The association among cytochrome P450 3A, progesterone receptor polymorphisms, plasma 17-alpha hydroxyprogesterone caproate concentrations, and spontaneous preterm birth

Background Infants born <37 weeks’ gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children <5 years of age and a major cause of morbidity and lifelong disability. The administration of 17-alpha hydroxyprogesterone caproate reduces preterm birth by 33% in women with history of spontaneous preterm birth. We demonstrated previously that plasma concentrations of 17-alpha hydroxyprogesterone caproate vary widely among pregnant women and that women with 17-alpha hydroxyprogesterone caproate plasma concentrations in the lowest quartile had spontaneous preterm birth rates of 40% vs rates of 25% in those women with higher concentrations. Thus, plasma concentrations are an important factor in determining drug efficacy but the reason 17-alpha hydroxyprogesterone caproate plasma concentrations vary so much is unclear. Predominantly, 17-alpha hydroxyprogesterone caproate is metabolized by CYP3A4 and CYP3A5 enzymes. Objective We sought to: (1) determine the relation between 17-alpha hydroxyprogesterone caproate plasma concentrations and single nucleotide polymorphisms in CYP3A4 and CYP3A5; (2) test the association between progesterone receptor single nucleotide polymorphisms and spontaneous preterm birth; and (3) test whether the association between plasma concentrations of 17-alpha hydroxyprogesterone caproate and spontaneous preterm birth varied by progesterone receptor single nucleotide polymorphisms. Study Design In this secondary analysis, we evaluated genetic polymorphism in 268 pregnant women treated with 17-alpha hydroxyprogesterone caproate, who participated in a placebo-controlled trial to evaluate the benefit of omega-3 supplementation in women with history of spontaneous preterm birth. Trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were measured between 25-28 weeks of gestation after a minimum of 5 injections of 17-alpha hydroxyprogesterone caproate. We extracted DNA from maternal blood samples and genotyped the samples using TaqMan (Applied Biosystems, Foster City, CA) single nucleotide polymorphism genotyping assays for the following single nucleotide polymorphisms: CYP3A4*1B, CYP3A4*1G, CYP3A4*22, and CYP3A5*3; and rs578029, rs471767, rs666553, rs503362, and rs500760 for progesterone receptor. We adjusted for prepregnancy body mass index, race, and treatment group in a multivariable analysis. Differences in the plasma concentrations of 17-alpha hydroxyprogesterone caproate by genotype were evaluated for each CYP single nucleotide polymorphism using general linear models. The association between progesterone receptor single nucleotide polymorphisms and frequency of spontaneous preterm birth was tested using logistic regression. A logistic model also tested interaction between 17-alpha hydroxyprogesterone caproate concentrations with each progesterone receptor single nucleotide polymorphism for the outcome of spontaneous preterm birth. Results The association between CYP single nucleotide polymorphisms *22, *1G, *1B, and *3 and trough plasma concentrations of 17-alpha hydroxyprogesterone caproate was not statistically significant (P =.68,.44,.08, and.44, respectively). In an adjusted logistic regression model, progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 were not associated with the frequency of spontaneous preterm birth (P =.29,.10,.76,.09, and.43, respectively). Low trough plasma concentrations of 17-alpha hydroxyprogesterone caproate were statistically associated with a higher frequency of spontaneous preterm birth (odds ratio, 0.78; 95% confidence ratio, 0.61–0.99; P =.04 for trend across quartiles), however no significant interaction with the progesterone receptor single nucleotide polymorphisms rs578029, rs471767, rs666553, rs503362, and rs500760 was observed (P =.13,.08,.10,.08, and.13, respectively). Conclusion The frequency of recurrent spontaneous preterm birth appears to be associated with trough 17-alpha hydroxyprogesterone caproate plasma concentrations. However, the wide variation in trough 17-alpha hydroxyprogesterone caproate plasma concentrations is not attributable to polymorphisms in CYP3A4 and CYP3A5 genes. Progesterone receptor polymorphisms do not predict efficacy of 17-alpha hydroxyprogesterone caproate. The limitations of this secondary analysis include that we had a relative small sample size (n = 268) and race was self-reported by the patients

Near- Real-Time Control of Human Figure Models

Includes bibliography. Animating human figures is one of the major problems in computer animation. A recent approach is the use of dynamic analysis to compute the movement of a human figure, given the forces and torques operating within and upon the body. One of the problems with this technique is computing the forces and torques required for particular motions: this has been called the control problem of dynamic analysis. To develop a better understanding of this problem, an interactive interface to a dynamics package has been produced. This interface, along with a collection of low-level motion processes, can be used to control the motion of a human figure model. This article describes both the user interface and the motion processes, along with experiences with this approac

Descriptive circular of Lake George Nurseries for the season 1893-94 /

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Descriptive catalogue of Lake George Nurseries : winter 1887-8 /

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Descriptive catalogue and price list of the Lake George Nurseries : season 1896-97 /

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NuSTAR and XMM-Newton Observations of Luminous, Heavily Obscured, WISE-selected Quasars at z \~ 2

We report on a NuSTAR and XMM-Newton program that has observed a sample of three extremely luminous, heavily obscured WISE-selected active galactic nuclei (AGNs) at z ~ 2 across a broad X-ray band (0.1 – 79 keV). The parent sample, selected to be faint or undetected in the WISE 3.4 μm (W1) and 4.6 μm (W2) bands but bright at 12 μm (W3) and 22 μm (W4), are extremely rare, with only ~1000 so-called "W1W2-dropouts" across the extragalactic sky. Optical spectroscopy reveals typical redshifts of z ~ 2 for this population, implying rest-frame mid-IR luminosities of νL ν(6 μm) ~ 6 × 1046 erg s–1 and bolometric luminosities that can exceed L bol ~ 1014 L ☉. The corresponding intrinsic, unobscured hard X-ray luminosities are L(2-10 keV) ~ 4 × 1045 erg s–1 for typical quasar templates. These are among the most AGNs known, though the optical spectra rarely show evidence of a broad-line region and the selection criteria imply heavy obscuration even at rest-frame 1.5 μm. We designed our X-ray observations to obtain robust detections for gas column densities N H ≤ 1024 cm–2. In fact, the sources prove to be fainter than these predictions. Two of the sources were observed by both NuSTAR and XMM-Newton, with neither being detected by NuSTAR (f 3-24 keV lsim 10–13 erg cm–2 s–1), and one being faintly detected by XMM-Newton (f 0.5-10 keV ~ 5 × 10–15 erg cm–2 s–1). A third source was observed only with XMM-Newton, yielding a faint detection (f 0.5-10 keV ~ 7 × 10–15 erg cm–2 s–1). The X-ray data imply these sources are either X-ray weak, or are heavily obscured by column densities N H gsim 1024 cm–2. The combined X-ray and mid-IR analysis seems to favor this second possibility, implying the sources are extremely obscured, consistent with Compton-thick, luminous quasars. The discovery of a significant population of heavily obscured, extremely luminous AGNs would not conform to the standard paradigm of a receding torus, in which more luminous quasars are less likely to be obscured, and instead suggests that an additional source of obscuration is present in these extreme sources