Diagnostic and Therapeutic Approaches for a Diabetic Patient Presenting with Secondary Syphilis and Severe Odynophagia.

Syphilis, an infectious disease caused by the spirochete Treponema pallidum, represents a pervasive global epidemic. Secondary syphilis is typically marked by the emergence of highly contagious mucocutaneous manifestations, including non-pruritic rashes on the palms and soles of the feet, alopecia, mucous patches, and condyloma lata. Here, we report a rare case of a 30-year-old male with newly discovered type 2 diabetes mellitus who presented with severe odynophagia due to secondary syphilis, confirmed by both nontreponemal VDRL/RPR and treponemal TPHA tests. Following the administration of a single-dose intramuscular injection of benzathine penicillin G 2.4 million units, the symptoms gradually decreased, allowing the patient to regain his health.

Electrophysiological and calcium-handling development during long-term culture of human-induced pluripotent stem cell-derived cardiomyocytes.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used for personalised medicine and preclinical cardiotoxicity testing. Reports on hiPSC-CM commonly describe heterogenous functional readouts and underdeveloped or immature phenotypical properties. Cost-effective, fully defined monolayer culture is approaching mainstream adoption; however, the optimal age at which to utilise hiPSC-CM is unknown. In this study, we identify, track and model the dynamic developmental behaviour of key ionic currents and Ca2+-handling properties in hiPSC-CM over long-term culture (30-80 days). hiPSC-CMs > 50 days post differentiation show significantly larger ICa,L density along with an increased ICa,L-triggered Ca2+-transient. INa and IK1 densities significantly increase in late-stage cells, contributing to increased upstroke velocity and reduced action potential duration, respectively. Importantly, our in silico model of hiPSC-CM electrophysiological age dependence confirmed IK1 as the key ionic determinant of action potential shortening in older cells. We have made this model available through an open source software interface that easily allows users to simulate hiPSC-CM electrophysiology and Ca2+-handling and select the appropriate age range for their parameter of interest. This tool, together with the insights from our comprehensive experimental characterisation, could be useful in future optimisation of the culture-to-characterisation pipeline in the field of hiPSC-CM research.

Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes.

[Figure: see text].

Complex Refractory Esophageal Stricture Due to Chronic Gasoline Ingestion: A Case Report.

Esophageal stricture is a narrowing of the esophageal lumen which is often characterized by impaired swallowing or dysphagia. It can be induced by inflammation, fibrosis or neoplasia which damages the mucosa and/or submucosa of the esophagus. Corrosive substance ingestion is one of the major causes of esophageal stricture, particularly in children and young adults. For instance, accidental ingestion or attempted suicide with corrosive household products is not uncommon. Gasoline is a liquid mixture of aliphatic hydrocarbons derived from the fractional distillation of petroleum, which is then combined with additives such as isooctane and aromatic hydrocarbons (e.g., toluene and benzene). Gasoline also contains several other additives including ethanol, methanol and formaldehyde, which make it a corrosive agent. Interestingly, to the best of our knowledge, the incidence of esophageal stricture caused by chronic gasoline ingestion has not been reported. In this paper, we report the case of a patient with dysphagia due to complex esophageal stricture due to chronic gasoline ingestion who underwent a series of esophago-gastro-duodenoscopy (EGD) procedures and repeated esophageal dilation.

Disentangling the Pathogenesis of Systemic Lupus Erythematosus: Close Ties between Immunological, Genetic and Environmental Factors.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that attacks various organ systems with a variety of clinical implications, ranging from mild skin and mucosal manifestations to severe central nervous system manifestations and death. Cases of SLE have been documented nearly two centuries ago when scholars used the terms 'erythema centrifugum' and 'seborrhea congestiva' to describe the discoid skin lesions and the butterfly or malar rash in SLE. Since then, knowledge about this disease has developed rapidly, especially knowledge related to the underlying pathogenesis of SLE. To date, it is known that immune system dysregulation, supported by genetic and environmental predisposition, can trigger the occurrence of SLE in a group of susceptible individuals. Various inflammatory mediators, cytokines and chemokines, as well as intra- and intercellular signaling pathways, are involved in the pathogenesis of SLE. In this review, we will discuss the molecular and cellular aspects of SLE pathogenesis, with a focus on how the immune system, genetics and the environment interact and trigger the various clinical manifestations of SLE.

The Efficacy and Safety of Monoclonal Antibody Treatments Against COVID-19: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: The use of monoclonal antibody as the proposed treatment of COVID-19 showed different results in various prior studies, and Efficacy remains open in literature. This study aimed to comprehensively determine the effect of monoclonal antibodies on clinical, laboratory, and safety outcomes in COVID-19 patients. METHODS: Sixteen RCTs were analyzed in this meta-analysis using RevMan 5.4 to measure the pooled estimates of risk ratios (RRs) and standardized mean differences (SMDs) with 95% CIs. RESULTS: The pooled effect of Monoclonal antibodies demonstrated efficacy on mortality risk reduction (RR=0,89 (95%CI 0.82-0.96), I2=13%, fixed-effect), Tocilizumab also show efficacy on mortality risk reduction for severe-critical disease (RR=0.90 (95%CI 0.83-0.97), I2=12%, fixed-effect)), need for mechanical ventilation (RR=0.76 (95%CI 0.62-0.94), I2=42%, random-effects), and hospital discharge (RR=1.07 (95%CI 1.00-1.14), I2=60%, random-effects). Bamlanivimab monotherapy did not reduce viral load (SMD=-0.07 (95%CI -0.21-0.07), I2=44%, fixed-effect). Monoclonal antibodies did not differ from placebo/standard therapy for hospital discharge at day 28-30 (RR=1.05 (95%CI 0.99-1.12), I2=71%, random-effects) and safety (RR=1.04 (95%CI 0.76-1.43), I2=54%, random-effects). CONCLUSION: Tocilizumab should be used for severe to critical COVID-19 because it is not harmful and can improve mortality risk, mechanical ventilation, and hospital discharge. Bamlanivimab-Etesevimab and REGN-COV2 reduced viral load in mild-moderate outpatients.

Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation.

RATIONALE: Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown. OBJECTIVE: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery. METHODS AND RESULTS: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca2+]i-recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca2+-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca2+-release events and L-type Ca2+-current alternans occurred more frequently. CaMKII (Ca2+/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca2+-content was unchanged in POAF despite greater SR Ca2+-leak, with a trend towards increased SR Ca2+-ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1ß caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca2+-release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca2+-uptake are sufficient to reproduce the Ca2+-handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1ß. CONCLUSIONS: Preexisting Ca2+-handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca2+-releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.

Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias.

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses.

Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca2+-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular- and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced INa, ICa,L, Ito, IKr and IKur, dual effects on IK1 and IK,ACh (inhibition at low and augmentation at high concentrations), and increased INCX and SR Ca2+ leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.

Maastricht antiarrhythmic drug evaluator (MANTA): A computational tool for better understanding of antiarrhythmic drugs.

Cardiac arrhythmias are a global health burden, contributing significantly to morbidity and mortality worldwide. Despite technological advances in catheter ablation therapy, antiarrhythmic drugs (AADs) remain a cornerstone for the management of cardiac arrhythmias. Experimental and translational studies have shown that commonly used AADs exert multiple effects in the heart, the manifestation of which strongly depends on the exact experimental or clinical conditions. This diversity makes the optimal clinical application of AADs challenging. Here, we present a novel computational tool designed to facilitate a better understanding of the complex mechanisms of action of AADs (the Maastricht Antiarrhythmic Drug Evaluator, MANTA). In this tool, we integrated published computational cardiomyocyte models from different species (mouse, guinea pig, rabbit, dog, and human), regions (atrial, ventricular, and Purkinje cells) and disease conditions (atrial fibrillation- and heart failure-related remodeling). Subsequently, we investigated the effects of clinically available AADs (Vaughan-Williams Classes I, III, IV and multi-channel blockers) on action potential (AP) properties and the occurrence of proarrhythmic effects such as early afterdepolarizations. Steady-state drug effects were simulated based on a newly compiled overview of published IC50 values for each cardiac ion channel and by integrating state-dependent block of the cardiac Na+-current by Class I AADs using a Markov-model approach. Using MANTA, we demonstrated and characterized important species-, rate-, cell-type-, and disease-state-specific AAD effects, including 1) a stronger effect of Class III AADs in large mammals than in rodents; 2) a rate-dependent decrease in upstroke velocity with Class I AADs and reverse rate-dependent effects of Class III AADs on action potential duration; 3) ventricular-predominant effects of pure IKr blockers; 4) preferential reduction in atrial AP upstroke velocity with vernakalant; and 5) excessive AP prolongation with Class III AADs other than amiodarone under heart failure conditions. In conclusion, the effects of AADs are highly complex and strongly dependent on the experimental or clinical conditions. MANTA is a powerful and freely available tool reproducing a wide range of AAD characteristics that enables analyses of the underlying ionic mechanisms. Use of MANTA is expected to improve our understanding of AAD effects on cellular electrophysiology under a wide range of conditions, which may provide clinically-relevant information on the safety and efficacy of AAD treatment.

Transforming clinical cardiology through neural networks and deep learning: A guide for clinicians.

The rapid evolution of neural networks and deep learning has revolutionized various fields, with clinical cardiology being no exception. As traditional methods in cardiology encounter limitations, the integration of advanced computational techniques offers unprecedented opportunities in diagnostics and patient care. This review explores the transformative role of neural networks and deep learning in clinical cardiology, particularly focusing on their applications in electrocardiogram (ECG) analysis, imaging technologies, and cardiac prediction models. Among others, Deep Neural Networks (DNNs) have significantly surpassed traditional approaches in accuracy and efficiency in automatic ECG diagnosis. Convolutional Neural Networks (CNNs) are successfully applied in PET/CT and PET/MR imaging, enhancing diagnostic capabilities. Furthermore, deep learning algorithms have shown potential in improving cardiac prediction models, although challenges in interpretability and clinical integration remain. The review also addresses the 'black box' nature of neural networks and the ethical considerations surrounding their use in clinical settings. Overall, this review underscores the significant impact of neural networks and deep learning in cardiology, providing insights into current applications and future directions in the field.

Brugada phenocopy vs. Brugada syndrome: Delineating the differences for optimal diagnosis and management.

Brugada syndrome (BrS) is a genetic disorder known for its characteristic electrocardiogram (ECG) patterns and increased risk of sudden cardiac death. Brugada phenocopy (BrP) presents similar ECG patterns but is distinguished by its reversible nature when the underlying conditions are resolved. This article delineates the intricacies of BrP, emphasizing its etiology, clinical presentation, diagnosis, treatment, and prognosis. The article categorizes BrP based on various underlying causes, including metabolic disturbances, myocardial infarction, and mechanical compression, among others. It also underscores the critical importance of differentiating BrP from BrS to avoid misdiagnosis and inappropriate treatment, such as unnecessary implantation of cardioverter-defibrillators. The reversible aspect of BrP underlines the necessity for an etiology-specific approach to treatment, which not only prevents cardiac death but also highlights the significance of understanding the dynamic nature of ECG patterns. Through an exploration of case studies and current research, this review advocates for increased awareness and further investigation into BrP. It aims to enhance the diagnostic accuracy and management strategies, thereby improving the prognosis for patients presenting with Brugada-like ECG patterns. The review culminates in a call for further research to close existing knowledge gaps and improve patient outcomes.

Peripartum cardiomyopathy unveiled: Etiology, diagnosis, and therapeutic insights.

Peripartum cardiomyopathy (PPCM) remains a significant challenge in maternal health, marked by its unpredictable onset and varied clinical outcomes. With rising incidence rates globally, understanding PPCM is vital for improving maternal care and prognosis. This review aims to consolidate current knowledge on PPCM, highlighting recent advancements in its diagnosis, management, and therapeutic approaches. This comprehensive review delves into the epidemiology of PPCM, underscoring its global impact and demographic variations. We explore the complex etiology of the condition, examining known risk factors and discussing the potential pathophysiological mechanisms, including oxidative stress and hormonal influences. The clinical presentation of PPCM, often similar yet distinct from other forms of cardiomyopathy, is analyzed to aid in differential diagnosis. Diagnostic challenges are addressed, emphasizing the role of advanced imaging and biomarkers. Current management strategies are reviewed, focusing on the absence of disease-specific treatments and the application of general heart failure protocols. The review also discusses the prognosis of PPCM, factors influencing recovery, and the implications for future pregnancies. Finally, we highlight emerging research directions and the urgent need for disease-specific therapies, aiming to provide a roadmap for future studies and improved patient care. This review serves as a crucial resource for clinicians and researchers, contributing to a deeper understanding and better management of PPCM.

Risk of Thrombosis during and after a SARS-CoV-2 Infection: Pathogenesis, Diagnostic Approach, and Management.

Coronavirus disease 2019 (COVID-19) increases the risk of thromboembolic events, especially in patients with severe infections requiring intensive care and cardiorespiratory support. COVID-19 patients with thromboembolic complications have a higher risk of death, and if they survive, these complications are expected to negatively affect these patients' quality of life. Moreover, recent data reported that the risk of thromboembolism remains high months after a COVID-19 infection. Therefore, understanding the pathogenesis of thrombosis in the setting of COVID-19 may facilitate the early prevention and treatment of COVID-19-associated thromboembolism to reduce concomitant morbidity, mortality, and disability. This review will first discuss the clinical characteristics of COVID-19 infections, particularly with regard to the underlying pathophysiology. Then, the pathogenesis of COVID-19-associated thrombosis at the molecular and cellular levels will be comprehensively reviewed. Next, the clinical manifestations of venous and arterial thromboembolism in COVID-19 as well as the potential benefits of several laboratory markers of thrombosis will be further discussed. Lastly, the preventive and therapeutic management of thromboembolism during and after COVID-19 will also be explained.

Current Insights into Cellular Determinants of Peritoneal Fibrosis in Peritoneal Dialysis: A Narrative Review.

Peritoneal fibrosis is the final process of progressive changes in the peritoneal membrane due to chronic inflammation and infection. It is one of the main causes of discontinuation of peritoneal dialysis (PD), apart from peritonitis and cardiovascular complications. Over time, morphological changes occur in the peritoneal membranes of patients who use PD. Of those are mesothelial-to-mesenchymal transition (MMT), neoangiogenesis, sub-mesothelial fibrosis, and hyalinizing vasculopathy. Several key molecules are involved in the complex pathophysiology of peritoneal fibrosis, including advanced glycosylation end products (AGEs), transforming growth factor beta (TGF-ß), and vascular endothelial growth factor (VEGF). This narrative review will first discuss the physiology of the peritoneum and PD. Next, the multifaceted pathophysiology of peritoneal fibrosis, including the effects of hyperglycemia and diabetes mellitus on the peritoneal membrane, and the promising biomarkers of peritoneal fibrosis will be reviewed. Finally, the current and future management of peritoneal fibrosis will be discussed, including the potential benefits of new-generation glucose-lowering medications to prevent or slow down the progression of peritoneal fibrosis.

Myocarditis and coronavirus disease 2019 vaccination: A systematic review and meta-summary of cases.

Vaccination is significant to control, mitigate, and recover from the destructive effects of coronavirus disease 2019 (COVID-19). The incidence of myocarditis following COVID-19 vaccination has been increasing and growing public concern; however, little is known about it. This study aimed to systematically review myocarditis following COVID-19 vaccination. We included studies containing individual patient data of myocarditis following COVID-19 vaccination published between January 1, 2020 and September 7, 2022 and excluded review articles. Joanna Briggs Institute critical appraisals were used for risk of bias assessment. Descriptive and analytic statistics were performed. A total of 121 reports and 43 case series from five databases were included. We identified 396 published cases of myocarditis and observed that the majority of cases was male patients, happened following the second dose of mRNA vaccine administration, and experienced chest pain as a symptom. Previous COVID-19 infection was significantly associated (p < 0.01; OR, 5.74; 95% CI, 2.42-13.64) with the risk of myocarditis following the administration of the first dose, indicating that its primary mechanism is immune-mediated. Moreover, 63 histopathology examinations were dominated by non-infective subtypes. Electrocardiography and cardiac marker combination is a sensitive screening modality. However, cardiac magnetic resonance is a significant noninvasive examination to confirm myocarditis. Endomyocardial biopsy may be considered in confusing and severe cases. Myocarditis following COVID-19 vaccination is relatively benign, with a median length of hospitalization of 5 days, intensive care unit admission of <12%, and mortality of <2%. The majority was treated with nonsteroidal anti-inflammatory drugs, colchicine, and steroids. Surprisingly, deceased cases had characteristics of being female, older age, non-chest pain symptoms, first-dose vaccination, left ventricular ejection fraction of <30%, fulminant myocarditis, and eosinophil infiltrate histopathology.

Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico Study.

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (INa, Ito, ICaL, IKur, IKr, IKs, IK1, INCX and INaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of ICaL and INCX resulted in AP shortening, while the inhibition of IKur, IKr, IKs, IK1 and INaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of IKr and IKs only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of IKr and IKs significantly prolonged APD and vice versa. Additionally, a 50% reduction of Ito density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable IK1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca2+ concentration, promoting a repolarization failure in ICaL upregulation above 150% and facilitating reentrant spiral waves stabilization by ICaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of IKr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model's accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.