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In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.

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The essential oil from Lippia origanoides (EOLO) is employed in traditional medicine as it has both antimicrobial and anti-inflammatory properties. The current investigation first evaluated the EOLO's cytotoxic activity in tumour (SiHa and HT-29) and non-tumour (human lymphocyte) cells by MTT. The effect on ROS production was further evaluated in cancer cells by fluorimetry. The oil's mutagenic and antifungal activities were also evaluated using, respectively, the in vitro micronucleus test and the broth microdilution method. The EOLO displayed significant cytotoxicity in both cancer cell lines, with IC50 values of 20.2 µg/mL and 24.3 µg/mL for HT-29 and for SiHa cell lines, respectively. EOLO increased ROS production, was unable to raise the micronucleus frequencies and significantly reduced the cytokinesis block proliferation indices, revealing its anti-proliferative action. The results demonstrate that EOLO is devoid of mutagenic activity but possesses significant activity against tumour and non-tumour human cells, reinforcing its biological potential.

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The development of wind turbines for regions with low wind speeds imposes a challenge to the expansion of the corresponding energy generation capacity. The present work consists of an evaluation of the potential carded jute fiber and jute yarn to be used in the construction of a wind blade for regions of low wind intensity. The fibers used were supplied by Company Textile of Castanhal (Castanhal-Para-Brazil) and used in the study without chemical treatment in the form of single-filament fibers and yarns with a surface twist of 18.5°. The composites were produced through the resin infusion technique and underwent tensile and shear tests using 120-Ohm strain gauges and a blade extensometer to obtain the Young's modulus. In the analysis of the results, the ANOVA test was applied with a 0.05 significance level, followed by Tukey's test. The results showed that long, aligned jute fibers can be a good option for laminated structures applied in composites for small wind turbine blades.

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Mechanical properties of composites reinforced with lignocellulosic fibers have been researched in recent decades. Jute and mallow fibers are reinforcement alternatives, as they can contribute to increase the mechanical strength of composite materials. The present work aims to predict the Young's modulus with application of continuous and aligned lignocellulosic fibers to be applied as reinforcement in polyester matrix. Fibers were manually separated and then arranged and aligned in the polyester matrix. Composites with addition 5, 15, and 25 vol% jute and mallow fibers were produced by vacuum-assisted hand lay-up/vaccum-bagging procedure. Samples were tested in tensile and the tensile strength, elasticity modulus, and deformation were determined. Results showed that the intrinsic Young's modulus of the fibers was set at values around 17.95 and 11.72 GPa for jute and mallow fibers, respectively. Statistical analysis showed that composites reinforced with 15 and 25 vol% jute and mallow presented the highest values of tensile strength and Young's modulus. The incorporation of 25 vol% of jute and mallow fibers increased the matrix Young's modulus by 534% and 353%, respectively, effectively stiffening the composite material. Prediction models presented similar values for the Young's modulus, showing that jute and mallow fibers might be used as potential reinforcement of polymeric matrices.

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Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), is the largest pandemic in modern history with very high infection rates and considerable mortality. The disease, which emerged in China's Wuhan province, had its first reported case on December 29, 2019, and spread rapidly worldwide. On March 11, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a pandemic and global health emergency. Since the outbreak, efforts to develop COVID-19 vaccines, engineer new drugs, and evaluate existing ones for drug repurposing have been intensively undertaken to find ways to control this pandemic. COVID-19 therapeutic strategies aim to impair molecular pathways involved in the virus entrance and replication or interfere in the patients' overreaction and immunopathology. Moreover, nanotechnology could be an approach to boost the activity of new drugs. Several COVID-19 vaccine candidates have received emergency-use or full authorization in one or more countries, and others are being developed and tested. This review assesses the different strategies currently proposed to control COVID-19 and the issues or limitations imposed on some approaches by the human and viral genetic variability.

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Physical adsorption has shown to be facile and highly effective to deposit chitosan nanowhiskers (CsNWs, 60 % deacetylated, length: 247 nm, thickness: 4-12 nm, width:15 nm) on electrospun cellulose acetate nanofibers (CANFs, 560 nm) to effect complete surface charge reversal from negatively charged CANFs (-40 mV) to positively charged CsNWs-adsorbed CANFs (+8 mV). The CsNWs coverage did not alter the smooth and homogeneous morphology of fibers, as observed from SEM images. Biological assays showed the CsNWs covered nanofibers were effective against the Gram-negative bacterium E. coli, reducing 99 % of colony forming units (CFU) in 24 h and atoxic to healthy Vero cells. The use of CsNWs to modify cellulose fiber surfaces has been proved to be efficient and may be applied to a broad scope of fields, especially as biomaterials and biomedical applications.

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Leishmania parasites infect macrophages causing a wide spectrum of human diseases encompassing from cutaneous to visceral forms. The drugs currently used in leishmaniasis treatment are highly toxic and associated with acquired resistance. Seeking novel therapeutic targets, we conducted a comprehensive in vitro study to investigate the action of trans-chalcone (TC) against Leishmania amazonensis promastigote and amastigote forms. TC is a common precursor of flavonoids, however, no extensive research has been developed regarding its pharmacological properties. In silico predictions showed good drug-likeness potential for TC with high oral bioavailability and intestinal absorption. The TC-treatment had a direct action on promastigote forms leading to death by late apoptosis-like process resulting from an increased production of reactive oxygen species (ROS), loss of mitochondrial integrity, phosphatidylserine exposure, and damage on the membrane. Similar results were found for L. amazonensis-axenic amastigotes. The TC-treatment of L.amazonensis-infected macrophages proved to reduce the percentage of infected cells as well as the number of amastigotes per macrophage, consequently, the number of promastigotes recovered without cytotoxic effects on macrophages, having indicated a selectivity index (SI) of 53.8 for the parasite. Such leishmanicidal effect was followed by a decrease in the levels of TNF-α, TGF-ß, IL-10, ROS and NO, in addition to upregulation mRNA expression of Nrf2, heme oxygenase 1, and ferritin, modulating iron metabolism, depleting available iron for parasite replication, and survival within macrophages. These results suggested trans-chalcone as a satisfactory support for further studies as well as a possible further lead molecule for the design of new prototypes of antileishmanial drugs.

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Despite many efforts, the currently available treatments for leishmaniasis are not fully effective. To discover new medications, drug repurposing arises as a promising strategy. We present data that supports the use of the antidepressant clomipramine against Leishmania amazonensis. The drug presented selective activity at micromolar range against both the parasite forms and stimulated nitric oxide production in host macrophages. Regarding the mechanism of action, clomipramine led parasites do mitochondrial depolarization, which coupled with the inhibition of trypanothione reductase induced strong oxidative stress in the parasites. The effects observed in promastigotes included lipoperoxidation, plasma membrane permeabilization, and apoptosis hallmarks (i.e., DNA fragmentation, phosphatidylserine exposure, and cell shrinkage). The mechanism of action in both parasitic forms was quite similar, but amastigotes also exhibited energetic stress, reflected by a reduction of adenosine triphosphate levels. Such differential effects might be attributable to the metabolic particularities of each form of the parasitic. Ultrastructural alterations of the endomembrane system and autophagy were also observed, possibly indicating an adaptive response to oxidative stress. Our results suggest that clomipramine interferes with the redox metabolism of L. amazonensis. In spite of the cellular responses to recover the cellular homeostasis, parasites underwent programmed cell death.

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The word "ontology" was introduced to information systems when only closed-world reasoning systems were available. It was "borrowed" from philosophy, but literal links to its philosophical meaning were explicitly disavowed. Since then, open-world reasoning systems based on description logics have been developed, OWL has become a standard, and philosophical issues have been raised. The result has too often been confusion. The question "What statements are ontological" receives a variety of answers. A clearer vocabulary that is better suited to today's information systems is needed. The project to base ICD-11 on a "Common Ontology" required addressing this confusion. This paper sets out to systematise the lessons of that experience and subsequent discussions. We explore the semantics of open-world and closed-world systems. For specifying knowledge bases and software, we propose "invariants" or, more fully, "the first order invariant part of the background domain knowledge base" as an alternative to the words "ontology" and "ontological." We discuss the role and limitations of OWL and description logics and how they are complementary to closed world systems such as frames and to less formal "knowledge organisation systems". We illustrate why the conventions of classifications such as ICD cannot be formulated directly in OWL, but can be linked to OWL knowledge bases by queries. We contend that while OWL and description logics are major advances for representing invariants and terminologies, they must be combined with other technologies to represent broader background knowledge faithfully. The ICD-11 architecture is one approach. We argue that such hybrid architectures can and should be developed further.

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In natural environments, stimuli and events learned by animals usually occur in a combination of more than one sensory modality. An important problem in experimental psychology has been thus to understand how organisms learn about multimodal compounds and how they discriminate this compounds from their unimodal constituents. Here we tested the ability of honey bees to learn bimodal patterning discriminations in which a visual-olfactory compound (AB) should be differentiated from its visual (A) and olfactory (B) elements. We found that harnessed bees trained in classical conditioning of the proboscis extension reflex (PER) are able to solve bimodal positive and negative patterning (NP) tasks. In positive patterning (PP), bees learned to respond significantly more to a bimodal reinforced compound (AB+) than to non-reinforced presentations of single visual (A-) or olfactory (B-) elements. In NP, bees learned to suppress their responses to a non-reinforced compound (AB-) and increase their responses to reinforced presentations of visual (A+) or olfactory (B+) elements alone. We compared the effect of two different inter-trial intervals (ITI) in our conditioning approaches. Whereas an ITI of 8 min allowed solving both PP and NP, only PP could be solved with a shorter ITI of 3 min. In all successful cases of bimodal PP and NP, bees were still able to discriminate between reinforced and non-reinforced stimuli in memory tests performed one hour after conditioning. The analysis of individual performances in PP and NP revealed that different learning strategies emerged in distinct individuals. Both in PP and NP, high levels of generalization were found between elements and compound at the individual level, suggesting a similar difficulty for bees to solve these bimodal patterning tasks. We discuss our results in light of elemental and configural learning theories that may support the strategies adopted by honey bees to solve bimodal PP or NP discriminations.

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INTRODUCTION: This systematic review and meta-analysis assessed the available evidence regarding the effect of apical patency versus nonpatency on postendodontic pain in adult patients. METHODS: The study adhered strictly to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Scopus, MEDLINE via Ovid, Google Scholar, and the Web of Science databases were searched up to April 2018 to retrieve the most relevant studies. Two authors evaluated the studies for eligibility criteria and assessed the risk of bias using the Cochrane tool. The weighted means were calculated using a fixed effects model. When statistically significant (P < .1) heterogeneity was detected, a random effects model was used to assess the significance of treatment effects. RESULTS: Five studies were identified for this systematic review; 4 were included in the meta-analyses. Two studies revealed a low risk of bias, whereas 3 studies revealed a high risk of bias. Because of the significant heterogeneity between studies, a random effects model was used. The meta-analysis showed that the apical patency resulted in less postoperative pain compared with nonpatency, but the difference was not statistically significant. Moreover, no statistically significant difference was found with regard to analgesic consumption. CONCLUSIONS: Considering the limitations of this study, it was concluded that maintaining apical patency during routine endodontic treatment was not associated with an increased incidence of postoperative pain in adult patients.

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Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.

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An important SNOMED CT use case is to support semantic interoperability between electronic health records and aggregation terminologies such as ICD. From the ongoing alignment exercise between SNOMED CT and the new version of ICD, now in its pre-final form, we studied whether the ambiguity of clinical language as displayed by SNOMED CT synonyms hampers the quality of SNOMED CT axioms following the SNOMED CT "concept model". We measure the rate of synonyms in the semantic misalignment between classes from the chapter on circulatory diseases of the ICD-11 beta version and SNOMED CT concepts with the same description names. Our study confirms that SNOMED CT synonyms are ambiguous and that there is a need to increase the number of SNOMED CT fully defined representations of Fully Specified Names (FSN), and of synonyms independently of their relations.

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Introdução: Plasmocitoma é um tumor maligno, originado da proliferação irreversível e autônoma dos plasmócitos, podendo se apresentar como massa circunscrita ou infiltração difusa. Quando há mais de um tumor de células plasmáticas, ocorre o chamado Mieloma Múltiplo. Essa neoplasia maligna de células B apresenta produção exagerada de uma das imunoglobulinas de cadeias leves Kappa ou Lambda. Objetivo: Avaliar possíveis associações entre dados epidemiológicos e a carga tumoral em pacientes com Mieloma Múltiplo. Material eMétodos: Trata-se de um estudo transversal, quantitativo, descritivo, realizado em prontuários de pacientes diagnosticados com Mieloma Múltiplo no Laboratório de Patologia do Hospital de Base do município de São José do Rio Preto, São Paulo, entre 2010 e 2014. Foram consideradas as variáveis: sexo, idade, presença de cadeia leve (Kappa, Lambda, ambas e não especificada), carga tumoral (leve, moderada e acentuada). Resultados:Analisamos 42 laudos de pacientes diagnosticados com Mieloma Múltiplo, sendo que 69% dos pacientes apresentaram idade igual ou superior a 60 anos, presença de imunoglobulina de cadeia leve Kappa em 59% e carga tumoral acentuada em 67% dos casos. Em relação ao sexo, observamos que o nível de carga tumoral acentuada ocorreu de maneira similar entre homens e mulheres. As mulheres diagnosticadas com carga tumoral leve ou moderada configuraram 71% dos pacientes, do estudo. Conclusão: A idade e sexo não constituem fator de risco para o Mieloma Múltiplo na amostragem avaliada, este fato pode estar relacionado ao tamanho amostral.

Introduction: Plasmocytoma is a malignant tumor, originated from the irreversible and autonomous proliferation of the plasmacytes, being able to present as circumscribed mass or diffuse infiltration. When there is more than one plasma cell tumor, the so-called Multiple Myelomas occurs. This malignant B cell neoplasm exhibits overproduction of one of the Kappa or Lambda light chain. Objective: To evaluate possible ssociation of epidemiological data with tumor burden in patients with multiple myelomas. Patients and Methods:It is a cross-sectional study conducted with medical records of patients diagnosed with multiple myeloma by the Pathology Laboratory in Hospital de Base in the city of São José do Rio Preto, São Paulo, between 2010 and 2014. We considered the variables gender, age, light chain presence (Kappa, Lambda, both and unspecified), and tumor burden (mild, moderate or severe). Results: We analyzed 42 medical records of patients diagnosed with multiple myelomas. Of these, 69% of patients were aged 60 and over. Immunoglobulin Kappa light chain was found in 59% patients, and severe tumor burden in 67% of them. Regarding sex, we observed that severe tumor burden level occurred in a similar manner in men and women, without significant associations. Women diagnosed with mild to moderate tumor burden corresponded to 71% of patients, but no significant association was found. Conclusion: Age and sex were not a risk factor for multiple myelomas in this evaluated sample. This may be due to the sample size evaluated.

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The phytochemical study of Laelia marginata (Lindl.) L. O. Williams (Orchidaceae) led to the isolation of a new natural product named crispoic acid (1), together with six other known compounds (2-7). The new natural product was identified as a dimer of eucomic acid and was structurally characterised based upon 1D and 2D NMR and HRMS data. Biological assays with plant crude extract, fractions and isolated compounds were performed against two human cancer cell lines (Hela and Siha), and the tropical parasites Trypanosoma cruzi and Leishmania (Leishmania) amazonensis. The phenantrenoid 9,10-dihydro-4-methoxyphenanthren-2,7-diol 2 was active against Hela and Siha cells (CC50 5.86 ± 0.19 and 20.78 ± 2.72 µg/mL, respectively). Sub-lethal concentrations of the flavone rhamnazin 4 were not able to rescue the viability of the Vero cells infected by Zika virus.

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American Cutaneous Leishmaniasis (ACL) is a zoonosis caused by Leishmania protozoa. The ACL chemotherapy available is unsatisfactory motivating researches to seek alternative treatments. In this study, we investigated the action of biogenic silver nanoparticle (AgNp-bio) obtained from Fusarium oxysporium, against Leishmania amazonensis promastigote and amastigote forms. The AgNp-bio promastigote treatment results in promastigote death leading to apoptosis-like events due an increased production of reactive oxygen species (ROS), loss of mitochondrial integrity, phosphatidylserine exposure and damage on promastigotes membrane. In L. amazonensis infected macrophages, AgNp-bio treatment was still able to reduce the percentage of infected macrophages and the amount of amastigotes per macrophage, consequently, the amount of promastigotes recovered. This leishmanicidal effect was also accompanied by a decrease in the levels of ROS and nitric oxide. By observing the ultrastructural integrity of the intracellular amastigotes, we found that the AgNp-bio treatment made a significant damage, suggesting that the compound has a direct effect on intracellular amastigotes. These results demonstrated that AgNp-bio had a direct effect against L. amazonensis forms and acted on immunomodulatory ability of infected macrophages, reducing the infection without inducing the synthesis of inflammatory mediators, which continuous stimulation can generate and aggravate leishmaniotic lesions. Overall, our findings suggest that the use of AgNp-bio stands out as a new therapeutic option to be considered for further in vivo investigations representing a possible treatment for ACL.

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BACKGROUND: and purpose: Acute stroke care is to detect, diagnose, and treat patients in the shortest amount of time. Access to acute stroke care may however be limited in some areas and telemedicine has been thus used to increase its access. Coding acute stroke care as a health intervention had limited attention in the past. METHODS: The International Classification of Health Interventions (ICHI) currently under development was used to identify existing codes relevant for coding acute stroke care interventions, including telestroke. A review of the ICHI was conducted to identify codes relevant for acute stroke care by two independent reviewers. RESULTS: A matching ICHI code was found for each of the steps in the acute stroke care process but no ICHI codes were available to specifically capture telestroke. CONCLUSION: As telemedicine intervention is likely to become more common in the future, it will be imperative that the ICHI is able to code such interventions.

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Leishmaniasis is a disease caused by hemoflagellate protozoa, affecting millions of people worldwide. The difficulties of treating patients with this parasitosis include the limited efficacy and many side effects of the currently available drugs. Therefore, the search for new compounds with leishmanicidal action is necessary. Photodynamic therapy has been studied in the medical field because of its selectivity, utilizing a combination of visible light, a photosensitizer compound, and singlet oxygen to reach the area of treatment. The continued search for selective alternative treatments and effective targets that impact the parasite and not the host are fundamentally important for the development of new drugs. Pheophorbide a is a photosensitizer that may be promising for the treatment of leishmaniasis. The present study evaluated the in vitro biological effects of pheophorbide a and its possible mechanisms of action in causing cell death in L. amazonensis. Pheophorbide a was active against promastigote and amastigote forms of the parasite. After treatment, we observed ultrastructural alterations in this protozoan. We also observed changes in promastigote macromolecules and organelles, such as loss of mitochondrial membrane potential [∆Ψm], lipid peroxidation, an increase in lipid droplets, DNA fragmentation, phosphatidylserine exposure, an increase in caspase-like activity, oxidative imbalance, and a decrease in antioxidant defense systems. These findings suggest that cell death occurred through apoptosis. The mechanism of cell death in intracellular amastigotes appeared to involve autophagy, in which we clearly observed an increase in reactive oxygen species, a compromised ∆Ψm, and an increase in the number of autophagic vacuoles. The present study contributes to the development of new photosensitizers against L. amazonensis. We also elucidated the mechanism of action of pheophorbide a, mainly in intracellular amastigotes, which is the most clinically relevant form of this parasite.

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Among different used healthcare terminology resources there is a need to link them to ease their interoperability. SNOMED CT is the most detailed clinical reference terminology for procedure used in the Electronic Health Record (EHR). WHO developed since 2006 an aggregated classification named ICHI required for statistics and resource allocation. It is based on an ontology framework defined in ISO 1828 named Categorial Structure (CAST) for surgical procedures. We present ICHI coding structure, ISO 1828 CAST standard for surgical procedures and SNOMED CT procedures hierarchy concept model and their relations. We demonstrate the obstacles to align ICHI coding structure with ISO 1828 CAST which can be linked with SNOMED CT procedures hierarchy concept model. We recommend to update ICHI coding structure to decrease the gap with ISO 1828 CAST and SNOMED CT concept model for procedures hierarchy to allow users to share the different terminology resources.

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Leishmaniasis is a neglected tropical disease that affects millions of people worldwide. Current therapies mainly rely on antimonial drugs that are inadequate because of their high toxicity and increased drug resistance. An urgent need exists to discover new, more effective, more affordable, and more target-specific drugs. Pathways that are associated with apoptosis-like cell death have been identified in unicellular eukaryotes, including protozoan parasites. In the present study, we studied the mechanism of cell death that is induced by A3K2A3 against L. amazonensis. A3K2A3 is a dibenzylideneacetone that has an acyclic dienone that is attached to aryl groups in both ß-positions, which is similar to curcuminoids and chalcone structures. This compound was previously shown to be safe with regard to cytotoxicity and active against the parasite. Biochemical and morphological approaches were used in the present study. The results suggested that A3K2A3 caused mitochondrial dysfunction in L. amazonensis promastigotes, leading to mechanisms of cell death that share some common phenotypic features with metazoan apoptosis, such as an increase in reactive oxygen species production, a decrease in the adenosine triphosphate ratio, phosphatidylserine exposure, a decrease in cell volume, caspase production, and DNA fragmentation. Altogether, these findings indicate that apoptosis can indeed be triggered by chemotherapeutic agents.

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