bluuebunny/crossref_metadata_2025 huggingface dataset:
Approximation of time‐dependent, viscoelastic fluid flow: Crank‐Nicolson, finite element approximation
Authors: Ervin Vincent J. , Heuer Norbert
Published: October 2003

In this article we analyze a fully discrete approximation to the time dependent viscoelasticity equations with an Oldroyd B constitutive equation in ℝ$^{\acute{d}}$, $\acute{d}$ = 2, 3. We use a Crank‐Nicolson discretization for the time derivatives. At each time level a linear system of equations is solved. To resolve the nonlinearities we use a three‐step extrapolation for the prediction of the velocity and stress at the new time level. The approximation is stabilized by using a discontinuous Galerkin approximation for the constitutive equation. For the mesh parameter, h, and the temporal step size, Δt, sufficiently small and satisfying Δt ≤ Ch$^{\acute{d}/4}$, existence of the approximate solution is proven. A priori error estimates for the approximation in terms of Δt and h are also derived. © 2003 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 20: 248–283, 2004
Wavelets‐Galerkin scheme for a Stokes problem
Authors: Zhou Xiaolin
Published: October 2003

This note presents a wavelets‐Galerkin scheme for the numerical solution of a Stokes problem by using the scaling function of a symmetric biorthogonal spline wavelets that can be modified to generate the divergence‐free wavelets. © 2003 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 20: 193–198, 2004
A second‐order linearized difference scheme on nonuniform meshes for nonlinear parabolic systems with Neumann boundary value conditions
Authors: Zhang Ling‐yun , Sun Zhi‐zhong
Published: October 2003

A linearized three‐level difference scheme on nonuniform meshes is derived by the method of the reduction of order for the Neumann boundary value problem of a nonlinear parabolic system. It is proved that the difference scheme is uniquely solvable and second‐order convergent in L∞‐norm. A numerical example is given. © 2003 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 20: 230–247, 2004
Synthesis and characterization of guar gum‐graft‐polyacrylonitrile
Authors: Thimma Reddy T. , Reddy N. Subbarami , Tammishetti Shekharam
Published: October 2003

Cerium(IV) mediated grafting of polyacrylonitrile on to guar gum was studied. Grafting parameters were studied gravimetrically, as a function of temperature, initiator concentration and Guar to acrylonitrile ratio. Higher temperatures resulted in higher monomer conversion and homopolymer formation. Both monomer conversion and extent of grafting increased with increase in cerium ion concentration in the range studied (0.91–9.12 mmol/l). Similar results were obtained with increase in monomer to guar gum ratio from 1 to 5. Grafting with this initiator was found to be generally good with high grafting efficiencies and low homopolymer formation for most experiments. The copolymers obtained were subjected to alkaline hydrolysis to convert nitrile groups in to carboxylic acid groups and the water absorbency of the resulting anionic guar gum was studied. Materials with water absorption up to 300 g/g could be obtained from this study. Copyright © 2003 John Wiley & Sons, Ltd.
Extrudate swell behavior of PS and LLDPE melts in a dual die with mixed circular/slit flow channels in an extrusion rheometer
Authors: Sombatsompop N. , O‐Charoen N.
Published: October 2003

Extrudate swell behaviors of polystyrene (PS) and linear low‐density polyethylene (LLDPE) melts in a dual channel die, having mixed circular/slit flow channels, in a constant shear rate rheometer were examined. The extrudate swell ratio for PS melt was observed to be higher than that for LLDPE melt for all cases, this being associated with the differences in molecular structures that could be described in terms of power law indexes and secondary flows near the die entrance. In single channel die, the extrudate swell of both PS and LLDPE melts in circular flow channel die was greater than that in slit flow channel, whereas, in dual channel die the slit channel exhibited a higher extrudate swell ratio, the results being explained by revealing the flow patterns of the melt in the barrel and die of the rheometer. It was found that the dimensionless size of the vortex flows near the entrance, and the extent of disentanglement of molecular chains on entering the die were the important factors for the differences in the extrudate swell ratios of the melts at the die exit influenced by the die designs used. Copyright © 2003 John Wiley & Sons, Ltd.
Effect of proton irradiation on structure and optical property of PTFE film
Authors: Peng Guirong , Yang Dezhuang , He Shiyu
Published: October 2003

Effects of protons on chemical structure and optical properties of polytetrafluoroethylene (PTFE) film were investigated in the energy range of 60 to 170 keV to simulate the effects of space proton irradiation environment. The results show that for PTFE film irradiated with protons, the change in C1s spectrum, along with those in F1s and the FT‐IR spectrum after irradiation, demonstrates that two processes take place simultaneously. One is substitution in which carbon to fluorine bonds can be broken by the protons and some positions of fluorine are occupied by active protons; the other is the carbonification, which results in the change of surface color and an increase of carbon percentage on the irradiated surface. For the PTFE film irradiated with 150 keV protons, the spectral absorbance ΔAλ in the wavelengths longer than 300 nm increase unmonotonously with proton fluence, and an abnormally recovery decrease of the ΔAλ with the increase of fluence in the range of 5×1013 cm−2 to 1015 cm−2 is observed. The change of the ΔAλ could be related to the competition of the carbonification and the substituting effect. The carbonification increases the ΔAλ, while the substituting increases the amorphousness amount, leading to an increase in the transparency of the film. In addition, the creation of radicals can also contribute to the increase in absorbance. Copyright © 2003 John Wiley & Sons, Ltd.
Enzyme degradability of benzylated sisal and its self‐reinforced composites
Authors: Lu Xun , Zhang Ming Qiu , Rong Min Zhi , Yang Gui Cheng
Published: October 2003

To produce natural polymer based composite materials, sisal fibers were slightly benzylated and then molded into sheets. Because the modified skin portions of the fibers acquired certain thermoplasticity and the unmodified core parts remain constant, the resultant composites fall into the category of self‐reinforced ones. The present article is devoted to the evaluation of the materials biodegradability with the help of cellulase. It was found that the inherent biodegradability of plant fibers is still associated with the benzylated sisal and the molded composites, as characterized by structural variation, weight loss and deterioration of mechanical performance of the materials. Reaction temperature and time, pH value of the enzyme solution, and dosage of the enzyme had significant influences on the decomposition behavior of the materials. In principle, the enzymolysis of sisal and its self‐reinforced composites is a diffusion‐controlled process. Due to the insusceptibility of lignin to cellulase and the hindrance of it to the cellulase solution, the degradation rates of the materials are gradually slowed down with an increase in time. Copyright © 2003 John Wiley & Sons, Ltd.
Are non‐functional, unfolded proteins (‘junk proteins’) common in the genome?
Authors: Lovell Simon C
Published: October 2003

It has recently been shown that many proteins are unfolded in their functional state. In addition, a large number of stretches of protein sequences are predicted to be unfolded. It has been argued that the high frequency of occurrence of these predicted unfolded sequences indicates that the majority of these sequences must also be functional. These sequences tend to be of low complexity. It is well established that certain types of low‐complexity sequences are genetically unstable, and are prone to expand in the genome. It is possible, therefore, that in addition to these well‐characterised functional unfolded proteins, there are a large number of unfolded proteins that are non‐functional. Analogous to ‘junk DNA’ these protein sequences may arise due to physical characteristics of DNA. Their high frequency may reflect, therefore, the high probability of expansion in the genome. Such ‘junk proteins’ would not be advantageous, and may be mildly deleterious to the cell.
Protecting Children under Financial Constraints: ‘Foster Mother Villages’ in Datong
Authors: SHANG XIAOYUAN , WU XIAOMING
Published: October 2003

China has a long tradition of Confucianism, it has also been dominated by a communist ideology for a few decades. How did these different beliefs and principles influence its welfare system in the past? Towards which direction is the system shifting when the balance of power between the state (the dominant ideology) and society (with its own traditions) has been changed? This article analyses the case of ‘Foster Mother Villages’ and the Datong Social Welfare Institution. The case of Datong shows that, although the influence of official communist ideology was dominant in the overall system of child protection in China, traditional factors were also influential. The dominant role of official ideology has to be underpinned by financial support from the state. Where the government failed to provide the support, the traditional factor became dominant in the main institutional arrangements: that is the reason why institutional care failed to replace foster care in Datong city. In the past 50 years, spanning the eras of both planned economy and market reform in China, the Datong Social Welfare Institution has protected more than 6,500 orphaned, lost and abandoned children, and most of these children have finally achieved a normal family life.
The Wobbly Pillar? Housing and the British Postwar Welfare State
Authors: MALPASS PETER
Published: October 2003

The image of housing as the wobbly pillar under the welfare state has been widely used in recent years, and is clearly an attractive metaphor in the present period as residualisation deepens and privatisation continues. However, this paper is concerned with the early years of the postwar welfare state, when conditions for a securely founded housing service were, arguably, more conducive than they are today. Accordingly the paper focuses on policy work in the 1940s, drawing on new research on Public Record Office files, to reveal the amount of wartime planning within Whitehall for postwar housing policy, and the extent of continuity between the pre and post 1945 periods. It is shown that under the wartime coalition government there was considerably more planning for housing after the war than is acknowledged in the existing literature, and that this work shaped policy under the Labour government of 1945–51. Housing emerged as the wobbly pillar under the welfare state because of the amount of detailed wartime planning and Labour's acceptance of its analysis and prescriptions. Whereas most accounts concentrate on the size of the late 1940s building programme (and judge the government accordingly), the argument here is that to understand how housing emerged as the wobbly pillar it is necessary to look beyond quantity to the question of why a self-proclaimed socialist government failed to challenge the market dominance of housing provision.
Venue Shopping, Political Strategy, and Policy Change: The Internationalization of Canadian Forest Advocacy
Authors: Pralle Sarah B.
Published: October 2003

A key component of any political strategy is finding a decision setting that offers the best prospects for reaching one's policy goals, an activity referred to as venue shopping. This article supports the theory of venue shopping as laid out in Baumgartner and Jones (1993), but presents a more complicated analysis of its practice than most empirical studies to date. First, venue shopping can be more experimental, and less deliberate or calculated, than is commonly perceived. Second, advocacy groups choose venues not only to advance substantive policy goals but also to serve organizational needs and identities. Finally, venue choice is shaped by policy learning. Advocacy groups choose venues not only for short-term strategic reasons, but also because they have embraced a new understanding of the nature of a policy problem. These factors shape the frequency of venue shopping and thus the pace of policy reform.
Music Makers: cultural perspectives in textbook development in Kenya, 1985–1995
Authors: Floyd Malcolm
Published: October 2003

This article draws on my other writings about developments in the teaching of music in Kenya, and on the decision to promote traditional musics and to make music one of the compulsory examinable subjects at the end of primary school. It considers two textbooks published by Oxford University Press in Nairobi: Music Makers for Standards 7 and 8, by Brian Hocking and me, was issued in 1985, and Music Makers for Standards 5 and 6, this time with George Mutura as co-author, was published in 1989. The music education syllabus was revised in 1993, and both books were adapted to adjust the placing and progression of the material. This case study sets out the background of developments in Kenyan educational policy, notes the changes in curricular music, explores how the adaptation happened in practice, tracks the process, comments on its implications and considers responses to the completed project.
On the syntactic and semantic status of anticipatory it
Authors: KALTENBÖCK GUNTHER
Published: October 2003

So-called anticipatory it has been variously classified as a semantically empty prop it, as a referential pronoun, and as a category with an inherently cataphoric function. This article, which is based on a corpus study of actually occurring instances of anticipatory it, examines some of the arguments put forward for each of these classifications and – following Bolinger (1977) – argues for an analysis as ‘definite nominal’ with some referential force which can establish a referential link with a clausal constituent in the immediate context. As such, anticipatory it takes an intermediate position between prop it and referring it, all of which are linked by a scale of gradience specifying their scope of reference (wide vs. narrow). This view of anticipatory it, which allows for both anaphoric and cataphoric reference, can account for all informational types of it-extraposition as well as it-extraposition with complement omission, and provides a possible explanation for cases of it-omission.
Right-branching in English derivational morphology
Authors: BERG THOMAS
Published: October 2003

The aim of this article is to establish whether the structure of morphologically complex words in English is flat or hierarchical and, in case of the latter possibility, whether it is left- or right-branching, and whether the branching direction is consistent throughout the lexicon. Six criteria (three phonological, one morphological, one lexical, and one semantic) are introduced as arguments bearing on the internal structure of words. These criteria are applied to the complete set of prefix-stem-derivational suffix sequences in English. The overall evidence clearly weighs in favour of the hierarchical right-branching model. Right-branching is argued to be a concomitant of translating meaning into form. No branching-direction preference emerges on the semantic criterion. Right-branching is relatively weak on the lexical criterion, stronger on the morphological criterion, and strongest on the phonological criteria. Left-branching is observed to play a certain role in words with unproductive prefixes and is understood as a symptom of demorphologization. The branching direction is found to be largely, though not entirely, consistent. The six criteria generate a low percentage of conflicting outcomes, suggesting that branching paradoxes are a rather uncommon phenomenon. The reason for hierarchical right-branching structure in English is claimed to lie in the processing advantage that it incurs. This explanation applies not only to the morphological but also to the syntactic and phonological levels. Processing ease thus leads to crosslevel harmony in the English language.
Classifying conditionals: form and function
Authors: DANCYGIER BARBARA
Published: October 2003

Renaat Declerck and Susan Reed, Conditionals: a comprehensive empirical analysis. Topics in English Linguistics 37. Berlin and New York: Mouton de Gruyter, 2001. Pp. xviii + 565. Hardback €98.00/sFr169/$108, ISBN 3 11 017144 9.
New technologies in scanning probe microscopy for studying molecular interactions in cells
Authors: Horton Mike A. , Lehenkari Petri P. , Charras Guillaume T. , Nesbitt Stephen A.
Published: October 2003

Atomic force microscopy (AFM) is a specialised form of scanning probe microscopy, which was invented by Binnig and colleagues in 1986. Since then, AFM has been increasingly used to study biomedical problems. Because of its high resolution, AFM has been used to examine the topography or shape of surfaces, such as during the molecular imaging of proteins. This, combined with the ability to operate under known force regimes, makes AFM technology particularly useful for measuring intermolecular bond forces and assessing the mechanical properties of biological materials. Many of the constraints (e.g. complex instrumentation, slow acquisition speeds and poor vertical range) that previously limited the use of AFM in cell biology are now beginning to be resolved. Technological advances will enable AFM to challenge both confocal laser scanning microscopy and scanning electron microscopy as a method for carrying out three-dimensional imaging. Its use as both a precise micro-manipulator and a measurement tool will probably result in many novel and exciting applications in the future. In this article, we have reviewed some of the current biological applications of AFM, and illustrated these applications using studies of the cell biology of bone and integrin-mediated adhesion.
Molecular targets for existing and novel immunosuppressive drugs
Authors: Stepkowski Stanislaw M.
Published: October 2003

Anti-neoplastic cytostatic antiproliferative agents, such as methotrexate, 6-mercaptopurine and cyclophosphamide, were originally used as immunosuppressive drugs. Although these agents induced only modest anti-rejection activity, they caused serious non-specific bone marrow suppression, impairing host resistance and increasing the incidence of infections. Unlike these non-selective agents, cyclosporine A, tacrolimus and sirolimus act more selectively on different stages of the T-lymphocyte (T-cell) and B-lymphocyte (B-cell) activation cycles; however, cyclosporine and tacrolimus are nephrotoxic, whereas sirolimus causes hypertriglyceridaemia. Thus, despite this progress, continued efforts must be made to develop and test new, potentially very selective agents. The agent 15-deoxyspergualin moderately inhibits both mitogen-stimulated T-cell proliferation and the generation of cytotoxic T lymphocytes (CTLs) but does not affect the production of interleukin 2 (IL-2). Another drug, FTY720, has a unique action to prevent rejection, by altering the homing of lymphocytes to the lymphoid compartments. The newest members of the family of antiproliferative agents, namely mycophenolate mofetil, leflunomide and brequinar, are potentially more selective than their predecessors. However, the most promising agents are produced using antisense technology. This approach involves the design of antisense oligodeoxynucleotides; these novel drugs are designed to block allograft rejection by blocking selected messenger RNA (mRNA). This review outlines the mechanisms of action, the limitations of application and the molecular or cellular targets of traditional agents, newly developed drugs and also antisense technology, which is an example of a new application of molecular medicine.
Islet cell transplantation for insulin-dependent diabetes mellitus: perspectives from the present and prospects for the future
Authors: Gray Derek W.R. , Titus Nicolas , Badet Lionel
Published: October 2003

The long-term complications of insulin-dependent diabetes mellitus have become a major health care problem, and it is now clear that they arise from inadequate homeostatic control of blood glucose by injected replacement insulin. Transplantation of pancreatic islets is arguably the most logical approach to restoring metabolic homeostasis in people with diabetes. This review looks at the current status of human islet transplantation and the problems that remain. These include: (1) the limited supply of human islet tissue available for transplantation; (2) the adverse effects of current immunosuppressive protocols on diabetic patients; (3) the problems of primary nonfunction of the transplanted islets; (4) the rejection of islets; and (5) the recurrence of autoimmune diabetic disease. Some of the approaches that might solve these problems are then examined: (1) immune modulation to reduce or prevent immune attack by the recipient's immune system; (2) immunoisolation to prevent recognition of the islet graft; (3) induction of tolerance; (4) xenotransplantation using islets derived from animals; and (5) gene therapy.
The role of cytokines in immunological tolerance: potential for therapy
Authors: McNeil Nicole , Ried Thomas
Published: October 2003

Molecular cytogenetic techniques that are based on fluorescence in situ hybridisation (FISH) have become invaluable tools for the diagnosis and identification of the numerous chromosomal aberrations that are associated with neoplastic disease, including both haematological malignancies and solid tumours. FISH can be used to identify chromosomal rearrangements, by detecting specific DNA sequences with fluorescently labelled DNA probes. The technique of comparative genomic hybridisation (CGH) involves two-colour FISH. It can be used to establish ratios of fluorescence intensity values between tumour DNA and control DNA along normal reference metaphase chromosomes, and thereby to detect DNA copy-number changes such as gains and losses of specific chromosomal regions and gene amplifications. Spectral karyotyping (SKY) is a novel molecular cytogenetic method for characterising numerical and structural chromosomal aberrations. SKY involves the simultaneous hybridisation of 24 differentially labelled chromosome-painting probes, followed by spectral imaging and chromosome classification, and produces a colour karyotype of the entire genome. The use of SKY has contributed significantly to the identification of chromosomal anomalies that are associated with constitutional and cancer cytogenetics, and has revealed many aberrations that go undetected by traditional banding techniques. In this article, we have reviewed these new molecular cytogenetic techniques and described their various applications in molecular medicine.
Chaperonins are cell-signalling proteins: the unfolding biology of molecular chaperones
Authors: Ranford Julia C. , Coates Anthony R.M. , Henderson Brian
Published: October 2003

The chaperonins are a subgroup of oligomeric molecular chaperones; the best-studied examples are chaperonin 60 (GroEL) and chaperonin 10 (GroES), both from the bacterium Escherichia coli. At the end of the 20th century, the paradigm of chaperonins as protein folders had emerged, but it is likely that during the 21st century these proteins will come to be viewed as intercellular signals. Indeed, it is possible that the chaperonins were among the first intercellular signalling proteins to evolve. During the past few years, it has emerged that chaperonin 10 and chaperonin 60 can be found on the surface of various prokaryotic and eukaryotic cells, and can even be released from cells. Secreted chaperonins can interact with a variety of cell types, including leukocytes, vascular endothelial cells and epithelial cells, and activate key cellular activities such as the synthesis of cytokines and adhesion proteins. Much has been made of the high degree of sequence conservation among the chaperonins, particularly in terms of the immunogenicity of these proteins. However, different chaperonin 60 proteins can bind to different cell-surface receptors, including the Toll-like receptors, suggesting that this family of proteins cannot be treated as one biological entity and that several subfamilies may exist. Chaperonins have been implicated in human diseases on the basis of their immunogenicity. The finding that chaperonins can also induce tissue pathology suggests that they may play roles in infections and in idiopathic diseases such as atherosclerosis and arthritis.
The role of cytokines in immunological tolerance: potential for therapy
Authors: Harber Mark , Sundstedt Anette , Wraith David
Published: October 2003

Current immunosuppression protocols, although often effective, are nonspecific and therefore hazardous. Consequently, immunological tolerance that is antigen specific and does not globally depress the patient's immune system has become one of the Holy Grails of immunology. Since the discovery that cytokines have immunomodulatory effects, extensive research has investigated the potential of these molecules to induce and maintain specific immunological tolerance in the context of transplantation, allergy and autoimmunity. In this article, we review the possible mechanisms by which cytokines can modulate the immune response and the animal models that frequently confound the theory that a single cytokine, or group of cytokines, can induce tolerance in a predictable manner. Finally, we discuss the role of cytokines at a paracrine level, particularly in the context of inducing and maintaining antigen-specific, regulatory T cells with the clinical potential to suppress specific immune responses.
The role of the Y chromosome in male infertility
Authors: Affara Nabeel A.
Published: October 2003

It was suggested by Ronald Fisher in 1931 that genes that benefit the male (including those required for spermatogenesis) would accumulate on the Y chromosome. Following the discovery that microdeletions of the Y chromosome were associated with diverse spermatogenic phenotypes, at least three intervals that contain one or more genes controlling male germ-cell differentiation have been identified in humans. These intervals, named AZFa, AZFb and AZFc, have been mapped, cloned and examined in detail for the presence of functional genes. In this review, I have discussed the genes that map to the AZF intervals and the evidence indicating which ones are the most likely candidates underlying Y-linked male infertility. In addition, I have considered the analysis of key intervals on the mouse Y chromosome, where it provides comparative data supporting the role of a candidate gene in an infertility phenotype.
Tetraspanins and malignancy
Authors: Boucheix Claude , Duc Guy Huynh Thien , Jasmin Claude , Rubinstein Eric
Published: October 2003

Tetraspanins, also called tetraspans or the transmembrane 4 superfamily (TM4SF), are cell-surface proteins that span the membrane four times and are found on many different cell types in many organisms. They display numerous properties that indicate their physiological importance in cell adhesion, motility, activation and proliferation, as well as their contribution to pathological conditions such as metastasis or viral infection. A major characteristic of tetraspanins is their ability to form cell-surface complexes with other molecules participating in cell adhesion, either to the extracellular matrix (ECM) or to other cells, and with molecules required for signalling. It is not yet known how the structure of the complexes might affect the functions of other molecules or what basic biochemical mechanisms allow their formation and regulation. Nevertheless, an intriguing association between tetraspanin expression and metastatic potential indicates that these molecules may provide novel insights into tumour progression.
Intracellular trafficking of influenza virus: clinical implications for molecular medicine
Authors: Whittaker Gary R.
Published: October 2003

The trafficking and processing steps that occur in cells that are infected with influenza virus play a crucial role in the outcome of infection. These steps are targets for new and future anti-viral drugs, and can affect the relative virulence of the virus and its ability to cause disease. The virus first binds to its host cell via specific sialic acid residues, which can control the species tropism of the virus. The internalisation of the virus, into the nucleus of the cell, is dependent on a low pH, and this process is therapeutically targeted by the drug amantadine. Following replication, the newly formed viral genomes leave the nucleus and assemble into infectious particles at the plasma membrane. The targeting and processing of the various viral components at this late stage of the infectious cycle can have a major effect on the ability of the virus to spread and cause disease in its host. Finally, the release of viruses is dependent on the enzyme neuraminidase (NA), and this function has recently been targeted by the NA inhibitors, a new generation of drugs against influenza virus.
T-cell receptor binding kinetics in T-cell development and activation
Authors: Gascoigne Nicholas R.J. , Zal Tomasz , Alam S. Munir
Published: October 2003

T-cell activation is of central importance to the generation of an immune response and is also required as part of the host's ability to recognise self proteins. T cells are activated to differing extents by different ligands. Agonist ligands cause the full range of T-cell activation phenotypes – from activation of signalling cascades, to cytokine secretion or target cell killing, to T-cell proliferation. Partial agonists, which can differ from the agonist by as little as a single amino acid residue, can induce some of these responses but not all. Antagonist ligands can disable the signalling of an agonist ligand. These different types of interaction between ligand and T-cell receptor (TCR) also determine the developmental fate of maturing T cells. Much recent work has focused on how the T cell distinguishes between ligands. At least part of the answer lies in the kinetics of its binding to ligand.
Fulminant viral hepatitis: molecular and cellular basis, and clinical implications
Authors: Liu Mingfeng , Chan Camie W.Y. , McGilvray Ian , Ning Qin , Levy Gary A.
Published: October 2003

Fulminant hepatic failure is defined by the sudden onset of severe liver injury accompanied by hepatic encephalopathy in an individual who previously had no evidence of liver disease. This disease causes multiple organ failure and is associated with a high mortality. The most frequently recognised cause of fulminant or subfulminant hepatic failure is viral hepatitis. Data are now emerging to support the hypothesis that, irrespective of the aetiology of fulminant hepatic failure, the host's immune response (including production of proinflammatory cytokines and mediators) contributes to microcirculatory disturbances that result in hypoxic injury and cell death (apoptosis). Impairment of the scavenger function of the reticuloendothelial cell system further contributes to reduced hepatic blood flow and ischaemic necrosis. An increased understanding of the molecular pathogenesis of fulminant hepatic failure now enables new molecular therapeutic modalities to be tested. Given the complexity of this multi-dimensional disorder, the challenge is to provide a rational basis for treatment. This might include enhancement or suppression of immune responsiveness by manipulation of endogenous cytokine synthesis or by cytokine administration and, at the same time, use of strategies to increase hepatic regeneration.
Degeneration of intervertebral discs: current understanding of cellular and molecular events, and implications for novel therapies
Authors: Freemont Tony J. , LeMaitre Christine , Watkins Alex , Hoyland Judith A.
Published: October 2003

Recent advances in surgical techniques have made it possible to study the changes that are known as degeneration of the intervertebral disc (IVD) in greater depth than ever before. This is an important area of study because degeneration of the lumbar IVDs is associated, perhaps causally, with low back pain: one of the most common and debilitating conditions in the western world. The term degeneration implies an inevitable progression that is characteristic of wear-and-tear-associated conditions. However, modern research on human tissue has shown that this is not the case. Here, disruption of the micro-anatomy that is described as degeneration is an active process, which is probably regulated by locally produced cytokines. This one observation opens up the possibility of inhibiting or even reversing the processes of degeneration. The immediate question is how can the slowly progressive changes of degeneration be treated, particularly as connective tissue repair is thought to be a slow and highly regulated process. In this review, the possibility of using gene therapy as a single-shot, long-lasting therapeutic strategy is discussed, together with an outline of developments in this area to date.
Transgenic models of the transmissible spongiform encephalopathies
Authors: Manson Jean C. , Tuzi Nadia L.
Published: October 2003

The transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases that are also transmissible. The PrP protein is central to the disease process and has been hypothesised to be the infectious agent. Polymorphisms in the PrP gene have been linked to the incubation time of TSE disease, and mutations in the human PrP gene have been suggested to result in genetic TSE disease. Several PrP transgenic models have been developed. These models express PrP from different species, with and without PrP mutations, and at different levels of gene expression. This article discusses the contribution of these transgenic models to our present understanding of the TSE diseases.
The molecular biology of Wilms' tumour
Authors: Brown Keith W. , Malik Karim T.A.
Published: October 2003

Wilms' tumour (WT; nephroblastoma), a kidney neoplasm, is one of the most frequently occurring solid tumours of childhood. It arises from the developing kidney by genetic and epigenetic changes that lead to the abnormal proliferation of renal stem cells (metanephric blastema). WT serves as a paradigm for understanding the relationship between loss of developmental control and gain of tumourigenic potential. In particular, loss of function of tumour suppressor genes has been implicated in the development of WT, and the Wilms' tumour suppressor gene WT1 (at chromosome 11p13) was the second tumour suppressor gene to be cloned, after the retinoblastoma gene RB-1. WT1 plays an essential role in kidney development, but is mutated in only approximately 20% of WTs, which suggests that further lesions and genetic loci are involved in Wilms' tumourigenesis. Other chromosomal regions associated with WT include 7p, 11p15, 16q and 17q. Although many of these loci probably contain tumour suppressor genes, imprinted genes (genes showing expression of only one parental allele) and oncogenes have also been implicated in WT. Some loci have been shown to be associated with particular clinical outcomes, suggesting that they might be used to determine prognosis, and especially to identify poor prognostic subgroups that can be targeted for aggressive and/or novel therapies.
Diverse functions of BRCA1 in the DNA damage response
Authors: Lee Jong-Soo , Chung Jay H.
Published: October 2003

Breast cancer is one of the most common causes of cancer-related mortality in women. It affects more than one in nine women over their lifetime. Although most breast cancers are sporadic, the genetics and molecular biology of the heritable forms of breast cancer have provided valuable insights into not only breast cancer but also cancers in general. Among the mutations linked to heritable breast cancers, the mutations in the breast cancer 1 (BRCA1) gene are the best characterised. The BRCA1 gene encodes a nuclear protein that is important for maintaining genome integrity. However, a growing list of BRCA1-associated proteins suggests that BRCA1 has diverse and unexpected functions.
Current theories for the molecular and cellular pathogenesis of Alzheimer's disease
Authors: Gouras Gunnar K.
Published: October 2003

Over the past decade, the prevailing view for the molecular and cellular pathogenesis of Alzheimer's disease (AD) has centred on the β-amyloid (Aβ) peptide that accumulates in vulnerable brain areas in the disease. The amyloid cascade hypothesis postulates that the build up of Aβ in the brain causes damage to neurons, leading to dysfunction and loss of neurons, and the clinical phenotype of the amnestic dementia characteristic of AD. All known mutations that result in autosomal dominant forms of early-onset familial AD cause increased production of Aβ42, a form of Aβ that is particularly relevant in AD. Other proteins that are crucial to the pathogenesis of AD are the presenilins 1 and 2, which are intimately involved with Aβ production and when mutated in familial forms of AD cause increases in Aβ42. Currently, challenges in AD research include determining the earliest pathological effects of Aβ42, how the important AD risk factor apolipoprotein E affects the disease process, whether presenilin is the elusive γ-secretase, and how levels of Aβ can be effectively reduced therapeutically.
Molecular mechanisms of immunity in corneal allotransplantation and xenotransplantation
Authors: Qian Ying , Dana M. Reza
Published: October 2003

Corneal allotransplantation is the most common and successful form of solid organ transplantation in humans. In uncomplicated cases, the two-year graft survival rate is over 90%. This extraordinary success can be attributed in part to various features of the normal cornea and anterior segment that together account for their ‘immune-privileged’ status. However, despite this success, a significant number of corneal grafts fail and immunological rejection remains by far the leading cause of graft failure. Studies on animal models of corneal transplantation have yielded a wealth of information on the molecular and cellular features of graft rejection, and have established that this process is mediated primarily by CD4+ T cells of the T helper 1 (Th1) phenotype. In addition, studies have elucidated that certain facets of allosensitisation differ between corneal and other solid organ transplants. On the basis of these findings, novel experimental strategies selectively targeting the afferent or efferent arms of corneal alloimmunity have provided promising results in preventing corneal allograft rejection in the laboratory. Finally, because of the global shortage of human donor corneas, there is currently renewed interest in the possibility of using corneas from other species for transplantation into human eyes (xenotransplantation). Preliminary studies on animal models of corneal xenotransplantation have documented both antibody-mediated and cell-mediated responses that might play important roles in the accelerated rejection observed in corneal xenotransplants. This review synthesises the principal concepts emerging from studies of the molecular mechanisms in corneal transplant immunology.
Chemokines in cancer
Authors: Frederick Mitchell J. , Clayman Gary L.
Published: October 2003

Chemokines are small, chemotactic cytokines that direct migration of leukocytes, activate inflammatory responses and participate in many other pleiotropic functions, including regulation of tumour growth. Chemokines modulate tumour behaviour by three important mechanisms: regulation of tumour-associated angiogenesis, activation of a host tumour-specific immunological response, and direct stimulation of tumour cell proliferation in an autocrine fashion. All of these mechanisms are promising points of cancer intervention, and preclinical mouse models suggest that chemokine antagonists and agonists could become important in the development of new anticancer therapies.
Immunological pathomechanisms in vitiligo
Authors: Kemp E. Helen , Waterman Elizabeth A. , Weetman Anthony P.
Published: October 2003

Vitiligo is a depigmenting disorder characterised by the loss of melanocytes from the cutaneous epidermis. Although the exact aetiology of vitiligo has not yet been established, the abnormal immune responses frequently observed in vitiligo patients have led to the suggestion that, in some cases, the condition has an autoimmune component. Briefly, circulating autoantibodies and autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. In addition, vitiligo is often associated with other disorders that have an autoimmune origin, including Hashimoto's thyroiditis, Graves' disease, type 1 insulin-dependent diabetes mellitus and Addison's disease. Furthermore, effective use of immunosuppressive therapies to treat vitiligo, the association of vitiligo with certain major histocompatibility complex antigens, and evidence from animal models of the disease have all added credence to the hypothesis that immune reactions play a role in vitiligo pathogenesis. This review presents and discusses the evidence for immunological pathomechanisms in vitiligo.
Mechanisms of cell entry by influenza virus
Authors: Cross Karen J. , Burleigh Laura M. , Steinhauer David A.
Published: October 2003

A wide range of viruses, including many human and animal pathogens representing various taxonomic groups, contain genomes that are enclosed in lipid envelopes. These envelopes are generally acquired in the final stages of assembly, as viruses bud from regions of the membrane of the infected cell at which virally encoded membrane proteins have accumulated. The viruses procure their membranes during this process and mature particles ‘pinch off’ from the cellular membranes. Under most circumstances, initiation of another round of infection is dependent on two critical functions supplied by the envelope proteins. The virus must bind to cell-surface receptors of a new host cell, and fusion of the viral and cellular membranes must occur to transfer the viral genome into the cell. Enveloped viruses have evolved a variety of mechanisms to execute these two basic functions. Owing to their relative simplicity, studies of binding and fusion using enveloped viruses and their components have contributed significantly to the overall understanding of receptor–ligand interactions and membrane fusion processes – fundamental activities involved in a plethora of biological functions.
Molecular markers of metastasis in breast cancer: current understanding and prospects for novel diagnosis and prevention
Authors: Braun Stephan , Harbeck Nadia
Published: October 2003

The early and clinically occult spread of viable tumour cells throughout the body is increasingly considered as a hallmark of cancer progression, because recent data suggest that these cells are precursors of subsequent distant relapse. Using monoclonal antibodies to epithelial cytokeratins or tumour-associated cell-membrane glycoproteins, individual carcinoma cells can be detected in cytological bone marrow preparations at frequencies of 10-5 to 10-6. Prospective clinical studies have shown that the presence of these immunostained micrometastatic cells in bone marrow, as a frequent site of overt metastases, is prognostically relevant with regard to relapse-free period and overall survival. This screening approach might therefore be used to improve tumour staging and to guide stratification of patients for adjuvant therapy in clinical trials. Another promising clinical application is the use of these micrometastatic cells to monitor response to adjuvant therapies, which at present can be assessed only retrospectively after an extended period of clinical follow-up. This review summarises current data on the clinical significance of occult metastatic breast cancer cells in bone marrow.
Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?
Authors: Pockley A. Graham
Published: October 2003

For many years, heat shock or stress proteins have been regarded as intracellular molecules that have a range of housekeeping and cytoprotective functions, only being released into the extracellular environment in pathological situations such as necrotic cell death. However, evidence is now accumulating to indicate that, under certain circumstances, these proteins can be released from cells in the absence of cellular necrosis, and that extracellular heat shock proteins have a range of immunoregulatory activities. The capacity of heat shock proteins to induce pro-inflammatory responses, together with the phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins, has led to the proposition that these proteins provide a link between infection and autoimmune disease. Indeed, both elevated levels of antibodies to heat shock proteins and an enhanced immune reactivity to heat shock proteins have been noted in a variety of pathogenic disease states. However, further evaluation of heat shock protein reactivity in autoimmune disease and after transplantation has shown that, rather than promoting disease, reactivity to self-heat shock proteins can downregulate the disease process. It might be that self-reactivity to heat shock proteins is a physiological response that regulates the development and progression of pro-inflammatory immunity to these ubiquitously expressed molecules. The evolving evidence that heat shock proteins are present in the extracellular environment, that reactivity to heat shock proteins does not necessarily reflect adverse, pro-inflammatory responses and that the promotion of reactivity to self-heat shock proteins can downregulate pathogenic processes all suggest a potential role for heat shock proteins as therapeutic agents, rather than as therapeutic targets.
Unique molecular markers in human endometriosis: implications for diagnosis and therapy
Authors: Blumenthal Rosalyn D. , Taylor Alice , Samoszuk Michael , Goldenberg David M.
Published: October 2003

Endometriosis originates in the uterine lining and affects ~20% of reproductive-age women. The disease often causes chronic pelvic pain, affects ovulatory function and influences fertility. Although laparoscopic diagnosis of uterine endometriosis is quite specific, direct visualisation can be difficult or inaccurate in some circumstances, and it is not useful for diagnosing extra-abdominal disease. Laparoscopy is an invasive procedure, has significant morbidity and cannot be carried out frequently to monitor efficacy of therapy and the possibility of recurrence. Thus, a specific, non-invasive diagnostic test is required. One intriguing area of research uses the technology of radioimmunotargeting, which has previously been used for cancer detection. This technique could have potential for the specific detection and eventual treatment of endometriosis. A marker, eosinophil peroxidase (EPO), has been identified that is expressed in ~90% of endometriosis specimens, and is not expressed or only weakly expressed in normal endometrium. The US Food and Drug Administration has approved a monoclonal antibody to EPO for investigation as an immunoimaging agent in cancers that exhibit eosinophilia. EPO targeting using this antibody could be useful for detecting and/or treating endometriosis.