Intracellular delivery of doxorubicin encapsulated in novel pH-responsive chitosan/heparin nanocapsules

A novel polyelectrolyte nanocapsule system composed of biopolymers, chitosan and heparin has been fabricated by the layer-by-layer technique on silica nanoparticles followed by dissolution of the silica core. The nanocapsules were of the size range 200 +/- 20 nm and loaded with the positively charged anticancer drug doxorubicin with an efficiency of 89%. The loading of the drug into the capsule happens by virtue of the pH-responsive property of the capsule wall, which is determined by the pKa of the polyelectrolytes. As the pH is varied, about 64% of the drug is released in acidic pH while 77% is released in neutral pH. The biocompatibility, efficiency of drug loading, and enhanced bioavailability of the capsule system was confirmed by MTT assay and in vivo biodistribution studies.

Nanolipodendrosome-loaded glatiramer acetate and myogenic differentiation I as augmentation therapeutic strategy approaches in muscular dystrophy

Backgrond: Muscular dystrophies consist of a number of juvenile and adult forms of complex disorders which generally cause weakness or efficiency defects affecting skeletal muscles or, in some kinds, other types of tissues in all parts of the body are vastly affected. In previous studies, it was observed that along with muscular dystrophy, immune inflammation was caused by inflammatory cells invasion - like T lymphocyte markers (CD8+/CD4+). Inflammatory processes play a major part in muscular fibrosis in muscular dystrophy patients. Additionally, a significant decrease in amounts of two myogenic recovery factors (myogenic differentation 1 MyoD] and myogenin) in animal models was observed. The drug glatiramer acetate causes anti-inflammatory cytokines to increase and T helper (Th) cells to induce, in an as yet unknown mechanism. MyoD recovery activity in muscular cells justifies using it alongside this drug. Methods: In this study, a nanolipodendrosome carrier as a drug delivery system was designed. The purpose of the system was to maximize the delivery and efficiency of the two drug factors, MyoD and myogenin, and introduce them as novel therapeutic agents in muscular dystrophy phenotypic mice. The generation of new muscular cells was analyzed in SW1 mice. Then, immune system changes and probable side effects after injecting the nanodrug formulations were investigated. Results: The loaded lipodendrimer nanocarrier with the candidate drug, in comparison with the nandrolone control drug, caused a significant increase in muscular mass, a reduction in CD4+/CD8+ inflammation markers, and no significant toxicity was observed. The results support the hypothesis that the nanolipodendrimer containing the two candidate drugs will probably be an efficient means to ameliorate muscular degeneration, and warrants further investigation.

Formulation of nanotized curcumin and demonstration of its antimalarial efficacy

Aim: The present study was conducted to overcome the disadvantages associated with the poor water solubility and low bioavailability of curcumin by synthesizing nanotized curcumin and demonstrating its efficacy in treating malaria. Materials and methods: Nanotized curcumin was prepared by a modified emulsion-diffusion-evaporation method and was characterized by means of transmission electron microscopy, atomic force microscopy, dynamic light scattering, Zetasizer, Fourier transform infrared spectroscopy, and differential thermal analysis. The novelty of the prepared nanoformulation lies in the fact that it was devoid of any polymeric matrices used in conventional carriers. The antimalarial efficacy of the prepared nanotized curcumin was then checked both in vitro and in vivo. Results: The nanopreparation was found to be non-toxic and had a particle size distribution of 20-50 nm along with improved aqueous dispersibility and an entrapment efficiency of 45%. Nanotized curcumin (half maximal inhibitory concentration IC50]: 0.5 mu M) was also found to be ten-fold more effective for growth inhibition of Plasmodium falciparum in vitro as compared to its native counterpart (IC50: 5 mu M). Oral bioavailability of nanotized curcumin was found to be superior to that of its native counterpart. Moreover, when Plasmodium berghei-infected mice were orally treated with nanotized curcumin, it prolonged their survival by more than 2 months with complete clearance of parasites in comparison to the untreated animals, which survived for 8 days only. Conclusion: Nanotized curcumin holds a considerable promise in therapeutics as demonstrated here for treating malaria as a test system.

Impact of depressive symptoms on subjective well-being: the importance of patient-reported outcomes in schizophrenia

Objective: The subjective experience of psychotic patients toward treatment is a key factor in medication adherence, quality of life, and clinical outcome. The aim of this study was to assess the subjective well-being in patients with schizophrenia and to examine its relationship with the presence and severity of depressive symptoms. Methods: A multicenter, cross-sectional study was conducted with clinically stable outpatients diagnosed with schizophrenia. The Subjective Well-Being under Neuroleptic Scale - short version (SWN-K) and the Calgary Depression Scale for Schizophrenia (CDSS) were used to gather information on well-being and the presence and severity of depressive symptoms, respectively. Spearman's rank correlation was used to assess the associations between the SWN-K total score, its five subscales, and the CDSS total score. Discriminative validity was evaluated against that criterion by analysing the area under the curve (AUC). Results: Ninety-seven patients were included in the study. Mean age was 35 years (standard deviation = 10) and 72% were male. Both the total SWN-K scale and its five subscales correlated inversely and significantly with the CDSS total score (P < 0.0001). The highest correlation was observed for the total SWN-K (Spearman's rank order correlation [ rho] = -0.59), being the other correlations: mental functioning (-0.47), social integration (-0.46), emotional regulation (-0.51), physical functioning (-0.48), and self-control (-0.41). A total of 33 patients (34%) were classified as depressed. Total SWN-K showed the highest AUC when discriminating between depressive severity levels (0.84), followed by emotional regulation (0.80), social integration (0.78), physical functioning and self-control (0.77), and mental functioning (0.73). Total SWN-K and its five subscales showed a significant linear trend against CDSS severity levels (P < 0.001). Conclusion: The presence of moderate to severe depressive symptoms was relatively high, and correlated inversely with patients' subjective well-being. Routine assessment of patient-reported measures in patients with schizophrenia might reduce potential discrepancy between patient and physician assessment, increase therapeutic alliance, and improve outcome.

Hacia el encuentro de mi anthropos: la muerte, dinamo estructural de la vida

559 p. - Sobresaliente cum laudem por unanimidad. La presidenta del tribunal hace la petición al departamento, en el acto de calificación de la defensa, de publicación de esta tesis por considerarla de interés científico.

A autotutela pelo inadimplemento nas relações contratuais

A presente tese tem por objetivo revisitar os instrumentos de autotutela e repensar os seus pressupostos de admissibilidade, limites e mecanismos de controle no ordenamento brasileiro, em particular nas situações de inadimplemento contratual. A necessidade de tal abordagem advém essencialmente de duas demandas aparentemente inconciliáveis da pós-modernidade: reforçar a autonomia privada, reduzindo a ingerência estatal, e, ao mesmo tempo, controlá-la, coibindo abusos. Para tanto, busca-se desatrelar a autotutela da noção primitiva de vingança privada, concebendo-se uma renovada perspectiva, constitucionalizada e controlada, inconfundível com a conduta criminalmente tipificada do exercício arbitrário das próprias razões. O reconhecimento de um fundamento constitucional para a autonomia negocial é determinante para conferir legitimidade também constitucional - à autotutela contratual, que é expressão daquela autonomia. Por conseguinte, rompe-se com o dogma da excepcionalidade dos instrumentos de autotutela, que passa a ser entendida como um poder merecedor de respaldo pelo ordenamento. A solução proposta preconiza a abertura aos contratantes de mais espaço para reger e defender os seus próprios interesses independentemente da chancela estatal, mas sem prejuízo de um posterior controle judicial para corrigir eventuais inadequações de conduta (na hipótese de contrariedade à boa-fé) ou abusos (no caso de desvio da função do remédio adotado). Uma vez assentadas tais premissas, empreende-se a análise da estrutura e função, bem como, e sobretudo, das potencialidades expansivas dos principais remédios de autotutela pelo inadimplemento, classificados segundo um critério funcional, a saber: (i) remédios com função conservativo-cautelar, que abrangem as exceções de contrato não cumprido e a retenção preventiva; (ii) remédios com função resolutiva, abrangendo a cláusula resolutiva expressa e outros possíveis instrumentos de resolução extrajudicial; e (iii) remédios com função satisfativa, compreendendo a retenção definitiva, o pacto marciano e algumas medidas de mitigação de perdas e danos pelo próprio credor, a exemplo das contratações substitutivas. O resultado alcançado demonstra a relevância da metodologia civil-constitucional tanto para justificar restrições à autonomia privada quanto, e em igual medida, para reforçá-la.

Ritualizando o enterro e o luto evangélico: compartilhamento e incomunicabilidade na experiência da finitude humana

Esta tese tem como objetivo analisar as formas a partir das quais os evangélicos vivenciam a morte. Tendo em vista uma revisão da bibliografia, a autora aponta para o fato de que a ortodoxia pentecostal apresenta a morte como um evento irreversível diante do qual não existem possibilidades de negociação com o sagrado em favor dos que partiram nem mecanismos de interação entre vivos e mortos. Esse modelo contrasta com o que foi convencionalizado pela tradição católica e que é reconhecido como sendo indicativo da riqueza dos ritos de morte no Brasil. Nesta tese, a autora desenvolve um trabalho etnográfico no distrito da Praia de Mauá, em Magé, no Rio de Janeiro, procurando compreender como os evangélicos experimentam o enlutamento e o ritualizam para além do que rege a sua ortodoxia. Ao observar os contextos da cidade, do cemitério, das igrejas e das casas dos evangélicos durante processos de enterro e luto, a autora argumenta que o enfrentamento da morte e a avaliação do destino dos mortos levam em consideração negociações que têm como referência a cosmologia do catolicismo, que é re-interpretada a partir de diversos termos, tais como os modelos de pessoa socialmente aceitos e a possibilidade de conforto emocional dos enlutados. Neste sentido, na relação entre as religiões, a tese coloca em destaque antes dinâmicas de encapsulamento e compartilhamento do que de colapso e contraste.

Undertreatment of human immunodeficiency virus in psychiatric inpatients: a cross-sectional study of seroprevalence and associated factors

Background: The aims of this study were to evaluate the prevalence of HIV and its associated demographic and clinical factors among psychiatric inpatients of a general hospital. Methods: This was a single-center, observational, cross-sectional study that included patients consecutively admitted to our unit aged 16 years or older and with no relevant cognitive problems. The patients were evaluated using a semistructured interview and an appropriate test for HIV infection. Results: Of the 637 patients who were screened, 546 (86%) who consented to participate were included in the analyses. Twenty-five (4.6%, 95% confidence interval [CI] 3.0-6.8) patients were HIV-positive. The prevalence was higher among patients with substance misuse (17.4%, 95% CI 9.7-28.8). All except one of the 25 patients knew of their seropositive condition prior to participation in the study. Only 14 (56%) of the 25 seropositive patients had previously received pharmacological treatment for their infection. According to the multiple logistic regression analysis, the likelihood of HIV infection was lower in patients with higher levels of education and higher among patients who were single, had history of intravenous drug use, and had an HIV-positive partner, particularly if they did not use condoms. Among the patients with HIV infection, 18 (72%) had a history of suicide attempts compared with 181 (34.7%) of the patients without HIV infection (relative risk 2.1, 95% CI 1.6-2.7; P<0.001). Conclusion: HIV infection is highly prevalent in patients admitted to a psychiatric unit, especially those with a diagnosis of substance misuse. Seropositive patients show very poor treatment adherence. The risk of suicide seems to be very high in this population. Implementing interventions to reduce the suicide risk and improve adherence to antiretroviral therapy and psychotropic medications seems crucial.

El proceso de deshumanización del morir en la literatura hispánica medieval

354 p.

Morte e subjetividade na hipermodernidade: a perspectiva do Budismo da Nova Tradição Kadampa

A proposta do trabalho é analisar como a morte é entendida pela visão da hipermodernidade e pela visão do Budismo. Na contemporaneidade cuja lógica capitalista é embasada na lógica do mercado onde o consumo assume o papel principal, a morte se tornou um tabu, onde ela é evitada, esvaziada de sentido e descaracterizada. A dor e o sofrimento são depreciados e é exigido do homem uma inabalável postura performática e um desempenho cada vez melhor. Há ainda a crença de que o discurso tecnocientífico trará todas as soluções para as mazelas humanas. A felicidade é, portanto, um imperativo da sociedade hipermoderna e sua busca é exteriorizada isentando os indivíduos de um olhar crítico. Assim, a morte e o luto perdem seu lugar para a busca incessante de satisfação e bem-estar. O Budismo tem uma lógica que segue na contramão. Ensina que a existência humana no Samsara é constituída por principalmente quatro sofrimentos básicos: nascimento, envelhecimento, doença e morte. O Budismo ensina que a morte, assim como a vida, é um fenômeno comum a todos os seres vivos e que o exercício budista possibilita compreender o real significado da vida e da morte. A meditação sobre a impermanência, uma das práticas budistas, visa familiarizar o adepto budista a três pensamentos: certamente vou morrer; a hora da minha morte é totalmente incerta e na hora da minha morte e, depois dela, só a prática do Dharma vai me ajudar. Postula que para alcançar a verdadeira felicidade o homem deve provocar uma mudança interior, exercitar a compaixão e se desapegar da crença de que os fenômenos são permanentes e imutáveis. Tais considerações foram possíveis a partir da pesquisa sobre o Budismo da Nova Tradição Kadampa a partir de uma metodologia etnográfica que incluíram visitas ao campo de estudo, a confecção de um diário de campo e a realização de entrevistas com os praticantes budistas da Nova Tradição Kadampa.

Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson's disease

Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson's disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson's disease.

Development of nucleic acid vaccines: use of self-amplifying RNA in lipid nanoparticles

Self-amplifying RNA or RNA replicon is a form of nucleic acid-based vaccine derived from either positive-strand or negative-strand RNA viruses. The gene sequences encoding structural proteins in these RNA viruses are replaced by mRNA encoding antigens of interest as well as by RNA polymerase for replication and transcription. This kind of vaccine has been successfully assayed with many different antigens as vaccines candidates, and has been shown to be potent in several animal species, including mice, nonhuman primates, and humans. A key challenge to realizing the broad potential of self-amplifying vaccines is the need for safe and effective delivery methods. Ideally, an RNA nanocarrier should provide protection from blood nucleases and extended blood circulation, which ultimately would increase the possibility of reaching the target tissue. The delivery system must then be internalized by the target cell and, upon receptor-mediated endocytosis, must be able to escape from the endosomal compartment into the cell cytoplasm, where the RNA machinery is located, while avoiding degradation by lysosomal enzymes. Further, delivery systems for systemic administration ought to be well tolerated upon administration. They should be safe, enabling the multiadministration treatment modalities required for improved clinical outcomes and, from a developmental point of view, production of large batches with reproducible specifications is also desirable. In this review, the concept of self-amplifying RNA vaccines and the most promising lipid-based delivery systems are discussed.

Combining rimonabant and fentanyl in a single entity: preparation and pharmacological results

Based on numerous pharmacological studies that have revealed an interaction between cannabinoid and opioid systems at the molecular, neurochemical, and behavioral levels, a new series of hybrid molecules has been prepared by coupling the molecular features of two well-known drugs, ie, rimonabant and fentanyl. The new compounds have been tested for their affinity and functionality regarding CB1 and CB2 cannabinoid and mu opioid receptors. In [S-35]-GTP.S (guanosine 5'-O-[gamma-thio] triphosphate) binding assays from the post-mortem human frontal cortex, they proved to be CB1 cannabinoid antagonists and mu opioid antagonists. Interestingly, in vivo, the new compounds exhibited a significant dual antagonist action on the endocannabinoid and opioid systems.

Prevalence, intensity, and effect of a nematode (Philometra saltatrix) in the ovaries of bluefish (Pomatomus saltatrix)

Examination of 203 adult bluefish (Pomatomus saltatrix) from Long Island, New York, in 2002 and 2003 and 66 from the Outer Banks, North Carolina, in 2003 revealed the presence of dracunculoid nematodes (Philometra saltatrix) in the ovaries of female fish. Percent prevalence reached 88% in July and then decreased after the peak of the spawning season. Bluefish contained up to 100 parasites per fish. Infection was associated with a range of disorders, including hemorrhage, inf lammation, edema, prenecrotic and necrotic changes, and follicular atresia, that may prevent proper development of oocytes and probably affect bluefish fecundity. Historical occurrences, life cycle, and geographical distribution of this nematode remain largely unknown, but may play important roles in recruitment processes of bluefish.

Aqui se jaz, aqui se paga : o mercado da morte e do morrer em tempos de imortalidade

Esta tese busca compreender o que os rituais funerários contemporâneos revelam sobre as maneiras com as quais as pessoas têm lidado com a morte e o morrer na atualidade. Desse eixo central se ramificam reflexões sobre a relação dos homens com o tempo, com o envelhecimento e com a finitude. Evidenciando que os modos atuais de lidar com a morte e o morrer envolvem flagrantes processos de mercantilização, patologização, medicalização e espetacularização. O crescente uso de serviços funerários de tanatoestética apontam não somente técnicas de maquiagem dos mortos, mas também estratégias de maquiagem da morte. O investimento financeiro, antes direcionado às preocupações transcendentes com o futuro da alma do morto, se reverte em intervenções físicas no corpo morto, de maneira que ele não emita sinal algum da morte que o tomou e proteja os sobreviventes do contato com a finitude. Essa dissimulação é sinalizada pela redução progressiva do espaço que a sociedade contemporânea tem destinado ao luto e ao sofrimento, categorias com cada vez mais frequência equiparadas a condições patológicas. Utilizando metodologia qualitativa, com pesquisa de campo realizada tanto no Brasil como em Portugal, durante período de doutorado sanduíche no exterior, observou-se um acentuado estreitamento entre as realidades morte e consumo. Indicando uma transposição da lógica comercial de mercado às práticas funerárias tradicionais. Assim, funções simbólicas dos rituais fúnebres vem sendo modificadas e regidas pela lógica do consumo, apresentado na atualidade como alternativa unidimensional para a imperativa vivência initerrupta do prazer e da felicidade. Constatou-se que - apesar da crescente popularização de discussões sobre o tema morte no meio acadêmico, na área da saúde e na mídia - não há aceno de ruptura no seu enquadramento como tabu. Apenas é permitido socialmente que ela ocupe locais determinados: o lugar de espetáculo, de produto, da técnica, da banalização ou mesmo do humor publicitário. As observações e as reflexões realizadas em todo o processo de construção desta tese nos inclinam a considerar que continua vedado o aprofundamento de questões ligadas à expressão de sentimentos de dor e de pesar diante das perdas. Assim como se acentuam os processos de patologização do luto e de distanciamento das demandas existênciais promovidas pela consciência da própria finitude e da passagem do tempo; do tempo de vida de cada um