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Multiple Sclerosis Reviews: 2005

Zivadinov, R. (2005). "Steroids and brain atrophy in multiple sclerosis." J Neurol Sci 233(1-2): 73-81.

            In this review, we focus on different pathogenetic mechanisms of corticosteroids that induce short- and long-term brain volume fluctuations in a variety of systemic conditions and disorders, as well as on corticosteroid-induced immunomodulatory, immunosuppressive and anti-inflammatory mechanisms that contribute to the slowdown of brain atrophy progression in patients with multiple sclerosis (MS). It appears that chronic low-dose treatment with corticosteroids may contribute to irreversible loss of brain tissue in a variety of autoimmune diseases. This side effect of steroid therapy is probably mediated by steroid-induced protein catabolism mechanism. Evidence is mounting that high-dose corticosteroids may induce reversible short-term brain volume changes due to loss of intracellular water and reduction of abnormal vascular permeability, without there having been axonal loss. Other apoptotic and selective inhibiting mechanisms have been proposed to explain the nature of corticosteroid-induced brain volume fluctuations. It has been shown that chronic use of high dose intravenous methylprednisolone (IVMP) in patients with MS may limit brain atrophy progression over the long-term via different immunological mechanisms, including downregulation of adhesion molecule expression on endothelial cells, decreased cytokine and matrix metalloproteinase secretion, decreased autoreactive T-cell-mediated inflammation and T-cell apoptosis induction, blood-brain barrier closure, demyelination inhibition and, possibly, remyelination promotion. Studies in nonhuman primates have confirmed that short-term brain volume fluctuations may be induced by corticosteroid treatment, but that they are inconsistent, potentially reversible and probably dependent upon individual susceptibility to the effects of corticosteroids. Further longitudinal studies are needed to elucidate pathogenetic mechanisms contributing to brain volume fluctuations in autoimmune diseases and multiple sclerosis.

Zivadinov, R. and T. P. Leist (2005). "Clinical-magnetic resonance imaging correlations in multiple sclerosis." J Neuroimaging 15(4 Suppl): 10S-21S.

            Conventional magnetic resonance imaging (MRI) has routinely been used to improve the accuracy of multiple sclerosis (MS) diagnosis and monitoring, detect the effects of disease-modifying therapy, and refine the utility of clinical assessments. However, conventional MRI measures, such as the use of lesion volume and count of gadolinium-enhancing and T2 lesions, have insufficient sensitivity and specificity to reveal the true degree of pathological changes occurring in MS. Newer metrics of MRI analysis, including T1-weighted hypointense lesions (black holes) and central nervous system (CNS) atrophy measures, are able to capture a more global picture of the range of tissue alterations caused by inflammation, demyelination, axonal loss, and neurodegeneration. There is mounting evidence that these MRI measures correlate well with existing and developing neurological impairment and disability. In so doing, these MRI techniques can help elucidate the mechanisms underlying the pathophysiology and natural history of MS. The current understanding is that T1 black holes and CNS atrophy more accurately reflect the neurodegenerative and destructive components of the MS disease process. Therefore, the short and long-term studies that aim to measure the degree and severity of the neurodegenerative MS disease process should incorporate these MRI metrics as part of their standard routine MRI protocols.

Zingg, W. (2005). "[Does vaccination cause disease?]." Ther Umsch 62(10): 665-74.

            Not many inventions in medical history have influenced our society as much as vaccination. The concept is old and simple. When Edward Jenner published his work on cowpox, "variolation" was quite common. In this procedure, pus of patients with mild smallpox was transferred to healthy individuals. Meanwhile smallpox has been eradicated worldwide. Diseases such as poliomyelitis, diphtheria or tetanus almost disappeared in industrialized countries. The same happened with epiglottitis and meningitis due to Haemophilus influenzae type b (Hib) after vaccination against Hib was introduced in Switzerland in 1990. This success was possible because of routine vaccination. Immunization is a save procedure and adverse events are much lower than complications in the natural course of the prevented diseases. However vaccinations were accused to cause diseases themselves such as asthma, multiple sclerosis, diabetes mellitus, chronic arthritis or autism. Hitherto no large cohort study or case-control-study was able to proof responsibility of vaccines in any of these diseases. Public media are eager to publish early data from surveillance reports or case reports which are descriptive and never a principle of cause and effect. In large controlled trials there was no proof that vaccination causes asthma, hepatitis-B-vaccination causes multiple sclerosis or macrophagic myofasciitis, Hib-vaccination causes diabetes mellitus, rubella-vaccination causes chronic arthritis, measles-mumps-rubella-vaccination causes gait disturbance or thiomersal causes autism. These results are rarely published in newspapers or television. Thus, many caring parents are left with negative ideas about immunization. Looking for the best for their children they withhold vaccination and give way to resurgence of preventable diseases in our communities. This must be prevented. There is more evidence than expected that vaccination is safe and this can and must be told to parents.

Zijdenbos, A. P., J. P. Lerch, et al. (2005). "Brain imaging in drug R&D." Biomarkers 10 Suppl 1: S58-68.

            Magnetic resonance imaging (MRI), used as a clinical diagnostic tool since the early 1980s, is rapidly gaining traction as an integral part of the drug development process. Brain imaging research spans a wide area, covering both structure and function, and ranging from the physics and physiology associated with novel acquisition techniques, to the development of sophisticated image processing algorithms. This paper briefly describes two methods on either end of this spectrum: the "pipeline" framework for the fully automated morphometric analysis of brain imaging data, and molecular MRI, which holds promise for the non-invasive detection of molecular targets of new pharmacological compounds. The potential use of these technologies is illustrated by examples of their applications in multiple sclerosis, Alzheimer's disease, and oncology.

Ziemssen, T. and F. Ziemssen (2005). "The role of the humoral immune system in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE)." Autoimmun Rev 4(7): 460-7.

            The pathogenic events in multiple sclerosis (MS) that result in immune cell infiltration, multifocal demyelination and axonal loss have been focused by the strong impact of the classical MS model experimental autoimmune encephalomyelitis (EAE) towards the hypothesis that MS is an entirely T cell-mediated disease. Although conspicuous humoral immune responses have been known since Kabal's seminal finding of elevated immunoglobulins (Igs) in the cerebrospinal fluid (CSF), only in the past few years evidence derived from recent studies of the MS lesion of anti-myelin antibodies (Abs) in patients with early MS and of MS animal models has led to a renewed interest in the role for B cells, plasma cells and their products in the pathogenesis of MS. This review surveys the actual data concerning the role of the humoral immune system in MS and EAE and explains potential modes of action and long-time persistence in the inflamed brain tissue as a B cell-supportive microenvironment in MS. These mechanisms include the modulation of antigen presentation and costimulation to T cells, increased myelin opsonisation und recruitment of inflammatory cells to the CNS, but also immunoregulatory influences on the remyelination by anti-myelin B cells and Abs. So, affecting the humoral immune system in MS would be a reasonable therapeutic option.

Ziemssen, T. (2005). "Modulating processes within the central nervous system is central to therapeutic control of multiple sclerosis." J Neurol 252 Suppl 5: v38-45.

            Historically considered to be an autoimmune demyelinating disease, multiple sclerosis is now recognized to be characterized by significant axonal and neuronal pathology. Addressing this neurodegenerative component of the disease is an important treatment objective, since axonal injury is believed to underlie the accumulation of disability and disease progression. The precise relationship between the inflammatory and neurodegenerative components in multiple sclerosis remains poorly elucidated, although neurodegeneration appears to be at least partially independent from neuroinflammation. The mechanisms underlying axonal injury appear complex and are likely to be multifactorial. Specific treatment strategies need to be developed that act within the central nervous system to prevent neurodegeneration and need to be provided from the earliest stages of disease. It is likely that immunomodulatory treatments acting purely in the periphery will provide only indirect and not direct neuroprotection. A promising approach is to enhance neuroprotective autoimmunity inside the brain, believed to be mediated, at least in part, by the release of neurotrophic factors within the nervous system from infiltrating immune cells. Such a beneficial process would be inhibited by a non-selective immunosuppressive strategy. In summary, treatments of multiple sclerosis should take into account the heterogeneous pathophysiology of the disease. The pathogenic process in the central nervous system itself should be the major focus in multiple sclerosis therapy in order to protect against demyelination and axonal loss and to promote remyelination and regeneration directly in the target tissue, independently of peripheral immune status. In conclusion, selective treatment strategies aimed at preventing axonal injury within the central nervous system are required to complement existing, peripherally acting treatments targeting the immune system.

Zhao, C., S. P. Fancy, et al. (2005). "Mechanisms of CNS remyelination--the key to therapeutic advances." J Neurol Sci 233(1-2): 87-91.

            There are two components to the treatment of multiple sclerosis (MS); the first is to prevent damage occurring, and the second is to repair the residual damage. While considerable progress has been made in the recent years with the former through the development of anti-inflammatory and immunomodulatory therapies, there are currently no effective repair therapies routinely used in MS patients. This represents a significant gap in the MS clinician's therapeutic armoury. In this article we argue that a clear understanding of the repair mechanisms following CNS demyelination is fundamental to filling this gap. We discuss (1) the cellular events involved in remyelination, (2) changes in transcription factor expression within oligodendrocyte precursor cells associated with their activation in response to demyelination, (3) the role of platelet derived growth factor in the OPC recruitment phase of remyelination, and (4) the significance of the inflammatory response associated with demyelination in creating a signalling environment that favours remyelination.

Zhao, C., S. P. Fancy, et al. (2005). "Stem cells, progenitors and myelin repair." J Anat 207(3): 251-8.

            Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent progenitor cells contributing to regeneration of the injured central nervous system (CNS). This process can occur with remarkable efficiency in both clinical disease, such as multiple sclerosis, and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in multiple sclerosis, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. Identifying potential targets will depend on a detailed understanding of the cellular and molecular mechanisms of remyelination. In this article we address two important issues. First, we consider the nature of the cell or cells that respond to demyelination and generate new oligodendrocytes, identifying current areas of uncertainty and addressing the role of adult CNS stem and progenitor cells. Second, we discuss the concept of adult progenitor activation following demyelination, focusing on the increased expression of (1) olig transcription factors, (2) bone morphogenetic proteins and (3) fyn, a member of the src-family of tyrosine kinases.

Zhang, J. and G. Hutton (2005). "Role of magnetic resonance imaging and immunotherapy in treating multiple sclerosis." Annu Rev Med 56: 273-302.

            Significant advances in magnetic resonance imaging (MRI) technology and treatment of multiple sclerosis (MS) have been made during the past decade. These advances have revealed evidence of profound heterogeneity in MS. There is a clear need to revisit the key issues in MS pathogenesis and treatment strategies, taking new data into consideration. This paper provides an overview of recent progress in MS research, including (a) a review of clinical, pathologic, and immunologic aspects of MS, (b) a discussion of the mechanism of action of currently available disease-modifying drugs for MS, (c) an account of the role of MRI in clinical management and clinical trials in MS, and (d) an overview of some emerging treatments for MS.

Zajicek, J. (2005). "Diagnosis and disease modifying treatments in multiple sclerosis." Postgrad Med J 81(959): 556-61.

            Multiple sclerosis (MS) refers to scattered areas of hardening found on sectioning central nervous system tissue of affected people, usually after many years of illness. It rarely causes early death but is the commonest cause of neurological disability among young people. Overall results from controlled trials over the past 50 years have been rather disappointing but the comparatively recent licensing of drugs such as interferon beta and glatiramer acetate has led to a reappraisal of many aspects of MS. There are now new diagnostic criteria, which encompass developments in magnetic resonance imaging. Older clinical methods of measuring disease impact are now being re-evaluated to facilitate clinical trials of the approximate 150 new products currently being developed as potential disease modifying agents. The success and failure of agents that should be effective on theoretical grounds, together with advances in neuropathology, have led to fundamental questions regarding our basic understanding of disease pathogenesis being re-addressed.

Zaffaroni, M. (2005). "Treatment optimisation in multiple sclerosis." Neurol Sci 26 Suppl 4: S187-92.

            Not all patients with multiple sclerosis (MS) respond equally to available disease modifying agents (DMA). Rational and reliable criteria are needed to identify responders and non responders in order to optimize the treatment. Natural history of the disease, clinical evolution and magnetic resonance imaging are the putative indicators to be considered with this respect, but neutralizing antibodies, possible immunological markers and pathological or genetic diversity may also represent future additional indicators. Clinical recommendations and consensus criteria for defining a suboptimal response to DMA have been proposed by different international panels of experts, but all need validation in experimental settings to provide solid guidelines for establishing when and how to take action on MS treatment with DMA.

Yorkston, K. M., K. L. Johnson, et al. (2005). "Taking part in life: enhancing participation in multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 583-94.

            Health care professionals participating in rehabilitation for people with MS can play a critical role in enhancing limited outcomes such as enhanced mobility, reductions in symptoms such as pain and depression, and the metaoutcome-participation. This role will be significantly more effective if the health care professional acknowledges and validates the different perspectives of the professional and the patient and recognizes the expertise of the patient who has lived with MS in the context of his or her life.Assuming this role effectively requires that the health care professional develop a collaborative relationship with the patient and understand that the role may change depending on the stage of MS and the individual's circumstances.

Yang, C. C. (2005). "[Diagnosis of multiple sclerosis]." Acta Neurol Taiwan 14(4): 213-20.

            Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system. The disorder displays marked clinical heterogeneity. In certain cases, making diagnosis can be challenging. Diagnosis of MS has become more important in the era of treatments that change the natural history of the disease. Several general diagnostic principles are useful to guide the diagnostic approach to MS. Clinically, MS requires neurological problems associated with objective abnormalities. Certain basic principles, first outlined by Schumacher et al. (1965) are still pertinent. Poser et al. (1983) have further modified the criteria using data derived from clinical evaluation and laboratory studies, including cerebrospinal fluid analysis, evoked potentials, and imaging studies. Poser criteria have long been familial for most neurologists. The most recent addition to our diagnostic armamentarium are the McDonald criteria (2001), which are the first attempt to incorporate standardized MRI criteria into the MS diagnostic process. The most innovative use of MRI to support an MS diagnosis is dissemination of demyelination can be demonstrated by MRI alone, in the absence of any new clinical attacks. Diagnosing MS by such sensitive MRI criteria will occur more quickly than waiting for a second clinical event. This has added some sensitivity, some controversy, and a lot of confusion. The application of the new criteria on Asian MS patients remains to be validated. Each of the criteria will be discussed, with major emphasis on the McDonald criteria.

Yamamura, T., K. Takahashi, et al. (2005). "[Multiple sclerosis and regulatory cells]." Nippon Rinsho 63 Suppl 5: 422-6.

Yamamura, T. (2005). "[Synthetic glycolipid ligands as novel therapeutics for multiple sclerosis]." Rinsho Shinkeigaku 45(11): 909-11.

            Our previous works indicate that regulatory cells such as natural killer (NK) cells and NKT cells could play an active role in maintaining the remission state of MS. We have therefore adopted a strategy for developing the future MS therapy by targeting NKT cells. The unique glycolipid-reactive lymphocytes are known to produce a large quantity of Th2 cytokines such as IL-4 when encountering their ligands like alpha-galactosylceramide (alpha-GC). Whereas most of the NKT ligands so far described would stimulate both Th1 and Th2 cytokine production by NKT cells, the synthetic compound OCH, an analogue of alpha-GC with a shorter lipid tail, is the one which selectively induces IL-4 production. Given this property, oral or intraperitoneal OCH administration would prohibit the development of a variety of Th1-meediated pathology, including EAE, collagen-induced arthritis, type 1 diabetes, DSS-induced colitis and acute GVHD by inducing Th2 bias. This review paper summarizes the recent publications and our unpublished results related to the efficacy of OCH and to the molecular mechanism accounting for the Th2 inducing property of OCH.

Yamamoto, Y. (2005). "[Palmitoleic acid]." Nippon Rinsho 63 Suppl 8: 803-5.

Wucherpfennig, K. W. (2005). "The structural interactions between T cell receptors and MHC-peptide complexes place physical limits on self-nonself discrimination." Curr Top Microbiol Immunol 296: 19-37.

            The activation and expansion of T cells in an antimicrobial immune response is based on the ability of T cell receptors (TCR) to discriminate between MHC-bound peptides derived from different microbial agents as well as self-proteins. However, the specificity of T cells is constrained by the limited number of peptide side chains that are available for TCR binding. By considering the structural requirements for peptide binding to MHC molecules and TCR recognition of MHC-peptide complexes, we demonstrated that human T cell clones could recognize a number of peptides from different organisms that were remarkably distinct in their primary sequence. These peptides were particularly diverse at those sequence positions buried in pockets of the MHC binding site, whereas a higher degree of similarity was present at a limited number of peptide residues that created the interface with the TCR. These T cell clones had been isolated from multiple sclerosis patients with human myelin basic protein, demonstrating that activation of such autoreactive T cells by microbial peptides with sufficient structural similarity may contribute to the disease process. Similar findings have now been made for a variety of human and murine T cell clones, indicating that specificity and cross-reactivity are inherent properties of TCR recognition. The observations that particular TCR are highly sensitive to changes at particular peptide positions but insensitive to many other changes in peptide sequence are not contradictory, but rather the result of structural interactions in which a relatively flat TCR surface contacts a limited number of side chains from a peptide that is deeply embedded in the MHC binding site.

Wong, M. (2005). "Advances in the pathophysiology of developmental epilepsies." Semin Pediatr Neurol 12(2): 72-87.

            Pediatric epilepsies display unique characteristics that differ significantly from epilepsy in adults. The immature brain exhibits a decreased seizure threshold and an age-specific response to seizure-induced brain injury. Many idiopathic epilepsy syndromes and symptomatic epilepsies commonly present during childhood. This review highlights recent advances in the pathophysiology of developmental epilepsies. Cortical development involves maturational regulation of multiple cellular and molecular processes, such as neurogenesis, neuronal migration, synaptogenesis, and expression of neurotransmitter receptors and ion channels. These normal developmental changes of the immature brain also contribute to the increased risk for seizures and unique responses to seizure-induced brain injury in pediatric epilepsies. Recent technological advances, especially in genetics and imaging, have yielded exciting discoveries about the pathophysiology of specific pediatric epilepsy syndromes, such as the emergence of channelopathies as the cause of many idiopathic epilepsies and identification of malformations of cortical development as a major source of symptomatic epilepsies in children.

Wolfovitz, E. (2005). "[The pleiotropic effects of statins]." Harefuah 144(8): 577-82, 597.

            Statins (HMG-CoA reductase inhibitors) are the most commonly used lipid lowering drugs. Recent experimental evidence suggest that these agents appear to display additional cholesterol independent or pleiotropic effects, contributing to prevention and inhibition of atherosclerosis. In addition, clinical trials have demonstrated different effects of statins on diseases that are not directly related to accelerated atherosclerosis. The statins' vascular pleiotropic effects include improvement of endothelial function, slowing the inflammation process, inhibition of the thrombus formation, enhancement of plaque stability and decreasing oxidative stress. Clinical benefits were observed with statins therapy for cardiovascular diseases - ischemic heart disease, cerebral vascular accidents and peripheral vascular disease. Lately, clinical trials have suggested their role in Alzheimer's disease, multiple sclerosis, malignant diseases, osteoporosis, chronic renal diseases, transplantations, macular degeneration and autoimmune diseases. The objective of this review is to summarize the data related to the pleiotropic effects of the statin drugs, beyond their lipid lowering effect.

Wojtera, M., B. Sikorska, et al. (2005). "Microglial cells in neurodegenerative disorders." Folia Neuropathol 43(4): 311-21.

            Microglia are resident immune cells of the CNS. They are involved in the pathogenesis of diverse neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion diseases as well as multiple sclerosis, amyotrophic lateral sclerosis and AIDS dementia complex. It is widely accepted that microglia contribute to the neurodegeneration through a release of a variety of proinflammatory substances. In fact, they are not the only cells which contribute to immunological processes inside the nervous system. The CNS is composed of different cell populations that answer to pathological factors and influence each other and modulate their reactions. These complex interactions are responsible for the development of brain pathology. This paper reviews the available information on microglial cells contribution to AD, PD and prion diseases development.

Wirenfeldt, M., R. Ladeby, et al. (2005). "[Microglia--biology and relevance to disease]." Ugeskr Laeger 167(33): 3025-30.

            Microglia, the resting macrophage population in the brain and spinal cord, has a central role in inflammatory processes and in acute and chronic degenerative diseases of the central nervous system. The possibility of utilizing microglia diagnostically has emerged with the prospect of visualization of reactive microgliosis via positron emission tomography. Microglia might also have a therapeutic potential by way of recruitment of microglial precursors from the blood with the opportunity to introduce genetically modified cells lesion-specifically into the central nervous system via the bloodstream. Knowledge about microglial function has preferentially been obtained via studies in experimental animal models of the pathological central nervous system. In spite of the rather extensive knowledge regarding the pathophysiological implications of these cells, their function in the normal central nervous system remains rather unknown.

Wills, A. and S. Ormerod (2005). "Casebook: paraesthesia and numbness." Practitioner 249(1674): 604, 606, 608 passim.

Wessely, R. (2005). "Interference by interferons: Janus faces in vascular proliferative diseases." Cardiovasc Res 66(3): 433-43.

            Interferons (IFNs) display pleiotropic properties; not only do they protect cells from viral infections but they may also modulate cell growth and differentiation as well as innate and adaptive immune responses. Therapeutic applications of IFNs have proven efficacy in a variety of illnesses, including hepatitis, multiple sclerosis, and some forms of cancer. Emerging evidence has been obtained during recent years that interferons impact on molecular and cellular mechanisms implicated in the development of vascular proliferative diseases such as atherosclerosis, restenosis, and cardiac allograft vasculopathy. Further appreciation and delineation of the precise mechanisms on how interferons influence vascular proliferative disease processes could potentially facilitate the development of novel treatment options attenuating these common causes of cardiovascular morbidity and mortality.

Werner, H. (2005). "The benefits of the dysphagia clinical nurse specialist role." J Neurosci Nurs 37(4): 212-5.

            Dysphagia is a major health problem associated with multiple neurological diseases such as stroke, multiple sclerosis, and Parkinson's disease, among others. Staff nurses lack a consistent approach to managing dysphagia patients. A dysphagia clinical nurse specialist (CNS) may facilitate a consistent approach. As a member of the interdisciplinary team, the dysphagia CNS carries a caseload and serves as a liaison between the interdisciplinary team and the nursing staff to oversee dysphagia nursing care.

Welshman, A. (2005). "Palliative care. Some organisational considerations." Minerva Anestesiol 71(7-8): 439-43.

            Managing pain effectively is one of the biggest challenges in medicine, let alone when dealing with the dying patient and his family. For palliative care specialists this is a daily challenge. However, ''To cure when possible, to give comfort always'' is an empty credo if physicians don't use every weapon in the medical arsenal to relieve the suffering caused by chronic pain. It's of course the opioids: morphine, heroin, their synthetic derivatives and other narcotics, a class of medications that conjure up visions of drug addiction and narcotic squads. To say that opioids are stigmatised by such allusions is putting it mildly. An unhealthy proportion of doctors and patients alike are afraid to have anything to do with them, even in when facing their final stages of life. This is particularly so in the Mediterranean society. It is here in Italy that an effort must be made to educate both physicians and the general public, an arduous task to change a long standing belief which requires a quick cultural turn around. Those who refuse opioids because they are afraid of addiction, and the doctors who refuse to prescribe them out of fear or pure unwillingness to address an apprehensive attitude on behalf of his patient, need to be better informed. Most misconceptions about opioids have to do with terminology, because words like ''morphine, addiction, dependency'' and ''tolerance'' mean entirely different things in popular and medical parlance. Add to this the perceptions and attitudes the patient can have with this terminology which then can have a profound effect on the success or failure of a pain control programme. In fact, most people think that medication such as morphine are only for people who are dying and as a consequence is synonymous with death itself. Is this why Italian physicians are not prescribing morphine even though great efforts have been made recently by the Health Ministry to facilitate prescribing laws and costs? It is worthy of serious consideration. Another important issue faced daily by palliative care physicians is the broad number of chronic conditions which could make use of opioids. Severe cancer pain is the most obvious example of an appropriate use of opioids, but hardly the only one. The North American Chronic Pain Association of Canada (NACPAC) advocates the use of opioids for a wide range of conditions causing severe chronic pain, including lower back pain, inflammatory bowel disease, migraines, AIDS, multiple sclerosis and arthritis. Concerns regarding under treatment of chronic pain have captured the attention of patient advocacy groups, policy makers and scientific organisations. Misconceptions of opioid laws, negative social stigma and lack of valid prescribing alternatives to overcome this, together with paucity of formal provider education confound the issue. Much education needs to be done before opioids will be seen as a safe and reasonable treatment for chronic pain here in Italy.

Weiss, S. R. and S. Navas-Martin (2005). "Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus." Microbiol Mol Biol Rev 69(4): 635-64.

            Coronaviruses are a family of enveloped, single-stranded, positive-strand RNA viruses classified within the Nidovirales order. This coronavirus family consists of pathogens of many animal species and of humans, including the recently isolated severe acute respiratory syndrome coronavirus (SARS-CoV). This review is divided into two main parts; the first concerns the animal coronaviruses and their pathogenesis, with an emphasis on the functions of individual viral genes, and the second discusses the newly described human emerging pathogen, SARS-CoV. The coronavirus part covers (i) a description of a group of coronaviruses and the diseases they cause, including the prototype coronavirus, murine hepatitis virus, which is one of the recognized animal models for multiple sclerosis, as well as viruses of veterinary importance that infect the pig, chicken, and cat and a summary of the human viruses; (ii) a short summary of the replication cycle of coronaviruses in cell culture; (iii) the development and application of reverse genetics systems; and (iv) the roles of individual coronavirus proteins in replication and pathogenesis. The SARS-CoV part covers the pathogenesis of SARS, the developing animal models for infection, and the progress in vaccine development and antiviral therapies. The data gathered on the animal coronaviruses continue to be helpful in understanding SARS-CoV.

Weinberg, A. D. and R. Montler (2005). "Modulation of TNF receptor family members to inhibit autoimmune disease." Curr Drug Targets Inflamm Allergy 4(2): 195-203.

            Certain members of the TNF-receptor family have shown proinflammatory function during immune activation and can be directly involved with the pathogenic effects observed during an autoimmune episode. The TNF-R family members summarized in this review includes: TNF-RI + II, OX40, and 4-1BB and they are expressed on a variety of leukocytes within the body. Studies within the last decade suggest that all of these proteins or their natural ligands can be targeted with various agents designed to diminish clinical signs of disease in autoimmune models. The data from the preclinical models specifically involving TNF-blockade have led to the development of clinical trials for patients with multiple sclerosis and rheumatoid arthritis. This review will chronicle the preclinical development of agents designed to inhibit OX40 and 4-1BB functions in autoimmunity and discuss relevant preclinical and clinical data associated with TNF-blockade.

Wehman-Tubbs, K., S. H. Yale, et al. (2005). "Insight into multiple sclerosis." Clin Med Res 3(1): 41-4.

Weber, M. S., T. Prod'homme, et al. (2005). "Drug Insight: using statins to treat neuroinflammatory disease." Nat Clin Pract Neurol 1(2): 106-12.

            Statins, a family of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are used primarily to reduce atherogenesis and cardiovascular morbidity. Surprisingly, they have also been shown to have immunomodulatory properties that might be of benefit for the treatment of autoimmune disorders. Statins can prevent and even reverse ongoing paralysis in experimental autoimmune encephalomyelitis--the mouse model for multiple sclerosis--and on the basis of these findings, statins are now being tested in patients with multiple sclerosis in clinical trials.

Waxman, S. G. (2005). "Cerebellar dysfunction in multiple sclerosis: evidence for an acquired channelopathy." Prog Brain Res 148: 353-65.

            Cerebellar dysfunction in multiple sclerosis (MS) is a significant contributor to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents. Thus, there is a need for better understanding of its pathophysiology. This chapter reviews a growing body of evidence which suggests that mis-tuning of Purkinje cells, due to expression of an abnormal repertoire of sodium channels, contributes to cerebellar deficits in MS. Within the normal nervous system, sodium channel Na(v)1.8 is expressed in a highly specific manner within spinal sensory and trigeminal neurons, and is not present within Purkinje cells, Na(v)1.8 mRNA and protein are, however, expressed within Purkinje cells both in models of MS (experimenal autoimmume encephalomyelitis; EAE), and in postmortem tissue from humans with MS. Expression of Na(v)1.8 within Purkinje cells in vitro alters electrogenesis in these cells in several ways: first, by increasing duration and amplitude of action potentials; second, by decreasing the proportion of action potentials that are conglomerate and the number of spikes per conglomerate action potential; and third, by supporting sustained, pacemaker-like impulse trains in response to depolarization, which are not seen in the absence of Na(v)1.8. Similar changes are observed in recordings from Purkinje cells in vivo from mice with EAE. Taken together, these results suggest that expression of Na(v)1.8 within Purkinje cells distorts their pattern of firing in MS.

Warren, J. D., J. M. Schott, et al. (2005). "Brain biopsy in dementia." Brain 128(Pt 9): 2016-25.

            Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Virley, D. J. (2005). "Developing therapeutics for the treatment of multiple sclerosis." NeuroRx 2(4): 638-49.

            Multiple sclerosis (MS) is both a complex and chronic neurological disease of the CNS. This poses unique challenges for drug discovery in terms of delineating specific targets related to disease mechanisms and developing safe and effective molecules for clinical application. Preclinical animal models of MS provide the necessary test bed for evaluating the effects of novel therapeutic strategies. Because the clinical manifestations and pathological consequences of disease vary dramatically from individual to individual, as well as treatment response to existing therapies, this creates a significant research endeavor in terms of translating preclinical methodologies to the clinical domain. Potentially exciting treatments have emerged in the form of natalizumab (Tysabri), an alpha4 integrin antagonist, and more recently FTY720, a sphinogosine-1 phosphate receptor modulator, providing a compelling proof-of-principle from bench to bedside. However, further research is required to discharge safety concerns associated with these therapeutic avenues. Future prospects in the guise of disease-modifying therapies that target the inflammatory and neurodegenerative components of disease have come to the forefront of preclinical research with the sole aim of reducing the underlying irreversible progressive disability of MS. Significant progress with novel therapies will be made by implementing biomarker strategies that extrapolate robustly from animal models to the divergent patient populations of MS. The future therapeutic options for MS will depend on improvements in understanding the precise factors involved in disease onset and progression and subsequently the development of oral therapeutics that translate sustained benefit from the preclinical context into clinical reality.

Viel, E., F. Pellas, et al. (2005). "[Peripheral neurolytic blocks and spasticity]." Ann Fr Anesth Reanim 24(6): 667-72.

            Peripheral nerve blockade is one of the therapeutic possibilities to treat spasticity of various muscles. Percutaneous nerve stimulation allows accurate location of nerves and neurolysis can be performed using intraneural injection of 65% ethanol or 5 to 12% phenol. Spastic contraction of various muscle groups is a common source of pain and disability which prevents from having efficient rehabilitation. Test-blocks as well as neurolytic blocks are possible in most of motor nerves of the upper and lower limbs and main indications are spastic sequelae of stroke and spinal trauma but also of multiple sclerosis, cerebral palsy and chronic coma. The use of percutaneous nerve stimulation allows accurate location and four nerves are more frequently treated: pectoral nerve loop, median, obturator and tibial nerves. In patients with spasticity of the adductor thigh muscles, nerve blocks are performed via a combined approach using fluoroscopy and nerve stimulation to identify the obturator nerve. No complications occurred and minor side effects are transient painful phenomena during injection. These approaches proved to be accurate, fast, simple, highly successful and reproducible. Percutaneous neurolytic procedures should be done as early as possible, as soon as spasticity becomes painful and disabling in patients with neurological sequelae of stroke, head trauma or any lesion of the motor neuron.

Vermersch, P., T. Stojkovic, et al. (2005). "Mycophenolate mofetil and neurological diseases." Lupus 14 Suppl 1: s42-5.

            We describe experience with the use of mycophenolate mofetil (MMF) in neurological diseases. Although only small series of patients or case reports were described, MMF is promising in immune-mediated neuromuscular disorders. MMF has been used for the treatment of polymyositis, chronic inflammatory demyelinating polyradiculoneuropathy, and multifocal motor neuropathy. These studies showed that MMF is well tolerated and may be useful in some patients. MMF can be effective alone but mainly as an adjuvant therapy by reducing steroid requirements or the frequency of infusions of IVIg. MMF has also been tested alone as a single drug treatment or in combination with immunomodulatory drugs in multiple sclerosis in open surveillance trials or in phase II studies. None of these studies have been designed to demonstrate a clinical efficacy but preliminary results are very promising.

Verbeek, M. M., M. A. Willemsen, et al. (2005). "[Diagnosis in cerebrospinal fluid: possible applications in neurological practice]." Ned Tijdschr Geneeskd 149(33): 1833-8.

            Examination of the cerebrospinal fluid (CSF) is part of the modern diagnostics of many neurological diseases. When an acute or chronic meningitis or encephalitis is suspected, the distinction between an acute viral and a bacterial intrathecal infection can generally be rapidly made via examination of the CSF. In case of a chronic infection this will determine the direction of further microbiological analysis. When there are clinical indications for subarachnoid haemorrhage but no abnormalities on the CT-scan, it can be either demonstrated or excluded by means of spectrophotometric analysis of blood pigments in the CSF. In case of possible multiple sclerosis (MS) and contraindications for MRI, or if the combination of the clinical symptoms and MRI does not yield a definitive diagnosis, then the demonstration of unique oligoclonal IgG-bands in the CSF is an important parameter in confirming a diagnosis of 'MS'. In practice, metastases to the leptomeninges are often detected by means of (repeated) cytopathological analysis of the CSF, which has a higher sensitivity and specificity than MRI. Examination of the CSF also plays an important role in the diagnosis of (hereditary) metabolic encephalopathies in childhood. In case of watery discharge from the nose or ear following trauma or neurosurgery, it can be determined whether or not this is leaking CSF. Analysis of certain brain-specific proteins in the CSF can contribute to the differential diagnosis of dementia syndromes. The added diagnostic value of examination of the CSF in hypokinetic rigidity syndromes is still unclear. The complications of a spinal puncture often remain limited to post-puncture headache. Contraindications include intracranial space-occupying abnormalities, compression of the spinal cord, haemorrhagic diathesis and abnormalities around the puncture site.

Vandevelde, M. and A. Zurbriggen (2005). "Demyelination in canine distemper virus infection: a review." Acta Neuropathol (Berl) 109(1): 56-68.

            Canine distemper virus (CDV) causes severe immunosuppression and neurological disease in dogs, associated with demyelination, and is a model for multiple sclerosis in man. In the early stage of the infection, demyelination is associated with viral replication in the white matter. In acute demyelinating lesions there is massive down-regulation of myelin transcription and metabolic impairment of the myelin-producing cells, but there is no evidence that these cells are undergoing apoptosis or necrosis. Oligodendroglial change is related to restricted infection of these cells (transcription but no translation) and marked activation of microglial cells in acute lesions. Concomitant with immunological recovery during the further course of the disease, inflammation occurs in the demyelinating plaques with progression of the lesions in some animals. A series of experiments in vitro suggests that chronic inflammatory demyelination is due to a bystander mechanism resulting from interactions between macrophages and antiviral antibodies. Autoimmune reactions are also observed, but do not correlate with the course of the disease. The progressive or relapsing course of the disease is associated with viral persistence in the nervous system. Persistence of CDV in the brain appears to be favored by non-cytolytic selective spread of the virus and restricted infection, in this way escaping immune surveillance in the CNS. The CDV Fusion protein appears to play an important role in CDV persistence. Similarities between canine distemper and rodent models of virus-induced demyelination are discussed.

Vandenbark, A. A. (2005). "TCR peptide vaccination in multiple sclerosis: boosting a deficient natural regulatory network that may involve TCR-specific CD4+CD25+ Treg cells." Curr Drug Targets Inflamm Allergy 4(2): 217-29.

            Vaccination with self peptides contained within T cell receptor (TCR) chains, expressed by pathogenic Th1 cells can induce a second set of regulatory T cells that can reverse paralysis in rodents with experimental encephalomyelitis, and similarly, may have the potential to regulate myelin-reactive Th1 cells in patients with multiple sclerosis (MS). In this review, we discuss our recent discovery that TCR-reactive T cells generally possess classical inhibitory activity associated with Treg cells. CD4+CD25+ TCR-reactive T cells can inhibit CD4+CD25- indicator cells stimulated with anti-CD3/anti-CD28 antibody in a dose-dependent and cell-contact-dependent manner. Additionally, CD4+CD25+ T cells from blood of healthy control donors have significant responses to a pool of discriminatory TCR peptides, including BV10S1P, BV19S20, BV13S7, BV12S2A2T, BV11S1A1T, BV21S3A1T, AV15S1, and BV12S1A1N1. Patients with MS have varying degrees of deficient responses to TCR peptides, and by association, a defect in Treg cell function as well. TCR peptide vaccination using a new tripeptide mixture emulsified in IFA produced strong T cell responses in 100% of MS recipients, a dramatic improvement over previous vaccines given i.d. in saline that induced TCR-reactive T cell responses in about 50% of recipients. Responders to vaccination had a tendency towards reduced MRI lesions, and an early indication of enhanced Treg activity mediated by TCR-reactive T cells that could provide suppression of target as well as bystander T cells. These data provide a strong foundation for future TCR vaccination studies that will critically test the ability of the tripeptide mixture to induce significantly enhanced Treg activity and possible clinical and MRI benefits in vivo.

van Meeteren, M. E., C. E. Teunissen, et al. (2005). "Antioxidants and polyunsaturated fatty acids in multiple sclerosis." Eur J Clin Nutr 59(12): 1347-61.

            Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.

van den Broek, H. H., J. G. Damoiseaux, et al. (2005). "The influence of sex hormones on cytokines in multiple sclerosis and experimental autoimmune encephalomyelitis: a review." Mult Scler 11(3): 349-59.

            The female predominance of multiple sclerosis (MS) has suggested that hormonal differences between the sexes must confer some protective effect on males or enhance the susceptibility of females to this disease. There has been evidence that gonadal hormones can modulate the immune response regulated by antigen presenting cells and T cells. These cells control the immune response by the production of interacting pro- and anti-inflammatory cytokines. The first include the acute phase pro-inflammatory cytokines of the innate immune response as well as the T-helper 1 (Th1) cytokines, while the later contain the Th2 cytokines as well as the suppressor cytokines. There is some evidence that MS and experimental autoimmune encephalitis (EAE) are Th1 cell-mediated diseases. For this reason many studies have been done to influence the pro-inflammatory cytokine production of these Th1 cells in favour of an anti-inflammatory immune response as mediated by Th2 cells. However the role of the regulatory T cells in this context is not clearly understood. Here we review the studies concerning the role of sex hormones on the cytokine production in relation to the disease course of MS and EAE and in particular in the light of the recent revival of the regulatory T cells and their suppressive cytokines.

Ursell, M. R. and P. W. O'Connor (2005). "Natalizumab and other monoclonal antibodies." Neurol Clin 23(1): 233-46, viii.

Tzakos, A. G., A. Troganis, et al. (2005). "Structure and function of the myelin proteins: current status and perspectives in relation to multiple sclerosis." Curr Med Chem 12(13): 1569-87.

            Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and loss of neurological function, local macrophage infiltrate and neuroantigen-specific CD4(+)T cells. MS arises from complex interactions between genetic, immunological, infective and biochemical mechanisms. Although the circumstances of MS etiology remain hypothetical, one persistent theme involves immune system recognition of myelin-specific antigens derived from myelin basic protein, the most abundant extrinsic myelin membrane protein, and/or another equally suitable myelin protein or lipid. Knowledge of the biochemical and physico-chemical properties of myelin proteins and lipids, particularly their composition, organization, structure and accessibility with respect to the compacted myelin multilayers, becomes central to understanding how and why myelin-specific antigens become selected during the development of MS. This review focuses on the current understanding of the molecular basis of MS with emphasis: (i) on the physical-chemical properties, organization, morphology, and accessibility of the proteins and lipids within the myelin multilayers; (ii) on the structure-function relationships and characterization of the myelin proteins relevant to the manifestation and evolution of MS; (iii) on conformational relationships between myelin epitopes which might become selected during the development of MS; (iv) on the structure of MHC/HLA in complex with MBP peptides as well as with TCR, which is crucial to the understanding of the pathogenesis of MS with the ultimate goal of designed antigen-specific treatments.

Tyndall, A. and R. Saccardi (2005). "Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions." Clin Exp Immunol 141(1): 1-9.

            Around 700 patients have received an autologous haematopoietic stem cell transplant (HSCT) as treatment for a severe autoimmune disease (AD). The majority of these have been within the context of phase I/II clinical trials and following international guidelines proposed 7 years ago. In general, a positive benefit/risk ratio has led to phase III prospective randomized controlled trials in multiple sclerosis (MS), systemic sclerosis (SSc) and rheumatoid arthritis (RA) in Europe. In the US, similar trials are being planned for SSc, MS and systemic lupus erythematosus (SLE). Transplant related mortality (TRM) has fallen in all disease subgroups since the inception due to more appropriate patient selection, and so far a clear advantage of the more intense myeloablative regimens in terms of remission induction and relapse rate has not emerged. Although each AD has a different profile, over a third of patients have sustained a durable remission, often with no further need for immunosuppressive drugs. In those who relapsed, many responded to agents which pre transplant had been ineffective. The study of immune reconstitution and gene expression pre and post HSCT is being undertaken to further understand the mechanism of autoimmunity.

Tyndall, A. and T. Daikeler (2005). "Autologous hematopoietic stem cell transplantation for autoimmune diseases." Acta Haematol 114(4): 239-47.

            Ten years have passed since the first published consensus statement on the use of hematopoietic stem cell transplantation (HSCT) in the treatment of severe autoimmune disease (AD) appeared. During that time, around 700 patients suffering from severe AD have undergone HSCT in the frame of phase I/II clinical trials from over 20 countries including the US. The majority have received an autologous HSCT using one of a limited number of regimens, consistent with the original consensus statement. Long-term drug-free remissions, remission then relapse, no response and treatment-related mortality (TRM) were seen in all the subgroups of AD. An overall TRM of 7% was observed, with marked variation between ADs, i.e. 11% in systemic lupus erythematosus (SLE) and only 1 patient in rheumatoid arthritis (RA). Phase III prospective, comparative randomized trials are running or being planned in multiple sclerosis (MS), systemic sclerosis (SSc), SLE and RA. Basic science programs are also being undertaken to study the immunological mechanisms underlying the clinical events observed.

Tullman, M. J. and F. D. Lublin (2005). "Combination therapy in multiple sclerosis." Curr Neurol Neurosci Rep 5(3): 245-8.

            Over the past decade, multiple sclerosis (MS) has become a treatable neurologic illness. However, given the rather modest benefit of the currently available disease-modifying agents, as well as the challenges associated with performing placebo-controlled, equivalence, and superiority trials, the logic of combining therapies in MS has considerable appeal. Selecting agents for combination requires careful consideration, as the immunomodulating activity of one drug could potentially interfere with the therapeutic effect of another, and certain combinations may be associated with unforeseen adverse effects. Rigorously controlled studies are needed to determine the safest and most effective use of new and existing MS therapies.

Trotter, J. (2005). "NG2-positive cells in CNS function and the pathological role of antibodies against NG2 in demyelinating diseases." J Neurol Sci 233(1-2): 37-42.

            NG2 is expressed by a variety of immature glia in the CNS including oligodendrocyte progenitor cells, paranodal astrocytes and perisynaptic glia. The protein has a large extracellular domain with two LNS/Lam G domains at the N-terminus and a short intracellular tail with a PDZ-recognition domain at the C-terminus. Experiments suggest that the protein plays a role in migration. The PDZ protein GRIP was identified as an intracellular binding partner of NG2 in immature glial cells. A complex is formed between GRIP, NG2 and the AMPA class of glutamate receptors: this may position these glial receptors towards sites of neuronal glutamate release at synapses and during myelination. Identification of neuronal receptors and links to the cytoskeleton of NG2 is of critical importance. Some Multiple Sclerosis patients have autoantibodies to NG2 in the cerebral spinal fluid: such antibodies could interfere with remyelination by lysing oligodendrocyte progenitor cells or blocking their migration but may also cause pathology by disrupting glial-neuronal signalling at synapses and paranodes.

Trebst, C. and M. Stangel (2005). "[Cannabinoids in multiple sclerosis -- therapeutically reasonable?]." Fortschr Neurol Psychiatr 73(8): 463-9.

            For centuries extracts from the Cannabis sativa plant have been used for recreational use and as remedies. Anecdotal reports from patients with multiple sclerosis (MS) experiencing relief of their spasticity and pain after smoking marihuana have prompted discussions about a potential therapeutic application of cannabis preparations in MS. Only recently the first large, multicenter, double-blind, placebo controlled study was conducted evaluating the use of cannabinoids for treatment of spasticity and other symptoms related to MS. Based on this trial and previous uncontrolled observations together with insights from basic research and animal experiments there is reasonable evidence for the therapeutical employment of cannabinoids in the treatment of MS related symptoms. Furthermore, data are arising that cannabinoids have immunomodulatory and neuroprotective properties. However, results from clinical trials do not allow the recommendation for the general use of cannabinoids in MS. This article summarizes the present knowledge of clinical and experimental research regarding the therapeutic potential of cannabinoids for the treatment of MS.

Traboulsee, A., G. Zhao, et al. (2005). "Neuroimaging in multiple sclerosis." Neurol Clin 23(1): 131-48, vii.

Totolian, N. A. (2005). "[Magnetic-resonance tomography in differential diagnosis of brain lesions in demyelinating and systemic autoimmune diseases]." Zh Nevrol Psikhiatr Im S S Korsakova 105(5): 42-6.

            An aim of the study was to establish MRT signs that may be useful for differential diagnosis of multiple sclerosis (MS). Three groups of patients have been examined: 300 patients with MS, 35 with demyelinating diseases (acute disseminated encephalomyelitis, neuromyelitis optica--Devic's syndrome); 90 patients with systemic autoimmune diseases (systemic lupus erythematosus, primary antiphospholipid syndrome, sclerodermatitis, Sjugren's syndrome, autoimmune thyroiditis, vasculitis and vasculopathy). Classification of MRT syndromes in MS and their frequency are presented: syndrome of chronic inflammatory demyelination (79%), syndrome of acute inflammatory demyelination (9%), syndrome of multifocal degenerative leucoencephalopathy (8%), syndrome of combined multifocal diffusive leucoencephalopathy (4%). The similarity and differences in MRT semiotics of the above diseases and MS are described.

Totolian, N. A. (2005). "[Betaferon in the treatment of multiple sclerosis: efficacy standards]." Zh Nevrol Psikhiatr Im S S Korsakova 105(7): 63-6.

Titelbaum, D. S., A. Degenhardt, et al. (2005). "Anti-tumor necrosis factor alpha-associated multiple sclerosis." AJNR Am J Neuroradiol 26(6): 1548-50.

            A case of multiple sclerosis presenting during anti-tumor necrosis factor treatment for rheumatoid arthritis is discussed. This association has been reported in the nonradiological literature, but is an important association for radiologists to be aware of, as they may be in a position to first suggest the diagnosis.

Thomson, T. D. and W. J. Taylor (2005). "Evidence for inpatient rehabilitation as an effective intervention." Hosp Med 66(4): 200-4.

            Rehabilitation in inpatient settings is expensive and staff-intensive. It is necessary for such services to demonstrate effectiveness to justify this. In contrast to popular notions, evidence for the effectiveness of inpatient rehabilitation does exist and is reviewed in this article. In particular, there is very good evidence for specialized inpatient stroke care and rehabilitation.

Thompson, A. J. (2005). "Neurorehabilitation in multiple sclerosis: foundations, facts and fiction." Curr Opin Neurol 18(3): 267-71.

            PURPOSE OF REVIEW: This review of recent work in the area of neurorehabilitation of multiple sclerosis patients surveys progress and underscores the need for further work to evaluate the effectiveness of treatments. RECENT FINDINGS: Several recent review documents have summarized the current position regarding neurorehabilitation and symptomatic management in multiple sclerosis. They have highlighted the paucity of evidence underpinning current practice, thereby identifying the need for more scientifically sound studies in both neurorehabilitation and symptomatic treatment. However, as will be apparent from this review, there has been a welcome increase in studies evaluating both aspects of neurorehabilitation and specific areas such as the role of cannabinoids in spasticity and pain and new treatments for cognitive impairment. SUMMARY: Overall, there is an encouraging trend both in questioning our current practice and in designing more scientifically sound trials incorporating new and more appropriate outcome measures. There is, however, much more to be done before we are in a position to provide the expert, comprehensive, joined-up, care that is required to meet the complex, ever-changing needs of patients with multiple sclerosis.

Thaut, M. H., D. A. Peterson, et al. (2005). "Temporal entrainment of cognitive functions: musical mnemonics induce brain plasticity and oscillatory synchrony in neural networks underlying memory." Ann N Y Acad Sci 1060: 243-54.

            In a series of experiments, we have begun to investigate the effect of music as a mnemonic device on learning and memory and the underlying plasticity of oscillatory neural networks. We used verbal learning and memory tests (standardized word lists, AVLT) in conjunction with electroencephalographic analysis to determine differences between verbal learning in either a spoken or musical (verbal materials as song lyrics) modality. In healthy adults, learning in both the spoken and music condition was associated with significant increases in oscillatory synchrony across all frequency bands. A significant difference between the spoken and music condition emerged in the cortical topography of the learning-related synchronization. When using EEG measures as predictors during learning for subsequent successful memory recall, significantly increased coherence (phase-locked synchronization) within and between oscillatory brain networks emerged for music in alpha and gamma bands. In a similar study with multiple sclerosis patients, superior learning and memory was shown in the music condition when controlled for word order recall, and subjects were instructed to sing back the word lists. Also, the music condition was associated with a significant power increase in the low-alpha band in bilateral frontal networks, indicating increased neuronal synchronization. Musical learning may access compensatory pathways for memory functions during compromised PFC functions associated with learning and recall. Music learning may also confer a neurophysiological advantage through the stronger synchronization of the neuronal cell assemblies underlying verbal learning and memory. Collectively our data provide evidence that melodic-rhythmic templates as temporal structures in music may drive internal rhythm formation in recurrent cortical networks involved in learning and memory.

Thakur, G. A., S. P. Nikas, et al. (2005). "CB1 cannabinoid receptor ligands." Mini Rev Med Chem 5(7): 631-40.

            The CB1 receptor is expressed in the central nervous system and numerous other tissues including heart, lung and uterus and has been recognized as an important therapeutic target for pain, appetite modulation, glaucoma, multiple sclerosis and other indications. An interesting feature of this GPCR is its ability to be activated by a number of structurally different classes of compounds, thus, raising the possibility of multiple activated forms of the receptor. Understanding of the structure-activity relationships of cannabinergic ligands has paved the road for the development of novel ligands exhibiting receptor subtype selectivity and efficacy. This review highlights the important CB1 cannabinergic ligands developed to date.

Teunissen, C. E., M. P. van Boxtel, et al. (2005). "Homocysteine in relation to cognitive performance in pathological and non-pathological conditions." Clin Chem Lab Med 43(10): 1089-95.

            Elevated serum homocysteine has been associated with increased risk of Alzheimer's disease. Furthermore, elevated homocysteine levels are related to cognitive dysfunction in the elderly. The aim of the present study was to explore the disease specificity of the relation between serum total homocysteine levels and cognitive function. For this, we summarize data from several studies on homocysteine levels in both normal and pathological conditions performed in our laboratories and evaluate possible mechanisms of effects of elevated homocysteine levels in the central nervous system. Total homocysteine levels were measured in serum of: 1) healthy aging individuals; 2) patients with Alzheimer's and Parkinson's disease and patients with other cognitive disorders; and 3) patients with multiple sclerosis. Increased serum homocysteine concentration was related to worse cognitive performance over a 6-year period in the normal aging population (r=-0.36 to -0.14, p<0.01 for the Word learning tests; r=0.76, p<0.05 for the Stroop Colored Word test). Homocysteine was only increased in patients with Parkinson's disease on L-Dopa therapy (18.9 vs. 16.5 micromol/L in healthy controls), and not in dementia patients. Homocysteine was elevated in patients with progressive multiple sclerosis (15.0 micromol/L, n=39, compared to 12.0 micromol/L in 45 controls) and correlated to both cognitive and motor function (r=-0.33 and -0.33, p<0.05, respectively). The relationship between homocysteine and cognitive function in non-pathological and pathological situations indicates that changes in its levels may play a role in cognitive functioning in a broad spectrum of conditions.

Tepavcevic, V. and W. F. Blakemore (2005). "Glial grafting for demyelinating disease." Philos Trans R Soc Lond B Biol Sci 360(1461): 1775-95.

            Remyelination of demyelinated central nervous system (CNS) axons is considered as a potential treatment for multiple sclerosis, and it has been achieved in experimental models of demyelination by transplantation of pro-myelinating cells. However, the experiments undertaken have not addressed the need for tissue-type matching in order to achieve graft-mediated remyelination since they were performed in conditions in which the chance for graft rejection was minimized. This article focuses on the factors determining survival of allogeneic oligodendrocyte lineage cells and their contribution to the remyelination of demyelinating CNS lesions. The immune status of the CNS as well as the suitability of different models of demyelination for graft rejection studies are discussed, and ways of enhancing allogeneic oligodendrocyte-mediated remyelination are presented. Finally, the effects of glial graft rejection on host remyelination are described, highlighting the potential benefits of the acute CNS inflammatory response for myelin repair.

Tench, C. R., P. S. Morgan, et al. (2005). "Spinal cord imaging in multiple sclerosis." J Neuroimaging 15(4 Suppl): 94S-102S.

            Multiple sclerosis (MS) is a chronic neurological condition characterized pathologically by axonal loss, demyelination, inflammation, and gliosis. Magnetic resonance imaging (MRI) has had a major impact on diagnosing MS, understanding the condition, and monitoring the effects of treatments. Recently, spinal cord MRI has received increased attention. Advanced techniques have been used to image the spinal cord, particularly the cervical cord, and measure quantitative parameters such as T1 relaxation time, magnetization transfer ratio, and diffusivity. These metrics show central nervous system abnormalities in MS patients and various correlations with disability and might reflect specific pathological processes. Image analysis techniques have also been developed and combined with high-resolution MRI to measure the cord cross-sectional area (CSA), a metric that relates to cord atrophy. The cord CSA is reduced in MS patients compared to normal controls and correlates with disability. Furthermore, changes in CSA are detectable and correlate with changes in disability. Despite the technical difficulties of performing spinal cord MRI, imaging studies, particularly of the cervical cord, are becoming more common. Significant focus has been placed on measuring cord atrophy, and reproducible techniques have been developed to measure the cervical cord CSA. Spinal cord MRI may provide information about disease progression that is not readily available from brain MRI scans and could be useful in diagnosing MS in some cases, as well as for monitoring the effects of treatments.

Tedeschi, G. and A. Gallo (2005). "Multiple sclerosis patients and immunomodulation therapies: the potential role of new MRI techniques to assess responders versus non-responders." Neurol Sci 26 Suppl 4: S209-12.

            Disease-modifying drugs (DMD) are effective in reducing relapses and magnetic resonance imaging (MRI) lesions in multiple sclerosis (MS). Nevertheless, individual treatment responses are variable, and accurate and reliable methods to identify DMD responsiveness have not been validated. Although extremely relevant in the study and management of MS, MRI data have not been systematically tested to answer this question yet. Here we present non-conventional MRI data, including magnetisation transfer imaging (MTI), diffusion-weighted imaging (DWI) and proton magnetic resonance spectroscopy ((1)HMRS). As these techniques are more sensitive to microstructural tissue changes and more specific for the heterogeneous pathological substrates of MS lesions, we anticipate their potential role for detecting relevant changes of tissue pathology during treatment of MS patients and, consequently, for a better definition of response status to therapy.

Teare, L. and J. Zajicek (2005). "The use of cannabinoids in multiple sclerosis." Expert Opin Investig Drugs 14(7): 859-69.

            Naturally occurring cannabinoids including Delta9-tetrahydrocannabinol and cannabidiol as well as endocannabinoids and synthetic cannabinoids may have a role in modulating experimental models of multiple sclerosis. Recent clinical studies to treat symptoms of multiple sclerosis have shown varying results, which may reflect issues relating to the way in which such studies were conducted. There is now increasing interest in the potential role of cannabinoids not only in symptom relief, but also for their possible neuroprotective actions.

t Hart, B. A., J. Bauer, et al. (2005). "Non-human primate models of experimental autoimmune encephalomyelitis: Variations on a theme." J Neuroimmunol 168(1-2): 1-12.

            Despite years of intensive research into multiple sclerosis (MS) scientists have not yet succeeded in developing an absolute therapy for the treatment of this disabling disease of the human central nervous system. The wide immunological gap between inbred rodent strains and the heterogeneous human population is probably the single most important factor that hampers the translation of scientific principles developed in rodents into effective therapies for MS. Because of the closer immunological proximity to humans, non-human primates provide useful experimental models that may help to bridge this gap. Here we review the models of experimental autoimmune encephalomyelitis in rhesus macaques and common marmosets. We will discuss the salient points of the models and suggest how these may represent the spectrum of inflammatory demyelinating diseases of the central nervous system in humans.

t Hart, B. A. and K. Heije (2005). "Broad spectrum immune monitoring in immune-mediated inflammatory disorders." Drug Discov Today 10(20): 1348-51.

Szczepanik, M., M. Tutaj, et al. (2005). "[Experimental methods in the treatment of multiple sclerosis--new possibilities and hopes]." Przegl Lek 62(2): 115-8.

            Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelinization. Although our knowledge on the pathomechanism of MS has evolved dramatically in recent years; however there is still no effective cure for MS. So far, non-specific immune suppressive agents are used to slow down the disease. Recently, there are many efforts to find a new method that would allow to control specifically unwanted immune response. It might be achieved by affecting antigen recognition or induction of "immune deviation".

Sykes, M. and B. Nikolic (2005). "Treatment of severe autoimmune disease by stem-cell transplantation." Nature 435(7042): 620-7.

            Transplantation of haematopoietic stem cells--cells capable of self renewing and reconstituting all types of blood cell--can treat numerous lethal diseases, including leukaemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis. Studies in animal models show that the transfer of haematopoietic stem cells can reverse autoimmunity, and several mechanistic pathways may explain this phenomenon. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.

Suchkov, S. V., Z. S. Alekberova, et al. (2005). "[Achievements and prospects of clinical abzymology]." Vestn Ross Akad Med Nauk(9): 38-43.

            Catalytic autoantibodies (abzymes) are autoantibodies that are potentially ready to realize certain effects in the organism, first of all antibody-mediated catalysis and cytotoxicity. Natural abzymes with protolytic (protabzymes) and DNA-hydrolyzing DNA-abzymes) activity are of the greatest interest. The most impressive example of the catalytic activity of protabzymes is hydrolysis of specific proteins, revealed in patients with autoimmune diseases, such as bronchial asthma (vasoactive intestinal neuropeptide), autoimmune thyroiditis (thyroglobulin), multiple sclerosis (myelin basic protein), and autoimmune myocarditis (cardiomyosin). The pathogenic role of DNA-abzymes is not quite clear yet. However, it has been proven that they present a powerful regulator of apoptosis and other cytotoxicity mechanisms in systemic autoimmune diseases and tumors. The most promising is use of abzymes as illness activity markers, and as therapeutic agents capable of catalyzing specific proteins or activating antitumoral chemotherapeutic preparations.

Suarez Alvarez, L., G. R. Hughes, et al. (2005). "[Neurological manifestations of the antiphospholipid syndrome]." Med Clin (Barc) 124(16): 630-3.

            Antiphospholipid syndrome can be associated with several neurological manifestations. The most common symptom is headache. It has also been associated with cognitive dysfunction, probably due to ischemia. A high prevalence of antiphospholipid antibodies has been found in patients with epilepsy and in transverse myelitis. The most common thrombotic manifestation is stroke. Venous thrombosis can also be found, yet it is less frequent. A stroke in a young person obliges to rule out the antiphospholipid syndrome. The neurological manifestations can mimic multiple sclerosis. Thus, determination of antiphospholipid antibodies is recommended in the study of patients with atypical manifestations of multiple sclerosis. Other manifestations associated with antiphospholipid antibodies include chorea, neurosensorial deafness, Guillain-Barre syndrome, and psychotic disorders.

Stys, P. K. (2005). "General mechanisms of axonal damage and its prevention." J Neurol Sci 233(1-2): 3-13.

            Axonal degeneration is a prominent pathological feature in multiple sclerosis observed over a century ago. The gradual loss of axons is thought to underlie irreversible clinical deficits in this disease. The precise mechanisms of axonopathy are poorly understood, but likely involve excess accumulation of Ca ions. In healthy fibers, ATP-dependent pumps support homeostasis of ionic gradients. When energy supply is limited, either due to inadequate delivery (e.g., ischemia, mitochondrial dysfunction) and/or excessive utilization (e.g., conduction along demyelinated axons), ion gradients break down, unleashing a variety of aberrant cascades, ultimately leading to Ca overload. During Na pump dysfunction, Na can enter axons through non-inactivating Na channels, promoting axonal Na overload and depolarization by allowing K egress. This will gate voltage-sensitive Ca channels and stimulate reverse Na-Ca exchange, leading to further Ca entry. Energy failure will also promote Ca release from intracellular stores. Neurotransmitters such as glutamate can be released by reverse operation of Na-dependent transporters, in turn activating a variety of ionotropic and metabotropic receptors, further exacerbating overload of cellular Ca. Together, this Ca overload will inappropriately stimulate a variety of Ca-dependent enzyme systems (e.g., calpains, phospholipases), leading to structural and functional axonal injury. Pharmacological interruption at key points in these interrelated injury cascades (e.g., at voltage-gated Na channels or AMPA receptors) may confer significant neuroprotection to compromised central axons and supporting glia. Such agents may represent attractive adjuncts to currently available immunomodulatory therapies.

Strupp, M. and T. Brandt (2005). "[Neurology--current treatment concepts]." Dtsch Med Wochenschr 130(25-26): 1536-9.

Strong, M. J., S. Kesavapany, et al. (2005). "The pathobiology of amyotrophic lateral sclerosis: a proteinopathy?" J Neuropathol Exp Neurol 64(8): 649-64.

            Amyotrophic lateral sclerosis (ALS) is increasingly considered to be a disorder of multiple etiologies that have in common progressive degeneration of both upper and lower motor neurons, ultimately giving rise to a relentless loss of muscle function. This progressive degeneration is associated with heightened levels of oxidative injury, excitotoxicity, and mitochondrial dysfunction--all occurring concurrently. In this article, we review the evidence that suggests, in common with other age-dependent neurodegenerative disorders, that ALS can be considered a disorder of protein aggregation. Morphologically, this is evident as Bunina bodies, ubiquitin-immunoreactive fibrils or aggregates, neurofilamentous aggregates, mutant copper/zinc superoxide dismutase (SOD1) aggregates in familial ALS variants harboring mutations in SOD1, peripherin-immunoreactive aggregates within spinal motor neurons and as neuroaxonal spheroids, and in an increasingly greater population of patients with ALS with cognitive impairment, both intra- and extraneuronal tau aggregates. We review the evidence that somatotopically specific patterns of altered kinase and phosphatase activity are associated with alterations in the phosphorylation state of these proteins, altering either solubility or assembly characteristics. The role of nonneuronal cells in mediating motor neuronal injury is discussed in the context of alterations in tyrosine kinase activity and enhanced protein phosphorylation.

Stewart, T. M. and A. C. Bowling (2005). "Polyunsaturated fatty acid supplementation in MS." Int MS J 12(3): 88-93.

            This article focuses on polyunsaturated fatty acid (PUFA) supplementation, which is a popular form of complementary and alternative therapy among people with MS. Owing to their popularity, clinicians should be knowledgeable about the PUFA supplements that are widely available, and the efficacy and safety data from clinical studies. Small-scale studies have demonstrated trends towards some beneficial effects. PUFA supplementation is generally well tolerated, although some specific supplements are best avoided and some clinical situations warrant caution. A review of the efficacy and safety data suggests that PUFA supplementation may be a promising approach. Large-scale trials are required to confirm the benefits.

Steultjens, E. M., J. Dekker, et al. (2005). "Evidence of the efficacy of occupational therapy in different conditions: an overview of systematic reviews." Clin Rehabil 19(3): 247-54.

            OBJECTIVE: To summarize the research evidence available from systematic reviews of the efficacy of occupational therapy (OT) for practitioners, researchers, purchasing organizations and policy-makers. DATA SOURCE: The search for systematic reviews was conducted in PubMed and the Cochrane Library (October 2004). METHODS: The reviews included were those that utilized a systematic search for evidence with regard to OT for specific patient groups. Data were summarized for patient group, interventions, outcome domains, type of study designs included, method of data synthesis and conclusions. RESULTS: Fourteen systematic reviews were included. Three reviews related to rheumatoid arthritis, four reviewed stroke and four focused on elderly people. Reviews of Parkinson's disease, multiple sclerosis, Huntington's disease, cerebral palsy and mental illnesses were also identified. The reviews of rheumatoid arthritis, stroke and elderly people showed evidence of the efficacy of OT in increasing functional abilities. Positive results were presented for quality of life and social participation in elderly people and stroke respectively. The efficacy of OT in all other patient groups is unknown due to insufficient evidence. CONCLUSION: This summary shows that elderly people and people with stroke or rheumatoid arthritis can expect to benefit from comprehensive OT. Evidence of the efficacy of specific interventions is sparse and should be addressed in future research. The evidence that does exist should be incorporated into OT practice.

Stepien, K., M. Tomaszewski, et al. (2005). "Neuroprotective properties of statins." Pharmacol Rep 57(5): 561-9.

            Treatment with statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) reduces the risk of ischemic stroke among patients with increased risk of vascular disease. Recent experimental data point to neuroprotective properties of statins in acute cerebral ischemia. There is a proven link between bioavailability of nitric oxide and the activity of statins and ischemic stroke. Due to their ability to up-regulate nitric oxide synthase, statins have been considered in the therapy of a number of the central nervous system disorders, including cerebral ischemia, Alzheimer's disease, Parkinson's disease, tumors, and trauma. It has been claimed that they suppress inflammatory response and secondary injury after acute ischemia.

Steinman, L. (2005). "Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab." Nat Rev Drug Discov 4(6): 510-8.

            Immunologists have long hypothesized that particular 'molecular addresses' govern lymphocyte entry to a given organ. In 1992, alpha4beta1 integrin was identified as the key molecule involved in homing to inflamed regions of the brain. An antibody to alpha4beta1integrin blocked paralysis in an animal model of multiple sclerosis, and the humanized monoclonal antibody natalizumab, which binds alpha4beta1 integrin, reduced relapses 66% in clinical trials in multiple sclerosis. Three months after its expedited approval by the FDA, natalizumab was removed from the market after two cases of deadly progressive multifocal leukoencephalopathy were reported among the few thousand patients who had taken this drug in those clinical trials.

Steinman, L. and S. S. Zamvil (2005). "Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis." Trends Immunol 26(11): 565-71.

            Experimental autoimmune encephalomyelitis (EAE) is a useful model for aiding the development of new treatments for MS. All therapies approved for MS ameliorate EAE. Two approved medications, glatiramer acetate and Natalizumab, were developed directly from studies in EAE. Several trials are ongoing in MS after success in EAE, including altered peptide ligands of myelin, DNA vaccines and statins. However, EAE has failed to predict the outcome of certain approaches. The reasons underlying such failures are discussed here.

Steinman, L., P. J. Utz, et al. (2005). "Suppression of autoimmunity via microbial mimics of altered peptide ligands." Curr Top Microbiol Immunol 296: 55-63.

            Molecular mimics of self-antigens can behave as altered peptide ligands and serve to ameliorate autoimmune disease. Analysis of experimental autoimmune encephalomyelitis with proteomic autoantibody microarrays reveals that there might exist a wide variety of microbes with features that mimic self-epitopes. Autoimmunity could therefore be modulated via microbial immunity, which may account for relapse and remission of ongoing disease.

Steck, A. J. (2005). "[Use of intravenous immunoglobulin in neurological disorders]." Rev Med Suisse 1(17): 1167-70.

            The use of intravenous immunglobulin in the treatment of Guillain-Barre-Syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathies is well established. Other conditions, such as dysglobulinemic neuropathy, myasthenia gravis, multiple sclerosis and inclusion body myositis may also benefit from the administration of intravenous immunoglobulins.

Stangel, M. and R. Gold (2005). "[High-dose intravenous immunoglobulins in the treatment of multiple sclerosis. An update]." Nervenarzt 76(10): 1267, 1269-70, 1272.

            The immunomodulatory treatment of multiple sclerosis (MS) with high-dose intravenous immunoglobulins (IVIg) has been discussed with some controversy in the context of evidence-based medicine. The recent publication of eight trials investigating several aspects of MS has shed some more light on the role of IVIg treatment in MS. Here we summarize and critically discuss the new data in the context of previous studies on this treatment. In relapsing-remitting MS, IVIg remain a second-line treatment when other licensed treatments are not possible. Currently there is no role for IVIg in secondary progressive MS. Similarly, the use of IVIg during an acute relapse shows no benefit in addition to standard steroid treatment. The initiation of IVIg therapy after a clinically isolated syndrome has delayed the occurrence of definite MS, and this may become a new indication. Furthermore, previous data suggesting that IVIg can reduce the incidence of postpartal relapses have been substantiated. However, those trials unfortunately lack appropriate internal control groups. By and large, previous recommendations for the use of IVIg in MS are supported by the new data.

Sriram, S. and I. Steiner (2005). "Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis." Ann Neurol 58(6): 939-45.

            Despite many years of intensive research, multiple sclerosis (MS) defies understanding and treatment remains suboptimal. The prevailing hypothesis is that MS is immune mediated and that experimental allergic encephalomyelitis (EAE) is a suitable model to elucidate pathogenesis and devise therapy. This review examines critically the validity that EAE is an adequate and useful animal model of MS and finds credible evidence lacking. EAE represents more a model of acute central nervous system inflammation than the counterpart of MS. We propose to reconsider the utilization of EAE, especially when this model is used to define therapy. This will also force us to examine MS without the restraints imposed by EAE, as to what it is, rather than what it looks like.

Spitsberg, V. L. (2005). "Invited review: Bovine milk fat globule membrane as a potential nutraceutical." J Dairy Sci 88(7): 2289-94.

            For the last 15 yr, a great deal of knowledge has been accumulated on health beneficial factors, protein and nonprotein, of bovine milk fat globule membrane (MFGM). Among the health-beneficial components of the MFGM are cholesterolemia-lowering factor, inhibitors of cancer cell growth, vitamin binders, inhibitor of Helicobacter pylori, inhibitor of beta-glucuronidase of the intestinal Escherichia coli, xanthine oxidase as a bactericidal agent, butyrophilin as a possible suppressor of multiple sclerosis, and phospholipids as agents against colon cancer, gastrointestinal pathogens, Alzheimer's disease, depression, and stress. All of the above compel us to consider bovine MFGM as a potential nutraceutical.

Sospedra, M. and R. Martin (2005). "Immunology of multiple sclerosis." Annu Rev Immunol 23: 683-747.

            Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.

Sospedra, M. and R. Martin (2005). "Antigen-specific therapies in multiple sclerosis." Int Rev Immunol 24(5-6): 393-413.

            During recent years, many new therapies for human autoimmune diseases such as multiple sclerosis (MS) have been considered based on promising in vitro data or animal experiments. A number of them have proceeded to early clinical testing. However, very few finally advanced to approval by the regulatory agencies and are currently available to patients. The main reasons for failure were either lack of efficacy in humans and/or unexpected and untolerable adverse events. Although previous attempts toward antigen-specific immunomodulation have often been disappointing, these difficulties have led to renewed interest in therapies that aim at reestablishing tolerance to autoantigens at the level of either T cell-mediated or antibody-mediated immune responses or both. Such antigen-specific immunotherapies offer the prospect of correcting pathological immune reactivity against autoantigens in a highly specific and effective manner and also achievement of this goal with relatively little side effects. Here we will review the various approaches that are currently being considered for antigen-specific immunotherapies in MS.

Sorensen, P. S., F. Deisenhammer, et al. (2005). "Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis." Eur J Neurol 12(11): 817-27.

            Therapy-induced binding and neutralizing antibodies is a major problem in interferon (IFN)-beta treatment of multiple sclerosis. The objective of this study was to provide guidelines outlining the methods and clinical use of the measurements of binding and neutralizing antibodies. Systematic search of the Medline database for available publications on binding and neutralizing antibodies was undertaken. Appropriate publications were reviewed by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. Measurements of binding antibodies are recommended for IFN-beta antibody screening before performing a neutralizing antibody (NAB) assay (Level A recommendation). Measurement of NABs should be performed in specialized laboratories with a validated cytopathic effect assay or MxA production assay using serial dilution of the test sera. The NAB titre should be calculated using the Kawade formula (Level A recommendation). Tests for the presence of NABs should be performed in all patients at 12 and 24 months of therapy (Level A recommendation). In patients who remain NAB-negative during this period measurements of NABs can be discontinued (Level B recommendation). In patient with NABs, measurements should be repeated, and therapy with IFN-beta should be discontinued in patients with high titres of NABs sustained at repeated measurements with 3- to 6-month intervals (Level A recommendation).

Solari, A. (2005). "Role of health-related quality of life measures in the routine care of people with multiple sclerosis." Health Qual Life Outcomes 3: 16.

            Health-related quality of life instruments are expected to be of particular value in routine care of people with multiple sclerosis (MS), where they may facilitate the detection of disease aspects that would otherwise go unrecognised, help clinicians appreciate patient priorities particularly in terms of treatment goals, facilitate physician-patient communication, and promote shared decision-making. However, it appears that these instruments are little used routine clinical approaches to people with MS. To address this issue, I performed a bibliographic search of studies that evaluated the efficacy of generic or disease-specific health-related quality of life (HRQOL) instruments in MS clinical practice from clinicians' or patients' perspectives. I found only one cross-sectional study, which compared preferences for three instruments, and assessed acceptability in people with MS.Reasons for lack of transfer of HRQOL measurements to clinical practice may be cultural, methodological, or practical. With regard to MS, the proliferation of instruments seems to constitute a barrier, with no particular instrument having gained wide popularity or consensus. Other barriers are lack of resources for the administration, collection and storage of the data, and inability of clinicians to score, interpret, and use HRQOL instrument to guide clinical care. It is therefore important to refine existing tools, extending clinical validation to wider contexts and cultures. More studies assessing acceptability and clinicians' and patients' preferences for different instruments are also required.

Solanky, M., D. Van Engel, et al. (2005). "Aggressive central nervous system demyelination in an adolescent." Rev Neurol Dis 2(1): 35-8.

            A 15-year-old boy diagnosed with a severe, active, and aggressive form of multiple sclerosis (MS) failed conventional, evidence-based therapy. The optimal treatment of the child or adolescent failing federally approved therapy for MS is unclear, similar to the situation in adults. This case history demonstrates that aggressive immunosuppression might be of at least short-term value in controlling disease acutely in an adolescent, as in adults with MS, when evidence-based therapies do not provide an adequate response.

Sobel, R. M., S. Lotkowski, et al. (2005). "Update on depression in neurologic illness: stroke, epilepsy, and multiple sclerosis." Curr Psychiatry Rep 7(5): 396-403.

            The risk of depression is increased in chronic neurologic illness and can adversely affect the course of disease. Recent literature is reviewed for depression in stroke, epilepsy, and multiple sclerosis. Depression can share pathophysiologic aspects of the comorbid illness, such as neurotransmitter pathway disturbances, hypothalamus-pituitary-adrenal pathway disturbances, and changes in immunologic function. Depression also can be a psychologic reaction to the burden of the neurologic condition. Risk factors for development of depression are reviewed. Depression and other medical conditions can have shared symptoms (eg, fatigue, psychomotor retardation) that can complicate the diagnosis of depression in neurologic illness. Proper selection of antidepressant treatment is necessary to avoid worsening the neurologic disorder.

Smith, P. F. (2005). "The safety of cannabinoids for the treatment of multiple sclerosis." Expert Opin Drug Saf 4(3): 443-56.

            The evidence for the therapeutic efficacy of cannabinoids in the treatment of multiple sclerosis (MS) is increasing but is not as yet convincing. Although several trials have reported no significant effect, the majority of the evidence which supports a beneficial effect on spasticity and pain is based on subjective measurements in trials where unblinding was likely to be a problem. The available clinical trial data suggest that the adverse side effects associated with using cannabis-based medicinal extracts (CBMEs) are generally mild, such as dry mouth, dizziness, somnolence, nausea and intoxication, and in no case did toxicity develop. However, most of these trials were run over a period of months and it is possible that other adverse side effects, not seen in these short-term studies, could develop with long-term use. Despite the evidence that cannabinoids can disrupt cognitive function and promote depression, on the basis of current data, such adverse effects seem unlikely to be associated with the use of CBMEs. Likewise, there is no evidence to suggest that their effects on balance and motor control, or immune function, may be clinically significant. There is, however, reason to be concerned about the use of therapeutic cannabinoids by people predisposed to psychosis and by pregnant women, given the increasing evidence of their adverse effects on the fetus. In conclusion, given the modest therapeutic effects of cannabinoids demonstrated so far, and the risk of long-term adverse side effects, there is reason to be cautious about their use in the treatment of MS.

Sloka, J. S. and M. Stefanelli (2005). "The mechanism of action of methylprednisolone in the treatment of multiple sclerosis." Mult Scler 11(4): 425-32.

            Methylprednisolone plays an important role in the current treatment of multiple sclerosis (MS), particularly in the acute phase of relapse. It acts in various ways to decrease the inflammatory cycle including: dampening the inflammatory cytokine cascade, inhibiting the activation of T cells, decreasing the extravasation of immune cells into the central nervous system, facilitating the apoptosis of activated immune cells, and indirectly decreasing the cytotoxic effects of nitric oxide and tumor necrosis factor alpha. This paper reviews the most recent observations on these mechanisms both to understand the disease mechanism and its treatment. As more becomes known about these mechanisms, it may become possible to design treatment regimes that are more specific towards both the individual and the disease state.

Skundric, D. S. (2005). "Experimental models of relapsing-remitting multiple sclerosis: current concepts and perspective." Curr Neurovasc Res 2(4): 349-62.

            Multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE) are debilitating paralytic diseases caused by inflammation, demyelination and axonal degeneration of the central nervous system (CNS). Whilst the autoimmune nature of MS is strongly suggested by evidence of myelin specific autoreactive T cells and antibodies, EAE is an experimentally induced CNS specific autoimmune disease. As opposed to the majority of MS patients, which exhibit a relapsing-remitting course of the disease, only a handful of available EAE models displays relapsing-remitting course. In this review, we will summarize differences in regulation of acute and relapsing disease with emphasis on relapsing-remitting EAE models, and outline advantages and limitations of available relapsing EAE models pertinent for studies of relapsing human disease. We will discuss current concepts of relapse regulation by focusing on immune and molecular mechanisms of neuroinflammation, oligodendrocyte damage, myelin loss and axonal degeneration. This review will compare our present understanding of relapse regulation in human versus experimental autoimmune disease. Translation of mechanisms learned from relapsing EAE into development of new therapies for MS will be evaluated. Finally, perspectives in further optimization and development of more suitable experimental models to study human relapsing-remitting MS will be discussed.

Sipe, J. C. (2005). "Cladribine for multiple sclerosis: review and current status." Expert Rev Neurother 5(6): 721-7.

            In the 1990s, cladribine was developed as an adenosine deaminase-resistant nucleoside analog with selective lymphotoxic specificity in the hope that it might become useful in the treatment of some lymphoid neoplasms and autoimmune disorders. Several clinical trials demonstrated very significant effectiveness and safety of cladribine in the cure of hairy-cell leukemia, and the control of many other lymphoid malignancies. Cladribine was also extensively tested in selected autoimmune disorders, most notably in multiple sclerosis, with evidence of efficacy, tolerability and acceptable side effects/toxicity. The previous clinical studies and current status of cladribine for the treatment of multiple sclerosis are considered in this drug profile. In January 2005, Serono and IVAX announced plans to initiate a Phase III study of a specially formulated oral tablet of cladribine (Mylinax, Serono and IVAX) for the treatment of relapsing forms of multiple sclerosis. The proposed study will be the first large multicenter randomized controlled clinical trial of oral cladribine in multiple sclerosis.

Simon, J. H. (2005). "MRI in multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 383-409, viii.

            MRI provides multiple uses and applications in multiple sclerosis(MS). The basic features of the MRI-detected lesions, including the underlying pathology, are discussed. MRI allows assessment of the normal-appearing white and gray matter, and neuronal tract and functional system disturbances. An overview of the clinical significance of these MRI measures is included, as a basis for understanding their role as outcome measures in clinical trials. MRI recently assumed greater importance in its role in establishing an earlier diagnosis of MS after a first clinical event, and in monitoring subclinical disease before or subsequent to the formal diagnosis.The background to these applications and practical issues are discussed.

Simmons, D. L. (2005). "Anti-adhesion therapies." Curr Opin Pharmacol 5(4): 398-404.

            Cell adhesion molecules are key mediators of inflammatory processes and are attractive targets for discovery of novel therapeutics. There have been significant positive advances in both basic research and clinical development in this area. Basic research has yielded detailed insight into the structural basis of cell adhesion molecule function, especially the interaction of integrins with their ligands. Co-crystals of several integrin-ligand complexes have been published, including alpha v beta3 with ligand fragments, alpha IIb beta3 with multiple therapeutic ligands and alpha L beta2 (leukocyte function-associated antigen-1 [LFA-1]) with its cell-based ligand intercellular adhesion molecule-1. This has stimulated development of models of integrin function and also the mode of action of small-molecule inhibitors. The most exciting recent advances in the field of clinical development have come with the successful approval of two new anti-adhesion therapeutics: efalizumab (Raptiva) targeting LFA-1 for the treatment of chronic plaque psoriasis, and natalizumab (Tysabri/Antegren) targeting very late antigen-4 for the treatment of relapsing-remitting multiple sclerosis. However, the latter therapeutic ran into a surprising safety issue earlier this year and was withdrawn from the market, casting a shadow over what had seemed a promising new drug.

Siegert, R. J. and D. A. Abernethy (2005). "Depression in multiple sclerosis: a review." J Neurol Neurosurg Psychiatry 76(4): 469-75.

            Several studies have reported high rates of depression in multiple sclerosis (MS) with a lifetime prevalence of approximately 50% and an annual prevalence of 20% not uncommon. Concern about the potential of new drug treatments to exacerbate or precipitate depression in MS has led to increased interest in the relation between MS and depression. This review on MS and depression identifies the following key issues: How common is depression in people with MS? Is depression in MS associated with lesions in specific regions of the central nervous system? Is there an increased risk of suicide in MS? Is there a higher than expected incidence of anxiety disorders in MS? Are fatigue and depressed mood related in MS? Is there a relation between depression and cognitive impairment in MS? Which psychosocial variables affect the development of depression in MS? Does treatment with interferon increase the risk of depression? How effective are treatments for MS patients with depression? Each of these issues is briefly reviewed with critical commentary, and some priorities for future research are suggested.

Siddiqui, M. A. and K. Wellington (2005). "Intramuscular interferon-beta-1a: in patients at high risk of developing clinically definite multiple sclerosis." CNS Drugs 19(1): 55-61; discussion 63-4.

            Intramuscular interferon-beta-1a, a recombinant interferon-beta approved in the US for the treatment of relapsing forms of multiple sclerosis (MS), has also been evaluated in the treatment of patients with a first clinical demyelinating episode and brain lesions consistent with MS confirmed by magnetic resonance imaging (MRI). In a randomised, double-blind trial, patients at high risk of developing clinically definite MS who received intramuscular interferon-beta-1a 30 microg once weekly had a 44% reduction in the cumulative probability of developing MS, compared with placebo recipients (rate ratio 0.56; p = 0.002), over a 3-year period after a first, MRI-confirmed demyelinating event. These results were supported by MRI findings that showed significantly smaller increases in the volume of brain lesions and the number of new/enlarging and gadolinium-enhancing lesions in interferon-beta-1a recipients than in those receiving placebo. A nonblind extension of this trial demonstrated that early treatment with interferon-beta-1a significantly reduced the probability of developing MS by 35% (p = 0.03), compared with delayed treatment, over a 5-year period. Intramuscular interferon-beta-1a was generally well tolerated; however, influenza-like syndrome was documented in >50% of patients at high risk of developing clinically definite MS who received the drug.

Shternshis Iu, A., V. V. Sveranovskaia, et al. (2005). "[Epitope mimicry and its role in the development of autoimmune reactions]." Zh Mikrobiol Epidemiol Immunobiol(1): 96-100.

            The role of molecular mimicry in the development of some autoimmune diseases, such as rheumatism, rheumatoid arthritis, the Julian-Barre syndrome, the antiphospholipid syndrome, multiple sclerosis, is reviewed. The data on the presence in bacteria and viruses antigenic determinants similar to those in human tissues are presented. The phenomenon of epitope mimicry is considered in the light of the latest research in the field of IgE autoreactivity, which may take part in the pathogenesis of allergic diseases.

Sheremata, W. A., A. Minagar, et al. (2005). "The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications." CNS Drugs 19(11): 909-22.

            Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease.Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule alpha4beta1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS.Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market.The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy.

Shaw, P. J. (2005). "Molecular and cellular pathways of neurodegeneration in motor neurone disease." J Neurol Neurosurg Psychiatry 76(8): 1046-57.

            The process of neuronal degeneration in motor neurone disease is complex. Several genetic alterations may be involved in motor neurone injury in familial amyotrophic lateral sclerosis, less is known about the genetic and environmental factors involved in the commoner sporadic form of the disease. Most is known about the mechanisms of motor neurone degeneration in the subtype of disease caused by SOD1 mutations, but even here there appears to be a complex interplay between multiple pathogenic processes including oxidative stress, protein aggregation, mitochondrial dysfunction excitotoxicity, and impaired axonal transport. There is new evidence that non-neuronal cells in the vicinity of motor neurones may contribute to neuronal injury. The final demise of motor neurones is likely to involve a programmed cell death pathway resembling apoptosis.

Sergott, R. C. (2005). "Optical coherence tomography: measuring in-vivo axonal survival and neuroprotection in multiple sclerosis and optic neuritis." Curr Opin Ophthalmol 16(6): 346-50.

            PURPOSE OF REVIEW: This review considers the latest developments in the use of optical coherence tomography in neuro-ophthalmology. RECENT FINDINGS: Optical coherence tomography can accurately and reproducibly quantitate the micron thickness of the peripapillary retinal nerve fiber layer, as well as the thickness and volume of the macula. It is able to perform both cross-sectional and longitudinal studies in patients with multiple sclerosis and optic neuritis. It is able to measure and assess axonal preservation and protection when used in clinical trials. SUMMARY: Specific guidelines when undertaking optical coherence tomography analyses for patients with multiple sclerosis and optic neuritis are needed to ensure uniformity among clinical trials; this development would be similar to the parameters devised when magnetic resonance imaging emerged as an important technology.

Seifert, T., C. Enzinger, et al. (2005). "Relapsing acute transverse myelitis: a specific entity." Eur J Neurol 12(9): 681-4.

            Acute transverse myelitis (ATM) not related to systemic disease may present in a relapsing manner. Data in the literature about this condition are scarce. We describe three patients suffering from relapsing myelitis in whom no association with systemic disease, i.e. infectious or connective tissue disease was found. Magnetic resonance imaging (MRI) findings were also distinctly different from multiple sclerosis and consistent with a necrotizing type of inflammation. Despite various treatment strategies, all patients became severely disabled. Relapsing ATM not related to systemic disease appears to be a specific entity which accounts for severe disability and currently lacks effective treatment.

Scott, T. F., S. L. Kassab, et al. (2005). "Acute partial transverse myelitis with normal cerebral magnetic resonance imaging: transition rate to clinically definite multiple sclerosis." Mult Scler 11(4): 373-7.

            OBJECTIVE: To determine the long-term risk of developing clinically definite multiple sclerosis (CDMS) in patients with acute partial transverse myelitis (APTM) and normal cerebral magnetic resonance imaging (MRI) scans. METHODS: We retrospectively studied 30 consecutive patients with clinical evidence of APTM. Patients with symmetric severe acute transverse myelitis were considered to have complete transverse myelitis and were excluded. All patients underwent spinal and cerebral MRIs, 13 underwent cerebrospinal fluid analysis and 11 patients underwent evoked potential studies. Various other studies were performed to assess for connective tissue disease and causes of APTM other than demyelinating disease. RESULTS: After an average follow-up of 61 months, all laboratory and clinical evidence, including relapse history, indicated that three patients developed lesions on cerebral MRI and could be classified as CDMS by either Poser criteria (two patients) or MacDonald criteria (one patient). Relapses limited to the spinal cord seen clinically were seen in 14/30 (46.6%) patients. Oligoclonal bands were seen in 8/13 (62%) patients; one patient transitioned to CDMS. Unifocal lesions of the cord were seen in 19/30 (63%) patients, multifocal lesions were seen in 8/30 (27%) and 3/30 (10%) had negative MRIs. The three patients who converted to CDMS did so within five years of the onset of myelitis. CONCLUSION: APTM with normal cerebral MRI had a low rate of conversion to CDMS in this long-term study. To date, there have been only a few follow-up studies that have addressed this issue.

Schwarz, S. and H. Leweling (2005). "Multiple sclerosis and nutrition." Mult Scler 11(1): 24-32.

            Benefits from any particular diet in multiple sclerosis (MS) have not yet been proven. It is, however, frequent that malnutrition may potentially exacerbate the symptoms of MS. There is some evidence that a high intake of saturated fat increases the incidence of MS. Epidemiological studies imply that unsaturated fatty acids may have a positive effect on the course of MS. However, the results of controlled studies are ambiguous. A meta-analysis of three small controlled clinical trials suggests a benefit from linoleic acid. Intake of Vitamin D is associated with a lower incidence of MS. In MS, the risk of osteoporosis is high, and prophylactic vitamin D and calcium should be considered at an early stage. The role of minerals, trace elements, antioxidants, vitamins or fish oil is unclear. The possible relationships between diet and MS have not been subjected to adequate study. It seems possible that in the future, diets or dietary supplements may become recommended forms of treatment for MS.

Schwarz, S., H. Leweling, et al. (2005). "[Alternative and complementary therapies in multiple sclerosis]." Fortschr Neurol Psychiatr 73(8): 451-62.

            Most MS patients use unconventional therapies, usually as complementary measures in addition to the conventional treatment. Only a few adequate clinical trials exist in this field. By definition, the efficacy of these therapies is unproven. Moreover, the possible risks are also largely unknown. Some therapies rely on rational pathophysiological considerations, other must be regarded as potentially harmful. The influence of diet on MS is unproven. Possibly, unsaturated fatty acids are beneficial. However, a few randomized trials yielded inconclusive results. Long-term supplementation of Vitamin D is associated with a decreased MS incidence. There is, however, insufficient evidence for an influence of Vitamin D on the course of the disease. Because of the high prevalence of osteoporosis in MS patients, prophylaxis with Vitamin D and Calcium is widely accepted. The effects of various minerals, selenium, antioxidant compounds, fish oil or vitamins remain speculative. Many patients use cannabis to alleviate spasticity and pain. Small series indicated positive effects, but randomized trials were negative for spasticity. However, many patients report subjective improvement under cannabis even if their objective parameters remain unchanged. Hyperbaric oxygenation was the subject of several small studies with heterogeneous results which, overall, do not support its use. Generally, physical therapies are perceived as an established therapy for MS. Short-term effects are probable, whereas the possible favourable long-term effects are unclear.

Schwartz, M. and J. Kipnis (2005). "Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases." J Neurol Sci 233(1-2): 163-6.

            Autoimmune diseases are traditionally viewed as an outcome of a malfunctioning of the immune system, in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis (MS), a disease of the white matter of the central nervous system (CNS), the attack is directed against myelin proteins. In this article we summarize a paradigm shift proposed by us in the perception of autoimmune disease. Observations by our group indicating that an autoimmune response is the body's mechanism for coping with CNS damage led us to suggest that all individuals are apparently endowed with a purposeful autoimmune response to CNS injuries, but have only limited inherent ability to control this response so that its effect will be beneficial. In animals susceptible to autoimmune diseases, the same autoimmune T cells are responsible both for neuroprotection and for disease development; the timing and strength of their activity will determine which of these effects is expressed. Individuals with non-inflammatory neurodegenerative diseases need a heightened autoimmunity. We discovered that autoimmunity could be boosted without risk of disease induction, even in susceptible strains, by the use of Copolymer-1 (Copaxone(R)), a weak agonist of a wide range of self-reactive T cells. Here we summarize the basic findings that led us to formulate the concept of protective autoimmunity, the mechanisms underlying its constitutive presence and its on/off regulation, and its therapeutic implications. We also offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals.

Schulz, K. H. and C. Heesen (2005). "[Effects of exercise in chronically ill patients. Examples from oncology and neurology]." Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 48(8): 906-13.

            Epidemiologic studies increasingly have demonstrated a correlation between physical inactivity and certain chronic diseases. Already in the 1970s exercise programs for cardiovascular patients were established, whereas in other severe chronic illnesses such as breast cancer or multiple sclerosis exposure to physical stress seemed to be a contraindication. Today there is a grow ing body of evidence demonstrating positive physical as well as psychic effects of exercise training in patients with these diseases. These studies are summarized and complementary studies of our group are described in more detail. In patients with breast cancer we were able to demonstrate persistent psychosocial effects even 1 year after completion of the training program. In patients with multiple sclerosis we could confirm an induction of neurotrophic factors in trained individuals. Correspondingly, there is accumulating evidence showing positive effects of exercise on cognitive function, especially in the aged. Potential pathophysiological pathways regarding a progression to dementia are presented. Consequently exercise programs could play a pivotal role in the prevention and therapy of the cognitive decline in the aged in an aging society.

Schulz, K. H., C. Heesen, et al. (2005). "[The concept of allostasis and allostatic load: psychoneuroimmunological findings]." Psychother Psychosom Med Psychol 55(11): 452-61.

            Classical theories have conceptualized stress as a reaction to threat to the homeostasis within the organism requiring an adaptive response. However, postulating mechanisms that could link such responses to long-term detrimental health outcomes remains difficult. The allostatic load concept enables us to think about how mediators can be protective in the short run but may have damaging effects when overused and/or not shut off. It further facilitates the formulation of cause-effects cascades to explain the link of dysregulations in stress mediators such as glucocorticoids and catecholamines and increased susceptibility for certain diseases. In the first section, we briefly summarize the theoretical background. We then employ the concept to integrate findings from basic and clinical research on dysregulations of the stress response systems in multiple sclerosis and breast cancer. Based on this model, it seems likely that such dysregulations are implicated in progression and possibly pathogenesis of these diseases. When using allostatic load as a heuristic model, one needs to consider that stress mediators and outcomes are interconnected in a non-linear network.

Schroeter, M. and S. Jander (2005). "T-cell cytokines in injury-induced neural damage and repair." Neuromolecular Med 7(3): 183-95.

            T-cell cytokines are involved in beneficial immune responses, pathological autoimmunity, and tissue inflammation. In this review, we focus on the role of interferon-gamma, interleukin (IL)-2, IL-4, IL-6, and IL-10 in autoimmune diseases such as multiple sclerosis, and primarily "nonimmune" injury of the central nervous system (CNS), in particular focal ischemia and trauma. Resident CNS cells such as microglia and astroglia are additional, and on some occasions major, cellular sources of T-cell cytokines in CNS disease. Collectively, they mediate harmful as well as beneficial functions that depend on the dynamics, cellular source, and compartmental site of their release, the pathophysiological context, and the presence of coexpressed factors. Furthermore, direct neurotoxic and neuroprotective effects of cytokines are evident that are independent from their immunoregulating properties. Whereas these complex interactions are only beginning to be understood, T-cell cytokines nevertheless hold promise as therapeutic targets in a variety of neurological disease conditions.

Schreiner, B., B. C. Kieseier, et al. (2005). "[Blocking adhesion molecules with natalizumab in multiple sclerosis]." Nervenarzt 76(8): 999-1005.

            Natalizumab is a humanized, monoclonal antibody, that inhibits adhesion molecules (alpha(4)-integrins) on the surface of immune cells. These adhesion molecules are important for binding of lymphocytes to endothelial cells of blood vessels and infiltration of inflammatory cells into tissues. Natalizumab is currently being tested in large clinical trials for the treatment of multiple sclerosis (MS) and other autoimmune diseases (inflammatory bowel diseases, rheumatoid arthritis). After demonstrating the safety and potential effectiveness of natalizumab in MS therapy during shorter treatment periods (</=6 months) in clinical phase I and II studies, two ongoing large, double-blinded, placebo-controlled phase III trials (named AFFIRM and SENTINEL) are evaluating its efficacy for patients with relapsing-remitting MS in respect to primary clinical endpoints (relapse rate, disease progression). Based a 1-year interim analysis of these studies, natalizumab was recently authorized by the U.S. Food and Drug Administration for treatment in reducing the frequency of clinical surges in multiple sclerosis, and an application was also made for its use in Europe. After more than 2 years of combined natalizumab (Tysabri) and interferon beta-1a (Avonex) therapy in the so-called Sentinel Study, there was one unexpected death and one appearance of progressive multifocal leukoencephalopathy. As a result, in February 2005 the manufacturers (Biogen/Elan) stopped all running studies of natalizumab and removed the drug from the market. New studies are underway to gain more understanding and especially to determine the risk to patients treated in the Sentinel Study. This article summarizes and updates the results of previous and ongoing natalizumab trials in the context of MS.

Schofield, P. (2005). "Dementia associated with toxic causes and autoimmune disease." Int Psychogeriatr 17 Suppl 1: S129-47.

            Toxic causes of dementia include exposure to heavy metals such as lead, mercury and aluminum as well as to carbon monoxide and solvents. Autoimmune conditions include such entities as multiple sclerosis, systemic lupus erythematosus, Behcet's disease and Sjogren's syndrome. These conditions share broadly similar cognitive effects giving rise to impairments with subcortical features. Individuals are often affected at a relatively young age. Optimal preventative strategies include avoidance of toxic substances. Comprehensive neuropsychological assessment is valuable not only diagnostically and for monitoring but also to identify the patients' strengths and weaknesses, so that compensatory strategies can be recommended.

Schneider, U., J. Seifert, et al. (2005). "[The endogenous cannabinoid system. Therapeutic implications for neurologic and psychiatric disorders]." Nervenarzt 76(9): 1062, 1065-6, 1068-72 passim.

            For about 5,000 years, cannabis has been used as a therapeutic agent. There has been growing interest in the medical use of cannabinoids. This is based on the discovery that cannabinoids act with specific receptors (CB1 and CB2). CB1 receptors are located in specific brain areas (e.g. cerebellum, basal ganglia, and hippocampus) and CB2 receptors on cells of the immune system. Endogenous ligands of the cannabinoid receptors were also discovered (e.g. anandamids). Many physiologic processes are modulated by the two subtypes of cannabinoid receptor: motor functions, memory, appetite, and pain. These innovative neurobiologic/pharmacologic findings could possibly lead to the use of synthetic and natural cannabinoids as therapeutic agents in various areas. Until now, cannabinoids were used as antiemetic agents in chemotherapy-induced emesis and in patients with HIV-wasting syndrome. Evidence suggests that cannabinoids may prove useful in some other diseases, e.g. movement disorders such as Gilles de la Tourette's syndrome, multiple sclerosis, and pain. These new findings also explain the acute adverse effects following cannabis use.

Schneider, K. M. (2005). "AANA Journal course: update for nurse anesthetists--an overview of multiple sclerosis and implications for anesthesia." Aana J 73(3): 217-24.

            Multiple sclerosis is the most common demyelinating, chronic disease of the central nervous system diagnosed in and affecting young adults. This disease can significantly alter the life of affected people, and there is no known cure. It is important to understand and review this disease process because anesthesia providers are likely to encounter patients with multiple sclerosis in their practice. The purpose of this AANA Journal course is to present an overview of multiple sclerosis. The pathophysiologic features, symptoms, manifestations, diagnosis, and pharmacologic treatment are discussed, with a focus on the implications of multiple sclerosis for general and regional anesthesia.

Schmidt, E. Z., P. Hofmann, et al. (2005). "Sexuality in multiple sclerosis." J Neural Transm 112(9): 1201-11.

            Sexuality and partnership have an important influence on the quality of life of every person and also on people with chronic disorders such as multiple sclerosis. The findings in literature show high evidence that people with multiple sclerosis experience high levels of sexual dysfunction, most of them with hypoactive sexual behaviour often associated with dissatisfaction in relationship, and also the partners seem to show lower sexual and partnership satisfaction. The most common problems in women are lack of sexual interest and decreased libido, often with problems in orgasmic capacity, while men report erectile dysfunction and also lack of sexual interest. The impact of the level of disability and duration of the illness remains unclear. Positive familial support can often help the patient in coping with the illness, nonetheless problems with changing roles and multiple-sclerosis-minimizing can improve the need of contacts to outstanding persons.

Scherder, E., E. Wolters, et al. (2005). "Pain in Parkinson's disease and multiple sclerosis: its relation to the medial and lateral pain systems." Neurosci Biobehav Rev 29(7): 1047-56.

            Although pain is one of the major clinical symptoms of Parkinson's disease (PD) and multiple sclerosis (MS), it is often neglected and therefore undertreated. The question why the perception of pain in stages without cognitive impairment is not affected by the neuropathology has not been addressed so far. Furthermore, changes in the experience of pain as a result of cognitive impairment have not been clinically studied in PD and MS. These issues which are very relevant for pain assessment and treatment, will be addressed by discussing the neuropathology in the medial and lateral pain systems in cognitively intact versus cognitively impaired patients with PD and MS. Since there are no clinical studies that specifically address pain in cognitively impaired PD and MS patients, hypotheses will be generated about the impact of cognitive impairment on pain experience in these patients. These hypotheses should be a challenge for new research in this important but neglected area.

Scheinfeld, N. (2005). "Adalimumab: a review of side effects." Expert Opin Drug Saf 4(4): 637-41.

            Adalimumab (Humira) is a human monoclonal TNF-alpha antibody that blocks the effects of TNF-alpha. It is administered by subcutaneous injection. It has been approved alone or in combination with methotrexate for the treatment of rheumatoid arthritis in the EU and US. Approval for its use for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis is expected in the near future. Its side effect profile is favourable when compared with traditional systemic treatments for these diseases. It does not require laboratory monitoring. The most common side effects of adalimumab are injection site reactions. Adalimumab increases the risk of rare serious infections. There is a two-fold risk of serious infections with the use of adalimumab, as reported in the Premier trial. This risk should not be minimised in this way. It should not be used during periods of active infection. Its most notable infectious complication is the reactivation of tuberculosis. Tuberculosis screening should be according to country standards and may or may not include purified protein derivative test or chest X-ray. Deep fungal and other serious and atypical infection can also be promoted by adalimumab. It has been associated infrequently with skin rashes. Rare side effects include: worsening or initiation of congestive heart failure, a lupus-like syndrome, a promotion of lymphoma, medically significant cytopenias, and worsening or initiation of a multiple sclerosis/neurological disease. There has been reported pancytopenia and elevated transamines with the use of adalimumab, which suggest that laboratory monitoring blood counts and liver functions, at least intermittently, are useful. In patients with any of the foregoing problems, its use should be extremely carefully considered. Adalimumab is a useful medication which can be safely used if its side effects are recognised.

Schattner, A. (2005). "Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines." Vaccine 23(30): 3876-86.

            BACKGROUND: Viruses and virus-induced lymphokines may have an important role in the pathogenesis of autoimmunity (Schattner A. Clin Immunol Immunopathol; 1994). The occurrence and significance of autoimmune manifestations after the administration of viral vaccines remain controversial. METHODS: Medline search of all relevant publications from 1966 through June 2004 with special emphasis on search of each individual autoimmune manifestation and vaccination, as well as specifically searching each viral vaccine for all potential autoimmune syndromes reported. All relevant publications were retrieved and critically analyzed. RESULTS: The most frequently reported autoimmune manifestations for the various vaccinations, were: hepatitis A virus (HAV)--none; hepatitis B virus (HBV)--rheumatoid arthritis, reactive arthritis, vasculitis, encephalitis, neuropathy, thrombocytopenia; measles, mumps and rubella vaccine (MMR)--acute arthritis or arthralgia, chronic arthritis, thrombocytopenia; influenza--Guillain-Barre syndrome (GBS), vasculitis; polio--GBS; varicella--mainly neurological syndromes. Even these 'frequent' associations relate to a relatively small number of patients. Whenever controlled studies of autoimmunity following viral vaccines were undertaken, no evidence of an association was found. CONCLUSIONS: Very few patients may develop some autoimmune diseases following viral vaccination (in particular - arthropathy, vasculitis, neurological dysfunction and thrombocytopenia). For the overwhelming majority of people, vaccines are safe and no evidence linking viral vaccines with type 1 diabetes, multiple sclerosis (MS) or inflammatory bowel disease can be found.

Schapiro, R. T. (2005). "Managing symptoms of multiple sclerosis." Neurol Clin 23(1): 177-87, vii.

Scardi, S. and A. Cherubini (2005). "[Can we prevent the progression of aortic valve sclerosis and stenosis? The need for a prospective, randomized trial]." Ital Heart J Suppl 6(7): 403-12.

            Cardiologists long assumed that aortic valve sclerosis/stenosis is a wear-and-tear, degenerative process; recent studies suggested that lipoproteins can play a key role in the development of both sclerosis/stenosis in the aortic valve. Thus, sclerosis/stenosis cannot be considered as a simple degenerative process, but on the contrary it is complex and involves multiple pathogenetic mechanisms. Experimental, clinical and epidemiological data support the link between aortic valvulopathy and atherosclerosis: both are caused by inflammation, lipid deposition, and accumulation of extracellular bone matrix protein. In non-randomized clinical studies, hydroxy-methylglutaryl-coenzyme A reductase inhibitors minimized the progression of aortic valvulopathy. The major pharmacological effect, supposed to underlie the inferred (but still unproven) impact of statins on aortic sclerosis/stenosis is plasma cholesterol reduction. Lately, retrospective clinical studies supported this hypothesis and suggested a key role for statins in delaying the progression of aortic valvulopathy. However, the potential favorable effects of statins require confirmation. Prospective trials in Canada and Europe are now ongoing (ASTRONOMER--Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin; SEAS--Simvastatin and the Ezetimibe in Aortic Stenosis) and will address the use of cholesterol-lowering drugs in reducing the progression of aortic valve stenosis and in improving clinical outcomes.

Scalabrino, G. (2005). "Cobalamin (vitamin B(12)) in subacute combined degeneration and beyond: traditional interpretations and novel theories." Exp Neurol 192(2): 463-79.

            Subacute combined degeneration (SCD) is a neuropathy due to cobalamin (Cbl) (vitamin B(12)) deficiency acquired in adult age. Hitherto, the theories advanced to explain the pathogenesis of SCD have postulated a causal relationship between SCD lesions and the impairment of either or both of two Cbl-dependent reactions. We have identified a new experimental model, the totally gastrectomized rat, to reproduce the key morphological features of the disease [spongy vacuolation, intramyelinic and interstitial edema of the white matter of the central nervous system (CNS), and astrogliosis], and found new mechanisms responsible for the pathogenesis of SCD: the neuropathological lesions in TGX rats are not only due to mere vitamin withdrawal but also to the overproduction of the myelinolytic tumor necrosis factor (TNF)-alpha and the reduced synthesis of the two neurotrophic agents, epidermal growth factor (EGF) and interleukin-6. This deregulation of the balance between TNF-alpha and EGF synthesis induced by Cbl deficiency has been verified in the sera of patients with pernicious anemia (but not in those with iron-deficient anemia), and in the cerebrospinal fluid (CSF) of SCD patients. These new functions are not linked to the coenzyme functions of the vitamin, but it is still unknown whether they involve genetic or epigenetic mechanisms. Low Cbl levels have also been repeatedly observed in the sera and/or CSF of patients with Alzheimer's disease or multiple sclerosis, but whether Cbl deficit plays a role in the pathogenesis of these diseases is still unclear.

Sayre, L. M., P. I. Moreira, et al. (2005). "Metal ions and oxidative protein modification in neurological disease." Ann Ist Super Sanita 41(2): 143-64.

            This review highlights the role of oxidative stress and imbalances in metal ion homeostasis in the neurodegenerative diseases Alzheimer's disease and Parkinson's disease and in the progressive demyelinating disease multiple sclerosis. The chemistry and biochemistry of oxidative stress-induced protein damage are first described, followed by the evidence for a pathological role of oxidative stress in these disease states. It is tempting to speculate that free radical oxygen chemistry contributes to pathogenesis in all these conditions, though it is as yet undetermined what types of oxidative changes occur early in the disease, and what types are secondary manifestations of neuronal degeneration.

Saunamaki, T., R. Hanninen, et al. (2005). "[Neuropsychologic examination and rehabilitation of multiple sclerosis patients]." Duodecim 121(5): 537-44.

Sastre-Garriga, J., I. Galan-Cartana, et al. (2005). "[Neurorehabilitation in multiple sclerosis.]." Neurologia 20(5): 245-54.

            Neurorehabilitation is predominantly an educational, dynamic process based on the adaptation of the individual and his environment to the actual neurological impairment and focuses on decreasing the impact of disabling neurological conditions on the individual in order to achieve optimum quality of life. It has been suggested by some that neurorehabilitation is the only approach available to us which can improve the limitations in activity and restrictions in social participation of people with multiple sclerosis. The neurorehabilitation approach is a holistic one and is a fundamental part of neurological care; it should not be forgotten by neurologists, especially when dealing with people with chronic disabling conditions such as multiple sclerosis. Together with the social model of disability, the concept of restorative neurology, as a scientific and therapeutic attempt to minimize those impairments directly responsible for the disability presented by the person, is recently gaining ground among neuroscientists and clinicians. In this review the conceptual basis for neurorehabilitation will be presented together with a review of the literature concerning the biological aspects of neurorehabilitative therapy (neuroplasticity) and the clinical trials evaluating the effectiveness of neurorehabilitation in people with multiple sclerosis. Finally, we will consider the practical aspects of neurorehabilitation.

Sarlani, E., E. G. Grace, et al. (2005). "Trigeminal neuralgia in a patient with multiple sclerosis and chronic inflammatory demyelinating polyneuropathy." J Am Dent Assoc 136(4): 469-76.

            BACKGROUND: Trigeminal neuralgia (TN) is characterized by unilateral, severe, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Symptomatic or secondary TN involves TN-like pain that develops owing to a central nervous system lesion (benign or malignant) or to multiple sclerosis (MS). CASE DESCRIPTION: The authors present a report of a unique case of a 43-year-old patient with unilateral TN, MS and concomitant chronic inflammatory demyelinating polyneuropathy. The facial pain preceded any other manifestations of the systemic disorders, and only after repeated neurological examinations were these diagnoses established. CLINICAL IMPLICATIONS: Magnetic resonance imaging of the brain and repeated neurological evaluations should be implemented in all patients with TN to rule out the presence of underlying disease. The dental practitioner should be familiar with TN to avoid unnecessary dental interventions and ensure prompt initiation of appropriate treatment.

Sanders, S., C. Del Mar, et al. (2005). "Evidence in practice--number 8. What is the prognosis of optic neuritis? How often does it lead to multiple sclerosis?" Br J Gen Pract 55(521): 972-3.

Sandberg-Wollheim, M. (2005). "Interferon-beta1a treatment for multiple sclerosis." Expert Rev Neurother 5(1): 25-34.

            Although multiple sclerosis is probably the most common cause of neurologic disability in young adults, the cause is unknown, the prognosis uncertain and available treatments unsatisfactory. Multiple sclerosis is an inflammatory autoimmune disorder of the CNS and the result of both environmental factors and susceptibility genes. The prognosis is difficult or impossible to predict at the time of diagnosis. Treatments that modulate the course of the disease have only recently become available but the long-term aim to prevent disability and promote repair remains distant. Interferon-beta is the most widely used therapy. The efficacy of interferon-beta in the short term is well documented in many large treatment trials, but the treatment effects are only modest and many issues relating to efficacy in the long term are unresolved. These include uncertain benefit on conversion to secondary-progressive multiple sclerosis, the relevance of neutralizing antibodies and the controversial effect on multiple sclerosis-related brain atrophy.

Sandberg-Wollheim, M., D. Frank, et al. (2005). "Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis." Neurology 65(6): 802-6.

            BACKGROUND: Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment. METHODS: We examined individual patient data from eight clinical trials with IFNbeta-1a. RESULTS: Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNbeta-1a (in utero exposure group), 22 were patients who discontinued IFNbeta-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy). CONCLUSIONS: The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNbeta therapy before becoming pregnant.

Rzazewska-Makosa, B. (2005). "[The mechanism of glucocorticoid resistance in multiple sclerosis]." Postepy Hig Med Dosw (Online) 59: 457-63.

            Glucocorticoids (GCs) are used in the treatment of multiple sclerosis (MS) and other autoimmunological diseases due to their significant anti-inflammatory and immunosuppressive effects. In MS, GCs are mainly used in the treatment of clinical relapses. Most patients benefit from GCs, except for some who are resistant. These patients pose a serious clinical problem. GC resistance in MS has not been widely elaborated. Less than 5% of MS patients do not respond to GCs in the early phase of the disease, and these are considered as having primary resistance to GCs. There is also a group of patients who develop GC resistance later, after a good therapeutic response at the beginning of therapy. This secondary type of resistance is more common and may apply to as many as 30% of all patients. Primary GC resistance has a genetic origin and is associated with a mutation within the GR. The mechanisms of secondary GC resistance are more diverse. There is only one receptor for GCs, but it can occur in three isoforms: GR alpha, GR beta, and GR gamma. GR alpha secures the appropriate GC signaling transmission, whereas GR beta and gamma bind to GC, but prevent the GC/GR complex from DNA activation. Thus both these latter forms of GR inhibit GC activity. The beta and gamma isoforms of GR become more common in cells at the inflammatory foci. Another mechanism of secondary GC resistance depends on the induction of cytokines during inflammatory processes. Interleukins 2, 4, and 13 are overproduced and lead to the induction of transcriptional factor AP-1. AP-1 competes with the GC/GR complex for the binding site on DNA. In addition, IL-2 slows the transport of the GC/GR complex to cell nuclei. In assessing GC resistance it is important to consider additional factors, such as patient compliance with the treatment.

Rutella, S., F. Zavala, et al. (2005). "Granulocyte colony-stimulating factor: a novel mediator of T cell tolerance." J Immunol 175(11): 7085-91.

            In recent years, several investigators have unraveled a previously unrecognized role for G-CSF in the regulation of T cell and dendritic cell functions. The experimental evidence in favor of G-CSF-mediated immune regulation includes the ability to switch T cell cytokine secretion profile to Th2 responses and the promotion of regulatory T cell and tolerogenic dendritic cell differentiation. Interestingly, G-CSF is beneficial in animals for the prevention and/or treatment of immune-mediated diseases, e.g., graft-vs-host disease, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and diabetes, suggesting a potential role in human autoimmune diseases. This review summarizes the growing body of evidence that supports a critical role for G-CSF as a novel mediator of T cell tolerance.

Rus, H., C. Cudrici, et al. (2005). "C5b-9 complement complex in autoimmune demyelination and multiple sclerosis: dual role in neuroinflammation and neuroprotection." Ann Med 37(2): 97-104.

            Complement system activation plays an important role in innate and acquired immunity. Activation of complement leads to the formation of C5b-9 terminal complex. While C5b-9 can promote cell lysis, sublytic assembly of C5b-9 on plasma membranes induces cell cycle activation and survival. Multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE) are inflammatory demyelinating diseases of the central nervous system (CNS) mediated by activated lymphocytes, macrophages/microglia and the complement system. Complement activation may contribute to the pathogenesis of these diseases through its dual role: the ability of activated terminal complex C5b-9 to promote demyelination and the capacity of sublytic C5b-9 to protect oligodendrocytes (OLG) from apoptosis. By inducing EAE in C5-deficient mice, we showed that complement C5 promotes remyelination and protects oligodendrocytes from apoptotic cell death. These findings indicate that activation of complement C5b-9 plays a pro-inflammatory role in the acute phase of the disease, but may also be neuroprotective during the chronic phase of the disease.

Rowbotham, M. C. (2005). "Is fibromyalgia a neuropathic pain syndrome?" J Rheumatol Suppl 75: 38-40.

            The fibromyalgia syndrome (FM) seems an unlikely candidate for classification as a neuropathic pain. The disorder is diagnosed based on a compatible history and the presence of multiple areas of musculoskeletal tenderness. A consistent pathology in either the peripheral or central nervous system (CNS) has not been demonstrated in patients with FM, and they are not at higher risk for diseases of the CNS such as multiple sclerosis or of the peripheral nervous system such as peripheral neuropathy. A large proportion of FM sufferers have accompanying symptoms and signs of uncertain etiology, such as chronic fatigue, sleep disturbance, and bowel/bladder irritability. With the exception of migraine headaches and possibly irritable bowel syndrome, the accompanying disorders are clearly not neurological in origin. The impetus to classify the FM as a neuropathic pain comes from multiple lines of research suggesting widespread pain and tenderness are associated with chronic sensitization of the CNS. An examination of how the term neuropathic pain is defined reveals a conceptual split into 2 partially overlapping groups of disorders: those with demonstrable pathology in the nervous system and those characterized primarily by enduring dysfunction in the nervous system. Requiring demonstrable pathology in the nervous system in the definition of neuropathic pain is the traditional approach. The expansion of the definition to require only enduring nervous system dysfunction is less palatable because it opens the classification to many disorders of uncertain etiology, including complex regional pain syndrome. As it is uncertain which of the many different chronic pain syndromes include an enduring component of central sensitization, restricting the term "neuropathic pain" to those disorders with a primary etiology clearly related to the peripheral or CNS is prudent and consistent with clinical practice.

Rovaris, M., G. Comi, et al. (2005). "Can glatiramer acetate reduce brain atrophy development in multiple sclerosis?" J Neurol Sci 233(1-2): 139-43.

            The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of progressive atrophy reflecting the neurodegenerative aspects of multiple sclerosis (MS) pathology. The present article reviews the results of studies assessing the effect of glatiramer acetate (GA) treatment in preventing MS-related, MRI-measurable brain volume decrease. Whilst data from the extended, open-label follow-up of the US trial seem to indicate that long-term treatment with GA might prevent the loss of brain parenchyma in relapsing-remitting MS patients, longitudinal data from the European/Canadian MRI trial suggest that, over a short-term period of treatment, GA does not have a clear-cut impact on the decrease of brain volume. The effect of GA on MS-related brain atrophy might, therefore, be delayed and dissociated in time from those exerted on other clinical and MRI measures of disease activity. However, the modest magnitude of this effect makes it difficult to evaluate its impact on the actual disease progression. Further studies of adequate duration are now required to address this issue, as well as to confirm the sustained efficacy of GA treatment over long periods of follow-up.

Rovaris, M., A. Gass, et al. (2005). "Diffusion MRI in multiple sclerosis." Neurology 65(10): 1526-32.

            Diffusion imaging is a quantitative, MR-based technique potentially useful for the study of multiple sclerosis (MS), due to its increased pathologic specificity over conventional MRI and its ability to assess in vivo the presence of tissue damage occurring outside T2-visible lesions, i.e., in the so-called normal-appearing white and gray matter. The present review aims at critically summarizing the state-of-the-art and providing a background for the planning of future diffusion studies of MS. Several pieces of evidence suggest that diffusion-weighted and diffusion tensor MRI are sensitive to MS damage and able to detect its evolution over relatively short periods of time. Although a significant relationship between diffusion-weighted MRI findings and MS clinical disability was not found in the earliest studies, with improved diffusion imaging technology correlations between diffusion abnormalities and MS clinical aspects are now emerging. However, the best acquisition and postprocessing strategies for MS studies remain a matter of debate and the contribution of newer and more sophisticated techniques to diffusion tensor MRI investigations in MS needs to be further evaluated. Although changes in diffusion MRI indices reflect a net loss of structural organization, at present we can only speculate on their possible pathologic substrates in the MS brain. Postmortem studies correlating diffusion findings with histopathology of patients with MS are, therefore, also warranted.

Rovaris, M. and M. Filippi (2005). "Defining the response to multiple sclerosis treatment: the role of conventional magnetic resonance imaging." Neurol Sci 26 Suppl 4: S204-8.

            During the last two decades, conventional MRI (cMRI) has been extensively used in the diagnostic workup of multiple sclerosis (MS) patients, to monitor the natural history of the disease and to evaluate the efficacy of experimental treatments in randomised, controlled clinical trials. In the latter context, a major issue is represented by the high intra- and inter-individual heterogeneity of the MS patterns of disease activity and evolution. Such heterogeneity might explain, at least partially, the weak correlations found between clinical and cMRI aspects in patients with established MS, which is particularly evident when individual patients are considered. As a consequence, the definition of response to MS treatment, when based upon cMRI aspects, is still a challenging task. Although the use of cMRI-derived quantities as a standalone approach to define treatment options and strategies at an individual patient level should be discouraged, an evidence-based integration of clinical and cMRI data might be helpful in selected cases for an optimal work-up of patients undergoing immunomodulating or immunosuppressive treatments.

Rostasy, K. M. (2005). "Inflammation and neuroaxonal injury in multiple sclerosis and AIDS dementia complex: implications for neuroprotective treatment." Neuropediatrics 36(4): 230-9.

            Multiple sclerosis (MS) and AIDS dementia complex (ADC), also termed HIV-associated dementia (HAD), are two examples of CNS diseases with a strong inflammatory component. In particular, macrophage/microglia activation in the deep white matter (DWM) is a key feature of both diseases. Activated macrophages/microglia have been shown to produce multiple cellular substances which can cause injury and apoptosis to all cell types in the CNS. This potentially provides a link between the initial pathogenic event and subsequent widespread neuroaxonal injury, which recent studies have found to be an early finding and an important determinant of clinical burden in both diseases. This review summarizes important immunopathological and neurobiological aspects of MS and ADC, with a special focus on the relation between macrophage/microglia activation and neuroaxonal injury, and discusses potential neuroprotective strategies.

Rosenberg, J. H. and R. Shafor (2005). "Fatigue in multiple sclerosis: a rational approach to evaluation and treatment." Curr Neurol Neurosci Rep 5(2): 140-6.

            With the publication of the Multiple Sclerosis Council Guideline on the management of multiple sclerosis (MS) fatigue, there has been increased appreciation for the role fatigue can play in MS. Secondary fatigue is fatigue caused by other etiologies than those directly related to MS. Once these causes are ruled out, fatigue is related to MS. Secondary MS-related fatigue comes as result of the symptoms of MS that drain energy. Once secondary MS causes are ruled out, then the patient is deemed as having primary MS fatigue. Fatigue management is both nonpharmacologic and pharmacologic. Occupational therapists are the major allied health providers that address the role fatigue plays in MS patients. Over the past two decades, numerous clinical trials have been conducted on drugs for treating MS-related fatigue. Of these agents, amantadine has been studied for the longest period, and has shown efficacy in about one third of patients with MS-related fatigue on several commonly used scales. Two randomized -trials of the central nervous system stimulant pemoline have yielded unimpressive results; efficacy was seen at higher doses but coupled with an unacceptable risk of adverse events. The wake-promoting agent modafinil is the only agent to show efficacy compared with placebo on the Fatigue Severity Scale, a measure that is highly resistant to "impulse answering" and is thus viewed as one of the most difficult scales on which to show -benefit. This article reviews fatigue in MS and proposes a rational strategy for evaluation and management of this most common MS symptom.

Rooney, W. D. and P. K. Coyle (2005). "Recent advances in the neuroimaging of multiple sclerosis." Curr Neurol Neurosci Rep 5(3): 217-24.

            Neuroimaging studies continue to provide important insights into the central nervous system disease pathology of multiple sclerosis (MS). Although conventional magnetic resonance imaging remains the mainstay of diagnosis and laboratory assessment of therapeutic response in MS, quantitative techniques continue to extend our understanding of both macroscopic and microscopic disease processes. Over the past year, many published studies have investigated measures of brain atrophy, gray matter involvement, vascular properties, and myelin and neuronal loss and have examined their relationship to clinical disease expression, genotype, and therapy. An important trend continuing over the past year is the development of targeted agents to improve the pathologic specificity of imaging measures. Specific disease measures such as endothelial activation, microglial activation, and cell trafficking are accessible to neuroimaging and offer significant promise for improved characterization of central nervous system involvement in MS.

Romeo, M. J., V. Espina, et al. (2005). "CSF proteome: a protein repository for potential biomarker identification." Expert Rev Proteomics 2(1): 57-70.

            Proteomic analysis is not limited to the analysis of serum or tissues. Synovial, peritoneal, pericardial and cerebrospinal fluid represent unique proteomes for disease diagnosis and prognosis. In particular, cerebrospinal fluid serves as a rich source of putative biomarkers that are not solely limited to neurologic disorders. Peptides, proteolytic fragments and antibodies are capable of crossing the blood-brain barrier, thus providing a repository of pathologic information. Proteomic technologies such as immunoblotting, isoelectric focusing, 2D gel electrophoresis and mass spectrometry have proven useful for deciphering this unique proteome. Cerebrospinal fluid proteins are generally less abundant than their corresponding serum counterparts, necessitating the development and use of sensitive analytical techniques. This review highlights some of the promising areas of cerebrospinal fluid proteomic research and their clinical applications.

Rodi, D., R. Couture, et al. (2005). "Targeting kinin receptors for the treatment of neurological diseases." Curr Pharm Des 11(10): 1313-26.

            Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and nociception. They are believed to play a role in disease states like asthma, allergies, rheumatoid arthritis, cancer, diabetes, endotoxic and pancreatic shock, and to contribute to the therapeutic effects of ACE inhibitors in cardiovascular diseases. Although kinins are also neuromediators in the central nervous system, their involvement in neurological diseases has not been intensively investigated thus far. This review analyzes the potential of central kinin receptors as therapeutic targets for neurological disorders. Initial data highlight potential roles for B(1) receptor antagonists as antiepileptic agents, and for B(2) receptor antagonists (and/or B(1) agonists) in the treatment of stroke. Functional B(1) receptors located on T-lymphocytes and on the blood brain-barrier are also putative targets for the management of multiple sclerosis. However, successful elucidation of the therapeutic value of these new pharmacological approaches will require refinement of our knowledge on the physiology and cellular localization of central kinin receptors.

Rode, G., C. Thomas-Anterion, et al. (2005). "[Assessment of disability and quality of life in patients with cognitive disorders]." Ann Readapt Med Phys 48(6): 376-91.

            OBJECTIVE: To identify disability, handicap and quality of life questionnaires available for patients with cognitive impairment. MATERIALS AND METHODS: We systematically reviewed the literature in Medline using the keywords assessment, evaluation, deficiency, disability, disadvantage, handicap, quality of life, scale, index, questionnaire, ICIDH-1, and ICIDH-2, combined with the cognitive deficits dysexecutive syndrome, memory deficits, attention deficits, neglect, apraxia, aphasia, agnosia and mood disorders. We focused on validated scales and distinguished scales dedicated to assess disability, handicap and quality of life. RESULTS: At the level of disability, global and specific scales are available. Specific scales exist for dysexecutive syndrome, memory deficits, attention deficits, unilateral neglect, aphasia and mood disorders. French adaptations of foreign language tests and original tests developed in French have been validated in these areas. No specific tool is available for isolated apraxia or agnosia. Generic scales and pathology-specific scales (for stroke, traumatic brain injury, and multiple sclerosis) are available for quality of life. For aphasia, specific tools are available for incapacity handicap and quality of life. CONCLUSION: Previous results show the impact of the ICIDH-1 framework on functional outcome assessment of cognitive impairments. This approach is often limited by the lack of theoretical background and by the difficulty to assess the involvement of environment and anosognosia.

Rocca, M. A., S. J. Hickman, et al. (2005). "Imaging the optic nerve in multiple sclerosis." Mult Scler 11(5): 537-41.

            Although multiple sclerosis (MS) frequently involves the optic nerves, imaging this structure is not yet performed routinely in clinical practice. The recent improvement of magnetic resonance (MR) technology and the development of new MR strategies, capable of providing an, in vivo, overall assessment of MS pathology has allowed objective metrics to be obtained for monitoring disease evolution, essentially in the brain. However, despite this progress, the correlation between brain MR metrics of the disease and clinical disability are still disappointing. An objective and accurate estimate of the presence and extent of optic nerve involvement might help to overcome this clinical/MRI paradox. This review summarizes the main results obtained from the application of conventional and modern MR-based techniques for the evaluation of optic nerve damage in MS.

Rocca, M. A., S. J. Hickman, et al. (2005). "Imaging spinal cord damage in multiple sclerosis." J Neuroimaging 15(4): 297-304.

            During the past 2 decades, the considerable improvement of magnetic resonance (MR) technology and the development of new MR strategies capable of providing an in vivo overall assessment of multiple sclerosis (MS) pathology have allowed us to obtain important novel pieces of information on disease evolution in the brain. However, despite this, the correlation between brain MR imaging metrics and clinical disability are still suboptimal. A reason for this discrepancy might be the involvement of clinically eloquent structures, such as the spinal cord, which owing to technical challenges have not been extensively studied using MR imaging until very recently. An objective and accurate estimate of the presence and extent of spinal cord damage might indeed contribute to increasing the strength of the correlations between clinical and MRI metrics. This review summarizes the main results obtained from the application of conventional and modern MR-based techniques for the evaluation of spinal cord damage in MS.

Robson, P. (2005). "Human studies of cannabinoids and medicinal cannabis." Handb Exp Pharmacol(168): 719-56.

            Cannabis has been known as a medicine for several thousand years across many cultures. It reached a position of prominence within Western medicine in the nineteenth century but became mired in disrepute and legal controls early in the twentieth century. Despite unremitting world-wide suppression, recreational cannabis exploded into popular culture in the 1960s and has remained easily obtainable on the black market in most countries ever since. This ready availability has allowed many thousands of patients to rediscover the apparent power of the drug to alleviate symptoms of some of the most cruel and refractory diseases known to humankind. Pioneering clinical research in the last quarter of the twentieth century has given some support to these anecdotal reports, but the methodological challenges to human research involving a pariah drug are formidable. Studies have tended to be small, imperfectly controlled, and have often incorporated unsatisfactory synthetic cannabinoid analogues or smoked herbal material of uncertain composition and irregular bioavailability. As a result, the scientific evaluation of medicinal cannabis in humans is still in its infancy. New possibilities in human research have been opened up by the discovery of the endocannabinoid system, a rapidly expanding knowledge of cannabinoid pharmacology, and a more sympathetic political environment in several countries. More and more scientists and clinicians are becoming interested in exploring the potential of cannabis-based medicines. Future targets will extend beyond symptom relief into disease modification, and already cannabinoids seem to offer particular promise in the treatment of certain inflammatory and neurodegenerative conditions. This chapter will begin with an outline of the development and current status of legal controls pertaining to cannabis, following which the existing human research will be reviewed. Some key safety issues will then be considered, and the chapter will conclude with some suggestions as to future directions for human research.

Roberts-Thomson, P. J., R. A. Roberts-Thomson, et al. (2005). "Immune dysfunction in Australian Aborigines." Asian Pac J Allergy Immunol 23(4): 235-44.

            An examination of the prevalence and phenotype of immune disorders in different ethnic groups may provide important clues to the etiopathogenesis of these disorders. Whilst still conjectural the restricted and somewhat unique polymorphisms of the MHC (and other genetic loci involving host defences) of the Australian Aborigines may provide an explanation for their apparent heightened susceptibility to newly encountered infections and their resistance to many (auto) immune and allergic disorders. In comparison with non-Aboriginal Australians, Australian Aborigines have heightened frequencies of rheumatic fever, systemic lupus erythematosus, various infections and post-streptococcal glomerulonephritis. In contrast various autoimmune disorders (e.g. rheumatoid arthritis, multiple sclerosis, CREST, biliary cirrhosis, coeliac disease, pernicious anaemia, vitiligo), B27 related arthropathies, psoriasis, lymphoproliferative disorders and atopic disorders appear infrequent or absent. Similarly various autoantibodies occur with increased or diminished frequency. With continuing racial admixture, social deprivation and deleterious lifestyles of these people it is likely that further changes in both the frequencies and phenotype of these immune disorders will occur. It is only with a full understanding of the pathogenic mechanisms involved in these immune disorders that meaningful and clinical relevant interventions will be possible.

Roberts, R. (2005). "Lysosomal cysteine proteases: structure, function and inhibition of cathepsins." Drug News Perspect 18(10): 605-14.

            Lysosomal cysteine proteases, a subgroup of the cathepsin family, are critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. In the past decade, the number of identified human cathepsins has more than doubled and their known role in several pathologies has expanded rapidly. Increased understanding of the structure and mechanism of this class of enzymes has brought on a new fervor in the design of small molecule inhibitors with the hope of producing specific, therapeutic drugs for diseases such as arthritis, allergy, multiple sclerosis, atherosclerosis, Alzheimer's disease and cancer.

Rio, J. and X. Montalban (2005). "Interferon-beta 1b in the treatment of multiple sclerosis." Expert Opin Pharmacother 6(16): 2877-86.

            Ever since IFN-beta1b was first approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the US and Europe, other disease-modifying drugs have become available. Phase III clinical trials have shown the efficacy of IFN-beta1b in the treatment of RRMS and secondary progressive MS in that it can reduce the annual relapse rate as well as magnetic resonance imaging parameters of activity and progression. There is mounting evidence that the best time to initiate treatment is early in the course of the disease, and available data suggest that efficacy is sustained for at least 5 years. IFN-beta1b is safe and well tolerated, although there are adverse events such as the flu-like complex and skin reactions. In the face of a proportion of RRMS patients experiencing a poor response to the drug, other therapeutic approaches need to be considered.

Rinaldi, L. and P. Gallo (2005). "Immunological markers in multiple sclerosis: tackling the missing elements." Neurol Sci 26 Suppl 4: S215-7.

            Multiple sclerosis (MS) is a complex disease in which several pathophysiological mechanisms are involved: inflammation, demyelination, axonal damage and repairing. Further complicating the picture, such processes are variably represented in MS patient populations, thus accounting for the heterogeneity in phenotypic expression of the disease, its prognosis and response to therapies. In the last decade a huge effort has been made in the attempt to "capture" the gold fish, i. e., biological markers either specific for the disease and/or capable to predict, in newly diagnosed MS patients, disease course and response to therapy. Moreover, these biomarkers would be extremely useful in the development of new process-specific therapies. Unfortunately such markers are far from being "fished", but recent studies have pointed out new interesting candidates, driving new energies and hopes in the MS research community. In this review we briefly discuss the latest news on immune markers in MS.

Rietberg, M. B., D. Brooks, et al. (2005). "Exercise therapy for multiple sclerosis." Cochrane Database Syst Rev(1): CD003980.

            BACKGROUND: No intervention has proven effective in modifying long-term disease prognosis in Multiple Sclerosis (MS) but exercise therapy is considered to be an important part of symptomatic and supportive treatment for these patients. OBJECTIVES: To assess the effectiveness of exercise therapy for patients with MS in terms of activities of daily living and health-related quality of life. SEARCH STRATEGY: We searched the Cochrane MS Group Specialised Register (searched: March 2004), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2004), MEDLINE (from 1966 to March 2004), EMBASE (from 1988 to March 2004 ), CINAHL (from 1982 to March 2004), PEDro (from 1999 to March 2004) . Manual search in the journal 'Multiple Sclerosis' and screening of the reference lists of identified studies and reviews. We also searched abstracts published in proceedings of conferences. SELECTION CRITERIA: Randomised Controlled Trials (RCTs) that reported on exercise therapy for adults with MS, not presently experiencing an exacerbation; outcomes that include measures of activity limitation or health-related quality of life or both. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and methodological quality of the included trials. Disagreements were resolved by discussion. The results were analysed using a best-evidence synthesis based on methodological quality. MAIN RESULTS: Nine high-methodological-quality RCTs(260 participants) met the inclusion criteria. Six trials focussed on comparison of exercise therapy versus no exercise therapy, whereas three trials compared two interventions that both met our definition of exercise therapy. Best evidence synthesis showed strong evidence in favour of exercise therapy compared to no exercise therapy in terms of muscle power function, exercise tolerance functions and mobility-related activities. Moderate evidence was found for improving mood. No evidence was observed for exercise therapy on fatigue and perception of handicap when compared to no exercise therapy. Finally, no evidence was found that specific exercise therapy programmes were more successful in improving activities and participation than other exercise treatments. No evidence of deleterious effects of exercise therapy was described in included studies. AUTHORS' CONCLUSIONS: The results of the present review suggest that exercise therapy can be beneficial for patients with MS not experiencing an exacerbation. There is an urgent need for consensus on a core set of outcome measures to be used in exercise trials. In addition, these studies should experimentally control for 'dose' of treatment, type of MS and should include sufficient contrast between experimental and control groups.

Rieckmann, P. (2005). "Multiple sclerosis therapy: new strategies." Neurol Sci 26 Suppl 1: S20.

Rickards, H. (2005). "Depression in neurological disorders: Parkinson's disease, multiple sclerosis, and stroke." J Neurol Neurosurg Psychiatry 76 Suppl 1: i48-52.

Rice, G. P., H. P. Hartung, et al. (2005). "Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale." Neurology 64(8): 1336-42.

            The symptoms, severity, and course of multiple sclerosis (MS) vary among patients, leading to complex treatment issues. In recent years, research has focused on specific adhesion molecules that participate in the activation and function of lymphocytes, especially the migration of these cells to sites of inflammation. In particular, the integrin, very late activation antigen (VLA)-4, has been implicated in mediating adhesion and migration of immune cells through interaction with its ligand, vascular cell adhesion molecule (VCAM)-1. VLA-4 is comprised of alpha4/beta1 and is critical in mediating Th-1 cell migration in the animal model of MS, experimental autoimmune encephalomyelitis, and has been the target of several recent clinical trials in MS. The humanized monoclonal antibody to alpha4 integrin, natalizumab (Tysabri, Biogen Idec/Elan), was recently approved in the United States for the treatment of relapsing MS. The authors discuss the mechanisms by which alpha4 integrins alter lymphocyte function as a rationale for anti-alpha4 integrin use in MS.

Restrepo, C. S., A. Largoza, et al. (2005). "CT and MR imaging findings of benign cardiac tumors." Curr Probl Diagn Radiol 34(1): 12-21.

            This imaging review describes the appearance of benign cardiac tumors on CT and MRI. Although rare, benign tumors outnumber their primary malignant counterparts three to one. Since mortality varies directly with invasion, identifying the neoplasm at an early stage helps focus treatment, especially in benign cases, which generally respond well to surgical resection. In adults and children, myxomas and rhabdomyomas, respectively, represent the most common benign tumors, which can be grouped into tissue-specific subtypes, such as rhabdomyomas, fibromas, lipomas, teratomas, etc. Besides their variable prevalence in particular age groups, these tumors also differ with regard to their gender predilection, location, and number. For example, myxomas appear predominantly in women and generally as a solitary mass in the left or right atrium, whereas rhabdomyomas present equally in boys and girls and chiefly as multiple masses in the ventricles. Despite their differences, however, both types share an association with heritable syndromes like the Carney complex for myxomas and tuberous sclerosis for rhabdomyomas. As with all cardiac tumors, echocardiographic findings usually suggest the initial diagnosis but cross-sectional imaging with CT and MRI can help resolve diagnostically challenging cases. For example, with its direct multiplanar capability, excellent contrast resolution, and large field of view, MRI permits a detailed examination of the entire mediastinum, helping to rule out an equivocal mass on echocardiography. Through dynamic techniques, MRI, in addition to morphologic characterization, can depict the pathophysiological effects of these tumors, for instance, with regard to myocardial contraction, valvular function, or blood flow.

Reske, D., H. F. Petereit, et al. (2005). "Difficulties in the differentiation of chronic inflammatory diseases of the central nervous system--value of cerebrospinal fluid analysis and immunological abnormalities in the diagnosis." Acta Neurol Scand 112(4): 207-13.

            OBJECTIVES: A number of neurological syndromes may be evoked by involvement of the nervous system due to systemic diseases such as lupus erythematodes, sarcoidosis, Behcet's disease and Sjogren's syndrome (SS) and may be confounded with another chronic inflammatory disease which is restricted to the central nervous system, e.g. multiple sclerosis (MS). Because of different treatment strategies, it is important to distinguish between these different autoimmune diseases. RESULTS: Neither clinical signs nor additional analyses such as serological findings or cerebrospinal fluid (CSF) analysis are able to differentiate between the diseases with certainty. Nevertheless, taking all findings together, diagnosis may be possible. CONCLUSION: Here we compare typical clinical and CSF findings in MS, neurosarcoidosis, neurolupus, neuro-Behcet and nervous system involving SS with special emphasis on those findings allowing differentiation of the respective diseases by reviewing the literature.

Regenauer, A. (2005). "[New challenges in multiple sclerosis]." Versicherungsmedizin 57(3): 115-21.

            After decades of prevailing fatalism concerning multiple sclerosis new hopes emerge at the horizon of both the diagnostic and therapeutic section catalyzed by a new understanding of the neurodegenerative disease process. The rapidly evolving MRI techniques enabled an analysis of CNS tissue injury in terms of structure and chemical composition. Based on studies with serial MRI scans, multiple sclerosis is increasingly considered as a dynamic disease process, in which not only the myelin but also the axons are damaged already in a very early stage. The introduction of interferon therapy caused much attention and great hope both among patients and clinicians. Unfortunately clinical studies require a large number of patients and long periods. Obviously if treated early enough and consistently, patients with the relapsing-remitting form of multiple sclerosis suffer less exacerbations, MRI lesions and disease progression in comparison to patients not treated by interferons. But sustained improvement in terms of extramortality and extramorbidity can only be expected in the medium term.

Ray, K. K. and C. P. Cannon (2005). "The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes." J Am Coll Cardiol 46(8): 1425-33.

            Emerging data suggest that acute presentations of coronary artery disease may involve a complex interplay between the vessel wall, inflammatory cells, and the coagulation cascade. Although a culprit thrombotic lesion may be treated effectively by antithrombotic therapy and revascularization, this will have little effect on the global processes that determine recurrent events at non-culprit sites. Thus, additional systemic treatment is required to modulate the adverse biological features that are the hallmark of acute coronary syndromes (ACS). Statins possess multiple beneficial effects that are independent of low-density-lipoprotein cholesterol (LDL-C) lowering and that have favorable effects on inflammation, the endothelium, and the coagulation cascade. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, differences were seen based on achieved LDL-C that could be further discriminated by the achieved C-reactive protein level. Studies of non-vascular disease such as multiple sclerosis have shown that statins reduce inflammation, supporting the presence of lipid-independent effects of statins. This review focuses on the potential importance of these effects in the management of ACS.

Ray, A. and E. Wyllie (2005). "Treatment options and paradigms in childhood temporal lobe epilepsy." Expert Rev Neurother 5(6): 785-801.

            Temporal lobe epilepsy in adults is a relatively homogenous syndrome with hippocampal sclerosis being its most common pathologic substrate. In the pediatric age group, low-grade neoplasms and cortical dysplasia are much more common than hippocampal sclerosis. Pediatric temporal lobe epilepsy has distinct semiologic, electrophysiologic and imaging characteristics as compared with its adult counterpart. The various treatment options for pediatric temporal lobe epilepsy include antiepileptic drugs, resective surgery, vagal nerve stimulation and the ketogenic diet. In spite of the multiple antiepileptic drugs currently available, 5-10% of all newly diagnosed cases will remain intractable to medical therapy and should be referred for presurgical evaluation. Resective surgery offers the best chance of seizure freedom in carefully selected patients. Future areas of research include new drug development, better imaging and localization techniques, and brain stimulation.

Ransohoff, R. M. (2005). "Immunologic correlates of MS pathologic subtypes." Mult Scler 11(1): 101-2.

Ramos-Casals, M., A. Pares, et al. (2005). "Antimitochondrial antibodies in patients with chronic hepatitis C virus infection: description of 18 cases and review of the literature." J Viral Hepat 12(6): 648-54.

            To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton-fixed criosections and FITC-conjugated rabbit anti-human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjogren's syndrome (n = 7), systemic sclerosis (n = 3) and systemic lupus erythematosus (n = 2). Fourteen (78%) of the HCV-AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia (n = 4), cirrhotic complications (n = 2) and hepatopulmonary syndrome (n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated SAD, mainly Sjogren's syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia.

Racke, M. K., W. Hu, et al. (2005). "PTX cruiser: driving autoimmunity via TLR4." Trends Immunol 26(6): 289-91.

            Although the cause of autoimmune diseases is unknown, it has long been speculated that an infectious agent might have a role in their initiation and progression. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), has been used to study factors in disease pathogenesis. A recent study shows that pertussis toxin, which is used as an adjuvant in EAE, uses Toll-like receptor 4 signaling to mediate its disease-inducing effect.

Quintana, H. (2005). "Transcranial magnetic stimulation in persons younger than the age of 18." J Ect 21(2): 88-95.

            OBJECTIVES: To review the use of transcranial magnetic stimulation (single-pulse TMS, paired TMS, and repetitive TMS [rTMS]) in persons younger than the age of 18 years. I discuss the technical differences, as well as the diagnostic, therapeutic, and psychiatric uses of TMS/rTMS in this age group. METHODS: I evaluated English-language studies from 1993 to August 2004 on nonconvulsive single-pulse, paired, and rTMS that supported a possible role for the use of TMS in persons younger than 18. Articles reviewed were retrieved from the MEDLINE database and Clinical Scientific index. RESULTS: The 48 studies reviewed involved a total of 1034 children ages 2 weeks to 18 years; 35 of the studies used single-pulse TMS (980 children), 3 studies used paired TMS (20 children), and 7 studies used rTMS (34 children). Three studies used both single and rTMS. However, the number of subjects involved was not reported. CONCLUSIONS: Single-pulse TMS, paired TMS, and rTMS in persons younger than 18 has been used to examine the maturation/activity of the neurons of various central nervous system tracts, plasticity of neurons in epilepsy, other aspects of epilepsy, multiple sclerosis, myoclonus, transcallosal inhibition, and motor cortex functioning with no reported seizure risk. rTMS has been applied to psychiatric disorders such as ADHD, ADHD with Tourette's, and depression. Adult studies support an antidepressant effect from repetitive TMS, but there is only one study that has been reported on 7 patients that used rTMS to the left dorsal prefrontal cortex on children/adolescents with depression (5 of the 7 subjects treated responded). Although there are limited studies using rTMS (in 34 children), these studies did not report significant adverse effects or seizures. Repetitive TMS safety, ethical, and neurotoxicity concerns also are discussed.

Pryce, G. and D. Baker (2005). "Emerging properties of cannabinoid medicines in management of multiple sclerosis." Trends Neurosci 28(5): 272-6.

            Use of cannabis as a medicine for numerous conditions has a well-documented history stretching back thousands of years. With the identification of an endogenous system of receptors and ligands in recent years, abundant experimental data have reinforced the anecdotal claims of people who perceive medicinal benefit from the currently illegal consumption of cannabis. This, combined with data from recent clinical trials, points to the prospect of cannabis as a medication in the treatment of multiple sclerosis and numerous other medical conditions.

Provenzale, J. M., M. Escolar, et al. (2005). "Quantitative analysis of diffusion tensor imaging data in serial assessment of Krabbe disease." Ann N Y Acad Sci 1064: 220-9.

            Krabbe disease is a rare autosomal recessive pediatric white matter (WM) disorder that is due to deficiency of a specific enzyme, beta-galactocerebrosidase. This report reviews our experience with use of diffusion tensor imaging (DTI) in serial assessment of WM changes in Krabbe disease following stem cell transplantation. DTI appears to be a sensitive means to monitor effects of stem cell transplantation on WM development in Krabbe disease. The group of early transplantation infants was clearly distinguishable from the group of late transplantation infants based on anisotropy measurements. Good correlation also was seen between neurodevelopmental scores and anisotropy measurements. The work described here in Krabbe disease may serve as a model for application of DTI to other therapies in various WM disorders such as multiple sclerosis and dysmyelinating disorders of childhood.

Prince, H. E. (2005). "Biomarkers for diagnosing and monitoring autoimmune diseases." Biomarkers 10 Suppl 1: S44-9.

            The goal of studies of autoimmune disease biomarkers is to identity markers that fluctuate with disease development and severity, but then normalize following successful therapy. The perfect marker could thus serve as a diagnostic tool, as well as a monitoring device for therapeutic drug efficacy. Current biomarker discovery efforts are focused on three groups of proteins reflective of the autoimmune disease process: (1) degradation products arising from destruction of affected tissues, (2) enzymes that play a role in tissue degradation and (3) cytokines and other proteins associated with immune activation. Potential biomarkers for two autoimmune diseases, rheumatoid arthritis and multiple sclerosis, have been described in recent publications. For rheumatoid arthritis, these markers (by group) include (1) aggrecan fragments, C-propeptide of type II collagen and cartilage oligomeric matrix protein, (2) matrix metalloprotease (MMP)-1, MMP-3 and MMP-1/inhibitor complexes and (3) thioredoxin, IL-16 and tumour necrosis factor (TNF)-alpha. For multiple sclerosis, they include (1) neurofilament light protein and glial fibrillary acidic protein, (2) MMP-2 and MMP-9 and (3) TNF-alpha and soluble vascular adhesion molecule-1. The utility of most of these markers is limited by their restriction to relatively inaccessible anatomic sites (synovial or cerebrospinal fluid). Thus, from a practical standpoint, the most useful autoimmune biomarkers will be those measurable in serum or plasma.

Prat, A. and J. Antel (2005). "Pathogenesis of multiple sclerosis." Curr Opin Neurol 18(3): 225-30.

            PURPOSE OF REVIEW: The aim of this article is to describe recent observations regarding the basis for the initiation and disease evolution of multiple sclerosis. RECENT FINDINGS: A current debate is where and what initiates the neuroinflammatory reaction that characterizes the acute multiple sclerosis lesion. Immune sensitization to neural antigens could develop within the systemic compartment consequent to exposure to cross-reacting, possibly viral derived, peptides (molecular mimicry). Although CD4 T cells are considered central to initiating central nervous system inflammation, the actual extent and specificity of tissue injury reflects the array of adaptive (CD8 T cells and antibody) and innate (microglia/macrophages) immune constituents present in the lesions. Neuropathologic studies indicate that lethal changes in neural cells (oligodendrocytes) could also be the initiating event, reflecting as yet unidentified acquired insults (e.g. exogenous virus or reactivated endogenous retrovirus) or intrinsic abnormalities ('neurodegenerative' hypothesis). Recurrence or persistence of the disease process can reflect events occurring at multiple sites including expansion of the immune repertoire in response to neural antigens transported to regional lymph nodes (determinant spreading), especially if immune regulatory mechanisms are defective; alterations in blood-brain barrier properties consequent to initial cellular transmigration; and participation of endogenous (microglia, astrocytes) or long lived infiltrating cells (macrophages, B cells in ectopic germinal centers) in regulating and effecting immune functions within the central nervous system. Accumulating neurologic deficit reflects the balance between injury and repair; the latter also being negatively or positively (trophic support and clearance of tissue debris) impacted by inflammatory processes. SUMMARY: Understanding the full spectrum of multiple sclerosis presents a continuing challenge for both immunology and neurobiology.

Poser, C. M. (2005). "The diagnosis and management of multiple sclerosis." Acta Neurol Scand 112(3): 199-201.

Poppe, A. Y., Y. Lapierre, et al. (2005). "Neuromyelitis optica with hypothalamic involvement." Mult Scler 11(5): 617-21.

            We describe two cases of neuromyelitis optica (NMO) with clinical and radiographically confirmed features of hypothalamic involvement, in the absence of other parenchymal brain lesions. Their course is otherwise typical of Devic's form of NMO. A review of the literature identifies additional cases of NMO in which clinical features attributable to under-recognized dysfunction of the hypothalamic-pituitary axis were present. We propose that the currently accepted criteria for the diagnosis of NMO could be revisited to recognize the possibility of lesions developing within hypothalamic structures.

Ponsonby, A. L., R. M. Lucas, et al. (2005). "UVR, vitamin D and three autoimmune diseases--multiple sclerosis, type 1 diabetes, rheumatoid arthritis." Photochem Photobiol 81(6): 1267-75.

            We review the evidence indicating a possible beneficial role for UVR on three Th1-mediated autoimmune diseases: multiple sclerosis, type 1 diabetes and rheumatoid arthritis in relation to recent developments in photoimmunology. Recent work suggests that UVR exposure may be one factor that can attenuate the autoimmune activity leading to these three diseases through several pathways involving UVB and UVA irradiation, UVR-derived vitamin D synthesis and other routes such as alpha-melanocyte-stimulating hormone, calcitonin gene related peptide and melatonin. Ecological features, particularly a gradient of increasing prevalence of multiple sclerosis and type 1 diabetes with higher latitude, provide some support for a beneficial role of UVR. Analytical studies provide additional support, particularly as low vitamin D has been prospectively associated with disease onset for all three diseases, but are not definitive. Randomized controlled trial data are required. Further, we discuss how associated genetic studies may assist the accumulation of evidence with regard to the possible causal role of low UVR exposure and/or low vitamin D status in the development of these diseases.

Pompeii, L. A., S. D. Moon, et al. (2005). "Measures of physical and cognitive function and work status among individuals with multiple sclerosis: a review of the literature." J Occup Rehabil 15(1): 69-84.

            The purpose of this review was to critically evaluate the multiple sclerosis (MS) literature that has examined physical and cognitive function in relation to ability to work. Although numerous factors may be considered when determining work ability, physical and/or cognitive functional limitations associated with MS are presumably the primary determinants of work capacity. An exhaustive search of the literature produced 20 research articles that described 18 studies. Findings from these studies support that limitations in physical or cognitive function can hinder one's ability to work; however, ability to work could not be based solely on these measures of function. Work ability among individuals extended beyond measures of impairment to include level of education, job characteristics, and disease symptoms such as fatigue. In summary, measures of physical and cognitive function can guide physicians when clinically evaluating an individual with MS, but are poor indicators for precluding an individual from working.

Polman, C. H., J. S. Wolinsky, et al. (2005). "Multiple sclerosis diagnostic criteria: three years later." Mult Scler 11(1): 5-12.

            New diagnostic criteria for multiple sclerosis (MS) were developed by an International Panel in 2001 and have had wide distribution and discussion since publication. These provided the first formal incorporation of magnetic resonance imaging (MRI) in a diagnosis work-up for patients suspected of having MS. The so-called McDonald criteria have been studied in retrospective and prospective analyses for sensitivity, specificity and utility, and have been proven to compare favourably or to be an improvement upon prior MS diagnostic criteria. The purpose of the current review is to present and evaluate the key studies that have been performed using the McDonald criteria since 2001 and to set the stage for an upcoming re-evaluation of the new criteria based on data-driven information gathered since their development.

Polman, C. H., S. C. Reingold, et al. (2005). "Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"." Ann Neurol 58(6): 840-6.

            New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Pollmann, W., C. Busch, et al. (2005). "[Quality of life in multiple sclerosis. Measures, relevance, problems, and perspectives]." Nervenarzt 76(2): 154-69.

            Measuring quality of life (QOL) has made essential contributions for the management of patients with multiple sclerosis (MS). QOL measures may be used for helping to assess the complex changes which patients with MS have to go through during the disease trajectory, and they may be used for pharmacoeconomic research. The large number of tests available includes generic ones such as Short Form SF-36 and Sickness Impact Profile, health-related ones such as MSQOL-54, FAMS, or HAQUAMS, and patient generated measures such as the Patient Generated Index and SEIQOL-DW. Depression, cognitive impairment, and fatigue are important factors influencing QOL. Since the different tests measure quite different facets of QOL, this review intends to help the reader select a tool suited to the aim and specific question. It is hoped that QOL measures may help to better understand patients, to become a more helpful medical partner, to assist patients to develop perspectives for their future, and to decide about therapies or even palliative interventions.

Pollmann, W., W. Feneberg, et al. (2005). "[Therapy of pain syndromes in multiple sclerosis -- an overview with evidence-based recommendations]." Fortschr Neurol Psychiatr 73(5): 268-85.

            While pain is a common problem in multiple sclerosis (MS) patients, it is frequently overlooked and has to be asked for actively. Pain can be classified into 4 diagnostically and therapeutically relevant categories. 1. PAIN DIRECTLY RELATED TO MS: Painful paroxysmal symptoms like trigeminal neuralgia or painful tonic spasms are treated with carbamazepine as first choice, or lamotrigine, gabapentin, oxcarbazepine and other anticonvulsants. Painful "burning" dysaesthesia, the most frequent chronic pain syndrome, are treated with tricyclic antidepressants or carbamazepine, further options include gabapentin or lamotrigine. While escalation therapy may require opioids, the role of cannabinoids in the treatment of pain still has to be determined. 2. PAIN INDIRECTLY RELATED TO MS: Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents like baclofen or tizanidine, alternatively gabapentin. In severe cases botulinum toxin injections or intrathecal baclofen merit consideration. Physiotherapy and physical therapy may ameliorate malposition-induced joint and muscle pain. Moreover, painful pressure lesions should be avoided using optimally adjusted aids. 3. Treatment-related pain can occur with subcutaneous injections of beta interferons or glatiramer acetate and may be reduced by optimizing the injection technique and by local cooling. Systemic side effects of interferons like myalgias can be reduced by paracetamol or ibuprofen. 4. Pain unrelated to MS such as back pain or headache are frequent in MS patients and may be worsened by the disease. Treatment should be follow established guidelines. In summary, a careful analysis of the pain syndrome will allow the design of the appropriate treatment plan using various medical and non-medical options and thus will help to ameliorate the patients' quality of life.

Pluchino, S. and G. Martino (2005). "The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders." J Neurol Sci 233(1-2): 117-9.

            Spontaneous remyelination occurs in multiple sclerosis (MS) patients. However, this process is not robust enough to promote a functional and stable recovery of the myelin architecture in demyelinated areas of the central nervous system (CNS). As a consequence of this incomplete reparative process, the disease invariably progresses and patchy areas of demyelination-in which axonal damage and/or loss is a constant accompanying factor-increase over time and lead to the accumulation of irreversible neurological deficits. Thus, the development of cell-based therapies aimed to promote multifocal remyelination in MS represents one of the most challenging areas of investigation. Several cell-replacement strategies have been developed in the last few years. However, most of these therapeutic approaches-although consistently able to form new myelin sheaths around the transplantation site-are unrealistic owing to the multifocality of the demyelinating process and the inability to in vitro growth and differentiate large number of myelin-forming cells. Recently, promising cell-replacement therapies based on the use of stem cells have been proposed. However, before envisaging any potential human applications of such therapies we need to confront with some preliminary and still unsolved questions: (i) the ideal stem cell source for transplantation, (ii) the route of cell administration, (iii) the differentiation and persistence of stem cells into the targeted tissue and, last but not least, (iv) the functional and long-lasting integration of transplanted cells into the host tissue.

Piedrola Angulo, G. (2005). "[Human herpesvirus 6 and multiple sclerosis]." An R Acad Nac Med (Madr) 122(2): 377-89; discussion 389-92.

            In this work the possible etiologic relationship among the multiple sclerosis and the herpesvirus 6 (VHH-6) has been studied, subject debated in the last years. They have been carried out two studies using blood and LCR of sick of multiple sclerosis, and control in healthy fellows and with other neurological illnesses. The followed techniques are described to isolate the virus, their DNA, and the antibodies IgG and IgA in front of the VHH-6. The presente of the VHH-6 has not been demonstrated neither of its DNA in any case, but if it has been proved, with statistical significance that in the sick persons with buds of multiple sclerosis, the antibodies of the type IgG, as much in plasm as in LCR, was more present and in higher levels that in the controls.

Pickett, G. E., D. Bisnaire, et al. (2005). "Percutaneous retrogasserian glycerol rhizotomy in the treatment of tic douloureux associated with multiple sclerosis." Neurosurgery 56(3): 537-45; discussion 537-45.

            OBJECTIVE: Patients with multiple sclerosis (MS) have a relatively high incidence of tic douloureux (TD) and often do not tolerate medical therapy well. The minimally invasive nature of percutaneous retrogasserian glycerol rhizotomy (PRGR) renders it ideal for first-line surgical treatment of TD. We sought to ascertain the benefits of PRGR in patients with MS and to determine whether hypalgesia after PRGR correlates with efficacy. METHODS: We assessed 97 glycerol procedures performed in 53 patients followed prospectively for treatment of TD associated with MS. Factors assessed included degree of pain relief, postoperative hypalgesia, procedural morbidity, medication use, time to pain recurrence, and number and type of subsequent procedures. RESULTS: Complete pain relief was obtained in 78% of patients after the initial glycerol injection, and partial relief was obtained in 13% of patients. Long-term follow-up (mean, 81 mo) demonstrated a recurrence rate of 59%, with a mean time to recurrence of 17 months. Actuarial recurrence rates were 50% at 12 months and 60% at 24 months. Twenty-four patients underwent a second or subsequent PRGR for recurrent pain and achieved similar rates of pain relief and time to recurrence. Facial sensory loss was associated with a higher likelihood of pain relief (P < 0.05), with longer time to pain recurrence (P < 0.05), and with decreased use of medication after surgery (P < 0.01.) CONCLUSION: PRGR is an effective, low-morbidity surgical procedure in the management of TD complicating MS. The presence of facial sensory loss after PRGR is associated with prolonged efficacy.

Phillips, W. J., D. J. Smith, et al. (2005). "Recombinant immunoglobulin-based epitope delivery: a novel class of autoimmune regulators." Int Rev Immunol 24(5-6): 501-17.

            Over the past decades, there has been significant progress in understanding the mechanisms of autoimmune diseases at a molecular level. Diseases such as juvenile diabetes, multiple sclerosis, celiac disease, rheumatoid arthritis, and others appear to be mediated by pathogenic T cells that recognize self-epitopes and escape natural tolerance. Seminal observations correlating autoimmunity with HLA and disease-associated epitopes, in conjunction with recent characterization of T regulatory (Treg) cells, promoted a renewed interest in antigen or epitope-based methods of interfering with pathogenic autoimmune reactions. Recombinant immunoglobulin-peptides encompassing disease-associated self-epitopes (IgPP) integrate effective targeting of antigen-presenting cells (APCs) with a potential to generate Treg cells and thus are being developed for treatment of selected autoimmune disorders. In the current review, we outline the main features of this new class of active immunotherapeutics and directions of future development.

Petzold, A. (2005). "Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss." J Neurol Sci 233(1-2): 183-98.

            This review on the role of neurofilaments as surrogate markers for axonal degeneration in neurological diseases provides a brief background to protein synthesis, assembly, function and degeneration. Methodological techniques for quantification are described and a protein nomenclature is proposed. The relevance for recognising anti-neurofilament autoantibodies is noted. Pathological implications are discussed in view of immunocytochemical, cell-culture and genetic findings. With reference to the present symposium on multiple sclerosis, the current literature on body fluid levels of neurofilaments in demyelinating disease is summarised.

Peterson, J. W. and B. D. Trapp (2005). "Neuropathobiology of multiple sclerosis." Neurol Clin 23(1): 107-29, vi-vii.

Peterlik, M. and H. S. Cross (2005). "Vitamin D and calcium deficits predispose for multiple chronic diseases." Eur J Clin Invest 35(5): 290-304.

            There is evidence from both observational studies and clinical trials that calcium malnutrition and hypovitaminosis D are predisposing conditions for various common chronic diseases. In addition to skeletal disorders, calcium and vitamin D deficits increase the risk of malignancies, particularly of colon, breast and prostate gland, of chronic inflammatory and autoimmune diseases (e.g. insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis), as well as of metabolic disorders (metabolic syndrome, hypertension). The aim of the present review was to provide improved understanding of the molecular and cellular processes by which deficits in calcium and vitamin D cause specific changes in cell and organ functions and thereby increase the risk for chronic diseases of different aetiology. 1,25-Dihydroxyvitamin D(3) and extracellular Ca(++) are both key regulators of proliferation, differentiation and function at the cellular level. However, the efficiency of vitamin D receptor-mediated intracellular signalling is limited by the negative effects of hypovitaminosis D on extrarenal 25-hydroxyvitamin D-1alpha-hydroxylase activity and thus on the production of 1,25-dihydroxyvitamin D(3). Calcium malnutrition eventually causes a decrease in calcium concentration in extracellular fluid compartments, resulting in organ-specific modulation of calcium-sensing receptor activity. Hence, attenuation of signal transduction from the ligand-activated vitamin D receptor and calcium-sensing receptor seems to be the prime mechanism by which calcium and vitamin D insufficiencies cause perturbation of cellular functions in bone, kidney, intestine, mammary and prostate glands, endocrine pancreas, vascular endothelium, and, importantly, in the immune system. The wide range of diseases associated with deficits in calcium and vitamin D in combination with the high prevalence of these conditions represents a special challenge for preventive medicine.

Perennou, D., P. Decavel, et al. (2005). "[Evaluation of balance in neurologic and geriatric disorders]." Ann Readapt Med Phys 48(6): 317-35.

            OBJECTIVE: To analyse the clinical usefulness and metrological properties of the main techniques and indices used to assess balance disorders. METHODS: More than 4000 abstracts referenced in MEDLINE and dealing with postural control and postural disorders (wide screening) were reviewed to determine the main postural techniques and indices used in a clinical context. We retained abstracts with a high citation frequency and those with interesting findings. Corresponding key words were identified for a specific search of articles that we analysed. RESULTS: Postural assessment tools can be classified as scales of ordinal items, tests based on metric or chronometric measurement, posturography, and verticality perception. These techniques are complementary, and their association is recommended in a clinical context. Regarding generic tools, the Falls-related Efficacy Scale (FES) and the Activities-specific Balance Confidence scale (ABC scale) would be enhanced if comparatively analysed and reworked to allow for a feasible and reliable assessment of the fear of falling. Despite a wide diffusion in numerous postural fields worldwide, the Berg Balance Scale (BBS) and the Functional Reach Test (FRT) do not have the required criteria to remain the gold standards they were in the 1990s. Static posturography should be normalised and yield more reliable indices. The clinical relevance of the subjective assessment of visual, haptic, and postural verticals are questionable, especially to explain postural disability. Regarding specific tools, the Tinetti test (TT) and the Time Up and Go test (TUG) are the most suited to assess postural capacities in very elderly people, in whom the predictive validity of the postural assessment of falls is still modest. In stroke patients, the Postural Assessment Scale for Stroke (PASS), posturography, lateropulsion assessment, and vertically perception are interesting and complementary techniques. Postural assessment relies mainly upon the 5 postural items of the Unified Parkinson Disease Rating Scale (UPDRS) in people with Parkinson disease and upon the Romberg test and posturography in patients with cerebellar or proprioceptive ataxia. Some novel postural scales for patients with multiple sclerosis or spinal cord injury are also emerging. CONCLUSION: Among numerous tools that contribute to the assessment of postural disorders, only the most recent ones (developed in the last 10 years) have undergone complete validation. It is now crucial to compare these tools, not only in terms of reproducibility and internal consistency, but also overall, in terms of feasibility, responsiveness, and predictive validity for a given population.

Pepping, M. and D. M. Ehde (2005). "Neuropsychological evaluation and treatment of multiple sclerosis: the importance of a neuro-rehabilitation focus." Phys Med Rehabil Clin N Am 16(2): 411-36, viii.

            This article describes the components of a neuropsychologic evaluation and some of the primary indications for its use in multiple sclerosis (MS). We also detail the kinds of neurocognitive and neurobehavioral problems that are cited commonly in the relevant literature and seen in the clinical setting. We provide a brief overview of the brain structures that are affected commonly by MS, and their implications for neuropsychologic function. We have included an overview of some of the current medications that are used to target cognitive and emotional symptoms that can be a direct result of the disease. We also present four representative case examples of composite patients, and briefly review the ways in which neuropsychologic evaluation and neuro-rehabilitation treatments can help people who have MS.

Pelczynska, K., I. Jaroszewicz, et al. (2005). "[Biological activity of calcitriol and its new analogues -- potential therapeutic applications]." Postepy Hig Med Dosw (Online) 59: 129-39.

            Calcitriol is effective not only in the regulation of calcium-phosphate homeostasis, but also in promoting the differentiation and inhibition of proliferation of various cells. Calcitriol seems to be a potent drug with various therapeutic applications, such as regulation of calcium-phosphate homeostasis and treatment of psoriasis, autoimmune diseases, and cancer. Since clinical use of calcitriol is largely limited, due to its undesirable side effect of hypercalcemia, numerous calcitriol analogues have been synthesized to obtain compounds with better therapeutic profiles. This paper summarizes the current state of knowledge concerning the cellular mechanisms of calcitriol's biological activity and their clinical implications. Such medical application includes treatment (as a single-drug or in combination) of osteoporosis, renal osteodystrophy, psoriasis (calcipotriol or tacalcitol ointment), autoimmunological diseases (including multiple sclerosis), and some cancers. The efforts to obtain new vitamin D3 analogues are also briefly reviewed. The structures and roles of vitamin D receptors in the biological effects of calcitriol and its analogues are discussed.

Pease, J. E. and R. Horuk (2005). "CCR1 antagonists in clinical development." Expert Opin Investig Drugs 14(7): 785-96.

            Chemokines (chemotactic cytokines) are a family of low-molecular-weight proteins that direct the cellular migration of leukocytes by binding to and activating the G protein-coupled receptors displayed on the leukocyte cell surface. The inadvertent or excessive generation of chemokines has been associated with the inflammatory component of several disease processes, and consequently, considerable efforts have been made to characterise chemokine/chemokine receptor interactions with the ultimate aim of therapeutic intervention. This review focuses on the biology of CC chemokine receptor 1, which together with its ligands is thought to recruit leukocytes during the progression of rheumatoid arthritis, multiple sclerosis and organ transplant rejection. The developments made in antagonising this receptor and efficacies of these compounds in the clinical setting are also highlighted.

Pearce, J. M. (2005). "Neuromyelitis optica." Spinal Cord 43(11): 631-4.

            The combination of optic neuritis and myelitis, the so-called Neuromyelitis optica is an uncommon pattern of demyelinating disorder. In 1870, Sir Thomas Clifford Allbutt first reported the association and Erb published a comparable report. Gowers and Dreschfeld described other instances in the 19th century. This paper attempts to review the syndrome to consider whether it merits recognition as a disease, sui generis, or rather as a syndrome symptomatic of multiple sclerosis, acute disseminated encephalomyelitis, and other immunological disorders. Two forms are distinguished: a monophasic illness, and a relapsing form. The claimed differential features separating it from classical multiple sclerosis are appraised. Modern immunology suggests an antibody-dependent, complement-mediated pathogenesis.

Patwardhan, M. B., D. B. Matchar, et al. (2005). "Cost of multiple sclerosis by level of disability: a review of literature." Mult Scler 11(2): 232-9.

            We performed a review of the economic literature to identify what is known about the relationship between Expanded Disability Status Scale (EDSS) categories and cost of multiple sclerosis (MS). We sought cohort studies of patients with multiple sclerosis that described the costs attributed to each EDSS score and utilized specific inclusion criteria for the selection of 10 studies. We found that both direct and indirect costs rise continuously with increasing EDSS category, and this rise is qualitatively exponential. The rise in indirect costs appears at lower EDSS scores. The cost of a relapse occurring in any given EDSS category exceeds that associated with that particular EDSS category. Few studies comprehensively assessed the entire spectrum of the costs, and much of the literature is based on EDSS categories in coarse groupings. In spite of several variations between studies, one important conclusion that we can draw is that rise in cost is positively correlated to scores on the EDSS categories, and therefore agents with a capacity to prevent or arrest the rate of MS progression may affect the overall cost of MS.

Patten, S. B. (2005). "Treatment of neuropsychiatric syndromes in multiple sclerosis." Expert Rev Neurother 5(3): 413-20.

            The treatment of multiple sclerosis has been revolutionized during the past 10 years by the introduction of disease-modifying therapies. However, day-to-day management of the symptoms and complications of this condition will, for the foreseeable future, continue to be important management concerns. Among the most problematic and troublesome manifestations of multiple sclerosis are its neuropsychiatric manifestations. Most prominent among these are depression, pathologic laughing and crying, fatigue, cognitive problems, sleep disorders and disorders of sexual function. There have been relatively few randomized controlled trials of pharmacologic treatments for these conditions. Available treatments for the management of fatigue and cognitive deficits remain inadequate and patients must often accommodate these symptoms in their lifestyle.

Panyi, G. (2005). "Biophysical and pharmacological aspects of K+ channels in T lymphocytes." Eur Biophys J 34(6): 515-29.

            Voltage-gated Kv1.3 and Ca2+-activated IKCa1 K+ channels play a pivotal role in antigen-dependent activation and proliferation of lymphocytes.These channels primarily determine the membrane potential of T cells, and thus regulate the magnitude of the Ca2+ signal required for efficient gene transcription and subsequent proliferation. Although these facts are generally well described and acknowledged, some recent discoveries have motivated research in this field, which is reviewed herein along with the basic biophysical characterization of Kv1.3 and IKCa1. The discovery of T cell subset-specific expression of Kv1.3 points towards the potential therapeutic use of high affinity and high specificity Kv1.3 inhibitors as specific immunosuppressors in the management of autoimmune diseases, such as Multiple Sclerosis. In meeting the demands for an ideal immunosuppressor, several laboratories have discovered potent natural Kv1.3- specific inhibitors and engineered peptides which have a better pharmacological profile based on the biophysical characterization of the interaction surface between the channel pore and the toxins. In contrast to the generally accepted permissive role of Kv1.3 during lymphocyte activation, the discovery of the localization of Kv1.3 in the immunological synapse might open new opportunities in the regulation of T cell activation by this channel species.

Ozgen, H. M., W. C. Overweg-Plandsoen, et al. (2005). "Cerebellar hypoplasia-endosteal sclerosis: a long term follow-up." Am J Med Genet A 134(2): 215-9.

            Cerebellar hypoplasia with endosteal sclerosis is an infrequent entity that has been described in only four cases. Major clinical symptoms are cerebellar hypoplasia causing ataxia, hypotonia, mild to moderate developmental delay, microcephaly, growth retardation, endosteal sclerosis, tooth eruption disturbances, and hip dislocations. We report on a girl with this entity, whom we followed for 11 years. The endosteal sclerosis remained stationary over time, as were the clinical neurological symptoms, but neuroadiological symptoms were slowly progressive. We provide a short review of this probably autosomal recessively inherited disorder. (c) 2005 Wiley-Liss, Inc.

Osoegawa, M. (2005). "[Atopic myelitis]." Nippon Rinsho 63 Suppl 5: 125-30.

Oppenheim, J. J., H. F. Dong, et al. (2005). "Autoantigens act as tissue-specific chemoattractants." J Leukoc Biol 77(6): 854-61.

            We have investigated the chemoattractant properties of self-antigens associated with autoimmune diseases and solid tumors. Many autoantigens induced leukocyte migration, especially by immature dendritic cells (iDC) by interacting with various chemoattractant Gi-protein-coupled receptors (GiPCR). Our initial observation that myositis-associated autoantigens, histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, were chemotactic for CC chemokine receptor 5 (CCR5)- and CCR3-expressing leukocytes, while other nonautoantigenic aminoacyl-tRNA synthesases were not, suggested that only self-antigens capable of interacting with receptors on antigen-presenting cells were immunogenic. We next determined that self-antigens associated with autoimmune diseases, e.g., multiple sclerosis or experimental autoimmune encephalomyelitis, type I diabetes, scleroderma, systemic lupus erythematosus, autoimmune uveitis, or experimental autoimmune uveitis (EAU), were chemotactic for GiPCR expressed by iDC. The majority of autoantigens were DC chemoattractants at 10-100 ng/ml, but did not induce DC maturation until they reached 1000-fold higher concentrations. Interphotoreceptor retinoid-binding protein and retinal arrestin (S-antigen) are targets of autoantibodies in human uveitis and are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or CXCR3-expressing iDC. However, although S-antigen does not induce EAU in wild-type mice, it is nevertheless a chemoattractant for murine iDC. These unexpected observations suggested that the chemotactic activity of these tissue-specific self-antigens could be involved in promotion of tissue repair and restoration. Thus, the primary role of autoantigens may be to alert the immune system to danger signals from invaded and damaged tissues to facilitate repair, and autoimmune responses subsequently develop only in subjects with impaired immunoregulatory function.

Olsson, T., F. Piehl, et al. (2005). "Genetic dissection of neurodegeneration and CNS inflammation." J Neurol Sci 233(1-2): 99-108.

            Inflammation and neurodegeneration characterize multiple sclerosis, as well as many other diseases of the central nervous system (CNS). The understanding of the molecular pathways that regulate these processes is of fundamental importance for the development of new therapies. Nerve lesions paradigms in animals can serve as important tools to dissect central features of human CNS disease and by using these models certain key regulators have also been identified. However, our knowledge of how aspects of neurodegeneration and CNS inflammation are regulated on a genomic level is very limited. Such knowledge may help to unravel disease mechanisms. By using a standardized nerve trauma model, ventral root avulsion (VRA), in a series of inbred rat strains we here demonstrate a potent genetic regulation of the degree of neuron death and glial activation. Genome wide mapping of these phenotypes in experimental rat strain crosses identifies several quantitative trait loci (QTLs) controlling nerve lesion-induced nerve cell death, local T cell accumulation and expression of MHC class II on microglia. This approach may lead to the identification of evolutionary conserved genetic polymorphisms in key controlling genes, which can serve as prime candidates for association studies in several human CNS diseases.

Olson, J. K., A. M. Ercolini, et al. (2005). "A virus-induced molecular mimicry model of multiple sclerosis." Curr Top Microbiol Immunol 296: 39-53.

            Multiple sclerosis1 (MS) is an immune-mediated autoimmune demyelinating disease in humans. The initiating event in MS is unknown, but epidemiological evidence suggests that virus infections may be important and one possible mechanism for induction of infection-induced autoimmune disease is molecular mimicry. To test the ability of a virus encoding a self myelin mimic epitope to induce an autoimmune response, we have developed a mouse model wherein the immunodominant myelin epitope PLP139-151, or mimics of this epitope, were inserted into a nonpathogenic variant of Theiler's murine encephalomyelitis virus (TMEV). SJL mice infected with TMEV containing PLP139-151 or a mimic of PLP139-151 expressed by the protease IV protein of Haemophilus influenzae, sharing only 6/13 amino acids with the native epitope, developed an early-onset demyelinating disease associated with activation of CD4+ T cells reactive with PLP139-151. We have used this molecular mimicry model to further address the requirements for mimic epitope processing and presentation during infection and the requirements for TCR recognition and MHC binding of mimic epitopes. We have also investigated whether molecular mimicry may require multiple infections, with either the mimic-encoding virus or an unrelated virus, to initiate autoimmune disease. Finally, we have asked whether a virus encoding a molecular mimic has to directly infect the target organ to induce autoimmune disease. Overall, this virus-induced molecular mimicry model has provided critical information regarding the mechanisms by which infection-induced molecular mimicry can induce autoimmune diseases.

Oksenberg, J. R. and S. L. Hauser (2005). "Genetics of multiple sclerosis." Neurol Clin 23(1): 61-75, vi.

Oksenberg, J. R. and L. F. Barcellos (2005). "Multiple sclerosis genetics: leaving no stone unturned." Genes Immun 6(5): 375-87.

            Compelling epidemiologic and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how someone responds to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and significant environmental influences. Equally significant, it is also likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others. With the aid of novel analytical algorithms, the combined study of genomic, transcriptional, proteomic, and phenotypic information in well-controlled study groups will define a useful conceptual model of pathogenesis and a framework for understanding the mechanisms of action of existing therapies for this disorder, as well as the rationale for novel curative strategies.

Ohta, M. and K. Ohta (2005). "[Immunologic tests: Myelin basic protein and anti-myelin basic protein antibody]." Nippon Rinsho 63 Suppl 7: 596-8.

Offner, H. and A. A. Vandenbark (2005). "Congruent effects of estrogen and T-cell receptor peptide therapy on regulatory T cells in EAE and MS." Int Rev Immunol 24(5-6): 447-77.

            Both estrogen (E2) and T-cell receptor (TCR) peptides have beneficial effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and possibly multiple sclerosis (MS) that involve distinct but congruent mechanisms. Of interest, these two approaches share an ability to enhance expression of the FoxP3 gene and associated activity of regulatory T (Treg) cells. E2 increases the number and activity of FoxP3(+) T cells through Esr-1 signaling during TCR activation of CD4(+)CD25(-) T cells. In contrast, TCR peptide therapy appears to increase the frequency of regulatory FoxP3(+) T cells specific for self-TCR determinants expressed by targeted pathogenic T cells. The combined effects on Treg expansion and activation induced by these distinct immunoregulatory approaches may account for their potent effects on clinical EAE and argue for a similar combined therapeutic approach for MS.

Oertelt, S., C. Selmi, et al. (2005). "Genes and goals: an approach to microarray analysis in autoimmunity." Autoimmun Rev 4(7): 414-22.

            A significant body of data on gene expression patterns in autoimmune diseases has been generated by microarray analysis. Although results are very promising, there are many factors that have detracted from the data. Indeed, no common methodological directions are available. Similarly, collection techniques, processing methods, and statistical approaches are often different. The impact of future studies will depend on the comparison of large datasets to validate results and must include rigorous statistical analysis. To better illustrate the issue we review herein the gene expression patterns observed in five representative autoimmune diseases, i.e. systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, dermatomyositis, and primary biliary cirrhosis. We also emphasize how, once potential chromosome regions or pathways are identified, specific array design will be a powerful resource when used on large and representative populations.

Norman, M. U. and M. J. Hickey (2005). "Mechanisms of lymphocyte migration in autoimmune disease." Tissue Antigens 66(3): 163-72.

            The recruitment of leukocytes to inflamed tissues plays an essential role in combating infection and promoting wound healing. However, in autoimmune diseases such as multiple sclerosis and diabetes, leukocytes enter tissues and contribute to inappropriate inflammatory responses, which cause tissue injury and dysfunction. In diseases of this type, lymphocytes play critical roles in initiating and maintaining these aberrant inflammatory responses. The aim of this review is to examine the mechanisms whereby T-lymphocytes enter tissues in autoimmune diseases and to compare these mechanisms between various organs and diseases. An overview of the mechanisms of leukocyte recruitment and the techniques used to study leukocyte trafficking is provided, focusing on the use of intravital microscopy as a tool to assess the functional microvasculature in vivo. We also discuss the series of tissue homing events which allow naive lymphocytes to first enter lymph nodes and undergo activation, then subsequently to home to the peripheral organ where their cognate antigen is present. Finally, we examine mechanisms of leukocyte recruitment in diseases such as multiple sclerosis, autoimmune diabetes, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and asthma.

Nishino, S. and T. Kanbayashi (2005). "Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system." Sleep Med Rev 9(4): 269-310.

            Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

Nicholson, M. J., M. Hahn, et al. (2005). "Unusual features of self-peptide/MHC binding by autoimmune T cell receptors." Immunity 23(4): 351-60.

            Structural studies on T cell receptors (TCRs) specific for foreign antigens demonstrated a remarkably similar topology characterized by a central, diagonal TCR binding mode that maximizes interactions with the MHC bound peptide. However, three recent structures involving autoimmune TCRs demonstrated unusual interactions with self-peptide/MHC complexes. Two TCRs from multiple sclerosis patients bind with unconventional topologies, and both TCRs are shifted toward the peptide N terminus and the MHC class II beta chain helix. A TCR from the experimental autoimmune encephalomyelitis (EAE) model binds in a conventional orientation, but the structure is unusual because the self-peptide only partially fills the binding site. For all three TCRs, interaction with the MHC bound self-peptide is suboptimal, and only two or three TCR loops contact the peptide. Optimal TCR binding modes confer a competitive advantage for antimicrobial T cells during an infection, whereas altered binding properties may permit survival of a subset of autoreactive T cells during thymic selection.

Neuhaus, O., O. Stuve, et al. (2005). "Putative mechanisms of action of statins in multiple sclerosis--comparison to interferon-beta and glatiramer acetate." J Neurol Sci 233(1-2): 173-7.

            Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are widely prescribed as cholesterol-lowering agents. They are promising candidates for future treatment in multiple sclerosis (MS) as they have been shown to exhibit immunomodulatory effects. Recent reports have demonstrated that statins are effective in preventing and reversing chronic and relapsing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Furthermore, in vitro experiments with human immune cells have documented an immunomodulatory mode of action of statins comparable to that of interferon (IFN)-beta. An open label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. This article reviews data thus far present on the putative mechanisms of action of statins in the immunopathogenesis of MS. Furthermore, the role of statins as potential pharmacotherapy for MS is discussed in the context of the mechanisms of approved immunotherapies in MS, namely IFN-beta and glatiramer acetate (GA).

Natarajan, N. and R. Weinstein (2005). "Therapeutic apheresis in neurology critical care." J Intensive Care Med 20(4): 212-25.

            Therapeutic apheresis has been widely accepted in the treatment of neurological disorders that are understood to be mediated by humoral and/or cellular immunity. The clinical presumption is that well-established and/or unknown insults cause damage to nerves or their myelin sheaths. The rationale for apheresis treatments for these neurological disorders relates to removal of offending immune (or other) mediators, thus blunting the attack and permitting recovery of nerve and/or myelin. This review will concentrate on the role of therapeutic apheresis, in particular therapeutic plasma exchange, in neurological disorders that may frequently be seen by intensivists.

Nash, P. T. and T. H. Florin (2005). "Tumour necrosis factor inhibitors." Med J Aust 183(4): 205-8.

            The cytokine, tumour necrosis factor-alpha (TNF-alpha) plays a key role in the pathogenesis of many chronic inflammatory and rheumatic diseases, in particular, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Controlled trials have shown that the TNF inhibitors (etanercept, infliximab and adalimumab) significantly reduce symptoms and signs, improve function and quality of life, and reduce radiologically evident damage in patients with rheumatoid diseases. For reasons that are not entirely clear, etanercept does not work in Crohn's disease. Injection site and intravenous reactions and increased risk of infection (in particular, reactivation of tuberculosis) are associated with the use of these agents. Increased risk of lymphoproliferative disease, the development of lupus-like syndromes and demyelination, including optic neuritis and reactivation of multiple sclerosis, are under evaluation in long-term follow-up studies. The TNF inhibitors are expensive (about $18 000 per year), and in some patients need to be given continuously to maintain benefit, even in the presence of other immunosuppressive therapy.

Narayana, P. A. (2005). "Magnetic resonance spectroscopy in the monitoring of multiple sclerosis." J Neuroimaging 15(4 Suppl): 46S-57S.

            In addition to providing information on tissue structure, magnetic resonance (MR) technology offers the potential to investigate tissue metabolism and function. MR spectroscopy (MRS) offers a wealth of data on the biochemistry of a selected brain tissue volume, which represent potential surrogate markers for the pathology underlying multiple sclerosis (MS). In particular, the N-acetylaspartate peak in an MR spectrum is a putative marker of neuronal and axonal integrity, and the choline peak appears to reflect cell-membrane metabolism. On this basis, a diminished N-acetylaspartate peak is interpreted to represent neuronal/axonal dysfunction or loss, and an elevated choline peak represents heightened cell-membrane turnover, as seen in demyelination, remyelination, inflammation, or gliosis. Therefore, MRS may provide a unique tool to evaluate the severity of MS, establish a prognosis, follow disease evolution, understand its pathogenesis, and evaluate the efficacy of therapeutic interventions, which complements the information obtained from the various forms of assessment made by conventional MR imaging.

Napoli, S. Q. and R. Bakshi (2005). "Magnetic resonance imaging in multiple sclerosis." Rev Neurol Dis 2(3): 109-16.

            Magnetic resonance imaging (MRI) has played a central role in the clinical management and scientific investigation of multiple sclerosis (MS) and has become the most important ancillary tool for diagnosing and monitoring the disease. Conventional MRI techniques are used to assess overt lesions and atrophy in the central nervous system and include spin-echo T2-weighted, pre- and post-gadolinium-enhanced spin-echo T1-weighted, and fluid-attenuated inversion-recovery images. Advanced MRI techniques such as diffusion-weighted imaging, magnetization transfer imaging, magnetic resonance spectroscopy, and functional MRI have increased our understanding of the pathogenesis of MS. The role of these newer techniques in clinical practice remains under investigation. In this review, we will focus on the role of MRI in the diagnosis and management of MS. We will also review how advanced MRI techniques contribute to our understanding of MS.

Nakasaka, Y., M. Atsumi, et al. (2005). "[Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with relapsing multiple sclerosis]." No To Shinkei 57(1): 51-5.

            We report a 47-year-old man with multiple sclerosis (MS) with previous history of recurrent sensorimotor disturbance and visual deficit. The patient developed bilateral motor weakness in the upper limbs, and systemic malaise. An administration of 20 mg/day of prednisolone was ineffective for his symptoms and he complained dyspnea a week later. On admission, his clinical findings included brainstem dysfunction with optic nerve atrophy, motor disturbance in the bilateral upper limbs, hyperreflexia, and superficial sensory disturbance. Biochemical examination revealed marked reduction in serum Na (117 mEq/l) and C1 (85 mEq/l) with increased urinary Na excretion. Although his plasma osmotic pressure decreased to 233 mOsm/kg, urinary osmotic pressure increased to 409 mOsm/kg. Serum antidiuretic hormone (ADH) concentration was 26.1 pg/ml and plasma renin activity was 0.1 ng/ml/ hour. Renal function and adrenal function were normal. Cerebrospinal fluid contained increased protein concentration, IgG, and myelin basic protein. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with MS was diagnosed. Intravenous Na infusion with restricted supplemental fluid and serial administration of methylprednisolone (1,000 mg/day for three days) improved his neurological abnormalities and normalized his serum serum Na level and plasma osmotic pressure. This suggests that demyelinating lesions in the hypothalamus due to MS may cause the transient increased ADH secretion.

Nagpal, S., S. Na, et al. (2005). "Noncalcemic actions of vitamin D receptor ligands." Endocr Rev 26(5): 662-87.

            1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.

Mutter, J., J. Naumann, et al. (2005). "[Amalgam risk assessment with coverage of references up to 2005]." Gesundheitswesen 67(3): 204-16.

            Amalgam, which has been in use in dentistry for 150 years, consists of 50 % elemental mercury and a mixture of silver, tin, copper and zinc. Minute amounts of mercury vapour are released continuously from amalgam. Amalgam contributes substantially to human mercury load. Mercury accumulates in some organs, particularly in the brain, where it can bind to protein more tightly than other heavy metals (e. g. lead, cadmium). Therefore, the elimination half time is assumed to be up to 1 - 18 years in the brain and bones. Mercury is assumed to be one of the most toxic non-radioactive elements. There are pointers to show that mercury vapour is more neurotoxic than methyl-mercury in fish. Review of recent literature suggests that mercury from dental amalgam may lead to nephrotoxicity, neurobehavioural changes, autoimmunity, oxidative stress, autism, skin and mucosa alterations or non-specific symptoms and complaints. The development of Alzheimer's disease or multiple sclerosis has also been linked to low-dose mercury exposure. There may be individual genetical or acquired susceptibilities for negative effects from dental amalgam. Mercury levels in the blood, urine or other biomarkers do not reflect the mercury load in critical organs. Some studies regarding dental amalgam reveal substantial methodical flaws. Removal of dental amalgam leads to permanent improvement of various chronic complaints in a relevant number of patients in various trials. Summing up, available data suggests that dental amalgam is an unsuitable material for medical, occupational and ecological reasons.

Mutch, K. (2005). "Information for young people when multiple sclerosis enters the family." Br J Nurs 14(14): 758-67.

            Multiple sclerosis (MS) typically affects people aged 20-40 years and, by its very nature, is characterized by unpredictability, uncertainty and variability, and is therefore bound to have an impact on children who have a parent with MS. There has been little work done to assess the needs of young people living with MS in their family. A series of workshops specifically aimed at 9-14-year-olds who have a parent with MS have been successfully conducted. This article reviews the background to setting up the workshop and identifies implications for future MS specialist nurses to help this potentially vulnerable group of people. By breaking the silence and talking about MS with young people, the myths can be removed and the anxieties reduced.

Murdoch, D. and K. A. Lyseng-Williamson (2005). "Subcutaneous recombinant interferon-beta-1a (Rebif): a review of its use in relapsing-remitting multiple sclerosis." Drugs 65(9): 1295-312.

            Subcutaneous recombinant interferon-beta-1a (Rebif) 22 or 44 microg three times weekly is a valuable option in the first-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS). It has shown benefits on outcome measures related to relapses, progression of disability and magnetic resonance imaging (MRI) in clinical trials. A significant efficacy advantage for subcutaneous interferon-beta-1a three times weekly over intramuscular interferon-beta-1a 30 microg once weekly was shown at 24 and 48 weeks. The most common adverse events are generally mild and clinically manageable. Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous interferon-beta-1a 44 microg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat RRMS.

Muller-Forell, W. (2005). "[Neuroradiology of the intracranial visual pathway. Part II]." Radiologe 45(11): 1043-55.

            Part 2 mainly presents intrinsic lesions as the most common brain tumors (astrocytoma of all grades, ependymoma), arising in the region of the visual pathway. A second focus is on vascular pathology, not only infarction, but cavernoma and venous malformation in Sturge-Weber syndrome. The third topic deals with inflammatory processes such as multiple sclerosis or sarcoidosis.

Mukhtar, M., E. Acheampong, et al. (2005). "T-Cells and excitotoxicity: HIV-1 and other neurodegenerative disorders." Neuromolecular Med 7(3): 265-73.

            Until recently the central nervous system (CNS) was considered an immune-privileged site, however, technological and immunological advances have resulted in the CNS being reclassified as an "immune-specialized site." The immune cells, particularly T-cells, continuously patrol the brain and are involved in neuroimmune responses. As such, any changes in the brain microenvironment could affect the physiological functioning of T-cells. Particularly, neurotransmission- associated abnormalities, such as excitotoxicity associated with hypersecretion of glutamate, could severely affect the neuroimmune function of T-cells. Excitotoxicity is involved in the pathogenesis of a number of neurodegenerative disorders. The specific excitotoxicity triggered by the excitatory amino acid neurotransmitter, glutamate, is considered a key mechanism involved in neuronal death. The inability of brain immune cells to overcome these aberrant changes is an active area of investigation. In the systemic circulation, glutamate is inversely related to the number of CD4+ T-cells; however, the effects of elevated glutamate and glutamate-induced exicitotoxicity on cells homing in the brain are critical for understanding neuropathogenesis of neurodegenerative disorders.

Moynagh, P. N. (2005). "The interleukin-1 signalling pathway in astrocytes: a key contributor to inflammation in the brain." J Anat 207(3): 265-9.

            A dysregulated inflammatory response in the central nervous system (CNS) lies at the heart of many neuropathological conditions such as multiple sclerosis and Alzheimer's disease. A key component of these inflammatory conditions is the accumulation of leukocytes in the CNS. The infiltration of leukocytes into the brain is dependent on the induction of leukocyte adhesion molecules and chemoattractant chemokines. Recent studies have suggested the astrocyte to be a key cell in mediating the inflammatory process in the brain and in expressing adhesion molecules and chemokines. Here I overview work in my laboratory and others that demonstrates interleukin-1 (IL-1) to be a key inducer of the expression of these molecules in astrocytes. The temporal expression is sustained in nature and this is due to prolonged activation of the transcription factor NFkappaB. The molecular basis to the sustained activation of NFkappaB is also discussed. The IL-1 signalling pathway thus emerges as a valuable therapeutic target in the treatment of presently incurable neuropathological conditions.

Mouzaki, A., S. Deraos, et al. (2005). "Advances in the treatment of autoimmune diseases; cellular activity, type-1/type-2 cytokine secretion patterns and their modulation by therapeutic peptides." Curr Med Chem 12(13): 1537-50.

            Autoimmune diseases are many, have an overall prevalence of about 3% of the world population, affecting more women than men, and their incidence is influenced by genetics and the environment. It is currently thought that the immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate or non-functional immunoregulatory mechanisms, can lead to the development of an autoimmune disease. Advances in the treatment of autoimmune diseases follow a better understanding of the abnormalities in the cellular activity pathways and the resulting, often permanent, imbalance of the pro- and anti-inflammatory cytokine expression profiles. Over the past few years, there has been a dramatic change in the therapeutic regimens employed in autoimmune diseases, with soluble receptors, monoclonal antibodies and molecular mimetics enhancing or gradually replacing conventional immunosuppressive therapies. New biologicals have been developed, targeting defined pathways of the adaptive immune response. One approach towards the therapeutic management of autoimmune diseases involves the design and use of peptide analogs of disease-associated epitopes to be used as immunomodulatory drugs. Peptides can target cell-functions directly, by interfering with the formation of the tri-molecular complex MHC-Peptide-TCR, and/or they can target soluble mediators such as cytokines or their receptors, eventually replacing monoclonal antibody therapies. This review offers an update on the treatment modalities of certain prototypic autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on cell activation and cytokine expression profiles.

Mourich, D. V. and N. B. Marshall (2005). "Antisense approaches to immune modulation for transplant and autoimmune diseases." Curr Opin Pharmacol 5(5): 508-12.

            Antisense oligomers have been shown to be effective tools for inhibiting gene expression in a highly specific manner. This technology has proven to be invaluable for determining gene function in conventional molecular and cellular studies. However, the promise of an antisense-based drug technology, suggested by antiviral efficacy shown nearly 25 years ago, is just now coming of age. Since then, numerous antisense approaches have been shown to be effective in animal models against numerous viruses and some tumors. Not surprisingly, antisense agents targeting these diseases are taking the lead in human clinical trials and FDA approval. Although comparatively smaller in scope, approaches for modulating immune responses to treat Crohn's disease, diabetes, multiple sclerosis and transplant rejection appear to be the next burgeoning phase of development in antisense therapy.

Morrissey, S. P., E. Le Page, et al. (2005). "Mitoxantrone in the treatment of multiple sclerosis." Int MS J 12(3): 74-87.

            Mitoxantrone is useful for the treatment of cancer and MS and, as with other chemotherapeutic agents, many studies have examined its tolerability. The suitability of mitoxantrone in MS is particularly interesting because of its role in treating various stages of the disease. Evidence shows that mitoxantrone could be a first-line treatment for malignant forms of MS, and a second-line drug in relapsing-remitting or secondary progressive MS that is unresponsive to interferon beta-1a, -1b or glatiramer acetate. Mitoxantrone should, however, be restricted to patients with demonstrable inflammatory disease activity, and should only be prescribed by neurologists with previous experience in both MS and mitoxantrone therapy. This review examines the properties of mitoxantrone, its tolerability, and discusses its suitability for treating various forms of MS, referring to several important studies.

Morand, E. F. (2005). "New therapeutic target in inflammatory disease: macrophage migration inhibitory factor." Intern Med J 35(7): 419-26.

            The cytokine macrophage migration inhibitory factor (MIF) participates in fundamental events in innate and adaptive immunity. The profile of activities of MIF in vivo and in vitro is strongly suggestive of a role for MIF in the pathogenesis of many inflammatory diseases, including rheumatoid arthritis (RA), and hence antagonism of MIF is suggested as a potential therapeutic strategy in inflammatory disease. The best developed case for therapeutic antagonism of MIF is in RA. In RA, MIF is abundantly expressed in serum and synovial tissue. MIF induces synovial expression of key pro-inflammatory genes, regulates the function of endothelial cells and leucocytes, and is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumour suppressor protein p53. In animal models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. A similar case has been made, for example using MIF-deficient mice, in models of atheroma, colitis, multiple sclerosis and other inflammatory diseases. The relationship with p53 also means MIF may be important in the link between inflammatory disease and cancer, such as is seen in RA or colitis. MIF also has a unique relationship with glucocorticoids, in that despite antagonizing their effects, the expression of MIF is in fact induced by glucocorticoids. Thus, MIF functions as a physiological counter-regulator of the anti-inflammatory effects of glucocorticoids. This may be entrained by selective activation of mitogen-activated protein kinases rather than nuclear factor kappa B. Therapeutic MIF antagonism may therefore provide a specific means of 'steroid sparing'. Exploitation of antibody, soluble receptor or small molecule technologies may soon lead to the ability to test in the clinic the importance of MIF in human inflammatory diseases.

Moore, G. R. (2005). "Mri correlates of MS pathologic subtypes." Mult Scler 11(1): 103-5.

Moon, S. J., A. A. Fryer, et al. (2005). "Ultraviolet radiation, vitamin D and risk of prostate cancer and other diseases." Photochem Photobiol 81(6): 1252-60.

            Most common diseases appear to result from complex, poorly understood interactions between genetic and environmental factors. Relatively few factors have been unequivocally linked with disease risk or outcome. Evidence from various studies using different experimental approaches has been interpreted as showing that, apart from its harmful effects on the pathogenesis of the common skin cancers, ultraviolet radiation (UVR) may exert a beneficial effect on development of various internal cancers and other pathologies. This concept is supported by parallel studies showing that hypovitaminosis D is linked with increased risk of various diseases including insulin resistance and multiple sclerosis. These findings suggest that, first, host factors such as skin pigmentation that affect UVR-induced synthesis of vitamin D and, second, polymorphism in genes that mediate the effectiveness of vitamin D action are susceptibility candidates for a variety of diseases. Collectively, these data suggest the hypothesis that, via effects on vitamin D synthesis, UVR exposure has beneficial effects on susceptibility and outcome to a variety of complex diseases. We describe evidence from studies in various diseases, but mainly from prostate cancer patients, that supports this hypothesis, but we emphasize that, although supportive data are available, the concept is unproven. Indeed, other explanations are possible. However, given the potentially important public health implications of the hypothesis and the potential for the development of novel therapeutic modalities, we believe the concept is worthy of further investigation.

Montalban, X. (2005). "Primary progressive multiple sclerosis." Curr Opin Neurol 18(3): 261-6.

            PURPOSE OF REVIEW: The present article reviews the currently ongoing scientific debate on the specific characteristics of primary progressive multiple sclerosis. RECENT FINDINGS: The most important observations come from the studies using magnetic resonance imaging showing involvement of the normal-appearing brain tissue and also from the clinical and magnetic-resonance-imaging descriptions in longitudinal studies. SUMMARY: Progress in the diagnosis of primary progressive multiple sclerosis has been made. Long- and short-term natural history are now better known, which will allow the designing of clinical trials in the near future. Magnetic-resonance-imaging studies have demonstrated damage of the normal-appearing brain tissue, which may explain in part the apparent clinical and radiological paradox, common to all clinical forms of multiple sclerosis but perhaps more evident in the primary progressive form. Preliminary results from exploratory trials seem to indicate that these patients should no longer be excluded from therapeutic trials.

Miyake, S. and T. Yamamura (2005). "Therapeutic potential of glycolipid ligands for natural killer (NK) T cells in the suppression of autoimmune diseases." Curr Drug Targets Immune Endocr Metabol Disord 5(3): 315-22.

            NKT cells emerge as important regulatory cells in autoimmune responses. Abnormalities in the numbers and functions of natural killer T (NKT) cells have been observed in patients with autoimmune diseases as well as in a variety of mouse strains that are genetically predisposed for development of autoimmune diseases. Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens presented by the non-polymorphic MHC class I-like protein, CD1d. Recently, we and other groups have demonstrated that administration of glycolipid ligands such as alpha-galactosylceramide (alpha-GC ) or its sphingosine truncated derivative, OCH suppressed autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), diabetes in NOD mice and collagen-induced arthritis (CIA) by inducing T helper (Th) 2 bias of autoimmune T cells. OCH is a unique ligand to stimulate NKT cells to selectively produce Th2 cytokines whereas alpha-GC induces both interleukin (IL)-4 and interferon (IFN)-gamma, and is more beneficial for treatment of a wide variety of Th1-mediated autoimmune diseases. The lack of polymorphism of CD1d and cross-reactive responses of mouse and human NKT cells to the same ligand indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as type I diabetes (T1D), multiple sclerosis (MS) and rheumatoid arthritis (RA). The present review will focus on the potential roles of NKT cells in the pathogenesis of autoimmune diseases and the recent advances in glycolipid therapy for autoimmune disease models. The molecular mechanism of OCH-induced Th2-selective cytokine secretion will also be discussed.

Mitchell, A. J., J. Benito-Leon, et al. (2005). "Quality of life and its assessment in multiple sclerosis: integrating physical and psychological components of wellbeing." Lancet Neurol 4(9): 556-66.

            Health-related quality of life (HRQoL) has been more intensively studied in multiple sclerosis (MS) than in any other neurological disorder. Traditional medical models of impairment and disability are an incomplete summary of disease burden. Quality of life can be thought of as the sum of all sources of satisfaction (including anticipated sources) minus all threats (including anticipated threats). Many psychosocial factors-including coping, mood, self-efficacy, and perceived support-influence the quality of life of patients with MS more than biological variables such as weakness or extent of MRI lesions. Neuropsychiatric complications such as cognitive impairment and fatigue are also important predictors, even in those patients in the early stages of the disease. We review generic and specific HRQoL measures to help clinicians choose the most appropriate therapies. Subjective (self-report) HRQoL measures may serve to alert clinicians to areas that would otherwise be overlooked. Studies of new interventions should include an assessment of HRQoL not just impairment or disability alone.

Mitchell, R. J., P. B. Osborne, et al. (2005). "Dental amalgam restorations: daily mercury dose and biocompatibility." J Long Term Eff Med Implants 15(6): 709-21.

            Over the past 150 years, silver-tin-copper amalgam has been the most frequently used dental restorative material. Amalgam may be the single most frequently used implant material. In the early 1980s, researchers discovered that amalgam restorations release mercury vapor during chewing. This review describes the research that has led to an estimate of the daily dose of mercury that will be absorbed by a subject with a large number of amalgam restorations. Along the way, the history and chemistry of dental amalgam are outlined. The routes of absorption of liquid mercury, ionic mercury, organic mercury, and mercury vapor are also briefly described. The daily dose is found to be 14% of the threshold above which observable adverse neurological symptoms are expected. The review concludes with a summary of the research on the adverse effects of dental amalgam. As expected from the low daily dose, few adverse neurological symptoms have been reported. There is also little evidence of an association of amalgam restorations with neurodegenerative diseases, altered renal function, adverse pregnancy outcomes, or autoimmune diseases. There is a lack of data on neurobiological and neurodevelopmental effects on children who may be exposed to mercury from maternal amalgam restorations during gestation. Additional data on the role of amalgam, if any, in Alzheimers disease and multiple sclerosis are needed.

Minagar, A., E. Gonzalez-Toledo, et al. (2005). "Neuroimaging in multiple sclerosis." Int Rev Neurobiol 67: 165-201.

Miller, A. E. (2005). "Glatiramer acetate in the treatment of multiple sclerosis." Neurol Clin 23(1): 215-31, viii.

Miller, D., F. Barkhof, et al. (2005). "Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis." Lancet Neurol 4(5): 281-8.

            In 85% of young adults with multiple sclerosis (MS), onset is a subacute clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord. Methods of assessing the prognosis for patients who present with a CIS have been sought, because only 30-70% of patients with a CIS develop MS. When clinically silent brain lesions are seen on MRI, the likelihood of developing MS is high. MS can be diagnosed within 3 months of CIS presentation with certain MRI and CSF criteria. Disability from MS is less likely in patients with a CIS of optic neuritis or sensory symptoms only, few or no MRI lesions, a long period to the first relapse, and no disability after the first 5 years. Development of more reliable prognostic markers will enable new treatments to be targeted for those who are most likely to benefit. We encourage continued clinical and laboratory assessment of patients with a CIS.

Miller, A., M. Korem, et al. (2005). "Vitamin B12, demyelination, remyelination and repair in multiple sclerosis." J Neurol Sci 233(1-2): 93-7.

            Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.

Miller, D., F. Barkhof, et al. (2005). "Clinically isolated syndromes suggestive of multiple sclerosis, part 2: non-conventional MRI, recovery processes, and management." Lancet Neurol 4(6): 341-8.

            The onset of multiple sclerosis (MS) in 85% of young adults is with a subacute clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord. Whereas multifocal brain lesions are present on MRI in many patients with a CIS, some patients have additional abnormalities on quantitative MRI in otherwise normal-appearing white and grey matter that suggest an extensive pathological process. Functional outcome for patients with symptomatic CIS lesions is determined by the interplay of inflammation, demyelination, axonal damage, remyelination, and cortical adaptation. Recovery of function may be accelerated by high dose corticosteroids, and although interferon beta delays the development of a second relapse, its long-term effect is unknown. A better understanding of pathological and pathogenetic processes in patients with a CIS will facilitate the development of disease-modifying treatments for patients with MS before they become disabled. Continued clinical and laboratory investigation of patients with a CIS should be encouraged.

Mihai, C. and B. Jubelt (2005). "Post-infectious encephalomyelitis." Curr Neurol Neurosci Rep 5(6): 440-5.

            The term post-infectious encephalomyelitis (PIEM) is frequently used interchangeably with acute disseminated encephalomyelitis (ADEM), although technically PIEM occurs after a known infection whereas with ADEM there is no antecedent infection. PIEM represents one of the primary demyelinating disorders of the central nervous system, along with multiple sclerosis and Devic's disease. There is no specific diagnostic test for any of these conditions and at onset it may be difficult to differentiate between ADEM and the first attack of multiple sclerosis. However, there are clinical and magnetic resonance imaging features that allow differentiation between PIEM/ADEM and a relapsing disease such as multiple sclerosis. Some patients improve spontaneously; most improve with methylprednisolone. If that fails, plasma exchange or intravenous immunoglobulin may be effective.

Mezzapesa, D. M., M. Rovaris, et al. (2005). "Glatiramer acetate in multiple sclerosis." Expert Rev Neurother 5(4): 451-8.

            Glatiramer acetate (Copaxone) is a disease-modifying agent approved by several health authorities worldwide for the treatment of relapsing-remitting multiple sclerosis. Although its primary target is the inflammatory component of the disease, there are emerging pieces of evidence suggesting that glatiramer acetate might also have a neuroprotective effect. In this review, the results of glatiramer acetate clinical trials and other relevant studies as well as the place of glatiramer acetate among other approved disease-modifying treatments for relapsing-remitting multiple sclerosis are discussed critically.

Meyers, J. H., C. A. Sabatos, et al. (2005). "The TIM gene family regulates autoimmune and allergic diseases." Trends Mol Med 11(8): 362-9.

            The recently identified TIM gene family encodes cell-surface receptors that are involved in the regulation of Th1- and Th2-cell-mediated immunity. Tim-3 protein is specifically expressed on Th1 cells and negatively regulates Th1 responses, whereas Tim-2 is preferentially expressed in Th2 cells. Tim-1, previously identified as the hepatitis A virus receptor, co-stimulates T-cell expansion and cytokine production. Tim-4, which is preferentially expressed on mature dendritic cells, is the ligand for Tim-1. In mouse models of asthma and multiple sclerosis, affecting the function of Tim molecules altered disease phenotype. Because TIM molecules are differentially expressed on effector Th1 and Th2 cells, further understanding of the mechanisms by which they regulate Th1- and Th2-effector functions will probably provide opportunities for the therapeutic modulation of immune-mediated diseases.

Menge, T., H. P. Hartung, et al. (2005). "Statins--a cure-all for the brain?" Nat Rev Neurosci 6(4): 325-31.

            'Statins' are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors - oral cholesterol-lowering drugs that are used to treat hypercholesterolaemia. It is widely accepted that statins have anti-inflammatory effects that are independent of their ability to lower cholesterol. Animal studies and observational clinical studies have indicated that statins might also be effective in treating certain neurological diseases - in particular, multiple sclerosis, Alzheimer's disease and ischaemic stroke. At present, however, results from ongoing prospective, randomized clinical trials are not available.

Menge, T., B. Hemmer, et al. (2005). "Acute disseminated encephalomyelitis: an update." Arch Neurol 62(11): 1673-80.

            Acute disseminated encephalomyelitis (ADEM) is a monophasic autoimmune demyelinating disease of the central nervous system that typically follows a febrile infection or a vaccination. Children are predominantly affected. A plethora of viral and bacterial pathogens and a number of vaccinations have been associated with ADEM. Experimental animal studies indicate that both primary and secondary autoimmune responses contribute to central nervous system inflammation and subsequent demyelination. The clinical diagnosis of ADEM is strongly suggested by a close temporal relationship between an infectious incident or an immunization and the onset of leukoencephalopathic neurological symptoms. Paraclinical tests may support the diagnosis. Particularly helpful are acute signs of newly developed extensive, multifocal, subcortical white matter abnormalities on magnetic resonance images of the brain. The cerebrospinal fluid may disclose a mild lymphocytic pleocytosis and elevated albumin levels. Oligoclonal bands are not always present in ADEM and, if so, may be transient. The major differential diagnosis of ADEM is multiple sclerosis. Treatment options for ADEM consist of anti-inflammatory and immunosuppressive agents. In general, the disease is self-limiting and the prognostic outcome favorable. In the absence of widely accepted clinical or paraclinical diagnostic guidelines, a number of recently conducted observational case series have substantially broadened our understanding about the clinical phenotype, diagnosis, and prognosis of ADEM.

McFarland, H. F. and S. C. Reingold (2005). "The future of multiple sclerosis therapies: redesigning multiple sclerosis clinical trials in a new therapeutic era." Mult Scler 11(6): 669-76.

            Due to past success in testing and gaining regulatory approval for a variety of therapies in multiple sclerosis (MS), the conduct of future clinical trials has become increasingly problematic. An international workshop has met to discuss the issues facing the MS clinical trial community and to examine possible new strategies for the design of trials. Particular focus has been placed on trials that either avoid the use of a placebo because of ethical considerations or on designs that allow new therapies to be studied more rapidly or with fewer patients than needed in a conventional placebo-controlled trial. The discussions resulting from the workshop should provide a basis for the examination and implementation of innovative clinical trial designs in MS.

McCrery, R. J. and R. A. Appell (2005). "Female neurogenic vesicourethral dysfunction: evaluation and management." Curr Urol Rep 6(5): 348-55.

            This paper outlines the evaluation and management of neurogenic vesicourethral dysfunction (NVUD). The anatomy and neurophysiology involved with lower urinary tract functions are reviewed. Multiple sclerosis, diabetes, lumbar disc prolapse, and Parkinson's disease are specifically addressed. Proper evaluation of patients suspected of having NVUD, which is fundamental to making an accurate diagnosis, is discussed. This is followed by options for initiating individualized management plans that focus on protecting and preserving renal function, in addition to relieving the symptoms of NVUD.

Maurelli, M., R. Bergamaschi, et al. (2005). "Cerebral venous thrombosis and demyelinating diseases: report of a case in a clinically isolated syndrome suggestive of multiple sclerosis onset and review of the literature." Mult Scler 11(2): 242-4.

            Cerebral venous thrombosis (CVT) has been described in several cases of clinically definite multiple sclerosis (MS). In the majority of these, lumbar puncture followed by intravenous corticosteroid treatment was suspected as the cause. We report what is, to our knowledge, the first case of a patient with a multifocal clinically isolated syndrome suggestive of MS onset, who developed multiple CVT after lumbar puncture and during high-dose i.v. corticosteroid treatment We conclude that the sequence 'lumbar puncture followed by corticosteroid treatment' may be a contributory risk factor for the development of CVT when associated with other risk factors.

Matute, C. and F. Perez-Cerda (2005). "Multiple sclerosis: novel perspectives on newly forming lesions." Trends Neurosci 28(4): 173-5.

            The mechanisms underlying lesion formation in multiple sclerosis are unknown. The prevailing view is that macrophages are primary mediators of myelin destruction in the relapsing and remitting forms of this disease. However, recent findings have revealed widespread oligodendrocyte apoptosis in the absence of a clear cellular immune response. These observations unveil a novel aspect of the pathogenesis of multiple sclerosis that is worthy of further exploration.

Mattle, H. P. (2005). "[Multiple sclerosis--update]." Schweiz Rundsch Med Prax 94(30-31): 1167-70.

            Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Its etiology is not known, but it is well established that auto-reactive T-cells and monocytes play an important pathogenetic role. The inflammation causes focal demyelination and loss of axons, neurons and glial cells. Typical symptoms and signs are monocular blurred vision, double vision, sensory symptoms and motor weakness, and eventually also cognitive deficits and a disturbed micturition. In younger patients the neurological deficits tend to be present for a limited time and then to improve and disappear, only to be followed by new and different deficits later on. Each relapse may leave neurological deficits which in a later course tend to progress slowly, uninterrupted by remissions. When older patients present for the first time with MS, they tend to present with primary progressive spasticity. Important ancillary tests and findings to confirm the diagnosis are multiple focal lesions on MR images, oligoclonal bands in the cerebrospinal fluid, and slowed evoked potentials. Relapses are treated with corticosteroids. Immunomodulation with beta-interferons or glatiramer acetate reduce the number and severity of relapses and long-term disability. Very active forms can be treated with immunosuppression using mitoxantrone. Individual manifestations such as urinary tract infections or paroxysmal phenomena should be treated accordingly with medication.

Mastronardi, F. G. and M. A. Moscarello (2005). "Molecules affecting myelin stability: a novel hypothesis regarding the pathogenesis of multiple sclerosis." J Neurosci Res 80(3): 301-8.

            In this Mini-Review we present a new hypothesis in support of the neurodegenerative theory as a mechanism for the pathogenesis of multiple sclerosis (MS). The pathogenesis of MS results from changes in two distinct CNS compartments. These are the "myelin" and "nonmyelin" compartments. The myelin compartment is where primary demyelination, amidst attempts at remyelination, is superseded in the CNS by ongoing disease. Recent evidence obtained via magnetic resonance imaging and spectroscopy techniques supports the view that the normal-appearing white matter (NAWM) in the MS brain is altered. Several biochemical changes in NAWM have been determined. These include the cationicity of myelin basic protein (MBP) as a result of the action of peptidyl argininedeiminase (PAD) activity converting arginyl residues to citrulline. The accompanying loss of positive charge makes myelin susceptible to vesiculation and MBP more susceptible to proteolytic activity. An increase of MBP autocatalysis in the MS brain might also contribute to the generation of immunodominant epitopes. Accompanying the destruction of myelin in the myelin compartment is the activation of astrocytes and microglia. These contribute to the inflammatory response and T-cell activation leading to autoimmunity. The complex environment that exists in the demyelinating brain also affects the "nonmyelin" compartment. The inappropriate up-regulation of molecules, including those of the Jagged-1-Notch-1 signal transduction pathway, affects oligodendrocyte precursor cell (OPC) differentiation. Other effectors of oligodendrocyte maturation include stathmin, a microtubule-destabilizing protein, which prevents healing in the demyelinating brain. The hypothesis we present suggests a therapeutic strategy that should 1) target the effectors within the myelin compartment and 2) enable resident OPC maturation in the nonmyelin compartment, allowing for effective repair of myelin loss. The net effect of this new therapeutic strategy is the modification of the disease environment and the stimulation of healing and repair.

Masson, C. (2005). "[Acute transverse myelopathy: inflammatory or ischemic?]." Presse Med 34(12): 869-77.

            The rapid development of paraparesis or tetraparesis combined with a bilateral sensory deficit that has a clearly defined rostral border and bladder dysfunction are the principal features of acute transverse myelopathy. Acute partial transverse myelopathy is far much more frequent: its symptoms are asymmetric, sometimes unilateral, and sensory deficit may predominate. An urgent MRI is required to exclude acute spinal cord compression. Diagnosis of ischemic acute transverse myelopathy includes the following elements: sudden onset, neurologic symptoms compatible with infarction in the anterior spinal artery area (by far the most frequent location for spinal cord infarction), and presence of a specific cause of spinal cord ischemia. In all other cases where it is difficult to distinguish spinal cord infarction from myelitis, analysis of the cerebrospinal fluid is essential. Most cases of inflammatory acute transverse myelopathy can be linked to a defined cause. Multiple sclerosis is a major cause of partial acute transverse myelopathy. MRI lesions are usually small, located in the lateral or posterior part of the spinal cord. Diagnostic elements include multiple lesions of multifocal demyelination on the cerebral MRI, oligoclonal bands in the cerebrospinal fluid, and the absence of clinical or laboratory abnormalities that suggest systemic disease. Neuromyelitis optica, also known as Devic's disease, has often been considered a variant form of multiple sclerosis. Recent immunologic studies confirm the hypothesis that it is a distinct entity. Infectious transverse acute myelitis is often of viral origin. It may result from direct viral stress but more frequently follows immunologically-mediated indirect stress. This acute parainfectious myelitis, like postvaccinal myelitis, may be considered as a spinal single-focus form of acute disseminated encephalomyelitis (ADEM). It is important to distinguish the latter from an initial episode of multiple sclerosis, because their prognosis and treatment differ.

Mascalchi, M., M. Filippi, et al. (2005). "Diffusion-weighted MR of the brain: methodology and clinical application." Radiol Med (Torino) 109(3): 155-97.

            Clinical diffusion magnetic resonance (MR) imaging in humans started in the last decade with the demonstration of the capabilities of this technique of depicting the anatomy of the white matter fibre tracts in the brain. Two main approaches in terms of reconstruction and evaluation of the images obtained with application of diffusion sensitising gradients to an echo planar imaging sequence are possible. The first approach consists of reconstruction of images in which the effect of white matter anisotropy is averaged -- known as the isotropic or diffusion weighted images, which are usually evaluated subjectively for possible areas of increased or decreased signal, reflecting restricted and facilitated diffusion, respectively. The second approach implies reconstruction of image maps of the apparent diffusion coefficient (ADC), in which the T2 weighting of the echo planar diffusion sequence is cancelled out, and their objective, i.e. numerical, evaluation with regions of interest or histogram analysis. This second approach enables a quantitative and reproducible assessment of the diffusion changes not only in areas exhibiting signal abnormality in conventional MR images but also in areas of normal signal. A further level of image post-processing requires the acquisition of images after application of sensitising gradients along at least 6 different spatial orientations and consists of computation of the diffusion tensor and reconstruction of maps of the mean diffusivity (D) and of the white matter anisotropic properties, usually in terms of fractional anisotropy (FA). Diffusion-weighted imaging is complementary to conventional MR imaging in the evaluation of the acute ischaemic stroke. The combination of diffusion and perfusion MR imaging has the potential of providing all the information necessary for the diagnosis and management of the individual patient with acute ischaemic stroke. Diffusion-weighted MR, in particular quantitative evaluation based on the diffusion tensor, has a fundamental role in the assessment of brain maturation and of white matter diseases in the fetus, in the neonate and in the child. Diffusion MR imaging enables a better characterisation of the lesions demonstrated by conventional MR imaging, for instance in the hypoxic-ischaemic encephalopathy, in infections and in the inherited metabolic diseases, and is particularly important for the longitudinal evaluation of these conditions. Diffusion-weighted MR imaging has an established role in the differential diagnosis between brain abscess and cystic tumour and between epidermoid tumour and arachnoid cyst. On the other hand, the results obtained with diffusion MR in the characterisation of type and extension of glioma do not yet allow decision making in the individual patient. Diffusion is one of the most relevant MR techniques to have contributed to a better understanding of the pathophysiological mechanisms of multiple sclerosis (MS). In fact, it improves the specificity of MR in characterising the different pathological substrata underlying the rather uniform lesion appearance on the conventional images and enables detection of damage in the normal-appearing white and grey matter. In MS patients the ADC or D values in the normal-appearing white matter are increased as compared to control values, albeit to a lesser degree than in the lesions demonstrated by T2-weighted images. In addition, the D of the normal appearing grey matter is increased in MS patients and this change correlates with the cognitive deficit of these patients. Histogram analysis in MS patients shows that the peak of the brain D is decreased and right-shifted, reflecting an increase of its value, and the two features correlate with the patient's clinical disability. Ageing is associated to a mild but significant increase of the brain ADC or D which is predominantly due to changes in the white matter. Region of interest and histogram studies have demonstrated that D or ADC are increased in either the areas of leukoaraiosis or the normal-appearing white matter in patients with inherited cerebral autosomal dominant arteriopathy with subcortical infarcts and stroke or sporadic ischaemic leukoencephalopathy. Diffusion changes might be a more sensitive marker for progression of the disease than conventional imaging findings. In neurodegenerative diseases of the central nervous system such as Alzheimer's disease, Huntington's disease, hereditary ataxias and motor neuron disease, quantitative diffusion MR demonstrates the cortical and subcortical grey matter damage, which is reflected in a regional increase of D or ADC, but also reveals the concomitant white matter changes that are associated with an increase in D or ADC and decrease in FA. In all these diseases the diffusion changes are correlated to the clinical deficit and are potentially useful for early diagnosis and longitudinal evaluation, especially in the context of pharmacological trials.

Martinelli Boneschi, F., M. Rovaris, et al. (2005). "Mitoxantrone for multiple sclerosis." Cochrane Database Syst Rev(4): CD002127.

            BACKGROUND: Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. OBJECTIVES: The objective was to assess the efficacy and safety of MX in relapsing-remitting MS (RRMS), progressive relapsing MS (PRMS) and secondary progressive MS (SPMS). SEARCH STRATEGY: We searched the Cochrane MS Group Trials Register (searched April 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (Pub Med) (January 1966 to April 2005), EMBASE (January 1974 to April 2005), and reference lists of articles. We also undertook hand searching and contacting trialists and pharmaceutical companies. SELECTION CRITERIA: The trials were selected if double-blinded, placebo-controlled, randomised, irrespective of eventual additive therapy (such as steroids). DATA COLLECTION AND ANALYSIS: Three reviewers independently selected articles for inclusion, assessed trials' quality and extracted data. MAIN RESULTS: Four trials involving 270 participants were included. MX was found to reduce the progression of disability at 2 years follow-up (proportion of participants with 6-months confirmed progression of disability: Odds Ratios (OR) 0.3, p = 0.05). Similar figures were found regarding the reduction in annualised relapse rate and the proportion of patients free from relapses at 1 and 2 years, as well as the number of patients with active MRI lesions at 6 months/ 1 year only. Side effects reported in the trials were more frequent in treated patients than in controls. Caution must be exercised in drawing conclusions from such data because of the heterogeneous quality and characteristics of the included trials, which are different in terms of treatment schedule and type of enrolled patients. More than half of the included patients came from a single study. Moreover, from the included trials, it was not possible to estimate the long-term efficacy and safety of MX, which may raise concerns about the risk of cardiotoxicity and therapy-related leukemias, which is increasingly reported in the literature. AUTHORS' CONCLUSIONS: MX is moderately effective in reducing the disease progression and the frequency of relapses in patients affected by RR, PR and SP MS in the short-term follow-up (2 years), even if the results are based on trials heterogeneous in terms of drug dosage and inclusion criteria. No major neoplastic or symptomatic cardiotoxicity related to MX have been reported from the trials. However, longer follow-up studies are highly warranted to better explore the efficacy and safety of the drug, mainly as regards the long-term risk of therapy-related leukemias and cardiotoxicity.As a conclusion, MX has a partial efficacy, but, due to its unclear long-term safety profile, it should be used to treat patients with worsening RR and SP MS with evidence of worsening disability.

Martinelli, V. and G. Comi (2005). "Induction versus escalation therapy." Neurol Sci 26 Suppl 4: S193-9.

            Most of the consensus groups in Europe and America support an early decision-making therapeutic approach in patients with a diagnosis of multiple sclerosis (MS), either with interferon-beta or glatiramer acetate, which have been demonstrated to be a reasonable therapeutic strategy because of their benefit. The "treat-early approach" within disease management is based on the assumption, particularly during the early phase of the disease, of the reduction of both relapse rate and of the ongoing inflammatory processes may delay irreversible neurological damages. As soon as the MS diagnosis is certain or even in patients with a first episode suggestive of MS, with negative prognostic factors and a typical presentation, "induction therapy", which is more aggressive on the immune system, seems to have more relevant short- and long-lasting beneficial effects. However, if the disease course is suboptimally controlled, an "escalating strategy", using mitoxantrone, cyclophosphamide, various other immunoactive agents or a combination of different drugs, is suggested. The current challenge in therapeutic strategy is to identify the most effective drug, or combination of drugs, during a specific phase of the disease for each single patient. Anyhow, the decision to adopt a combination therapy in patients with a low response to monotherapy should not be delayed until severe irreversible disability is evident.

Marjanovic, Z., I. Gerber, et al. (2005). "[Therapeutic intensification and autologous stem cell transplantation in autoimmune diseases]." Presse Med 34(4): 311-8.

            THE PATHOPHYSIOLOGY of most autoimmune diseases is often poorly understood. EXPERIMENTAL CONSIDERATIONS and clinical experience suggest that high doses immunoablation followed by stem cell transplantation is a therapeutic option to consider for certain severe autoimmune disorders. THE CONCEPT OF RESTORING NORMAL IMMUNE REACTIVITY must in part br true since current results of 466 transplants (445 autologous, 21 allogeneic) patients suffering from various autoimmune diseases show a beneficial outcome in approximately 2/3 of the patients. TO IMPROVE THE EFFICACY AND SAFETY OF SUCH AN AGGRESSIVE PROCEDURE in patients with potentially affected vital organs by the underlying autoimmune disease, it is especially important to follow international consensus guidelines and to centrally collect clinical data for in depth analysis in the EBMT International Stem Cell Project for Autoimmune Disease in Basel, Switzerland. PHASE III STUDIES ARE RUNNING FOR SYSTEMIC SCLEROSIS (Astis, Autologous Stem cell Transplantation International Rheumatoid Arthritis Trial) started in 2003. A STUDY PROJECT IS PLANNED FOR MULTIPLE SCLEROSIS (Astims, Autologous Stem cell Transplantation International Multiple Sclerosis).

Marchetti, B. and M. P. Abbracchio (2005). "To be or not to be (inflamed)--is that the question in anti-inflammatory drug therapy of neurodegenerative disorders?" Trends Pharmacol Sci 26(10): 517-25.

            A sustained inflammatory reaction is present in acute (e.g. stroke) and chronic (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis) neurodegenerative disorders. Inflammation, which is fostered by both residential glial cells and blood-circulating cells that infiltrate the diseased brain, probably starts as a time- and site-specific defense mechanism that could later evolve into a destructive and uncontrolled reaction. In this article, we review the crucial dichotomy of brain inflammation, where failure to resolve an acute beneficial response could lead to a vicious and anarchic state of chronic activation. The possible use of non-steroidal anti-inflammatory drugs for the management of neurodegenerative diseases is discussed in light of recent data demonstrating a neuroprotective role of local innate and adaptive immune responses. Novel therapeutic approaches must rely on potentiation of endogenous anti-inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies.

Manzoni, G. C. and P. Torelli (2005). "Epidemiology of typical and atypical craniofacial neuralgias." Neurol Sci 26 Suppl 2: s65-7.

            Trigeminal neuralgia (TN) has a prevalence of 0.1-0.2 per thousand and an incidence ranging from about 4-5/100,000/year up to 20/100,000/year after age 60. The female-to-male ratio is about 3:2. A review of several case series shows that pain is more predominant on the right side, but the difference is not statistically significant. TN is significantly associated with arterial hypertension, Charcot-Marie-Tooth neuropathy, glossopharyngeal neuralgia (GN) and multiple sclerosis. GN has an incidence of 0.7/100,000/year and epidemiological studies have shown it to be less severe than previously thought. Post-herpetic neuralgia has a comparable incidence to idiopathic TN. The epidemiology of the central causes of facial pain is still unclear, but it is known that persistent idiopathic facial pain is a widespread, not easily manageable problem.

Mantzourani, E. D., T. M. Mavromoustakos, et al. (2005). "Structural requirements for binding of myelin basic protein (MBP) peptides to MHC II: effects on immune regulation." Curr Med Chem 12(13): 1521-35.

            Confronting Multiple Sclerosis requires as an underlying step the manipulation of immune response through modification of Myelin Basic Protein peptides. The aim is to design peptidic or nonpeptidic molecules that compete for recognition of self-antigens at the level of antigen presentation. The rational approach is to substitute residues that serve as anchors for the T-Cell Receptor with others that show no binding at all, and those that serve as Major Histocompatibility Complex II anchors with others that present increased binding affinity. The resulting structure, hence, retains normal or increased MHC II binding properties, but fails to activate disease-inducing T-cells. This rational design can only be achieved by identifying the structural requirements for binding of the natural peptide to MHC II, and the anchor residues with their corresponding specific pockets in the binding groove. The peptide-MHC II complex then interacts with the TCR; thus, an additional way to trigger the desired immune response is to alter secondary anchor residues as well as primary ones. In this review, the structural requirements for binding of MBP peptides to MHC II are presented, as are the mechanism and key features for TCR recognition of the peptide-MHC II complex.

Manganas, L. N. and M. Maletic-Savatic (2005). "Stem cell therapy for central nervous system demyelinating disease." Curr Neurol Neurosci Rep 5(3): 225-31.

            Recent advances in cell-based therapies for demyelinating central nervous system diseases have demonstrated the ability to restore damaged neuronal architecture and function. Demyelinated axons in patients with multiple sclerosis can spontaneously remyelinate over time; however, the rate and extent at which remyelination occurs is inadequate for complete recovery. Previous attempts aimed at regenerating myelin-forming cells have been successful but limited by the multifocal nature of the lesions and the inability to produce large numbers of myelin-producing cells in culture. Stem cell-based therapy can overcome these limitations to some extent and may prove useful in the future treatment of demyelinating diseases.

Mancardi, G. L. (2005). "Autologous haematopoietic stem cell transplantation." Neurol Sci 26 Suppl 1: S19.

Malfitano, A. M., G. Matarese, et al. (2005). "From cannabis to endocannabinoids in multiple sclerosis: a paradigm of central nervous system autoimmune diseases." Curr Drug Targets CNS Neurol Disord 4(6): 667-75.

            An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of multiple sclerosis, including spasticity and pain. Endogenous molecules with cannabinoid-like activity, such as the "endocannabinoids", have been shown to mimic the anti-inflammatory properties of cannabinoids through the cannabinoid receptors. Several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis. Indeed, they can down regulate the production of pathogenic T helper 1-associated cytokines enhancing the production of T helper 2-associated protective cytokines. A shift towards T helper 2 has been associated with therapeutic benefit in multiple sclerosis. In addition, cannabinoids exert a neuromodulatory effect on neurotransmitters and hormones involved in the neurodegenerative phase of the disease. In vivo studies using mice with experimental allergic encephalomyelitis, an animal model of multiple sclerosis, suggest that the increase of the circulating levels of endocannabinoids might have a therapeutic effect, and that agonists of endocannabinoids with low psychoactive effects could open new strategies for the treatment of multiple sclerosis.

Maiese, K., Z. Z. Chong, et al. (2005). "Driving cellular plasticity and survival through the signal transduction pathways of metabotropic glutamate receptors." Curr Neurovasc Res 2(5): 425-46.

            Metabotropic glutamate receptors (mGluRs) share a common molecular morphology with other G protein-linked receptors, but there expression throughout the mammalian nervous system places these receptors as essential mediators not only for the initial development of an organism, but also for the vital determination of a cell's fate during many disorders in the nervous system that include amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, Multiple Sclerosis, epilepsy, trauma, and stroke. Given the ubiquitous distribution of these receptors, the mGluR system impacts upon neuronal, vascular, and glial cell function and is activated by a wide variety of stimuli that includes neurotransmitters, peptides, hormones, growth factors, ions, lipids, and light. Employing signal transduction pathways that can modulate both excitatory and inhibitory responses, the mGluR system drives a spectrum of cellular pathways that involve protein kinases, endonucleases, cellular acidity, energy metabolism, mitochondrial membrane potential, caspases, and specific mitogen-activated protein kinases. Ultimately these pathways can converge to regulate genomic DNA degradation, membrane phosphatidylserine (PS) residue exposure, and inflammatory microglial activation. As we continue to push the envelope for our understanding of this complex and critical family of metabotropic receptors, we should be able to reap enormous benefits for both clinical disease as well as our understanding of basic biology in the nervous system.

Magdzik, W. and A. Zielinski (2005). "[Vaccination against hepatitis B and the risk of multiple sclerosis]." Przegl Epidemiol 59(1): 11-9.

            A paper on sclerosis multiplex as sequellae of vaccination against hepatitis B with recombinant vaccine was published in the journal of "Neurology" in September 2004. Problem was evaluated in United Kingdom on the ground of General Practice Research Database (GPRD). In 1996 similar problem was evaluated with negative results in several studies. Just now in opinions of many institutions as well as many persons vaccination against hepatitis B with recombinant vaccine should be continued in similar way as it was performed to this time.

Maclean, C. H., A. M. Issa, et al. (2005). "Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases." Evid Rep Technol Assess (Summ)(114): 1-3.

Macciardi, F., F. M. Boneschi, et al. (2005). "Pharmacogenetics of autoimmune diseases: research issues in the case of Multiple Sclerosis and the role of IFN-beta." J Autoimmun 25 Suppl: 1-5.

            Pharmacogenetics of auto-immune diseases is a complex field of application for this relatively new discipline, since we still have a partial knowledge of the biological mechanisms of the disease and of the drugs currently used to treat it. We address a few key issues that emerge when planning a pharmacogenetic investigation in Multiple Sclerosis and that relate to the complexities existing at the biological-genetic level and at the phenotypic characterization. In fact, we think that a clearer characterization of the clinical phenotype representing the end-point of the investigation together with a critical appraisal of the multi-faceted dimension of the genetic component of either the disease and the pharmacogenetic profile of the drug investigated, will help to design more thorough study and to achieve deeper understanding of the practical results. We will primarily focus our research considerations on the role of Interferon Beta (IFN-beta) as a prototypal therapeutic agent in Multiple Sclerosis.

MacAllister, W. S. and L. B. Krupp (2005). "Multiple sclerosis-related fatigue." Phys Med Rehabil Clin N Am 16(2): 483-502.

            Fatigue is a significant factor in the lives of many MS patients and the most commonly reported symptom in many studies. Fatigue is an important symptom to consider because it affects patients' social lives, occupations, and activities of daily living. Efforts to predict fatigue have been mixed, but it appears to be related to overall quality of life and mood. From a pathophysiologic perspective, fatigue in MS is multifactorial and complex,involving dysregulation of the immune system, changes in the nervous system related to the disease process, neuroendocrine and neurotransmitter changes, and other factors such as physical deconditioning, sleep disturbance, pain, and medication side effects. Various attempts to assess fatigue have been made, and many measures are now available for use in clinical practice and research. In clinical practice, these measures help guide treatment considerations. Recent research has provided valuable strategies to ameliorate fatigue in MS, and although many patients continue to experience fatigue despite interventions, many receive substantial relief.Nonpharmacologic approaches-considered the first step in treatment-include exercise programs, cooling, dietary considerations, and energy conservation strategies. For patients who continue to experience significant fatigue, several medications (although not specifically approved for use in the reduction of MS-related fatigue) have proved effective in this regard.The first-line agents include amantadine for mild fatigue and modafinil for more severe cases. Second-line agents include pemoline and antidepressant medications. Other pharmacologic agents have also shown some promise.

Lycklama a Nijeholt, G. J. (2005). "Reduction of brain volume in MS. MRI and pathology findings." J Neurol Sci 233(1-2): 199-202.

            Atrophy is one of the hallmarks in multiple sclerosis (MS), especially in the advanced stage. Modern magnetic resonance (MR) techniques can reliably measure brain volume and changes therein. Depending on the technique used, changes of about 1% may be detected. Clinicoradiological studies show good correlation between atrophy measures, both in brain and spinal cord, and clinical measures. The exact relationship between focal MS lesions and global atrophy has yet to be established. Number of lesions early in the disease seems to predict later atrophy. The exact pathomechanism of atrophy in MS probably may be explained by both demyelination and axonal loss--which may occur independently from each other.

Ludwin, S. K. (2005). "Pathologic classification systems in MS: what is their significance?" Mult Scler 11(1): 106-7.

Lucchinetti, C. F., J. Parisi, et al. (2005). "The pathology of multiple sclerosis." Neurol Clin 23(1): 77-105, vi.

Lucchinetti, C. F. (2005). "Update on the international project on pathologic correlates in MS." Mult Scler 11(1): 99-100.

Lublin, F. D. (2005). "Clinical features and diagnosis of multiple sclerosis." Neurol Clin 23(1): 1-15, v.

Lublin, F. (2005). "History of modern multiple sclerosis therapy." J Neurol 252 Suppl 3: iii3-iii9.

            Although the earliest recorded description of multiple sclerosis (MS) dates back to the 14(th) century, it was not until the latter years of the 20(th) that treatments for this disabling condition were found. However, the "road to success" has not been without hurdles. Trials with both interferon alpha and gamma proved unsuccessful, as did treatment with oral myelin, cladribine, sulfasalazine and inhibitors of tumour necrosis factor. In 1993, interferon beta-1b (IFNbeta-1b) became the first therapy proven to be effective in altering the natural history of relapsing-remitting MS (RRMS). This was followed by successful trials with IFNbeta-1a and glatiramer acetate. In 1998, a European trial showed IFNbeta-1b to be also beneficial in the treatment of secondary progressive MS (SPMS). A similar trial in North America failed to reach its primary endpoint but was effective across secondary endpoints, highlighting how different methodology and patient populations can lead to inconsistent results and, thus, making comparisons across trials difficult. The trend for early intervention in MS with IFNbeta was recently supported by the CHAMPS (Controlled High-risk Avonex MultiPle Sclerosis) and ETOMS (Early Treatment of Multiple Sclerosis) studies using once-weekly IFNbeta-1a. Both trials demonstrated delayed conversion to clinically definite MS in patients with a clinically isolated syndrome and magnetic resonance imaging (MRI) findings suggestive of MS. Two directly comparative trials of high- (250 microg IFNbeta-1b or 44 microg IFNbeta-1a) and low-dose (30 microg IFNbeta-1a) IFNbeta (INCOMIN [INdependent COMparison of INterferons] and EVIDENCE [EVidence of Interferon Dose-response: European North American Comparative Efficacy]) support the superior efficacy of the higher dose and/or more frequent administration for treating RRMS. Since MS entered the treatment era in 1993, therapies for RRMS, SPMS and, more recently, progressive- relapsing MS have been developed. There is now a much better understanding of the pathogenesis of the disease, but new and improved therapeutic approaches are still needed.

Lublin, F. (2005). "Multiple sclerosis trial designs for the 21st century: building on recent lessons." J Neurol 252 Suppl 5: v46-53.

            Starting with the first positive pilot study of glatiramer acetate, trial design in multiple sclerosis has advanced considerably over the past two decades, successively building and improving on previous successes in the implementation and analysis of new clinical trials. Most of these trials have been successful and this has led to the regulatory approval and commercial availability of six agents for the treatment of multiple sclerosis. During this period, outcome measures have been validated to determine the efficacy and safety of such agents, notably those useful in reducing the inflammatory aspects of disease. These include measurements of relapse reduction (annualized relapse rate, time to first relapse, proportion of subjects relapse free), disability (change in EDSS score, change in MSFC score) and MRI metrics (measurements of gadolinium-enhancing lesions, T1 and T2 lesion load). Recent trial design has shown that one can answer some clinical questions after one year on study and that these results may be predictive of more robust two-year trial data. The other important recent lesson involves emergence of rare complications of immunomodulatory therapy, namely progressive multifocal leucoencephalopathy with natalizumab that blocks the access of immune cells to the nervous system. In addition to the increased need for enhanced safety assessment, this issue will have an impact both on the study of combination therapies and on the use of combinations in clinical practice.

Lubetzki, C., A. Williams, et al. (2005). "Promoting repair in multiple sclerosis: problems and prospects." Curr Opin Neurol 18(3): 237-44.

            PURPOSE OF REVIEW: Despite recent progress in treating the inflammatory component of multiple sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (myelin and axon) injury. Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy. RECENT FINDINGS: Several hypotheses have been raised to explain the failure of remyelination, including depletion of remyelinating cells, quiescence of oligodendrocyte precursor cells and axonal inhibitory signals. Success in remyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous remyelinating cells. Several neurotrophic factors have been shown to enhance endogenous remyelination, and many immature cells have been shown to induce efficient exogenous remyelination in animal models. Although effective remyelination probably represents the best way to prevent neurodegeneration, several alternative neuroprotective strategies are emerging. Statins, cyclins and immunophilin ligands are orally available immunomodulatory agents that may protect neurones. Other promising possibilities include the modulation of excitotoxicity, nitric oxide synthesis, or cationic channels. SUMMARY: Despite the increasing number of putative therapeutic targets, no treatment to achieve remyelination or neuroprotection has yielded positive clinical results in humans. Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of neurotrophic factors, and better defining the indications for and limitations of transplantation.

Lovett-Racke, A. E., P. D. Cravens, et al. (2005). "Therapeutic potential of small interfering RNA for central nervous system diseases." Arch Neurol 62(12): 1810-3.

Liu, L., M. K. Callahan, et al. (2005). "Chemokine receptor CXCR3: an unexpected enigma." Curr Top Dev Biol 68: 149-81.

            CXCR3, the receptor for CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC, is preferentially expressed on activated Th1 T cells and has been predicted to play an important role in their trafficking. However, this simplistic view of the function of CXCR3 and its ligands has not been borne out by studies of disease models, including experimental autoimmune encephalomyelitis (EAE), using varied methods of receptor blockade, as well as knockout or transgenic mice. This review focuses on the current understanding of the enigmatic role of CXCR3 and its ligands in CNS inflammatory/autoimmune disorders. The conflicting results among varied models of CNS inflammation suggest complex and multiple roles for CXCR3 and its ligands in the pathogenesis of CNS inflammatory/autoimmune diseases. Thus, further study is needed to determine how CXCL10 neutralizing agents or CXCR3 receptor antagonists might be applied to treating human disease.

Liu, L., D. Meier, et al. (2005). "Multiple sclerosis medical image analysis and information management." J Neuroimaging 15(4 Suppl): 103S-117S.

            Magnetic resonance imaging (MRI) has become a central tool for patient management, as well as research, in multiple sclerosis (MS). Measurements of disease burden and activity derived from MRI through quantitative image analysis techniques are increasingly being used. There are many complexities and challenges in building computerized processing pipelines to ensure efficiency, reproducibility, and quality control for MRI scans from MS patients. Such paradigms require advanced image processing and analysis technologies, as well as integrated database management systems to ensure the most utility for clinical and research purposes. This article reviews pipelines available for quantitative clinical MRI research in MS, including image segmentation, registration, time-series analysis, performance validation, visualization techniques, and advanced medical imaging software packages. To address the complex demands of the sequential processes, the authors developed a workflow management system that uses a centralized database and distributed computing system for image processing and analysis. The implementation of their system includes a web-form-based Oracle database application for information management and event dispatching, and multiple modules for image processing and analysis. The seamless integration of processing pipelines with the database makes it more efficient for users to navigate complex, multistep analysis protocols, reduces the user's learning curve, reduces the time needed for combining and activating different computing modules, and allows for close monitoring for quality-control purposes. The authors' system can be extended to general applications in clinical trials and to routine processing for image-based clinical research.

Lipton, H. L., A. S. Kumar, et al. (2005). "Theiler's virus persistence in the central nervous system of mice is associated with continuous viral replication and a difference in outcome of infection of infiltrating macrophages versus oligodendrocytes." Virus Res 111(2): 214-23.

            Theiler's murine encephalomyelitis virus (TMEV) infection of mice, in which persistent central nervous system (CNS) infection induces Th1 CD4+ T cell responses to both virus and myelin proteins, provides a relevant experimental animal model for MS. During persistence, >10(9) TMEV genome equivalents per spinal cord are detectable by real-time reverse transcription-polymerase chain reaction (RT-PCR). Because of the short half-life of TMEV (<1 day), continual viral replication is needed to sustain these very high TMEV copy numbers. An essential role for macrophages in TMEV persistence has been documented and, although limited by host anti-viral immune responses, TMEV nonetheless spreads during persistence to infect other cells, particularly oligodendrocytes, in which the infection is productive and lytic. Virus factors influencing persistence of TMEV are expression of the out-of-frame L* protein and use of sialic acid co-receptors.

Linsen, L., V. Somers, et al. (2005). "Immunoregulation of autoimmunity by natural killer T cells." Hum Immunol 66(12): 1193-202.

            Natural killer T (NKT) cells are a conserved subpopulation of lymphocytes that recognize glycolipid antigens in a CD1d context. Upon activation through their semi-invariant T cell receptor, these cells rapidly release large amounts of immunomodulating Th1 and Th2 cytokines. NKT cells have therefore been implicated in immune responses controlling various diseases, including infection, cancer, transplantation, and autoimmunity. Stimulation of the immunoregulatory capacity of NKT cells by the prototypical antigen alpha-galactosylceramide results in amelioration of disease in several animal models. This review will focus on the current knowledge of human NKT cells and their role in autoimmune diseases. The features of these cells and their importance in regulation of autoimmunity suggest that NKT cell-based therapies might be an interesting approach for the treatment of autoimmune diseases.

Linker, R. A., M. Sendtner, et al. (2005). "Mechanisms of axonal degeneration in EAE--lessons from CNTF and MHC I knockout mice." J Neurol Sci 233(1-2): 167-72.

            The major pathological hallmarks of multiple sclerosis (MS) comprise inflammation, demyelination with associated gliosis and axonal damage, which most likely correlates with persisting disability. Axonal damage can occur by several mechanisms. This article focuses on myelin disintegration and direct immune attack on axons by CD8-positive T-cells as two possible scenarios for axonal injury. As protoypic models, we investigated experimental autoimmune encephalomyelitis (EAE) in ciliary neurotrophic factor gene knockout mice (CNTF-/- mice) with severe myelin pathology and EAE in beta-2 microglobulin gene knockout mice (beta2m-/- mice) lacking CD8-positive T-cells. The results from these studies indicate that the trigger attack for axonal injury even in a well-defined experimental design can be multi-faceted. No single factor seems to be absolutely necessary for the initiation of the process, but they rather act in concert and orchestrate tissue destruction, inflammation and regeneration. Some mechanisms of primary or secondary axonal damage may be shared between inflammatory and degenerative diseases of the nervous system, thereby establishing a link which might be of importance for future therapeutic strategies.

Linker, R. A., C. Stadelmann, et al. (2005). "[Recent advances in pathogenesis and therapy of multiple sclerosis]." Fortschr Neurol Psychiatr 73(12): 715-27.

            In this article, recent advances in the research on pathogenesis and therapy of multiple sclerosis (MS) will be summarized. New evidence from clinical studies, imaging, histopathology and experimental models are discussed with a focus on neurodegenerative aspects and evidence from recent therapeutic studies. During the last decade, important advances in immunotherapy have been achieved, which proved especially useful for patients with relapsing remitting MS. The introduction of interferons and glatiramer acetate into MS therapy often leads to a stabilization of the disease course if administered adequately and early. The pathogenetic insights presented here may open new avenues for innovative immunomodulatory approaches and lead to an individualized MS therapy in the future. Neuroprotective treatment strategies aim at the protection of glial and neuronal cells.

Lim, E. T. and G. Giovannoni (2005). "Immunopathogenesis and immunotherapeutic approaches in multiple sclerosis." Expert Rev Neurother 5(3): 379-90.

            Multiple sclerosis is an organ-specific autoimmune disease, characterized pathologically by cell-mediated inflammation, demyelination and variable degrees of axonal loss. Although inflammation is considered central to the pathogenesis of multiple sclerosis, to date, the only licensed and hence widely used multiple sclerosis immunotherapies are interferon-beta, glatiramer acetate and mitoxantrone. This review discusses the immunopathogenesis of multiple sclerosis, focusing on a number of emerging immunotherapies. A number of new approaches likely to manipulate the immunopathogenesis of multiple sclerosis and which may ultimately allow for the development of more effective immunotherapy are also highlighted.

Lee, S. M., Y. Morcos, et al. (2005). "HTLV-1 induced molecular mimicry in neurological disease." Curr Top Microbiol Immunol 296: 125-36.

            As a model for molecular mimicry, we study patients infected with human T-lymphotropic virus type 1 (HTLV-1) who develop a neurological disease called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease with important biological similarities to multiple sclerosis (MS) (Khan et al. 2001; Levin et al. 1998, 2002a; Levin and Jacobson 1997). The study of HAM/TSP, a disease associated with a known environmental agent (HTLV-1), allows for the direct comparison of the infecting agent with host antigens. Neurological disease in HAM/TSP patients is associated with immune responses to HTLV-1-tax (a regulatory and immunodominant protein) and human histocompatibility leukocyte antigen (HLA) DRB1*0101 (Bangham 2000; Jacobson et al. 1990; Jeffery et al. 1999; Lal 1996). Recently, we showed that HAM/TSP patients make antibodies to heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), a neuron-specific autoantigen (Levin et al. 2002a). Monoclonal antibodies to tax cross-reacted with hnRNP A1, indicating molecular mimicry between the two proteins. Infusion of cross-reactive antibodies with an ex vivo system completely inhibited neuronal firing indicative of their pathogenic nature (Kalume et al. 2004; Levin et al. 2002a). These data demonstrate a clear link between chronic viral infection and autoimmune disease of the central nervous system (CNS) in humans and, we believe, in turn will give insight into the pathogenesis of MS.

Leary, S. M., B. Porter, et al. (2005). "Multiple sclerosis: diagnosis and the management of acute relapses." Postgrad Med J 81(955): 302-8.

            Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that may result in a wide range of neurological symptoms and accumulating disability. Its course is unpredictable resulting in a changing pattern of clinical need. Diagnostic criteria for multiple sclerosis require objective evidence for dissemination in space and time. The diagnostic and management process should follow good practice guidelines with the person at the centre of the process. Appropriate support and information should be available from the time of diagnosis. Continuing education is key in enabling the person to actively participate in their management. In the event of an acute relapse the person should have direct access to the most appropriate local service. Provided medical causes have been excluded, corticosteroid treatment to hasten the recovery from the relapse should be considered. Management of an acute relapse should be comprehensive addressing any medical, functional, or psychosocial sequelae.

Leary, S. M. and A. J. Thompson (2005). "Primary progressive multiple sclerosis : current and future treatment options." CNS Drugs 19(5): 369-76.

            Approximately 10% of patients with multiple sclerosis (MS) run a primary progressive course characterised by an accumulation of neurological deficits without relapse or remission. Designing therapeutic trials in primary progressive MS (PPMS) has presented several problems. Patient recruitment may be difficult because of the relative rarity of PPMS and historically has been hindered by the lack of specific diagnostic criteria. There has been a limited choice of validated outcome measures, although, in recent studies, the MS functional composite measure and magnetic resonance imaging measures of lesion load and atrophy have been widely used. Despite these problems, several trials have been designed specifically for PPMS, including exploratory randomised controlled trials of interferon-beta-1a and interferon-beta-1b and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole. Patients with PPMS have also been included in randomised controlled trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin and cyclophosphamide, and open-label studies of haematopoietic stem cell transplantation and pirfenidone in progressive MS. However, no treatment has been proven definitively to modify the course of the disease. Looking to the future, therapeutic agents should aim to target the underlying pathogenic mechanisms in PPMS. As a result of the relative lack of inflammation in PPMS, neuroprotective agents that target neuronal loss directly, rather than inflammation, may be more worthwhile. However, further investigation into the pathogenic mechanisms in PPMS is required to guide the development of future therapeutic agents.

Lazzeri, E. and P. Romagnani (2005). "CXCR3-binding chemokines: novel multifunctional therapeutic targets." Curr Drug Targets Immune Endocr Metabol Disord 5(1): 109-18.

            The goal to attenuate inflammation without inducing generalized immunosuppression has focused the attention on chemokines, a family of chemotactic peptides that regulate the leukocyte traffick into tissues. However, the development of drugs that block ckemokine activity may be hampered by the observation that some chemokines display pleiotropic biologic functions. For example, the chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC exhibit the ability to recruit different leukocytes subsets, the capacity to induce the proliferation of vascular pericytes as well as powerful anti-tumor effects, which are mediated by a common receptor, named CXCR3. Because of their pleiotropic biologic effects, these chemokines have been proposed as possible therapeutic targets in cancer, allograft rejection, glomerulonephritis, diabetes, multiple sclerosis, and autoimmune disorders of the thyroid. The chemokine CXCL4/PF4 shares several activities with CXCL9, CXCL10, and CXCL11, including angiostatic effects, although its specific receptor has remained unknown for a long time. Recently, we provided evidence that the different functions of CXCL9, CXCL10, and CXCL11 on distinct cell types can be at least partly explained by the interaction of these chemokines with two distinct receptors. Indeed, in addition to the classic form of CXCR3 receptor, which we have renamed as CXCR3-A, a novel CXCR3 receptor variant (CXCR3-B) was identified, that not only mediates the angiostatic activity of CXCR3 ligands, but also acts as functional receptor for CXCL4. In this review, we focus on the accumulating evidence demonstrating the pivotal role of CXCR3-binding chemokines in several human diseases. Studies based on CXCR3 targeting have shown its importance in different pathologic conditions and orally active small molecules capable of inhibiting this receptor are now being developed in order to be tested for their activity in humans.

Lassmann, H. (2005). "Stem cell and progenitor cell transplantation in multiple sclerosis: the discrepancy between neurobiological attraction and clinical feasibility." J Neurol Sci 233(1-2): 83-6.

            Recent developments in our understanding of stem- and progenitor cell differentiation raises hopes that brain damage in chronic neurological diseases may become repaired by systemic or focal transplantation of such cells. In this review the potential of such an approach is discussed, but it is also highlighted that many aspects regarding its feasibility or safety are currently unresolved. Furthermore, recent findings on the pathogenesis of multiple sclerosis lesions indicate that major problems in this disease rather are related to axonal pathology and neurodegeneration rather than to the absence of oligodendrocyte progenitor cells within the lesions. In light of this complex situation, it is concluded that clinical trials of stem- or progenitor cell transplantation in multiple sclerosis are currently premature.

Lassmann, H. (2005). "Multiple sclerosis pathology: evolution of pathogenetic concepts." Brain Pathol 15(3): 217-22.

            This historical review describes the evolution of pathogenetic concepts of multiple sclerosis (MS) from the viewpoint of pathology. MS research is based on studies of descriptive neuropathology, performed during the 19th and early-20th century, which defined the basic nature of the inflammatory demyelinating lesions. Advances in basic immunology and neurobiology, performed during the second half of the 20th century, paved the way for the understanding of the molecular mechanims involved in inflammation and well as tissue destruction in this disease. However, recent clinical and neuroradiological studies on the evolution of the disease and its brain lesions as well as ongoing attempts to define the genetic basis of the disease indicate that our current pathogenetic concepts may be too simple and that essential aspects of MS pathology have to be redefined.

Lassmann, H. (2005). "Heterogeneity of multiple sclerosis: implications for therapy targeting regeneration." Ernst Schering Res Found Workshop(53): 11-22.

Langgartner, M., I. Langgartner, et al. (2005). "The patient's journey: multiple sclerosis." Bmj 330(7496): 885-8.

Lan, R. Y., A. A. Ansari, et al. (2005). "Regulatory T cells: development, function and role in autoimmunity." Autoimmun Rev 4(6): 351-63.

            The crucial role of regulatory cells in self-tolerance and autoimmunity has been clearly established in numerous types of regulatory cells, the majority of which are CD4(+) T cells. Much focus has been placed on thymically derived CD4(+)CD25(+) regulatory T cells, given that the depletion of this subset in murine models results in the spontaneous development of autoimmune diseases. These naturally occurring regulatory T cells are found to be functionally mature in the thymus, and exert suppression in a contact-dependent manner. Another important category of immunosuppressive cells consists of conditionally induced regulatory T cells such as Tr1, Th3, and various other CD4(+) lymphocytes. Understanding the development and regulatory functions of immunoregulatory cells may elucidate the etiology for loss of self-tolerance. This review will summarize the characteristics, developmental pathways, and functions of regulatory T cells, as well as their role in human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, Myasthenia Gravis, Kawasaki disease, autoimmune polyglandular syndrome type II, type 1 diabetes, autoimmune lymphoproliferative syndrome, and systemic lupus erythematosus.

Lamprecht, P. (2005). "TNF-alpha inhibitors in systemic vasculitides and connective tissue diseases." Autoimmun Rev 4(1): 28-34.

            The introduction of TNF-alpha inhibitors in the treatment of rheumatoid arthritis and several other diseases meant a major progress in the management and to the understanding of these chronic inflammatory diseases. In this article, the evidence of the role of TNF-alpha and for TNF-alpha inhibitors in systemic vasculitides and connective tissue diseases is reviewed. TNF-alpha is expressed in inflammatory lesions. TNF-alpha acts as a proinflammatory cytokine in most disease processes analyzed so far, but it might have anti-inflammatory properties under certain conditions as well, e.g. with respect to B-cell regulation in systemic lupus erythematosus. It is not clear to what extent such aspects will be important in the treatment of connective tissue diseases and systemic vasculitides with TNF-alpha inhibitors. So far, most case reports and case series have suggested favourable results with TNF-alpha inhibitor therapy in systemic lupus erythematosus, dermato- and polymyositis, giant cell arteritis, Churg-Strauss syndrome, Wegener's granulomatosis and microscopic polyangiitis. Results of randomized, placebo-controlled trials are awaited for several connective tissue diseases and systemic vasculitides. One randomized, placebo-controlled trial has found no efficacy of infliximab treatment in primary Sjogren's syndrome recently.

Kwiatkowski, D. J. and B. D. Manning (2005). "Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways." Hum Mol Genet 14 Spec No. 2: R251-8.

            Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is characterized by benign tumors (hamartomas and hamartias) involving multiple organ systems, due to inactivating mutations in TSC1 or TSC2. Here, we review recent advances in our understanding of the growth and signaling functions of the TSC1 and TSC2 proteins. Led by seminal studies in Drosophila, the TSC1/TSC2 complex has been positioned in an ancestrally conserved signaling pathway that regulates cell growth. TSC1/TSC2 receives inputs from at least three major signaling pathways in the form of kinase-mediated phosphorylation events that regulate its function as a GTPase activating protein (GAP): the PI3K-Akt pathway, the ERK1/2-RSK1 pathway and the LKB1-AMPK pathway. TSC1/TSC2 functions as a GAP towards Rheb, which is a major regulator of the mammalian target of rapamycin (mTOR). In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and deregulated protein synthesis and cell growth. As a specific inhibitor of mTOR, rapamycin has therapeutic potential for the treatment of TSC hamartomas.

Kutzelnigg, A. and H. Lassmann (2005). "Cortical lesions and brain atrophy in MS." J Neurol Sci 233(1-2): 55-9.

            Multiple sclerosis is generally considered a disease of the white matter. However, this is only one pathological aspect of the disease as demyelination is prominent in the grey matter of deep cerebral nuclei and the cerebral cortex. In this review, we discuss the possibility that disease involvement of grey matter structures may significantly contribute to clinical disability in multiple sclerosis patients.

Kurzepa, J., H. Bartosik-Psujek, et al. (2005). "[Role of matrix metalloproteinases in the pathogenesis of multiple sclerosis]." Neurol Neurochir Pol 39(1): 63-7.

            Multiple sclerosis (MS) is an autoimmune disease whose features include a massive lymphocyte recruitment into the central nervous system and segmental demyelinization of the white matter. One of the MS development factors is an increase of matrix metalloproteinases (MMPs) activity with a coincidental decrease of tissue inhibitors of MMPs (TIMPs) activity. Investigations of serum, cerebrospinal fluid and brain tissue of patients showed an increase of MMP-1, -2, -3, -7, -9 and MMP-12 activity. MMPs disrupt the blood-brain barrier (BBB), increase lymphocyte migration into the central nervous system and are involved in degradation of myelin proteins. MMPs induce the appearance of an active form of tumor necrosis factor alpha, a strong proinflammatory cytokine. The drugs used in MS treatment decrease MMPs expression. Multiple actions of MMPs prove their involvement in the pathogenesis and treatment of MS.

Kundra, O. (2005). "[The role of evoked potentials in neurological clinical practice]." Ideggyogy Sz 58(11-12): 364-79.

            The author provides an overview on the value of evoked potential (EP) methods (VEP, SEP, BAEP, MEP) in the diagnosis and follow-up of various neurological diseases (multiple sclerosis, cerebrovascular disorders, degenerative diseases, coma, epilepsy, migraine) by reviewing the literature supported by his own clinical experience. While in the past EP was mainly used for establishing the diagnosis, recently, with the expansion of neuroradiology, it has gained a wider use in the assessment of the severity and extent of the pathologic process and especially in longitudinal follow-up. Its role in the diagnostic phase has diminished. In patients with multiple sclerosis the abnormality of the evoked potentials correlate better with the clinical state than with the MRI results. The method is also suitable to monitor the response to therapy. The importance of the EP tests is illustrated by several case demonstrations.

Krishnan, K. R. (2005). "Psychiatric and medical comorbidities of bipolar disorder." Psychosom Med 67(1): 1-8.

            OBJECTIVES: This review summarizes the literature on psychiatric and medical comorbidities in bipolar disorder. The coexistence of other Axis I disorders with bipolar disorder complicates psychiatric diagnosis and treatment. Conversely, symptom overlap in DSM-IV diagnoses hinders definition and recognition of true comorbidity. Psychiatric comorbidity is often associated with earlier onset of bipolar symptoms, more severe course, poorer treatment compliance, and worse outcomes related to suicide and other complications. Medical comorbidity may be exacerbated or caused by pharmacotherapy of bipolar symptoms. METHODS: Articles were obtained by searching MEDLINE from 1970 to present with the following search words: bipolar disorder AND, comorbidity, anxiety disorders, eating disorder, alcohol abuse, substance abuse, ADHD, personality disorders, borderline personality disorder, medical disorders, hypothyroidism, obesity, diabetes mellitus, multiple sclerosis, lithium, valproate, lamotrigine, carbamazepine, atypical antipsychotics. Articles were prioritized for inclusion based on the following considerations: sample size, use of standardized diagnostic criteria and validated methods of assessment, sequencing of disorders, quality of presentation. RESULTS: Although the literature establishes a strong association between bipolar disorder and substance abuse, the direction of causality is uncertain. An association is also seen with anxiety disorders, attention-deficit/hyperactivity disorder, and eating disorders, as well as cyclothymia and other axis II personality disorders. Medical disorders accompany bipolar disorder at rates greater than predicted by chance. However, it is often unclear whether a medical disorder is truly comorbid, a consequence of treatment, or a combination of both. CONCLUSION: To ensure prompt, appropriate intervention while avoiding iatrogenic complications, the clinician must evaluate and monitor patients with bipolar disorder for the presence and the development of comorbid psychiatric and medical conditions. Conversely, physicians should have a high index of suspicion for underlying bipolar disorder when evaluating individuals with other psychiatric diagnoses (not just unipolar depression) that often coexist with bipolar disorder, such as alcohol and substance abuse or anxiety disorders. Anticonvulsants and other mood stabilizers may be especially helpful in treating bipolar disorder with significant comorbidity.

Kriesel, J. D. and W. A. Sibley (2005). "The case for rhinoviruses in the pathogenesis of multiple sclerosis." Mult Scler 11(1): 1-4.

Kraus, T. A. and L. Mayer (2005). "Oral tolerance and inflammatory bowel disease." Curr Opin Gastroenterol 21(6): 692-6.

            PURPOSE OF REVIEW: Oral tolerance refers to the ability of the mucosal immune system to actively inhibit systemic immune responses to fed antigens. Recently, clinical trials have used oral tolerance as a therapy for certain chronic inflammatory and autoimmune diseases such as multiple sclerosis and type I diabetes. Inflammatory bowel disease is now widely thought to be caused by the breakdown of oral tolerance through a combination of genetic and environmental factors. Therefore, it seems incongruous that clinicians would try to use oral tolerance therapy to alleviate the symptoms of inflammatory bowel disease. Yet, armed with the results of select animal models, trials have begun for oral tolerance therapy for Crohn's disease. This review will outline the recent advances in understanding oral tolerance, explore the relation between oral tolerance and inflammatory bowel disease, and comment on the likelihood of successful oral tolerance therapy for inflammatory bowel disease. RECENT FINDINGS: The results of an oral tolerance trial in Crohn's disease patients in Israel have shown some promising results, whereas the results of studies of experimentally induced oral tolerance in patients with inflammatory bowel disease from the authors' laboratory have shown that feeding a neoantigen in an attempt to induce oral tolerance is not successful in patients with inflammatory bowel disease. SUMMARY: The fundamental difference in the mechanisms of oral tolerance in mice and humans requires a more focused effort to understand the human mucosal immune system before oral tolerance therapy for autoimmune and chronic inflammatory disorders reaches its full potential.

Kranc, K. R., A. M. Taylor, et al. (2005). "Control of autoimmunity by "epitope theft"." Trends Mol Med 11(1): 1-4.

            We all possess T cells with autoaggressive potential. Knowledge of their regulation is crucial for elucidating pathogenetic pathways and designing effective treatments for autoimmune diseases. A novel mechanism of T-cell silencing--in an autoimmune model--has recently been identified and is termed "epitope theft". The "thieves" are naive CD8+ T cells, which apparently "steal" MHC-class-I-antigen complexes from antigen-presenting cells (APCs). The deprived APCs can no longer activate other potentially pathogenic naive CD8+ T cells that are specific for the same epitope. This phenomenon is a previously unrecognized antigen-specific mode of protection against autoimmunity.

Kotter, I., T. Daikeler, et al. (2005). "Autologous stem cell transplantation of treatment-resistant systemic vasculitis--a single center experience and review of the literature." Clin Nephrol 64(6): 485-9.

            AIMS: Autologous peripheral blood stem cell transplantation (autoPBSCT) is increasingly and successfully applied to patients with treatment-resistant autoimmune diseases, mainly multiple sclerosis and systemic sclerosis, but also juvenile idiopathic arthritis and systemic lupus erythematosus. We intended to analyze the effects of autoPBSCT in patients with treatment-resistant systemic vasculitis by analyzing the outcome of 4 patients from our own hospital, and comparing them to cases reported in the literature. METHODS: 4 patients with treatment-resistant vasculitis (Wegener granulomatosis, Churg Strauss syndrome, Takayasu arteritis and relapsing polychondritis) received an autologous PBSCT. Stem cell mobilization was performed with cyclophosphamide (CY) and G-CSF, stem cells were purged by positively selecting CD34+ stem cells over a CliniMacs device, and the conditioning was performed with high dose CY and anti-thymocyte globulin (ATG). RESULTS: AutoPBSCT was well tolerated in all 4 patients. The patient with WG achieved complete remission although cANCA persisted, the other patients are in good partial remissions and respond to maintenance treatments which had been ineffective before PBSCT (CSA, azathioprin). Glucocorticosteroids (GC) could be reduced to a maximum of 10 mg in all patients. Shortly after the procedure, reactivation of viruses from the herpes family occurred in 3 of the patients and had to be treated. In the data base, 25 patients transplanted for severe systemic vasculitis are registered, in the literature, 6 additional vasculitis patients remitting after autoPBSCT are reported. CONCLUSIONS: Autologous PBSCT is feasible and effective in severe, treatment-resistant forms of systemic vasculitis. Data are sparse, further prospective studies are needed. These should also aim at evaluating more optimal regimens for conditioning and purging during PBSCT, as in most of the vasculitis patients reported until now, mostly good partial remissions, but less complete remissions were achieved.

Korsak, J., B. Zaleska, et al. (2005). "[Use of high dose intravenous immunoglobulin in neurologic disease]." Pol Merkur Lekarski 19(109): 98-101.

            Intravenous immunoglobulin has been used generally as a supplement therapy in hypogammaglobulinemia patients. Then it has been shown to be effective in the treatment of patients with thrombocytopenic purpura, and in the last decade, IVIG has been used in the treatment of many autoimmune and systemic inflammatory diseases. In neurologic diseases intravenous immunoglobulin (IVIG) exhibits immunomodulatory properties, depending on the Fc portion of immunoglobulin G. The number of diseases in which IVIG therapy is effective has been demonstrated by controlled clinical trials. The indications for IVIG therapy in neurologic diseases are in four groups: A+ - the basic indication, they have been demonstrated in controlled clinical trials, A - recommended but they have not been proved by clinical trials, B - confirmed by singular trials, C - recommended as a last resort: the indications have not been confirmed any trials. IVIG clinical effect has been shown in trials in patients with GBS, chronic inflammatory demyelinating polyneuropathy, dermatomyositis and multiple sclerosis. An optimal dose and the frequency of IVIG administration depend on the knowledge of the pathophysiology of autoimmune diseases and the mechanism of IVIG action.

Kornhuber, M. E., P. Presek, et al. (2005). "[Differential influence of immune therapy on relapses and progression in multiple sclerosis: interpretation and therapeutic consequences.]." Fortschr Neurol Psychiatr 73(3): 143-9.

            It is well established that relapses can be suppressed by different substances in patients with relapsing-remitting multiple sclerosis (MS). In contrast, patients with progressive forms of MS do hardly respond to immune therapy. Therefore, start of immune therapy after the first relapse has been proposed, especially in order to prevent degeneration and disability. This view is challenged in the present review. Actually no evidence exists in support of a retardation or an attenuation of secondary progression by early immune therapy. Widespread degeneration occurs early and progresses independently from inflammatory plaques. Therefore, autoimmunity per se is no adequate paradigm to explain MS-pathogenesis entirely. A virus/superantigen-dualism is proposed to explain the different parts of MS, instead. It is concluded that evidence-based immune therapy should be adapted to the actual inflammatory activity of the disease. A suitable parameter for this purpose is the interval between 2 relapses.

Korf, B. R. (2005). "The phakomatoses." Clin Dermatol 23(1): 78-84.

            The "phakomatosis" concept was formulated early in the twentieth century by the ophthalmologist van der Hoeve. He included 3 disorders in the group-neurofibromatosis, tuberous sclerosis complex, and von Hippel-Lindau syndrome--on the basis of the occurrence of patchy ophthalmologic manifestations in each disorder. Since the name was coined, much has been learned about the pathogenesis of these 3 disorders. It is clear that 2 of them--neurofibromatosis and tuberous sclerosis--are collective terms for multiple disorders. Each of the conditions is caused by distinct genetic defects, with little commonality in terms of protein function. Yet, in some respects, the disorders share a pathogenetic mechanism, that of the tumor suppressor gene. This review will briefly describe these disorders in light of what has been learned about underlying molecular pathogenesis. In each case, genetic testing is beginning to be available; principles of the use of genetic tests will be described.

Kohm, A. P., D. M. Turley, et al. (2005). "Targeting the TCR: T-cell receptor and peptide-specific tolerance-based strategies for restoring self-tolerance in CNS autoimmune disease." Int Rev Immunol 24(5-6): 361-92.

            A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for the onset and progression of most autoimmune diseases, they are a logical target for therapeutic interventions. One technique for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T-cell activation. In this review, we discuss promising techniques with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of non-mitogenic anti-CD3 and peptide-specific tolerance strategies that specifically target the T-cell receptor (TCR) in the absence of costimulatory signals. These approaches produce a TCR signal of insufficient strength to cause CD4(+) T-cell activation and instead induce functional T-cell anergy or deletion while avoiding generalized long-term immunosuppression.

Knutson, K. L. and M. L. Disis (2005). "Tumor antigen-specific T helper cells in cancer immunity and immunotherapy." Cancer Immunol Immunother 54(8): 721-8.

            Historically, cancer-directed immune-based therapies have focused on eliciting a cytotoxic T cell (CTL) response, primarily due to the fact that CTL can directly kill tumors. In addition, many putative tumor antigens are intracellular proteins, and CTL respond to peptides presented in the context of MHC class I which are most often derived from intracellular proteins. Recently, increasing importance is being given to the stimulation of a CD4+ T helper cell (Th) response in cancer immunotherapy. Th cells are central to the development of an immune response by activating antigen-specific effector cells and recruiting cells of the innate immune system such as macrophages and mast cells. Two predominant Th cell subtypes exist, Th1 and Th2. Th1 cells, characterized by secretion of IFN-gamma and TNF-alpha, are primarily responsible for activating and regulating the development and persistence of CTL. In addition, Th1 cells activate antigen-presenting cells (APC) and induce limited production of the type of antibodies that can enhance the uptake of infected cells or tumor cells into APC. Th2 cells favor a predominantly humoral response. Particularly important during Th differentiation is the cytokine environment at the site of antigen deposition or in the local lymph node. Th1 commitment relies on the local production of IL-12, and Th2 development is promoted by IL-4 in the absence of IL-12. Specifically modulating the Th1 cell response against a tumor antigen may lead to effective immune-based therapies. Th1 cells are already widely implicated in the tissue-specific destruction that occurs during the pathogenesis of autoimmune diseases, such as diabetes mellitus and multiple sclerosis. Th1 cells directly kill tumor cells via release of cytokines that activate death receptors on the tumor cell surface. We now know that cross-priming of the tumor-specific response by potent APC is a major mechanism of the developing endogenous immune response; therefore, even intracellular proteins can be presented in the context of MHC class II. Indeed, recent studies demonstrate the importance of cross-priming in eliciting CTL. Many vaccine strategies aim to stimulate the Th response specific for a tumor antigen. Early clinical trials have shown that focus on the Th effector arm of the immune system can result in significant levels of both antigen-specific Th cells and CTL, the generation of long lasting immunity, and a Th1 phenotype resulting in the development of epitope spreading.

Klegeris, A. and P. L. McGeer (2005). "Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease." Curr Alzheimer Res 2(3): 355-65.

            Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen, celecoxib and rofecoxib in AD clinical trials. Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy.

Kim, S. U. and J. de Vellis (2005). "Microglia in health and disease." J Neurosci Res 81(3): 302-13.

            Microglia, one of three glial cell types in the central nervous system (CNS), play an important role as resident immunocompetent and phagocytic cells in the CNS in the event of injury and disease. It was del Rio Hortega in 1927 who determined that microglia belong a distinct glial cell type apart from astrocytes and oligodendrocytes, and since 1970s there has been wide recognition that microglia are immune effectors in the CNS that respond to pathological conditions and participate in initiation and progression of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and acquired immune deficiency syndrome dementia complex by releasing potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. There is also evidence to suggest that microglia are capable of secreting neurotrophic or neuron survival factors upon activation via inflammation or injury. It is thus timely to review current status of knowledge on biology and immunology of microglia, and consider new directions of investigation on microglia in health and disease.

Killestein, J. and C. H. Polman (2005). "Current trials in multiple sclerosis: established evidence and future hopes." Curr Opin Neurol 18(3): 253-60.

            PURPOSE OF REVIEW: The aim of the present report is to briefly review multiple sclerosis therapeutic trials published or presented in 2004 to provide an up-to-date overview of the established evidence and new insights. RECENT FINDINGS: New data have come available that help us understand how currently approved disease modifying drugs can best be used. Nonetheless, their limited effectiveness - especially in progressive forms of multiple sclerosis - as well as the inconvenience and toxicity associated with their use, emphasize the need for new treatment strategies. A substantial number of reports on new emerging treatment modalities were published in 2004, and one of these modalities was newly approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis. SUMMARY: Further advances have been made in the treatment of multiple sclerosis patients. On the one hand, we know better how and in whom to use existing medications. On the other hand, it is exciting to witness how increased insight in the pathophysiology of the disease and its symptoms has led to a series of new, innovative treatment modalities.

Kieseier, B. C., B. Hemmer, et al. (2005). "Multiple sclerosis--novel insights and new therapeutic strategies." Curr Opin Neurol 18(3): 211-20.

            PURPOSE OF REVIEW: This review focuses on novel aspects of the pathogenesis and advances in the therapy of multiple sclerosis (MS). RECENT FINDINGS: Recent observations suggest that early lesion development in MS may start in some forms with oligodendrocyte death and that inflammation appears as a secondary phenomenon only. The lack of sufficient remyelination in MS may be the result of a disturbed function of basic helix-loop-helix transcription factors. Clinically the identification of patients with a clinically isolated syndrome at high risk to develop clinically definite MS remains difficult; the predictive value of serum antibodies against myelin proteins remains controversial. The role of neutralizing antibodies in interferon therapy is discussed. New therapeutic approaches in MS are emerging. SUMMARY: The existing view on the pathogenesis of MS is still changing. The original assumption that cell-mediated demyelination is the key event in lesion development dictating clinical disability is critically reviewed and alternative pathways have been suggested. Oligodendrocyte death, axonal loss, the role of CD8 T lymphocytes, T regulatory cells, and B lymphocytes have come into the focus of newly evolving concepts in MS pathogenesis. A deepened understanding of the immunopathogenesis of this disease translates into innovative therapeutic approaches, such as blockade of alpha4 integrins by a humanized monoclonal antibody. In various animal models cell-replacement strategies yield promising results; however, turning these findings into an effective therapy in MS patients has a long way to go.

Kidd, P. M. (2005). "Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management." Altern Med Rev 10(4): 268-93.

            Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.

Kesselring, J. and S. Beer (2005). "Symptomatic therapy and neurorehabilitation in multiple sclerosis." Lancet Neurol 4(10): 643-52.

            Multiple sclerosis (MS) is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap. Symptoms that contribute to loss of independence and restrictions in social activities lead to continuing decline in quality of life. Our aim is to give an updated overview on the management of symptoms and rehabilitation measures in MS. Appropriate use of these treatment options might help to reduce long-term consequences of MS in daily life. First, we review treatment of the main symptoms of MS: fatigue, bladder and bowel disturbances, sexual dysfunction, cognitive and affective disorders, and spasticity. Even though these symptomatic therapies have benefits, their use is limited by possible side-effects. Moreover, many common disabling symptoms, such as weakness, are not amenable to drug treatment. However, neurorehabilitation has been shown to ease the burden of these symptoms by improving self-performance and independence. Second, we discuss comprehensive multidisciplinary rehabilitation and specific treatment options. Even though rehabilitation has no direct influence on disease progression, studies to date have shown that this type of intervention improves personal activities and ability to participate in social activities, thereby improving quality of life. Treatment should be adapted depending on: the individual patient's needs, demands of their surrounding environment, type and degree of disability, and treatment goals. Improvement commonly persists for several months beyond the treatment period, mostly as a result of reconditioning and adaptation and appropriate use of medical and social support at home. These findings suggest that quality of life is determined by disability and handicap more than by functional deficits and disease progression.

Keeley, K. A., M. P. Rivey, et al. (2005). "Natalizumab for the treatment of multiple sclerosis and Crohn's disease." Ann Pharmacother 39(11): 1833-43.

            OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and pivotal clinical trials for natalizumab in the treatment of multiple sclerosis (MS) and inflammatory bowel disease. DATA SOURCES: A PubMed/MEDLINE search was conducted (1966-June 2005), and information was obtained from Iowa Drug Information Services. Additional data sources included meeting abstracts, bibliographies from identified articles, and information from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles examining natalizumab were evaluated. All published, randomized clinical trials evaluating natalizumab in MS and IBD were included in this review. DATA SYNTHESIS: Natalizumab is the first drug in a new class of agents called selective adhesion molecule inhibitors. It has shown promising results in MS and inflammatory bowel disease and appears superior compared with current therapies in reducing relapse rates. However, 3 recent, confirmed case reports of progressive multifocal leukoencephalopathy (PML) create concern about natalizumab's use in combination with existing therapies or in undefined patient subgroups. Natalizumab was voluntarily withdrawn from the market in March 2005 while the drug's safety is further evaluated. CONCLUSIONS: Although long-term efficacy and safety of natalizumab have not been established, available data indicate that it is a novel drug for patients with MS or inflammatory bowel disease. Analysis of its possible association with PML will determine the risk-benefit evaluation and eventual place in therapy for natalizumab.

Keane, J. R. (2005). "Internuclear ophthalmoplegia: unusual causes in 114 of 410 patients." Arch Neurol 62(5): 714-7.

            Internuclear ophthalmoplegia (INO) is a sign of exquisite localizing value, often due to either multiple sclerosis or infarction. To demonstrate that unusual causes of INO are more common than the 11% reported in previous series, this review considers a case series of 410 inpatients whom I personally examined during a 33-year period. In this series, the cause of INO was infarction in 157 patients (38%), multiple sclerosis in 139 (34%), and unusual causes in 114 (28%). Unusual causes included trauma (20 cases), tentorial herniation (20 cases), infection (17 cases), tumor (17 cases), iatrogenic injury (12 cases), hemorrhage (13 cases), vasculitis (7 cases), and miscellaneous (8 cases). Internuclear ophthalmoplegia was unilateral in 136 of the infarct cases (87%), 38 of those with multiple sclerosis (27%), and 48 of the unusual cases (42%). Because unusual causes compose more than one quarter of the cases, the differential diagnosis of INO should be tripartite: multiple sclerosis, stroke, and other causes.

Karnad, D. R. and K. K. Guntupalli (2005). "Neurologic disorders in pregnancy." Crit Care Med 33(10 Suppl): S362-71.

            BACKGROUND: Neurologic dysfunction, coma, and seizures are common in obstetric patients in the intensive care unit. OBJECTIVE: To review common neurologic disorders resulting in critical illness in pregnancy. REVIEW: Obstetric disorders causing coma and seizures include eclampsia, acute fatty liver of pregnancy, and amniotic fluid embolism. Preexisting disorders such as epilepsy may worsen in one-third of pregnant patients, and seizures are common during labor. Changes in hemodynamics, blood volume, and hormonal effects on the vessel wall increase risk of bleeding from berry aneurysms and arteriovenous malformations during pregnancy and the postpartum period. Acute intermittent porphyria produces seizures and hypertension, closely mimicking eclampsia. Cerebral venous sinus thrombosis is common in postpartum patients, especially in developing countries. Brain tumors invariably enlarge during pregnancy because of fluid retention and the presence of estrogen and progesterone receptors on tumor cells. Infections such as cerebral malaria and acute viral hepatitis with fulminant hepatic failure are common causes of coma and seizures during pregnancy in tropical regions of Asia, Africa, and Latin America. Patients may be admitted to the intensive care unit with type II respiratory failure due to myasthenic crisis, Guillain-Barre syndrome and spinal cord disease. Relapses of multiple sclerosis are infrequent during pregnancy but increase in the postpartum period. CONCLUSIONS: In all instances, the effects of the disorders, diagnostic tests, and treatment on the fetus must be carefully weighed. Prompt delivery may be lifesaving for mother and fetus in conditions such as eclampsia and acute fatty liver of pregnancy; expectant treatment may be more appropriate in others.

Karlinska, I. and K. Selmaj (2005). "[Cognitive impairment in multiple sclerosis]." Neurol Neurochir Pol 39(2): 125-33.

            In this article we present a review of problems associated with cognitive dysfunctions in multiple sclerosis (MS). Neuropsychological investigations demonstrated that cognitive dysfunctions are common in MS patients and affect 40-65% of them. Cognitive deficits were found mainly on measures of memory, attention, information-processing speed, executive functions and abstract reasoning. The differences and degree of cognitive dysfunctions in MS are highlighted and usually related to different clinical appearance (clinical course, duration, disability level, treatment type). Furthermore, we have reviewed published correlations between psychopathological dysfunctions and neuroimaging results (mainly MRI techniques and functional imaging). The results of these correlations showed that an important role in cognitive impairment is related to the total lesion area, the severity of the pathological damage of the normal-appearing brain tissue (NABT), and brain atrophy.

Karbowniczek, M. and E. P. Henske (2005). "The role of tuberin in cellular differentiation: are B-Raf and MAPK involved?" Ann N Y Acad Sci 1059: 168-73.

            Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. The products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, heterodimerize and inhibit the mammalian target of rapamycin (mTOR). This review focuses on the genetic and biochemical basis of the renal and pulmonary manifestations of TSC, angiomyolipomas, and lymphangiomyomatosis, respectively. Genetic analyses of sporadic angiomyolipomas revealed that all three components (smooth muscle, vessels, and fat) derive from a common progenitor cell, indicating the ability of cells lacking tuberin to differentiate into multiple lineages. Other genetic studies showed that the benign smooth muscle cells of pulmonary lymphangiomyomatosis have the ability to migrate to other organs. These findings suggest that tuberin and hamartin play a role in the regulation of cellular migration and differentiation. We have found that tuberin activates B-Raf kinase and p42/44 MAPK and that cells lacking tuberin have low levels of B-Raf activity. We hypothesize that aberrant B-Raf activity in angiomyolipomas leads to abnormal cellular differentiation and migration.

Kappos, L. (2005). "Interferons in multiple sclerosis." Neurol Clin 23(1): 189-214, vii-viii.

Kappos, L. and H. P. Hartung (2005). "10 years of interferon beta-1b (Beta feron therapy." J Neurol 252 Suppl 3: iii1-iii2.

Kappos, L., L. Achtnichts, et al. (2005). "Genomics and proteomics: role in the management of multiple sclerosis." J Neurol 252 Suppl 3: iii21-iii27.

            Epidemiological studies and neuro-imaging have provided important insights into the natural course and prognostic factors of multiple sclerosis (MS), but our ability to predict different courses of the disease, and especially its response to treatment, is still very limited. Pharmacogenetic, pharmacogenomic and proteomic studies aim to assess gene and protein function in disease and promise to help to fill this important gap in our knowledge. Such studies may increase our understanding of disease mechanisms and responses to therapeutic compounds. Large-scale transcriptional expression profiling can be performed using gene chip microarrays; this technology allows screening for differentially expressed genes without having well-defined underlying hypotheses ("discovery-driven research"). To complement the technique, real time reverse transcription and polymerase chain reaction (RT-PCR) can be used for more targeted profiling and provides quantitative data on pre-selected genes. However, to maximise their clinical utility, expression profiling results need to be combined with well-documented clinical and imaging data.Two forthcoming studies will investigate the long-term effects of early treatment with interferon beta-1b (IFNbeta) on the course of MS. The BENEFIT (BEtaseron/Betaferon in Newly Emerging MS for Initial Treatment) study will incorporate pharmacogenetic and pharmacogenomic analyses to determine the genetic elements controlling treatment response. BEST-PGx (Betaferon/Betaseron in Early relapsing-remitting MS Surveillance Trial-Pharmacogenomics) is an exploratory 2-year study that will investigate the value of RNA expression profiling and pharmacogenetics in predicting treatment response to IFNbeta in patients with early relapsing MS. The main goal of BEST-PGx is the identification of differences in gene expression profiles of patients showing differential treatment responses. In addition, this study may reveal new information relevant to the mechanism of action of interferon treatment in MS and also to differences in the underlying pathology of the immune system. These data may help us approach the goal of a really "individualised therapy" with increased efficacy, reduced adverse drug reactions and more efficient use of health care resources.

Kapoor, D. S., R. Thakar, et al. (2005). "Combined urinary and faecal incontinence." Int Urogynecol J Pelvic Floor Dysfunct 16(4): 321-8.

            Combined urinary and faecal (liquid or solid) incontinence (double incontinence) is the most severe and debilitating manifestation of pelvic floor dysfunction. The community prevalence is 9-19% (urinary) and 5-10% (faecal), increasing with age. Pathophysiological factors include childbirth-associated external anal sphincter injury and pudendal nerve damage, pelvic floor descent, menopause, collagen disorders and multiple sclerosis-like conditions. The presence of crossed reflexes between the bladder, urethra, anorectum and pelvic floor in animal studies may explain the comorbidity of urinary and faecal urgency. Surgical treatment is based on aetiology and combined optimum techniques such as colposuspension or suburethral sling with overlapping sphincteroplasty. Other methods for improving sphincteric control include sacral nerve neuromodulation, bulking agents and artificial sphincters.

Kanwar, J. R. (2005). "Anti-inflammatory immunotherapy for multiple sclerosis/experimental autoimmune encephalomyelitis (EAE) disease." Curr Med Chem 12(25): 2947-62.

            Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas with demyelination. Disease is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory cytokines, nitric oxide (NO) that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, NO, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy, trauma and MS has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Inflammation can be blocked with anti-cell adhesion molecules MAb, simultaneously protected oligodendrocytes and neurons against glutamate-mediated damage with the AMPA/kainate antagonist NBQX, and the NMDA receptor antagonist GPE, could thus be effective therapies for multiple sclerosis.

Kantarci, O. H. and B. G. Weinshenker (2005). "Natural history of multiple sclerosis." Neurol Clin 23(1): 17-38, v.

Kanner, A. M. (2005). "Should neurologists be trained to recognize and treat comorbid depression of neurologic disorders? Yes." Epilepsy Behav 6(3): 303-11.

            Depression is a relatively common psychiatric comorbidity of most neurological disorders, with prevalence rates ranging between 20 and 50% among patients with stroke, multiple sclerosis, epilepsy, Parkinson's disease and dementia. Furthermore, depression is an independent predictor of poor quality of life in these patients and has a negative impact on the response to treatment, course and recovery of neurological deficits. Thus, treatment of depression has become an integral part of the management of these neurologic disorders. This article discusses the rationale for neurologists to be trained in recognizing depressive disorders in neurologic patients and identifies the type of mood disorders in which neurologists can provide pharmacotherapy and those that need to be referred to the care of the psychiatrist.

Kang, B. Y., E. Kim, et al. (2005). "Regulatory mechanisms and their therapeutic implications of interleukin-12 production in immune cells." Cell Signal 17(6): 665-73.

            Studies with neutralizing anti-interleukin (IL)-12 antibodies and IL-12-deficient mice have suggested that endogenous IL-12 plays an important role in the normal host defense against infection by a variety of intracellular microorganisms. However, IL-12 also appears to play a central role in the pathogenesis of autoimmune diseases such as multiple sclerosis or rheumatic arthritis. Therefore, it is crucial to understand how IL-12 is produced and its production is regulated at the molecular level. IL-12 production is differentially regulated through multiple pathways, which can be classified as follows: nuclear factor-kappaB (NF-kappaB) and other transcription factors, p38 mitogen-activated protein (MAP) kinase, cyclic adenosine monophosphate (cyclic AMP)-modulating molecules, cell membrane ion channels and pumps, nitric oxide (NO), and receptors. In this review we describe the regulatory mechanisms of IL-12 production in immune cells and also some agents to control IL-12 production for the treatment of immune-related diseases.

Kalsi, V. and C. J. Fowler (2005). "Therapy Insight: bladder dysfunction associated with multiple sclerosis." Nat Clin Pract Urol 2(10): 492-501.

            Bladder dysfunction is a common problem for patients with multiple sclerosis. The severity of symptoms often correlate with the degree of spinal cord involvement and, hence, the patient's general level of disability. The emphasis of management is now mainly medical and is increasingly offered by nonurologists. Treatments can be highly effective, relieving patients of what are otherwise very troublesome symptoms that would compound their neurological disability. This article gives an overview of the neural control of the bladder, followed by an explanation of the pathophysiology of detrusor overactivity secondary to neurological disease. A review of methods available for treating bladder dysfunction in multiple sclerosis then follows. The treatment options for this disorder are largely medical and include established first-line measures such as anticholinergics, clean intermittent self-catheterization and the use of desmopressin, as well as potential second-line agents, such as cannabinoids, intravesical vanilloids and intradetrusor botulinum neurotoxin type A. The diminishing role of surgical intervention is also discussed.

Kachuck, N. J. (2005). "Challenges and opportunities: what we are learning from the clinical natalizumab experience." Expert Rev Neurother 5(5): 605-15.

            The approval of natalizumab for relapsing forms of multiple sclerosis, and the subsequent voluntary suspension of its use due to an unexpected viral infection, is a cautionary tale of how much we have to learn about how to prioritize and perform the necessary research and development of novel therapeutics for human diseases, the ethics of placebo-controlled trials and the relationships between researchers, regulatory authorities and the pharmaceutical industry.

Kaaja, R. J. and I. A. Greer (2005). "Manifestations of chronic disease during pregnancy." Jama 294(21): 2751-7.

            CONTEXT: Physiologic changes of pregnancy include insulin resistance, thrombophilia, immunosuppression, and hypervolemia. These changes may herald the development of disease in later life. OBJECTIVE: To summarize current evidence on how pregnancy reveals risk of chronic disease. EVIDENCE ACQUISITION: MEDLINE was searched for articles published between 1990 and 2005 relating pregnancy conditions to the development of chronic disease. Bibliographies and the Web sites of the International Society of Obstetric Medicine and International Society for the Study of Hypertension in Pregnancy were also reviewed. EVIDENCE SYNTHESIS: Pregnancy exaggerates atherogeniclike responses, including insulin resistance and dyslipidemia, manifesting as preeclampsia or gestational diabetes. These complications herald an increased risk of postpartum cardiovascular disease, with a 2-fold increased risk of coronary artery disease and stroke. Women with gestational diabetes mellitus can progress to type 2 diabetes mellitus. The rate of progression varies from 6% to 92% depending on diagnostic criteria, race/ethnicity, and duration of surveillance (from 6 months to 28 years). Pregnancy increases risk of venous thrombosis by 7- to 10-fold. Heritable thrombophilia is present in at least 15% of Western populations and underlies at least 50% of gestational venous thromboses. Thus, the procoagulant changes during pregnancy can unmask hereditary thrombophilia. An important adaptation leading to immunotolerance of the fetoplacental unit is a switch from helper T-cell (T(H)) 1 dominance to T(H)2 dominance. Patients with a T(H)1-dominant immune disease, such as rheumatoid arthritis or multiple sclerosis, improve during pregnancy. However, rheumatoid arthritis is 5 times more likely to develop after delivery than at any other time. During pregnancy, there is a 50% increase in plasma volume, which can unmask glomerulopathies, peripartum cardiomyopathy, arterial aneurysms, or arteriovenous malformations. Development of intrahepatic cholestasis of pregnancy predicts increased risk of later cholelithiasis. CONCLUSIONS: The physiologic changes of pregnancy can reveal risk of chronic diseases. Exaggerated responses reflective of the metabolic syndrome are seen in preeclampsia and gestational diabetes and can herald future cardiovascular and metabolic disease. Pregnancy is therefore an important screening opportunity for cardiovascular and metabolic disease risk factors, with the possibility of early intervention.

Johnson, L. N. and S. S. Morey (2005). "Repeated intervals of high-dose corticosteroid: an overlooked therapy in multiple sclerosis." Mo Med 102(1): 47-50.

            The rate of conversion to multiple sclerosis is about 6% per year for five years after the first episode of optic neuritis. While the new MS agents have garnered much attention as promising agents to prevent MS relapses, an overlooked therapy is pulse high-dose corticosteroid (10 mg per kg or greater) as an intervention to delay or prevent the development of MS. Data from Optic Neuritis Treatment Trial (ONTT) and other studies underscore the need to investigate the efficacy of high-dose corticosteroid in MS.

Johnson, K. L. and R. T. Fraser (2005). "Mitigating the impact of multiple sclerosis on employment." Phys Med Rehabil Clin N Am 16(2): 571-82, x-xi.

            This article reviews the employment status of people with MS, the importance of employment, key barriers to employment, and compensatory and accommodation strategies to enhance employment.Resources and recommendations for health care providers to assist their patients in maintaining, securing, or leaving employment are presented.

Johanson, C. E., J. A. Duncan, et al. (2005). "Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route." Pharm Res 22(7): 1011-37.

            The choroid plexus (CP), i.e., the blood-cerebrospinal fluid barrier (BCSFB) interface, is an epithelial boundary exploitable for drug delivery to brain. Agents transported from blood to lateral ventricles are convected by CSF volume transmission (bulk flow) to many periventricular targets. These include the caudate, hippocampus, specialized circumventricular organs, hypothalamus, and the downstream pia-glia and arachnoid membranes. The CSF circulatory system normally provides micronutrients, neurotrophins, hormones, neuropeptides, and growth factors extensively to neuronal networks. Therefore, drugs directed to CSF can modulate a variety of endocrine, immunologic, and behavioral phenomema; and can help to restore brain interstitial and cellular homeostasis disrupted by disease and trauma. This review integrates information from animal models that demonstrates marked physiologic effects of substances introduced into the ventricular system. It also recapitulates how pharmacologic agents administered into the CSF system prevent disease or enhance the brain's ability to recover from chemical and physical insults. In regard to drug distribution in the CNS, the BCSFB interaction with the blood-brain barrier is discussed. With a view toward translational CSF pharmacotherapy, there are several promising innovations in progress: bone marrow cell infusions, CP encapsulation and transplants, neural stem cell augmentation, phage display of peptide ligands for CP epithelium, CSF gene transfer, regulation of leukocyte and cytokine trafficking at the BCSFB, and the purification of neurotoxic CSF in degenerative states. The progressively increasing pharmacological significance of the CP-CSF nexus is analyzed in light of treating AIDS, multiple sclerosis, stroke, hydrocephalus, and Alzheimer's disease.

Jackson, S. J., L. T. Diemel, et al. (2005). "Cannabinoids and neuroprotection in CNS inflammatory disease." J Neurol Sci 233(1-2): 21-5.

            The current failure of potent immunosuppressive agents to control progressive disease in multiple sclerosis has moved a focus from immunotherapy towards the need for neuroprotection. There is increasing evidence for cannabinoid-mediated control of symptoms, which is being more supported by the underlying biology. However there is accumulating evidence in vitro and in vivo to support the hypothesis that the cannabinoid system can limit the neurodegenerative possesses that drive progressive disease, and may provide a new avenue for disease control.

Jack, C., F. Ruffini, et al. (2005). "Microglia and multiple sclerosis." J Neurosci Res 81(3): 363-73.

            Microglia participate in all phases of the multiple sclerosis (MS) disease process. As members of the innate immune system, these cells have evolved to respond to stranger/danger signals; such a response within the central nervous system (CNS) environment has the potential to induce an acute inflammatory response. Engagement of Toll-like receptors (TLRs), a major family of pattern-recognition receptors (PRRs), provides an important mechanism whereby microglia can interact with both exogenous and endogenous ligands within the CNS. Such interactions modulate the capacity of microglia to present antigens to cells of the adaptive immune system and thus contribute to the initiation and propagation of the more sophisticated antigen-directed responses. This inflammatory response introduces the potential for bidirectional feedback between CNS resident and infiltrating systemic cells. Such interactions acquire particular relevance in the era of therapeutics for MS because the infiltrating cells can be subjected to systemic immunomodulatory therapies known to change their functional properties. Phagocytosis by microglia/macrophages is a hallmark of the MS lesion; however, the extent of tissue damage and the type of cell death will dictate subsequent innate responses. Microglia/macrophages are armed with a battery of effector molecules, such as reactive nitrogen species, that may contribute to CNS tissue injury, specifically to the injury of oligodendrocytes that is associated with MS. A therapeutic challenge is to modulate the dynamic properties of microglia/macrophages so as to limit potentially damaging innate responses, to protect the CNS from injury, and to promote local recovery.

Izzedine, H., V. Launay-Vacher, et al. (2005). "PPAR-gamma-agonists' renal effects." Minerva Urol Nefrol 57(4): 247-60.

            PPAR-gamma ligands, including thiazolidinediones, have recently become clinically available for treating insulin-resistant diabetes mellitus. Accumulating evidence suggests that these drugs not only significantly improve insulin sensitivity but also may have antiproteinuric effects in genetically obese diabetic rodents and patients with type II diabetes and diabetic nephropathy. Moreover, troglitazone reduced expression of ECM proteins and transforming growth factor-beta in glomeruli from streptozotocin-induced diabetic rats. Many other properties including antiproteinuric, hemodynamic, and antihypertensive effects in insulin-dependent diabetes mellitus suggest that PPAR-gamma ligands might have a direct, beneficial renal effect, independent of their capacity to improve glucose tolerance. Besides their antidiabetic effects, thiazolidinediones have been shown to lower blood pressure in diabetic patients with hypertension and patients with diabetic nephropathy through multiple mechanisms. Several studies showed the efficacy of PPAR-gamma agonists to ameliorate the progression of glomerulosclerosis. The effect is independent of insulin effects and could only be partially due to lipid effects. These renal protective effects of PPAR-gamma agonists suggest that they may provide a novel intervention strategy to prevent vascular and glomerular sclerosis.

Inglese, M., B. Benedetti, et al. (2005). "The relation between MRI measures of inflammation and neurodegeneration in multiple sclerosis." J Neurol Sci 233(1-2): 15-9.

            Gadolinium-enhanced magnetic resonance imaging (MRI) and measures of brain volume have been extensively applied in large-scale studies to assess disease activity and irreversible tissue damage in multiple sclerosis (MS). Although histopathological studies of MS demonstrated that axonal transection occurs at sites of inflammatory changes, the correlation between brain tissue loss and gadolinium enhancement was found to be either absent or poor in virtually all in vivo MRI studies. This review discusses the reasons of this "inflammation/neurodegeneration mismatch" in MS and proposes possible strategies for a better in vivo characterization of the complex pathological process of this disease.

Inglese, M., R. I. Grossman, et al. (2005). "Magnetic resonance imaging monitoring of multiple sclerosis lesion evolution." J Neuroimaging 15(4 Suppl): 22S-29S.

            The characteristic feature of multiple sclerosis (MS) pathology is the demyelinated plaque distributed throughout the central nervous system. Although MS is a primary demyelinating disease, acute axonal injury is common in actively demyelinating MS lesions and it is considered one of the major determinants of neurological deficit. Magnetic resonance imaging (MRI) has had a dramatic impact on MS in both the clinical practice and basic science settings. Techniques such as T2-weighted and gadolinium-enhanced T1-weighted MRI are very sensitive in detecting lesions and, thus, increase the level of certainty of MS diagnosis. Conventional MRI has also improved our understanding of the pathogenesis of the disease and has provided objective and reliable measures to monitor the effect of experimental treatments in clinical trials. However, conventional MRI does not provide specific information on the heterogeneous pathologic substrate of MS lesions. Advanced MRI techniques, such as magnetization transfer imaging, diffusion tensor imaging, and proton MR spectroscopy, offer the unprecedented ability to observe and quantify pathological changes in lesions and normal-appearing brain tissue over time. The present review will discuss the major contributions of conventional MRI and quantitative MRI techniques to understand how individual MS lesions evolve.

Imitola, J., T. Chitnis, et al. (2005). "Cytokines in multiple sclerosis: from bench to bedside." Pharmacol Ther 106(2): 163-77.

            Cytokines play an important role in the pathogenesis of inflammatory diseases including multiple sclerosis (MS). Experimental models have played a critical role in unraveling the roles of individual cytokines in this disease; however, these studies occasionally yield conflicting results, highlighting the complex role cytokines play in the disease process. Efforts to modulate cytokine function in MS have shown that effective treatments alter cytokine expression in the central nervous system (CNS) and in activated mononuclear cells, indicating that they are important therapeutic targets. In this review, we will summarize the current knowledge on the role of cytokine pathways in MS and what we learned from investigation of its animal model: experimental autoimmune encephalomyelitis (EAE).

Igietseme, J., F. Eko, et al. (2005). "Delivery of Chlamydia vaccines." Expert Opin Drug Deliv 2(3): 549-62.

            The plethora of ocular, genital and respiratory diseases of Chlamydia, including nongonococcal urethritis, cervicitis pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, conjunctivitis, blinding trachoma and interstitial pneumonia, and chronic diseases that may include atherosclerosis, multiple sclerosis, adult onset asthma and Alzheimer's disease, still pose a considerable public health challenge to many nations. Although antibiotics are effective against Chlamydia when effectively diagnosed, asymptomatic infections are rampart, making clinical presentation of complications often the first evidence of an infection. Consequently, the current medical opinion is that an effective prophylactic vaccine would constitute the best approach to protect the human population from the most severe consequences of these infections. Clinical and experimental studies have demonstration that Chlamydia immunity in animals and humans is mediated by T cells and a complementary antibody response, and the completion of the genome sequencing of several isolates of Chlamydia is broadening our knowledge of the immunogenic antigens with potential vaccine value. Thus, major advances have been made in defining the essential elements of a potentially effective subunit vaccine design and parameters for evaluation. However, the challenge to develop effective delivery systems and human compatible adjuvants that would boost the immune response to achieve long-lasting protective immunity remains an elusive objective in chlamydial vaccine research. In response to evolving molecular and cellular technologies and novel vaccinology approaches, considerable progress is being made in the construction of novel delivery systems, such as DNA and plasmid expression systems, viral vectors, living and nonliving bacterial delivery systems, the use of chemical adjuvants, lipoprotein constructs and the codelivery of vaccines and specific immuno-modulatory biological agonists targeting receptors for chemokines, Toll-like receptors, and costimulatory molecules. The application of these novel delivery strategies to Chlamydia vaccine design could culminate in timely achievement of an efficacious vaccine.

Ibrahim, S. M. and R. Gold (2005). "Genomics, proteomics, metabolomics: what is in a word for multiple sclerosis?" Curr Opin Neurol 18(3): 231-5.

            PURPOSE OF REVIEW: Multiple sclerosis (MS) is the most common chronic inflammatory neurological disease. Despite major advances the aetiology of this disease it is still not completely understood. In the post-genome era, advances in global screening technologies offer an opportunity to accelerate the search of new pathological pathways and to identify new therapeutic targets. Some recent publications using novel global screening methods at the genome, transcriptome, proteome and metabolome levels are discussed. RECENT FINDINGS: The genetic association of susceptibility to MS with loci outside the MHC has been reconfirmed. Evidence of parent-of-origin and seasonal effects on disease susceptibility add further complexity to the genetics of MS. The search for MS susceptibility genes continues using the candidate-gene approach as well as large-scale single-nucleotide-polymorphism association studies and novel cross-species synteny analysis. Genome-wide expression profiling using microarrays produced numerous therapeutic targets and is progressing towards profiling of rare cells. Advances in classical proteomics methods paved the way to new initiatives aiming at determining the proteome of the nervous system in normal and diseased states. Although progress is still slow, array-based methods are making an impact on the MS field. SUMMARY: The complexity of MS is clearly reflected in the latest findings using global profiling methods. Nevertheless, these new technologies are confirming some of the basic aspects of the disease pathophysiology, i.e. its polygenicity, the central role of neuroinflammation and the emerging neurodegenerative processes. These data are primarily the results of genomic approaches, yet promising attempts are also made using proteomics and metabolomics.

Humle Jorgensen, S. and P. S. Sorensen (2005). "Intravenous immunoglobulin treatment of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis." J Neurol Sci 233(1-2): 61-5.

            Intravenous immunoglobulin (IVIG) is an established treatment of immune-mediated demyelinating neuropathy. Since IVIG possesses multiple immunomodulatory and anti-inflammatory properties, IVIG therapy may represent a way of interfering with the disease process in multiple sclerosis (MS). In the MS animal model experimental autoimmune encephalomyelitis (EAE), infusions of IVIG significantly reduced disease symptoms as well as the underlying CNS pathology. IVIG was only effective in EAE when administered in a prophylactic treatment protocol, since IVIG infusions during the established phase of EAE did not alter the disease course or the degree of inflammation found in the central nervous system. IVIG also has the potential to act through myelin repair mechanisms as evidenced by work done in the Theilers murine encephalomyelitis virus model of demyelination. Together these observations have led to certain expectations for IVIG as a treatment for MS, and have resulted in various clinical trials. Several controlled trials report beneficial effects of IVIG on relapse rate, new MRI lesions, and disease progression in relapsing-remitting MS, while a remyelinating effect of IVIG has not been documented. IVIG is, therefore, presently regarded as a second-line therapy of MS.

Huang, Y., N. Erdmann, et al. (2005). "The role of TNF related apoptosis-inducing ligand in neurodegenerative diseases." Cell Mol Immunol 2(2): 113-22.

            A hallmark of all forms of neurodegenerative diseases is impairment of neuronal functions, and in many cases neuronal cell death. Although the etiology of neurodegenerative diseases may be distinct, different diseases display a similar pathogenesis, for example abnormal immunity within the central nervous system (CNS), activation of macrophage/microglia and the involvement of proinflammatory cytokines. Recent studies show that neurons in a neurodegenerative state undergo a highly regulated programmed cell death, also called apoptosis. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, has been shown to be involved in apoptosis during many diseases. As one member of a death ligand family, TRAIL was originally thought to target only tumor cells and was not present in CNS. However, recent data showed that TRAIL was unregulated in HIV-1-infected and immune-activated macrophages, a major disease inducing cell during HIV-1-associated dementia (HAD). TRAIL is also induced on neuron by beta-amyloid protein, an important pathogen for Alzheimer's disease. In this review, we summarize the possible common aspects that TRAIL involved those neurodegenerative diseases, TRAIL induced apoptosis signaling in the CNS cells, and specific role of TRAIL in individual diseases.

Hough, R. E., J. A. Snowden, et al. (2005). "Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective." Br J Haematol 128(4): 432-59.

            The potential of haemopoietic stem cell transplantation (HSCT) for the treatment of autoimmune and inflammatory diseases was originally supported by almost three decades of animal experiments and by the serendipitous remissions of autoimmune disease observed in patients undergoing transplantation for haematological disorders. Improved safety of both autologous and allogeneic HSCT over the last decade has been followed by increasing acceptance of HSCT as an experimental treatment for severe autoimmune diseases that are resistant to conventional treatment. International databases have collated over 700 procedures performed specifically for a variety of autoimmune diseases. Phase III clinical trials are in progress for some diseases. This review provides a comprehensive update on the efficacy and toxicity of HSCT in severe autoimmune disease. Future directions in the context of other evolving therapies are discussed.

Horuk, R. (2005). "BX471: a CCR1 antagonist with anti-inflammatory activity in man." Mini Rev Med Chem 5(9): 791-804.

            Chemokines belong to a large family of chemoattractant molecules involved in the directed migration of immune cells. They achieve their cellular effects by direct interaction with cell surface receptors. The chemokine receptor CCR1 appears to be involved in a variety of proinflammatory and autoimmune diseases and this makes it a very attractive therapeutic target. This review discusses the identification, chemistry, biology and therapeutic potential of BX 471 a potent CCR1 antagonist that is currently in the clinic for a variety of indications.

Horsfield, M. A. (2005). "Magnetization transfer imaging in multiple sclerosis." J Neuroimaging 15(4 Suppl): 58S-67S.

            Magnetization transfer (MT) is a relatively new way of generating contrast in magnetic resonance (MR) images that is sensitive to the density of the macromolecules found throughout tissue structures such as membranes, myelin, and organelles. MT imaging (MTI) can provide a quantitative measure of macromolecular density, and therefore of tissue damage, and has been applied in the central nervous system in multiple sclerosis (MS) and other diseases. This article introduces the contrast mechanisms behind MTI and gives some practical guidance about implementing MTI and about quantitative analysis of the MT scans. An overview of MT measurements made in animal studies, in postmortem tissue samples, and in other demyelinating diseases attempts to rationalize the pathological basis of changes in MT contrast in MS. The application of MTI to MS is reviewed, with emphasis on the contribution that MTI has made to the current understanding of the MS disease process, both its natural history and the response to treatment. The pathological basis of abnormal MT contrast is still open to debate, with many conflicting reports; indeed, it is unlikely that a simple measure of MT effect will reveal the details of pathology that is a combination of inflammation, demyelination, remyelination, and axonal loss. There is no doubt, however, that MT measurements have contributed to the current understanding of both disease progression and the response to treatment and will prove to be a valuable tool in the future, particularly if more refined techniques can be applied practically in multicenter studies.

Holland, N. J. and M. Madonna (2005). "Nursing grand rounds: multiple sclerosis." J Neurosci Nurs 37(1): 15-9.

            Multiple sclerosis (MS) is a highly variable, unpredictable disease and one of the most life-altering diagnoses a person can receive. Because it usually strikes in the prime of life, frequently progresses to disability, and has no cure, MS can make a strong emotional impact--not only on those who suffer from it, but also the healthcare team. Because MS is such a complex, multifaceted disorder, nurses who care for people with MS are faced with numerous clinical challenges. Many of the challenges are unique to MS, demanding, and time-consuming. Well-informed nurses are positioned to evaluate and explain the disease process, assist in the alleviation of symptoms, educate partners and families, and help improve quality of life. A case example can help nurses understand the real-life concerns of a person with MS.

Holick, M. F. (2005). "Vitamin D for health and in chronic kidney disease." Semin Dial 18(4): 266-75.

            Vitamin D is taken for granted and is not appreciated for its importance in overall health and well-being. Vitamin D, known as the sunshine vitamin, is appreciated as being important for the prevention of rickets in children. It is now recognized that vitamin D is important for not only the growing skeleton, but for the maintenance of a healthy musculoskeletal system throughout life. Vitamin D deficiency in adults precipitates and exacerbates osteoporosis and causes the painful bone disease osteomalacia. The revelation that vitamin D is biologically inactive and requires sequential hydroxylations in the liver and kidney to form 1,25-dihydroxyvitamin D helps explain why patients with renal failure are often resistant to vitamin D and suffer from secondary hyperparathyroidism and renal osteodystrophy. In addition to its role in maintaining calcium and phosphorus homeostasis, vitamin D is now being recognized as important for maintaining maximum muscle strength and for the prevention of many chronic diseases, including type I diabetes, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and many common cancers. Vitamin D status is best determined by the measurement of circulating levels of 25-hydroxyvitamin D. Vigilance for maintaining a 25-hydroxyvitamin D level of at least 20 ng/ml and preferably 30-50 ng/ml has important benefits for both healthy children and adults, as well as children and adults suffering from chronic kidney disease.

Holick, M. F. (2005). "Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers." South Med J 98(10): 1024-7.

            Vitamin D is very important for overall health and wellbeing. A major source of vitamin D comes from exposure to sunlight. Measurement of 25-hydroxyvitamin D in the blood and not 1,25-dihydroxyvitamin D is used to determine vitamin D status. A blood level of 25-hydroxyvitamin D of at least 20 ng/mL is considered to be vitamin D sufficient. Vitamin D deficiency increases the risk of many common cancers, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and type I diabetes.

Hohlfeld, R., M. Kerschensteiner, et al. (2005). "The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis." Ernst Schering Res Found Workshop(53): 23-38.

Hess Ch, W. (2005). "[Non-traumatic acute transverse spinal cord syndromes]." Schweiz Rundsch Med Prax 94(30-31): 1151-9.

            Differential diagnosis of non-traumatic, acute transverse spinal cord syndromes should cover compressive myelopathy (mostly hematomas or tumors), inflammatory myelitis and vascular myelopathies. Since acute pathologies of the spinal cord primarily result in flaccid para- or tetraparesis accompanied by areflexia or hyporeflexia (spinal shock), acute polyradiculoneuritis and the cauda equina syndrome must also be weighed into the differential diagnosis. Paraplegia may ultimately also be of psychogenic origin. The clinical picture is characterized by the rapidity of progression, the possible involvement of pain, and the specific pattern of the deficits. When the latter occurs, localization of the rostrocaudal level and transverse spread are crucial factors. Depending on the affected structure, one differentiates between anterior spinal cord syndromes (anterior spinal artery syndrome, selective involvement of the anterior horn, centromedullary syndromes), long pathway syndrome (isolated in the posterior bundle or combined with pyramidal pathways) and the unilateral Brown-Sequard's syndrome. Infectious myelitis is usually caused by neurotropic viruses or mycoplasmata in conjunction with meningitis or encephalitis; these in turn either induce transverse myelitis accompanied by severe sensomotor deficits or chiefly affect the gray matter, then producing a pattern similar to anterior spinal artery syndrome. In the case of non-infectious inflammatory myelitis, one must differentiate between multiple sclerosis, acute disseminated encephalomyelitis (ADEM), idiopathic transverse myelitis and that of the neuromyelitis optica or Devic's disease. Symptomatic transverse myelitis can also be present in association with connective tissue diseases (e.g. SLE, Behcet's disease, Sjogren's syndrome) or sarcoidosis. Notably, when ischemic spinal infarcts are involved, their onset is frequently painful and their manifestation typically subacute, rather than apoplectiform.

Henze, T. (2005). "Managing specific symptoms in people with multiple sclerosis." Int MS J 12(2): 60-8.

            Besides immunomodulation and immunosuppression, symptomatic treatment is an important part of MS therapy. Its goals are the elimination and reduction of symptoms that impair functional ability and quality of life, and also the avoidance of secondary complications. There are many treatment recommendations for MS symptoms, therefore clear and consensually developed therapeutic strategies are needed. This paper reviews some recommendations for the treatment of MS-related spasticity, fatigue, pain and neurogenic bladder dysfunction that have been established by the Multiple Sclerosis Treatment Consensus Group of the German MS Society.

Hendriks, J. J., C. E. Teunissen, et al. (2005). "Macrophages and neurodegeneration." Brain Res Brain Res Rev 48(2): 185-95.

            Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Demyelination is a classical feature of MS lesions, and neurological deficits are often ascribed to the reduced signal conduction by demyelinated axons. However, recent studies emphasize that axonal loss is an important factor in MS pathogenesis and disease progression. Axonal loss is found in association with cellular infiltrates in MS lesions. In this review, we discuss the possible contribution of the innate immune system in this process. In particular, we describe how infiltrated macrophages may contribute to axonal loss in MS and in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. An overview is given of the possible effects of mediators, which are produced by activated macrophages, such as such as pro-inflammatory cytokines, free radicals, glutamate and metalloproteases, on axonal integrity. We conclude that infiltrated macrophages, which are activated to produce pro-inflammatory mediators, may be interesting targets for therapeutic approaches aimed to prevent or reduce axonal loss during exacerbation of inflammation. Interference with the process of infiltration and migration of monocytes across the blood-brain barrier is one of the possibilities to reduce the damage by activated macrophages.

Hemmer, B., O. Stuve, et al. (2005). "Immune response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis." Lancet Neurol 4(7): 403-12.

            Interferon beta was the first therapy to be approved for the treatment of relapsing-remitting multiple sclerosis (MS) more than 10 years ago. Interferon beta reduces relapse rates and disease burden and activity, and it may have beneficial effects on the progression of long-term disease disability. The occurrence of neutralising interferon-beta antibodies has been postulated as a possible cause of the failure of interferon beta in some patients with MS. Here we discuss the basic mechanisms that may account for the generation of an interferon-beta antibody response and its biological implications. We review the evidence for neutralising antibodies as a consequence of interferon-beta treatment, and discuss the implications for the treatment of MS. Strategies to assess and manage the long-term impact of neutralising antibodies will be outlined.

Heffernan, C. and C. Jenkinson (2005). "Measuring outcomes for neurological disorders: a review of disease-specific health status instruments for three degenerative neurological conditions." Chronic Illn 1(2): 131-42.

            Health-related quality-of-life measures have been increasingly used in research into neurological disorders in recent years. The aim of this paper is to provide an objective appraisal of the evidence in regard to disease-specific quality-of-life measures used in research on health interventions for three degenerative neurological disorders: multiple sclerosis, motor neurone disease/amyotrophic lateral sclerosis and Parkinson's disease. A comprehensive search strategy was developed to include nine relevant electronic databases. Only studies pertaining to patient-based outcome measurements in multiple sclerosis, motor neurone disease and Parkinson's disease were included. We identified 76 eligible studies. As studies consisted of descriptive and cross-sectional survey study designs, results were reported qualitatively rather than in the form of a meta-analysis. Four disease-specific measures were found for Parkinson's disease, 11 for multiple sclerosis and one for motor neurone disease. We conclude that health-related quality-of-life measures are useful in assessing the impact of treatments and interventions for neurological disorders. However, further research is needed on the development of instruments using psychometric methods and on the validation, utilization and responsiveness of instruments to change.

Hawkes, C. H. (2005). "Are multiple sclerosis patients risk-takers?" Qjm 98(12): 895-911.

            Several factors appear to be associated with multiple sclerosis (MS), and each has a postulated immune or environmental explanation, but a common theme is lacking. This article suggests that a unifying premise could be risk-associated behaviour. Evidence is reviewed for associations with smoking, alcohol, recreational drug use, oral contraception, cholesterol intake, risk attitude and behaviour, ultraviolet light and vitamin D exposure, frequency of MS in healthy societies, and viral infection. The evidence associated with smoking, not taking vitamin D supplements and Epstein-Barr viral infection appears good. There may be a pattern of risk-associated behaviour that characterizes patients with MS and brings them into contact with one or more causative agents. Of the possible agents, viral infection seems the most likely.

Havrdova, E. (2005). "Aggressive multiple sclerosis-is there a role for stem cell transplantation?" J Neurol 252 Suppl 3: iii34-iii37.

            Conventional drugs, including disease-modifying drugs, various cytostatic regimens and steroids, are unable to control disease activity in a small group of patients with "malignant" multiple sclerosis (MS). This group of patients could be offered aggressive therapies, such as high-dose immunosuppression followed by haematopoietic stem cell transplant (HSCT). Bone marrow or peripheral blood HSCT has been proposed for the treatment of autoimmune diseases because of its immunosuppressive and immunomodulatory effects, and recapitulation of lymphocyte ontogeny may stabilise or improve the course of MS in some patients.There have been a few small studies conducted using high-dose immunoablation and HSCT. A recent clinical trial of 85 patients treated by HSCT revealed that more than 60% of patients may benefit from this procedure. Due to the perceived risks associated with HSCT, only patients with malignant MS who no longer benefit from more conventional therapies were enrolled. HSCT is thus a justified and feasible treatment in certain patient groups, although transplant-related mortality must be reduced.

Havrdova, E., D. Horakova, et al. (2005). "[Future possibilities of the multiple sclerosis treatment]." Cas Lek Cesk 144(10): 663-5.

            Multiple sclerosis is an autoimmune disease of the central nervous system. Pathogenetic mechanisms involve inflammation and neurodegeneration leading to myelin sheaths destruction and irreversible nerve fibre loss. At present mainly the inflammatory part can be influenced and undoubtedly only the earliest beginning of the treatment can effectively postpone irreversible disability. High-dose corticosteroids remain the "gold standard" in MS attack treatment. Interferon beta and glatiramer acetate represent disease modifying drugs. Both of these medicaments decrease the number of attacks for about 30 %, however each patient responds differently. In many cases new attacks appear and it is necessary to intensify the treatment--to add immunosuppresives, to use combinations of steroid and cytostatic treatment. Intravenous immunoglobulins represent second line treatment. In the case of rapid disease progression immunoablation and stem cells transplantation is available. From recently tested drugs the most successful was the monoclonal antibody natalizumab. Unfortunately because of serious adverse effects in patients treated by combination of interferon beta + natalizumab, the application has been stopped. Monoclonal antibody against inteleukin 12 and chemokine receptor CCR2, cytostatics fumarate, laquinimod and cladribine are also tested in the clinical studies. DNA vaccination represents revolutionary opportunity of inducing tolerance against myelin autoantigens.

Hauser, S. L. (2005). "An update on multiple sclerosis." J Neurol Sci 228(2): 193-4.

Haslam, C. (2005). "Managing bladder symptoms in people with multiple sclerosis." Nurs Times 101(2): 48-50, 52.

            Multiple sclerosis is a chronic disease of the central nervous system (brain and spinal cord). The cause is still unknown but there is evidence that suggests there is an autoimmune component to the disease that causes damage to the myelin sheath, a complex material that surrounds the axon of myelinated nerves (Fig 1). It affects 100-120 people per 100,000 population, approximately 75 per cent of whom will develop urinary symptoms (NICE, 2003). Bladder problems usually occur when the disease involves the spinal cord (Fig 2) and these can get worse as the disease progresses and the patient becomes less mobile. Bladder symptoms affect many aspects of daily life and their management is extremely important. As the disease progresses and symptoms worsen, a well-planned strategy can offer patients the most effective pathway to manage their bladder problems.

Haselkorn, J. K. and S. Loomis (2005). "Multiple sclerosis and spasticity." Phys Med Rehabil Clin N Am 16(2): 467-81.

            Spasticity is a common impairment in MS. It can result in significant medical complications and is associated with increased disability. Treatment strategies include skilled rehabilitation strategies, neuromuscular blocks, oral agents, intrathecal management, and surgery. Rehabilitation strategies are central, whereas other strategies are added based on the level of impairment and functional loss. Treatment strategies for spasticity management are far from optimal and are complicated in MS as a result of lesions in the brain and the spinal cord. Pharmaceutical management in MS is complicated by the numerous secondary impairments in MS and its associated polypharmacy.Head-to-head studies of the various agents are rare. The studies that exist are small and do not point to any one strategy over another. Although management is difficult, it is essential for the health, functional status, and well-being of the individual who has MS. Providers must use well-developed clinical skills to arrive at optimal individualized treatment programs and monitor them frequently. For spasticity that is unresponsive, referral to a MS Center with a spasticity program is ideal.

Hartung, H. P., F. Munschauer, 3rd, et al. (2005). "Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: expert opinions based on the Proceedings of an International Consensus Conference." Eur J Neurol 12(8): 588-601.

            On August 30, 2002, an international panel of neurologists who specialize in the treatment of multiple sclerosis (MS) was convened in Paris (France) to discuss the issue of neutralizing antibodies (NAb) to interferon beta (IFN-beta) therapy in patients with MS. The goals of this meeting were to: (i) review the most recent clinical information on NAb, (ii) come to a consensus on the clinical relevance of NAb in the management of patients with MS receiving IFN-beta therapy, and (iii) establish a framework for the development of patient management guidelines based on scientific consensus. The meeting was chaired by Hans-Peter Hartung (Heinrich-Heine University, Dusseldorf, Germany) and Huub Schellekens (Utrecht University, Utrecht, the Netherlands). This article summarizes the opinions of the expert panel on a number of key issues raised at the meeting.

Hartung, H. P. (2005). "Early treatment and dose optimisation BENEFIT and BEYOND." J Neurol 252 Suppl 3: iii44-iii50.

            The use of interferon beta (IFNbeta) in the treatment of multiple sclerosis (MS) has not changed greatly since its introduction. However, two new treatment paradigms have recently emerged-initiation of treatment as early in the course of the disease as possible and the use of higher doses with greater frequency to gain maximum therapeutic effect. The rationale for early treatment comes from evidence showing that early and irreversible pathology exists in very early stages of relapsing remitting MS (RRMS) often before significant disability is apparent and continues during remission. In addition, irreversible axonal damage begins early in the course of MS. Two relatively short-term studies indicate that it is possible to delay the onset of MS by early treatment with low-dose IFNbeta-1a. The BENEFIT (BEtaferon/Betaseron in Newly Emerging MS For Initial Treatment) study is being undertaken to investigate whether early intervention with a high-dose and more frequent administration of IFNbeta-1b (250 microg [8 MIU] every other day [eod]) has the ability to affect long-term clinical and magnetic resonance imaging (MRI) outcomes even more favourably. In addition, together with its follow-up study, BENEFIT will address the open question of long-term effects of early treatment on disease progression.Results from the pivotal IFNbeta-1b study, together with data from PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) showed the presence of a dose-response relationship for IFNbeta in the treatment of RRMS. This finding was confirmed by the results of INCOMIN (INdependent COMparison of INterferons) and EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy), direct comparative studies of high-dose (250 microg IFNbeta-1b, 44 microg IFNbeta-1a), high-frequency versus lower dose (30 microg IFNbeta-1a) and less frequent IFNbeta regimens. Results from a pilot study in patients with RRMS have indicated that increasing the dose of IFNbeta-1b to 500 microg (16 MIU) had a more pronounced biological effect compared with the standard 250 microg dose. The BEYOND (Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose) study is being undertaken to investigate whether IFNbeta-1b 500 microg eod is superior to the standard 250 microg eod dose in treatment-naive patients with RRMS. A third treatment arm will provide a comparison with glatiramer acetate 20mg subcutaneously once daily.

Hartung, H. P., B. C. Kieseier, et al. (2005). "Purely systemically active anti-inflammatory treatments are adequate to control multiple sclerosis." J Neurol 252 Suppl 5: v30-7.

            Collective evidence supports the notion that multiple sclerosis is principally an autoimmune disease. Much of it stems from models of experimental autoimmune encephalomyelitis, generated by inoculation of animals with central nervous system antigens such as MBP, PLP, S100 and MOG or peptides thereof. Different ways of immunization and different animal species and strains mirror different aspects of the neuropathology of multiple sclerosis, such as inflammation, demyelination or axonal damage, and reflect different clinical courses. In all these models, the first immune reactions take place in lymph nodes from which immune cells migrate into the circulation and then to the central nervous system. Adoptive transfer of myelin-reactive T cells from these animals produces pathology and disease in the central nervous system of naive healthy recipients. In the human disease, autoreactive T and B cells specific for a variety of central antigens are present in the immune repertoire. These cells appear to be activated in the periphery through a number of mechanisms which causes them to home to the central nervous system. Contact with the local immune circuitry of the brain stimulates clonal expansion of autoreactive T cells, initiating a cascade of immuno-inflammatory events in situ. Numerous ways of disrupting this complex sequence of events, either by non-specific immunosuppression or by targeting specific checkpoints, abrogate or ameliorate disease in animal models. All approved disease-modifying drugs have an impact on components of the systemic immune compartment. All have been shown to reduce the number of gadolinium-enhancing T1 lesions observed with magnetic resonance imaging, an index of acute inflammatory invasion of the central nervous system.

Han, H. S. and K. Suk (2005). "The function and integrity of the neurovascular unit rests upon the integration of the vascular and inflammatory cell systems." Curr Neurovasc Res 2(5): 409-23.

            The neurovascular unit is composed of a microvascular endothelium, neuron, and glial cell elements that are in physical proximity to the endothelium. The vascular system provides oxygen, glucose, and hormones for brain cells and guides the cells to appropriately respond to the local environment. Conversely, the brain cells, especially glial cells, can regulate the function of blood vessels in response to local requirements. The disruption of the neurovascular coordination was observed in a variety of inflammation-related diseases in brain, such as infectious diseases, stroke, vascular dementia, and multiple sclerosis. Inflammatory responses resulting from infections or injury of the brain activate the endothelium and glial cells to various degrees depending on the type, titer, or strength and duration of exposure to the agents or insults. The activation of endothelial and microglial cells may be modulated by the action of cytokines or other substances secreted from these cells. In an effort to understand the pathogenesis and find rational treatments against inflammatory disorders in brain, studies have been separately carried out using either endothelial cells or microglia. Increasing evidence, however, indicates that a crosstalk between these two cell types is important for the brain inflammation. Here, we review recent advances that provide insights into the coordinated interaction between the vascular and microglial systems, including the role of the specialized endothelium in regulating the immune response that occurs within CNS, the influence of microglial cells on the properties of endothelial cells, and the effects of endothelium on the state of microglial activation.

Halcomb, E. and P. Davidson (2005). "Using the illness trajectory framework to describe recovery from traumatic injury." Contemp Nurse 19(1-2): 232-41.

            This paper seeks to highlight the utility of the Corbin and Strauss Chronic Illness Trajectory Framework in describing recovery from traumatic injury and encourages consideration of its implementation into contemporary trauma nursing (Corbin and Strauss, 1991; 1992). To date, few such frameworks have been proposed to sensitize health professionals to the path of recovery following traumatic injury. Although this framework was initially conceived for use in the domain of chronic illness, the lasting effects of severe traumatic injury have significant parallels to chronic conditions such as stroke (Burton, 2000) and multiple sclerosis (Miller, 1993) to which the framework has previously been applied. This paper demonstrates the Trajectory Framework as a useful structure to potentially enhance the development of post-discharge interventions for trauma survivors and encourages consideration of its implementation into the nursing management of this complex patient group.

Hafler, D. A. and P. L. De Jager (2005). "Applying a new generation of genetic maps to understand human inflammatory disease." Nat Rev Immunol 5(1): 83-91.

            The sequencing of the human genome and the intense study of its variation in different human populations have improved our understanding of the genome's architecture. It is now becoming clear that segments of the genome that are unbroken by reshuffling or recombination during meiosis create a mosaic of DNA 'haplotype blocks'. Here, we discuss the advantages and limitations of this block structure. Haplotype blocks hold the promise of reducing the complexity of analysing the human genome for association with disease. But can they deliver on this promise? First generation maps of these block patterns, such as the admixture and haplotype maps, are now emerging and, it is to be hoped, will accelerate the discovery of alleles that contribute to susceptibility to human inflammatory diseases.

Hafler, D. A., J. M. Slavik, et al. (2005). "Multiple sclerosis." Immunol Rev 204: 208-31.

            Multiple sclerosis (MS) is a complex genetic disease associated with inflammation in the central nervous system (CNS) white matter and is thought to be mediated by autoimmune processes. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. The association of the disease with major histocompatibility complex genes, the inflammatory white matter infiltrates, similarities with animal models, and the observation that MS can be treated with immunomodulatory and immunosuppressive therapies support the hypothesis that autoimmunity plays a major role in the disease pathology. This review discusses the immunopathology of MS with particular focus given to regulatory T cells and the role of B cells and antibodies, immunomodulatory therapeutics, and finally new directions in MS research, particularly new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understandings and therapies for this disease.

Haacke, E. M., N. Y. Cheng, et al. (2005). "Imaging iron stores in the brain using magnetic resonance imaging." Magn Reson Imaging 23(1): 1-25.

            For the last century, there has been great physiological interest in brain iron and its role in brain function and disease. It is well known that iron accumulates in the brain for people with Huntington's disease, Parkinson's disease, Alzheimer's disease, multiple sclerosis, chronic hemorrhage, cerebral infarction, anemia, thalassemia, hemochromatosis, Hallervorden-Spatz, Down syndrome, AIDS and in the eye for people with macular degeneration. Measuring the amount of nonheme iron in the body may well lead to not only a better understanding of the disease progression but an ability to predict outcome. As there are many forms of iron in the brain, separating them and quantifying each type have been a major challenge. In this review, we present our understanding of attempts to measure brain iron and the potential of doing so with magnetic resonance imaging. Specifically, we examine the response of the magnetic resonance visible iron in tissue that produces signal changes in both magnitude and phase images. These images seem to correlate with brain iron content, perhaps ferritin specifically, but still have not been successfully exploited to accurately and precisely quantify brain iron. For future quantitative studies of iron content we propose four methods: correlating R2' and phase to iron content; applying a special filter to the phase to obtain a susceptibility map; using complex analysis to extract the product of susceptibility and volume content of the susceptibility source; and using early and late echo information to separately predict susceptibility and volume content.

Gross, M. and R. Eliashar (2005). "Update on Susac's syndrome." Curr Opin Neurol 18(3): 311-4.

            PURPOSE OF VIEW: We review recent developments in the clinical course and imaging modalities for Susac's syndrome, a clinical triad consisting of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss. RECENT FINDINGS: Susac's syndrome has variable clinical presentations; recently described presentations include epileptic seizures and transient inverted vision. Advances in neuroradiology suggest that magnetic resonance imaging demonstrates distinctive patterns in the white and grey matter and in the leptomeninges. Reports have verified that Susac's syndrome is under-diagnosed because of its multisystem involvement and confusion with other imitating disorders (such as multiple sclerosis), and because of the fact that neuroradiologists are not acquainted with this syndrome. SUMMARY: The precise aetiology of Susac's syndrome is still unknown and many areas have not yet been explored. Magnetic resonance imaging is the neuroimaging study of choice. Findings include multiple small hyperintense foci on T2-weighted images and contrast enhancement in white and grey matter of both supratentorial and infratentorial structures, corpus callosum and, occasionally, leptomeninges. Callosal lesions typically involve the central fibres and are probably pathognomonic for Susac's syndrome. When assessing patients with unexplained encephalopathy involving white and grey matter, leptomeninges and corpus callosum, the findings of sensorinueral hearing loss or visual disturbances may yield important clues regarding the possibility of Susac's syndrome.

Grigoriadis, N., T. Tselios, et al. (2005). "Animal models of central nervous system immune-mediated diseases: therapeutic interventions with bioactive peptides and mimetics." Curr Med Chem 12(13): 1513-9.

            Experimental allergic encephalomyelitis (EAE) is a T helper 1 (Th1) mediated autoimmune disease and the principal animal model for multiple sclerosis (MS). Like MS, EAE is characterized by a coordinated inflammatory attack on the myelin sheath in the central nervous system (CNS), with damage to axons. No matter whether the ideal animal model is not yet available, much knowledge concerning the pathogenesis of MS has been achieved through studies on EAE. Dissecting the underlying immune mechanisms provided recognition of several myelin antigens that are vulnerable in autoimmune attack. The beneficial effect and the mechanism of action of a number of the currently used immunomodulating agents in MS therapy were first indicated in EAE. Altered peptide ligands (APL) can modulate T-cell responses to native peptide antigens implicated in the pathogenesis of autoimmune diseases such as MS and EAE. However, peptide therapy is hindered due to the sensitivity of peptides to proteolytic enzymes as well as due to some immune-mediated side effects. A number of cyclic myelin peptide analogs seem to be potential candidates in maintaining the biological function of the original peptide and effective in controlling inflammation in EAE. Additional data regarding the immunomodulating and neuroprotective effect of these much promising agents is required. Based on the data from studies on EAE models, clinical trials should also be designed in order to elucidate the impact of such APL-induced immune responses in MS disease activity. These clinical trials should carefully incorporate monitoring of both clinical, neuroimaging and immunological parameters.

Gregory, G. D., A. Bickford, et al. (2005). "MASTering the immune response: mast cells in autoimmunity." Novartis Found Symp 271: 215-25; discussion 225-31.

            Mast cells are established participants in allergic disease and in protection against extracellular parasites. Recently, it has become apparent that mast cells exert many profound effects on a variety of both innate and adaptive immune responses. Using mast cell-deficient WBB6F1/J-kitW/kitWv (W/Wv) mice, we have demonstrated that mast cells are critical for severe disease in a murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). Reconstitution of the mast cell population in the periphery, but not the CNS, restores EAE severity. Mast cells exert their effects at both the inductive and effector phases of disease. EAE is mediated by autoreactive T cells that enter the CNS and initiate inflammatory responses, leading to demyelination within the spinal cord and brain. Although there are no intrinsic defects in W/Wv-derived T cells, both CD4+ and CD8+ autoreactive T cell responses are attenuated during early disease in W/Wv mice. Thus mast cells are essential for the optimal priming of autoreactive T cells. The entry of encephalitogenic T cells into the CNS is compromised in these mice as well. The effects on early T cell responses are due, in part, to the reduced percentage of activated dendritic cells in the lymph nodes of W/Wv mice after disease induction compared with wild-type mice. The finding that mast cells can alter T cell responses in EAE has much broader implications for understanding the impact of these cells on all T cell-mediated responses.

Greenberg, S. A. and R. J. Walsh (2005). "Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease." Muscle Nerve 31(4): 431-51.

            Molecular genetic advances have led to refinements in the classification of inherited neuromuscular disease, and to methods of molecular testing useful for diagnosis and management of selected patients. Testing should be performed as targeted studies, sometimes sequentially, but not as wasteful panels of multiple genetic tests performed simultaneously. Accurate diagnosis through molecular testing is available for the vast majority of patients with inherited neuropathies, resulting from mutations in three genes (PMP22, MPZ, and GJB1); the most common types of muscular dystrophies (Duchenne and Becker, facioscapulohumeral, and myotonic dystrophies); the inherited motor neuron disorders (spinal muscular atrophy, Kennedy's disease, and SOD1 related amyotrophic lateral sclerosis); and many other neuromuscular disorders. The role of potential multiple genetic influences on the development of acquired neuromuscular diseases is an increasingly active area of research.

Grant, W. B. and M. F. Holick (2005). "Benefits and requirements of vitamin D for optimal health: a review." Altern Med Rev 10(2): 94-111.

            Vitamin D sufficiency is required for optimal health. The conditions with strong evidence for a protective effect of vitamin D include several bone diseases, muscle weakness, more than a dozen types of internal cancers, multiple sclerosis, and type 1 diabetes mellitus. There is also weaker evidence for several other diseases and conditions. There are good reasons that vitamin D sufficiency be maintained during all stages of life, from fetal development to old age. Adequate calcium intake is also recommended. The current vitamin D requirements in the United States are based on protection against bone diseases. These guidelines are being revised upward in light of new findings, especially for soft-tissue health. The consensus of scientific understanding appears to be that vitamin D deficiency is reached for serum 25-hydroxyvitamin D (25OHD) levels less than 20 ng/mL (50 nmol/L), insufficiency in the range from 20-32 ng/mL, and sufficiency in the range from 33-80 ng/mL, with normal in sunny countries 54-90 ng/mL, and excess greater than 100 ng/mL. Solar ultraviolet-B (UVB) irradiation is the primary source of vitamin D for most people. In general, the health benefits accruing from moderate UV irradiation, without erythema or excess tanning, greatly outweigh the health risks, with skin pigmentation (melanin) providing much of the protection. In the absence of adequate solar UVB irradiation due to season, latitude, or lifestyle, vitamin D can be obtained from fortified food, oily fish, vitamin D supplements, and artificial sources of UVB radiation.

Goverman, J., A. Perchellet, et al. (2005). "The role of CD8(+) T cells in multiple sclerosis and its animal models." Curr Drug Targets Inflamm Allergy 4(2): 239-45.

            The role of CD8(+) T cells in multiple sclerosis (MS) and its animal models has been enigmatic. Most studies of MS have focused on the role of CD4(+) Th1 T cells and many therapeutic strategies have been directed toward ameliorating the activity of this subset. Some of these strategies were effective in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS dependent on CD4(+) T cells, but paradoxically have worsened disease in MS patients. A great deal of evidence suggests that CD8(+) T cells contribute to the pathogenesis of MS and should be considered in designing therapies. CD8(+) T cells outnumber CD4(+) T cells in MS lesions, and both clonal expansion and enrichment of memory cells is preferentially seen in the CD8(+) T cell subset in the brain and cerebrospinal fluid of MS patients. New animal models have been developed that employ myelin-specific CD8(+) T cells to induce central nervous system autoimmunity. In a CD8(+) T cell model targeting myelin basic protein, clinical signs and pathology distinct from CD4(+) T cell-mediated disease were observed that exhibited similarities to some aspects of MS. These differences are consistent with distinct effector mechanisms employed by CD8(+) and CD4(+) T cells in mediating tissue damage and suggest a need to consider the activity of CD8(+) T cells in drug design. This review will focus on our current understanding of the role of CD8(+) T cells in MS and the new animal models that allow us to investigate further the pathogenicity of this subset.

Goodin, D. S. (2005). "Treatment of multiple sclerosis with human beta interferon." Int MS J 12(3): 96-108.

            The present manuscript uses an evidence-based approach to review and analyse evidence for the use of human beta interferon in the treatment of MS. Human beta interferon modulates many of the biological processes believed to be involved in MS development. Beta interferon is a member of a large family of secreted proteins that are involved in an organisms defence against viral infections, cell growth regulation and in modulation of immune response. The therapeutic efficacy of beta interferon in relapsing-remitting and secondary progressive MS has been established in several clinical trials, and evidence indicates that the total weekly dosage of beta interferon and/or the frequency of beta interferon administration are important factors in its clinical use. Future therapeutic developments in MS will be fuelled by our increasing understanding of the physical and biological roles of the interferons, in health and in MS pathogenesis.

Goodin, D. S. (2005). "Evidence-based medicine." Int MS J 12(3): 94-5.

            Evidence-based medicine (EBM) describes a structured (non-consensus-based) process, in which medical literature is assessed critically to define the value of different therapeutic interventions. Ultimately, the goal is to improve both physician decision making and patient outcome. These assessments begin by defining the specific clinical questions to be answered. Following a structured literature search, evidence that bears on these questions is assembled and classified with respect to the quality of the evidence provided by each study. Lastly, using a set of pre-specified rules, this evidence is translated into specific conclusions and recommendations. Its relative objectivity means that evidence-based medicine can be a powerful tool for practising physicians. As a result, it is important for them to become familiar with this analytical method.

Gonzalez-Amaro, R., M. Mittelbrunn, et al. (2005). "Therapeutic anti-integrin (alpha4 and alphaL) monoclonal antibodies: two-edged swords?" Immunology 116(3): 289-96.

            Anti-alpha4 and anti-alphaL integrin chain monoclonal antibodies have shown a clear-cut beneficial effect in different animal models of autoimmune and inflammatory disorders as well as in human diseases, including multiple sclerosis, inflammatory bowel disease, and psoriasis. It has been widely assumed that this therapeutic effect is mainly consequence of the blockade of leucocyte adhesion to endothelium, inhibiting thus their extravasation and the inflammatory phenomenon. However, it is evident that both alpha4beta1 (very late antigen-4) and alphaLbeta2 (leucocyte function-associated antigen-1) integrins have additional important roles in other immune phenomena, including the formation of the immune synapse and the differentiation of T helper 1 lymphocytes. Therefore, it is very feasible that the long-term administration of blocking agents directed against these integrins to patients with inflammatory/autoimmune conditions may have undesirable or unexpected effects.

Goldberg-Zimring, D., A. U. Mewes, et al. (2005). "Diffusion tensor magnetic resonance imaging in multiple sclerosis." J Neuroimaging 15(4 Suppl): 68S-81S.

            Multiple sclerosis (MS), a demyelinating disease, occurs principally in the white matter (WM) of the central nervous system. Conventional magnetic resonance imaging (MRI) is sensitive to some, but not all, brain changes associated with MS. Diffusion-weighted imaging (DWI) provides information about water diffusion in tissue and diffusion tensor MRI (DT-MRI) about fiber direction, allowing for the identification of WM abnormalities that are not apparent on conventional MRI images. These techniques can quantitatively characterize the local microstructure of tissues. MS-associated disease processes lead to regions characterized by an increased amount of water diffusion and a decrease in the anisotropy of diffusion direction. These changes have been found to produce different patterns in MS patients presenting different courses of the disease. Changes in water diffusion may allow examination of the type, appearance, enhancement, and location of lesions not readily visible by other means. Ongoing studies of MS are integrating conventional MRI and DT-MRI measures with connectivity-based regional assessment, aiming to provide a better understanding of the nature and the location of WM lesions. This integration and the development of novel image-processing and visualization techniques may improve the understanding of WM architecture and its disruption in MS. This article presents a brief history of DWI, its basic principles and applications in the study of MS, a review of the properties and applications of DT-MRI, and their use in the study of MS. In addition, this article illustrates the methodology for the analysis of DT-MRI in ongoing studies of MS.

Gold, S. M., D. C. Mohr, et al. (2005). "The role of stress-response systems for the pathogenesis and progression of MS." Trends Immunol 26(12): 644-52.

            Disease progression in multiple sclerosis (MS)--an inflammatory demyelinating and neurodegenerative disease with a presumed T-cell driven autoimmune origin--has long been hypothesized to be associated with stress. However, this notion has only recently been supported by prospective clinical studies. Several clinical and molecular studies in MS and its animal models have recently shown disruptions in the communication between the immune system and the two major stress response systems, the hypothalamo-pituitary-adrenal (HPA) axis and the autonomic nervous system. Insensitivity to glucocorticoid and beta-adrenergic modulation might be involved in overshooting inflammation in MS, whereas hyperactivity of the HPA axis has been linked to neurodegeneration and increased disability. Here, we integrate findings from molecular, cellular, experimental, clinical and epidemiological research to describe the involvement of stress response systems in MS pathogenesis and progression.

Godessart, N. (2005). "Chemokine receptors: attractive targets for drug discovery." Ann N Y Acad Sci 1051: 647-57.

            Studies of two antibodies, efalizumab and natalizumab, have recently demonstrated that the blockade of leukocyte migration is of therapeutic benefit for the treatment of diseases such as psoriasis and multiple sclerosis. The role of chemokines in the control of cell traffic led to their receptors being considered one of the most promising family of targets aimed at disrupting cell recruitment in chronic inflammatory processes. Choosing the appropriate chemokine receptor for each disease was not easy, and the interpretation of target validation studies proved to be extremely difficult. Despite an intense effort in the search for chemokine receptor antagonists in the last decade, no compounds in advanced clinical trials exist as such. The inherent complexity of the family, the differences between the chemokine system in mice and men, and the species selectivity of small-molecule compounds could account for this fact. Pharmaceutical companies still believe in chemokine receptors as therapeutic targets, as demonstrated by the number of compounds reported to be in development. In the next years, the developmental progression of these compounds will reveal which target within the chemokine family is of real therapeutic value.

Gilden, D. H. (2005). "Infectious causes of multiple sclerosis." Lancet Neurol 4(3): 195-202.

            Multiple sclerosis (MS) is a serious chronic neurological disorder in which demyelination and inflammation occur in the white matter of the CNS. The findings of many epidemiological studies and a discordance of MS in monozygotic twins suggest that the disorder is acquired. The most likely cause is a virus because more than 90% of patients with MS have high concentrations of IgG, manifest as oligoclonal bands, in the brain and CSF. Most chronic inflammatory CNS disorders are infectious. More indirect evidence that MS is caused by a virus is the association of several viruses with demyelinating encephalomyelitis in human beings, and the induction of demyelination in animals infected with viruses in research. Nevertheless, no virus has been isolated from the brains of patients who had MS. Molecular analysis of IgG gene specificity in the brain and CSF of those with MS has shown features of an antigen-driven response: clonal amplification and extensive somatic mutations. A viral antigen against which the IgG in MS brain and CSF is directed might be identified.

Ghezzi, A. (2005). "Childhood-juvenile multiple sclerosis: clinical characteristics and treatment." Expert Rev Neurother 5(3): 403-11.

            The characteristics of multiple sclerosis with onset during childhood or adolescence are presented in this review. The clinical findings are similar to those of the adult form, but some aspects are peculiar: the high female to male ratio, occurrence of hyperacute forms, occurrence of encephalopatic symptoms and high relapse rate. The evolution is relapsing-progressive in most cases. Mild and severe disability are reached after a longer interval than in the adult form but, in spite of this, at a given age disability is higher. A high relapse rate, short interval between first and second attack and high disability after the first year are negative prognostic factors. Magnetic resonance imaging and cerebrospinal fluid data are discussed, with particular reference to differential diagnosis from acute disseminated encephalomyelitis. Currently, there are no controlled trials concerning subjects aged under 16 years. Some observations demonstrate that immunomodulatory drugs are well tolerated and have a beneficial effect, reducing the relapse rate and progression of the disease.

Gee, J. R. and J. N. Keller (2005). "Astrocytes: regulation of brain homeostasis via apolipoprotein E." Int J Biochem Cell Biol 37(6): 1145-50.

            Astrocytes are derived from the ventricular and subventricular zones of the neural plate, though there is controversy over their derivation from astrocyte-specific precursor cells or radial glia intermediates. Astrocytes are the most abundant cell type in the brain and contribute to brain homeostasis in several ways, including buffering of extracellular K+, regulating neurotransmitter release, forming the blood-brain barrier (BBB), releasing growth factors, and regulating the brain immune response. In addition, astrocytes have been shown to release apolipoprotein E (ApoE), which has been shown to regulate neurotransmission, growth factor release, and immune responses. Due to the diverse functions of astrocytes, they may play a role in a variety of diseases such as hepatic encephalopathy, multiple sclerosis, epilepsy, and age-related diseases including Alzheimer's disease and Parkinson's disease. This review highlights many of the diverse roles played by astrocytes in regulating brain homeostasis and discusses their potential role in a variety of disorders.

Gee, C. E. and I. M. Mansuy (2005). "Protein phosphatases and their potential implications in neuroprotective processes." Cell Mol Life Sci 62(10): 1120-30.

            Several neurological disorders such as stroke, amyotrophic lateral sclerosis and epilepsy result from excitotoxic events and are accompanied by neuronal cell death. These processes engage multiple signalling pathways and recruit numerous molecular components, in particular several families of protein kinases and protein phosphatases. While many investigations have examined the importance of protein kinases in excitotoxicity, protein phosphatases have not been well studied in this context. However, recent advances in understanding the functions of protein phosphatases have suggested that they may play a neuroprotective role. In this review, we summarize some of the recent findings that illustrate the pleiotropic and complex functions of tyrosine and serine/threonine protein phosphatases in the cascade of events leading to neuronal cell death, and highlight their potential intervention in limiting the extent of neuronal death.

Gebicke-Haerter, P. J. (2005). "Microarrays and expression profiling in microglia research and in inflammatory brain disorders." J Neurosci Res 81(3): 327-41.

            Expression profiling by using microarrays is a powerful tool for investigating transcriptional changes in a variety of diseases. In this survey, microarray data selected from the literature from in vivo and in vitro studies are scrutinized to find differentially expressed genes in common within specific inflammatory conditions in brain or microglial cell cultures, if there are at least two independent investigations available. Viral encephalitis, multiple sclerosis, epileptic seizures, ischemic lesions, and traumatic brain injury are the disorders covered. Moreover, by taking into account expression data obtained from cultured microglia, two examples are presented of how one can deal (or should not deal) with lists of candidate genes showing up in these kinds of studies without sophisticated software programs. Finally, some general remarks are made about pivotal issues when beginning to use microarray technology.

Ge, Y., M. Law, et al. (2005). "Applications of diffusion tensor MR imaging in multiple sclerosis." Ann N Y Acad Sci 1064: 202-19.

            Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that is the most common cause of nontraumatic disability in young adults in the United States. In recent years, magnetic resonance imaging (MRI) has been established as an important paraclinical tool in MS for the assessment of clinical diagnosis, natural history, and treatment effects. In MS studies, there are many advantages to having a sensitive and reliable in vivo method for investigating the specific pathological changes of white matter and its integrity during the disease process. As a consequence, in the past decade, the application of MRI to the study of MS has been explored from conventional MRI to new advanced quantitative techniques with greater pathological specificity and sensitivity. Diffusion tensor imaging (DTI) is one of the most promising techniques with regard to MS. It quantifies the amount of nonrandom water diffusion within tissues and provides unique in vivo information about the pathological processes that affect water diffusion as a result of brain microstructural damage. This review outlines the current state of the art and future direction of DTI and fiber tractography in the study of MS disease.

Gauthier, S. A., G. J. Buckle, et al. (2005). "Immunosuppressive therapy for multiple sclerosis." Neurol Clin 23(1): 247-72, viii-ix.

Galvez, R., J. Rejas, et al. (2005). "[Prevalence of neuropathic pain in Spain: clinical, working and health care implications]." Med Clin (Barc) 125(6): 221-9.

            A narrative systematic medical literature review on prevalence of neuropathic pain (NP) in Spain from 1990 to 2004 was conducted. The average number of publications was 3 per year. Prevalence data varied depending on studied population, definition of pain/pathology and time of pain evolution. The most commonly studied pathologies included: mononeuropathies and polyneuropathies: 42%, multiple sclerosis: 35% and entrapment neuropathies: 16%. Some episodes of NP were left untreated. One third of patients with back pain receiving analgesic treatment still had high intensity pain. Future studies on the prevalence of NP should use work definitions and criteria reached by consensus. An awareness of the clinical presentation of NP and an appropriate and early treatment could minimize its clinical, working and health care implications. NP is a diverse and highly prevalent condition in Spain. Efforts should be conducted towards the achievement of diagnostic criteria consensus and higher rates of analgesic success.

Galetta, S. L. and C. Markowitz (2005). "US FDA-approved disease-modifying treatments for multiple sclerosis: review of adverse effect profiles." CNS Drugs 19(3): 239-52.

            Several disease-modifying agents (DMAs) are approved for the treatment of multiple sclerosis, including three interferon (IFN)-beta products, glatiramer acetate and mitoxantrone. This article reviews the adverse event profiles of these DMAs based on the pivotal phase III trials, and provides practical guidelines for managing adverse effects. In general, the most common adverse events associated with IFN beta therapy are flu-like symptoms, including fever, chills and myalgias, and headache. The flu-like symptoms typically resolve within 24 hours and may be mitigated by over-the-counter anti-inflammatory agents. Adverse events related to glatiramer acetate therapy include injection-site reactions and a systemic reaction consisting of flushing, chest tightness, palpitation, anxiety or dyspnoea. The systemic reaction is transient (30 seconds to 30 minutes) and self-limited. Mitoxantrone may cause nausea, vomiting, alopecia, amenorrhoea and myelosuppression; isolated cases of acute leukaemia and dose-related cardiotoxicity have been reported in the literature. Longer-term tolerability data on mitoxantrone as a treatment for multiple sclerosis are needed. It is important for physicians to counsel patients on DMA-related adverse effects, most of which are transient and of mild-to-moderate severity. Various strategies that can be employed to prevent or manage these adverse effects and lessen their impact on the patient are discussed.

Fukaura, H. and S. Kikuchi (2005). "[Anti-MOG immunoglobulin IgM]." Nippon Rinsho 63 Suppl 7: 593-5.

Frohman, E. M., T. C. Frohman, et al. (2005). "The neuro-ophthalmology of multiple sclerosis." Lancet Neurol 4(2): 111-21.

            Multiple sclerosis (MS) is the most common disabling neurological disease in young people. Most CNS lesions involve neuroanatomically non-eloquent zones that often do not result in symptomatic complaints. By contrast, tissue-injury mechanisms involving inflammatory demyelination can involve more eloquent sites, such as the optic nerve and brainstem, which can correspondingly produce the development of well recognised syndromes such as optic neuritis and internuclear ophthalmoplegia, respectively. In this review we discuss the broad landscape of abnormalities that affect the afferent visual system and the ocular motor apparatus, and emphasise relevant features, the recognition and treatment of which are of importance to general neurological practice. The commonness of visual sensory and eye movement abnormalities in MS highlights the importance of understanding the principles addressed in this review.

Frohman, E. M., M. Filippi, et al. (2005). "Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions." Arch Neurol 62(9): 1345-56.

            Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

Frohman, E. M., O. Stuve, et al. (2005). "Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations." Arch Neurol 62(10): 1519-30.

            In the management of patients with multiple sclerosis (MS), providers are all faced with the highly formidable challenge of ascertaining whether, and to what degree, disease-modifying therapy is effective in the individual patient. While much has been learned in randomized, controlled clinical trials, we cannot simply extrapolate the outcomes of these initiatives and apply them to the care of a single patient. In the future, the application of pharmacogenetic techniques, proteomics, and microarray analysis will yield novel profiling information on individual patients that will substantially refine the specific therapeutic questions of relevance: (1) What is the best treatment for an individual patient? (2) Which patients require intensive therapeutic combination regimens to optimize control of the disease process? (3) What are the appropriate drug dosing targets for an individual patient? and (4) Which patients will be predisposed to the development of drug-related adverse events? Such data may provide a novel variable of drug responsiveness that will mandate its inclusion into the process of covariate analyses for clinical trials.

Frisoni, G. B. and M. Filippi (2005). "Multiple sclerosis and Alzheimer disease through the looking glass of MR imaging." AJNR Am J Neuroradiol 26(10): 2488-91.

Friese, M. A. and L. Fugger (2005). "Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy?" Brain 128(Pt 8): 1747-63.

            Multiple sclerosis afflicts more than 1 million individuals worldwide and is widely considered to be an autoimmune disease. Traditionally, CD4(+) T helper cells have almost exclusively been held responsible for its immunopathogenesis, partly because certain MHC class II alleles clearly predispose for developing multiple sclerosis and also, because of their importance in inducing experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. However, several strategies that target CD4(+) T cells beneficially in EAE have failed to ameliorate disease activity in multiple sclerosis, and some have even triggered exacerbations. Recently, the potential importance of CD8(+) T cells has begun to emerge. Physiologically, CD8(+) T cells are essential for detecting and eliminating abnormal cells, whether infected or neoplastic. In multiple sclerosis, genetic associations with MHC class I alleles have now been established, and CD8(+) as well as CD4(+) T cells have been found to invade and clonally expand in inflammatory central nervous system plaques. Recent animal models induced by CD8(+) T cells show interesting similarities to multiple sclerosis, in particular, in lesion distribution (more inflammation in the brain relative to the spinal cord), although not all of the features of the human disease are recapitulated. Here we outline the arguments for a possible role for CD8(+) T cells, a lymphocyte subset that has long been underrated in multiple sclerosis and should now be considered in new therapeutic approaches.

Friese, M. A., E. Y. Jones, et al. (2005). "MHC II molecules in inflammatory diseases: interplay of qualities and quantities." Trends Immunol 26(11): 559-61.

            It is generally accepted that MHC II molecules confer susceptibility to inflammatory diseases because of the different abilities they possess for binding and presenting peptides to T cells. A new study suggests that the level of MHC II gene expression is also a risk factor for such diseases. It shows that a polymorphism in the promoter of the MHC II transactivator (MHC2TA) gene (which encodes CIITA), leads to reduced MHC2TA expression, and hence reduced production of MHC II molecules. This predisposes to rheumatoid arthritis, multiple sclerosis and myocardial infarction.

Fregni, F. and A. Pascual-Leone (2005). "Transcranial magnetic stimulation for the treatment of depression in neurologic disorders." Curr Psychiatry Rep 7(5): 381-90.

            Depression is commonly associated with neurologic disorders. Although depression in neurologic conditions often is associated with a negative impact on quality of life, it frequently is poorly managed. Some factors, such as a multidrug regimen, lack of efficacy, and side effects of antidepressants may explain why depression is not adequately treated in patients with neurologic disorders. Therefore, this population needs new approaches for depression treatment, and repetitive transcranial magnetic stimulation (rTMS) may be one of them because it has been shown to be effective for the treatment of depression alone and depression in certain neurologic diseases such as Parkinson's disease and stroke. rTMS is a noninvasive, focal, and painless treatment associated with few, mild side effects. It may be effective in the treatment of neurologic diseases such as Parkinson's disease, stroke, and epilepsy. In this paper, we discuss the potential risks and benefits of rTMS treatment for depression in Parkinson's disease, epilepsy, stroke, multiple sclerosis, and Alzheimer's disease. Lastly, a framework that includes the parameters of stimulation (intensity, frequency, number of pulses, and site of stimulation) for the treatment of depression in neurologic diseases is proposed.

Francois, G., P. Duclos, et al. (2005). "Vaccine safety controversies and the future of vaccination programs." Pediatr Infect Dis J 24(11): 953-61.

            In the years following the hepatitis B vaccination/multiple sclerosis controversy, a number of new issues regarding vaccine safety have been raised, in some cases leading to more debate and confusion. Against this background, an international group of experts was convened to review the current points of view concerning the use of thimerosal as a preservative and its potential risks; the suggested link between thimerosal-containing vaccines and acute lymphoblastic leukemia; the alleged association between aluminum-containing vaccines/macrophagic myofasciitis and general systemic complaints; a possible link between vaccination and autoimmune pathology; and a hypothetical link between measles-mumps-rubella vaccination and autism. At present, there are no data to conclude that childhood vaccines, and in particular hepatitis B vaccine, pose a serious health risk or justify a change in current immunization practice. However, vaccine "scares" continue to have an international impact on immunization coverage. Creating a positive environment for immunization can be achieved by repositioning the value of vaccines and vaccination, supported by evidence-based information. The role of international organizations, the media, and the industry in the implementation of communication strategies was discussed and the impact of litigation issues on vaccination was evaluated. The Viral Hepatitis Prevention Board confirms its commitment to current recommendations for universal and risk group hepatitis B vaccination and further encourages the conduct of vaccine safety studies and the dissemination of their results.

Fotheringham, J. and S. Jacobson (2005). "Human herpesvirus 6 and multiple sclerosis: potential mechanisms for virus-induced disease." Herpes 12(1): 4-9.

            Multiple sclerosis (MS) is a debilitating neurological disease of unknown cause that affects people between 20 and 40 years of age. While several viruses have been associated with MS, none has proven causative. Human herpesvirus 6 (HHV-6) is one agent that may play a role in MS. Some studies have demonstrated an association between HHV-6 and MS based on immunological and molecular data, suggesting that a subset of MS patients may have reactivation of this widespread herpesvirus. New studies investigating the biology of HHV-6 have given insights towards understanding how HHV-6 may play a role in MS pathology. By inducing molecular mimicry or excessive complement activation, HHV-6 reactivation may have the potential to trigger autoimmunity and tissue damage associated with MS lesion development.

Ford, H. and R. Nicholas (2005). "Multiple sclerosis." Clin Evid(14): 1637-51.

Foran, J. R., S. Steinman, et al. (2005). "Structural and mechanical alterations in spastic skeletal muscle." Dev Med Child Neurol 47(10): 713-7.

            Spasticity, a neurological problem secondary to an upper motor neuron lesion, has a significant effect on skeletal muscle. The upper motor neuron lesions may be secondary to a cerebral vascular accident, head injury, spinal cord injury, or degenerative diseases such as multiple sclerosis, or perinatal brain injuries such as cerebral palsy. Functional ability in these patients can be severely compromised but the basic mechanisms underlying these deficits are not clearly understood. In this review we evaluate the current evidence in the literature that suggests that skeletal muscle tissue itself is altered in spastic conditions. Experimental studies were evaluated that included a variety of methods encompassing joint mechanics, tissue mechanics, and muscle morphology. Taken together, the literature strongly supports the assertion that 'spastic muscles' are altered in a way that is unique among muscle plasticity models and inconsistent with simple transformation due to chronic stimulation or disuse. Further studies are required to detail the intra- and extracellular modifications of skeletal muscle that occur secondary to spasticity so that novel therapeutic treatments can be developed for this impairment.

Fontoura, P., H. Garren, et al. (2005). "Antigen-specific therapies in multiple sclerosis: going beyond proteins and peptides." Int Rev Immunol 24(5-6): 415-46.

            Multiple sclerosis (MS) is a complex immune-mediated disease resulting largely from an autoimmune attack against components of central nervous system myelin, including several proteins and lipids. Knowledge about the details of this anomalous immune response has come mostly from studies in the animal model experimental autoimmune encephalomyelitis (EAE). In this model, it has been possible to prevent and effectively treat established disease through several antigen-specific therapeutic strategies, which have included administration of whole myelin or myelin proteins by various routes, random copolymers consisting of the main major histocompatability complex (MHC) and T-cell receptor (TCR) contact amino acid residues, altered peptide ligands of dominant myelin epitopes in which one or more residues are selectively substituted, and lately DNA vaccination encoding self-myelin antigens. However, there have been difficulties in making successful transitions from animal models to human clinical trials, due either to lack of efficacy or unforeseen complications. Despite these problems, antigen-specific therapies have retained their attraction for clinicians and scientists alike, and hopefully the upcoming generation of agents--including altered peptide ligands and DNA vaccines--will benefit from the increasing knowledge about this disease and surmount existing difficulties to make an impact in the treatment of multiple sclerosis.

Fleming, W. E. and C. P. Pollak (2005). "Sleep disorders in multiple sclerosis." Semin Neurol 25(1): 64-8.

            Sleep disorders are pervasive in patients with multiple sclerosis (MS) although clinically underrecognized by most physicians. The most common sleep disorders seen in patients with MS include insomnia, nocturnal movement disorders, sleep-disordered breathing, narcolepsy, and rapid eye movement sleep behavior disorder. Factors that influence the quality of sleep in this patient population include pain, nocturia, depression, medication effect, location of lesions, and disease severity. Disrupted sleep has the potential to cause daytime somnolence, increased fatigue, and nonrefreshing sleep, and it may be associated with dangerous respiratory events. Awareness and treatment of these conditions is vital to improving health and quality of life in patients with MS.

Fleming, K. K., J. A. Bovaird, et al. (2005). "Statistical analysis of data from studies on experimental autoimmune encephalomyelitis." J Neuroimmunol 170(1-2): 71-84.

            Research in multiple sclerosis often employs animal models of the disease, especially experimental autoimmune encephalomyelitis (EAE) in rodents. The statistical analysis procedures chosen for these studies are often suboptimal, either because of violations of the assumptions of the procedure or because the analysis selected is inappropriate for the research question. In this paper, we discuss the types of research questions frequently asked in EAE studies and suggest appropriate and useful research designs and statistical methods that will optimize the information contained within the data. We also discuss other troublesome issues such as missing data, atypical disease profiles, and power analysis.

Filippi, M., A. Falini, et al. (2005). "Magnetic resonance techniques for the in vivo assessment of multiple sclerosis pathology: consensus report of the white matter study group." J Magn Reson Imaging 21(6): 669-75.

            On October 9-11, 2003, the third meeting of the White Matter Study Group of the International Society for Magnetic Resonance in Medicine was held in Venice, Italy. This article is the report of the meeting on how to use MRI in the diagnostic workup of multiple sclerosis (MS) and allied white matter disorders, and to define the nature and the extent of MS pathology in vivo. Both of these steps are central to the design of future treatment strategies aimed at limiting the functional consequences of the most disabling aspects of this disease.

Filippi, M. and M. A. Rocca (2005). "MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system." J Neurol 252 Suppl 5: v16-24.

            The classical view of MS as a chronic inflammatory demyelinating disease leading to the formation of focal central nervous system (CNS) white matter (WM) lesions has been recently challenged by pathological studies and by the extensive application of modern MRI-based techniques. There is now overwhelming evidence supporting the following statements: MS causes widespread tissue damage in the normal-appearing white matter (NAWM) of the brain and spinal cord, whose extent and severity is more strictly associated to the clinical manifestations of the disease than the extent of focal pathology. Discrete, macroscopic lesions are just the tip of the iceberg of MS pathology. Grey matter (GM) damage is a consistent feature of all MS phenotypes, which is progressive from the start of the relapsing-remitting phase of the disease. As is the case for WM, GM damage is also a mixture of focal lesions and diffuse pathology. High-field strength MR scanners are improving our ability to image focal GM lesions and modern MR-based techniques are enabling us to quantify in vivo the extent and severity of GM pathology, which have been shown to correlate only moderately with the amount of WM changes. At least part of GM pathology in MS is not secondary to retrograde degeneration of fibers traversing WM lesions. The neurodegenerative component of the disease is not a late phenomenon and it is not completely driven by inflammatory demyelination. In fact, neurodegeneration occurs very early in the course of MS and the correlation between MRI measures of inflammation and neurodegeneration is weak in all disease phases. The interplay of inflammation and neurodegeneration is a complex and still poorly understood phenomenon. At least part of MS-related neurodegeneration is not directly driven by Wallerian degeneration. Functional cortical changes can be seen in virtually all MS patients and are likely to play a central role in the ability of the MS brain to respond to tissue injury and, hence, limit the functional consequences of structural damage. MS disability is not just the result of tissue destruction but rather a balance between tissue destruction, tissue repair and adaptive cortical reorganization.All of this calls for the concept of MS as a focal, inflammatory demyelinating, WM disease to be reexamined and to start viewing MS as a diffuse CNS disease with an important neurodegenerative component. This is central for identifying novel and effective treatment strategies.

Filho, A. M., A. de Castro Domingos, et al. (2005). "Osteopetrosis--a review and report of two cases." Oral Dis 11(1): 46-9.

            We present a brief review of the rare condition of osteopetrosis together with two case reports of this disease in the same family affecting the jaws. The first in a 41-year-old woman, and the second in her 39-year-old brother. Plain films and computed tomography showed marked sclerosis of the affected bones with obliteration of the medullary cavities and thickening of the cortices as well as multiple absent and unerupted teeth. In addition radiographs showed discrete mixed radiopaque/radiolucent areas consistent with the appearance of fibro-cemento-osseous dysplasia, but which may also represent part of the overall spectrum of bone changes in osteopetrosis.

Ferreira, S., D. P. D'Cruz, et al. (2005). "Multiple sclerosis, neuropsychiatric lupus and antiphospholipid syndrome: where do we stand?" Rheumatology (Oxford) 44(4): 434-42.

            Multiple sclerosis (MS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are chronic, immune-mediated, relapsing-remitting disorders affecting young adults, the pathogenesis of which is still largely unknown. Neurological manifestations and magnetic resonance imaging (MRI) can be indistinguishable and there are no specific diagnostic tools. Treatment and prognosis are quite different. There is controversy about the prevalence and significance of antiphospholipid antibodies (aPL) in MS. A significant number of patients with APS/SLE are misdiagnosed as MS but evidence suggests they are distinct nosological entities. However, it is essential to differentiate them since APS may be responsive to anticoagulation. When assessing MS patients, clinicians should consider APS/SLE, especially if the MS has atypical features. A trial of anticoagulation might be worthwhile in some patients with atypical MS and consistently positive aPL.

Fernie, K. J. and S. J. Reynolds (2005). "The effects of electromagnetic fields from power lines on avian reproductive biology and physiology: a review." J Toxicol Environ Health B Crit Rev 8(2): 127-40.

            Electrical power lines are ubiquitous in the developed world and in urban areas of the developing world. All electrical currents, including those running through power lines, generate electric and magnetic fields (EMFs). Electrical power lines, towers,and distribution poles are used by birds for perching, hunting, and nesting. Therefore, many bird species, like humans, are exposed to EMFs throughout their lives. EMFs have been implicated in adversely affecting multiple facets of human health,including increasing the risks of life-threatening illnesses such as leukemia, brain cancer, amyotrophic lateral sclerosis, clinical depression, suicide, and Alzheimer's disease. A great deal of research and controversy exists as to whether or not exposure to EMFs affects the cellular, endocrine, immune, and reproductive systems of vertebrates. Laboratory work has used mice, rats, and chickens as models for this EMF research in an effort to understand better the possible implications of EMF exposure for humans. However, EMF exposure of wild birds may also provide insight into the impacts of EMFs on human health. This review focuses on research examining the effects of EMFs on birds; most studies indicate that EMF exposure of birds generally changes, but not always consistently in effect or in direction, their behavior, reproductive success, growth and development, physiology and endocrinology, and oxidative stress under EMF conditions. Some of this work has involved birds under aviary conditions, while other research has focused on free-ranging birds exposed to EMFs. Finally, a number of future research directions are discussed that may help to provide a better understanding of EMF effects on vertebrate health and conservation.

Fernandez-Ruiz, J. and S. Gonzales (2005). "Cannabinoid control of motor function at the basal ganglia." Handb Exp Pharmacol(168): 479-507.

            Classic and novel data strengthen the idea of a prominent role for the endocannabinoid signaling system in the control of movement. This finding is supported by three-fold evidence: (1) the abundance of the cannabinoid CB1 receptor subtype, but also of CB2 and vanilloid VR1 receptors, as well as of endocannabinoids in the basal ganglia and the cerebellum, the areas that control movement; (2) the demonstration of a powerful action, mostly of an inhibitory nature, of plant-derived, synthetic, and endogenous cannabinoids on motor activity, exerted by modulating the activity of various classic neurotransmitters; and (3) the occurrence of marked changes in endocannabinoid transmission in the basal ganglia of humans affected by several motor disorders, an event corroborated in animal models of these neurological diseases. This three-fold evidence has provided support to the idea that cannabinoid-based compounds, which act at key steps of the endocannabinoid transmission [receptors, transporter, fatty acid amide hydrolase (FAAH)], might be of interest because of their potential ability to alleviate motor symptoms and/or provide neuroprotection in a variety of neurological pathologies directly affecting basal ganglia structures, such as Parkinson's disease and Huntington's chorea, or indirectly, such as multiple sclerosis and Alzheimer's disease. The present chapter will review the knowledge on this issue, trying to establish future lines for research into the therapeutic potential of the endocannabinoid system in motor disorders.

Fergusson, D., B. Hutton, et al. (2005). "Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review." Transfusion 45(10): 1640-57.

            BACKGROUND: Given the increasing use of intravenous immunoglobulin (IVIG) for various neurologic conditions and uncertainty pertaining to its benefits and harms, a systematic review was conducted of randomized controlled trials (RCTs) evaluating IVIG for all neurologic indications for which there was at least one published trial. STUDY DESIGN AND METHODS: For this systematic review, a systematic search strategy was applied to MEDLINE (1966-June 2003) and the Cochrane Register of Controlled Trials (June 2003) to identify potentially eligible RCTs comparing IVIG to placebo or an active control. All dosage regimens were considered. Abstracts were excluded, and no restriction was placed on language of publication. Two investigators independently performed data extraction with a standardized form. Measures of effect were calculated for each trial independently, and studies were pooled based on clinical and methodologic judgment as to its appropriateness. Where pooling of trials was inappropriate, a qualitative discussion of findings is provided. RESULTS AND CONCLUSIONS: Thirty-seven trials representing 14 conditions were identified. IVIG is more effective than placebo for treatment of relapsing-remitting multiple sclerosis and idiopathic chronic inflammatory demyelinating polyneuropathy. There is also potential benefit for treatment of multifocal motor neuropathy, myasthenia gravis, dermatomyositis, stiff-person syndrome, and Lambert-Eaton myasthenic syndrome. There was insufficient evidence to determine whether IVIG therapy was more effective than plasma exchange for Guillain-Barre syndrome. There was also insufficient evidence regarding paraprotein-associated polyneuropathy. No evidence of benefit was observed for secondary progressive multiple sclerosis or inclusion body myositis.

Fergani, A., L. Dupuis, et al. (2005). "Reticulons as markers of neurological diseases: focus on amyotrophic lateral sclerosis." Neurodegener Dis 2(3-4): 185-94.

            Reticulons (RTNs) are a family of proteins that are primarily associated with the endoplasmic reticulum. In mammals, four genes have been identified and referred as to rtn1, 2, 3 and the neurite outgrowth inhibitor rtn4/nogo. These genes generate multiple isoforms that contain a common C-terminal reticulon homology domain of 150-200 amino-acid residues. The N-terminal regions of RTNs are highly variable, and result from alternative splicing or differential promoter usage. Although widely distributed, the functions of RTNs are still poorly understood. Much interest has been focused on rtn4/nogo because of its activity as a potent inhibitor of axonal growth and repair. In the present study, we update recent knowledge on mammalian RTNs paying special attention to the involvement of these proteins as markers of neurological diseases. We also present recent data concerning RTN expression in amyotrophic lateral sclerosis, a fatal degenerative disorder characterized by loss of upper and lower motor neurons, and muscle atrophy. The rearrangement of RTN expression is regulated not only in suffering skeletal muscle but also preceding the onset of symptoms, and may relate to the disease process.

Faure, E. (2005). "Multiple sclerosis and hepatitis B vaccination: could minute contamination of the vaccine by partial hepatitis B virus polymerase play a role through molecular mimicry?" Med Hypotheses 65(3): 509-20.

            Reports of multiple sclerosis developing after hepatitis B vaccination have led to the concern that this vaccine might be a cause of multiple sclerosis in previously healthy subjects. Some articles evidenced that minor Hepatitis B virus (HBV) polymerase proteins could be produced by alternative transcriptional or translational strategies. Their detection is very difficult because they are in minute concentration and probably enzymatically inactive, however, it was shown that they could be exposed on the outside of the virus particles and also be immunogenic. In addition, HBV polymerase shares significant amino acid similarities with the human myelin basic protein. We hypothesise that some of the apparent adverse reactions to the vaccine could be due to a process called of molecular mimicry, the HBV polymerase, which could be a contaminant in the recombinant or plasma-derived vaccines, could act as autoantigens and induce autoimmune demyelinating diseases such as multiple sclerosis.

Farrell, R., D. Heaney, et al. (2005). "Emerging therapies in multiple sclerosis." Expert Opin Emerg Drugs 10(4): 797-816.

            Multiple sclerosis (MS) is the most common neurological cause of disability in young people. The disease-modifying treatments, IFN-beta and glatiramer acetate, have been widely available over the last decade and have shown a beneficial effect on relapse rate and magnetic resonance imaging parameters of disease activity; however, their effect on disease progression and disability is modest. Therefore, the search for alternative treatment strategies continues. As understanding of the heterogeneous pathophysiology of MS has increased, emphasis has shifted to more selective therapy that targets components of the inflammatory cascade and the promotion of remyelination and neuroprotection. These agents target the blood-brain barrier, systemic immune dysfunction, local inflammation and neurodegeneration. Combination therapies are being investigated for patients who fail first-line treatments. Many new drugs are being developed and tested that address these issues with the aim of finding a more effective and convenient therapy. These include humanized monoclonal antibodies such as daclizumab (IL-2 antagonist), oral immunomodulators such as sirolimus and statins and neuroprotective agents such as NMDA antagonists and Na+-channel blockers. Many of the treatments discussed in this review are still at early stages of development, but provide exciting potential treatment options; others have proved disappointing in larger extended-phase studies.

Farina, C., M. S. Weber, et al. (2005). "Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action." Lancet Neurol 4(9): 567-75.

            Glatiramer acetate is a synthetic random copolymer approved for the immunomodulatory therapy of relapsing-type multiple sclerosis (MS). Previous work has focused on the effects of this drug on T cells, especially the glatiramer-acetate-induced shift of the cytokine profile towards those characteristic of T-helper-2 (Th2) cells. Glatiramer acetate was thought to bring about this Th2 shift by acting like an altered peptide ligand but more recent work has shown that the drug notably affects the properties of antigen-presenting cells, such as monocytes and dendritic cells. These new observations might offer an explanation for the previously observed Th2 shift. In this review, we focus on these new findings. We address several controversial issues, including the possible neurotrophic effects of glatiramer acetate, the potential role of neutralising antibodies to the drug, and attempts to develop biomarkers of the treatment response. Finally, we will think about how a better understanding of glatiramer acetate might help the development of new immunomodulatory agents for MS.

Faria, A. M. and H. L. Weiner (2005). "Oral tolerance." Immunol Rev 206: 232-59.

            Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy.

Espejo, C. and E. M. Martinez-Caceres (2005). "The role of methallothioneins in experimental autoimmune encephalomyelitis and multiple sclerosis." Ann N Y Acad Sci 1051: 88-96.

            Multiple sclerosis is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) in which oxidative stress plays a pathogenic role. Metallothioneins are antioxidant proteins induced in the CNS under conditions where oxidative stress has taken place, such as tissue injury, stress, and some neurodegenerative diseases, which have been postulated to play a neuroprotective role. In this review we summarize recent progress in understanding the regulation and function of methallothioneins during experimental autoimmune encephalomyelitis and multiple sclerosis.

Ercolini, A. M. and S. D. Miller (2005). "Role of immunologic cross-reactivity in neurological diseases." Neurol Res 27(7): 726-33.

            Although the immune system evolved to protect the host from foreign infection, it can sometimes recognize and attack host tissues, a phenomenon known as autoimmunity. In addition to genetic factors, environmental elements such as viruses and bacteria are thought to play a role in the development of autoimmune diseases. The major hypothesized mechanism by which infection with these agents can lead to autoimmunity is termed molecular mimicry. Here, immune responses initiated against foreign antigens are cross-reactive with self-antigens. This is thought to occur especially if the foreign antigen is similar in structure or amino acid sequence to the self-antigen. In this review, we explore evidence for the role of molecular mimicry in neurological diseases.

Engelhardt, B. and R. M. Ransohoff (2005). "The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms." Trends Immunol 26(9): 485-95.

            This review addresses current knowledge of the molecular trafficking signals involved in the migration of circulating leukocytes across the highly specialized blood-central nervous system (CNS) barriers during immunosurveillance and inflammation. In this regard, adhesion molecules and activating and chemotactic factors are also discussed and the regional variability in the brain and spinal cord parenchyma are also considered. Furthermore, direct passage into cerebrospinal fluid (CSF) is discussed, in the context of CNS immunosurveillance. The potential differences that characterize leukocyte entry into these varied anatomical sites are highlighted, with special emphasis on studies of the pathogenesis of multiple sclerosis and its animal models. An update on findings from clinical trials of natalizumab is also provided.

Engelhardt, B. and M. J. Briskin (2005). "Therapeutic targeting of alpha 4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit?" Eur J Immunol 35(8): 2268-73.

            Inhibition of leukocyte trafficking via alpha4-integrin antibody blockade has recently become a validated therapeutic approach for several inflammatory diseases, including multiple sclerosis, ulcerative colitis and Crohn's disease. In the midst of this recent success, 3 patients receiving chronic treatment with the anti-alpha4 antagonist natalizumab (Tysabri) for the treatment of multiple sclerosis or Crohn's disease, developed JC-virus related progressive multifocal leukoencephalopathy (PML). These unforeseen consequences suggest that long term blockade of alpha4-integrins might prevent trafficking of non-pathogenic lymphocytes that are essential for viral immunosurveillance. In the current issue of the European Journal of Immunology Bjursten and colleagues report that long term treatment with anti-alpha4-integrin antibodies results in exacerbation of the murine model of colitis induced by the targeted deletion of the heterotrimeric G protein subunit Galphai2. In order to properly evaluate the efficacy and safety of anti-alpha4-integrin therapy, the relationship between these observations in an immunologically altered animal model and human clinical disease needs to be carefully measured.

Engel, C., B. Greim, et al. (2005). "[Cognitive dysfunctions in multiple sclerosis patients]." Nervenarzt 76(8): 943-4, 946-8, 951-3.

            Cognitive dysfunctions are frequent symptoms of multiple sclerosis (MS) and occur in up to 65% of patients. Especially memory, attention, executive and visual constructive functions are impaired. These problems strongly affect patients' ability to work, social relationships, and quality of life. Symptoms of physical disabilities can arise independently. Cognitive dysfunctions are clear indicators of MS progression, since they represent highly complex functions depending on the integrity of neuronal networks. Once manifested after a relapse, they remain stable. Given a differentiating diagnosis, it is possible to treat these dysfunctions by cognitive training and pharmacologically for example by immunomodulating drugs. However, treatment options are limited at present. This report provides a detailed description of cognitive functions and performance in MS patients, their comorbidities such as fatigue and depression, currently available diagnostic tools, and therapeutic options.

Encinas, J. M., L. Manganas, et al. (2005). "Nitric oxide and multiple sclerosis." Curr Neurol Neurosci Rep 5(3): 232-8.

            Nitric oxide (NO) is a free radical signaling molecule with remarkably complex biochemistry. Its involvement in multiple sclerosis (MS) had been postulated soon after the discovery of the critical role NO plays in inflammation. However, the extent of NO's contribution to MS is not yet understood, party due to the often opposing roles that NO can play in cellular processes. This review briefly covers new developments in the area of NO that may be relevant to MS. It also describes recent progress in understanding the role of NO in MS, new potential targets of the action of NO in the cell, and prospects for NO-based therapies.

El-Etr, M., S. Vukusic, et al. (2005). "Steroid hormones in multiple sclerosis." J Neurol Sci 233(1-2): 49-54.

            The possible influence of steroid hormones in multiple sclerosis (MS) has been a matter of great interest. A first illustration comes from the analyses of the influence of gender on susceptibility to MS and on MS severity. A series of arguments emerge in favour of a possible influence of steroid hormones in MS. The menstrual cycle, and even more pregnancy, may influence the clinical evolution of MS. In the PRIMS study, there was a dramatic decrease in the relapse rate during pregnancy, especially in the third trimester, with a rebound increase in the 3 months post partum. Animal studies have provided further confirmatory results. Many experiments have shown that sex steroids may have immunological effects, in preventing or treating experimental allergic encephalomyelitis. They could also have an effect on myelinating and remyelinating the peripheral and possibly the central nervous system. These clinical and experimental data have led to consider sexual steroids as potential therapeutic tools for preventing relapses in women with MS, in particular in the post-partum period.

Ehde, D. M. and C. H. Bombardier (2005). "Depression in persons with multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 437-48, ix.

            This article provides a critical review of what is currently known concerning the nature and scope of depression in persons who have MS. It begins with a discussion of relevant terminology,which is followed by a summary of the research literature concern-ing the prevalence; severity; and risk factors for, and impact of, depression in MS. Assessment issues also are reviewed. Gaps in the literature on the treatment of depression in persons who have MS also are discussed. The article concludes with a discussion of future directions that will improve our understanding of depression, its treatment, and the other side-resilience in the face of a serious neurologic condition.

Ehde, D. M., T. L. Osborne, et al. (2005). "Chronic pain in persons with multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 503-12.

            The MS literature clearly indicates that chronic pain is a significant problem for many, although not all, persons with MS. The rates of pain have been found to vary in different studies, from 44% to 80%, depending on the sample and the specific questions used to assess the incidence and severity of pain. What is not clear is the proportion of persons who have acute pain relative to chronic pain. Although the specific frequency of pain problems in patients with MS may not be clear, there is a subgroup of patients (about 38% of those with pain in one sample) who report experiencing severe pain [8]. Preliminary research suggests that chronic pain can have a significant negative impact on a number of aspects of functioning in persons with MS, such as the ability to engage in household work and psychologic functioning. A biopsychosocial model of chronic pain, which has proved to be useful in understanding chronic pain as a primary condition and chronic pain in persons with other physical disabilities, may also be useful for understanding pain in persons with MS. Research,however, has not yet tested the utility of this model among MS populations.Longitudinal research is needed to help us learn how MS-related pain may fluctuate over time and with changes in disease status. There also is a strong need for research that examines access to pain treatment and that evaluates the efficacy of currently available pain treatments in persons with MS. The results of such research, as it is applied to help patients with MS, should contribute to an overall increase in well-being and a decrease in suffering among persons with MS and chronic pain.

Edan, G. (2005). "Immunosuppressive therapy in multiple sclerosis." Neurol Sci 26 Suppl 1: S18.

Ebringer, A., L. Hughes, et al. (2005). "Acinetobacter immune responses in multiple sclerosis: etiopathogenetic role and its possible use as a diagnostic marker." Arch Neurol 62(1): 33-6.

            Multiple sclerosis (MS) is the most common cause of neurologic disability among young people. The etiology of MS is controversial, but immune responses are considered to somehow be involved. The diagnosis of MS depends on a combination of various clinical and laboratory features, but apart from some myelin-neuronal autoantibody profiles or oligoclonal bands in the cerebrospinal fluid no other serologic diagnostic test or marker has yet been discovered. However, the presence of antibodies to Acinetobacter species in MS patients opens the possibility of developing a composite laboratory diagnostic marker, the myelin-Acinetobacter-neurofilament index. Whether Acinetobacter is the triggering agent of MS remains to be determined, but the measurement of anti-Acinetobacter antibodies could be used as a marker of disease activity. To evaluate this, prospective randomized controlled studies should be performed with MS patients, especially in the early stages of the disease.

Ebringer, A., T. Rashid, et al. (2005). "Bovine spongiform encephalopathy, multiple sclerosis, and creutzfeldt-jakob disease are probably autoimmune diseases evoked by Acinetobacter bacteria." Ann N Y Acad Sci 1050: 417-28.

            Bovine spongiform encephalopathy (BSE) belongs to a group of conditions named together as transmissible spongiform encephalopathies (TSE). They are fatal neurodegenerative diseases that include "scrapie" in sheep, Creutzfeldt-Jakob disease (CJD) and kuru in humans, and chronic wasting disease in deers. BSE-affected animals suffer from "hindquarters" paralysis, which is also one of the main features of "experimental allergic encephalomyelitis" (EAE). EAE is considered an animal model of multiple sclerosis (MS) and lower limb ataxia is often observed in MS patients. The presence of clinical and histopathological similarities in these diseases suggests a common pathology. Specific brain peptides, which produce EAE, were shown to have "molecular mimicry" with the soil and skin saprophytic microbe, Acinetobacter. BSE-affected animals and patients suffering from MS have been found to have elevated levels of antibodies to both Acinetobacter and Pseudomonas bacteria, as well as autoantibodies to both white and gray matter brain components. The hypothesis is proposed that Acinetobacter/Pseudomonas bacteria may have evoked both BSE and MS through the mechanism of "molecular mimicry" and autoimmunity in a similar way to Streptococcus microbes producing rheumatic fever and Sydenham's chorea. The possibility that CJD patients may show similar features remains to be determined.

Ebers, G. C. (2005). "Prognostic factors for multiple sclerosis: the importance of natural history studies." J Neurol 252 Suppl 3: iii15-iii20.

            Detailed studies of the natural history of untreated multiple sclerosis (MS) have been carried out in London, Ontario, Canada, over the past generation. There are now some 25,000 patient-years of follow-up in a cohort of slightly more than 1,000 individuals. From the data, it is clear that a number of factors are associated with long-term outcome of the disease.The Ontario database reveals several prognostic variables that are clinical in nature, which can be used to evaluate prognosis in any clinical subtype. The most important factors include the development of a progressive deficit and time to onset of progressive deficit. In addition, and independently, a high number of relapses in the first and second year is associated with poor long-term outcome, as is the development of early unremitting disability. An important question is whether or not primary-progressive (PP) MS represents an independent entity separate from secondary-progressive (SP) MS. No specific category of PP disease is distinguishable from SP disease using available clinical measures. There is reason to believe that magnetic resonance imaging (MRI) activity (when appropriately controlled for other unequally distributed factors, such as age) will be found to be very similar.

Durelli, L. and M. Clerico (2005). "The importance of maintaining effective therapy in multiple sclerosis." J Neurol 252 Suppl 3: iii38-iii43.

            The INCOMIN study (INdependent COMparison of INterferons) lends further support to the growing body of evidence that both dose and frequency of interferon beta (IFNbeta) administration are important in the treatment of multiple sclerosis (MS). High-dose, high-frequency IFNbeta (IFNbeta-1b 250 microg eod sc and IFNbeta-1a 44 microg sc) treatment offers greater therapeutic benefit, in terms of clinical and magnetic resonance imaging (MRI) outcome measures, compared with low-dose, once-weekly administration of IFNbeta. The importance of maintaining the most effective treatment regimen has been shown in another study. The data from this study suggested that patients who have 'stable' disease (i. e. no evidence of clinical or MRI disease activity) during long-term treatment with IFNbeta-1b 250 microg, who are subsequently treated with low-dose, once-weekly IFNbeta-1a 30 microg, are more likely to experience relapses, disease progression or MRI activity compared with those remaining on IFNbeta-1b 250 microg. These data clearly indicate that frequently administered therapy must be maintained to achieve the optimal therapeutic benefit for patients. Those patients who had their IFNbeta-1b 250 microg therapy reduced to low-dose, once-weekly IFNbeta-1a and experienced a resumption of disease activity were returned to their previous regimen. However, after 1 year of additional follow-up, many of these patients still had clinical or MRI signs of disease activity, highlighting further the risks associated with the reduction of IFNbeta dose and frequency of administration.Taking into consideration the evidence supporting the greater efficacy of IFNbeta-1b 250 microg or IFNbeta-1a 44 microg in MS it is of considerable interest to examine whether it is useful to increase the dose of IFNbeta-1b in patients who do not respond satisfactorily to the approved standard dose. This is the rationale for the recently completed OPTIMS (OPTimization of Interferon for MS) study, in which partially responding patients were randomised to IFNbeta-1b 250 or 375 microg every other day. An interim safety analysis of OPTIMS patients has not raised any safety or tolerability concerns.In summary, there is consistent evidence to support the importance of maintaining frequently administered IFNbeta (IFNbeta-1b 250 microg or IFNbeta-1a 44 microg) for the treatment of MS.

Duncan, A. J. and S. J. Heales (2005). "Nitric oxide and neurological disorders." Mol Aspects Med 26(1-2): 67-96.

            This article aims to give a broad overview of some of the potential targets for nitric oxide (NO) in the brain. The relevance of NO in both physiological and pathological scenarios is considerable. There is substantial evidence that neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, involve NO in their pathogenesis. Here we describe a number of cellular components which may be affected by NO, with particular relevance to neurological diseases. As the mitochondrion (in particular the electron transport chain) would appear to be of importance when considering the deleterious effects of NO, this review has a particular emphasis on that organelle. Cellular and mitochondrial antioxidants such as glutathione and ubiquinone are also discussed. In addition, the pivotal role of the astrocyte in both neuroprotection or neurodegeneration are examined.

Duncan, I. D. (2005). "Remyelination and restoration of axonal function by glial cell transplantation." Ernst Schering Res Found Workshop(53): 115-32.

Dumont, F. J. (2005). "Fingolimod. Mitsubishi Pharma/Novartis." IDrugs 8(3): 236-53.

            Mitsubishi Pharma Corp and Novartis AG are developing fingolimod, an orally active immunosuppressant affecting lymphocyte re-circulation, for the potential prevention of transplant rejection and the treatment of autoimmune diseases, including multiple sclerosis. Fingolimodis a synthetic sphingosine analog that becomes phosphorylated in vivo and acts as a sphingosine-1-phosphate receptor agonist.

Dubois-Dalcq, M., C. Ffrench-Constant, et al. (2005). "Enhancing central nervous system remyelination in multiple sclerosis." Neuron 48(1): 9-12.

            Recent studies on adult neural stem cells and the developmental biology of myelination have generated the expectation that neural precursors can repair the damaged central nervous system of multiple sclerosis patients where the endogenous remyelination process has failed. As a result, many laboratories are engaged in translational studies in which the goal is to design ways to promote remyelination and repair. Here we raise issues highlighted by prior experimental and human work that should be considered lest these studies become "lost in translation."

Drew, P. D., P. D. Storer, et al. (2005). "Hormone regulation of microglial cell activation: relevance to multiple sclerosis." Brain Res Brain Res Rev 48(2): 322-7.

            Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses. Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-alpha that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. Previously, we and others demonstrated that PPAR-gamma agonists including 15d-PGJ(2) are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-gamma modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ(2) is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ(2) acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ(2) and 9-cis RA inhibit cell activation through the formation of PPAR-gamma/RXR heterodimers. Interestingly, PGA(2), which like 15d-PGJ(2) is a cyclopentenone prostaglandin, but which unlike 15d-PGJ(2) does not bind PPAR-gamma, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ(2) inhibits microglial cell activation by PPAR-gamma-dependent as well as PPAR-gamma-independent mechanisms. The studies further suggest that the PPAR-gamma agonist 15d-PGJ(2) in combination with retinoids may be effective in the treatment of MS.

Dressler, D. and R. Benecke (2005). "Diagnosis and management of acute movement disorders." J Neurol 252(11): 1299-306.

            Most movement disorders, reflecting degenerative disorders, develop in a slowly progressive fashion. Some movement disorders, however, manifest with an acute onset. We wish to give an overview of the management and therapy of those acute-onset movement disorders.Drug-induced movement disorders are mainly caused by dopamine-receptor blockers (DRB) as used as antipsychotics (neuroleptics) and antiemetics. Acute dystonic reactions usually occur within the first four days of treatment. Typically, cranial pharyngeal and cervical muscles are affected. Anticholinergics produce a prompt relief.Akathisia is characterized by an often exceedingly bothersome feeling of restlessness and the inability to remain still. It is a common side effect of DRB and occurs within few days after their initiation. It subsides when DRB are ceased.Neuroleptic Malignant Syndrome is a rare, but life-threatening adverse reaction to DRB which may occur at any time during DRB application. It is characterised by hyperthermia, rigidity, reduced consciousness and autonomic failure. Therapeutically immediate DRB withdrawal is crucial.Additional dantrolene or bromocriptine application together with symptomatic treatment may be necessary.Paroxysmal dyskinesias are childhood onset disorders characterised by dystonic postures, chorea, athetosis and ballism occurring at irregular intervals. In Paroxysmal Kinesigenic Dyskinesia they are triggered by rapid movements, startle reactions or hyperventilation. They last up to 5 minutes, occur up to 100 times per day and are highly sensitive to anticonvulsants. In Paroxysmal Non-Kinesiogenic Dyskinesia they cannot be triggered, occur less frequently and last longer.Other paroxysmal dyskinesias include hypnogenic paroxysmal dyskinesias, paroxysmal exertional dyskinesia, infantile paroxysmal dystonias, Sandifer's syndrome and symptomatic paroxysmal dyskinesias.In Hereditary Episodic Ataxia Type 1 attacks of ataxia last for up to two minutes, may be accompanied by dysarthria and dystonia and usually respond to phenytoin. In Type 2 they can last for several hours, may be accompanied by vertigo, headache and malaise and usually respond to acetazolamide. Symptomatic episodic ataxias can occur in a number of metabolic disorders, but also in multiple sclerosis and Behcet's disease.

Drachman, D. B. and R. A. Brodsky (2005). "High-dose therapy for autoimmune neurologic diseases." Curr Opin Oncol 17(2): 83-8.

            PURPOSE OF REVIEW: Autoimmune neurologic diseases are being increasingly recognized, and treated with conventional immunosuppressive agents. Patients with 'refractory' conditions have been treated with high-dose therapy, with or without autologous stem cell transplants. This paper reviews the rationale, methods, and recent results of high-dose therapy and the questions that it raises. RECENT FINDINGS: High-dose therapy has been used in progressive multiple sclerosis and in myasthenia gravis and autoimmune neuropathies that are refractory to conventional immunotherapy. A variety of methods of immune ablation have been used; most require hematopoietic 'rescue' with stem cell transplantation. High-dose cyclophosphamide alone is immunoablative but not myeloablative, permitting the patient's endogenous stem cells to repopulate the hematopoietic/immune systems. The results have been highly encouraging in many but not all cases, with durable responses in the limited time they have been followed up. The treatments carry some risks and have been reserved for refractory cases until now. SUMMARY: High-dose therapy, without or with stem cell transplantation, is a valuable resource for the treatment of patients with refractory autoimmune neurologic diseases. It is important to define the diseases and patient characteristics likely to lead to benefit, to optimize the methods of treatment and to establish when in the patient's course to administer it. High-dose therapy may eventually become the standard for treatment of severe progressive autoimmune neurologic disorders.

Doria, A., E. Sabadini, et al. (2005). "[Non SLE connective tissue diseases: general aspects and kidney]." G Ital Nefrol 22 Suppl 33: S11-20.

            Connective tissue diseases represent a group of heterogeneous disorders that share certain common features, including inflammation of the skin, joints and other structures rich in connective tissue, as well as altered immunoregulation patterns, including autoantibody production and cell-mediated immunity abnormalities. While certain distinct clinical entities can be defined, manifestations can vary considerably from patient to patient, and the overlap of clinical features between and among specific diseases is common. Genetic, environmental and sex hormonal factors are likely to be of pathogenic importance. Among these diseases, systemic lupus erythematosus is the most frequent, followed by systemic sclerosis or scleroderma (SSc), Sjogren's disease, polymyositis and dermatomyositis and mixed connective tissue disease. Systemic sclerosis involves multiple organs in a process consisting of disseminated sclerosis affecting all compartments. Prominent vascular lesions typify the renal lesions. Scleroderma crisis is a major complication of SSc, characterized by severe hypertension, rapidly progressive renal failure, thrombotic microangiopathy with hemolitic anemia and low platelet count: the prompt use of angiotensin-converting enzyme (ACE) inhibitors significantly increased the 1-yr survival rate from 15 to 76%. Sjogren's syndrome is an immunologic disorder characterized by progressive lymphocytic destruction of the exocrine gland, frequently resulting in symptomatic eye and mouth dryness. The interstitial lesions constitute the principal renal manifestations: interstitial infiltrates and small lymphocytes, which can be homogenous and massive. In polymyositis and dermatomyositis renal involvement is rare.

Dolei, A. (2005). "MSRV/HERV-W/syncytin and its linkage to multiple sclerosis: the usability and the hazard of a human endogenous retrovirus." J Neurovirol 11(2): 232-5.

Dib, M. (2005). "Issues for clinical drug development in neurodegenerative diseases." Drugs 65(17): 2463-79.

            Neurodegenerative diseases pose specific challenges for drug development. These diseases typically have a slow and variable clinical course, an insidious onset, and symptom expression is only observed when a significant proportion of neurons are already lost. It is important to identify vulnerability factors and other determinants of clinical course in order to be able in the future to select patient populations for clinical trials with a predictable prognosis. The neurodegenerative process itself is not amenable to direct observation and, thus, cannot be monitored in clinical trials. For this reason, surrogate biomarkers are required for use as outcome parameters. In this respect, magnetic resonance imaging has proved valuable for assessing disease activity and progression in multiple sclerosis. Rating scales are of use as outcome measures but, as these generally measure symptom severity, they are most appropriate for use in assessing symptomatic treatments. Survival has been used with success as an outcome measure in trials in amyotrophic lateral sclerosis, where disease progression is rapid. The optimal outcome measure, the sample size required and the treatment duration need to be chosen in relation to the phase of the disease. Potential new treatments can be chosen based upon new knowledge of the genetics and physiopathology of neurodegenerative diseases and, in some cases, screened in transgenic mouse models, although it should be recognised that the validity of these models in terms of treatment response has yet to be established empirically.

Diamond, A. and J. Jankovic (2005). "The effect of deep brain stimulation on quality of life in movement disorders." J Neurol Neurosurg Psychiatry 76(9): 1188-93.

            Deep brain stimulation (DBS) is a viable treatment alternative for patients with Parkinson's disease (PD), essential tremor (ET), dystonia, and cerebellar outflow tremors. When poorly controlled, these disorders have detrimental effects on the patient's health related quality of life (HRQoL). Instruments that measure HRQoL are useful tools to assess burden of disease and the impact of therapeutic interventions on activities of daily living, employment, and other functions. We systematically and critically reviewed the literature on the effects of DBS on HRQoL in PD, ET, dystonia, and cerebellar outflow tremor related to multiple sclerosis.

Deng, X. and S. Sriram (2005). "Role of microglia in multiple sclerosis." Curr Neurol Neurosci Rep 5(3): 239-44.

            Microglia are the resident macrophages of the nervous system. They serve to protect and preserve neuronal cells from pathogens and facilitate recovery from metabolic insults. In addition, they appear to play a role in the neuropathology of noninfectious inflammatory disorders of the central nervous system, especially those that are autoimmune. Presentation of neural autoantigens to autoreactive T cells by microglia and the attendant secretion of proinflammatory cytokines are thought to facilitate the inflammatory process in diseases such as multiple sclerosis. They also serve as scavengers of damaged myelin following death of oligodendrocytes and the destruction of myelin and may, therefore, promote recovery of myelin damaged by the inflammatory insult. This review examines the current controversies on the pathology of multiple sclerosis and the role played by microglia in the development of central nervous system demyelination.

Demina, T. L., N. V. Khachanova, et al. (2005). "[Use of beta-interferon in the treatment of multiple sclerosis: high-rate injectable dose therapy]." Zh Nevrol Psikhiatr Im S S Korsakova 105(5): 76-9.

Delilovic-Vranic, J. (2005). "[Multiple sclerosis therapy]." Med Arh 59(3): 191-5.

            Although still with the unclear etiology, multiple sclerosis (MS) is, according to the majority of researchers, autoimmune disease which affects people with the genetic predisposition. This is illness of the white mass of the brain and spinal cord which is causing damage to the myelin, but also to the degeneration of the axons, with the accompanying inflammatory reaction. Clinical course of the illness is characterized by wide distribution in time and space. It is more common among women than man (in some cases that ratio could be (3:1), among white than black, and it shows different geographical distribution. It is most frequent at the age from 20 to 40 years, but it is not uncommon in younger and older ages. Related to its still unknown ethiology the therapy in best case is imunomodulational or immunosuppressive, but in the majority of cases symptolmatological. After all of this question occurred: WHEN AND WHICH THERAPY WE SHOULD USE FOR THE PATIENTS?

De Stefano, N., M. L. Bartolozzi, et al. (2005). "Magnetic resonance spectroscopy as a measure of brain damage in multiple sclerosis." J Neurol Sci 233(1-2): 203-8.

            Recent MR studies have emphasised the importance of neuronal and axonal damage in multiple sclerosis. In this respect, proton MR spectroscopy (by monitoring levels of N-acetylaspartate, a putative marker of axonal integrity) has been particularly illuminating by showing indirect evidence of neurodegeneration in both lesional and non-lesional brain tissues from the earliest stages of the disease. The importance of these changes to patients' clinical disability argues for the primary role of neuronal pathology in the pathogenesis of the disease.

de Seze, J., S. Delalande, et al. (2005). "[Neurological manifestations in Sjogren syndrome]." Rev Med Interne 26(8): 624-36.

            PURPOSE: To describe clinical and physiopathological aspects of neurological involvement in neurological Sjogren syndrome (SS) and to overview biological markers and therapeutical aspects. CURRENT KNOWLEDGE AND KEY POINTS: Neurological complications during SS may occur between 8.5 and 70%. Peripheral nervous system (PNS) involvement is well none but data concerning central nervous system (CNS) symptoms have been rarely described. In the present study we detail more precisely the heterogeneity of the neurological manifestation in SS. Recently new biological of SS such as alpha-fodrin antibodies have been described but there interest remain controversial. Furthermore, therapeutical data are scarce and there is to date no consensual guidelines for the therapeutical approach. PERSPECTIVE: Recent data concerning neurological involvement in SS confirm the heterogeneity of clinical presentations that may mimic stroke or multiple sclerosis. They underline the need for new biological markers. Furthermore, multicentric, randomized trials should be assessed in order to give us some therapeutical guidelines.

De Ridder, D., D. Ost, et al. (2005). "Conservative bladder management in advanced multiple sclerosis." Mult Scler 11(6): 694-9.

            Anticholinergics and intermittent catheterization are the cornerstones of bladder management in early multiple sclerosis (MS). In advanced MS however, bladder management is based more on tradition than on evidence. Nurses seem to deal with catheter problems and chronic incontinence. Despite the abundant use of indwelling catheters, there is a lack for guidelines on catheter-induced problems. The psychosexual and social impact of bladder problems in advanced MS is often neglected. The international multidisciplinary special interest group on sexual, urological and bowel dysfunction in MS (SUBDIMS) as a special interest group of the Rehabilitation in Multiple Sclerosis (RIMS) was confronted with a high variability in practice and a lack of guidelines. A literature review was prepared during three multidisciplinary expert meetings. This review will be the basis of further initiatives to improve the urological treatment of patients with advanced MS.

de Castro, F. and A. Bribian (2005). "The molecular orchestra of the migration of oligodendrocyte precursors during development." Brain Res Brain Res Rev 49(2): 227-41.

            During development of the central nervous system (CNS), postmitotic cells (including neurons and myelin-generating cells, the oligodendrocytes) migrate from the germinal areas of the neural tube where they originate to their final destination sites. The migration of neurons during development has been extensively studied and has been the topic of detailed reviews. The migration of oligodendrocyte precursor cells (OPCs) is also an extremely complex and precise event, with a widespread migration of OPCs across many regions to colonize the entire CNS. Different mechanisms have been shown to direct the migration of OPCs, among them contact-mediated mechanisms (adhesion molecules) and long-range cues (chemotropic molecules). This review provides a detailed overview and discussion of the cellular and molecular basis of OPCs migration during development. Because it has been shown that neuronal and oligodendroglial lineages share some of these mechanisms, we briefly summarize similarities and differences between these two types of neural cells. We also summarize the changes in the normal migration of OPCs during development that would be relevant for different neurological diseases (including demyelinating diseases, such as multiple sclerosis, and glial cancers). We also examine the relevance of these migratory properties of the oligondendrocytic cell lineage for the repair of neural damage.

Dayer, J. M., N. Molnarfi, et al. (2005). "From cellular receptors to transduction-transcription pathways for cytokines: at which level should the inhibition be targeted in inflammation?" Expert Opin Biol Ther 5 Suppl 1: S83-96.

            An imbalance in cytokine homeostasis is considered to play a major part in the pathogenesis of immuno-inflammatory diseases. Since the identification and cloning of cytokines and their receptors, therapeutic approaches have been developed with the purpose of impeding the interaction between the ligand (cytokine) and its specific receptor, or interactions that involve the use of anti-inflammatory cytokines to switch off inflammation. Although some diseases have been treated successfully with cytokines or anticytokines (i.e., anti-TNF, and to a lesser extent recombinant IL-1 receptor antagonist, in rheumatoid arthritis; IFN-beta in multiple sclerosis), the fact remains that these therapies do not abrogate the concomitant use of steroids or immunosuppressive drugs, and that a significant percentage of patients do not respond to such therapies; these are important limitations. The identification of signalling pathways preferentially used in inflammatory conditions has boosted approaches that target these intracellular mechanisms. This review examines the different therapeutic approaches that may be considered for the treatment of immuno-inflammatory diseases, and discusses the advantages and disadvantages of targeting extracellular or intracellular mechanisms.

Davignon, J. and L. A. Leiter (2005). "Ongoing clinical trials of the pleiotropic effects of statins." Vasc Health Risk Manag 1(1): 29-40.

            BACKGROUND: The multiple effects (ie, pleiotropic effects of statins) have received increasing recognition and may have clinical applicability across a broad range of cardiovascular and noncardiovascular conditions. OBJECTIVE: To determine the relevance and significance of ongoing clinical trials of the pleiotropic effects of statins, focusing on nonlipid effects. METHOD: Ongoing trials were identified through personal communication, reports presented at scientific meetings (2000-2004), and queries made to AstraZeneca, Bristol-Myers Squibb Co, Merck & Co, Novartis, and Pfizer, manufacturers of the currently marketed statins. Published trials and other source material were identified through electronic searches on MEDLINE (1990-2003), abstract books, and references identified from bibliographies of pertinent articles. Eligible studies were the clinical trials of statins currently under way in which primary or secondary outcomes included the statins' nonlipid (ie, pleiotropic) effect(s). Data were extracted and trial quality was assessed by the authors. RESULTS: Of the 22 ongoing trials of the nonlipid effects of statins identified, 10 assessed inflammatory markers and plaque stabilization, 4 assessed oxidized low density lipoprotein/vascular oxidant stress, 3 assessed end-stage renal disease, 3 assessed fibrinogen/viscosity, 2 assessed endothelial function, 2 assessed acute coronary syndrome, 2 assessed aortic stenosis progression, and 1 each assessed hypertension, osteoporosis, ischemic burden, Alzheimer's disease, multiple sclerosis, and stroke (outcomes often overlapped). CONCLUSION: Given the excellent safety and tolerability of statins as a class, full exploration of their pleiotropic effects has the potential to provide additional benefits to many patients.

Darlington, C. L. (2005). "The potential role for statins in the treatment of multiple sclerosis." Curr Opin Investig Drugs 6(7): 667-71.

            In 1995, it was observed that the administration of statins to heart transplant patients resulted in fewer episodes of rejection, thus a role for statins in the treatment of inflammatory disease was suggested. To date, the results of a single, open-label trial in multiple sclerosis patients have demonstrated that treatment with one of the statins, simvastatin, reduced the number and volume of lesions, as observed using gadolinium-enhancing magnetic resonance imaging. While the results of this first study seem promising, the rationale for using a cholesterol-lowering drug in a demyelinating disease must be addressed, in addition to the potential problems that the side effects of statins may produce in multiple sclerosis patients.

Darlington, C. L. (2005). "NBI-5788 Neurocrine." Curr Opin Investig Drugs 6(7): 747-51.

            Neurocrine Biosciences is developing NBI-5788, an analog of an immunodominant epitope of myelin basic protein for the potential intravenous treatment of multiple sclerosis. By April 2005, enrollment for phase II trials was complete, with results expected early in 2006.

Dalgas, U. and E. Stenager (2005). "[Multiple sclerosis and physical training]." Ugeskr Laeger 167(14): 1495-9.

Dale, R. C. and J. A. Branson (2005). "Acute disseminated encephalomyelitis or multiple sclerosis: can the initial presentation help in establishing a correct diagnosis?" Arch Dis Child 90(6): 636-9.

            The differential diagnosis of CNS white matter disease is broad, and can be divided into vascular, metabolic, infective, or inflammatory aetiologies. Isolated inflammatory disorders of the CNS are often associated with demyelination, and the two terms (inflammatory and demyelinating) are often used in conjunction. When the disease is monophasic, the term acute disseminated encephalomyelitis (ADEM) is used. ADEM typically occurs as a post-infectious phenomenon, and by definition, must be an isolated (monophasic) episode. If a relapse occurs shortly after the ADEM presentation in association with a further infection or steroid withdrawal, the term MDEM (multiphasic disseminated encephalomyelitis) is used. When there are relapses or progressive disease, the term multiple sclerosis (MS) is used (for full recommended diagnostic criteria for multiple sclerosis refer to McDonald and colleagues).

D'Aversa, T. G., E. A. Eugenin, et al. (2005). "NeuroAIDS: contributions of the human immunodeficiency virus-1 proteins Tat and gp120 as well as CD40 to microglial activation." J Neurosci Res 81(3): 436-46.

            Microglia are the resident phagocytes of the brain and are an important source of proinflammatory mediators. Human immunodeficiency virus (HIV)-1 infects the central nervous system early in the course of disease, and it is believed that this occurs, in part, through the transmigration of HIV-1-infected cells across the blood-brain barrier. Infected cells release viral proteins, such as Tat and gp120. After microglia interact with these proteins, they become activated and secrete chemokines; up-regulate key surface receptors, such as CD40, and also activate resident cells. This review focuses on the consequences of microglial activation in NeuroAIDS, with an emphasis on chemokine production and CD40 up-regulation after interaction with tat or gp120. The importance of microglial CD40 in two other neurological diseases, Alzheimer's disease and multiple sclerosis, is also discussed.

D'Arcy, C. (2005). "Managing multiple sclerosis: working in partnership." Nurs Manag (Harrow) 12(6): 32-5.

Czlonkowska, A., A. Ciesielska, et al. (2005). "Estrogen and cytokines production - the possible cause of gender differences in neurological diseases." Curr Pharm Des 11(8): 1017-30.

            Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders. These include head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases (Parkinson's disease (PD), Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). Accumulating evidence suggests that observed differences between men and women could result from estrogen's wide range of effects within the mammalian central nervous system (CNS), with it's neuroprotective effect being one of the most important. It seems possible that neuroprotective activity of estrogen could be partially a result of it's anti-inflammatory action. It has been well established that inflammation plays an important role in the etiopathogenesis and manifestation of brain pathological changes. In this regard, an important role has been suggested for pro-inflammatory cytokines produced by activated glial cells, neurons and immune cells that invade brain tissue. Within the CNS, cytokines stimulate inflammatory processes that may impair blood-brain barrier permeability as well as promote apoptosis of neurons, oligodendrocytes and induce myelin damage. Given that estrogen may modulate cytokine expression, coupled with the fact that gender differences of cytokine production are apparent in animal models of PD and MS, suggests an important connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS patients and mice subjected to experimental autoimmune encephalomyelitis (EAE) display gender specific alterations of IFN-gamma and IL-12, variations of TNF and IL-6 were associated with PD. Also in case of more acute neurodegenerative conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was different in males and females. Given that our understanding of the role of estrogen on cytokine production and accompanying CNS pathological conditions is limited, the present reviews aims to present some of our recent findings in this area and further evaluate the evidence that may be relevant to the design of new hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.

Curis, E., I. Nicolis, et al. (2005). "Almost all about citrulline in mammals." Amino Acids 29(3): 177-205.

            Citrulline (Cit, C6H13N3O3), which is a ubiquitous amino acid in mammals, is strongly related to arginine. Citrulline metabolism in mammals is divided into two fields: free citrulline and citrullinated proteins. Free citrulline metabolism involves three key enzymes: NO synthase (NOS) and ornithine carbamoyltransferase (OCT) which produce citrulline, and argininosuccinate synthetase (ASS) that converts it into argininosuccinate. The tissue distribution of these enzymes distinguishes three "orthogonal" metabolic pathways for citrulline. Firstly, in the liver, citrulline is locally synthesized by OCT and metabolized by ASS for urea production. Secondly, in most of the tissues producing NO, citrulline is recycled into arginine via ASS to increase arginine availability for NO production. Thirdly, citrulline is synthesized in the gut from glutamine (with OCT), released into the blood and converted back into arginine in the kidneys (by ASS); in this pathway, circulating citrulline is in fact a masked form of arginine to avoid liver captation. Each of these pathways has related pathologies and, even more interestingly, citrulline could potentially be used to monitor or treat some of these pathologies. Citrulline has long been administered in the treatment of inherited urea cycle disorders, and recent studies suggest that citrulline may be used to control the production of NO. Recently, citrulline was demonstrated as a potentially useful marker of short bowel function in a wide range of pathologies. One of the most promising research directions deals with the administration of citrulline as a more efficient alternative to arginine, especially against underlying splanchnic sequestration of amino acids. Protein citrullination results from post-translational modification of arginine; that occurs mainly in keratinization-related proteins and myelins, and insufficiencies in this citrullination occur in some auto-immune diseases such as rheumatoid arthritis, psoriasis or multiple sclerosis.

Cui, J. Y. (2005). "Multiple sclerosis: an immunologic perspective." Phys Med Rehabil Clin N Am 16(2): 351-8.

            The precise cause of MS remains unknown, although immunopathologic studies provide solid evidence of participation of activated immune cells in the formation of MS lesions. Cell-mediated and antibody-mediated(humoral) immune responses are involved in the immunopathogenesis of MS. The Thl and Th2 cells, by releasing a variety of pro- or anti-inflammatory cytokines, work in opposition to balance the immune response and to determine the net effect of the inflammation. The current understanding of immunopathogenesis shapes the contemporary approach to the treatment of MS. The article also reviewed the mechanisms of action of commonly used immunotherapy agents and their impact on the immune response of patients who have MS.

Cross, A. H. and J. L. Stark (2005). "Humoral immunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis." Immunol Res 32(1-3): 85-97.

            Abnormal immunoglobulin synthesis within the central nervous system is a common finding in patients with multiple sclerosis (MS) that is often used for diagnosis. However, it is not clear whether antibodies, or the B-cells and plasma cells that make them, are critical to the pathogenesis of MS. Here we review the descriptive data that suggest a role for antibody in the pathogenesis of MS. The results of B-cell and antibody depletion studies in the animal model for MS, experimental autoimmune encephalomyelitis, are summarized, as well as early data using a chimeric monoclonal antibody to deplete B-cells in patients with MS.

Crimeen-Irwin, B., K. Scalzo, et al. (2005). "Failure of immune homeostasis -- the consequences of under and over reactivity." Curr Drug Targets Immune Endocr Metabol Disord 5(4): 413-22.

            The immune system is a tightly regulated network that is able to maintain a balance of immune homeostasis under normal physiological conditions. Normally, when challenged with foreign antigen, specific appropriate responses are initiated that are aimed at restoring homeostasis. However under particular circumstances, this balance is not maintained and immune responses either under or over react. Cancer is an example of a situation where the immune response can be inefficient or unresponsive, resulting in uncontrolled growth of the cancer cells. Conversely, when the immune response over-reacts, this can result in conditions such as autoimmunity or pathology following infection. Many drug therapies have been developed that aim to alleviate or prevent such immune disorders and restore immune homeostasis. This review highlights recent advances in immunotherapies, with an emphasis on specific examples in the treatment of cancer, autoimmune disease (multiple sclerosis) and viral infection (respiratory syncytial virus).

Crane, I. J. and J. V. Forrester (2005). "Th1 and Th2 lymphocytes in autoimmune disease." Crit Rev Immunol 25(2): 75-102.

            This review reconsiders how the Th1/Th2 paradigm can be applied to Th1-mediated autoimmune disease. Although there is evidence that autoimmune diseases such as multiple sclerosis, type 1 insulin-dependent diabetes mellitus, and posterior uveitis are Th1 mediated and that in some cases reduction of the Th1 response or a Th2 type shift may alleviate disease, many apparent exceptions are now well documented. These exceptions center around the contradictory actions of the Th1 cytokine IFN-gamma and the evidence that Th2 lymphocytes can also cause disease. Recent information on the regulation of Th1 and Th2 lymphocytes in terms of the innate immune response and by other T cells helps to clarify the reasons for some of these discrepancies and enables the Th1/Th2 concept to be accepted as an integral part of the complex interactions occurring as autoimmune disease develops.

Coyle, P. K. (2005). "Gender issues." Neurol Clin 23(1): 39-60, v-vi.

Correa, F., L. Mestre, et al. (2005). "The role of cannabinoid system on immune modulation: therapeutic implications on CNS inflammation." Mini Rev Med Chem 5(7): 671-5.

            There is a growing amount of evidence suggesting that cannabinoids may be neuroprotective in CNS inflammatory conditions. Advances in the understanding of the physiology and pharmacology of the cannabinoid system have increased the interest of cannabinoids as potential therapeutic targets. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in cells of the immune system, as well as in brain glial cells. In the present review it is summarized the effects of cannabinoids on immune reactivity and on the regulation of neuroinflammatory processes associated with brain disorders with special attention to chronic inflammatory demyelinating diseases such as multiple sclerosis.

Corey, S. (2005). "Recent developments in the therapeutic potential of cannabinoids." P R Health Sci J 24(1): 19-26.

            OBJECTIVE: To examine the recent evidence that marijuana and other cannabinoids have therapeutic potential. METHODS: Literature published since 1997 was searched using the following terms: cannabinoid, marijuana, THC, analgesia, cachexia, glaucoma, movement, multiple sclerosis, neurological, pain, Parkinson, trial, vomiting. Qualifying clinical studies were randomized, double-blind, and placebo-controlled. Selected open-label studies and surveys are also discussed. RESULTS: A total of 15 independent, qualifying clinical trials were identified, of which only three had more than 100 patients each. Two large trials found that cannabinoids were significantly better than placebo in managing spasticity in multiple sclerosis. Patients self-reported greater sense of motor improvement in multiple sclerosis than could be confirmed objectively. In smaller qualifying trials, cannabinoids produced significant objective improvement of tics in Tourette's disease, and neuropathic pain. A new, non-psychotropic cannabinoid also has analgesic activity in neuropathic pain. No significant improvement was found in levodopa-induced dyskinesia in Parkinson's Disease or post-operative pain. No difference from active placebo was found for management of cachexia in a large trial. Some immune system parameters changed in HIV-1 and multiple sclerosis patients treated with cannabinoids, but the clinical significance is unknown. Quality of life assessments were made in only three of 15 qualifying clinical trials. CONCLUSION: Cannabinoids may be useful for conditions that currently lack effective treatment, such as spasticity, tics and neuropathic pain. New delivery systems for cannabinoids and cannabis-based medicinal extracts, as well as new cannabinoid derivatives expand the options for cannabinoid therapy. More well-controlled, large clinical tests are needed, especially with active placebo.

Corcione, A., F. Aloisi, et al. (2005). "B-cell differentiation in the CNS of patients with multiple sclerosis." Autoimmun Rev 4(8): 549-54.

            Clonally expanded populations of Ig variable gene-mutated B cells are found in the central nervous system (CNS) of subjects with multiple sclerosis (MS), suggesting the occurrence of a germinal center-like reaction. Recent studies have demonstrated that the cerebrospinal fluid (CSF) of MS patients is enriched with centroblasts and B cells with a memory phenotype compared to peripheral blood. In the same individuals, antibody-secreting cells (ASC) are detected in the CSF and appear to correlate with CNS inflammation. These B-cell subsets are the output of a germinal center reaction, which is likely to occur in the CNS. Recent findings suggest that the inflamed brain can become a favorable niche for B-cell survival and proliferation and, under some circumstances, sustain the formation of ectopic lymphoid structures. Thus, B cells are likely to expand and mature inside the CNS, giving rise to ASC, which may play an effector role in the pathogenesis of MS.

Cook, S. D. (2005). "A clinician's approach to modulate disease activity in MS." Rev Neurol Dis 2(3): 117-23.

            All multiple sclerosis (MS) patients should have their treatment profile carefully evaluated as to disease control, optimal therapy, and adverse side effects at every clinical visit, with the goal of safely minimizing disease activity. There is a general consensus among clinicians that therapy should be initiated early in the course of the disease and should be continued indefinitely unless disease activity continues, intolerable side effects develop, patient transitions to a primary progressive course, or more effective and safer drugs become available. Patients for whom treatment is delayed should be seen at least every 6 months, and therapy should be initiated if new disease activity is found. Magnetic resonance imaging is the most practical laboratory test currently available for monitoring ongoing tissue injury and is useful when evaluating the efficacy of a given therapy. Four immunomodulators and 2 immunosuppressants are currently approved for the treatment of relapsing or secondary progressive forms of MS; in addition, various immunosuppressive or immunomodulating drugs have been used off-label, alone or in combination, in clinical practice. Many issues remain to be resolved in attempting to modulate disease activity in MS patients. Consequently, the art of medicine and clinical judgment become important aspects of MS patient care.

Comi, G. (2005). "Optimisation of immunomodulatory therapies." Neurol Sci 26 Suppl 1: S15-7.

Comi, G. and M. Filippi (2005). "Clinical trials in multiple sclerosis: methodological issues." Curr Opin Neurol 18(3): 245-52.

            PURPOSE OF REVIEW: The availability of partially effective immunomodulatory and immunosuppressive treatments for relapsing multiple sclerosis (MS) opens important ethical, methodological and practical issues in the design and conduct of new clinical trials in these patients. RECENT FINDINGS: The recommendation of the National Health Authorities to prioritize phase III clinical trials using placebo arm raises ethical questions. In addition, patients are reluctant to be involved in such trials. Alternative clinical trial designs will be discussed. Relapses and active lesions are accepted measures of disease activity; new/enlarging T2 lesions and/or enhancing lesions are accepted surrogate markers of disease activity in phase II clinical trials. On the contrary, there are no accepted magnetic resonance imaging (MRI) surrogate markers of disease progression and also the clinical measures to monitor the degenerative aspects of the disease are not without important limitations. New scales of impairment, disability and quality of life will be reviewed extensively. We will also focus on the value of modern and quantitative MRI techniques, which hold substantial promise as tools to estimate the extent of MS-related irreversible tissue loss. SUMMARY: The use of an active comparator in a superior clinical-trial design is becoming an attractive option for testing the efficacy of new drugs in relapsing MS. At present there are no fully reliable and sensitive clinical markers of the accumulation of irreversible tissue damage in MS. Although additional extensive application in longitudinal studies is needed, modern MRI techniques are promising tools to monitor the neurodegenerative aspects of MS.

Coman, I., G. Barbin, et al. (2005). "Axonal signals in central nervous system myelination, demyelination and remyelination." J Neurol Sci 233(1-2): 67-71.

            Axonal signals are key players in central nervous system myelination. During development, the onset of myelination depends on a balance between positive and negative axonal signals. Among negative signals are inhibitory adhesion molecules that need to be removed from the cell surface for the myelination process to proceed. Positive signals necessary to initiate myelination consist of both interactions with specific adhesion molecules and electrical activity-induced release of promyelinating factors. In multiple sclerosis, demyelination induces major modifications of axonal surface components. The disruption of these factors might participate to the failure of the myelin repair process.

Coleman, M. P., R. Adalbert, et al. (2005). "Neuroprotective strategies in MS: lessons from C57BL/Wld(S) mice." J Neurol Sci 233(1-2): 133-8.

            Valuable clues about how axons degenerate in MS can be gained from axon pathology in other disorders and experimental models. We discuss the similarities in mechanism and morphology of axon pathology in diverse circumstances revealed using mutant mice. The slow Wallerian degeneration mutation, Wld(S), delays three types of axon degeneration previously considered distinct: Wallerian degeneration of injured axons, 'dying-back' of axons in peripheral nervous system disease, and axonal spheroid pathology in gracile axonal dystrophy (gad) mice. Therefore, axon degeneration mechanisms are more uniform than previously thought and, in gad at least, axonal swelling is either related to or a consequence of Wallerian degeneration. Both axonal swelling and the accumulation of amyloid precursor protein through impaired axonal transport are common to MS, gad, and many other CNS disorders, indicating a degree of shared mechanism. YFP-H transgenic mice express YFP in a representative subset of neurons enabling unprecedented imaging of axon morphology and pathology over considerable longitudinal distances. Using this method, we have observed unbroken axons with multiple constrictions and dilatations in VEGF(delta/delta) mice, a model of amyotrophic lateral sclerosis (ALS). Similar morphologies have been described in MS, stroke, and other disorders, again suggesting a uniformity of axon degeneration mechanisms.

Cohen-Kaminsky, S. and F. Jambou (2005). "Prospects for a T-cell receptor vaccination against myasthenia gravis." Expert Rev Vaccines 4(4): 473-92.

            T-cell receptor (TCR) vaccination has been proposed as a specific therapy against autoimmune diseases. It is already used in clinical trials, which are supported by pharmaceutical companies for the treatment of multiple sclerosis, rheumatoid arthritis and psoriasis. Current vaccine developments are focusing on enhancement of immunogenicity as well as selecting the best route of immunization and adjuvant to favor the therapeutic effect. In the meantime, academic laboratories are tackling the regulatory mechanisms involved in the beneficial effect of the vaccines to further understand how to control the therapeutic tool. Indeed, several examples in experimental models of autoimmune diseases indicate that any specific therapy may rely on a delicate balance between the pathogenic and regulatory mechanisms. This review presents a critical analysis of the potential of such therapy in myasthenia gravis, a prototype antibody-mediated disease. Indeed, a specific pathogenic T-cell target population and a TCR-specific regulatory mechanism mediated by anti-TCR antibodies and involved in protection from the disease have recently been identified in a patient subgroup. The presence of spontaneous anti-TCR antibodies directed against the pathogenic T-cells that may be boosted by a TCR vaccine provides a rationale for such therapy in myasthenia gravis. The development of this vaccine may well benefit from experience gained in the other autoimmune diseases in which clinical trials are ongoing.

Christensen, T. (2005). "Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses." Rev Med Virol 15(3): 179-211.

            The hypothesis that human endogenous retroviruses (HERVs) play a role in autoimmune diseases is subject to increasing attention. HERVs represent both putative susceptibility genes and putative pathogenic viruses in the immune-mediated neurological disease multiple sclerosis (MS). Gammaretroviral HERV sequences are found in reverse transcriptase-positive virions produced by cultured mononuclear cells from MS patients, and they have been isolated from MS samples of plasma, serum and CSF, and characterised to some extent at the nucleotide, protein/enzyme, virion and immunogenic level.Two types of sequences, HERV-H and HERV-W, have been reported. No known HERV-H or HERV-W copy contains complete ORFs in all prerequisite genes, although several copies have coding potential, and several such sequences are specifically activated in MS, apparently resulting in the production of complete, competent virions. Increased antibody reactivity to specific Gammaretroviral HERV epitopes is found in MS serum and CSF, and cell-mediated immune responses have also been reported. Further, HERV-encoded proteins can have neuropathogenic effects.The activating factor(s) in the process resulting in protein or virion production may be members of the Herpesviridae. Several herpes viruses, such as HSV-1, VZV, EBV and HHV-6, have been associated with MS pathogenesis, and retroviruses and herpes viruses have complex interactions. The current understanding of HERVs, and specifically the investigations of HERV activation and expression in MS are the major subjects of this review, which also proposes to synergise the herpes and HERV findings, and presents several possible pathogenic mechanisms for HERVs in MS.

Chitnis, T., J. Imitola, et al. (2005). "Therapeutic strategies to prevent neurodegeneration and promote regeneration in multiple sclerosis." Curr Drug Targets Immune Endocr Metabol Disord 5(1): 11-26.

            Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease of the central nervous system (CNS), with lesions predominantly occurring in the CNS white matter. The current treatment for MS relies on therapies that primarily target the peripheral immune response. However, it is clear that these strategies alone are insufficient for treating the chronic progressive disability that is the ultimate outcome of the disease. Axonal degeneration may be the primary determinant of fixed neurological deficits in MS. Here, we will discuss the contribution of axonal damage to MS pathogenesis, and potential cellular and molecular targets in the prevention of neurodegeneration. In addition, we will discuss potential molecular approaches to promote repair of CNS components in multiple sclerosis.

Chihara, J. (2005). "[Immunoglobulin super family (ICAM, VCAM, NCAM)]." Nippon Rinsho 63 Suppl 8: 139-41.

Chiba, K. (2005). "FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors." Pharmacol Ther 108(3): 308-19.

            FTY720 is the first of a new immunomodulator class: sphingosine 1-phosphate (S1P) receptor agonist. In 1994, an immunosuppressive natural product, ISP-I (myriocin), was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp. The chemical modification of ISP-I yielded a new compound, FTY720, which has more potent immunosuppressive activity and less toxicity than ISP-I does. FTY720 has been shown to be highly effective in experimental allotransplantation models and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood T- and B-cells at doses that show immunosuppressive activity in these models. Reportedly, FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinase 2 in vivo, and FTY720-P acts as a potent agonist at S1P receptors. Recently, it has been suggested that FTY720-P internalizes S1P1 on lymphocytes and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is likely that the reduction of circulating lymphocytes by FTY720 is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus. Because FTY720 displays a novel mechanism of action that has not been observed with other immunosuppressive agents and shows a synergism with cyclosporin A (CsA) and tacrolimus, it is presumed that FTY720 provides a useful tool for the prevention of transplant rejection and a new therapeutic approach for autoimmune diseases including multiple sclerosis and rheumatoid arthritis.

Chen, L. and L. K. Gordon (2005). "Ocular manifestations of multiple sclerosis." Curr Opin Ophthalmol 16(5): 315-20.

            PURPOSE OF REVIEW: Multiple sclerosis is an autoimmune demyelinating disorder of the nervous system that is commonly manifested by visual system involvement and that may initially present with ophthalmologic symptoms. This paper reviews recent findings regarding the ocular manifestations in multiple sclerosis. RECENT FINDINGS: Manifestations of multiple sclerosis in the eye include both the afferent and efferent visual pathways. Optic neuritis, the most common ocular manifestation of multiple sclerosis, may be the initial clinical disease manifestation. Recent long-term follow-up data show that most patients with demyelinating optic neuritis have an excellent prognosis for recovery of central visual acuity. Evidence is emerging, however, for significant and broad reduction in both contrast sensitivity and color perception in multiple sclerosis patients despite near-normal visual acuities. Ocular motor deficits in multiple sclerosis include internuclear ophthalmoplegia and nystagmus, resulting in diplopia, oscillopsia, blurred visual, loss of stereopsis, and reading fatigue. Multiple sclerosis also may be associated with ocular inflammatory diseases, in particular pars planitis and retinal periphlebitis. SUMMARY: Ocular findings may be initial manifestations of multiple sclerosis and may predict additional demyelinating events. Recognizing these syndromes and signs will help clinicians to properly evaluate the patient, formulate an appropriate differential diagnosis, be able to discuss the prognosis with the patient, and help develop an effective therapeutic plan.

Chabas, D. (2005). "[Osteopontin, a multi-faceted molecule]." Med Sci (Paris) 21(10): 832-8.

            Osteopontin (OPN) was initially isolated from bovine bone cortex, as a complex syalilated phospho-glyco-protein of around 60 kDa, with many postranslational modifications. It has been long considered a structural bone protein linking bone cells to the bone extracellular matrix (osteo : bone, pontin : bridge). It has been cloned for the first time in 1986. Since then, it was established that it is part of a protein family called SIBLINGs, which genes share common expression in bone and tooth, and encode among others a RGD motif. OPN is an intracellular as well as secreted protein, which binds to multiple organic or mineral ligands, like the integrin receptor alphaVbeta3, CD44, factor H and hydroxyapatite, depending on its final configuration (phosphorylation state). Pleiotropic functions of osteopontin have been demonstrated, and the osteopontin knock out phenotype in mice gave some new insight on the implication of the molecule in vivo. Osteopontin inhibits mineralization in bone and urine. Besides, it is a strong chemoattractive and proinflammatory molecule, implicated in tumors, like breast or prostate cancers, and in the defense against various infectious agents like tuberculosis, listeria or herpes. More recently, its key implication in TH1 mediated autoimmune diseases like multiple sclerosis and its animal model experimental autoimmune encephalomyelitis has been demonstrated. Osteopontin is a valuable therapeutic target in the animal model, and a biological tool correlating with clinical disease activity in humans. Structural, functional and pathological aspects of osteopontin are reviewed, as well as the osteopontin deficient phenotype in mouse.

Cerovski, B., T. Vidovic, et al. (2005). "Multiple sclerosis and neuro-ophthalmologic manifestations." Coll Antropol 29 Suppl 1: 153-8.

            The authors report clinical features of ocular manifestations in patients with multiple sclerosis (MS), those that affect the visual sensory system and those that affect the ocular motor system. Disturbances of visual sensory function may precede, manifest coincidentally or follow the neurologic manifestations. Visual disturbances are common in MS and often a result of acute demyelinating optic neuropathy. Careful examination of MS patients, who have never suffered optic neuritis, may also reveal asymptomatic visual loss. Asymptomatic visual loss seems to be a universal feature of MS. Patients with multiple sclerosis may develop disorders of fixation, ocular motility and ocular alignment. Disorders of ocular motor system are frequently the initial sign of multiple sclerosis and occur as its presenting sign weeks, month, or years before other neurologic symptoms and signs develop.

Cartier, L., O. Hartley, et al. (2005). "Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases." Brain Res Brain Res Rev 48(1): 16-42.

            Chemokines were originally described as chemotactic cytokines involved in leukocyte trafficking. Research over the last decade, however, has shown that chemokine receptors are not restricted to leukocytes. In the brain, chemokine receptors are not only found in microglia (a brain macrophage), but also in astrocytes, oligodendrocytes and neurons. In this review, we describe the spatial and cellular distribution of chemokine receptors in the brain, distinguishing between constitutively and inducibly expressed receptors. We then discuss possible physiological functions, including neuronal migration, cell proliferation and synaptic activity. Evidence is emerging that chemokine receptors are also involved in neuronal death and hence neurodegenerative diseases. Chemokines may induce neuronal death either indirectly (e.g. through activation of microglia killing mechanisms) or directly through activation of neuronal chemokine receptors. Disease processes in which chemokines and their receptors are likely to be involved include multiple sclerosis (MS), Alzheimer's disease (AD), HIV-associated dementia (HAD) and cerebral ischemic disease. The study of chemokines and their receptors in the central nervous system (CNS) is not only relevant for the understanding of brain physiology and pathophysiology, but may also lead to the development of targeted treatments for neurodegenerative diseases.

Carrick, C., K. A. Collins, et al. (2005). "Sudden death due to asphyxia by esophageal polyp: two case reports and review of asphyxial deaths." Am J Forensic Med Pathol 26(3): 275-81.

            Asphyxia, not an uncommon cause of sudden death, may result from numerous etiologies. Foreign-body aspiration and strangulation are 2 extrinsic causes. Airway obstruction may also be caused by laryngeal edema, asthma, infection, or anaphylaxis. Chronic causes of asphyxia include musculoskeletal diseases (eg, muscular dystrophy, amyotrophic lateral sclerosis), neurologic disorders (eg, myasthenia gravis, multiple sclerosis), respiratory disease (eg, emphysema, chronic bronchitis), or tumors. The manner of death in cases of asphyxiation may be natural, accidental, homicide, or suicide. For the death investigator, determining the cause and manner of death can often be quite challenging.We report here 2 cases of an esophageal fibrovascular polyp causing sudden asphyxial death, review of the literature, and discussion of other differential diagnoses in the case of asphyxial death.

Carrera, E. and J. Bogousslavsky (2005). "[Neurology]." Rev Med Suisse 1(1): 44-50.

            In this paper, we present the last studies with impact on daily practice and up-to-date guidelines which can lead to a rational approach of the patient with neurological disease. In cerebrovascular diseases, several strategies are discussed to increase the number of patients who can benefit from thrombolysis, whereas in secondary prevention, the association of clopidogrel and aspirin versus clopidogrel has not shown to be beneficial. In Parkinson's disease, the inclusion criteria and benefits of deep brain stimulation are more precisely known. New genetic targets have been found in the field of myopathies, which open new therapeutic perspectives.

Caramanos, Z., S. Narayanan, et al. (2005). "1H-MRS quantification of tNA and tCr in patients with multiple sclerosis: a meta-analytic review." Brain 128(Pt 11): 2483-506.

            Meta-analysis was performed on the results of 75 comparisons from the 30 peer-reviewed publications that used proton magnetic resonance spectroscopy (1H-MRS) or spectroscopic imaging to (i) quantify the mean concentrations of total creatine (tCr, found in neurons, astrocytes and oligodendrocytes), and/or total N-acetyl groups (tNA, found only in neurons), in the lesional and/or non-lesional white matter (WM) and/or the grey matter (GM) of patients with multiple sclerosis (MS) and (ii) compare these values with those in the homologous tissues of normal controls (NC). For mean [tNA] values, there was (i) a large-effect-sized overall decrease in patients' lesional WM relative to NC WM (25 comparisons), (ii) a medium-effect-sized overall decrease in patients' non-lesional WM relative to NC WM (36 comparisons) and (iii) a medium-effect-sized overall decrease in patients' GM relative to NC GM (14 comparisons). Patients' mean [tNA] values were sometimes statistically normal but were never statistically increased. For mean [tCr] values, there was (i) no statistically significant overall change in the patients' lesional WM relative to NC WM (24 comparisons), although statistically significant increases and decreases were sometimes found, (ii) a medium-effect-sized overall increase in patients' non-lesional WM relative to NC WM (33 comparisons) and (iii) no statistically significant overall change in patients' GM relative to NC GM (12 comparisons), although a significant decrease was found in one comparison. Of 41 comparisons with statistically significant changes, 38 combined in a way that would probably result in decreased mean [tNA]/[tCr] ratios such that (i) 66% had statistically decreased mean [tNA] and statistically unchanged mean [tCr] values, (ii) 13% had statistically decreased mean [tNA] and statistically increased mean [tCr] values and (iii) 21% had statistically unchanged mean [tNA] values and statistically increased mean [tCr] values. Of the 25 comparisons that came from studies that also analysed [tNA]/[tCr] ratios, the direction of change in mean [tNA] values and mean [tNA]/[tCr] ratios was concordant in 84%. In comparisons that quantified both [tNA] and [tCr], there was a similar amount of variability in both measures in each of the different tissue types studied, both in patients and NCs. Together, these results suggest that within-voxel tNA/tCr ratios can be interpreted as valid and accurate surrogate measures of 'cerebral tissue integrity'-with decreased tNA/tCr ratios indicating some combination of neuroaxonal disturbance, oligodendroglial disturbance, and astrocytic proliferation. These results also suggest that, although within-voxel tNA/tCr ratios are not perfect indicators of [tNA] content, they do represent a practical compromise to acquiring surrogate measures of within-voxel neuroaxonal integrity.

Campbell, A. K., J. P. Waud, et al. (2005). "The molecular basis of lactose intolerance." Sci Prog 88(Pt 3): 157-202.

            A staggering 4000 million people cannot digest lactose, the sugar in milk, properly. All mammals, apart from white Northern Europeans and few tribes in Africa and Asia, lose most of their lactase, the enzyme that cleaves lactose into galactose and glucose, after weaning. Lactose intolerance causes gut and a range of systemic symptoms, though the threshold to lactose varies considerably between ethnic groups and individuals within a group. The molecular basis of inherited hypolactasia has yet to be identified, though two polymorphisms in the introns of a helicase upstream from the lactase gene correlate closely with hypolactasia, and thus lactose intolerance. The symptoms of lactose intolerance are caused by gases and toxins produced by anaerobic bacteria in the large intestine. Bacterial toxins may play a key role in several other diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis and some cancers. The problem of lactose intolerance has been exacerbated because of the addition of products containing lactose to various foods and drinks without being on the label. Lactose intolerance fits exactly the illness that Charles Darwin suffered from for over 40 years, and yet was never diagnosed. Darwin missed something else--the key to our own evolution--the Rubicon some 300 million years ago that produced lactose and lactase in sufficient amounts to be susceptible to natural selection.

Calza, L., M. Fernandez, et al. (2005). "Thyroid hormone and remyelination in adult central nervous system: a lesson from an inflammatory-demyelinating disease." Brain Res Brain Res Rev 48(2): 339-46.

            Re-myelination in the adult CNS has been demonstrated in different experimental models of demyelinating diseases. However, there is no clear evidence that re-myelination is effective in multiple sclerosis (MS), the most diffuse demyelinating disease. Moreover, chronic disabilities in MS are believed to be due to remyelination failure and consequent neuron damage and degeneration. Due to the presence of numerous oligodendrocyte precursors inside demyelination plaques, reasons for remyelination failure are unknown. In this paper, we reviewed data from embryonic development and in vitro studies supporting the primary role of thyroid hormone in oligodendrocyte maturation. We also reviewed personal data on the possibility of promoting myelination in chronic experimental allergic encephalomyelitis (EAE), a widely used experimental model of MS, by recruiting progenitors and channeling them into oligodendroglial lineage through the administration of thyroid hormone.

Calender, A., S. Dupasquier, et al. (2005). "[Genetics of endocrine tumours]." Ann Pathol 25(6): 463-86.

            Major advances have been made in the understanding of the genetic mechanisms underlying endocrine tumorigenesis, through the study of several syndromes of genetic predisposition and the identification of the genes involved. The syndrome of type 1 multiple endocrine neoplasia (MEN-1) is one of the best known; this autosomal dominant hereditary syndrome predisposes to the development of endocrine tumors of the pituitary, the parathyroids, the foregut and the adrenals. The responsible gene, known as MEN-1, encodes an original protein, menin, involved in several major cellular functions, such as the control of cell proliferation and differentiation. Type 2 multiple endocrine neoplasia (MEN-2) is an autosomal dominant hereditary syndrome associated with the development of medullary carcinomas of the thyroid, pheochromocytomas and hyperparathyroidism; the corresponding gene, RET, encodes a transmembrane receptor with tyrosine kinase activity. Endocrine tumors are also associated with non Hippel-Lindau disease and with phacomatoses, such as type 1 neurofibromatosis and tuberous sclerosis. Finally, isolated familial syndromes of endocrine tumors have been described: isolated familial hyperparathyroidism type II (HRPT2), associated with alterations in a gene coding for an original protein, parafibromin, or isolated familial syndromes of pheochromocytomas and paragangliomas (PRG) associated with mutations in the genes SDHB, SDHC or SDHD, which encode succinate-dehydrogenase subunits. The understanding of the genetic mechanisms underlying these syndromes of predisposition is essential for the diagnosis and management of these patients and their family; it also gives insight on the molecular mechanisms of endocrine tumorigenesis.

Calabrese, V., R. Lodi, et al. (2005). "Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia." J Neurol Sci 233(1-2): 145-62.

            There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.

Cabrera-Gomez, J. A., N. Echazabal-Santana, et al. (2005). "Hereditary Melkersson-Rosenthal syndrome and multiple sclerosis." Mult Scler 11(3): 364-6.

            The revision of MEDLINE from 1966 to 2003 did not report any association between multiple sclerosis (MS) and Melkersson-Rosenthal syndrome (MRS). This is a case report of a 51-year-old woman, with history of four recurrent Bell's palsies. In 1999 she developed a right facial paralysis due to a supranuclear pyramidal lesion with right monoparesis. The family history showed five relatives with recurrent Bell's paralysis and plicata tongue. Physical examination: right Bell's paralysis, left supranuclear facial paralysis, furrowed tongue, right hemiparesis with pallor of the optic disks. Brain magnetic resonance imaging (MRI) demonstrated the typical lesions of MS and CSF oligoclonal bands. This is the first observation of a patient with hereditary MRS and MS. The link between both diseases is discussed.

Burt, R. K., B. Cohen, et al. (2005). "Hematopoietic stem cell transplantation for multiple sclerosis." Arch Neurol 62(6): 860-4.

Burrows, G. G. (2005). "Systemic immunomodulation of autoimmune disease using MHC-derived recombinant TCR ligands." Curr Drug Targets Inflamm Allergy 4(2): 185-93.

            Human autoimmune disease involves local activation of antigen-specific CD4(+) T cells that produce inflammatory Th1 cytokines leading to the further recruitment and activation of lymphocytes and monocytes, resulting ultimately in the destruction of target tissue. Antigen presenting cells (APCs) initiate activation of CD4(+) T cells in a multistep process that minimally involves co-ligation of the TCR and CD4 by the MHC class II/peptide complex and costimulation through additional T cell surface molecules such as CD28. Disruption of this highly orchestrated series of events can result in the direct modulation of CD4(+) T cell behavior. The interaction between MHC and TCR holds unique promise as a focal point for therapeutic intervention in the pathology of CD4(+) T cell-mediated diseases, and MHC class II-derived Recombinant TCR Ligands ("RTLs") have emerged as a new class of therapeutics with potent clinical efficacy in a diverse set of animal models for multiple sclerosis. Here I review the systemic effect that RTL therapy has on the intact immune system and present an overview of a molecular mechanism by which RTL therapy could induce these systemic changes.

Burks, J. (2005). "Interferon-beta1b for multiple sclerosis." Expert Rev Neurother 5(2): 153-64.

            Interferon-beta1b (Betaseron/Betaferon) was the first approved therapy for relapsing-remitting multiple sclerosis. The US Food and Drug Administration has expanded the indication to include relapsing forms of multiple sclerosis which encompasses secondary-progressive multiple sclerosis if relapses are present. In one scientifically sound head-to-head comparison (Independent Comparison of Interferon trial), interferon-beta1b was shown to be clinically superior to low-dose interferon-beta1a (Avonex). Current studies are underway to compare it with a double dosage of interferon-beta1b [corrected] as well as glatiramer acetate. Neutralizing antibodies are more likely to occur with interferon-beta1b, but their clinical significance has shown conflicting and confusing results making the utility of measuring neutralizing antibodies uncertain. Up to 12 years of follow-up data suggest that the drug remains effective on T2 magnetic resonance imaging burden of disease in those who stay on therapy. Initially, the major problem with interferon-beta1b was a lack of tolerability due to high incidents of skin reactions and influenza-like side effects. Patient adherence has improved dramatically with the introduction of autoinjectors and protocol changes including initial dose escalation, prophylactic ibuprofen or acetaminophen, evening administration of drug and an attentive nurse support system. Interferon-beta1b remains a first-line treatment for relapsing-remitting multiple sclerosis and relapsing forms of secondary-progressive multiple sclerosis based on robust efficacy data and a long-term safety profile.

Burks, J. S. (2005). "A practical approach to immunomodulatory therapy for multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 449-66, ix.

            This article provides a current overview of the definition and pathogenesis of the disease, the different types of MS, a new diagnostic criteria, the rationale for early therapy, a review of the approved MS therapies, the strategies to evaluate ongoing treatment efficacy,the management of suboptimal treatment responders, and the prospects for future therapies. The article focuses on relapsing remitting MS because most of the therapeutic data deal with this type of MS. The role of mitoxantrone as a "rescue therapy" for suboptimal responders to IMTs is discussed.

Bureeva, S., J. Andia-Pravdivy, et al. (2005). "Drug design using the example of the complement system inhibitors' development." Drug Discov Today 10(22): 1535-42.

            Undesired activation of the complement system, a part of the immune system, is a major pathogenic factor contributing to various diseases, such as ischemia-reperfusion injury, sepsis, asthma, allergic reactions, rheumatoid arthritis, Alzheimer's disease, myasthenia, multiple sclerosis and others. The history of the development of complement system inhibitors, preventing its destructive action on the body, represents the evolution of the main methods of drug design. This review illustrates the main approaches of drug design, ranging from screening and modification of natural products to structure-based ligand design, on the basis of complement inhibitors' creation. The current status of the field of complement inhibitors is also discussed.

Burdett, S. K. (2005). "A tangled web: don't miss multiple sclerosis." Adv Nurse Pract 13(11): 51-3, 56.

Buckle, G. J. (2005). "Functional magnetic resonance imaging and multiple sclerosis: the evidence for neuronal plasticity." J Neuroimaging 15(4 Suppl): 82S-93S.

            Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has emerged as a powerful technique to visualize the localization of cerebral activity in both healthy and diseased brains. BOLD fMRI has been used to assess brain function in a variety of diseases, including multiple sclerosis (MS), and has shown that altered patterns of connectivity are used to recruit more widespread eloquent brain networks engaged in tasks relating to motor activity, sensory and cognitive function, and memory when compared to normal controls. This review will examine the evidence that functional reorganization is a consequence of demyelination and tissue loss in MS that may serve as an adaptive response to limit clinical disability. It remains unclear whether cerebral plasticity is a marker of permanent functional restructuring or a short-term compensatory response to injury. Long-term longitudinal studies that correlate fMRI activity with other MRI markers of disease burden and activity, as well as with clinical measures of disease activity and progression, are badly needed to determine fMRI's relevance to clinical practice and its place as a surrogate outcome measure in MS.

Bruck, W. and C. Stadelmann (2005). "The spectrum of multiple sclerosis: new lessons from pathology." Curr Opin Neurol 18(3): 221-4.

            PURPOSE OF REVIEW: This review will focus on recent developments in multiple sclerosis (MS) pathology with particular emphasis on the patterns and mediators of lesion formation in MS, the mechanisms of oligodendrocyte and axon damage and the magnetic resonance imaging-pathological correlation of MS lesions. RECENT STUDIES: The inflammatory cascade in the MS plaque has been characterized in more detail, and other factors such as hypoxia-like injury or excitotoxicity, besides immunological effector mechanisms, have been found to play a role in MS pathogenesis. Cortical demyelination and mechanisms of neuroaxonal damage are discussed in detail. The radiological correlate of basic histopathologic findings is being approached with quantitative methods. Similar quantitative approaches are used in MS-gene expression studies that compare patterns of gene expression in different lesion areas. SUMMARY: These studies will lead to better understanding of the pathogenesis of MS lesions and will hopefully identify new therapeutic targets to modulate inflammation, support remyelination and protect axons and neurons in MS.

Bruck, W. (2005). "Clinical implications of neuropathological findings in multiple sclerosis." J Neurol 252 Suppl 3: iii10-iii14.

            Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The pathological hallmarks of MS lesions in the brain and spinal cord are inflammation, demyelination, axon loss and gliosis. Recent studies revealed heterogeneity in the mechanisms leading to the formation of lesions, which include typical autoimmune patterns of demyelination involving T cells and macrophages, as well as antibody/complement as characteristic effector mechanisms. Additionally, oligodendrocyte dystrophy patterns of demyelination, with disturbances of oligodendroglial myelin protein expression and oligodendrocyte apoptosis, were observed. Treatment of MS has advanced dramatically in recent years, with the introduction of beta-interferons, glatiramer acetate and mitoxantrone. However, not all MS patients respond well to treatment with these drugs, and this may be a consequence of disease heterogeneity. Although immunomodulatory therapy has been clinically proven to be effective in patients with relapsing-remitting MS, studies in secondary-progressive MS patients have only demonstrated a positive therapeutic effect with interferon beta-1b. The pathology and pathogenesis of lesions suggest the need for a subtype-specific treatment, which may be possible when observations from pathology can be acted upon in the living MS patient. In addition to myelin and oligodendrocyte damage, the loss of axons represents another key element of MS lesions that lacks a therapeutic approach. However, axon-protective therapy is yet to be established and the mechanisms and effector molecules involved in axonal degeneration are still to be defined.

Bruck, W. (2005). "Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis." J Neurol 252 Suppl 5: v10-5.

            Multiple sclerosis is a disease of the central nervous system that destroys myelin, oligodendrocytes, neurons and axons. Historically considered to be caused by an autoimmune process mainly affecting myelin and oligodendrocytes in the white matter, recent data provide evidence that a generalized, diffuse neurodegenerative process plays an important role in the pathogenesis of MS. There is a high density of axonal transections in active demyelinating lesions, but also persistent low-level axonal damage in inactive plaques and diffuse axonal and neuronal loss throughout the nervous system. Initial axonal injury appears to be closely related to inflammation, but is not restricted to the lesions themselves. Damage may be propagated throughout the nervous system by anterograde Wallerian, retrograde or transynaptic degeneration. Cumulative tissue loss in the grey and white matter, especially of axons, is important and probably the principal determinant of accumulation of irreversible neurological disability and of conversion to a progressive disease course.

Bruck, W. (2005). "The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage." J Neurol 252 Suppl 5: v3-9.

            Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system manifested morphologically by inflammation, demyelination, axonal loss and gliosis. The inflammatory lesions are characterized by massive infiltration by a heterogeneous population of cellular and soluble mediators of the immune system, including T cells, B cells, macrophages and mi croglia, as well as a broad range of cytokines, chemokines, antibodies, complement and other toxic substances. The appearance of such lesions is associated with clinical relapses. Recent detailed immunopathological studies of early, acute lesions revealed profound heterogeneity in the patterns of demyelination and the factors of the immune system involved. During remission, resolution of inflammation is the main factor which leads to clinical improvement of patients. However, the immune system can play a beneficial role at this stage, promoting remyelination perhaps by production of growth factors such as BDNF. In contrast, the progressive irreversible neurological deficit in multiple sclerosis is associated with neurodegenerative processes resulting in axonal and neuronal loss. The mechanisms behind damage to axons in multiple sclerosis lesions are poorly understood. However, the close proximity of areas with prominent axonal loss and areas containing inflammatory infiltrates (e. g., T cells, macrophages) suggest that axonal damage is closely associated with inflammation. Different soluble or cellular mediators of the immune response have been shown to damage axons in experimental systems, and these may be responsible for neurodegeneration in human disease.

Brown, T. R. and G. H. Kraft (2005). "Exercise and rehabilitation for individuals with multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 513-55.

            It is the coexistence of physical and cognitive impairments, together with emotional and social issues in a disease with an uncertain course, that makes MS rehabilitation unique and challenging. Inpatient rehabilitation improves functional independence but has only limited success improving the level of neurologic impairment. Benefits are usually not long lasting. Severely disabled people derive equal or more benefit than those who are less disabled, but cognitive problems and ataxia tend to be refractory. There is now good evidence that exercise can improve fitness and function for those with mild MS and helps to maintain function for those with moderate to severe disability. Therapy can be performed over 6 to 15 weeks in outpatient or home-based settings or as a weekly day program lasting several months.Several different forms of exercise have been investigated. For most individuals, aerobic exercise that incorporates a degree of balance training and socialization is recommended. Time constraints, access, impairment level, personal preferences, motivations, and funding sources influence the prescription for exercise and other components of rehabilitation. Just as immunomodulatory drugs must be taken on a continual basis and be adjusted as the disease progresses, so should rehabilitation be viewed as an ongoing process to maintain and restore maximum function and QOL.

Brown, R. F., C. C. Tennant, et al. (2005). "A review of stress-relapse interactions in multiple sclerosis: important features and stress-mediating and -moderating variables." Mult Scler 11(4): 477-84.

            Studies do not provide a consensus opinion of the relationship between stress and relapse in relapsing-remitting multiple sclerosis (RRMS). Few studies have defined the critical features of these stressful situations, or examined the role of stress-mediating and -moderating variables. Available evidence indicates that the relationship between life stress and relapse is complex, and is likely to depend on factors such as stressor chronicity, frequency, severity and type, and individual patient characteristics such as depression, health locus of control and coping strategy use. Little is known about how these factors, individually or in combination, are related to MS disease activity. Viral infections are also likely to precipitate relapse in MS, and significant life-stress may further enhance this relationship. The nature and strength of these interrelationships have strong clinical implications. MS patients are particularly vulnerable to a deteriorating cycle of stressful life events, illness episodes and disability. Timely multidisciplinary care interventions aimed at both minimizing psychological distress and physical symptoms may halt this downward reciprocal cycle. Little is known of the pathogenesis of these putative stress-induced changes in disease activity, and almost all stressor studies suffer from some biases or limitations.

Brown, R. C., A. H. Lockwood, et al. (2005). "Neurodegenerative diseases: an overview of environmental risk factors." Environ Health Perspect 113(9): 1250-6.

            The population of the United States is aging, and an ever-increasing number of Americans are afflicted with neurodegenerative diseases. Because the pathogenesis of many of these diseases remains unknown, we must consider that environmental factors may play a causal role. This review provides an overview of the epidemiologic evidence for environmental etiologies for neurodegenerative diseases such as Alzheimer disease, Parkinson disease, parkinsonian syndromes (multiple system atrophy and progressive supranuclear palsy), and amyotrophic lateral sclerosis. Epidemiologic evidence for an association between environmental agents' exposure and neurodegenerative diseases is not conclusive. However, there are indications that there may be causal links, and the need for more research is obvious.

Brahic, M., J. F. Bureau, et al. (2005). "The genetics of the persistent infection and demyelinating disease caused by Theiler's virus." Annu Rev Microbiol 59: 279-98.

            Theiler's virus causes a persistent and demyelinating infection of the central nervous system of the mouse, which is one of the best animal models to study multiple sclerosis. This review focuses on the mechanism of persistence. The virus infects neurons for a few weeks and then shifts to white matter, where it persists in glial cells and macrophages. Oligodendrocytes are crucial host cells, as shown by the resistance to persistent infection of mice bearing myelin mutations. Two viral proteins, L and L*, contribute to persistence by interfering with host defenses. L, a small zinc-finger protein, restricts the production of interferon. L*, a unique example of a picornaviral protein translated from an overlapping open reading frame, facilitates the infection of macrophages. Susceptibility to persistent infection, which varies among inbred mouse strains, is multigenic. H2 class I genes have a major effect on susceptibility. Among several non-H2 susceptibility loci, Tmevp3 appears to regulate the expression of important cytokines.

Bowen, J. (2005). "Diagnosing multiple sclerosis and its imitators." Phys Med Rehabil Clin N Am 16(2): 359-81.

            The diagnosis of MS requires central nervous system symptoms that are disseminated in time and space, and that have no better explanation.Dissemination in time and space may be demonstrated clinically or by MRI imaging. The differential diagnosis is broad, and requires the exclusion of several diseases that are described in the text. Following the new guidelines for the diagnosis of MS allows an early and accurate diagnosis of the disease.

Borhani Haghighi, A., R. Pourmand, et al. (2005). "Neuro-Behcet disease. A review." Neurologist 11(2): 80-9.

            BACKGROUND: Behcet disease is a vasculitis with mucocutaneous, ocular, arthritic, vascular, and other manifestations. Its neurologic manifestations (neuro-Behcet disease) are relatively rare, but they must be thoroughly investigated due to their grave prognosis. REVIEW SUMMARY: The frequency of neurologic manifestations, more common in male Behcet patients, is between 5% and 30%. Both the central and peripheral nervous systems can be involved. Central nervous system manifestations can be divided into 2 main groups: (1) parenchymal involvement, which includes brainstem involvement, hemispheric manifestations, spinal cord lesions, and meningoencephalitic presentations; (2) nonparenchymal involvement, including dural sinus thrombosis, arterial occlusion, and/or aneurysms. Peripheral neuropathy and myopathy are relatively rare. Cerebrospinal fluid analysis reveals pleocytosis and elevated protein levels. Magnetic resonance imaging is the investigation of choice which often reveals iso-/hypointense lesions in T1-weighted images and hyperintense lesions in T2-weighted images, mostly in the mesodiencephalic junction, cerebellar peduncles, and other parts of the brainstem. Corticosteroids and adjuvant immunosuppressive therapy are used for parenchymal manifestations, and corticosteroids and anticoagulants are used for treatment of dural sinus thrombosis. CONCLUSION: Neuro-Behcet disease must be considered in the differential diagnosis of stroke in young adults, multiple sclerosis, movement disorders, intracranial hypertension, intracranial sinovenous occlusive diseases, and other neurologic syndromes.

Bonfioli, A. A., F. M. Damico, et al. (2005). "Intermediate uveitis." Semin Ophthalmol 20(3): 147-54.

            Intermediate uveitis is an intraocular inflammation involving the anterior vitreous, peripheral retina and pars plana. It usually affects patients from 5 to 30 years old, without gender or racial preferences. The etiology is unknown but there are several associated diseases: multiple sclerosis, idiopathic optic neuritis, autoimmune corneal endotheliopathy, sarcoidosis, thyroid diseases and inflammatory bowel diseases. Symptoms are blurry vision, floaters and distortion of central vision. The syndrome is bilateral in 80% of the patients and chronic with periods of exacerbation and remission. Clinical presentation includes: mild to moderate anterior chamber inflammation, thin keratic precipitates in the inferior portion of the cornea, autoimmune endotheliopathy, vitreitis, vasculitis in the peripheral retina, intravitreal "snowballs," retinal "snowbanking," optic neuritis and cystoid macular edema. Cataract and glaucoma are frequent complications. Treatment of intermediate uveitis is based on periocular and oral corticosteroids. Cryotherapy or laser photocoagulation of the peripheral retina are options in patients with snowbanking when there is an insufficient response to periocular or systemic corticosteroids. Imunosuppression may also be used when other therapies fail, and Cyclosporin A is the first drug of choice. Pars plana vitrectomy is indicated in patients with chronic significant inflammation, non-responsive cystoid macular edema, non-clearing vitreous hemorrhage, tractional retinal detachment and epiretinal membranes. The long-term prognosis of intermediate uveitis is usually good, particularly with strict control of inflammation and with proper management of complications. Patients can often maintain a vision of 20/50 or better.

Bombardier, C. H., R. Wadhwani, et al. (2005). "Health promotion in people with multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 557-70.

            Chronic diseases like MS present unique challenges and opportunities for patients and the medical care system. Patients are challenged because they are under tremendous pressure to actively engage themselves in multiple prevention, treatment, and health maintenance behaviors, often before they feel ready. Health care providers are challenged because health-promotion activities require more time, counseling skills, and organizational resources than traditional, acute medical care. Patients, clinicians, and researchers face the challenge of determining which health-promotion activities are not only supported by the evidence but also appropriate for a given patient.New models of health promotion are being developed that integrate self-help and professional help. These approaches have been applied in other chronic diseases and should be adapted and studied among people with MS.

Boiko, A. N. and E. I. Gusev (2005). "[Differential diagnosis of multiple sclerosis and some systemic connective tissue diseases with vasculitis]." Zh Nevrol Psikhiatr Im S S Korsakova 105(5): 67-71.

Bien, C. G. and J. Bauer (2005). "T-cells in human encephalitis." Neuromolecular Med 7(3): 243-53.

            Encephalitis literally means inflammation of the brain. In general, this inflammation can result from a viral or bacterial infection in the brain itself or alternatively from a secondary autoimmune reaction against an infection or a tumor in the rest of the body. Besides this, encephalitis is present in (believed autoimmune) diseases with unknown etiology, such as multiple sclerosis or Rasmussen encephalitis (RE). This article summarizes the existing data on the role of T-cells in the pathogenesis of three types of human encephalitis: RE, paraneoplastic encephalomyelitis, and virus encephalitis. In all of them, T-cells play a major role in disease pathogenesis, mainly mediated by major histocompatiblity complex class I-restricted CD8+ T-lymphocytes.

Bhidayasiri, R. (2005). "Differential diagnosis of common tremor syndromes." Postgrad Med J 81(962): 756-62.

            Tremor is one of the most common involuntary movement disorders seen in clinical practice. In addition to the detailed history, the differential diagnosis is mainly clinical based on the distinction at rest, postural and intention, activation condition, frequency, and topographical distribution. The causes of tremor are heterogeneous and it can present alone (for example, essential tremor) or as a part of a neurological syndrome (for example, multiple sclerosis). Essential tremor and the tremor of Parkinson's disease are the most common tremors encountered in clinical practice. This article focuses on a practical approach to these different forms of tremor and how to distinguish them clinically. Evidence supporting various strategies used in the differentiation is then presented, followed by a review of formal guidelines or recommendations when they exist.

Bethoux, F. (2005). "[Evaluation and multiple sclerosis]." Ann Readapt Med Phys 48(6): 369-75.

            We conducted a review of existing assessment tools that can be useful to physical medicine and rehabilitation professionals involved in the management of patients with multiple sclerosis (MS). Most generic tools traditionally used in neurorehabilitation, such as gait tests, the functional independence measure, or the SF-36, can be applied to MS, but few have been tested on large patient samples. Disease-specific scales often seem more pertinent and sensitive to change, and their qualities and limitations are better known through clinical trials of disease-modifying therapies.

Bennett, K. A. (2005). "Pregnancy and multiple sclerosis." Clin Obstet Gynecol 48(1): 38-47.

Ben-Hur, T., O. Einstein, et al. (2005). "Stem cell therapy for myelin diseases." Curr Drug Targets 6(1): 3-19.

            Advances in cell biology have encouraged the hope that stem cell-based therapy can be used to heal central nervous system (CNS) diseases. Here, we will review the potential application of neural cell transplantation for the treatment of multiple sclerosis (MS) and other demyelinating disorders, mention some problematic issues that still face this therapeutic approach, and describe novel noninvasive methods for in vivo tracking of transplanted cells.

Bellet, D. and V. Dangles-Marie (2005). "[Humanized antibodies as therapeutics]." Med Sci (Paris) 21(12): 1054-62.

            Since 1997, nine humanized antibodies received the approval of the FDA to be used as drugs for the treatment of various diseases including transplant rejections, metastatic breast and colon cancers, leukaemia, non-Hodgkin lymphomas, allergic conditions or multiple sclerosis. This review describes techniques used to engineer these antibodies and presents the recent evolutions of these techniques : SDRs grafting or << abbreviated >> CDRs grafting. Based on the illustrative examples of several antibodies, Mylotarg, Herceptin or Xolair, the therapeutic effectiveness of humanized antibodies are underlined and, with the example of Tysabri, the sometimes dramatic adverse effects associated with their clinical use is stressed. In a second part, this review presents some future and realistic avenues to improve the effectiveness of the humanized antibodies, to decrease their immunogenicity and to reduce their cost.

Beeton, C. and K. G. Chandy (2005). "Potassium channels, memory T cells, and multiple sclerosis." Neuroscientist 11(6): 550-62.

            Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system characterized by demyelination and axonal damage that result in disabling neurological deficits. Here the authors explain the rationale for the use of inhibitors of the Kv1.3 K+ channel in immune cells as a therapy for multiple sclerosis and other autoimmune disorders.

Bechtold, D. A. and K. J. Smith (2005). "Sodium-mediated axonal degeneration in inflammatory demyelinating disease." J Neurol Sci 233(1-2): 27-35.

            Axonal degeneration is a major cause of permanent neurological deficit in multiple sclerosis (MS). The mechanisms responsible for the degeneration remain unclear, but evidence suggests that a failure to maintain axonal sodium ion homeostasis may be a key step that underlies at least some of the degeneration. Sodium ions can accumulate within axons due to a series of events, including impulse activity and exposure to inflammatory factors such as nitric oxide. Recent findings have demonstrated that partial blockade of sodium channels can protect axons from nitric oxide-mediated degeneration in vitro, and from the effects of neuroinflammatory disease in vivo. This review describes some of the reasons why sodium ions might be expected to accumulate within axons in MS, and recent observations suggesting that it is possible to protect axons from degeneration in neuroinflammatory disease by partial sodium channel blockade.

Bebo, B. F., Jr. and G. S. Dveksler (2005). "Evidence that pregnancy specific glycoproteins regulate T-Cell function and inflammatory autoimmune disease during pregnancy." Curr Drug Targets Inflamm Allergy 4(2): 231-7.

            The capacity of the pregnancy state to regulate T-cell function is well documented. A consequence of this regulation is that many T-cell mediated autoimmune disorders, including multiple sclerosis (MS) are suppressed during pregnancy. The suppression of MS during pregnancy is more potent than the currently available treatments for this disease. Thus, the study of immunoregulatory factors of pregnancy could potentially result in the discovery of novel MS treatments. The regulation of T-cell function during pregnancy is likely the result of significant hormonal changes and may well involve immunoregulatory proteins derived from the placenta. Pregnancy specific glycoproteins (PSGs) are the most abundant placentally derived glycoproteins in the maternal serum. The levels of PSGs are highest during the third trimester of pregnancy, a time marked by the most profound suppression of MS disease attacks. Recent studies by our laboratories, and others, suggest that PSGs regulate T-cell function. We propose this regulation occurs by two distinct, but complementary mechanisms. PSGs may regulate T-cell function by (1) directly signaling tetraspanins present on the cell surface and by (2) regulating T-cell function indirectly through signaling of tetraspanins expressed by macrophages and dendritic cells. In this report, we will review evidence implicating PSGs as important immunoregulatory proteins and discuss our recent findings regarding the mechanisms by which PSGs regulate T-cell function.

Barger, S. W., A. M. Moerman, et al. (2005). "Molecular mechanisms of cytokine-induced neuroprotection: NFkappaB and neuroplasticity." Curr Pharm Des 11(8): 985-98.

            Since the first attempts to understand the mechanisms of learning, memory, development, and other instances of neuroplasticity, gene expression has been an attractive explanation for the persistence of such processes. It has been hypothesized that changes in the levels of expression of a gene, or a coordinated set of genes, would be necessary for dramatic structural changes like the growth of new neurites. And more subtle biochemical changes at existing synapses might also result from an alteration in the array of gene products being manufactured in the relevant cells. However, a great deal of what is classified as neuroplasticity is dependent on primary changes in electrophysiological activity or other conditions at synapses. Therefore, a seminal question to those interested in the molecular underpinnings of neuroplasticity is that of signal transduction: How do changes in synaptic activity get communicated to the nucleus? To many who learn about the regulation of the transcription factor NFkappaB with this question in mind, its utility seems clear. Furthermore, NFkappaB is an important signaling factor for cytokines that appear to participate in several pathological conditions (e.g., Parkinson's disease, multiple sclerosis, and depression), so understanding its mechanisms of action and its relationship to other elements of cytokine signaling may be fundamental to determining the role of the inflammatory system in psychiatric and neurodegenerative conditions. For these reasons, NFkappaB has garnered considerable attention in various aspects of neuroplasticity, from long-term potentiation to the most dramatic forms of plasticity: cell birth and death. In a few cases, elegant experimental design has resulted in convincing evidence for the involvement of NFkappaB in specific phenomena. However, the complexity of this transcription factor-including confusion over what exactly is meant by "NFkappaB"-has led to some misleading conclusions, as well. This chapter highlights some of the potential red herrings to be encountered in the study of NFkappaB and will summarize the data and interpretations in which some degree of confidence can be placed. The final answers will depend on the application of models and tools only now in development.

Baranzini, S. E. and J. R. Oksenberg (2005). "Genomics and new targets for multiple sclerosis." Pharmacogenomics 6(2): 151-61.

            Compelling epidemiological and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how MS individuals respond to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and environmental influences. Equally significant, it is likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others.

Bar-Or, A. (2005). "Immunology of multiple sclerosis." Neurol Clin 23(1): 149-75, vii.

Banwell, B. (2005). "Treatment of children and adolescents with multiple sclerosis." Expert Rev Neurother 5(3): 391-401.

            The onset of multiple sclerosis is being increasingly recognized in children and adolescents. There are now approved immunomodulatory therapies for adults with multiple sclerosis. Treatment early in the disease course appears to have a greater impact on disease outcome, an issue of particular importance for children who face decades of multiple sclerosis disease activity. This review summarizes the multiple sclerosis therapies currently available, efficacy data available from studies of these medications in adults and limited information on the use of these medications in children. Future directions in multiple sclerosis therapeutics and specific issues relating to pediatric multiple sclerosis are discussed.

Bakshi, R., A. Minagar, et al. (2005). "Imaging of multiple sclerosis: role in neurotherapeutics." NeuroRx 2(2): 277-303.

            Magnetic resonance imaging (MRI) plays an ever-expanding role in the evaluation of multiple sclerosis (MS). This includes its sensitivity for the diagnosis of the disease and its role in identifying patients at high risk for conversion to MS after a first presentation with selected clinically isolated syndromes. In addition, MRI is a key tool in providing primary therapeutic outcome measures for phase I/II trials and secondary outcome measures in phase III trials. The utility of MRI stems from its sensitivity to longitudinal changes including those in overt lesions and, with advanced MRI techniques, in areas affected by diffuse occult disease (the so-called normal-appearing brain tissue). However, all current MRI methodology suffers from limited specificity for the underlying histopathology. Conventional MRI techniques, including lesion detection and measurement of atrophy from T1- or T2-weighted images, have been the mainstay for monitoring disease activity in clinical trials, in which the use of gadolinium with T1-weighted images adds additional sensitivity and specificity for areas of acute inflammation. Advanced imaging methods including magnetization transfer, fluid attenuated inversion recovery, diffusion, magnetic resonance spectroscopy, functional MRI, and nuclear imaging techniques have added to our understanding of the pathogenesis of MS and may provide methods to monitor therapies more sensitively in the future. However, these advanced methods are limited by their cost, availability, complexity, and lack of validation. In this article, we review the role of conventional and advanced imaging techniques with an emphasis on neurotherapeutics.

Bakshi, R. (2005). "Magnetic resonance imaging advances in multiple sclerosis." J Neuroimaging 15(4 Suppl): 5S-9S.

            Magnetic resonance imaging (MRI) has become a core component of clinical management and scientific research in multiple sclerosis (MS), providing essential information about tissue structure and function. MRI is now the most important laboratory diagnostic and longitudinal monitoring technology. A number of conventional MRI techniques, which include T2-weighted, T1-weighted, and gadolinium-enhanced imaging, are used to identify overt lesions and quantify tissue atrophy. MRI is highly sensitive in detecting brain and spinal cord involvement in MS and can visualize multifocal lesions, occult disease, and macroscopic atrophy. Advanced MRI techniques, such as magnetization transfer imaging, spectroscopy, diffusion-weighted imaging, and functional MRI, have added to our understanding of the pathogenesis of the disease. The precise role of these newer imaging approaches continues to be defined. In this supplement to the Journal of Neuroimaging, the authors review the role of conventional and advanced MRI techniques in detecting tissue changes in MS, diagnosing and monitoring patients, and charting the progression of disease in new and established patients.

Bakshi, R., V. S. Dandamudi, et al. (2005). "Measurement of brain and spinal cord atrophy by magnetic resonance imaging as a tool to monitor multiple sclerosis." J Neuroimaging 15(4 Suppl): 30S-45S.

            Evaluation of brain and spinal cord atrophy by magnetic resonance imaging (MRI) has become an increasingly important component of understanding the multiple sclerosis (MS) disease process. These destructive aspects of the disease develop early in the disease course. A growing body of data links brain and spinal cord atrophy to clinical impairment more closely than can be linked with conventional measures of overt lesions. Thus, irreversible tissue damage may be a key factor leading to disease progression. In this review, the authors present the proposed mechanisms leading to central nervous system (CNS) atrophy. They describe the available MRI-based techniques to measure regional and global atrophy of the brain and spinal cord. They compare the rate of atrophy among MS phenotypes and summarize the emerging data linking atrophy to neurological and neuropsychological impairment. Finally, they discuss the effect of disease-modifying immunotherapies on the rate of CNS atrophy in patients with MS. Future research to clarify the etiology and pathophysiology of brain and spinal cord atrophy should provide new targets for therapeutic development.

Bach, J. F. (2005). "Infections and autoimmune diseases." J Autoimmun 25 Suppl: 74-80.

            The high percentage of disease-discordant pairs of monozygotic twins demonstrates the central role of environmental factors in the etiology of autoimmune diseases. Efforts were first focussed on the search for triggering factors. The study of animal models has clearly shown that infections may trigger autoimmune diseases, as in the case of Coxsackie B4 virus in type I diabetes and the encephalomyocarditis virus in autoimmune myositis, two models in which viruses are thought to act by increasing immunogenicity of autoantigens secondary to local inflammation. The induction of a Guillain-Barre syndrome in rabbits after immunization with a peptide derived from Campylobacter jejuni is explained by mimicry between C. jejuni antigens and peripheral nerve axonal antigens. Other models involve chemical modification of autoantigens, as in the case of iodine-induced autoimmune thyroiditis. These mechanisms have so far only limited clinical counterparts (rheumatic fever, Guillain-Barre syndrome and drug-induced lupus or myasthenia gravis) but one may assume that unknown viruses may be at the origin of a number of chronic autoimmune diseases, such as type I diabetes and multiple sclerosis) as illustrated by the convergent data incriminating IFN-alpha in the pathophysiology of type I diabetes and systemic lupus erythematosus. Perhaps the difficulties met in identifying the etiologic viruses are due to the long lag time between the initial causal infection and onset of clinical disease. More surprisingly, infections may also protect from autoimmune diseases. Western countries are being confronted with a disturbing increase in the incidence of most immune disorders, including autoimmune and allergic diseases, inflammatory bowel diseases, and some lymphocyte malignancies. Converging epidemiological evidence indicates that this increase is linked to improvement of the socio-economic level of these countries, posing the question of the causal relationship and more precisely the nature of the link. Epidemiological and clinical data support the hygiene hypothesis according to which the decrease of infections observed over the last three decades is the main cause of the incessant increase in immune disorders. The hypothesis does not exclude an etiological role for specific pathogens in a given immune disorder as might notably be the case in inflammatory bowel diseases. Even in this setting, infections could still have a non-specific protective role. Independently of the need for confirmation by epidemiological prospective studies, the hygiene hypothesis still poses numerous questions concerning the nature of protective infectious agents, the timing of their involvement with regard to the natural history of immune diseases and, most importantly, the mechanisms of protection. Four orders of mechanisms are being explored. Antigenic competition is the first hypothesis (immune responses against pathogens compete with autoimmune and allergic responses). This is probably an important mechanism but its modalities are still elusive in spite of considerable experimental data. Its discussion in the context of homeostatic regulation of lymphocyte pools has shed new light on this hypothesis with possible competition for self MHC peptide recognition and interleukin-7. Another hypothesis deals with immunoregulation. Infectious agents stimulate a large variety of regulatory cells (Th2, CD25+, Tr1, NKT, ...) whose effects extend to other specificities than those which triggered their differentiation (bystander suppression). Infectious agents may also intervene through components which are not recognized as antigens but bind to specific receptors on cells of the immune system. Major attention has recently been drawn to Toll receptors (expressed on macrophages and possibly on regulatory T cells) and TIM proteins present on Th cells, which may express the function of the virus receptor (as in the case of the Hepatitis A virus and Tim-1). Experimental data will be presented to support each of these hypotheses. In any event, the final proof of principle will be derived from therapeutic trials where the immune disorders in question will be prevented or better cured by products derived from protective infectious agents. Numerous experimental data are already available in several models. Preliminary results have also been reported in atopic dermatitis using bacterial extracts and probiotics.

Ayerbe, I. and M. Negrevergne (2005). "[Vertigo and pathology of the cerebellospinal system]." Rev Laryngol Otol Rhinol (Bord) 126(4): 227-33.

            Central vertigo is most often expressed by a feeling of dizziness, non or badly systematized, but it can also appear, more seldom, like an isolated acute vertigo or associated to other neurological signs. A precise clinical exam can lead to evidence essential clinical informations (significant ataxia, neurological signs, gaze nystagmus, pursuit anomaly,...). Almost all acute lesions of central vestibular pathways, as for the peripheral ones, lead to a harmonious vestibular syndrome. The vascular lesion of the vertebro-basilar territory and multiple sclerosis are two main causes to it. The pseudo-labyrinthine forms are essentially described in occlusion infarcts of the AICA and PICA, but a hematoma can lead to the same picture; the diagnostic of multi- or monosymptomatic forms with a peripheral lesion is often very difficult, the classical classification of the central and peripheral vestibular syndromes has become obsolete and should be abandoned.

Atkins, H. and M. Freedman (2005). "Immunoablative therapy as a treatment aggressive multiple sclerosis." Neurol Clin 23(1): 273-300, ix.

Asadi-Lari, M. and D. Gray (2005). "Health needs assessment tools: progress and potential." Int J Technol Assess Health Care 21(3): 288-97.

            OBJECTIVES: Health needs has attracted the interest of policy-makers, health economists, and health professionals as modern health services try to satisfy individual and population health needs to optimize resource utilization. Health needs can be assessed by administering various types of survey or interview-based instruments. If health needs are to be satisfied in changing health agendas in developed and developing countries, it is essential to employ valid and reliable tools. Despite the importance of needs assessment, no comprehensive review of tools is currently available. We carried out a literature search to define and categorize existing health needs assessment tools. METHODS: We reviewed medical and social search engines for items containing specific health needs-related words to identify needs tools across a range of specialties. Papers were reviewed in terms of design, subject matter, psychometric features, and method of administration method. RESULTS: Thirty-one employed in 52 studies including cancer, mental health, palliative care, multiple sclerosis, and cardiovascular disease tools were identified. CONCLUSIONS: This report summarizes available health needs instruments in a range of diseases to assist researchers in accessing health needs resources more easily and to encourage further research in this field.

Artlett, C. M. (2005). "Immunology of systemic sclerosis." Front Biosci 10: 1707-19.

            Systemic sclerosis (scleroderma; SSc) is an autoimmune disorder of unknown etiology characterized by severe and progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immunological abnormalities. Clinically, systemic sclerosis is very heterogeneous, ranging from mild limited forms of skin sclerosis (LcSSc) with minimal internal organ involvement to severe skin to multiple internal organ fibrosis and extensive skin fibrosis (DcSSc). Mortality and morbidity in systemic sclerosis is very high and are directly related to the extent of the fibrotic and microvascular alterations. The interactions between blood vessels, fibroblast activity, and immunological processes play an important role in the pathogenesis of SSc.

Arnold, A. C. (2005). "Evolving management of optic neuritis and multiple sclerosis." Am J Ophthalmol 139(6): 1101-8.

            PURPOSE: To review the relation of optic neuritis to multiple sclerosis (MS) and the indications, modalities, and results of therapy for optic neuritis, for both visual and general neurologic function. DESIGN: Literature review and author's experience. METHODS: Analysis of both laboratory and clinical evidence supporting the use of corticosteroids, immunomodulation agents, and other modalities in the treatment of optic neuritis and MS. RESULTS: Although treatment of optic neuritis with corticosteroids may hasten visual recovery to a minor degree, it has no long-term beneficial effect on visual outcome. Optic neuritis is frequently the initial manifestation of multiple sclerosis. The risk of later development of clinically definite MS (CDMS) correlates with white matter demyelinative lesions on magnetic resonance imaging (MRI). The role of corticosteroid therapy alone in reducing the risk of subsequent MS is unclear, but recent studies suggest that the combination of immunomodulation agents (IMAs) and corticosteroids significantly reduces the later development of MS. Current research indicates that, contrary to previous doctrine, axonal damage is an early finding in MS. CONCLUSIONS: The risk of MS after optic neuritis may be predicted. The use of corticosteroids and IMAs, particularly in those at substantial risk, reduces the frequency and severity of developing CDMS. Earlier, more aggressive therapy in optic neuritis may be proven to reduce permanent axonal injury and progressive disability in MS.

Arnold, D. L. (2005). "Changes observed in multiple sclerosis using magnetic resonance imaging reflect a focal pathology distributed along axonal pathways." J Neurol 252 Suppl 5: v25-9.

            Multiple sclerosis has long been recognized as a multifocal inflammatory demyelinating disease of the central nervous system. The fact that patients with multiple sclerosis can develop a secondary progressive phase of their disease which is resistant to anti-inflammatory therapies, together with the fact that brain atrophy can develop in patients with a relatively low volume of white matter lesions, has led to suggestions that multiple sclerosis may be a degenerative disease. However, primary degenerative disorders are not usually associated with recurrent episodes of inflammatory demyelination. Support for neurodegeneration in MS being associated with focal lesions comes from topographical mapping of the spatial relationship of axonal injury and tissue loss to lesions using advanced image analysis methods.

Arnold, D. L. and J. Chen (2005). "Measuring injury and repair of myelin and neurons in multiple sclerosis." Ernst Schering Res Found Workshop(53): 173-86.

            Neuroprotection in MS needs to be considered in the context of several pathological processes: limitation of acute inflammatory injury to myelin and axons, remyelination, survival of demyelinated axons, and limitation of more diffuse, nonlesional pathology that affects myelin and axons. Advanced MRI techniques are capable of reporting on all of these different pathological features of MS and will be an important aspect of the assessment of neuroprotection strategies in MS, when these become available.

Arnason, B. G. (2005). "Long-term experience with interferon beta-1b (Betaferon)in multiple sclerosis." J Neurol 252 Suppl 3: iii28-iii33.

            The interferon beta-1b (IFNbeta-1b, Betaferon/Betaseron) molecule was cloned some 20 years ago. In a pilot dose-finding trial involving 30 multiple sclerosis (MS) patients, the 10 MS patients receiving 250 microg (8 MIU) IFNbeta-1b every other day at 6 months showed a reduced attack frequency relative to 6 patients receiving placebo. Based on these extremely preliminary results a Phase III placebo-controlled trial was undertaken. Treatment with IFNbeta-1b was shown to reduce attack frequency and severity and to markedly reduce magnetic resonance imaging-(MRI) measured activity and disease burden. IFNbeta-1b therapy was subsequently shown to reduce MRI activity within 2 weeks of starting treatment. The benefits of treatment with IFNbeta-1b observed in the original pivotal study are maintained in the longer term, with consistent treatment effects seen after 5 years. IFNbeta-1b has subsequently been shown to reduce accumulation of disability in MS patients with early active secondary progressive disease, to increase cerebral metabolism, and to improve cognitive performance.IFNbeta-1b therapy is generally well tolerated. Classical systemic side effects related to all beta interferons can effectively be managed by dose escalation, and the use of an autoinjector minimises injection site reactions.About one-third of MS patients receiving IFNbeta-1b develop anti-interferon antibodies, typically within the first year of therapy. These antibodies have variable titres that fall with time and ultimately disappear in most patients. The clinical consequences of the presence of antibodies are presently unclear and inconsistent-some patients without antibodies respond poorly to treatment, whereas others with high-titre antibodies respond well to treatment. It is possible that immune complexes formed when anti-interferon antibodies encounter IFNbeta may enhance some of the immunomodulatory actions of the drug by improving CD8 cell-mediated suppressor function. Until the clinical relevance of antibodies is better understood, treatment decisions should be based on clinical grounds only.

Aranyi, Z. (2005). "[Transcranial magnetic stimulation: physiology and applications]." Ideggyogy Sz 58(11-12): 417-24.

            Transcranial magnetic stimulation (TMS) is a relatively new technique that allows painless activation of cortical motor neurons. In the clinical setting, TMS is primarily used for the investigation of the corticospinal tract in various neurological diseases, being especially useful in the detection of subclinical dysfunction. In addition to the motor cortex, TMS can be applied to examine other structures inaccessible to electrical stimulation, such as the canalicular portion of the facial nerve. In healthy individuals, TMS can be utilized to monitor excitability changes of the motor system in various situations and muscles, providing valuable information to the understanding of the physiology of motor control. Furthermore, TMS can be used to explore interhemispheric connections as well as intracortical inhibitory and excitatory processes both in health and disease. Finally, with the help of TMS cortical maps of the representation areas of muscles can be constructed, giving insight to both short and long-term cortical plasticity and to the reorganisation of the motor cortex following damage to the brain or acquisition of new motor skills.

Antonelli, G., F. Bagnato, et al. (2005). "Considerations on the development of serum antibodies to interferon-beta." New Microbiol 28(3): 183-92.

            The phenomenon of antibodies to interferon (IFN) beta in patients with multiple sclerosis has attracted the attention of numerous research groups over the years, and has been examined from various different points of view. In this review we describe and discuss some of the aspects that we believe to be most worthy of consideration. The main considerations are as follows: There is a lack of substantial information on the biological/immunological phenomenon of neutralising antibodies in vivo development. Nevertheless, sufficient experimental data are available to provide a rationale for monitoring the presence of anti-IFN antibodies in patients treated with IFN beta; A standardised quantitative assay to detect antibody to IFNs must be agreed. Only when results can be compared, both in terms of the qualitative presence and quantitative measurement of antibodies, will it be possible to monitor fully the ability of antibodies to cause a relapse during treatment; Although there is increasing evidence to indicate that the development of antibodies to IFN beta may be associated with a failure of the beneficial effects of the therapy, the use of the seropositivity for neutralising antibodies to IFN beta as the only surrogate marker for clinical and therapeutic decision-making is questionable.

Amor, S., P. A. Smith, et al. (2005). "Biozzi mice: of mice and human neurological diseases." J Neuroimmunol 165(1-2): 1-10.

            In 1972 Guido Biozzi selectively bred mice to study the immunopathological mechanisms underlying polygenic diseases. One line, the Biozzi antibody high (AB/H) mouse (now designated the ABH strain) was later found to be highly susceptible to many experimentally induced diseases such as autoimmune encephalomyelitis, autoimmune neuritis, autoimmune uveitis, as well as virus-induced demyelination and has thus been a key mouse strain to study human inflammatory neurological diseases. In this paper we discuss the background of the Biozzi ABH mouse and review how studies with these mice have shed light on the pathogenic mechanisms operating in chronic neurological disease.

Allen, S. D., S. V. Rawale, et al. (2005). "Therapeutic peptidomimetic strategies for autoimmune diseases: costimulation blockade." J Pept Res 65(6): 591-604.

            Cognate interactions between immune effector cells and antigen-presenting cells (APCs) govern immune responses. Specific signals occur between the T-cell receptor peptide and APCs and nonspecific signals between pairs of costimulatory molecules. Costimulation signals are required for full T-cell activation and are assumed to regulate T-cell responses as well as other aspects of the immune system. As new discoveries are made, it is becoming clear how important these costimulation interactions are for immune responses. Costimulation requirements for T-cell regulation have been extensively studied as a way to control many autoimmune diseases and downregulate inflammatory reactions. The CD28:B7 and the CD40:CD40L families of molecules are considered to be critical costimulatory molecules and have been studied extensively. Blocking the interaction between these molecules results in a state of immune unresponsiveness termed 'anergy'. Several different strategies for blockade of these interactions are explored including monoclonal antibodies (mAbs), Fab fragments, chimeric, and/or fusion proteins. We developed novel, immune-specific approaches that interfere with these interactions. Using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis mediated by central nervous system (CNS)-specific T-cells, we developed a multi-targeted approach that utilizes peptides for blockade of costimulatory molecules. We designed blocking peptide mimics that retain the functional binding area of the parent protein while reducing the overall size and are thus capable of blocking signal transduction. In this paper, we review the role of costimulatory molecules in autoimmune diseases, two of the most well-studied costimulatory pathways (CD28/CTLA-4:B7 and CD40:CD40L), and the advantages of peptidomimetic approaches. We present data showing the ability of peptide mimics of costimulatory molecules to suppress autoimmune disease and propose a mechanism for disease suppression.

Alisauskiene, M., A. Truffert, et al. (2005). "Transcranial magnetic stimulation in clinical practice." Medicina (Kaunas) 41(10): 813-24.

            Transcranial magnetic stimulation allows a non-invasive and painless stimulation of the human brain and cranial nerves. The method is in use since 1985. Transcranial magnetic stimulation can use single stimuli, pairs of stimuli separated by different intervals (to the same or to several brain areas), or trains of repetitive stimuli at various frequencies. Single stimuli give rise to motor evoked potentials that have clinical use and serve diagnostic and prognostic purposes. Repetitive transcranial magnetic stimulation can modify excitability of cerebral cortex. Repetitive transcranial magnetic stimulation has opened a new field of investigation of the neural circuitry, and is developing into a therapeutic tool. This general review considers basic principles of transcranial magnetic stimulation, discusses methodological aspects and techniques, and analyses their utility in clinical practice.

Agresti, C., M. E. Meomartini, et al. (2005). "ATP regulates oligodendrocyte progenitor migration, proliferation, and differentiation: involvement of metabotropic P2 receptors." Brain Res Brain Res Rev 48(2): 157-65.

            Extracellular nucleotides act as potent signaling molecules in the neuron-glia and glia-glia communication, via the activation of specific ligand-gated P2X and G-protein-coupled metabotropic P2Y receptors. Most of the data available about the effects of P2 receptor activation in the CNS concern astrocytes, microglia, and neurons. To gain insights into the role of purinergic receptors in oligodendrocyte development, we characterized the expression and functional activity of P2 receptors in rat oligodendrocyte progenitors (OPs) and investigated the effects of ATP and its breakdown products on their functions. We describe here that rat OPs express different types of P2 receptors and that nucleotide-induced Ca(2+) raises in these progenitor cells are mainly due to the activation of P2X(7) ionotropic and ADP-sensitive P2Y(1) metabotropic receptors. We also show that ATP and ADP stimulate OP migration, inhibit the mitogenic response of OPs to PDGF and promote oligodendrocyte differentiation. The pharmacological profile of the nucleotide-induced effects demonstrates the important regulatory role of P2Y(1) receptor signaling in OP functions. These findings suggest that ATP, which is released in high amounts under inflammatory conditions and following cell death, might regulate remyelination processes in inflammatory demyelinating diseases of the CNS, like multiple sclerosis.

Achiron, A., Y. Barak, et al. (2005). "Cancer incidence in multiple sclerosis and effects of immunomodulatory treatments." Breast Cancer Res Treat 89(3): 265-70.

            Multiple sclerosis (MS) has been linked to reduced rates of cancer prior to the era of immunomodulating treatments. We assessed the incidence of cancer in a cohort of 1338 MS patients and evaluated the effect of exposure to immunomodulatory treatment. Cancer incidence in the MS population was compared with the expected age- and gender-matched incidence rates in the Israeli population for the period 1960-2003. Time-dependant Cox model analysis was used to estimate hazard ratios for glatiramer acetate, beta-interferons (1a and 1-b) and intravenous immunoglobulins (IVIg). Among 892 female MS patients, 15 (1.7%) developed breast cancer, and 31 (3.5%) developed cancers of any type. Seventeen of 446 (3.8%) male MS patients developed cancer. The standardized incidence ratios (SIRs) computed until the time of first immunomodulatory treatment were 0.60 (95% CI, 0.38-0.92, p = 0.02) for all female cancer, and 1.11 (95% CI, 0.64-1.91) for all male cancer. Time-dependent covariate analyses for female breast cancer yielded a relative risk for glatiramer acetate of 3.10 (95% CI, 0.86-11.1) and 0.52 (95% CI, 0.07-4.05) for beta-interferons. For IVIg, the analyses were uninformative. Our findings indicate that cancer incidence is significantly lower in female MS patients than in the general population. Female MS patients treated with glatiramer acetate showed an elevated rate of breast cancer and all MS patients treated with beta-interferons showed an elevated risk of non-breast cancers though not statistically significant (p = 0.122 and 0.072, respectively). Further study is needed to assess possible associations between long-term exposure to the novel immunomodulatory treatments in MS and rate of cancer.

Achiron, A., S. Miron, et al. (2005). "Does the flap of a butterfly's wings in Brazil set off a tornado in Texas?--The JC Virus Story in multiple sclerosis." Isr Med Assoc J 7(5): 283-5.

Achiron, A. and S. Miron (2005). "Intravenous immunoglobulin and multiple sclerosis." Clin Rev Allergy Immunol 29(3): 247-54.

            Intravenous immunoglobulin (IVIg) has been used as an immunomodulatory therapy for the treatment of multiple sclerosis (MS). In the current review, we summarize the up-to-date data related to IVIg clinical trials in MS, and the suggested mechanisms of action by which IVIg modulates the relevant immunological pathways impaired in MS.

Aboussouan, L. S. (2005). "Respiratory disorders in neurologic diseases." Cleve Clin J Med 72(6): 511-20.

            Various neurologic diseases such as multiple sclerosis and Parkinson disease can cause pulmonary complications. Pulmonary disorders often manifest late in a neuromuscular disease, but occasionally a respiratory problem may be the first sign. Often the first signs are sleep disturbances and nocturnal desaturation. Although the diseases are diverse, common principles apply in their management.

Aboul-Enein, F. and H. Lassmann (2005). "Mitochondrial damage and histotoxic hypoxia: a pathway of tissue injury in inflammatory brain disease?" Acta Neuropathol (Berl) 109(1): 49-55.

            The immunological mechanisms leading to tissue damage in inflammatory brain diseases are heterogeneous and complex. They may involve direct cytotoxicity of T lymphocytes, specific antibodies and activated effector cells, such as macrophages and microglia. Here we describe that in certain inflammatory brain lesions a pattern of tissue injury is present, which closely reflects that found in hypoxic conditions of the central nervous system. Certain inflammatory mediators, in particular reactive oxygen and nitrogen species, are able to mediate mitochondrial dysfunction, and we suggest that these inflammatory mediators, when excessively liberated, can result in a state of histotoxic hypoxia. This mechanism may play a major role in multiple sclerosis, not only explaining the lesions formed in a subtype of patients with acute and relapsing course, but also being involved in the formation of diffuse "neurodegenerative" lesions in chronic progressive forms of the disease.

Abe, Y., T. Takeuchi, et al. (2005). "[Lymphotoxin (lymphotoxin/TNF-beta)]." Nippon Rinsho 63 Suppl 8: 86-8.

(2005). "Dextromethorphan/quinidine: AVP 923, dextromethorphan/cytochrome P450-2D6 inhibitor, quinidine/dextromethorphan." Drugs R D 6(3): 174-7.

            Avanir Pharmaceuticals in the US is developing a fixed-dose combination of dextromethorphan (30 mg), a weak NMDA antagonist/sigma 1 agonist, and quinidine (30 mg), a cytochrome P450-2D6 (CYP2D6) enzyme inhibitor [AVP 923, Neurodextrade mark]. Quinidine sustains therapeutic levels of dextromethorphan over a 12-hour dosing schedule by inhibiting oxidative first-pass metabolism of the drug, and is used in the combination product at 2.5-5.0% of its normal daily therapeutic dose. A rolling NDA for the treatment of emotional lability has been initiated, and phase II trials with dextromethorphan/quinidine for the treatment of neuropathic pain have been completed. Avanir is exploring partnering opportunities for dextromethorphan/quinidine in Europe and Japan. Prospective partners would carry out development and commercialisation in the licensed territory. Additionally, a co-promotion partner for the US is sought. Avanir Pharmaceuticals sublicensed this formulation of dextromethorphan from IriSys Research and Development. Avanir has exclusive rights to develop, manufacture and market dextromethorphan/quinidine for four potential indications: emotional lability, neuropathic pain, chronic cough and weaning drug-dependent patients from narcotics and antidepressants. Avanir will make milestone payments to Irisys upon US FDA acceptance of filing, marketing approval, and royalties based on product sales. Medison Pharma (Israel) has obtained development, marketing and distribution rights to the dextromethorphan/quinidine combination for the treatment of emotional lability in patients with multiple sclerosis in Israel. Avanir will fund all clinical development of the dextromethorphan/quinidine combination for the treatment of emotional lability. The phase II clinical trials with dextromethorphan/quinidine for the treatment of neuropathic pain have been completed. Results indicated that the combination significantly improved pain scores in patients with diabetic neuropathy. Phase III trials in this indication are expected to begin in 2005. Avanir has been issued with six patents in the US regarding dextromethorphan/quinidine and has a total of 14 pending applications, 12 of which are in Europe.

(2005). "The Goldman Consensus statement on depression in multiple sclerosis." Mult Scler 11(3): 328-37.

            BACKGROUND: In January 2002 the New York City Chapter of the National Multiple Sclerosis Society convened a panel of experts to review the issue of depressive affective disorders associated with multiple sclerosis (MS). This Consensus Conference was supported by a grant from the Goldman family of New York City. RESULTS: The panel reviewed summaries of current epidemiologic, neurobiologic, and therapeutic studies having to do with depressive disorders among MS patient populations. Depressive disorders occur at high rates among patients with MS, and there is reason to believe that the immunopathology of the disease is involved in the clinical expression of affective disorders. The depressive syndromes of MS have a major, negative impact on quality of life for MS sufferers, but are treatable. At the present time, most MS patients with depression do not receive adequate recognition and treatment. CONCLUSIONS: The Goldman Consensus Conference Study Group provides recommendations for improved screening, diagnosis, and clinical management for depressive affective disorders among patients suffering from MS.

(2005). "BG 12: BG 00012, BG 12/Oral Fumarate, FAG-201, second-generation fumarate derivative--Fumapharm/Biogen Idec." Drugs R D 6(4): 229-30.

            Fumapharm AG has developed a second-generation fumarate (fumaric acid) derivative, BG 12 [BG 00012, FAG-201, BG 12/Oral Fumarate], for the oral treatment of psoriasis. Biogen Idec is currently evaluating the product in clinical trials as an oral treatment for multiple sclerosis (phase II) and psoriasis (phase III) trials.BG 12 has an immunomodulatory mechanism of action. It seems that this product has been developed to reduce the adverse effects associated with a first-generation product containing fumaric acid esters (mixed dimethylfumarate and monoethylfumarate salts), Fumaderm. Fumaderm was approved in Germany in August 1994 and is currently the leading oral systemic therapy for moderate-to-severe psoriasis in Germany. One of the problems associated with Fumaderm capsules has been its gastrointestinal adverse effects (including diarrhoea and nausea). In September 2003, Biogen (now Biogen Idec) licensed exclusive worldwide rights (excluding Germany) from Fumapharm to develop and market BG 12. Biogen plans to collaborate with Fumapharm to accelerate phase III development for psoriasis and the registration programme worldwide. Financial terms of the agreement were not disclosed. Development plans for BG 12 include other autoimmune and inflammatory disorders, such as multiple sclerosis. In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Fumapharm completed phase II trials of this second-generation fumarate derivative for psoriasis prior to licensing of the product to Biogen, also with positive results.

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