Pharmacokinetic studies on protoporphyrin IX induced by 5-aminolevulinic acid and its esters in a three-dimensional lung tumor mini-organ culture model

Lung cancer is one of the most common malignancies in the world and remains the leading cause of cancer death among men and women in developed countries, accounting for more deaths than breast, prostate and colorectal cancers combined. The cure for lung cancer is low (<15%) due to the lack of screening methods, the propensity for early spread, and the inability to cure metastatic disease. However, when people are diagnosed with early stage lung cancer, their chances of 5-year survival can be as high as 90%, hence the importance of methods for early diagnopromising technologies. The purpose of this thesis was to establish an in vitro model for lung cancer and to investigate clinically relevant pharmacokinetic parameters for the optimization of 5-aminolevulinic acid (5-ALA) application. The present study suggests that the in vitro three-dimensional mini-organ model consisting of normal human bronchial mucosa co-cultivated with human lung tumor cells (EPLC-32M1) is a good alternative to mono-layer or even spheroid cell culture due to a much closer similarity to the in vivo situation. It largely obviates the necessity for animal experiments to investigate various clinically relevant questions, e.g. drug pharmacokinetics. The three-dimensional mini-organ model has been applied to elucidate the accumulation ofthe fluorescing photosensitizer protoporphyrin IX (PPIX) after delivery of 5-aminolevulinic acid (5-ALA) or some of its esters: • The optimal concentration for maximal achexyl ester. Fluorescence intensity was taken as parameter for the amount of PPIX in the tissue. • The co-culture model was used to study the pharmacokinetics of 5-ALA-induced PPIX fluorescence and its esters in normal epithelium and in tumorous areas. • The tim• Improvement of the three-dimensional mini-organ model by using GFP-transfected EPLC-32M1 lung tumor cells in the organ co-culture system was studied. SUMMARY 62 tumor and her than in lipophilic nature, an enhanced tissue penetration has been an attempt to further enhance the co-culture model, green fluorescent protein (GFP) expression plasmid-transfected lung tumor cells were used in the mini-organ model. Comparable results were obtained in the pharmacokinetics of 5-ALA between co-cultures made with GFP transfected and untransfected lung tumor cells. But GFP expression highly improved the experiment conditions, whereby a higher contrast was reached at the tumor/ normal epithelium boundaries. 5-ALA-induced PPIX fluorescence showed marked differences in the kinetics in normal epithelium as the concentration of PPIX within tumorous areas was hignormal tissue. PPIX fluorescence in tumor increased faster in most of the cases than in normal tissue, but also tended to decay earlier. The results of this study show that the relative fluorescence intensities of PPIX in tumor and normal epithelium are a function of the incubation time, concentration, distribution, and kinetics in tumorous and normal tissue. A number of 5-ALA derivatives are being used in order to modify and improve the tissuedistribution of the PPIX. The tumor/normal epithelium ratios (T/NE ratio) of PPIX fluorescence induced by 5-ALA and its esters were comparable and showed in general a good contrast in the three-dimensional mini-organ model. However, comparing 5-ALA with 5-ALA hexyl ester, 5-ALA hexyl ester induced a 2-fold higher PPIX fluorescence intensity in tumor as well as in normal epithelium at a 5 times lower concentration (0.24 mM). A slight tendency to a rapid PPIX accumulation in tumor and in normal epithelium was observed in co-cultures incubated with 5-ALA methyl ester. In addition, maximal PPIX fluorescence intensities in these co-cultures show individual variations in tumor as well as in normal epithelium. The highest T/NE ratio was observed with 5-ALA butyl ester, but also an inhomogeneous distribution of PPIX in tumorous and normal areas. In general, it was possible to use the same mini-organ model for further experiments, which indicates that 5-ALA esters at their optimal concentrations are not toxic. Amongst the 5-ALA esters, 5-ALA hexyl ester is clearly to be favored as it combines homogeneous distribution, high T/NE ratio, high fluorescence intensities, and the lowest drug concentration needed. Due to itsassumed compared to the other esters as well as 5-ALA. In clinical studies 5-ALA hexyl ester has been used successfully to detect early carcinoma in the urinary bladder by fluorescence imaging. In SUMMARY 63 present work was to establish a model which allows the taken into consideration in the present mini- can be applied to localize One of the main targets of theoptimization of application parameters for 5-ALA-based fluorescence diagnosis for the early detection of lung cancer. The maximum of PPIX fluorescence intensity in the co-culture model was detected between 130 and 180 min after the beginning of incubation with 5-ALA. Clinical results obtained by Huber et al. indicate that a photodynamic diagnosis should be performed approximately 2 hours after topical administration of 5-ALA to patients. Thus the co-culture model corroborates the clinical observation and yields a quantitative confirmation both for the time delay between drug application and fluorescence bronchoscopy (or endobronchial PDT) and for the T/NE contrast that can be expected. The results also suggest that inhalation of 5-ALA hexyl ester at a lower concentration and slightly shorter time interval could enhance the procedures. Since the transport of 5-ALA by blood are notorgan model, the results of this study could primarily be applied to topical application of 5-ALA and its derivatives, in the case of lung cancer per inhalation of these compounds. In order to obtain a significant improvement of patient survival, the number of tumors identified in early stages has to be increased. This could be achieved by enhanced sputum cytology screening. Then, optimized fluorescence bronchoscopyearly lesions with high sensitivity and endoluminal PDT can treat these lesions minimally invasive

El personaje histórico Pedro de Alvarado dentro de la obra Tierra del escritor salvadoreño Ricardo Lindo

La propuesta de esta investigación se construyó en base a los aportes elaborados por Ricardo Lindo en su novela histórica Tierra, para lo cual se tomó como objeto de estudio al personaje Pedro de Alvarado. El trabajo se estructuró para su desarrollo en cuatro partes: en la primera se da a conocer la evolución de la novela histórica desde sus inicios en Europa y Latinoamérica, en Centroamérica y por último en El Salvador. La segunda parte constituye un Marco Teórico-Metodológico conteniendo los diferentes conceptos y teorías propuestos por Bajtin y otros, que son aplicados al momento de realizar el análisis. La tercera parte y fundamental del trabajo, ya que es allí donde se desarrollan los temas pertinentes a esta investigación está conformada por un argumento, las funciones que desempeña el personaje dentro de la obra y las formas expresivas utilizadas por el narrador al momento de referirse a Pedro de Alvarado. Finalmente se realizó una conclusión en la que en forma resumida se explican los resultados obtenidos de esta investigación, haciendo un contraste entre la visión de Ricardo Lindo y el concepto que tiene la historia oficial sobre el personaje Pedro de Alvarado dentro de la historia salvadoreñ

El rol de la Gobernación Política Departamental de Sonsonate y su contribución en los procesos de desarrollo en los territorios

Este informe presenta una investigación sobre el rol de la Gobernación Política Departamental de Sonsonate en el contexto del desarrollo local sostenible. El objetivo principal de este estudio es fortalecer el rol y la contribución de la Gobernación Política Departamental de Sonsonate en los procesos de desarrollo en el territorio y analizar cuál es su contribución y la mejora de la calidad de vida de las personas en el departamento de Sonsonate, El Salvado

Comportamiento Innovador del Hostal la Buena Onda en el Municipio de Matagalpa, departamento de Matagalpa, durante el periodo 2016

La presente investigación aborda el tema del comportamiento innovador de las Pymes del Departamento de Matagalpa en el periodo 2016. El estudio del comportamiento innovador del Hostal la Buena Onda del departamento de Matagalpa en el periodo 2016, ayuda a identificar los diferentes tipos de innovación que se han implementado en la empresa en cuanto a sus servicios y productos que ofrecen. Así mismo se determina en cuales de los procesos de trabajo presentan mayores dificultades en cuanto a innovación se refiere. Esto con el propósito de brindarle una herramienta a la empresa sobre los tipos de innovación que se pueden aplicar a los diferentes procesos de trabajo que utilizan. A través de los procesos de innovación la empresa logra identificar con mayor facilidad el grado de satisfacción por parte de los usuarios. El proceso de Innovación es muy importante en el desarrollo de las empresas y para el Hostal la Buena Onda representa su estabilidad y mantenimiento en el mercado, para marcar la diferencia con los demás hostal. A la vez es de gran ayuda ya que pueden implementar estrategias de innovación para ser cada vez más competitivos. Valorando siempre la calidad, higiene y la rapidez con que brindan sus servicios. Hostal la Buena Onda se caracteriza por ser una empresa líder e innovadora en los servicios que ofrece, esto debido a la constante capacitación que se les brinda a sus colaboradores, ya que ha venido desarrollando un comportamiento innovador tanto reactivo como proactivo, implementando una política de innovación agresiva en investigación y desarrollo, para lograr satisfacer las expectativas de sus clientes y lograr posicionarse como una empresa pionera en el mercado al que se encuentra dirigido como es el alojamiento para extranjeros, quienes se caracterizan como gringos mochilero

Kinetics of 5-aminolevulinic acid-induced fluorescence in organ cultures of bronchial epithelium and tumor

Background: 5-Aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPIX) fluorescence improves the differentiation of tumor and normal tissue in the bladder, skin and brain. Objective: The kinetics of 5-ALA-induced protoporphyrin IX (PPIX) fluorescence in organ cultures of normal human bronchial epithelium and cocultures of bronchial epithelium and tumor have been studied. Methods: Cultured biopsies of bronchial epithelium were exposed for 5 or 15 min, or continuously to 5-ALA. PPIX fluorescence was quantified for up to 300 min by spectroscopy. Cocultures of normal bronchial epithelium and a non-small-cell lung cancer cell line (EPLC-32M1) were incubated with 5-ALA. Space-resolved fluorescence microscopy was used to quantify PPIX fluorescence kinetics in the tumor and normal epithelium. Results: In cultures of normal epithelium, PPIX fluorescence kinetics were shown to depend on the duration of exposure to 5-ALA. There was a trend to higher fluorescence intensities with longer exposure times. In cocultures of bronchial epithelium and tumor, increases of fluorescence intensity were significantly greater in the tumor. Best tumor/normal tissue fluorescence ratios were found between 110 and 160 min after exposure to 5-ALA. Conclusion: Data obtained in this coculture system of bronchial epithelium and tumor is valuable to optimize modalities of fluorescence bronchoscopy for the diagnosis of early bronchial carcinoma. Copyright (C) 2002 S. Karger AG, Basel

Correlação entre ultrassonometria quantitativa de calcâneo e densitometria óssea duo-energética de coluna e fêmur na avaliação óssea

The dual-energy X-ray absorptiometry (DEXA) is the most commonly used technique for bone mass density (DMO), although the quantitative calcaneus bone ultrasonometry (USQ) shows good results as a predictor for fracture risk. We compared the results obtained by these two methods in patients referred to the Endocrine Division at the Universidade Federal de São Paulo (UNIFESP) for DEXA evaluation. A total of 189 patients were studied, 165 women / 24 men, with ages from 20 to 84 years (Mi: 51 and 53, respectively for women and men) with distinct diagnosis. All were submitted on the same day to DEXA (Lunar,DPX-L) for lumbar spine (LOMB), neck (COLO) and major throcanter (TROC) and to USQ of calcaneus (Lunar, Aquilles), measuring speed of sound (SOS) and broadband ultrasound attenuation (BUA). A significant positive correlation was found between DEXA values in all sites and USQ. The best correlation was seen in men, between TROC and SOS (r=0.82). When only individuals 50 years or older (n=102) were evaluated, the coefficient of correlation was lower than in the younger than 50, but still significant. In evaluating the utility of USQ as a screening for DEXA measurement, we found that 21.4% of patients with normal values for T score on USQ were osteopenic or osteporotic on TROC. This discrepancy was even more evident on LOMB, where 29.9% of the patients with normal DMO presented T<-1 on USQ, and 35.8% of the patients with normal USQ had T<-1 on DMO of the same region. The coefficient of variation of USQ obtained after 9 measurements in the same person on different days was 0.66% for SOS and 2.75% for BUA. In conclusion, the USQ is only moderately related to DMO and has little utility as a screening for DEXA examination. Its value to determine fracture risk is already established, however prospective studies are necessary to evaluate its usefulness in the diagnosis and follow-up of osteoporosis.A densitometria óssea com raio X duo-energético (DEXA) é o método atualmente mais utilizado para medição de massa óssea; porém, a ultrassonometria óssea quantitativa (USQ) vem apresentando resultados promissores na predição de fraturas. Visando comparar DEXA e USQ, correlacionamos os resultados obtidos com estes métodos em pacientes rotineiramente encaminhados para realização de DEXA em nosso serviço. Estudamos 165 mulheres e 24 homens com idades entre 20 e 84 anos (Mi: 51 e 53 anos, para mulheres e homens respectivamente) com diagnósticos variados. Todos foram submetidos a medição da densidade mineral óssea (DMO) pela DEXA (Lunar DPX-L) em coluna lombar (LOMB) e em colo (COLO) e trocanter maior (TROC) e USQ em calcâneo (Lunar- Aquilles), onde foram considerados os parâmetros de velocidade do som (SOS) e atenuação do som (BUA). Houve correlação positiva significante entre as medidas de DMO em todos os sítios e SOS e BUA. Quando separamos por sexo, a melhor correlação foi observada nos homens, entre TROC e SOS, com r= 0,82. Quando separamos por idade, a correlação foi menor naqueles com mais de 50 anos, comparados aos com menos de 50 anos. Dentre os 89 pacientes considerados normais pela DEXA em LOMB, 29,8% apresentavam valores abaixo de 1 DP na USQ. Por outro lado, 35,8% dos indivíduos cujos valores de USQ estavam a menos de 1 DP abaixo da média, apresentavam-se com osteopenia ou osteoporose (T<-1) pela DEXA de LOMB. O coeficiente de variação dos valores obtidos de USQ para as 9 medidas realizadas na mesma pessoa foi de 0,66% para SOS e 2,75% para BUA. Concluindo, a USQ correlaciona-se apenas moderadamente com DMO e, portanto, sua utilização como um teste de rastreamento para a realização de DEXA é de pouca utilidade, uma vez que a discordância entre os métodos para um mesmo indivíduo é elevada. O valor da USQ na avaliação do risco de fratura já está estabelecido, porém estudos prospectivos são necessários para que se padronize sua utilidade no diagnóstico e acompanhamento das doenças ósseas.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de MedicinaUNIFESP, EPM, Depto. de MedicinaSciEL

Metodología interactiva en educación por competencias en niños y niñas con capacidades diferentes.

La igualdad de los derechos es uno de los legados otorgados a todo hombre dentro de su contexto social, en cuanto a la educación todo niño y niñas, joven o adulto sin considerar su condición sea físico intelectual, asume el reto de igualdad en la superación de sus condiciones que “impidan” a ser considerado como aportación para el desarrollo de una sociedad, ante esta realidad y a las grandes oportunidades que en la actualidad se está presentando de parte de los gobiernos y autoridades a esta población, como universitarias presentamos este trabajo investigativo, que como educadores hacemos latentes esta problemática mediante la adaptación de los contenidos curriculares de la educación diferentes a los contenidos curriculares regular innovando bajo el término competencias con la aptitud de demostrar que los conocimientos y destrezas al ser utilizados y consolidados a través de metodología interactivo; es así que para Jean PIAGET determina los desarrollos psíquicos predeterminados genéticamente y que los conocimientos iniciales determinan el aprendizaje Glen DOMAN para quien el conocimiento se lo va estructurando por estímulos que asimilan el conocimiento con resultados de avances en la operacionalización del pensamiento pueden ser aplicados a todo tipo de persona sin diferencias físicas e intelectuales