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Multiple Sclerosis Reviews: 2003

(181 References)

Aktas, O. and F. Zipp (2003). "Regulation of self-reactive T cells by human immunoglobulins--implications for multiple sclerosis therapy." Curr Pharm Des 9(3): 245-56.

            The intravenous administration of high doses of immunoglobulins pooled from the plasma of healthy donors (IVIg therapy) has beneficial effects in patients with a variety of autoimmune disorders. These clinical observations indicate that IVIg have potent antiinflammatory characteristics, and identification of the precise mode of action may open up perspectives for future therapeutic strategies. In certain tissue-specific autoimmune disorders like multiple sclerosis (MS), self-reactive T cells recognizing autoantigens play a significant role for disease pathogenesis, as these cells are able to initiate, maintain, and propagate the harmful immune attack in experimental animal models of disease. These findings render self-reactive T cells an important therapeutic target for autoimmune diseases. Here, we review the effects of IVIg on the homeostasis of T cells and discuss the possible therapeutic implications for multiple sclerosis. As supported by several experimental studies, IVIg regulate crucial steps of T cell-mediated immune responses. These effects involve the modulation of activation, proliferation, differentiation, apoptosis, and effector mechanisms of T cells. The pattern of IVIg-T cell interactions is complex, as IVIg may directly bind to regulatory structures on T cells, or modulate T cell functions indirectly via soluble or cellular components of the immune system.

Alizadeh, M., M. C. Babron, et al. (2003). "Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients." Ann Neurol 54(1): 119-22.

            Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122

Alvarez-Linera Prado, J., J. Escribano Vera, et al. (2003). "[Hydrogen spectroscopy in neurology]." Neurologia 18(6): 324-40.

            for a long time to the research field despite its unquestionable diagnostic value. The availavility of programs able to automatically obtain a spectrum, and the current possibility of estimating easily the relationship among its different peaks, have approached this diagnostic technology to the current clinical situation. With hydrogen MRI spectroscopy (MRS) it is possible to obtain additional information which make it possible to distinguish among different neurological alterations with similar morphological appearance, such as cerebral tumors and pseudotumoral types of inflammatory processes, or tumor recurrence and radionecrosis. On other occasions, it makes it possible to detect alterations which are invisible by imaging study, such as medial temporal sclerosis, or multiple sclerosis. It is also very useful in following-up many alterations, either in their natural history, as in Alzheimers disease, or in order to monitor treatments on cerebral tumors or infectious processes. However, MRS does not often show pathognomonic patterns, so it is always recommended to consider it not just in the clinical context, but as inseparable part of an MR study, either structural or functional (diffusion, perfusion), since it is this is how it provides more useful information from a clinical point of view.

Aruoma, O. I. (2003). "Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods." Mutat Res 523-524: 9-20.

            The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Downs syndrome) and aging challenges continue to emerge from difficulties associated with methods used in evaluating antioxidant actions in vivo. Our interest presently is focused on development of neurodegeneration models based on the integrity of neuronal cells in the central nervous system and how they are protected by antioxidants when challenged by neurotoxins as well as Fenton chemistry models based on the profile of polyunsaturated fatty acids (PUFAs) for the assessment of antioxidant actions in vivo. Use continues to be made of several in vitro analytical tools to characterise the antioxidant propensity of bioactive compounds in plant foods and supplements. For example, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), total oxidant scavenging capacity (TOSC), the deoxyribose assay, assays involving oxidative DNA damage, assays involving reactive nitrogen intermediates (e.g. ONOO(-)), Trolox equivalent antioxidant capacity (TEAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. There is need to agree governance on in vitro antioxidant methods based on an understanding of the mechanisms involved. Because some of the assays are done in non-physiological pH values, it is impossible to extrapolate the results to physiological environment. The consensus of opinion is that a mix of these tools should be used in assessing the antioxidant activities in vitro. The proof of bio-efficacy must emanate from application of reliable in vivo models where markers of baseline oxidative damage are examined from the standpoint of how they are affected by changes in diet or by antioxidant supplements.

Avolio, C., F. Giuliani, et al. (2003). "Adhesion molecules and matrix metalloproteinases in Multiple Sclerosis: effects induced by Interferon-beta." Brain Res Bull 61(3): 357-64.

            In Multiple Sclerosis (MS) pathology, early inflammation involves leukocyte migration across the blood-brain barrier (BBB) within the central nervous system. In this process, adhesion molecules (AMs), both membrane-bound and soluble-circulating forms, and matrix metalloproteinases (MMPs) certainly play a regulatory role. In MS, recombinant Interferon-beta (rIFNbeta) is effective in reducing gadolinium contrast-enhancing lesions on magnetic resonance imaging and this suggests that it may reduce BBB damage or even restore its integrity by different mechanisms that include interference with both AM and MMP pathways. This review will highlight the effects induced by rIFNbeta, both in vitro and in vivo, on cell-bound and soluble forms of AMs and on MMPs.

Babcock, A. and T. Owens (2003). "Chemokines in experimental autoimmune encephalomyelitis and multiple sclerosis." Adv Exp Med Biol 520: 120-32.

Bagnato, F. and C. Pozzilli (2003). "Pharmacological methods to overcome IFN-beta antibody formation in the treatment of multiple sclerosis." Expert Opin Investig Drugs 12(7): 1153-63.

            Diminished efficacy in terms of clinical relapses and lesion load on magnetic resonance images for patients developing neutralising antibodies (NAbs) to recombinant IFN-beta may be found in multiple sclerosis. NAbs become detectable over the first few years of therapy, disappearing during the treatment course in some patients and persisting longer in some others. Therefore, the administration of concomitant therapies to recombinant IFNbeta to prevent the formation of NAbs could be indicated mainly in the latter group of patients at the early stage of the treatment. Among those therapies, steroids meet the best criteria in terms of either safety or impact on the development of NAbs, at the present time.

Bagnato, F. and J. A. Frank (2003). "The role of nonconventional magnetic resonance imaging techniques in demyelinating disorders." Curr Neurol Neurosci Rep 3(3): 238-45.

            The use of nonconventional magnetic resonance imaging techniques (eg, magnetization transfer, magnetic resonance spectroscopy, and diffusion weighted imaging) allows for an accurate characterization of lesions as compared with conventional or standard approaches in demyelinating diseases. Magnetization transfer, magnetic resonance spectroscopy, and diffusion weighted imaging have revolutionized our understanding of demyelinating diseases because these techniques have been used to identify pathologic changes of normal-appearing brain tissue and characterize the differences in lesions. Metrics derived from these methods correlate with clinical disability and provide more accurate tools for monitoring disease activity and treatment effect over time. Quantitative T1 and T2 relaxation time maps provide additional information on demyelinating diseases, allowing for the evaluation of myelin water and distribution of water within tissues. Finally, the measurement of central nervous system atrophy has become a valuable element in determining the course of multiple sclerosis.

Baker, D., G. Pryce, et al. (2003). "The therapeutic potential of cannabis." Lancet Neurol 2(5): 291-8.

            Research of the cannabinoid system has many similarities with that of the opioid system. In both instances, studies into drug-producing plants led to the discovery of an endogenous control system with a central role in neurobiology. Few compounds have had as much positive press from patients as those of the cannabinoid system. While these claims are investigated in disorders such as multiple sclerosis spasticity and pain, basic research is discovering interesting members of this family of compounds that have previously unknown qualities, the most notable of which is the capacity for neuroprotection. Large randomised clinical trials of the better known compounds are in progress. Even if the results of these studies are not as positive as many expect them to be, that we are only just beginning to appreciate the huge therapeutic potential of this family of compounds is clear.

Baker, D. and D. J. Hankey (2003). "Gene therapy in autoimmune, demyelinating disease of the central nervous system." Gene Ther 10(10): 844-53.

            Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), where suspected autoimmune attack causes nerve demyelination and progressive neurodegeneration and should benefit from both anti-inflammatory and neuroprotective strategies. Although neuroprotection strategies are relatively unexplored in MS, systemic delivery of anti-inflammatory agents to people with MS has so far been relatively disappointing. This is most probably because of the limited capacity of these molecules to enter the target tissue, because of exclusion by the blood-brain barrier. The complex natural history of MS also means that any therapeutic agents will have to be administered long-term. Gene therapy offers the possibility of site-directed, long-term expression, and is currently being preclinically investigated in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. While some immune effects may be targeted in the periphery using DNA vaccination, strategies both viral and nonviral are being developed to target agents into the CNS either via direct delivery or using the trafficking properties of cell-carrier systems. Targeting of leucocyte activation, cytokines and nerve growth factors have shown some promising benefit in animal EAE systems, the challenge will be their application in clinical use.

Baker, D. and G. Pryce (2003). "The therapeutic potential of cannabis in multiple sclerosis." Expert Opin Investig Drugs 12(4): 561-7.

            There has been renewed interest in the therapeutic applications of cannabis, and people, particularly those with multiple sclerosis, claim that it may offer benefit in symptom control. Cannabis exerts many of its effects because it taps into an endogenous cannabinoid system. Recent advances have begun to shine light on the biology of this system and may support some of the anecdotal medical claims. The problem with cannabis as a drug is that both the positive and negative aspects are largely the work of the same receptor. However, it may be possible to avoid these through modulation of the endogenous system. Cannabinoids provide a novel therapeutic target, not only for controlling symptoms, but also slowing disease progression through inhibition of neurodegeneration, which is the cause of accumulating irreversible disability.

Bakke, S. J., F. Lilleas, et al. (2003). "[Use of MR in the diagnosis of multiple sclerosis]." Tidsskr Nor Laegeforen 123(10): 1349-51.

Benito-Leon, J. and P. Martinez-Martin (2003). "[Health-related quality of life in multiple sclerosis]." Neurologia 18(4): 210-7.

            The clinical scales used to assess disease severity in multiple sclerosis (MS) patients share a common feature: assessment is made and interpreted by neurologists, and, therefore, someone other than the patient. Furthermore, these scales do not assess the health factors that are important components of patient's experienced quality of life. Health-related quality of life (HRQoL) instruments include several domains, which are regarded by patients as being more important determinants of their overall health states. In fact, HRQoL measurements in MS are becoming important in assessing the effect of treatment and progression of the disease. This article will provide a review of the most significant studies on HRQoL in MS.

Birnboim, S. (2003). "The automatic and controlled information-processing dissociation: is it still relevant?" Neuropsychol Rev 13(1): 19-31.

            The purpose of this paper is to examine the "dual-process" information-processing model of Schneider and Shiffrin (Schneider, W., and Shiffrin, R. M., Psychol. Rev. 84: 1-66, 1977; see also Shiffrin, R. M., and Schneider, W., Psychol. Rev. 84: 127-190, 1977) in light of the research data that have accumulated since the model was introduced more than 20 years ago. First, a brief introduction of the basic model of automatic and controlled information processing will be given. Second, some alternatives to the basic model that were developed over the last two decades will be reviewed. Third, data from neuropsychology and cognitive neuroscience that have a bearing upon this framework will be considered. Finally, some comments on the current usefulness of the dual-process framework for neuropsychological research will be offered.

Bjartmar, C., J. R. Wujek, et al. (2003). "Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease." J Neurol Sci 206(2): 165-71.

            Axonal degeneration has been identified as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory demyelination influences axon pathology during relapsing-remitting MS (RR-MS). This axonal loss remains clinically silent for many years, and irreversible neurological disability develops when a threshold of axonal loss is reached and compensatory CNS resources are exhausted. Experimental support for this view-the axonal hypothesis-is provided by data from various animal models with primary myelin or axonal pathology, and from pathological or magnetic resonance studies on MS patients. In mice with experimental autoimmune encephalomyelitis (EAE), 15-30% of spinal cord axons can be lost before permanent ambulatory impairment occurs. During secondary progressive MS (SP-MS), chronically demyelinated axons may degenerate due to lack of myelin-derived trophic support. In addition, we hypothesize that reduced trophic support from damaged targets or degeneration of efferent fibers may trigger preprogrammed neurodegenerative mechanisms. The concept of MS as an inflammatory neurodegenerative disease has important clinical implications regarding therapeutic approaches, monitoring of patients, and the development of neuroprotective treatment strategies.

Blevins, G. and R. Martin (2003). "Future immunotherapies in multiple sclerosis." Semin Neurol 23(2): 147-58.

            Immunotherapy of multiple sclerosis (MS) will continue to benefit from an increasing understanding of this disease. This knowledge results in newly defined targets for novel therapies. In this article the development of future immunotherapies will be discussed by classifying the approaches into three main types: (1) antigen-specific therapies; (2) agents with a defined target in pathogenic steps of the MS lesion; and (3) therapies with broad immunomodulatory activity. Success in developing new immunotherapies depends on understanding the underlying complexity and heterogeneity of the disease. The current practice of employing a single therapy across a heterogeneous group of MS patients is in part a likely reason for their modest efficacy. The mechanism of action of a single agent may target the appropriate defect in one individual but not others. The therapy of MS in the future will most likely use a combination of agents that are directed at the underlying disease state and stage in the individual patient.

Bobholz, J. A. and S. M. Rao (2003). "Cognitive dysfunction in multiple sclerosis: a review of recent developments." Curr Opin Neurol 16(3): 283-8.

            PURPOSE OF REVIEW: Nearly half of all patients diagnosed with multiple sclerosis will develop cognitive dysfunction, a symptom associated with significant decline in activities of daily living. The purpose of this review is to discuss recent literature investigating issues related to cognitive dysfunction in multiple sclerosis. RECENT FINDINGS: Recent studies, examined in this review, have provided increased understanding regarding specific cognitive processes affected in multiple sclerosis, as well as a characterization of its natural history. Studies have also continued to emphasize the extent to which cognitive deficits in the condition are associated with decline in daily living skills. Recent concerns regarding driving performance have been documented among cognitively impaired individuals. Studies have also examined correlates of cognitive dysfunction, with particular emphasis on neuroimaging techniques reflecting disease activity or lesion burden. With increased understanding of neurobiological correlates of cognitive deficits, investigators have begun to examine potential treatments for managing cognitive dysfunction. SUMMARY: This area of research has suggested that disease modifying medications can have an impact on magnetic resonance imaging disease activity by altering the cerebral demyelinating process resulting in a slower decline in cognitive functions over time and improved activities of daily living for patients with multiple sclerosis.

Bode, R. K., J. S. Lai, et al. (2003). "Issues in the development of an item bank." Arch Phys Med Rehabil 84(4 Suppl 2): S52-60.

            OBJECTIVE: To describe and illustrate 2 issues involved in the development of an item bank that can be used to improve measurement across settings and over time. DESIGN: Secondary (psychometric) analysis of data collected on existing quality of life (QOL) instruments. SETTING: Five cancer clinics in hospital settings in various parts of the United States; 523 solo or group practices in 3 major US cities; and an inpatient rehabilitation hospital in a large metropolitan area. PARTICIPANTS: Illustration 1: 399 persons being treated for or having a history of cancer, 170 persons being treated for human immunodeficiency virus (HIV), 328 persons with stroke assessed during and after acute rehabilitation, and 433 persons being treated for multiple sclerosis. Illustration 2: 1714 persons with cancer and/or HIV participating in a large-scale multisite study, 3429 persons with prevalent treatable chronic health conditions, and 125 persons with stage IV metastatic breast cancer. INTERVENTIONS: Not applicable. Main Outcomes Measures: QOL as measured by 10 different instruments. RESULTS: The illustrations show that (1). core items, which functioned similarly across 4 diagnostic groups, can be identified and used to construct instruments measuring physical function that are tailored to each of these groups, and (2). items from 3 separate datasets can be linked to create a dataset that can serve as an initial pain item bank. CONCLUSION: The methodology exists to develop item banks to develop better measures of QOL.

Borchmann, P. and M. Reiser (2003). "Pixantrone (Novuspharma)." IDrugs 6(5): 486-90.

            Novuspharma is developing pixantrone, a second-generation, well-tolerated anthracenedione analog, for the potential treatment of lymphoma and multiple sclerosis.

Bruck, W., T. Kuhlmann, et al. (2003). "Remyelination in multiple sclerosis." J Neurol Sci 206(2): 181-5.

            Remyelination in multiple sclerosis (MS) lesions has been described in several studies. It depends on the presence of myelinating oligodendrocytes and a functional interaction between these myelinating cells and axons. The imaging signal of remyelination in magnetic resonance imaging or spectroscopy is not yet defined. The present review will focus on the morphological appearance of remyelinating MS lesions, their correlation with oligodendrocyte pathology, and possible markers for remyelination in imaging.

Bunin, A. and A. A. Iakovlev (2003). "[Pathology of the lateral geniculate body and visual function]." Vestn Oftalmol 119(1): 46-9.

Calza, L., M. Fernandez, et al. (2003). "Nerve growth factor in the central nervous system: more than neuron survival." Arch Ital Biol 141(2-3): 93-102.

Cazzato, G. and M. Zorzon (2003). "[Clinical surveillance of patients with multiple sclerosis]." Recenti Prog Med 94(4): 173-6.

            Clinical management of people with multiple sclerosis (MS) is based not only on the control of side-effects of disease-modifying drugs but also on the recognition and treatment of disease exacerbations, on the evaluation of disease progression and on the management of the wide range of MS symptoms. A multidisciplinary approach is essential to achieve the best results and improve the quality of life of MS patients.

Cetta, F. (2003). "[Gastro-enteropathic neuroendocrine tumors in diverse hereditary multiple tumor syndromes of multiple endocrine neoplasms (MEN)]." G Chir 24(1-2): 5-10.

Cheema, J. I., L. E. Grissom, et al. (2003). "Radiographic characteristics of lower-extremity bowing in children." Radiographics 23(4): 871-80.

            Lower-extremity bowing is common in infants and children and can result from a variety of conditions. At radiography, developmental bowing shows varus angulation centered at the knee, "metaphyseal beaking," thickening of the medial tibial cortices, and tilted ankle joints. Tibia vara (Blount disease) demonstrates genu varum and depression of the proximal tibia medially. Congenital bowing manifests as posteromedial bowing with cortical thickening along the concavity of the curvature and, in some cases, diaphyseal broadening. In rickets, radiographic changes occur primarily at sites of rapid growth and are predominantly metaphyseal, with widening of the zone of provisional calcification. Achondroplasia is characterized by shortening and thickening of the long bones with metaphyseal flaring and cupping. In neurofibromatosis, there may be anterolateral bowing of the tibia, and there is often focal narrowing and intramedullary sclerosis or cystic change at the apex of the angulation. The tibia is typically involved at the junction of the middle and distal thirds. Osteogenesis imperfecta demonstrates bowing from softening due to osteoporosis and multiple fractures and typically involves the entire skeleton. In camptomelic dysplasia, lower-extremity bowing is associated with a short trunk, short limbs, and deficiencies in pelvic bone development. Recognition of these pathologic conditions is important for differentiating those that will resolve spontaneously from those that require surgery or other treatment.

Chitnis, T. and S. J. Khoury (2003). "20. Immunologic neuromuscular disorders." J Allergy Clin Immunol 111(2 Suppl): S659-68.

            Immune-mediated disorders of each of the structural subdivisions of the nervous and neuromuscular system have been described. Despite the immune privilege of the central nervous system, and to a lesser extent the peripheral nervous system, immune dysregulation is not uncommon. Environmental, genetic, and immunologic factors have been postulated to be involved in the development of these disorders. Major immune-mediated neurologic diseases of the central nervous system include multiple sclerosis and acute disseminated encephalomyelitis. Immune-mediated diseases of the peripheral nervous system include myasthenia gravis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, idiopathic polymyositis, dermatomyositis, and inclusion body myositis. Some of these disorders, such as myasthenia gravis and certain forms of acute inflammatory demyelinating polyneuropathy, are clearly autoimmune in nature, whereas the immune system plays an important role in pathogenesis in others. Understanding the immune mechanisms of disease and uncovering potential therapeutic targets are essential for the design of new treatments. The epidemiology, pathogenesis, diagnostic criteria, and current therapeutic approaches to the major neuroimmunologic diseases are reviewed.

Choyke, P. L., G. M. Glenn, et al. (2003). "Hereditary renal cancers." Radiology 226(1): 33-46.

            Hereditary renal cancer syndromes can lead to multiple bilateral kidney tumors that occur at a younger age than do nonhereditary renal cancers. Imaging plays an important role in the diagnosis and management of these syndromes. During the past decade, several new hereditary renal syndromes have been discovered but are not yet widely known. Whereas previously, the list of hereditary renal cancers in adults included von Hippel-Lindau disease and a rare form of chromosomal translocation, the list now includes the following syndromes: tuberous sclerosis, hereditary papillary renal cancer, Birt-Hogg-Dube syndrome, hereditary leiomyoma renal cell carcinoma, familial renal oncocytoma, hereditary nonpolyposis colon cancer, and medullary carcinoma of the kidney. In addition, a number of newly described but poorly understood syndromes are under investigation. Even at this early stage, it is clear that elucidation of the underlying genetic mutations that cause hereditary renal cancer syndromes will have profound implications for understanding the origins of nonhereditary renal tumors. These studies will likely culminate in a better understanding of the causes of renal cancer, its prevention, and, ultimately, its cure.

Christensen, T. and A. Moller-Larsen (2003). "[Human endogenous retroviruses and disease?]." Ugeskr Laeger 165(6): 556-61.

            Endogenous retroviruses represent sequences descended from ancient virus infections integrated in the host genome. They participate in processes, such as speciation, recombination, ontogenesis, and regulation of tissue specificity and gene expression. It has been suggested in recent years that human endogenous retroviruses may play a role in certain types of cancer and autoimmune diseases. Human endogenous retroviruses represent both putative susceptibility genes and putative pathogenic viruses in diseases like systemic lupus erythematosus, Sjogren's disease, rheumatoid arthritis, and possibly type 1 diabetes. Multiple sclerosis is specifically associated with expression of human endogenous retroviruses as virions. It is not yet known if the human endogenous retroviruses also represent causal factors, but several pathogenic mechanisms are possible.

Clanet, M., E. Cassol, et al. (2003). "Clinical-MRI correlations in the secondary progressive phase of MS: lessons from the treatment trials." J Neurol Sci 206(2): 139-44.

            Conventional MRI techniques are sensitive to detect MS lesions and their change overtime. In relapsing-remitting MS correlations with clinical measures are weak suggesting a pathological heterogeneity of these lesions. There are less data available in secondary progressive phase of the disease. The best source for clinical MRI correlations analysis is the placebo arm of the published interferon beta trials. This review presents the main clinical-MRI findings from these trials then focuses on recent promising observations obtained with non conventional MRI techniques in SP MS patients.

Clausen, J. (2003). "Endogenous retroviruses and MS: using ERVs as disease markers." Int MS J 10(1): 22-8.

            Multiple sclerosis (MS) has an unknown cause, but its epidemiology suggests an interplay between environmental factors, possibly including viruses, and genetic components. Endogenous retroviruses (ERVs) are elements of the human genome that potentially may act as either genetic markers for polymorphisms related to MS, or markers of environmental/endogenous stress. Activation of the ERVs HERV-H/RGH, HERV-W and ERV-9 was reported when specific cell types (mainly B cells) from MS patients were cultivated in vitro. Viral RNA from these ERVs has been detected by reverse-transcriptase polymerase chain reaction in sera/plasma and brain tissues from MS patients, although not exclusively from these patients. ERVs play unknown roles in MS: their activation may represent an inflammatory cytokine-mediated epiphenomenon; alternatively, preliminary evidence suggests that specific ERVs may act as auto-, super- or neoantigens with the potential to enhance inflammatory responses or induce autoimmune reactions. ERVs that occur in few copies in the human genome (e.g. ERV-3 and human endogenous retrovirus, HRES-1) may show polymorphic patterns in MS. Studies show that the sequences encoding the envelope protein of ERV-3 are polymorphic to a degree where it becomes impossible to link them with MS. In contrast, the HRES-1 long terminal repeat sequence has a polymorphic pattern with haplotypes characteristic of MS. Haplotypes from non-MS control groups were identical between different topographic areas, but haplotypes from MS patients were different, depending on the population.

Cohen, Y., A. Polliack, et al. (2003). "Treatment of refractory autoimmune diseases with ablative immunotherapy using monoclonal antibodies and/or high dose chemotherapy with hematopoietic stem cell support." Curr Pharm Des 9(3): 279-88.

            Immunological manipulations are the basis for modern treatments of autoimmune diseases (AID). Targeted immune suppression with lymphopenic based chemotherapy, and monoclonal anti B or T lymphocytic antibodies, are integral part of the conditioning for stem cell transplantation (SCT). Immune manipulation by Cyclophosphamide (Cy), ATG, Campath and recently rituximab (RI), with or without stem cell support are the basis for emerging therapeutic modalities aiming to eradicate the autoreactive clone in various autoimmune disorders. Couple of hundreds of SCTs have been recently performed in various autoimmune disorders, mainly multiple sclerosis (MS), progressive systemic sclerosis (PSS), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA). Preliminary results are encouraging. Better selection of patients and earlier treatment, before irreversible organ failure develops will probably improve results. Current ongoing multicenter studies are evaluating the role of SCT in MS, RA, SLE, and PSS.

Compston, A. (2003). "Revisiting The pathogenesis of multiple sclerosis revisited." Int MS J 10(1): 29-31.

Cooper, G. S. and B. C. Stroehla (2003). "The epidemiology of autoimmune diseases." Autoimmun Rev 2(3): 119-25.

            Autoimmune diseases are among the leading causes of death among young and middle-aged women in the United States. Incidence rates vary among the autoimmune diseases, with estimates ranging from less than one newly-diagnosed case of systemic sclerosis to more than 20 cases of adult-onset rheumatoid arthritis per 100,000 person-years. Prevalence rates range from less than 5 per 100,000 (e.g. chronic active hepatitis, uveitis) to more than 500 per 100,000 (Grave disease, rheumatoid arthritis, thyroiditis). At least 85% of thyroiditis, systemic sclerosis, systemic lupus erythematosus, and Sjogren disease patients are female. Although most diseases can occur at any age, some diseases primarily occur in childhood and adolescence (e.g. type 1 diabetes), in the mid-adult years (e.g. myasthenia gravis, multiple sclerosis), or among older adults (e.g. rheumatoid arthritis, primary systemic vasculitis). Ethnic and geographic differences in incidence of specific autoimmune diseases have been documented, but specific groups may be at higher risk for some diseases and lower risk for other diseases. The incidence of type 1 diabetes increased but the rates of rheumatoid arthritis declined over the past 40 years. Thus although there are commonalities, there are also important demographic differences between diseases. Disease-specific research, as well as studies that focus on potentially related diseases, needs to be conducted.

Costello, K. and C. Harris (2003). "Differential diagnosis and management of fatigue in multiple sclerosis: considerations for the nurse." J Neurosci Nurs 35(3): 139-48.

            Fatigue is one of the most disabling aspects of multiple sclerosis (MS), affecting an estimated 70%-90% of patients. Yet, despite its prevalence, it is also one of the most difficult MS symptoms to accurately diagnose and effectively treat. This is because of numerous factors, including the subjective and nonspecific nature of fatigue; its variable manifestations; its similarity to psychological, motor, cognitive, respiratory, and non-MS-related disturbances and conditions; and a lack of understanding of its precise etiology. In contrast to fatigue experienced by people without MS, MS fatigue is characterized by its persistence and sensitivity to core and ambient temperatures. Differential diagnosis of MS fatigue is largely dependent on delineating chronic versus acute onset and determining whether fatigue is a symptom in and of itself (primary MS fatigue) or an aspect of an MS-related or non-MS-related etiology (secondary MS fatigue). Once the presence of fatigue is established, a through medical history, physical examination, and fatigue assessments can guide effective management, which includes education, self-care strategies, and pharmacological treatment. As patient advocates and gatekeepers, MS nurses are in an optimal position to establish and evaluate fatigue as a symptom in and of itself and effectively guide this process.

Croxford, J. L. (2003). "Therapeutic potential of cannabinoids in CNS disease." CNS Drugs 17(3): 179-202.

            The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.

Cymet, T. C. (2003). "A practical approach to fibromyalgia." J Natl Med Assoc 95(4): 278-85.

            Fibromyalgia is the name given to a collection of symptoms with no clear physiologic cause, The constellation of symptoms are clearly recognizable as a distinct pathologic entity. The diagnosis is made through clinical observations made by the examiner. Differential diagnosis must include other somatic syndromes as well as disease entities like hepatitis, hypothyroidism, diabetes mellitus, electrolyte imbalance, multiple sclerosis, and cancer. Diagnostic criteria are given as guidelines for the diagnosis, not as absolute requirements. Treatment of this condition remains individualized and relies heavily on having a therapeutic relationship with a provider. Treatment of this syndrome needs to be looked at as an ongoing process. Goal oriented treatment aimed at maintaining specific functions can be directed at helping a patient get restorative sleep, alleviating the somatic pains that ail the patient, keeping a person productive, regulating schedules or through goal oriented agreements made with the patient. Since this syndrome is chronic and may effect all areas of a persons functioning the family and social support system of the person being treated need to be evaluated. Patients often seek alternative medical treatments for this problem including diet therapy, acupuncture, and herbal therapy. Treatment must involve more than just the symptoms presented and the patient can only be treated successfully if they are willing to work at changing their own perceptions, and ways of relating to stressors in their world.

D'Agati, V. (2003). "Pathologic classification of focal segmental glomerulosclerosis." Semin Nephrol 23(2): 117-34.

            Focal segmental glomerulosclerosis (FSGS) is defined as a clinical-pathologic syndrome manifesting proteinuria and focal and segmental glomerular sclerosis with foot process effacement. The pathologic approach to the classification of FSGS is complicated by the existence of primary (idiopathic) forms and multiple subcategories with etiologic associations, including human immunodeficiency virus (HIV)-associated nephropathy, heroin nephropathy, familial forms, drug toxicities, and a large group of secondary FSGS mediated by structural-functional adaptations to glomerular hyperfiltration. A number of morphologic variants of primary and secondary focal sclerosis are now recognized, including FSGS not otherwise specified (NOS), perihilar, cellular, tip, and collapsing variants. The defining features of these morphologic variants and of the major subcategories of FSGS are discussed with emphasis on distinguishing light microscopic patterns and clinical-pathologic correlations.

D'Ambrosio, D., P. Panina-Bordignon, et al. (2003). "Chemokine receptors in inflammation: an overview." J Immunol Methods 273(1-2): 3-13.

            Chemokine receptors play a key role in directing the migration of inflammatory cells into various injured or infected organs. However, migration of inflammatory cells into tissues can in itself be a cause and amplifier of tissue damage and disease, particularly in chronic autoimmune or allergic disorders. On this basis, much effort is currently devoted at the identification of molecular signals regulating the recruitment of inflammatory cells into tissues and at developing novel strategies to inhibit discrete pathways in this process. Great progress has recently been made in identification of a number of chemokine receptors involved in the process of leukocyte migration. The challenge is now to elucidate the specific contribution and involvement of the different receptors in distinct inflammatory processes and diseases and to prove that interference with any of these pathways may lead to development of novel therapeutics.

DasGupta, R. and C. J. Fowler (2003). "Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies." Drugs 63(2): 153-66.

            Although patients with multiple sclerosis (MS) are likely to have problems with bladder, bowel and sexual function, these problems have often been neglected in the past. Bladder dysfunction produces symptoms of urgency, frequency and urge incontinence (due to bladder overactivity and incomplete emptying), and is found in up to 75% of patients with MS. The mainstay of drug treatment for neurogenic bladder overactivity is anticholinergic medication, although intravesical treatments have also been proposed, such as the vanilloids and botulinum toxin, as well as sublingual cannibanoids. There has been much progress with pro-erectile agents in recent years, notably the use of sildenafil citrate, which has been shown to be particularly efficacious in these patients. Other agents include apomorphine hydrochloride and newer phosphodiesterase 5 inhibitors; however, the efficacy of these drugs in patients with MS remains to be proven. Research in female sexual dysfunction is also progressing, although this aspect of patient well being has only recently been addressed; the reported development of a classification system for the condition is likely to help categorise future treatments. Unlike bladder and sexual dysfunction, there have been rather limited advances in the treatment of faecal incontinence and constipation specifically for patients with MS, despite a prevalence of up to 50%. This review highlights the strategies for these types dysfunction commonly seen in patients with MS, with report of recent pharmacological developments.

Davis, D. P. and A. Marino (2003). "Acute cerebellar ataxia in a toddler: case report and literature review." J Emerg Med 24(3): 281-4.

            Acute cerebellar ataxia (ACA) is an inflammatory CNS disease that is characterized by rapid onset of ataxia in a child under 6 years of age. Symptoms typically occur in association with a relatively benign viral illness and have been reported after vaccination as well. Immunological studies suggest that both involve autoimmune destruction of axon tracts, with pathological and radiographic evidence of a link with multiple sclerosis. The emergency approach should be focused on excluding more significant illnesses, such as meningitis or an intracranial mass lesion. Here we present a case of a young girl with ACA and review the relevant literature.

De Keyser, J., E. Zeinstra, et al. (2003). "Are astrocytes central players in the pathophysiology of multiple sclerosis?" Arch Neurol 60(1): 132-6.

            An interaction between antimyelin T cells and antigen-presenting glial cells is a crucial step in the cascade of immune events that lead to the inflammatory lesions in multiple sclerosis (MS). One of the most debated and controversial issues is whether microglial cells or astrocytes are the key players in initiating the (auto)immune reactions in the central nervous system in MS. Many investigators consider microglia to be the responsible intrinsic immunoeffector cells. In this review, we speculate that in MS astrocytes may serve as primary (facultative) antigen-presenting cells due to a failure of noradrenergic suppression of class II major histocompatibility complex molecules, which is caused by a loss of beta(2)-adrenergic receptors. If this hypothesis is correct, pharmacologic suppression of the antigen-presenting capacities of astrocytes may be a potential therapy for MS.

Delgado, M., C. Abad, et al. (2003). "PACAP in immunity and inflammation." Ann N Y Acad Sci 992: 141-57.

            The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the VIP/secretin/glucagon family of peptides, produced by the lymphoid cells, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, PACAP has been clearly identified as a potent anti-inflammatory factor that exerts its function by regulating the production of both anti- and proinflammatory mediators. In this sense, PACAP prevents death by septic shock, an acute inflammatory disease with a high mortality. In addition, PACAP regulates the expression of costimulatory molecules, inasmuch as this related to the modulation in the shift from Th1 towards Th2 differentiation. We recently reported that PACAP prevents the deleterious effects of arthritis by downregulating both inflammatory and autoimmune components of the disease. Therefore, PACAP and analogs have been proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, arthritis, multiple sclerosis, Crohn's disease, or autoimmune diabetes.

Devendra, D. and G. S. Eisenbarth (2003). "17. Immunologic endocrine disorders." J Allergy Clin Immunol 111(2 Suppl): S624-36.

            Immune-mediated tissue destruction or disregulation is the cause of multiple common, as well as rare, endocrine disorders including type 1 diabetes, Graves' disease, Hashimoto thyroiditis, and Addison's disease. Each of these disorders can be divided into a series of stages beginning with genetic susceptibility, environmental triggering events, and active autoimmunity, followed by metabolic abnormalities with overt disease. Common genetic susceptibility is suggested by the clustering of a series of disorders in the same individual and his or her family. A major portion of the genetic susceptibility lies in the HLA region, but for several disorders, mutation of transcription factors underlies disease susceptibility (eg, X-linked polyendocrinopathy, immune deficiency and diarrhea, and autoimmune polyendocrine syndrome type 1). With improving immunogenetic and pathogenic understanding, type 1A diabetes is now predictable, and excellent autoantibody screening assays are available. This knowledge, combined with studies in animal models, has led to trials for the prevention of diabetes. In addition, aberrant immunologic reactions (eg, insulin autoantibodies after insulin therapy, Graves' disease after monoclonal anti-T-cell therapy in multiple sclerosis) can complicate standard and experimental therapies. We therefore believe that an understanding of the immunogenetics and immunopathogenesis of endocrine disorders can aid in the prevention of morbidity and mortality for these related diseases.

Dharmasaroja, P. (2003). "Specificity of autoantibodies to epitopes of myelin proteins in multiple sclerosis." J Neurol Sci 206(1): 7-16.

            An autoimmune response to one or more myelin-protein components is thought to be part of the pathogenesis of multiple sclerosis (MS). The immunodominant-autoantibody epitope may be localized on a linear peptide segment, on a conformation-sensitive epitope, or on an epitope resulting from post-translational modifications. Primary, secondary, and tertiary structures of myelin proteins may determine the specific site for binding of autoantibodies. A myelin protein-specific autoantibody can bind to either a linear or conformational epitope, whereas all of the T cell epitopes are linear. At present, the conformational epitopes of myelin proteins have not been identified; most of the methods used to identify the myelin-protein epitopes corresponding to the pathogenesis of multiple sclerosis are involved in the linear epitope mapping. Polymorphism or mutations may cause inappropriate expression of the myelin proteins with alterations to their linear and/or conformational epitopes, and make them susceptible to autoantibody binding, especially if these changes occur at the surface of the protein. This review focuses on the specificity of autoantibodies to the epitopes of myelin proteins and correlates this to the structures of proteins. Factors that influence the expression of myelin-protein epitopes such as the alpha-helical or beta-sheet structure of the protein, the tri-proline site, and the post-translational modifications as well as physicochemical properties of amino acid changed are included.

Dhib-Jalbut, S. (2003). "Glatiramer acetate (Copaxone) therapy for multiple sclerosis." Pharmacol Ther 98(2): 245-55.

            Glatiramer acetate (GA) (Copaxone(R)) is a worldwide-approved drug for the treatment of relapsing multiple sclerosis (MS), an autoimmune disease of the CNS. The drug is a synthetic copolymer with an amino acid composition based on the structure of myelin basic protein, one of the autoantigens implicated in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE). Developed initially as a "tool" to study EAE, the drug unexpectedly inhibited disease and was subsequently developed for the treatment of MS. The drug has been shown in controlled clinical trials to significantly reduce relapse rate and progression of disability in MS with long-term efficacy, remarkable safety, and tolerability. Efficacy as measured by magnetic resonance imaging parallels its clinical benefits as manifested by a reduction in gadolinium-enhancing lesions and brain atrophy. The mechanism of action of the drug in humans is believed to involve the induction of glatiramer-reactive regulatory cells, including CD4+ and CD8+ T-cells. Glatiramer-reactive Th2 cells are believed to enter the brain and, through cross-reactivity with myelin antigens, produce bystander suppression, antiinflammatory effects, and neuroprotection.

Dianzani, U., A. Chiocchetti, et al. (2003). "Role of inherited defects decreasing Fas function in autoimmunity." Life Sci 72(25): 2803-24.

            Fas is a death receptor belonging to the TNFR superfamily and induces cell apoptosis by both activating a caspase cascade and altering mitochondria. In the immune system, Fas is involved in the switching-off of the immune responses and cell mediated cytotoxicity. In humans, genetic defects decreasing Fas function cause the Autoimmune Lymphoproliferative Syndrome (ALPS) where autoimmunities are associated with accumulation of polyclonal lymphocytes in the secondary lymphoid tissues and expansion of T cells lacking both CD4 and CD8 (DN cells). Expansion of DN cells is absent in an ALPS variant, named Dianzani's Autoimmune Lymphoproliferative Disease (DALD). The observation that DALD patients' families display increased frequency of autoimmune diseases different from ALPS suggests that defects of Fas function may also play a role in development of "common" autoimmune diseases. This possibility is supported by detection of defective Fas function in substantial proportions of patients with the multiple autoimmune syndrome or aggressive forms of type 1 diabetes or multiple sclerosis. This article reviews data suggesting that development of autoimmune/lymphoproliferative patterns may involve several alterations hitting the Fas system, but might also involve alterations in other systems contributing to the switching-off or proliferation of lymphocytes.

Duclos, P. (2003). "Safety of immunisation and adverse events following vaccination against hepatitis B." Expert Opin Drug Saf 2(3): 225-31.

            Hepatitis B vaccines (HBVs) are composed of highly purified preparations of hepatitis B virus surface antigen (HBsAg). An adjuvant, either aluminium phosphate or aluminium hydroxide, is added to the vaccines, which are sometimes preserved with thiomersal. In placebo-controlled studies, common side effects other than local reactions were reported no more frequently among vaccine recipients than among individuals receiving a placebo. A number of controversial adverse events have, however, been purported to be associated with HBVs, including rheumatoid arthritis (RA), diabetes, demyelinating diseases (e.g., multiple sclerosis [MS]), chronic fatigue syndrome, and more recently, lymphoblastic leukaemia. In addition, the safety of the thiomersal and aluminium contained in the vaccine has also been under close scrutiny. These issues have been reviewed by a number of country-specific or international independent review committees such as that of the US Institute of Medicine (IOM) and the World Health Organization's (WHO) Global Advisory Committee on Vaccine Safety (GACVS). Upon review of the scientific evidence, none of the serious allegations have so far been confirmed. On the contrary, scientific evidence has accumulated to disprove many of the allegations. In particular, the IOM committee has concluded that the evidence favoured rejection of a causal relationship between HBV administered to adults and incident MS or MS relapse. Whilst it is important to continue monitoring some of the safety issues, there is no evidence to suggest that the WHO should consider altering its recommendation that all countries should have universal infant and/or adolescent immunisation programmes. The risks of hepatitis B vaccination are only theoretical in comparison with clear benefits in terms of cirrhosis and cancer prevention, and the HBV remains one with an excellent safety profile.

Ehde, D. M., M. P. Jensen, et al. (2003). "Chronic pain secondary to disability: a review." Clin J Pain 19(1): 3-17.

            BACKGROUND: Until recently, very little has been written regarding chronic pain as a secondary problem in persons who already have a physical disability, despite the potential for pain to increase the negative impact of what may already be a very disabling condition. The purpose of this review is to summarize what is currently known concerning the nature and scope of chronic pain as a secondary condition to disability, specifically spinal cord injury, acquired amputations, cerebral palsy, multiple sclerosis, neuromuscular disease, and postpolio syndrome. METHOD: What is known concerning the frequency, severity, impact, and treatment of pain in these specific conditions is reviewed, as are the factors that contribute to, or are associated with, adjustment to chronic pain in these disability groups. The authors conclude with several research questions that emerge from this knowledge, the answers to which will contribute to the long-term goal of the reduction of pain and suffering in persons with disabilities. CONCLUSIONS: The existing literature clearly documents that many persons with disabilities experience chronic pain. Many questions remain unanswered regarding the scope, severity, and treatment of chronic pain in these groups.

Fazakerley, J. K. and R. Walker (2003). "Virus demyelination." J Neurovirol 9(2): 148-64.

            A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.

Feve, A. (2003). "[Spasticity and botulinum toxin in 2003. An update]." Neurochirurgie 49(2-3 Pt 2): 265-70.

            After the spastic foot in cerebral palsy, there are now wider indications for botulinum toxin injections in spasticity. Post stroke upper limb spasticity has been usefully treated by botulinum toxin in several studies, including double blind placebo-controlled studies. Two serotypes and one serotype B are marketed, with various properties. Botulinum toxin has been studied in multiple etiologies of spasticity. In multiple sclerosis, few studies revealed an efficacy in angulations and comfort. In spinal cord injuries, gait and sphincter disorders can be improved. In post stroke spasticity, lower limb angulations are improved, but gait remained difficult to evaluate. In upper limb spasticity, angulation, function and quality of life were improved in double blind, placebo controlled studies. Comparisons of costs and efficacy are made between botulinum toxin and the other antispastic methods.

Filippi, M. and M. A. Rocca (2003). "Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging." Curr Opin Neurol 16(3): 275-82.

            PURPOSE OF REVIEW: This review is intended to provide an up-to-date summary of the main functional magnetic resonance imaging studies conducted in patients with multiple sclerosis, and to show how such studies are changing our views on the ability of the multiple sclerosis brain to limit the clinical consequences of irreversible structural tissue damage. RECENT FINDINGS: Brain cortical reorganization is a common phenomenon occurring in patients with multiple sclerosis, independent of disease duration and clinical phenotype, which can be elicited by macroscopic lesions, as well as by the presence of 'occult' multiple sclerosis-related damage of the brain and cervical cord. An increased recruitment of the cerebral networks involved in the performance of given tasks might represent a first step in cortical reorganization with the potential to maintain a normal level of function in the course of multiple sclerosis. The progressive failure of these mechanisms, because of accumulating tissue damage, might, on the one hand, result in the activation of previously silent 'second-order' compensatory areas, and, on the other, contribute to the accumulation of irreversible disability. SUMMARY: Functional magnetic resonance imaging has the potential to provide important information about cortical reorganization following multiple sclerosis-related tissue damage, which should improve our understanding of the factors associated with the accumulation of irreversible disability in this disease. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for multiple sclerosis.

Filippi, M. (2003). "MRI-clinical correlations in the primary progressive course of MS: new insights into the disease pathophysiology from the application of magnetization transfer, diffusion tensor, and functional MRI." J Neurol Sci 206(2): 157-64.

            Despite patients with primary progressive multiple sclerosis (PPMS) experience a progressive disease course from onset, the burden and activity of lesions on conventional magnetic resonance imaging (MRI) scans of the brain are lower than in all other main clinical phenotypes of MS. This review outlines the major contributions given by magnetization transfer MRI, diffusion tensor MRI and functional MRI to the understanding of the pathophysiology of PPMS and provides evidence that, at least, three factors might explain this clinical/MRI discrepancy: (a) the presence of a diffuse tissue damage at a microscopic level; (b) a prevalent involvement of the cervical cord, and (c) an impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical structural damage.

Filippi, M. (2003). "Magnetization transfer MRI in multiple sclerosis and other central nervous system disorders." Eur J Neurol 10(1): 3-10.

            The present review summarizes the major contributions given by magnetization transfer-magnetic resonance imaging to provide an accurate in vivo picture of the heterogeneity of central nervous system pathology and, ultimately, to improve our ability to monitor the evolution of various neurological conditions.

Filippini, G., L. Munari, et al. (2003). "Interferons in relapsing remitting multiple sclerosis: a systematic review." Lancet 361(9357): 545-52.

            BACKGROUND: Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs. METHODS: With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo. FINDINGS: The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0.81, 0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life. INTERPRETATION: Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.

Finesilver, C. (2003). "Multiple sclerosis." Rn 66(4): 36-43; quiz 44.

Forbes, A., A. While, et al. (2003). "Impact of clinical nurse specialists in multiple sclerosis--synthesis of the evidence." J Adv Nurs 42(5): 442-62.

            BACKGROUND: Multiple sclerosis is a chronic neurological condition demanding a broad range of interventions and support. Multiple sclerosis nurse specialists are emerging as a leading force in providing care to this group of patients. AIM: This review aimed to identify and synthesize the evidence on the role of clinical nurse specialists in meeting the care needs of people with multiple sclerosis. METHODS: A systematic review of the literature addressing the role of the multiple sclerosis nurse specialist was undertaken. The review examined both the appropriateness and effectiveness of the multiple sclerosis nurse specialist role. The content of each item identified in the review was analysed, examining the structure, process and outcomes variables associated with the role. Materials containing an explicit methodology were critically appraised using established schedules and graded as strong, moderate or weak. The data were then synthesized in tables, thematically and using a quasi-judicial approach called the 'System of Reasoning'. FINDINGS: Fifty-five items were examined and most (53%; n = 18) were descriptive in nature. There was insufficient evidence to demonstrate that the multiple sclerosis nurse role makes a difference to care. However, evidence was found to support current descriptions of the role - meaning? and there appeared to be a good fit between the role and the care needs of people with multiple sclerosis. CONCLUSION: A systematic overview of the attributes of the multiple sclerosis nurse role is provided which should help service providers, nurses and other professionals consider how multiple sclerosis nurse specialists roles can contribute to the care of people with this condition. While there is little current evidence of effectiveness for the multiple sclerosis nurse specialist role, there is evidence for its appropriateness, although more rigorous primary research is required to test this.

Foxman, B. (2003). "Epidemiology of urinary tract infections: incidence, morbidity, and economic costs." Dis Mon 49(2): 53-70.

            Urinary tract infections (UTIs) are considered to be the most common bacterial infection. According to the 1997 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, UTI accounted for nearly 7 million office visits and 1 million emergency department visits, resulting in 100,000 hospitalizations. Nevertheless, it is difficult to accurately assess the incidence of UTIs, because they are not reportable diseases in the United States. This situation is further complicated by the fact that accurate diagnosis depends on both the presence of symptoms and a positive urine culture, although in most outpatient settings this diagnosis is made without the benefit of culture.Women are significantly more likely to experience UTI than men. Nearly 1 in 3 women will have had at least 1 episode of UTI requiring antimicrobial therapy by the age of 24 years. Almost half of all women will experience 1 UTI during their lifetime. Specific subpopulations at increased risk of UTI include infants, pregnant women, the elderly, patients with spinal cord injuries and/or catheters, patients with diabetes or multiple sclerosis, patients with acquired immunodeficiency disease syndrome/human immunodeficiency virus, and patients with underlying urologic abnormalities. Catheter-associated UTI is the most common nosocomial infection, accounting for >1 million cases in hospitals and nursing homes. The risk of UTI increases with increasing duration of catheterization. In noninstitutionalized elderly populations, UTIs are the second most common form of infection, accounting for nearly 25% of all infections.There are important medical and financial implications associated with UTIs. In the nonobstructed, nonpregnant female adult, acute uncomplicated UTI is believed to be a benign illness with no long-term medical consequences. However, UTI elevates the risk of pyelonephritis, premature delivery, and fetal mortality among pregnant women, and is associated with impaired renal function and end-stage renal disease among pediatric patients. Financially, the estimated annual cost of community-acquired UTI is significant, at approximately $1.6 billion.

Frohman, E. M. (2003). "Multiple sclerosis." Med Clin North Am 87(4): 867-97, viii-ix.

            Multiple sclerosis (MS) is the most common disabling neurologic disease of young people affecting between 350 and 450,000 individuals in the United States. Substantial advances have been made in the diagnostic assessment and treatment interventions over the last 10 years such that we are now able effectively to treat both the disease process and the associated symptomatic complaints associated with MS. Most patients consult with their primary care physician at the time when the first clinical manifestations of MS emerge. These physicians play a central role in the early identification and treatment of patients with MS. This article emphasizes the expanding diagnostic and therapeutic capabilities evolving for the MS patient and the crucial role played by primary care physicians in collaboration with neurologists in the coordination of the initial diagnostic and treatment plan.

Furlan, R., S. Pluchino, et al. (2003). "The therapeutic use of gene therapy in inflammatory demyelinating diseases of the central nervous system." Curr Opin Neurol 16(3): 385-92.

            PURPOSE OF REVIEW: Gene therapy protocols aimed to deliver therapeutic molecules into the central nervous system may represent an alternative therapeutic strategy in patients affected by inflammatory demyelinating diseases of the central nervous system where systemic therapies have shown limited therapeutic efficacy possibly owing to the blood-brain barrier, a major obstacle for the entry of therapeutic molecules into the central nervous system. RECENT FINDINGS: Among inflammatory demyelinating diseases of the central nervous system, gene therapy approaches have been so far developed almost exclusively for multiple sclerosis. However, the chronic/relapsing nature of the disease, the restriction to the central nervous system of the pathological process as well as the necessity to inhibit the ongoing inflammatory process but also to foster endogenous remyelinating pathways, have posed several questions which still need to be properly addressed for the development of a successful gene therapy strategy in multiple sclerosis patients. SUMMARY: The gene therapy approaches for multiple sclerosis have been so far developed and tested only in rodents and monkeys with experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The results of these studies clearly indicate that the delivery of therapeutic genes within the central nervous system is superior to the peripheral delivery. In particular, the intracerebral delivery of genes coding for anti-inflammatory and/or neurotrophic molecules, using gene vectors derived from non-replicative viruses, showed to inhibit not only the detrimental function of blood-borne mononuclear effector cells but also to foster proliferation and differentiation of surviving oligodendrocytes within demyelinated areas. Here, we summarize the most recent findings of this novel area of research.

Gadoth, N. (2003). "Multiple sclerosis in children." Brain Dev 25(4): 229-32.

            Multiple sclerosis (MS) is traditionally the domain of adult neurologists due to its characteristic presentation during early adult life. Although descriptions of infants with MS appeared in the beginning of the last century and the first autopsy was described even earlier, it was not until 1980 that childhood onset MS was recognized and subsequently well characterized. In spite of this, the awareness of pediatricians and pediatric neurologists to the occurrence of MS especially in infants and young children is still unsatisfactory. It is not infrequent that a meticulous, time consuming and costly search for metabolic and degenerative disorders other that MS is initiated before the diagnosis of MS is considered. This leads to a significant diagnostic and therapeutic delay in many young patients. Moreover, when the presentation is acute and characterized by confusion, seizures, CSF pleocytosis following a viral infection, a diagnosis of meningoencephalitis will be frequently reached. In this review, updated data on frequency, epidemiology, some special clinical and radiological features of childhood onset MS, outcome and treatment will be briefly discussed with the purpose of alerting physicians to the possibility of the occurrence of MS even in infants and young children.

Garg, R. K. (2003). "Acute disseminated encephalomyelitis." Postgrad Med J 79(927): 11-7.

            Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, and is characterised by multifocal white matter involvement. Diffuse neurological signs along with multifocal lesions in brain and spinal cord characterise the disease. Possibly, a T cell mediated autoimmune response to myelin basic protein, triggered by an infection or vaccination, underlies its pathogenesis. ADEM is a monophasic illness with favourable long term prognosis. The differentiation of ADEM from a first attack of multiple sclerosis has prognostic and therapeutic implications; this distinction is often difficult. Most patients with ADEM improve with methylprednisolone. If that fails immunoglobulins, plasmapheresis, or cytotoxic drugs can be given. Recent literature suggests that a significant proportion of patients with ADEM will later develop multiple sclerosis; however, follow up experience from developing countries does not support this view.

Gatehouse, P. D. and G. M. Bydder (2003). "Magnetic resonance imaging of short T2 components in tissue." Clin Radiol 58(1): 1-19.

            The most widely used clinical magnetic resonance imaging techniques for the diagnosis of parenchymal disease employ heavily T(2)-weighted sequences to detect an increase or decrease in the signal from long T(2) components in tissue. Tissues also contain short T(2) components that are not detected or only poorly detected with conventional sequences. These components are the majority species in tendons, ligaments, menisci, periosteum, cortical bone and other related tissues, and the minority in many other tissues that have predominantly long T(2) components.The development and clinical application of techniques to detect short T(2) components are just beginning. Such techniques include magic angle imaging, as well as short echo time (TE), and ultrashort TE (Ute) pulse sequences. Magic angle imaging increases the T(2) of highly ordered, collagen-rich tissues such as tendons and ligaments so signal can be detected from them with conventional pulse sequences. Ute sequences detect short T(2) components before they have decayed, both in tissues with a majority of short T(2) components and those with a minority. In the latter case steps usually need to be taken to suppress the signal from the majority of long T(2) components. Fat suppression of different types may also be helpful. Once signal from short T(2) components has been detected, different pulse sequences can be used to determine increases or decreases in T(1) and T(2) and study contrast enhancement.Using these approaches, signals have been detected from normal tissues with a majority of short T(2) components such as tendons, ligaments, menisci, periosteum, cortical bone, dentine and enamel (the latter four tissues for the first time) as well as from the other tissues in which short T(2) components are a minority. Some diseases such as chronic fibrosis, gliosis, haemorrhage and calcification may increase the signal from short T(2) components while others such as loss of tissue, loss of order in tissue and an increase in water content may decrease them. Changes of these types have been demonstrated in tendonopathy, intervertebral disc disease, ligament injury, haemachromatosis, pituitary perivascular fibrosis, gliomas, multiple sclerosis and angiomas.Use of these techniques has reduced the limit of clinical detectability of short T(2) components by about two orders of magnitude from about 10 ms to about 100 micros. As a consequence it is now possible to study tissues that have a majority of short T(2) components with both "bright" and "dark" approaches, with the bright (high signal) approach offering options for developing tissue contrast of different types, as well as the potential for tissue characterization. In addition, tissues with a minority of short T(2) components may demonstrate changes in disease that are not apparent with conventional heavily T(2)-weighted sequences.

Geschwind, D. H. (2003). "DNA microarrays: translation of the genome from laboratory to clinic." Lancet Neurol 2(5): 275-82.

            As the complete sequences of human and other mammalian genomes become available we are faced with the challenge of understanding how variation in sequence and gene expression contributes to neurological and psychiatric disorders. DNA microarrays, or DNA chips, provide the means to measure simultaneously where and when thousands of genes are expressed. Microarrays are changing the way that researchers approach work at the bench and have already yielded new insights into brain tumours, multiple sclerosis, acute neurological insults such as stroke and seizures, and schizophrenia. The study of disease-related changes in gene expression is the first step in the long process in translation of genome research to the clinic. Eventually, the changes observed in microarray studies will need to be independently confirmed and we wil need to understand how gene expression changes translate into functional effects at the cellular level in the nervous system. Progress in these studies will translate into array-based disease classification schemes and help optimise therapy for individual patients based on gene expression patterns or their genetic background.

Gherardi, R. K. (2003). "[Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome]." Rev Neurol (Paris) 159(2): 162-4.

            Macrophagic myofasciitis is a condition first reported in 1998, which cause remained obscure until 2001. Over 200 definite cases have been identified in France, and isolated cases have been recorded in other countries. The condition manifests by diffuse myalgias and chronic fatigue, forming a syndrome that meets both Center for Disease Control and Oxford criteria for the so-called chronic fatigue syndrome in about half of patients. One third of patients develop an autoimmune disease, such as multiple sclerosis. Even in the absence of overt autoimmune disease they commonly show subtle signs of chronic immune stimulation, and most of them are of the HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and rheumatoid arthritis. Macrophagic myofasciitis is characterized by a stereotyped and immunologically active lesion at deltoid muscle biopsy. Electron microscopy, microanalytical studies, experimental procedures, and an epidemiological study recently demonstrated that the lesion is due to persistence for years at site of injection of an aluminum adjuvant used in vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid. Aluminum hydroxide is known to potently stimulate the immune system and to shift immune responses towards a Th-2 profile. It is plausible that persistent systemic immune activation that fails to switch off represents the pathophysiologic basis of chronic fatigue syndrome associated with macrophagic myofasciitis, similarly to what happens in patients with post-infectious chronic fatigue and possibly idiopathic chronic fatigue syndrome. Therefore, the WHO recommended an epidemiological survey, currently conducted by the French agency AFSSAPS, aimed at substantiating the possible link between the focal macrophagic myofasciitis lesion (or previous immunization with aluminium-containing vaccines) and systemic symptoms. Interestingly, special emphasis has been put on Th-2 biased immune responses as a possible explanation of chronic fatigue and associated manifestations known as the Gulf war syndrome. Results concerning macrophagic myofasciitis may well open new avenues for etiologic investigation of this syndrome. Indeed, both type and structure of symptoms are strikingly similar in Gulf war veterans and patients with macrophagic myofasciitis. Multiple vaccinations performed over a short period of time in the Persian gulf area have been recognized as the main risk factor for Gulf War syndrome. Moreover, the war vaccine against anthrax, which is administered in a 6-shot regimen and seems to be crucially involved, is adjuvanted by aluminium hydroxide and, possibly, squalene, another Th-2 adjuvant. If safety concerns about long-term effects of aluminium hydroxide are confirmed it will become mandatory to propose novel and alternative vaccine adjuvants to rescue vaccine-based strategies and the enormous benefit for public health they provide worldwide.

Gomez, G. and M. V. Sitkovsky (2003). "Targeting G protein-coupled A2a adenosine receptors to engineer inflammation in vivo." Int J Biochem Cell Biol 35(4): 410-4.

            G protein-coupled adenosine receptors are the subject of intense study as immunomodulators of inflammation especially since the recent demonstration that the A2a receptor acts to down-regulate inflammation and inhibit tissue damage in vivo [Nature 414 (6866) (2001) 916]. The adverse effects of overactive inflammation are evident in diseases e.g. sepsis, rheumatoid arthritis, and multiple sclerosis underscoring the importance of inhibiting inflammation or selectively enhancing inflammatory processes. It has been shown recently that the A2a adenosine receptor is a critical component of an endogenous "immunosuppressive loop" in which extracellular adenosine that accumulates due to local hypoxia caused by inflammatory insult signals through cAMP-elevating A2a receptors in a delayed negative feedback manner. Understanding how tissues regulate inflammation will provide the information necessary to allow for the engineering, or selective targeting, of endogenous inflammatory pathways. Recognition of A2a receptors as "natural" or endogenous brakes of inflammation provides the intellectual scaffolding needed to pursue these goals.

Gonsette, R. E. (2003). "Mitoxantrone in progressive multiple sclerosis: when and how to treat?" J Neurol Sci 206(2): 203-8.

            Mitoxantrone (MX) has been approved by the Food and Drug Administration (FDA) for the treatment of patients with worsening relapsing-remitting (RR) or secondary progressive (SP) multiple sclerosis (MS). However, indications should be refined and mitoxantrone reserved as a rescue therapy to: (1) patients in the relapsing-remitting phase with frequent and disabling exacerbations likely leading to permanent severe disability and (2) to patients in the secondary progressive phase whose disability progression rate increases by one EDSS point or more per year and who do not respond to other current therapies. An induction phase with the monthly intravenous administration of 12 mg/m(2) followed by a maintenance phase with 12 mg/m(2) every 3 months for 2 years seems the most effective and safe treatment regimen, not exceeding the maximum cumulative dose of 140 mg/m(2). Given the potent myelosuppressive activity of mitoxantrone, dosage should be carefully adapted to the body surface and hematological changes. Long-term toxicities (amenorrhoea and therapy-related leukemia) seem acceptable but a valid evaluation will need a longer follow-up in more patients. Cardiotoxicity, the major long-term toxicity, is clearly dose-dependent and is a strict treatment duration limiting factor. To reduce the risk of cardiac events, the drug should be administered by slow infusion (over 30 min). Analogs of mitoxantrone with a much lower cardiotoxicity are currently investigated in animal experimental models.

Gudiene, D. and B. Burba (2003). "[Mental disorders and their relation to brain lesion location: diagnostic problems]." Medicina (Kaunas) 39(2): 114-21.

            Knowledge of symptoms of appropriate brain areas lesion helps to differ psychiatric and neurological disorders. The objective of our work was to find out the situation in scientific research about mental disorder relation to brain lesion location and to except the location of lesions, which are most complicated in differential diagnosis. We discussed the relation of most important mental disorders to brain lesion location. The study of discrete organic cerebral lesions resulting in clearly definable psychiatric disorders may provide an understanding of the underlying pathophysiological basis of these disorders. Different nervous functions need the integrational work of various brain areas. The regions differ from each other by the importance of playing part in corresponding functions. The differential problems appear because various structural brain lesions provide symptoms, similar to mental disorder symptoms. The development of mental disorders and lesion location questions are very urgent. While analyzing the location of lesion, it is important to motivate the theories of development of schizophrenia, organic depression, emotional lability and other disorders.

Halper, J., P. Kennedy, et al. (2003). "Rethinking cognitive function in multiple sclerosis: a nursing perspective." J Neurosci Nurs 35(2): 70-81.

            Cognitive impairment is a common problem in multiple sclerosis (MS); up to 65% of patients exhibit some neuropsychological dysfunction during the course of their disease. It is a major contributing factor to unemployment, accidents, impairment of daily functioning, and loss of social activity in those affected by MS. The areas of cognition typically impaired are memory, attention, information processing, executive functions, and visuospatial skills. Cognitive dysfunction is independent of disease duration and level of disability; cognitive decline may begin in the earliest stages of MS before patients become even mildly disabled. Structural brain imaging studies show a positive correlation between the extent of brain atrophy and cognitive dysfunction. Despite its prevalence in MS, cognitive dysfunction often goes undiagnosed or is misdiagnosed as depression, stress, stubbornness, lack of intelligence, or psychosis. Because nurses play such an important role in the care of patients with MS, they are in a position to identify patients with cognitive dysfunction, educate patients and their families on ways to cope with cognitive deficits, and counsel patients on available treatment options. Practical guidelines help nurses identify and care for cognitively impaired MS patients.

Harting, I., J. Sellner, et al. (2003). "[Multiple sclerosis: imaging, diagnostic criteria and differential diagnosis]." Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 175(5): 613-22.

            Multiple sclerosis (MS) is the most common demyelinating inflammatory disease of the central nervous system (CNS), presenting with multifocal, disseminated inflammatory lesions referred to as plaques. Magnetic resonance imaging (MRI) typically depicts multiple, round to oval, circumscript lesions predominantly involving periventricular and subcortical white matter, brainstem and cerebellum. More recent investigations have demonstrated that the macroscopically visible plaques only present the tip of the iceberg: Already early in its course, MS causes neuroaxonal damage and diffusely involves the entire brain parenchyma including normal appearing white matter. These changes are reflected by strongly T1w hypointense lesions and atrophy of early onset, by reduction of the neuronal Marker N-acetylaspartate (NAA) on spectroscopy, by a decrease of the magnetization transfer ratio (MTR), by an increased in diffusibility and decreased anisotropy on diffusion-weighted imaging (DWI). MRI imaging is an important tool in the diagnosis of MS by revealing the characteristic spatial and temporal dissemination of the cerebral and spinal manifestations of this disease. Diagnostic criteria increase the diagnostic specificity and allow better differentiation from other diseases with multifocal white matter abnormalities.

Heinrich, P. C., I. Behrmann, et al. (2003). "Principles of interleukin (IL)-6-type cytokine signalling and its regulation." Biochem J 374(Pt 1): 1-20.

            The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.

Hemmer, B., B. Kieseier, et al. (2003). "New immunopathologic insights into multiple sclerosis." Curr Neurol Neurosci Rep 3(3): 246-55.

            Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. Although the immune system seems to play an important role in the pathogenesis of disease, target antigens are still uncertain and pathways leading to tissue destruction have not been fully elucidated. Recent studies have significantly contributed to a better understanding of the disease process and broadened our view on possible scenarios of disease initiation and progression. We review the role of the immune system for the manifestation and evolution of MS and discuss different pathogenetic concepts. We conclude with an outlook on future strategies to identify the cause of MS.

Hensel, M., C. Fiehn, et al. (2003). "[Stem cell transplantation in primary systemic vasculitis]." Med Klin (Munich) 98(1): 13-8.

            BACKGROUND: Many patients with various autoimmune diseases fail to respond to conventional immunosuppressive therapy and develop irreversible organ damage. In some cases the complications might be fatal. Furthermore, prolonged immunosuppression with cyclophosphamide or corticosteroids often leads to long-term side effects, cumulative organ damage, and development of secondary malignancies. THERAPY: Thus, short-term, high-dose immunosuppressive therapy with autologous stem cell transplantation might be an alternative for otherwise refractory patients. This concept has been used mainly in patients with scleroderma, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. PATIENTS: Patients with primary systemic vasculitis (PSV) seem to be suitable candidates for high-dose chemotherapy (HDCT). Although complete, long-term remissions are possible with standard immunosuppressive therapy, there is a subgroup of patients who cannot be cured by standard therapy. They need long-term immunosuppression and eventually die due to progression of the disease or cumulative therapy-related toxicity. In large series, the 5-year mortality rate was > 20%. The severity of vasculitis rather than the distinction between subgroups should determine whether HDCT might be a life-saving treatment. RESULTS AND CONCLUSION: Careful patient selection with the help of scoring systems and determination of the optimal time in the course of disease are now the major goals in the approach to HDCT. First reports as well as our own single-center experience in HDCT with a limited number of patients with severe PSV have shown that long-term remissions are possible even in patients refractory to conventional immunosuppression.

Hensiek, A. E., S. J. Sawcer, et al. (2003). "Searching for needles in haystacks-the genetics of multiple sclerosis and other common neurological diseases." Brain Res Bull 61(3): 229-34.

            Recent years have witnessed considerable advances in our understanding of monogenic neurodegenerative diseases, such as hereditary motor sensory neuropathy and Huntington's Chorea. Progress has been slower in the genetic dissection of other more common neurological diseases with a complex mode of inheritance. The identification of relevant genes in some, such as Alzheimer's disease (AD) or Parkinson's disease (PD), has been facilitated by characteristic pathological findings and autosomal dominant inheritance in a proportion of early onset families. Attempts to identify relevant genes for multiple sclerosis have highlighted the role of the major histocompatibility complex, but so far failed to unequivocally implicate other immunologic or structural candidate genes. Six linkage-based whole genome screens have been completed in mult