Kv1.3 channels can modulate cell proliferation during phenotypic switch by an ion-flux independent mechanism

Producción CientíficaObjective: Phenotypic modulation of vascular smooth muscle cells has been associated with a decreased expression of all voltage-dependent potassium channel (Kv)1 channel encoding genes but Kcna3 (which encodes Kv1.3 channels). In fact, upregulation of Kv1.3 currents seems to be important to modulate proliferation of mice femoral vascular smooth muscle cells in culture. This study was designed to explore if these changes in Kv1 expression pattern constituted a landmark of phenotypic modulation across vascular beds and to investigate the mechanisms involved in the proproliferative function of Kv1.3 channels. Methods and Results: Changes in Kv1.3 and Kv1.5 channel expression were reproduced in mesenteric and aortic vascular smooth muscle cells, and their correlate with protein expression was electrophysiologicaly confirmed using selective blockers. Heterologous expression of Kv1.3 and Kv1.5 channels in HEK cells has opposite effects on the proliferation rate. The proproliferative effect of Kv1.3 channels was reproduced by “poreless” mutants but disappeared when voltagedependence of gating was suppressed. Conclusion: These findings suggest that the signaling cascade linking Kv1.3 functional expression to cell proliferation is activated by the voltage-dependent conformational change of the channels without needing ion conduction. Additionally, the conserved upregulation of Kv1.3 on phenotypic modulation in several vascular beds makes this channel a good target to control unwanted vascular remodeling.Instituto de Salud Carlos III (grant R006/009)Ministerio de Ciencia, Innovación y Universidades (grant BFU2010-15898)Junta de Castilla y León (grant VA094A11-2

Neuropathic post-COVID pain symptomatology is not associated with serological biomarkers at hospital admission and hospitalization treatment in COVID-19 survivors

OBJECTIVE: Evidence suggests that individuals who had survived to coronavirus disease, 2019 (COVID-19) could develop neuropathic post-COVID pain. This study investigated the association of serological biomarkers and treatments received during hospitalization with development of neuropathic-associated symptoms.METHODS: One hundred and eighty-three (n = 183) previously hospitalized COVID-19 survivors during the first wave of the pandemic were assessed in a face-to-face interview 9.4 months after hospitalization. Nineteen serological biomarkers, hospitalization data, and treatment during hospitalization were obtained from medical records. Neuropathic pain symptoms (Self-Report Leeds Assessment of Neuropathic Scale), sleep quality (Pittsburgh Sleep Quality Index), pain catastrophizing (Pain Catastrophizing Scale) and anxiety/depressive levels (Hospital Anxiety and Depression Scale) were assessed.RESULTS: The prevalence of post-COVID pain was 40.9% (n = 75). Fifteen (20%) patients reported neuropathic symptoms. Overall, no differences in hospitalization data and serological biomarkers were identified according to the presence or not of neuropathic-associated symptoms. Patients with post-COVID pain had the highest neutrophil count, and post hoc analysis revealed that patients with neuropathic post-COVID associated symptoms had lower neutrophil count (p = 0.04) compared with those without neuropathic pain, but differences were small and possible not clinically relevant. No differences in fatigue, dyspnea, brain fog, anxiety or depressive levels, poor sleep, or pain catastrophism between patients with and without neuropathic symptoms were found.CONCLUSION: It seems that neuropathic-like post-COVID pain symptoms are not associated with neither of assessed serological biomarkers at hospital admission nor hospitalization treatments received in this cohort of hospitalized COVID-19 survivors.</p

Implantación de una Clínica jurídica pro bono en los estudios de la Facultad de Derecho de la Universidad Complutense

Fac. de DerechoFALSEsubmitte

The impact of ABCDE bundle implementation on patient outcomes: a nationwide cohort study

Background: The ABCDE bundle is a set of evidence-based practices to systematically reduce the risks of sedation, delirium, and immobility in intensive care patients. Implementing the bundle improves clinical outcome. Aims and Objectives: To investigate the association between patient outcomes and compliance with bundle components ABC (analgosedation algorithms), D (delirium protocol), and E (early mobilization protocol). Design: A Spanish multicentre cohort study of adult patients receiving invasive mechanical ventilation (IMV) for ≥48 h until extubation. Methods: The primary outcome was pain level, cooperation to permit Medical Research Council Scale administration, patient days of delirium, and mobility. The secondary outcome was cumulative drug dosing by IMV days. Tertiary outcomes (ICU days, IMV days, bed rest days, ICU mortality, ICUAW) and independent variables (analgosedation, delirium, early mobilization protocols) were also studied. Results: Data were collected from 605 patients in 80 ICUs and 5214 patient days with IMV. Two-thirds of the ICUs studied applied no protocols. Pain was not assessed on 83.6% of patient days. Patient cooperation made scale administration feasible on 20.7% of days. Delirium and immobility were found on 4.2% and 69.9% of days, respectively. Patients had shorter stays in ICUs with bundle protocols and fewer days of IMV in ICUs with delirium and mobilization bundle components (P = 0.006 and P = 0.03, respectively). Analgosedation protocols were associated with more opioid dosing (P = 0.02), and delirium and early mobilization protocols with more propofol (P = 0.001), dexmedetomidine (P = 0.001), and lower benzodiazepine dosing (P = 0.008). Conclusions: The implementation rate of ABCDE bundle components was very low in our Spanish setting, but when implemented, patients had a shorter ICU stay, more analgesia dosing, and lighter sedation. Relevance to clinical practice: Applying some but not all the bundle components, there is increased analgesia and light sedation drug use, decreased benzodiazepines, and increased patient cooperation and mobility, resulting in a shorter ICU stay and fewer days of IMV

Neuropathic post-COVID pain symptomatology is not associated with serological biomarkers at hospital admission and hospitalization treatment in COVID-19 survivors

ObjectiveEvidence suggests that individuals who had survived to coronavirus disease, 2019 (COVID-19) could develop neuropathic post-COVID pain. This study investigated the association of serological biomarkers and treatments received during hospitalization with development of neuropathic-associated symptoms.MethodsOne hundred and eighty-three (n = 183) previously hospitalized COVID-19 survivors during the first wave of the pandemic were assessed in a face-to-face interview 9.4 months after hospitalization. Nineteen serological biomarkers, hospitalization data, and treatment during hospitalization were obtained from medical records. Neuropathic pain symptoms (Self-Report Leeds Assessment of Neuropathic Scale), sleep quality (Pittsburgh Sleep Quality Index), pain catastrophizing (Pain Catastrophizing Scale) and anxiety/depressive levels (Hospital Anxiety and Depression Scale) were assessed.ResultsThe prevalence of post-COVID pain was 40.9% (n = 75). Fifteen (20%) patients reported neuropathic symptoms. Overall, no differences in hospitalization data and serological biomarkers were identified according to the presence or not of neuropathic-associated symptoms. Patients with post-COVID pain had the highest neutrophil count, and post hoc analysis revealed that patients with neuropathic post-COVID associated symptoms had lower neutrophil count (p = 0.04) compared with those without neuropathic pain, but differences were small and possible not clinically relevant. No differences in fatigue, dyspnea, brain fog, anxiety or depressive levels, poor sleep, or pain catastrophism between patients with and without neuropathic symptoms were found.ConclusionIt seems that neuropathic-like post-COVID pain symptoms are not associated with neither of assessed serological biomarkers at hospital admission nor hospitalization treatments received in this cohort of hospitalized COVID-19 survivors

Role of asymptomatic bacteriuria on early periprosthetic joint infection after hip hemiarthroplasty. BARIFER randomized clinical trial

[Purpose] To evaluate preoperative asymptomatic bacteriuria (ASB) treatment to reduce early-periprosthetic joint infections (early-PJIs) after hip hemiarthroplasty (HHA) for fracture.[Methods] Open-label, multicenter RCT comparing fosfomycin-trometamol versus no intervention with a parallel follow-up cohort without ASB. Primary outcome: early-PJI after HHA.[Results] Five hundred ninety-four patients enrolled (mean age 84.3); 152(25%) with ASB (77 treated with fosfomycin-trometamol/75 controls) and 442(75%) without. Despite the study closed without the intended sample size, ASB was not predictive of early-PJI (OR: 1.06 [95%CI: 0.33–3.38]), and its treatment did not modify early-PJI incidence (OR: 1.03 [95%CI: 0.15–7.10]). [Conclusions] Neither preoperative ASB nor its treatment appears to be risk factors of early-PJI after HHA. ClinicalTrials.gov Identifier: Eudra CT 2016-001108-47.This work was supported by the Spanish Clinical Research Network (SCReN), co-finaced by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, through the project PI15/02161 and by the Plan Nacional de I+D+i 2013-016 and ISCIIII, Subdireccion General de Redes y Centros de Investigacion Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003)-co-financed by European Development Regional Fund “A way to achieve Europe,” Operative program Intelligent Growth 2014-2020.Peer reviewe

Erythrocyte Membrane Nanomechanical Rigidity Is Decreased in Obese Patients

This work intends to describe the physical properties of red blood cell (RBC) membranes in obese adults. The hypothesis driving this research is that obesity, in addition to increasing the amount of body fat, will also modify the lipid composition of membranes in cells other than adipocytes. Forty-nine control volunteers (16 male, 33 female, BMI 21.8 ± 5.6 and 21.5 ± 4.2 kg/m2, respectively) and 52 obese subjects (16 male and 36 female, BMI 38.2± 11.0 and 40.7 ± 8.7 kg/m2, respectively) were examined. The two physical techniques applied were atomic force microscopy (AFM) in the force spectroscopy mode, which allows the micromechanical measurement of penetration forces, and fluorescence anisotropy of trimethylammonium diphenylhexatriene (TMA-DPH), which provides information on lipid order at the membrane polar–nonpolar interface. These techniques, in combination with lipidomic studies, revealed a decreased rigidity in the interfacial region of the RBC membranes of obese as compared to control patients, related to parallel changes in lipid composition. Lipidomic data show an increase in the cholesterol/phospholipid mole ratio and a decrease in sphingomyelin contents in obese membranes. ω-3 fatty acids (e.g., docosahexaenoic acid) appear to be less prevalent in obese patient RBCs, and this is the case for both the global fatty acid distribution and for the individual major lipids in the membrane phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS). Moreover, some ω-6 fatty acids (e.g., arachidonic acid) are increased in obese patient RBCs. The switch from ω-3 to ω-6 lipids in obese subjects could be a major factor explaining the higher interfacial fluidity in obese patient RBC membranes.This work was supported in part by the Basque Government Department of Economic Development, grant No. KK-2019/00028 (OBINTER); the Basque Government Department of Education, grants No. IT1264-19, IT1281-19, IT1270-19, and IT1625-22; the Basque Government Department of Health, grants No. 2019-222030, 2020-333023; Fundación Ramón Areces; and by Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under the grant agreement: TECNOMIFOOD project (CER-20191010) and Basque Government: IT1625-22

Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study

BACKGROUND: The objective of this study is to analyze the factors that are associated with the adequacy of empirical antibiotic therapy and its impact in mortality in a large cohort of patients with extended-spectrum β-lactamase (ESBL)--producing Escherichia coli and Klebsiella spp. bacteremia. METHODS: Cases of ESBL producing Enterobacteriaceae (ESBL-E) bacteremia collected from 2003 through 2008 in 19 hospitals in Spain. Statistical analysis was performed using multivariate logistic regression. RESULTS: We analyzed 387 cases ESBL-E bloodstream infections. The main sources of bacteremia were urinary tract (55.3%), biliary tract (12.7%), intra-abdominal (8.8%) and unknown origin (9.6%). Among all the 387 episodes, E. coli was isolated from blood cultures in 343 and in 45.71% the ESBL-E was multidrug resistant. Empirical antibiotic treatment was adequate in 48.8% of the cases and the in hospital mortality was 20.9%. In a multivariate analysis adequacy was a risk factor for death [adjusted OR (95% CI): 0.39 (0.31-0.97); P = 0.04], but not in patients without severe sepsis or shock. The class of antibiotic used empirically was not associated with prognosis in adequately treated patients. CONCLUSION: ESBL-E bacteremia has a relatively high mortality that is partly related with a low adequacy of empirical antibiotic treatment. In selected subgroups the relevance of the adequacy of empirical therapy is limited

The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23

[Background]: Chronic kidney disease (CKD) is associated with increased propensity for arrhythmias. In this context, ventricular repolarization alterations have been shown to predispose to fatal arrhythmias and sudden cardiac death. Between mineral bone disturbances in CKD patients, increased fibroblast growth factor (FGF) 23 and decreased Klotho are emerging as important effectors of cardiovascular disease. However, the relationship between imbalanced FGF23-Klotho axis and the development of cardiac arrhythmias in CKD remains unknown. [Methods]: We carried out a translational approach to study the relationship between the FGF23–Klotho signaling axis and acquired long QT syndrome in CKD-associated uremia. FGF23 levels and cardiac repolarization dynamics were analyzed in patients with dialysis-dependent CKD and in uremic mouse models of 5/6 nephrectomy (Nfx) and Klotho deficiency (hypomorphism), which show very high systemic FGF23 levels. [Results]: Patients in the top quartile of FGF23 levels had a higher occurrence of very long QT intervals (> 490 ms) than peers in the lowest quartile. Experimentally, FGF23 induced QT prolongation in healthy mice. Similarly, alterations in cardiac repolarization and QT prolongation were observed in Nfx mice and in Klotho hypomorphic mice. QT prolongation in Nfx mice was explained by a significant decrease in the fast transient outward potassium (K+) current (Itof), caused by the downregulation of K+ channel 4.2 subunit (Kv4.2) expression. Kv4.2 expression was also significantly reduced in ventricular cardiomyocytes exposed to FGF23. Enhancing Klotho availability prevented both long QT prolongation and reduced Itof current. Likewise, administration of recombinant Klotho blocked the downregulation of Kv4.2 expression in Nfx mice and in FGF23-exposed cardiomyocytes. [Conclusion]: The FGF23–Klotho axis emerges as a new therapeutic target to prevent acquired long QT syndrome in uremia by minimizing the predisposition to potentially fatal ventricular arrhythmias and sudden cardiac death in patients with CKD.This work was supported by projects from the Instituto de Salud Carlos III, Ministry of Economy, Industry and Competitiveness (PI17/01093, PI17/01193, PI20/00763, CP15/00129, F18/00261, CPII20/00022, SAF2017-84777-R, PID2020-113238RB-I00), from the Sociedad Española de Cardiología (SEC), and from the Fundación Renal Íñigo Alvarez de Toledo (FRIAT), co-funded by the European Regional Development Fund (Fondos FEDER)

Clinical characteristics and outcomes of thymoma-associated myasthenia gravis

[Background and purpose] Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG.[Methods] This multicenter study was based on data from a Spanish neurologist-driven MG registry. All patients were aged >18 years at onset and had anti-acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed.[Results] We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6 years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95–4.68, p < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15–2.21, p = 0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43–3.63, p = 0.001; hazard ratio: 2.46, 95% CI: 1.47–4.14, p = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up.[Conclusions] Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.This work is supported by Fondo de Investigaciones Sanitarias (FIS) grant FIS19/01774, Instituto de Salud Carlos III and cofunded by the European Union (ERDF/ESF, A Way to Make Europe/Investing in Your Future). Rodrigo Álvarez-Velasco was supported by a PhD for Medical Doctors grant from the Pla Estratègic de Recerca i Innovació en Salut (PERIS), Generalitat de Catalunya (SLT008/18/00207). Elena Cortés-Vicente was supported by a Juan Rodés grant (JR19/00037) from the Fondo de Investigación en Salud, Instituto de Salud Carlos III, Ministry of Health (Spain).Peer reviewe