Background and objective: By reviewing our current understanding of oxidative injury as a cause of focal segmental glomerulosclerosis (FSGS), we hope to advance the use of antioxidants as a promising treatment in addition to the other therapeutic modalities to slow the rate of progression. Methods: Key references from the past concerning oxidative injury and FSGS were analyzed, together with those from a PubMed search of the literature from 1997 to 2007, to form the basis of this commentary. Results: In animal studies in FSGS produced by subtotal nephrectomy or puromycin injections, evidence of oxidant injury provided the rationale for disease reversal with an antioxidant such as high dose vitamin E. Clinical trial in children with FSGS using vitamin E resulted in significant reduction in proteinuria. Other treatment modalities in children with FSGS over the past four decades were reviewed. These consisted of one or more of the following medications: oral prednisone, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and intravenous methylprednisolone with and without cyclophosphamide or cyclosporine. The prognosis with these recent therapeutic interventions improved the outcome of children with FSGS compared to no treatment as advocated earlier. However, when the current regimen of combined treatment was compared with the regimen of prednisone plus cyclophosphamide, there was no difference in Kaplan-Meier kidney survival rate at a mean follow-up of 12 to 16 years. Conclusion: In reviewing current concepts of oxidant injury and other mechanisms of injury in the development of FSGS and the available modalities of treatment, we call into question, whether the cost and side effects of intravenous methylprednisolone is justifiable on the basis of unchanged kidney survival rates with continuing this particular mode of intervention.

Le cancer pancréatique représente la cinquième cause de décès par cancer dans les pays occidentaux. Son mauvais pronostic (survie à 5 ans inférieure à 3,5 % des cas) est dû à l’absence de facteurs de risques spécifiques interdisant une prévention efficace, et à un diagnostic tardif qui révèle un cancer agressif chez environ 90% des patients. Actuellement, le seul traitement curatif de ce cancer est la chirurgie, mais celle-ci ne peut être envisagée que dans 10 à 15 % des cas. L’adressage de molécules thérapeutiques vers l’organe, le tissu ou la cellule malade constitue aujourd’hui un défi majeur pour le traitement des maladies humaines notamment infectieuses, cancéreuses ou d’origine génétique. C’est pour ces raisons que le développement de nanotechnologies, en tant que vecteurs de médicaments, a pris un essor considérable au cours des dernières années. Dans ce contexte, le concept de squalènisation repose sur le couplage chimique entre le squalène (SQ), un lipide naturel précurseur de la synthèse du cholestérol, et des principes actifs (notamment des molécules anticancéreuses). Les bioconjugués ainsi formés sont alors capables de s’auto-assembler en solution aqueuse pour former des nanoparticules stables de diamètres compris entre 100 et 300 nm. L’exemple de référence dans ce domaine est la nanoparticule de gemcitabine-squalène (SQdFdC) qui a donné lieu à des résultats spectaculaires in vitro sur des lignées de cellules cancéreuses humaines In vivo, les nanoparticules de gemcitabine-squalène se sont avérées beaucoup plus efficaces que la gemcitabine libre sur des tumeurs solides greffées par voie sous-cutanée ainsi que sur des modèles murins de leucémies agressives métastatiques.Au vu de ces résultats encourageants, le projet de thèse a été développé autour de deux axes de recherche. (I) Dans un premier temps, les nanoparticules de gemcitabine-squalène ont été fonctionnalisées par un peptide capable de reconnaître et de cibler spécifiquement les cellules cancéreuses pancréatiques. (II) Le deuxième axe de recherche a visé l’encapsulation d’un second principe actif au sein des nanoparticules de gemcitabine-squalène afin de développer le concept de nanoparticule « multi-thérapeutique ». / Pancreatic cancer is a lethal disease with the worst prognosis among all solid tumors. In the last decades, progresses in pancreatic cancer therapy had remained exceedingly slow and disappointing offering minimal benefits in median survival which remains of less than 6 months and the maximum of 5 years in the 6% of patients. One of the major requirements for a successful cancer therapy is its ability to selectively kill cancer cells with minimal damage to healthy tissues. In this context, a great deal of attention focused on advanced nanoscale systems (i.e., nanomedicines) with the aim to overcome the limits associated to the traditional drug delivery modalities. Nanomedicines can indeed enhance drug properties by (i) offering protection from degradation, (ii) enabling controlled release and distribution and increasing bioavailability while reducing undesired side effects.In the current work we aimed to propose novel nanoscale-based strategies to optimize pancreatic cancer treatment taking into account the specific physio-pathology of this tumor. The first approach relied on the design of a targeted nanomedicine able to specifically bind receptors mainly expressed onto pancreatic cancer cells in order to selectively increase drug accumulation in these cells saving healthy ones.In a second approach, by combining two therapeutic agents in the same nanoparticle we constructed a multi-therapeutic drug delivery system capable to increase the therapeutic index of the combined therapy. In particular, taking advantages from the “squalenoylation prodrug approach”, the research activity of this Ph.D. work lead to the to design of (i) a novel peptide-functionalized squalenoyl gemcitabine nanoparticle and (ii) a tyrosine kinase inhibitor-loaded squalenoyl gemcitabine nanoparticle. Obtained nanoparticles were investigated with respect to their physico-chemical properties and in vitro antitumor activity. The efficacy of peptide-functionalized nanoparticles in impairing tumor growth was assessed in vivo on an experimental model of pancreatic cancer.

A Fibromialgia (FM) é uma síndrome de dor crônica caracterizada pelo aparecimento de dor difusa, intermitente e crônica por todo o corpo. A prática de exercícios aeróbicos demonstra resultados no alívio da dor, porém com uma dificuldade de aderência aos protocolos. A Estimulação Transcraniana com Corrente Contínua (ETCC), promove modulação da atividade cerebral e tem demonstrado resultados positivos para redução da dor. O objetivo deste estudo foi determinar o efeito da terapia combinada utilizando a técnica de ETCC associada ao treino de Exercício Aeróbico (EA) em pacientes portadores de fibromialgia. Para tanto, 45 pacientes foram randomizados em um dos seguintes três grupos: Grupo ETCC / EA, Grupo EA (com ETCC simulada), e Grupo ETCC (com EA simulado). Durante a intervenção os sujeitos passaram por uma etapa de uma semana de ETCC (cinco dias consecutivos) associado ao treino de EA por três dias desta semana; e uma segunda etapa de quatro semanas (sendo realizadas três vezes em cada semana) apenas com o treino de EA. A ETCC foi aplicada posicionando o eletrodo anodal sobre o córtex motor primário e o eletrodo catodal sobre a região supra-orbital contralateral com 2mA por 20 minutos. O EA utilizou uma intensidade de 60 a 70% da frequência cardíaca máxima. A escala visual numérica de dor foi utilizada como desfecho primário, sendo utilizadas avaliações de ansiedade, limiar de dor à pressão, resposta condicionada a dor (DNIC), preenchimento de mapa corporal, questionário de qualidade de vida SF-36, inventário de depressão de Beck, tarefa go-no-go, teste de caminhada de seis minutos, timed up-and-go, e avaliação da excitabilidade cortical utilizando estimulação magnética transcraniana. Houve efeito significativo para a interação tempo X grupo para a intensidade da dor, demonstrando que ETCC / EA foi superior ao AE apenas (F (13,364) = 2.25, p = 0,007) e ETCC (F (13,364) = 2.33, p = 0,0056). Análise ajustada do post hoc demostrou uma diferença entre ETCC / AE e grupo ETCC após a primeira semana de estimulação e depois do período de um mês de intervenção (p = 0,02 e p = 0,03, respectivamente). Além disso, após o tratamento houve uma diferença significativa entre os grupos nos níveis de ansiedade e de humor. O tratamento combinado apresentou a maior resposta. Nenhum dos grupos apresentou diferenças significativas em relação a respostas da plasticidade do córtex motor, tal como avaliado pela EMT. A combinação de ETCC com o exercício aeróbico é superior em comparação com cada intervenção individual (tamanho do efeito pelo teste d de Cohen> 0,55). Este estudo demonstrou que a neuromodulação com ETCC associado ao treino de EA levou a uma melhora na resposta de dor mais intensa do que quando comparado a cada modalidade de intervenção isolada. Os níveis de ansiedade também demonstraram melhora no grupo de associação. Notavelmente, o nível inicial de dor e humor parece ser um preditor do resultado. Observou-se que os indivíduos com níveis de dor mais altos e níveis mais elevados de depressão responderam melhor ao tratamento. Por fim, a intervenção combinada teve um efeito significativo sobre a dor, ansiedade e humor. É provável que a intervenção combinada pode ter afetado outros circuitos neurais, tais como aqueles que controlam os aspectos afetivo-emocionais de dor / Fibromyalgia (FM) is a chronic pain syndrome characterized by the appearance of diffuse pain, intermittent and chronic throughout the body. The aerobic exercise demonstrates results in relieving but with a difficulty of adherence to protocols. The transcranial direct current stimulation (tDCS) promotes modulation of brain activity and have demonstrated positive results in reducing pain. The aim of this study was to determine the effect of a combination therapy protocol using tDCS technique associated with Aerobic Exercise training (AE) in fibromyalgia patients. Therefore, 45 patients were randomized into one of three groups: tDCS/AE group, AE group (sham tDCS), and tDCS group (sham AE). During the intervention subjects went through a stage of a week of tDCS (five consecutive days) associated with AE training for three days per week; and a second step with four weeks duration (being performed three times per week) only with AE training. The tDCS was applied by placing the anodal electrode on the primary motor cortex and catodal electrode on the contralateral supraorbital region, using 2mA for 20 minutes. AE used an intensity of 60 to 70% of maximum heart rate. The visual numeric pain scale was used as the primary outcome, and as secondary outcome: VNS anxiety ratings, pressure pain threshold, conditioned pain modulation (DNIC), SF-36 questionnaire, beck depression inventory, an emotional go-no-go task, six-minute walk test, timed up-and-go test, and evaluation of cortical excitability using TMS. There was a significant effect for the interaction time X group to the intensity of pain, demonstrating that tDCS / AE was higher than the AE only (F (13.364) = 2.25, p = 0.007) and tDCS (F (13.364) = 2.33, p = 0, 0056). Adjusted post hoc analysis demonstrated a difference between tDCS / AE and tDCS group after first week of stimulation, and after one month\'s intervention (p = 0.02 and p = 0.03, respectively). In addition, after treatment there was a significant difference between the groups in the level of anxiety and mood. The combined treatment showed the greatest response. Neither group showed significant differences from the motor cortex plasticity responses, as assessed by EMT. The combination of tDCS with aerobic exercise is higher compared to each individual intervention (effect size for the test Cohen d> 0.55). This study demonstrated that neuromodulation with tDCS associated with AE training led to an improvement in the intensity of pain greater than when compared to each intervention modality alone. Anxiety levels also showed improvement in the combination group. Notably, the initial level of pain and mood seems to be a predictor of the outcome. It was observed that individuals with higher levels of pain and higher levels of depression responded better to the treatment. Finally, the combined intervention had a significant effect on pain, anxiety and mood. It is likely that the combined intervention may have affected other neural circuits, such as those that control the affective and emotional aspects of pain

Uma das principais doenças degenerativas, conhecida internacionalmente pelo nome de osteoartrite (OA), é uma condição patológica crônica e prevalente que traz prejuízos sociais, psicológicos e financeiros a 10% da população em geral e a mais de 50% dos idosos. Acima dos 75 anos de idade aproximadamente 85% dos idosos são acometidos por essa doença. A população no Brasil envelhece rápido, envelhecerá em 30 anos tanto quanto a Europa envelheceu em 200 anos. Assim, novas técnicas para o tratamento da OA de joelho são muito relevantes. Este trabalho teve por objetivo estudar os efeitos de uma Terapia Combinada (TC) sobre o comportamento de ratos submetidos a um modelo experimental de osteoartrite de joelho. Ratos Wistar machos e adultos foram submetidos à lesão do joelho direito pela injeção intra-articular de iodoacetato monosódico (IM). Quinze dias após a lesão foram aplicados 3 tratamentos por 14 dias: Laserterapia de Baixa Potência (LBP), Estimulação Elétrica Artificial (EEA) e TC (i.e., LBP + EEA). Foram observados os efeitos agudos e crônicos destes tratamentos sobre o comportamento dos animais em 3 testes comportamentais: campo aberto, analgesímetro e descarga de peso. Os principais resultados do presente estudo indicam que (i) o modelo experimental de OA de joelho proposto foi induzido com sucesso e resultou em déficits agudos e crônicos ao longo de 30 dias de experimento; (ii) o tratamento com LBP resultou em diminuição dos déficits devido à hiperalgesia primária e secundária à lesão, porém não teve impacto sobre a funcionalidade geral do sistema de movimento dos animais; (iii) o treinamento com EEA resultou em diminuição dos déficits de hiperalgesia primária e teve impacto sobre a funcionalidade geral do sistema de movimento e (iv) a TC resultou em diminuição dos déficits de hiperalgesia primária e efeito moderado sobre a hiperalgesia secundária, além de impacto positivo sobre a funcionalidade geral do sistema de movimento. Com base nestes resultados, a TC apresentou efeitos benéficos tanto sobre o controle da dor, quanto para a menor incapacitação e melhor funcionalidade, sendo indicada para combater os efeitos deletérios da OA de joelho sobre o sistema de movimento. / A major degenerative disease, internationally known as osteoarthritis (OA) is a prevalent and chronic pathological condition which results in social, psychological and financial impairments to 10% of the general population and to over 50% of the elderly. Above 75 years of age approximately 85% of the elderly are affected by this disease. In Brazil there is a fast ageing of population who will age during 30 years as much as Europe aged in 200 years. Thus, new techniques for the treatment of knee OA are very relevant. This work aimed to study the effects of a combined therapy (TC) on the behavior of rats submitted to an experimental model of knee osteoarthritis. Male adult Wistar rats underwent right knee injury by intra-articular injection of monosodium iodoacetate (IM). Fifteen days after injury received 3 treatments for 14 days: Low Power Laser Therapy (LBP), Artificial Electrical Stimulation (EEA) and TC (i.e., LBP + EEA). We observed the acute and chronic effects of these treatments on the behavior of animals in 3 behavioral tests: open field, analgesymeter and weight bearing. The main results of this study indicate that (i) the proposed experimental model of knee OA was successfully induced and resulted in acute and chronic deficits over 30 days of experiment, (ii) treatment with LBP resulted in reduction of deficits due to primary and secondary hyperalgesia to the lesion, but had no impact on the overall functionality of the movement system, (iii) the training with EEA resulted in decreased deficits of primary hyperalgesia and impacted the overall functionality of the movement system (iv) the TC resulted in reduction of deficits due to primary hyperalgesia and moderate effect on secondary hyperalgesia, and positive impact on the overall functionality of the movement system. Based on these results, the TC showed beneficial effects on pain control and on less disability and better functionality, thus TC is indicated to combat the deleterious effects of knee OA on the motion system.

Uma das principais doenças degenerativas, conhecida internacionalmente pelo nome de osteoartrite (OA), é uma condição patológica crônica e prevalente que traz prejuízos sociais, psicológicos e financeiros a 10% da população em geral e a mais de 50% dos idosos. Acima dos 75 anos de idade aproximadamente 85% dos idosos são acometidos por essa doença. A população no Brasil envelhece rápido, envelhecerá em 30 anos tanto quanto a Europa envelheceu em 200 anos. Assim, novas técnicas para o tratamento da OA de joelho são muito relevantes. Este trabalho teve por objetivo estudar os efeitos de uma Terapia Combinada (TC) sobre o comportamento de ratos submetidos a um modelo experimental de osteoartrite de joelho. Ratos Wistar machos e adultos foram submetidos à lesão do joelho direito pela injeção intra-articular de iodoacetato monosódico (IM). Quinze dias após a lesão foram aplicados 3 tratamentos por 14 dias: Laserterapia de Baixa Potência (LBP), Estimulação Elétrica Artificial (EEA) e TC (i.e., LBP + EEA). Foram observados os efeitos agudos e crônicos destes tratamentos sobre o comportamento dos animais em 3 testes comportamentais: campo aberto, analgesímetro e descarga de peso. Os principais resultados do presente estudo indicam que (i) o modelo experimental de OA de joelho proposto foi induzido com sucesso e resultou em déficits agudos e crônicos ao longo de 30 dias de experimento; (ii) o tratamento com LBP resultou em diminuição dos déficits devido à hiperalgesia primária e secundária à lesão, porém não teve impacto sobre a funcionalidade geral do sistema de movimento dos animais; (iii) o treinamento com EEA resultou em diminuição dos déficits de hiperalgesia primária e teve impacto sobre a funcionalidade geral do sistema de movimento e (iv) a TC resultou em diminuição dos déficits de hiperalgesia primária e efeito moderado sobre a hiperalgesia secundária, além de impacto positivo sobre a funcionalidade geral do sistema de movimento. Com base nestes resultados, a TC apresentou efeitos benéficos tanto sobre o controle da dor, quanto para a menor incapacitação e melhor funcionalidade, sendo indicada para combater os efeitos deletérios da OA de joelho sobre o sistema de movimento. / A major degenerative disease, internationally known as osteoarthritis (OA) is a prevalent and chronic pathological condition which results in social, psychological and financial impairments to 10% of the general population and to over 50% of the elderly. Above 75 years of age approximately 85% of the elderly are affected by this disease. In Brazil there is a fast ageing of population who will age during 30 years as much as Europe aged in 200 years. Thus, new techniques for the treatment of knee OA are very relevant. This work aimed to study the effects of a combined therapy (TC) on the behavior of rats submitted to an experimental model of knee osteoarthritis. Male adult Wistar rats underwent right knee injury by intra-articular injection of monosodium iodoacetate (IM). Fifteen days after injury received 3 treatments for 14 days: Low Power Laser Therapy (LBP), Artificial Electrical Stimulation (EEA) and TC (i.e., LBP + EEA). We observed the acute and chronic effects of these treatments on the behavior of animals in 3 behavioral tests: open field, analgesymeter and weight bearing. The main results of this study indicate that (i) the proposed experimental model of knee OA was successfully induced and resulted in acute and chronic deficits over 30 days of experiment, (ii) treatment with LBP resulted in reduction of deficits due to primary and secondary hyperalgesia to the lesion, but had no impact on the overall functionality of the movement system, (iii) the training with EEA resulted in decreased deficits of primary hyperalgesia and impacted the overall functionality of the movement system (iv) the TC resulted in reduction of deficits due to primary hyperalgesia and moderate effect on secondary hyperalgesia, and positive impact on the overall functionality of the movement system. Based on these results, the TC showed beneficial effects on pain control and on less disability and better functionality, thus TC is indicated to combat the deleterious effects of knee OA on the motion system.

Uma das principais doenças degenerativas, conhecida internacionalmente pelo nome de osteoartrite (OA), é uma condição patológica crônica e prevalente que traz prejuízos sociais, psicológicos e financeiros a 10% da população em geral e a mais de 50% dos idosos. Acima dos 75 anos de idade aproximadamente 85% dos idosos são acometidos por essa doença. A população no Brasil envelhece rápido, envelhecerá em 30 anos tanto quanto a Europa envelheceu em 200 anos. Assim, novas técnicas para o tratamento da OA de joelho são muito relevantes. Este trabalho teve por objetivo estudar os efeitos de uma Terapia Combinada (TC) sobre o comportamento de ratos submetidos a um modelo experimental de osteoartrite de joelho. Ratos Wistar machos e adultos foram submetidos à lesão do joelho direito pela injeção intra-articular de iodoacetato monosódico (IM). Quinze dias após a lesão foram aplicados 3 tratamentos por 14 dias: Laserterapia de Baixa Potência (LBP), Estimulação Elétrica Artificial (EEA) e TC (i.e., LBP + EEA). Foram observados os efeitos agudos e crônicos destes tratamentos sobre o comportamento dos animais em 3 testes comportamentais: campo aberto, analgesímetro e descarga de peso. Os principais resultados do presente estudo indicam que (i) o modelo experimental de OA de joelho proposto foi induzido com sucesso e resultou em déficits agudos e crônicos ao longo de 30 dias de experimento; (ii) o tratamento com LBP resultou em diminuição dos déficits devido à hiperalgesia primária e secundária à lesão, porém não teve impacto sobre a funcionalidade geral do sistema de movimento dos animais; (iii) o treinamento com EEA resultou em diminuição dos déficits de hiperalgesia primária e teve impacto sobre a funcionalidade geral do sistema de movimento e (iv) a TC resultou em diminuição dos déficits de hiperalgesia primária e efeito moderado sobre a hiperalgesia secundária, além de impacto positivo sobre a funcionalidade geral do sistema de movimento. Com base nestes resultados, a TC apresentou efeitos benéficos tanto sobre o controle da dor, quanto para a menor incapacitação e melhor funcionalidade, sendo indicada para combater os efeitos deletérios da OA de joelho sobre o sistema de movimento. / A major degenerative disease, internationally known as osteoarthritis (OA) is a prevalent and chronic pathological condition which results in social, psychological and financial impairments to 10% of the general population and to over 50% of the elderly. Above 75 years of age approximately 85% of the elderly are affected by this disease. In Brazil there is a fast ageing of population who will age during 30 years as much as Europe aged in 200 years. Thus, new techniques for the treatment of knee OA are very relevant. This work aimed to study the effects of a combined therapy (TC) on the behavior of rats submitted to an experimental model of knee osteoarthritis. Male adult Wistar rats underwent right knee injury by intra-articular injection of monosodium iodoacetate (IM). Fifteen days after injury received 3 treatments for 14 days: Low Power Laser Therapy (LBP), Artificial Electrical Stimulation (EEA) and TC (i.e., LBP + EEA). We observed the acute and chronic effects of these treatments on the behavior of animals in 3 behavioral tests: open field, analgesymeter and weight bearing. The main results of this study indicate that (i) the proposed experimental model of knee OA was successfully induced and resulted in acute and chronic deficits over 30 days of experiment, (ii) treatment with LBP resulted in reduction of deficits due to primary and secondary hyperalgesia to the lesion, but had no impact on the overall functionality of the movement system, (iii) the training with EEA resulted in decreased deficits of primary hyperalgesia and impacted the overall functionality of the movement system (iv) the TC resulted in reduction of deficits due to primary hyperalgesia and moderate effect on secondary hyperalgesia, and positive impact on the overall functionality of the movement system. Based on these results, the TC showed beneficial effects on pain control and on less disability and better functionality, thus TC is indicated to combat the deleterious effects of knee OA on the motion system.

A Fibromialgia (FM) é uma síndrome de dor crônica caracterizada pelo aparecimento de dor difusa, intermitente e crônica por todo o corpo. A prática de exercícios aeróbicos demonstra resultados no alívio da dor, porém com uma dificuldade de aderência aos protocolos. A Estimulação Transcraniana com Corrente Contínua (ETCC), promove modulação da atividade cerebral e tem demonstrado resultados positivos para redução da dor. O objetivo deste estudo foi determinar o efeito da terapia combinada utilizando a técnica de ETCC associada ao treino de Exercício Aeróbico (EA) em pacientes portadores de fibromialgia. Para tanto, 45 pacientes foram randomizados em um dos seguintes três grupos: Grupo ETCC / EA, Grupo EA (com ETCC simulada), e Grupo ETCC (com EA simulado). Durante a intervenção os sujeitos passaram por uma etapa de uma semana de ETCC (cinco dias consecutivos) associado ao treino de EA por três dias desta semana; e uma segunda etapa de quatro semanas (sendo realizadas três vezes em cada semana) apenas com o treino de EA. A ETCC foi aplicada posicionando o eletrodo anodal sobre o córtex motor primário e o eletrodo catodal sobre a região supra-orbital contralateral com 2mA por 20 minutos. O EA utilizou uma intensidade de 60 a 70% da frequência cardíaca máxima. A escala visual numérica de dor foi utilizada como desfecho primário, sendo utilizadas avaliações de ansiedade, limiar de dor à pressão, resposta condicionada a dor (DNIC), preenchimento de mapa corporal, questionário de qualidade de vida SF-36, inventário de depressão de Beck, tarefa go-no-go, teste de caminhada de seis minutos, timed up-and-go, e avaliação da excitabilidade cortical utilizando estimulação magnética transcraniana. Houve efeito significativo para a interação tempo X grupo para a intensidade da dor, demonstrando que ETCC / EA foi superior ao AE apenas (F (13,364) = 2.25, p = 0,007) e ETCC (F (13,364) = 2.33, p = 0,0056). Análise ajustada do post hoc demostrou uma diferença entre ETCC / AE e grupo ETCC após a primeira semana de estimulação e depois do período de um mês de intervenção (p = 0,02 e p = 0,03, respectivamente). Além disso, após o tratamento houve uma diferença significativa entre os grupos nos níveis de ansiedade e de humor. O tratamento combinado apresentou a maior resposta. Nenhum dos grupos apresentou diferenças significativas em relação a respostas da plasticidade do córtex motor, tal como avaliado pela EMT. A combinação de ETCC com o exercício aeróbico é superior em comparação com cada intervenção individual (tamanho do efeito pelo teste d de Cohen> 0,55). Este estudo demonstrou que a neuromodulação com ETCC associado ao treino de EA levou a uma melhora na resposta de dor mais intensa do que quando comparado a cada modalidade de intervenção isolada. Os níveis de ansiedade também demonstraram melhora no grupo de associação. Notavelmente, o nível inicial de dor e humor parece ser um preditor do resultado. Observou-se que os indivíduos com níveis de dor mais altos e níveis mais elevados de depressão responderam melhor ao tratamento. Por fim, a intervenção combinada teve um efeito significativo sobre a dor, ansiedade e humor. É provável que a intervenção combinada pode ter afetado outros circuitos neurais, tais como aqueles que controlam os aspectos afetivo-emocionais de dor / Fibromyalgia (FM) is a chronic pain syndrome characterized by the appearance of diffuse pain, intermittent and chronic throughout the body. The aerobic exercise demonstrates results in relieving but with a difficulty of adherence to protocols. The transcranial direct current stimulation (tDCS) promotes modulation of brain activity and have demonstrated positive results in reducing pain. The aim of this study was to determine the effect of a combination therapy protocol using tDCS technique associated with Aerobic Exercise training (AE) in fibromyalgia patients. Therefore, 45 patients were randomized into one of three groups: tDCS/AE group, AE group (sham tDCS), and tDCS group (sham AE). During the intervention subjects went through a stage of a week of tDCS (five consecutive days) associated with AE training for three days per week; and a second step with four weeks duration (being performed three times per week) only with AE training. The tDCS was applied by placing the anodal electrode on the primary motor cortex and catodal electrode on the contralateral supraorbital region, using 2mA for 20 minutes. AE used an intensity of 60 to 70% of maximum heart rate. The visual numeric pain scale was used as the primary outcome, and as secondary outcome: VNS anxiety ratings, pressure pain threshold, conditioned pain modulation (DNIC), SF-36 questionnaire, beck depression inventory, an emotional go-no-go task, six-minute walk test, timed up-and-go test, and evaluation of cortical excitability using TMS. There was a significant effect for the interaction time X group to the intensity of pain, demonstrating that tDCS / AE was higher than the AE only (F (13.364) = 2.25, p = 0.007) and tDCS (F (13.364) = 2.33, p = 0, 0056). Adjusted post hoc analysis demonstrated a difference between tDCS / AE and tDCS group after first week of stimulation, and after one month\'s intervention (p = 0.02 and p = 0.03, respectively). In addition, after treatment there was a significant difference between the groups in the level of anxiety and mood. The combined treatment showed the greatest response. Neither group showed significant differences from the motor cortex plasticity responses, as assessed by EMT. The combination of tDCS with aerobic exercise is higher compared to each individual intervention (effect size for the test Cohen d> 0.55). This study demonstrated that neuromodulation with tDCS associated with AE training led to an improvement in the intensity of pain greater than when compared to each intervention modality alone. Anxiety levels also showed improvement in the combination group. Notably, the initial level of pain and mood seems to be a predictor of the outcome. It was observed that individuals with higher levels of pain and higher levels of depression responded better to the treatment. Finally, the combined intervention had a significant effect on pain, anxiety and mood. It is likely that the combined intervention may have affected other neural circuits, such as those that control the affective and emotional aspects of pain

Prostate cancer is one of the most common cancer-related causes of death among men. Chemotherapy is mainly used for treatment of its later stages, accompanied by unpleasant side effects. So far, the treatment of advanced stages of prostate cancer has not been sufficient, and new more effective alternatives are needed. The application of the TRAIL cytokine, which induces apoptosis in tumor cell, but is not toxic to nonmalignant cells, seems to be a promissing approach. However, TRAIL-based therapy is often limited by the emerging cancer cell resistance. Overcoming the resistance can be achieved by combination therapy of TRAIL with effective sensitizers. Within this work, a combination of TRAIL with platinum-based chemotherapeutic drugs such as cisplatin or its novel derivative LA-12 was applied in order to facilitate the elimination of prostate cancer cells. In the experimental part of this work, using Western blot and flow cytometry analysis it was shown that TRAIL in combination with CDDP or LA-12 effectively enhanced apoptosis in three human prostate cancer cell lines. This effect was accompanied with increased activation/amount of several proapoptotic Bcl-2 family proteins, while no changes in the level of the receptors for TRAIL were observed. These results demonstrated that especially the combination...

The presented doctoral thesis is focused on the role of the Hedgehog (HH) signaling pathway in cancer pathogenesis. HH signaling pathway is an evolutionarily conserved signaling pathway that plays an essential role in embryonic development. Its activity is strictly limited to stem and progenitor cells for example in brain, lung, skin or prostate. HH pathway also plays a key role in tissue homeostasis and regeneration. Aberrantly activated HH pathway is essential in cancer progression. The aim of the presented thesis was to elucidate new details about the HH signaling pathway. We identified a new target gene of the HH pathway - the anti-apoptotic protein survivin. Survivin is considered to be an important tumor marker associated with a poor prognosis of patients. We showed that the inhibitor of HH pathway effectors GLI1 and GLI2 GANT61 reduced the survivin level in cancer cells. Subsequently, we used GANT61 and the inhibitor of the anti-apoptotic BCL2 protein family obatoclax to inhibit melanoma cells growth. We showed that the combination of these inhibitors was very effective in the eradication of melanoma cells in vitro. We also proved that GANT61 triggers the process of apoptosis in melanoma cells. We found out that the HH signaling pathway is canonically activated in many cell lines of various...

Purpose. The use of antiplatelet agents in patients hospitalized with ischemic stroke was studied. Methods. Patients with a primary or secondary diagnosis of noncardiogenic, thrombotic ischemic stroke from January 2002 through December 2004 were included in the analysis. Patients were then subdivided into four treatment groups and one no-treatment group based on whether they were charged for any of four antiplatelet regimens (low-dose aspirin [≤325 mg daily], extended-release dipyridamole 200 mg with aspirin 25 mg, clopidogrel 75 mg, and clopidogrel 75 mg [as the bisulfate] plus low-dose aspirin) at any time during hospitalization. Patients who did not receive any of these medications during hospitalization were defined as the no-treatment group. A patient's illness severity was measured and compared with other patients in the data set. Results. A total of 44,108 patients were assigned to the treatment group, and 14,255 patients were assigned to the no-treatment group. In general, longer lengths of stay and higher institutional costs were associated with the no-treatment group. Patients in the no-treatment group consistently displayed more comorbid conditions than did patients in the treatment group. The no-treatment group exhibited higher usage rates of both fibrinolytic agents and vitamin K. More patients in the treatment group were discharged to home or rehabilitation, while more patients in the no-treatment group were either discharged to another nursing facility or died before discharge. Conclusion. A retrospective analysis of a large national hospital database revealed that one quarter of patients who suffered an acute stroke did not receive antiplatelet drugs during their patient stay. Outcomes for such patients were poorer than for patients who had received antiplatelet therapy.