Design of a neutron microscope based on Wolter mirrors.

The predominant geometry for a neutron imaging experiment is that of a pinhole camera. This is primarily due to the difficulty in focusing neutrons due to the weak refractive index, which is also strongly chromatic. Proof of concept experiments demonstrated that neutron image forming lenses based on reflective Wolter mirrors can produce quantitative, high spatial resolution neutron images while also increasing the time resolution compared to the conventional pinhole camera geometry. Motivated by these results, we report the design of a neutron microscope where two Wolter mirrors replace condensing and objective lenses, in direct analogy with typical visible light microscopes. Ray tracing results indicate that this system will yield 3 µm spatial resolution images with an acquisition time of order <1 s (104 faster than currently possible at this spatial resolution) with a field of view of about 5 mm in diameter.

Color, composition, and thermal environment of Kuiper Belt object (486958) Arrokoth.

The outer Solar System object (486958) Arrokoth (provisional designation 2014 MU69) has been largely undisturbed since its formation. We studied its surface composition using data collected by the New Horizons spacecraft. Methanol ice is present along with organic material, which may have formed through irradiation of simple molecules. Water ice was not detected. This composition indicates hydrogenation of carbon monoxide-rich ice and/or energetic processing of methane condensed on water ice grains in the cold, outer edge of the early Solar System. There are only small regional variations in color and spectra across the surface, which suggests that Arrokoth formed from a homogeneous or well-mixed reservoir of solids. Microwave thermal emission from the winter night side is consistent with a mean brightness temperature of 29 ± 5 kelvin.

Detection of ammonia on Pluto's surface in a region of geologically recent tectonism.

We report the detection of ammonia (NH3) on Pluto's surface in spectral images obtained with the New Horizons spacecraft that show absorption bands at 1.65 and 2.2 µm. The ammonia signature is spatially coincident with a region of past extensional tectonic activity (Virgil Fossae) where the presence of H2O ice is prominent. Ammonia in liquid water profoundly depresses the freezing point of the mixture. Ammoniated ices are believed to be geologically short lived when irradiated with ultraviolet photons or charged particles. Thus, the presence of NH3 on a planetary surface is indicative of a relatively recent deposition or possibly through exposure by some geological process. In the present case, the areal distribution is more suggestive of cryovolcanic emplacement, however, adding to the evidence for ongoing geological activity on Pluto and the possible presence of liquid water at depth today.

The formation of Charon's red poles from seasonally cold-trapped volatiles.

A unique feature of Pluto's large satellite Charon is its dark red northern polar cap. Similar colours on Pluto's surface have been attributed to tholin-like organic macromolecules produced by energetic radiation processing of hydrocarbons. The polar location on Charon implicates the temperature extremes that result from Charon's high obliquity and long seasons in the production of this material. The escape of Pluto's atmosphere provides a potential feedstock for a complex chemistry. Gas from Pluto that is transiently cold-trapped and processed at Charon's winter pole was proposed as an explanation for the dark coloration on the basis of an image of Charon's northern hemisphere, but not modelled quantitatively. Here we report images of the southern hemisphere illuminated by Pluto-shine and also images taken during the approach phase that show the northern polar cap over a range of longitudes. We model the surface thermal environment on Charon and the supply and temporary cold-trapping of material escaping from Pluto, as well as the photolytic processing of this material into more complex and less volatile molecules while cold-trapped. The model results are consistent with the proposed mechanism for producing the observed colour pattern on Charon.

The small satellites of Pluto as observed by New Horizons.

The New Horizons mission has provided resolved measurements of Pluto's moons Styx, Nix, Kerberos, and Hydra. All four are small, with equivalent spherical diameters of ~40 kilometers for Nix and Hydra and ~10 kilometers for Styx and Kerberos. They are also highly elongated, with maximum to minimum axis ratios of ~2. All four moons have high albedos (~50 to 90%) suggestive of a water-ice surface composition. Crater densities on Nix and Hydra imply surface ages of at least 4 billion years. The small moons rotate much faster than synchronous, with rotational poles clustered nearly orthogonal to the common pole directions of Pluto and Charon. These results reinforce the hypothesis that the small moons formed in the aftermath of a collision that produced the Pluto-Charon binary.

Surface compositions across Pluto and Charon.

The New Horizons spacecraft mapped colors and infrared spectra across the encounter hemispheres of Pluto and Charon. The volatile methane, carbon monoxide, and nitrogen ices that dominate Pluto's surface have complicated spatial distributions resulting from sublimation, condensation, and glacial flow acting over seasonal and geological time scales. Pluto's water ice "bedrock" was also mapped, with isolated outcrops occurring in a variety of settings. Pluto's surface exhibits complex regional color diversity associated with its distinct provinces. Charon's color pattern is simpler, dominated by neutral low latitudes and a reddish northern polar region. Charon's near-infrared spectra reveal highly localized areas with strong ammonia absorption tied to small craters with relatively fresh-appearing impact ejecta.

The Pluto system: Initial results from its exploration by New Horizons.

The Pluto system was recently explored by NASA's New Horizons spacecraft, making closest approach on 14 July 2015. Pluto's surface displays diverse landforms, terrain ages, albedos, colors, and composition gradients. Evidence is found for a water-ice crust, geologically young surface units, surface ice convection, wind streaks, volatile transport, and glacial flow. Pluto's atmosphere is highly extended, with trace hydrocarbons, a global haze layer, and a surface pressure near 10 microbars. Pluto's diverse surface geology and long-term activity raise fundamental questions about how small planets remain active many billions of years after formation. Pluto's large moon Charon displays tectonics and evidence for a heterogeneous crustal composition; its north pole displays puzzling dark terrain. Small satellites Hydra and Nix have higher albedos than expected.

Design and estimated performance of a new neutron guide system for the NCNR expansion project.

An integral part of the National Institute of Standards and Technology Center for Neutron Research (NCNR) expansion project is the addition of five cold neutron guide tubes serving multiple experimental stations in an expanded guide hall. The guides have curved-straight arrangements in the horizontal plane, employing horizontally or vertically defocusing and focusing sections in some cases to improve transmission efficiency or for beam reshaping. The horizontally curved sections eliminate direct lines of sight between the source and the experimental stations, and the outer (concave) surfaces generally have higher critical angles than the inner (convex) surfaces. These features result in well-filtered cold neutron beams with no intensity losses at shorter wavelengths with respect to curved guides having the higher critical angle coatings on both surfaces. For all guides the critical angle of the outer coating of the curved section is selected to achieve a desirable characteristic wavelength, consistent with the instrument requirements. On guides where the scattering-plane beam divergence must be strictly limited, the inner radial coatings of the curved sections and the side coatings and lengths of the final straight sections are chosen to produce the desired beam divergence while the outer radial coating is selected so as to obtain a spatial-angular uniformity of the transmitted beam that is not achievable using a curved guide alone. The long-wavelength transmission of such guides tends to exceed that of equivalent straight guides using crystal filters.

Quasielastic neutron scattering study of hydrogen motion in NbC(0.71)H(0.28).

In order to study the mechanism and parameters of H jump motion in the nonstoichiometric Nb carbides, we have performed quasielastic neutron scattering (QENS) measurements for NbC(0.71)H(0.28) over the temperature range 11- 475 K. Our results indicate that about 30% of H atoms in this system participate in a fast diffusive motion. The temperature dependence of the corresponding H jump rate in the range 298-475 K follows the Arrhenius law with an activation energy of 328 ± 9 meV. The Q dependence of the QENS data suggests that the observed jump motion corresponds to long-range diffusion of H atoms along chains of the off-centre sites in carbon vacancies.

Development of a new measure of health-related quality of life for people with dementia: DEMQOL.

BACKGROUND: We identified the need to develop a scientifically rigorous measure of health-related quality of life (HRQL) in dementia that would be appropriate for use at all stages of dementia severity and would be available in both self- and proxy-report versions. METHOD: We used standard psychometric methods to eliminate items with poor psychometric properties (item-reduction field test) and to assess the acceptability, reliability and validity of the item-reduced instruments (psychometric evaluation field test). We developed and validated two versions of DEMQOL: a 28-item interviewer-administered questionnaire that is self-reported by the person with dementia (DEMQOL) and a 31-item interviewer-administered questionnaire that is proxy-reported by a caregiver (DEMQOL-Proxy). RESULTS: DEMQOL shows high reliability (internal consistency and test-retest) and moderate validity in people with mild/moderate dementia. DEMQOL-Proxy shows good acceptability and internal consistency and moderate evidence of validity in people with mild/moderate and severe dementia. Test-retest reliability and performance in people with severe dementia need further testing. CONCLUSIONS: DEMQOL and DEMQOL-Proxy show psychometric properties that are comparable with the best available dementia-specific measures of HRQL. We recommend that DEMQOL and DEMQOL-Proxy are used together. Reliability and validity need to be confirmed in independent samples and responsiveness needs to be evaluated.

Combined treatment potentiates the developmental toxicity of ibuprofen and acetazolamide in rats.

Aspirin (ASA), an irreversible cyclooxygenase (COX) inhibitor, induces ventricular septal defect (VSD) and diaphragmatic hernia (DH) in rat fetuses when administered on gestation days (GDs) 9-10, a critical period for cardiovascular (CV) and midline development. Evaluation of a spectrum of nonsteroidal antiinflammatory drugs (NSAIDs; reversible COX inhibitors) showed that while some NSAIDs induced VSD in rats, none of the NSAIDs evaluated produced DH. In addition to inhibiting COX, ASA also inhibits carbonic anhydrase. The purpose of this study was to determine whether concurrent inhibition of COX and carbonic anhydrase would produce a teratogenic profile that includes both VSD and DH. To inhibit both COX and carbonic anhydrase, ibuprofen (COX inhibitor) and acetazolamide (carbonic anhydrase inhibitor) were coadministered on GDs 9-10. Groups of 20 female Crl:CD(SD)IGS BR rats were given either 300 mg kg(-1) day(-1) ibuprofen, 1000 mg kg(-1) day(-1) acetazolamide, or both (combination of ibuprofen and acetazolamide). Fetuses were evaluated on GD 21 for external and visceral development. Ibuprofen induced VSD in 3.7% of fetuses per litter; no defects in appendicular skeletal development were noted. Acetazolamide induced VSD in 5.9% of the fetuses per litter and appendicular defects in 41% of the fetuses per litter. Coadministration of ibuprofen and acetazolamide produced VSD in 18.7% of the fetuses per litter and appendicular defects in 77% of the fetuses per litter; however, there were no DH. Therefore, while concurrent inhibition of COX and carbonic anhydrase did not produce DH, potentiation was noted for the induction of VSD and appendicular anomalies.

Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

OBJECTIVES: To develop and validate a psychometrically rigorous measure of health-related quality of life (HRQoL) for people with dementia: DEMQOL. DATA SOURCES: Literature review. Expert opinion. Interviews and questionnaires. REVIEW METHODS: Gold standard psychometric techniques were used to develop DEMQOL and DEMQOL-Proxy. A conceptual framework was generated from a review of the literature, qualitative interviews with people with dementia and their carers, expert opinion and team discussion. Items for each component of the conceptual framework were drafted and piloted to produce questionnaires for the person with dementia (DEMQOL) and carer (DEMQOL-Proxy). An extensive two-stage field-testing was then undertaken of both measures in large samples of people with dementia (n = 130) and their carers (n = 126) representing a range of severity and care arrangements. In the first field test, items with poor psychometric performance were eliminated separately for DEMQOL and DEMQOL-Proxy to produce two shorter, more scientifically robust instruments. In the second field test, the item-reduced questionnaires were evaluated along with other validating measures (n = 101 people with dementia, n = 99 carers) to assess acceptability, reliability and validity. RESULTS: Rigorous evaluation in two-stage field testing with 241 people with dementia and 225 carers demonstrated that in psychometric terms: (1) DEMQOL is comparable to the best available dementia-specific HRQoL measures in mild to moderate dementia, but is not appropriate for use in severe dementia [Mini Mental State Examination (MMSE) <10]; and (2) DEMQOL-Proxy is comparable to the best available proxy measure in mild to moderate dementia, and shows promise in severe dementia. In addition, the DEMQOL system has been validated in the UK in a large sample of people with dementia and their carers, and it provides separate measures for self-report and proxy report, which allows outcomes assessment across a wide range of severity in dementia. CONCLUSIONS: The 28-item DEMQOL and 31-item DEMQOL-Proxy provide a method for evaluating HRQoL in dementia. The new measures show comparable psychometric properties to the best available dementia-specific measures, provide both self- and proxy-report versions for people with dementia and their carers, are appropriate for use in mild/moderate dementia (MMSE >/= 10) and are suitable for use in the UK. DEMQOL-Proxy also shows promise in severe dementia. As DEMQOL and DEMQOL-Proxy give different but complementary perspectives on quality of life in dementia, the use of both measures together is recommended. In severe dementia, only DEMQOL-Proxy should be used. Further research with DEMQOL is needed to confirm these findings in an independent sample, evaluate responsiveness, investigate the feasibility of use in specific subgroups and in economic evaluation, and develop population norms. Additional research is needed to address the psychometric challenges of self-report in dementia and validating new dementia-specific HRQoL measures.

Increase in thyroid follicular cell tumors in nelfinavir-treated rats observed in a 2-year carcinogenicity study is consistent with a rat-specific mechanism of thyroid neoplasia.

The carcinogenic potential of nelfinavir mesylate (nelfinavir) was evaluated in a 2-year oral (gavage) study on Sprague-Dawley rats at dose levels of 0 (control), 0 (vehicle control), 100, 300 and 1000 mg/kg per day. At the end of the treatment, increased incidences of thyroid follicular cell hyperplasia and neoplasms were observed at 300 (males) and 1000 mg/kg per day (both sexes). There were no other treatment-related effects and no tumors at other sites. Results from previous studies indicated a number of effects in the liver and thyroid, as well as metabolic profiles that suggested nelfinavir might cause thyroid hyperplasia/neoplasia secondary to hormone imbalance by altering thyroid hormone disposition. To investigate this hypothesis, the effects of nelfinavir on gene expression in rat hepatocytes and liver slices (in vitro), thyroxine plasma clearance, and thyroid gland function were evaluated. Compared to controls, gene expression analyses demonstrated an increased expression of glucuronyltransferase (UDPGT) and CYP450 3A1 in nelfinavir-treated rat hepatocytes and liver slices. In rats treated with nelfinavir (1000 mg/kg per day) for 4 weeks, liver weights and centrilobular hepatocellular hypertrophy were increased and minimal to mild diffuse thyroid follicular cell hypertrophy and follicular cell hyperplasia were evident in the thyroid gland. Thyroid-stimulating hormone (TSH) levels were significantly increased (three-fold), while tri-iodothyronine (T3)/tetra-iodothyronine (T4) and reverse T3(rT3) levels were unchanged, indicating that a compensated state to maintain homeostasis of T3/T4 had been achieved. Plasma 125I-thyroxine clearance was increased and the plasma thyroxine AUC0-48 was decreased (24%) compared to control. In conclusion, these data indicate that thyroid neoplasms observed in the nelfinavir-treated rats were secondary to thyroid hormone imbalance. Increased thyroxine clearance contributes to the effects of nelfinavir on thyroid gland function and is probably a result of UDPGT induction that leads to elevated TSH levels in the rat and eventual thyroid neoplasia. These results are consistent with a well-recognized rat-specific mechanism for thyroid neoplasms.

Comparison of the developmental toxicity of aspirin in rabbits when administered throughout organogenesis or during sensitive windows of development.

BACKGROUND: A review of the nonsteroidal anti-inflammatory drug (NSAID) literature suggested occurrences of low-level incidences of cardiovascular and midline defects in rabbit fetuses exposed in utero. Aspirin (acetylsalicylic acid, ASA) is a widely used NSAID that irreversibly inhibits cyclooxygenases (COXs) 1 and 2. ASA has been studied extensively in rats and has consistently increased low-incidence cardiovascular malformations and defects in midline closure. The objectives of the current study were to comprehensively define the developmental toxicology profile of ASA in rabbits by using a dosing paradigm encompassing the period of organogenesis and to test the hypothesis that maternal gastrointestinal toxicity after repeated dose administrations hampers the detection of low-incidence malformations with ASA in rabbits by limiting ASA administration to sensitive windows for cardiovascular development and midline closure. METHODS: ASA was administered to pregnant New Zealand White rabbits from gestation days (GDs) 7 to 19 at dose levels of 125, 250, and 350 mg/kg per day and as single doses of 500, 750, or 1000 mg/kg on GD 9, 10, or 11. Cesarean sections were performed on GD 29, and the fetuses were examined for external, visceral and skeletal development. RESULTS: In the repeated dose study, maternal toxicity was exhibited in the 250- and 350-mg/kg per day groups by mortality and decreased food consumption and body weight gain. In the single dose studies, maternal toxicity was exhibited at all doses by reductions in body weight gain and food consumption for 3 days after treatment. Fetal body weight was significantly reduced in the repeated dose study at 350 mg/kg per day. Fetal weights were not affected by single doses of ASA on GD 9, 10, or 11. There were no treatment-related external, visceral or skeletal malformations associated with ASA administration throughout organogenesis or with single doses administered during critical developmental windows. CONCLUSION: These findings supported previous work demonstrating that ASA is not teratogenic in rabbits, as opposed to rats, even when large doses are administered on single days during specific windows of development.

Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure.

BACKGROUND: A review of the scientific literature suggested the occurrence of low-level incidences of ventricular septal defect (VSD) and midline defect (MD) in rat fetuses and diaphragmatic hernia (DH), VSD, and MD in rabbit fetuses after maternal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin, an NSAID that irreversibly inhibits cyclooxygenase 1 (COX-1) and COX-2, induces DH, VSD, and MD when administered as one dose during the sensitive periods of development in rats. Unlike aspirin, other NSAIDs, including selective COX-2 inhibitors, reversibly inhibit COX activity. To evaluate whether the dysmorphogenesis observed after maternal NSAID exposure correlates with COX-1 or COX-2 inhibition, a series of compounds with different capacities to inhibit COX-1 and COX-2 were administered to pregnant rats and rabbits during the sensitive period for heart development and midline closure. METHODS: The compounds selected, ranked from the most COX-2 selective to the most COX-1 selective based onCOX inhibition in a human whole blood assay, were CJ-19,209, meloxicam, diclofenac, diflunisal, ibuprofen, and ketorolac. Rat dams were treated on gestation days (GDs) 9 and 10, and rabbit does were treated on GDs 9, 10, and 11. The doses selected for evaluation represented the maximum tolerable dose for the compound, with the exception of CJ-19,209, which was dosed at 1000 mg/kg. Fetuses were collected by cesarean section on GDs 21 and 29 for rats and rabbits, respectively, and all fetuses were examined for external and visceral developmental anomalies. RESULTS: In rabbits, diflunisal induced DH, VSD, and MD (omphalocele) and single incidences of VSD and MD (gastroschisis) were noted in the ibuprofen group; no other developmental findings were associated with treatment. In rats, ibuprofen, diflunisal, and ketorolac induced increases in the incidence of VSD. In general the induction of developmental defects was associated with compounds that selectively inhibit COX-1 or have a high ratio of COX-1 to COX-2 inhibition. CONCLUSIONS: Inhibition of COX-1 may be involved in the disruption of heart development, whereas the selective inhibition of COX-2 (as assessed with CJ-19,209) appears to have no effect on heart development and midline closure in rats and rabbits.

Dynamic scaling of quasielastic neutron scattering spectra from interfacial water.

A method for analysis of high-resolution quasielastic neutron scattering (QENS) spectra of water in porous media is proposed and applied to the case of water in hydrated tricalcium and dicalcium silicates. We plot the normalized frequency-dependent susceptibility as a function of a scaling variable [omega]/omega(p), where omega(p) is the peak position of the susceptibility function. QENS data have been scaled into a single master curve and fitted with an empirical formula proposed by Bergman to obtain three independent parameters describing the relaxation dynamics of hydration water in calcium silicates.

An enhanced and scalable process for the purification of SIV Gag-specific MHC tetramer.

A recently developed method for the identification and quantitation of antigen-specific T lymphocytes involves the use of complexes of biotinylated major histocompatibility complex (MHC) and avidin conjugated to a fluorescent reporter group. This complex, dubbed the "tetramer," binds to antigen-specific T lymphocytes in vitro, which can then be sorted and counted by fluorescence-activated flow cytometry to measure immune response. Our research has focused on developing the purification process for preparing tetramer reagent. Our goal was to reengineer a published lab-scale purification process to reduce the number of processing steps and to make the process scalable. In our reengineered process, recombinant MHC alpha chain is isolated from Escherichia coli as inclusion bodies by tangential flow filtration. The purified MHC alpha chain is refolded with beta-2-microglobulin and the target peptide antigen to form the class I MHC. The resulting MHC is purified by hydrophobic interaction chromatography (HIC) and biotinylated enzymatically, and the biotinylated MHC is purified by a second HIC step. The tetramer is prepared by mixing biotinylated MHC with an avidin-fluorophore conjugate. The tetramer is further purified to remove any excess MHC or avidin components. Analysis by flow cytometry confirmed that the tetramers generated by this new process gave bright staining and specific binding to CD3+/CD8+ cells of vaccinated monkeys and led to results that were equivalent to those generated with tetramer produced by the original process.

Antibody, cytokine and cytotoxic T lymphocyte responses in chimpanzees immunized with human papillomavirus virus-like particles.

We evaluated antibody, cytokine (IFN-gamma, IL-5, TNF-alpha), and cytotoxic T lymphocyte (CTL) responses in chimpanzees immunized with monovalent or quadrivalent (HPV-6, -11, -16, -18) L1 virus-like particle (VLP) vaccines administered i.m. on aluminum hydroxyphosphate (alum) at weeks 0, 8 and 24. Maximum serum antibody titers to type-specific, neutralizing, conformational epitopes on HPV-11 or -16 L1 VLPs were detected by radioimmunoassay (RIA) four weeks after the second and third immunizations. HPV-11 and -16 neutralizing antibodies were also detected at similar time points with an Human papillomaviruses (HPV) neutralization assay using pseudovirions. Depending on the VLP type used for immunization, HPV type-specific cytokine responses were most frequently seen four weeks after the second or third immunizations and between weeks 44-52. Transient HPV-16 L1-specific CTL activity was observed only between weeks 16-24 in 3 of 22 (13.6%) chimpanzees immunized with HPV-16 L1 VLPs. These findings provide evidence that immunization with multivalent L1 VLPs on alum can evoke both neutralizing antibodies and Th1 and Th2 cytokine responses to several HPV types; however, induction of CTLs is infrequent.

Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats.

Wyeth-14,643 (WY) and ammonium perfluorooctanoate (C8) belong to a diverse class of compounds which have been shown to produce hepatic peroxisome proliferation in rodents. From previous work, WY, but not C8, has been shown to produce hepatocellular carcinoma in rats, while C8 has been shown to produce Leydig cell adenomas. In addition, based on a review of bioassay data a relationship appears to exist between peroxisome-proliferating compounds and Leydig cell adenoma and pancreatic acinar cell hyperplasia/adenocarcinoma formation. To further investigate the relationship between peroxisome-proliferating compounds and hepatic, Leydig cell, and pancreatic acinar cell tumorigenesis, a 2-year feeding study in male CD rats was initiated to test the hypothesis that peroxisome proliferating compounds induce a tumor triad (liver, Leydig cell, pancreatic acinar cell), and to examine the potential mechanism for the Leydig cell tumors. The study was conducted using 50 ppm WY and 300 ppm C8. The concentration of WY in the diet was decreased to 25 ppm on test day 301 due to increased mortality. In addition to the ad libitum control, a second control was pair-fed to the C8 group. Interim sacrifices were performed at 1- or 3-month intervals. Peroxisome proliferation measured by beta-oxidation activity and cell proliferation were measured in the liver and testis at all time points and in the pancreas beginning at the 9-month time point (cell proliferation only). Serum hormone concentrations (estradiol, testosterone, LH, FSH, and prolactin) were also measured at each time point. Increased relative liver weights and hepatic beta-oxidation activity were observed in both the WY- and C8-treated rats at all time points. In contrast, hepatic cell proliferation was significantly increased only in the WY-treated group. Neither WY nor C8 significantly altered the rate of Leydig cell beta-oxidation or Leydig cell proliferation when compared to the control groups. Moreover, the basal rate of beta-oxidation in Leydig cells was approximately 20 times less than the rate of hepatic beta-oxidation. There were no biologically meaningful differences in serum testosterone, FSH, prolactin, or LH concentrations in the WY- and C8-treated rats when compared to their respective controls. There were, however, significant increases in serum estradiol concentrations in the WY- and C8-treated rats at 1, 3, 6, 9, 15, 18, and 21 months. At 12 months, only the C8-treated rats had elevated serum estradiol concentrations when compared to the pair-fed control. Histopathological evaluation revealed compound-related increases in liver, Leydig cell, and pancreatic acinar cell tumors in both WY- and C8-treated rats. The data support the hypothesis that the peroxisome-proliferating compounds induce the previously described tumor triad. In addition, both C8 and WY produced a sustained increase in serum estradiol concentrations that correlated with the potency of the 2 compounds to induce Leydig cell tumors (i.e., WY caused a more consistent sustained increase in serum estradiol throughout the entire study, and more specifically at the end of the study, than did C8). This study suggests that estradiol may play a role in enhancement of Leydig cell tumors in the rat, and that peroxisome proliferators may induce tumors via a non-LH type mechanism.

Neutralization of human papillomavirus (HPV) pseudovirions: a novel and efficient approach to detect and characterize HPV neutralizing antibodies.

The development of vaccines against human papillomaviruses (HPVs) has long been hampered by the inability to grow HPVs in tissue culture and the lack of an efficient neutralization assay. To date, less than 10% of more than 100 different HPV types can be grown in athymic and "SCID" mouse xenograft systems or raft culture systems. Recently, the in vitro generation of HPV pseudovirions and their use in neutralization assays were demonstrated. The major shortcomings of the current approaches to HPV neutralization are the lack of HPV virions for most types for the xenograft methods and the time-consuming and inefficient generation of infective pseudovirions for the latter methods, which precludes their use in large-scale HPV clinical trials or epidemiological studies. We describe here a novel and efficient approach to generating pseudovirions in which HPV virus-like particles (VLPs) are coupled to the beta-lactamase gene as a reporter. We show that it is not necessary to encapsidate the reporter gene constructs into the pseudovirions. Using sera from human volunteers immunized with HPV-11 VLPs expressed in yeast, we demonstrate that our novel neutralization assay compares favorably with the athymic mouse neutralization assay. Furthermore, our assay was used to define neutralizing monoclonal antibodies to HPV-6, which were previously unknown.