Successful embolization of a clinically significant pulmonary arteriovenous malformation.

The authors present the clinical case of a 59-year-old female patient with a history of peripheral desaturation, which was detected in the perioperative period 4 years earlier. She reported exertional dyspnea, quantified as grade 2 on the Modified Medical Research Council (mMRC) Dyspnea Scale (walks slower than people of the same age because of dyspnea or has to stop for breath when walking at her own pace), and morning cough with mucoid sputum and denied platypnea, epistaxis, telangiectasias and hemoptysis. A computed chest tomography scan revealed a contrast-enhanced lesion on the right upper lobe with an afferent and two efferent vessels compatible with pulmonary arteriovenous malformation. The transesophageal echocardiogram revealed an important right-left shunt compatible with arteriovenous fistula in the pulmonary circulation. An angiography confirmed the diagnosis and a selective embolization of the afferent artery was performed with resolution of symptoms.

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective.

Since the beginning of the XXI century, Leishmaniasis has been integrated into the World Health Organization's list of the 20 neglected tropical diseases, being considered a public health issue in more than 88 countries, especially in the tropics, subtropics, and the Mediterranean area. Statistically, this disease presents a world prevalence of 12 million cases worldwide, with this number being expected to increase shortly due to the 350 million people considered at risk and the 2-2.5 million new cases appearing every year. The lack of an appropriate and effective treatment against this disease has intensified the interest of many research groups to pursue the discovery and development of novel treatments in close collaboration with the WHO, which hopes to eradicate it shortly. This paper intends to highlight the quinoline scaffold's potential for developing novel antileishmanial agents and provide a set of structural guidelines to help the research groups in the medicinal chemistry field perform more direct drug discovery and development programs. Thus, this review paper presents a thorough compilation of the most recent advances in the development of new quinoline-based antileishmanial agents, with a particular focus on structure-activity relationship studies that should be considerably useful for the future of the field.

Identification of Inflammatory Mediators in Saliva Samples From Hospitalized Newborns: Potential Biomarkers?

Saliva measurements serve as a noninvasive tool for clinically monitoring newborns (NB) and children, a vulnerable population with promising potential for both research and clinical practice. Saliva acts as a repository for various inflammatory biomarkers involved in diverse biological functions. Particularly for children, it offers numerous advantages when compared to plasma and urine sampling. Nevertheless, there is a significant knowledge gap regarding detectable levels of cytokines in the saliva of newborns and children, as well as studies aiming to assess the relationship of this content with physiological and pathological processes. OBJECTIVES: To characterize the levels of 11 inflammatory mediators (IFNg, IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL17, TNF, and VEGF) in saliva samples from NB on the first and second day of hospitalization in the Neonatal Intensive Care Unit (NICU). METHOD: Exploratory study, descriptive, nested within a primary clinical, observational, and prospective study, conducted in the NICU of a public hospital in São Paulo, Brazil. Demographic data and vital signs were recorded in the clinical records of 90 NB, and five saliva samples from 5 NB were collected between the first and second day of life (D1-D2) at approximately 8-hr intervals (8-9 am, 4-5 pm, and 11-12 pm). Saliva samples were used for the measurement of 11 cytokines (IFNg, IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL17, TNF, and VEGF). RESULTS: Five NBs participated in this exploratory study, and the vital signs showed variability from the first (D1) to the second day (D2) of hospitalization, variability similar to that of the total population of the primary study. The presence and levels of the 11 cytokines were detected in the saliva samples, as well as a statistical correlation between 10 cytokines (IFNg, IL1b, IL2, IL4, IL6, IL10, IL12, IL17, TNF, and VEGF) and vital signs. CONCLUSIONS: The novelty of measuring inflammatory mediators in saliva samples from hospitalized NBs in the NICU is highlighted, providing support and new perspectives for the development of clinical and experimental research and an opportunity for developing and implementing new salivary biomarkers in different population segments.

SCCmec transformation requires living donor cells in mixed biofilms.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen that has emerged through the horizontal acquisition of the staphylococcal cassette chromosome mec (SCCmec). Previously, we showed that SCCmec from heat-killed donors can be transferred via natural transformation in biofilms at frequencies of 10-8-10-7. Here, we show an improved transformation assay of SCCmec with frequencies up to 10-2 using co-cultured biofilms with living donor cells. The Ccr-attB system played an important role in SCCmec transfer, and the deletion of ccrAB recombinase genes reduced the frequency ∼30-fold. SCCmec could be transferred from either MRSA or methicillin-resistant coagulase-negative staphylococci to some methicillin-sensitive S. aureus recipients. In addition, the transformation of other plasmid or chromosomal genes is enhanced by using living donor cells. This study emphasizes the role of natural transformation as an evolutionary ability of S. aureus and in MRSA emergence.

Beneficial Effect of Exogenously Applied Calcium Pyruvate in Alleviating Water Deficit in Sugarcane as Assessed by Chlorophyll a Fluorescence Technique.

The growing demand for food production has led to an increase in agricultural areas, including many with low and irregular rainfall, stressing the importance of studies aimed at mitigating the harmful effects of water stress. From this perspective, the objective of this study was to evaluate calcium pyruvate as an attenuator of water deficit on chlorophyll a fluorescence of five sugarcane genotypes. The experiment was conducted in a plant nursery where three management strategies (E1-full irrigation, E2-water deficit with the application of 30 mM calcium pyruvate, and E3-water deficit without the application of calcium pyruvate) and five sugarcane genotypes (RB863129, RB92579, RB962962, RB021754, and RB041443) were tested, distributed in randomized blocks, in a 3 × 5 factorial design with three replications. There is dissimilarity in the fluorescence parameters and photosynthetic pigments of the RB863129 genotype in relation to those of the RB041443, RB96262, RB021754, and RB92579 genotypes. Foliar application of calcium pyruvate alleviates the effects of water deficit on the fluorescence parameters of chlorophyll a and photosynthetic pigments in sugarcane, without interaction with the genotypes. However, subsequent validation tests will be necessary to test and validate the adoption of this technology under field conditions.

Viper Venom Phospholipase A2 Database: The Structural and Functional Anatomy of a Primary Toxin in Envenomation.

Viper venom phospholipase A2 enzymes (vvPLA2s) and phospholipase A2-like (PLA2-like) proteins are two of the principal toxins in viper venom that are responsible for the severe myotoxic and neurotoxic effects caused by snakebite envenoming, among other pathologies. As snakebite envenoming is the deadliest neglected tropical disease, a complete understanding of these proteins' properties and their mechanisms of action is urgently needed. Therefore, we created a database comprising information on the holo-form, cofactor-bound 3D structure of 217 vvPLA2 and PLA2-like proteins in their physiologic environment, as well as 79 membrane-bound viper species from 24 genera, which we have made available to the scientific community to accelerate the development of new anti-snakebite drugs. In addition, the analysis of the sequenced, 3D structure of the database proteins reveals essential aspects of the anatomy of the proteins, their toxicity mechanisms, and the conserved binding site areas that may anchor universal interspecific inhibitors. Moreover, it pinpoints hypotheses for the molecular origin of the myotoxicity of the PLA2-like proteins. Altogether, this study provides an understanding of the diversity of these toxins and how they are conserved, and it indicates how to develop broad, interspecies, efficient small-molecule inhibitors to target the toxin's many mechanisms of action.

IL-10-induced STAT3/NF-κB crosstalk modulates pineal and extra-pineal melatonin synthesis.

Immune-pineal axis activation is part of the assembly of immune responses. Proinflammatory cytokines inhibit the pineal synthesis of melatonin while inducing it in macrophages by mechanisms dependent on nuclear factor-κB (NF-κB) activation. Cytokines activating the Janus kinase/signal transducer and activator of transcription (STAT) pathways, such as interferon-gamma (IFN-γ) and interleukin-10 (IL-10), modulate melatonin synthesis in the pineal, bone marrow (BM), and spleen. The stimulatory effect of IFN-γ upon the pineal gland depends on STAT1/NF-κB interaction, but the mechanisms controlling IL-10 effects on melatonin synthesis remain unclear. Here, we evaluated the role of STAT3 and NF-κB activation by IL-10 upon the melatonin synthesis of rats' pineal gland, BM, spleen, and peritoneal cells. The results show that IL-10-induced interaction of (p)STAT3 with specific NF-κB dimmers leads to different cell effects. IL-10 increases the pineal's acetylserotonin O-methyltransferase (ASMT), N-acetylserotonin, and melatonin content via nuclear translocation of NF-κB/STAT3. In BM, the nuclear translocation of STAT3/p65-NF-κB complexes increases ASMT expression and melatonin content. Increased pSTAT3/p65-NF-κB nuclear translocation in the spleen enhances phosphorylated serotonin N-acetyltransferase ((p)SNAT) expression and melatonin content. Conversely, in peritoneal cells, IL-10 leads to NF-κB p50/p50 inhibitory dimmer nuclear translocation, decreasing (p)SNAT expression and melatonin content. In conclusion, IL-10's effects on melatonin production depend on the NF-κB subunits interacting with (p)STAT3. Thus, variations of IL-10 levels and downstream pathways during immune responses might be critical regulatory factors adjusting pineal and extra-pineal synthesis of melatonin.

First record of intraspecific cleaning behavior by the threatened Leuciscidae Squalius alburnoides (Steindachner, 1866) at the Guadiana River basin (Portugal).

Squalius alburnoides (Steindachner, 1866) is an endemic threatened species from the Iberian Peninsula. Here, we report the first observations of intraspecific cleaning behavior in isolated summer pools in the Guadiana River Basin (Portugal). We found that focal S. alburnoides solicited cleaning by adopting an immobile tail-stand position known as "posing," which immediately signaled a response to a few conspecifics that approached and inspect them. Our study expands the list of cleanerfish species in freshwaters, giving emphasis to the importance of mutual positive behavior within an endangered species, particularly when facing seasonal disturbance.

Standardization of the Radiographic Study of the Foot Using the Niza Box.

Objective This study proposes the Niza box, a device created to reduce interpretive errors among professionals and facilitate the correct positioning of structures by standardizing orthopedic radiography of the foot in anteroposterior, loaded, and Saltzman views. Methods Descriptive study based on material collected at an Orthopedics Ambulatory from a tertiary service in a large Brazilian city. The X-ray device was a Lotus X, model HF 500 M, 500 milliamperes and 125 kilovolts capacity, 100 cm focus-film distance, and 24 × 30 cm radiographic chassis. Device controls were set at 100 mA, 5 mA/sec, and 60 kilovolts, depending on the variable size of the foot. The same team of previously trained radiography technicians performed the tests under the authors' supervision. The chassis were positioned in three specific Niza box spaces per the proposed incidence. Data from 50 images from people between 18 and 70 years old were analyzed. Results Radiographs taken using the proposed device usually had a satisfactory quality, allowing correct identification of the anatomical elements of the foot and ankle and angular reconstruction. Small image variations due to foot size were acceptable and expected, allowing radiograph standardization. Conclusion The Niza box is a good method for minimizing interference and avoiding radiographic interpretation errors, providing quality and agility to the examination, and reducing cost and unnecessary repetitions. It is an innovative, low-cost device made of recyclable and biodegradable material.

Linezolid and vancomycin for nosocomial infections in pediatric patients: a systematic review.

OBJECTIVE: To investigate the effectiveness of linezolid and vancomycin for the treatment of nosocomial infections in children under 12 years old. DATA SOURCES: This is a systematic review in which five randomized clinical trials about the effectiveness of linezolid and vancomycin, involving a total of 429 children with nosocomial infections, were evaluated. They were searched in scientific databases: PubMed, Bvs, and SciELO. SUMMARY OF FINDINGS: The main nosocomial infections that affected children were bacteremia, skin, and soft tissue infections followed by nosocomial pneumonia. Most infections were caused by Gram-positive bacteria, which all studies showed infections caused by Staphylococcus aureus, with methicillin-resistant S. aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci strains being isolated. Both linezolid and vancomycin showed high therapeutic efficacy against different types of nosocomial infections, ranging from 84.4% to 94% for linezolid and 76.9% to 90% for vancomycin. Patients receiving linezolid had lower rates of rash and red man syndrome compared to those receiving vancomycin. However, despite the adverse reactions, antimicrobials can be safely administered to children to treat nosocomial infections caused by resistant Gram-positive bacteria. CONCLUSION: Both linezolid and vancomycin showed good efficacy in the treatment of bacterial infections caused by resistant Gram-positive bacteria in hospitalized children. However, linezolid stands out regarding its pharmacological safety. Importantly, to strengthen this conclusion, further clinical trials are needed to provide additional evidence.

The Effects of Irrigation Water Salinity on the Synthesis of Photosynthetic Pigments, Gas Exchange, and Photochemical Efficiency of Sour Passion Fruit Genotypes.

The objective of this study was to evaluate the synthesis of photosynthetic pigments, gas exchange, and photochemical efficiency of sour passion fruit genotypes irrigated with saline water under the conditions of the semi-arid region of Paraíba state, Brazil. The experiment was conducted at the experimental farm in São Domingos, PB. A randomized block design was adopted, in a 5 × 3 factorial scheme, with five levels of electrical conductivity of irrigation water-ECw (0.3, 1.1, 1.9, 2.7, and 3.5 dS m-1)-and three genotypes of sour passion fruit (Gigante Amarelo-'BRS GA1'; Sol do Cerrado-'BRS SC1'; and Catarina-'SCS 437'. The increase in the electrical conductivity of irrigation water negatively affected most of the physiological characteristics of the sour passion fruit at 154 days after transplanting. Significant differences were observed between sour passion fruit genotypes when its tolerance was subjected to the salinity of irrigation water. There was an increase in the percentage of damage to the cell membrane with the increase in the electrical conductivity of irrigation water, with maximum values of 70.63, 60.86, and 80.35% for the genotypes 'BRS GA1', 'BRS SC1', and SCS 437', respectively, when irrigated with water of 3.5 dS m-1. The genotype 'BRS Sol do Cerrado' showed an increase in the synthesis of photosynthetic pigments when irrigated with water of 3.5 dS m-1, with maximum values estimated at 1439.23 µg mL-1 (Chl a); 290.96 µg mL-1 (Chl b); 1730.19 µg mL-1 (Chl t); and 365.84 µg mL-1 (carotenoids). An increase in photosynthetic efficiency parameters (F0, Fm, and Fv) of the genotype 'BRS Gigante Amarelo' was observed when cultivated with water with high electrical conductivity (3.5 dS m-1).

Septic Shock After Intravesical Therapy With Bacillus Calmette-Guerin: A Case Report of a Rare Life-Threatening Complication.

Intravesical therapy with Bacillus Calmette-Guerin (BCG) is the mainstay treatment for high-risk non-muscle invasive bladder cancer. The side effects are usually local and mild. Systemic dissemination of BCG is rare, typically develops soon after instillation, and may present as a severe life-threatening condition. We present a case of a 49-year-old man under chronic haemodialysis who developed septic shock after the first BCG maintenance instillation for bladder carcinoma in situ (CIS). Supportive measures and empiric broad-spectrum antibiotic therapy were promptly started after sample collection for cultures. Lastly, the recurrence of fever raised the initial suspicion of BCG dissemination. The diagnosis was confirmed by the identification of the Mycobacterium tuberculosis complex in blood samples collected and anti-tuberculosis therapy was then initiated. We would like to highlight the need for early recognition of a systemic BCG infection and the importance of starting anti-tuberculosis treatment as early as possible.

Structural and dynamical changes of the Streptococcus gordonii metalloregulatory ScaR protein induced by Mn2+ ion binding.

Divalent metal ions are essential micronutrients for many intercellular reactions. Maintaining their homeostasis is necessary for the survival of bacteria. In Streptococcus gordonii, one of the primary colonizers of the tooth surface, the cellular concentration of manganese ions (Mn2+) is regulated by the manganese-sensing transcriptional factor ScaR which controls the expression of proteins involved in manganese homeostasis. To resolve the molecular mechanism through which the binding of Mn2+ ions increases the binding affinity of ScaR to DNA, a variety of computational (QM and MD) and experimental (ITC, DSC, EMSA, EPR, and CD) methods were applied. The computational results showed that Mn2+ binding induces a conformational change in ScaR that primarily affects the position of the DNA binding domains and, consequently, the DNA binding affinity of the protein. In addition, experimental results revealed a 1:4 binding stoichiometry between ScaR dimer and Mn2+ ions, while the computational results showed that the binding of Mn2+ ions in the primary binding sites is sufficient to induce the observed conformational change of ScaR.

A penile fracture hidden behind a urethral bleeding.

Penile fracture with urethral injury is uncommon. Diagnosis is usually based on clinical history and physical examination. Nonetheless, atypical presentation obliges complementary examinations to be performed. We report a case of a 45-years-old man with urethral bleeding after a blunt penile trauma that was ultimately diagnosed as having a cavernous body laceration on top of an urethral rupture.

Deciphering the Catalytic Mechanism of Virginiamycin B Lyase with Multiscale Methods and Molecular Dynamics Simulations.

Due to the emergence of antibiotic resistance, the need to explore novel antibiotics and/or novel strategies to counter antibiotic resistance is of utmost importance. In this work, we explored the molecular and mechanistic details of the degradation of a streptogramin B antibiotic by virginiamycin B (Vgb) lyase of Staphylococcus aureus using classical molecular dynamics simulations and multiscale quantum mechanics/molecular mechanics methods. Our results were in line with available experimental kinetic information. Although we were able to identify a stepwise mechanism, in the wild-type enzyme, the intermediate is short-lived, showing a small barrier to decay to the product state. The impact of point mutations on the reaction was also assessed, showing not only the importance of active site residues to the reaction catalyzed by Vgb lyase but also of near positive and negative residues surrounding the active site. Using molecular dynamics simulations, we also predicted the most likely protonation state of the 3-hydroxypicolinic moiety of the antibiotic and the impact of mutants on antibiotic binding. All this information will expand our understanding of linearization reactions of cyclic antibiotics, which are crucial for the development of novel strategies that aim to tackle antibiotic resistance.

Foliar Applications of Salicylic Acid on Boosting Salt Stress Tolerance in Sour Passion Fruit in Two Cropping Cycles.

Brazil stands out as the largest producer of sour passion fruit; however, the water available for irrigation is mostly saline, which can limit its cultivation. This study was carried out with the objective of evaluating the effects of salicylic acid in the induction of tolerance in sour passion fruit to salt stress. The assay was conducted in a protected environment, using a completely randomized design in a split-plot scheme, with the levels of electrical conductivity of the irrigation water (0.8, 1.6, 2.4, 3.2, and 4.0 dS m-1) considering the plots and concentrations of salicylic acid (0, 1.2, 2.4, and 3.6 mM) the subplots, with three replications. The physiological indices, production components, and postharvest quality of sour passion fruit were negatively affected by the increase in the electrical conductivity of irrigation water, and the effects of salt stress were intensified in the second cycle. In the first cycle, the foliar application of salicylic acid at concentrations between 1.0 and 1.4 mM partially reduced the harmful effects of salt stress on the relative water content of leaves, electrolyte leakage, gas exchange, and synthesis of photosynthetic pigments, in addition to promoting an increase in the yield and quality parameters of sour passion fruit.

New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies.

Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin-proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC50 values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign.

Irrigation Strategies with Controlled Water Deficit in Two Production Cycles of Cotton.

Water scarcity is one of the main abiotic factors that limit agricultural production. In this sense, the identification of genotypes tolerant to water deficit associated with irrigation management strategies is extremely important. In this context, the objective of this study was to evaluate the morphology, production, water consumption, and water use efficiency of colored fiber cotton genotypes submitted to irrigation strategies with a water deficit in the phenological phases. Two experiments were conducted in succession. In the first experiment, a randomized block design was used in a 3 × 7 factorial scheme, corresponding to three colored cotton genotypes (BRS Rubi, BRS Jade, and BRS Safira) in seven irrigation management strategies with 40% of the real evapotranspiration (ETr) varying the phenological stages. In the second experiment, the same design was used in a 3 × 10 factorial arrangement (genotypes × irrigation management strategies). The water deficit in the vegetative phase can be used in the first year of cotton cultivation. Among the genotypes, 'BRS Jade' is the most tolerant to water deficit in terms of phytomass accumulation and fiber production.