Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics - an update

Heat-shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of a growing number of signalling proteins that have been implicated in cancer cell survival, including several mutated proteins that are only found in specific cancers. Furthermore, a growing body of evidence suggests that cancer cells are particularly dependent on Hsp90 for their growth and survival, and, therefore, are more sensitive to the effects of its inhibition than are non-transformed cells and tissues. Several chemically distinct Hsp90 inhibitors have shown encouraging antitumour activity in multiple preclinical model systems, and one Hsp90 inhibitor, the benzoquinone ansamycin 17-allylamino, 17-demethoxygeldanamycin, has completed five Phase I clinical trials, with a number of Phase II trials soon to be underway or in progress. Other Hsp90 inhibitors are either in Phase I clinical trial or under development. This update will focus on how the latest developments in Hsp90 biology may better inform the clinical development of Hsp90 inhibitors.     

Phenoxyacetic acid herbicide exposure for women on Ontario farms

Women living and working on farms would be expected to have higher exposure to pesticides than the general nonoccupationally exposed population. Urinary concentrations of the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and (4-chloro-2-methyl) phenoxyacetic acid (MCPA) were measured in 125 women living on farms in Ontario where these herbicides had recently been used for the first time that growing season. The women collected a spot urine void prior to the start of herbicide handling by spouses, followed by 2 consecutive 24-h urine samples. The pesticide applicator provided questionnaire data on pesticides that were used on the farm. Approximately 80% of the women had no detectable level of either herbicide in their urine. Geometric mean urinary concentrations of 2,4-D and MCPA in the d-2 samples were 0.7 microg/L. The responses to the questions on herbicide use on the farm were compared with urinary levels of the herbicide and the sensitivity for MCPA was determined to be 95-100%; however, the false positive rate for exposure was 70%. For 2,4-D, the sensitivity and specificity were approximately 70%, with a false positive rate of 30%. A simple question on whether the herbicide was used recently can accurately identify people who are likely not exposed; however, further research is required to be able to more validly predict those individuals who are exposed. Based on our study, it was concluded that exposure estimates based on questionnaire data alone may be fraught with uncertainties, which may differ depending on the particular pesticide of interest.     

Informed consent in clinical practice: pre-registration house officers' knowledge, difficulties and the need for postgraduate training

In clinical practice consent is often obtained by junior doctors. This study investigates the involvement of pre-registration house officers (PRHOs) in the process of obtaining consent, the supervision they receive and their knowledge on the subject. Some 74% of the PRHOs in post completed the questionnaire; 68% had often or sometimes obtained consent during their year as PRHO; 18% stated that on the occasions when they had obtained consent they were always the only person eliciting consent; 62% of the doctors perceived some lack of knowledge with regard to the nature of the procedure as a difficulty. Despite a comprehensive undergraduate programme in ethics, law and communication there is a need for applied education regarding the clinical procedures for which PRHOs are obtaining consent.     

State health insurance market reforms and access to insurance for high-risk employees

A specific focus for state regulations of the small group insurance market was to increase offers and stabilize premiums for firms with high-risk workers. We examine the effect of reforms implemented from 1993 through 1996 on the likelihood of employer sponsored insurance coverage. We find that packages of reforms that included both guaranteed issue of some products and some form of rate variance restriction had significant positive effects (4.5 percentage points) on ESI coverage for high-risk compared with low-risk workers within small firms and a small negative effect (-1.7 percentage points) on low-risk workers in small compared with large firms. The mechanism for these effects was an increase in take-up, rather than offer. Reform packages that included both guaranteed issue of all products and rate variance restrictions had similar effects overall, although they did not meet criteria for significance. These effects seemed to act through increased offer rather than take-up.     

A multimedia violence prevention program increases pediatric residents' and childcare providers' knowledge about responding to childhood aggression

A pre-post knowledge test using alternate forms was used to determine if a multimedia violence prevention program can increase knowledge about management of childhood aggression. The participants were pediatric residents and childcare workers who attended lectures about aggression management in young children. The intervention was a presentation of a 30 minute CD-ROM program, Play Nicely, which teaches how to manage aggression in young children ages 1 to 7 years. A pretest and posttest multiple-choice knowledge assessment that focused on the program's most important recommendations was administered. Childcare workers and pediatric residents had significantly increased knowledge scores after viewing the CD-ROM demonstration (F=6.8, p = 0.01). Childcare workers' scores improved by 2.6 points (p< 0.001) and residents' scores by 3.8 points (p< 0.001). A relatively short CD-ROM can improve knowledge about how to manage aggression in young children, indicating its usefulness as a violence prevention resource.