Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Analysis of tablet compaction. I. Characterization of mechanical behavior of powder and powder/tooling friction.

In this first of two articles on the modeling of tablet compaction, the experimental inputs related to the constitutive model of the powder and the powder/tooling friction are determined. The continuum-based analysis of tableting makes use of an elasto-plastic model, which incorporates the elements of yield, plastic flow potential, and hardening, to describe the mechanical behavior of microcrystalline cellulose over the range of densities experienced during tableting. Specifically, a modified Drucker-Prager/cap plasticity model, which includes material parameters such as cohesion, internal friction, and hydrostatic yield pressure that evolve with the internal state variable relative density, was applied. Linear elasticity is assumed with the elastic parameters, Young's modulus, and Poisson's ratio dependent on the relative density. The calibration techniques were developed based on a series of simple mechanical tests including diametrical compression, simple compression, and die compaction using an instrumented die. The friction behavior is measured using an instrumented die and the experimental data are analyzed using the method of differential slices. The constitutive model and frictional properties are essential experimental inputs to the finite element-based model described in the companion article.

Analysis of tablet compaction. II. Finite element analysis of density distributions in convex tablets.

A Drucker-Prager/cap constitutive model, where the elastic and plastic model parameters are expressed as a function of relative density (RD), was presented in a companion article together with experimental calibration procedures. Here, we examine the RD distribution in curved-faced tablets with special reference to the die wall lubrication conditions. The compaction of powders is examined using finite element analysis, which involves the following factors: constitutive behavior of powder, friction between powder and tooling, geometry of die and punches, sequence of punch motions, and initial conditions that result from die fill. The predictions of the model are validated using experimental RD maps. It is shown that different die wall lubrication conditions induce opposite density distribution trends in identical tablets (weight, height, and material). The importance of the internal tablet structure is illustrated with respect to break force, failure mode, and friability: it is demonstrated that for a given average tablet density the break force and failure mode are not unique. Also, tablet regions having lower density locally have higher propensity for damage. The applicability of finite element analysis for optimizations of formulation design, process development, tablet image, and tool design is discussed.

Measurement of density variations in tablets using X-ray computed tomography.

In this paper the application of X-ray computed tomography (CT) to measure the material density distribution in pharmaceutical tablets is discussed. X-ray CT is a non-destructive inspection technique which provides cross-sectional images in different planes through a component. The CT image values provide information on the local X-ray attenuation coefficients. For a particular material and X-ray energy, X-ray attenuation is approximately proportional to material density. Determination of quantitative density distributions requires consideration of non-linear instrumental effects including scatter and "beam hardening". Density maps in tablets manufactured under controlled conditions are presented. The results are discussed with reference to the local properties of the material within the tablet and the tablet design features.

Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy.

Dystrophin is a cytoskeletal protein of muscle fibers; its loss in humans leads to Duchenne muscular dystrophy, an inevitably fatal wasting of skeletal and cardiac muscle. mdx mice also lack dystrophin, but are only mildly dystrophic. Utrophin, a homolog of dystrophin, is confined to the postsynaptic membrane at skeletal neuromuscular junctions and has been implicated in synaptic development. However, mice lacking utrophin show only subtle neuromuscular defects. Here, we asked whether the mild phenotypes of the two single mutants reflect compensation between the two proteins. Synaptic development was qualitatively normal in double mutants, but dystrophy was severe and closely resembled that seen in Duchenne. Thus, utrophin attenuates the effects of dystrophin deficiency, and the double mutant may provide a useful model for studies of pathogenesis and therapy.

Passive exhalation technique correlates with esophageal balloon measurements of respiratory mechanics in beagle pups.

We correlated respiratory system mechanics measured by passive exhalation technique with pulmonary mechanics assessed by esophageal balloon technique to determine the ability of each to detect histamine-aerosol-induced changes in conductance and compliance. Eight beagle pups were anesthetized with chloralose and mechanically ventilated 6 times over a 2-wk period of an acute canine parainfluenza II infection. Measurements of respiratory mechanics were obtained by both methods after aerosol challenge with 5 breaths of saline and after each of 9 increasing doses of histamine. Pulmonary conductance and static compliance of the lung were measured by the esophageal balloon method. The rate constant of the respiratory system was calculated by computer-assisted analysis of passive exhalation. Static compliance of the respiratory system was measured after 2 s of apnea, and conductance of the respiratory system was calculated as compliance multiplied by rate constant. Paired data were obtained on 349 measurements. As expected, both conductance and compliance decreased significantly (p less than 0.05) after histamine aerosol challenge by both techniques. Rate constant did not change significantly by either method. The 2 techniques were highly correlated (p less than 0.001) for conductance (r = 0.76), compliance (r = 0.94), and rate constant (r = 0.66). We conclude that analysis of respiratory mechanics using the passive exhalation method correlates well with esophageal balloon data. Furthermore, passive exhalation techniques are technically simple and can detect changes in respiratory mechanics associated with histamine challenges.

Lipoid pneumonia secondary to baby oil aspiration: a case report and review of the literature.

Baby oil is a common household product that is frequently used when there are infants or toddlers in the house. However, it is often overlooked as a potential source of danger to these youngsters. In 1983, 36,700 cases of ingestion were reported to the poisoning surveillance and epidemiology branch of the Food and Drug Administration. Topical preparations used in the care of infants accounted for 480 of the cases. Ten percent of these required hospitalization. In 36 cases, the product ingested was baby oil. This figure does not include baby lotions and other skin products with a mineral oil base. Aspiration of mineral oil, the main component of baby oil, has been described as a cause of lipoid pneumonia and oleomas. However, there is very little information in the modern literature concerning acute lipoid pneumonitis in children. We herein present a patient with lipoid pneumonia caused by aspirated baby oil, who followed a severe clinical course. The paucity of information regarding this subject points to the need for increased public and physician awareness of the problem and for their direct participation in the prevention of this potentially fatal condition.

Replication and serial passage of a singly enveloped baculovirus of Orgyia leucostigma in homologous cell lines.

A singly enveloped nuclear polyhedrosis virus (SNPV) of the white-marked tussock moth, Orgyia leucostigma, was successfully grown in four continuous cell lines developed from minced neonate larvae of this insect. Level of infection in two cell lines, IPRI-OL-12 and IPRI-OL-13, was 65-90%, but in the other two, IPRI-OL-4 and IPRI-OL-9, it was about 3%. Polyhedral inclusion bodies (PIBs) appeared in the nuclei of cells within 24 h postinoculation. Cytopathological changes and morphogenesis of the virus, as revealed by light and electron microscopy, were in general typical of an SNPV. However, some of the PIBs contained very few virions, and some were fractured. Rate zonal centrifugation of alkali-released occluded virions further confirmed the singly enveloped characteristics of the virus. The SNPV was serially passaged 60 times each in OL-12 and OL-13 cells. Percentage infected cells and PIB production stayed generally high throughout serial passaging in OL-13 cells, but declined sharply after the 41st passage in OL-12 cells. PIBs from the 4th passage of the virus in OL-12 cells were tested and found to be pathogenic to O. leucostigma larvae.

Effects of red-headed in sawfly, Neodiprion lecontei, nuclear polyhedrosis virus on rainbow trout, Salmo gairdneri, and Daphnia pulex.

The effects of a nuclear polyhedrosis virus (NPV) of the red-headed pine sawfly, Neodiprion lecontei, on rainbow trout, Salmo gairdneri, were investigated. The fish were exposed to this virus by intubation and topical application and no ill-effects were observed. Similarly, no ill-effects were detected in Daphnia pulex when the same NPV was added to their culture medium. The materials were lyophilized, NPV-infected sawfly larvae (normally used for insect control), lyophilized, uninfected larvae and purified, polyhedral inclusion bodies. On the basis of these laboratory tests, this virus, when disseminated as a biocontrol agent, should present no hazard to rainbow trout or to the aquatic invertebrate Daphnia pulex, two species frequently used in toxicity tests of chemical pesticides.