bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimation of the mutagenic potency of environmental chemicals using short‐term bioassay
Authors: Gentleman Jane F. , Whitmore G. A.
Published: June 2006

The Ames Salmonella test is a widely used bioassay method for assessing the mutagenic potency of a potential carcinogen. The test is quick and reliable, and exploits the correlation that exists between mutagenic potential and carcinogenic potential. The data for this case study came from an international study involving 20 laboratories in nine countries. The laboratories participated in a designed experiment in which substances (complex chemical mixtures of the type encountered in the environment) were evaluated for mutagenicity using the Ames test. A stringent protocol was followed. The study's principal aim was to investigate intra‐ and inter‐laboratory variation in test results. The data consist of counts of revertant Salmonella colonies at each of six dose levels of a substance. The data were obtained for each of five test substances from each participating laboratory. The bioassays were carried out according to a prescribed factorial experimental design. Three sets of analysts participated in this case study. They were asked to model the dose‐response relationship for two substances, to develop an index of the strength of the relationship, and to assess intra‐ and inter‐laboratory variation in bioassay results.
An application of the Bernoulli part to local limit theorems for moving averages on stationary sequences
Authors: Dabrowski André Robert , Mcdonald David
Published: June 2006

We consider partial sums Sn of a general class of stationary sequences of integer‐valued random variables, and we provide sufficient conditions for Sn to satisfy a local limit theorem. To prove this result, we introduce a concept called the Bernoulli part. The amount of Bernoulli part in Sn determines the extent to which the density of Sn is relatively flat. If in addition Sn satisfies a global central limit theorem, the local limit theorem follows.
A simple test of symmetry about an unknown median
Authors: Cabilio Paul , Masaro Joe
Published: June 2006

A simple test statistic for testing symmetry of a distribution function about an unknown value is presented. The asymptotic distributions under symmetry and asymmetry are derived. Using the normal as a “calibration” distribution, the critical values of the test are calculated by Monte Carlo methods. Comparisons with other tests indicate that this procedure performs well.
Robust estimation of variance components
Authors: Gervini Daniel , Yohai Victor J.
Published: June 2006

New robust estimates for variance components are introduced. Two simple models are considered: the balanced one‐way classification model with a random factor and the balanced mixed model with one random factor and one fixed factor. However, the method of estimation proposed can be extended to more complex models. The new method of estimation we propose is based on the relationship between the variance components and the coefficients of the least‐mean‐squared‐error predictor between two observations of the same group. This relationship enables us to transform the problem of estimating the variance components into the problem of estimating the coefficients of a simple linear regression model. The variance‐component estimators derived from the least‐squares regression estimates are shown to coincide with the maximum‐likelihood estimates. Robust estimates of the variance components can be obtained by replacing the least‐squares estimates by robust regression estimates. In particular, a Monte Carlo study shows that for outlier‐contaminated normal samples, the estimates of variance components derived from GM regression estimates and the derived test outperform other robust procedures.
Laplace approximations for censored linear regression models
Authors: Papandonatos George D. , Geisser Seymour
Published: June 2006

We consider approximate Bayesian inference about scalar parameters of linear regression models with possible censoring. A second‐order expansion of their Laplace posterior is seen to have a simple and intuitive form for logconcave error densities with nondecreasing hazard functions. The accuracy of the approximations is assessed for normal and Gumbel errors when the number of regressors increases with sample size. Perturbations of the prior and the likelihood are seen to be easily accommodated within our framework. Links with the work of DiCiccioet al.(1990) and Viveros and Sprott (1987) extend the applicability of our results to conditional frequentist inference based on likelihood‐ratio statistics.
Pearson‐type goodness‐of‐fit tests for regression
Authors: Akritas M. G. , Torbeyns A. F.
Published: June 2006

A procedure for testing the goodness of fit of linear regression models is introduced. For a given partition of the real line into cells, the proposed test is a quadratic form based on the vector of observed minus expected frequencies of the residuals obtained by maximum‐likelihood estimation of the regression parameters. The quadratic form is of the same computational difficulty as the traditional Pearson‐type tests with uncensored data. A statistic based on only one cell is particularly easy to apply and is used for testing the normality assumption in a real data set from astronomy. A simulation study examines the finite‐sample properties of the proposed tests.
On testing the number of components in finite mixture models with known relevant component distributions
Authors: Chen Jiahua , Cheng Ping
Published: June 2006

The limiting distribution of the log‐likelihood‐ratio statistic for testing the number of components in finite mixture models can be very complex. We propose two alternative methods. One method is generalized from a locally most powerful test. The test statistic is asymptotically normal, but its asymptotic variance depends on the true null distribution. Another method is to use a bootstrap log‐likelihood‐ratio statistic which has a uniform limiting distribution in [0,1]. When tested against local alternatives, both methods have the same power asymptotically. Simulation results indicate that the asymptotic results become applicable when the sample size reaches 200 for the bootstrap log‐likelihood‐ratio test, but the generalized locally most powerful test needs larger sample sizes. In addition, the asymptotic variance of the locally most powerful test statistic must be estimated from the data. The bootstrap method avoids this problem, but needs more computational effort. The user may choose the bootstrap method and let the computer do the extra work, or choose the locally most powerful test and spend quite some time to derive the asymptotic variance for the given model.
Bayesian analysis of screening data: Application to AIDS in blood donors
Authors: Gastwirth Joseph L. , Johnson Wesley O. , Reneau Dana M.
Published: June 2006

The rapid increase in the number of AIDS cases during the 1980s and the spread of the disease from the high‐risk groups into the general population has created widespread concern. In particular, assessing the accuracy of the screening tests used to detect antibodies to the HIV (AIDS) virus in donated blood and determining the prevalance of the disease in the population are fundamental statistical problems.

Because the prevalence of AIDS varies widely by geographic region and data on the number of infected blood donors are published regularly, Bayesian methods, which utilize prior results and update them as new data become available, are quite useful. In this paper we develop a Bayesian procedure for estimating the prevalence of a rare disease, the sensitivity and specificity of the screening tests, and the predictive value of a positive or negative screening test. We apply the procedure to data on blood donors in the United States and in Canada. Our results augment those described in Gastwirth (1987) using classical methods. Indeed, we show that the inclusion of sound prior knowledge into the statistical analysis does not yield sufficiently precise estimates of the predictive value of a positive test. Hence confirmatory testing is needed to obtain reliable estimates.

The emphasis of the Bayesian predictive paradigm on prediction intervals for future data yields a valuable insight. We demonstrate that using them might have detected a decline in the specificity of the most frequently used screening test earlier than it apparently was.
Multivariate extreme‐value distributions with applications to environmental data
Authors: Joe Harry
Published: June 2006

Some parametric families of multivariate extreme‐value distributions have been proposed in recent years; several additional parametric families are derived here. The parametric models are fitted, using numerical maximum likelihood, to some environmental multivariate extreme data sets consisting of extreme concentrations of a pollutant at several monitoring stations in a region. Some multivariate nonnormal data analysis techniques are proposed to aid in the likelihood analysis. The new models, together with previous models, appear to be adequate for inferences in that they cover a wide range of possible dependence patterns.
Variation in height acceleration in the Fels growth data
Authors: Ramsay J.O. , Altman N. , BOCK R. Darrell
Published: June 2006

The Fels growth data record at half‐yearly intervals the heights of children from birth to adulthood, and are the basis for pediatricians' growth charts used throughout North America. Aspects of human growth are the subject of a large medical and statistical literature. This paper uses smoothing splines to study the variation in height acceleration. By use of a functional version of principal‐components analysis, we find that variation in the acceleration curve is essentially three‐dimensional in nature. Evidence for a small growth spurt between the ages of six and eight, reported for data collected in Switzerland, is examined, and little support is found for the existence of this phenomenon in the Fels data.
Conditions for consistent estimation in mixed‐effects models for binary matched‐pairs data
Authors: Neuhaus J.M. , Kalbfleisch J.D. , Hauck W.W.
Published: June 2006

Parametric mixed‐effects logistic models can provide effective analysis of binary matched‐pairs data. Responses are assumed to follow a logistic model within pairs, with an intercept which varies across pairs according to a specified family of probability distributions G. In this paper we give necessary and sufficient conditions for consistent covariate effect estimation and present a geometric view of estimation which shows that when the assumed family of mixture distributions is rich enough, estimates of the effect of the binary covariate are typically consistent. The geometric view also shows that under the conditions for consistent estimation, the mixed‐model estimator is identical to the familar conditional‐likelihood estimator for matched pairs. We illustrate the findings with some examples.
Approximate and estimated saddlepoint approximations
Authors: Ohman‐Strickland Pamela , Casella George
Published: June 2006

Classical saddlepoint methods, which assume that the cumulant generating function is known, result in an approximation to the distribution that achieves an error of orderO(n−1). The authors give a general theorem to address the accuracy of saddlepoint approximations in which the cumulant generating function has been estimated or approximated. In practice, the resulting saddlepoint approximations are typically of the orderO(n−1/2). The authors give simulation results for small sample examples to compare estimated saddlepoint approximations.
Box‐Cox transformations in linear models: Large sample theory and tests of normality
Authors: Chen Gemai , Lockhart Richard A. , Stephens Michael A.
Published: June 2006

The authors provide a rigorous large sample theory for linear models whose response variable has been subjected to the Box‐Cox transformation. They provide a continuous asymptotic approximation to the distribution of estimators of natural parameters of the model. They show, in particular, that the maximum likelihood estimator of the ratio of slope to residual standard deviation is consistent and relatively stable. The authors further show the importance for inference of normality of the errors and give tests for normality based on the estimated residuals. For non‐normal errors, they give adjustments to the log‐likelihood and to asymptotic standard errors.
Exact and approximate sum representations for the Dirichlet process
Authors: Ishwaran Hemant , Zarepour Mahmoud
Published: June 2006

The Dirichlet process can be regarded as a random probability measure for which the authors examine various sum representations. They consider in particular the gamma process construction of Ferguson (1973) and the “stick‐breaking” construction of Sethuraman (1994). They propose a Dirichlet finite sum representation that strongly approximates the Dirichlet process. They assess the accuracy of this approximation and characterize the posterior that this new prior leads to in the context of Bayesian nonpara‐metric hierarchical models.
Linear functional regression: The case of fixed design and functional response
Authors: Cuevas Antonio , Febrero Manuel , Fraiman Ricardo
Published: June 2006

The authors consider the problem of simple linear regression when the exogenous and endogenous variables are functional and the design is fixed. They propose an estimator for the underlying linear operator and prove its consistency under some conditions which ensure that the design is sufficiently informative. They consider the classical calibration (or inverse regression) problem and analyze a consistent estimator. They also give a simulation study. The proposed method is not hard to implement in practice.
Smooth estimates of normal mixtures
Authors: Tong Barbara , Viele Kert
Published: June 2006

Posterior distributions for mixture models often have multiple modes, particularly near the boundaries of the parameter space where the component variances are small. This multimodality results in predictive densities that are extremely rough. The authors propose an adjustment of the standard normal‐inverse‐gamma prior structure that directly controls the ratio of the largest component variance to the smallest component variance. The prior adjustment smooths out modes near the boundary of the parameter space, producing more reasonable estimates of the predictive density.
Adaptive estimation in partially linear autoregressive models
Authors: Gao Jiti , Yee Thomas
Published: June 2006

The authors consider a partially linear autoregressive model and construct kernel‐based estimates for both the parametric and nonparametric components. They propose an estimation procedure for the model and illustrate it through simulated and real data. Their work shows that the proposed estimation procedure not only has good asymptotic properties but also works well numerically. It also suggests that a partially linear autoregression is more appropriate than a completely nonparametric autoregression for some sets of data.
Differential equation models for statistical functions
Authors: Ramsay James O.
Published: June 2006

Differential equations have been used in statistics to define functions such as probability densities. But the idea of using differential equation formulations of stochastic models has a much wider scope. The author gives several examples, including simultaneous estimation of a regression model and residual density, monotone smoothing, specification of a link function, differential equation models of data, and smoothing over complicated multidimensional domains. This paper aims to stimulate interest in this approach to functional estimation problems, rather than provide carefully worked out methods.
Effects of omitting a covariate in poisson models when the data are balanced
Authors: Petersen Martin R. , Deddens James A.
Published: June 2006

The authors show that for balanced data, the estimates of effects of interest and of their standard errors are unaffected when a covariate is removed from a multiplicative Poisson model. As they point out, this is not verified in the analogous linear model, nor in the logistic model. In the first case, only the estimated coefficients remain the same, while in the second case, both the estimated effects and their standard errors can change.
Spatial prediction and temporal backcasting for environmental fields having monotone data patterns
Authors: Le Nhu , Sun Li , Zidek James V.
Published: June 2006

The authors develop a methodology for predicting unobserved values in a conditionally lognormal random spatial field like those commonly encountered in environmental risk analysis. These unobserved values are of two types. The first come from spatial locations where the field has never been monitored, the second, from currently monitored sites which have been only recently installed. Thus the monitoring data exhibit a monotone pattern, resembling a staircase whose highest step comes from the oldest monitoring sites. The authors propose a hierarchical Bayesian approach using the lognormal sampling distribution, in conjunction with a conjugate generalized Wishart distribution. This prior distribution allows different degrees of freedom to be fitted for individual steps, taking into account the differential amounts of information available from sites at the different steps in the staircase. The resulting hierarchical model is a predictive distribution for the unobserved values of the field. The method is demonstrated by application to the ambient ozone field for the southwestern region of British Columbia.
Omitted variables in longitudinal data models
Authors: Frees Edward W.
Published: June 2006

The omission of important variables is a well‐known model specification issue in regression analysis and mixed linear models. The author considers longitudinal data models that are special cases of the mixed linear models; in particular, they are linear models of repeated observations on a subject. Models of omitted variables have origins in both the econometrics and biostatistics literatures. The author describes regression coefficient estimators that are robust to and that provide the basis for detecting the influence of certain types of omitted variables. New robust estimators and omitted variable tests are introduced and illustrated with a case study that investigates the determinants of tax liability.
Corrigenda: Confidence curves and improved exact confidence intervals for discrete distribution
Authors: Blaker Helge
Published: June 2006

Due to a typesetting error, the second sentence in the proof of Theorem 2 on page 792 was garbled. It should read, “It suffices to consider confidence intervals when x = 1 is observed, although this phenomenon always occurs if the rejection regions involve probabilities from both tails.”
The behrens‐fisher problem revisited: A bayes‐frequentist synthesis
Authors: Ghosh Malay , Kim Yeong‐Hwa
Published: June 2006

The Behrens‐Fisher problem concerns the inference for the difference between the means of two normal populations whose ratio of variances is unknown. In this situation, Fisher's fiducial interval differs markedly from the Neyman‐Pearson confidence interval. A prior proposed by Jeffreys leads to a credible interval that is equivalent to Fisher's solution but it carries a different interpretation. The authors propose an alternative prior leading to a credible interval whose asymptotic coverage probability matches the frequentist coverage probability more accurately than the interval of Jeffreys. Their simulation results indicate excellent matching even in small samples.
Probability matching priors for an extended statistical calibration model
Authors: Eno Daniel R. , Ye Keying
Published: June 2006

Statistical calibration or inverse prediction involves data collected in two stages. In the first stage, several values of an endogenous variable are observed, each corresponding to a known value of an exogenous variable; in the second stage, one or more values of the endogenous variable are observed which correspond to an unknown value of the exogenous variable. When estimating the value of the latter, it has been suggested that the variability about the regression relationship should not be assumed to be equal for the two stages of data collection. In this paper, the authors present a Bayesian method of analysis based on noninformative priors that takes this heteroscedasticity into account.
Evaluating fit in functional data analysis using model embeddings
Authors: Viele Kert
Published: June 2006

The author proposes a general method for evaluating the fit of a model for functional data. His approach consists of embedding the proposed model into a larger family of models, assuming the true process generating the data is within the larger family, and then computing a posterior distribution for the Kullback‐Leibler distance between the true and the proposed models. The technique is illustrated on biomechanical data reported by Ramsay, Flanagan & Wang (1995). It is developed in detail for hierarchical polynomial models such as those found in Lindley & Smith (1972), and is also generally applicable to longitudinal data analysis where polynomials are fit to many individuals.
Simple and accurate one‐sided inference from signed roots of likelihood ratios
Authors: Diciccio Thomas J. , Martin Michael A. , Stern Steven E.
Published: June 2006

The authors propose two methods based on the signed root of the likelihood ratio statistic for one‐sided testing of a simple null hypothesis about a scalar parameter in the présence of nuisance parameters. Both methods are third‐order accurate and utilise simulation to avoid the need for onerous analytical calculations characteristic of competing saddlepoint procedures. Moreover, the new methods do not require specification of ancillary statistics. The methods respect the conditioning associated with similar tests up to an error of third order, and conditioning on ancillary statistics to an error of second order.
Projection de hájek et polynômes de bernstein
Authors: Hallin Marc , Mellouk Amal , Rifi Khalid
Published: June 2006

Les auteurs établissent la forme explicite, sous l'hypothèse de bruit blanc, de la représentation asymptotique fournie (sous forme non explicite) par le célèbre lemme de projection de Hájek (1968) pour les statistiques de rangs linéaires dans le cas des scores dits approchés. Fondée sur les polynômes de Bernstein, cette représentation est meilleure, au sens de la norme quadratique, que celle de Hájek (1961, 1962) qui est habituellement considérée. Cette représentation polynomiale permet de redémontrer les résultats classiques (normalité asymptotique et borne de Berry‐Esséen). Les simulations indiquent, par ailleurs, que la qualité de l'approximation fournie est significativement meilleure, pour les échantillons de taille finie, que celle qui résulte de la représentation traditionnelle.
The likelihood ratio test for homogeneity in finite mixture models
Authors: Chen Hanfeng , Chen Jiahua
Published: June 2006

The authors study the asymptotic behaviour of the likelihood ratio statistic for testing homogeneity in the finite mixture models of a general parametric distribution family. They prove that the limiting distribution of this statistic is the squared supremum of a truncated standard Gaussian process. The autocorrelation function of the Gaussian process is explicitly presented. A re‐sampling procedure is recommended to obtain the asymptotic p‐value. Three kernel functions, normal, binomial and Poisson, are used in a simulation study which illustrates the procedure.
Asymptotics for L1‐estimators of regression parameters under heteroscedasticityY
Authors: Knight Keith
Published: June 2006

We consider the asymptotic behaviour of L1 ‐estimators in a linear regression under a very general form of heteroscedasticity. The limiting distributions of the estimators are derived under standard conditions on the design. We also consider the asymptotic behaviour of the bootstrap in the heteroscedastic model and show that it is consistent to first order only if the limiting distribution is normal.
Robust inference for bivariate point processes
Authors: Ng Edmund T. M. , Cook Richard J.
Published: June 2006

In the analysis of recurrent events where the primary interest lies in studying covariate effects on the expected number of events occurring over a period of time, it is appealing to base models on the cumulative mean function (CMF) of the processes (Lawless & Nadeau 1995). In many chronic diseases, however, more than one type of event is manifested. Here we develop a robust inference procedure for joint regression models for the CMFs arising from a bivariate point process. Consistent parameter estimates with robust variance estimates are obtained via unbiased estimating functions for the CMFs. In most situations, the covariance structure of the bivariate point processes is difficult to specify correctly, but when it is known, an optimal estimating function for the CMFs can be obtained. As a convenient model for more general settings, we suggest the use of the estimating functions arising from bivariate mixed Poisson processes. Simulation studies demonstrate that the estimators based on this working model are practically unbiased with robust variance estimates. Furthermore, hypothesis tests may be based on the generalized Wald or generalized score tests. Data from a trial of patients with bronchial asthma are analyzed to illustrate the estimation and inference procedures.
A prior for the variance in hierarchical models
Authors: Daniels Michael J.
Published: June 2006

The choice of prior distributions for the variances can be important and quite difficult in Bayesian hierarchical and variance component models. For situations where little prior information is available, a ‘nonin‐formative’ type prior is usually chosen. ‘Noninformative’ priors have been discussed by many authors and used in many contexts. However, care must be taken using these prior distributions as many are improper and thus, can lead to improper posterior distributions. Additionally, in small samples, these priors can be ‘informative’. In this paper, we investigate a proper ‘vague’ prior, the uniform shrinkage prior (Strawder‐man 1971; Christiansen & Morris 1997). We discuss its properties and show how posterior distributions for common hierarchical models using this prior lead to proper posterior distributions. We also illustrate the attractive frequentist properties of this prior for a normal hierarchical model including testing and estimation. To conclude, we generalize this prior to the multivariate situation of a covariance matrix.
On maximum likelihood estimation of the binomial parameter n
Authors: Gupta A. K. , Nguyen T. T. , Wang Yining
Published: June 2006

This paper gives a necessary and sufficient condition for the existence of a finite conditional maximum‐likelihood estimate for the binomial parameter n. Upper bounds for the conditional and beta‐binomial maximum‐likelihood estimators are derived. An example is given to show that the conditional likelihood function and the beta‐binomial likelihood function may not be unimodal.
A generalized‐moments specification test for the logistic link
Authors: Fokianos Konstantinos , Peng Amy , Qin Jing
Published: June 2006

The authors consider the problem of testing the validity of the logistic regression model using a random sample. Given the values of the response variable, they observe that the sample actually consists of two independent subsets of observations whose density ratio has a known parametric form when the model is true. They are thus led to propose a generalized‐moments specification test in detail. In addition, they show that this test can be derived using Neyman's smooth tests for goodness of fit. They present simulation results and apply the methodology to the analysis of two real data sets.
Minimax designs for approximately linear models with AR(1) errors
Authors: Wiens Douglas P. , Zohu Julie
Published: June 2006

We obtain designs for linear regression models under two main departures from the classical assumptions: (1) the response is taken to be onlyapproximatelylinear, and (2) the errors are not assumed to be independent, but to instead follow a first‐order autoregressive process. These designs have the property that they minimize (a modification of) the maximum integrated mean squared error of the estimated response, with the maximum taken over a class of departures from strict linearity and over all autoregression parameters ρ,|ρ,| < 1, of fixed sign. Specific methods of implementation are discussed. We find that an asymptotically optimal procedure for AR(1) models consists of choosing points from that design measure which is optimal for uncorrelated errors, and then implementing them in an appropriate order.
The weighted likelihood
Authors: Hu Feifang , Zidek James V.
Published: June 2006

The authors consider a weighted version of the classical likelihood that applies when the need is felt to diminish the role of some of the data in order to trade bias for precision. They propose an axiomatic derivation of the weighted likelihood, for which they show that aspects of classical theory continue to obtain. They suggest a data‐based method of selecting the weights and show that it leads to the James‐Stein estimator in various contexts. They also provide applications.
Score tests for heterogeneity and overdispersion in zero‐inflated Poisson and binomial regression models
Authors: Hall Daniel B. , Berenhaut Kenneth S.
Published: June 2006

Hall (2000) has described zero‐inflated Poisson and binomial regression models that include random effects to account for excess zeros and additional sources of heterogeneity in the data. The authors of the present paper propose a general score test for the null hypothesis that variance components associated with these random effects are zero. For a zero‐inflated Poisson model with random intercept, the new test reduces to an alternative to the overdispersion test of Ridout, Demério & Hinde (2001). The authors also examine their general test in the special case of the zero‐inflated binomial model with random intercept and propose an overdispersion test in that context which is based on a beta‐binomial alternative.
A dual tyrosine‐leucine motif mediates myelin protein P0 targeting in MDCK cells
Authors: Kidd Grahame J. , Yadav Vijay K. , Huang Ping , Brand Stacey L. , Low Seng Hui , Weimbs Thomas , Trapp Bruce D.
Published: June 2006

Differential targeting of myelin proteins to multiple, biochemically and functionally distinct Schwann cell plasma membrane domains is essential for myelin formation. In this study, we investigated whether the myelin protein P0 contains targeting signals using Madin‐Darby canine kidney (MDCK) cells. By confocal microscopy, P0 was localized to MDCK cell basolateral membranes. C‐terminal deletion resulted in apical accumulation, and stepwise deletions defined a 15‐mer region that was required for basolateral targeting. Alanine substitutions within this region identified the YAML sequence as a functional tyrosine‐based targeting signal, with the ML sequence serving as a secondary leucine‐based signal. Replacement of the P0 ectodomain with green fluorescent protein altered the distribution of constructs lacking the YAML signal. Coexpression of the myelin‐associated glycoprotein did not alter P0 distribution in MDCK cells. The results indicate that P0 contains a hierarchy of targeting signals, which may contribute to P0 localization in myelinating Schwann cells and the pathogenesis in human disease. © 2006 Wiley‐Liss, Inc.
Survival and differentiation of embryonic neural explants on different biomaterials
Authors: Soria José Miguel , Martínez Ramos Cristina , Salmerón Sánchez Manuel , Benavent Veronique , Campillo Fernández Alberto , Gómez Ribelles José Luis , García Verdugo José Manuel , Pradas Manuel Monleón , Barcia Juan Antonio
Published: June 2006

Biomaterials prepared from polyacrylamide, ethyl acrylate (EA), and hydroxyethyl acrylate (HEA) in various blend ratios, methyl acrylate and chitosan, were tested in vitro as culture substrates and compared for their ability to be colonized by the cells migrating from embryonic brain explants. Neural explants were isolated from proliferative areas of the medial ganglionic eminence and the cortical ventricular zone of embryonic rat brains and cultured in vitro on the different biomaterials. Chitosan, poly(methyl acrylate), and the 50% wt copolymer of EA and HEA were the most suitable substrates to promote cell attachment and differentiation of the neural cells among those tested. Immunofluorescence microscopy analysis showed that progenitor cells had undergone differentiation and that the resulting glial and neuronal cells expressed their intrinsic morphological characteristics in culture. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006
Closing capacity of cranial bone defects using porous calcium phosphate cement implants in a rabbit animal model
Authors: Kroese‐Deutman H.C. , Wolke J.G.C. , Spauwen P.H.M. , Jansen J.A.
Published: June 2006

Calcium phosphate (Ca‐P) cement is a well established material for bone repair. The bone biological properties of Ca‐P cement can even be further improved by creating porosity in the material. The current study aimed on the evaluation of the osteoconductive behavior of porous Ca‐P cement. Therefore, circular defects (6, 9, and 15 mm in diameter) were created in the cranium of 3 months old rabbits and filled with porous Ca‐P cement implants. The total porosity of implants was calculated to be 71, 74 and 74% respectively and the average pore diameter was 150 μm. In addition, empty control defects were prepared. After 12 weeks implantation time the animals were sacrificed and radiographic, histological, and histomorphometrical evaluation was performed. The Critical Size Defect (CSD) of this species at this location for an implantation time of 12 weeks was confirmed to be 15 mm. Bone was observed to be present over and through almost all porous Ca‐P cement implants. Only, in one out of eight animals with a 15 mm implant complete bone bridging of the defect did not occur. The size of the defect was found not to affect the total percentage of bone formation in the cement; (17 ± 7)%, (18 ± 6)% and (17 ± 3)% for respectively 6, 9, and 15 mm diameter implants. We concluded that porous Ca‐P cement is an excellent osteoconductive material in non weight bearing situations and complete bridging of a critical sized skull defect occurs in this rabbit model after 12 weeks of implantation. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006
Micromolding of photocrosslinkable hyaluronic acid for cell encapsulation and entrapment
Authors: Khademhosseini Ali , Eng George , Yeh Judy , Fukuda Junji , Blumling James , Langer Robert , Burdick Jason A.
Published: June 2006

Micropatterning of hydrogels is potentially useful for a variety of applications, including tissue engineering, fundamental biological studies, diagnostics, and high‐throughput screening. Although synthetic polymers have been developed for these applications, natural polymers such as polysaccharides may have advantages for biological samples and cell‐based devices because they are natural components of the in vivo microenvironment. In this study, we synthesized and used hyaluronic acid (HA) modified with photoreactive methacrylates to fabricate microstructures as functional components of microfabricated devices. To demonstrate the universality of this approach, two types of microstructures were formed. In the first approach, HA microstructures were fabricated and used as docking templates to enable the subsequent formation of cell microarrays within low shear stress regions of the patterns. Cells within these microwells remained viable, could generate spheroids, and could be retrieved using mechanical disruption. In the second approach, cells were encapsulated directly within the HA hydrogels. Arrays of viable embryonic stem (ES) cells or fibroblasts were encapsulated within HA hydrogels and could later be recovered using enzymatic digestion of the microstructures. These results demonstrate that it is possible to incorporate photocrosslinkable HA, a natural, versatile, degradable, and biocompatible biopolymer, into micro‐electromechanical systems. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006
Localization of CYP4B1 in the rat nasal cavity and analysis of CYPs as secreted proteins
Authors: Genter Mary Beth , Yost Garold S. , Rettie Allan E.
Published: June 2006

CYP4B1 is highly expressed in rat nasal respiratory mucosa, and to a lesser extent in olfactory mucosa. Examination of high‐power photomicrographs suggests that CYP4B1 may be a secreted protein, based on the fact that immunoreactivity appears to be present in the lumens of ducts of Bowman's glands (rather than intracellular localization, as we observed with an antibody recognizing CYP2F4) and in secretory granules in respiratory mucosa. Furthermore, anti‐CYP4B1 immunoreactivity is present on the surface of both respiratory and olfactory mucosa. We used SignalP 3.0 analysis to ascertain the likelihood that rat CYP4B1 is a secreted protein. While this analysis does not suggest that rat CYP4B1 is a secreted protein, several other cytochrome P450 enzymes were predicted to be secreted proteins. The observation that multiple human cytochrome P450s appear to be secreted proteins helps to explain the appearance of anti‐cytochrome P450 antigens in cases of human autoimmune liver diseases. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:139–141, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20123
The effect of intron location on the splicing of BmKK2 in 293T cells
Authors: Zhijian Cao , Chao Dai , Dahe Jiang , Wenxin Li
Published: June 2006

Previously reported results showed that the BmKK2's intron could be recognized and spliced in cultured HEK 293T cells. At the same time, a cryptic splicing site of BmKK2 gene was found in the second exon. Moreover, replacing BmKK2's intron with BmP03's intron (an artificial BmKK2‐BmP03 mosaic gene) did not affect the intron's recognition and splicing, but increased the expression level of the toxin‐GFP fusion protein (Cao et al., J Biochem Mol Toxicol 2006;20:1–6). In this investigation, the BmKK2's intron with 79 nucleotides length was artificially shifted from the 49th nt (the 17th Gly codon between the first base and the second base) to the 100th nt (the 34th Gly codon between the first base and the second base). Based on the constructed intron‐splicing system, the results of RT‐PCR and the western blotting analysis showed that the BmKK2's shifted‐intron (named BmKK2‐s) was not recognized and spliced correctly, but the cryptic splicing site of BmKK2 gene was still spliced in the second exon, which possibly indicated that locations of introns were very important to the recognition and splicing of introns, and splicing of introns was very much associated with the corresponding upstream and downstream exons. This result possibly provides evidence for splice‐site recognition across the exons. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:127–132, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20127
In vivo molecular imaging of adenoviral versus lentiviral gene therapy in two bone formation models
Authors: Feeley Brian T. , Conduah Augustine H. , Sugiyama Osamu , Krenek Lucie , Chen Irvin S. Y. , Lieberman Jay R.
Published: June 2006

Regional gene therapy techniques are promising methods to enhance bone formation in large bone defects that would be difficult to treat with allograft or autograft bone stock. In this study, we compared in vivo temporal expression patterns of adenoviral‐ and lentiviral‐mediated gene therapy in two bone formation models. Primary rat bone marrow cells (RBMC) were transduced with lentiviral or adenoviral vectors containing luciferase (Luc) or BMP‐2 cDNA, or cotransduced with vectors containing Luc and bone morphogenetic protein 2 (BMP‐2). In vitro protein production was determined with luciferase assay or ELISA (for BMP‐2 production) weekly for 12 weeks. Two bone formation models were used—a hind limb muscle pouch or radial defect—in SCID mice. A cooled charged‐coupled device (CCD) camera was used to image in vivo luciferase expression weekly for 12 weeks. In vitro, adenoviral expression of BMP‐2 and luciferase was detected by ELISA or luciferase assay, respectively, for 4 weeks. Lentiviral expression of BMP‐2 and luciferase was sustained in culture for 3 months. Using the CCD camera, we found that adenoviral vectors expressed luciferase expression for up to 21 days, but lentiviral vectors expressed target gene expression for 3 months in vivo in both bone formation models. There was no detectable difference in the amount of bone formed between the adenoviral and lentiviral groups. Lentiviral‐mediated delivery of BMP‐2 can induce long term in vitro and in vivo gene expression, which may be beneficial when developing tissue engineering strategies to heal large bone defects or defects with a compromised biologic environment. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1709–1721, 2006
Porfimer sodium photodynamic therapy for management of Barrett's esophagus with high‐grade dysplasia
Authors: Panjehpour Masoud , Overholt Bergein F.
Published: June 2006

Porfimer sodium photodynamic therapy (ps‐PDT) for Barrett's esophagus is a powerful endoscopic treatment that can eliminate high‐grade dysplasia (HGD) and Barrett's mucosa and reduce the risk of development of cancer in these patients. Ps‐PDT typically results in destruction of Barrett's esophagus in the majority of the treated area. However, residual small island of Barrett's mucosa may persist after PDT. Therefore, adjuvant thermal ablation should be available during follow‐up endoscopies for ablation of residual islands of Barrett's mucosa. PDT should be applied concurrent with effective proton pump inhibitor therapy. This article provides a practical guide for application of porfimer sodium balloon PDT for management of Barrett's esophagus with HGD. Recommendations are provided for patient selection and screening, delivery of PDT to include light dosimetry, methodology for follow‐up endoscopies, as well as discussing the potential side effects and complications. Lasers Surg. Med. 38:390–395, 2006. © 2006 Wiley‐Liss, Inc.
Clinical and research applications of photodynamic therapy in dermatology: Experience of the scottish PDT centre
Authors: Moseley H. , Ibbotson S. , Woods J. , Brancaleon L. , Lesar A. , Goodman C. , Ferguson J.
Published: June 2006

Background and Objectives

The Scottish PDT Centre has carried out 3,442 treatments on 762 patients with superficial skin lesions, especially superficial basal cell carcinoma (sBCC), Bowen's disease (BD) and actinic keratosis (AK).

Study Design Materials and Methods

The article reviews our experience of various light sources and associated dosimetry; thereafter we discuss clinical outcome followed by some of our research studies in clinically important areas.

Results

We show that improved dosimetry is required to ensure an optimal light dose is delivered to the tumour. We have shown that photosensitizers and proteins interact in such a way that their photophysical and photochemical properties are modified. We have also demonstrated the presence of DNA strand breaks with two different photosensitizers, but there is no evidence that PDT is significantly mutagenic in clinical practice.

Conclusions

In our experience, topical PDT is generally well tolerated and is an effective treatment of sBCC, BD, AK, field change and lesions at sites of poor healing. Lasers Surg. Med. 38:403–416, 2006. © 2006 Wiley‐Liss, Inc.
Indole, a core nucleus for potent inhibitors of tubulin polymerization
Authors: Brancale Andrea , Silvestri Romano
Published: June 2006

Microtubules are the basic components of cell structure, which take part in a wide number of pivotal cellular functions. Drugs that are able to modulate the microtubule assembly either by inhibition of tubulin polymerization or by blocking microtubule disassembly are of great interest in anti‐cancer therapy. Several tubulin polymerization inhibitors characterized by the presence of an indole nucleus have been obtained from natural sources or have been prepared by semi‐synthesis. In the last decade an ever increasing number of synthetic indoles have been reported. We have reviewed anti‐tubulin agents obtained by synthesis having an indole as core nucleus. The synthesis, the biological activity, and the structure–activity relationship aspects of 3‐formyl‐2‐phenylindoles, heterocombretastatins, diarylindoles, 2‐aroylindoles, D‐24851, 2‐aryl‐3‐aroylindoles, 3‐aroyl‐ and 1‐aroylindoles, and arylthioindoles are discussed. © 2006 Wiley Periodicals, Inc. Med Res Rev
Log‐Euclidean metrics for fast and simple calculus on diffusion tensors
Authors: Arsigny Vincent , Fillard Pierre , Pennec Xavier , Ayache Nicholas
Published: June 2006

Diffusion tensor imaging (DT‐MRI or DTI) is an emerging imaging modality whose importance has been growing considerably. However, the processing of this type of data (i.e., symmetric positive‐definite matrices), called “tensors” here, has proved difficult in recent years. Usual Euclidean operations on matrices suffer from many defects on tensors, which have led to the use of manyad hocmethods. Recently, affine‐invariant Riemannian metrics have been proposed as a rigorous and general framework in which these defects are corrected. These metrics have excellent theoretical properties and provide powerful processing tools, but also lead in practice to complex and slow algorithms. To remedy this limitation, a new family of Riemannian metrics called Log‐Euclidean is proposed in this article. They also have excellent theoretical properties and yield similar results in practice, but with much simpler and faster computations. This new approach is based on a novel vector space structure for tensors. In this framework, Riemannian computations can be converted into Euclidean ones once tensors have been transformed into their matrix logarithms. Theoretical aspects are presented and the Euclidean, affine‐invariant, and Log‐Euclidean frameworks are compared experimentally. The comparison is carried out on interpolation and regularization tasks on synthetic and clinical 3D DTI data. Magn Reson Med 56, 2006. © 2006 Wiley‐Liss, Inc.
Imaging composite dike propagation (Etna, 2002 case)
Authors: Aloisi Marco , Bonaccorso Alessandro , Gambino Salvatore
Published: June 2006

Late on the night of 26 October 2002, a dike intrusion started suddenly at Mount Etna, producing intense explosive activity and lava effusion on the southern flank. Five to six hours afterward, a long field of eruptive fractures propagated radially along the northeastern flank of the volcano, producing marked variations at the permanent tilt network. The dike propagation velocity was inferred by the associated seismicity. We modeled the temporal evolution of the continuously recorded tilt data, both during the vertical dike propagation on the high south flank on 26 October and during the radial propagation along the northeast flank, between 27 and 28 October. The reproduction of the recorded tilt signal allowed us to describe the geometry and characteristics of the two dikes in greater detail than the previous static inversion. We deduced that the eruption was characterized by an unusual composite mechanism, clearly showing a transition from a nearly pure opening mode displacement to a mechanism characterized by an equally strong normal dip‐slip component and a smaller left lateral strike‐slip component. In this study we demonstrate the interaction between the final segment of the dike and a preexisting structure that was reactivated in response to the intrusion. We show that tilt and its modeling represent a powerful tool to verify and constrain dike intrusions in detail.