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RATIONALE & OBJECTIVE: Glomerulonephritis (GN) is a leading cause of chronic kidney disease (CKD). Major adverse cardiovascular events (MACE) are prolific in CKD. The risk of MACE in GN cohorts is multifactorial. We investigated the prognostic significance of routine cardiac biomarkers, Troponin I and N-terminal pro-BNP (NT-proBNP) in predicting MACE within 5 years of GN diagnosis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Data were obtained from TriNetX, a global federated health research network of electronic health records (EHR). EXPOSURE OR PREDICTOR: Biomarker thresholds: Troponin I: 18 ng/L, NT-proBNP: 400 pg/mL. OUTCOMES: Primary outcome: Incidence of major adverse cardiovascular events (MACE). SECONDARY OUTCOME: was the risk for each individual component of the composite outcome. ANALYTICAL APPROACH: 1:1 propensity score matching using logistic regression. Cox proportional hazard models were used to assess the association of cardiac biomarkers with the primary and secondary outcomes, reported as Hazard Ratio (HR) and 95% confidence intervals (CI). Survival analysis was performed which estimates the probability of an outcome over a 5-year follow-up from the index event. RESULTS: Following PSM, 34,974 and 18,218 patients were analysed in the Troponin I and NTproBNP cohorts, respectively. In the Troponin I all cause GN cohort, 3,222 (9%) developed composite MACE outcome HR 1.79; (95% CI, 1.70, 1.88, p < 0.0001). In the NTproBNP GN cohort, 1,686 (9%) developed composite MACE outcome HR 1.99; (95% CI, 1.86, 2.14, p < 0.0001). LIMITATIONS: The data are derived from EHR for administrative purposes; therefore, there is the potential for data errors or missing data. CONCLUSIONS: In GN, routinely available cardiac biomarkers can predict incident MACE. The results suggest the clinical need for cardiovascular and mortality risk profiling in glomerular disease using a combination of clinical and laboratory variables.
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Biomarcadores , Enfermedades Cardiovasculares , Glomerulonefritis , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Troponina I , Humanos , Masculino , Femenino , Biomarcadores/sangre , Troponina I/sangre , Glomerulonefritis/sangre , Glomerulonefritis/epidemiología , Glomerulonefritis/diagnóstico , Fragmentos de Péptidos/sangre , Persona de Mediana Edad , Estudios Retrospectivos , Péptido Natriurético Encefálico/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/mortalidad , Anciano , Bases de Datos Factuales , Adulto , Incidencia , Pronóstico , Estudios de Cohortes , Valor Predictivo de las PruebasRESUMEN
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) are the primary physiological inhibitors of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but their roles in PAH are unsettled. Here, we report that: 1) PAI-1, but not PAI-2, is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared with controls; 2) PAI-1-/- mice spontaneously develop pulmonary vascular remodeling associated with upregulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and 3) pharmacological inhibition of uPA in human PAH PASMCs suppresses proproliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation, and induces apoptosis in vitro, and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in vivo in mice. These data strongly suggest that downregulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent upregulation of mTOR and transforming growth factor-ß (TGF-ß) signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH.NEW & NOTEWORTHY This study identifies a novel role for the deficiency of plasminogen activator inhibitor (PAI)-1 and resultant unrestricted uPA activity in PASMC remodeling and PH in vitro and in vivo, provides novel mechanistic link from PAI-1 loss through uPA-induced Akt/mTOR and TGFß-Smad3 upregulation to pulmonary vascular remodeling in PH, and suggests that inhibition of uPA to rebalance the uPA-PAI-1 tandem might provide a novel approach to complement current therapies used to mitigate this pulmonary vascular disease.
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Hipertensión Pulmonar , Músculo Liso Vascular , Inhibidor 1 de Activador Plasminogénico , Remodelación Vascular , Animales , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratones , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Transducción de Señal , Masculino , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proliferación Celular , Ratones Noqueados , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Apoptosis , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/genética , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Inhibidor 2 de Activador Plasminogénico/metabolismo , Inhibidor 2 de Activador Plasminogénico/genéticaRESUMEN
Introduction Existing randomised controlled trials assessing the safety and efficacy of left atrial appendage occlusion (LAAO) in atrial fibrillation (AF) were of relatively small sample size, or included patients who could receive oral anticoagulant treatment after device implantation. We compared the outcomes of patients with newly diagnosed AF who received percutaneous LAAO or direct oral anticoagulants (DOAC) treatment, in a large population from a global federated health network (TriNetX). Methods Patients with AF treated with percutaneous LAAO were matched with those treated with DOAC between 1st December 2010 and 1st October 2018. Outcomes were all-cause mortality, ischaemic stroke and intracranial haemorrhage (ICH) at 5 years. Results We included 200 patients with AF, who received either LAAO or DOAC. The risk of all-cause mortality, ischaemic stroke and ICH at 5 years was not significantly different between the two groups (Risk Ratio [RR] for all-cause mortality: 1.52, 95% confidence interval (CI): 0.97- 2.38, RR for ischaemic stroke: 1.09, 95% CI: 0.51- 2.36, and RR for ICH: 1.0, 95% CI: 0.44- 2.30). Conclusion Patients newly diagnosed with AF, eligible for DOAC, showed similar 5-year risk of death, ischemic stroke, and ICH when comparing those who underwent percutaneous LAAO to those receiving DOAC. Future randomised controlled trials are needed to confirm the findings and advise changes in guidelines.
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The human Na+/H+ exchanger (NHE1) plays a crucial role in maintaining intracellular pH by regulating the electroneutral exchange of a single intracellular H+ for one extracellular Na+ across the plasma membrane. Understanding the molecular mechanisms governing ion transport and the binding of inhibitors is of importance in the development of anticancer therapeutics targeting NHE1. In this context, we performed molecular dynamics (MD) simulations based on the recent cryo-electron microscopy (cryo-EM) structures of outward- and inward-facing conformations of NHE1. These simulations allowed us to explore the dynamics of the protein, examine the ion-translocation pore, and confirm that Asp267 is the ion-binding residue. Our free energy calculations did not show a significant difference between Na+ and K+ binding at the ion-binding site. Consequently, Na+ over K+ selectivity cannot be solely explained by differences in ion binding. Our MD simulations involving NHE1 inhibitors (cariporide and amiloride analogues) maintained stable interactions with Asp267 and Glu346. Our study highlights the importance of the salt bridge between the positively charged acylguanidine moiety and Asp267, which appears to play a role in the competitive inhibitory mechanism for this class of inhibitors. Our computational study provides a detailed mechanistic interpretation of experimental data and serves the basis of future structure-based inhibitor design.
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Simulación de Dinámica Molecular , Intercambiadores de Sodio-Hidrógeno , Humanos , Microscopía por Crioelectrón , Intercambiadores de Sodio-Hidrógeno/metabolismo , Transporte Iónico , Membrana Celular/metabolismo , Concentración de Iones de HidrógenoAsunto(s)
Enfermedades Cardiovasculares , Sistema Cardiovascular , Accidente Cerebrovascular , Humanos , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Corazón , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/complicacionesRESUMEN
BACKGROUND AND AIM: Atrial fibrillation (AF) is associated with increased risk of dementia. Whether direct oral anticoagulation (DOAC) reduce this risk compared to vitamin-K antagonist (VKA) is unclear. The aim of this study was to assess the risk of new all-cause dementia and vascular dementia in AF patients, treated with either DOAC or VKAs. METHODS: Anonymized electronic medical records from the TriNetX federated research network were used. AF patients treated with DOACs within 1 month of AF diagnosis, were 1:1 propensity score-matched with those treated with a VKA. The analysis included patients who completed 5 and 10 years of follow-up and were assessed for all-cause dementia and vascular dementia. Cox proportional hazard models were used to hazard ratios (HR), respectively with 95% confidence intervals (CIs). RESULTS: Among patients who completed 5 years of follow-up, after propensity score matching the final cohort consisted of 215,404 well-matched AF patients. All-cause dementia was diagnosed in 4,153 (3.9%) patients among those treated with DOACs and 4,150 (3.9%) among the VKA-treated patients (HR: 1.01, 95%CI: 0.96-1.05). Among patients 65-74 years old who were followed, DOAC treatment was associated with lower risk of dementia compared to VKAs (HR: 0.72; 95%CI: 0.59-0.86). Among patients who completed 10 years of follow-up, after propensity score matching the final cohort consisted of 19,208 well-matched AF patients. All-cause dementia was diagnosed in 314 (3.3%) patients among those treated with DOACs and 451 (4.7%) among the VKA-treated patients. DOAC treatment was associated with significantly lower risk of all-cause dementia during a follow-up period of 10 years compared to VKA treatment (HR: 0.72, 95%CI: 0.62-0.83), which remained consistent in patiens ≥65 years old. CONCLUSION: This propensity-score matched analysis showed that among AF patients, treatment with a DOACs for a period of 10 years was associated with lower risk of all-cause dementia and vascular dementia compared to VKA treatment, an effect which was not apparent in those treated for shorter duration. This finding requires confirmation in ongoing randomised controlled trials.
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Fibrilación Atrial , Demencia Vascular , Accidente Cerebrovascular , Humanos , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Demencia Vascular/inducido químicamente , Demencia Vascular/complicaciones , Demencia Vascular/tratamiento farmacológico , Anticoagulantes/uso terapéutico , Fibrinolíticos/uso terapéutico , Administración Oral , Vitamina K , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & controlRESUMEN
Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M. tuberculosis and synergizes with several tuberculosis drugs. Target identification experiments, supported by docking studies, showed that BB2-50F targets the membrane-embedded c-ring of the F1Fo-ATP synthase and the catalytic subunit (substrate-binding site) of succinate dehydrogenase. Biochemical assays and metabolomic profiling showed that BB2-50F inhibits succinate oxidation, decreases the activity of the tricarboxylic acid (TCA) cycle, and results in succinate secretion from M. tuberculosis. Moreover, we show that the lethality of BB2-50F under aerobic conditions involves the accumulation of reactive oxygen species. Overall, this study identifies BB2-50F as an effective inhibitor of M. tuberculosis and highlights that targeting multiple components of the mycobacterial respiratory chain can produce fast-acting antimicrobials.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Succinato Deshidrogenasa/metabolismo , Succinato Deshidrogenasa/farmacología , Antituberculosos/química , Tuberculosis/tratamiento farmacológico , Adenosina Trifosfato , Inhibidores Enzimáticos/farmacología , SuccinatosRESUMEN
Background: Despite pharmacological therapies to improve outcomes of pulmonary hypertension (PH), poor long-term survival remains. Exercised-based cardiac rehabilitation (ExCR) may be an alternative strategy to improve prognosis. Therefore, using an electronic medical record (EMR) database, the objective of this study was to compare mortality between patients with primary PH with ExCR vs. propensity-matched PH patients without ExCR. Methods: The retrospective analysis was conducted on February 15, 2023 using anonymized data within TriNetX, a global federated health research network. All patients were aged ≥18 years with primary PH recorded in EMRs with at least 1-year follow-up from ExCR. Using logistic regression models, patients with PH with an EMR of ExCR were 1:1 propensity score-matched with PH patients without ExCR for age, sex, race, and comorbidities, and cardiovascular care. Results: In total, 109,736 patients with primary PH met the inclusion criteria for the control group and 784 patients with primary PH met the inclusion criteria for the ExCR cohort. Using the propensity score-matched cohorts, 1-year mortality from ExCR was proportionally lower with 13.6% (n = 101 of 744 patients) in the ExCR cohort compared to 23.3% (n = 174 of 747 patients) in the controls (OR 0.52, 95% CI 0.40-0.68). Conclusion: The present study of 1,514 patients with primary PH suggests that ExCR is associated with 48% lower odds of 1-year mortality, when compared to propensity score-matched patients without ExCR.
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Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. PAI1-/- male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.
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BACKGROUND: Telemonitoring for the remote patient self-management of chronic conditions can be a cost-effective method for delivering care in chronic disease; nonetheless, its implementation in clinical practice remains low. The aim of this meta-synthesis is to explore barriers and facilitators associated with the use of remote patient monitoring of chronic disease, drawing on qualitative research, and assessing participant interactions with this technology. METHOD: A meta-synthesis of qualitative studies was performed. MEDLINE, SCOPUS and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from database date of inception to 5 February 2021. The Critical Appraisal Skills Programme (CASP) was used to critically appraise each study. Thematic synthesis was performed to identify user (patients, carers and healthcare professionals) perspectives and experiences of patient remote monitoring of chronic disease (Type 2 diabetes mellitus, chronic obstructive pulmonary disease, and cardiovascular disease). RESULTS: Searches returned 10,401 studies and following independent screening by two reviewers, nine studies were included in this meta-synthesis. Data were synthesised and categorised into four key themes: (1) Improved care; (2) Communication; (3) Technology feasibility & acceptability; and (4) Intervention concerns. Most patients using patient remote devices felt motivated in managing their own lifestyles and felt reassured by the close monitoring and increased communication. Barriers identified involved generational differences and difficulties with the technology used. CONCLUSION: Most studies showed a positive attitude to telemonitoring, with patients preferring the convenience of telemonitoring in comparison to attending regular clinics. Further research is required to assess the most effective technology for chronic disease management, how to maintain long-term patient adherence, and identify effective approaches to address generational variation in telemonitoring up-take.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Enfermedad Pulmonar Obstructiva Crónica , Automanejo , Humanos , Enfermedad CrónicaRESUMEN
BACKGROUND: Atrial fibrillation (AF) has consistently been associated with a higher risk of incident dementia. Observational evidence has suggested catheter ablation may be associated with a lower risk of dementia in patients with AF, but further research is needed. The objectives of this study were to use a global health research network to examine associations between catheter ablation, incident dementia and mortality in older adults with AF, and amongst subgroups by age, sex, co-morbidity status, and oral anticoagulant use. METHODS: The research network primarily included healthcare organizations in the United States. This network was searched on 28th September 2022 for patients aged ≥65 years with a diagnosis of AF received at least 5 years prior to the search date. Cox proportional hazard models were run on propensity-score matched cohorts. RESULTS: After propensity score matching, 20,746 participants (mean age 68 years; 59% male) were included in each cohort with and without catheter ablation. The cohorts were well balanced for age, sex, ethnicity, co-morbidities, and cardiovascular medications received. The risk of dementia was significantly lower in the catheter ablation cohort (Hazard Ratio 0.52, 95% confidence interval: 0.45-0.61). The catheter ablation cohort also had a lower risk of all-cause mortality (Hazard Ratio 0.58, 95% confidence interval: 0.55-0.61). These associations remained in subgroup analyses in individuals aged 65-79 years, ≥80 years, males, females, participants who received OACs during follow-up, participants with paroxysmal and non-paroxysmal AF, and participants with and without hypertension, diabetes mellitus, ischemic stroke, chronic kidney disease and heart failure, including heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. CONCLUSION: The observed lower risk of dementia and mortality with catheter ablation could be an important consideration when determining appropriate patient-centered rhythm control strategies for patients with AF. Further studies including data on the success of ablation are required.
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Fibrilación Atrial , Ablación por Catéter , Demencia , Insuficiencia Cardíaca , Femenino , Humanos , Masculino , Estados Unidos/epidemiología , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/cirugía , Fibrilación Atrial/epidemiología , Comorbilidad , Demencia/complicacionesRESUMEN
AIMS: There is conflicting evidence on whether the type of atrial fibrillation (AF) is associated with risk of cardiovascular events, including acute myocardial infarction (MI) and ischemic stroke. The aim of the present study was to investigate whether the risk of MI and ischemic stroke differs between individuals with first-diagnosed paroxysmal vs. non-paroxysmal AF treated with anticoagulants. METHODS AND RESULTS: De-identified electronic medical records from the TriNetX federated research network were used. Individuals with a new diagnosis of paroxysmal AF who had no evidence of other types of AF in their records were 1:1 propensity score-matched with individuals with non-paroxysmal AF, defined as persistent or chronic AF, who had no evidence of other types of AF in their records. All patients were followed for three years for the outcomes of MI and ischemic stroke. Cox proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). In the propensity-matched cohort, among 24 848 well-matched AF individuals [mean age 74.4 ± 10.4; 10 101 (40.6%) female], 410 (1.7%) were diagnosed with acute MI and 875 (3.5%) with ischemic stroke during the three-year follow-up. Individuals with paroxysmal AF had significantly higher risk of acute MI (HR: 1.65, 95%CI: 1.35-2.01) compared to those with non-paroxysmal AF. First diagnosed paroxysmal AF was associated with higher risk of non-ST elevation MI (nSTEMI) (HR: 1.89, 95%CI: 1.44-2.46). No significant association was observed between the type of AF and risk of ischemic stroke (HR: 1.09, 95%CI: 0.95-1.25). CONCLUSION: Patients with first-diagnosed paroxysmal AF had higher risk of acute MI compared to individuals with non-paroxysmal AF, attributed to the higher risk of nSTEMI among patients with first-diagnosed paroxysmal AF. There was no significant association between type of AF and risk of ischemic stroke.
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Fibrilación Atrial , Accidente Cerebrovascular Isquémico , Infarto del Miocardio , Infarto del Miocardio sin Elevación del ST , Accidente Cerebrovascular , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Infarto del Miocardio sin Elevación del ST/complicaciones , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/complicaciones , Anticoagulantes/efectos adversos , Factores de RiesgoRESUMEN
Acid-sensing ion channels (ASICs) are transmembrane sensors of extracellular acidosis and potential drug targets in several disease indications, including neuropathic pain and cancer metastasis. The K+-sparing diuretic amiloride is a moderate nonspecific inhibitor of ASICs and has been widely used as a probe for elucidating ASIC function. In this work, we screened a library of 6-substituted and 5,6-disubstituted amiloride analogs using a custom-developed automated patch clamp protocol and identified 6-iodoamiloride as a potent ASIC1 inhibitor. Follow-up IC50 determinations in tsA-201 cells confirmed higher ASIC1 inhibitory potency for 6-iodoamiloride 94 (hASIC1 94 IC50 = 88 nM, cf. amiloride 11 IC50 = 1.7 µM). A similar improvement in activity was observed in ASIC3-mediated currents from rat dorsal root ganglion neurons (rDRG single-concentration 94 IC50 = 230 nM, cf. 11 IC50 = 2.7 µM). 6-Iodoamiloride represents the amiloride analog of choice for studying the effects of ASIC inhibition on cell physiology.
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Canales Iónicos Sensibles al Ácido , Amilorida , Ratas , Animales , Canales Iónicos Sensibles al Ácido/farmacología , Canales Iónicos Sensibles al Ácido/fisiología , Amilorida/farmacología , NeuronasRESUMEN
BACKGROUND: Atrial fibrillation (AF) associates with higher Alzheimer's disease (AD) and vascular dementia risks but the clinical implications have been scarcely investigated. We examined the association between AD or vascular dementia and adverse outcomes in AF patients. METHODS: Cohort study between January 2000 and 2017. AF patients were divided into two groups according to vascular dementia or AD, and balanced using propensity score matching (PSM). During 4-years of follow-up, incident intracranial hemorrhages (ICH), the composite of ischemic stroke/transient ischemic attack (TIA), hospitalizations, and all-cause deaths, were recorded. RESULTS: Two thousand three hundred seventy-seven AF patients with dementia (1225 with vascular dementia, and 1152 with AD) were identified. Following a PSM, 615 patients were included in each cohort (i.e., 1:1) and all variables were well-matched. After PSM, 22 (3.6%) patients with vascular dementia and 55 (8.1%) patients with AD had incident ICH during follow-up (hazard ratio [HR]: 2.22, 95% confidence interval [CI]: 1.33-3.70, log-rank p = 0.002). Overall, 237 (38.5%) patients with vascular dementia and 193 (31.4%) patients with AD, developed an ischemic stroke/TIA. The risk of ischemic stroke/TIA was 1.32-fold higher in vascular dementia (HR: 1.32, 95% CI: 1.09-1.59, log-rank p = 0.003). The risk of rehospitalization (HR: 1.14, 95% CI: 1.01-1.31), and mortality (HR: 1.25, 95% CI: 1.01-1.58) were also higher among AF patients with vascular dementia compared to AD. CONCLUSIONS: The two forms of dementia in AF patients are associated with different prognosis, with AD being associated with a higher risk of ICH, and vascular dementia with a higher risk of stroke/TIA, hospitalization, and mortality.
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Fibrilación Atrial , Demencia Vascular , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Ataque Isquémico Transitorio/epidemiología , Ataque Isquémico Transitorio/etiología , Estudios de Cohortes , Anticoagulantes/efectos adversos , Demencia Vascular/inducido químicamente , Demencia Vascular/complicaciones , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/complicaciones , Accidente Cerebrovascular Isquémico/inducido químicamente , Accidente Cerebrovascular Isquémico/complicaciones , Factores de RiesgoRESUMEN
The role of inflammation in predicting early cardiac complications among stroke patients is unclear. Electronic medical records from TriNetX, a global federated health research network, were used for this retrospective analysis. Patients with ischemic stroke and C-Reactive Protein (CRP) levels measured within 24 h post-stroke were categorized into three groups: (i) < 1 mg/L, (ii)1-3 mg/L and (iii) > 3 mg/L. The primary outcome was a composite outcome of cardiac complications (heart failure (HF), ischemic heart disease, atrial fibrillation (AF), ventricular arrhythmias and Takotsubo cardiomyopathy) or death at 30 days from the index event. Cox-regression analyses were used to produce hazard ratios (HRs) and 95% confidence intervals (CI) following 1:1 propensity score matching (PSM). Of the 104,741 patients enrolled, 51% were female and the mean age was 66 ± 16 years. After PSM, a new cardiac complication or death within 30 days occurred in 5624 (33.1%) patients with CRP > 3 mg/L, in 4243 (25.6%) patients with CRP 1-3 mg/L and in 3891 (23.5%) patients with CRP < 1 mg/L. Patients with CRP levels of 1-3 mg/L and > 3 mg/L had higher risk of the composite outcome (HR 1.10, 95%CI 1.05-1.52; HR 1.51, 95%CI 1.45-1.58), death (HR 1.43, 95%CI 1.24-1.64; HR 3.50, 95%CI 3.01-3.96), HF (HR 1.08, 95%CI 1.01-1.16; HR 1.51, 95%CI 1.41-1.61), AF (HR 1.10, 95% CI:1.02-1.18; HR 1.42, 95%CI 1.33-1.52) and ventricular arrhythmias (HR 1.25, 95%CI 1.02-1.52; HR 1.67, 95% CI 1.38-2.01) compared to those with CRP < 1 mg/L. Ischemic heart disease were more common among patients with CRP levels > 3 mg/L compared to those with CRP < 1 mg/L (HR:1.33, 95% CI:1.26-1.40), while no association with Takotsubo cardiomyopathy was found in all the analyses. CRP levels within the first 24 h of an ischemic stroke predict 30-day cardiac complications or death.
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Fibrilación Atrial , Insuficiencia Cardíaca , Accidente Cerebrovascular Isquémico , Isquemia Miocárdica , Accidente Cerebrovascular , Cardiomiopatía de Takotsubo , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Proteína C-Reactiva/metabolismo , Accidente Cerebrovascular Isquémico/complicaciones , Estudios Retrospectivos , Cardiomiopatía de Takotsubo/complicaciones , Factores de Riesgo , Insuficiencia Cardíaca/complicaciones , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/epidemiología , Fibrilación Atrial/complicacionesRESUMEN
Fungal infections have become an increasing threat as a result of growing numbers of susceptible hosts and diminishing effectiveness of antifungal drugs due to multi-drug resistance. This reality underscores the need to develop novel drugs with unique mechanisms of action. We recently identified 5-(N,N-hexamethylene)amiloride (HMA), an inhibitor of human Na+/H+ exchanger isoform 1, as a promising scaffold for antifungal drug development. In this work, we carried out susceptibility testing of 45 6-substituted HMA and amiloride analogs against a panel of pathogenic fungi. A series of 6-(2-benzofuran)amiloride and HMA analogs that showed up to a 16-fold increase in activity against Cryptococcus neoformans were identified. Hits from these series showed broad-spectrum activity against both basidiomycete and ascomycete fungal pathogens, including multidrug-resistant clinical isolates.
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Cryptococcus neoformans , Micosis , Humanos , Amilorida/farmacología , Antifúngicos/farmacología , Hongos , Micosis/tratamiento farmacológico , Pruebas de Sensibilidad MicrobianaRESUMEN
INTRODUCTION: People with atrial fibrillation (AF) frequently have competing mechanisms for ischaemic stroke, including extracranial carotid atherosclerosis. The objective of this study was to determine associations between use of oral anticoagulants (OACs) plus antiplatelet agents (APA) after ischaemic stroke and outcomes for patients with AF and carotid artery disease. PATIENTS AND METHODS: A retrospective cohort study was conducted. Participants receiving OACs with or without APA were propensity score-matched for age, sex, ethnicity, co-morbidities and presence of cardiac and vascular implants and grafts. Outcomes were 1-year mortality, recurrent stroke and major bleeding. RESULTS: Of 5708 patients, 24.1% (n=1628) received non-vitamin K antagonist OACs (NOACs) with no APA, 26.0% (n=1401) received NOACs plus APA, 20.7% (n=1243) received warfarin without APA and 29.2% (n=1436) received warfarin plus APA. There was no significant difference in risk of recurrent stroke between the groups. Compared to receiving NOACs without APA, receiving warfarin plus APA was associated with a higher risk of mortality (hazard ratio (HR) 1.51 (95% confidence interval (CI) 1.20, 1.89)) and major bleeding (HR 1.66 (95% CI 1.40, 1.96)). Receiving NOACs plus APA was also associated with a higher risk of major bleeding compared to NOACs without APA (HR 1.27 (95% CI 1.07, 1.51), respectively). CONCLUSIONS: The results suggest for patients with AF and carotid artery disease after ischaemic stroke, receiving NOACs without APA is associated with a lower risk of major bleeding with no negative impact on recurrent stroke or mortality. Evidence from randomised trials is needed to confirm this finding.
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BACKGROUND: Atrial fibrillation (AF) often remains undetected following stroke. Documenting AF is critical to initiate oral anticoagulation, which has proven benefit in reducing recurrent stroke and mortality in patients with AF. The accuracy and acceptability of using smart wearables to detect AF in patients following stroke is unknown. METHODS: The aims of the Liverpool-Huawei Stroke Study are to determine the effectiveness, cost-effectiveness and patient and staff acceptability of using Huawei smart wearables to detect AF following ischemic stroke. The study plans to recruit 1,000 adults aged ≥18 years following ischemic stroke from participating hospitals over 12 months. All participants will be asked to wear a Huawei smart band for 4 weeks postdischarge. If participants do not have access to a compatible smartphone required for the study, they will be provided with a smartphone for the 4-week AF monitoring period. RESULTS: Participants with suspected AF detected by the smart wearables, without previous known AF, will be referred for further evaluation. To determine the effectiveness of the Huawei smart wearables to detect AF, the positive predictive value will be determined. Patient acceptability of using this technology will also be examined. Additional follow-up assessments will be conducted at 6 and 12 months, and clinical outcomes recorded in relation to prevalent and incident AF post-stroke. The study opened for recruitment on May 30, 2022, and is currently open at 4 participating hospitals; the first 106 participants have been recruited. One further hospital is preparing to open for recruitment. CONCLUSIONS: This prospective study will examine the effectiveness and acceptability of the use of smart wearables in patients following ischemic stroke. This could have important implications for detection of AF and therefore, earlier prophylaxis for recurrent stroke. The study is registered on https://www.isrctn.com/ (Identifier ISRCTN30693819).
Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Dispositivos Electrónicos Vestibles , Adulto , Humanos , Adolescente , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Estudios Prospectivos , Cuidados Posteriores , Alta del Paciente , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Infarto CerebralRESUMEN
AIM: To investigate the effectiveness of exercise and the most effective types of exercise for patients with atrial fibrillation (AF) to improve health-related quality of life (HRQoL) and exercise capacity, and reduce AF burden, AF recurrence and adverse events. METHODS AND RESULTS: Systematic search in PubMed, Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL Plus, and SPORTDiscus for randomized controlled trials (RCTs) and nonrandomized pre-post intervention studies investigating the effect of different types of exercise on AF patients. After exclusion, 12 studies (11 RCTs, 1 prepost) with a total of 670 participants were included. Exercise interventions consisted of aerobic exercise, aerobic interval training (AIT), Qigong, yoga, and exercise-based cardiac rehabilitation (CR). There were significant positive effects of exercise on general health {mean difference [MD]â=â6.42 [95% confidence interval (CI): 2.90, 9.93]; Pâ=â0.0003; I2â=â17%} and vitality [MDâ=â6.18 (95% CI: 1.94, 10.41); Pâ=â0.004; I2â=â19%)] sub-scales of the Short Form 36-item questionnaire (SF-36). Qigong resulted in a significant improvement in the 6-min walk test [MDâ=â105.00m (95% CI: 19.53, 190.47)]. Exercise-based CR and AIT were associated with a significant increment in VÌO2peak, and AIT significantly reduced AF burden. Adverse events were few and one intervention-related serious adverse event was reported for exercise-based CR. CONCLUSION: Exercise led to improvements in HRQoL, exercise capacity, and reduced AF burden. The available exercise interventions for AF patients are few and heterogeneous. Future studies are needed for all types of exercise intervention in this patient group to (co-)develop an optimized exercise training intervention for AF patients.