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Abstract Objectives Current recommendations support surgical treatment of atrial fibrillation (AF) in patients indicated for cardiac surgery. These procedures are referred to as concomitant and may be carried out using radiofrequency energy or cryo-ablation. This study aimed to assess the electrophysiological findings in patients undergoing concomitant cryo-ablation. Methods Patients with non-paroxysmal AF undergoing coronary artery bypass grafting and/or valve repair/replacement were included in the trial if concomitant cryo-ablation was part of the treatment plan according to current guidelines. The patients reported in this study were assigned to undergo staged percutaneous radiofrequency catheter ablation (PRFCA), i.e., hybrid treatment, as a part of the SURHYB trial protocol. Results We analyzed 103 patients who underwent PRFCA 105 ± 35 days after surgery. Left and right pulmonary veins (PVs) were found isolated in 65 (63.1%) and 63 (61.2%) patients, respectively. The LA posterior wall isolation and mitral isthmus conduction block were found in 38 (36.9%) and 18 (20.0%) patients, respectively. Electrical reconnections (gaps) in the left PVs were more often localized superiorly than inferiorly (57.9% vs. 26.3%, P = 0.005) and anteriorly than posteriorly (65.8% vs. 31.6%, P = 0.003). Gaps in the right PVs were more equally distributed anteroposteriorly but dominated in superior segments (72.5% vs. 40.0%, P = 0.003). There was a higher number of gaps on the roof line compared to the inferior line (131 (67.2%) vs. 67 (42.2%), P

The asymmetric transfer hydrogenation (ATH) of imines catalyzed by the Noyori-Ikariya [RuCl(η6-arene)(N-arylsulfonyl-DPEN)] (DPEN = 1,2-diphenylethylene-1,2-diamine) half-sandwich complexes is a research topic that is still being intensively developed. This article focuses on selected aspects of this catalytic system. First, a great deal of attention is devoted to the N-arylsulfonyl moiety of the catalysts in terms of its interaction with protonated imines (substrates) and amines (components of the hydrogen-donor mixture). The second part is oriented toward the role of the η6-coordinated arene. The final part concerns the imine substrate structural modifications and their importance in connection with ATH. Throughout the text, the summary of known findings is complemented with newly-presented ones, which have been approached both experimentally and computationally.

Objectives: To search for optimal markers in the exhaled breath condensate (EBC), plasma and urine that would reflect the activity/ severity of occupational asthma (OA) after the withdrawal from the exposure to the allergen. Material and Methods: Markers of oxidative stress: 8-iso-prostaglandin F2α (8-isoprostane, 8-ISO), malondialdehyde (MDA), 4-hydroxy-trans-2-nonenale (HNE), cysteinyl leukotrienes (LT) and LTB4 were determined using liquid chromatography and mass spectrometry in 43 subjects with immunological OA (49.3±11.8 years), removed from the exposure to the sensitizing agent 10.5±6.5 years ago; and in 20 healthy subjects (49.0±14.9 years). EBC was harvested both before and after the methacholine challenge test. In parallel, identical markers were collected in plasma and urine. The results were analyzed together with forced expiratory volume in one second (FEV1), blood eosinophils, immunoglobulin E (IgE) and eosinophilic cationic protein (ECP) and statistically evaluated (Spearman rank correlation rS, two- or one-sample t tests and alternatively Kruskal Wallis or pair Wilcoxon tests). Results: Several parameters of lung functions were lower in the patients (FEV1% predicted, MEF25% and MEF50%, Rtot%, p < 0.001). Shorter time interval since the removal from the allergen exposure correlated with higher ECP (rS = 0.375) and lower FEV1%, MEF25% and MEF50% after methacholine challenge (rS = -0.404, -0.425 and -0.532, respectively). In the patients, IgE (p < 0.001) and ECP (p = 0.009) was increased compared to controls. In EBC, 8-ISO and cysteinyl LTs were elevated in the asthmatics initially and after the challenge. Initial 8-ISO in plasma correlated negatively with FEV1 (rS = -0.409) and with methacholine PD20 (rS = -0.474). 8-ISO in plasma after the challenge correlated with IgE (rS = 0.396). Conclusions: The improvement in OA is very slow and objective impairments persist years after removal from the exposure. Cysteinyl LTs and 8-ISO in EBC and 8-ISO in plasma might enrich the spectrum of useful objective tests for the follow-up of OA.

This review is oriented toward the asymmetric transfer hydrogenation (ATH) of imines regarding mostly fundamental, yet important topics from the practical point of view. Development of analytical methods for the monitoring of ATH (i.e., kinetics and stereoselectivity) belongs to those topics, as well as studies on the influence of reaction conditions and structural variations on the reaction performance. The second part is devoted to the reaction mechanism with the emphasis on imine ATH and catalyst behaviour under acidic conditions. The review also addresses the asymmetric hydrogenation (AH) of ketones and imines using molecular hydrogen and the application of ATH in pharmaceutical projects. The contributions of our group to each area are included.

Methods for the asymmetric transfer hydrogenation (ATH) of ketones and imines are still being intensively studied and developed. Of foremost interest is the use of Noyori’s [RuCl(η6-arene)(N-TsDPEN)] complexes in the presence of a hydrogen donor (i-PrOH, formic acid). These complexes have found numerous practical applications and have been extensively modified. The resulting derivatives have been heterogenized, used in ATH in water or ionic liquids and even some attempts have been made to approach the properties of biocatalysts. Therefore, an appropriate modification of the catalyst that suits the specific requirements for the reaction conditions is very often readily available. The mechanism of the reaction has also been explored to a great extent. Model substrates, acetophenone (a ketone) and 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (an imine), are both reduced by this Ru catalytic system with almost perfect selectivity. However, in each case the major product is a different enantiomer (S- for an alcohol, R- for an amine when the S,S-catalyst is used), which demanded an in-depth mechanistic investigation. Full-scale molecular modelling of this system enabled us to visualize the plausible 3D structures of the transition states, allowing the proposition of a viable explanation of previous experimental findings.

Background. Monitoring nociception during general anaesthesia remains a substantial challenge. The Conox monitor uses two EEG indices, the qCon and the qNox. The qNox refers to the probability that a nociceptive stimulation triggers a movement of the patient and the response probability of reaction to nociceptive stimulation. We decided to test the feasibility of monitoring the qNOX index during adult cardiac surgery and to investigate whether this index correlates with hemodynamic and hormonal signs of nociceptive stimulation. Method. We enrolled 19 patients undergoing elective cardiac surgery. These were randomised to 2 groups receiving different doses of sufentanil via target controlled infusion: group A (n=9) 0.25 ng/mL and group B (n=10) 0.75 ng/mL. All patients were maintained at the same depth of anaesthesia. We recorded the Conox monitor indices (qNOX, qCON, electromyographic), hemodynamic variables and plasmatic levels of cortisol and noradrenaline. Results. There was significantly higher blood pressure (P=0.013) and plasmatic cortisol (P=0.003) in group A and a significant increase in plasmatic noradrenaline with increasing intensity of surgical stimulation in both groups: A (P=0.001), B (P=0.008). We found no significant corresponding changes in the qNOX index. There was a positive correlation between qNOX and hemodynamic signs of stimulation (P=0.012) and between the qNOX and EMG indices (P=0.013) after endotracheal intubation, but not later after EMG index dropped. Conclusion. Our results do not support the assumption that signs of nociceptive stimulation during adult cardiac surgery will be reflected by the qNOX index. This may be related to compounding of qNOX processing and use of muscle relaxants. Further investigation on this field is needed.

BackgroundSurgery for type A aortic dissection (TAAD) is associated with high risk of mortality. Current risk scoring methods have a limited predictive accuracy.MethodsSubjects were patients who underwent surgery for acute TAAD at 18 European centers of cardiac surgery from the European Registry of Type A Aortic Dissection (ERTAAD).ResultsOut of 3,902 patients included in the ERTAAD, 2,477 fulfilled the inclusion criteria. In the validation dataset (2,229 patients), the rate of in-hospital mortality was 18.4%. The rate of composite outcome (in-hospital death, stroke/global ischemia, dialysis, and/or acute heart failure) was 41.2%, and 10-year mortality rate was 47.0%. Logistic regression identified the following patient-related variables associated with an increased risk of in-hospital mortality [area under the curve (AUC), 0.755, 95% confidence interval (CI), 0.729–0.780; Brier score 0.128]: age; estimated glomerular filtration rate; arterial lactate; iatrogenic dissection; left ventricular ejection fraction ≤50%; invasive mechanical ventilation; cardiopulmonary resuscitation immediately before surgery; and cerebral, mesenteric, and peripheral malperfusion. The estimated risk score was associated with an increased risk of composite outcome (AUC, 0.689, 95% CI, 0.667–0.711) and of late mortality [hazard ratio (HR), 1.035, 95% CI, 1.031–1.038; Harrell's C 0.702; Somer's D 0.403]. In the validation dataset (248 patients), the in-hospital mortality rate was 16.1%, the composite outcome rate was 41.5%, and the 10-year mortality rate was 49.1%. The estimated risk score was predictive of in-hospital mortality (AUC, 0.703, 95% CI, 0.613–0.793; Brier score 0.121; slope 0.905) and of composite outcome (AUC, 0.682, 95% CI, 0.614–0.749). The estimated risk score was predictive of late mortality (HR, 1.035, 95% CI, 1.031–1.038; Harrell's C 0.702; Somer's D 0.403), also when hospital deaths were excluded from the analysis (HR, 1.024, 95% CI, 1.018–1.031; Harrell's C 0.630; Somer's D 0.261).ConclusionsThe present analysis identified several baseline clinical risk factors, along with preoperative estimated glomerular filtration rate and arterial lactate, which are predictive of in-hospital mortality and major postoperative adverse events after surgical repair of acute TAAD. These risk factors may be valuable components for risk adjustment in the evaluation of surgical and anesthesiological strategies aiming to improve the results of surgery for TAAD.Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT04831073.

Background: Acute type A aortic dissection (TAAD) is associated with significant mortality and morbidity. In this study we evaluated the prognostic significance of preoperative arterial lactate concentration on the outcome after surgery for TAAD. Methods: The ERTAAD registry included consecutive patients who underwent surgery for acute type A aortic dissection (TAAD) at 18 European centers of cardiac surgery. Results: Data on arterial lactate concentration immediately before surgery were available in 2798 (71.7 %) patients. Preoperative concentration of arterial lactate was an independent predictor of in-hospital mortality (mean, 3.5 ± 3.2 vs 2.1 ± 1.8 mmol/L, adjusted OR 1.181, 95%CI 1.129–1.235). The best cutoff value preoperative arterial lactate concentration was 1.8 mmol/L (in-hospital mortality, 12.0 %, vs. 26.6 %, p

Background. Post-infarction left ventricular free wall rupture (LVFWR) is a feared and catastrophic complication of myocardial infarction that carries a high surgical and hospital mortality. Due to the rarity of this complication, little information exists on surgical treatment and outcomes. Goal and Methods. The goal of this study was to present our experience with LVFWR. We present a retrospective cohort of 19 consecutive patients who were surgically treated in the Cardiac Centre of the Institute of Clinical and Experimental Medicine in Prague between January 2006 and December 2017. Results. Thirty-day mortality was 26%. Five patients died. Four patients died in the operating theatre and one patient on the ninth postoperative day following re-rupture. Seventy-four percent of the patient cohort survived and were discharged from hospital. The median length of follow-up was 45 months (range 0.75-150). No patient died during follow-up. Median postoperative ejection fraction was 45% (range 25-65%). Angina pectoris and dyspnea were investigated during follow-up and graded according to the Canadian cardiology society (CCS) and the New York Heart Association (NYHA) classifications. Fourteen patients had CCS class I, eight patients had NYHA class I dyspnea and six patients had NYHA class II. Re-rupture occurred after hospital discharge in one patient one month after the original surgery. The patient was treated successfully by urgent surgical intervention. Conclusion. LVFWR is a catastrophic and challenging complication of myocardial infarction. Good outcomes can be achieved by rapid diagnosis and urgent surgical intervention as shown by our results.

Abstract Background Aortic dissection is a relatively uncommon, but often catastrophic disease that requires early and accurate diagnosis. It often presents in patients with congenital connective tissue disorders. The current aortic surgical techniques are related with serious early and late complications. This case report emphasizes the importance of early diagnosis of aortic root dilatation and the risk of dissection, especially in patients with congenital connective tissue disorders. We present an alternative, contemporary and multidisciplinary approach based on the present state of knowledge. Case presentation We present a rare case of a young female patient with Loeys-Dietz syndrome who was admitted with an uncomplicated aortic dissection (Stanford type B / DeBakey type III) and a dilated aortic root. After a period of close surveillance and extensive vascular imaging, thoracic endovascular aortic repair was deemed to be technically not possible. Medical treatment was optimized and our patient successfully underwent a personalised external aortic root support procedure (PEARS) as a contemporary alternative to existing aortic root surgical techniques. Conclusions This case highlights the importance of interdisciplinary approach, close follow-up and multimodality imaging. The decision to intervene in a chronic type B aortic dissection is still challenging and should be made in experienced centers by an interdisciplinary team. However, if an acute complication occurs, thoracic endovascular aortic repair TEVAR is the method of choice. In all cases optimal medical treatment is important. There is increasing evidence that personalized external aortic root support procedure PEARS is effective in stabilizing the aortic root and preventing its dilatation and dissection not only in patients with Marfan syndrome, but also in other cases of aortic root dilation of other etiologies. Moreover, many publications have reported the additional benefit of reduction or even eradication of aortic regurgitation by improving coaptation of the aortic valve leaflets in dilated aortas.

Abstract Background and aims Dicarbonyl stress plays an important role in the pathogenesis of microvascular complications that precede the formation of advanced glycation end products, and contributes to the development of renal dysfunction. In renal cells, toxic metabolites like methylglyoxal lead to mitochondrial dysfunction and protein structure modifications. In our study, we investigated the effect of methylglyoxal on metabolic, transcriptomic, metabolomic and proteomic profiles in the context of the development of kidney impairment in the model of metabolic syndrome. Materials and methods Dicarbonyl stress was induced by intragastric administration of methylglyoxal (0.5 mg/kg bw for 4 weeks) in a strain of hereditary hypertriglyceridaemic rats with insulin resistance and fatty liver. Results Methylglyoxal administration aggravated glucose intolerance (AUC0–120 p

Abstract Clinical and experimental studies indicate that muscarinic acetylcholine receptors are potential pharmacological targets for the treatment of neurological diseases. Although these receptors have been described in human, bovine and rat cerebral microvascular tissue, a subtype functional characterization in mouse brain endothelium is lacking. Here, we show that all muscarinic acetylcholine receptors (M1-M5) are expressed in mouse brain microvascular endothelial cells. The mRNA expression of M2, M3, and M5 correlates with their respective protein abundance, but a mismatch exists for M1 and M4 mRNA versus protein levels. Acetylcholine activates calcium transients in brain endothelium via muscarinic, but not nicotinic, receptors. Moreover, although M1 and M3 are the most abundant receptors, only a small fraction of M1 is present in the plasma membrane and functions in ACh-induced Ca2+ signaling. Bioinformatic analyses performed on eukaryotic muscarinic receptors demonstrate a high degree of conservation of the orthosteric binding site and a great variability of the allosteric site. In line with previous studies, this result indicates muscarinic acetylcholine receptors as potential pharmacological targets in future translational studies. We argue that research on drug development should especially focus on the allosteric binding sites of the M1 and M3 receptors.

Introduction. The development of metabolic syndrome-associated renal dysfunction is exacerbated by a number of factors including dyslipidemia, ectopic deposition of lipids and their toxic metabolites, impairment of lipid metabolism, and insulin resistance. Renal dysfunction is also affected by the production of proinflammatory and profibrotic factors secreted from adipose tissue, which can in turn directly impair kidney cells and potentiate insulin resistance. In this study, we investigated the manifestation of renal lipid accumulation and its effect on renal dysfunction in a model of metabolic syndrome—the hereditary hypertriglyceridemic rat (HHTg)—by assessing microalbuminuria and targeted urinary proteomics. Male Wistar control rats and HHTg rats were fed a standard diet and observed over the course of ageing at 3, 12, and 20 months of age. Results. Chronically elevated levels of triglycerides in HHTg rats were associated with increased levels of NEFA during OGTT and over a period of 24 hours (+80%, P

The present pilot study tested the efficiency of nanoTiO2 sunscreen to prevent the oxidative stress/inflammation caused by ultraviolet (UV) radiation using biomarkers in subjects’ blood, urine, and exhaled breath condensate (EBC). In addition, the skin absorption of nanoTiO2 was studied. Six identical subjects participated in three tests: (A) nanoTiO2 sunscreen, (B) UV radiation, and (C) sunscreen + UV. The first samples were collected before the test and the second after sunscreen application and/or UV exposure. On day 4, the third samples were collected, and the sunscreen was washed off, and the fourth samples were collected on day 11. The following biomarkers were measured: malondialdehyde, 4-hydroxy-trans-hexenal, 4-hydroxy-trans-nonenal, aldehydes C6-C12, 8-iso-Prostaglandin F2α, o-tyrosine, 3-chlorotyrosine, 3-nitrotyrosine, 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine, 5-hydroxymethyl uracil, and leukotrienes, using liquid chromatography-electrospray ionisation-tandem mass spectrometry. Titania was measured using inductively coupled plasma mass spectrometry and TiO2 nanoparticles by transmission and scanning electron microscopy. Sunscreen alone did not elevate the markers, but UV increased the biomarkers in the plasma, urine, and EBC. The sunscreen prevented skin redness, however it did not inhibit the elevation of oxidative stress/inflammatory markers. Titania and nanoTiO2 particles were found in the plasma and urine (but not in the EBC) in all sunscreen users, suggesting their skin absorption.

Thousands of researchers and workers worldwide are employed in nanocomposites manufacturing, yet little is known about their respiratory health. Aerosol exposures were characterized using real time and integrated instruments. Aerosol mass concentration ranged from 0.120 mg/m3 to 1.840 mg/m3 during nanocomposite machining processes; median particle number concentration ranged from 4.8 × 104 to 5.4 × 105 particles/cm3. The proportion of nanoparticles varied by process from 40 to 95%. Twenty employees, working in nanocomposite materials research were examined pre-shift and post-shift using spirometry and fractional exhaled nitric oxide (FeNO) in parallel with 21 controls. Pro-inflammatory leukotrienes (LT) type B4, C4, D4, and E4; tumor necrosis factor (TNF); interleukins; and anti-inflammatory lipoxins (LXA4 and LXB4) were analyzed in their exhaled breath condensate (EBC). Chronic bronchitis was present in 20% of researchers, but not in controls. A significant decrease in forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) was found in researchers post-shift (p ˂ 0.05). Post-shift EBC samples were higher for TNF (p ˂ 0.001), LTB4 (p ˂ 0.001), and LTE4 (p ˂ 0.01) compared with controls. Nanocomposites production was associated with LTB4 (p ˂ 0.001), LTE4 (p ˂ 0.05), and TNF (p ˂ 0.001), in addition to pre-shift LTD4 and LXB4 (both p ˂ 0.05). Spirometry documented minor, but significant, post-shift lung impairment. TNF and LTB4 were the most robust markers of biological effects. Proper ventilation and respiratory protection are required during nanocomposites processing.

Researchers in nanocomposite processing may inhale a variety of chemical agents, including nanoparticles. This study investigated airway oxidative stress status in the exhaled breath condensate (EBC). Nineteen employees (42.4 ± 11.4 y/o), working in nanocomposites research for 18.0 ± 10.3 years were examined pre-shift and post-shift on a random workday, together with nineteen controls (45.5 ± 11.7 y/o). Panels of oxidative stress biomarkers derived from lipids, nucleic acids, and proteins were analyzed in the EBC. Aerosol exposures were monitored during three major nanoparticle generation operations: smelting and welding (workshop 1) and nanocomposite machining (workshop 2) using a suite of real-time and integrated instruments. Mass concentrations during these operations were 0.120, 1.840, and 0.804 mg/m3, respectively. Median particle number concentrations were 4.8 × 104, 1.3 × 105, and 5.4 × 105 particles/cm3, respectively. Nanoparticles accounted for 95, 40, and 61%, respectively, with prevailing Fe and Mn. All markers of nucleic acid and protein oxidation, malondialdehyde, and aldehydes C6–C13 were elevated, already in the pre-shift samples relative to controls in both workshops. Significant post-shift elevations were documented in lipid oxidation markers. Significant associations were found between working in nanocomposite synthesis and EBC biomarkers. More research is needed to understand the contribution of nanoparticles from nanocomposite processing in inducing oxidative stress, relative to other co-exposures generated during welding, smelting, and secondary oxidation processes, in these workshops.

Perinatal immune challenge leads to neurodevelopmental dysfunction, permanent immune dysregulation and abnormal behaviour, which have been shown to have translational validity to findings in human neuropsychiatric disorders (e.g. schizophrenia, mood and anxiety disorders, autism, Parkinson's disease and Alzheimer's disease). The aim of this animal study was to elucidate the influence of early immune stimulation triggered by systemic postnatal lipopolysaccharide administration on biochemical, histopathological and morphological measures, which may be relevant to the neurobiology of human psychopathology. In the present study of adult male Wistar rats we examined the brain and plasma levels of monoamines (dopamine, serotonin), their metabolites, the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid and the levels of tryptophan and its metabolites from the kynurenine catabolic pathway. Further, we focused on histopathological and morphological markers related to pathogenesis of brain diseases--glial cell activation, neurodegeneration, hippocampal volume reduction and dopaminergic synthesis in the substantia nigra. Our results show that early immune stimulation in adult animals alters the levels of neurotransmitters and their metabolites, activates the kynurenine pathway of tryptophan metabolism and leads to astrogliosis, hippocampal volume reduction and a decrease of tyrosine hydroxylase immunoreactivity in the substantia nigra. These findings support the crucial pathophysiological role of early immune stimulation in the above mentioned neuropsychiatric disorders.