Screening options for Down syndrome: how women choose in real clinical setting.

OBJECTIVE: To study pregnant women's preference among various screening options for Down syndrome (DS) in routine clinical setting, and its potential association with women's demographic characteristics. METHODS: Women aged 35 years and older carrying singleton pregnancy were offered a variety of screening tests for DS before 14 weeks of gestation. Their preference was confirmed by the test they actually underwent. The association between women's choice of test and a number of demographic characteristics was studied using multinomial regression. RESULTS: Among 1967 eligible women, 619 opted for first-trimester screening test (FTS), 924 for partial integrated test (PIT), and 424 for full integrated test (FIT). Nulliparous women and working mothers were more likely to choose FTS and FIT. Women with history of subfertility were more likely to choose FIT. Women with family history of chromosomal abnormalities were more likely to choose FTS. The choice of screening test could be predicted for 49.9% of women using four demographic characteristics. CONCLUSIONS: Among older women of predominantly Chinese ethnicity, integrated test is a favorite alternative to FTS. Their choice of DS screening test can be predicted by their obstetric and socioeconomic characteristics. Many women show willingness to pay for a test with a lower false-positive rate.

The NF-kappa B inhibitor, tepoxalin, suppresses surface expression of the cell adhesion molecules CD62E, CD11b/CD18 and CD106.

Tepoxalin, a dual enzyme inhibitor of cyclooxygenase and 5-lipoxygenase has been shown to inhibit T-cell activation. Its immunosuppressive property is distinct from cyclosporin because only tepoxalin, but not cyclosporin, suppresses NF-kappa B activation. Here we report that tepoxalin selectively inhibits intercellular adhesion molecule-1 (ICAM-1, CD54)/MAC-1 (CD11b/CD18) dependent adhesion of polymorphonuclear cells to IL-1 activated human umbilical vein endothelial cells. The mechanism of inhibition is related to the surface expression of several cell adhesion molecules. Flow cytometry analyses on cultured cells that were treated with tepoxalin or antisense oligonucleotides to the P65/p50 subunit of NF-kappa B, and then stimulated with PMA, revealed a reduced expression of CD11b/CD18 on monocytic HL60 cells, and endothelial adhesion molecule-1 (CD62E) and vascular adhesion molecule-1 (CD106) on human umbilical vein endothelial cells. Expression of other adhesion molecules such as lymphocyte function associated-antigen-1 (CD11a/CD18) and CD54 were unaffected. Tepoxalin also inhibited the secretion of a NF-kappa B regulated chemokine, IL-8, a known inducer of CD11b/CD18 expression. Thus the suppression of CD11b/CD18 expression by tepoxalin may involve IL-8. Our results suggest that by inhibiting NF-kappa B activation, surface expression of several adhesion molecules can be modulated and that tepoxalin may be useful in treating selected adhesion mediated events such as leukocyte migration or atherosclerotic plaque formation.

Novel intracellular signaling function of prostaglandin H synthase-1 in NF-kappa B activation.

Many potent nonsteroidal antiinflammatory drugs (NSAIDs) exert their effects by inhibiting the cyclooxygenase activity of prostaglandin H synthase-1 (PGHS1, thus disrupting prostaglandin biosynthesis. However, these drugs do not block the activation of NF-kappa B, an inducible transcription factor which regulates numerous inflammation-related genes. Here we demonstrate that PGHS1 peroxidase, a NSAID-insensitive activity of PGHS1, mediates NF-kappa B activation through an intracellular reactive oxygen signaling pathway. Overexpression of PGHS1 strongly potentiated NF-kappa B activation by phorbol esters and dramatically elevated the generation of intracellular reactive oxygen species (ROS) in response to low concentrations of t-butyl peroxide. Both functions were dependent on PGHS1 peroxidase activity and could be suppressed by the potent antioxidant pyrrolidine dithiocarbamate. In contrast, elimination of PGHS1 cyclooxygenase activity by NSAIDs or site-directed mutagenesis failed to block ROS production or NF-kappa B activation. Thus, PGHS1 peroxidase serves an intracellular signaling function leading to NF-kappa B activation, separable from its role in prostaglandin synthesis.

Wettability of pharmaceutical solids: estimates of solid surface polarity.

Contact angle measurements of water and methylene iodide with various organic solids were used to estimate the surface free energy per square centimeter, gammaS, and the contributions of nonpolar and polar forces, gammaSd and gammaSp, respectively. The ratio of gammaSp to gammaS was used as an estimate of solid surface polarity, and values ranging from 0 to 42% polarity were calculated for materials of pharmaceutical interest. Surface free energies per mole were calculated to compare the influence of different substituent groups on wettability. This approach offers a convenient means to quantitate the polarity of organic pharmaceutical solid surfaces.

Tepoxalin, a novel dual inhibitor of the prostaglandin-H synthase cyclooxygenase and peroxidase activities.

Prostaglandin-H synthase-1, the rate-limiting enzyme in prostaglandin synthesis, has both cyclooxygenase (CO) and peroxidase (PO) activities. While most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit only the CO activity, we describe an inhibitor, tepoxalin, that inhibits both the CO (IC50 = 0.1 microM) and the PO (IC50 = 4 microM) activities. Unlike many NSAIDs which are competitive inhibitors of CO, tepoxalin is a noncompetitive inhibitor of CO and its inhibitory effect on PO but not CO is reversed by excess heme. Moreover, inhibition of the PO activity by tepoxalin is not dependent on the enzymatic turnover of the CO activity. The hydroxamic acid of tepoxalin is responsible for the PO inhibition since a carboxylic acid derivative of tepoxalin retains full CO but not PO inhibition. We postulated that the hydroxamic group might confer the ability to inhibit PO on conventional CO inhibitors. This idea was supported by the observation that naproxen hydroxamic acid, but not naproxen showed PO inhibition. Furthermore, tepoxalin's carboxylic acid analogue and naproxen each competitively relieved PO inhibition by their respective hydroxamic acids. The intracellular activity of PO as monitored by the release of reactive oxygen species was also inhibited by both tepoxalin and naproxen hydroxamic acid. These observations suggest a strategy for design of novel compounds to inhibit prostaglandin synthase PO. The therapeutic implications of these novel PO inhibitors are discussed.

Tepoxalin enhances the activity of an antioxidant, pyrrolidine dithiocarbamate, in attenuating tumor necrosis factor alpha-induced apoptosis in WEHI 164 cells.

The nuclear transcription factor-kappaB (NF-kappaB) and free radicals are known to be involved in apoptosis. We studied the effects of a series of di-aryl-substituted pyrazole NF-kappaB inhibitors including tepoxalin on tumor necrosis factor alpha (TNFalpha)-induced apoptosis in murine fibrosarcoma WEHI 164 cells. We found that potent inhibitors of NF-kappaB were also effective in attenuating apoptosis. WEHI 164 cells that had been dually treated with tepoxalin and the antioxidant pyrrolidine dithiocarbamate (PDTC) were significantly protected from TNFalpha-induced killing. To study the role of free radicals in mediating TNFalpha-induced apoptosis, stable WEHI 164 cells overexpressing Bcl-2, an antioxidant protein, were generated. These cells were protected from TNFalpha-induced apoptosis and neither tepoxalin nor PDTC provided further significant protection. These results suggest that Bcl-2, PDTC, and tepoxalin may attenuate apoptosis in this system by affecting the same signaling pathway or converging pathways. Because tepoxalin suppresses the release of free radicals, PDTC scavenges free radicals and Bcl-2 is an antioxidant protein, free radicals are among the key mediators of this TNF-induced killing event. Tepoxalin and antioxidants may be useful in developing new therapeutics for treating neurodegenerative diseases, autoimmune deficiency syndrome, and ischemia-reperfusion injuries.