Frequent p53 and H-ras mutations in benzene- and ethylene oxide-induced mammary gland carcinomas from B6C3F1 mice

Benzene and ethylene oxide are multisite carcinogens in rodents and classified as human carcinogens by the National Toxicology Program. In 2-year mouse studies, both chemicals induced mammary carcinomas. We examined spontaneous, benzene-, and ethylene oxide-induced mouse mammary carcinomas for p53 protein expression, using immunohistochemistry, and p53 (exons 5-8) and H-ras (codon 61) mutations using cycle sequencing techniques. p53 protein expression was detected in 42% (8/19) of spontaneous, 43% (6/14) of benzene-, and 67% (8/12) of ethylene oxide-induced carcinomas. However, semiquantitative evaluation of p53 protein expression revealed that benzene- and ethylene oxide-induced carcinomas exhibited expression levels five- to six-fold higher than spontaneous carcinomas. p53 mutations were found in 58% (7/12) of spontaneous, 57% (8/14) of benzene-, and 67% (8/12) of ethylene oxide-induced carcinomas. H-ras mutations were identified in 26% (5/19) of spontaneous, 50% (7/14) of benzene-, and 33% (4/12) of ethylene oxide-induced carcinomas. When H-ras mutations were present, concurrent p53 mutations were identified in 40% (2/5) of spontaneous, 71% (5/7) of benzene-, and 75% (3/4) of ethylene oxide-induced carcinomas. Our results demonstrate that p53 and H-ras mutations are relatively common in control and chemically induced mouse mammary carcinomas although both chemicals can alter the mutational spectra and more commonly induce concurrent mutations.     

Characterization of the Left Atrial Vortex Flow by Two-Dimensional Transesophageal Contrast Echocardiography Using Particle Image Velocimetry

This article is the first clinical investigation of the quantitative left atrial (LA) vortex flow by two-dimensional (2-D) transesophageal contrast echocardiography (2-D-TECE) using vector particle image velocimetry (PIV). The aims of this study were to assess the feasibility of LA vortex flow analysis and to characterize and quantify the LA vortex flow in controls and in patients with atrial fibrillation (AF). Thirty-five controls and 30 patients with AF underwent transesophageal contrast echocardiography. The velocity vector was estimated by particle image velocimetry. The morphology and pulsatility of the LA vortex flow were compared between the control and AF groups. In all patients, quantitative LA vortex flow analysis was feasible. In the control group, multiple, pulsatile, compact and elliptical-shaped vortices were seen in the periphery of the LA. These vortices were persistently maintained and vectors were directed toward the atrioventricular inflow. In the AF group, a large, merged, lower pulsatile and round-shaped vortex was observed in the center of the LA. In comparisons of vortex parameters, the relative strength was significantly lower in the AF group (1.624 ± 0.501 vs. 2.105 ± 0.226, p < 0.001). It is feasible to characterize and quantify the LA vortex flow by transesophageal contrast echocardiography in patients with AF, which offers a new method to obtain additional information on LA hemodynamics. The approach has the potential for early detection of the LA dysfunction and in decisions regarding treatment strategy and guiding anticoagulation treatment in patients with AF.     

An empirical test of a mediation model of the impact of the traditional male gender role on suicidal behavior in men

BACKGROUND: Men die by suicide three to four times more often than women in Western countries. The adverse impact of the traditional male gender role as well as men's reluctance to seek help are possible explanations of this gender gap, but these hypotheses have not been well documented empirically. METHODS: This study compares two groups of men who experienced comparable severely stressful life events during the preceding 12 months: 40 men admitted to hospital emergency following suicide attempts, and 40 men with no history of suicide attempts. Structured interviews were conducted to measure adherence to the traditional male gender role, help seeking behaviour, social support, suicide acceptability and mental health. RESULTS: ANOVAS indicated that attempters are more likely to adhere to the traditional masculine gender role and regression analysis revealed that this relationship persists even when the presence of mental disorders is statistically controlled. Sequential regression analysis support the mediation model and show that the effects of the traditional male gender role on suicidal behavior are mediated through protective and risk factors for suicide, namely mental state, help seeking and social support. CONCLUSIONS: The traditional male gender role appears to increase the risk of suicidal behavior in men by undermining their mental state and by inhibiting the protective factors of help seeking and social support. This study underscores the importance of encouraging men to seek help.     

Organizational analysis of Canadian supported employment programs for people with psychiatric disabilities

Supported employment (SE) is widely considered to be the most effective intervention for helping people with psychiatric disabilities integrate into the competitive workforce. While fidelity to principles and standards of evidence-based SE, i.e., the Individual Placement and Support model, is positively associated with vocational outcomes, studies have revealed significant heterogeneity in SE programs implemented in Canada. This qualitative study thus aimed to shed light on organizational and contextual factors influencing SE implementation in three Canadian provinces (British Columbia, Ontario and Quebec). The study adopted several key concepts from the field of organizational studies (e.g., coalitions, archetypes, isomorphism) to guide data collection and analysis. Overall, 20 SE programs provided by 15 different agencies were examined. Findings revealed that agencies' exposure to different institutional pressures, their interactions and relationships with other groups and organizations, as well as their values, beliefs and ideologies played determining roles in shaping the evolution of SE services in each province.     

Adhesion of HT-29 colon carcinoma cells to endothelial cells requires sequential events involving E-selectin and integrin beta4

HT-29 colon carcinoma cells attach to TNFalpha-activated human umbilical vein endothelial cells (HUVECs) by their specific binding to E-selectin. This interaction activates, in the cancer cells, the MAPK SAPK2/p38, which leads to their transendothelial migration (Laferrière et al., J Biol Chem 2001; 276: 33762). In this study, we investigated the role of E-selectin in activating integrins to modulate adhesion and regulate integrin-mediated events. Blocking the integrins from HT-29 cells (alpha2, alpha3, alpha6, alphav/beta5, beta1 and beta4) with specific antibodies revealed a role for beta4 integrin in their adhesion to TNFalpha-treated HUVEC. The beta4 integrin-dependent adhesion was maximal after 30 min, whereas the-E-selectin-dependent adhesion was maximal after 15 min. Integrin beta4 became quickly phosphorylated upon addition of HT-29 cells to endothelial cells and the effect was independent of the expression of E-selectin. Moreover, a recombinant E-selectin/Fc chimera did not induce the phosphorylation of beta4. The phosphorylation of beta4 is not required for adhesion since adhesion was not affected in HT-29 cells that express a truncated form of beta4 that is deleted from its cytoplasmic phosphorylatable domain. However, the expression of the non-phosphorylatable deletant of beta4 was associated with decreased transendothelial cell migration underscoring the key role for the cytoplasmic domain of beta4 in cell migration. We suggest: 1) that the adhesion of HT-29 cells to activated endothelial cells follows at least two essential sequential steps involving the binding of E-selectin to its receptor on carcinoma cells and then the binding of beta4 to its own receptor on endothelial cells; 2) that the phosphorylation of integrin beta4 contributes to enhance the motile potential of cancer cells and increase their trans-endothelial migration. Overall, our results indicate that the interaction of metastatic cancer cells with endothelial cells implies a specific sequence of signaling events that ultimately leads to an increase in their efficient transendothelial migration.     

Effects of short-term treadmill exercise training or growth hormone supplementation on diastolic function and exercise tolerance in old rats

Whether the lusitropic potential of short-term exercise in aged rats is linked to an augmentation in the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and an alteration in the cardiac renin angiotensin system (RAS) is unknown. Old (28-month-old) male, Fischer 344xBrown Norway rats were randomized to 4 weeks of GH supplementation (300 microg subcutaneous, twice daily) or 4 weeks of treadmill running, or were used as sedentary controls. Six-month-old rats, sedentary or exercised, were used as young controls. Training improved exercise capacity in old animals. Exercise and GH attenuated age-related declines in myocardial relaxation despite an exercise-induced suppression of IGF-1. The regulatory protein, sarcoplasmic Ca2+ adenosine triphosphatase (SERCA2), increased with exercise but not GH. Among aged rats, the cardiac RAS was not altered by training or GH. Thus, the signaling pathway underlying the lusitropic benefit of short-term habitual exercise in the aged rat may be distinct from GH-mediated benefits and independent of the cardiac RAS.