899 resultados para subcellular targeting
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Background 29 autoimmune diseases, including Rheumatoid Arthritis, gout, Crohn’s Disease, and Systematic Lupus Erythematosus affect 7.6-9.4% of the population. While effective therapy is available, many patients do not follow treatment or use medications as directed. Digital health and Web 2.0 interventions have demonstrated much promise in increasing medication and treatment adherence, but to date many Internet tools have proven disappointing. In fact, most digital interventions continue to suffer from high attrition in patient populations, are burdensome for healthcare professionals, and have relatively short life spans. Objective Digital health tools have traditionally centered on the transformation of existing interventions (such as diaries, trackers, stage-based or cognitive behavioral therapy programs, coupons, or symptom checklists) to electronic format. Advanced digital interventions have also incorporated attributes of Web 2.0 such as social networking, text messaging, and the use of video. Despite these efforts, there has not been little measurable impact in non-adherence for illnesses that require medical interventions, and research must look to other strategies or development methodologies. As a first step in investigating the feasibility of developing such a tool, the objective of the current study is to systematically rate factors of non-adherence that have been reported in past research studies. Methods Grounded Theory, recognized as a rigorous method that facilitates the emergence of new themes through systematic analysis, data collection and coding, was used to analyze quantitative, qualitative and mixed method studies addressing the following autoimmune diseases: Rheumatoid Arthritis, gout, Crohn’s Disease, Systematic Lupus Erythematosus, and inflammatory bowel disease. Studies were only included if they contained primary data addressing the relationship with non-adherence. Results Out of the 27 studies, four non-modifiable and 11 modifiable risk factors were discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting): patients not understanding treatment (44%), side effects (41%), age (37%), dose regimen (33%), and perceived medication ineffectiveness (33%). An unanticipated finding that emerged was the need for risk stratification tools (81%) with patient-centric approaches (67%). Conclusions This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns.
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The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/endoplasmic Ca(2 +) ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications.
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Following cognitive behavioural therapy for child anxiety a significant minority of children fail to lose their diagnosis status. One potential barrier is high parental anxiety. We designed a pilot RCT to test claims that parental intolerance of the child’s negative emotions may impact treatment outcomes. Parents of 60 children with an anxiety disorder, who were themselves highly anxious, received either brief parent-delivered treatment for child anxiety or the same treatment with strategies specifically targeting parental tolerance of their child’s negative emotions. Consistent with predictions, parental tolerance of the child’s negative emotions significantly improved from pre- to post-treatment. However, there was no evidence to inform the direction of this association as improvements were substantial in both groups. Moreover, while there were significant improvements in child anxiety in both conditions, there was little evidence that this was associated with the improvement in parental tolerance. Nevertheless, findings provide important clinical insight, including that parent-led treatments are appropriate even when the parent is highly anxious and that it may not be necessary to adjust interventions for many families.
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Arginase (L-arginine amidinohydrolase, E.C. 3.5.3.1) is a metalloenzyme that catalyses the hydrolysis Of L-arginine to L-ornithine and urea. In Leishmania spp., the biological role of the enzyme may be involved in modulating NO production upon macrophage infection. Previously, we cloned and characterized the arginase gene from Leishmania (Leishmania) amazonensis. In the present work, we successfully expressed the recombinant enzyme in E. coli and performed biochemical and biophysical characterization of both the native and recombinant enzymes. We obtained K-M and V-max. values of 23.9(+/- 0.96) mM and 192.3 mu mol/min mg protein (+/- 14.3), respectively, for the native enzyme. For the recombinant counterpart, K-M was 21.5(+/- 0.90) mM and V-max was 144.9(+/- 8.9) mu mol/min mg. Antibody against the recombinant protein confirmed a glycosomal cellular localization of the enzyme in promastigotes. Data from light scattering and small angle X-ray scattering showed that a trimeric state is the active form of the protein. We determined empirically that a manganese wash at room temperature is the best condition to purify active enzyme. The interaction of the recombinant protein with the immobilized nickel also allowed us to confirm the structural disposition of histidine at positions 3 and 324. The determined structural parameters provide substantial data to facilitate the search for selective inhibitors of parasitic sources of arginase, which could subsequently point to a candidate for leishmaniasis therapy. (c) 2008 Elsevier B.V. All rights reserved.
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The aim of this study was to evaluate the anti-tumor activity of Amblyomin-X, a serine protease Kunitz-type inhibitor. Amblyomin-X induced tumor mass regression and decreased number of metastatic events in a B16F10 murine melanoma model. Alterations on expression of several genes related to cell cycle were observed when two tumor cell lines were treated with Amblyomin-X. PSMB2, which encodes a proteasome subunit, was differentially expressed, in agreement to inhibition of proteasomal activity in both cell lines. In conclusion, our results indicate that Amblyomin-X selectively acts on tumor cells by inducing apoptotic cell death, possibly by targeting the ubiquitin-proteasome system. (C) 2010 Elsevier Ltd. All rights reserved.
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We present a study on whether and to what extent subcellular localization may compete favorably with photosensitization efficiency with respect to the overall efficiency of photoinduced cell death. We have compared the efficiency with which two cationic photosensitizers, namely methylene blue (MB) and crystal violet (CV), induce the photoinduced death of human cervical adenocarcinoma (HeLa) cells. Whereas MB is well known to generate singlet oxygen and related triplet excited species with high quantum yields in a variety of biological and chemical environments (i.e., acting as a typical type II photosensitizer), the highly mitochondria-specific CV produces triplet species and singlet oxygen with low yields, acting mostly via the classical type I mechanism (e.g., via free radicals). The findings described here indicate that the presumably more phototoxic type II photosensitizer (MB) does not lead to higher degrees of cell death compared to the type I (CV) photosensitizer. In fact, CV kills cells with the same efficiency as MB, generating at least 10 times fewer photoinduced reactive species. Therefore, subcellular localization is indeed more important than photochemical reactivity in terms of overall cell killing, with mitochondrial localization representing a highly desirable property for the development of more specific/efficient photosensitizers for photodynamic therapy applications. (C) 2011 Elsevier Inc. All rights reserved.
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BACKGROUND: In northern Vietnam the Neonatal health - Knowledge Into Practice (NeoKIP, Current Controlled Trials ISRCTN44599712) trial has evaluated facilitation as a knowledge translation intervention to improve neonatal survival. The results demonstrated that intervention sites, each having an assigned group including local stakeholders supported by a facilitator, lowered the neonatal mortality rate by 50% during the last intervention year compared with control sites. This process evaluation was conducted to identify and describe mechanisms of the NeoKIP intervention based on experiences of facilitators and intervention group members. METHODS: Four focus group discussions (FGDs) were conducted with all facilitators at different occasions and 12 FGDs with 6 intervention groups at 2 occasions. Fifteen FGDs were audio recorded, transcribed verbatim, translated into English, and analysed using thematic analysis. RESULTS: Four themes and 17 sub-themes emerged from the 3 FGDs with facilitators, and 5 themes and 18 sub-themes were identified from the 12 FGDs with the intervention groups mirroring the process of, and the barriers to, the intervention. Facilitators and intervention group members concurred that having groups representing various organisations was beneficial. Facilitators were considered important in assembling the groups. The facilitators functioned best if coming from the same geographical area as the groups and if they were able to come to terms with the chair of the groups. However, the facilitators' lack of health knowledge was regarded as a deficit for assisting the groups' assignments. FGD participants experienced the NeoKIP intervention to have impact on the knowledge and behaviour of both intervention group members and the general public, however, they found that the intervention was a slow and time-consuming process. Perceived facilitation barriers were lack of money, inadequate support, and the function of the intervention groups. CONCLUSIONS: This qualitative process evaluation contributes to explain the improved neonatal survival and why this occurred after a latent period in the NeoKIP project. The used knowledge translation intervention, where facilitators supported multi-stakeholder coalitions with the mandate to impact upon attitudes and behaviour in the communes, has low costs and potential for being scaled-up within existing healthcare systems.
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We study the interplay between the central bank transparency, its credibility, and the ination target level. Based on a model developed in the spirit of the global games literature, we argue that whenever a weak central bank adopts a high degree of transparency and a low target level, a bad and self conrmed type of equilibrium may arise. In this case, an over-the-target ination becomes more likely. The central bank is considered weak when favorable state of nature is required for the target to be achieved. On the other hand, if a weak central bank opts for less ambitious goals, namely lower degree of transparency and higher target level, it may avoid condence crises and ensure a unique equilibrium for the expected ination. Moreover, even after ruling out the possibility of condence crises, less ambitious goals may be desirable in order to attain higher credibility and hence a better coordination of expectations. Conversely, a low target level and a high central bank transparency are desirable whenever the economy has strong fundamentals and the target can be fullled in many states of nature.
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O Regime de Meta de Inflação se Tornou Dominante na Formulação de Políticas dos Bancos Centrais nos Últimos 15 Anos. a Teoria Subjacente, Particularmente a Regra de Taylor, Pode ser Vista como uma Competente Generalização Desse Comportamento. de um Ponto de Vista Keynesiano, Ele Será Aceitável se Encararmos a Taxa de Juros de Equilíbrio como Apenas uma Convenção Variável e se a Combinarmos ou com uma Taxa de Câmbio ou com uma Meta de Emprego. no Caso do Brasil, Porém, Além Dessa Ressalva Teórica e da Condição do Duplo Mandato, o Regime de Metas de Inflação Enfrenta um Problema de Incoerência. esta é uma Política que se Destinava a ser Utilizada na Administração da Política Monetária, não na Mudança do Regime de Política Monetária . a Política de Metas de Inflação foi Introduzida no Brasil em 1999 como um Substituto para a Âncora Cambial, que Havia Sido Usada Desastrosamente entre 1995 e 1998. Durante Muitos Anos, o País Havia Enfrentado uma Armadilha de Alta Taxa de Juros / Taxa de Câmbio Valorizada E, Portanto, Precisava Mudar seu Regime de Política Monetária Antes de Eventualmente Adotar o Regime de Meta de Inflação. Essa Mudança, que Começou com a Flutuação de Janeiro de 1999, Deveria ter Sido Completada com Reformas Específicas (Fim da Indexação dos Serviços Públicos e dos Próprios Juros Básicos). no Entanto, em Lugar de Desenvolver uma Estratégia para Reduzir a Taxa de Juros, o Governo Continuou a Definir a Inflação como o Principal Problema a ser Enfrentado e Adotou uma Política Formal de Metas de Inflação. a Conseqüência é que Desde 1999 Essa Política se Tornou o Obstáculo que a Economia Brasileira Enfrenta para Escapar da Armadilha da Taxa de Juros
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The evolution of integrated circuits technologies demands the development of new CAD tools. The traditional development of digital circuits at physical level is based in library of cells. These libraries of cells offer certain predictability of the electrical behavior of the design due to the previous characterization of the cells. Besides, different versions of each cell are required in such a way that delay and power consumption characteristics are taken into account, increasing the number of cells in a library. The automatic full custom layout generation is an alternative each time more important to cell based generation approaches. This strategy implements transistors and connections according patterns defined by algorithms. So, it is possible to implement any logic function avoiding the limitations of the library of cells. Tools of analysis and estimate must offer the predictability in automatic full custom layouts. These tools must be able to work with layout estimates and to generate information related to delay, power consumption and area occupation. This work includes the research of new methods of physical synthesis and the implementation of an automatic layout generation in which the cells are generated at the moment of the layout synthesis. The research investigates different strategies of elements disposition (transistors, contacts and connections) in a layout and their effects in the area occupation and circuit delay. The presented layout strategy applies delay optimization by the integration with a gate sizing technique. This is performed in such a way the folding method allows individual discrete sizing to transistors. The main characteristics of the proposed strategy are: power supply lines between rows, over the layout routing (channel routing is not used), circuit routing performed before layout generation and layout generation targeting delay reduction by the application of the sizing technique. The possibility to implement any logic function, without restrictions imposed by a library of cells, allows the circuit synthesis with optimization in the number of the transistors. This reduction in the number of transistors decreases the delay and power consumption, mainly the static power consumption in submicrometer circuits. Comparisons between the proposed strategy and other well-known methods are presented in such a way the proposed method is validated.