstrated measurable cytotoxic effects, corroborated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and heat shock survival assays. Importantly, this study fills a critical gap in our understanding on the role of nonaromatic amino acids in amyloidogenesis and its implications for IEMs. Our findings provide a foundation for future investigations into the mechanisms of diseases associated with amino acid accumulation and offer potential avenues for the development of targeted therapeutic strategies.

Amyloidogenic Propensity of Metabolites in the Uric Acid Pathway and Urea Cycle Critically Impacts the Etiology of Metabolic Disorders.

Novel insights into the etiology of metabolic disorders have recently been uncovered through the study of metabolite amyloids. In particular, inborn errors of metabolism (IEMs), including gout, Lesch-Nyhan syndrome (LNS), xanthinuria, citrullinemia, and hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, are attributed to the dysfunction of the urea cycle and uric acid pathway. In this study, we endeavored to understand and mechanistically characterize the aggregative property exhibited by the principal metabolites of the urea cycle and uric acid pathway, specifically hypoxanthine, xanthine, citrulline, and ornithine. Employing scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM), we studied the aggregation profiles of the metabolites. Insights obtained through molecular dynamics (MD) simulation underscore the vital roles of π-π stacking and hydrogen bonding interactions in the self-assembly process, and thioflavin T (ThT) assays further corroborate the amyloid nature of these metabolites. The in vitro MTT assay revealed the cytotoxic trait of these assemblies, a finding that was substantiated by in vivo assays employing the Caenorhabditis elegans (C. elegans) model, which revealed that the toxic effects were more pronounced and dose-specific in the case of metabolites that had aged via longer preincubation. We hence report a compelling phenomenon wherein these metabolites not only aggregate but transform into a soft, ordered assembly over time, eventually crystallizing upon extended incubation, leading to pathological implications. Our study suggests that the amyloidogenic nature of the involved metabolites could be a common etiological link in IEMs, potentially providing a unified perspective to study their pathophysiology, thus offering exciting insights into the development of targeted interventions for these metabolic disorders.

Use of flow diverter stent for treatment of a cervical carotid artery dissection and pseudoaneurysm causing Horner's syndrome.

A 28-year-old man in 2004 was identified with a spontaneous pseudoaneurysm and distal left cervical internal carotid artery (ICA) dissection. The patient was followed conservatively for 12 years with cross-sectional imaging. The patient was initially diagnosed with an acute left ICA dissection, with significant luminal narrowing. Follow-up imaging revealed the dissection was not completely healed, and a small pseudoaneurysm, about 4 mm in size, was formed in the distal left cervical ICA. During the 12-year observation period, the patient's pseudoaneurysm expanded from 4.0 mm to 9.0 mm, and the patient presented with ptosis, anisocoria and myosis. Flow diverter embolisation resulted in a radiographic cure of the pseudoaneurysm and resolution of Horner's syndrome.

Growing home dialysis: The Ontario Renal Network Home Dialysis Initiative 2012-2019.

The Ontario Renal Network (ORN), a provincial government agency in Ontario, Canada, launched an initiative in 2012 to increase home dialysis use province-wide. The initiative included a new modality-based funding formula, a standard mandatory informatics system, targets for prevalent home dialysis rates, the development of a 'network' of renal programmes with commitment to home dialysis and a culture of accountability with frequent meetings between ORN and each renal programme leadership to review their results. It also included funding of home dialysis coordinators, encouragement and funding of assisted peritoneal dialysis (PD), and support for catheter insertion and urgent start PD. Between 2012 and 2017, home dialysis use rose from 21.9% to 26.5% and then between 2017 and 2019 stabilised at 26% to 26.5%. Over 7 years, the absolute number of people on home dialysis increased 40% from 2222 to 3105, while the number on facility haemodialysis grew 11% from 7935 to 8767. PD prevalence rose from 16.6% to 20.9%, a relative increase of 25%. The initiative showed that a sustained multifaceted approach can increase home dialysis utilisation.