bluuebunny/crossref_metadata_2025 huggingface dataset:
Micromechanics of saturated and unsaturated porous media
Authors: Chateau Xavier , Dormieux Luc
Published: October 2002

The homogenization method is used to determine the formulation of the behaviour of both saturated and unsaturated porous media. This approach makes it possible to assess the validity of the effective stress concept as a function of the properties of the porous media at the microscopic scale. Furthermore, the influence of the morphologies of the solid and fluid phases on the macroscopic behaviour is studied. The strain induced by drying is examined as a function of the morphological properties. Copyright © 2002 John Wiley & Sons, Ltd.
A self‐regulating TCP acknowledgment (ACK) pacing scheme
Authors: Aweya James , Ouellette Michel , Montuno Delfin Y.
Published: October 2002

We describe in this paper a new TCP ACK pacing scheme that dynamically tunes its behavior to account for variations or changes in the network load. The scheme does not require the knowledge of when TCP is in the slow‐start or congestion avoidance phase to determine the proper ACK pacing rate. Copyright © 2002 John Wiley & Sons, Ltd.
ECVBA traffic‐smoothing scheme for VBR media streams
Authors: Chao Han‐Chieh , Hung C. L. , Tsuei T. G.
Published: October 2002

We propose an effective and efficient traffic‐smoothing called the efficient changes and variability bandwidth allocation (ECVBA) scheme. This algorithm not only minimizes the peak rate of a stream but also increases the likelihood of successful VBR stream transmission. The main benefit is that it can immediately release bandwidth to other sites in the network. Copyright © 2002 John Wiley & Sons, Ltd.
A branch‐and‐price algorithm for switch‐box routing
Authors: Jørgensen David Grove , Meyling Morten
Published: October 2002

Routing in VLSI design concerns the wiring of a chip after the logical modules have been placed. A subproblem occurring in VLSI design is switch‐box routing. Switch‐box routing can be formulated as the problem of packing Steiner trees in a grid graph. The only previous exact solution method for switch‐box routing uses a branch‐and‐cut approach. The aim of this work was to solve the switch‐box routing problem to optimality by using a branch‐and‐price algorithm based on an IP model where variables represent Steiner trees and where the pricing problem becomes the problem of finding a Steiner tree in a graph. In the primal algorithm, the focal points are branching strategy, pricing strategy, perturbation of the linear program, and computation of lower bounds to terminate column generation early. The final implementation yielded optimal solutions in the knock‐knee model to seven classic switch‐box instances, of which three had not been solved to optimality prior to this work. © 2002 Wiley Periodicals, Inc.
Topology optimization in wavelet space
Authors: Poulsen Thomas A.
Published: October 2002

We investigate the use of wavelet methods for the design description in topology optimization. This is a new setting for topology optimization that does not take the material densities in the elements of the finite element model as the design space. This new approach has advantages and limitations which are discussed. It is shown how the control of wavelet coefficients can be used to prevent the formation of checkerboard patterns and to obtain some geometry control. Problems related to overlapping basis functions are analysed and solution methods are proposed. Examples of optimized designs using the described methods are given. Copyright © 2001 John Wiley & Sons, Ltd.
Variational principles for non‐conforming finite element methods
Authors: Chen Wanji
Published: October 2002

Variational principles with relaxed inter‐element continuity requirement for non‐conforming element methods in linear and non‐linear analyses are developed. Based on the principles, any non‐conforming element displacement can be used directly to derive the explicit expressions of non‐conforming displacement function, which can ensure the passage of the patch test C for the requirement of convergence Copyright © 2001 John Wiley & Sons, Ltd.
On time integration of viscoplastic constitutive models suitable for creep
Authors: Schreyer H. L.
Published: October 2002

Creep of critical components such as electrical solder connections may occur over long periods of time. Efficient numerical simulations of such problems generally require the use of quasi‐static formulations with conjugate‐gradient techniques for solving the large number of algebraic equations. Implicit in the approach is the need to solve the constitutive equation several times for large time steps and for loading directions that may have no resemblance to the actual solution. Therefore, an unconditionally stable and efficient algorithm for solving the constitutive equation is essential for the overall efficiency of the solution procedure. Unfortunately, constitutive equations suitable for simulating the materials of interest are notoriously difficult to solve numerically and most existing algorithms have a stability limit on the time step which may be several orders of magnitude smaller than the desired time step. Here an algorithm is proposed which is a combination of the use of a trapezoidal rule and an iterative Newton–Raphson method for solving implicitly the non‐linear equations. The key to the success of the proposed approach is to always use an initial guess based on the steady‐state solution to the constitutive equation. A representative viscoplastic constitutive equation is used as a model for illustrating the approach. The algorithm is developed and typical numerical results are provided to substantiate the claim that stability has been achieved. Copyright © 2001 John Wiley & Sons, Ltd.
Variable thermal singularity boundary elements in the study of neighbouring singularities
Authors: Mukhopadhyay N. K.
Published: October 2002

Two new boundary elements are presented for the simulation of variable order thermal singularities in two dimensions. The first can model the variable order temperature derivative and heat flux singularities at one end of the element. The second element can simulate the temperature derivative and heat flux singularities at both the ends of the element simultaneously. These elements are useful for studying the interaction of variable order thermal neighbouring singularities. They are employed here for the computation of stress intensity factors in the crack–crack interaction problems under thermal load. To improve the accuracy of such computations a modified crack closure integral based method is adapted. Examples of mode I and mode II centre crack, two collinear neighbouring cracks, kinked crack in a plate, and tee joint with a kinked edge crack under thermal or thermal and mechanical loading are studied to illustrate the usefulness of these elements in the study of neighbouring thermal singularities. Copyright © 2001 John Wiley & Sons, Ltd.
A hybrid boundary node method
Authors: Zhang Jianming , Yao Zhenhan , Li Hong
Published: October 2002

A new variational formulation for boundary node method (BNM) using a hybrid displacement functional is presented here. The formulation is expressed in terms of domain and boundary variables, and the domain variables are interpolated by classical fundamental solution; while the boundary variables are interpolated by moving least squares (MLS). The main idea is to retain the dimensionality advantages of the BNM, and get a truly meshless method, which does not require a ‘boundary element mesh’, either for the purpose of interpolation of the solution variables, or for the integration of the ‘energy’. All integrals can be easily evaluated over regular shaped domains (in general, semi‐sphere in the 3‐D problem) and their boundaries.

Numerical examples presented in this paper for the solution of Laplace's equation in 2‐D show that high rates of convergence with mesh refinement are achievable, and the computational results for unknown variables are most accurate. No further integrations are required to compute the unknown variables inside the domain as in the conventional BEM and BNM. Copyright © 2001 John Wiley & Sons, Ltd.
Convergence analysis of a hierarchical enrichment of Dirichlet boundary conditions in a mesh‐free method
Authors: Han Weimin , Wagner Gregory J. , Liu Wing Kam
Published: October 2002

Implementation of Dirichlet boundary conditions in mesh‐free methods is problematic. In Wagner and Liu (International Journal for Numerical Methods in Engineering 2001; 50:507), a hierarchical enrichment technique is introduced that allows a simple implementation of the Dirichlet boundary conditions. In this paper, we provide some error analysis for the hierarchical enrichment mesh‐free technique. We derive optimal order error estimates for the hierarchical enrichment mesh‐free interpolants. For one‐dimensional elliptic boundary value problems, we can directly apply the interpolation error estimates to obtain error estimates for the mesh‐free solutions. For higher‐dimensional problems, derivation of error estimates for the mesh‐free solutions depends on the availability of an inverse inequality. Numerical examples in 1D and 2D are included showing the convergence behaviour of mesh‐free interpolants and mesh‐free solutions when the hierarchical enrichment mesh‐free technique is employed. Copyright © 2001 John Wiley & Sons, Ltd.
Speeding up the solution of thermal EHL problems
Authors: Ford Judith M. , Chen Ke
Published: October 2002

This paper considers the fast solution of large, dense linear systems arising from thermal EHL problems.We present an efficient preconditioner for these, based on a novel combination of wavelet compression with the Schur complement. Numerical results illustrate the effectiveness of this approach. Copyright © 2002 John Wiley & Sons, Ltd.
A comparative study of axisymmetric finite elements for the vibration of thin cylindrical shells conveying fluid
Authors: Zhang YongLiang , Reese Jason M. , Gorman Daniel G.
Published: October 2002

A comparative study of the relative performance of several different axisymmetric finite elements, when applied to the dynamic problem of thin cylindrical shells conveying fluid, is presented. The methods used are based on (1) the Sanders' theory of thin shells and the potential flow theory, and (2) the theory of elasticity and the Euler equations. The elements studied are: linear, paralinear, parabolic and cubilinear. Extensive comparison with experiment is carried out for the free vibration of cylindrical shells in the absence of, and containing, quiescent and flowing fluid. The analysis of the relative competence of these elements is presented for shell length‐to‐radius ratios 1.95≤L/R≤32, shell radius‐to‐thickness ratios 10≤R/h≤375 and boundary conditions: clamped–clamped, clamped–free and simply supported. We show that natural frequencies of thin cylindrical shells in the absence of, and containing, quiescent and flowing fluid can be assessed accurately when using two‐ and eight‐noded elements, and the latter are also applicable to the dynamic problem of thick cylindrical shells. Copyright © 2002 John Wiley & Sons, Ltd.
An adaptive finite element framework for fatigue crack propagation
Authors: Givoli Dan , Zusman Ron
Published: October 2002

A new finite element (FE) framework for fatigue crack propagation (FCP) analysis is proposed. This framework combines the simplicity of standard industrial FCP analysis with the generality and accuracy of a full FE analysis and can be implemented on a small computer by combining standard existing computational tools. In this way it constitutes an attractive alternative to existing approaches. The framework is based on linear elastic fracture mechanics and on FE mesh adaptation. Some novel features are introduced in several of its steps in order to make it efficient and at the same time reasonably accurate. Various computational aspects of the scheme are discussed. A few two‐dimensional numerical examples involving FCP in thin sheets under plane‐stress conditions are presented to demonstrate the performance of the framework. Some of the numerical results are compared to those of laboratory experiments. Copyright © 2002 John Wiley & Sons, Ltd.
Physics‐based preconditioner for iterative algorithms in multi‐scatterer and multi‐boundary method of moments formulations
Authors: Hagen Jürgen v. , Wiesbeck Werner
Published: October 2002

An efficient method to solve electromagnetic scattering problems involving several metallic scatterers or bodies composed of dielectric and metallic regions is proposed. So far, the method of moments has successfully been applied to large arrays of identical scatterers when it was combined with preconditioned iterative algorithms to solve for the linear system of equations. Here, the method is generalized to geometries that are composed of several metallic elements of different shapes and sizes, and also to scatterers that are composed of metallic and dielectric regions. The method uses in its core an iterative algorithm, preferably the transpose‐free quasi‐minimum residual (TFQMR) algorithm, and a block diagonal Jacobi preconditioner. For best performance, the blocks for the preconditioner are chosen according to individual scatterers or groups of scatterers for the array case, and according to the electric and magnetic current basis functions for dielectric/metallic scatterers. The iterative procedure converges quickly for an optimally chosen preconditioner, and is robust even for a non‐optimal preconditioner. Reported run times are compared to run times of an efficiently programmed LU factorization, and are shown to be significantly lower. Copyright © 2002 John Wiley & Sons, Ltd.
Non‐local dispersive model for wave propagation in heterogeneous media: multi‐dimensional case
Authors: Fish Jacob , Chen Wen , Nagai Gakuji
Published: October 2002

Three non‐dispersive models in multi‐dimensions have been developed. The first model consists of a leading‐order homogenized equation of motion subjected to the secularity constraints imposing uniform validity of asymptotic expansions. The second, non‐local model, contains a fourth‐order spatial derivative and thus requires C1 continuous finite element formulation. The third model, which is limited to the constant mass density and a macroscopically orthotropic heterogeneous medium, requires C0 continuity only and its finite element formulation is almost identical to the classical local approach with the exception of the mass matrix. The modified mass matrix consists of the classical mass matrix (lumped or consistent) perturbed with a stiffness matrix whose constitutive matrix depends on the unit cell solution. Numerical results are presented to validate the present formulations. Copyright © 2002 John Wiley & Sons, Ltd.
A micro‐mechanical damage model based on gradient plasticity: algorithms and applications
Authors: Chen Jian , Yuan Huang
Published: October 2002

As soon as material failure dominates a deformation process, the material increasingly displays strain softening and the finite element computation is significantly affected by the element size. Without remedying this effect in the constitutive model one cannot hope for a reliable prediction of the ductile material failure process. In the present paper, a micro‐mechanical damage model coupled to gradient‐dependent plasticity theory is presented and its finite element algorithm is discussed. By incorporating the Laplacian of plastic strain into the damage constitutive relationship, the known mesh‐dependence is overcome and computational results are uniquely correlated with the given material parameters. The implicit C1 shape function is used and can be transformed to arbitrary quadrilateral elements. The introduced intrinsic material length parameter is able to predict size effects in material failure. Copyright © 2002 John Wiley & Sons, Ltd.
Behaviour of isoparametric quadrilateral family of Lagrangian fluid finite elements
Authors: Gopalakrishnan S.
Published: October 2002

This paper presents the formulation of both the consistent and inconsistent four‐, eight‐ and nine‐noded isoparametric quadrilateral fluid finite elements that are based on Lagrangian frame of reference. The mesh locking phenomenon due to simultaneous enforcement of twin constraints, namely the incompressibility and irrotationality constraints, is studied in detail. The study shows that the characteristic of the locked fluid elements is that it always generates numerous spurious acoustic (volume change) modes upon the enforcement of rotational constraints. That is, the rotational constraints change the character of certain volume change modes. The study further reinforces the necessity of rotational constraints in not only identifying the spurious pressure modes, but also in reducing the computational effort for determining the eigenvalues and eigenvectors. It is found that all fully integrated inconsistent models exhibit locking behaviour. However, the inconsistent eight‐ and nine‐noded elements, integrated with full integration of volumetric stiffness and one point integration of the rotational stiffness matrices, gives excellent performance, although they do not pass the inf–sup test. The four‐ and nine‐noded consistent models are found to give locking free performance while their eight‐noded counterpart exhibited locking behaviour. The study shows that only consistent nine‐noded element models pass the inf–sup test. The utility of these elements in the coupled fluid–structure interaction problem is also demonstrated. Copyright © 2002 John Wiley & Sons, Ltd.
Topology optimization of periodic microstructures with a penalization of highly localized buckling modes
Authors: Neves Miguel M. , Sigmund Ole , Bendsøe Martin P.
Published: October 2002

The problem of determining highly localized buckling modes in perfectly periodic cellular microstructures of infinite extent is addressed. A double scale asymptotic technique is applied to the linearized stability problem for a periodic structure built from linearly elastic microstructures. The obtained stability condition for the microscale level is then used to establish a comparative analysis between different material distributions in the base cell subjected to the same strain field at the macroscale level. The idea is illustrated by some two‐dimensional finite element examples and used to design materials with optimal elastic properties that are less prone to localized instability in the form of local buckling modes at the scale of the microstructure. Copyright © 2002 John Wiley & Sons, Ltd.
A fictitious domain decomposition method for the solution of partially axisymmetric acoustic scattering problems. Part I: Dirichlet boundary conditions
Authors: Farhat Charbel , Hetmaniuk Ulrich
Published: October 2002

We present a fictitious domain decomposition method for the fast solution of high‐frequency acoustic scattering problems characterized by a partially axisymmetric sound‐soft scatterer. We apply this method to the solution of various mockup submarine problems, and highlight its computational advantages and intrinsic parallelism. Copyright © 2002 John Wiley & Sons, Ltd.
Numerical integration of the stiff dynamics of geometrically exact shells: an energy‐dissipative momentum‐conserving scheme
Authors: Romero I. , Armero F.
Published: October 2002

This paper presents a new family of time‐stepping algorithms for the integration of the dynamics of non‐linear shells. We consider the geometrically exact shell theory involving an inextensible director field (the so‐called five‐parameter shell model). The main characteristic of this model is the presence of the group of finite rotations in the configuration manifold describing the deformation of the solid. In this context, we develop time‐stepping algorithms whose discrete solutions exhibit the same conservation laws of linear and angular momenta as the underlying physical system, and allow the introduction of a controllable non‐negative energy dissipation to handle the high numerical stiffness characteristic of these problems. A series of algorithmic parameters for the different components of the deformation of the shell (i.e. membrane, bending and transverse shear) fully control this numerical dissipation, recovering existing energy‐momentum schemes as a particular choice of these algorithmic parameters. We present rigorous proofs of the numerical properties of the resulting algorithms in the full non‐linear range. Furthermore, it is argued that the numerical dissipation is introduced in the high‐frequency range by considering the proposed algorithm in the context of a linear problem. The finite element implementation of the resulting methods is described in detail as well as considered in the final arguments proving the aforementioned conservation/dissipation properties. We present several representative numerical simulations illustrating the performance of the newly proposed methods. The robustness gained over existing methods in these stiff problems is confirmed in particular. Copyright © 2002 John Wiley & Sons, Ltd.
A coupled BEM‐flexibility force method for bending analysis of internally supported plates
Authors: Rashed Youssef F.
Published: October 2002

This paper presents a new method for the analysis of plates in bending with internal supports. The proposed method can be regarded as an extension of the well‐known force method (the flexibility matrix method) in the matrix analysis of structures. The solution is performed through two phases: the released plate phase, in which the plate is released from all internal supports and solved using the Boundary Element Method (BEM). The effect of internal supports is considered in the second phase, where a series of unit virtual loads is placed instead of the unknown redundant reactions at internal supports. The flexibility matrix is formed and compatibility of deformations at the locations of internal supports is satisfied. Hence, the corresponding system of equations is solved for the unknown redundant forces at internal supports. The final solution of the problem consists of the summation of two phases: the released plate phase and the cases of virtual unit loads phase. An efficient solution algorithm is developed to solve both phases simultaneously. The main advantages of the present formulation are: (1) the present formulation increases the versatility of the BEM as it allows the re‐usability of standard BEM codes for solution of plates in bending to be used in solving problems having internal supports, with even no modifications; and (2) the two solution phases are completely uncoupled; therefore it is easy to trace behaviour of the plate due to failure of one or more of the internal supports without re‐analysis.

Several numerical examples are analysed. The results are compared to those of analytical and finite element models to demonstrate the accuracy and the validity of the present formulation. The present formulation is used also to study the differences between the finite element and boundary element modelling for building slabs. Copyright © 2002 John Wiley & Sons, Ltd.
Finite element analyses of wave propagations due to a high‐speed train across bridges
Authors: Ju S. H.
Published: October 2002

The finite element mesh of the unbounded wave problem often contains a large number of degrees of freedom. Moreover, the wave reflection along the mesh boundary cannot be avoided if only the traditional time‐domain finite element method (FEM) is used. Thus, the main purpose of this study is to overcome those drawbacks and discuss how to use the three‐dimensional FEM to simulate the soil vibration due to a moving high‐speed train across bridges. A number of finite element analyses (FEA) including the isolation schemes of in‐filled and open trenches were performed. The appropriate mesh dimension in the direction of the railroad is suggested and validated. Moreover, the 3‐node wheel element for simulating the moving train and the least‐squares method for finding foundation properties are proposed. Since the finite element mesh contains a large number of degrees of freedom, the conjugated gradient method with the SSOR preconditioning scheme is recommended. In conclusion, this study indicates that the difficulty of the FEA for unbounded problems can be overcome efficiently even by using a personal computer. Copyright © 2002 John Wiley & Sons, Ltd.
Modelling of short wave diffraction problems using approximating systems of plane waves
Authors: Laghrouche O. , Bettess P. , Astley R. J.
Published: October 2002

This paper describes a finite element model for the solution of Helmholtz problems at higher frequencies that offers the possibility of computing many wavelengths in a single finite element. The approach is based on partition of unity isoparametric elements. At each finite element node the potential is expanded in a discrete series of planar waves, each propagating at a specified angle. These angles can be uniformly distributed or may be carefully chosen. They can also be the same for all nodes of the studied mesh or may vary from one node to another. The implemented approach is used to solve a few practical problems such as the diffraction of plane waves by cylinders and spheres. The wave number is increased and the mesh remains unchanged until a single finite element contains many wavelengths in each spatial direction and therefore the dimension of the whole problem is greatly reduced. Issues related to the integration and the conditioning are also discussed. Copyright © 2002 John Wiley & Sons, Ltd.
Micromechanics of fibre glass composites at elevated temperatures
Authors: Tesar Alexander , Sotakova Darina , Minar Michal
Published: October 2002

The micromechanical assessment of ultimate response of moulded fibre glass (MFG) composites used in structural engineering and acting at elevated temperatures is treated in the present paper. The advanced crystal simulation model of the MFG‐material at elevated temperatures, based on Washizu's variational principle, is presented. The numerical treatment of non‐linear problems possibly appearing is made using the updated Lagrangian formulation of motion. Each step of iteration approaches the solution of the linear problem and the feasibility of the parallel processing FETM‐simulation approach is established. Some numerical and experimental results are presented in order to demonstrate the efficiency of procedures suggested. Copyright © 2002 John Wiley & Sons, Ltd.
Meshless formulations for simply supported and clamped plate problems
Authors: Sladek J. , Sladek V. , Mang H. A.
Published: October 2002

In this paper, simply supported and clamped thin elastic plates are analysed. The biharmonic differential equation, representing the basis of the Kirchhoff theory, is decomposed into two Poisson equations. Local boundary integral equations are derived for this system of equations. The meshless approximation based on the moving least‐squares method is employed for the implementation. In the case of simply supported plates, it is sufficient to use the local boundary integral equations. For the case of clamped plates we propose to use a combination of the local boundary integral equations and the global ones. Then, two groups of nodal unknowns are computed separately. This leads to a reduced system of algebraic equations. Copyright © 2002 John Wiley & Sons, Ltd.
A computer‐based training system for breast fine needle aspiration cytology
Authors: Diamond James , Anderson Neil H. , Thompson Deborah , Bartels Peter H. , Hamilton Peter W.
Published: October 2002

Fine‐needle aspiration (FNA) cytology is a rapid and inexpensive technique used extensively in the diagnosis of breast disease. To remove diagnostic subjectivity, a diagnostic decision support system (DDSS) called CytoInform© has been developed, based on a Bayesian belief network (BBN) for the diagnosis of breast FNAs. In addition to acting as a DDSS, the system implements a computer‐based training (CBT) system, providing a novel approach to breast cytology training. The system guides the trainee cytopathologist through the diagnostic process, allowing the user to grade each diagnostic feature using a set of on‐screen reference images as visual clues. The trainee positions a slider on a spectrum relative to these images, reflecting the similarity between the reference image and the microscope image. From this, an evidence vector is generated, allowing the current diagnostic probability to be updated by the BBN. As the trainee assesses each clue, the evidence entered is compared with that of the expert through the use of a defined teaching file. This file records the relative severity of each clue and a tolerance band within which the trainee must position the slider. When all clues in the teaching case have been completed, the system informs the user of inaccuracies and offers the ability to reassess problematic features. In trials with two pathologists of different experience and a series of ten cases, the system provided an effective tool in conveying diagnostic evidence and protocols to trainees. This is evident from the fact that each pathologist only misinterpreted one case and a total of 86%/88% (experienced/inexperienced) of all clues assessed were interpreted correctly. Significantly, in all cases that produced the correct final diagnostic probability, the route taken to that solution was consistent with the expert's solution. Copyright © 2001 John Wiley & Sons, Ltd.
Granulocyte macrophage‐colony stimulating factor (GM‐CSF) recruits immune cells to the pancreas and delays STZ‐induced diabetes
Authors: Krakowski Michelle , Abdelmalik Robin , Mocnik Lorraine , Krahl Troy , Sarvetnick Nora
Published: October 2002

Granulocyte macrophage‐colony stimulating factor (GM‐CSF) is one of the most widely used growth factors for enhancing immune responses and is known to recruit and activate antigen‐presenting cells (APCs). This study hypothesized that overexpression of this cytokine within the pancreatic β‐cells would recruit, expand, and activate APCs. The question was whether this would lead to tolerance or autoimmunity to pancreatic antigens. This possibility was tested by preparing transgenic mice (ins‐GM‐CSF) whose islets expressed murine GM‐CSF. By 6–8 weeks of age, these mice developed a profound mononuclear cell infiltration that often overwhelmed the exocrine pancreas, although no changes in enzyme or hormone function were apparent. The majority of the mononuclear infiltrate within the pancreas was identified as F4/80+ macrophages. Transgenic ins‐GM‐CSF mice had splenomegaly due to a massive increase in the macrophage population. Additionally, mononuclear cells were found within the livers of transgenic mice, with F4/80+ cells also identified within the infiltrate, indicating that GM‐CSF‐activated mononuclear cells circulated to organs other than the pancreas. To assess the disease potential, this study tested whether macrophage recruitment to the pancreas might accelerate or protect the islets from diabetes. It was found that the induction of diabetes by low‐dose streptozotocin (STZ) was delayed and reduced within ins‐GM‐CSF transgenic mice, in comparison with negative littermates. Together, these data highlight the role of GM‐CSF in recruiting APCs such as macrophages. Advanced cellular infiltration does not overtly harm, and may even protect, pancreatic function, as seen with the delay in chemically induced diabetes. Copyright © 2001 John Wiley & Sons, Ltd.
Gene expression patterns in melanocytic cells: candidate markers for early stage and malignant transformation†
Authors: Meije Clifton B. , Hakvoort Theodorus B. M. , Swart Guido W. M. , Westerhof Wiete , Lamers Wouter H. , Das Pranab K.
Published: October 2002

Different stages of differentiation of human melanocytic cells, such as normal melanocytes, naevus and melanoma cells, reflect distinct gene expression patterns. A PCR‐based subtractive hybridization and display method was applied to identify genes that are differentially expressed in melanocytic cells in relation to early stage and malignant transformation. This resulted in the identification of a number of candidate cDNAs differentially expressed among melanocytes, naevus cells, and (non)‐metastatic melanoma cells. Out of this collection of cDNAs, 16 clones were screened that comprised 12 novel genes, one previously identified expressed sequence tag related to vesicular trafficking (Ras‐related protein Rab5b). The other three were also known genes that were either related to cell motility (β‐tubulin), pre‐mRNA splicing (small nuclear protein U1A), or of unknown function (the human TI227‐H gene). The differential expression patterns of Rab5b and two novel gene fragments (pCMa1, pCMn2) were further assessed in melanocytic cells. pCMa1 was expressed more in metastatic melanoma than in primary melanoma cells. In contrast, pCMn2 was expressed in both non‐metastatic and metastatic melanoma cells, but was not detectable in either normal melanocytes or naevus cells. The Ras‐related protein Rab5b showed lower levels of expression in highly metastatic than in other melanoma cells. These three cDNAs may therefore be involved in the early stage and malignant transformation of melanocytes. Copyright © 2001 John Wiley & Sons, Ltd.
Fas receptor‐mediated apoptosis: a clinical application?
Authors: Timmer Tineke , de Vries Elisabeth G. E. , de Jong Steven
Published: October 2002

Fas is a membrane protein belonging to the death receptor family. Cross‐linking of Fas by its ligand, FasL, or agonistic anti‐Fas antibodies, induces apoptosis of cells expressing Fas on the membrane by triggering a cascade of caspases. Since many different tumours express Fas on their membrane, targeting Fas‐mediated apoptosis by anti‐Fas antibodies may be a promising anticancer therapy. Unfortunately, not all Fas‐expressing cells are sensitive to Fas‐mediated apoptosis. This has resulted in the discovery of many different inhibition mechanisms of Fas‐mediated apoptosis. In addition, mutations in the Fas or p53 gene can also influence the sensitivity for Fas‐mediated apoptosis. However, the role of wild‐type p53 in Fas expression is still controversial. Because several different cytotoxic drugs are able to induce Fas membrane expression, combination therapy of anticancer drugs with anti‐Fas antibodies or FasL is conceivable as an anticancer strategy. The efficiency of the induction of Fas‐mediated apoptosis by anti‐Fas antibodies, FasL‐expressing cells or recombinant FasL (rFasL) in tumours has been demonstrated in vivo in solid tumours implanted in mice. Unfortunately, systemic treatment with anti‐Fas antibodies or rFasL causes severe damage to the liver, so most preclinical studies are now focusing on circumvention of this problem by local administration of FasL, or on the use of inducible FasL‐expressing vectors as gene therapy. Copyright © 2001 John Wiley & Sons, Ltd.
Screening for prostatic cancer and its evolution within Britain
Authors: Parkinson M. C. , Bott S. R. J. , Montironi R. , Melia J.
Published: October 2002

The arguments for and against screening for prostatic cancer are frequently discussed (Albertsen PC. Screening for prostate cancer is neither appropriate nor cost‐effective. Urol Clin North Am 1996; 23: 521–530; Schroder FH, Alexander FE, Bangma CH, Hugosson J, Smith DS. Screening and early detection of prostate cancer. Prostate 2000; 44: 255–263). In contrast, this paper outlines how screening became possible, why the decision was made not to initiate a national screening programme in Britain, the other pathways being pursued, and the current problems, in particular the issue of histopathology workload. Copyright © 2002 John Wiley & Sons, Ltd.
Short‐term preoperative radiotherapy interferes with the determination of pathological parameters in rectal cancer
Authors: Nagtegaal Iris D. , Marijnen Corrie A. M. , Klein Kranenbarg Elma , Mulder‐Stapel Adri , Hermans Jo , van de Velde Cornelis J. H. , Han J. M. van Krieken J. ,   The Pathology Review Committee
Published: October 2002

Short‐term preoperative radiotherapy in combination with surgery has been shown to decrease the rate of local recurrence in rectal cancer patients. The effects of this type of radiotherapy on the histopathology of rectal carcinoma has been hitherto unknown. Since various histopathological factors are associated with prognosis, the study of alterations induced by irradiation is an important issue. This paper examines the histopathology of resection specimens from 1306 patients who were treated in a randomized trial that evaluated the benefits of preoperative radiotherapy. In this trial, patients were treated with short‐term radiotherapy (5×5 Gy) and operated on within 5 days after radiation. Histopathological parameters were determined by the Pathology Review Committee of the trial and we compared tumours of patients with and without preoperative radiotherapy. Tumours of patients who were treated with preoperative radiotherapy were smaller, more often mucinous carcinomas (13% versus 7%, p<0.001) and more often poorly differentiated (35% versus 24%, p<0.001). After radiotherapy, there was less inflammatory reaction around the tumour (extensive in 7% versus 18%, p<0.001), which was mainly caused by a decrease in T lymphocytes and neutrophil granulocytes. The fibroblastic reaction was more pronounced in the radiotherapy group (extensive in 22% versus 10%, p<0.001). Remarkable histological alterations occurred within a week after 5 days of irradiation of rectal carcinomas. The prognostic value of these factors therefore needs to be re‐evaluated for irradiated patients. Copyright © 2002 John Wiley & Sons, Ltd.
Reduction of hypoxia‐inducible heme oxygenase‐1 in the myocardium after left ventricular mechanical support
Authors: Grabellus Florian , Schmid Christof , Levkau Bodo , Breukelmann Dirk , Halloran Philip F. , August Christian , Takeda Nobuakira , Takeda Atsushi , Wilhelm Markus , Deng Mario C. , Baba Hideo A.
Published: October 2002

Left ventricular assist devices (LVAD) may improve cardiac function. The pathogenesis of this phenomenon, called ‘reverse remodelling’, is not completely elucidated. To examine the hypothesis that LVAD support eliminates tissue stress by reducing local hypoxia, the distribution of heme oxygenase‐1 (HO‐1), a stress protein inducible by hypoxia, was examined in vivo and in vitro. The immunoreactivity for HO‐1 was semi‐quantitatively analysed in left ventricular tissue of 23patients (14 dilated cardiomyopathy (DCM), six ischaemic heart disease (IHD), three myocarditis/congenital heart disease) with end‐stage heart failure before and after LVAD support, while two unused donor hearts served as controls. Control hearts stained almost negative for HO‐1, while failing hearts showed immunoreactivity mainly in cardiomyocytes, but also in endothelial cells, some smooth muscle cells and fibroblasts. Hearts with IHD showed significantly higher HO‐1 immunoreactivity than hearts with DCM or myocarditis/congenital heart disease. After LVAD support, the HO‐1 content decreased significantly in the DCM and IHD group and was significantly higher in the subendocardium than in the subepicardium. In vitro, under hypoxic conditions, neonatal rat cardiomyocytes showed an increase of HO‐1 protein content up to sixfold above the normal level, which returned to normal values after normoxic cultivation. Mechanical support reduces the HO‐1 content of the failing heart and HO‐1 is inducible in vitro under hypoxia and is reversible under normoxia. This supports the concept that restoration of cardiac normoxia by mechanical unloading, particularly in the subendocardium, may be in part responsible for the phenomenon of ‘reverse remodelling’. Copyright © 2002 John Wiley & Sons, Ltd.
New classification of pancreatic intraductal papillary–mucinous tumour by mucin expression: its relationship with potential for malignancy
Authors: Nakamura Akiko , Horinouchi Michiko , Goto Masamichi , Nagata Kohji , Sakoda Koro , Takao Sonshin , Imai Kohzoh , Kim Young S. , Sato Eiichi , Yonezawa Suguru
Published: October 2002

In previous studies of the expression of MUC1 (membrane‐bound type mucin) and MUC2 (intestinal type secretory mucin) in pancreatic tumours, invasive ductal carcinoma (IDC) usually showed MUC1+ and MUC2− expression, whereas intraductal papillary–mucinous tumour (IPMT) showed MUC1− and MUC2+ expression. Recently, however, many IPMTs have been collected, a considerable number of which have shown MUC1− and MUC2− expression. In the present study, the clinicopathological features were examined of 18 IPMTs with MUC2+ and 32 IPMTs with MUC2−, and their potential for malignancy was compared. Most of the IPMTs with MUC2+ were composed of dark columnar cells, whereas most of the IPMTs with MUC2− were composed of clear columnar cells. The incidence of carcinomatous change and invasive proliferation of the carcinoma in the MUC2+ tumours was significantly higher than in the MUC2− tumours. The clinical outcome for the patients with IPMT showing the MUC2+ pattern tended to be worse than for those with IPMT showing the MUC2− pattern, although the overall outcome for the two types of IPMT was significantly better than for those with IDC. Because of the differences in mucin expression pattern, morphological appearance and potential for malignancy between the two types of IPMT, we believe that they belong to different neoplastic lineages and that it may be reasonable to classify them as different entities, although the WHO classification contains a single clinicopathological entity of IPMT forming an adenoma–carcinoma sequence. In conclusion, our classification of IPMTs by MUC2 expression pattern may be of value in the better assessment of the biological behaviour of IPMTs and their potential for malignancy. Copyright © 2002 John Wiley & Sons, Ltd.
Progressive loss of PAX9 expression correlates with increasing malignancy of dysplastic and cancerous epithelium of the human oesophagus
Authors: Gerber Josef‐Karl , Richter Thomas , Kremmer Elisabeth , Adamski Jerzy , Höfler Heinz , Balling Rudi , Peters Heiko
Published: October 2002

Pax genes encode a family of transcription factors that play key roles in embryonic development. Whereas the functions of Pax genes in the adult organism are largely unknown, upregulated Pax gene expression has been implicated in tumourigenesis. In this study, PAX9‐specific monoclonal antibodies have been generated and it has been shown that PAX9 protein is expressed in the normal epithelium of the adult human oesophagus. PAX9 expression was either lost or significantly reduced in the majority of invasive carcinomas and epithelial dysplasias, the latter representing precancerous lesions. Notably, the percentage of PAX9‐positive cells within the epithelium decreased with increasing malignancy of the epithelial lesion. These results identify PAX9 as a sensitive marker for deregulated differentiation of oesophageal keratinocytes and indicate a role for PAX9 in the normal differentiation process of internal stratified squamous epithelia. These data suggest that upregulated PAX9 expression is not required for the formation of the majority of squamous cell carcinomas of the human oesophagus. Copyright © 2002 John Wiley & Sons, Ltd.
Vascularization of cutaneous melanoma involves vessel co‐option and has clinical significance
Authors: Döme Balázs , Paku Sándor , Somlai Beáta , Tímár József
Published: October 2002

This study was undertaken to determine the role and the fate of the peritumoural vascular plexus during the vascularization of human malignant melanoma (hMM) and in an appropriate murine melanoma model system. The prognostic significance of the vascularity of different tumour areas was also evaluated. Despite morphometry revealing several‐fold higher microvessel densities (MVDs) in the peritumoural tissue than at the centre of the tumour, the development of visceral metastases of hMM was exclusively correlated with the MVD of the tumour centre. Furthermore, the 5‐year survival of the patient group with low tumour centre MVD (<30/mm2, n=29) was 100%, compared to 1/16 patients alive with high tumour centre MVD (>30/mm2, n=16). Morphometric analysis and three‐dimensional reconstruction of vessel networks of both human and murine melanomas showed clearly that the peritumoural vascular plexus present at the melanoma base is continuously being incorporated into the growing tumour mass. Once vessels become incorporated, sprouting ceases and the proliferating endothelial cells (EC) take part only in vessel dilatation. Moreover, the immunohistochemical and ultrastructural characterization of microvessels demonstrated that the pericyte coverage of endothelial tubes was complete in all of the investigated areas, in both human and murine melanomas. Copyright © 2002 John Wiley & Sons, Ltd.
Molecular cytogenetic differences between histological subtypes of malignant mesotheliomas: DNA cytometry and comparative genomic hybridization of 90 cases
Authors: Krismann Michael , Müller Klaus‐Michael , Jaworska Malgorzata , Johnen Georg
Published: October 2002

It is established that subtypes of human malignant mesotheliomas (MM) are associated with different survival times. Ninety cases of MM were examined using DNA cytometry and comparative genomic hybridization (CGH), with emphasis on the main histological subtypes; epithelioid, sarcomatoid and biphasic. A comparison by DNA cytometry revealed moderate differences, with the rare subgroup of mesodermomas having the highest and the sarcomatoid group the lowest rate of aneuploidy. Using CGH, 6.2 chromosomal imbalances per case on average could be detected. Losses (4.1/case) were more common than gains of chromosomal material (2.1/case). MM show no single, specific defect, but a typical pattern of genomic defects can be attributed to this tumour entity. Common losses are clustered at the chromosomal regions 9p21 (34%), 22q (32%), 4q31–32 (29%), 4p12–13 (25%), 14q12–24 (23%), 1p21 (21%), 13q13–14 (19%), 3p21, 6q22, 10p13–pter and 17p12–pter (16% each). Common gains are located on 8q22–23 (18%), 1q23/1q32 (16%), 7p14–15 and 15q22–25 (14% each). While differences in the frequencies of the defects between epithelioid and sarcomatoid MM are not as pronounced as are seen with the pleomorphic mesodermomas, several chromosomal locations (3p, 7q, 15q, 17p) show significant variations. The most pronounced distinguishing feature of sarcomatoid MM is a more than fourfold higher number of amplicons. These data indicate that MM has a distinctive tumour biology with a broad spectrum of heterogeneity, as reflected in morphology and also, more subtly, in the patterns of chromosomal imbalances of the subtypes. Copyright © 2002 John Wiley & Sons, Ltd.
The expression of E‐cadherin and catenins in colorectal tumours from familial adenomatous polyposis patients
Authors: El‐Bahrawy Mona A. , Talbot Ian C. , Poulsom Richard , Jeffery Rosemary , Alison Malcolm R.
Published: October 2002

Familial adenomatous polyposis patients (FAP) harbour a germline mutation of the adenomatous polyposis coli gene (APC), and APC mutations are early events in the development of sporadic colorectal neoplasms. The APC protein interacts with β‐catenin and γ‐catenin and APC mutations are believed to play a role in the altered levels of β‐catenin in colorectal tumours. Immunohistochemical studies have shown changes in the expression and distribution of E‐cadherin and catenins in sporadic colorectal neoplasms. This study assessed the expression and distribution of E‐cadherin and catenins in colorectal neoplasms and non‐neoplastic mucosa from FAP patients. The expression and cellular distribution of E‐cadherin and catenins were studied by immunohistochemistry in 61 adenomas, five carcinomas, and non‐neoplastic mucosa from 18 FAP patients. mRNA levels in the carcinomas were studied by in situ hybridization. The expression of E‐cadherin and catenins was increased in over 80% of the adenomas, with evident cytoplasmic immunoreactivity. There was increased expression of E‐cadherin and catenin in the carcinomas, with a notable increase in the levels of mRNA, in comparison with the non‐neoplastic mucosa. Copyright © 2002 John Wiley & Sons, Ltd.