Synthesis of flexible sulfur-containing heteroarotinoids that induce apoptosis and reactive oxygen species with discrimination between malignant and benign cells

Regulation of growth, differentiation, and apoptosis by synthetic retinoids can occur through mechanisms that are dependent and independent of their ability to bind and activate nuclear retinoic acid receptors. The objective of this study was to determine if increasing flexibility of the heteroarotinoid structure would affect the specificity of the synthetic retinoids for the receptors and for their regulation of cancerous and nonmalignant cells. Methods were developed to produce the first examples of heteroarotinoids 15a-15h, which contain urea and/or thiourea linking groups between two aryl rings. Substituents at the para position of the single phenyl ring were either an ester, a nitro group, or a sulfonamide group. Ovarian cancer cell lines Caov-3, OVCAR-3, SK-OV-3, UCI-101, and 222 were utilized, and the inhibitory prowess of the heteroarotinoids was referenced to that of 4-HPR (25). Similar to 4-HPR (25), the heteroarotinoids inhibited growth of all cell lines at micromolar concentrations. Although the heteroarotinoids did not activate retinoic acid receptors, the agents induced potent growth inhibition against the cancer cells with weak activity against normal and benign cells. The growth inhibition was associated with cell loss and induction of reactive oxygen species.     

Toward critical research ethics: transforming ethical conduct in qualitative health care research

Based on research conducted with women injection drug users (WIDUs), I discuss the ethical conflicts that researchers and sub-contractors face in gaining access to the life narratives of WIDUs. Foremost among these is the potentially exploitative nature of the study participant-researcher relationship. I suggest that federal and institutional guidelines for human subject research must incorporate additional safeguards to protect study populations such as WIDUs. Moreover, the ethical concerns related to health care research should be addressed in guidelines for ethical conduct with human subjects, research ethics seminars, and required training programs for researchers and subcontractors separately.     

Maintaining respectability and responsibility: gendered labor patterns among women injection drug users

Gender-related factors and the social and economic conditions that impact the lives and health of women injection drug users (IDUs) in Chicago are described. Although study participants are highly imaginative and resourceful in terms of income-generating self-sufficiency, they engage in a variety of behaviors that put them at risk of contracting infectious diseases such as HIV and hepatitis B and C viruses. We point out that labor inequalities experienced by women IDUs, together with the gender ideologies that support those inequalities, provide reduced opportunities to practice harm reduction and other health care options.     

Diminished experience-dependent neuroanatomical plasticity: evidence for an improved biomarker of subtle neurotoxic damage to the developing rat brain

Millions of children are exposed to low levels of environmental neurotoxicants as their brains are developing. Conventional laboratory methods of neurotoxicology can detect maldevelopment of brain structure but are not designed to detect maldevelopment of the brain's capacity for plasticity that could impair learning throughout life. The environmental complexity (EC) paradigm has become classic for demonstrating the modifications in brain structure that occur in response to experience and thus provides a set of indices for plasticity in the healthy brain. In this study, we have tested the hypothesis that if degradation of experience-dependent cortical plasticity is used as a biomarker, then developmental neurotoxic effects will be detected at doses below those that alter cortical morphogenesis overtly. Pregnant Long-Evans hooded rats received a single injection of either saline vehicle or 1, 5, 10, or 25 mg/kg of the well-characterized developmental neurotoxicant methylazoxymethanol acetate (MAM) on the 16th or 17th day of gestation. On postnatal days 35-39, male offspring were assigned to either a complex environment (EC) or an individual cage (IC) for 28 days to stimulate neuroanatomical plasticity. This response was measured as the difference between the thickness of visual cortex of IC and EC littermates at a given dose. The threshold dose for significant reduction of cortical thickness was 25 mg/kg, but the threshold dose for failure of plasticity was much lower and could be detected at 1 mg/kg, the lowest dose used. No other method of assessment has detected lasting effects of prenatal exposure to MAM at such a low dose. These data suggest that this simple test of plasticity could be an efficient way to detect subtle neurotoxic damage to the developing brain.     

Mechanisms underlying DNA damage resistance in a Xiphophorus melanoma cell line

The Xiphophorus hybrid fish model is an important resource for investigating the genetics and molecular biology of melanoma. Consistent with studies using human melanoma cell lines, the Xiphophorus melanoma cell line PSM, survives the lethal effects of ultraviolet-B radiation (UV-B) radiation much better than a cell line derived from normal fish tissue. In contrast to human melanoma cells, which show enhanced nucleotide excision repair, we do not see any differences in the efficiencies of photoenzymatic or nucleotide excision repair in normal and melanoma cell lines. We do, however, observe a significantly reduced growth rate in the melanoma cell line compared with the normal cell line and considerably less effect of UV-B radiation on DNA synthesis. The data suggest that the UV resistance phenotype of PSM cells is due more to the rate of proliferation and increased ability to replicate on a damaged template rather than enhanced repair of DNA photoproducts as observed in human melanoma cells. The putative increase in lesion bypass by DNA polymerase could result in higher mutation frequencies and enhanced genetic lability in fish melanoma cells.     

Audiometric correlates of the unaided APHAB

The Abbreviated Profile of Hearing Aid Benefit (APHAB) is a self-report questionnaire that is used to quantify the impact of a hearing problem on an individual's daily life. In this investigation, the relationships were explored between typical clinical audiometric data and the four subscale scores of the APHAB administered in the unaided (without-amplification) condition. Sixty subjects provided APHAB scores, audiograms, and speech recognition data. Analyses revealed significant relationships between audiometric data and each of the three APHAB subscales that reflect speech communication (EC, RV, and BN). None of these subscales was significantly more strongly related to any specific audiological variable. However, the pattern of associations between audiometric variables and subscale scores was consistent with predictions based on item content for subscales EC and RV, but not for BN. As predicted, no relationship was found between audiometric data and scores for the Aversiveness subscale (AV). Even for the subscales with the strongest associations, differences in audiometric data could be used to explain half or less of the variance in self-report data.