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Background: Fetal aortic valvuloplasty (FAV) is proposed to prevent hypoplastic left heart syndrome due to fetal critical aortic stenosis., Objective: to report our experience on FAV as the first step in a complex therapeutic strategy., Method: Series of patients with FAV over an 18-year period., Results: 27 FAVs were performed in 26 fetuses, with technical success in 82% (22/27) and periprocedural fetal demise in 22% (6/27), decreasing to 15% in the second half-cohort. Loss to follow-up was due to birth or postnatal therapy in other centers (5) and termination of pregnancy (1), A normal-sized LV at birth was observed in 46% (6/13), 4 neonates underwent aortic valvuloplasty and 2 cardiac surgeries, with 5/6 achieving biventricular circulation at 28 days, and 3 transplant-free survival at mid-term follow-up. The 7/13 born with a borderline LV underwent LV rehabilitation strategy, with survival at 28 days in 4/7 and at mid-term in 3: one with biventricular circulation, one with a ventricle-and-a-half repair, and one lost to follow-up., Conclusion: FAV was feasible in most cases, with no maternal complications, and biventricular circulation at 28 days in ∼40% of survivors. After FAV, a diverse range of postnatal cardiac interventions are performed, reflecting the challenging innovation in current cardiovascular therapy., (© 2024 John Wiley & Sons Ltd.)

The aim of this work was to propose a preliminary local diagnostic reference levels (DRL) for pediatric interventional cardiology (PIC) procedures in Argentina, for different ranges of age and weight. This work has been conducted in the framework of the "Optimization of Protection in Pediatric Interventional Radiology in Latin America and the Caribbean" (OPRIPALC) program coordinated by the World Health Organization and the Pan American Health Organization in cooperation with the International Atomic Energy Agency to ensuring that radiation exposures of pediatric patients are the minimum necessary during fluoroscopy-guided interventional procedures. The local DRL values presented in this paper by weight group and age group were 7.1 Gy·cm 2 (<5 kg), 10.7 Gy·cm 2 (5-15 kg), 18.0 Gy·cm 2 (15-30 kg), 15.9 Gy·cm 2 (30-50 kg), and 28.2 Gy·cm 2 (50-80 kg) and 5.3 Gy·cm 2 (<1), 11.2 Gy·cm 2 (1 to 5<), 19.6 Gy·cm 2 (5 to 10<), and 21.4 Gy·cm 2 (10 to 16<), respectively. Our dose results are among the values found in other international studies; however, there is great potential for dose optimization.

In crystal structures of melatonin MT 1 and MT 2 receptors, a lipophilic subpocket has been characterized which accommodates the phenyl ring of the potent agonist 2-phenylmelatonin. This subpocket appears a key structural element to achieve high binding affinity and selectivity for the MT 2 receptor. A series of 2-arylindole ligands was synthesized to probe the requirements for the optimal occupation and interaction with the 2-phenyl binding pocket. Thermodynamic integration simulations applied to MT 1 and MT 2 receptors in complex with the α-naphthyl derivative provided a rationale for the MT 2 -selectivity and investigation on the binding mode of a couple of atropisomers allowed to define the available space and arrangement of substituents inside the subpocket. Interestingly, more hydrophilic 2-aza-substituted compounds displayed high binding affinity and molecular dynamics simulations highlighted polar interaction with residues from the subpocket that could be responsible for their potency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

(1) Background: Cystic fibrosis (CF) is characterized by chronic pulmonary inflammation and persistent bacterial infections. P. aeruginosa is among the main opportunistic pathogens causing infections in CF. P. aeruginosa is able to form a biofilm, decreasing antibiotic permeability. LOX, a lipoxygenase enzyme, is a virulence factor produced by P. aeruginosa and promotes its persistence in lung tissues. The aim of this study is to evaluate if antibiotics currently used for aerosol therapy in CF are able to interfere with the production of lipoxygenase from open isolates of P. Aeruginosa from patients with CF. (2) Methods: Clinical isolates of P. aeruginosa from patients with CF were grown in Luria broth (LB). Minimum inhibitory concentration (MIC) was performed and interpreted for all isolated strains according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. We selected four antibiotics with different mechanisms of action: aztreonam, colistin, amikacin, and levofloxacin. We used human pulmonary epithelial NCI-H929 cells to evaluate LOX activity and its metabolites according to antibiotic action at increasing concentrations. (3) Results: there is a correlation between LOX secretion by clinical isolates of P. aeruginosa and biofilm production. Levofloxacin exhibits highly significant inhibitory activity compared to the control. Amikacin also exhibits significant inhibitory activity against LOX production. Aztreonam and colistin do not show inhibitory activity. These results are also confirmed for LOX metabolites. (4) Conclusions: among the evaluated antibiotics, levofloxacin and amikacin have an activity on LOX secretion.

Bacterial biofilms form on inert and living surfaces and display high levels of resistance to antibiotics, making it difficult to eradicate biofilm-related infections. Erdosteine, a thiol-based drug used in the treatment of acute and chronic respiratory diseases, has multiple pharmacodynamic properties (mucolytic, anti-inflammatory, antioxidant), suggesting that it may have potential in controlling biofilm-related infections. This in vitro study aimed to evaluate the effects of erdosteine in combination with different antibiotics against methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) biofilms. Biofilm production/mass and bacterial viability were measured using crystal violet absorbance and resorufin resonance, respectively, in young (6 h) and mature (24 h) biofilms incubated with antibiotics [at concentrations from 0 to 200 times the minimum inhibitory concentration (MIC)] for 24 h in the absence or presence of erdosteine (2, 5 and 10 mg/L). In 6-h MRSA biofilms, vancomycin and linezolid displayed concentration-dependent reductions in biofilm mass and viability, which was enhanced in the presence of increasing concentrations of erdosteine. Similar results were seen for amoxicillin/clavulanate and levofloxacin against 6-h MSSA biofilms. Antibiotics alone had reduced efficacy against 24-h biofilms, while the effect of the erdosteine-antibiotic combination was significantly greater against 24-h biofilms (MRSA and MSSA). These results suggest that erdosteine enhances the activity of the antibiotic by facilitating its penetration into biofilms and by disrupting the extracellular polymeric substance matrix, which should be confirmed with further studies. The potential clinical value of erdosteine in treating biofilm-related infections warrants further investigation., Competing Interests: Competing interests FS has received speaking fees from GSK, Pfizer and MSD in the past 3 years. All other authors declare no competing interests., (Copyright © 2022. Published by Elsevier Ltd.)

Transcatheter pulmonary valve replacement has become an attractive alternative to surgical approach in patients with dysfunctional right ventricular outflow tract. However, in certain cases, an unfavorable anatomy might complicate optimal valve deployment and stability. Several techniques have been described to reshape the landing zone and allow proper implantation of the transcatheter valve. Among them, the hybrid approach has gained attention as an interesting method for off-pump pulmonary valve replacement in patients with dilated right ventricular outflow tract. But to date, there is no standardized method to resize and reshape the landing zone for the stented valve. Here, we describe a reproducible method based on simple geometric rules to allow adequate remodeling of the main pulmonary artery to the desired dimensions in a single attempt, followed by perventricular implantation of a Venus P-valve.

N -anilinoethylamides are a class of melatoninergic agents with the aniline portion mimicking the indole ring of the natural ligand and the ethylamide chain reproducing that of melatonin. The simplest compound in this class, N -{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (UCM793), has nanomolar binding affinity for MT 1 and MT 2 membrane receptors. To explore the effect of chain conformation on receptor binding, a methyl group was inserted on the methylene alpha or beta to the amide nitrogen and conformational equilibria were investigated by NMR spectroscopy and molecular dynamics simulations. Receptor affinity was conserved only for the beta-methyl derivative, which also showed significant stereoselectivity, with the ( S ) enantiomer being the eutomer. Molecular dynamics simulations, validated by NMR spectroscopy, showed that the beta-methyl group affects the conformational preferences of the ethylamide chain. Docking into the receptor crystal structure provides a rationale for the observed chiral recognition, suggesting that the ( S )-beta-methyl group favors the conformation that better fits the receptor binding site.

Activation of melatonin receptors and inhibition of fatty acid amide hydrolase (FAAH) have both shown potential benefits for the treatment of glaucoma. To exploit the combination of these biological activities in single therapeutic agents, we designed dual-acting compounds sharing the pharmacophore elements required for the two targets, in search for balanced potencies as MT 1 /MT 2 agonists and FAAH inhibitors. In particular, the N-anilinoethylamide scaffold, previously developed for melatonergic ligands, was decorated at meta position with a polymethylene linker bound to an O-arylcarbamate group, substituted according to known structure-activity relationships for FAAH inhibition. For the most active series, the N-anilinoethylamide portion was also replaced with the indole scaffold of melatonin. O-Biphenyl-3-ylcarbamate derivatives were characterized by remarkable and balanced activity at both targets, in the nanomolar range for compound 29. Topical administration reduced elevated intraocular pressure in rabbits, with a longer action and improved efficacy compared to the reference compounds melatonin and URB597.

Melatonin has been indicated as a possible oncostatic agent in different types of cancer, its antiproliferative role being demonstrated in several in vitro and in vivo experimental models of tumors. Specifically, melatonin was proven to inhibit cell growth of both androgen-dependent and independent prostate cancer cells, through various mechanisms. A number of melatonin derivatives have been developed and tested for their role in the prevention and treatment of neoplastic diseases. We recently proved the in vitro and in vivo anticancer activity of UCM 1037, a newly-synthetized melatonin analogue, on melanoma and breast cancer cells. In this study we evaluated UCM 1037 effects on cell proliferation, cell cycle distribution, and cytotoxicity in LNCaP, PC3, DU145, and 22Rv1 prostate cancer cells. We demonstrated significant dose- and time-dependent UCM 1037 antiproliferative effects in androgen-sensitive LNCaP and 22Rv1 cells. Data from flow cytometric studies suggest that UCM 1037 is highly cytotoxic in androgen-sensitive prostate cancer cells, although no substantial increase in the apoptotic cell fraction has been observed. UCM 1037 cytotoxic effects were much less evident in androgen-insensitive PC3 and DU145 cells. Experiments performed to gain insights into the possible mechanism of action of the melatonin derivative revealed that UCM 1037 down-regulates androgen receptor levels and Akt activation in LNCaP and 22Rv1 cells.

A new family of melatonin receptor ligands, characterized by a tetrahydroquinoline (THQ) scaffold carrying an amide chain in position 3, was devised as conformationally constrained analogs of flexible N-anilinoethylamides previously developed. Molecular superposition models allowed to identify the patterns of substitution conferring high receptor binding affinity and to support the THQ ring as a suitable scaffold for the preparation of melatonin ligands. The biological activity of 3-acylamino-THQs was compared with that of the corresponding tetralin derivatives. The THQ ring proved to be a versatile scaffold for easy feasible MT 1 and MT 2 ligands, which resulted as more polar bioisosteres of their tetralin analogs. Potent partial agonists, with subnanomolar binding affinity for the MT 2 receptor, were obtained, and a new series of THQ derivatives is presented. The putative binding mode of potent THQs and tetralines was discussed on the basis of their conformational equilibria as inferred from molecular dynamics simulations and experimental NMR data.

Due to increasing bacterial resistance and poor availability of new antibiotics, physicians need to use old, still active antibiotics more frequently. In this study, we focused on clo-foctol and aimed to verify the emergence of clofoctol resistance over time. Additionally, the ability of clofoctol to induce resistance under static and dynamic conditions was evaluated. The minimum inhibitory concentration (MIC) values measured in pathogens isolated from 1990 to 1995 were compared to those isolated from 2017 to 2018. The behaviour of clofoctol is similar to that of amoxicillin, while erythromycin shows a different behaviour with an increase in MIC. A rapid decline in CFUs with complete eradication at 96 and 120 h in the case of clofoctol and amoxicillin, respectively, was observed in a dynamic in vitro model of a pharmacokinetic simulation. Erythromycin provides a reduction in CFUs of approximately one order of magnitude for up to 72 h, and then re-growth is observed. The MIC trend was observed during 5 days of kinetic simulation. The clofoctol MICs remain almost stable up to 96 h, after which the colonies are no longer detectable. The MICs of amoxicillin show a 2-fold increase starting from 36 h; however, at 120 h the colonies are no longer detectable. The MICs of erythromycin show a progressive increase starting from 72 h and reaching 32-fold. Clofoctol maintains its activity towards the common pathogens of respiratory tract infections and, similarly to amoxicillin, does not induce resistance in a strain of Streptococcus pneumoniae, resulting in complete eradication, while erythromycin was able to select resistant mutants., (© 2019 S. Karger AG, Basel.)

Melatonin plays different physiological functions ranging from the regulation of circadian rhythms to tumor inhibition, owing to its antioxidant, immunomodulatory and anti-aging properties. Due to its pleiotropic functions, melatonin has been shown to elicit cytoprotective processes in normal cells and trigger pro-apoptotic signals in cancer cells. The therapeutic potential of melatonin analogues prompted us to investigate the in vitro and in vivo antitumor activity of new melatonin derivatives and explore the underlying molecular mechanisms. The experiments revealed that the new melatonin analogues inhibited the growth of melanoma and breast cancer cells in a dose- and time-dependent manner. In addition, our results indicated that melatonin derivative UCM 1037 could induce apoptosis in melanoma and breast cancer cells, as well as cell necrosis, in MCF-7. Together, apoptosis and necrosis could be two possible mechanisms to explain the cytotoxic effect of the melatonin analogue against cancer cells. The suppression of tumor growth by the melatonin analogues was further demonstrated in vivo in a xenograft mice model. A decrease in the activation of MAPK pathway was observed in all cancer cells following UCM 1037 treatment. Overall, this study describes a promising antitumor compound showing antiproliferative and cytotoxic activity in melanoma and breast cancer cells., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interests for the manuscript.

Molecular superposition models guided the design of novel melatonin receptor ligands characterized by a 2-acylaminomethyltetrahydroquinoline scaffold. Starting from the structure of N-anilinoethylamide ligands, the flexible chain was conformationally constrained to reproduce the bioactive conformation of melatonin. Structure-activity relationships were investigated, focusing on the substituent at the nitrogen atom, the position of the methoxy group, and the replacement of the amide side chain by urea and thiourea groups. The compounds were tested for binding affinity and intrinsic activity at human MT1 and MT2 receptors. Structural optimization resulted in N-[(1-benzyl-1,2,3,4-tetrahydro-5-methoxyquinolin-2-yl)methyl]propionamide (UCM1014), with picomolar MT2 binding affinity (K(i) = 0.001 nM), more than 10000-fold selectivity over the MT1 receptor, and a full agonist profile (GTPγS test), being the most potent MT2-selective full agonist reported to date. Molecular dynamics simulations provided a rationale for high binding affinity, stereoselectivity, and agonist behavior of these novel melatonin receptor ligands based on superposition models and conformational preference.

Background: Transcatheter closure of a moderate to large patent ductus arteriosus (PDA) using conventional techniques is challenging. The Nit-Occlud® PDA-R trial can close a PDA up to 8 mm in diameter. We sought to report procedural and six-month efficacy and safety results of the multicenter Nit-Occlud® PDA-R trial., Methods: From June 2010 to February 2011, 43 patients were enrolled in three centers from Argentina. Median age was 4.5 (range 1.4-18.4 years) years old at catheterization, 70% were females and weight was 17.7 (range 10-67 kg)., Results: PDAs mean diameter was 2.98 ± 1.03 and ranged from 2 to 6.19 mm. About 11.6% were large (≥4 mm), whereas 32.6% were <2.5 mm. Median pulmonary artery mean pressure was 17 mm Hg (range 9-26 mm Hg). The device was implanted successfully in all patients. By echocardiography, trivial residual shunt was observed in 42% at the end of the procedure, in 28% at 24 hr, in 12.1% at one week, and none at three-months. There was one case of embolization (due to undersizing), that was treated successfully with a larger study device. There were no major short- or long-term complications., Conclusions: PDAs ranging from 2 to 6 mm can be effectively and safely closed using the Nit-Occlud® PDA-R device, with good procedural and six-month results. The Nit-Occlud® PDA-R emerges as an optimal alternative for closure of small to moderate PDAs., (© 2015 Wiley Periodicals, Inc.)