Computer-Aided Ankle Ligament Injury Diagnosis from Magnetic Resonance Images Using Machine Learning Techniques.

Ankle injuries caused by the Anterior Talofibular Ligament (ATFL) are the most common type of injury. Thus, finding new ways to analyze these injuries through novel technologies is critical for assisting medical diagnosis and, as a result, reducing the subjectivity of this process. As a result, the purpose of this study is to compare the ability of specialists to diagnose lateral tibial tuberosity advancement (LTTA) injury using computer vision analysis on magnetic resonance imaging (MRI). The experiments were carried out on a database obtained from the Vue PACS-Carestream software, which contained 132 images of ATFL and normal (healthy) ankles. Because there were only a few images, image augmentation techniques was used to increase the number of images in the database. Following that, various feature extraction algorithms (GLCM, LBP, and HU invariant moments) and classifiers such as Multi-Layer Perceptron (MLP), Support Vector Machine (SVM), k-Nearest Neighbors (kNN), and Random Forest (RF) were used. Based on the results from this analysis, for cases that lack clear morphologies, the method delivers a hit rate of 85.03% with an increase of 22% over the human expert-based analysis.

Mammogram Image Enhancement Techniques for Online Breast Cancer Detection and Diagnosis.

Breast cancer is the type of cancer with the highest incidence and global mortality of female cancers. Thus, the adaptation of modern technologies that assist in medical diagnosis in order to accelerate, automate and reduce the subjectivity of this process are of paramount importance for an efficient treatment. Therefore, this work aims to propose a robust platform to compare and evaluate the proposed strategies for improving breast ultrasound images and compare them with state-of-the-art techniques by classifying them as benign, malignant and normal. Investigations were performed on a dataset containing a total of 780 images of tumor-affected persons, divided into benign, malignant and normal. A data augmentation technique was used to scale up the corpus of images available in the chosen dataset. For this, novel image enhancement techniques were used and the Multilayer Perceptrons, k-Nearest Neighbor and Support Vector Machines algorithms were used for classification. From the promising outcomes of the conducted experiments, it was observed that the bilateral algorithm together with the SVM classifier achieved the best result for the classification of breast cancer, with an overall accuracy of 96.69% and an accuracy for the detection of malignant nodules of 95.11%. Therefore, it was found that the application of image enhancement methods can help in the detection of breast cancer at a much earlier stage with better accuracy in detection.

The effect of short-term resistance training on hand reaction time improvement is independent of sexual dimorphism / El efecto del entrenamiento de resistencia a corto plazo en la mejora del tiempo de reacción manual es independiente del dimorfismo sexual / O efeito do treinamento resistido de curto prazo sobre a melhora do tempo de reação é independente do dimorfismo sexual

Objectiveː The aim was to evaluate the effects of four weeks of resistance training and sexual dimorphism on Manual reaction time in apparently healthy subjects.Methods: The subjects of the sample were randomly allocated in two groups, as follow: Control (CTRL) - kept 4 weeks without any systematized physical activity (Nmales= 8, age= 24±3 yrs., body weight= 76.9±15.4 kg; Nfemales= 8, age= 22.5±4 yrs., body weight= 70.8±17.5 kg); Experimental (EXP) - 4 weeks of resistance training (Nmales= 8, age= 23±3 yrs., weight= 69.6±11 kg; Nfemales= 8, age= 22.5±1 yrs., body weight= 59.77±6.8 kg). The resistance training consisted of 4 exercises for upper limbs (3 sets x 8-12 reps) and 4 exercises for lower (3 sets x 12-15 reps). Manual reaction time was evaluated in a manufactured Arduino-based reaction time device connected to a computer.Results: For men, there was a significant decrease in Manual reaction time after resistance training within EXP (p<0.0001) and between groups (p<0.0001). Women showed the same results within EXP (p<0.0001) and between groups (p<0.0001). Additionally, there was no sexual dimorphism before or after four weeks of resistance training.Conclusion: The results suggest that just four weeks of resistance training was sufficient to improve Manual reaction time, regardless of sexual dimorphism. Therefore, resistance training inclusion in the training periodization seems essential to improve or rehabilitate the fast voluntary motor response, especially for activities or sports that require it. (AU)

Objetivo: El objetivo fue evaluar los efectos de cuatro semanas de entrenamiento de resistencia y dimorfismo sexual sobre el tiempo de reacción manual en jóvenes aparentemente sanos.Métodos: Los sujetos de la muestra fueron asignados aleatoriamente en dos grupos, como sigue: Control (CTRL) - mantenido 4 semanas sin ninguna actividad física sistematizada (Nhombres= 8, edad= 24 ± 3 años, peso corporal= 76.9 ± 15.4 kg; Nmujeres= 8, edad= 22.5 ± 4 años, peso corporal= 70.8 ± 17.5 kg); Experimental (EXP) - 4 semanas de entrenamiento de resistencia (Nhombres= 8, edad= 23 ± 3 años, peso corporal= 69.6 ± 11 kg; Nmujeres= 8, edad= 22.5 ± 1 año, peso corporal= 59.77 ± 6.8 kg). El entrenamiento de resistencia consistió en 4 ejercicios para las extremidades superiores (3 series x 8-12 repeticiones) y 4 ejercicios para las inferiores (3 series x 12-15 repeticiones). El tiempo de reacción manual se evaluó utilizando una placa Arduino fabricada conectada a la computadora.Resultados: Para los hombres, hubo una reducción significativa en tiempo de reacción manual después de entrenamiento de resistencia intra EXP (p <0.0001) y entre grupos (p <0.0001). Los mismos resultados se observaron en mujeres, intra EXP (p <0.0001) y entre grupos (p <0.0001). Además, no hubo dimorfismo sexual antes y después de 4 semanas de entrenamiento de resistencia.Conclusión: Los resultados sugieren que solo cuatro semanas de entrenamiento de resistencia fueron suficientes para mejorar la tiempo de reacción manual, independientemente del dimorfismo sexual. La inclusión del entrenamiento de resistencia en la periodización del entrenamiento parece importante para mejorar o rehabilitar la respuesta motora voluntaria rápida, especialmente para actividades o deportes que lo requieran. (AU)

Objetivo: O objetivo foi avaliar os efeitos de quatro semanas de treinamento resistido e do dimorfismo sexual sobre o tempo de reação manual em jovens aparentemente saudáveis.Metodos: 32 jovens destreinados de ambos os sexos compuseram a amostra. Eles foram aleatoriamente alocados em 2 grupos: Controle (CTRL) – ficaram 4 semanas sem exercícios físicos (Nhomens= 8, idade= 24±3 anos, peso corporal= 76.9±15.4 kg; Nmulheres= 8, idade= 22.5±4 anos, peso corporal= 70.8±17.5 kg); Experimental (EXP) - 4 semanas de treinamento resistido (Nhomens= 8, idade= 23±3 anos, peso corporal= 69.6±11 kg; Nmulheres= 8, idade= 22.5±1 anos, peso corporal= 59.77±6.8 kg). O treinamento resistido consistiu em 4 exercícios para membros superiores (3 séries x 8-12 reps) e 4 para inferiores (3 sets x 12-15 reps). tempo de reação manual foi avaliado através de uma placa manufaturada de Arduino conectada ao computador.Resultados: Para os homens, houve uma redução significativa no tempo de reação manual após treinamento resistido intra EXP (p<0.0001) e entre os grupos (p<0.0001). Os mesmos resultados foram observados em mulheres, intra EXP (p<0.0001) e entre os grupos (p<0.0001). Adicionalmente não houve dimorfismo sexual antes ou após 4 semanas de treinamento resistido.Conclusão: Os resultados sugerem que apenas quatro semanas de treinamento resistido foram suficientes para melhorar o tempo de reação manual, independente do dimorfismo sexual. Portanto, a inclusão do treinamento resistido na periodização de treinamento parece importante para melhorar ou reabilitar a resposta motora voluntária rápida, principalmente para atividades ou esportes que assim necessitem. (AU)

The role of internal auditing in promoting accountability in Higher Education Institutions / El papel de la auditoría interna en la promoción de la accountability en las Instituciones de Educación Superior / O papel da auditoria interna na promoção da accountability nas Instituições de Ensino Superior

Abstract This paper discusses the link between accountability and internal auditing, particularly analyzing the extent to which the latter contributes to improve the former, in Higher Education Institutions (HEIs). This study applied a questionnaire to the management boards of a sample of HEIs, to empirical analyze the relationship between internal auditing and accountability. The main focus was on internal auditing carried out by the offices or departments in those institutions. The paper contributes to understand how management boards perceive internal auditing to foster transparency and accountability in HEIs, allowing to corroborate that auditing, and particularly internal auditing, favors the institutions' accountability. In effect, it promotes the principles underlying accountability practices. The information provided in the scope of internal audits is acknowledged as contributing to improve management effectiveness and helping in decision-making. HEIs wanting to create an internal auditing office or to enhance the role of an existing one, should develop this office's activities so that it becomes an instrument to support accountability and good governance of the organization. The sample consisted of Portuguese public HEIs, universities and polytechnics. Despite a certain international convergence regarding this type of public sector organizations, and regarding their purposes and governance, certain contextual specificities might limit the generalization of the findings for other jurisdictions.

Resumen Este artículo discute la asociación entre la accountability y la auditoría interna, en particular analizando hasta qué punto esta última contribuye a mejorar la primera, en las Instituciones de Educación Superior (IES). Para analizar empíricamente la relación entre la auditoría interna y la accountability, el estudio se basa en los resultados de una encuesta enviada a los consejos de administración de una muestra de IES, con el enfoque principal en la auditoría interna realizada por las oficinas o departamentos en esas instituciones. El artículo contribuye a comprender cómo los consejos de administración perciben la auditoría interna para fomentar la transparencia y accountability en las IES, lo que permite corroborar que la auditoría, y particularmente la auditoría interna, sirve a la accountability. De hecho, ella promueve los principios subyacentes a las prácticas de accountability. Se reconoce que la información proporcionada en el ámbito de las auditorías internas contribuye a mejorar la efectividad de la gestión y ayuda en la toma de decisiones. Las IES que desean crear una oficina de auditoría interna o mejorar el papel de una existente, deben desarrollar las actividades de esta oficina para que se convierta en un instrumento de apoyo a la accountability y al buen gobierno de la organización. La muestra consistió en IES públicas portuguesas, universidades y politécnicos. A pesar de una cierta convergencia internacional con respecto a este tipo de organizaciones, así como con respecto a sus propósitos y gobernanza, ciertas especificidades contextuales pueden limitar la generalización de los resultados a otras jurisdicciones.

Resumo Este artigo discute a associação entre accountability e auditoria interna, analisando particularmente até que ponto a última contribui para melhorias na primeira, nas Instituições de Ensino Superior (IES). Para analisar empiricamente a relação entre auditoria interna e accountability, o estudo baseia-se nos resultados de um questionário enviado aos órgãos de gestão de uma amostra de IES, com o foco principal na auditoria interna desenvolvida pelos gabinetes ou departamentos nessas instituições. O artigo contribui para entender como os órgãos de gestão percebem a auditoria interna para promover a transparência e a accountability nas IES, permitindo corroborar que a auditoria e, principalmente, a auditoria interna, serve a accountability. Com efeito, ela promove os princípios subjacentes às práticas de accountability. A informação proporcionada no âmbito das auditorias internas é reconhecida como contribuindo para melhorar a eficácia da gestão e ajudar na tomada de decisões. As IES que desejem criar um gabinete de auditoria interna ou aprimorar o papel de um gabinete já existente, devem desenvolver as atividades desse serviço de modo a que se torne um instrumento para apoiar a accountability e a boa governança da organização. A amostra foi constituída por IES públicas portuguesas, universidades e institutos politécnicos. Apesar de existir uma certa convergência internacional em relação a este tipo de organizações do setor público, bem como em relação aos seus propósitos e governança, certas especificidades contextuais podem limitar a generalização dos resultados desta pesquisa, para outras jurisdições.

Axial Length and Prevalence of Myopia among Schoolchildren in the Equatorial Region of Brazil.

The prevalence of myopia is increasing globally, and the outdoor light environment is considered as a possible factor that can retard myopia. The aim of this study was to evaluate the prevalence of myopia and the light environment in Aracati, equatorial Brazil. We surveyed 421 children (421 right eyes; mean age, 10.6 years) and performed ocular examinations that included non-cycloplegic refraction and axial length (AL). Multiple regression analyses were performed to identify factors affecting myopia such as time spent outdoors and in near work. We measured illuminance and violet light irradiance in Aracati. The mean spherical equivalent (SE) and AL were -0.44 ± 1.38 diopters (D) and 22.98 ± 0.87 mm, respectively. The prevalence of myopia (SE ≤ -0.75 D) and high myopia (SE ≤ -6.0 D/AL ≥ 26.0 mm) was 20.4 and 1.4/0.48%, respectively. Multiple regression analyses showed that myopia was not associated with lifestyle factors. The average illuminance in Aracati was about 100,000 lux from morning to evening. The current results reflect the ALs and the prevalence of myopia among Brazilian schoolchildren. There is a possibility that the light environment in addition to other confounding factors including racial differences affects the ALs and refractive errors.

Physico-chemical stability of co-formulation of PEGylated human amylin with insulin.

Since the discovery of amylin no combined formulation with insulin has been made available. Amylin or its triple proline analog pramlintide are not compatible in solution with insulin. The drug candidate hAmy-PEG5k is a novel monoPEGylated amylin derivative with improved physicochemical properties and retained similar pharmacological activity compared to free amylin and pramlintide. We have investigated the short- and long-term physicochemical compatibility of hAmy-PEG5k co-formulated with slow-acting human insulin analogs glargine or detemir. While human amylin promptly aggregates over a large range of pH, and both free and in the presence of regular, glargine or detemir insulin, the hAmy-PEG5k analog is stable at these conditions as shown by Thioflavin T (ThT) binding assay. When hAmy-PEG5k (100 or 500 µg/mL) was added to the commercial formulations of either insulin glargine or detemir (95 IU/mL), the combinations remained stable after 6 months stored at 4 °C, as probed by ThT, dynamic light scattering (DLS) measurements and high performance liquid chromatography (HPLC) analyses, confirming the absence of amyloid fibers, minor aggregation products or loss of material. These results suggest hAmy-PEG5k and the insulin analogs glargine and detemir are physicochemically compatible and are candidate ready-to-use fixed-dose combinations.

BZ043, a novel long-acting amylin analog, reduces gastric emptying, food intake, glycemia and insulin requirement in streptozotocin-induced diabetic rats.

Amylin analogs are important adjunctive drugs in the treatment of diabetes mellitus. However, a dual therapy with insulin involves inconvenient multiple injections. Here we describe a novel n-terminal PEGylated human amylin analog - BZ043 - and its potential to improve the control of glycemia using lower doses of insulin. The effect of BZ043 over the insulin-mediated control of fed-glycemia was investigated in rats with streptozotocin-induced diabetes treated with the basal analog glargine (GLAR). Fasted rats (3 h) received a single treatment of BZ043 (16, 64 or 128 nmol/kg), GLAR (1.5 IU or 6.0 IU) or BZ043 plus GLAR low dose (1.5 IU) in separate injections, and had free access to 5% glucose rich chow and water. BZ043 dose-proportionally prevented the meal-related increase of glycemia, and the co-treatment (64 or 128 nmol/kg) with GLAR restored normoglycemia without abrupt variations of glycemia. BZ043 showed a prolonged anti-hyperglycemic effect and, together with GLAR, promoted a long-lasting normoglycemia, in vivo. We conceive that combining BZ043 and GLAR in a fixed-ratio co-formulation might conveniently improve the control of diabetes mellitus.

Psicologia social e cras: a experiência de uma oficina de fotografia como dispositivo ressignificador de sentidos / Social psychology and cras: the experience of a photography workshop as a resigner device of senses / Psicología social y “cras”: la experiencia de una oficina de fotografía como dispositivo resignificador de sentidos

Este trabalho compartilha a experiência de uma oficina realizada com jovens, em um Centro de Referência em Assistência Social (CRAS) da cidade de Florianópolis (Brasil), durante o ano de 2013. As oficinas tiveram como foco a linguagem fotográfica, a qual pôde fazer-se mediadora dos processos de significação e ressignificação dos sujeitos em relação ao território. As oficinas envolveram a apropriação de técnicas fotográficas e a discussão de questões ligadas à relação dos participantes com o território. As informações, examinadas por meio da análise de conteúdo, foram produzidas via observações registradas em diário de campo, material publicado em redes sociais e entrevistas com os sujeitos ao fim dos encontros da oficina. Os resultados apontam que a linguagem fotográfica se coloca como mediadora na criação de espaços de reflexão acerca de si e de seu contexto, estabelecendo relações capazes de aumentar suas potências de vida e de ampliação de perspectivas de futuro.

This work shares the experience of a workshop held with young people, in a Social Assistance Reference Center (CRAS) in the city of Florianópolis (Brazil), during the year 2013. The workshops focused on the photographic language, which can mediate the processes of signification and resignification of the subjects in regard with the territory. The workshops involved the appropriation of photographic techniques and the discussion of issues related to the relation of the participants with the territory. The information, analyzed through content analysis, was produced through observations recorded in field diary, material published in social networks and interviews with the subjects at the end of the workshop meetings. The results show that the photographic language is a mediator in the creation of spaces for reflection about oneself and its context, establishing relationships capable of increasing their potencies of life and expanding future perspectives.

Este trabajo comparte la experiencia de un taller realizado con jóvenes, en un Centro de Referencia en Asistencia Social (CRAS) de la ciudad de Florianópolis (Brasil), durante el año 2013. Los talleres tuvieron como foco el lenguaje fotográfico, el cual puede actuar como mediador de los procesos de significación y resignificación de los sujetos en relación al territorio. Los talleres involucraron la apropiación de técnicas fotográficas y la discusión de cuestiones vinculadas a la relación de los participantes con el territorio. Las informaciones, estudiadas por medio del análisis de contenido, fueron producidas a través de observaciones registradas en diario de campo, material publicado en redes sociales y entrevistas con los sujetos al final de los encuentros del taller. Los resultados muestran que el lenguaje fotográfico se coloca como mediador en la creación de espacios de reflexión acerca de sí y de su contexto, estableciendo relaciones capaces de aumentar sus potencias no sólo de vida sino también de ampliación de perspectivas de futuro.

15-Deoxy-Delta-12,14-Prostaglandin J2 Inhibits Lung Inflammation and Remodeling in Distinct Murine Models of Asthma.

15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) has been described as an anti-inflammatory lipid mediator in several in vitro and in vivo studies, but its effect on allergic pulmonary inflammation remains elusive. The aim of this study was to investigate the therapeutic potential of 15d-PGJ2 based on distinct murine models of allergic asthma triggered by either ovalbumin (OVA) or house dust mite extract (HDM). Characteristics of lung inflammation, airway hyper-reactivity (AHR), mucus exacerbation, and lung remodeling in sensitized A/J mice treated or not with 15d-PGJ2 were assessed. 15d-PGJ2 treatments were carried out systemically or topically given via subcutaneous injection or intranasal instillation, respectively. Analyses were carried out 24 h after the last allergen provocation. Irrespective of the route of administration, 15d-PGJ2 significantly inhibited the peribronchial accumulation of eosinophils and neutrophils, subepithelial fibrosis and also mucus exacerbation caused by either OVA or HDM challenge. The protective effect of 15d-PGJ2 occurred in parallel with inhibition of allergen-induced AHR and lung tissue production of pro-inflammatory cytokines, such as interleukin (IL)-5, IL-13, IL-17, and TNF-α. Finally, 15d-PGJ2 was found effective in inhibiting NF-κB phosphorylation upon HDM challenge as measured by Western blotting. In conclusion, our findings suggest that 15d-PGJ2 can reduce crucial features of asthma, including AHR, lung inflammation, and remodeling in distinct murine models of the disease. These effects are associated with a decrease in lung tissue generation of pro-inflammatory cytokines by a mechanism related to downregulation of NF-κB phosphorylation.

Uveitis in São Paulo, Brazil: 1053 New Patients in 15 Months.

PURPOSE: To describe the clinical profile of uveitis and analyze changes over a 34-year period in the frequency of different entities and demographics, anatomic data, diagnoses, and systemic associations in São Paulo, Brazil. METHODS: A total of 1053 consecutive patients who presented for the first time at the outpatient uveitis clinic were analyzed in a prospective, observational study, conducted between July 2012 and September 2013. Age, gender, clinical characteristics, visual acuity, and clinical and etiologic diagnoses in patients with and without human immunodeficiency virus (HIV) were studied. RESULTS: Mean age was 39.8 ± 17.8 years (56.8% female), with most between 41 and 64 years (41.79%); 10.9% of the patients were HIV-positive and 8.1% were legally blind (best-corrected visual acuity (BCVA): ≤ 20/400) at the first evaluation. The posterior, bilateral, and chronic forms of uveitis occurred most frequently and toxoplasmosis was the main cause (24.03%) but was less frequent than in 1980; the same was true for Fuchs heterochromic iridocyclitis. Syphilis, tuberculosis, Vogt-Koyanagi-Harada disease, and juvenile idiopathic arthritis-related uveitis had increased incidence rates. CONCLUSIONS: The current results can help determine the present epidemiology of uveitis and its changes over time in Brazil and increases essential information about the disease. Many uveitic entities are curable and visual damage can be prevented or limited if treated early and appropriately.

Windows of opportunities and technological innovation in the Brazilian pharmaceutical industry.

The Brazilian pharmaceutical industry is heavily dependent on external sources of inputs, capital, and technology. However, the emergence of technological opportunities and the development of biotechnology and the decline of the patent boom and resulting advances by generic drugs have opened windows of opportunities for the local industry. The article examines the Brazilian industry's innovative behavior vis-à-vis these opportunities, showing that although the industry as a whole invests little in innovation, a few large Brazilian companies have expanded their market share and stepped up their investments in research and development, supported by public policies for innovation. Resumo: A indústria farmacêutica brasileira caracteriza-se pela grande dependência de fontes externas de insumos, capital e tecnologia. O surgimento de oportunidades tecnológicas, associadas ao desenvolvimento da biotecnologia e ao fim do boom das patentes com o consequente avanço dos medicamentos genéricos, entretanto, vem abrindo janelas de oportunidades para a indústria local. Este artigo examina o comportamento inovador da indústria brasileira à luz dessas oportunidades, revelando que, embora o conjunto da indústria mantenha baixos níveis de investimentos em inovação, um pequeno grupo de grandes empresas nacionais vem ampliando sua participação no mercado e intensificando seus investimentos em pesquisa e desenvolvimento, apoiados por políticas públicas de inovação.

Windows of opportunities and technological innovation in the Brazilian pharmaceutical industry / Ventanas de oportunidades e innovación tecnológica en la industria brasileña de medicamentos / Janelas de oportunidades e inovação tecnológica na indústria brasileira de medicamentos

Abstract: The Brazilian pharmaceutical industry is heavily dependent on external sources of inputs, capital, and technology. However, the emergence of technological opportunities and the development of biotechnology and the decline of the patent boom and resulting advances by generic drugs have opened windows of opportunities for the local industry. The article examines the Brazilian industry's innovative behavior vis-à-vis these opportunities, showing that although the industry as a whole invests little in innovation, a few large Brazilian companies have expanded their market share and stepped up their investments in research and development, supported by public policies for innovation.

Resumen: La industria farmacéutica brasileña se caracteriza por su gran dependencia de fuentes externas de insumos, capital y tecnología. El surgimiento de oportunidades tecnológicas, asociadas al desarrollo de la biotecnología, y al fin del boom de las patentes -con el consecuente avance de los medicamentos genéricos-, es paralelo a la apertura de ventanas de oportunidad para la industria local. Este artículo examina el comportamiento innovador de la industria brasileña a la luz de esas oportunidades, revelando que, aunque el conjunto de la industria mantenga bajos niveles de inversión en innovación, un pequeño grupo de grandes empresas nacionales está ampliando su participación en el mercado e intensificando sus inversiones en pesquisa y desarollo, apoyados por políticas públicas de innovación.

Resumo: A indústria farmacêutica brasileira caracteriza-se pela grande dependência de fontes externas de insumos, capital e tecnologia. O surgimento de oportunidades tecnológicas, associadas ao desenvolvimento da biotecnologia e ao fim do boom das patentes com o consequente avanço dos medicamentos genéricos, entretanto, vem abrindo janelas de oportunidades para a indústria local. Este artigo examina o comportamento inovador da indústria brasileira à luz dessas oportunidades, revelando que, embora o conjunto da indústria mantenha baixos níveis de investimentos em inovação, um pequeno grupo de grandes empresas nacionais vem ampliando sua participação no mercado e intensificando seus investimentos em pesquisa e desenvolvimento, apoiados por políticas públicas de inovação.

IL-13 immunotoxin accelerates resolution of lung pathological changes triggered by silica particles in mice.

Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13-PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13-PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13-PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13-PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-ß, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13-PE. In addition, IL-13-PE inhibited both IL-13-induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13-PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.

Avaliação do potencial antiasmático da 7-Epiclusianona e do complexo metálico 7-Epiclusianona/cobre / Evaluation of potential anti-asthmatic 7-epiclusianone and the metal complex 7-Epiclusianona/cobre

A triagem de compostos de origem natural é uma estratégia importante na busca por candidatos antiasmáticos. Neste contexto, estudos anteriores evidenciaram a marcada atividade antiespasmódica e antialérgica da substância 7-Epiclusianona (7-Epi). Essa benzofenona é integrante do extrato hexânico do fruto da Garcínia brasiliensis e, portanto, de difícil proteção patentária. A complexação da 7-Epi com um íon de cobre (7-EpiCu 2+ ) tornou-a estruturalmente inédita e patenteável. Assim, são três os principais objetivos deste estudo: (i) investigar os efeitos de 7-Epi sobre as características patológicas de modelos murinos de asma alérgica; (ii) caracterizar a atividade antiespasmódica de 7-EpiCu 2+ sobre modelos in vitro e in vivo, tal qual já demonstrado para a 7-Epi, bem como os efeitos do complexo sobre a hiper -reatividade das vias aéreas in vivo; (iii) investigar possíveis alvos celulares dessas substâncias. Os resultados mostraram que, em modelos animais relevantes, a administração oral de 7-Epi, tanto em regime preventivo quanto terapêutico, foi capaz de prevenir e reverter a hiper-reatividade das vias aéreas e outros aspectos fisiopatológicos importantes na asma...

Em paralelo, demonstramos que o complexo metálico 7-EpiCu 2+ possui eficácia antiespasmódica in vitro e in vivo, seguindo um mecanismo de ação dependente da integridade do epitélio da via aérea, tal qual já descrito para a 7-Epi. Por outro lado, o tratamento preventivo com o complexo 7-EpiCu 2+ não impediu o desenvolvimento da hiper-reatividade, tendo por base o modelo de asma alérgica aguda. Os estudos com células da linhagem de epitélio pulmonar humano (A549) revelaram a capacidade da 7-Epi de inibir a produção de MCP-1 induzida por IL-1β. Em sistemas baseados em fibroblastos pulmonares primários murinos, ambos os compostos foram claramente ativos em bloquear a proliferação celular e a geração de eotaxina-1 promovidas por IL-13. Entretanto, em ambos os casos, o efeito inibitório apareceu fortemente associado a uma ação aparentemente citotóxica dos compostosEm conjunto, nossos resultados caracterizam o composto 7-Epi como um agente oralmente ativo, com capacidade de inibir sinais patológicos cruciais da asma, tanto em regime profilático como terapêutico. Além disso, apesar da marcada atividade antiespasmódi ca apresentada em sistemas in vitro, o composto 7-EpiCu 2+ mostrou-se inativo em inibir o desenvolvimento da hiper-reatividade na asma aguda in vivo, o que somado às propriedades citotóxicas diretas sobre fibroblastos pulmonares murinos e células epiteliais alveolares humanas, compromete o potencial antiasmático e clínico dessa substância...