Silvia Rosado

We investigated the role of Lgi3-4 proteins in cardiac electrophysiology, with a specific focus on I_Kur, and their potential contribution to the pathophysiology of atrial fibrillation (AF). In human atrial tissue and heterologous cells, Lgi3 and Lgi4 interacted with K_V1.5 channels. In a mouse model of AAV9-mediated cardiac-specific Lgi4 expression, sinoatrial and atrioventricular conduction were impaired, resulting in a prolonged QRS interval. Action potential repolarisation was delayed in atrial and ventricular cardiomyocytes from Lgi4 mice. In HEK293 cells, Lgi3-4 impaired K_V1.5/K_Vβ association, partially reversing the K_Vβ-induced inactivation and reducing I_Kur amplitude. These results correlated with the reduced K_V1.5 membrane expression and I_Kur density observed in Lgi4 cardiomyocytes and HEK293 cells. Notably, Lgi4 protein expression was lower in atrial tissue from patients with AF than in sinus rhythm patients. The reduced Lgi4 protein levels in AF were also associated with an altered colocalisation with K_V1.5 channels, suggesting potential disruption in their functional interactions. We conclude that Lgi3-4 proteins are new components of the cardiac K_V1.5 channelosome. They modulate I_Kur by interfering with the K_V1.5-K_Vβ interaction. Significantly, Lgi4 is dysregulated differently in paroxysmal vs. permanent AF. The results identify Lgi3-4 proteins as novel regulators of the K_V1.5 channelosome, opening new pathways for investigating the role of I_Kur dysfunction in the mechanism of atrial fibrillation.

Background: Differentiating between nonsuicidal self‐injury (NSSI) and suicide attempts (SA) in adolescents is crucial due to distinct underlying motivations, treatment needs, and potential outcomes associated with each behavior. This study explores biomarkers, specifically β ‐endorphin and endocannabinoids [anandamide (AEA), 2‐arachidonoylglycerol (2‐AG), N‐palmitoylethanolamide (PEA), and oleoylethanolamide (OEA)], in adolescents admitted for NSSI and/or SA. Objectives: We aimed to explore potential differences in different variables among adolescents hospitalized for NSSI, SA, or both. Method: This pilot study enrolled 68 adolescents admitted for NSSI and/or SA at Puerta de Hierro University Hospital. Excluding those with endocrine issues, participants underwent clinical assessments, blood collection, and serum analysis for ACTH, cortisol, and β ‐endorphin, with endocannabinoids measured via LC–MS. Clinical tools, such as the MINI Kid and CTQ and statistical analyses via SPSS and Stata aimed to elucidate behavioral and biological differences between NSSI and SA groups. Results: No sociodemographic factor differentiated the groups. Gestational diabetes and depression during pregnancy were more frequent in the NSSI group ( p = 0.047 and p = 0.003, respectively). Abnormal presentation at birth was overrepresented in the SA group ( p = 0.001). Familial antecedents of either suicide or SB were more frequently reported in the NSSI + SA group ( p = 0.027 and p = 0.035, respectively). Blood PEA and β ‐endorphin were significantly elevated in the SA group ( p < 0.006 and 0.014, respectively). Discussion: This study identified shared risk factors across NSSI and SA, with distinct variables for each group, including β ‐endorphin and PEA biomarker elevations linked to SA.

We aimed to explore the role of interleukin (IL)‐6, interferon‐gamma (IFNγ), IL‐10, and tumor necrosis factor (TNF) as predictors of systemic lupus erythematosus (SLE) clinical and serological activity, and their correlation with the treatment received. We performed a retrospective analysis of 77 patients with SLE according to the 2012 Systemic Lupus International Collaborative Clinics (SLICC) criteria. The outcomes were serological activity (SA), active disease (AD), complete remission (CR), the low‐disease activity state (LDAS), and immunosuppressive treatment. SA was present in 17.1%, AD in 17.3%, CR in 13%, and LDAS in 64.9% of patients. IL‐6 values were higher in patients in SA, in AD, in those receiving steroids alone, and in patients without CR or LDAS (p < 0.05). IFNγ was associated with anti‐double stranded DNA (dsDNA) antibodies positivity and immunosuppression, whereas IL‐10 values were higher in patients with CR (p < 0.05). The IL6‐IFN product was able to predict anti‐double stranded DNA (anti‐dsDNA) antibodies positivity (area under the receiver operating characteristic curve [AUC‐ROC] = 0.705, 95% confidence interval [CI] 0.563–0.847), SA (AUC‐ROC = 0.720, 95% CI 0.542–0.899), AD (AUC‐ROC = 0.701, 95% CI 0.520–0.882), steroid treatment (AUC‐ROC = 0.751, 95% CI 0.622–0.879), and the absence of LDAS (AUC‐ROC = 0.700, 95% CI 0.558–0.834). The IL6‐IFN/IL10 ratio predicted AD (AUC‐ROC = 0.742, 955 CI 0.540–0.944), steroid treatment (AUC‐ROC = 0.721, 95% CI 0.572–0.870), and the absence of LDAS (AUC‐ROC = 0.694, 95% CI 0.536–0.853). In conclusion, IL‐6, IL‐10, and IFNγ might help to assess SLE serological and clinical activity. Their combination in the IL‐6‐IFN product and the IL‐6xIFN to IL‐10 ratio results in novel tools to determine and predict SA, AD, and LDAS. Prompt detection of SLE activity might allow a rapid intervention to avoid established or chronic damage.

Introduction: Cytokine storm control is the main target for improving severe COVID-19 by using immunosuppressive treatment. Effective renal replacement therapy (RRT) could give us an advantage removing cytokines in patients with RRT requirements superimposed on COVID-19. Methods: This is a prospective observational study in COVID-19 patients who required hemodialysis (HD). Patients were assigned to online hemodiafiltration (OL-HDF) and expanded HD (HDx) according to Brescia group recommendations. We measured several cytokines, β2 microglobulin and albumin levels pre/post-dialysis and on 1st–2nd week. We compared levels among both techniques and control group (HD without COVID-19). Results: We included 26 patients: 18 with COVID-19 on RRT (5 of them had acute kidney injury [AKI]) and 8 controls. We confirm higher cytokine levels in COVID-19 patients than controls and even higher in patients with AKI than in those with chronic kidney disease. Most cytokines raised during HD session, except IL-10 and TNFα. IL-10 was eliminated by any dialysis technique, while clearance of TNFα was higher in the HDx group. HDx achieved a deeper normalization of cytokines and β2 microglobulin reduction. Mortality was higher in the OL-HDF group than the HDx group. Discussion: Not all cytokines behave equally along HD session. The following characteristics should be taken into account, such as intrinsic kinetic profile during a HD session. HDx seems to get better performance, probably due to the combination of different factors; however, we did not reach statistical significance due to the small sample size, dropout, and reduction of AKI incidence during the 2nd pandemic wave. Conclusion: HDx appears to provide better clearance for TNFα and β2 microglobulin during HD session and associates lower mortality. We propose the HDx technique for COVID-19 patients with RRT requirements since it seems to be safe and more effective than OL-HDF. Further studies are still needed, but we hope that our preliminary data may help us in future pandemic waves of SARS-CoV-2 or other viruses still to come.

Background: the admission and death causes of SLE patients might have changed over the last years. Methods: Analysis of the Spanish National Hospital Discharge database. All individuals admitted with SLE, according to ICD-9, were selected. The following five admission categories were considered: SLE, cardiovascular disease (CVD), neoplasm, infection, and venous-thromboembolic disease (VTED), along four periods of time (1997–2000, 2001–2005, 2006–2010, and 2011–2015). Results: The admissions (99,859) from 43.432 patients with SLE were included. The absolute number of admissions increased from 15,807 in 1997–2000 to 31,977 in 2011–2015. SLE decreased as a cause of admission (from 47.1% to 20.8%, p < 0.001), while other categories increased over the time, as follows: 5% to 8.6% for CVD, 8.2% to 13% for infection, and 1.4% to 5.5% for neoplasm (p < 0.001 for all). The admission mortality rate rose from 2.22% to 3.06% (p < 0.001) and the causes of death evolved in parallel with the admission categories. A significant trend to older age was observed over time in the overall population and deceased patients (p < 0.001). Conclusions: Better control of SLE over the past two decades has led to a decrease in early admissions, and disease chronification. As a counterpart, CVD, infections, and neoplasm have become the main causes of admissions and mortality.

An increased risk of cardiovascular morbidity has been reported in lithiasic patients. In this context, endothelial dysfunction (ED), an earlier status of atherogenesis, has been identified in hyperoxaluria rat models of urolithiasis. Objective: The purpose of this study was to determine the endothelial vascular function in patients with urolithiasis in relation to systemic inflammatory, oxidative stress, and vascular function serum markers. Methods: A cross-sectional study was performed between 27 urolithiasic patients, matched for age and sex, with 27 healthy patients. Endothelial function was assessed by measuring flow-mediated dilation (Celermajer method). Fasting blood was collected to determine metabolic parameters (glucose and lipid profile), along with serum CRP, IL-6, MDA, ADMA, and VCAM-1. Results: Both the control and urolithiasis groups were homogenous in anthropometric, exploration, and general laboratory measures. Flow-mediated dilation (%FMD) was 11.85% (SE: 2.78) lower in the lithiasis group (p < 0.001). No significant differences were achieved between groups when CRP, IL-6, MDA, ADMA, and VCAM-1 were compared, although slightly higher values of CRP, ADMA, and VCAM-1 were detected in the lithiasic group. A correlation was not reached in any of the serum markers when they were related to flow-mediated values, although a slight negative correlation trend was observed in MDA, VCAM-1, and IL-6 values. Conclusions: Endothelial dysfunction constitutes an important disorder related to urolithiasis patients. It must be considered as an early feature responsible for future cardiovascular events. Our study did not find a significant association between inflammatory, oxidative stress, endothelial serum markers, and flow-mediated dilation.