Back to Multiple Sclerosis (MS)
Enhanced by
Neuroinformation
Multiple Sclerosis Reviews: 2006
Zwolinska, K. (2006). "[Retroviruses-derived sequences in the human genome. Human endogenous retroviruses (HERVs)]." Postepy Hig Med Dosw (Online) 60: 637-52.
Retroviruses-derived elements in the human genome constitute 90% of non-coding mobile sequences. Reverse transcriptase (RT) plays an essential role in their transposition as do long terminal repeats (LTRs), which contain promotors, enhancers, and regulatory sequences. Some retroelements (pseudogens and retrogenes, e.g. SINE) are non-autonomic and do not possess their own RT. These elements are dependent on autonomic elements (retroposons, e.g. LINE, retrotransposons, exo- and endogenous retroviruses). The genome of retroviruses is composed of gag, pol, and env genes flanked by long terminal repeats. Endogenous retroviruses are probably the remnants of ancient germ cell infection by exogenous retroviruses and are transmissible to the next generation in a Mendelian way. Most of them are defective (because of mutation accumulation), but some are still active and their expression is regulated by different factors (UV radiation, inflammatory cytokines, steroid hormones, and exogenous virus products). Retroelements as well as their gene products exert influence on the organism's functions. They influence the plasticity and evolution of genomes, are a source of promotors and regulatory sequences, but they also supply additional signals of transcription initiation, mRNA splicing, and STOP codons. One of the positive aspects of human endogenous retroviruses (HERVs) is the participation of their products in normal syncytiotrophoblast formation. They also block exogenous retrovirus replication by receptor interference or antisense mRNA. Their presence is considered to be connected with a number of autoimmunological diseases (multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus), cancer, or even psychiatric disorders (schizophrenia). There are also other problems connected with the potential role of ERVs in genomic therapy (with retroviruses vectors) and transplantology (xenotransplantation).
Zuckerman, J. N. (2006). "Protective efficacy, immunotherapeutic potential, and safety of hepatitis B vaccines." J Med Virol 78(2): 169-77.
Hepatitis B vaccines are highly effective and safe and have been incorporated into national immunization programs in over 150 countries. The major humoral immune response is to the common a determinant of the surface antigen protein of the virus. Approximately 5-10% of healthy immunocompetent subjects do not mount an antibody response (anti-HBs). Non-response is associated with different HLA-DR alleles and impaired Th cell response, among other factors such as route of injection, age, gender, body mass, and other factors. Important hepatitis B surface antigen variants have also been identified, which may have a potential impact on immunization and routine screening of blood, blood products and tissues, and organs for transplantation. Strategies for hepatitis B immunization are reviewed. Over 1,000 million doses of hepatitis B vaccine have been used with an outstanding record of safety. There is no evidence of an association between hepatitis B vaccines and the sudden infant death syndrome, chronic fatigue syndrome, and multiple sclerosis (MS). Several studies are in progress on treatment of chronic hepatitis B infection by immunization with multiple antigenic components, combination of vaccine with antiviral drugs and cytokines, T cell vaccines, DNA vaccines alone or with DNA encoded immunomodulatory cytokines, and direct genetic manipulation of antigen presenting cells.
Zuber, J. P., C. Chizzolini, et al. (2006). "[Pathogenic mechanisms in systemic sclerosis and their therapeutical consequences. Part 1: pathogenesis]." Rev Med Suisse 2(62): 1052-7.
Systemic sclerosis I(cleroderma) is a connective tissue disease caracterized by an aberrant immune activation, a vasculopathy and a fibrosis of skin and multiple internal organs (lung, kidneys, gut, among others). At present no unifying pathogenetic hypothesis exists to explain all aspects of this disease. The current hypothesis is that in patients with a favourable genetic background, certain environmental factors could produce alterations of cellular and humoral immunity and alterations of the microcirculation resulting in excessive fibrosis. A crucial component in systemic sclerosis pathogenesis is the persistent and unregulated activation of genes encoding the various extracellular matrix proteins. This is in correlation with different cytokines and growth factors produced mainly by T lymphocytes.
Zuber, J. P., C. Chizzolini, et al. (2006). "[Pathogenic mechanisms in systemic sclerosis and their therapeutical consequences. Part 2: treatment]." Rev Med Suisse 2(62): 1058, 1060-6.
Systemic sclerosis (scleroderma) is considered as the most severe connective tissue disease. It is characterized by an abnormal immune activation, a vasculopathy and a fibrosis of the skin and of multiple internal organs. Numerous progress in the understanding of the pathogenesis with identification of key molecules have permit to introduce novel treatments that improve the management of some aspects of the disease. ACE inhibitors are effective in resolving renal crisis. Cyclophosphamide is useful for treatment of fibrosing alveolitis. Prostaglandins, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors permit to improve the treatment of the vascular complications (digital ulcerations, pulmonary arterial hypertension) of scleroderma.
Zohar, Y., G. Wildbaum, et al. (2006). "Beneficial autoimmunity participates in the regulation of rheumatoid arthritis." Front Biosci 11: 368-79.
Antigen specific T cells and B cells recognize their target determinants by antigen specific receptors that are being rearranged in a random manner. These cells then undergo negative and positive selection processes that limit, albeit not eliminate, the escape of self-reactive T and B cells capable of eliciting autoimmune responses. The above processes are referred to as "central selection", and their outcome is the "central tolerance". Auto-reactive T and B cells escaping central tolerance are then subjected to peripheral mechanisms that restrain their auto-aggressive behavior. Different types of regulatory T cells are key players in maintaining actively induced peripheral tolerance. In patients suffering from various autoimmune disorders autoreactive T and/or B cells that escaped central tolerance also circumvented regulatory T cells that could, potentially, eradicate their pathogenicity in the periphery. We have found an additional regulatory mechanism that restrains the harmful activity of these cells at that time. It includes autoimmune B cells that produce neutralizing autoantibodies against numerous inflammatory mediators, mostly cytokines and chemokines, which participate in destructive autoimmunity. These autoantibodies restrain the harmful consequences of inflammatory autoimmune conditions such as in rheumatoid arthritis. Interestingly, this antibody production is elicited during autoimmune diseases, and to a much lesser extent during local inflammation. The specificity of this response is highly restricted to determinants with minimal cross reactivity to other known gene products. Thus, the immune system allows selective breakdown of tolerance in autoimmune conditions. The findings that this beneficial response is turned on by the autoimmune condition, and then regulated by its progression further imply for the existence of a programmed regulatory response of "beneficial autoimmunity". In the current review we describe how this mechanism was discovered in experimental models of rheumatoid arthritis and multiple sclerosis, demonstrate its importance in the natural regulation of these diseases, and finally explore its relevance to human diseases.
Zivadinov, R. and J. Sepcic (2006). "[Use of magnetic resonance imaging in the diagnosis and prognosis of multiple sclerosis]." Lijec Vjesn 128(9-10): 295-308.
Multiple sclerosis is an autoimmune disease characterized by demyelination and axonal loss. Conventional magnetic resonance imaging allows the demonstration of spatial and temporal dissemination of multiple sclerosis lesions earlier than is possible from clinical assessments. A variety of conventional magnetic resonance imaging protocols, in conjunction with clinical assessment, are now routinely used to increase the accuracy of diagnosis and long-term prognosis of multiple sclerosis. T2-weighted hyperintense lesions are related primarily to increased water content and thus cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss, whereas the contrast gadolinium-enhanced lesions on T1-weighted images reflect increased blood-brain barrier permeability associated with active inflammatory activity. Conventional magnetic resonance imaging metrics are not sufficiently sensitive to detect invisible brain damage in the normal appearing brain tissue, and they do not show a reliable correlation with clinical measures of disability. However, numerous studies showed that they can improve accuracy in the diagnosis and prognosis of multiple sclerosis. Recently, non-conventional magnetic resonance imaging techniques have been introduced to increase the accuracy of diagnosis and prognosis of multiple sclerosis. Several studies have used brain atrophy, T1-hypointense lesion volume, magnetization transfer imaging, diffusion-weighted imaging and magnetic resonance spectroscopy to test whether the extent and severity of tissue loss in lesions and in normal appearing gray and white matter at the time of clinically isolated syndrome may have diagnostic and prognostic value. These magnetic resonance imaging techniques represent a powerful tool to non-invasively study different pathological substrates of lesions and microscopic tissue changes. Additional short- and long-term prospective studies are requested to establish their value in the diagnosis and prognosis of multiple sclerosis.
Zipp, F. and O. Aktas (2006). "The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases." Trends Neurosci 29(9): 518-27.
Classical knowledge distinguishes between inflammatory and non-inflammatory diseases of the brain. Either the immune system acts on the CNS and initiates a damage cascade, as in autoimmune (e.g. multiple sclerosis) and infectious conditions, or the primary insult is not inflammation but ischemia or degeneration, as in stroke and Alzheimer's disease, respectively. However, as we review here, recent advances have blurred this distinction. On the one hand, the classical inflammatory diseases of the brain also exhibit profound and early neurodegenerative features - remarkably, it has been known for more than a century that neuronal damage is a key feature of multiple sclerosis pathology, yet this was neglected until very recently. On the other hand, immune mechanisms might set the pace of progressive CNS damage in primary neurodegeneration. Despite differing initial events, increasing evidence indicates that even in clinically heterogeneous diseases, there might be common immunological pathways that result in neurotoxicity and reveal targets for more efficient therapies.
Zarei, M. (2006). "Clinical characteristics of cortical multiple sclerosis." J Neurol Sci 245(1-2): 53-8.
There are several articles in this special issue in which authors eloquently describe neurobehavioural and cognitive complications of multiple sclerosis with relevant neuropsychological assessments and neuroimaging findings. However behavioural and cognitive presentation of multiple sclerosis remains poorly understood. Two years ago, we reported a series of patients with multiple sclerosis who presented with neurobehavioural symptoms and had neuropsychological deficits consistent with cortical dysfunction. Based on previous case reports, pathological studies of cerebral cortex in multiple sclerosis and advanced neuroimaging studies we suggested that neurobehavioural presentation of multiple sclerosis represents a new variant called "cortical multiple sclerosis". The condition is characterised by predominant or exclusive cortical pathology presenting with neurobehavioural symptoms, such as depression, amnesia or distinct cortical syndromes. Since the publication of our report, there has been further neuroimaging and neuropathological findings that further supported the above concept. In addition, observation of more patients with this condition helped us to formulate a logical approach in the detection of these patients. This article focuses on their clinical characteristics.
Zamboni, P. (2006). "The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis." J R Soc Med 99(11): 589-93.
Zaffaroni, M., A. Ghezzi, et al. (2006). "Intensive immunosuppression in multiple sclerosis." Neurol Sci 27 Suppl 1: S13-7.
Immunosuppressive drugs have been used out of label in multiple sclerosis (MS) for over 30 years and around 10% of patients are actually under immunosuppressive treatment. The rationale for immunosuppression in MS lies in the hypothesis that MS is an inflammatory immune-mediated disease that can take advantage of strong anti-inflammatory activity. Azathioprine, methotrexate, cyclophosphamide and mitoxantrone are the most utilised agents, but only the latter has been approved for clinically active MS. Many of them are safe in combination with interferon-beta and are under investigation in controlled trials. Plasma exchange is limited to catastrophic attacks in refractory MS whilst bone marrow transplantation is considered in patients with an extremely severe, active disease as the final option in escalation therapy. Although immunosuppressants are best effective in induction therapy, their use is limited by toxicity and potential long-term risk.
Yadav, V. and D. Bourdette (2006). "Complementary and alternative medicine: is there a role in multiple sclerosis?" Curr Neurol Neurosci Rep 6(3): 259-67.
Despite effective conventional therapies for multiple sclerosis (MS), many people with MS explore complementary and alternative medicine (CAM) therapies for their symptoms. Common CAM therapies that people use include dietary modification, nutritional and herbal supplementation, and mind-body therapies. There is a revival of interest among MS researchers about the therapeutic potential of low-fat diet and essential fatty acid supplementation in MS. The efficacy of specific vitamin supplementation remains unclear. Recently, cannabis and yoga have been studied in more controlled studies and have provided evidence that they may have some benefit. The research on CAM therapies in MS is still exploratory, but considering peoples' interest and common use of these therapies, further research in this area is clearly warranted.
Wong, R. (2006). "NMDA receptors expressed in oligodendrocytes." Bioessays 28(5): 460-4.
Oligodendrocytes are known to express (Ca2+)-permeable glutamate receptors and to have low resistance to oxidative stress, two factors that make them potentially susceptible to injury. Oligodendrocyte injury is intrinsic to the loss of function experienced in conditions ranging from cerebral palsy to spinal cord injury, focal ischaemia and multiple sclerosis. NMDA receptors, a subtype of glutamate receptors, are vital to the remodeling of synaptic connections during postnatal development and associative learning abilities in adults and possibly in improvements in oligodendrocyte function. Previous studies had failed to detect NMDA receptor mRNA or current in oligodendrocytes but three new papers demonstrate NMDA receptor expression in oligodendrocytes and discuss its implications for ischaemia therapy.
Wolinsky, J. S. (2006). "The use of glatiramer acetate in the treatment of multiple sclerosis." Adv Neurol 98: 273-92.
Glatiramer acetate is a collection of synthetic polypeptides indicated as therapy for relapsing a remitting multiple sclerosis (MS). Current understanding of the immunological and neuroprotective mechanisms of action of GA makes it unique among current MS therapies. The clinical efficacy of GA appears similar to that of the recombinant beta interferons. GA has a favorable side effect profile with excellent patient compliance and long-term acceptance. The results of pivotal controlled clinical trials and long-term data derived from organized extension studies are reviewed. Supportive data from open-label comparison, combination treatment and therapeutic switch studies are also provided to enable informed decisions on the appropriate place for GA among other immunomodulatory treatments for relapsing MS.
Witzig, T. E. and S. H. Kaufmann (2006). "Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies." Curr Treat Options Oncol 7(4): 285-94.
The phosphatidylinositol 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signal transduction pathway integrates signals from multiple receptor tyrosine kinases to control cell proliferation and survival. Key components of the pathway are the lipid kinase PI3-K, the small guanosine triphosphate-binding protein Rheb, and the protein kinases Akt and mTOR. Important natural inhibitors of the pathway include the lipid phosphatase PTEN and the tuberous sclerosis complex. Several components of this pathway are targeted by investigational antineoplastic agents. Rapamycin (sirolimus), the prototypic mTOR inhibitor, exhibits activity in acute myeloid leukemia. Three rapamycin analogs, temsirolimus, everolimus, and AP23573, are in clinical trials for various hematologic malignancies. Temsirolimus has produced a 38% overall response rate in relapsed mantle cell lymphoma, and AP23573 has demonstrated activity in acute leukemia. Everolimus is undergoing clinical testing in lymphoma (Hodgkin and non-Hodgkin) and multiple myeloma. In addition, perifosine, an inhibitor of Akt activation that exhibits substantial antimyeloma activity in preclinical models, is being examined in relapsed multiple myeloma. Based on results obtained to date, it appears that inhibitors of the PI3-K/mTOR pathway hold promise as single agents and in combination for hematologic malignancies.
Witman, P. M. (2006). "More than just a bump: the hamartoma syndromes." Adv Dermatol 22: 157-80.
The hamartoma syndromes detailed in this review are just a few examples of the many genodermatoses now known to be associated with uncontrolled tumor proliferation secondary to mutations in tumor suppressor genes. Knowledge gained through the study of these syndromes has not only improved our understanding of patients afflicted with such conditions, but has also led to significant insight into the important role tumor suppressor genes play in preventing tumor formation and in carcinogenesis. As major strides continue to be made in the identification of causative mutations in the hamartoma syndromes, options for genetic testing will continue to expand. Identification of mutations in PTEN in the various disorders that compose the PTEN hamartoma tumor syndrome illustrates just how such genetic knowledge has altered the way we both categorize and manage certain genetic conditions. As advances continue to be made in this arena, it is quite conceivable that many of the genetic syndromes will be renamed or categorized based on genetic mutations rather than the characteristic clinical features. However, despite these advances, it will still be the astute clinician's recognition of key clinical features that allows the diagnosis of a hamartoma syndrome to be considered.
Wingerchuk, D. M. (2006). "Acute disseminated encephalomyelitis: distinction from multiple sclerosis and treatment issues." Adv Neurol 98: 303-18.
Wingerchuk, D. M. (2006). "Multiple sclerosis disease-modifying therapies: adverse effect surveillance and management." Expert Rev Neurother 6(3): 333-46.
There are five approved, partially effective, parenteral disease-modifying therapies for multiple sclerosis (MS), including three interferon-beta preparations, glatiramer acetate and the antineoplastic agent mitoxantrone. A sixth drug, natalizumab, was withdrawn from the market in 2005 but could return with increased safety measures. Careful surveillance for, and management of, the minor and serious adverse effects associated with these therapies in routine practice provides the best opportunity for maintaining compliance and achieving maximal therapeutic efficacy. This review outlines the strategies for the prevention, identification and management of the complications associated with administration and ongoing use of current MS therapies. These skills will become increasingly important to those caring for MS patients as contemporary treatment regimens become increasingly complex.
Wingerchuk, D. M. (2006). "The clinical course of acute disseminated encephalomyelitis." Neurol Res 28(3): 341-7.
The objective of this review is to describe recent advances in understanding the clinical course of pediatric and adult acute disseminated encephalomyelitis (ADEM), especially the risk of relapse and conversion to multiple sclerosis (MS). The diagnosis of ADEM is reached on clinical grounds, typically in the setting of a post-infectious meningoencephalitic syndrome associated with multifocal neurological symptoms and signs, magnetic resonance imaging (MRI) evidence of white matter lesions and exclusion of other causes. Although typically monophasic, several case series demonstrate 'multiphasic' or 'recurrent' forms of ADEM with clinical relapses occurring within a short interval of disease onset. Furthermore, the estimated risk of developing MS is substantial for both children (0-33%) and adults (approximately 35%). Advances in neuroimaging have identified some MRI features that have predictive value for a relapsing course but they are not accurate enough for therapeutic decision-making; a diagnosis of monophasic ADEM should be made with caution in all cases, especially those presenting in adulthood. Research in ADEM and related disorders remains hampered by lack of prospective studies, specific and reproducible clinical case definitions and variable follow-up methods. Standardization of these variables would facilitate identification of more accurate diagnostic and prognostic variables, discovery and testing of potential objective biomarkers that would, in turn, allow early prediction of a relapsing course and appropriate therapeutic interventions.
Wingerchuk, D. M. (2006). "Evidence for humoral autoimmunity in neuromyelitis optica." Neurol Res 28(3): 348-53.
Neuromyelitis optica (NMO) is an idiopathic central nervous system (CNS) demyelinating syndrome that may be distinguished from typical multiple sclerosis (MS). Although the cause of the disorder is not known, several lines of evidence suggest that the fundamental immunological process is driven by humoral mechanisms. These observations include the frequent coexistence of systemic autoimmune disease or positive serum autoantibodies with NMO, immunopathologic studies that demonstrate prominent complement activation and immunoglobulin deposition and the discovery of the serum autoantibody NMO-IgG, a potential NMO biomarker that targets aquaporin-4. Furthermore, clinical experience suggests that plasmapheresis and immunosuppressive therapies are beneficial for treatment and prevention of acute attacks but that standard MS immunomodulatory drugs may not alter the course of NMO. This evidence is reviewed in the context of its implications for future laboratory and clinical research in NMO.
Williamson, D. M. (2006). "Studies of multiple sclerosis in communities concerned about environmental exposures." J Womens Health (Larchmt) 15(7): 810-4.
Multiple sclerosis (MS) is an autoimmune disease that differentially affects women, people 30-60 years old, and Caucasians. Evidence indicates that it is a complex disease determined by both environmental factors and genetic susceptibility. People across the United States have expressed concern about perceived clusters of MS in their communities and the role of environmental exposures in the development of the disease. The Agency for Toxic Substances and Disease Registry (ATSDR) has funded several studies to address this issue, including a cluster investigation, several prevalence studies, and a case-control study. The cluster investigation illustrated that there are few data regarding the number of individuals with MS in the United States. Prevalence studies were conducted in Ohio, Missouri, and Texas to address this deficiency. The results support a regional difference in MS prevalence, although the reason for this difference is unclear. The results also underscore the need for additional epidemiological information about the distribution of MS in other areas of the United States and information on the underlying etiology of the disease. A case-control study is currently being conducted to examine potential risk factors for MS, including the role of environmental exposures and genetic susceptibility. Future research on MS should focus on large-scale studies and include collaboration among researchers with varied fields of expertise, such as epidemiology, neurology, and genetics.
Whiting, P., R. Harbord, et al. (2006). "Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review." Bmj 332(7546): 875-84.
OBJECTIVE: To determine the accuracy of magnetic resonance imaging criteria for the early diagnosis of multiple sclerosis in patients with suspected disease. DESIGN: Systematic review. DATA SOURCES: 12 electronic databases, citation searches, and reference lists of included studies. Review methods Studies on accuracy of diagnosis that compared magnetic resonance imaging, or diagnostic criteria incorporating such imaging, to a reference standard for the diagnosis of multiple sclerosis. RESULTS: 29 studies (18 cohort studies, 11 other designs) were included. On average, studies of other designs (mainly diagnostic case-control studies) produced higher estimated diagnostic odds ratios than did cohort studies. Among 15 studies of higher methodological quality (cohort design, clinical follow-up as reference standard), those with longer follow-up produced higher estimates of specificity and lower estimates of sensitivity. Only two such studies followed patients for more than 10 years. Even in the presence of many lesions (> 10 or > 8), magnetic resonance imaging could not accurately rule multiple sclerosis in (likelihood ratio of a positive test result 3.0 and 2.0, respectively). Similarly, the absence of lesions was of limited utility in ruling out a diagnosis of multiple sclerosis (likelihood ratio of a negative test result 0.1 and 0.5). CONCLUSIONS: Many evaluations of the accuracy of magnetic resonance imaging for the early detection of multiple sclerosis have produced inflated estimates of test performance owing to methodological weaknesses. Use of magnetic resonance imaging to confirm multiple sclerosis on the basis of a single attack of neurological dysfunction may lead to over-diagnosis and over-treatment.
Weinshenker, B. G., D. M. Wingerchuk, et al. (2006). "NMO-IgG: a specific biomarker for neuromyelitis optica." Dis Markers 22(4): 197-206.
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that principally targets the optic nerves and spinal cord and often leads to severe disability and occasionally life threatening respiratory failure. Although its clinical manifestations overlap with those of multiple sclerosis (MS), in established cases these two conditions can be distinguished on the basis of clinical, radiological, and routine spinal fluid studies. The diagnosis in early cases or limited forms of NMO is difficult. We recently discovered a unique IgG autoantibody (NMO-IgG) that is highly specific to patients with NMO and thus a valuable diagnostic aid. Its antigen, aquaporin-4 (AQP4), is the central nervous system's predominant water channel protein. This antibody has not yet been proven to be pathogenic, but several facts suggest that it might be, including the similarity of the immunohistochemical pattern of NMO-(AQP4) IgG binding to mouse CNS tissues to the pattern of immune complex deposition in autopsied patients' spinal cord tissue. The spectrum of diseases identified by NMO-IgG is broader than has previously been recognized clinically and includes incomplete forms of NMO, such as recurrent transverse myelitis without optic neuritis and recurrent optic neuritis without myelitis.
Weiller, C., A. May, et al. (2006). "Role of functional imaging in neurological disorders." J Magn Reson Imaging 23(6): 840-50.
Neuroimaging in recent years has greatly contributed to our understanding of a wide range of aspects related to central neurological diseases. These include the classification and localization of disease, such as in headache; the understanding of pathology, such as in Parkinson's disease (PD); the mechanisms of reorganization, such as in stroke and multiple sclerosis (MS); and the subclinical progress of disease, such as in amyotrophic lateral sclerosis (ALS). Apart from presurgical mapping, however, the clinical applications so far are limited. Nevertheless, functional imaging does enable the formulation of neurobiological hypotheses that can be tested clinically, and thus is well suited for testing classic clinical hypotheses about how the brain works. Understanding the mechanisms and sites of pathology, such as has been achieved in cluster headaches, facilitates the development of new therapeutic strategies.
Weightman, C. (2006). "Long-term management of patients with multiple sclerosis." Br J Community Nurs 11(7): 303-7.
This article explores the challenges of long-term case management for patients who have multiple sclerosis (MS). Currently there is scant research into district nursing input into long-term management of patients who have MS. Until now the role of the community nurses has been confined to palliation or terminal care, focusing on the more physical manifestations of MS. The contemporary role of district nurse is going to evolve to include proactive approaches. Governmental initiatives demand proactive services, and place emphasis on self-care for patients with MS. Themes that emerge from this article relate to the pre-existing skills--such as managing patients with complex needs and the advanced assessment skills--that will be required to achieve this. What is clear is that community nurses already possess many of the prerequisite skills needed for long-term management, and they should not be daunted by this prospect.
Wegrzyn, D., A. Czarnywojtek, et al. (2006). "[The role of tobacco smoking in etiology of multiple sclerosis--review study]." Przegl Lek 63(10): 1144-5.
This article is focusing on the etiology of the multiple sclerosis (MS). MS is the disease of autoimmune origin, concerning mainly young people with its complicated nature. The course of the degenerative and inflammatory process is variable and unexpected, from featureless to the vast and rapidly progressing nature, leading to the considerable disability. The etiological factors are not still well known. We can distinguish different agents: genetic, immunological and environmental, among them tobacco smoking also. Authors survey the etiopathological basis of the disease.
Weber, M. S., S. Youssef, et al. (2006). "Statins in the treatment of central nervous system autoimmune disease." J Neuroimmunol 178(1-2): 140-8.
Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, are widely prescribed for their cholesterol-lowering properties to reduce atherogenesis and cardiovascular morbidity. Over recent years, statins have also been shown to exert pleiotropic immunomodulatory effects that might be of therapeutic benefit in autoimmune disorders. The primary mechanism by which statins alter immune function appears to be mediated through the inhibition of post-translational protein prenylation of small GTP-binding proteins and is largely independent of lipid-lowering. In experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS), statins prevent or reverse paralysis and were recently shown to exert synergistic benefit when combined with agents approved for MS therapy. Based primarily upon the beneficial effects in EAE, statins are now being tested in patients in MS clinical trials.
Waxman, S. G. (2006). "Axonal conduction and injury in multiple sclerosis: the role of sodium channels." Nat Rev Neurosci 7(12): 932-41.
Multiple sclerosis (MS) is the most common cause of neurological disability in young adults. Recent studies have implicated specific sodium channel isoforms as having an important role in several aspects of the pathophysiology of MS, including the restoration of impulse conduction after demyelination, axonal degeneration and the mistuning of Purkinje neurons that leads to cerebellar dysfunction. By manipulating the activity of these channels or their expression, it might be possible to develop new therapeutic approaches that will prevent or limit disability in MS.
Waubant, E. (2006). "Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis." Dis Markers 22(4): 235-44.
Blood-brain barrier (BBB) disruption is one of the hallmarks of multiple sclerosis (MS). It is incompletely understood whether BBB disruption is the initial MS event leading to MS lesion formation or whether it is merely a consequence of cellular infiltration in the central nervous system (CNS). The presence of gadolinium enhancing (Gd+) lesions on serial brain MRI scans is frequently used to evaluate BBB disruption. The presence of Gd enhancement has therefore been used as a reference for most works evaluating promising biomarkers of BBB disruption that are reviewed here. These promising biomarkers include cytokines and chemokines, and their receptors, cell surface markers, and matrix metalloproteinases and their natural inhibitors. At this time, none of these markers have been shown as sensitive as the presence of Gd enhancement to reflect BBB disruption. However, MRI scanning is not only unpractical and expensive; it may also under represent the overall extent of BBB disruption. Developing new MS biomarkers that are sensitive and specific for BBB disruption could 1) improve the monitoring of disease activity; 2) improve the monitoring of response to MS therapies which target BBB disruption; and 3) advance our understanding of dynamic MS processes participating in BBB disruption.
Watson, G. S. and S. Craft (2006). "Insulin resistance, inflammation, and cognition in Alzheimer's Disease: lessons for multiple sclerosis." J Neurol Sci 245(1-2): 21-33.
Insulin resistance (reduced ability of insulin to stimulate glucose utilization) is common in North American and Europe, where as many as one third of all older adults suffer from prodromal or clinical type 2 diabetes mellitus. It has long been known that insulin-resistant conditions adversely affect general health status. A growing body of findings suggests that insulin contributes to normal brain functioning and that peripheral insulin abnormalities increase the risk for memory loss and neurodegenerative disorders such as Alzheimer's disease. Potential mechanisms for these effects include insulin's role in cerebral glucose metabolism, peptide regulation, modulation of neurotransmitter levels, and modulation of many aspects of the inflammatory network. An intriguing question is whether insulin abnormalities also influence the pathophysiology of multiple sclerosis (MS), an autoimmune disorder characterized by elevated inflammatory biomarkers, central nervous system white matter lesions, axonal degeneration, and cognitive impairment. MS increases the risk for type 1 diabetes mellitus. Furthermore, the lack of association between MS and type 2 diabetes may suggest that insulin resistance affects patients with MS and the general population at the same alarming rate. Therefore, insulin resistance may exacerbate phenomena that are common to MS and insulin-resistant conditions, such as cognitive impairments and elevated inflammatory responses. Interestingly, the thiazolidinediones, which are used to treat patients with type 2 diabetes, have been proposed as potential therapeutic agents for both Alzheimer's disease and MS. The agents improve insulin sensitivity, reduce hyperinsulinemia, and exert anti-inflammatory actions. Ongoing studies will determine whether thiazolidinediones improve cognitive functioning for patients with type 2 diabetes or Alzheimer's disease. Future studies are needed to examine the effects of thiazolidinediones on patients with MS.
Wasay, M., I. A. Khatri, et al. (2006). "MS in Asian countries." Int MS J 13(2): 58-65.
This paper reviews all available English language literature on MS from Asian countries published between 1970 and 2005. Although limited data are available, the review reveals that western Asia--including the Middle East--has the highest prevalence of MS across the continent, and that MS in Asia largely resembles conventional MS in western countries. Opticospinal MS (a distinct clinical entity from conventional MS) is more common in eastern Asian regions. Larger epidemiological and genetic studies, with more complete ascertainment in various Asian populations, are needed so that we can understand the diversity of Asian MS.
Waldman, A., E. O'Connor, et al. (2006). "Childhood multiple sclerosis: a review." Ment Retard Dev Disabil Res Rev 12(2): 147-56.
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) that is increasingly recognized as a disease that affects children. Similar to adult-onset MS, children present with visual and sensory complaints, as well as weakness, spasticity, and ataxia. A lumbar puncture can be helpful in diagnosing MS when CSF immunoglobulins and oligoclonal bands are present. White matter demyelinating lesions on MRI are required for the diagnosis; however, children typically have fewer lesions than adults. Many criteria have been proposed to diagnose MS that have been applied to children, mostly above 10 years of age. The recent revisions to the McDonald criteria allow for earlier diagnosis, such as after a clinically isolated event. However, children are more likely than adults to have monosymptomatic illnesses. None of the approved disease-modifying therapies used in adult-onset MS have been approved for pediatrics; however, a few studies have verified their safety and tolerability in children. Although children and adults with MS have similar neurological symptoms, laboratory (cerebrospinal fluid) data, and neuroimaging findings, the clinical course, pathogenesis, and treatment of childhood onset MS require further investigation.
Wagner, S., H. J. Breyholz, et al. (2006). "Molecular imaging of matrix metalloproteinases in vivo using small molecule inhibitors for SPECT and PET." Curr Med Chem 13(23): 2819-38.
Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent secreted or membrane anchored endopeptidases. MMPs are involved in many physiological processes but also take part in the pathophysiological mechanisms responsible for a wide range of diseases. Pathological expression and activation of MMPs are associated with cancer, atherosclerosis, stroke, arthritis, periodontal disease, multiple sclerosis and liver fibrosis. Thus, noninvasive visualisation and quantification of MMP activity in vivo are of great interest in basic research and clinical application. This can be achieved by scintigraphic molecular imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) provided suitable radiolabelled tracers exist, e.g. radioactive inhibitors of matrix metalloproteinases (MMPIs). The approach to monitor MMP activity in vivo using radiolabelled small molecule inhibitors suitable for SPECT and PET is summarised in this review. Briefly, latest advances in scintigraphic imaging are introduced and followed by a report about the enzyme class of MMPs. The involvement of MMPs in cancer and atherosclerosis is exemplified and small molecule MMPIs are classified. Subsequently, the development of radiolabelled small molecule MMPIs, their synthesis and in vitro and in vivo evaluation is reviewed. Finally, an outlook on the clinical potential of labelled MMPIs in diagnostic algorithms is given.
Wada, A. (2006). "Roles of voltage-dependent sodium channels in neuronal development, pain, and neurodegeneration." J Pharmacol Sci 102(3): 253-68.
Besides initiating and propagating action potentials in established neuronal circuits, voltage-dependent sodium channels sculpt and bolster the functional neuronal network from early in embryonic development through adulthood (e.g., differentiation of oligodendrocyte precursor cells into oligodendrocytes, myelinating axon; competition between neighboring equipotential neurites for development into a single axon; enhancing and opposing functional interactions with attractive and repulsive molecules for axon pathfinding; extending and retracting terminal arborization of axon for correct synapse formation; experience-driven cognition; neuronal survival; and remyelination of demyelinated axons). Surprisingly, different patterns of action potentials direct homeostasis-based epigenetic selection for neurotransmitter phenotype, thus excitability by sodium channels specifying expression of inhibitory neurotransmitters. Mechanisms for these pleiotropic effects of sodium channels include reciprocal interactions between neurons and glia via neurotransmitters, growth factors, and cytokines at synapses and axons. Sodium channelopathies causing pain (e.g., allodynia) and neurodegeneration (e.g., multiple sclerosis) derive from 1) electrophysiological disturbances by insults (e.g., ischemia/hypoxia, toxins, and antibodies); 2) loss-of-physiological function or gain-of-pathological function of mutant sodium channel proteins; 3) spatiotemporal inappropriate expression of normal sodium channel proteins; or 4) de-repressed expression of otherwise silent sodium channel genes. Na(v)1.7 proved to account for pain in human erythermalgia and inflammation, being the convincing molecular target of pain treatment.
Vukusic, S. and C. Confavreux (2006). "Pregnancy and multiple sclerosis: the children of PRIMS." Clin Neurol Neurosurg 108(3): 266-70.
The influence of pregnancy on multiple sclerosis (MS) has long been a matter of controversy. Women with MS were often discouraged to consider pregnancy. The PRegnancy In Multiple Sclerosis (PRIMS) study was the first large prospective study aimed at assessing the possible influence of pregnancy and delivery on the clinical course of MS. Two hundred and fifty-four women with the diagnosis of MS were included during pregnancy and followed until the end of the second year post partum. The results were a reduction in the relapse rate during pregnancy, in comparison to the year before pregnancy, especially marked in the third trimester, and a significant increase in the relapse rate in the first trimester post partum. Starting in the second trimester post partum, the relapse rate did not significantly differ from the pre-pregnancy rate. About one third of the women experienced a post partum relapse. Pregnancy did not influence disability progression. Women with greater disease activity in the year before and during pregnancy had a higher risk of relapse in the first three months post partum. Neither breastfeeding, nor epidural analgesia correlated with the presence of a post partum relapse. When comparing predicted and observed status, 72% of the women were correctly classified by the multivariate model; it therefore seems unwise to use such a model to select women who would benefit from a putative preventive therapy. The PRIMS study had other major consequences: it fostered the development of specific therapeutic strategies to prevent post partum relapses (i.v. immunoglobulins, i.v. methylprednisolone), and suggested a potential role for sex hormones in the natural history of MS during pregnancy and the post partum. The preventive effect of progesterone combined with estradiol on post partum relapses is about to be tested in a large randomized and placebo-controlled European trial, the POPART'MUS study.
Vukusic, S. and C. Confavreux (2006). "[Multiple sclerosis and pregnancy]." Rev Neurol (Paris) 162(3): 299-309.
The influence of pregnancy in multiple sclerosis (MS) has been a matter of controversy for a long time. Women with MS were often discouraged to envisage pregnancy. The Pregnancy in Multiple Sclerosis (PRIMS) study was the first large-scale prospective study aimed at assessing the possible influence of pregnancy and delivery on the clinical course of MS. Two hundred and fifty-four women with a diagnosis of MS were included during pregnancy and followed-up till the end of the second year post partum. The results were a reduction in the relapse rate during pregnancy, in comparison to the year before pregnancy, especially marked in the third trimester, and a significant increase in the relapse rate in the first trimester post partum. From the second trimester post partum on however, the relapse rate did not significantly differ from the pre-pregnancy rate. About one third of the women experienced a post partum relapse. Pregnancy did not influence disability progression. The clinical factors likely to predict a relapse in the three months after delivery were analyzed by logistic regression analysis. Women with a greater disease activity in the year before pregnancy and during pregnancy had a higher risk of relapse in the post partum three months. Neither breast-feeding, nor epidural analgesia correlated with presence of a post partum relapse. When comparing the predicted and observed status however, only 72 percent of the women were correctly classified by the multivariate model. It seems unwise therefore to use this kind of model to select women that would benefit from a putative preventive therapy. The PRIMS study had other major consequences: it fostered the development of specific therapeutic strategies to prevent post partum relapses (IV immunoglobulins, IV methylprednisolone), and suggested a potential role of sexual hormones in the natural history of MS during pregnancy and the post partum, therefore identifying them as a preferential target for prevention. The preventive effect of progesterone combined with estradiol on post partum relapses will be tested in a large-scale randomized and placebo-controlled European trial, the POPART'MUS study.
Venneti, S., B. J. Lopresti, et al. (2006). "The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging." Prog Neurobiol 80(6): 308-22.
Microglia constitute the primary resident immune surveillance cell in the brain and are thought to play a significant role in the pathogenesis of several neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and HIV-associated dementia. Measuring microglial activation in vivo in patients suffering from these diseases may help chart progression of neuroinflammation as well as assess efficacy of therapies designed to modulate neuroinflammation. Recent studies suggest that activated microglia in the CNS may be detected in vivo using positron emission tomography (PET) utilizing pharmacological ligands of the mitochondrial peripheral benzodiazepine receptor (PBR (recently renamed as Translocator protein (18kDa)). Beginning with the molecular characterization of PBR and regulation in activated microglia, we examine the rationale behind using PBR ligands to image microglia with PET. Current evidence suggests these findings might be applied to the development of clinical assessments of microglial activation in neurological disorders.
van Laar, J. M. and A. Tyndall (2006). "Adult stem cells in the treatment of autoimmune diseases." Rheumatology (Oxford) 45(10): 1187-93.
During the past 10 yrs, over 700 patients suffering from severe autoimmune disease (AD) have received an autologous haematopoietic stem cell transplant as treatment of their disorder with durable remission being obtained in around one-third. The most commonly transplanted ADs have been systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. A fewer number of patients have received an allogeneic transplant. The initially reported overall treatment-related mortality of 7% has since fallen, with no further cases being reported in systemic sclerosis or multiple sclerosis in the past 3 yrs. This is thought to be due to more careful patient selection.The phase I/II data has led to currently running prospective randomised trials in systemic sclerosis, multiple sclerosis and systemic lupus erythematosus in Europe and North America. Immune reconstitution data suggests a 'resetting' of autoimmunity in those patients achieving stable remission, rather than simply prolonged immunosuppression. Recent results from in vitro experiments, animal models and early human experience in severe acute graft vs host disease suggest that multipotent mesenchymal stromal cells obtained from the bone marrow and expanded ex vivo, may exert a clinically useful immunomodulatory effect. Such cells are immune privileged and apparently of low toxicity. Further characterization of these cells and consideration of their possible clinical application in AD is underway.
Van der Schyf, C. J., W. J. Geldenhuys, et al. (2006). "Multifunctional drugs with different CNS targets for neuropsychiatric disorders." J Neurochem 99(4): 1033-48.
The multiple disease etiologies that lead to neuropsychiatric disorders, such as Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, Huntington disease, schizophrenia, depressive illness and stroke, offer significant challenges to drug discovery efforts aimed at preventing or even reversing the progression of these disorders. Transcriptomic tools and proteomic profiling have clearly indicated that such diseases are multifactorial in origin. Further, they are thought to be initiated by a cascade of molecular events that involve several neurotransmitter systems. In response to this complexity, a new paradigm has recently emerged that challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' in therapeutic approaches aimed at the prevention or treatment of neuropsychiatric diseases. A similar pattern of drug development has occurred in strategies for the treatment of cancer, AIDS and cardiovascular diseases. In this review, we offer an overview of therapeutic strategies and novel investigative drugs discovered or developed in our own and other laboratories, that address multiple CNS etiological targets associated with an array of neuropsychiatric disorders.
van der Heijden, M., A. Kraneveld, et al. (2006). "Free immunoglobulin light chains as target in the treatment of chronic inflammatory diseases." Eur J Pharmacol 533(1-3): 319-26.
Immunoglobulin free light chains were long considered irrelevant bystander products of immunoglobulin synthesis by B lymphocytes. To date, different studies suggest that free light chains may have important functional activities. For instance, it has been shown that immunoglobulin free light chains can elicit mast cell-driven hypersensitivity responses leading to asthma and contact sensitivity. Free light chains also show other biologic actions such as anti-angiogenic and proteolytic activities or can be used as specific targeting vehicles. Levels of free light chain levels in body fluids increase markedly in diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. In this review, we will focus on the unexpected biological activities of immunoglobulin free light chains with special attention to its possible role in the induction of chronic inflammatory diseases.
Vallat, J. M., L. Magy, et al. (2006). "[Inflammation and demyelinization: IgIV mode of action]." Rev Neurol (Paris) 162 Spec No 1: 3S12-3S16.
Immunoglobulins have a variety of actions in dysimmune disorders. In neurological conditions such as the dysimmune neuropathies and multiple sclerosis, immunoglobulins are thought to exert a twofold effect: an immunomodulating action and a positive action on remyelination. We outline well recognized immunomodulator actions including the suppression of antibody production and neutralization of pathogenic antibodies, action on T lymphocytes and endothelial cells, modulation of complement proteins, and modulation of the expression of Fc gamma receptors on the surface of macrophages. Along with these actions in dysimmune disorders of the central and peripheral nervous systems, recent studies have provided evidence for an action on remyelination. In cultures of oligodendrocytes or myelinating cocultures of rat embryo brains, we have noted a direct action of immunoglobulins (tegeline) on myelination of the central nervous system. Our investigations have also indicated that immunoglobulins have an action on myelination of the peripheral nervous system. We employed the experimental acute neuritis model as well as in vitro models such as cultures of embryonic dorsal root ganglia and isolated Schwann cells. Interestingly the typical IgM immunoglobulins seemed more active than typical IgG ones. This observation may prompt new therapeutic options.
Vajnar, J. (2006). "MRI confirms cause of facial numbness." Jaapa 19(8): 55-6.
Uttner, I. and H. Tumani (2006). "[Effects of high-dose cortisone therapy on cognition]." Nervenarzt 77(6): 647-8, 650-1.
Treatment with high-dose corticosteroids over 3-5 days reduces the duration and severity of relapses in patients with multiple sclerosis. Since the benefit of this treatment appears to be dose-dependent, application of ultrahigh steroid doses becomes important. On the other hand, data from basic research and clinical studies indicate potential side effects on mnestic functions. Three recently published studies show that treatment with pulsed corticosteroids induces reversible impaired memory. The effects were independent of the dose administered.
Uchino, A., Y. Takase, et al. (2006). "Acquired lesions of the corpus callosum: MR imaging." Eur Radiol 16(4): 905-14.
In this pictorial review, we illustrate acquired diseases or conditions of the corpus callosum that may be found by magnetic resonance (MR) imaging of the brain, including infarction, bleeding, diffuse axonal injury, multiple sclerosis, acute disseminated encephalomyelitis, Marchiafava-Bignami disease, glioblastoma, gliomatosis cerebri, lymphoma, metastasis, germinoma, infections, metabolic diseases, transient splenial lesion, dilated Virchow-Robin spaces, wallerian degeneration after hemispheric damage and focal splenial gliosis. MR imaging is useful for the detection and differential diagnosis of corpus callosal lesions. Due to the anatomical shape and location of the corpus callosum, both coronal and sagittal fluid-attenuated inversion recovery images are most useful for visualizing lesions of this structure.
Uccelli, A., E. Zappia, et al. (2006). "Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection." Expert Opin Biol Ther 6(1): 17-22.
In recent years much excitement has been generated over the possibility that adult stem cells may attempt repair of the injured central nervous system (CNS), thus setting the stage for their utilisation in the treatment of neurodegenerative disorders. Recent studies have shown that some subsets of stem cells can also modulate the (auto)immune response, thus providing a rationale for their use as therapy for experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). This article reviews the scientific evidence supporting the possible use of neural stem cells (NSCs) and mesenchymal stem cells (MSCs) for the treatment of MS. In addition, possible mechanisms sustaining the beneficial mode of action of haematopoietic stem cells (HSCs) following transplantation in MS individuals are discussed. Overall, it is proposed that limited subsets of adult stem cells may have a dual function that may be effective for the treatment of MS, an autoimmune disease of the CNS where degeneration of neural cells follows inflammation.
Ubogu, E. E., M. B. Cossoy, et al. (2006). "The expression and function of chemokines involved in CNS inflammation." Trends Pharmacol Sci 27(1): 48-55.
Chemokines and their receptors have principal roles in leukocyte trafficking under normal physiological and pathological conditions. The differential expression of the chemokine system in different parts of the CNS provides insights into the processes that are required for normal immune surveillance and pathological immune-mediated effector processes. Insights derived from studying multiple sclerosis, an inflammatory disorder of the CNS in humans, and experimental autoimmune encephalomyelitis, an animal model of this disorder, aid in further understanding the complexities of chemokine-mediated inflammation. Knowledge of the molecular biology of chemokines and their receptors, and the roles of specific chemokine ligands and receptors in the CNS in health and in disease have made these proteins targets for therapeutic intervention in neuroinflammation. We also discuss currently proposed and potentially useful chemokine receptor antagonists.
Tutaj, M. and M. Szczepanik (2006). "[Mechanisms involved in the regulation of immune response in experimental autoimmune encephalomyelitis in mice]." Postepy Hig Med Dosw (Online) 60: 571-83.
Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by the presence of cellular infiltrates consisting primarily of lymphocytes and macrophages and localized areas of demyelination in the CNS. MS is thought to be initiated by self-reactive CD4(+) Th1 T cells. Thus far, treatment modalities for MS are limited, with the most common acting nonspecifically on the immune system, resulting in a general immunosuppression accompanied by severe side effects. There is a large demand for developing MS therapy that particularly targets pathogenic myelin-specific T cells. Experimental allergic encephalomyelitis (EAE) is a well-characterized animal model that mimics many of the disease symptoms of MS, including the presence of cellular infiltrates and demyelination. EAE can be actively induced in genetically susceptible strains of mice, rats, and monkeys and is mediated by activated autoreactive CD4(+) T cells that are specific to MBP (myelin basic protein). The knowledge acquired using EAE allows us to better understand the pathogenesis of MS and thus manipulate particular components of the immune response in order to develop an efficient therapy.
Tsuchida, K. (2006). "[Development of therapies against neuromuscular diseases causing muscle atrophy]." Nihon Shinkei Seishin Yakurigaku Zasshi 26(5-6): 229-33.
Skeletal muscles become atrophied by muscular disorders such as muscular dystrophy, wasting and even aging. In addition to muscle atrophy, progressive muscle damage, inflammation and replacement of muscle fibers with fibrous and fatty tissues are observed in muscular dystrophy. Neuronal innervation is required for skeletal muscle, and muscles become atrophic when motor neurons are affected by neurodegenerative disorders such as amyotrophic lateral sclerosis. Restoring muscle mass and function lost by diseases such as muscular dystrophy and neurodegenerative disorders is important. There are three rational therapies for muscular dystrophy and related diseases: gene therapy, cell therapy and drug therapy. Gene therapies to replace the defective genes have been tried with various degrees of effectiveness. Multiple myogenic stem cells including satellite cells, bone marrow cells, muscle side population cells, muscle-derived stem cells and mesoangioblast have been characterized. Cell therapies using these stem cells are one of the promising therapies for neuromuscular diseases causing muscle atrophy. As pharmacological drug therapies, increasing skeletal muscle mass by myostatin inhibition is quite promising and will be applied clinically in the near future.
Tselis, A. C. and R. P. Lisak (2006). "Other demyelinating diseases." Adv Neurol 98: 335-49.
Trebst, C., H. Wiendl, et al. (2006). "[Concepts of lesion development in multiple sclerosis. Current approaches and clinical-therapeutic implications ]." Nervenarzt 77(2): 158, 160-2, 164.
The pathogenesis and development of lesions in multiple sclerosis (MS) are still unexplained and are the subject of some controversy. On the basis of histopathological analysis of a small set of MS cases, a recently published study postulates primary oligodendroglial damage as the initiator of MS lesions, with infiltration of leukocytes into the central nervous system (CNS) as a secondary phenomenon. In this paper we outline the current controversial discussion and different concepts of lesion development in MS. We conclude that demyelination can result from different pathogenic mechanisms, with either primary autoimmune inflammation or primary oligodendroglial damage and a secondary inflammatory reaction. Lesions can be divided into four subtypes (patterns I-IV) on the basis of histopathological characteristics, which supports the idea that MS lesions develop in different ways. These new aspects may have major implications for treatment. However, except in a few specific forms, most MS patients cannot currently be assigned to one of these lesion subtypes by means of clinical and paraclinical parameters. Without this, individual treatments tailored to the pathogenesis will not be possible.
Trebst, C. and M. Stangel (2006). "Promotion of remyelination by immunoglobulins: implications for the treatment of multiple sclerosis." Curr Pharm Des 12(2): 241-9.
During the last decade immunomodulatory treatments have been shown to influence the natural course of multiple sclerosis (MS). However, demyelination in the central nervous system (CNS) still occurs and repair mechanisms are incomplete leading to neurological deficits. Currently, there is no therapy available to promote remyelination and thus enhance repair mechanisms. Both immunoglobulins directed against spinal cord homogenate and polyclonal immunoglobulins for intravenous use (IVIg) have been shown to support remyelination in the animal model of Theiler's virus encephalomyelitis (TMEV). Further studies have identified monoclonal antibodies that lead to remyelination in TMEV and a toxic demyelination model using lysolecithin. The shared characteristics of these monoclonal antibodies are an IgM isotype and the capacity to bind oligodendrocytes, independent of epitope specificity. Recently, two human monoclonal antibodies with remyelinating properties were described. Clinical trials with IVIg have so far failed to demonstrate clinical improvement in MS patients, but these studies only employed IgG preparations. However, recent experimental data both in vivo and in vitro underline the importance of IgM for remyelination. Thus future clinical trials are needed to evaluate the remyelination potential of IgM in human diseases. The design of monoclonal antibodies capable of promoting remyelination is a telling example for the design of new specific therapies derived from biological products like polyclonal immunoglobulins.
Traboulsee, A. L. and D. K. Li (2006). "The role of MRI in the diagnosis of multiple sclerosis." Adv Neurol 98: 125-46.
There is no single test that is diagnostic of MS, including MRI. The lesions detected with MRI are pathologically nonspecific. The principles of MS diagnosis are based on showing dissemination of white matter lesions in space and time. MRI is the most sensitive method for revealing asymptomatic dissemination of lesions in space and time. The pattern and evolution of MRI lesions, in the appropriate clinical setting, has made MRI abnormalities invaluable criteria for the early diagnosis of MS. The first important role for MRI in the diagnosis of MS allows for an early diagnosis of MS for CIS patients using the IP diagnostic criteria, including MRI for dissemination in space (DIS) and time (DIT). The sensitivity of diagnosing MS within the first year after a single attack is 94%, with a specificity of 83%. The MRI evidence required to support the diagnosis varies, depending on the strength of the clinical findings. Allowing a new MRI lesion to substitute for a clinical attack doubles the number of CIS patients who can be diagnosed as having MS within 1 year of symptom onset. Increasing the sensitivity of the test with more lenient criteria, as recommended by the AAN subcommittee, can result in decreased specificity. The second important role for MRI in the diagnostic work-up of suspected MS patients is to rule out alternative diagnoses obvious on MRI, such as spinal stenosis and most brain tumors. Characteristic lesions that favor MS include Dawson Fingers, ovoid lesions, corpus callosum lesions, and asymptomatic spinal cord lesions. However, other white matter diseases can have similar appearances on MRI. Persistent gadolinium enhancement greater than three months, lesions with mass effect, and meningeal enhancement suggest other disorders. A standardized MRI protocol for brain and spinal cord is crucial for comparing across studies or between centers. T2W MRI cannot distinguish between acute and chronic lesions. Gadolinium provides useful information about new lesion activity and is helpful in ruling out alternative diagnoses such as neoplasm, vascular malformations, and leptomeningeal disease. A single gadolinium-enhanced MRI can potentially provide evidence for dissemination in space and time. Spinal cord imaging is equally valuable to rule out spinal stenosis or tumor, and for detecting asymptomatic lesions when brain imaging is nondiagnostic in patients suspected of having MS. Precise criteria may be too suggestive that MS can be diagnosed by MRI and a negative MRI at the time of CIS does not rule out MS. MRI evidence plays a supportive role in what is ultimately a clinical diagnosis of MS, in the appropriate clinical situation, and always at the exclusion of alternative diagnoses.
Touil, T., D. Fitzgerald, et al. (2006). "Pathophysiology of interleukin-23 in experimental autoimmune encephalomyelitis." Drug News Perspect 19(2): 77-83.
Interleukin-23 (IL-23) is a heterodimeric cytokine that is composed of a p40 subunit, shared with the closely related cytokine IL-12, and a smaller IL-23p19 subunit. It belongs to a family of heterodimeric cytokines that also includes IL-12 and IL-27. Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease that serves as a model for multiple sclerosis, an inflammatory demyelinating disease of the central nervous system that is a frequent cause of disability in young adults. EAE is thought to be initiated by CD4+ T cells. The production of interferon-gamma and tumor necrosis factor-alpha (T helper 1 [Th1] phenotype) was considered a marker for the ability of such cells to induce disease. Consistent with this view, IL-12, a cytokine that induces the differentiation of Th1 cells, was considered essential for EAE susceptibility. However, it is now clear that IL-23 rather than IL-12 is required for EAE susceptibility. IL-23 induces a population of IL-17-producing cells that is more critically involved in EAE pathogenesis than Th1 cells. Here, we review the role of the IL-23 system in the pathophysiology of EAE.
Torkildsen, O., C. A. Vedeler, et al. (2006). "FcgammaR and multiple sclerosis: an overview." Acta Neurol Scand Suppl 183: 61-3.
Receptors for the Fc domain of IgG (FcgammaR) play a key role in the immune system by linking the cellular and humoral immune systems. Despite extensive documentation of CNS-specific antibodies in cerebrospinal fluid and plaques in multiple sclerosis (MS) patients, the role of FcgammaR in this disease remains largely unexplored. Studies indicate however, that polymorphisms in some FcgammaR genes and treatment that induces FcgammaR on immune-competent cells could influence disease progression and treatment response.
Tomassini, V. and C. Pozzilli (2006). "Sex hormones: a role in the control of multiple sclerosis?" Expert Opin Pharmacother 7(7): 857-68.
Several lines of evidence suggest that gender affects the susceptibility and course of multiple sclerosis. A higher disease prevalence, as well as an overall better prognosis, in women than men is observed. This sex dimorphism may be explained by the effect of sex hormones on brain damage and repair mechanisms. Experimental, clinical and MRI evidence confirms a pathogenetic link between sex hormones and multiple sclerosis, also suggesting sex-specific effects of hormones in multiple sclerosis pathology and therapy. A gender-based approach to multiple sclerosis could provide further benefits for its treatment and management.
Tienari, P., A. Bonetti, et al. (2006). "Multiple sclerosis in G: genes and geography." Clin Neurol Neurosurg 108(3): 223-6.
Multiple sclerosis (MS) shows uneven geographic distribution globally as well as within countries. In epidemiological studies we have previously demonstrated that there is a high-risk focus for MS in the southern Ostrobothnian region of western Finland. In genetic studies we recently identified haplotypes that associate with MS specifically in patients originating from southern Ostrobothnia suggesting a founder effect. Such haplotypes can be used as molecular tools for tracing common ancestry between patients in different geographic locations. In addition to providing clues to the historical origin, such a genetic archeological approach should help narrow the size of the shared haplotype, thus facilitating the identification of etiological variants and possibly define a superfamily of MS patients with common pathogenetic mechanisms.
Thompson, E. J. and M. S. Freedman (2006). "Cerebrospinal fluid analysis in the diagnosis of multiple sclerosis." Adv Neurol 98: 147-60.
Thompson, P. R. and W. Fast (2006). "Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock?" ACS Chem Biol 1(7): 433-41.
Protein citrullination, a once-obscure post-translational modification (PTM) of peptidylarginine, has recently become an area of significant interest because of its suspected role in human disease states, including rheumatoid arthritis and multiple sclerosis, and also because of its newfound role in gene regulation. One protein isozyme responsible for this modification, protein arginine deiminase 4 (PAD4), has also been proposed to "reverse" epigenetic histone modifications made by the protein arginine methyltransferases. Here, we review the in vivo and in vitro studies of transcriptional regulation by PAD4, evaluate conflicting evidence for its ability to use methylated peptidylarginine as a substrate, and highlight promising areas of future work. Understanding the interplay of multiple arginine PTMs is an emerging area of importance in health and disease and is a topic best addressed by novel tools in proteomics and chemical biology.
Thomas, P. W., S. Thomas, et al. (2006). "Psychological interventions for multiple sclerosis." Cochrane Database Syst Rev(1): CD004431.
BACKGROUND: The unpredictable, variable nature of Multiple Sclerosis (MS), and the possibility of increasing disability, means that a diagnosis can have substantial psychological consequences. OBJECTIVES: To assess the effectiveness of psychological interventions for people with MS. SEARCH STRATEGY: We searched 19 databases up to December 2004; Cochrane MS Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsychINFO, CINAHL and 14 others. We searched reference lists of articles, wrote to corresponding authors of the 13 papers identified by June 2004, and searched for trials in progress using 3 research registers. SELECTION CRITERIA: Randomised controlled trials of interventions described as wholly or mostly based on psychological theory and practice, in people with MS. Primary outcome measures were disease specific and general quality of life, psychiatric symptoms, psychological functioning, disability, and cognitive outcomes. Secondary outcome measures were number of relapses, pain, fatigue, health care utilisation, changes in medication, and adherence to other therapies. DATA COLLECTION AND ANALYSIS: Pertinent studies were identified from abstracts by one author. Full papers were independently compared to selection criteria by four authors. Key details were extracted from relevant papers using a standard format, and studies scored on three dimensions of quality. The review is organised into four mini-reviews (MR) dependent on the intervention's target population; people with cognitive impairments (MR1), people with moderate to severe disability (MR2), people with MS (no other criteria) (MR3), and people with depression (MR4). MAIN RESULTS: Overall 16 studies were identified and included. MR1: three trials (n=145). Some evidence of effectiveness of cognitive rehabilitation on cognitive outcomes, although this was difficult to interpret because of the large number of outcome measures used. MR2: three trials (n=80). One small trial suggesting psychotherapy may help with depression. MR3: seven studies (n=688). Some evidence that cognitive behavioural therapy may help people adjust to, and cope with, having MS (three trials). The other trials were diverse in nature and some difficult to interpret because of multiple outcome measures. MR4: three trials (n=93). Two small studies of cognitive behavioural therapy showed significant improvements in depression. AUTHORS' CONCLUSIONS: The diversity of psychological interventions identified indicates the many ways in which they can potentially help people with MS. No definite conclusions can be made from this review. However there is reasonable evidence that cognitive behavioural approaches are beneficial in the treatment of depression, and in helping people adjust to, and cope with, having MS.
Theodoridou, A. and L. Settas (2006). "Demyelination in rheumatic diseases." J Neurol Neurosurg Psychiatry 77(3): 290-5.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterised by multifocal areas of demyelination in the white matter of the brain and spinal cord. Autoantibodies, for example antinuclear antibodies, can also be present. MS and other demyelinating processes, such as transverse myelitis and optic neuritis (which may be clinically isolated cases or be part of the clinical spectrum of MS), are sometimes difficult to differentiate from CNS involvement in systemic autoimmune diseases like systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Sjoegren's syndrome (SS), and Adamantiades-Behcet disease (BD). An acute isolated neurological syndrome presents the biggest diagnostic problem, since it is common in MS, but can also be the only feature or first manifestation in SLE, APS, SS, and BD. Indeed, the clinical presentation and lesions evidenced by magnetic resonance imaging may be similar.
Thacker, E. L., F. Mirzaei, et al. (2006). "Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis." Ann Neurol 59(3): 499-503.
OBJECTIVE: To characterize the association between infectious mononucleosis (IM), a frequent clinical manifestation of primary Epstein-Barr virus infection after childhood, and the risk for multiple sclerosis (MS). METHODS: We conducted a systematic review and meta-analysis of case-control and cohort studies of IM and MS. RESULTS: The combined relative risk of MS after IM from 14 studies was 2.3 (95% confidence interval, 1.7-3.0; p < 10(-8)). Potential sources of heterogeneity (ie, study design, MS definition, and latitude) barely influenced our results. INTERPRETATION: We conclude that Epstein-Barr virus infection manifesting as IM in adolescents and young adults is a risk factor for MS.
Terskikh, A. V., P. J. Bryant, et al. (2006). "Mammalian stem cells." Pediatr Res 59(4 Pt 2): 13R-20R.
Stem cells are quickly coming into focus of much biomedical research eventually aiming at the therapeutic applications for various disorders and trauma. It is important, however, to keep in mind the difference between the embryonic stem cells, somatic stem cells and somatic precursor cells when considering potential clinical applications. Here we provide the review of the current status of stem cell field and discuss the potential of therapeutic applications for blood and Immune system disorders, multiple sclerosis, hypoxic-ischemic brain injury and brain tumors. For the complimentary information about various stem cells and their properties we recommend consulting the National Institutes of Health stem cell resources (http://stemcells.nih.gov/info/basics).
Terenyi, N., J. Prechl, et al. (2006). "The role of the complement system in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis." Adv Exp Med Biol 586: 177-88.
Tekok-Kilic, A., R. H. Benedict, et al. (2006). "Update on the relationships between neuropsychological dysfunction and structural MRI in multiple sclerosis." Expert Rev Neurother 6(3): 323-31.
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS, characterized by demyelination and neurodegeneration. Besides the sensory and motor deficits that are the hallmark of this disease, approximately 50% of MS patients are cognitively impaired. Over the years, structural neuroimaging has been used widely in MS patients for both diagnostic and research purposes. Various conventional and nonconventional magnetic resonance imaging (MRI) measures have provided important information about the degree and mechanisms of cerebral pathology, and these measures correlate with cognitive and affective disturbances. In this article, recent contributions to the literature regarding the correlation between MRI and neuropsychological function in MS are reviewed.
Tateishi, N., T. Shimoda, et al. (2006). "[S100B: astrocyte specific protein]." Nihon Shinkei Seishin Yakurigaku Zasshi 26(1): 11-6.
The S100B is a Ca2+ binding proteins of EF-hand type and is produced primarily by astrocytes in the central nervous system. This protein has been implicated in the Ca2+-dependent regulation of a variety of intracellular functions such as protein phosphorylation, enzyme activities, cell proliferation and differentiation, dynamics of cytoskeleton constituents, structural organization of membranes, intracellular Ca2+ homeostasis, inflammation, and protection from oxidative cell damage. Recent studies suggest that released S100B exerts paracrine and autocrine effects on neurons and glia. On the other hand, elevations of S100B levels in blood or cerebrospinal fluid have been observed in patients with Alzheimer's disease, Down's syndrome, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, depression, cerebral stroke and traumatic brain injury, and the levels have reached micromol/L-order at focal regions. It has been documented that the excessive S100B promotes the expression of inducible nitric oxide synthase or pro-inflammatory cytokines and exhibits detrimental effects on neurons. On studies using some animal models of the cerebral stroke or Alzheimer's disease, it is suggested that the excessive S100B produced by activated astrocytes precedes neurodegenerations. Authors discussed the relationship between neurological disorders and the S100B.
Tartaglia, M. C. and D. L. Arnold (2006). "The role of MRS and fMRI in multiple sclerosis." Adv Neurol 98: 185-202.
Multiple sclerosis is now recognized as more than simply a disease of inflammation and demyelination in the brain and spinal cord. Conventional MRI has been established as the most important paraclinical tool in the diagnostic assessment of patients with suspected MS, and in the monitoring of treatment efficacy in clinical trials, at least in relapsing disease. Magnetization-transfer, diffusion-weighted MRI, 1H-MRS, and fMRI improve our ability to quantify the pathological changes in MS in vivo. Although we have gained some insight into the disease and are starting to uncover some of the structural and physiological substrates for the disability that develops in MS patients, we are far from understanding what causes MS and how to prevent its progression. Imaging can be used as a tool to better understand the pathophysiology of MS and ultimately improve on the treatment of MS.
t Hart, B. A., P. Smith, et al. (2006). "MRI-guided immunotherapy development for multiple sclerosis in a primate." Drug Discov Today 11(1-2): 58-66.
Multiple sclerosis is a serious neurological disease that affects 1 in 1000 young adults in Europe and the USA. The development of an effective therapy for this enigmatic disease is plagued by the failure of many treatments to reproduce in patients the promising effects observed in animal models. This review describes a new preclinical model in a non-human primate that might help to bridge the gap between currently used animal models and the patients.
Szczucinski, A. and J. Losy (2006). "[Infectious agents in the pathogenesis of multiple sclerosis]." Przegl Epidemiol 60 Suppl 1: 160-5.
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) of a still unknown etiology. Genetic factors, environmental agents and an autoimmune response may play an important role in the pathogenesis of MS. In the paper the current opinion on the role of infectious agents in the pathogenesis of MS is presented. The results of epidemiological and serological studies are discussed as well as the results of viral isolation attempts and the search for virus structures in the CNS of MS patients. The most important findings in the field e.g. a potential role of Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6) and bacteria Chlamydia pneumoniae in MS are presented. Postulated mechanisms of virus-induced demyelination are also described.
Sundararajan, S., Q. Jiang, et al. (2006). "PPARgamma as a therapeutic target in central nervous system diseases." Neurochem Int 49(2): 136-44.
Diseases of the central nervous system present a challenge for the development of new therapeutic agents. Nuclear receptors are ligand-activated transcription factors that have proven to be valuable targets for development of new drugs owing to their ability to directly regulate gene expression. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), has been investigated for its action in ameliorating the development and progression of a number of CNS diseases. PPARgamma agonists exhibit potent anti-inflammatory effects and appear to have direct neuroprotective actions. PPARgamma agonists have been shown to be efficacious in animal models of Alzheimer's disease, stroke, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis. The availability of FDA-approved agonists of this receptor will facilitate the rapid translation of these findings into clinical trials for a number of CNS diseases.
Strous, R. D. and Y. Shoenfeld (2006). "To smell the immune system: olfaction, autoimmunity and brain involvement." Autoimmun Rev 6(1): 54-60.
Aside from its recognition and warning functions, olfaction serves many purposes in the CNS and remains one of the most important means of communication with the environment. In addition to olfactory tract input, the olfactory bulb also receives and provides input to other brain centers that modify neuronal activity. Research in the field of immunology as well as in various brain illnesses is beginning to indicate the increasing relevance of smell in pathophysiology. Much of this is based on the many intricate interactions that exist between the immune system and the nervous system, and evidence exists that there may be something unique about the olfactory system that is inextricably related to immunological function. In addition, accumulating evidence confirms the existence of olfactory dysfunction in brain disease, much of which appears at early stages including multiple sclerosis, Alzheimer's Disease, Parkinson's Disease, schizophrenia and depression. Such observations may further suggest that under certain circumstances, olfactory abnormalities may be associated with autoimmune conditions. Since the organization of the olfactory system is so sensitive, impairment may be noted at an early stage. This may become important in the prediction of certain brain illnesses. While preliminary evidence may suggest a role for olfaction in the management and alleviation of various disorders, investigation of its clinical relevance remains limited.
Stratton, C. W. and D. B. Wheldon (2006). "Multiple sclerosis: an infectious syndrome involving Chlamydophila pneumoniae." Trends Microbiol 14(11): 474-9.
The concept of autoimmune myelinopathy as the primary pathology in multiple sclerosis (MS) is problematic. Vasculitis is seen in the MS brain, both within lesions and in adjacent normal-appearing white matter. The first observation in acute relapse is the sudden, orderly death of oligodendrocytes; inflammatory removal of unsupported myelin seems to be a secondary process. An alternative explanation for these findings is that oligodendrocyte infection might trigger an inflammatory response. Many pathogens, including Chlamydophila (Chlamydia) pneumoniae, have been associated with MS. MS might be an infectious syndrome in which C. pneumoniae has a role in a subset of patients. Mechanisms by which such a cryptic infection could engender relapsing-remitting and, ultimately, progressive disease patterns are discussed.
Steinman, L. and S. S. Zamvil (2006). "How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis." Ann Neurol 60(1): 12-21.
In their Point of View entitled "Experimental Allergic Encephalomyelitis: A Misleading Model of Multiple Sclerosis," Sriram and Steiner(1) wrote, "The most disappointing aspect of EAE [experimental allergic encephalomyelitis] as a potential model for MS is its almost total inability to point toward a meaningful therapy or therapeutic approach for MS." Actually, EAE has led directly to the development of three therapies approved for use in multiple sclerosis (MS): glatiramer acetate, mitoxantrone, and natalizumab. Several new approaches to MS are in clinical trials based on positive indications in preclinical work relying on EAE. New clues to the pathogenesis of MS and new potential surrogate markers for MS are shown from research involving EAE when it is critically coupled with actual findings in MS. There are pitfalls in overreliance on the EAE model, or on any animal model for any human disease. Nevertheless, over the past 73 years, the EAE model has proved itself remarkably useful for aiding research on MS.
Steinman, L. (2006). "State of the art. Four easy pieces: interconnections between tissue injury, intermediary metabolism, autoimmunity, and chronic degeneration." Proc Am Thorac Soc 3(6): 484-6.
Four questions are posed: (1) Can tissue damage itself provoke autoimmunity? (2) Can genetic mutations of key structures produce tissue pathology and thus provoke autoimmunity? (3) Can acute immune damage produce tissue degeneration without further hallmarks of an immune response? (4) Can intermediary metabolism modulate immune damage to tissues? Four answers are given: (1) Tissue injury itself may lead to autoimmunity. Both innate and adaptive immunity may arise as a response to tissue injury, and the immune attack can further damage tissue. (2) Genetic mutations can lead to an immune response indistinguishable from autoimmunity, exemplified from Duchenne's Muscular Dystrophy and X-linked adrenoleukodystrophy. (3) Chronic immune damage may lead to tissue degeneration, with or without further hallmarks of an immune response. Variations on this theme, including inverse scenarios, are also possible: Inborn errors of metabolism may lead to tissue damage that may provoke an adaptive and or innate immune response. The immune response might further damage tissue. (4) Finally, perturbations of intermediary metabolism may modulate the immune response, controlling the extent of immune-mediated damage. Examples are taken from perturbations in the cholesterol pathway that influence the characteristics of the immune response, and with tryptophan metabolites that modulate autoimmunity and graft rejection. Inflammatory, degenerative, and autoimmune neurological disease will be discussed in terms of their implications for pathogenic mechanisms underlying chronic obstructive pulmonary disease.
Steffens, S. and F. Mach (2006). "Drug insight: Immunomodulatory effects of statins--potential benefits for renal patients?" Nat Clin Pract Nephrol 2(7): 378-87.
Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase, an enzyme crucial to cholesterol synthesis. Drugs of this class reduce the risk of coronary heart disease and stroke, in large part through lipid modulation. Emerging evidence indicates that statins have additional modes of action. These actions, which encompass modification of endothelial function, plaque stability, thrombus formation and inflammatory pathways, are widely referred to as 'pleiotropic effects'. These pleiotropic effects indicate that the therapeutic potential of statins might extend beyond cholesterol lowering and cardiovascular disease to other inflammatory disorders or conditions such as transplantation, multiple sclerosis, rheumatoid arthritis and chronic kidney disease. Experimental and clinical data provide evidence to support these broader applications of statins; however, more large-scale trials are needed to clarify the therapeutic benefit.
Stangel, M., R. Gold, et al. (2006). "Current issues in immunomodulatory treatment of multiple sclerosis--a practical approach." J Neurol 253 Suppl 1: I32-6.
Stangel, M. and C. Trebst (2006). "Remyelination strategies: new advancements toward a regenerative treatment in multiple sclerosis." Curr Neurol Neur