The Multilevel Structure of Four Adolescent Problems

This paper examines variability in adolescent self-reported behavior at the individual, cohort, and school levels for 8th and 11th graders. We examine four adolescent behaviors: substance use, antisocial behavior, depression, and academic performance. Research staff collected the data as part of the Oregon Healthy Teens survey of a population-based sample of 60,837 adolescents over three years in 92 communities. The results indicate that schools vary over time, but not necessarily systematically, and grade-level cohorts account for important variance within schools. The school and cohort combined, however, accounted for at most 4% of the overall variance. The results have implications for research and practice in schools and communities. For example, selection of communities for interventions based on high levels of adolescent problems may be unproductive if individuals account for at least 96% of the variance. Furthermore, in non-experimental designs, cohort variability, not an intervention, may account for apparent improvement across     

Integration of hepatic drug transporters and phase II metabolizing enzymes: Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites

The liver is the primary site of drug metabolism in the body. Typically, metabolic conversion of a drug results in inactivation, detoxification, and enhanced likelihood for excretion in urine or feces. Sulfation, glucuronidation, and glutathione conjugation represent the three most prevalent classes of phase II metabolism, which may occur directly on the parent compounds that contain appropriate structural motifs, or, as is usually the case, on functional groups added or exposed by phase I oxidation. These three conjugation reactions increase the molecular weight and water solubility of the compound, in addition to adding a negative charge to the molecule. As a result of these changes in the physicochemical properties, phase II conjugates tend to have very poor membrane permeability, and necessitate carrier-mediated transport for biliary or hepatic basolateral excretion into sinusoidal blood for eventual excretion into urine. This review summarizes sulfation, glucuronidation, and glutathione conjugation reactions, as well as recent progress in elucidating the hepatic transport mechanisms responsible for the excretion of these conjugates from the liver. The discussion focuses on alterations of metabolism and transport by chemical modulators, and disease states, as well as pharmacodynamic and toxicological implications of hepatic metabolism and/or transport modulation for certain active phase II conjugates. A brief discussion of issues that must be considered in the design and interpretation of phase II metabolite transport studies follows.     

Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma.

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.     

Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial.

PURPOSE: Vasomotor symptoms, such as hot flashes and night sweats, in breast cancer survivors are often worsened by chemotherapy and tamoxifen, and/or the discontinuation of hormone replacement therapy at diagnosis. This study evaluated the acceptability and effectiveness of a soy beverage containing phytoestrogens as a treatment for hot flashes in postmenopausal women with breast cancer. METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted in postmenopausal women with moderate hot flashes who were previously treated for early-stage breast cancer. Women were stratified for tamoxifen use and randomized to a soy beverage (n = 59) containing 90 mg of isoflavones or to a placebo rice beverage (n = 64). Women recorded the number and severity of hot flashes daily with a daily menopause diary for 4 weeks at baseline and for 12 weeks while consuming 500 mL of a soy or placebo beverage. RESULTS: There were no significant differences between the soy and placebo groups in the number of hot flashes or hot flash scores. However, presumably because of a strong placebo effect, both groups had significant reductions in hot flashes. Mild gastrointestinal side effects were experienced by both groups but occurred with greater frequency and severity with soy. The mean serum genistein concentration at 6 weeks was significantly higher in women who consumed soy (0.61 +/- 0.43 micromol/L) compared with placebo (0.43 +/- 0.37 micromol/L) (P =.02). Overall acceptability and compliance were high and similar in both groups. CONCLUSION: The soy beverage did not alleviate hot flashes in women with breast cancer any more than did a placebo. Future research into other compounds is recommended to identify safe and effective therapies for hot flashes in breast cancer survivors.     

Is there a role for Notch signalling in human breast cancer?

Aberrant Notch signalling has been observed in several human cancers, including acute T-cell lymphoblastic leukaemia and cervical cancer, and is strongly implicated in tumourigenesis. Unregulated Notch signalling in the mouse mammary gland leads to tumour formation. These results raise the possibility that Notch signalling might play a role in human breast cancer. There are currently few reports that address this question directly and this appears to be an area worthy of further investigation.     

How much are patients willing to pay to avoid postoperative nausea and vomiting?

Postoperative nausea and vomiting (PONV) are unpleasant experiences. However, there is no drug that is completely effective in preventing PONV. Whereas cost effectiveness analyses rely on specific health outcomes (e.g., years of life saved), cost-benefit analyses assess the cost and benefit of medical therapy in terms of dollars. We hypothesized that patients were willing to pay for a hypothetical new drug that would eliminate PONV. Eighty elective day surgical patients using general anesthesia participated in the study. After their recovery in the postanesthetic care unit, they were asked to complete an interactive computer questionnaire on demographics, the value of avoiding PONV, and their willingness to pay for an antiemetic. Patients were willing to pay US$56 (US$26--US$97; median, 25%--75%) for an antiemetic that would completely prevent PONV. Patients who developed nausea (n = 21; 26%) and vomiting (n = 9; 11%) were willing to pay US$73 (US$44--US$110) and $100 (US$61--US$200; median, 25%--75%), respectively (P < 0.05). Seventy-six percent of patients considered avoiding postoperative nausea and 78% of patients considered avoiding vomiting as important (> or = 50 mm on a 0--100-mm visual analog scale). Nausea or vomiting in the postanesthetic care unit, greater patient income, previous history of PONV, more importance placed on avoiding nausea and vomiting, increasing age, and being married are independent covariates that increase the willingness to pay estimates. Patients associated a value with the avoidance of PONV and were willing to pay between US$56 and US$100 for a completely effective antiemetic.