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High-power short-duration (HPSD) ablation is an increasingly used ablation strategy for pulmonary vein isolation (PVI) procedures, but Lesion Index (LSI)-guided HPSD radiofrequency (RF) applications have not been described in this clinical setting. We evaluated the procedural efficiency and safety of an LSI-guided HPSD strategy for atrial fibrillation (AF) ablation. Paroxysmal and persistent AF patients scheduled for AF ablation were prospectively enrolled and divided into two groups, according to the ablation power used (≥45 W for the LSI-HP Group and ≤40 W for the LSI-LP group). All patients underwent only PVI LSI-guided ablation (5.5 to 6 anteriorly; 5 to 5.5 superiorly, 4.5 to 5 posteriorly) with a point-by-point strategy and an inter-lesion distance <6 mm. Forty-six patients with AF (25 in the LSI-HP Group vs 21 in the LSI-LP Group)-59% paroxysmal, 78% male, with low-intermediate CHA 2 DS 2 -Vasc scores (2 [1-3]), a preserved ejection fraction (65 ± 6%) and a mean left atrial index volume of 39 ± 13 mL/m 2 were prospectively enrolled. Baseline clinical characteristics were comparable between groups. PVI was successful in all patients. The RF time (29 (23-37) vs. 49 (41-53) min, p < 0.001), total procedure time (131 (126-145) vs. 155 (139-203) min, p = 0.007) and fluoroscopy time (12 (10-18) vs. 21 (16-26) min, p = 0.001) were significantly lower in the LSI-HP Group. No complications or steam pops were seen in either group. LSI-HP AF ablation significantly improved procedural efficiency-reducing ablation time, total procedural duration, and fluoroscopy use, while maintaining a comparable safety profile to lower-power procedures.

Introduction: Transcatheter atrial fibrillation (AF) ablation is still carried out with continuous invasive radial arterial blood pressure (IBP) monitoring in many centers. Continuous noninvasive blood pressure (CNBP) measurement using the volume-clamp method is a noninvasive alternative method used in ICU. No data on CNBP reliability are available in the electrophysiology lab during AF ablation, where rhythm variations are common., Background: The objective of the present study was to compare continuous noninvasive arterial pressure measured with the ClearSight device (Edwards Lifesciences, Irvine, CA, USA) with invasive radial artery pressure used as the reference method during AF ablation., Methods: We prospectively enrolled 55 consecutive patients (age 62 ± 11 years, 80% male) undergoing transcatheter AF ablation (62% paroxysmal, 38% persistent) at our center. Standard of care IBP monitoring via a radial cannula and a contralateral noninvasive finger volume-clamp CNBP measurement device were positioned simultaneously in all patients for the entire procedure. Bland-Altman analysis was used to analyze the agreement between the two techniques., Results: A total of 1219 paired measurements for systolic, diastolic, and mean arterial pressure were obtained in 55 subjects, with a mean (SD) of 22 (9) measurements per patient. The mean bias (SD) was -12.97 (13.89) mmHg for systolic pressure (level of agreement -14.24-40.20; correlation coefficient 0.84), -1.85 (8.52) mmHg for diastolic pressure (level of agreement -18.54-14.84; correlation coefficient 0.77) and 2.31 (8.75) mmHg for mean pressure (level of agreement -14.84-19.46; correlation coefficient 0.85)., Conclusion: In patients undergoing AF ablation, CNBP monitoring with the ClearSight device showed acceptable agreement with IBP monitoring. Larger studies are needed to confirm the potential clinical implications of continuous noninvasive BP monitoring during AF ablation.

During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid ( trans - 1 ). For the preparation of racemic trans - 1 , the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans - 1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-( 2R,3R )- 1 represents a reference compound for the configurational study of structurally related lactams.

Introduction: Marrubium vulgare is a herbal remedy presents in several European Pharmacopoeias and commonly marketed as white horehound. The chemotaxonomic marker of Marrubium genus is marrubiin and its content may change in response to biotic and abiotic stress., Objective: Development of a microwave-assisted solvent extraction (MASE) methodology suitable for exhaustively extracting marrubiin from M. vulgare leaves, easily applicable to large sets of samples. Evaluation of the influence of copper(II) on marrubiin production., Material and Methods: M. vulgare leaves were dried, extracted exploiting MASE and analysed via high-performance liquid chromatography ultraviolet photodiode array detection (HPLC-UV/PAD) system. A design of experiments approach was adopted to select the best extraction conditions. Extraction parameters (solvent composition, extraction time and temperature), were studied applying two full factorial experimental designs in a sequential approach. To analyse samples, a rapid HPLC-UV/PAD method was set up., Results: The best results in terms of marrubiin extraction yield were obtained extracting samples at 120°C with 100% ethanol, for 15 min (3 × 5 min microwave cycles). The developed methodology was successfully applied to matrices grown in Greenhouse conditions and under stress induced by copper(II), selected as model agent for abiotic stress. Progressively decreasing production of marrubiin was evidenced in connection with treatment with 80, 200 and 300 mg/L copper sulphate., Conclusion: An efficient methodology for the extraction and determination of the amount of marrubiin in large sets of samples of M. vulgare plants was developed. Results demonstrated that marrubiin is an easily detectable marker useful for evaluating M. vulgare reaction to stress., (© 2019 John Wiley & Sons, Ltd.)

The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies ( i.e. , cancer and neurodegeneration) have highlighted their potential as therapeutic targets. In this scenario, Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs have been gaining growing attention. Compounds able to modulate the complex stability could constitute an innovative pharmacological strategy for the treatment of numerous diseases. Nevertheless, medicinal-chemistry efforts aimed at developing such compounds are still at an early stage. As part of our ongoing research in this field, we hereby present the rational design and synthesis of structurally novel HuR ligands, potentially acting as HuR-RNA interferers. The following assessment of the structural features of their interaction with HuR, combining saturation-transfer difference NMR and in silico studies, provides a guide for further research on the development of new effective interfering compounds of the HuR-RNA complex., Competing Interests: The authors declare no competing financial interest.

Post-transcriptional processes have been recognised as pivotal in the control of gene expression, and impairments in RNA processing are reported in several pathologies (i.e., cancer and neurodegeneration). Focusing on RNA-binding proteins (RBPs), the involvement of Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs in the aetiology of various dysfunctions, has suggested the great potential of compounds able to interfere with the complex stability as an innovative pharmacological strategy for the treatment of numerous diseases. Here, we present a rational follow-up investigation of the interaction between ELAV isoform HuR and structurally-related compounds (i.e., flavonoids and coumarins), naturally decorated with different functional groups, by means of STD-NMR and Molecular Modelling. Our results represent the foundation for the development of potent and selective ligands able to interfere with ELAV-RNA complexes.

Effective therapies for chronic or non-healing wounds are still lacking. These tissue insults often result in severe clinical complications (i.e., infections and/or amputation) and sometimes lead to patient death. Accordingly, several research groups have focused their efforts in finding innovative and powerful therapeutic strategies to overcome these issues. On the basis of these considerations, the comprehension of the molecular cascades behind these pathological conditions could allow the identification of molecules against chronic wounds. In this context, the regulation of the Protein Kinase C (PKC) cascade has gained relevance in the prevention and/or reparation of tissue damages. This class of phosphorylating enzymes has already been considered for different physiological and pathological pathways and modulation of such enzymes may be useful in reparative processes. Herein, the recent developments in this field will be disclosed, highlighting the pivotal role of PKC α and δ in regenerative medicine. Moreover, an overview of well-established PKC ligands, acting via the modulation of these isoenzymes, will be deeply investigated. This study is aimed at re-evaluating widely known PKC modulators, currently utilized for treating other diseases, as fruitful molecules in wound-healing., Competing Interests: The authors declare no conflict of interest.

Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania infections. As a part of our ongoing study on the phytochemical characterization and biological investigation of plants used in the traditional medicine of western and central Asia, in the present study, we focused on Eremurus persicus root extract in order to evaluate its potential in the treatment of leishmaniosis. As a result of our study, aloesaponol III 8-methyl ether (ASME) was isolated for the first time from Eremurus persicus root extract, its chemical structure elucidated by means of IR and NMR experiments and the ( R ) configuration assigned by optical activity measurements: chiroptical aspects were investigated with vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies and DFT (density functional theory) quantum mechanical calculations. Concerning biological investigations, our results clearly proved that ( R )-ASME inhibits Leishmania infantum promastigotes viability (IC 50 73 µg/mL), inducing morphological alterations and mitochondrial potential deregulation. Moreover, it is not toxic on macrophages at the concentration tested, thus representing a promising molecule against Leishmania infections.

20-(S)-Camptothecin (CPT) is a natural alkaloid extracted from the bark of Camptotheca acuminata (Chinese happy tree). It acts as a DNA topoisomerase 1 poison with an interesting antitumor activity and its use is limited by low stability and solubility and unpredictable drug-drug interactions. Since the late 20th century, it has been widely used in cancer therapy and, since extraction yields from plant tissues are very low, various synthetic routes have been developed to satisfy the increase in demand for CPT. Moreover, SAR studies have allowed for the development of more potent CPT analogues topotecan and irinotecan. Unfortunately, resistance has already occurred in several tumour lines. Additional studies are needed to better understand the relationship between substituents and resistance, its clinical relevance and the impact of related gene polymorphism. One of the latest research approaches focuses on modifying the delivery mode to improve tumour cell uptake and reduce toxicity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

X-ray crystal structures of acetylcholine binding proteins (AChBPs) have revealed two different possible extensions to the classical ligand binding pocket known to accommodate various nicotinic agonists. One of the pockets is limited in size while the other is of considerable dimensions and protrudes along the interfacial cleft between subunits. To probe these putative extensions in functional nicotinic acetylcholine receptors (nAChRs), elongated analogs of 3-(dimethylamino)butyl dimethylcarbamate (DMABC) and 1-(pyridine-3-yl)-1,4-diazepane were prepared and characterized pharmacologically at neuronal heteromeric nAChRs. Although the new analogs, relative to parent compounds, displayed lower binding affinities, functional characterization of selected compounds revealed that they had retained partial α4β2 nAChR agonist activity. The structure-activity relationship data did not indicate an upper limit to the size of substituents as would have been expected if the ligand was bound in the smaller pocket. The data were better in agreement with a binding mode in which substituents protrude along the interfacial cleft of the receptor. This was further supported by docking into a homology model of the α4-β2 nAChR interface and by surface plasmon resonance biosensor analysis of binding of the compounds to acetylcholine-binding proteins, where they exhibit preference for Lymnaea stagnalis ACh binding protein (Ls-AChBP) over the Aplysia california ACh binding protein (Ac-AChBP). These results suggest new opportunities for expanding chemical space in the development of partial agonist and may be of interest in relation to development of novel smoking cessation aids., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Renin and aldosterone are involved in an organ perfusion pathway that may be an estimate of disease severity. The primary objective was to explore the relationship between outcome and aldosterone and renin levels at medical intensive care unit (MICU) admissions in comparison to SAPS II scores., Methods: This retrospective study was conducted on patients admitted to the adult MICU during 12 months. Exclusion: subjects with creatinine >176 mmol/l, chronic arrhythmia and ACE-inhibitor therapy. Admission aldosterone and renin plasma levels were measured and SAPS II scores were calculated., Results: Eighty-two patients were included. Only the plasma renin median concentration difference between survivors and non-survivors was significant (P=0.0168). The area under the ROC curve for mortality and plasma renin concentration was similar to that of SAPS II. The correlation between mortality and renin >84 pg/mL showed an odds ratio of 5.78±3.45, P=0.003., Conclusion: Renin was correlated to outcome in critically ill medical patients.