A trivalent approach for determining in vitro toxicology: Examination of oxime K027.

Unforeseen toxic effects contribute to compound attrition during preclinical evaluation and clinical trials. Consequently, there is a need to correlate in vitro toxicity to in vivo and clinical outcomes quickly and effectively. We propose an expedited evaluation of physiological parameters in vitro that will improve the ability to predict in vivo toxicity of potential therapeutics. By monitoring metabolism, mitochondrial physiology and cell viability, our approach provides insight to the extent of drug toxicity in vitro. To implement our approach, we used human hepatocellular carcinoma cells (HepG2) and neuroblastoma cells (SH-SY5Y) to monitor hepato- and neurotoxicity of the experimental oxime K027. We utilized a trivalent approach to measure metabolism, mitochondrial stress and induction of apoptosis in 96-well formats. Any change in these three areas may suggest drug-induced toxicity in vivo. K027 and pralidoxime, an oxime currently in clinical use, had no effect on glycolysis or oxygen consumption in HepG2 and SH-SY5Y cells. Similarly, these oximes did not induce oxidant generation nor alter mitochondrial membrane potential. Further, K027 and pralidoxime failed to activate effector caspases, and these oximes did not alter viability. The chemotherapeutic agent, docetaxel, negatively affected metabolism, mitochondrial physiology and viability. Our studies present a streamlined high-throughput trivalent approach for predicting toxicity in vitro, and this approach reveals that K027 has no measurable hepatotoxicity or neurotoxicity in vitro, which correlates with their in vivo data. This approach could eliminate toxic drugs from consideration for in vivo preclinical evaluation faster than existing toxicity prediction panels and ultimately prevent unnecessary experimentation.

Inflammation, fibrosis and E1 glycoprotein persistence in joint tissue of patients with post-Chikungunya chronic articular disease.

INTRODUCTION: Chikungunya chronic joint disease causes debilitating arthralgia, significantly impacting the quality of life of affected individuals. METHODS: In this study, patients underwent clinical follow-ups, joint biopsies, and pre-biopsy and 24 months post-biopsy serum dosage of cytokines. RESULTS: All participants were female and had pain in 12 joints on average, with 41.17% exhibiting moderate disease activity. Histopathological analysis revealed collagen deposition. Indirect immunofluorescence detected the CHIKV glycoprotein E1 antigen, and an increase in cytokines. CONCLUSIONS: Persistent inflammation and ineffective antiviral immune responses leading to antigen persistence may contribute to chronic CHIKV arthritis.

Inflammation, fibrosis and E1 glycoprotein persistence in joint tissue of patients with post-Chikungunya chronic articular disease

ABSTRACT Introduction: Chikungunya chronic joint disease causes debilitating arthralgia, significantly impacting the quality of life of affected individuals. Methods: In this study, patients underwent clinical follow-ups, joint biopsies, and pre-biopsy and 24 months post-biopsy serum dosage of cytokines. Results: All participants were female and had pain in 12 joints on average, with 41.17% exhibiting moderate disease activity. Histopathological analysis revealed collagen deposition. Indirect immunofluorescence detected the CHIKV glycoprotein E1 antigen, and an increase in cytokines. Conclusions: Persistent inflammation and ineffective antiviral immune responses leading to antigen persistence may contribute to chronic CHIKV arthritis.

In Vivo Antitumor Effect of Supercritical CO2 Extract of Mango Ginger ( Curcuma amada Roxb) in U-87MG Human Glioblastoma Nude Mice Xenografts.

Glioblastoma multiforme (GBM) is one the most aggressive and lethal human neoplasms with poor prognosis and very limited positive treatment options. The antitumor effect of supercritical CO2 extract of mango ginger ( Curcuma amada Roxb) (CA) with and without irinotecan (IR) was analyzed in U-87MG human glioblastoma multiforme (GBM) cells in vitro and in nude mice xenografts. CA is highly cytotoxic to GBM cells and is synergistic with IR as indicated by the combination index values of <1 in the CompuSyn analysis. CA inhibits tumor growth rate in GBM xenografts, the inhibition rate being higher than in IR treated group. GBM xenograft mice treated with IR + CA combination showed almost complete inhibition of tumor growth rate. Gene expression analysis of xenograft tumors indicated that IR + CA treatment significantly downregulated anti-apoptotic (Bcl-2 and mutant p53), inflammation-associated (COX-2) and cell division-associated (CCNB2) genes and upregulated pro-apoptotic genes (p21 and caspase-3). These results confirmed the therapeutic efficiency of IR + CA combination against GBM and the need for further clinical investigations.

Literatura e Psicopedagogia: Em busca do sujeito leitor / Literature and Psychopedagogy: In search of the reader subject

Este artigo foi escrito a muitas mãos. As autoras, psicopedagogas voluntárias no Projeto Social da Associação Brasileira de Psicopedagogia e participantes do curso "A literatura na construção do sujeito", ministrado no primeiro semestre de 2021 pela Profª Drª Leda Barone, buscam através dele registrar o que aprenderam naqueles encontros literários e, sobretudo, o modo como eles ecoaram singularmente sobre cada uma. Tem, assim, por objeto a constituição do sujeito-psicopedagogo pelo viés da literatura. Principia pelo conceito de sujeito aportado pela psicanálise e a relação entre literatura e constituição subjetiva. Resgata na sequência as memórias afetivas das autoras relativamente ao ato de ler, cerne do artigo e mote para refletir acerca de seu próprio processo singular de subjetivação e formação profissional, revivido e reelaborado no decorrer daqueles meses de estudo. Por fim, aponta para novas perspectivas no modo de ser psicopedagogo a partir dessa experiência.

This article was written by many hands. The authors, volunteer psycho pedagogues in the Social Project of the Brazilian Association of Psychopedagogy and participants of the course "Literature in the construction of the subject", taught in the first semester of 2021 by Professor Dr. Leda Barone, seek through him to record what they learned in those literary encounters and, above all, the way they echoed uniquely on each one. Its object, therefore, is the constitution of the subject-psychopedagogue from the perspective of literature. It begins with the concept of subject provided by psychoanalysis and the relationship between literature and subjective constitution. It then rescues the affective memories of the authors regarding the act of reading, the core of the article and a theme to reflect on their own unique process of subjectivation and professional training, revived and re-elaborated during those months of study. Finally, it points to new perspectives in the way of being a psychopedagogue based on this experience.

Pathway, inhibition and regulation of methyl tertiary butyl ether oxidation in a filamentous fungus, Graphium sp.

The filamentous fungus Graphium sp. (ATCC 58400) co-metabolically oxidizes the gasoline oxygenate methyl tertiary butyl ether (MTBE) after growth on gaseous n-alkanes. In this study, the enzymology and regulation of MTBE oxidation by propane-grown mycelia of Graphium sp. were further investigated and defined. The trends observed during MTBE oxidation closely resembled those described for propane-grown cells of the bacterium Mycobacterium vaccae JOB5. Propane-grown mycelia initially oxidized the majority ( approximately 95%) of MTBE to tertiary butyl formate (TBF), and this ester was biotically hydrolyzed to tertiary butyl alcohol (TBA). However, unlike M. vaccae JOB5, our results collectively suggest that propane-grown mycelia only have a limited capacity to degrade TBA. None of the products of MTBE exerted a physiologically relevant regulatory effect on the rate of MTBE or propane oxidation, and no significant effect of TBA was observed on the rate of TBF hydrolysis. Together, these results suggest that the regulatory effects of MTBE oxidation intermediates proposed for MTBE-degrading organisms such as Mycobacterium austroafricanum are not universally relevant mechanisms for MTBE-degrading organisms. The results of this study are discussed in terms of their impact on our understanding of the diversity of aerobic MTBE-degrading organisms and pathways and enzymes involved in these processes.

Moradia para o idoso: uma política ainda não garantida / Housing for the elderly: a policy not yet guaranteed

O envelhecimento populacional já é um fato constatado por pesquisas. Este texto trata de como fazer para garantir habitação com qualidade de vida a esta população que está envelhecendo. No primeiro momento aponta os dispositivos legais que obrigam o poder publico a implantar políticas para viabilizar uma melhor qualidade de moradia à população que está envelhecendo. Cita o programa da OMS, Cidade Amiga do Idoso. Comenta o projeto, desenvolvido pela Secretaria de Habitação do Estado de São Paulo, de habitação de interesse social com o conceito de desenho universal, entre outros. Na segunda parte apresenta dicas de cuidados construtivos e de detalhamento a serem observados no projeto e na construção, para um maior conforto e segurança desta faixa etária da população.

The aging of the population is a fact that has been well documented in studies. This text examines how to ensure housing with quality of life for this aging population. First, it indicates the legal provisions that require the government to implement policies to ensure better housing for the aging population. It refers to the WHO Age-friendly cities Program, and comments on the project developed by the São Paulo State Housing Office Program of social interest housing with the concept of universal design, and others. In the second part it presents suggestions on the care and details to be considered in the design and construction of housing to ensure greater comfort and security for this age range.

Infección estreptocóccica, insuficiencia renal aguda y nefritis intersticial / Streptococcal infection, acute kidney failure and interstitial nephritis

The relationship between streptococcal infection and renal disease has been object of multiple studies. Streptococcal infection may induce acute glomerulonephritis or interstitial nephritis. We report a patient with a streptococcal infection who developed acute renal failure. The renal biopsy showed an acute interstitial nephritis, with an interstitium infiltrate with a significant number of eosinophils. We review the causes of acute renal failure associated with streptococcal infection, specially acute interstitial nephritis.

Idosos, cidade e moradia: acolhimento ou confinamento? / Elderly citizens, city and home: sheltering or confinement?

O objetivo deste artigo é discutir uma das causas que dificulta e, muitas vezes, até impede o idoso de participar mais intensamente da vida em sociedade: a falta de acessibilidade na estrutura urbana, nas edificações, nos meios de transporte e de comunicação. Considerando que a qualidade de vida das pessoas depende, em grande parte, do meio em que vivem e se locomovem, os espaços que construímos para viver devem sofrer profundas alterações, passando a incorporar o princípio da eqüidade e o respeito às necessidades diferenciadas dos seres humanos, para que não sigam atuando como importantes fatores de exclusão social.

Interacción entre ciclosporina A y rifampicina en un caso de transplante renal / Cyclosporin A and rifampicin interaction in renal transplantation

Se presenta el caso de un transplante renal donde debió usarse conjuntamente ciclosporina A (CyA) y drogas tuberculostáticas. Se comprobó que la concentración sanguínea de CyA (medida por radioinmunoensayo Sandoz) permaneció alrededor de 200ng/ml a pesar de dosis de CyA de 17mg/kg/d. Tras la suspensión del tratamiento antituberculoso, el nível sanguíneo de CyA ascendió rápidamente a 600 y 1300ng/ml, 7 y 11 días después de la suspensión de las drogas, respectivamente. Del análisis de los datos y de la literatura se concluye que la reifampicina fue la droga inductora del sistema enzimático microsomal hepático de las monooxigenasas dependientes del citrocromo P-450, que a su vez metaboliza también la CyA. Se concluye que la asociación CyA-rifampicina debe evitarse. En caso de que esta última deba ser necesariamente administrada, las dosis de CyA deben elevarse considerablemente por encima de las usuales y disminuirse bruscamente tras lo suspensión de la rifampicina para evitar fenómenos tóxicos

Peritonitis en diálisis peritoneal contínua ambulatoria: evaluación microbiológica y clínica / Peritonitis in continuous ambulatory peritoneal dialysis: Microbiological and clinical evaluation

La infección peritoneal continúa siendo el más común y frecuente factor de morbilidad en pacientes sometidos a DPCA, hemos realizado una evaluación de nuestra metodologia microbiológica para su diagnóstico, de la incidencia de agentes etiológicos y de la evolución a través del tratamiento antibiótico, en un estudio retrospectivo de 18 pacientes con insuficiencia renal crónica terminal en plan de episodios/paciente/año. El método de diagnóstico microbiológico por centrifuhgación de 2000 ml del liquido mostró una sensibilidad del 85% en los 73 episodios estudiados. De los agentes etiológicos aislados, los bacilos gram negativos respresentaron el 59,1% y los cocos gram positivos el 37,3%. Los gérmenes más frecuentes fueron los estafilococos coagulasa negativos (12,8%). El tratamiento empírico inicial, cefalotina 250 mg/l y gentamicina 8 mg/l i.p., resultó eficaz en el 61,1% de los episodios

A arte de bem morar na velhice / The art of well live in the aging

Moradia é uma das necessidades básicas de qualquer ser humano. Esse espaço tem o papel de prover abrigo e proteção. À medida que envelhecemos, a casa passa a ter uma importância muito grande em nossa vida, pois contém o significado das conquistas e das memórias dos momentos que lá vivemos, que foram sendo construídos ao longo dos anos