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Josep Garre-Olmo,1–3 Anna Ponjoan,1,4–5 José Maria Inoriza,6,7 Jordi Blanch,4 Inma Sánchez-Pérez,6 Rafel Cubí,4 Rosa de Eugenio,7 Oriol Turró-Garriga,1,2 Joan Vilalta-Franch On behalf of the Registry of Dementia of Girona Study Group (ReDeGi Study Group)11Research Group on Ageing, Disability and Health, Girona Biomedical Research Institute (IDIBGI), Catalonia, Spain; 2Registry of Dementia of Girona, Health Assistance Institute, Catalonia, Spain; 3Department of Medical Sciences, School of Medicine, University of Girona, Catalonia, Spain; 4Vascular Health Research Group (ISV-Girona), Foundation University Institute for Primary Health Care Research Jordi Gol I Gurina, Catalonia, Spain; 5Autonomous University of Barcelona, Catalonia, Spain; 6Research Group on Health Services and Health Outcomes (GRESSIRES), Integrated Health Services Baix Empordà (SSIBE), Catalonia, Spain; 7Hospital de Palamós, Integrated Health Services Baix Empordà (SSIBE), Catalonia, SpainBackground: Knowledge on survival after diagnosis is important for all stakeholders. We aimed to estimate the survival and life expectancy after a dementia diagnosis, and to quantify the impact of dementia subtypes on mortality.Methods: Retrospective matched cohort study using a linkage between a dementia-specific registry and two primary care electronic medical records databases. Between 1 January 2007 and 31 December 2015 there were 5,156 subjects aged 60 years and over registered by the Registry of Dementia of Girona and matched to 15,468 age-sex and comorbidity individuals without dementia attended by general practitioners in the province of Girona (Catalonia, Spain).Results: The median survival was 5.2 years (95% CI 5.0 to 5.4), the median life expectancy was 74.7 years (95% CI 71.9 to 76.5), and there were differences by gender. The mortality rate was 127.1 per 1,000 person-years (95% CI 121.6 to 132.7), and the hazard ratio for mortality in persons with dementia ranged between 1.63 (95% CI 1.52 to 1.76) for Alzheimer’s disease and 2.52 (95% CI 1.90 to 3.35) for Parkinson-plus syndromes. There was one death per year attributable to dementia for every 18.6 persons with dementia, and for every 2.4 persons with dementia who die, one death was attributable to dementia.Conclusion: The prognosis after dementia diagnosis is conditioned by demographic and clinical features. Although survival is larger for women, they also experience a higher number of years of life lost. Parkinson-plus syndromes and dementia due to multiple etiologies are among the most malignant subtypes regarding mortality.Keywords: epidemiology, diagnosis, dementia, mortality

Treatment of non-small cell lung cancer (NSCLC) with cisplatin has a level of antitumor activity still modest. We have shown previously that MKP1/DUSP1 inhibits cisplatin-induced apoptosis in NSCLC cells and is overexpressed in tumors from most patients with stage I-II NSCLC. Here, using different NSCLC cell lines we found that MKP1 and NF-kappaB are differentially expressed. We studied whether targeting MKP1, NF-kappaB or both affects cisplatin-induced cell death. MKP1 is expressed in H460 and H727 cells. H727 and H1299 cells showed constitutive phosphorylation of Akt and increased NF-kappaB activity than did H460 cells. H460-MKP1-siRNA-expressing cells (but not H727-MKP1-siRNA or H1299-MKP1-siRNA cells) exhibit a marked increase in cisplatin response compared with parental cells. Treatment with the PI3K inhibitor LY294002 or the NF-kappaB inhibitor BAY11-7082 enhanced cisplatin antitumor activity in parental H1299 cells but only weakly affected responses of H727 and H460 cells. MKP1-siRNA expression enhanced the chemosensitization effect of LY294002 and BAY11-7082 on H727 and H460 cells. Additionally, NSCLC cell lines with higher NF-kappaB-constitutive activation were the most sensitive to PS-341 (Bortezomib), a non-specific NF-kappaB inhibitor. This finding suggests the proteasome as a suitable strategy in treating NSCLC tumors with high constitutive NF-kappaB activity. Altogether, these results showed that either an activated PI3K/Akt/NF-kappaB pathway and/or high MKP1 was linked to reduced sensitivity to cisplatin in NSCLC cells. Inhibition of NF-kappaB or PI3K potently enhanced cisplatin cytotoxicity in cells with endogenous or genetically induced low MKP1 levels. These findings support the potential improvement in cisplatin responses by co-targeting NF-kappaB or Akt and MKP1. [ABSTRACT FROM AUTHOR]

Introduction: Pulsed-field ablation (PFA) is a novel nonthermal energy that shows unique features that can be of use beyond pulmonary vein ablation, like tissue selectivity or proximity rather than contact dependency., Methods and Results: We report three cases of right focal atrial tachycardias arising from the superior cavoatrial junction and the crista terminalis, in close relationship with the phrenic nerve, effectively ablated using a commercially available PFA catheter designed for pulmonary vein isolation without collateral damage., Conclusion: PFA can be useful for treating right atrial tachycardias involving sites near the phrenic nerve, avoiding the need for complex nerve-sparing strategies., (© 2024 Wiley Periodicals LLC.)

Gastric cancer prognosis is still notably poor despite efforts made to improve diagnosis and treatment of the disease. Chemotherapy based on platinum agents is generally used, regardless of the fact that drug toxicity leads to limited clinical efficacy. In order to overcome these problems, our group has been working on the synthesis and study of trans platinum (II) complexes. Here, we explore the potential use of two phosphine-based agents with the general formula trans -[Pt(amine)Cl 2 (PPh 3 )], called P1 and P2 (with dimethylamine or isopropylamine, respectively). A cytotoxicity analysis showed that P1 and especially P2 decrease cell viability. Specifically, P2 exhibits higher activity than cisplatin in gastric cancer cells while its toxicity in healthy cells is slightly lower. Both complexes generate Reactive Oxygen Species, produce DNA damage and mitochondrial membrane depolarization, and finally lead to induced apoptosis. Thus, an intrinsic apoptotic pathway emerges as the main type of cell death through the activation of BAX/BAK and BIM and the degradation of MCL1. Additionally, we demonstrate here that P2 produces endoplasmic reticulum stress and activates the Unfolded Protein Response, which also relates to the impairment observed in autophagy markers such as p62 and LC3. Although further studies in other biological models are needed, these results report the biomolecular mechanism of action of these Pt(II)-phosphine prototypes, thus highlighting their potential as novel and effective therapies.

Premature vascular aging and endothelial cell senescence are major risk factors for cardiovascular diseases and atherothrombotic disturbances, which are main complications of both acute and long COVID-19. The S protein of SARS-CoV2, which acts as the receptor binding protein for the viral infection, is able to induce endothelial cells inflammation and it has been found as an isolated element in the circulation and in human tissues reservoirs months after infection. Here, we investigated whether the S protein is able to directly induce endothelial cell senescence and deciphered some of the mechanisms involved. In primary cultures of human umbilical vein endothelial cells (HUVEC), SARS-CoV-2 S protein enhanced in a concentration-dependent manner the cellular content of senescence and DNA damage response markers (senescence-associated-β galactosidase, γH2AX), as well as growth-arrest effectors (p53, p21, p16). In parallel, the S protein reduced the availability of cytoprotective proteins, such as the anti-aging protein klotho, Nrf2 or heme oxygenase-1, and caused functional harm by impairing ex vivo endothelial-dependent vasorelaxation in murine microvessels. These effects were prevented by the pharmacological inhibition of the NLRP3 inflammasome with MCC950. Furthermore, the supplementation with either recombinant klotho or angiotensin-(1-7), equally protected against the pro-senescence, pro-inflammatory and pro-oxidant action of the S protein. Globally, this study proposes novel mechanisms of disease in the context of COVID-19 and its vascular sequelae and provides pharmacological clues in order to prevent such complications.

Cisplatin-based chemotherapy has associated clinical disadvantages, such as high toxicity and resistance. Thus, the development of new antitumor metallodrugs able to overcome different clinical barriers is a public healthcare priority. Here, we studied the mechanism of action of the isomers trans and cis-[PtI 2 (isopropylamine) 2 ] (I5 and I6, respectively) against gastrointestinal cancer cells. We demonstrate that I5 and I6 modulate mitochondrial metabolism, decreasing OXPHOS activity and negatively affecting ATP-linked oxygen consumption rate. Consequently, I5 and I6 generated Reactive Oxygen Species (ROS), provoking oxidative damage and eventually the induction of senescence. Thus, herein we propose a loop with three interconnected processes modulated by these iodido agents: (i) mitochondrial dysfunction and metabolic disruptions; (ii) ROS generation and oxidative damage; and (iii) cellular senescence. Functionally, I5 reduces cancer cell clonogenicity and tumor growth in a pancreatic xenograft model without systemic toxicity, highlighting a potential anticancer complex that warrants additional pre-clinical studies., (© 2024. The Author(s).)

Introduction: Electrical cardioversion (ECV) is a frequently used procedure for restoring sinus rhythm in atrial fibrillation (AF); however, the rate of recurrence is high. The identification of patients at high risk of recurrence could influence the decision-making process. The present study evaluates the predictive value of risk scores in atrial fibrillation recurrence after elective electrical cardioversion., Methods: Unicentric, observational, and prospective study of adult patients who have undergone an elective ECV as rhythm control strategy between July 2017 and September 2022., Results: From the 283 analyzed patients (mean age 63.95 ± 10.76212, 74.9% male); 99 had paroxysmal AF (35%) and 159 (59%) presented AF recurrence during a follow-up of 6 months. In patients with post-ECV AF recurrence, the period of time from diagnosis until the performance of the procedure was longer (393 ± 891 vs. 195 ± 527, p = .02). No paroxysmal AF (71.3% vs. 57.8%, p = .02) and LA dilatation with >40 mL/m 2 (35.9% vs. 23.3%, p = .02) volumes were more frequent within these patients. AF recurrence was more frequent in patients who had previous ECV (HR = 1.32; 95% CI: 1.12-2.35; p = .01) and more than 1 shock to recover sinus rhythm (HR = 1.62; 95% CI: 1.07-1.63; p = .01). The SLAC, ALARMEc, ATLAS, and CAAP-AF scores were statistically significant, although with a moderate predictive capacity for post-ECV recurrence., Conclusions: Risk scores analyzed showed a modest value predicting AF recurrence after ECV. Previous ECV, and greater difficulty in restoring SR were independent predictors of recurrence., (© 2023 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Introduction and Objectives: This article presents the annual activity report of the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC) for the year 2022., Methods: All Spanish centers with catheterization laboratories were invited to participate. Data were collected online and were analyzed by an external company in collaboration with the members of the board of the ACI-SEC., Results: A total of 111 centers participated. The number of diagnostic studies increased by 4.8% compared with 2021, while that of percutaneous coronary interventions (PCI) remained stable. PCIs on the left main coronary artery increased by 22%. The radial approach continued to be preferred for PCI (94.9%). There was an upsurge in the use of drug-eluting balloons, as well as in intracoronary imaging techniques, which were used in 14.7% of PCIs. The use of pressure wires also increased (6.3% vs 2021) as did plaque modification techniques. Primary PCI continued to grow and was the most frequent treatment (97%) in ST-segment elevation myocardial infarction. Most noncoronary procedures maintained their upward trend, particularly percutaneous aortic valve implantation, atrial appendage closure, mitral/tricuspid edge-to-edge therapy, renal denervation, and percutaneous treatment of pulmonary arterial disease., Conclusions: The Spanish cardiac catheterization and coronary intervention registry for 2022 reveals a rise in the complexity of coronary disease, along with a notable growth in procedures for valvular and nonvalvular structural heart disease., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Dithiobiureas coordination chemistry towards palladium (II) ions and their possible application is presented and discussed. 1,6-(4-Methoxyphenyl)-2,5-dithiobiurea and 1,6-(4-chlorophenyl)-2,5-dithiobiurea afford two Pd(II) complexes with the general formula [Pd 2 (H 2 L)Cl 2 (PPh 3 ) 2 ]. The metal ion forms one chelate ring with the dithiobiurea, and binds to a triphenylphosphine and an additional leaving group cisplatin like. One of the complexes (1) is endowed not only with stability in DMSO and aqua solutions containing a biological buffer but also with cytotoxicity versus gastric cancer cell lines. Complex 1 does not interact covalently to DNA models, neither activates p53 or Checkpoint Kinase 1 key proteins for DNA damage response. Thus, we propose that complex 1 exerts its action by activating Mitogen-Activated Protein Kinases [p38, Extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs)] as cell death inductors., Competing Interests: Declaration of Competing Interest Adoracion Gomez Quiroga reports financial support was provided by Spanish Ministry of Science Technology and Innovation (MINECO)., (Copyright © 2023 Elsevier Inc. All rights reserved.)