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PubMed2001

The protective role of endogenous estrogens in carrageenan-induced lung injury in the rat.

BACKGROUND: We have recently demonstrated that 17beta-estradiol (E2) inhibits the increase of inducible nitric oxide synthetase (iNOS) activity in selected model systems such as macrophages, microglia, smooth muscle cells, and proposed that this effect might be associated with an anti-inflammatory activity of this hormone. Here we investigate the effects of endogenous estrogens in rats subjected to carrageenan-induced pleurisy. MATERIALS AND METHODS: Adult female rats were ovariectomized 3 weeks before the experiments to deplete circulating estrogens. Selected inflammatory markers, landmarks of the delayed phase of carrageenan-induced pleurisy, were measured in intact (N-OVX), and ovariectomized (OVX) female rats. In addition, the effect of hormone replacement was evaluated in ovariectomized rats with intraperitoneal injection of 17beta-estradiol (E2; 50 microg/kg) 1 hr before carrageenan treatment (OVX + E2). RESULTS: Ovariectomy enhanced the carrageenan-induced degree of pleural exudation and polymorphonuclear leukocyte migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly increased in estrogens-deprived rats. The iNOS in lung samples was significantly increased by the surgery. The increase of iNOS activity was correlated with a marked enhancement in the production of TNF-alpha and IL-1beta. Immunohistochemical analysis for P-selectin and ICAM-I, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS) revealed a positive staining in lungs from carrageenan-treated rats, which was markedly enhanced in ovariectomized rats when compared to cycling rats, particularly in the estrous phase of the cycle. Estrogen replacement counteracted the effect of surgery on all of the above indicators of lung inflammation, suggesting that in the cycling rat this hormone plays a key role in the increased sensitivity to inflammatory injury observed in the OVX rat. CONCLUSION: This study demonstrates that endogenous estrogens production plays an important protective role against carrageenan-induced acute inflammation by decreasing the expression of specific markers of the delayed phase of this well-known model of acute inflammation.

Animals↗
PubMed1991

Differentiation of reperfused-viable (stunned) from reperfused-infarcted myocardium at 1 to 3 days postreperfusion by in vivo phosphorus-31 nuclear magnetic resonance spectroscopy.

Thrombolytic therapy has increased the need for a technique to assess the viability of recently reperfused myocardium. This study examined the ability of in vivo phosphorus-31 (P-31) nuclear magnetic resonance (NMR) spectroscopy to distinguish reperfused-viable (stunned) from reperfused-infarcted myocardium at 6, 30, and 54 hours following coronary artery occlusion in a canine model. A 15-minute occlusion produced reperfused-viable myocardium in five animals and a 360-minute occlusion produced reperfused-infarcted myocardium in six animals. Postreperfusion risk zone myocardial phosphocreatine (PCr) concentration measured by P-31 NMR spectroscopy was significantly depressed throughout the 3-day study period in infarcted but not in viable myocardium (p less than 0.01 between groups, all time points). The postreperfusion ratio of inorganic phosphate (Pi) to PCr concentration, as determined by NMR spectroscopy, was elevated throughout the study period in infarcted but not in viable reperfused myocardium (p less than 0.01 between groups, all time points). Postreperfusion Pi concentration was elevated at 6 hours but not subsequently in reperfused-infarcted myocardium, and was not elevated in reperfused-viable myocardium. Logistic regression models selected PCr concentration and the Pi/PCr ratio as providing the best discrimination between reperfused-viable and reperfused-infarcted myocardium. The accuracy of P-31 NMR variables selected by logistic regression analysis for determining myocardial viability ranged from 97% to 100%.

Animals↗
PubMed2006

Farm Scale Evaluations of spring-sown genetically modified herbicide-tolerant crops: a statistical assessment.

Primary results from the Farm Scale Evaluations (FSEs) of spring-sown genetically modified herbicide-tolerant crops were published in 2003. We provide a statistical assessment of the results for count data, addressing issues of sample size (n), efficiency, power, statistical significance, variability and model selection. Treatment effects were consistent between rare and abundant species. Coefficients of variation averaged 73% but varied widely. High variability in vegetation indicators was usually offset by large n and treatment effects, whilst invertebrate indicators often had smaller n and lower variability; overall, achieved power was broadly consistent across indicators. Inferences about treatment effects were robust to model misspecification, justifying the statistical model adopted. As expected, increases in n would improve detectability of effects whilst, for example, halving n would have resulted in a loss of significant results of about the same order. 40% of the 531 published analyses had greater than 80% power to detect a 1.5-fold effect; reducing n by one-third would most likely halve the number of analyses meeting this criterion. Overall, the data collected vindicated the initial statistical power analysis and the planned replication. The FSEs provide a valuable database of variability and estimates of power under various sample size scenarios to aid planning of more efficient future studies.

Agriculture↗
PubMed2000

A Bayesian approach to finite mixture models in bioassay via data augmentation and Gibbs sampling and its application to-insecticide resistance.

After continued treatment with an insecticide, within the population of the susceptible insects, resistant strains will occur. It is important to know whether there are any resistant strains, what the proportions are, and what the median lethal doses are for the insecticide. Lwin and Martin (1989, Biometrics 45, 721-732) propose a probit mixture model and use the EM algorithm to obtain the maximum likelihood estimates for the parameters. This approach has difficulties in estimating the confidence intervals and in testing the number of components. We propose a Bayesian approach to obtaining the credible intervals for the location and scale of the tolerances in each component and for the mixture proportions by using data augmentation and Gibbs sampler. We use Bayes factor for model selection and determining the number of components. We illustrate the method with data published in Lwin and Martin (1989).

Algorithms↗
PubMed1985

Dominance in physiological phenotypes and fitness at an enzyme locus.

Aminopeptidase-I allozymes, which are products of the Lap locus in the marine mussel, Mytilus edulis, differ in their catalytic efficiencies. These biochemical differences result in genotype-specific rates of change in the free amino acid pool, that is, cell volume regulation, when mussels are subjected to changes in salinity. A high degree of dominance was found among genotypes for these biochemical and physiological phenotypes. Selection models that incorporate dominance adequately predict observed genotypic properties at the Lap locus among natural populations that exhibit clinical allele frequency. This suggests that a high degree of dominance for fitness must also occur at this locus in natural populations. These results provide additional evidence that the maintenance of an allele frequency cline is operating by natural selection at the Lap locus.

Alleles↗
PubMed2001

Structure-based focusing using pharmacophores derived from the active site of 17beta-hydroxysteroid dehydrogenase.

Structure-based focusing constitutes a powerful approach to design libraries of compounds with a given biological profile. Computers with special software can be used to analyse the large amount of data usually available for the compounds. Pharmacophores can be used to identify new compounds that present a specific arrangement of features responsible for a certain type of activity. When available, information about the 3D structure of a biological target can also be included in the building of pharmacophore models. These pharmacophores can then be used as queries to search and/or focus large compound libraries. Multiple pharmacophores were generated from the 3D structure 17beta-hydroxystreoid dehydrogenase type1 complexed with different inhibitors. The validity of these pharmacophores was assessed against a test database containing known active and inactive 17beta-hydroxystreoid dehydrogenase type1 inhibitors. The most selective models were then used to search commercial databases for new structural lead molecules. This approach has allowed us to identify a few new compounds possessing structural features common to flavonoids, a structural class of compounds known to contain good inhibitors of 17beta-hydroxystreoid dehydrogenase type1 enzyme. A structure-based focusing approach is demonstrated to be a meaningful and powerful technique for identifying new lead candidates, which can be taken into the lead optimization process.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Oviposition site selection in a complex and variable environment: the role of habitat quality and conspecific cues.

In many organisms reproductive success is strongly dependent on several breeding site characteristics, which often vary in space and time. Although we have a good understanding of how ovipositing organisms respond to single factors, we still have little information about how they respond under more complex natural conditions. We examined the oviposition behavior of a tree-hole breeding frog, Phrynobatrachus guineensis, with respect to abiotic and biotic oviposition site characteristics, including desiccation risk and the presence of conspecific offspring using both observation and experiments. Based on daily monitoring data, compiled from 69 natural oviposition sites during a complete reproductive season, we developed oviposition site-selection models. A model based on water presence, sediment depth and maximal possible water depth showed the best predictive performance and was transferable to the subsequent season. Field observations and experiments revealed that frogs could estimate water-holding capacity of sites and timed oviposition with respect to future water presence. Despite the negative effects on larval growth and the availability of sites without conspecifics, data suggest that ovipositing individuals are attracted to conspecific offspring because they serve as a cue for low predation risk. Our results imply that a site's potential for being used at least once for oviposition was determined by abiotic factors, whereas the relative use of breeding sites was determined by a response to conspecifics. Our study demonstrates the importance of including multiple biotic and abiotic factors in the analysis of oviposition site-selection.

Animals↗
PubMed2000

Wildlife population assessment: past developments and future directions.

We review the major developments in wildlife population assessment in the past century. Three major areas are considered: mark-recapture, distance sampling, and harvest models. We speculate on how these fields will develop in the next century. Topics for which we expect to see methodological advances include integration of modeling with Geographic Information Systems, automated survey design algorithms, advances in model-based inference from sample survey data, a common inferential framework for wildlife population assessment methods, improved methods for estimating population trends, the embedding of biological process models into inference, substantially improved models for conservation management, advanced spatiotemporal models of ecosystems, and greater emphasis on incorporating model selection uncertainty into inference. We discuss the kind of developments that might be anticipated in these topics.

Algorithms↗
PubMed1989

Structure of conformationally constrained peptides: from model compounds to bioactive peptides.

The use of backbone conformational constraints has acquired increasing importance in the design and synthesis of structurally restricted agonists and antagonists of bioactive peptides. Here I discuss the preferred conformations of four among the most popular types of such peptide surrogates: (a) Peptides from C alpha, alpha-dialkylated residues, (b) tetrazolyl peptides, (c) (gamma- and delta-) lactam-containing peptides, and (d) thiated peptides. Emphasis is given to conformational energy computations and x-ray diffraction analyses of selected model compounds and analogues of small bioactive peptides such as the formylmethionyl tripeptide chemoattractant and MIF.

Models, Molecular↗
PubMed2005

Seasonal trends in usnic acid concentrations of Arctic, alpine and Patagonian populations of the lichen Flavocetraria nivalis.

The widespread secondary metabolite usnic acid, a dibenzofuran derivative, is the principal acetone-soluble compound in the lichen Flavocetraria nivalis. Seasonal variation in concentrations were studied in four populations of this lichen, three from Arctic-alpine habitats in the Northern Hemisphere, and one from Patagonian heathland in the Southern Hemisphere. Usnic acid is produced in large amounts, making up between 4% and 8% of thallus dry weight. Large seasonal variation is seen, with a trend towards peak levels in late spring and early summer, and generally low levels during autumn and winter. However, at an Arctic steppe in Central West Greenland, remarkably high levels were also detected during late autumn and early winter. Comparisons with environmental data using model selection procedures show that usnic acid levels of three of the populations are positively correlated with time of season, as measured by the proximity in time to nearest summer solstice, solar radiation levels, and temperature conditions. All these three variables are intercorrelated, thus indicating the same overall trend. For the three driest sites, precipitation rates are included in the models that best explain the variation in usnic acid. However, the explanatory powers of the models are generally low, partly due to high variation between thalli growing together and sampled at the same time. This is the first attempt to compare statistically seasonal variation in usnic acid concentrations and environmental variables, and thus also the first time it is shown that the concentration in various populations of the same lichen species shows different types of correlation with seasonal climatic changes.

Arctic Regions↗
PubMed2004

The genetic architecture of response to long-term artificial selection for oil concentration in the maize kernel.

In one of the longest-running experiments in biology, researchers at the University of Illinois have selected for altered composition of the maize kernel since 1896. Here we use an association study to infer the genetic basis of dramatic changes that occurred in response to selection for changes in oil concentration. The study population was produced by a cross between the high- and low-selection lines at generation 70, followed by 10 generations of random mating and the derivation of 500 lines by selfing. These lines were genotyped for 488 genetic markers and the oil concentration was evaluated in replicated field trials. Three methods of analysis were tested in simulations for ability to detect quantitative trait loci (QTL). The most effective method was model selection in multiple regression. This method detected approximately 50 QTL accounting for approximately 50% of the genetic variance, suggesting that >50 QTL are involved. The QTL effect estimates are small and largely additive. About 20% of the QTL have negative effects (i.e., not predicted by the parental difference), which is consistent with hitchhiking and small population size during selection. The large number of QTL detected accounts for the smooth and sustained response to selection throughout the twentieth century.

Computer Simulation↗
PubMed2005

Building multivariable regression models with continuous covariates in clinical epidemiology--with an emphasis on fractional polynomials.

OBJECTIVES: In fitting regression models, data analysts must often choose a model based on several candidate predictor variables which may influence the outcome. Most analysts either assume a linear relationship for continuous predictors, or categorize them and postulate step functions. By contrast, we propose to model possible non-linearity in the relationship between the outcome and several continuous predictors by estimating smooth functions of the predictors. We aim to demonstrate that a structured approach based on fractional polynomials can give a broadly satisfactory practical solution to the problem of simultaneously identifying a subset of 'important' predictors and determining the functional relationship for continuous predictors. METHODS: We discuss the background, and motivate and describe the multivariable fractional polynomial (MFP) approach to model selection from data which include continuous and categorical predictors. We compare our results with those from other approaches in examples. We present a small simulation study to compare the functional form of the relationship obtained by fitting fractional polynomials and splines to a single predictor variable. RESULTS: We illustrate the advantages of the MFP approach over standard techniques of model construction in two real example datasets analyzed with logistic and Cox regression models, respectively. In the simulation study, fractional polynomial models had lower mean square error and more realistic behaviour than comparable spline models. CONCLUSIONS: In many practical situations, the MFP approach can satisfy the aim of finding models that fit the data well and also are simple, interpretable and potentially transportable to other settings.

Algorithms↗
PubMed1997

Estimation of radioactive calcium absorption based on expanding Ca-exchangeable space.

Anthropological interest in calcium metabolism is partially connected with the genetic basis of skeletal metabolism that could provide additional optimism for people suffering from osteoporosis. The present investigation is aimed at deal with a of model describing Ca intestinal absorption, suitable for other descriptions currently investigated in anthropology (migration and gene flow). The purpose of this investigation was to establish features of the reflection of the Ca isotopic absorption tests in serum using the concept of an expanding Ca-space and to assess the reliability of the estimation of absorption (ABS) from one serum sample. Double tracer method, using 85Sr as the iv tracer, was used as the referent. The study included 100 subjects (49 females, 51 males) of which 34 were considered healthy. The mean value of ABS was 68 (+/-17.45 SD) % of dose. Serum radioactivity during the 24 hours following oral administration of 47Ca (together with 100 mg elemental Ca), o.s(t), from five blood samples was determined. The relationship between o.s(t) and ABS was found to be connected to an expanding Ca-space, V(t): ABS = o.s(t)V(t) = 26 + 11.8t0.35 o.s(t). After the absorption process was finished, an approximate value of V(t) is (100/S1)(t-x)b. The constants "S1" and "b" describe power function of iv s(t), whereas parameter "x" represents delay of V(t) Ca-space at oral administration in comparison to the iv administration. Statistical models selected on the basis of their low values of the SEE (from 8.71 to 8.90% of dose) include body surface index or body weight index (BW0.425). The CV expressed as (SEE/mean x ABS(Ca/Sr) x 100 were about 13% and the observed greatest difference between the estimated and measured ABS(Ca/Sr) was 20% of dose. The authors believe that models presented permit, to a limited extent, comparison of results obtained by different procedures. The results, according to variability of the sample of subjects, permit judgment on upper limits of error at estimation of absorption from one blood sample radioactivity.

Adult↗
PubMed1992

Some factors influencing the proportion of periplasmic hepatitis B virus pre-S2 antigen in the recombinant yeast Hansenula polymorpha.

A central composite design (CCD) was used to evaluate, for the purpose of future process optimization, the influence of pH, yeast extract and ammonium chloride concentrations on the proportion of periplasmic hepatitis B pre-S2 antigen in the recombinant yeast Hansenula polymorpha. Each factor was tested at five levels, and a second order polynomial model for the proportion of periplasmic antigen was fitted to the treatment combinations. pH showed the greatest effect: the proportion of periplasmic antigen was greatly increased at the higher pH levels. At the higher pH levels used, the proportion of periplasmic antigen was enhanced by a high concentration of ammonium chloride. Additional experiments have confirmed both the validity of the selected model and the optimal conditions found. A significant correlation was found between the proportion of periplasmic antigen and the total yield of antigen. These results indicated that it should be possible to modulate the distribution of the pre-S2 antigen between the periplasm and the cytoplasm of the yeast.

Ammonium Chloride↗
PubMed2004

Dimension reduction in the linear model for right-censored data: predicting the change of HIV-I RNA levels using clinical and protease gene mutation data.

With rapid development in the technology of measuring disease characteristics at molecular or genetic level, it is possible to collect a large amount of data on various potential predictors of the clinical outcome of interest in medical research. It is often of interest to effectively use the information on a large number of predictors to make prediction of the interested outcome. Various statistical tools were developed to overcome the difficulties caused by the high-dimensionality of the covariate space in the setting of a linear regression model. This paper focuses on the situation, where the interested outcomes are subjected to right censoring. We implemented the extended partial least squares method along with other commonly used approaches for analyzing the high-dimensional covariates to the ACTG333 data set. Especially, we compared the prediction performance of different approaches with extensive cross-validation studies. The results show that the Buckley-James based partial least squares, stepwise subset model selection and principal components regression have similar promising predictive power and the partial least square method has several advantages in terms of interpretability and numerical computation.

HIV Infections↗
PubMed2006

MANTIS: combined x-ray, electron and optical Monte Carlo simulations of indirect radiation imaging systems.

We describe MANTIS (Monte carlo x-rAy electroN opTical Imaging Simulation), a tool for simulating imaging systems that tracks x-rays, electrons and optical photons in arbitrary materials and complex geometries. The x-ray and electron transport and involved physics models are from the PENELOPE package, and the optical transport and corresponding physics models are from DETECT-II and include Fresnel refraction and reflection at material boundaries, bulk absorption and scattering. Complex geometries can be handled with the aid of the geometry routines included in PENELOPE. When x-rays or electrons interact and deposit energy in the scintillator, the code generates a number of optical quanta according to a user-selected model for the conversion process. The optical photons are then tracked until they reach an absorption event, which in some cases contributes to the output signal, or escape from the geometry. We demonstrate the capabilities of this new tool with respect to the statistics of the optical signal detected and to the three-dimensional point-response functions corresponding to columnar phosphor screens.

Computer Simulation↗
PubMed1999

Bayesian design and analysis of active control clinical trials.

We consider the design and analysis of active control clinical trials, i.e., clinical trials comparing an experimental treatment E to a control treatment C considered to be effective. Direct comparison of E to placebo P, or no treatment, is sometimes ethically unacceptable. Much discussion of the design and analysis of such clinical trials has focused on whether the comparison of E to C should be based on a test of the null hypothesis of equivalence, on a test of a nonnull hypothesis that the difference is of some minimally medically important size delta, or on one or two-sided confidence intervals. These approaches are essentially the same for study planning. They all suffer from arbitrariness in specifying the size of the difference delta that must be excluded. We propose an alternative Bayesian approach to the design and analysis of active control trials. We derive the posterior probability that E is superior to P or that E is at least k% as good as C and that C is more effective than P. We also derive approximations for use with logistic and proportional hazard models. Selection of prior distributions is discussed, and results are illustrated using data from an active control trial of a drug for the treatment of unstable angina.

Angina, Unstable↗
PubMed2003

[Structure and function of several intercropping ecosystems in newly built orchard].

Sloping wildland is the important potential land resource in China. Structures and functions of five optimized models selected from more than 10 intercropping patterns in the newly built orchards in the uncultivated sloping field were analyzed in this paper. The results showed that organic matter was increased by 5-20%, total N by 7-40%, total P by 8-70%, and total K by 15-80% yearly. Considering its benefit in soil and water conservation, the intercropping model of peanut and autumn soybean was the best, and followed by spring soybean and autumn soybean, tomato and Chinese cabbage, cayenne and tomato, and drought rice and red turnip. Compared with the control, the average soil erosion module and runoff amount of the 5 models were decreased by 44.19%, 38.24%, 39.52%, 37.56%, 37.30%, and 22.40%, 9.28%, 24.11%, 21.60%, 15.93%, respectively. The intercropping model of cayenne and tomato had the highest biomass, and its annual biomass averaged 1,00,267 kg.hm-2. The biomass of intercropping model of peanut and autumn soybean was the second, and the annual value averaged 77,026 kg.hm-2. Intercropping model of peanut and autumn had the highest annual productivity, which averaged 15,619 kg.hm-2, and that of intercropping model of tomato and Chinese cabbage was the second, averaged 15,394 kg.hm-2. The efficiency of energy introjection was in order of cayenne and tomato, tomato and Chinese cabbage, peanut and autumn soybean, spring soybean and autumn soybean, and dry rice and red turnip, and their values were 3.06, 2.16, 2.15, 2.06, and 0.71, respectively.

Crops, Agricultural↗