Long-term safety of monthly zoledronic acid therapy beyond 1 year in patients with advanced cancer involving bone (LoTESS): A multicentre prospective phase 4 study.

Malignant bone disease can cause significant morbidity. Monthly zoledronic acid (ZOL) reduces skeletal complications; however, limited data are available regarding long-term safety. We aimed to assess efficacy and safety of ZOL beyond 1 year of treatment. We prospectively evaluated 73 patients; breast cancer (n = 29), castrate-resistant prostate cancer (n = 13), multiple myeloma (n = 31) from 2006 to 2008 in 19 cancer centres. All patients were diagnosed with bone disease and had completed 1-2 years of monthly ZOL (4 mg) and received a further 1-2 years of therapy following contemporary guidelines for managing risks of osteonecrosis of the jaw (ONJ) and renal toxicity. Overall rates of skeletal-related events (SREs), renal impairment and ONJ were assessed. Over the additional 1 year of treatment, only 5.5% (n = 4) of patients developed a new SRE. The overall Kaplan-Meier estimate for SRE incidence after 48 weeks on study was 6.75% (95 CI: 2.5-17.3). Although 51% of patients reported serious adverse events, only two cases were suspected as ZOL related. No patients had confirmed ONJ. The observed incidence of new renal impairment was 11% (none due to ZOL). Our study confirms the benefit over risk of continuing monthly ZOL for at least 2 years in patients with advanced cancer involving bone.

The impact of two-dimensional versus three-dimensional ultrasound exposure on maternal-fetal attachment and maternal health behavior in pregnancy.

OBJECTIVE: To explore the impact of timing and type of ultrasound, particularly three-dimensional (3D), exposure on maternal-fetal attachment and maternal health behavior during pregnancy. METHODS: Subjects were 68 women aged 18 years or older expecting their first child who presented for a routine ultrasound scan at around either 12 or 18 weeks' gestation in Nepean Hospital, Western Sydney. Women completed questionnaires assessing maternal-fetal attachment and health behavior, and were then allocated arbitrarily to either two-dimensional (2D) or 3D ultrasound examination. Repeat questionnaires were completed 1 week later. RESULTS: Maternal-fetal attachment increased after both 2D and 3D ultrasound exposure, and the effect was moderated by the timing of exposure, with women receiving their first ultrasound examination at around 12 weeks showing the greatest change. Alcohol consumption was the only behavior to show significant change following ultrasound exposure, with a reduction in the reported average number of drinks per week. There was no significant difference in the pattern of change for 2D compared with 3D ultrasound exposure, and no effect of ultrasound exposure on maternal perception of the fetus. CONCLUSIONS: Ultrasound has a positive impact on maternal-fetal attachment, particularly in the first trimester. 3D ultrasound did not offer enhanced benefits. Associations between ultrasound exposure and alcohol consumption warrant further investigation. Larger samples are needed to clarify the moderating effects of gestational age and type of ultrasound exposure.

The p85 subunit of phosphoinositide 3-kinase is associated with beta-catenin in the cadherin-based adhesion complex.

Cell adhesion is fundamental to establishing and maintaining the discrete tissues in multicellular organisms. Adhesion must be sufficiently strong to preserve tissue architecture, whilst having the capacity to readily dissociate to permit fundamental processes, such as wound repair, to occur. However, very little is known about the signalling mechanisms involved in temporary down-regulation of cell adhesion to facilitate such processes. Cadherins are the principal mediators of cell-cell adhesion in a wide variety of tissues and species and form multi-protein complexes with cytosolic and cytoskeletal proteins to express their full adhesive capacity. In the present study we report that the p85 subunit of phosphoinositide 3-kinase (PI 3-kinase) is associated with the cadherin-based adhesion complex in human epithelial cells. The interaction of p85 with the complex is via beta-catenin. We also show that the interaction of p85 and beta-catenin is direct, involves the N-terminal Src homology domain 2 of p85 and is regulated by tyrosine phosphorylation. These data suggest that PI 3-kinase may play a role in the functional regulation of the cadherin-based adhesion complex.

Nature over nurture: temperament, personality, and life span development.

Temperaments are often regarded as biologically based psychological tendencies with intrinsic paths of development. It is argued that this definition applies to the personality traits of the five-factor model. Evidence for the endogenous nature of traits is summarized from studies of behavior genetics, parent-child relations, personality structure, animal personality, and the longitudinal stability of individual differences. New evidence for intrinsic maturation is offered from analyses of NEO Five-Factor Inventory scores for men and women age 14 and over in German, British, Spanish, Czech, and Turkish samples (N = 5,085). These data support strong conceptual links to child temperament despite modest empirical associations. The intrinsic maturation of personality is complemented by the culturally conditioned development of characteristic adaptations that express personality; interventions in human development are best addressed to these.

Phosphatidylinositol 3'-kinase-independent p70 S6 kinase activation by fibroblast growth factor receptor-1 is important for proliferation but not differentiation of endothelial cells.

p70(s6k) has a role in cell cycle progression in response to specific extracellular stimuli. The signal transduction pathway leading to activation of p70(s6k) by fibroblast growth factor receptor-1 (FGFR-1) was examined in FGF-2-treated rat L6 myoblasts. p70(s6k) was activated in a biphasic and rapamycin-sensitive manner. Although phosphatidylinositol 3'-kinase was not activated in the FGF-2 treated cells, as judged from in vitro and in vivo analyses, wortmannin and LY294002 treatment inhibited p70(s6k) activation. Inhibition of protein kinase C (PKC), by bisindolylmaleimide or by chronic phorbol ester treatment of the FGFR-1 cells, suppressed but did not block p70(s6k) activation. In cells expressing a point-mutated FGFR-1, Y766F, unable to mediate PKC activation, p70(s6k) was still activated, in a bisindolylmaleimide- and phorbol ester-resistant manner. The involvement of S6 kinase in FGFR-1-dependent biological responses was examined in murine brain endothelial cells. In response to FGF-2, these cells differentiate to form tube-like structures in collagen gel cultures and proliferate when cultured on fibronectin. p70(s6k) was not activated in endothelial cells on collagen, whereas activation was observed during proliferation on fibronectin. In agreement with this finding, rapamycin inhibited the proliferative but not the differentiation response. Our results indicate that FGFR-1 mediates p70(s6k) activation by a phosphatidylinositol 3'-kinase-independent mechanism that does not require PKC activation and, furthermore, proliferation, but not differentiation of endothelial cells in response to FGF-2, is associated with p70(s6k) activation.

Embedded Figures Test performance before and after childbirth.

Performance on the Embedded Figures Test was investigated before and after childbirth when biochemical changes are marked. Females comprising a first experimental group were tested in their 38th to 40th week of pregnancy. Their husbands who comprised a male control group were tested concurrently. The females were again tested in the sixth week following delivery. There was a significant (P less than 0.001) test-retest difference in EFT scores. Testing of a second female experimental group, to investigate the possibility of a practice effect, indicated that a factor over and above the practice effect was operating in the scores of the first experimental group.