Olanzapine, an atypical antipsychotic, alleviates symptoms of schizophrenia while producing fewer side effects compared to first generation antipsychotics. However, chronic usage remains problematic due to the propensity of olanzapine to induce weight gain and metabolic disturbances. Moreover, the cellular mechanisms underlying the metabolic side effects are poorly understood. The central nervous system (CNS) exerts both hormonal and neuronal control over whole body homeostasis. The dorsal motor nucleus of the vagus (DMV) participates in this regulation through modulation of the parasympathetic outflow to subdiaphragmatic organs. We hypothesized that olanzapine disrupts neurotransmission of the DMV, and thus contributes to the dysregulation of metabolism. We used whole-cell patch-clamp recordings from female C57BL/6J to assess the effect of olanzapine on DMV neurons. First, we investigated the effect of acute olanzapine administration on the activity of DMV neurons. Acute application of 10 µM olanzapine on DMV neurons induced both pre- and postsynaptic effects. Voltage-clamp recordings revealed that, in 5 out of 9 DMV neurons, excitatory inputs to DMV neurons were significantly increased by 71.6 ± 22.1%. In addition, in current-clamp mode, olanzapine induced a robust hyperpolarization from -49.00 ± 0.64 mV to -60.82 ± 2.78 mV. The hyperpolarization suppressed action potential firing. As a next step, we investigated the subchronic effect of olanzapine on the activity of DMV neurons. Daily subcutaneous injections were made for 20 days (5 mg/kg/day of olanzapine and vehicle). We did not find significant differences in body weight, blood glucose, and insulin or leptin levels. Subchronic administration of olanzapine generated presynaptic changes in DMV neurons. In treated animals, additional infusion of 10 µM olanzapine on DMV neurons significantly reduced excitatory neurotransmission by 41.0 ± 3.1% in 10 out of 17 neurons. Our findings indicate that olanzapine directly modulates the neuronal activity in DMV neurons, and could thus contribute to the metabolic disturbances seen in long-term treatments. / acase@tulane.edu

Submitted by Danilo Morilha Rodrigues (danilomrodrigues@outlook.com.br) on 2018-09-19T20:55:34Z No. of bitstreams: 1 Dissertação_DaniloMRodrigues_2018_Temperatura_nas_propriedades_físicas_da_calda_de_pulverização_e_eficácia_ de_herbicidas_Versão_Definitiva.pdf: 1746308 bytes, checksum: 2d48d88e01c85f0161c7723944124e86 (MD5) / Approved for entry into archive by Maria Lucia Martins Frederico null (mlucia@fca.unesp.br) on 2018-09-20T12:17:15Z (GMT) No. of bitstreams: 1 rodrigues_dm_me_botfca.pdf: 1746308 bytes, checksum: 2d48d88e01c85f0161c7723944124e86 (MD5) / Made available in DSpace on 2018-09-20T12:17:15Z (GMT). No. of bitstreams: 1 rodrigues_dm_me_botfca.pdf: 1746308 bytes, checksum: 2d48d88e01c85f0161c7723944124e86 (MD5) Previous issue date: 2018-07-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O principal método de manejo das plantas daninhas é o controle químico. As aplicações de herbicidas são realizadas durante todo do ano e podem estar sujeitas à ação das condições climáticas, como por exemplo, a temperatura. O objetivo do presente estudo foi avaliar o efeito da temperatura da calda de pulverização sobre a eficácia de controle de herbicidas aplicados em diferentes espécies de plantas daninhas, bem como nas características físicas da pulverização. Para isso, foram realizados experimentos avaliando cinco temperaturas da calda (5, 10, 20, 30 e 40°C) contendo herbicidas. Os experimentos de eficácia e controle foram conduzidos no Departamento de Proteção Vegetal da FCA /UNESP – Campus de Botucatu. Seis espécies de plantas daninhas (Conyza sp, Amaranthus viridis, Richardia brasiliensis, Digitaria insularis, Digitaria horizontalis e Eleusine indica) foram submetidas a pulverizações de herbicidas (Glyphosate, Glufosinato de amônio, 2,4-D amine, Lactofen, Haloxyfop-methyl e Cletodim) nas cinco temperaturas da calda. A pulverização foi realizada com o auxílio de pulverizador propelido a ar comprimido, equipado com pontas de pulverização de jato plano, modelo AXI 11002, sob pressão de 138 kPa, e velocidade de trabalho de 7,0 km h-1, fornecendo uma taxa de aplicação de 98 L ha-1. A temperatura da calda foi ajustada por banho-maria até atingir a temperatura desejada, e, na sequência, adicionado o herbicida para aplicação. A partir deste experimento foi avaliado: deposição da pulverização em cartão hidrossensível, eficiência de controle e porcentagem de redução da massa seca de plantas daninhas. As características tensão superficial e ângulo de contato das caldas herbicidas em diferentes temperaturas, foram avaliadas em experimento no laboratório de tecnologia de aplicação da FCAV/Unesp de Jaboticabal. Estas avaliações foram realizadas em tensiômetro da marca DataPhysics® modelo OCA 15 Plus. Os dados obtidos foram submetidos e análise de variância pelo teste F e as médias comparadas pelo teste Tukey (P<0,05). O controle de plantas daninhas indicou diferença na eficiência de acordo com a temperatura da calda. A temperatura que proporcionou o melhor controle pode depender do herbicida e da espécie de planta daninha avaliada, porém no âmbito geral, calda com temperaturas de 20 e 30°C proporcionaram melhor controle. A tensão superficial e o ângulo de contato apresentaram comportamento aleatório em relação ao incremento das temperaturas da calda, não permitindo generalizações do efeito da temperatura em relação a essas variáveis. Com relação aos dados das características das gotas, caldas com temperaturas mais elevadas, resultam no aumento do número e densidade de gotas, e também na redução do diâmetro mediano volumétrico. / The most weed management tactics is the chemical control. The herbicides applications can be made during the whole year and it may be subject to the action of climatic conditions such as temperature. The objective of the present study was to evaluate the temperature effect on the spray solution at the moment of spraying on the herbicides efficacy applied in different weeds species control, as well as on the physical characteristics of spraying. Some experiments were performed to evaluate five spray solution temperatures (5, 10, 20, 30 and 40° C) containing herbicides. The experiments involving the weed control were conducted in the Department of Plant Protection from Sao Paulo State University (UNESP), School of Agronomy, Botucatu. Six species of weeds (Conyza sp, Richardia brasiliensis, Amaranthus viridis, Digitaria insularis, Digitaria horizontalis and Eleusine indica), were sprayed with herbicides (glyphosate, glufosinato-ammonium, 2,4-D amine, lactofen, haloxyfop-methyl e clethodim) at the five temperatures of the spray mixture. It was carried out using a compressed-air sprayer, fitted with flat-fan nozzles, model AXI 11002, at 138 kPa of pressure, and operating at 7.0 km h-1, providing a spray rate of 98 L ha-1. The spray mixture temperature was adjusted using a water bath until it reaches the ideal temperature, and, thus, the herbicide was added for application. From this experiment, it was evaluated: spray deposition through a water sensitive card, weed control and its dry mass reduction percentage. The spray solution characteristics, like: surface tension and contact angle from the spray solution in different temperatures, were evaluated in another experiment which was conducted in the spraying technology laboratory of São Paulo State University (UNESP), School of Agricultural and Veterinarian Sciences, Jaboticabal city. The evaluations were carried out in a tension meter device: DataPhysics model OCA brand ® 15 Plus. The data was submitted to the ANOVA by Fischer test and compared by Tukey test (P < 0.05).The weed control indicated difference according to the spray mixture temperature. The temperature that provides the best control depends on the herbicide and weed, but in general, temperatures of 20 and 30° C can provide a satisfactory control. Surface tension and contact angle presented a random behavior according to the temperature increase of the spray solution, not allowing generalizations of the effect of the temperature in relation to these variables. According to the droplet data characteristics, spray mixture with higher temperatures, increased droplet number and density, as well as reduced the volumetric median diameter.

Introduction : L'angiogenèse tumorale conduit au développement de nouveaux vaisseaux destinés à permettre la croissance de la tumeur. Les vaisseaux tumoraux sont caractérisés notamment par des anomalies des cellules murales (cellules musculaires périvasculaires), responsables d'anomalies de la fonctionnalité et de la maturation. Dans ce travail de thèse, nous avons étudié un modèle tumoral de thérapie cellulaire par injection de cellules murales en IRM et vidéomicroscopie de fluorescence. Matériels et méthodes : Notre étude a porté sur un modèle sous cutané de carcinome épidermoïde chez la souris nude. Les animaux étaient divisés en trois groupes : contrôle (n=17), contrôle négatif (n=16) et " traité " avec injection locale de cellules murales humaines (n=17). Les animaux bénéficiaient d'une IRM et d'une exploration par vidéomicroscopie avant (J7) et après traitement (J14). Les paramètres mesurés étaient la taille tumorale (pied-à-coulisse et IRM), la densité microvasculaire (DMV par IRM, vidéomicroscopie et histologie), l'ADC, f, Dr et D* (IRM de diffusion), les variations de R2* sous air, oxygène et carbogène (IRM par effet BOLD) et " l'index leakage " (reflétant la perméabilité capillaire, en vidéomicroscopie). Résultats : Lors de la croissance tumorale, le groupe contrôle a montré une diminution des vaisseaux circulants (ou fonctionnels) qui se reflétait par une diminution du D* et du R2* sous air, une perte de la capacité à répondre au carbogène qui se reflétait par une augmentation du delta R2* sous carbogène, et une augmentation de la perméabilité capillaire qui se traduisait par un " index leakage " plus élevé. Dans le groupe traité par injection de cellules murales, nous avons observé un ralentissement de la croissance tumorale et une stabilisation de ces paramètres de microcirculation et maturation vasculaire. Conclusion : Nous avons montré un effet biologique de notre thérapie cellulaire par injection locale de cellules murales qui se traduisait par un ralentissement de la croissance tumorale, une stabilisation de l'hémodynamique microcirculatoire et de la maturation, et une perméabilité capillaire diminuée, concordants avec l'effet présumé stabilisateur et normalisateur des cellules murales sur les microvaisseaux.

Introduction : L’angiogenèse tumorale conduit au développement de nouveaux vaisseaux destinés à permettre la croissance de la tumeur. Les vaisseaux tumoraux sont caractérisés notamment par des anomalies des cellules murales (cellules musculaires périvasculaires), responsables d’anomalies de la fonctionnalité et de la maturation. Dans ce travail de thèse, nous avons étudié un modèle tumoral de thérapie cellulaire par injection de cellules murales en IRM et vidéomicroscopie de fluorescence. Matériels et méthodes : Notre étude a porté sur un modèle sous cutané de carcinome épidermoïde chez la souris nude. Les animaux étaient divisés en trois groupes : contrôle (n=17), contrôle négatif (n=16) et « traité » avec injection locale de cellules murales humaines (n=17). Les animaux bénéficiaient d’une IRM et d’une exploration par vidéomicroscopie avant (J7) et après traitement (J14). Les paramètres mesurés étaient la taille tumorale (pied-à-coulisse et IRM), la densité microvasculaire (DMV par IRM, vidéomicroscopie et histologie), l’ADC, f, Dr et D* (IRM de diffusion), les variations de R2* sous air, oxygène et carbogène (IRM par effet BOLD) et « l’index leakage » (reflétant la perméabilité capillaire, en vidéomicroscopie). Résultats : Lors de la croissance tumorale, le groupe contrôle a montré une diminution des vaisseaux circulants (ou fonctionnels) qui se reflétait par une diminution du D* et du R2* sous air, une perte de la capacité à répondre au carbogène qui se reflétait par une augmentation du delta R2* sous carbogène, et une augmentation de la perméabilité capillaire qui se traduisait par un « index leakage » plus élevé. Dans le groupe traité par injection de cellules murales, nous avons observé un ralentissement de la croissance tumorale et une stabilisation de ces paramètres de microcirculation et maturation vasculaire. Conclusion : Nous avons montré un effet biologique de notre thérapie cellulaire par injection locale de cellules murales qui se traduisait par un ralentissement de la croissance tumorale, une stabilisation de l’hémodynamique microcirculatoire et de la maturation, et une perméabilité capillaire diminuée, concordants avec l’effet présumé stabilisateur et normalisateur des cellules murales sur les microvaisseaux. / Introduction : Tumor angiogenesis leads to the development of new vessels enabling the growth of the tumor. Tumor vessels are characterized by abnormalities including mural cells (perivascular muscular cells) responsible for abnormal vessel function and maturation. In this thesis, we studied cellular therapy in a tumor model by injection of mural cells using MRI and fluorescence videomicroscopy. Materiels and methods: Nude mice were injected with squamous cell TC1 tumors and animals were divided in three groups: control (n=17), sham control (n=16) and treated by local injection of human mural cells (n=17). Animals underwent MRI and videomicroscopy before (D7) and after (D14) treatment. Measured parameters included tumor size (caliper and MRI), microvessels density (MVD using MRI, videomicroscopy and pathology), ADC, f, Dr, D* (diffusion MRI), R2* variations under air, oxygen and carbogen (BOLD MRI), and ‘index leakage’ (reflecting capillary permeability, using videomicroscopy). Results: During tumor growth, the control group showed a decrease in circulating (or functional) vessels reflected by a decrease in D* and R2* under air, the loss of vessel ability to respond to carbogen reflected by an increase of the delta R2* under carbogen, and increased capillary permeability resulting in a higher ”index leakage”. In the group treated by injection of mural cells, we observed a slowing of tumor growth and stabilization of these parameters of microcirculation and vessel maturation. Conclusion : Therapy by local injection of mural cells was effective resulting in slower tumor growth, stabilization of microcirculatory hemodynamics and maturation, and decreased capillary permeability, consistent with the alleged ‘stabilizing’ and ‘normalizing’ effects of mural cells on microvessels.