779 resultados para Prospect


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Bovine tuberculosis (bTB) caused by infection with Mycobacterium bovis is causing considerable economic loss to farmers and Government in the United Kingdom as its incidence is increasing. Efforts to control bTB in the UK are hampered by the infection in Eurasian badgers (Metes metes) that represent a wildlife reservoir and source of recurrent M. bovis exposure to cattle. Vaccination of badgers with the human TB vaccine, M. bovis Bacille Calmette-Guerin (BCG), in oral bait represents a possible disease control tool and holds the best prospect for reaching badger populations over a wide geographical area. Using mouse and guinea pig models, we evaluated the immunogenicity and protective efficacy, respectively, of candidate badger oral vaccines based on formulation of BCG in lipid matrix, alginate beads, or a novel microcapsular hybrid of both lipid and alginate. Two different oral doses of BCG were evaluated in each formulation for their protective efficacy in guinea pigs, while a single dose was evaluated in mice. In mice, significant immune responses (based on lymphocyte proliferation and expression of IFN-gamma) were only seen with the lipid matrix and the lipid in alginate microcapsular formulation, corresponding to the isolation of viable BCG from alimentary tract lymph nodes. In guinea pigs, only BCG formulated in lipid matrix conferred protection to the spleen and lungs following aerosol route challenge with M. bovis. Protection was seen with delivery doses in the range 10(6)-10(7) CFU, although this was more consistent in the spleen at the higher dose. No protection in terms of organ CFU was seen with BCG administered in alginate beads or in lipid in alginate microcapsules, although 10(7) in the latter formulation conferred protection in terms of increasing body weight after challenge and a smaller lung to body weight ratio at necropsy. These results highlight the potential for lipid, rather than alginate, -based vaccine formulations as suitable delivery vehicles for an oral BCG vaccine in badgers.

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OBJECTIVE: To determine the accuracy, acceptability and cost-effectiveness of polymerase chain reaction (PCR) and optical immunoassay (OIA) rapid tests for maternal group B streptococcal (GBS) colonisation at labour. DESIGN: A test accuracy study was used to determine the accuracy of rapid tests for GBS colonisation of women in labour. Acceptability of testing to participants was evaluated through a questionnaire administered after delivery, and acceptability to staff through focus groups. A decision-analytic model was constructed to assess the cost-effectiveness of various screening strategies. SETTING: Two large obstetric units in the UK. PARTICIPANTS: Women booked for delivery at the participating units other than those electing for a Caesarean delivery. INTERVENTIONS: Vaginal and rectal swabs were obtained at the onset of labour and the results of vaginal and rectal PCR and OIA (index) tests were compared with the reference standard of enriched culture of combined vaginal and rectal swabs. MAIN OUTCOME MEASURES: The accuracy of the index tests, the relative accuracies of tests on vaginal and rectal swabs and whether test accuracy varied according to the presence or absence of maternal risk factors. RESULTS: PCR was significantly more accurate than OIA for the detection of maternal GBS colonisation. Combined vaginal or rectal swab index tests were more sensitive than either test considered individually [combined swab sensitivity for PCR 84% (95% CI 79-88%); vaginal swab 58% (52-64%); rectal swab 71% (66-76%)]. The highest sensitivity for PCR came at the cost of lower specificity [combined specificity 87% (95% CI 85-89%); vaginal swab 92% (90-94%); rectal swab 92% (90-93%)]. The sensitivity and specificity of rapid tests varied according to the presence or absence of maternal risk factors, but not consistently. PCR results were determinants of neonatal GBS colonisation, but maternal risk factors were not. Overall levels of acceptability for rapid testing amongst participants were high. Vaginal swabs were more acceptable than rectal swabs. South Asian women were least likely to have participated in the study and were less happy with the sampling procedure and with the prospect of rapid testing as part of routine care. Midwives were generally positive towards rapid testing but had concerns that it might lead to overtreatment and unnecessary interference in births. Modelling analysis revealed that the most cost-effective strategy was to provide routine intravenous antibiotic prophylaxis (IAP) to all women without screening. Removing this strategy, which is unlikely to be acceptable to most women and midwives, resulted in screening, based on a culture test at 35-37 weeks' gestation, with the provision of antibiotics to all women who screened positive being most cost-effective, assuming that all women in premature labour would receive IAP. The results were sensitive to very small increases in costs and changes in other assumptions. Screening using a rapid test was not cost-effective based on its current sensitivity, specificity and cost. CONCLUSIONS: Neither rapid test was sufficiently accurate to recommend it for routine use in clinical practice. IAP directed by screening with enriched culture at 35-37 weeks' gestation is likely to be the most acceptable cost-effective strategy, although it is premature to suggest the implementation of this strategy at present.

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The enteroinsular axis (EIA) constitutes a physiological signalling system whereby intestinal endocrine cells secrete incretin hormones following feeding that potentiate insulin secretion and contribute to the regulation of blood glucose homeostasis. The two key hormones responsible are named glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent years have witnessed sustained development of antidiabetic therapies that exploit the EIA. Current clinical compounds divide neatly into two classes. One concerns analogues or mimetics of GLP-1, such as exenatide (Byetta) or liraglutide (NN2211). The other group comprises the gliptins (e.g. sitagliptin and vildagliptin) which boost endogenous incretin activity by inhibiting the enzyme dipeptidyl peptidase 4 (DPP 4) that degrades both GLP-1 and GIP. Ongoing research indicates that further incretin and gliptin compounds will become available for clinical use in the near future, offering comparable or improved efficacy. For incretin analogues there is the prospect of prolonged duration of action and alternative routes of administration. This review focuses on recent advances in pre-clinical research and their translation into clinical studies to provide future therapies for type 2 diabetes targeting the EIA. © 2009 Bentham Science Publishers Ltd.

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Design of casting entails the knowledge of various interacting factors that are unique to casting process, and, quite often, product designers do not have the required foundry-specific knowledge. Casting designers normally have to liaise with casting experts in order to ensure the product designed is castable and the optimum casting method is selected. This two-way communication results in long design lead times, and lack of it can easily lead to incorrect casting design. A computer-based system at the discretion of a design engineer can, however, alleviate this problem and enhance the prospect of casting design for manufacture. This paper proposes a knowledge-based expert system approach to assist casting product designers in selecting the most suitable casting process for specified casting design requirements, during the design phase of product manufacture. A prototype expert system has been developed, based on production rules knowledge representation technique. The proposed system consists of a number of autonomous but interconnected levels, each dealing with a specific group of factors, namely, casting alloy, shape and complexity parameters, accuracy requirements and comparative costs, based on production quantity. The user interface has been so designed to allow the user to have a clear view of how casting design parameters affect the selection of various casting processes at each level; if necessary, the appropriate design changes can be made to facilitate the castability of the product being designed, or to suit the design to a preferred casting method.

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Existing studies on the role of switching costs (SC) as moderator of the relationship between satisfaction and repurchase behavior are inconclusive. We attempt to explain these inconclusive findings by synthesizing an amplifying and a lock-in effect, and hypothesize a nonlinear moderating effect. In Study 1 (a main study and three replications), we find strong evidence for an inverted u-shaped moderating effect of overall SC. Our results suggest that satisfaction is a particularly important predictor of repurchase behavior in situations characterized by medium-levels of SC. Based on Prospect Theory, Study 2 (a main study and one replication) reveals that this inverted u-shaped moderating effect of SC is stronger for positive (relational and financial) SC than for negative (procedural) SC. We conclude with recommendations for satisfaction management of different customer segments, and describe possibilities to influence customer switching costs in various industries. © 2014 New York University.

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Objectives Particle delivery to the airways is an attractive prospect for many potential therapeutics, including vaccines. Developing strategies for inhalation of particles provides a targeted, controlled and non-invasive delivery route but, as with all novel therapeutics, in vitro and in vivo testing are needed prior to clinical use. Whilst advanced vaccine testing demands the use of animal models to address safety issues, the production of robust in vitro cellular models would take account of the ethical framework known as the 3Rs (Replacement, Reduction and Refinement of animal use), by permitting initial screening of potential candidates prior to animal use. There is thus a need for relevant, realistic in vitro models of the human airways. Key findings Our laboratory has designed and characterised a multi-cellular model of human airways that takes account of the conditions in the airways and recapitulates many salient features, including the epithelial barrier and mucus secretion. Summary Our human pulmonary models recreate many of the obstacles to successful pulmonary delivery of particles and therefore represent a valid test platform for screening compounds and delivery systems.

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Bangladesh has recently been enjoying significant economic growth mainly arising from an export led development strategy. However, in that process its natural environment has been degraded and become more vulnerable in geophysical terms (e.g. environmental pollution). Much of the Bangladeshi population are also vulnerable in socio-economic terms due primarily to widespread poverty. In this context we ask, albeit sceptically, whether there is any chance of holding corporations to account for their environmental responsibilities. Using the notions of vulnerability and ecological rifts we answer this question by providing evidence from published sources and a series of 32 semi-structured interviews with Bangladeshi stakeholder groups. Key findings include, inter alia, corporate reluctance to take responsibility for the environmental impact of their activities. Our interviewees discuss the possibility of a role for mandatory corporate reporting in enhancing corporate accountability and we argue that this is essential if the contradictions and irrationalities of the globalized capitalist system are to be made visible. Achieving such accountability, however, will not be easy due to a lack of political will and the prohibitive costs involved. Incurring such costs could raise the dangerous prospect of Bangladesh losing business to other, less regulated, economies.

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Full text: The idea of producing proteins from recombinant DNA hatched almost half a century ago. In his PhD thesis, Peter Lobban foresaw the prospect of inserting foreign DNA (from any source, including mammalian cells) into the genome of a λ phage in order to detect and recover protein products from Escherichia coli [ 1 and 2]. Only a few years later, in 1977, Herbert Boyer and his colleagues succeeded in the first ever expression of a peptide-coding gene in E. coli — they produced recombinant somatostatin [ 3] followed shortly after by human insulin. The field has advanced enormously since those early days and today recombinant proteins have become indispensable in advancing research and development in all fields of the life sciences. Structural biology, in particular, has benefitted tremendously from recombinant protein biotechnology, and an overwhelming proportion of the entries in the Protein Data Bank (PDB) are based on heterologously expressed proteins. Nonetheless, synthesizing, purifying and stabilizing recombinant proteins can still be thoroughly challenging. For example, the soluble proteome is organized to a large part into multicomponent complexes (in humans often comprising ten or more subunits), posing critical challenges for recombinant production. A third of all proteins in cells are located in the membrane, and pose special challenges that require a more bespoke approach. Recent advances may now mean that even these most recalcitrant of proteins could become tenable structural biology targets on a more routine basis. In this special issue, we examine progress in key areas that suggests this is indeed the case. Our first contribution examines the importance of understanding quality control in the host cell during recombinant protein production, and pays particular attention to the synthesis of recombinant membrane proteins. A major challenge faced by any host cell factory is the balance it must strike between its own requirements for growth and the fact that its cellular machinery has essentially been hijacked by an expression construct. In this context, Bill and von der Haar examine emerging insights into the role of the dependent pathways of translation and protein folding in defining high-yielding recombinant membrane protein production experiments for the common prokaryotic and eukaryotic expression hosts. Rather than acting as isolated entities, many membrane proteins form complexes to carry out their functions. To understand their biological mechanisms, it is essential to study the molecular structure of the intact membrane protein assemblies. Recombinant production of membrane protein complexes is still a formidable, at times insurmountable, challenge. In these cases, extraction from natural sources is the only option to prepare samples for structural and functional studies. Zorman and co-workers, in our second contribution, provide an overview of recent advances in the production of multi-subunit membrane protein complexes and highlight recent achievements in membrane protein structural research brought about by state-of-the-art near-atomic resolution cryo-electron microscopy techniques. E. coli has been the dominant host cell for recombinant protein production. Nonetheless, eukaryotic expression systems, including yeasts, insect cells and mammalian cells, are increasingly gaining prominence in the field. The yeast species Pichia pastoris, is a well-established recombinant expression system for a number of applications, including the production of a range of different membrane proteins. Byrne reviews high-resolution structures that have been determined using this methylotroph as an expression host. Although it is not yet clear why P. pastoris is suited to producing such a wide range of membrane proteins, its ease of use and the availability of diverse tools that can be readily implemented in standard bioscience laboratories mean that it is likely to become an increasingly popular option in structural biology pipelines. The contribution by Columbus concludes the membrane protein section of this volume. In her overview of post-expression strategies, Columbus surveys the four most common biochemical approaches for the structural investigation of membrane proteins. Limited proteolysis has successfully aided structure determination of membrane proteins in many cases. Deglycosylation of membrane proteins following production and purification analysis has also facilitated membrane protein structure analysis. Moreover, chemical modifications, such as lysine methylation and cysteine alkylation, have proven their worth to facilitate crystallization of membrane proteins, as well as NMR investigations of membrane protein conformational sampling. Together these approaches have greatly facilitated the structure determination of more than 40 membrane proteins to date. It may be an advantage to produce a target protein in mammalian cells, especially if authentic post-translational modifications such as glycosylation are required for proper activity. Chinese Hamster Ovary (CHO) cells and Human Embryonic Kidney (HEK) 293 cell lines have emerged as excellent hosts for heterologous production. The generation of stable cell-lines is often an aspiration for synthesizing proteins expressed in mammalian cells, in particular if high volumetric yields are to be achieved. In his report, Buessow surveys recent structures of proteins produced using stable mammalian cells and summarizes both well-established and novel approaches to facilitate stable cell-line generation for structural biology applications. The ambition of many biologists is to observe a protein's structure in the native environment of the cell itself. Until recently, this seemed to be more of a dream than a reality. Advances in nuclear magnetic resonance (NMR) spectroscopy techniques, however, have now made possible the observation of mechanistic events at the molecular level of protein structure. Smith and colleagues, in an exciting contribution, review emerging ‘in-cell NMR’ techniques that demonstrate the potential to monitor biological activities by NMR in real time in native physiological environments. A current drawback of NMR as a structure determination tool derives from size limitations of the molecule under investigation and the structures of large proteins and their complexes are therefore typically intractable by NMR. A solution to this challenge is the use of selective isotope labeling of the target protein, which results in a marked reduction of the complexity of NMR spectra and allows dynamic processes even in very large proteins and even ribosomes to be investigated. Kerfah and co-workers introduce methyl-specific isotopic labeling as a molecular tool-box, and review its applications to the solution NMR analysis of large proteins. Tyagi and Lemke next examine single-molecule FRET and crosslinking following the co-translational incorporation of non-canonical amino acids (ncAAs); the goal here is to move beyond static snap-shots of proteins and their complexes and to observe them as dynamic entities. The encoding of ncAAs through codon-suppression technology allows biomolecules to be investigated with diverse structural biology methods. In their article, Tyagi and Lemke discuss these approaches and speculate on the design of improved host organisms for ‘integrative structural biology research’. Our volume concludes with two contributions that resolve particular bottlenecks in the protein structure determination pipeline. The contribution by Crepin and co-workers introduces the concept of polyproteins in contemporary structural biology. Polyproteins are widespread in nature. They represent long polypeptide chains in which individual smaller proteins with different biological function are covalently linked together. Highly specific proteases then tailor the polyprotein into its constituent proteins. Many viruses use polyproteins as a means of organizing their proteome. The concept of polyproteins has now been exploited successfully to produce hitherto inaccessible recombinant protein complexes. For instance, by means of a self-processing synthetic polyprotein, the influenza polymerase, a high-value drug target that had remained elusive for decades, has been produced, and its high-resolution structure determined. In the contribution by Desmyter and co-workers, a further, often imposing, bottleneck in high-resolution protein structure determination is addressed: The requirement to form stable three-dimensional crystal lattices that diffract incident X-ray radiation to high resolution. Nanobodies have proven to be uniquely useful as crystallization chaperones, to coax challenging targets into suitable crystal lattices. Desmyter and co-workers review the generation of nanobodies by immunization, and highlight the application of this powerful technology to the crystallography of important protein specimens including G protein-coupled receptors (GPCRs). Recombinant protein production has come a long way since Peter Lobban's hypothesis in the late 1960s, with recombinant proteins now a dominant force in structural biology. The contributions in this volume showcase an impressive array of inventive approaches that are being developed and implemented, ever increasing the scope of recombinant technology to facilitate the determination of elusive protein structures. Powerful new methods from synthetic biology are further accelerating progress. Structure determination is now reaching into the living cell with the ultimate goal of observing functional molecular architectures in action in their native physiological environment. We anticipate that even the most challenging protein assemblies will be tackled by recombinant technology in the near future.

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Based primarily on archival evidence collected in Jamaica, this dissertation examined the nature of childhood in the plantation complex between 1750 and 1838, how colonial society and the slave community defined childhood, and how that definition changed over time. It proves how childhood and slavery influenced and changed each other during these years, with the abolitionist movement standing as the main catalyst for change. Although this project chronologically examined the changing nature of slave childhood in Jamaica through four shifts of Jamaican history, each chapter topically focused on slave childhood through the lenses of labor, family, resistance, race, status, culture, education, and freedom. ^ The research showed that although slavery forced slave children into an early adulthood, childhood was a contested process that changed with each generation of children. As the abolitionist movement motivated changes in planter opinion on the value of children to the plantation economy, planters placed increased responsibility on slave children to lead them towards economic stability and profitability. Meanwhile, slave children struggled to survive slavery by reinventing and modifying their ideas of family and kinship and reacting to their situation through various acts of resistance. Although slave parents gained many opportunities to raise their children on their own terms, they struggled to maintain control over that process as planters attempted to change the nature of African cultural identity in Jamaica by impressing Christian and English values on slave children. Under apprenticeship, childhood returned to its previous status as a liability in the eyes of the Jamaican planters. Yet, Jamaican children faced the prospect of an unwritten childhood, one that was free from planter control and gave Jamaican laborers hope for the future. In the end, this dissertation told the story of an overlooked childhood, one that was often defined by Jamaican planters, but frequently contested by the slaves themselves. ^

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The integration of automation (specifically Global Positioning Systems (GPS)) and Information and Communications Technology (ICT) through the creation of a Total Jobsite Management Tool (TJMT) in construction contractor companies can revolutionize the way contractors do business. The key to this integration is the collection and processing of real-time GPS data that is produced on the jobsite for use in project management applications. This research study established the need for an effective planning and implementation framework to assist construction contractor companies in navigating the terrain of GPS and ICT use. An Implementation Framework was developed using the Action Research approach. The framework consists of three components, as follows: (i) ICT Infrastructure Model, (ii) Organizational Restructuring Model, and (iii) Cost/Benefit Analysis. The conceptual ICT infrastructure model was developed for the purpose of showing decision makers within highway construction companies how to collect, process, and use GPS data for project management applications. The organizational restructuring model was developed to assist companies in the analysis and redesign of business processes, data flows, core job responsibilities, and their organizational structure in order to obtain the maximum benefit at the least cost in implementing GPS as a TJMT. A cost-benefit analysis which identifies and quantifies the cost and benefits (both direct and indirect) was performed in the study to clearly demonstrate the advantages of using GPS as a TJMT. Finally, the study revealed that in order to successfully implement a program to utilize GPS data as a TJMT, it is important for construction companies to understand the various implementation and transitioning issues that arise when implementing this new technology and business strategy. In the study, Factors for Success were identified and ranked to allow a construction company to understand the factors that may contribute to or detract from the prospect for success during implementation. The Implementation Framework developed as a result of this study will serve to guide highway construction companies in the successful integration of GPS and ICT technologies for use as a TJMT.

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The study explored when, under what conditions, and to what extent did European integration, particularly the European Union’s requirement for democratic conditionality, contribute to democratic consolidation in Spain, Poland, and Turkey? On the basis of a four-part definition, the dissertation examined the democratizing impact of European integration process on each of the following four components of consolidation: (i) holding of fair, free and competitive elections, (ii) protection of fundamental rights, including human and minority rights, (iii) high prospects of regime survival and civilian control of the military, and (iv) legitimacy, elite consensus, and stateness. To assess the relative significance of EU’s democratizing leverage, the thesis also examined domestic and non-EU international dynamics of democratic consolidation in the three countries. By employing two qualitative methods (case study and process-tracing), the study focused on three specific time frames: 1977–1986 for Spain, 1994–2004 for Poland, and 1999–present for Turkey. In addition to official documents, newspapers, and secondary sources, face-to-face interviews made with politicians, academics, experts, bureaucrats, and journalists in the three countries were utilized. The thesis generated several conclusions. First of all, the EU’s democratizing impact is not uniform across different components of democratic consolidation. Moreover, the EU’s democratizing leverage in Spain, Poland, and Turkey involved variations over time for three major reasons: (i) the changing nature of EU’s democratic conditionality over time (ii) varying levels of the EU’s credible commitment to the candidate country’s prospect for membership, and (iii) domestic dynamics in the candidate countries. Furthermore, the European integration process favors democratic consolidation but its magnitude is shaped by the candidate country’s prospect for EU membership and domestic factors in the candidate country. Finally, the study involves a major policy implication for the European Union: unless the EU provides a clear prospect for membership, its democratizing leverage will be limited in the candidate countries.

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Recent research makes clear that much of the Everglade’s flora and fauna have evolved to tolerate or require frequent fires. Nevertheless, restoration of the Everglades has thus far been conceptualized as primarily a water reallocation project. These two forces are directly linked by the influence of water flows on fire fuel moisture content, and are indirectly linked through a series of complex feedback loops. This interaction is made more complex by the alteration and compartmentalization of current water flows and fire regimes, the lack of communication between water and fire management agencies, and the already imperiled state of many local species. It is unlikely, therefore, that restoring water flows will automatically restore the appropriate fire regimes, leaving the prospect of successful restoration in some doubt. The decline of the Cape Sable seaside sparrow, and its potential for recovery, illustrates the complexity of the situation.

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Travel websites that enable hotel room reservations have created unprecedented business opportunities. However, they have also overloaded hotel customers with information. This situation is particularly true of China, an emerging country with the largest population in the world and the most promising growth prospect in tourism. This study investigated the room-rate pricing practice of five online distribution channels, measured by the lowest available rates. These online channels priced hotels of different categories in Shanghai, China’s largest city. Empirical findings indicated that local websites offered lower room rates than international websites for the selected hotels in different categories. Specifically, Chinatravel consistently offered the lowest room rates for the selected hotels.

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This study aimed to analyze the participation of mothers/caregivers from the perspective of the health care model that directs the collective monitoring of child growth and development. This is an exploratory and descriptive research with qualitative approach, carried out in two Family Health Units located in the city of Natal/RN. Data were collected between August and September 2014, through participant observation and semi-structured interview technique, with mothers of infants seen at follow-up visits collective child growth and development. A total of 13 mothers were included who met the following inclusion criteria: being a mother/caregiver responsible for the care of children who have attended one or more meeting of collective monitoring of child growth and development. Exclusion criteria was established: users outside the area covered by the Health Unit Family and who did not use the National Health System as the primary health care service. For the treatment of the collected material, the content analysis was used, thematic Bardin. The study followed the ethical and legal principles governing the scientific research on human subjects recommended by Resolution nº. 466/2012 of the National Health Council and its realization occurred with the approval of the project in the Research Ethics Committee of the Federal University of Rio Grande do North, which was approved by Opinion Embodied nº. 719 949, of June 27, 2014, and Certificate Presentation of Findings Ethics No 32510514.7.0000.5537. Although not conceptualize theoretically mothers demonstrated that collective consultations of child growth and development are actions aimed at health surveillance model, since most pointed monitoring your child to actions that can be measured. Even with that, it was established the existence of health promotion actions by reporting the exchange of experience and leadership of the subjects in collective action, factor facilitated by the link established between users and professionals and users. In this action there is the induction of permanent horizontal relationship where we seek to combine popular knowledge to scientific knowledge in order to promote the integral care for the child. However, it is still possible to find professionals who directs its assistance only to pathological processes and fail to create comprehensive care alternatives. In addition, there is still embezzlement in multi that should provide care to the child population. This factor may be related to their professional training, and thus an issue that can last for a few years. We conclude that it is necessary to incorporate alternatives and models of care that support overcoming limitations and enhancing the health of the population, involving it in the prospect of a better quality of life and therefore health.