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Objective: To evaluate the association between bone changes due to vaso-occlusive events in sickle cell disease (SCD) revealed by conventional MRI sequences and the fat fraction obtained using a 6-point DIXON technique (FFdix), in an attempt to use quantitative data as a biomarker for bone complications., Methods: Cross-sectional study, with 48 SCD patients, 26-homozygous (HbSS), and 22-compound heterozygous (HbSC). Forty-eight healthy individuals paired by age, weight, and sex with SCD patients. All participants underwent lumbar spine and pelvis MRI. Conventional sequences: bone complications related to vaso-occlusive events-femoral head avascular necrosis, bone infarctions, "H"-shaped vertebrae, bone marrow necrosis. Six-point DIXON technique: quantitative evaluation of the bone marrow at pre-established sites (lumbar vertebrae, sacrum, iliacs, femoral heads, greater femoral trochanters, femoral necks). Pearson's correlation, ROC curve, and binary logistic regression analysis were performed., Results: The most frequent findings in the SCD group included femoral head avascular necrosis (75%), bone infarctions (58.3%), "H"-shaped vertebrae (58.3%), and typical imaging findings of bone marrow necrosis (8.3%). Cortical bone thickness in the proximal femoral diaphysis in patients with SCD was moderately negatively correlated with FFdix in lumbar vertebrae, iliacs, femoral necks, and first sacral vertebrae. The ROC curves and odds ratios demonstrated excellent performance of FFdix in all the evaluated anatomical sites and identified patients having bone complications., Conclusions: FFdix could serve as a potential biomarker in SCD because of its association with bone complications secondary to vaso-occlusive events in patients with SCD, especially in femoral heads, femoral necks, and iliacs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aim: Patients with sickle cell disease (SCD) are submitted to multiple transfusions in order to increase the oxygen capacity of the blood, decrease blood viscosity, and suppress the sickling of the cells. Multiply transfused patients with SCD represent significant risk of acquiring parenterally transmitted infections. The analysis of the virome profile of high-risk multiply transfused patients with SCD can reveal the presence of parenterally transmitted viruses and therefore be used an indirect approach for evaluation of blood transfusion safety., Materials and Methods: Blood samples were collected from 45 patients with SCD receiving multiple transfusions and analyzed by metagenomic analyses. The samples were assembled in pools f which were submitted to nucleic acids extraction and sequencing by Illumina NextSeq 550 equipment. For bioinformatic analysis, we used a specific in-house developed pipeline specialized in identification of emerging viruses., Results: The virome composition of SCD patients revealed the presence of commensal viruses represented by anelloviruses and Human Pegivirus-1 (HPgV-1, GB virus C). Contaminant viral sequences belonging to human lentiviruses (rev, env genes), cytomegalovirus and murine leukemia virus were also identified and are attributed to vectors used in the laboratory practice. No novel or unsuspected pathogenic viruses were identified., Conclusion: This study evaluates for the first time the virome of multiply transfused patients with SCD. Exclusively genetic material of commensal viruses was annotated. Therefore, we believe that viral metagenomics applied in patients with high risk for acquiring parenterally transmitted infections can serve as a direct indicator for evaluation of transfusion safety., (Copyright © 2020 Société française de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved.)

Quality-by-Design (QbD) is a methodology used to build quality into products and is characterized by a well-defined roadmap. In this study, the application of Artificial Neural Networks (ANNs) in the QbD-based development of a test drug product is presented, where material specifications are defined and correlated with its performance in vivo. Along with other process parameters, drug particle size distribution (PSD) was identified as a critical material attribute and a three-tier specification was needed. An ANN was built with only five hidden nodes in one hidden layer, using hyperbolic tangent functions, and was validated using a random holdback of 33% of the dataset. The model led to significant and valid prediction formulas for the three responses, with R 2 values higher than 0.94 for all responses, both for the training and the validation datasets. The prediction formulas were applied to contour plots and tight limits were set based on the design space and feasible working area for the drug PSD, as well as for process parameters. The manufacturing process was validated through the production of three exhibit batches of 180,000 tablets in the industrial GMP facility, and the ANN model was applied to successfully predict the in vitro dissolution, with a bias of approximately 5%. The product was then tested on two clinical studies (under fasting and fed conditions) and the criteria to demonstrate bioequivalence to the Reference Listed Drug were met. In this study, ANNs were successfully applied to support the establishment of drug specifications and limits for process parameters, bridging the formulation development with in vitro performance and the positive clinical results obtained in the bioequivalence studies., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A novel human adenovirus was isolated from a pediatric case of acute respiratory disease in Panama City, Panama in 2011. The clinical isolate was initially identified as an intertypic recombinant based on hexon and fiber gene sequencing. Based on the analysis of its complete genome sequence, the novel complex recombinant Human mastadenovirus D (HAdV-D) strain was classified into a new HAdV type: HAdV-84, and it was designated Adenovirus D human/PAN/P309886/2011/84[P43H17F84]. HAdV-D types possess usually an ocular or gastrointestinal tropism, and respiratory association is scarcely reported. The virus has a novel fiber type, most closely related to, but still clearly distant from that of HAdV-36. The predicted fiber is hypothesised to bind sialic acid with lower affinity compared to HAdV-37. Bioinformatic analysis of the complete genomic sequence of HAdV-84 revealed multiple homologous recombination events and provided deeper insight into HAdV evolution., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Isatin is a versatile compound with a diversity of effects. We designed to investigate the inhibitory effect of isatin derivatives on lipopolysaccharide/interferon-gamma-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, production of prostaglandin E(2) (PGE(2)), nitric oxide (NO), tumor necrosis factor (TNF-alpha), and their capacity to scavenge NO. Isatins inhibit TNF-alpha production and iNOS and COX-2 protein expression resulting on reduced levels of NO and PGE(2). Our results indicate isatin and it derivatives as inhibitors of iNOS and COX-2 enzymes, which might be used as anti-inflammatory and antitumoral agents.

New nitrogen derivatives from norlapachol, including four new diastereomeric 1,2,3,4-tetrahydro-1-aza-anthraquinones obtained from the Prins cyclization on suitable aminoacetaldehyde dimethylacetal derivatives with formic acid, were found to exhibit molluscicidal activity against Biomphalaria glabrata. These derivatives showed low to medium LC(50) values, similar to those reported previously for the homologous series of nitrogen derivatives of lapachol. The toxicity profile against Artemia salina was also determined for all compounds.

Ten indole alkaloids from the chloroform extract of stalk of Tabernaemontana australis (Muell. Arg) Miers were tentatively identified by GC-MS, viz., coronaridine (1), voacangine (2), voacangine hydroxyindolenine (3), rupicoline (4), ibogamine (5), ibogaine (6), ibogaline (7), desethyl-voacangine (8), voachalotine (9), and affinisine (10). Of these, the first four were isolated by silica gel open column chromatography, identified by uni- and bidimensional NMR, IR, MS and showed anti-cholinesterasic activity at the same concentration as the reference compounds physostigmine and galanthamine (detection limit of 0.01mM) by TLC assay using the modified Ellman's method.

Previous studies have established the gastroprotective, hypoglycemic, and hypolipidemic effects of trans-dehydrocrotonin (t-DCTN), a major diterpene isolated from the Amazon medicinal plant Croton cajucara. This study aims to examine the potential effects of t-DCTN on hemodynamic parameters that include resting arterial blood pressure and heart rate in vivo, and on left atrial force, spontaneous beating atria, and aortic rings of rats in vitro. Intravenous bolus injections of t-DCTN (5, 10, or 15 mg/kg) to urethane anesthetized normotensive rats reduced the mean arterial pressure and heart rate in a dose-dependent manner. The hypotensive effect of t-DCTN (10 mg/kg) appears not mediated through effects on the muscarinic cholinergic receptor, beta-adrenoceptor, or ganglionic blockade, for it was not affected by atropine, propranolol, or hexamethonium but was abolished by N(w)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. The diterpene t-DCTN showed no significant influence on inotropism. In isolated rat aortic rings with intact or denuded endothelium, t-DCTN relaxed the tonic contraction induced by phenylephrine (1 microM). Its vasorelaxant effect seen at smaller concentrations in endothelium intact preparations was, however, abolished in endothelium denuded or in l-NAME treated tissues. These data indicate the hypotensive and bradycardia effects of t-DCTN, possibly related in part to the release of nitric oxide and in part to direct effects on vascular smooth muscle, and cardiac pacemaker activity.

A series of new amino derivatives and a new partially hydrogenated derivative of the natural naphthoquinone lapachol were assayed for molluscicidal activity against Biomphalaria glabrata. These derivatives showed low to medium LC(50) values, and a 3.1 microg/mL value for the most potent derivative of the series. The toxicity is in agreement with the decrease of polar character of the tested compounds.