El presente trabajo se desarrolló en dos etapas principales: la obtención, caracterización y evaluación de la actividad antiinflamatoria del extracto hidroalcohólico de la especie Baccharis latifolia “Chilco”; y, la obtención, caracterización y evaluación de la actividad antiinflamatoria de una forma farmacéutica de aplicación tópica conteniendo el extracto en estudio. En la obtención del extracto hidroalcohólico se emplearon hojas secas y pulverizadas de la planta recolectada en el departamento de Amazonas; este extracto fue caracterizado empleando técnicas fisicoquímicas y cromatográficas y un screening fitoquímico; se evaluó el efecto antiinflamatorio utilizando el método del edema plantar inducido por carragenina en ratones, empleándose concentraciones de 1,25 mg/g, 2,5 mg/g, 3,75 mg/g, 5 mg/g y 7 mg/g del extracto frente a un grupo control; se determinó que la menor concentración que mantiene una inhibición de la inflamación mayor al 70% después de 5 horas de la inyección de carragenina es la concentración de 2,5 mg/g. Esta concentración fue elegida para desarrollar la forma farmacéutica que permitiera la incorporación del extracto al 2% respecto al residuo seco, obteniéndose con la forma farmacéutica crema – gel características óptimas en el producto terminado, el mismo que fue evaluado fisicoquímica y cromatográficamente. Finalmente, se evaluó el efecto antiinflamatorio del producto terminado mediante el método del edema plantar inducido por carragenina en ratones, determinándose que el efecto antiinflamatorio es mayor al del extracto, comprobando que el efecto antiinflamatorio del extracto en crema-gel se mantiene y es incluso superior. Palabras clave: Baccharis latifolia, efecto antiinflamatorio, crema – gel. / The present work was developed in two main stages: the obtaining, characterization and evaluation of the anti-inflammatory activity of the hydroalcoholic extract of the species Baccharis latifolia “Chilco”; and, the obtaining, characterization and evaluation of the anti-inflammatory activity of a pharmaceutical dosage form of topical usage containing the extract in study satisfactorily. In the obtaining of the hydroalcoholic extract, dry and pulverized leaves of the plant collected in the department of Amazonas were used; this extract was characterized using physicochemical and chromatographic techniques and a phytochemical screening; the anti-inflammatory effect was evaluated using the carragenina-induced edema method in mice, concentrations of 1,25 mg/g, 2,5 mg/g, 3,75 mg/g, 5 mg/g and 7 mg/g of the extract were tested with respect to a control group, it was found that the minor dose which maintains an inhibition of the edema up to the 70% after 5 hours of the carrageenin injection was the 2,5 mg/g concentration. This concentration was chosen to develop the pharmaceutical dosage form that allowed the incorporation of the extract at 2% in relation to the dry residue, obtaining with the pharmaceutical dosage form cream – gel optimal characteristics in the finished product, which was evaluated using physicochemical and chromatographic techniques. Finally, the anti-inflammatory effect of the finished product was evaluated using the carragenina-induced edema method in mice, determining that the anti-inflammatory effect was greater than the effect of the extract, verifying that the anti-inflammatory effect of the extract in the cream-gel stays and is even superior. Key words: Baccharis latifolia, anti-inflammatory effect, cream - gel.

Se evaluó el efecto gastroprotector del extracto liofilizado del fruto de Capsicum annuum L administrado a 10, 100 y 1000 mg/kg en dos grupos de ratas subdivididos en 5 subgrupos de 10 animales c/u como sigue: G1: Vehículo, G2: Ranitidina 50 mg/kg, G3: Capsicum annuum L 10 mg/kg, G4: Capsicum annuum L 100 mg/kg y G5: Capsicum annuum L 1000 mg/kg; utilizando dos modelos. En el modelo de úlcera gástrica inducida por indometacina (primer grupo), los animales fueron tratados con indometacina 75 mg/kg y luego de ocho (8) horas los estómagos fueron removidos y se examinaron determinándose la valoración de la úlcera gástrica y el porcentaje de inhibición de la lesión ulcerosa. En el modelo de úlcera gástrica inducida por ligamento pilórico (segundo grupo), los animales fueron sometidos a ligamiento pilórico y tratados vía intraduodenal; seis (6) horas después se extrajeron los estómagos y se determinó el volumen y pH del contenido estomacal, la valoración de la úlcera gástrica y el porcentaje de inhibición de la lesión ulcerosa. Los resultados del primer modelo muestran que con Capsicum annuum L a las concentraciones de 10 mg/Kg y 100 mg/Kg se obtuvo un porcentaje de inhibición de la lesión ulcerosa de 60.4 % y 66.7 % respectivamente, presentándose la mayor eficacia antiulcerosa con ranitidina (95.8%). En el segundo modelo, Capsicum annuum L no presentó diferencias significativas en el volumen ni en el pH gástrico (p menor 0.05); sin embargo las concentraciones de 100 y 1000 mg/Kg protegieron la mucosa gástrica obteniéndose un porcentaje de inhibición de la lesión ulcerosa de 75.59% y 81.63% respectivamente, inclusive mayores que con ranitidina (75.51%). En conclusión queda demostrado que el extracto liofilizado del fruto de Capsicum annuum L tiene efecto gastroprotector en los dos modelos de úlcera gástrica inducido en ratas utilizados. / This study examined the gastroprotective effect of the Capsicum annuum L lyophilized fruit extract administered in 10, 100 and 1000 mg/kg in two groups of rats divided in 5 groups of 10 animals as follows: G1: Control, G2: Ranitidina 50 mg/ kg, G3: Capsicum annuum L 10 mg/ kg, G4: Capsicum annuum L 100 mg/ kg and G5: Capsicum annuumL 1000 mg/ kg; using two models. In the model of gastric ulcer induced by Indomethacin (first group), the animals were treated with Indomethacin 75 mg/ kg and after 8 hours their stomachs were removed and evaluated for the degree of the gastric ulcer and the inhibition percentage of the ulcer. In the model of gastric ulcer induced by Pylorus ligated (second group), the animals were under pylorus ligation and they were treated via intraduodenal; after six hours the stomachs were removed and the gastric volume, pH, degree of gastric ulcer and inhibition percentage of the ulcer were calculated.The results of the first model showed that there was an ulcer inhibition percentage with Capsicum annuum L at 10 mg/ Kg and 100 mg/ Kg of 60.4% and 66.7 % respectively, resulting in the greatest anti-ulcer efficacy with ranitidine (95.8%). In the second model, we found no statistically significant differences in either the volume average nor the gastric pH with Capsicum annuum L (p less 0.05); however with the concentrations of 100mg/kg and 1000 mg/kg there was a protective effect of the gastric mucous, resulting in an ulcer inhibition percentage of 75.59% and 81.63%, respectively, which were even greater than ranitidine (75.51%). To conclude, the Capsicum annuum L lyophilized fruit extract has a gastro protective effect in two gastric ulcer models in the rats studied.

Thesis (Ph. D.)--University of Hong Kong, 2001. / Includes bibliographical references.

Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in History." Includes bibliographical references (p. 209-250).

Habilitationsschrift--Mainz. / Includes indexes. Includes bibliographical references (p. [217]-226).

La presente tesis doctoral trata sobre recientes contribuciones en el contexto de super uidos holográ cos. Esto signi ca intentar preguntar y responder cuestiones relevantes acerca de super uidos fuertemente acoplados en el contexto de la conjetura de AdS/CFT. Siendo así, investigamos agujeros negros cargado y campos en un espacio asintóticamente AdS que consideramos buenos candidatos a duales gravitatorios de un super uido. Luego usando el diccionario holográ co vemos qué fenomenología obtenemos para los material que viven en el borde de AdS y esperamos que dicha fenomenología sea relevante. La tesis se organiza de la siguiente manera: Como toda tesis, comienza con una breve introducción al tema, donde se explican conceptos básicos de la conjetura de Maldacena y el Diccionario escrito por Gubser, Klebanov, Polyakov y Witten. Además en dicha introducción se habla sobre algunos de los desafíos actuales en el contexto de materia condensada y sobre cómo la holografía podría ayudar a superar algunos de estos desafíos. Luego se procede a narrar las contribuciones originales del autor al tema, que resumiremos a continuación. En el capítulo 2 se comenta el trabajo fundacional en el tema, por Hartnoll, Herzog y Horowitz para luego ir un paso más allá y estudiar el caso desordenado. El desorden se logra mediante considerando un potencial químico con una dependencia espacial aleatoria. Luego en el capítulo 3 se estudia la Entropía de entrelazamiento de un modelo con parámetro de orden vectorial. Extensión natural de estos dos modelos, imaginamos un super uido holográ co con simetría U(2), que nos acompañará desde el capítulo 4 en adelante. De este último modelo estudiaremos conductividades, modos quasinormales, y su comportamiento ante otras fuentes externas, como la velocidad o un segundo potencial químico.

published_or_final_version / Medicine / Master / Master of Research in Medicine

Influenza epidemics have become a major public health concern worldwide. According to the World Health Organization, the annual epidemics results in about three to five million cases of severe illness, and about 250 to 500 thousand deaths. Recurring emergence of new influenza viruses and viruses that are resistant to currently approved antiviral medications pose a critical need to explore new or alternative medications. A classical Traditional Chinese Medicine (TCM) decoction consisting of nine herbs, named Yinqiaosan (YQS, 銀翹散), has a long history for treating respiratory diseases in China. However, the efficacy of YQS has not been investigated mechanistically. In the present study, the effectiveness of YQS in treating influenza virus infection was examined. The potential mechanisms of action of two active compounds present in one of the component herbs of YQS were also investigated. Results showed that YQS increased the survival rate of the mice in an in vivo influenza virus infection model with significant reduction in lung viral titers. In order to further delineate the mechanisms of action of YQS, compounds present in a principal ingredient of YQS were examined for antiviral and immunomodulatory effects. In screening a panel of fractions extracted from YQS, forsythoside A was demonstrated to suppress the viral titers of a wide range of influenza viruses including the oseltamivir-resistant and the 2009 pandemic H1N1 viruses. Through electron microscopy, slow or abnormal viral budding events were observed upon forsythoside A treatment during influenza virus infection. Western blot analysis revealed a reduced influenza virus M1 protein expression. As previous report showed that assembly of viral components into an infectious particle required a threshold level of M1 protein, reduced M1 expression in the cells treated with forsythoside A may contribute to the virus replication suppression. On the other hand, innate immune responses provide first line protection against influenza virus infections. However, excessive responses often result in tissue damage. Cyclooxygenase (COX)-2 is an immunomodulatory factor that has been shown to play a role in the pathogenesis of influenza viruses. A previous COX-2 knock-out mice model showed that COX-2 deficiency is beneficial to the host during influenza viral infection, in which mortality was significantly reduced. Furthermore, during H5N1 infection, it has been shown that COX-2 level significantly increased and it played an essential role in coordinating the productions of inflammatory cytokines, while in another study, pharmacological inhibition of COX-2 suppressed H5N1 virus replication in primary human macrophages. In view of the roles of COX-2 during influenza virus infection, the presence of compound in YQS that reduces the influenza virus-induced COX-2 level was examined. Present results showed that jacaranone not only reduced the influenza virus-induced cyclooxygenase (COX)-2 mRNA level, it also suppressed the subsequent production of prostaglandin E2 level in primary human macrophages. At the same time, jacaranone inhibited the virus induced-activations of ERK1/2 and Akt, which are involved in the COX-2 induction. Jacaranone also suppressed, at least in part, the COX-2 mRNA level at the transcriptional level by inhibiting the nuclear translocation of NF-κB. To conclude, TCM has been recognized as an important part in complementary and alternative medicine and it is an ample source of antimicrobial drugs. The use of a mixture of herbs is the major therapeutic approach of TCM in which, the principal ingredients provide the main therapeutic actions while the others enhance the effects or diminish the side effects of the principal ones. Some components act mainly for symptomatic control. The present study not only supports the efficacy of YQS, but also gives evidences to an active antiviral compound and an immunomodulatory compound found in YQS. They may act as either principle or supporting components depending on the purpose of application. This study provides new insights on future novel drug development from the existing wisdom of TCM. / published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Anticipated Synchronization (AS) is a form of synchronization that occurs when a unidirectional influence is transmitted from an emitter to a receiver, but the receiver system leads the emitter in time. This counterintuitive phenomenon can be a stable solution of two dynamical systems coupled in a master-slave configuration when the slave is subject to a negative delayed self-feedback. Many examples of AS dynamics have been found in different systems, however, theoretical and experimental evidence for it in the brain has been lacking. In this thesis work we investigate the existence of AS in neuronal circuits when the delayed feedback is replaced by an inhibitory loop mediated by chemical synapses. At the neuronal level, we show the existence of AS in 3-neuron or 3-neuron-populations microcircuits, where the self-feedback is provided either by an interneuron or by a subpopulation of inhibitory neurons. A smooth transition from delayed synchronization (DS) to AS typically occurs when the inhibitory synaptic conductance is increased. The phenomenon is shown to be robust for a wide range of model parameters within a physiological range. The role of spiketiming- dependent plasticity in DS-AS transitions is also investigated. The results obtained from the model are compared with those obtained experimentally in monkeys performing certain cognitive tasks. In some cases a dominant directional influence from one cortical area to another is accompanied by either a negative or a positive time delay. We present a model for AS between two brain regions and compare its results to the experimental data, obtaining an excellent agreement. / La sincronización anticipada (SA) es una forma de sincronización que se produce cuando una influencia unidireccional se transmite desde un emisor a un receptor, pero el sistema receptor adelanta al emisor en el tiempo. Este fenómeno, contrario a la intuición, puede ser una solución estable de dos sistemas dinámicos acoplados en una configuración maestro – esclavo cuando el esclavo está sujeto a una retroalimentación negativa retardada. Hay muchos ejemplos de SA que se han encontrado en diferentes sistemas, sin embargo, no existe evidencia ni teórica ni experimental de que ocurra en el cerebro. En este trabajo de tesis se investiga la existencia la SA en circuitos neuronales cuando la realimentación retardada se sustituye por un bucle inhibitorio mediado por sinapsis químicas. A nivel neuronal, se muestra la existencia de SA en circuitos de 3 neuronas o 3 poblaciones de neuronas, donde la retroalimentación la proporciona una interneurona o una subpoblación de neuronas inhibitorias. Una transición de sincronización retrasada (SR) a SA se produce suavemente cuando se incrementa la conductancia sináptica inhibitoria. Se encuentra que el fenómeno es robusto para una amplio espectro de parámetros del modelo dentro del rango fisiológico. También se investiga el papel de la plasticidad neuronal en la transición SR-SA. Los resultados obtenidos a partir del modelo se comparan con los obtenidos experimentalmente en monos cuando realizan ciertas tareas cognitivas. En algunos casos, una influencia direccional dominante de un área cortical a otra se acompaña de un retardo que puede ser negativo o positivo. Se presenta un modelo para las relaciones entre dos regiones corticales del cerebro y se compararan los resultados numéricos con los datos experimentales, obteniendo un excelente acuerdo.

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