Longitudinal and cross-sectional changes in active commuting to school among Brazilian schoolchildren.

OBJECTIVE: The objective of the study is to evaluate cross-sectional and longitudinal changes in children's commuting to school in a representative sample of a Brazilian city. METHODS: Two school-based studies were carried out in 2002 (n=2936; 7-10years old) and 2007 (n=1232; 7-15years old) in Florianopolis, Brazil. Cross-sectional data were collected from children aged 7 to 10years in 2002 and 2007. Longitudinal analyses were performed with data from 733 children participating in both surveys. Children self-reported their mode of transportation to school using a validated illustrated questionnaire. Changes were tested with chi square statistics and McNemar's test. RESULTS: Cross-sectional data showed a 17% decline in active commuting; a decrease from 49% in 2002 to 41% in 2007. On the other hand, active commuting among the 733 children increased as they entered adolescence 5years later, rising from 40% to 49%. CONCLUSION: Active commuting to school decreased in Brazilian children aged 7-10years over a five year period; whereas, it increased among children entering adolescence. Policies should focus on safety and environmental determinants to increase active commuting.

A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without.

Identification of active oxalotrophic bacteria by Bromodeoxyuridine DNA labeling in a microcosm soil experiments

The oxalate-carbonate pathway (OCP) leads to a potential carbon sink in terrestrial environments. This process is linked to the activity of oxalotrophic bacteria. Although isolation and molecular characterizations are used to study oxalotrophic bacteria, these approaches do not give information on the active oxalotrophs present in soil undergoing the OCP. The aim of this study was to assess the diversity of active oxalotrophic bacteria in soil microcosms using the Bromodeoxyuridine (BrdU) DNA labeling technique. Soil was collected near an oxalogenic tree (Milicia excelsa). Different concentrations of calcium oxalate (0.5%, 1%, and 4% w/w) were added to the soil microcosms and compared with an untreated control. After 12days of incubation, a maximal pH of 7.7 was measured for microcosms with oxalate (initial pH 6.4). At this time point, a DGGE profile of the frc gene was performed from BrdU-labeled soil DNA and unlabeled soil DNA. Actinobacteria (Streptomyces- and Kribbella-like sequences), Gammaproteobacteria and Betaproteobacteria were found as the main active oxalotrophic bacterial groups. This study highlights the relevance of Actinobacteria as members of the active bacterial community and the identification of novel uncultured oxalotrophic groups (i.e. Kribbella) active in soils.

Predicting the evolution of Kaposi sarcoma, in the highly active antiretroviral therapy era.

BACKGROUND: The outcome of Kaposi sarcoma varies. While many patients do well on highly active antiretroviral therapy, others have progressive disease and need chemotherapy. In order to predict which patients are at risk of unfavorable evolution, we established a prognostic score. METHOD: The survival analysis (Kaplan-Meier method; Cox proportional hazards models) of 144 patients with Kaposi sarcoma prospectively included in the Swiss HIV Cohort Study, from January 1996 to December 2004, was conducted. OUTCOME ANALYZED: use of chemotherapy or death. VARIABLES ANALYZED: demographics, tumor staging [T0 or T1 (16)], CD4 cell counts and HIV-1 RNA concentration, human herpesvirus 8 (HHV8) DNA in plasma and serological titers to latent and lytic antigens. RESULTS: Of 144 patients, 54 needed chemotherapy or died. In the univariate analysis, tumor stage T1, CD4 cell count below 200 cells/microl, positive HHV8 DNA and absence of antibodies against the HHV8 lytic antigen at the time of diagnosis were significantly associated with a bad outcome.Using multivariate analysis, the following variables were associated with an increased risk of unfavorable outcome: T1 [hazard ratio (HR) 5.22; 95% confidence interval (CI) 2.97-9.18], CD4 cell count below 200 cells/microl (HR 2.33; 95% CI 1.22-4.45) and positive HHV8 DNA (HR 2.14; 95% CI 1.79-2.85).We created a score with these variables ranging from 0 to 4: T1 stage counted for two points, CD4 cell count below 200 cells/microl for one point, and positive HHV8 viral load for one point. Each point increase was associated with a HR of 2.26 (95% CI 1.79-2.85). CONCLUSION: In the multivariate analysis, staging (T1), CD4 cell count (<200 cells/microl), positive HHV8 DNA in plasma, at the time of diagnosis, predict evolution towards death or the need of chemotherapy.

Hypotensive effect of the active fragment derived from factor XII is mediated by an activation of the plasma kallikrein-kinin system.

Plasma protein fraction (PPF) contaminated by factor XII active fragment (XIIf) may cause hypotensive reactions when infused to patients. This study was planned to assess in conscious normotensive rats whether the blood pressure response to the factor XIIf is mediated by an activation of the plasma kallikrein-kinin system or by stimulation of prostaglandin synthesis. To test whether the factor XIIf-induced blood pressure fall is due partially to an enhanced generation of vasodilating prostaglandins, the blood pressure effect of XIIf (1 microgram i.v.) was investigated 15 min after treatment with indomethacin (5 mg i.v.), an inhibitor of cyclo-oxygenase. Factor XIIf reduced mean blood pressure similarly in indomethacin- and vehicle-treated rats (-23 +/- 4 mmHg, n = 5, and -23 +/- 5 mmHg, n = 4, respectively). Other rats received factor XIIf 15 min after depletion of circulating prekallikrein by the administration of dextran sulfate. Thirty minutes after a 0.25 mg i.v. dose of this agent, plasma prekallikrein activity averaged 0.12 +/- 0.015 mumol/min/ml (n = 6) as compared to 2.48 +/- 0.31 mumol/min/ml in control rats (n = 4, P less than .001). Factor XIIf decreased mean blood pressure by only 4 +/- 2 mm Hg in rats pretreated with dextran sulfate. Thus, it was possible to blunt the acute hypotensive effect of factor XIIf by depleting circulating prekallikrein, but not by inhibiting prostaglandin production. This strongly suggests that the blood pressure effects of factor XIIf is mediated by a stimulation of the plasma kallikrein-kinin system.

Pi*-pi* bonding interactions generated by halogen oxidation of zirconium(IV) redox-active ligand complexes.

The new complex, [Zr(pda)2]n (1, pda2- = N,N'-bis(neo-pentyl)-ortho-phenylenediamide, n = 1 or 2), prepared by the reaction of 2 equiv of pdaLi2 with ZrCl4, reacts rapidly with halogen oxidants to afford the new product ZrX2(disq)2 (3, X = Cl, Br, I; disq- = N,N'-bis(neo-pentyl)-ortho-diiminosemiquinonate) in which each redox-active ligand has been oxidized by one electron. The oxidation products 3a-c have been structurally characterized and display an unusual parallel stacked arrangement of the disq- ligands in the solid state, with a separation of approximately 3 A. Density functional calculations show a bonding-type interaction between the SOMOs of the disq- ligands to form a unique HOMO while the antibonding linear combination forms a unique LUMO. This orbital configuration leads to a closed-shell-singlet ground-state electron configuration (S = 0). Temperature-dependent magnetism measurements indicate a low-lying triplet excited state at approximately 750 cm-1. In solution, 3a-c show strong disq--based absorption bands that are invariant across the halide series. Taken together these spectroscopic measurements provide experimental values for the one- and two-electron energies that characterize the pi-stacked bonding interaction between the two disq- ligands.

Cancer du sein : la pathologie, pierre angulaire de la décision therapeutique [Breast cancer: pathology, the cornerstone of therapeutic decision]

Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors, most of which are currently established by histopathological analysis of tumors. The quality of the assessment of the former (i.e.: tumor size, lymph node status, tumor grade, HER2 status, and lymphovascular invasion) and the latter (estrogen and progesteron receptors expression, HER2 overexpression or amplification) is an essential prerequisite for an optimal therapeutic decision. If the prognostic and predictive values of multigenes signatures are confirmed by on-going clinical studies, this approach could enter the clinical practice in the coming years and result in improved accuracy of adjuvant therapies in breast cancer patients. This approach might especially allow avoiding overtreatment in patients at low risk of recurrence.

Constitutively active G protein-coupled receptors: potential mechanisms of receptor activation.

Mutations of G protein-coupled receptors can increase their constitutive (agonist-independent) activity. Some of these mutations have been artificially introduced by site-directed mutagenesis, others occur spontaneously in human diseases. The analysis of the constitutively active G protein-coupled receptors has provided important informations about the molecular mechanisms underlying receptor activation and drug action.

High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma.

Tumor-reactive T cells play an important role in cancer immunosurveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTLs in a melanoma patient with progressive lymph node metastases, consisting of 18 and 12.8% of total peripheral blood and tumor-infiltrating CD8+ T cells, respectively. Melan-A-specific CTLs revealed a high cytolytic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I antigen processing and presentation pathway. Mutations of the coding region of the HLA-A2 binding Melan-A26-35 peptide or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein 2 and low molecular weight protein 7 in the primary tumor cells, which affects the quantity and quality of generated T-cell epitopes and might explain the resistance to killing. This is supported by our data, demonstrating that the resistance to killing can be partially reversed by pre-exposure of the tumor cells to IFN-gamma, which is known to induce the immunoproteasomes. Overall, this is the first report of an extremely high frequency of tumor-specific CTLs that exhibit competent T-cell-effector functions but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust antitumor immune response, but should also have to target tumor immune escape mechanisms.