[Knowledge, attitudes and behaviours about AIDS in Portuguese adolescents in urban and non-urban environment].

The main objective of this investigation was to identify and compare preventive knowledge, attitudes and behaviors regarding AIDS between adolescents at the secondary school in urban and non-urban areas in Portugal. This is a descriptive study with a sample of 826 individuals (455 adolescents from urban environment and 371 from a non-urban environment). The instrument for data collection adopted was based on the Health Belief Model conceptual model.

The use of metabolomics for the discovery of new biomarkers of effect.

Will metabolomics have a greater chance of success in toxicology and biomarker assessment than genomics and proteomics? Metabolomics has the advantage that (1) it analyses the last step in a series of changes following a toxic insult, (2) many of the metabolites have a known function and (3) changes are detectable in blood. If the analysis of a great number of individual organs can be replaced by one matrix then this will provide significant advantages (less invasive method, no need to kill animals, time course analysis possible). We have chosen to perform the analysis of blood metabolites in such a way as to minimize the risk of artifacts and to have a high number of known metabolites.

A modern view of phenylalanine ammonia lyase.

Phenylalanine ammonia lyase (PAL; E.C.4.

1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel.

The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po).

Synthesis and biological evaluation of 5-substituted 1,4-dihydroindeno[1,2-c]pyrazoles as multitargeted receptor tyrosine kinase inhibitors.

We report the synthesis and biological evaluation of 5-substituted 1,4-dihydroindeno[1,2-c]pyrazoles as multitargeted kinase inhibitors. Initial efforts focused on the development of selective KDR inhibitors, while later strategies involved the improvement of potency toward multiple kinase targets. Thus, several compounds were identified as potent KDR, Flt1, Flt3, and c-Kit inhibitors.

Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor.

In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model.

Expression profiling of the mouse prostate after castration and hormone replacement: implication of H-cadherin in prostate tumorigenesis.

Mice have been used extensively for studying normal prostate development and for generation of transgenic or knock-out prostate cancer animal models. To understand systematically and thoroughly the androgen responsive program in the mouse prostate, we carried out microarray analysis to profile gene expression changes during prostate involution and re-growth triggered by castration and subsequent hormone replacement. Genes with significant changes in these two processes were identified and gene ontology analyses revealed that they were mainly involved in response mechanisms, cell adhesion, metabolism, protein metabolism, and cell-cycle progression.

Thienopyridine urea inhibitors of KDR kinase.

A series of substituted thienopyridine ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 2, are potent inhibitors of KDR (<10 nM) in both enzymatic and cellular assays. Further characterization of inhibitor 2 indicated that this analog possessed excellent in vivo potency (ED50 2.

Sulfasalazine-induced cystine starvation: potential use for prostate cancer therapy.

Background: Certain cancers depend for growth on uptake of cystine/cysteine from their environment. Here we examined advanced human prostate cancer cell lines, DU-145 and PC-3, for dependence on extracellular cystine and sensitivity to sulfasalazine (SASP), a potent inhibitor of the x(c)(-) cystine transporter.

Methods: Cultures were evaluated for growth dependence on exogenous cystine, x(c)(-) transporter expression, response to SASP (growth and glutathione content).

Anticonvulsant activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu.

The anticonvulsant effects of hydroalcoholic extracts (HAEs) from the stem bark of Erythrina velutina and Erythrina mulungu on pentylenetetrazole (PTZ) and strychnine-induced seizure tests and the potentiation of pentobarbital-induced sleeping time in mice with the extracts were examined in this study. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. The extracts of Erythrina velutina (intraperitoneally or orally) and Erythrina mulungu (intraperitoneally) were administered in mice at single doses (200 or 400mg/kg).

Mammalian sexual differentiation: lessons from the spotted hyena.

Female spotted hyenas (Crocuta crocuta) are the only female mammals that lack an external vaginal opening. Mating and birth take place through a urogenital canal that exits at the tip of a hypertrophied clitoris. This 'masculine' phenotype spurred a search for an alternate source of fetal androgens.

Endocrine differentiation of fetal ovaries and testes of the spotted hyena (Crocuta crocuta): timing of androgen-independent versus androgen-driven genital development.

Female spotted hyenas (Crocuta crocuta) have an erectile peniform clitoris and a pseudoscrotum but no external vagina, all established by day 35 of a 110-day gestation. Recent studies indicate that these events are androgen-independent, although androgen secretion by fetal ovaries and testis was hypothesized previously to induce phallic development in both sexes. We present the first data relating to the capacity of the ovaries and testes of the spotted hyena to synthesize androgens at different stages of fetal life.

Neuroprotective effects of caffeine in the model of 6-hydroxydopamine lesion in rats.

The work shows the effects of caffeine after the intrastriatal injection of 6-OHDA in rats, considered as a model of Parkinson disease (PD). Two weeks after the 6-OHDA lesion, rats exhibit a characteristic rotation behavior as a response to the apomorphine challenge. Our results showed significant increases in the number of apomorphine-induced rotations in 6-OHDA-lesioned rats, as compared to sham-operated animals.

Steroid receptors and mammalian penile development: an unexpected role for progesterone receptor?

Purpose: We investigated the role of steroid receptors in normal and abnormal genital tubercle development in males and females. We hypothesized that progesterone receptor expression might be involved in abnormal development in both sexes.

Materials And Methods: We examined the effects of medroxyprogesterone acetate on steroid receptor mRNA expression and assessed the involvement of androgen receptor in the action of medroxyprogesterone acetate on genital tubercle development using androgen receptor deficient (Tfm) mice.

Quebrachitol (2-O-methyl-L-inositol) attenuates 6-hydroxydopamine-induced cytotoxicity in rat fetal mesencephalic cell cultures.

Naturally occurring plant substances have the potential to prevent oxidative damage in various pathophysiological conditions including neurodegenerative disorders. Recent findings indicate that impaired energy metabolism plays a prominent role in neurodegeneration. The present study investigated whether quebrachitol (2-O-methyl-L-inositol) (QCT), a sugar like natural compound that was suggested to have both antioxidant and membrane stabilization activity prevents the cytotoxic effect of 6-hydroxydopamine (6-OHDA, 200 microM) on cultured rat fetal mesencephalic cells.

Increased density and synapto-protective effect of adenosine A2A receptors upon sub-chronic restraint stress.

Stress initially causes adaptive changes in the brain and can lead to neurodegeneration if continuously present. Noxious brain conditions trigger the release of adenosine that can control brain function and neurodegeneration through inhibitory A(1) and facilitatory A(2A) receptors. We tested the effect of restraint stress on the density of adenosine receptors and their effect on the outcome of stress, focusing in a known affected region, the hippocampus.

1,4-Dihydroindeno[1,2-c]pyrazoles as novel multitargeted receptor tyrosine kinase inhibitors.

A series of 1,4-dihydroindeno[1,2-c]pyrazoles with a 3-thiophene substituent carrying a urea-type side chain were identified as potent multitargeted (VEGFR and PDGFR families) receptor tyrosine kinase inhibitors. A KDR homology model suggested that the urea moiety is able to interact with a recognition motif in the hydrophobic specificity pocket of the enzyme.

Hit-to-lead optimization of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of KDR kinase inhibitors.

A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.

Isothiazolopyrimidines and isoxazolopyrimidines as novel multi-targeted inhibitors of receptor tyrosine kinases.

A series of isothiazolopyrimidines and isoxazolopyrimidines were synthesized and identified as potent KDR inhibitors. SAR studies led to isothiazolopyrimidine urea analogs that potently inhibit VEGFR tyrosine kinases (KDR enzymatic and cellular IC(50) values below 10 nM) as well as cKIT and TIE2. The selected compounds 8 and 13 display 56% and 48% oral bioavailability in mice, respectively.

[The effects of nonsupervised exercise program, via internet, on blood pressure and body composition in normotensive and prehypertensive individuals].

Objective: To verify the effects of a six-month non-supervised physical training program followed via the Internet on blood pressure and body composition in normotensive and borderline hypertensive individuals.

Methods: One hundred and thirty five individuals were divided into two groups: 1) normotensive individual (n = 57), 43 +/- 1 years of age, systolic blood pressure (SBP) < 120 and diastolic blood pressure (DBP) < 80 mmHg (GI); and 2) borderline hypertensive individual (n = 78), 46 +/- 1 years of age, SBP 120 to 139 and DBP 80 to 89 mmHg (GII).

Results: After a three and six-month physical training, GII individuals showed a significant reduction in SBP (-3.

Formation of human prostate tissue from embryonic stem cells.

Rodent models and immortalized or genetically modified cell lines are frequently used-but have limited utility-for studying human prostate development and maturation. Using rodent mesenchyme to establish reciprocal mesenchymal-epithelial cell interactions with human embryonic stem cells (hESCs), we generated human prostate tissue expressing prostate-specific antigen (PSA) within 8-12 weeks. This human prostate model shows species-conserved signalling mechanisms that could extend to integumental, gastrointestinal and genital tissues.

Fine structure and cytochemical analysis of the intestinal wall along the body of adult female of Litomosoides chagasfilhoi (Nematoda: Filarioidea).

Litomosoides chagasfilhoi is a filariid nematode parasite of the abdominal cavity of the wild rodent Akodon cursor (Winge, 1887), that has been described and used in Brazil as a new model for human filariasis. The fine structure of the intestine of this nematode was analyzed based on observations made by light and transmission electron microscopies of serial sections along the body. Cytochemical analysis was carried out to investigate the composition of the intestinal wall.

A neuroanatomical comparison of humans and spotted hyena, a natural animal model for common urogenital sinus: clinical reflections on feminizing genitoplasty.

Purpose: Surgical treatment of the common urogenital sinus phallus has been one of the most challenging areas in pediatric urology. To better understand the neuroanatomy of the common urogenital sinus phallus, we evaluated an animal model naturally having this condition, the spotted hyena, Crocuta crocuta. We compared the neuroanatomy of male and female humans and spotted hyenas using anatomical, immunohistochemical and 3D reconstruction techniques.

Stem/progenitor and intermediate cell types and the origin of human prostate cancer.

Theories of cell lineage in human prostatic epithelium, based on protein expression, propose that basal and luminal cells: 1) are either independently capable of self-renewal or 2) arise from stem cells expressing a full spectrum of proteins (p63, cytokeratins CK5/14, CK8/18, and glutathione-S-transferase-pi [GST-pi]) similar to cells of the embryonic urogenital sinus (UGS). Such embryonic-like stem cells are thought to give rise to mature basal cells and secretory luminal cells. By single cell cloning of an immortalized, normal human prostate-derived, non-tumorigenic RWPE-1 cell line, we isolated and characterized two epithelial cell types, WPE-stem and WPE-int.