Preparation of dearomatized p-coumaric acid derivatives as DNA damage response inhibitors with potent in vitro antitumor effect.

Our research group previously identified graviquinone (1) as a promising antitumor metabolite that is formed in situ when the antioxidant methyl caffeate scavenges free radicals. Furthermore, it exerted a DNA damaging effect on cancer cells and a DNA protective effect on normal keratinocytes. To expand and explore chemical space around qraviquinone, in the current work we synthesized 9 new alkyl-substituted derivatives and tested their in vitro antitumor potential. All new compounds bypassed ABCB1-mediated multidrug resistance and showed highly different cell line specificity compared with 1. All compounds were more potent in MDA-MB-231 than on MCF-7 cells. The n-butyl-substituted derivatives 2 and 8 modulated the cell cycle and inhibited the ATR-mediated phosphorylation of checkpoint kinase-1 in MCF-7 cells. As a significant expansion of our previous findings, our results highlight the potential antitumor value of alkyl-substituted graviquinone derivatives.

Loss-of-function W4645R mutation in the RyR2-caffeine binding site: implications for synchrony and arrhythmogenesis.

AIMS: Previous studies have identified RyR2 W4645R mutation, located in the caffeine-binding site, to associate with CPVT1 pathology. Caffeine binding to its site is thought to displace the carboxyl-terminal domain to Ca2+-binding, allowing the tryptophan residue (W4645) to regulate Ca2+ sensitivity of RyR2. To gain insights into regulation of RyR2 Ca2+-binding and its interaction with caffeine-binding site, we introduced W4645R-RyR2 point mutation via CRISPR/Cas9 gene-editing in human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) and characterized their Ca2+-signaling phenotype compared to WT hiPSCCMs. METHODS AND RESULTS: W4645R-RyR2 cardiomyocytes had: (1) no significant change in ICa magnitude or voltage-dependence; (2) slightly reduced CICR; (3) altered relaxation kinetics of Ca2+-transients with no change in isoproterenol sensitivity; (4) complete loss of caffeine-triggered Ca2+ release; (5) larger SR Ca2+ leak resulting in 40 % lower SR Ca2+ content, as determined by myocytes' response to 4-CmC; (6) lower incidence of calcium sparks and asynchronous spontaneous SR Ca2+ releases. CONCLUSIONS: W4645R-RyR2 mutation induces loss of caffeine-triggered SR Ca2+ release and enhances SR Ca2+ leak that underlie asynchronous spontaneous Ca2+ releases, triggering arrhythmia and impairing cardiac function.

Prognostic impact of the IASLC grading system of lung adenocarcinoma: a systematic review and meta-analysis.

AIMS: Tumour grading is an essential part of the pathologic assessment that promotes patient management. The International Association for the Study of Lung Cancer (IASLC) proposed a grading system for non-mucinous lung adenocarcinoma in 2020. We aimed to validate the prognostic impact of this novel grading system on overall survival (OS) and recurrence-free survival (RFS) based on literature data. METHODS AND RESULTS: The review protocol was registered in PROSPERO (CRD42023396059). We aimed to identify randomized or non-randomized controlled trials published after 2020 comparing different IASLC grade categories in Medline, Embase, and CENTRAL. Hazard ratios (HRs) with 95% confidence intervals (CIs) of OS and RFS were pooled and the Quality In Prognosis Studies (QUIPS) tool was used to assess the risk of bias in the included studies. Ten articles were eligible for this review. Regarding OS estimates, grade 1 lung adenocarcinomas were better than grade 3 both in univariate and multivariate analyses (HROSuni = 0.19, 95% CI: 0.05-0.66, p = 0.009; HROSmulti = 0.21, 95% CI: 0.12-0.38, p < 0.001). Regarding RFS estimates, grade 3 adenocarcinomas had a worse prognosis than grade 1 in multivariate analysis (HRRFSmulti: 0.22, 95% CI: 0.14-0.35, p < 0.001). CONCLUSION: The literature data and the result of our meta-analysis demonstrate the prognostic relevance of the IASLC grading system. This supports the inclusion of this prognostic parameter in daily routine worldwide.

Analysis of the ocular surface functional unit in episodic migraine.

AIM: Migraine is a chronic neurovascular disease that affects the trigeminovascular system. The purpose of this study was to evaluate corneal subbasal nerve fibers, dendritic cells and to measure tear film parameters in migraine. PATIENTS AND METHODS: 87 eyes of 44 patients suffering from migraine with a mean age of 33.23 ± 11.41 years were included in our study. 25 age-matched controls (mean age of 30.16 ± 12.59 years; P = 0.162) were recruited. The corneal subbasal plexus and the dendritic cells (DC) were analyzed using in vivo confocal microscopy (Heidelberg Retina Tomograph II Rostock Cornea Module; Heidelberg Engineering GmbH), and the tear film was imaged using LacryDiag (Quantel Medical, France). RESULTS: Regarding the subbasal nerve fibers of the cornea, none of the examined parameters differed significantly in migraine patients from controls. We found a significant increase in the corneal DC density (P < 0.0001) and DC area (P < 0.0001) in migraine patients compared to healthy volunteers. DC density showed a positive correlation with the monthly attack frequency (r = 0.32, P = 0.041) and the DC area a negative correlation with corneal nerve branch density (r = -0.233, P = 0.039), nerve fiber length (r = -0.232, P = 0.04) and total branch density (r = -0.233, P = 0.039). Using LacryDiag a significant loss of Meibomian gland area could be detected on the superior eyelid (P = 0.005) in migraine. CONCLUSIONS: Our results suggest the presence of neuroinflammation in the cornea of migraine patients affecting the peripheral trigeminal system. Dendritic cells surrounding the subbasal plexus may be involved in the activation and modulation of pain in migraine.

Calcium Signaling Consequences of RyR2-S4938F Mutation Expressed in Human iPSC-Derived Cardiomyocytes.

Type-2 ryanodine receptor (RyR2) is the major Ca2+ release channel of the cardiac sarcoplasmic reticulum (SR) that controls the rhythm and strength of the heartbeat, but its malfunction may generate severe arrhythmia leading to sudden cardiac death or heart failure. S4938F-RyR2 mutation in the carboxyl-terminal was expressed in human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 gene-editing technique. Ca2+ signaling and electrophysiological properties of beating cardiomyocytes carrying the mutation were studied using total internal reflection fluorescence microscopy (TIRF) and patch clamp technique. In mutant cells, L-type Ca2+ currents (ICa), measured either by depolarizations to zero mV or repolarizations from +100 mV to -50 mV, and their activated Ca2+ transients were significantly smaller, despite their larger caffeine-triggered Ca2+ release signals compared to wild type (WT) cells, suggesting ICa-induced Ca2+ release (CICR) was compromised. The larger SR Ca2+ content of S4938F-RyR2 cells may underlie the higher frequency of spontaneously occurring Ca2+ sparks and Ca2+ transients and their arrhythmogenic phenotype.

Proposal of a grading system for squamous cell carcinoma of the lung - the prognostic importance of tumour budding, single cell invasion, and nuclear diameter.

The prognostic markers of lung squamous cell carcinoma (LSCC) are less investigated. The aim of our study was to evaluate tumour budding (TB), minimal cell nest size, nuclear diameter (ND), and spread through air spaces (STAS) among patients with resected LSCC, semi-quantitatively. Furthermore, we aimed to identify a grading system for the best prognostic stratification of LSCC. Patients who underwent surgical resection at the Department of Surgery, University of Szeged between 2010 and 2016 were included. Follow-up data were collected from medical charts. Morphological characteristics were recorded from histologic revision of slides. Kaplan-Meier analysis, log rank test and Cox proportional-hazards model, ROC curve analysis, and intraclass correlation were utilised. Altogether 220 patients were included. In univariate analysis, higher degree of TB, infiltrative tumour border, larger ND, the presence of single cell invasion (SCI) and STAS were associated with adverse prognosis. Based on our results, we proposed an easily applicable grading scheme focusing on TB, ND, and SCI. In multivariate analysis, the proposed grading system (pOS < 0.001, pRFS < 0.001) and STAS (pOS = 0.008, pRFS < 0.001) were independent prognosticators. Compared to the previously introduced grading systems, ROC curve analysis revealed that the proposed grade had the highest AUC values (AUCOS: 0.83, AUCRFS: 0.78). Each category of the proposed grading system has good (ICC: 0.79-0.88) reproducibility. We validated the prognostic impact of TB, SCI, ND, and STAS in LSCC. We recommend a reproducible grading system combining TB, SCI, and ND for proper prognostic stratification of LSCC patients. Further research is required for validation of this grading scheme.

Results of a systematic review and meta-analysis of early studies on ivermectin in SARS-CoV-2 infection.

Ivermectin, an antiparasitic drug, has been repurposed for COVID-19 treatment during the SARS-CoV-2 pandemic. Although its antiviral efficacy was confirmed early in vitro and in preclinical studies, its clinical efficacy remained ambiguous. Our purpose was to assess the efficacy of ivermectin in terms of time to viral clearance based on the meta-analysis of available clinical trials at the closing date of the data search period, one year after the start of the pandemic. This meta-analysis was reported by following the PRISMA guidelines and by using the PICO format for formulating the question. The study protocol was registered on PROSPERO. Embase, MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), bioRvix, and medRvix were searched for human studies of patients receiving ivermectin therapy with control groups. No language or publication status restrictions were applied. The search ended on 1/31/2021 exactly one year after WHO declared the public health emergency on novel coronavirus. The meta-analysis of three trials involving 382 patients revealed that the mean time to viral clearance was 5.74 days shorter in case of ivermectin treatment compared to the control groups [WMD = -5.74, 95% CI (-11.1, -0.39), p = 0.036]. Ivermectin has significantly reduced the time to viral clearance in mild to moderate COVID-19 diseases compared to control groups. However, more eligible studies are needed for analysis to increase the quality of evidence of ivermectin use in COVID-19.

Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibility in a canine model of elite exercise.

The health benefits of regular physical exercise are well known. Even so, there is increasing evidence that the exercise regimes of elite athletes can evoke cardiac arrhythmias including ventricular fibrillation and even sudden cardiac death (SCD). The mechanism of exercise-induced arrhythmia and SCD is poorly understood. Here, we show that chronic training in a canine model (12 sedentary and 12 trained dogs) that mimics the regime of elite athletes induces electrophysiological remodeling (measured by ECG, patch-clamp, and immunocytochemical techniques) resulting in increases of both the trigger and the substrate for ventricular arrhythmias. Thus, 4 months sustained training lengthened ventricular repolarization (QTc: 237.1±3.4 ms vs. 213.6±2.8 ms, n=12; APD90: 472.8±29.6 ms vs. 370.1±32.7 ms, n=29 vs. 25), decreased transient outward potassium current (6.4±0.5 pA/pF vs. 8.8±0.9 pA/pF at 50 mV, n=54 vs. 42), and increased the short-term variability of repolarization (29.5±3.8 ms vs. 17.5±4.0 ms, n=27 vs. 18). Left ventricular fibrosis and HCN4 protein expression were also enhanced. These changes were associated with enhanced ectopic activity (number of escape beats from 0/hr to 29.7±20.3/hr) in vivo and arrhythmia susceptibility (elicited ventricular fibrillation: 3 of 10 sedentary dogs vs. 6 of 10 trained dogs). Our findings provide in vivo, cellular electrophysiological and molecular biological evidence for the enhanced susceptibility to ventricular arrhythmia in an experimental large animal model of endurance training.

The More Extensive the Spread through Air Spaces, the Worse the Prognosis Is: Semi-Quantitative Evaluation of Spread through Air Spaces in Pulmonary Adenocarcinomas.

INTRODUCTION: The extent of spread through air spaces (STAS) is less investigated among patients with lung adenocarcinoma who underwent sublobar resection. Therefore, we aimed to evaluate the extent of STAS semi-quantitatively, to assess its prognostic impact on overall survival (OS) and recurrence-free survival (RFS), and to investigate the reproducibility of this assessment. METHODS: The number of tumour cell clusters and single tumour cells within air spaces was recorded in three different most prominent areas (200x field of view). The extent of STAS was categorized into three groups, and the presence of free tumour cluster (FTC) was recorded. RESULTS: Sixty-one patients were included. Recurrence was more frequent with higher grade (p = 0.003), presence of lymphovascular invasion (p = 0.027), and presence of STAS of any extent (p = 0.007). In multivariate analysis, presence of FTC (HR: 5.89; 95% CI: 1.63-21.26; p = 0.005) and more pronounced STAS (HR: 7.46; 95% CI: 1.60-34.6; p = 0.01) had adverse impact on OS and RFS, respectively. Concerning reproducibility, excellent agreement was found among STAS parameters (ICC range: 0.92-0.94). DISCUSSION: More extensive STAS is an unfavourable prognostic factor in adenocarcinomas treated with sublobar resection. As the evaluation of extent of STAS is reproducible, further investigation is required to gather more evidence.

The reverse mode of the Na+/Ca2+ exchanger contributes to the pacemaker mechanism in rabbit sinus node cells.

Sinus node (SN) pacemaking is based on a coupling between surface membrane ion-channels and intracellular Ca2+-handling. The fundamental role of the inward Na+/Ca2+ exchanger (NCX) is firmly established. However, little is known about the reverse mode exchange. A simulation study attributed important role to reverse NCX activity, however experimental evidence is still missing. Whole-cell and perforated patch-clamp experiments were performed on rabbit SN cells supplemented with fluorescent Ca2+-tracking. We established 2 and 8 mM pipette NaCl groups to suppress and enable reverse NCX. NCX was assessed by specific block with 1 µM ORM-10962. Mechanistic simulations were performed by Maltsev-Lakatta minimal computational SN model. Active reverse NCX resulted in larger Ca2+-transient amplitude with larger SR Ca2+-content. Spontaneous action potential (AP) frequency increased with 8 mM NaCl. When reverse NCX was facilitated by 1 µM strophantin the Ca2+i and spontaneous rate increased. ORM-10962 applied prior to strophantin prevented Ca2+i and AP cycle change. Computational simulations indicated gradually increasing reverse NCX current, Ca2+i and heart rate with increasing Na+i. Our results provide further evidence for the role of reverse NCX in SN pacemaking. The reverse NCX activity may provide additional Ca2+-influx that could increase SR Ca2+-content, which consequently leads to enhanced pacemaking activity.

Antiarrhythmic and Inotropic Effects of Selective Na+/Ca2+ Exchanger Inhibition: What Can We Learn from the Pharmacological Studies?

Life-long stable heart function requires a critical balance of intracellular Ca2+. Several ion channels and pumps cooperate in a complex machinery that controls the influx, release, and efflux of Ca2+. Probably one of the most interesting and most complex players of this crosstalk is the Na+/Ca2+ exchanger, which represents the main Ca2+ efflux mechanism; however, under some circumstances, it can also bring Ca2+ into the cell. Therefore, the inhibition of the Na+/Ca2+ exchanger has emerged as one of the most promising possible pharmacological targets to increase Ca2+ levels, to decrease arrhythmogenic depolarizations, and to reduce excessive Ca2+ influx. In line with this, as a response to increasing demand, several more or less selective Na+/Ca2+ exchanger inhibitor compounds have been developed. In the past 20 years, several results have been published regarding the effect of Na+/Ca2+ exchanger inhibition under various circumstances, e.g., species, inhibitor compounds, and experimental conditions; however, the results are often controversial. Does selective Na+/Ca2+ exchanger inhibition have any future in clinical pharmacological practice? In this review, the experimental results of Na+/Ca2+ exchanger inhibition are summarized focusing on the data obtained by novel highly selective inhibitors.

[Changes of the T cell composition in the thymus during the COVID-19 pandemic]. / A csecsemomirigy T-sejtjeinek összetételében létrejövo változások a COVID­19-pandémia alatt.

INTRODUCTION: In our study, we aimed to investigate whether the COVID-19 infection itself or the vaccination against it affect the differentiation of T cells in the thymus, and whether the reduction in T cell counts observed in the blood of COVID-19-infected individuals is also observed at the tissue level in the thymus. METHOD: Data from a total of 55 thymectomy patients were processed to create three groups: 1) the pre-COVID-19 (PC) group included 22 patients, 12 women and 10 men, who underwent thymectomy between 2008 and 2013; 2) in the no-COVID-19 (NC) group (patients without verified infection or vaccination), 20 patients, 11 women and 9 men, underwent thymectomy in 2020-2021; 3) the vaccinated or infected COVID-19 (VIC) group included 13 patients, 4 women and 9 men, who underwent thymectomy also in 2020-2021. The pathological samples were immunohistochemically tested for CD4, CD8, CD25 and FOXP3 to verify the helper, cytotoxic and regulatory T cells. RESULTS: The VIC group had significantly lower values for CD4, compared to the PC and NC groups. The FOXP3 value was significantly lower in the VIC and NC groups compared to the PC group. No significant differences were found for CD8 and CD25 between the groups studied. DISCUSSION: The COVID-19 infection or vaccination affects the T cell composition of the thymus. Decreased expression of CD4 has been demonstrated in the VIC group, which confirms a decrease in the T cell counts that also occurs in the thymus. The low FOXP3 levels observed in the NC group during the COVID-19 era, compared to the PC group, may be indicative of a high rate of asymptomatic coronavirus infections and a worsening of immunetolerance. CONCLUSION: First in the world, we have verified that the helper T cell composition of the thymus in COVID-19 infection era is reduced, and in the asymptomatic patients the immune function is decreased as well. Orv Hetil. 2022; 163(52): 2062-2066.

Adjuvant chemotherapy could improve the survival of pulmonary sarcomatoid carcinoma: A systematic review and meta-analysis.

BACKGROUND: Complete surgical removal is currently considered to be the best treatment option for pulmonary sarcomatoid carcinoma (PSC) especially in early stage operable disease; however, the reported recurrence-free survival is low. Benefits of adjuvant chemotherapy in PSC patients are still controversial, and there is no obvious agreement on the optimal treatment modalities of this disease. Therefore, we aimed to investigate the prognosis in terms of overall survival (OS) in patients with PSC who received adjuvant chemotherapy. METHODS: The review protocol was registered in PROSPERO (CRD42022306084). Patients with PSC who underwent surgical therapy with or without adjuvant chemotherapy were included into the meta-analysis. Hazard ratios (HR) with 95% confidence intervals (CIs) for OS were pooled and ROBINS-I tool was used to assess risk of bias of the included studies. RESULTS: We identified four retrospective cohort studies with 6768 records from MEDLINE, Embase, and CENTRAL databases up to 9th September 2021, and altogether 1835 patients were included to the analysis. The present meta-analysis shows that patients receiving adjuvant chemotherapy had a significantly longer OS than patients who underwent surgical treatment alone (HR = 0.5657, 95%CI: 0.4391-0.7290, p < 0.0001). CONCLUSIONS: Despite the limited information on the chemotherapy regimens in the included studies, patients with PSC may benefit from adjuvant chemotherapy. More publications are required to evaluate and compare efficient adjuvant chemotherapy protocols in PSC cases.

Perioperative Systemic Inflammation in Lung Cancer Surgery.

Systemic inflammation (SI) is a response of the immune system to infectious or non-infectious injuries that defends the body homeostasis. Every surgical intervention triggers SI, the level of which depends on the extent of damage caused by the surgery. During the first few hours after the damage, the innate or natural immunity, involving neutrophils, macrophages, and natural killer cells, plays a main role in the defense mechanism, but thereafter the adaptive immune response ensues. The number of leukocytes is elevated, the levels of lymphocytes and natural killer cells are reduced, and the cytokines released after surgery correlate with surgical damage. Minimally invasive thoracic surgery procedures induce less inflammatory response and reduce the immune defense in patients to a more moderate level compared with the open surgery procedures; this immunosuppression can be further diminished in spontaneous ventilation cases. The normal functioning of the immune defense is important in controlling the perioperative circulatory tumor cells. Moreover, elevated levels of inflammatory cytokines before immune therapy have a negative impact on the response, and significantly shorten the progression-free survival. Clinically, the lower are the levels of cytokines released during lung surgery, the lesser is the postoperative morbidity, especially pneumonia and wound infection. The return to normal levels of lymphocytes and cytokines occurs faster after spontaneous ventilation surgery. The use of locoregional anesthesia can also reduce SI. Herein, we review the current knowledge on the effects of different operative factors on postoperative SI and defense mechanism in lung cancer surgery.

Metabolomic Analysis of Serum and Tear Samples from Patients with Obesity and Type 2 Diabetes Mellitus.

Metabolomics strategies are widely used to examine obesity and type 2 diabetes (T2D). Patients with obesity (n = 31) or T2D (n = 26) and sex- and age-matched controls (n = 28) were recruited, and serum and tear samples were collected. The concentration of 23 amino acids and 10 biogenic amines in serum and tear samples was analyzed. Statistical analysis and Pearson correlation analysis along with network analysis were carried out. Compared to controls, changes in the level of 6 analytes in the obese group and of 10 analytes in the T2D group were statistically significant. For obesity, the energy generation, while for T2D, the involvement of NO synthesis and its relation to insulin signaling and inflammation, were characteristic. We found that BCAA and glutamine metabolism, urea cycle, and beta-oxidation make up crucial parts of the metabolic changes in T2D. According to our data, the retromer-mediated retrograde transport, the ethanolamine metabolism, and, consequently, the endocannabinoid signaling and phospholipid metabolism were characteristic of both conditions and can be relevant pathways to understanding and treating insulin resistance. By providing potential therapeutic targets and new starting points for mechanistic studies, our results emphasize the importance of complex data analysis procedures to better understand the pathomechanism of obesity and diabetes.

The Inhibition of the Small-Conductance Ca2+-Activated Potassium Channels Decreases the Sinus Node Pacemaking during Beta-Adrenergic Activation.

Sinus pacemaking is based on tight cooperation of intracellular Ca2+ handling and surface membrane ion channels. An important player of this synergistic crosstalk could be the small-conductance Ca2+-activated K+-channel (ISK) that could contribute to the sinoatrial node (SAN) pacemaking driven by the intracellular Ca2+ changes under normal conditions and beta-adrenergic activation, however, the exact role is not fully clarified. SK2 channel expression was verified by immunoblot technique in rabbit SAN cells. Ionic currents and action potentials were measured by patch-clamp technique. The ECG R-R intervals were obtained by Langendorff-perfusion method on a rabbit heart. Apamin, a selective inhibitor of SK channels, was used during the experiments. Patch-clamp experiments revealed an apamin-sensitive current. When 100 nM apamin was applied, we found no change in the action potential nor in the ECG R-R interval. In experiments where isoproterenol was employed, apamin increased the cycle length of the SAN action potentials and enhanced the ECG R-R interval. Apamin did not amplify the cycle length variability or ECG R-R interval variability. Our data indicate that ISK has no role under normal condition, however, it moderately contributes to the SAN automaticity under beta-adrenergic activation.

Acetylcholine Reduces IKr and Prolongs Action Potentials in Human Ventricular Cardiomyocytes.

Vagal nerve stimulation (VNS) has a meaningful basis as a potentially effective treatment for heart failure with reduced ejection fraction. There is an ongoing VNS randomized study, and four studies are completed. However, relatively little is known about the effect of acetylcholine (ACh) on repolarization in human ventricular cardiomyocytes, as well as the effect of ACh on the rapid component of the delayed rectifier K+ current (IKr). Here, we investigated the effect of ACh on the action potential parameters in human ventricular preparations and on IKr in human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). Using standard microelectrode technique, we demonstrated that ACh (5 µM) significantly increased the action potential duration in human left ventricular myocardial slices. ACh (5 µM) also prolonged repolarization in a human Purkinje fiber and a papillary muscle. Optical mapping revealed that ACh increased the action potential duration in human left ventricular myocardial slices and that the effect was dose-dependent. Perforated patch clamp experiments demonstrated action potential prolongation and a significant decrease in IKr by ACh (5 µM) in hiPSC-CMs. Computer simulations of the electrical activity of a human ventricular cardiomyocyte showed an increase in action potential duration upon implementation of the experimentally observed ACh-induced changes in the fully activated conductance and steady-state activation of IKr. Our findings support the hypothesis that ACh can influence the repolarization in human ventricular cardiomyocytes by at least changes in IKr.

In vivo and cellular antiarrhythmic and cardiac electrophysiological effects of desethylamiodarone in dog cardiac preparations.

BACKGROUND AND PURPOSE: The aim of the present study was to study the antiarrhythmic effects and cellular mechanisms of desethylamiodarone (DEA), the main metabolite of amiodarone (AMIO), following acute and chronic 4-week oral treatments (25-50 mg·kg-1 ·day-1 ). EXPERIMENTAL APPROACH: The antiarrhythmic effects of acute iv. (10 mg·kg-1 ) and chronic oral (4 weeks, 25 mg·kg-1 ·day-1 ) administration of DEA were assessed in carbachol and tachypacing-induced dog atrial fibrillation models. Action potentials were recorded from atrial and right ventricular tissue following acute (10 µM) and chronic (p.o. 4 weeks, 50 mg·kg-1 ·day-1 ) DEA application using the conventional microelectrode technique. Ionic currents were measured by the whole cell configuration of the patch clamp technique in isolated left ventricular myocytes. Pharmacokinetic studies were performed following a single intravenous dose (25 mg·kg-1 ) of AMIO and DEA intravenously and orally. In chronic (91-day) toxicological investigations, DEA and AMIO were administered in the oral dose of 25 mg·kg-1 ·day-1 ). KEY RESULTS: DEA exerted marked antiarrhythmic effects in both canine atrial fibrillation models. Both acute and chronic DEA administration prolonged action potential duration in atrial and ventricular muscle without any changes detected in Purkinje fibres. DEA decreased the amplitude of several outward potassium currents such as IKr , IKs , IK1 , Ito , and IKACh , while the ICaL and late INa inward currents were also significantly depressed. Better drug bioavailability and higher volume of distribution for DEA were observed compared to AMIO. No neutropenia and less severe pulmonary fibrosis was found following DEA compared to that of AMIO administration. CONCLUSION AND IMPLICATIONS: Chronic DEA treatment in animal experiments has marked antiarrhythmic and electrophysiological effects with better pharmacokinetics and lower toxicity than its parent compound. These results suggest that the active metabolite, DEA, should be considered for clinical trials as a possible new, more favourable option for the treatment of cardiac arrhythmias including atrial fibrillation.

Effect of ivabradine in heart failure: a meta-analysis of heart failure patients with reduced versus preserved ejection fraction.

In clinical trials of heart failure reduced ejection fraction (HFrEF), ivabradine seemed to be an effective heart rate lowering agent associated with lower risk of cardiovascular death. In contrast, ivabradine failed to improve cardiovascular outcomes in heart failure preserved ejection fraction (HFpEF) despite the significant effect on heart rate. This meta-analysis is the first to compare the effects of ivabradine on heart rate and mortality parameters in HFpEF versus HFrEF. We screened three databases: PubMed, Embase, and Cochrane Library. The outcomes of these studies were mortality, reduction in heart rate, and left ventricular function improvement. We compared the efficacy of ivabradine treatment in HFpEF versus HFrEF. Heart rate analysis of pooled data showed decrease in both HFrEF (-17.646 beats/min) and HFpEF (-11.434 beats/min), and a tendency to have stronger bradycardic effect in HFrEF (p = 0.094) in randomized clinical trials. Left ventricular ejection fraction analysis revealed significant improvement in HFrEF (5.936, 95% CI: [4.199-7.672], p < 0.001) when compared with placebo (p < 0.001). We found that ivabradine significantly improves left ventricular performance in HFrEF, at the same time it exerts a tendency to have improved bradycardic effect in HFrEF. These disparate effects of ivabradine and the higher prevalence of non-cardiac comorbidities in HFpEF may explain the observed beneficial effects in HFrEF and the unchanged outcomes in HFpEF patients after ivabradine treatment.

Pulmonary necrotizing sarcoid granulomatosis / A tüdo nekrotizáló sarcoid granulomatosisa.

Összefoglaló. A nekrotizáló sarcoid granulomatosis a granulomatosus pulmonalis angitisek közé tartozó, ritka kórkép. Egyesek a sarcoidosis variánsának, mások primer pulmonalis vasculitisnek tartják. A kórkép klinikai és patológiai jellegzetességeit két eset bemutatásával ismertetjük. A 20 éves nobeteg sürgosséggel került pulmonológiai osztályra száraz köhögés, jobb oldali, mély belégzéssel összefüggo mellkasi fájdalom és láz miatt, a 63 éves férfi beteget pedig pneumoniát követo kontroll-mellkasröntgenfelvételen látott elváltozás kivizsgálása során észlelték. Az autoimmun panel vizsgálata, a mikrobiológiai tesztek mindkét betegnél negatívnak bizonyultak, a légzésfunkciós vizsgálat és a bronchoszkópos vizsgálat nem talált eltérést. A mellkas-CT-felvételen lágyrész-denzitású nodulusok látszottak egyoldali dominanciával, a folyamatot nem kísérte a hilusi nyirokcsomók szimmetrikus megnagyobbodása. A nodulusok szövettani vizsgálata vált indokolttá, melyet videoasszisztált torakoszkópos tüdoreszekciós mintavétellel biztosítottak. Mikroszkóposan a tüdoparenchymában gócos nekrózisokat, a környezetükben el nem sajtosodó epitheloid sejtes granulomatosus gócokat, az átfutó artériákban pedig granulomatosus arteritist láttak; a klinikai adatok figyelembevételével a tüdo nekrotizáló sarcoid granulomatosisa diagnózisát állították fel. A tüdobetegség mindkét betegnél egy év alatt spontán regrediált. Az irodalom adatait és az eseteket összegezve, a tüdo nekrotizáló sarcoid granulomatosisában mikrobiológiai vizsgálatokkal nem igazolható tüdofertozés, és az immunológiai kivizsgálás sem tár fel szisztémás autoimmun betegséget; a diagnózis a klinikai kép és a képalkotó vizsgálatok alapján indikált szövettani vizsgálattal állítható fel. A betegség szteroidkezelésre jól reagál, de elofordul spontán regresszió is, az utóbbira láttunk példát. Bár az entitás átmenetet képez a nekrotizáló vasculitisek és a sarcoidosis között, egyre több érv szól amellett, hogy a sarcoidosis spektrumába tartozik. Orv Hetil. 2021; 162(38): 1541-1547. Summary. Necrotizing sarcoid granulomatosis is a rare entity currently classified as a subtype of granulomatous pulmonary angiitis. It is considered to be either a variant of sarcoidosis or a primary pulmonary angiitis. Two cases are demonstrated to present its clinical and pathological features. A 20-year-old female patient was admitted to the department of pulmonology with dry cough, right-sided chest pain during hyperventilation and fever. A 63-year-old male patient was observed with a right-sided lesion on chest X-ray after pneumonia. In both cases, autoimmune panel examination, microbiology tests, spirometry function test and bronchoscopy were unremarkable. Chest CT scans have revealed nodules with soft-tissue density without bilateral hilar lymphadenopathy. In order to clarify the diagnosis, video-assisted thoracoscopic resection (biopsy) was performed. Microscopically, parenchymal focal necrosis with adjacent to non-caseating granulomas and granulomatous angiitis were detected. In both cases, spontaneous remission occurred within a year. Histological examination - integrated with clinical data and radiological tests' results - is the gold standard form of evaluation to confirm necrotizing sarcoid granulomatosis; furthermore, exclusion of pneumonia and autoimmune diseases are also required. The disease responds well to corticosteroids; moreover, spontaneous remission is often reported, as it happened in both cases. Necrotizing sarcoid granulomatosis is a transition between necrotizing vasculitides and sarcoidosis; although more and more evidence appears supporting the fact that necrotizing sarcoid granulomatosis may belong to the spectrum of sarcoidosis. Orv Hetil. 2021; 162(38): 1541-1547.