Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results.

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .

In Vitro and In Vivo Wound Healing and Anti-Inflammatory Activities of Babassu Oil (Attalea speciosa Mart. Ex Spreng., Arecaceae).

Babassu (Attalea speciosa Mart. ex Spreng., Arecaceae) is a palm tree endemic to Brazil and found mainly in the borders of Amazon forest, where the harvesting of its fruits is an important source of income for more than 300,000 people. Among the communities of coconut breakers women, babassu oil is used in culinary, as fuel, and mostly as medicinal oil for the treatment of skin wounds and inflammation. This study aimed to evaluate in vitro and in vivo the wound healing effects of babassu oil. In vitro, babassu oil increased the migration of L929 fibroblasts, inhibited the production of nitric oxide by LPS-stimulated peritoneal macrophages, and increased the levels of INF-γ and IL-6 cytokines production. In vivo, babassu oil accelerated the healing process in a full-thickness splinted wound model, by an increase in the fibroblasts number, blood vessels, and collagen deposition in the wounds. The babassu oil also increased the recruitment of inflammatory cells into the wound site and showed an anti-inflammatory effect in a chronic ear edema model, reducing ear thickness, epidermal hyperplasia, and myeloperoxidase activity. Thus, these data corroborate the use of babassu oil in folk medicine as a remedy to treat skin wounds.

Evaluation of the cytotoxicity, oral toxicity, genotoxicity, and mutagenicity of the latex extracted from Himatanthus drasticus (Mart.) Plumel (Apocynaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Himatanthus drasticus is a tree popularly known as janaguba. Endemic to Brazil, it is found in the Cerrado and Caatinga biomes, rock fields, and rainforests. Janaguba latex has been used in folk medicine for its antineoplastic, anti-inflammatory, analgesic, and antiallergic activities. However, studies investigating the safety of its use for medicinal purposes are limited. AIM OF THE STUDY: This study aimed to evaluate the toxicity of the latex extracted from H. drasticus. MATERIALS AND METHODS: The latex was extracted from H. drasticus specimens by removing a small area of bark (5 × 30 cm) and then dissolving the exudate in water and lyophilizing it. Phytochemical screening was performed by TLC and GC-MS, protein, and carbohydrate levels. Cell viability was performed by the MTT method. Acute oral toxicity, genotoxicity, and mutagenicity assays were performed in mice. RESULTS: TLC showed the presence of saponins and reducing sugars, as well as steroids and terpenes. The GC-MS analysis of the nonpolar fraction identified lupeol acetate, betulin, and α/ß-amyrin derivatives as the major compounds. The latex was toxic to S-180 cells at 50 and 100 µg/mL. No signals of toxicity or mutagenicity was found in mice treated with 2000 mg/kg of the latex, but genotoxicity was observed in the Comet assay. CONCLUSIONS: H. drasticus latex showed toxicity signals at high doses (2000 mg/kg). Although the latex was not mutagenic to mice, it was genotoxic in the Comet assay in our experimental conditions. Even testing a limit dose of 2000 mg/kg, which is between 10 to 35-fold the amount used in folk medicine, caution must be taken since there is no safe level for genotoxic compounds exposure. Further studies on the toxicological aspects of H. drasticus latex are necessary to elucidate its possible mechanisms of genotoxicity.

Diet-induced remission in chronic enteropathy is associated with altered microbial community structure and synthesis of secondary bile acids.

BACKGROUND: The microbiome has been implicated in the initiation and persistence of inflammatory bowel disease. Despite the fact that diet is one of the most potent modulators of microbiome composition and function and that dietary intervention is the first-line therapy for treating pediatric Crohn's disease, the relationships between diet-induced remission, enteropathy, and microbiome are poorly understood. Here, we leverage a naturally-occurring canine model of chronic inflammatory enteropathy that exhibits robust remission following nutritional therapy, to perform a longitudinal study that integrates clinical monitoring, 16S rRNA gene amplicon sequencing, metagenomic sequencing, metabolomic profiling, and whole genome sequencing to investigate the relationship between therapeutic diet, microbiome, and disease. RESULTS: We show that remission induced by a hydrolyzed protein diet is accompanied by alterations in microbial community structure marked by decreased abundance of pathobionts (e.g., Escherichia coli and Clostridium perfringens), reduced severity of dysbiosis, and increased levels of the secondary bile acids, lithocholic and deoxycholic acid. Physiologic levels of these bile acids inhibited the growth of E. coli and C. perfringens isolates, in vitro. Metagenomic analysis and whole genome sequencing identified the bile acid producer Clostridium hiranonis as elevated after dietary therapy and a likely source of secondary bile acids during remission. When C. hiranonis was administered to mice, levels of deoxycholic acid were preserved and pathology associated with DSS colitis was ameliorated. Finally, a closely related bile acid producer, Clostridium scindens, was associated with diet-induced remission in human pediatric Crohn's disease. CONCLUSIONS: These data highlight that remission induced by a hydrolyzed protein diet is associated with improved microbiota structure, an expansion of bile acid-producing clostridia, and increased levels of secondary bile acids. Our observations from clinical studies of exclusive enteral nutrition in human Crohn's disease, along with our in vitro inhibition assays and in vivo studies in mice, suggest that this may be a conserved response to diet therapy with the potential to ameliorate disease. These findings provide insight into diet-induced remission of gastrointestinal disease and could help guide the rational design of more effective therapeutic diets.

Conhecimento e práticas de usuários com diabetes mellitus sobre a automonitorização da glicemia capilar no domicilio / Knowledge and practices of users with diabetes mellitus on capillary blood glucose self-monitoring at home / Conocimientos y prácticas de los usuarios con diabetes mellitus en sangre capilar glucosa autocontrol en casa

Objective:To analyze the knowledge and practices of users with Diabetes Mellitus (DM) on the capillary blood glucose self-monitoring (AMGC) held at home. Methods: descriptive-exploratory study with qualitative methodology, developed in April and May 2013, with users with DM in the public health system of an interior. The data were collected through interviews and categorial analysis verified the sample. The theme was selected by saturation of the speech totaling 12 DM users that perform AMGC at home. Results: the content analysis of data made it possible to identify three categories: realization of non-rational AMGC; The absence of educational programmes to steer on the realization of AMGC; Insufficient availability of inputs to users who perform AMGC. Conclusion: Despite advances legally reached by public policies, users with DM are unaware of the legislation and how it directly interferes in the conduct of AMGC's

Objetivo: Analisar o conhecimento e as práticas de usuários com Diabetes Mellitus (DM) acerca da Automonitorização da Glicemia Capilar (AMGC) realizada no domicílio. Métodos: Estudo descritivo-exploratório, com metodologia qualitativa, desenvolvido em abril e maio 2013, com usuários com DM atendidos pelo sistema público de saúde de um interior pernambucano. Os dados foram coletados por meio de entrevistas e verificados por análise categorial temática, a amostra foi selecionada por meio da saturação do discurso totalizando 12 usuários com DM que realizam a AMGC no domicílio. Resultados: A análise de conteúdo dos dados possibilitou identificar três categorias: Realização da AMGC de forma não racional; Ausência de programas educativos para orientar sobre a realização da AMGC; Disponibilização insuficiente de insumos aos usuários que realizam a AMGC. Conclusão: Apesar dos avanços legalmente alcançados pelas políticas públicas, os usuários com DM desconhecem a legislação e como está interfere diretamente na realização da AMGC

Objetivo: Analizar los conocimientos y prácticas de los usuarios con Diabetes Mellitus (DM) de la glucosa en sangre capilar Self-monitoring (AMGC) llevó a cabo en casa. Métodos: estudio descriptivo exploratorio con metodología cualitativa, desarrollado en abril y mayo de 2013, con usuarios con DM en el sistema de salud pública de un interior. Los datos fueron recogidos a través de entrevistas y análisis categorial verificado que el tema de la muestra fue seleccionado por la saturación del discurso por un total de 12 DM usuarios que realizan la AMGC en casa. Resultados: el análisis del contenido de los datos permitió identificar tres categorías: realización de AMGC no racional; La ausencia de programas educativos para orientar en la realización de AMGC; Disponibilidad insuficiente de insumos a los usuarios que realizan AMGC. Conclusión: A pesar de los avances alcanzados legalmente por las políticas públicas, usuarios con DM desconocen la legislación y cómo está directamente interfiere en la AMGC de conducta

Assessment of the responsiveness of a public health service from the perspective of older adults.

OBJECTIVE: To assess the quality of health care of older adults using as a parameter the assessment of the responsiveness of the service. METHODS: This is a descriptive cross-sectional study conducted in a reference unit of the Brazilian Unified Health System at the outpatient level. The sample was probabilistic and had 385 older adults; data collection occurred in 2014. The domains assessed were: choice, autonomy, confidentiality, dignity, communication, physical facilities, and fast service. To this end, we used Pearson correlation test and Fisher's exact test. RESULTS: The domains of dignity, confidentiality, and communication reached the highest level of adequate responsiveness. On the other hand, freedom of choice and fast service received the worst assessments. Participation in decision-making regarding treatment was significantly lower among the older adults who had no education. In addition, the older adults that self-reported as black receive a lower quality of care regarding clear explanation and respected privacy in the appointment, when compared to users of any other race. CONCLUSIONS: Although most domains studied have receive a positive assessment, we have found a need for an equal care by the health professionals, regardless of race, education level, or any other adjective characteristic of older adults, users of public health services. OBJETIVO: Avaliar a qualidade da atenção à saúde da população idosa usando como parâmetro a avaliação da responsividade do serviço. MÉTODOS: Trata-se de um estudo descritivo, de corte transversal, realizado em uma unidade de referência do Sistema Único de Saúde em nível ambulatorial. A amostra foi probabilística composta por 385 idosos e a coleta de dados ocorreu em 2014. Foram avaliados os domínios: escolha, autonomia, confidencialidade, dignidade, comunicação, instalações físicas e atendimento rápido. Para tanto, foram utilizados o teste de correlação de Pearson e o teste de Fisher. RESULTADOS: Os domínios dignidade, confidencialidade e comunicação atingiram o maior nível de responsividade adequada. Por outro lado, a liberdade de escolha e o atendimento rápido receberam as piores avaliações. A participação na tomada de decisões a respeito do tratamento foi significativamente menor entre os idosos que não frequentaram a escola. Além disso, os idosos que se autodeclararam negros receberam um atendimento de menor qualidade no que diz respeito à explicação clara e a privacidade respeitada mediante consulta, quando comparados aos usuários de outra raça. CONCLUSÕES: Apesar de a maioria dos domínios estudados receberem uma avaliação positiva, evidenciou-se a necessidade de um atendimento igualitário por parte dos profissionais de saúde, independentemente de raça, nível de escolaridade ou qualquer outra característica adjetiva referente aos usuários idosos atendidos nos serviços de saúde públicos.

Assessment of the responsiveness of a public health service from the perspective of older adults / Avaliação da responsividade de um serviço de saúde público sob a perspectiva do usuário idoso

ABSTRACT OBJECTIVE To assess the quality of health care of older adults using as a parameter the assessment of the responsiveness of the service. METHODS This is a descriptive cross-sectional study conducted in a reference unit of the Brazilian Unified Health System at the outpatient level. The sample was probabilistic and had 385 older adults; data collection occurred in 2014. The domains assessed were: choice, autonomy, confidentiality, dignity, communication, physical facilities, and fast service. To this end, we used Pearson correlation test and Fisher's exact test. RESULTS The domains of dignity, confidentiality, and communication reached the highest level of adequate responsiveness. On the other hand, freedom of choice and fast service received the worst assessments. Participation in decision-making regarding treatment was significantly lower among the older adults who had no education. In addition, the older adults that self-reported as black receive a lower quality of care regarding clear explanation and respected privacy in the appointment, when compared to users of any other race. CONCLUSIONS Although most domains studied have receive a positive assessment, we have found a need for an equal care by the health professionals, regardless of race, education level, or any other adjective characteristic of older adults, users of public health services.

RESUMO OBJETIVO Avaliar a qualidade da atenção à saúde da população idosa usando como parâmetro a avaliação da responsividade do serviço. MÉTODOS Trata-se de um estudo descritivo, de corte transversal, realizado em uma unidade de referência do Sistema Único de Saúde em nível ambulatorial. A amostra foi probabilística composta por 385 idosos e a coleta de dados ocorreu em 2014. Foram avaliados os domínios: escolha, autonomia, confidencialidade, dignidade, comunicação, instalações físicas e atendimento rápido. Para tanto, foram utilizados o teste de correlação de Pearson e o teste de Fisher. RESULTADOS Os domínios dignidade, confidencialidade e comunicação atingiram o maior nível de responsividade adequada. Por outro lado, a liberdade de escolha e o atendimento rápido receberam as piores avaliações. A participação na tomada de decisões a respeito do tratamento foi significativamente menor entre os idosos que não frequentaram a escola. Além disso, os idosos que se autodeclararam negros receberam um atendimento de menor qualidade no que diz respeito à explicação clara e a privacidade respeitada mediante consulta, quando comparados aos usuários de outra raça. CONCLUSÕES Apesar de a maioria dos domínios estudados receberem uma avaliação positiva, evidenciou-se a necessidade de um atendimento igualitário por parte dos profissionais de saúde, independentemente de raça, nível de escolaridade ou qualquer outra característica adjetiva referente aos usuários idosos atendidos nos serviços de saúde públicos.

Uso de plantas medicinais por pessoas com hipertensão / Uso de plantas medicinales por personas con hipertensión / Use of medicinal plants by people with hypertension

Objetivo descrever o uso de plantas medicinais no tratamento da hipertensão arterial por pessoas com hipertensão, cadastradas no Programa Saúde da Família em um município do interior de Pernambuco. Métodos estudo descritivo, cujos dados foram obtidos através de roteiro de entrevistas semiestruturado aplicado a 172 pacientes. Resultados o uso de plantas medicinais para controle de hipertensão foi relatado por 39,5%, dentre os quais 57,4% usavam apenas uma planta medicinal. Entre as espécies citadas predominou uso do chuchu [Sechium edule (Jacq.) Sw.-34,8%]. Conclusão plantas medicinais constituem terapia adjuvante no tratamento de hipertensão, entretanto exigem monitorização do manuseio e espécies elencadas.

Objetivo describir el uso de plantas medicinales en el tratamiento de la hipertensión arterial por personas con hipertensión inscritas en el Programa de Salud Familiar en una ciudad del interior de Pernambuco. Métodos estudio descriptivo, cuyos datos se obtuvieron a través de guía de entrevistas semiestructuradas aplicada a 172 pacientes. Resultados el uso de plantas medicinales para el control de la hipertensión fue informado por 39,5%, de los cuales 57,4% utiliza sólo una planta medicinal. Entre las especies citadas predominó el uso de chayote [Sechium edule (Jacq.) Sw.-34.8%]. Conclusión plantas medicinales constituyen terapia coadyuvante en el tratamiento de hipertensión, sin embargo requiere monitoreo del manejo y de las especies seleccionadas.

Objective to describe the use of medicinal plants in the treatment of high blood pressure for people with hypertension enrolled in the Family Health Program in a city in Pernambuco State. Methods a descriptive study, whose data were obtained through semi-structured interview script applied to 172 patients. Results the use of medicinal plants for hypertension control was reported by 39.5%, of which 57.4% used only one medicinal plant. Among the species cited, there was predominant use of chayote [Sechium edule (Jacq.) Sw.-34.8%]. Conclusion medicinal plants constitute an adjunctive therapy in the treatment of hypertension. However, there is need for monitoring of handling and listed species.

Antinociceptive Effect of the Essential Oil Obtained from the Leaves of Croton cordiifolius Baill. (Euphorbiaceae) in Mice.

Croton cordiifolius Baill. is a shrub known as "quebra-faca" and is used to treat inflammation, pain, wounds, and gastrointestinal disturbances in the semiarid region in the northeast of Brazil. In an ethnobotanical survey in the state of Pernambuco, "quebra-faca" use was cited in 33% of the interviews. Thus, we decided to evaluate the antinociceptive effects of the essential oil from C. cordiifolius (CcEO). Chemical analysis by gas chromatography-mass spectrometry revealed 1,8-cineole (25.09%) and α-phellandrene (15.43%) as major constituents. Antinociceptive activity was evaluated using murine models of chemically induced pain (writhing induced by acetic acid, formalin, capsaicin, and glutamate tests). Opioid and central nervous systems (CNS) involvement were also investigated. Regarding antinociceptive activity, CcEO (50 and 100 mg/kg) reduced the number of writhing responses induced by acetic acid and decreased the licking times in both phases of the formalin test. CcEO also was evaluated in capsaicin- and glutamate-induced nociception. While no effect was observed in the capsaicin test, CcEO (100 mg/kg) was effective in the glutamate test. Naloxone, an opioid antagonist, did not affect the antinociceptive activity of CcEO in writhing test. In conclusion, the antinociceptive effect of CcEO could be explained, at least in part, by inhibition of the glutamatergic system.

Antinociceptive and wound healing activities of Croton adamantinus Müll. Arg. essential oil.

Leaves of Croton adamantinus have been used to treat inflammation and skin wounds in the semi-arid area of the Northeast of Brazil. In order to evaluate if the essential oil (EO) was responsible for the claimed activities; antinociceptive, wound healing and antimicrobial tests were carried out. Twenty constituents were identified in C. adamantinus EO by GC-MS, ¹H-NMR and ¹³C-NMR, the major compounds being methyl-eugenol (14.81%) and 1,8-cineol (13.74%). Antinociceptive activity was evaluated by the formalin test and the abdominal contortion assay in mice. The EO (50 and 100 mg/kg) decreased the licking time of both phases of the formalin test when compared to the vehicle, but not to morphine (7.5 mg/kg). In the abdominal contortion assay, the EO (50 and 100 mg/kg) reduced the number of contortions compared to the vehicle and to indometacin (10 mg/kg). The wound healing activity was verified also using two experimental models: excisional wound and dead space. Topical treatment with the EO (1%) increased the wound contraction from the third day of treatment (compared with nitrofurazone 0.2%), while systemic treatment (50 mg/kg/day) increased granulation tissue formation and reduced the water content. C. adamantinus EO also showed antimicrobial activity against Staphylococcus aureus in disk diffusion method. These results corroborate the ethnobotanical use of this specie by Brazilian population.

The renal effects of alginates isolated from brown seaweed Sargassum vulgare.

Alginates isolated from Sargassum vulgare, present a strong antitumor activity, associated with kidney reversible damage, as analysed by histopathology of treated animals. In the present study, the renal alteration mechanisms of S. vulgare alginates were investigated using the isolated perfused rat kidney and the isolated perfused rat mesenteric blood vessel methods. The results showed that the effects of Sargassum vulgare low viscosity (SVLV) alginate were more potent than those of Sargassum vulgare high viscosity (SVHV) alginate in the isolated rat kidney. The SVLV alginate caused considerable changes in renal physiology, as shown by an increase in parameters such as perfusion pressure, renal vascular resistance, glomerular filtration rate, urinary flow and sodium, potassium and chloride excretion and by reduction of chloride tubular transport. The effects of SVHV were weaker than those of SVLV. The effects of SVLV on kidney could be related to direct vascular action as demonstrated with SVLV alginate on mesenteric blood vessels. In conclusion, the Sargassum vulgare alginate altered the renal function parameters evaluated. S. vulgare low viscosity alginate renal effects were more potent than S. vulgare high viscosity alginate. It is suggested that physicochemical differences between SVHV and SVLV could explain the differences found in the results.

Análise laboratorial do líquido céfalo-raquidiano (líquor/LCR) / Clinical laboratory analysis cerebrospinal fluid (CSF)

Diversos trabalhos científicos publicados descrevem que, a exemplo do exame sumário de urina, os testes e os resultados do líquor, particularmente a citobioquímica, são realizados e descritos de diferentes formas nos laboratórios clínicos. Certamente, essa situação introduz a possibilidade de erros sistemáticos, provocados ou não pelo analista, além de dificultar a compreensão e a correta interpretação, do resultado por parte dos médicos assistente e/ou solicitante. A padronização de procedimentos é o único meio e, de fundamental importância, para se obter a precisão e a exatidão dos resultados, levando o laboratório a aumentar e melhorar o desempenho, no sentido de executar cada vez melhor sua função social a serviço do usuário. O presente artigo é uma revisão de vários trabalhos, publicados na literatura sobre o assunto, com a intenção de descrever o exame do líquido céfalo-raquidiano quanto às técnicas de coleta da amostra, características físicas, contagens celulares e análises bioquímicas, imunológicas e microbiológicas, bem como, apontar os problemas mais freqüentes nas etapas pré-analítica, analítica e pós-analítica e descrever o quadro característico das meningites, diante do resultado de alguns parâmetros laboratoriais.