Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. While the exact causes of ALS are still unclear, the discovery that familial cases of ALS are related to mutations in the Cu/Zn superoxide dismutase (SOD1), a key antioxidant enzyme protecting cells from the deleterious effects of superoxide radicals, suggested that alterations in SOD1 functionality and/or aberrant SOD1 aggregation strongly contribute to ALS pathogenesis. A new scenario was opened in which, thanks to the generation of SOD1 related models, different mechanisms crucial for ALS progression were identified. These include excitotoxicity, oxidative stress, mitochondrial dysfunctions, and non-cell autonomous toxicity, also implicating altered Ca²⁺ metabolism. While most of the literature considers motor neurons as primary target of SOD1-mediated effects, here we mainly discuss the effects of SOD1 mutations in non-neuronal cells, such as glial and skeletal muscle cells, in ALS. Attention is given to the altered redox balance and Ca²⁺ homeostasis, two processes that are strictly related with each other. We also provide original data obtained in primary myocytes derived from hSOD1(G93A) transgenic mice, showing perturbed expression of Ca²⁺ transporters that may be responsible for altered mitochondrial Ca²⁺ fluxes. ALS-related SOD1 mutants are also responsible for early alterations of fundamental biological processes in skeletal myocytes that may impinge on skeletal muscle functions and the cross-talk between muscle cells and motor neurons during disease progression.

Background and Purpose: Incidence of ischemic stroke differs between men and women, with substantially higher rates in men. The underlying mechanism of this difference remains poorly understood but may be because of differences in carotid atherosclerosis. Using an in-depth imaging-based approach, we investigated differences between carotid plaque composition and morphology in male and female patients with stroke, taking into account differences in total plaque burden. Additionally, we investigated all possible within-artery combinations of plaque characteristics to explore differences between various plaque phenotypes. Methods: We included 156 men and 68 women from the PARISK (Plaque At Risk) study, a prospective cohort study of patients with recent ischemic cerebrovascular symptoms and <70% ipsilateral carotid stenosis. Plaque characteristics (intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], calcifications, thin-or-ruptured fibrous cap, ulcerations, total plaque volume) were assessed with magnetic resonance imaging and multidetector-row computed tomography angiography. We used multivariable logistic and linear regression analyses to assess sex differences in plaque characteristics. Results: We found significant difference in total plaque volume between men and women (β=22.9 mm ³ [95% CI, 15.4–30.5]; mean volume in men 1399±425 mm ³ , in women 1011±242 mm ³ ). Additionally, men were more likely to have IPH (odds ratio [OR]=2.8 [95% CI, 1.3–6.3]; IPH proportion in men 49%, in women 16%) and LRNC (OR=2.4 [95% CI, 1.2–4.7]; LRNC proportion in men 73%, in women 41%) even after adjustment for total plaque volume. We found no sex-specific differences in plaque volume-corrected volumes of IPH, LRNC, and calcifications. In terms of coexistence of plaque characteristics, we found that men had more often a plaque with coexistence of calcifications, LRNC, and IPH (OR=2.7 [95% CI, 1.2–7.0]), with coexistence of thin-or-ruptured fibrous cap/ulcerations, LRNC, and IPH (OR=2.4 [95% CI, 1.1–5.9]), and with coexistence of all plaque characteristics (OR=3.0 [95% CI, 1.2–8.6]). Conclusions: In symptomatic patients with mild-to-moderate carotid stenosis, men are more likely to have a high-risk carotid plaque with IPH and LRNC than women, regardless of total plaque burden. Men also have more often a plaque with multiple vulnerable plaque components, which could comprise an even higher stroke risk. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01208025.

BACKGROUND: In symptomatic carotid stenosis, treatment decisions are currently primarily based on stenosis degree. We developed a clinical prediction model (Individualized Magnetic Resonance Imaging–Based Stroke Prediction Score Using Plaque Vulnerability for Patients With Symptomatic Carotid Artery Disease [IMPROVE]) incorporating the strong predictor, intraplaque hemorrhage on magnetic resonance imaging, stenosis degree, and risk factors to identify patients with high stroke risk. METHODS: IMPROVE was developed on data from 5 cohorts of 760 patients with symptomatic carotid disease on optimal medical treatment. Inclusion criteria included a recent transient ischemic attack/stroke (<6 months), magnetic resonance imaging–based information on intraplaque hemorrhage, no atrial fibrillation, and no immediate revascularization. IMPROVE was based on Cox regression using 5 expert-selected predictors and converted to 3-year ipsilateral ischemic stroke risk after internal validation. IMPROVE-based stratification was compared with care-as-usual using illustrative cutoffs: high risk was defined in IMPROVE as ≥ median 3-year IMPROVE risk, whereas in care-as-usual, it was ≥50% carotid stenosis. RESULTS: Sixty-five ipsilateral ischemic strokes occurred during a median follow-up of 1.2 years (interquartile range, 0.5–4.1). The IMPROVE model includes 5 predictors (hazard ratio [95% CI]): degree of stenosis (<50%: reference, 50%–69%: 4.54 [2.46–8.38], 70%–99% stenosis: 7.42 [3.45–15.95]), presence of intraplaque hemorrhage (5.61 [2.92–10.77]), classification of last event (ocular: reference, cerebral: 3.72 [1.11–12.52]), male sex (1.26 [0.64–2.48]), and age (1.14 [0.84–1.55] per 10-year increase). Internal validation revealed good accuracy (C statistic, 0.82 [95% CI, 0.77–0.87]) and no evidence of miscalibration (calibration slope, 0.93). Sensitivity for the illustrative IMPROVE cutoff was 92.6% (90.7–94.5) versus 80.6% (77.8–83.4) for care-as-usual. Specificity was 54.2% (50.7–57.8) for IMPROVE versus 52.9% (49.3–56.4) for care-as-usual. Patients stratified by IMPROVE as high risk had a higher incidence of ipsilateral ischemic stroke (24.0%) compared with the care-as-usual classification (20.7%). Among patients classified as lower-risk by IMPROVE and care-as-usual, 2.1% and 5.3%, respectively, experienced an ipsilateral ischemic stroke during follow-up. CONCLUSIONS: Using the presence of intraplaque hemorrhage on magnetic resonance imaging and 4 conventional parameters, the IMPROVE model provides accurate individual stroke risk estimates, which may facilitate stratification for revascularization after external validation.

Background/Objectives: Hematological toxicities (i.e., neutropenia, thrombocytopenia, and anemia), are common chemotherapy complications and may be exacerbated by renal or hepatic impairment due to altered drug exposure. This study assessed the association between renal and hepatic impairment and hematologic toxicities during chemotherapy in routine clinical practice. Methods: A single-center retrospective cohort study using the Utrecht Patient Oriented Database (UPOD) identified all chemotherapy administrations at the University Medical Centre Utrecht between 2011 and 2024. Regimens administered in ≥10 patients and ≥5 renally (GFR < 60 mL/min) or hepatically (bilirubin or AST > 1× ULN) impaired patients were included in descriptive analyses. Cox proportional hazards models estimated associations between organ impairment and grade ≥ 3 hematologic toxicities for regimens with ≥10 events per toxicity endpoint. Results: Overall, 4489 patients were included in renal analyses and 6218 in hepatic analyses, with smaller endpoint-specific subgroups for survival analyses. Renal impairment was associated with grade ≥ 3 neutropenia (HR: 1.43 [95% CI: 1.18–1.73]), thrombocytopenia (HR: 1.46 [95% CI: 1.15–1.86], and anemia (HR: 1.66 [1.27–2.16]). Hepatic impairment was similarly associated with neutropenia (HR: 1.25 [95% CI: 1.11–1.40]), thrombocytopenia (HR: 1.33 [95% CI: 1.13–1.57]), and anemia (HR: 1.62 [95% CI: 1.34–1.95]). Cyclophosphamide (pro-drug) regimens showed higher toxicity risk in renally impaired patients and reduced risk in hepatically impaired patients. Etoposide, melphalan and methotrexate were associated with increased toxicity in hepatically impaired patients. Conclusions: Renal and hepatic impairment significantly increase chemotherapy-induced hematologic toxicity. Several high-risk chemotherapy regimens were identified; however, larger multi-center datasets are needed to refine dosing guidance based on renal and hepatic function.