Roles of transmembrane domain 2 and the first intracellular loop in human noradrenaline transporter function: pharmacological and SCAM analysis

The aim was to investigate the roles of transmembrane domain 2 and the adjacent region of the first intracellular loop in determining human noradrenaline transporter (hNET) function by pharmacological and substituted-cysteine accessibility method (SCAM) analyses. It was first necessary to establish a suitable background NET for SCAM. Alanine mutants of endogenous hNET cysteines, hC86A, hC131A and hC339A, were examined and showed no marked effects on expression or function. hNET and the mutants were also resistant to methanethiosulfonate (MTS), ethylammonium (MTSEA) and MTStrimethylammonium (MTSET). Hence, wild-type hNET is an appropriate background for production of cysteine mutants for SCAM. Pharmacological investigation showed that all mutants except hT99C and hL109C showed reduced cell-surface expression, while all except hM107C showed a reduction in functional activity. The mutations did not markedly affect the apparent affinities of substrates, but apparent affinities of cocaine were decreased 7-fold for hP97C and 10-fold for hF101C and increased 12-fold for hY98C. [H-3]Nisoxetine binding affinities were decreased 13-fold for hP97C and 5-fold for hF101C. SCAM analysis revealed that only hL102C was sensitive to 1.25 mM MTSEA, and this sensitivity was protected by noradrenaline, nisoxetine and cocaine. The results suggest that this region of hNET is important for interactions with antidepressants and cocaine, but it is probably not involved in substrate translocation mechanisms.

Obstructive sleep apnoea predicts the development of preproliferative and proliferative retinopathy in patients with type 2 diabetes:a longitudinal analysis

Background and aims: Diabetic Retinopathy (DR) is a leading cause of blindness. OSA is associated with increased oxidative and nitrosative stress and endothelial dysfunction in patients with type 2 diabetes (T2DM). Hence, it is plausible that OSA can promote the development and progression of DR. Materials and methods: An observational longitudinal study in adults with T2DM. Patients with pre-existing OSA, end-stage renal disease and non-diabetic retinopathy were excluded. OSA (apnoea hypopnea index ≥ 5 events/hour) was assessed by a single overnight home-based cardio-respiratory monitoring (Alice PDX, etc.). DR was assesses using retinal images between 2007 and 2012. Sight threatening retinopathy (STR) was defined as pre-proliferative or proliferative DR, maculopathy or photocoagulation. Advanced DR was defined as pre-proliferative or proliferative DR. Results: 199 patients were included (57.3% men, 47.7% White Europeans). STR and OSA prevalence were 38.7 % and 62.8% respectively. STR preva-lence was higher in patients with OSA (OSA+) compared to those with-out (OSA-) [48.8% vs. 21.6%, p <0.001]. After adjustment for confounders, OSA remained independently associated with STR (OR 3.7, 95%CI 1.6-8.9, p=0.006, maculopathy (OR 4.5, 1.8-11.4, p=0.002) and advanced DR (OR 3.9, 1.02-15.3, p=0.047). Over 4.4±1 years, more OSA+ patients progressed from no or background DR to advanced DR (15.3% vs. 3%, p=0.01). OSA was an independent predictor of advanced DR development after adjustment (OR 6.6, 95%CI 1.2-35.1, p=0.03). OSA did not predict the development of maculopathy. Patients received continuous positive airway pressure treatment were less likely to develop advanced DR. Conclusion: OSA is independently associated with STR and predicts the development of preproliferative and proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on DR.Supported by: NIHR (UK) and The UK Novo Nordisk Research Foundation.

Mechanistic studies on the degradation of gasoline oxygenates by advanced oxidation technologies and the reaction of 4-methyl-1,2,4-triazoline-3,5-dione with tetracyclopropylethylene

Gasoline oxygenates (MTBE, methyl tert-butyl ether; DIPE, di-isopropyl ether; ETBE, ethyl tert-butyl ether; TAME, tert-amyl ether) are added to gasoline to boost octane and enhance combustion. The combination of large scale use, high water solubility and only minor biodegradability has now resulted in a significant gasoline oxygenate contamination occurring in surface, ground, and drinking water systems. Combination of hydroxyl radical formation and the pyrolytic environment generated by ultrasonic irradiation (665 kHz) leads to the rapid degradation of MTBE and other gasoline oxygenates in aqueous media. ^ The presence of oxygen promotes the degradation processes by rapid reaction with carbon centered radicals indicating radical processes involving O 2 are significant pathways. A number of the oxidation products were identified. The formation of products (alcohols, ketones, aldehydes, esters, peroxides, etc) could be rationalized by mechanisms which involve hydrogen abstraction by OH radical and/or pyrolysis to form carboncentered radicals which react with oxygen and follow standard oxidation chain processes. ^ The reactions of N-substituted R-triazolinediones (RTAD; R = CH 3 or phenyl) have attracted considerable interest because they exhibit a number of unusual mechanistic characteristics that are analogous to the reactions of singlet oxygen (1O2) and offer an easy way to provide C-N bond(s) formation. The reactions of triazolinedione with olefins have been widely studied and aziridinium imides are generally accepted to be the reactive intermediates. ^ We observed the rapid formation of an unusual intermediate upon mixing tetracyclopropylethylene with 4-methyl-1,2,4-triazoline-3,5-dione in CDCl 3. Detailed characterization by NMR (proton, 13C, 2-D NMRs) indicates the intermediate is 5,5,6,6-tetracyclopropyl-3-methyl-5,6-dihydro-oxazolo[3,2- b][1,2,4]-triazolium-2-olate. Such products are extremely rare and have not been studied. Upon warming the intermediate is converted to 2 + 2 diazetidine (major) and ene product (minor). ^ To further explore the kinetics and dynamics of the reaction activation energies were obtained using Arrhenius plots. Activation energies for the formation of the intermediate from reactants, and 2+2 adduct from the intermediate were determined as 7.48 kcal moll and 19.8 kcal mol−1 with their pre-exponential values of 2.24 × 105 dm 3 mol−1 sec−1 and 2.75 × 108 sec−1, respectively, meaning net slow reactions because of low pre-exponential values caused by steric hindrance. ^

Guerra sin fronteras para partir cuerpos y almas : I Guerra Mundial 2

Fondo Margaritainés Restrepo

Música de câmara de Rodil, Pla e Avondano: a flauta na 2ª metade do séc. XVIII e o estilo galante ibérico

O presente trabalho é uma abordagem teórica e interpretativa à música para traverso de António Rodil (c.1730-1787), Pedro Avondano (1714-1782) e dos irmãos Pla. A interação entre as duas componentes do discurso são fundamentos essenciais para uma global compreensão das obras, sendo por sua vez, foco central no tratamento do estilo galante ibérico. A dissertação esta dividida em 5 capítulos; 1. contextualização da prática musical em Portugal na segunda metade do séc. XVIII; 2. o percurso artístico do flautista António Rodil (c.1730-1787); 3. a música de câmara de Pedro Avondano (1714-1782) e a primeira obra conhecida para o traverso em Portugal A Collection ofLisbon Minuets for two Violins or two German flutes and bass (1766); 4. o traverso na obra dos irmãos PLA; 5. reflexões em torno das questões interpretativas.

The concept of low glycemic index and glycemic load foods as panacea for type 2 diabetes mellitus; prospects, challenges and solutions.

Background: This article examines the concepts of low glycemic indices (GIs) and glycemic load (GL) foods as key drivers in the dietary management of type 2 diabetes as well as their shortcomings. The controversies arising from the analysis of glycemic index (GI) and GL of foods such as their reproducibility as well as their relevance to the dietary management of type 2 diabetes are also discussed. Methods: Search was conducted in relevant electronic databases such as: Pubmed, Google Scholar, HINARI, the Cochrane library, Popline, LILACS, CINAHL, EMBASE, etc to identify the current status of knowledge regarding the controversies surrounding management of diabetes with low GI and GL foods. Conclusion: This article suggests that in view of discrepancies that surround the results of GI versus GL of foods, any assay on the GI and GL of a food with the aim of recommending the food for the dietary management of type 2 diabetes, could be balanced with glycated hemoglobin assays before they are adopted as useful antidiabetic foods.

Síntesis, caracterización y estudio de compuestos de coordinación con el ligando N,N¿dimetil-N-N-bis(2-hidroxi-3-metoxi-5-metilbencil) etilendiamina (H2L)

257 p.

Contribuciones sobre métodos óptimos y subóptimos de aproximaciones poligonales de curvas 2-D

Esta tesis versa sobre el an álisis de la forma de objetos 2D. En visión articial existen numerosos aspectos de los que se pueden extraer información. Uno de los más usados es la forma o el contorno de esos objetos. Esta característica visual de los objetos nos permite, mediante el procesamiento adecuado, extraer información de los objetos, analizar escenas, etc. No obstante el contorno o silueta de los objetos contiene información redundante. Este exceso de datos que no aporta nuevo conocimiento debe ser eliminado, con el objeto de agilizar el procesamiento posterior o de minimizar el tamaño de la representación de ese contorno, para su almacenamiento o transmisión. Esta reducción de datos debe realizarse sin que se produzca una pérdida de información importante para representación del contorno original. Se puede obtener una versión reducida de un contorno eliminando puntos intermedios y uniendo los puntos restantes mediante segmentos. Esta representación reducida de un contorno se conoce como aproximación poligonal. Estas aproximaciones poligonales de contornos representan, por tanto, una versión comprimida de la información original. El principal uso de las mismas es la reducción del volumen de información necesario para representar el contorno de un objeto. No obstante, en los últimos años estas aproximaciones han sido usadas para el reconocimiento de objetos. Para ello los algoritmos de aproximaci ón poligonal se han usado directamente para la extracci ón de los vectores de caracter ísticas empleados en la fase de aprendizaje. Las contribuciones realizadas por tanto en esta tesis se han centrado en diversos aspectos de las aproximaciones poligonales. En la primera contribución se han mejorado varios algoritmos de aproximaciones poligonales, mediante el uso de una fase de preprocesado que acelera estos algoritmos permitiendo incluso mejorar la calidad de las soluciones en un menor tiempo. En la segunda contribución se ha propuesto un nuevo algoritmo de aproximaciones poligonales que obtiene soluciones optimas en un menor espacio de tiempo que el resto de métodos que aparecen en la literatura. En la tercera contribución se ha propuesto un algoritmo de aproximaciones que es capaz de obtener la solución óptima en pocas iteraciones en la mayor parte de los casos. Por último, se ha propuesto una versi ón mejorada del algoritmo óptimo para obtener aproximaciones poligonales que soluciona otro problema de optimización alternativo.

¿Cómo llegó al alcohol? : me emborraché el día de mi primera comunión, ¿tendré problemas con el alcohol? : la última copa 2

Fondo Margaritainés Restrepo

Diseño de un sistema de calidad total para la optimización de los recursos del distrito No.2, dependencia de la Alcaldía municipal de San Salvador.

El 26 de abril de 1999 se crea el Distrito N° 2, dependencia de la Alcaldía Municipal de San Salvador, con la finalidad de desconcentrar los servicios municipales para llevarlos mas cerca de la ciudadanía. Esta institución ofrece servicios de saneamiento ambiental, parques y zonas verdes, ordenamiento territorial, desarrollo comunal, registro del estado familiar, pago de tasas e impuestos municipales, etc., para los cuales se necesitan recursos humanos, materiales, tecnológicos y financieros; siendo estos proporcionados por la Alcaldía Municipal de San Salvador Central. Cabe señalar que en la actualidad el Distrito N° 2, cuenta con una gestión administrativa, sin embargo algunas unidades no logran la ejecución total del Plan Anual Operativo y Estratégico, por falta de recursos, originando quejas continuas y expectativas insatisfechas de los usuarios. A raíz de la problemática anterior planteada fue necesario la realización de un diagnóstico para conocer las fortalezas y debilidades en la asignación y utilización de los recursos, para lo cual se utilizó el método sintético y analítico, así como las técnicas de la entrevista a jefes de unidades específicamente; la encuesta dirigida a los empleados de los niveles operativos-administrativos y además la observación directa, todo esto permitió concluir que el Distrito N° 2, no cuenta con una herramienta administrativa que garantice la buena asignación y utilización de los recursos; debido a que no existen manuales de procedimientos actualizados, la filosofía administrativa (misión, visión y organigrama) no ha sido totalmente difundida a todo el personal, no se cuenta con programas de capacitaciones constantes para todo el personal, etc.. Para corregir la problemática anterior surge la propuesta del Diseño de un Sistema de Calidad Total, el cual servirá de apoyo para el control de los recursos en general y de esta manera obtener una gestión de calidad. Se cree firmemente que sin la aplicación de este sistema, ésta y cualquier otra institución no lograria aprovechar los recursos en su totalidad y sobre todo nunca conseguiría brindar servicios que satisfagan las expectativas de los usuarios.

L’industrie osseuse des Iroquoiens du site Mailhot-Curran (BgFn-2) : une étude des déchets de fabrication

Bien que l’os soit une matière première ayant joué un rôle essentiel au sein des activités quotidiennes des Iroquoiens du Saint-Laurent, il existe à ce jour très peu d’analyses systématiques de l’outillage en os et des débris de fabrication retrouvés en Iroquoianie. Afin de pallier ces lacunes, ce mémoire de maitrise porte sur l’analyse des vestiges en os ouvragés récupérés sur le site villageois Mailhot-Curran (BgFn-2), occupé durant le Sylvicole supérieur tardif par une communauté iroquoienne du Saint-Laurent. Plus précisément, l’étude consiste à analyser l’industrie osseuse en portant une attention particulière aux déchets de fabrication. Cet examen attentif a pour principal objectif de documenter les modes de gestion et de sélection de la matière première ainsi que d’améliorer la compréhension des techniques préhistoriques employées pour la fabrication des objets en os. Au moyen d’analyses technologiques, zooarchéologiques et tracéologiques, il sera possible de classifier les déchets de fabrication, de documenter leur origine technologique et, ultimement, de reconstituer un certain nombre de chaines opératoires. Une étude détaillée de la distribution spatiale des artéfacts permettra également de mieux comprendre l’organisation des activités dans l’espace villageois. Ce mémoire a aussi pour objectif de fournir des balises méthodologiques et empiriques relatives à l’étude des déchets de fabrications en os, afin de démontrer la pertinence de considérer ces derniers dans la compréhension des systèmes socioéconomiques et culturels.

L’industrie osseuse des Iroquoiens du site Mailhot-Curran (BgFn-2) : une étude des déchets de fabrication

Bien que l’os soit une matière première ayant joué un rôle essentiel au sein des activités quotidiennes des Iroquoiens du Saint-Laurent, il existe à ce jour très peu d’analyses systématiques de l’outillage en os et des débris de fabrication retrouvés en Iroquoianie. Afin de pallier ces lacunes, ce mémoire de maitrise porte sur l’analyse des vestiges en os ouvragés récupérés sur le site villageois Mailhot-Curran (BgFn-2), occupé durant le Sylvicole supérieur tardif par une communauté iroquoienne du Saint-Laurent. Plus précisément, l’étude consiste à analyser l’industrie osseuse en portant une attention particulière aux déchets de fabrication. Cet examen attentif a pour principal objectif de documenter les modes de gestion et de sélection de la matière première ainsi que d’améliorer la compréhension des techniques préhistoriques employées pour la fabrication des objets en os. Au moyen d’analyses technologiques, zooarchéologiques et tracéologiques, il sera possible de classifier les déchets de fabrication, de documenter leur origine technologique et, ultimement, de reconstituer un certain nombre de chaines opératoires. Une étude détaillée de la distribution spatiale des artéfacts permettra également de mieux comprendre l’organisation des activités dans l’espace villageois. Ce mémoire a aussi pour objectif de fournir des balises méthodologiques et empiriques relatives à l’étude des déchets de fabrications en os, afin de démontrer la pertinence de considérer ces derniers dans la compréhension des systèmes socioéconomiques et culturels.

Vídeo da Unidade 2 - Gestão Local de Desastres Naturais para a Atenção Básica

Os vídeos são complementos do curso Gestão Local de Desastres Naturais para a Atenção Básica. O curso aborda aspectos que visam reduzir o impacto dos desastres naturais acometidas em várias regiões do Brasil. Apresenta duas situações-problema, uma relacionada à seca e outra à inundação e deslizamentos. Na unidade 1 são apresentados aspectos básicos em desastres naturais, conceitos, terminologias, dados etc. e o impacto no Brasil e na saúde. Na unidade 2 tem-se o processo de gestão do risco de desastres e nas unidades 3 e 4 aborda-se o impacto desse fator na saúde psicossocial da população atingida bem como a saúde dos trabalhadores que atuam nos desastres.

An Asp49 Phospholipase A2 From Snake Venom Induces Cyclooxygenase-2 Expression And Prostaglandin E2 Production Via Activation Of Nf-κb, P38mapk, And Pkc In Macrophages.

Phospholipases A2 (PLA2) are key enzymes for production of lipid mediators. We previously demonstrated that a snake venom sPLA2 named MT-III leads to prostaglandin (PG)E2 biosynthesis in macrophages by inducing the expression of cyclooxygenase-2 (COX-2). Herein, we explored the molecular mechanisms and signaling pathways leading to these MT-III-induced effects. Results demonstrated that MT-III induced activation of the transcription factor NF-κB in isolated macrophages. By using NF-κB selective inhibitors, the involvement of this factor in MT-III-induced COX-2 expression and PGE2 production was demonstrated. Moreover, MT-III-induced COX-2 protein expression and PGE2 release were attenuated by pretreatment of macrophages with SB202190, and Ly294002, and H-7-dihydro compounds, indicating the involvement of p38MAPK, PI3K, and PKC pathways, respectively. Consistent with this, MT-III triggered early phosphorylation of p38MAPK, PI3K, and PKC. Furthermore, SB202190, H-7-dihydro, but not Ly294002 treatment, abrogated activation of NF-κB induced by MT-III. Altogether, these results show for the first time that the induction of COX-2 protein expression and PGE2 release, which occur via NF-κB activation induced by the sPLA2-MT-III in macrophages, are modulated by p38MAPK and PKC, but not by PI3K signaling proteins.

Prognostic Value Of Dna And Mrna E6/e7 Of Human Papillomavirus In The Evolution Of Cervical Intraepithelial Neoplasia Grade 2.

This study aimed at evaluating whether human papillomavirus (HPV) groups and E6/E7 mRNA of HPV 16, 18, 31, 33, and 45 are prognostic of cervical intraepithelial neoplasia (CIN) 2 outcome in women with a cervical smear showing a low-grade squamous intraepithelial lesion (LSIL). This cohort study included women with biopsy-confirmed CIN 2 who were followed up for 12 months, with cervical smear and colposcopy performed every three months. Women with a negative or low-risk HPV status showed 100% CIN 2 regression. The CIN 2 regression rates at the 12-month follow-up were 69.4% for women with alpha-9 HPV versus 91.7% for other HPV species or HPV-negative status (P < 0.05). For women with HPV 16, the CIN 2 regression rate at the 12-month follow-up was 61.4% versus 89.5% for other HPV types or HPV-negative status (P < 0.05). The CIN 2 regression rate was 68.3% for women who tested positive for HPV E6/E7 mRNA versus 82.0% for the negative results, but this difference was not statistically significant. The expectant management for women with biopsy-confirmed CIN 2 and previous cytological tests showing LSIL exhibited a very high rate of spontaneous regression. HPV 16 is associated with a higher CIN 2 progression rate than other HPV infections. HPV E6/E7 mRNA is not a prognostic marker of the CIN 2 clinical outcome, although this analysis cannot be considered conclusive. Given the small sample size, this study could be considered a pilot for future larger studies on the role of predictive markers of CIN 2 evolution.