Active and passive smoking in breast cancer: prospective results from the Nurses' Health Study

BACKGROUND: The role of active and passive smoking in breast cancer remains controversial. METHODS: Using data collected in the prospective Nurses' Health Study, we examined the influence of active and passive smoking on the incidence of invasive breast cancer. The analysis was based on women responding to the 1982 questionnaire, which included questions on passive smoking exposure. Information on active smoking was collected in biennial questionnaires. A total of 78,206 women were followed prospectively from 1982 until June 1996. RESULTS: Of these women, 3,140 reported a diagnosis of invasive breast cancer during follow-up. Compared with never active smoking, relative risks (RR) of breast cancer were 1.04 (95% CI = 0.94-1.15) for current active smoking and 1.09 (95% CI = 1.00-1.18) for past active smoking. The RR for regular passive exposure at work and at home was 0.90 (95% CI = 0.67-1.22). For active smoking, a modest increase in risk was confined to women who began smoking before the age of 17 (RR = 1.19; 95% CI = 1.03-1.37). CONCLUSION: Results suggest that passive smoking is unrelated to breast cancer. However, results for active smoking are compatible with a small increase in risk when smoking is initiated at young ages.     

Heterogeneity in assessing self-reports of caffeine exposure: implications for studies of health effects

BACKGROUND: Coffee and its metabolite caffeine are widely studied for their health effects but with inconclusive results. Caffeine is particularly difficult to assess, and therefore we explore heterogeneity of caffeine exposure. METHODS: We categorized caffeine exposure among 2,478 pregnant women in southern New England during 1996-2000 by the traditional laboratory-based methods of M. Bunker and M. McWilliams. A subsample was examined to ascertain caffeine levels of brewed or purchased beverages actually consumed. RESULTS: More than half (56.6%) of women drank coffee since becoming pregnant. Serving sizes ranged from 2 to 32 oz and are considerably larger than laboratory standards, which are typically 8-10 oz, as compared with the standard of 5 to 6 oz. Conversely, caffeine content per serving of coffee was one-third the laboratory standard, eg, 100 mg caffeine compared with 300 mg for a 10-oz cup. Tea brewed more than 3 minutes contained 42 mg caffeine as compared with the standard of 94 mg. When the amount of caffeine actually consumed was measured, one-quarter (24.8%) of subjects traditionally classified as consuming 300+ gm caffeine daily were reclassified as consuming 150-299 mg. CONCLUSION: Misclassification of caffeine consumption increases difficulty in identifying health effects from caffeine. Some combination of more precise consumption data and a biomarker such as paraxanthine may more precisely estimate exposure.     

Correlation of year-to-year magnetic field exposure metrics among children in a leukemia survival study

The Childhood Leukemia Survival Study is examining the possible association between magnetic field exposure and survival of children with newly diagnosed acute lymphocytic leukemia (ALL). We report the results of serial 24-h personal magnetic field monitoring for 412 US and Canadian children and present the correlations between annual values. The mean time-weighted average (TWA) and geometric mean (GM) were similar for first, second, and third year measurements [TWA: 0.11 microT (n = 412), 0.13 microT (n = 304), and 0.12 microT (n = 134), respectively]. There were no consistent differences in mean TWA or GM based on age or gender. Significantly lower mean TWA and GM were found for children living in rural areas. Higher exposures were noted among children living in urban areas, among apartments dwellers, and those living in rental homes. Measurements taken during summer months and among children residing in the northeast and Canada also tended to be higher. Correlations for most metrics were increased among children who had annual measurements performed during the same season. The metric with the highest year-to-year correlation was the GM. The lowest correlations were found for metrics estimating field intermittency and temporal stability. First to second year GMs were well correlated when taken in the same home (Spearman rank correlation = 0.70), but a lower correlation (0.44) was noted among residentially mobile children. Our findings suggest that summarizing exposure using a single measurement of GM can estimate exposures for residentially stable children, but is not a good predictor of personal exposures among children who change residence during the study interval.     

Risks to the public from historical releases of radionuclides and chemicals at the Rocky Flats Environmental Technology Site

This paper summarizes the methods and results of estimating risks of cancer incidence resulting from plutonium, carbon tetrachloride, and beryllium releases from operations at the Rocky Flats Environmental Technology Site, near Denver, Colorado, from 1953 through 1989. The key findings show that people who lived near the facility were exposed to plutonium mainly through inhalation during routine operations, from a major fire in 1957, and from plutonium resuspended from contaminated soil from an outdoor drum storage area, called the 903 Area. Results were presented for five exposure scenarios that were location-independent. Individuals described by the laborer scenario received the highest risk of all scenarios considered. Upper bound (95th percentile) incremental lifetime cancer incidence risks for the laborer scenario were in about the 10(-4) range (1 chance in 10,000) for developing cancer from Rocky Flats plutonium releases during a lifetime. At the 5th percentile level, the maximum cancer risk was about 10(-7) (1 chance in 10 million) for developing cancer during a lifetime. Estimated cancer risks at the 95th percentile level are within the range of for acceptable risks established by the US Environmental Protection Agency of 10(-6) to 10(-4). Carbon tetrachloride was found to be the chemical that presented the highest risk to the public. The 5th and 95th percentile risk values for exposure to carbon tetrachloride were 9.2x10(-7) and 2.5x10(-5), respectively.     

Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms

OBJECTIVE: This randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of bupropion sustained-release (bupropion SR) in reducing weight and depressive symptoms in obese adults. RESEARCH METHODS AND PROCEDURES: Obese adults (body mass index, 30 to 44 kg/m(2)) not currently meeting criteria for major depression but with depressive symptoms (Beck Depression Inventory score 10-30) received bupropion SR 300 mg/d or placebo for 26 weeks with a 500 kcal/d-deficit diet. Patients who lost <5% of baseline weight at week 12 had bupropion SR dosage or placebo increased to 400 mg/d in a blinded fashion. RESULTS: The bupropion SR group (n = 193) lost an average of 4.4 kg (4.6% of baseline weight) vs. 1.7 kg (1.8% of baseline weight) on placebo (n = 191, p < 0.001, last-observation-carried-forward analysis). More patients in the bupropion SR group than in the placebo group (40% vs. 16% of intent-to-treat sample, 50% vs. 28% of completers, respectively) lost at least 5% of baseline weight (p < 0.05 at week 4, p < 0.001 at weeks 6 to 26). The percentage of patients reporting > or =50% decrease in depressive symptoms did not differ between groups, but depressive symptoms improved more with bupropion SR than with placebo among patients with a history of major depression (p < 0.05, weeks 4 to 26). In the sample as a whole, improvement in depressive symptoms was related to weight loss of > or =5% regardless of treatment (p < 0.0001). Bupropion SR was well-tolerated. DISCUSSION: Bupropion SR in combination with a 500 kcal/d-deficit diet facilitated weight loss. Weight loss of > or =5% may improve mood in obese patients with depressive symptoms.     

The critical role of transmembrane prolines in human prostacyclin receptor activation

The human prostacyclin receptor (hIP), a G protein-coupled receptor (GPCR), plays important roles in vascular smooth muscle relaxation as well as the prevention of platelet aggregation. It has been postulated that GPCR transmembrane (TM) prolines serve as molecular hinges or swivels and are necessary for proper binding and activation. By individually (as well as collectively) mutating these hIP prolines to alanine, the ability to form key structural and functional configurations was removed. Significant effects on both binding and activation were observed. Two highly conserved prolines across GPCRs, Pro-154, and Pro-254 (TMVI), showed the greatest effect on decreasing both binding and activation when changed to alanine. Along the extracellular boundary of the highly conserved transmembrane III domain, a proline-to-alanine mutation at position 89 (P89A) revealed normal binding affinity in comparison with the 1D4-epitope-tagged hIP (hIP1D4) wild-type control (K(i), iloprost = 3 +/- 2 versus 7 +/- 3 nM, respectively). In contrast, activation was markedly affected, with an EC(50) of 12.0 +/- 2.5 nM compared with that of 1.2 +/- 0.3 nM (10-fold difference) for the hIP1D4. Movement within TMIII has been shown to be necessary for effective GPCR activation. Both the extracellular location (above the putative binding pocket) along with an exclusive effect upon activation suggest that this movement is facilitated by the presence of Pro-89 and independent from the actions of ligand binding. This finding strongly supports a model in which proline residues serve as molecular hinges or swivels, essential for coupling receptor binding to activation.     

Oxidized phospholipids derived from ozone-treated lung surfactant extract reduce macrophage and epithelial cell viability

Ozone is known to be a highly toxic gas present in the urban air which exerts its effect on pulmonary tissue through its facile chemical reactions with target molecules in the airway. One of the first barriers encountered by ozone is epithelial lining fluid which contains pulmonary surfactant rich in glycerophosphocholine lipids. The reaction of ozone with calf lung surfactant extract was found to result in the production of 1-palmitoyl-2-(9'-oxo-nonanoyl)-glycerophosphocholine (16:0a/9-al-GPCho) as an expected product of the ozonolysis of abundant unsaturated phospholipids containing unsaturated fatty acyl groups with a double bond at carbon-9. This oxidized phospholipid was identified as a biologically active product in that it reduced elicited macrophage viability by necrosis with an ED(50) of 6 microM. Further studies of the biological activity of 16:0a/9-al-GPCho revealed that concentrations from 100 to 200 nM initiated apoptosis in pulmonary epithelial-like A549 cells as assessed by TUNEL staining, nuclear size, and caspase-3 activation with loss of viability indicated by reduction of mitochondrial dehydrogenase activity. The release of IL-8, a neutrophil chemokine, from A549 cells was also stimulated by 50-100 nM 16:0a/9-al-GPCho. Exposure of calf lung surfactant to low levels of ozone (62.5, 125, and 250 ppb) for various time periods from 2 to 48 h in a feedback-regulated ozone exposure chamber resulted in a dose- and time-dependent increase in the formation of 16:0a/9-al-GPCho as measured by a specific and sensitive LC/MS/MS assay. The quantity of this biologically active chain-shortened glycerophosphocholine lipid generated even at 125 ppb ozone for 2-4 h (50-100 nM) was consistent with this product mediating the toxic effects of ozone on cells in contact with surfactant.     

Recommended structure for reporting economic evaluation on pharmaceuticals in Belgium

Pharmacoeconomic evaluations become more important for the reimbursement of pharmaceuticals, and will be obligatory for new pharmaceutical drugs for which an added therapeutic value is claimed and a price premium is proposed by the manufacturer. Therefore, it is important to guide purchasers and providers of pharmaceutical care in their efforts related to the evaluation process. Standard Report Format can support the quality, transparency and exhaustiveness of the data submitted. A multidisciplinary task force developed a Standard Report Format for pharmacoeconomic evaluations in Belgium.