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Remote mountain lakes in protected areas are sentinels of the ecological impacts of extreme and novel environmental changes occurring at broad regional scales. Ecosystem responses to such stressors are often first detected as shifts in community composition. We surveyed phytoplankton communities across 82 mountain lakes to test the hypothesis that taxonomic composition is indicative of more environmental changes than are aggregate properties, such as total biomass. Phosphorus was the only significant predictor of chlorophyll-inferred algal biomass, a correlative finding supported by evidence from our nutrient amendment bioassays. Interlake variances in taxonomically diagnostic algal pigments and 78 genera were indicative of changes in total phosphorus, glacial coverage, underwater light availability, and dissolved organic carbon. Lack of concordance was observed between ordinations of pigment- and genus-based data as environmental variables captured more variance in the pigment data. Our findings provide a baseline for future lake monitoring programs in the Canadian Rockies as they increasingly experience interactive effects involving climate change and landscape features, such as variation in turbid glacial meltwaters and aeolian phosphorus deposition from wildfires.

Human-assisted introductions of exotic species are a leading cause of anthropogenic change in biodiversity; however, context dependencies and interactions with co-occurring stressors impede our ability to predict their ecological impacts. The legacy of historical sportfish stocking in mountainous regions of western North America creates a unique, natural quasiexperiment to investigate factors moderating invasion impacts on native communities across broad geographic and environmental gradients. Here we synthesize fish stocking records and zooplankton relative abundance for 685 mountain lakes and ponds in the Cascade and Canadian Rocky Mountain Ranges, to reveal the effects of predatory sportfish introduction on multiple taxonomic, functional and phylogenetic dimensions of prey biodiversity. We demonstrate an innovative analytical approach, combining exploratory random forest machine learning with confirmatory multigroup analysis using multivariate partial least-squares structural equation models, to generate and test hypotheses concerning environmental moderation of stocking impacts. We discovered distinct effects of stocking across different dimensions of diversity, including negligible (nonsignificant) impacts on local taxonomic richness (i.e. alpha diversity) and trophic structure, in contrast to significant declines in compositional uniqueness (i.e. beta diversity) and body size. Furthermore, we found that stocking impacts were moderated by cross-scale interactions with climate and climate-related land-cover variables (e.g. factors linked to treeline position and glaciers). Interactions with physical morphometric and lithological factors were generally of lesser importance, though catchment slope and habitat size constraints were relevant in certain dimensions. Finally, applying space-for-time substitution, a strong antagonistic (i.e. dampening) interaction between sportfish predation and warmer temperatures suggests redundancy of their size-selective effects, meaning that warming will lessen the consequences of introductions in the future and stocked lakes may be less impacted by subsequent warming. While both stressors drive biotic homogenization, our results have important implications for fisheries managers weighing the costs/benefits of stocking-or removing established non-native populations-under a rapidly changing climate.

Multiple factors operating across different spatial and temporal scales affect β-diversity, the variation in community composition among sites. Disentangling the relative influence of co-occurring ecological drivers over broad biogeographic gradients and time is critical to developing mechanistic understanding of community responses to natural environmental heterogeneity as well as predicting the effects of anthropogenic change. We partitioned taxonomic β-diversity in phytoplankton communities across 75 north-temperate lakes and reservoirs in Alberta, Canada, using data-driven, spatially constrained null models to differentiate between spatially structured, spatially independent, and spuriously correlated associations with a suite of biologically relevant environmental variables. Phytoplankton β-diversity was largely independent of space, indicating spatial processes (e.g., dispersal limitation) likely play a minor role in structuring communities at the regional scale. Our analysis also identified seasonal differences in the importance of environmental factors, suggesting a general shift toward greater relevance of local, in-lake (e.g., nutrients and Secchi depth) over regional, atmospheric and catchment-level (e.g., monthly solar radiation and grassland coverage) drivers as the open-water growing season progressed. Several local and regional variables explained taxonomic variation jointly, reflecting climatic and land-use linkages (e.g., air temperature and water column stability or pastureland and nutrient enrichment) that underscore the importance of understanding how phytoplankton communities integrate, and may serve as sentinels of, broader anthropogenic changes. We also discovered similar community composition in natural and constructed water bodies, demonstrating rapid filtering of regional species to match local environmental conditions in reservoirs comparable to those in natural habitats. Finally, certain factors related to human footprint (e.g., cropland development) explained the composition of bloom-forming and/or toxic cyanobacteria more than the overall phytoplankton community, suggesting their heightened importance to integrated watershed management.

Cumulative impacts of multiple stressors on freshwater biodiversity and ecosystem function likely increase with elevation, thereby possibly placing alpine communities at greatest risk. Here, consideration of species traits enables stressor effects on taxonomic composition to be translated into potential functional impacts. We analyzed data for 47 taxa across 137 mountain lakes and ponds spanning large latitudinal (491 km) and elevational (1399 m) gradients in western Canada, to assess regional and local factors of the taxonomic composition and functional structure of zooplankton communities. Multivariate community analyses revealed that small body size, clonal reproduction via parthenogenesis, and lack of pigmentation were species traits associated with both introduced non-native sportfish and also environmental conditions reflecting a warmer and drier climate – namely higher water temperatures, shallower water depths, and more chemically concentrated water. Thus, historical introductions of sportfish appear to have potentially induced greater tolerance in zooplankton communities of future climatic warming, especially in previously fishless alpine lakes. Although alpine lake communities occupied a relatively small functional space (i.e. low functional diversity), they were contained within the broader regional functional structure. Therefore, our findings point to the importance of dispersal by lower montane species to the future functional stability of alpine communities.

Exploratory analysis of biological communities and their environmental factors requires specialized tools to identify associations among variables and generate hypotheses about their causal relationships. Despite the ubiquity of multivariate data in ecology, the visualization and interpretation of such data can be challenging. This study introduces the application of parallel coordinates to ecologists, illustrating the utility of this tool to visualize and explore different types of multivariate data. We demonstrate this tool with two case studies in Canada to (i) explore water-quality associations with benthic macroinvertebrate indicators of stream condition in the St. Lawrence drainage basin, and (ii) identify environmental conditions that contribute to invasive zebra mussel (Dreissena polymorpha) proliferation across inland lakes of Ontario. We offer a novel demonstration of how parallel coordinates provide a practical alternative to current tools in the ecologist's toolbox for visualizing and exploring multivariate data, identifying hypotheses about causal relationships, and communicating science via interactive, web-based applications.

The purpose of this study was to assess the relationship between vitamin D status and dental caries in Canadian school-aged children participating in the Canadian Health Measures Survey (CHMS). The CHMS was a national cross-sectional study involving physical assessments, laboratory analysis, and interviews. Analysis was restricted to data for 1,017 children 6 to 11 y of age. Outcome variables included the presence of caries and overall total caries score (dmft/DMFT index). Levels of 25-hydroxyvitamin D (25(OH)D) were measured from serum samples obtained from participants. Bivariate analysis, logistic regression for the presence of caries, and multiple linear regression for total caries scores were used. Significance was set at P ≤ 0.05. Overall, 56.4% of children experienced caries, and the mean dmft/DMFT score was 2.47 (95% CI 2.09 to 2.84). The unadjusted odds of children with 25(OH)D levels ≥75 nmol/L having experienced caries was 0.57 (95% CI 0.39 to 0.82), while the odds for caries at the ≥50 nmol/L level was 0.56 (95% CI 0.39 to 0.89). After controlling for other covariates, backward logistic regression revealed that the presence of caries was significantly associated with 25(OH) levels

The accelerating rate of global change has focused attention on the cumulative impacts of novel and extreme environmental changes (i.e. stressors), especially in marine ecosystems. As integrators of local catchment and regional processes, freshwater ecosystems are also ranked highly sensitive to the net effects of multiple stressors, yet there has not been a large-scale quantitative synthesis. We analysed data from 88 papers including 286 responses of freshwater ecosystems to paired stressors and discovered that overall, their cumulative mean effect size was less than the sum of their single effects (i.e. an antagonistic interaction). Net effects of dual stressors on diversity and functional performance response metrics were additive and antagonistic, respectively. Across individual studies, a simple vote-counting method revealed that the net effects of stressor pairs were frequently more antagonistic (41%) than synergistic (28%), additive (16%) or reversed (15%). Here, we define a reversal as occurring when the net impact of two stressors is in the opposite direction (negative or positive) from that of the sum of their single effects. While warming paired with nutrification resulted in additive net effects, the overall mean net effect of warming combined with a second stressor was antagonistic. Most importantly, the mean net effects across all stressor pairs and response metrics were consistently antagonistic or additive, contrasting the greater prevalence of reported synergies in marine systems. Here, a possible explanation for more antagonistic responses by freshwater biota to stressors is that the inherent greater environmental variability of smaller aquatic ecosystems fosters greater potential for acclimation and co-adaptation to multiple stressors.

Purpose: It was the aim of this study to assess the risk of lung cancer in postmenopausal women who received hormone replacement therapy (HRT). Experimental Design: This case-control study involves women who received medical services at Roswell Park Cancer Institute (RPCI) in Buffalo, New York, between 1982 and 1998, and who agreed to complete an epidemiological questionnaire. Participants with missing smoking data were excluded. The case group consisted of 595 women with primary lung cancer. Controls included 1,195 women, randomly selected from a pool of 5,845 eligible individuals, who received medical services at RPCI for non-neoplastic conditions; they had come to RPCI with a suspicion of neoplastic disease, but were diagnosed with neither benign nor malignant conditions. Controls were frequency matched 2:1 to cases on 5-year age intervals and exposure to smoking (ever/never). Cases and controls were comparable for age (means 61.3 and 61.0 years) and ever smoking (90%). Results: There were more former smokers among the cases (67 vs. 59% in controls); cases were less likely to be high school educated, were thinner, and were less likely to report HRT use compared with controls. Overall, hormone use was associated with a significant reduction in risk of lung cancer (adjusted odds ratio = 0.67; 95% confidence interval 0.53–0.85). Stratified analyses showed significant reductions in lung cancer risk in former smokers and women with normal to low body mass index. Conclusion: This study supports the hypotheses that there is a protective effect of HRT use on lung cancer risk in women.

A new liquid chromatographic method is described for the determination of the anti-tumour agent bexarotene in human plasma over the range 0.500–1500 ng/ml, using 1 ml of sample. Sample preparation consists of liberating the analyte from plasma lipids by adding acetonitrile, followed by acidification of the plasma and liquid extraction using a mixture of isoamyl alcohol and pentane or hexane. Separation and quantitation are performed by reversed-phase column liquid chromatography with fluorescence detection. Parameters affecting the performance of these steps are discussed. Validation results on linearity, selectivity, accuracy, precision, recovery and stability are shown, as well as the application of the method to samples from clinical trials.

Preserved wilderness in Saskatchewan has value to both the users and to non-users. To determine such values, a study of Saskatchewan residents' level of willingness-to-pay (WTP) for wilderness preservation was carried out. Results suggest that 58% of sample non-aboriginal and only 7% of aboriginal respondents were satisfied with the current level of wilderness and wildlife protection in the province. Their reasons for preserving wilderness areas varied but protection of water quality, air quality, and wildlife habitats topped the list. The estimated annual WTP to ensure current wilderness protection prevails was approximately $61 per household for the non-aboriginal sample, and $80 for the aboriginal sample, which amounts to a value of $ 100 per hectare.

Transmission gratings have rarely been used for beam sampling because they require special properties from dielectric overcoatings, which, to the best of our knowledge, are described here for the first time. Although such gratings are often used as beam splitters, their nature can be modified along the same principles with thin metal coatings, which are described.

For lack of alternatives, echelle-grating diffraction behavior has in the past been modeled on scalar theory, despite observations that indicate significant deviations. To resolve this difficulty a detailed experimental, theoretical, and numerical study is performed for several echelles that work at low (8–13), medium (35–55), high (84–140), and very-high (to 660) diffraction orders. Noticeable deviations from the scalar model were detected both experimentally and numerically, on the basis of electromagnetic theory: (1) the shift of the observed blaze position was shown to decrease with the wavelength-to-period ratio, and it tends to zero more rapidly than the decrease of the maximum width, so that the TE- and TM-plane responses tend to merge into each other; (2) cut-off effects (Rayleigh anomalies) were found to play a significant role for high groove angles, where passing-off orders are close to the blaze order. A possibility for evaluation of the blaze angle from angular, rather than from spectral, measurements is discussed. Several reasons for the differences between real and ideal echelles (material-index deviations, profile deformations, and groove-angle errors) are analyzed, and their effects on the performance of echelles is studied.

Structural integrity in optical systems must be maintained to achieve submicron tolerances in optomechanical systems with moving parts—particularly important in microelectronics. Typical problems are illustrated with solutions.

An explanation is given for the effect of total absorption of light in grazing incidence by a sinusoidal grating, recently reported by us. The behavior of the zeros of both the first and the zeroth diffraction orders is studied numerically in the complex alpha plane. A link between the grating anomaly, non-Littrow perfect blazing, and plasmon excitation in relief metallic gratings is established. A total analysis of the behavior of the zeroth-order zero in grazing incidence is carried out, including groove depth, wavelength, and profile dependences.

The bulk of diffraction gratings used in the VUV and XUV regions are used at small angles of incidence and have shallow groove depths. Using rigorous electromagnetic theory, it is shown that such gratings behave in a scalar manner. It is then possible to derive universal efficiency curves from which one can obtain with simple rules the efficiencies of gratings with any metallic surface. The role of standard dielectric overcoatings is investigated and is found to be small. Some comparisons with experiments are given.

Recently developed rigorous theories have been used to investigate the diffraction efficiency behavior of both blazed and holographic gratings. In order to assist designers of spectrometric systems we have covered a complete range of blaze angles for triangular grooves and modulations for sinusoidal groove shape in first and second orders. Several types of mountings are included together with the role played by finite conductivity of aluminum. Useful classifications of both types of gratings are given, as they apply from the near uv to ir regions. Comparisons showing the close agreement between theory and experiment are presented.

Theoretical calculations predict that under certain special conditions a shallow fine pitch diffraction grating, given a precise dielectric overcoating, acts as a complete absorber of incident light of a specific wavelength and polarized in the P plane. Despite lack of a physical explanation, the phenomenon was confirmed by experiment.

Tests are described on new master echelles of very large size and on others having unusually high blaze angles, produced on interferometrically controlled ruling engines. Defects arising from the gravitational distortion of large grating blanks during ruling were reduced by the use of calibrated edge-supporting springs to diminish sag. The sixth echelle in a series of the largest yet produced (400 x 600 mm, or 16 x 24 in.), ruled on a fused silica blank 127 mm thick with 79 grooves/mm blazed at 63.4 degrees , gives high speed at resolutions well in excess of 10(6). A series of 254-mm echelles ruled at blaze angles whose tangents range from 2 to 8 were compared. Because an echelle blazed at 63 degrees can theoretically give 90% of the maximum resolving power available at any blaze angle, little resolution is gained by using steeper angles, and optical defects are likely to increase with groove asymmetry. Very high blaze angles are useful for raising intrinsic dispersion, however, making possible construction of echelle spectrometers of extreme compactness.

The development of grating ruling is presented in capsule form, from the first experiment of Rittenhouse in 1876 to the ruling of large echelles under interferometric control. The evolution of wavelength tables, especially in the United States, is described.

A simple formula is derived that allows evaluation by a single integration the diffraction efficiencies of transmission relief gratings when they support a great number of orders. Validity of the method is demonstrated by comparison with a rigorous differential method.

LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.

9-cis retinoic acid (ALRT 1057; 9cRA) is a promising new retinoid that binds to all known retinoic acid receptors (RAR and RXR), potentially providing it with a broader spectrum of biologic activity than either 13-cis retinoic acid or all-trans retinoic acid. It has been shown to be at least as active as all-trans retinoic acid as a differentiation-inducing and antiproliferative agent in both in vivo and in vitro tumor model systems.The New York Gynecologic Oncology Group undertook a prospective, multi-institutional phase II clinical and pharmacokinetic trial of 9cRA in patients with advanced or recurrent squamous cell or adenosquamous cell carcinoma of the uterine cervix. Patients received daily oral doses of 140 mg/m2 of 9cRA. 9cRA and its metabolites were determined by reversed-phase HPLC in plasma samples drawn at 0.5 to 8 hours.Sixteen patients with advanced or recurrent carcinoma of the cervix were enrolled. Therapy was well tolerated with no unexpected toxicities. There were no complete or partial responses observed, indicating that a response rate of 20% or greater to this agent could be ruled out with 95% confidence. Pharmacokinetic parameters for 9cRA on day 1 were in agreement with previous studies. The area under the plasma versus time curves for 9cRA declined by 69% between days 1 and 8 with daily 9cRA dosing and remained at this low level in those patients evaluated on day 28. 4-oxo-9-cis retinoic acid (4-oxo-9cRA) was identified as a major plasma metabolite of 9cRA. Plasma levels of 4-oxo-9-cRA were initially 71% of those of 9cRA, but in contrast to 9cRA, there was no decline in plasma levels on days 8 and 28. The ratio of the area under the curve for the 4-oxo metabolite relative to that of the parent compound increased from less than 1 on day 1 to approximately 2.4 on days 8 and 28. Thus, despite early induction of its own metabolism, levels of total retinoid metabolites persisted at pharmacologic levels at day 28.9cRA with this dose and schedule was inactive in women with advanced carcinoma of the cervix. Despite a decline in plasma levels of 9cRA over time, levels of the 4-oxo metabolite tended to persist. While the 4-oxo metabolite is less potent than the parent compound, these data nevertheless suggest that the lack of clinical activity in this patient population may not be attributable exclusively to suboptimal pharmacokinetic parameters.

The combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion followed by carboplatin infused over 30 minutes has been evaluated in a series of phase I studies and is currently being explored in a phase II study in patients with limited- and extensive-stage small cell lung cancer. Pharmacokinetic measurements were performed at all dose levels in the phase I studies, in which the use of granulocyte colony-stimulating factor in previously treated patients enabled more than twice the dose of paclitaxel to be given with low to moderate doses of carboplatin (dosed to a target area under the concentration-time curve of 4.0 mg x min x mL[-1]). Treatment-naive patients tolerated high paclitaxel doses (270 mg/m2) with carboplatin (dosed to a target area under the curve of 4.5 mg x min x mL[-1]) without granulocyte colony-stimulating factor support. Twenty-three patients (including previously treated and untreated) with non-small cell lung cancer were entered at a variety of paclitaxel doses in the phase I studies. At 100 to 205 mg/m2 paclitaxel, none of nine treated patients responded; at 230 to 290 mg/m2, four (29%) of 14 responded. In the phase II study of paclitaxel 250 mg/m2 in previously untreated patients with small cell lung cancer, two of five evaluable patients with extensive-stage disease have shown a partial response. In a preliminary analysis of the pharmacodynamics of paclitaxel in relation to neurotoxicity (dose limiting in two of three phase I studies), neurotoxicity correlated with the total dose of paclitaxel, the area under the curve, and the peak paclitaxel concentration, but not with the length of time plasma paclitaxel levels remained above 0.05 micromol/L. These correlations were not strong, however, and analysis of these data is ongoing.

In preparation for the design of phase II studies in lung cancer, low-dose carboplatin, fixed at a target area under the concentration-time curve (AUC) of 4.0 or 4.5 mg x min/mL, has been combined with escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in a series of studies to establish the maximum tolerated dose of the combination. In patients who had received prior chemotherapy, the maximum tolerated paclitaxel dose was 135 mg/m2 (carboplatin target AUC 4.0); the dose-limiting toxicity was febrile neutropenia. Without granulocyte colony-stimulating factor support in chemotherapy-naive patients (carboplatin target AUC 4.5), and with granulocyte colony-stimulating factor in chemotherapy-pretreated patients, the current paclitaxel dose is 290 mg/m2. The maximum tolerated dose has not been defined. In a study in which paclitaxel was given by 1-hour infusion with carboplatin (target AUC 4.5), a 205 mg/m2 dose was poorly tolerated. No evidence of pharmacokinetic interactions between paclitaxel and carboplatin was found. Twenty-one evaluable patients with lung cancer have been treated to date. There have been two partial responses, one minor response, and 10 patients with stable disease at paclitaxel doses of 100 to 270 mg/m2.

Diffractive Optics, defined as the use of diffraction to aid or perform the imaging process, belongs to the large familiy of 19th century concepts in optics that have moved from obscurity to important technology thanks to a fascinating confluence of recently discovered needs with development of a whole collection of new enabling technologies. These include computational methods, optical materials, and finally precision engineering processes that convert the impossible into the possible. Not one of these basic developments originated because of demands from the Diffraction Optics community. They came from the outside world and were conveniently appropriated as needs arose.

An ongoing phase I and pharmacokinetic trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin is evaluating the maximum tolerated dose (MTD) of a 3-hour paclitaxel infusion combined with fixed doses of carboplatin in previously treated and untreated patients with a variety of advanced cancers. A patient's previous treatment status determines the fixed carboplatin dose: target area under the concentration-time curves of 4.0 and 4.5 mg.min/mL in previously treated and untreated patients, respectively. Studies 1 and 2 entered previously treated patients to establish the paclitaxel MTD without and with cytokine support: study 1 established 135 mg/m2 paclitaxel as the MTD without such support. In study 2, granulocyte colony-stimulating factor is administered, and the MTD has not yet been reached with paclitaxel doses of 135 mg/m2 to 230 mg/m2 assessed thus far and 250 mg/m2 now being evaluated. Objective responses have been seen in three of five patients with squamous cell carcinoma of the head and neck and in patients with non-small cell lung cancer and metastatic cancer of unknown primary site as well. Myelosuppression has been the dose-limiting toxicity, although significant nausea and vomiting and myalgia have been documented occasionally. Paclitaxel apparently has nonlinear pharmacokinetics with a beta half-life of 6.7 hours (SD +/- 1.3 hours). Future trials of paclitaxel/carboplatin will address the management of squamous cell carcinoma of the head and neck and non-small cell carcinoma of the lung.

Bovine viral diarrhea virus continues to produce significant economic losses for the cattle industry and challenges investigators with the complexity of diseases it produces and the mechanisms by which it causes disease. This paper updates and attempts to clarify information regarding the roles of noncytopathic and cytopathic bovine viral diarrhea viruses in persistent infections and mucosal disease. It also covers, in brief, what is known of the new diseases: thrombocytopenia and hemorrhagic disease, and a disease resembling mucosal disease that is apparently caused solely by noncytopathic virus. Although a good understanding of the roles of the 2 biotypes in the production of persistent infections and the precipitation of mucosal disease has been obtained, there are still unanswered questions regarding the origin of cytopathic viruses and the mechanism by which they cause pathological changes in cells. It is apparent, however, that cytopathic bovine viral diarrhea viruses arise by mutation of noncytopathic viruses, and it is known that p80 is the marker protein for cytopathic viruses. The previous distinction between mild bovine viral diarrhea and fatal mucosal disease has been eroded with the emergence of new virulent bovine viral diarrhea viruses. The new diseases pose a threat to the cattle industry and present a new challenge for investigators. Index Veterinarius (1984-1994) and Medline (1985-1994) databases and personal files updated since 1987 from BIOSIS Previews and Biosciences Information Services were used to search the literature.

CI-959 is an antiallergic/antiinflammatory agent currently in development. In rats, daily bolus intravenous administration of CI-959 at doses > or = 10 mg/kg was associated with development of cardiac hypertrophy. There was no morphologic or biochemical evidence of myocyte injury, and cardiac hypertrophy rapidly reversed after treatment was discontinued. Cardiac hypertrophy was not evident when CI-959 was given orally or by continuous intravenous infusion with ALZA osmotic pumps. Maximum plasma drug concentrations (Cmax) were significantly higher when CI-959 was given by bolus intravenous injection, suggesting that cardiac effects were dependent on high Cmax concentrations. When neonatal rat cardiomyocytes were exposed to CI-959 in vitro, there was no evidence of myocyte enlargement or increased protein content. Cardiac hypertrophy was prevented by pretreatment with nonselective beta- and beta 1-selective adrenoceptor blockers as well as with central sympatholytics. beta 2- and alpha-adrenoceptor blockers were ineffective in preventing cardiac hypertrophy. Bolus intravenous CI-959 administration resulted in prolonged hypotension and associated increase in plasma catecholamine levels, with apparent inhibition of reflex tachycardia. We conclude that CI-959-associated cardiac hypertrophy in rats was not a direct drug effect but instead was probably mediated by endogenous catecholaminergic stimulation of cardiac beta 1-adrenoceptors.

Small cell lung cancer, an aggressive malignancy characterized by early dissemination, is highly responsive to radiotherapy and cytotoxic chemotherapy. Since the introduction of combined-modality regimens that incorporate both radiotherapy and chemotherapy, the median survival time for patients with localized disease has increased to 12 to 15 months, but median length of survival of patients with extensive disease has remained at a plateau of only 6 to 8 months. New cytotoxic agents, such as ifosfamide, etoposide, and carboplatin, have contributed to a reduced toxicity profile and an increase in complete response rates to combination regimens of 40% to 50%, but they have not contributed to any major increase in long-term survival. Potential strategies for improving efficacy and reducing toxicity of the chemotherapy of small cell lung cancer are reviewed.

3014 Background: IPI-926 is a novel, selective, oral, natural- product derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting Smoothened (Smo). Inhibition of Smo can repress malignant activation of the Hh pathway, making Smo a target for treatment of a broad range of cancers. We conducted a phase I dose-escalation study to evaluate the safety, maximum tolerated dose and anti-tumor activity of IPI-926. Methods: Eligible pts had advanced or metastatic solid tumors and adequate bone marrow, hepatic and renal function. IPI-926 was administered orally, daily (QD), in 1 to 6 pt cohorts. A cycle was 28 days in length. An expanded cohort in basal cell carcinoma (BCC) was implemented. All pts were evaluated for safety, pharmacokinetics, pharmacodynamics (PD) and tumor response. Dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Results: As of December 2010, 79 pts had been enrolled at dose levels of IPI-926 ranging from 20-210 mg QD. 31 pts had locally-advanced (LA) or metastatic (...

CI-986 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)- thione-2-hydroxy-N,N,N-trimethylethanaminium salt) is a novel anti-inflammatory compound classified as a dual inhibitor of cyclooxygenase and 5-lipoxygenase. Studies were undertaken to characterize the preclinical toxicology of the compound. CI-986 was administered to rats for 2 weeks (0, 50, 250, 750, and 1500 mg/kg) or 13 weeks (0, 20, 250, 500, and 1000 mg/kg), dogs for 2 weeks (0, 50, 150, and 500 mg/kg) or 13 weeks (0, 20, 100, and 200 mg/kg), and to monkeys for 2 weeks (0, 50, 250, and 1000 mg/kg). No drug-related deaths resulted. Mild clinical signs of toxicity were noted in rats given doses of 250 mg/kg and above. Drug-related emesis and diarrhea were absent at the low dose in the dog and monkey but increased in incidence and severity at higher doses. Severe clinical signs in monkeys (emesis and diarrhea) necessitated the lowering of the top dose to 500 mg/kg/day (administered b.i.d.) during the second week of the monkey study. Slight decreases (23%) in serum protein and/or albumin were noted in all studies at the higher doses. A dose-related increase in alkaline phosphatase was noted in both dog studies, with no other drug-related effect on clinical pathology parameters. A gastric ulcer occurred in one rat administered 500 mg/kg CI-986 for 13 weeks. Gastrointestinal ulcers were not noted at any other dose in rats or at any dose in dogs or monkeys. A dose-related eosinophilia of glandular stomach submucosa was noted in rats after 2 and 13 weeks of drug administration but not in dogs or monkeys. In the 2-week rat study, mean combined sex plasma drug concentrations monitored 2 hr after dose on Day 14 were 0.59, 1.10, 2.64, and 3.43 micrograms/ml for the 50, 250, 750, and 1,500 mg/kg dose groups, respectively. In the 2-week dog studies, maximum plasma drug concentrations on Day 10 or Day 11 were achieved within 2 hr of dose with mean combined sex Cmax values of 0.73, 2.05, and 2.62 micrograms/ml for the 50, 250, and 750 mg/kg groups, respectively. Hepatic microsomal induction characterized by increased microsomal protein, increased microsomal cytochrome P450 content, and increased p-nitroanisole O-demethylation activity was noted in dogs and monkeys but not rats. CI-986 was well tolerated in rats and dogs at the doses employed and in monkeys at doses up to 500 mg/kg (b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)

7518 Background: Cardiorespiratory fitness is a well-established independent predictor of all-cause mortality in a broad range of adult populations. The association between cardiorespiratory fitness and mortality has not been investigated among individuals diagnosed with cancer. We examined the association between cardiorespiratory fitness and all-cause mortality in 398 patients with non-small cell lung cancer (NSCLC). Methods: Using a prospective, observational design, patients with known or suspected NSCLC enrolled in CALGB 9238 were studied. Prior to pulmonary resection, all participants performed an incremental exercise test with expired gas analysis to assess cardiorespiratory fitness (i.e., peak oxygen consumption; VO2peak) and were observed for death or until June 2008. Cox proportional hazards models were used to estimate the risk of all-cause mortality according to cardiorespiratory fitness category defined by VO2peak (1.29 L.min-1) with adjustment for age, gender, and performance status. Results: Of the 398 patients, 335 underwent surgical resection and 63 were deemed not eligible for resection. Median follow-up was 30.8 months, 294 deaths were reported during this period. For the entire sample, mortality rates declined across increasing VO2peak categories (adjusted Ptrend= 0.012). Compared with patients achieving a VO2peak -1, the adjusted hazard ratio (HR) for all-cause mortality was 0.64 (95% CI, 0.46 to 0.88) for a VO2peak of 0.96–1.29 L.min-1, and 0.56 (95% CI, 0.39 to 0.80) for a VO2peak of >1.29 L.min-1. The corresponding HRs for surgical patients were 0.65 (95% CI, 0.44 to 0.96) and 0.62 (95% CI, 0.42 to 0.90) relative to the lowest VO2peak category (ptrend=0.03), respectively. For non-surgical patients, the HRs were 0.74 (95% CI, 0.32 to 1.75) and 0.43 (95% CI, 0.18 to 1.00) relative to the lowest category (ptrend2peak is associated with poorer survival among surgical candidates with NSCLC. Further work is required to investigate the prognostic value of objective measures of functional capacity in NSCLC and other cancer populations. No significant financial relationships to disclose.

We describe herein a field case of border disease (BD) in twin lambs. Both lambs were unthrifty, stunted, and one exhibited nervous signs characteristic of BD, with tremors of the head, neck, hind legs, and pelvis. Hairiness of the coat and excessive pigmentation, often seen in lambs with BD, were not observed. A noncytopathic virus, which showed cross-reactivity with bovine viral diarrhea (BVD) virus antiserum and BVD virus monoclonal antibodies, was isolated repeatedly from leukocytes from one lamb and from tissues of the other. Although the source of the virus is unknown, our results suggest that the dam of the affected twins had been infected during pregnancy. We used the BD virus isolated to inoculate pregnant ewes and experimentally reproduce the disease in a newborn lamb. Our findings indicate that leukocytes, rather than serum, should be utilized for BD virus isolation. Further, it is recommended that BD virus, rather than BVD virus, be used in serum neutralization tests when screening sheep for antibody titers.

We look at the behavior of three different plane gratings in spectral regions where they exhibit anomalous efficiency behavior. Circumstances are presented where anomalies are either shifted, reduced, or enhanced. The gratings chosen are 1200 grooves per mm blazed at 26.75 degree(s), 1200 grooves per mm holographic sinusoidal with 18% modulation, and an 1800 groove per mm holographic `self blazed' at 13 degree(s).© (1991) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.