Nanosystems, Drug Molecule Functionalization and Intranasal Delivery: An Update on the Most Promising Strategies for Increasing the Therapeutic Efficacy of Antidepressant and Anxiolytic Drugs.

Depression and anxiety are high incidence and debilitating psychiatric disorders, usually treated by antidepressant or anxiolytic drug administration, respectively. Nevertheless, treatment is usually given through the oral route, but the low permeability of the blood-brain barrier reduces the amount of drug that will be able to reach it, thus consequently reducing the therapeutic efficacy. Which is why it is imperative to find new solutions to make these treatments more effective, safer, and faster. To overcome this obstacle, three main strategies have been used to improve brain drug targeting: the intranasal route of administration, which allows the drug to be directly transported to the brain by neuronal pathways, bypassing the blood-brain barrier and avoiding the hepatic and gastrointestinal metabolism; the use of nanosystems for drug encapsulation, including polymeric and lipidic nanoparticles, nanometric emulsions, and nanogels; and drug molecule functionalization by ligand attachment, such as peptides and polymers. Pharmacokinetic and pharmacodynamic in vivo studies' results have shown that intranasal administration can be more efficient in brain targeting than other administration routes, and that the use of nanoformulations and drug functionalization can be quite advantageous in increasing brain-drug bioavailability. These strategies could be the key to future improved therapies for depressive and anxiety disorders.

Construção e validação de Bateria Multidisciplinar de Triagem do Desenvolvimento Infantil (TDI) / Construction and validation of the Multidisciplinary Battery for Child Development Screening (TDI) / Construcción y validación de Instrumento Multidisciplinar para la Selección del Desarrollo Infantil (TDI)

O estudo objetivou apresentar a construção da Bateria Multidisciplinar de Triagem do Desenvolvimento Infantil (TDI) e suas evidências de validade de conteúdo. A elaboração do TDI seguiu as recomendações internacionais com cinco etapas: definição da fundamentação teórica, construção da versão preliminar do instrumento, análise dos itens por juízes especialistas, análise semântica pela população-alvo e estudo piloto. Para o embasamento da construção dos itens, realizou-se revisão de literatura sobre o desenvolvimento infantil na fase de escolarização inicial, considerando os construtos envolvidos na prontidão escolar, incluindo artigos, instrumentos existentes, livros e manuais. As áreas selecionadas foram linguagem, funções executivas e habilidades motoras. Na versão preliminar, 110 itens foram elaborados. Após a realização das três últimas etapas, a versão final totalizou 81 itens, destinados à avaliação de crianças entre 6 e 8 anos de idade. A TDI apresentou evidências de validade de conteúdo, sendo de relevância nas áreas da saúde e educação brasileira.(AU)

This study aimed to present the development of the Multidisciplinary Battery for Child Development Screening (TDI) and its content validity evidence. The TDI construction followed international recommendations, consisting of five stages: description of the theoretical foundation; development of the preliminary version of the instrument; analysis of the items by experts; semantic analysis of the items by the target population; and a pilot study. To support the construction of the items, a literature review was conducted regarding child development in the initial education stage, considering the constructs involved in school readiness. Articles, existing instruments, books and manuals were included. The selected areas were language, executive functions and motor skills. In the preliminary version, 110 items were developed. After completing the last three stages, the final version totaled 81 items, directed toward the assessment of children between 6 and 8 years of age. The TDI presented content validity evidence, being relevant in the Brazilian health and education areas.(AU)

El estudio tuvo como objetivo presentar la construcción de la Batería Multidisciplinar para la Selección del Desarrollo Infantil (TDI) y sus evidencias de validez de contenido. La elaboración siguió las recomendaciones internacionales con cinco etapas: fundamentación teórica; desarrollo de la versión preliminar; análisis de los ítems por expertos; análisis semántico por la población-objetivo; y estudio piloto. Para apoyar la construcción se realizó una revisión de la literatura sobre el desarrollo infantil en la fase inicial de escolarización, considerando los constructos implicados en la preparación escolar, incluyendo artículos, instrumentos existentes, libros y manuales. Las áreas seleccionadas fueron lenguaje, funciones ejecutivas y habilidades motoras. La versión preliminar tuve 110 items preparados. Después de las últimas tres etapas, la versión final totalizó 81 ítems, destinados a la evaluación de niños entre 6 y 8 años, La TDI presentó evidencia de validez de contenido, siendo relevante en las áreas de salud y educación brasileñas.(AU)

In-air production of 3D co-culture tumor spheroid hydrogels for expedited drug screening.

Three-dimensional (3D) in vitro tumor spheroids are becoming popular as pre-clinical platforms for testing the performance of existing drugs or for discovery of innovative anti-cancer therapeutics. This focus is correlated with in vitro 3D tumor models ability to mimic the multicellular compact structure and spatial architecture of human solid tumors. However, these microphysiological systems generally lack the pre-existence of tumor-ECM, a critical aspect that can affect the overall therapeutic performance and the decision of advancing candidate drugs to later stages of the pipeline. Aiming to face this drawback and mimic tumors-ECM, herein we rapidly fabricated in-air hyaluronan-methacrylate (HA-MA) and gelatin-methacrylate (GelMA) photocrosslinkable 3D spheroid microgels by using superhydrophobic surfaces. These platforms were used for establishing heterotypic 3D co-culture models of prostate cancer cells (PC-3) and human osteoblasts (hOB) to mimic prostate cancer-to-bone metastasis cellular heterogeneity and the tumor-ECM microenvironment. 3D microgel microtumors morphology, size and cell number were easily controlled via digital droplet generation on polystyrene superhydrophobic surfaces and under solvent-free conditions when compared to microfluidics or electrospray. Co-culture 3D microgels formed by 2.5%HA-MA-5%GelMA and 5%HA-MA-5%GelMA ratios showed the highest calcium deposition after 14 days of culture, evidencing osteoblasts viability and the establishment of functional mineralization in the 3D hydrogel matrix. Cisplatin cytotoxicity evaluation showed that 3D microgels are more resistant to platin chemotherapeutics than single or co-culture 3D multicellular spheroid counterparts. Overall, our findings indicate that solvent-free, in-air produced 3D microgel microenvironments are cost-effective and robust tumor mimicking platforms for in vitro high-throughput screening of therapeutics targeted to prostate-to-bone metastasis microenvironments. STATEMENT OF SIGNIFICANCE: The generation of robust microphysiological systems that recapitulate the complexity of the metastatic prostate-to-bone tumor microenvironment is crucial for pre-clinical evaluation of new therapeutics that can eradicate these secondary tumors. In this study, we employed superhydrophobic (SH) surfaces to rapidly fabricate photocrosslinkable hyaluronan-methacrylate/gelatin-methacrylate 3D spheroid microgels for prostate cancer cells and human osteoblasts co-culture models that simultaneously mimic the cellular and ECM tumor components. The use of SH platforms overcomes the issues of standard in-liquid microgel production technologies by providing a robust control over 3D microgels size/morphology and cell-cell co-encapsulation numbers, while avoiding the use of oil-based microgel droplets generation. Overall, SH surfaces allowed a solvent-free, cost-effective, reproducible and adaptable fabrication of heterotypic 3D spherical microgels for high throughput drug screening.

Contribution of efflux to colistin heteroresistance in a multidrug resistant Acinetobacter baumannii clinical isolate.

PURPOSE: The mechanisms underlying colistin heteroresistance in Acinetobacter baumannii are not fully understood. Here, we investigated the role of efflux in colistin-heteroresistant populations of a multidrug-resistant (MDR) A. baumannii clinical isolate. METHODOLOGY: Three colistin-resistant A. baumannii strain variants isolated from the same clinical sample were studied for the presence of heteroresistance to colistin by drug susceptibility testing, genotyping and drug resistance target mutation analysis. The existence of active efflux was studied by synergism assays with efflux inhibitors, real-time efflux activity measurements and analysis of the mRNA transcriptional levels of selected efflux pump genes in response to colistin. RESULTS: All of the strain variants belong to the ST218, clonal complex 92, international clonal lineage II. Different colistin susceptibility levels were observed among the three strain variants, indicating that colistin-heteroresistant subpopulations were being selected upon exposure to colistin. No mutations were found in the genes lpxACD and pmrAB, which are associated with colistin resistance. The results showed the existence of synergistic interactions between efflux inhibitors and colistin and ethidium bromide. Real-time efflux assays demonstrated that the three strain variants had increased efflux activity that could be inhibited in the presence of the inhibitors. The efflux pump genes adeB, adeJ, adeG, craA, amvA, abeS and abeM were found to be overexpressed in the strain variants in response to colistin exposure. CONCLUSION: This study shows that efflux activity contributes to colistin heteroresistance in an MDR A. baumannii clinical isolate. The use of efflux inhibitors as adjuvants of the therapy can resensitize A. baumannii to colistin and prevent the emergence of drug resistance.

Pesquisa dos fatores de risco para quedas na população idosa de uma unidade básica do município de Itaúna - MG / Research of risk factors for falls in the elderly population of a basic unit of of Itaúna - MG

Introdução: As quedas constituem um problema de saúde pública e de grande impacto social nos países em que ocorre expressivo envelhecimento populacional. As quedas respondem mais de 50% das hospitalizações relacionadas a ferimentos ocorridas entre as pessoas com mais de 65 anos de idade. As quedas ocorrem devido à perda de equilíbrio postural e podem ser decorrentes de problemas primários do sistema osteoarticular/ neurológico ou condição clínica adversa que afete secundariamente os mecanismos do equilíbrio e estabilidade. Objetivo: Avaliar os fatores de risco para quedas na população idosa de uma unidade básica de saúde em Itaúna - MG. Metodologia: Realizou-se pesquisa nas bases de dados científicos on line (Google Acadêmico e SciELO), bem como em Manuais de Prevenção de Quedas em Idosos. Foram selecionados 84 prontuários de pacientes idosos, os quais abordados por meio de um formulário. Resultados: Em nossa abordagem, o fator de risco no qual os idosos estavam mais expostos foram corredores e banheiros em que 51 idosos não possuíam estrutura segura com barras de apoio e corrimãos. A marcha instável atingia 79% dos idosos e 69% apresentavam baixa acuidade visual. Vários fatores de risco tèm relação com o poder aquisitivo da população estudada como móveis inadequados (62%), iluminação (40%) e piso irregular (29%). Conclusões: O tema queda em idosos, a compreensão dos fatores de risco e adoção de medidas preventivas são fundamentais para qualquer profissional da saúde. A prevenção de quedas é importante, pois reduz morbimortalidade, custos hospitalares e asilamento consequente. (AU)

Introduction: Falls are a public health problem with great social impact in countries where there is a significant population aging. Falls account for 20% to 30% of minor injuries and more than 50% of hospitalizations related to injuries occurring among people over 65 years of age. Falls occur due to loss of postural balance, both resulting from primary problems of the osteoarticular/neurological system, from an adverse clinical condition or secondarily affects the mechanisms of balance and stability. Objective: To evaluate the risk factors for falls in the elderly population of a primary health unit in Itaúna - MG. Methodology: Research was carried out in the online scientific databases (Google Scholar and SciELO), as well as Manuals for Prevention of Falls in the Elderly. We selected 84 medical records of elderly patients, which were addressed through a form. Results: In our approach, the risk factor in which the elderly were most exposed were corridors and bathrooms in which 51 elderly people did not have a safe structure with grab bars and handrails. The unstable gait reached 79% of the elderly, and 69% had low visual acuity. Several risk factors are related to the purchasing power of the studied population as inadequate furniture (62%), lighting (40%) and irregular flooring (29%). Conclusions: The fall in the elderly, the understanding of risk factors and the adoption of preventive measures are fundamental for any health professional. The prevention of falls is important, as it reduces morbidity and mortality, hospital costs and consequent isolation. (AU)

Enriquecimento de microrganismos metanotróficos a partir de lodo de reator UASB tratando esgotos domésticos / Enrichment of methanotrophic microorganisms from sludge of UASB reactor treating domestic sewage

RESUMO Nesse estudo, microrganismos metanotróficos foram enriquecidos a partir de lodo proveniente de um reator UASB tratando esgotos domésticos em reator em batelada sequencial (RBS) com meio autotrófico contendo nitrito e nitrato. As eficiências médias de remoção de nitrito e nitrato foram de 68% e 53%, respectivamente, provavelmente devido à atividade heterotrófica desnitrificante. A detecção de arquéias dos grupos ANME-I e ANME-II foram realizadas por PCR durante todo período de cultivo. A estrutura da comunidade microbiana presente no inóculo e enriquecida no RBS após 100 dias de operação foi estudada por pirosequenciamento. Os resultados das análises demonstraram que a comunidade enriquecida no reator foi diferente à inoculada. Os filos dominantes no inóculo foram Synergistestes , Firmicutes e Euryarchaeota , ao passo que na biomassa enriquecida Planctomycetes, Verrucomicrobia, Chloroflexi e Proteobacteria predominaram. As condições de cultivo do RBS reduziram a abundância de Methanobacterium (8% para 1%) e selecionaram bactérias metanotróficas como Methylocaldum , Methylocistis e Methylosinus . As sequências de Methylocaldum sp. apresentaram abundância relativa de 2.5%. A presença e elevada predominância do filo Verrucomicrobia na biomassa enriquecida do RBS sugere que outras espécies de metanotróficas, ainda pouco conhecidas, relacionadas a este filo podem estar presentes no reator. O potencial de oxidação anaeróbia do metano foi determinado para ambas amostras e revelaram que a atividade metanotrófica da biomassa foi aproximadamente três vezes maior que a do inóculo. Em suma, estes resultados sugerem que o inóculo usado e as condições de cultivo aplicadas foram adequados para o enriquecimento de metanotróficas.

ABSTRACT In this study, methanotrophic microorganisms were enriched from sludge derived from a UASB reactor treating domestic sewage. The enrichment was performed in a sequencing batch reactor (RBS) with an autotrophic medium containing nitrite and nitrate. The nitrite and nitrate removal efficiencies were 68% and 53%, respectively, probably due to heterotrophic denitrification. Archaeal cells of the ANME-I and ANME-II groups were detected by PCR throughout the whole cultivation period. The microbial community composition of the biomass present in the inoculum and enriched in RBS after 100 days of operation was investigated and compared with the help of data obtained from pyrosequencing analyses. Pyrosequencing analysis demonstrated that the community enriched in the reactor had differing composition from the inoculum. The dominant phyla detected in the inoculum were Synergistestes , Firmicutes and Euryarchaeota while in the enriched biomass Planctomycetes, Verrucomicrobia, Chloroflexi and Proteobacteria predominated. The cultivation conditions applied decreased the abundance of Methanobacterium (from 8 to 1%) and selected for methanotrophic bacteria such as Methylocaldum , Methylocistis and Methylosinus . Sequences of Methylocaldum sp. accounted for 2.5% of the total reads. The presence and high predominance of Verrucomicrobia in the enriched biomass suggest that other unknown methanotrophic species related to this phylum might also have occurred in the reactor. The potential for anaerobic oxidation of methane was determined for both samples and revealed that the methanotrophic activity of the enriched biomass was almost three times greater than in the inoculum. Taken together these results indicated that the inoculum used and the cultivation conditions applied were adequate for the methanotrophic enrichment.

Characterization of pantropic canine coronavirus from Brazil.

Characterization of canine coronavirus (CCoV) strains currently in circulation is essential for understanding viral evolution. The aim of this study was to determine the presence of pantropic CCoV type IIa in tissue samples from five puppies that died in Southern Brazil as a result of severe gastroenteritis. Reverse-transcriptase PCR was used to generate amplicons for sequence analysis. Phylogenetic analysis of the CCoV-IIa strains indicated that they were similar to those found in other countries, suggesting a common ancestor of these Brazilian isolates. This is the first report of pantropic CCoV-II in puppies from Latin America and our findings highlight that CCoV should be included as a differential diagnosis when dogs present with clinical signs and lesions typically seen with canine parvovirus infection.