New approaches in antimalarial drug discovery and development: a review

Malaria remains a major world health problem following the emergence and spread of Plasmodium falciparum that is resistant to the majority of antimalarial drugs. This problem has since been aggravated by a decreased sensitivity of Plasmodium vivax to chloroquine. This review discusses strategies for evaluating the antimalarial activity of new compounds in vitro and in animal models ranging from conventional tests to the latest high-throughput screening technologies. Antimalarial discovery approaches include the following: the discovery of antimalarials from natural sources, chemical modifications of existing antimalarials, the development of hybrid compounds, testing of commercially available drugs that have been approved for human use for other diseases and molecular modelling using virtual screening technology and docking. Using these approaches, thousands of new drugs with known molecular specificity and active against P. falciparum have been selected. The inhibition of haemozoin formation in vitro, an indirect test that does not require P. falciparum cultures, has been described and this test is believed to improve antimalarial drug discovery. Clinical trials conducted with new funds from international agencies and the participation of several industries committed to the eradication of malaria should accelerate the discovery of drugs that are as effective as artemisinin derivatives, thus providing new hope for the control of malaria.

Insights from animal models on the immunogenetics of leprosy: a review

A variety of host immunogenetic factors appear to influence both an individual's susceptibility to infection with Mycobacterium leprae and the pathologic course of the disease. Animal models can contribute to a better understanding of the role of immunogenetics in leprosy through comparative studies helping to confirm the significance of various identified traits and in deciphering the underlying mechanisms that may be involved in expression of different disease related phenotypes. Genetically engineered mice, with specific immune or biochemical pathway defects, are particularly useful for investigating granuloma formation and resistance to infection and are shedding new light on borderline areas of the leprosy spectrum which are clinically unstable and have a tendency toward immunological complications. Though armadillos are less developed in this regard, these animals are the only other natural hosts of M. leprae and they present a unique opportunity for comparative study of genetic markers and mechanisms associable with disease susceptibility or resistance, especially the neurological aspects of leprosy. In this paper, we review the recent contributions of genetically engineered mice and armadillos toward our understanding of the immunogenetics of leprosy.

Severity of chronic experimental Chagas' heart disease parallels tumour necrosis factor and nitric oxide levels in the serum: models of mild and severe disease

Heart tissue inflammation, progressive fibrosis and electrocardiographic alterations occur in approximately 30% of patients infected by Trypanosoma cruzi, 10-30 years after infection. Further, plasma levels of tumour necrosis factor (TNF) and nitric oxide (NO) are associated with the degree of heart dysfunction in chronic chagasic cardiomyopathy (CCC). Thus, our aim was to establish experimental models that mimic a range of parasitological, pathological and cardiac alterations described in patients with chronic Chagas’ heart disease and evaluate whether heart disease severity was associated with increased TNF and NO levels in the serum. Our results show that C3H/He mice chronically infected with the Colombian T. cruzi strain have more severe cardiac parasitism and inflammation than C57BL/6 mice. In addition, connexin 43 disorganisation and fibronectin deposition in the heart tissue, increased levels of creatine kinase cardiac MB isoenzyme activity in the serum and more severe electrical abnormalities were observed in T. cruzi-infected C3H/He mice compared to C57BL/6 mice. Therefore, T. cruzi-infected C3H/He and C57BL/6 mice represent severe and mild models of CCC, respectively. Moreover, the CCC severity paralleled the TNF and NO levels in the serum. Therefore, these models are appropriate for studying the pathophysiology and biomarkers of CCC progression, as well as for testing therapeutic agents for patients with Chagas’ heart disease.

Reaching for the Holy Grail: insights from infection/cure models on the prospects for vaccines for Trypanosoma cruziinfection

Prevention of Trypanosoma cruzi infection in mammals likely depends on either prevention of the invading trypomastigotes from infecting host cells or the rapid recognition and killing of the newly infected cells byT. cruzi-specific T cells. We show here that multiple rounds of infection and cure (by drug therapy) fails to protect mice from reinfection, despite the generation of potent T cell responses. This disappointing result is similar to that obtained with many other vaccine protocols used in attempts to protect animals from T. cruziinfection. We have previously shown that immune recognition ofT. cruziinfection is significantly delayed both at the systemic level and at the level of the infected host cell. The systemic delay appears to be the result of a stealth infection process that fails to trigger substantial innate recognition mechanisms while the delay at the cellular level is related to the immunodominance of highly variable gene family proteins, in particular those of the trans-sialidase family. Here we discuss how these previous studies and the new findings herein impact our thoughts on the potential of prophylactic vaccination to serve a productive role in the prevention of T. cruziinfection and Chagas disease.

Instrumental and ethical aspects of experimental research with animal models

Experimental animal models offer possibilities of physiology knowledge, pathogenesis of disease and action of drugs that are directly related to quality nursing care. This integrative review describes the current state of the instrumental and ethical aspects of experimental research with animal models, including the main recommendations of ethics committees that focus on animal welfare and raises questions about the impact of their findings in nursing care. Data show that, in Brazil, the progress in ethics for the use of animals for scientific purposes was consolidated with Law No. 11.794/2008 establishing ethical procedures, attending health, genetic and experimental parameters. The application of ethics in handling of animals for scientific and educational purposes and obtaining consistent and quality data brings unquestionable contributions to the nurse, as they offer subsidies to relate pathophysiological mechanisms and the clinical aspect on the patient.

Study of parental models: building an instrument for their exploration

Objective: This research presents the construction of an attributional questionnaire concerning the different parental models and factors that are involved in family interactions. Method: A mixed methodology was used as a foundation to develop items and respective pilots that allowed checking the validity and internal consistency of the instrument using expert judgment. Results: An instrument of 36 statements was organized into 12 categories to explore the parental models according to the following factors: parental models, breeding patterns, attachment bonds and guidelines for success, and promoted inside family contexts. Analyzing these factors contributes to the children’s development within the familiar frown, and the opportunity for socio-educational intervention. Conclusion: It is assumed that the family context is as decisive as the school context; therefore, exploring the nature of parental models is required to understand the features and influences that contribute to the development of young people in any social context.





Technologies of birth and models of midwifery care

This article is based on a study of a reform in the organisation of maternity services in the United Kingdom, which aimed towards developing a more woman-centred model of care. After decades of fragmentation and depersonalisation of care, associated with the shift of birth to a hospital setting, pressure by midwives and mothers prompted government review and a relatively radical turnaround in policy. However, the emergent model of care has been profoundly influenced by concepts and technologies of monitoring. The use of such technologies as ultrasound scans, electronic foetal monitoring and oxytocic augmentation of labour, generally supported by epidural anaesthesia for pain relief, have accompanied the development of a particular ecological model of birth – often called active management –, which is oriented towards the idea of an obstetric norm. Drawing on analysis of women’s narrative accounts of labour and birth, this article discusses the impact on women’s embodiment in birth, and the sources of information they use about the status of their own bodies, their labour and that of the child. It also illustrates how the impact on women’s experiences of birth may be mediated by a relational model of support, through the provision of caseload midwifery care.

Children's health care assistance according to their families: a comparison between models of Primary Care

OBJECTIVE To compare the health assistance models of Basic Traditional Units (UBS) with the Family Health Strategy (ESF) units for presence and extent of attributes of Primary Health Care (APS), specifically in the care of children. METHOD A cross-sectional study of a quantitative approach with families of children attended by the Public Health Service of Colombo, Paraná. The Primary Care Assessment Tool (PCA-Tool) was applied to parents of 482 children, 235 ESF units and 247 UBS units covering all primary care units of the municipality, between June and July 2012. The results were analyzed according to the PCA-Tool manual. RESULTS ESF units reached a borderline overall score for primary health care standards. However, they fared better in their attributes of Affiliation, Integration of care coordination, Comprehensiveness, Family Centeredness and Accessibility of use, while the attributes of Community Guidance/Orientation, Coordination of Information Systems, Longitudinality and Access attributes were rated as insufficient for APS. UBS units had low scores on all attributes. CONCLUSION The ESF units are closer to the principles of APS (Primary Health Care), but there is need to review actions of child care aimed at the attributes of APS in both care models, corroborating similar studies from other regions of Brazil.