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Breast tissues undergo extensive physiologic changes during pregnancy, which may affect breast carcinogenesis. Gestational hypertension, preeclampsia/eclampsia, gestational diabetes, pregnancy weight gain, and nausea and vomiting (N&V) during pregnancy may be indicative of altered hormonal and metabolic profiles and could impact breast cancer risk. Here, we examined associations between these characteristics of a woman's pregnancy and her subsequent breast cancer risk. Participants were parous women that were recruited to a population-based case-control study (Western New York Exposures and Breast Cancer Study). Cases (n = 960), aged 35-79 years, had incident, primary, histologically confirmed breast cancer. Controls (n = 1,852) were randomly selected from motor vehicle records (< 65 years) or Medicare rolls (≥ 65 years). Women were queried on their lifetime pregnancy experiences. Multivariable-adjusted logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). N&V during pregnancy was inversely associated with breast cancer risk. Relative to those who never experienced N&V, ever experiencing N&V was associated with decreased risk (OR 0.69, 95% CI 0.56-0.84) as were increased N&V severity (p trend < 0.001), longer duration (p trend < 0.01), and larger proportion of affected pregnancies (p trend < 0.0001) among women with ≥ 3 pregnancies. Associations were stronger for more recent pregnancies (< 5 years). Findings did not differ by menopausal status or breast cancer subtype including estrogen receptor and HER2 expression status. Other pregnancy characteristics examined were not associated with risk. We observed strong inverse associations between pregnancy N&V and breast cancer risk. Replication of these findings and exploration of underlying mechanisms could provide important insight into breast cancer etiology and prevention.

An improved, validated HPLC assay was developed for the non-steroidal anti-inflammatory agent, nimesulide. In contrast to previous methods, the present assay requires smaller plasma volumes (0.2 ml) and utilizes a commercially available, structurally similar analogue of nimesulide, NS-398. The method involves a liquid-liquid extraction procedure that can be completed within 4 h, followed by reversed-phase HPLC analysis. Briefly, the extraction protocol required toluene extraction of acidified plasma samples, followed by back-extraction of the retained toluene phase with aqueous base. The retained aqueous alkaline phase was concentrated by toluene re-extraction. The retained toluene phase was evaporated to dryness and reconstituted with 100 microl of mobile phase. Extracted samples were injected (50 microl) onto a Shandon Hypersil BDS C18 column (5 microm particle size; 250x4.6 mm) equilibrated with 1.0 ml/min of 68:32 (v/v) methanol-citrate (0.08 M)-phosphate (0.04 M) buffer (pH 3.0) at room temperature, with detection at 240 nm. The chromatographic run time was 12 min with retention times of 5.9 min and 9.1 min for nimesulide and NS-398, respectively. The analytical method was successfully utilized for a pilot pharmacokinetic study.

During meningitis, the host produces a plethora of signaling agents as part of a coordinated defense mechanism against invading pathogens. Nitric oxide (NO) and prostaglandin E2 (PGE2) are two such inflammatory mediators produced in response to bacterial endotoxins. Disruption of the blood-brain barrier (BBB) is one of many pathophysiological consequences of meningitis. The present objective was to examine the time-course of NO and PGE2 production in relationship to BBB permeability alterations during experimentally-induced meningitis. Meningeal inflammation was elicited by intracisternal administration of the bacterial endotoxin, lipopolysaccharides (LPS; 200 microg), and NO, PGE2, and BBB integrity were monitored over the next 24 h. Meningeal NO production was assessed by headspace chemiluminescence; cerebrospinal fluid PGE2 was determined by enzyme-linked immunosorbent assay (ELISA) immunoassay; and BBB integrity was determined by the brain accumulation of 14C-sucrose. Similar time-course profiles for NO and PGE2 were observed, with a peak effect for both inflammatory mediators observed within 6-8 h after intracisternal LPS dosing. Statistically significant (p < 0.05) disruption of the BBB was observed in various brain regions. Strikingly similar temporal relationships were observed for NO and PGE2 production and BBB disruption. These results suggest the hypothesis that NO and PGE2 may act in conjunction to disrupt the BBB during experimental meningitis.