Systemic sclerosis is a systemic connective tissue disorder characterized by the fibrosis of the skin and certain visceral organs, vasculopathy, and immunological abnormalities. Several genetic and inducible animal models of SSc have been developed and are available for research studies. The purpose of this review is to summarize the various animal models of systemic sclerosis and describe the various contributions of these models in terms of understanding the pathophysiology of the condition and searching for new therapeutic strategies for this incurable disease.
Autoimmune bullous dermatoses (AIBD), such as pemphigus, bullous pemphigoid or epidermolysis bullosa acquisita, are prototypical organ-specific autoimmune diseases. Clinically they are characterized by widespread mucocutaneous blistering, which is often difficult to treat. Patients with AIBD suffer from a significant morbidity and an increased mortality. In AIBD blistering is caused by autoantibodies targeting structural proteins of the skin. During the past decades animal models of AIBD have been developed. These animal models have greatly contributed to our current understanding of AIBD pathogenesis. Most of these insights, however, still await their translation into clinical use. Recently, AIBD animal models have been used to test the efficacy of known and novel drugs. Hence, these models are now not only employed to unravel the pathogenesis of AIBD, but also to assess therapeutic approaches to address the so far unmet high medical need for new treatments. We here review animal model of AIBD: In addition to spontaneously arising AIBD in animals, AIBD can be induced, mostly in mice, by (i) transfer of (auto)-antibodies, (ii) transfer of (auto)-antigen specific lymphocytes, (iii) immunization or (iv) by genetic modifications leading to spontaneous blistering. In combined use, these models allow dissecting all aspects of AIBD pathogenesis, i.e. loss of tolerance, autoantibody production and blistering. Overall we aim to foster a broader use of AIBD animal models, especially in translational biomedical research, to deepen our understanding of AIBD pathogenesis and to develop novel treatments for patients.
This article reviews the commonly used murine strains for studying lupus and lupus nephritis, including strains that develop lupus spontaneously, congenic strains, induced models of lupus, as well as genetically engineered mouse models of lupus bearing transgenes or knockouts. The review then summarizes the main cellular and molecular pathways that lead to the pathogenesis of this autoimmune disease, including autoantibodies. Finally, it concludes with therapeutic insights gained from using mouse models of lupus. To sum, much of what we have learned about lupus has arisen from studying mouse models of the disease, and the laboratory mouse continues to be one of the best tools for studying human SLE.
Inflammation of blood vessels (vasculitis) results from many pathological processes and is found in many different diseases. However, in most situations, the pathological processes inducing vasculitis are unknown. The discovery of anti-neutrophil cytoplasmic autoantibodies (ANCAs) in the 1980s opened the door for studies that eventually led to the description of a new previously undescribed disease, ANCA-associated vasculitis (AAV). Unravelling the immunopathogenesis of this new disease resulted largely from the development of animal models. The major breakthroughs were the description of ANCA, its association with small vessel vasculitis and the discovery of its target autoantigens (myeloperoxidase and Proteinase 3). Three major disease syndromes comprise the AAVs, microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA). Recent human studies suggest that proteinase 3 and myeloperoxidase associated vasculitis are two separate but related diseases. The ability to induce murine autoimmunity to myeloperoxidase including ANCA (with the same immune staining patterns as human ANCA) and the capacity of this anti-myeloperoxidase autoimmunity to induce disease with many of the characteristic features of human AAV is well developed. However, the development of animal models of anti-proteinase 3 ANCA and EGPA is much less well developed. Animal models are important in understanding the human disease and in particular in defining potential therapeutic targets and in early stage therapeutic testing of potential drugs. Clearly the relevance of animal models depends on how closely they mimic human diseases. The current status of animal models of vasculitis will be described in detail with reference to these criteria.
Immune thrombocytopenia or ITP is a debilitating and life-threatening disorder affecting more than 4 in every 10, 000 adults annually. Following a basic understanding of the immunopathology underlying ITP, namely that production of anti-platelet antibodies results in accelerated platelet clearance and thrombocytopenia, animal models of ITP were quickly developed. Rodent models that develop ITP spontaneously or by passive transfer of anti-platelet sera or antibodies have become instrumental in investigating the mechanisms responsible for the breakdown of tolerance in human ITP, understanding the immunopathology that underlies the progression of platelet destruction, elucidating the mechanism(s) of therapeutic amelioration of the ITP, and driving the development of new therapeutic modalities. This review aims to capture the development history and methodology of currently available ITP disease models, and review their advantages and limitations in the study of various aspects of ITP. We also review how closely the various ITP models reflect the pathobiology of human ITP and their usefulness in advancing the development of new therapeutics, which are particularly needed to address the unmet need of patients who are refractory to the currently available repertoire of interventions.
Cardiovascular diseases are the leading cause of death in industrialized nations worldwide. Of all deaths resulting from cardiovascular diseases, 2% are caused by inflammatory heart disease; specifically, myocarditis. The etiology causing myocarditis still remains unclear. Both infectious and non-infectious factors are capable of triggering myocarditis. Acute myocarditis manifests itself in a variety of ways ranging from subclinical disease to sudden heart failure, as well as the occurrence of chest pain, palpitations, and syncope. Myocarditis can lead to dilated cardiomyopathy (DCM), this being the most frequent cause for heart transplantation. Since the underlying mechanism and the pathways behind the disease initiation and progression still need to be elucidated, the need for mouse models simulating the human disease is evident. Various mouse models are frequently used to study myocarditis. Inflammation of the myocardium as a result of infectious agents can be investigated with a widely used animal model where mice are infected with coxsackievirus B3 (CVB3). For autoimmune (non-viral) myocarditis, several mouse models (including induction with myosin or troponin I) have been established to better understand the role of autoantibodies and their influence on disease progression. With these different models, various phases of the disease can be investigated and these findings are used to develop more specific therapies that can be translated into the clinic as a "bench-to-bedside" approach.
Autoimmune diseases are a group of disorders mediated by self-reactive T cells and/or autoantibodies. Mice, as the most widely used animal for modeling autoimmune disorders, have been extensively used in the investigation of disease pathogenesis as well as in the search for novel therapeutics. Since the first mouse model of multiple sclerosis was established more than 60 years ago, hundreds of mouse models have been established for tens of autoimmune diseases. Each mouse model of autoimmune diseases means an individual way of breaking immune tolerance resulting in subsequent autoimmunity. These mouse models can be divided into three categories based on the approaches used for disease induction. The first one represents the induced models in which autoimmunity is initiated in mice by immunization, adoptive transfer or environmental factors. The second group is formed by the spontaneous models where mice develop autoimmune disorders without further induction. The third group refers to the humanized models in which mice bearing humanized cells, tissues, or genes, develop autoimmune diseases either spontaneously or by induction. This article reviews the history and highlights the milestones of the mouse models of autoimmune diseases.
Uveitis is a sight threatening intraocular inflammation accounting for approximately 10% of blindness worldwide. On the basis of aetiology, disease can be classified as infectious or non-infectious; and by anatomical localization of inflammation as anterior, posterior and panuveitis. Non-infectious uveitis is believed to be autoimmune in nature with Th1 and Th17 cells being identified as the prominent effector cell types. Numerous animal models of autoimmune uveitis were developed contributing to our understanding of this inflammatory condition. The classical peptide-induced experimental autoimmune uveoretinitis (EAU) model resembles human posterior uveitis due to the recurrent/relapsing nature of the disease; while the intraocular inflammation triggered by administration of bacterial lipopolisaccharide (endotoxin-induced uveitis, EIU) mimics closely anterior uveitis. The clinical need for novel, more targeted forms of anti-inflammatory therapy has emerged as currently available therapeutic strategies are associated with a number of adverse effects and intolerance in patients. This review summarises knowledge about existing mouse models of uveitis, discusses mechanisms driving intraocular inflammation and describes possible customised translational treatment strategies that can be potentially used in the clinic to prevent blindness in patients.
Myasthenia gravis is a muscle weakness disease characterized by autoantibodies that target components of the neuromuscular junction, impairing synaptic transmission. The most common form of myasthenia gravis involves antibodies that bind the nicotinic acetylcholine receptors in the postsynaptic membrane. Many of the remaining cases are due to antibodies against muscle specific tyrosine kinase (MuSK). Recently autoantibodies against LRP4 (another component of the MuSK signaling complex in the postsynaptic membrane) were identified as the likely cause of myasthenia gravis in some patients. Fatiguing weakness is the common symptom in all forms of myasthenia gravis, but muscles of the body are differentially affected, for reasons that are not fully understood. Much of what we have learnt about the immunological and neurobiological aspects of the pathogenesis derives from mouse models. The most widely used mouse models involve either passive transfer of autoantibodies, or active immunization of the mouse with acetylcholine receptors or MuSK protein. These models can provide a robust replication of many of the features of the human disease. Depending upon the protocol, acute fatiguing weakness develops 2 - 14 days after the start of autoantibody injections (passive transfer) or might require repeated immunizations over several weeks (active models). Here we review mouse models of myasthenia gravis, including what they have contributed to current understanding of the pathogenic mechanisms and their current application to the testing of therapeutics.
Multiple sclerosis (MS) is a chronic neurological disorder of the central nervous system (CNS) leading to progressive accumulation of neurological deficits arising from recurrent episodes of inflammation, demyelination and neuronal degeneration. While the aetiology of the disease is unknown MS is widely considered to be the result of aberrant T cell and antibody responses to CNS antigens giving rise to the common concept that MS is an autoimmune disease or that there is an autoimmune component in the pathogenesis. This idea has lead to the development of experimental autoimmune encephalomyelitis (EAE) mouse models of MS in which immunisation with CNS antigens induces neurological and pathological signs of disease in mice. In addition to EAE models, injection with neurotropic viruses has been used to examine how infections are implicated in the disease process and how they may generate autoimmune responses in the CNS. Viral models are also crucial to investigate the impact of blocking trafficking of immune responses into the CNS since an emerging side-effect of current immunotherapeutic approaches in MS is the reactivation of viruses within the CNS. To investigate myelin damage and repair in the absence of the adaptive immune response, toxin-induced demyelination using cuprizone, ethidium bromide and lysolecithin, which rapidly leads to remyelination when the toxins are withdrawn, are also reviewed. Mice also lend themselves to the vast array of transgenic technologies to probe specific pathways as well as the use of humanised transgenic mice to examine the impact of human molecules. Despite the vast array of mouse models EAE is the most frequently exploited paradigm used to develop therapeutic approaches. However, despite over one thousand compounds used in the treatment of EAE few have become licenced for treatment of MS so far. Thus, this review also debates the reasons for these failures in mouse models as well as discuss how mouse models can be better utilised to provide more powerful preclinical tools to develop rational therapies for multiple sclerosis.
Sjogren's syndrome (SjS) is a chronic autoimmune disorder characterized by immune cell infiltration and progressive injury to the salivary and lacrimal glands. As a consequence, patients with SjS develop xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). SjS is the third most common rheumatic autoimmune disorder, affecting 4 million Americans with over 90% of patients being female. Current diagnostic criteria for SjS frequently utilize histological examinations of minor salivary glands for immune cell foci, serology for autoantibodies, and dry eye evaluation by corneal or conjunctival staining. SjS can be classified as primary or secondary SjS, depending on whether it occurs alone or in association with other systemic rheumatic conditions, respectively. Clinical manifestations typically become apparent when the disease is relatively advanced in SjS patients, which poses a challenge for early diagnosis and treatment of SjS. Therefore, SjS mouse models, because of their close resemblance to the human SjS, have been extremely valuable to identify early disease markers and to investigate underlying biological and immunological dysregulations. However, it is important to bear in mind that no single mouse model has duplicated all aspects of SjS pathogenesis and clinical features, mainly due to the multifactorial etiology of SjS that includes numerous susceptibility genes and environmental factors that appear to play a role in SjS onset and progression. As such, various mouse models have been developed in the field to try to recapitulate SjS. In this review, we focus on recent mouse models of primary SjS xerostomia and describe them under three categories of spontaneous, genetically engineered, and experimentally induced development of SjS-like disease. In addition, we discuss future perspectives of SjS mouse models highlighting pros and cons of utilizing mouse models and demands for improved models.
This article outlines the main directions of the development of national innovation systems in the new EU member states as catch-up economies emerging from a period of systemic change. Attempts simply to copy the experience of the high-income economies in building national innovation systems are misconceived. That experience needs to be adapted to the specific conditions of catch-up countries with a unique systemic heritage. The dominant linear innovation model should be replaced as a basis for thinking and policy making by an interactive, learning-based approach. Catch-up economies such as these need to improve significantly their levels of innovation diffusion management and networking. A symbiotic approach to the balance of high- and low-tech industries is needed. Managerial and organisational competence is at least as important as technological competence.
The Coulomb barrier and electron screening cause difficulties in directly
measuring nuclear reaction cross sections of charged particles in astrophysical
energies. The Trojan-horse method has been introduced to solve the difficulties
as a powerful indirect tool. In order to understand experimental spectra
better, Geant4 is employed to simulate the method for the first time. Validity
and reliability of the simulation are examined by comparing the experimental
data with simulated results. The Geant4 simulation can give useful information
to understand the experimental spectra better in data analysis and is
beneficial to the design for future related experiments.
A new Hamiltonian model is introduced to study the spectrum of light hadrons.
It combines relativistic field theory with elements of the constituent quark
model. In addition to the standard linear confining and pseudoscalar meson
exchange interactions with predetermined parameters, an additional interaction
with different covariant spin structures is examined. Using a large scale Monte
Carlo variational procedure, the resulting model Hamiltonian provides a very
good, unified description of the light quark baryon (both octet and decuplet)
and meson spectra.
The dual-track approach is characteristic of evolutionary reforms in China. The most important aspect of this dualism has been the reform of the ownership structure. On the one track, new, basically market-oriented institutions emerged in a parallel economy comprising non-state enterprises. On the other track, stateowned enterprises were retained and reforms were restricted to conservative policy changes bringing minor productivity-enhancing measures. In order to highlight the performance of the two tracks, a widely neglected indicator is employed to check the performance of enterprises: namely a structural comparison of the resource reallocation processes of both tracks over time. It becomes clear that structural adjustment was basically generated by the new track. In addition, it is shown that the increasing competition from the new track will not accelerate structural adjustment of the old track as long as institutional reforms of SOEs are not significantly extended.
Foreign direct investment (FDI) has played an important role in the development of Laos since the country embarked on an economic transition and business liberalisation programme in the late 1980s. However, in recent years Laos has witnessed a marked contraction in its cumulative FDI inflows. This article provides a profile of FDI activity in Laos over the past decade and identifies the various factors behind the rise, and subsequent decline, in foreign investment inflows during the 1990s. The article concludes by suggesting some of the ways in which Lao policy makers might seek to revive the country's flagging FDI sector.
The aim of this article is to develop and deepen the discussion on this topic and analyse the methods of measuring hidden unemployment. This is important for giving an adequate overview of the situation of the labour market in Estonia and the scope of hidden unemployment and its development in the transition period. The following tasks are set to achieve this aim: to estimate different components of hidden unemployment in Estonia and to analyse the factors that influence this phenomenon in Estonia and thence form policy conclusions. In the analysis data from the Estonian Labour Force Survey (ELFS 97) carried out in 1997 are examined. Three logit models were calculated (for unemployed, underemployed and discouraged persons). The most important findings were that there are no general factors which could influence open and hidden unemployment at the same time, and that the factors influencing the components of hidden unemployment differ—underemployment is probably influenced more by economic factors and discouragement more by psychological factors.
The aim of this study is a detailed analysis of real economic convergence in 27 former socialist (or transition) countries. We focus on two concepts of convergence: absolute (unconditional) beta convergence and sigma convergence. The time frame of our study is 1990-2005. We provide a broad empirical picture of convergence. First, we analyse the catching-up process in the whole group of 27 countries as well as in several narrower sub-groups. Second, we carry out our calculations for the entire period 1990-2005 as well as for shorter sub-periods.
This article presents an overview of the development of Russian agricultural enterprises in 1990-2001. The multi-layered structure of agriculture represented by different categories of non-commercial and commercial producers requires a clear distinction of policies with respect to their targets and end results. The agricultural enterprises maintained their leading role in marketed agricultural production and represent the main focus group among the agricultural producers for policy makers. The article reviews organisational and structural changes to these enterprises in the period studied, and their economic and financial performance. It also examines current policies for resolving the problems in agriculture.
This article is based on 1990-95 data on the number of workers in 14 branches of the economy for most of Russia's regional divisions. This was a period during which the total labour force shrank substantially, but change was clearly uneven across branches. Branches that grew were likely to show an increase in the concentration of workers in a limited number of regions, that is, growing regional inequality. A closer look at the important area of credit, finance and insurance revealed the extremely favourable position of Moscow and St Petersburg. Limited data on gender differences suggest that, as in the past, men appear to benefit more from change than do women.
This article provides a brief overview of the Romanian transformation, pointing out the causes which led to the crisis in 1996. Then the corrective measures taken up to September 1997 to overcome the crisis will be outlined. In the final section the future prospects for political stability, economic growth and other performance indicators, including foreign investment, are presented, based on three forecasts-the IMF forecast, the Romanian government's forecast and the scenario reflecting the arguments developed in this article.
In the absence of secure private property rights, neo-classical political economy would have expected China and Vietnam to perform badly. However, both economies have recorded rapid growth in recent decades. This article attempts to explain this through an analysis of the property rights regime in state enterprises in Vietnam's second city and commercial centre, Ho Chi Minh City. It argues that by the late 1990s the property regime in many firms in the city had evolved so far that they had been effectively privatised. Enforcement of these private property rights rested not on the rule of law but on the ability of a company's real owners to resist outside encroachment. This in turn had to do with the relative strength of clientelist interests located at different levels of the party-state. Although not perfect, property rights were on this basis sufficiently clear and enforceable for economic growth to occur. The argument is illustrated with two case studies which offer rich insights into the real nature of property under a reforming state socialist regime.
Local administrations in Russia have a strong influence on the business environment. In St Petersburg the measures envisaged to assist small businesses have for the most part remained unimplemented and the specific legislation approved in the city has had little effect. Despite the absence of a clear policy by the local government to promote employment in the small business sector, it is approaching the levels registered in some Western countries. Officially St Petersburg, unlike Moscow, does not enjoy a particularly high standard of living—it is only slightly higher than the national average. The article analyses the main factors explaining the expansion of small business in the city.
Regional economic growth in Russia's regions in 1995-2000 is analysed with particular attention paid to FDI and how it influenced growth during this period. FDI appears to have been essential before the 1998 crisis in helping the economy grow despite the initial chaos of the transition. Larger regional economies that have garnered most FDI and perhaps gone further with institutional reforms that can assist in capturing the full benefits of FDI are likely to lead economic growth in the future. All regions need to take advantage now of the favourable economic environment to assess and learn from prior FDI experience to foster future growth should the price of oil and the remaining advantage of a depreciated currency change. No evidence was found that region-wide corruption hindered economic growth in the 1990s.