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.

Comparison of Questionnaire and Performance-Based Physical Frailty Scales to Predict Survival and Health-Related Quality of Life in Patients With Heart Failure.

Background Frailty is prevalent in older adults with heart failure and is associated with poor outcomes; however, there remains uncertainty on how to measure frailty in clinical practice. Methods and Results A multicentric prospective cohort study was assembled at 4 heart failure clinics to compare the prognostic value of 3 physical frailty scales in ambulatory patients with heart failure. Outcomes were all-cause death or hospitalization and health-related quality of life using the 36-Item Short Form survey questionnaire (SF-36) at 3 months. Multivariable regression was adjusted for age, sex, Meta-Analysis Global Group in Chronic Heart Failure score, and baseline SF-36 score. The cohort included 215 patients (mean age 77.6 years). All 3 frailty scales were independently associated with death or hospitalization at 3 months; the adjusted odds ratios standardized per 1 SD worsening of the Short Physical Performance Battery; Fried, and strength, assistance with walking, rising from a chair, climbing stairs, and falls scales were 1.67 (95% CI, 1.09-2.55), 1.60 (95% CI, 1.04-2.46), and 1.55 (95% CI, 1.03-2.35), respectively, with C statistics of 0.77 to 0.78. All 3 frailty scales were independently associated with worsening SF-36 scores, especially the Short Physical Performance Battery, for which 1 SD worsening of frailty translated to a decrement of -5.86 (-8.55 to -3.17) and -5.51 (-7.82 to -3.21) points in the Physical Component Score and Mental Component Score. Conclusions All 3 physical frailty scales were associated with death, hospitalization, and reduced health-related quality of life in ambulatory patients with heart failure. Questionnaire or performance-based physical frailty scales can be used to offer prognostic value and a therapeutic target in this vulnerable population. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03887351.

Sarcopenia in cardiac surgery: Dual X-ray absorptiometry study from the McGill frailty registry.

BACKGROUND: To determine the prevalence and prognostic value of sarcopenia measured by dual x-ray absorptiometry (DXA) and physical performance tests in patients undergoing coronary artery bypass surgery or heart valve procedures. METHODS: Adults undergoing cardiac surgery were prospectively enrolled and completed a questionnaire, physical performance battery, and a DXA scan (GE Lunar) to measure appendicular muscle mass indexed to height2 (AMMI). Patients were categorized as sarcopenic based on European Working Group 2 guidelines if they had low AMMI defined as <7 kg/m2 for men or <5.5 kg/m2 for women, and low muscle strength defined as 5 chair rise time ≥15 seconds. Cox proportional hazards regression was used to test the association between sarcopenia and all-cause mortality over a median follow-up of 4.3 years. RESULTS: The cohort consisted of 141 patients with a mean age of 69.7 ± 10.0 years and 21% females. The prevalence rates of low AMMI, slow chair rise time, and sarcopenia (low AMMI and slow chair rise time) were 24%, 57%, 13%, respectively. The 4-year survival rate was 79% in the non-sarcopenic group as compared to 56% in the sarcopenic group (Log-rank P = 0.01). In the multivariable model, each standard deviation of decreasing AMMI and increasing chair rise time was associated with a hazard ratio for all-cause mortality of 1.84 (95% CI 1.18, 2.86) and 1.79 (95% CI 1.26, 2.54), respectively. CONCLUSION: Lower-extremity muscle strength and DXA-based muscle mass are objective indicators of sarcopenia that are independently predictive of all-cause mortality in older cardiac surgery patients.

Fall-related deaths among older adults in British Columbia: cause and effect of policy change.

BACKGROUND: The British Columbia Coroners Service implemented a policy in 2010 advising the reclassification of underlying causes of deaths due to falls from 'natural' to 'accidental'. This study investigates whether observed data trends reflect this change in practice, are artefacts of inconsistent reporting, or indicate a true increase in fall-related deaths. METHODS: Mortality data were analysed from 2004 to 2017 for cases with International Statistical Classification of Diseases and Related Health Problems, 10th Revision fall codes W00-W19, occurring among adults aged 60 years and older. RESULTS: From 2010 to 2012, accidental fall-related deaths increased among those aged 80 years and older, followed by an increase in natural deaths with fall as the contributing cause. CONCLUSIONS: Changes in reporting resulting from the 2010 policy change were observed; however, post-2012 data indicate a reversion to previous reporting practices.