Combined target-based and ligand-based drug design approach as a tool to define a novel 3D-pharmacophore model of human A3 adenosine receptor antagonists: pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as a key study

A combined target-based and ligand-based drug design approach has been carried out to define a novel pharmacophore model of the human A(3) receptor antagonists. High throughput molecular docking and comparative molecular field analysis (CoMFA) have been used in tandem to assemble a new target based pharmacophore model. In parallel, to provide more accurate information about the putative binding site of these A(3) inhibitors, a rhodopsin-based model of the human A(3) receptor was built and a novel Y-shape binding motif has been proposed. Docking-based structure superimposition has been used to perform a quantitative study of the structure-activity relationships for binding of these pyrazolo-triazolo-pyrimidines to adenosine A(3) receptor using CoMFA. Both steric and the electrostatic contour plots obtained from the CoMFA analysis nicely fit on the hypothetical binding site obtained by molecular docking. On the basis of the combined hypothesis, we have designed, synthesized, and tested 17 new derivatives. Consistently, the predicted K(i) values were very close to the experimental values.     

Immunohistochemical study of tumor necrosis factor-alpha, matrix metalloproteinase-12, and tissue inhibitor of metalloproteinase-2 on alveolar macrophages of BALB/c mice exposed to short-term cigarette smoke

Alveolar cells were evaluated in BALB/c mice exposed to smoke from 9 cigarettes per day. The mice were sacrificed at 1, 5, and 10 days and examined by lung morphometry and immunohistochemical staining of alveolar macrophages for tumor necrosis factor (TNF)-alpha, matrix metalloproteinase (MMP)-12, and tissue inhibitor of metalloproteinase (TIMP)-2. Cigarette smoke (CS)-exposed mice showed a progressive increase in numbers of alveolar macrophages (AMs) up to 10 days. MMP-12 was increased in AMs compared to the control group. The number of AMs with TNF-alpha and TIMP-2 labeling was higher at 5 days but decreased at 10 days. Short-term CS exposure induced pulmonary inflammation with major participation of MMP-12-positive AMs.     

Infant feeding practices before implementing alternatives to prolonged breastfeeding to reduce HIV transmission through breastmilk in Abidjan, Cote d'Ivoire

The aim of this study was to describe baseline infant feeding practices in women of unknown HIV status in Abidjan, C?te d'Ivoire, before the implementation of infant feeding interventions aimed at the prevention of mother-to-child transmission of HIV through breastmilk. We conducted a cross-sectional survey in March 2000 among 225 mothers attending community-run health facilities with their own child for either immunization or weighting. All but two children had ever been breastfed, of whom 94 per cent were still being breastfed at 6 months of age. Exclusive breastfeeding was not practiced in this population since all women had given water to their child, starting in median one day after birth. Moreover, 20 per cent of the mothers had introduced infant formula in median three weeks after delivery. This study provides useful information for planning purposes in this urban African population, where exclusive breastfeeding is rare and the use of infant formula relatively common.     

Changes in family structure and regret following tubal sterilization

Tubal sterilization is one of the contraceptive methods whose use has increased the most in Brazil, but a growing number of women have expressed regret after the procedure. A case-control study was conducted at the Centro Integrado de Saúde Amaury de Medeiros (CISAM), Recife, Pernambuco, Brazil, in 1997 to investigate the association between changes in family structure and request for or submittal to surgical reversal of tubal sterilization, comparing 304 sterilized women who had requested or submitted to reversal of tubal sterilization and 304 women who were also sterilized but had not requested, had not submitted to, and who did not wish to submit to reversal. The simple and adjusted odds ratios were estimated using logistic regression. The results of the current study showed that death of children, partners without children prior to the current union, and partner change after tubal sterilization were associated with the request for or submittal to reversal of tubal sterilization. More strict criteria are suggested in the indication of tubal sterilization, including an in-depth profile of the woman requesting tubal sterilization and identification of risk factors for future regret.     

Humanization in health care: knowledge disseminated in Brazilian nursing literature

This qualitative research aims to analyze the scientific production about "humane health care/nursing", understanding what views on humanization have been developing. A bibliographic survey was carried out, covering the period from the end of the 1950's until today, in the periodicals Revista Brasileira de Enfermagem, Revista Paulista de Hospitais and Texto e Contexto, examining 42 articles, which were then subject to analysis and integrative synthesis. The issue has been developing from a charitable perspective to the current preoccupation with the valuation of health as a civil right, inserted in a political health project. Articles from all decades reveal the need to invest in workers, valuing the subjective dimension. Nevertheless, humanization receives little attention in education. Care humanization supposes the meeting of subjects who share knowledge, power and experiences, implying political, administrative and subjective transformations.     

Common cancer biomarkers

There is an increasing interest in complementing conventional histopathologic evaluation with molecular tools that could increase the sensitivity and specificity of cancer staging for diagnostic and prognostic purposes. This study strove to identify cancer-specific markers for the molecular detection of a broad range of cancer types. We used 373 archival samples inclusive of normal tissues of various lineages and benign or malignant tumors (predominantly colon, melanoma, ovarian, and esophageal cancers). All samples were processed identically and cohybridized with an identical reference RNA source to a custom-made cDNA array platform. The database was split into training (n = 201) and comparable prediction (n = 172) sets. Leave-one-out cross-validation and gene pairing analysis identified putative cancer biomarkers overexpressed by malignant lesions independent of tissue of derivation. In particular, seven gene pairs were identified with high predictive power (87%) in segregating malignant from benign lesions. Receiver operator characteristic curves based on the same genes could segregate malignant from benign tissues with 94% accuracy. The relevance of this study rests on the identification of a restricted number of biomarkers ubiquitously expressed by cancers of distinct histology. This has not been done before. These biomarkers could be used broadly to increase the sensitivity and accuracy of cancer staging and early detection of locoregional or systemic recurrence. Their selective expression by cancerous compared with paired normal tissues suggests an association with the oncogenic process resulting in stable expression during disease progression when the presently used differentiation markers are unreliable.     

Insulin-like growth factor binding protein 3 as an anticancer molecule in Ewing's sarcoma

The IGF/IGF-IR system plays a major role in the pathogenesis and progression of Ewing's sarcoma. In this article, the authors evaluated whether the insulin-like growth factor binding protein-3 (IGFBP-3), a molecule with growth-inhibitory and proapoptotic activities, may be exploited for therapeutic applications in the treatment of Ewing's sarcoma (EWS). Expression of IGFBP-3 was analyzed in a panel of EWS cell lines and clinical samples. Parameters related to malignancy (growth in anchorage-independent conditions, migration, invasion and angiogenesis properties) were studied to establish the potential in vitro anticancer effects of exogenous IGFBP-3. The activity of the molecule against metastasis was analyzed by taking advantage of selected clones in which IGFBP-3 endogenous production was induced by gene transfection. The authors observed a generally low expression of IGFBP-3 either in a panel of EWS cell lines or clinical samples. Exogenous IGFBP-3 remarkably inhibits EWS growth, both in monolayer and anchorage-independent conditions, and significantly reduces cell motility. Forced expression of IGFBP-3 in TC-71 EWS cells confirms the growth and migratory effects observed with the exogenous protein, decreases the production or activity of the matrixmetalloprotease MMP-9 and vascular endothelial factor (VEGF)-A and abrogates EWS metastasis ability. IGFBP-3 acts mainly through IGF-dependent mechanisms and the protein may therefore represent an alternative strategy to inhibit IGF-IR functions. The data indicate IGFBP-3 as a molecule of therapeutic potential in EWS.