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Multiple Sclerosis References 2003; Authors: N-O
(39 References)
Nagai, A., M. Terashima, et al. (2003). "Cathepsin B and H activities and cystatin C concentrations in cerebrospinal fluid from patients with leptomeningeal metastasis." Clin Chim Acta 329(1-2): 53-60.
BACKGROUND: Cysteine proteases are involved in the extension of cancer into the subarachnoid space. The presence of cathepsins B and H along with their potent inhibitor cystatin C in the cerebrospinal fluid (CSF) was investigated in patients with leptomeningeal metastasis of cancer (LM). MATERIALS AND METHODS: CSF samples were obtained in 16 cases of LM (10 solid tumors and 6 leukemia or lymphoma) and compared with 11 cancer cases without involvement of the central nervous system, 12 multiple sclerosis cases and 34 healthy volunteers. The activity of the enzymes was measured, their molecular forms were analyzed by the Western blotting, and the concentration of cystatin C was measured by ELISA. Immunohistochemistry of the leptomeningeal tissues was also performed in six autopsy cases of LM. RESULTS: High activities of cathepsins B and H along with decreased cystatin C concentration were observed in CSF of LM as compared with three control groups. Western blot analysis revealed higher concentration of the enzyme protein as well as its active forms in samples with higher enzyme activity. Cells metastasizing leptomeningeal tissue were clearly positive in immunohistochemical staining of cathepsins, indicating active production by tumor cells. CONCLUSION: Production of cathepsins B and H by tumor cells and their high activity along with concomitant decrease of their potent inhibitor, cystatin C, in the CSF might contribute in the process of metastasis and spread of the cancer cells in the leptomeningeal tissues. A high enzyme activity/cystatin C concentration ratio in the CSF could be useful when diagnosing LM in combination with other parameters.
Nakahara, J., C. Seiwa, et al. (2003). "Expression of Fc receptor for immunoglobulin M in oligodendrocytes and myelin of mouse central nervous system." Neurosci Lett 337(2): 73-6.
Recent advances in neuro-immunology are beginning to elucidate several essential roles of the humoral immunity in both repair and pathogenesis of central nervous system diseases. Immunoglobulin M (IgM) was reported to accelerate the rate of remyelination in a demyelinating disease model, while intrathecal IgM synthesis was shown to predict a more worse disease course in a human demyelinating disease, multiple sclerosis. Molecular mechanisms for either of these IgM functions remain to be studied. Here we report that a recently-found Fc receptor for IgM, namely Fcalpha/muR, is expressed in oligodendrocytes, their precursor cells, and myelin. These expressions were confirmed by immunocytochemistry of cultured cells, Western blot analysis of myelin fractions, and also by immunohistochemistry of mouse forebrains at different ages. Our findings suggest a possible direct interaction between IgM and Fcalpha/muR expressed in oligodendrocytes and myelin.
Nakanishi, H. (2003). "Microglial functions and proteases." Mol Neurobiol 27(2): 163-76.
There is accumulating evidence that intracellular and extracellular proteases of microglia contribute to various events in the central nervous system (CNS) through both nonspecific and limited proteolysis. Cathepsin E and cathepsin S, endosomal/lysosomal proteases, have been shown to play important roles in the major histocompatibility complex (MHC) class II-mediated antigen presentation of microglia by processing of exogenous antigens and degradation of the invariant chain associated with MHC class II molecules, respectively. Some members of cathepsins are also involved in neuronal death after secreted from microglia and clearance of phagocytosed amyloid- beta peptides. Tissue-type plasminogen activator, a serine protease, secreted from microglia participates in neuronal death, enhancement of N-methyl-D-aspartate receptor-mediated neuronal responses, and activation of microglia via either proteolytic or nonproteolytic activity. Calpain, a calcium-dependent cysteine protease, has been shown to play a pivotal role in the pathogenesis of multiple sclerosis by degrading myelin proteins extracellulary. Furthermore, matrix metalloproteases secreted from microglia also receive great attention as mediators of inflammation and tissue degradation through processing of pro-inflammatory cytokines and damage to the blood-brain barrier. The growing knowledge about proteolytic events mediated by microglial proteases will not only contribute to better understanding of microglial functions in the CNS but also may aid in the development of protease inhibitors as novel neuroprotective agents.
Napier, J. C., R. Francis, et al. (2003). "Shared scheme for assessing drugs for multiple sclerosis: cost effective provision of effective treatments for multiple sclerosis." Bmj 326(7400): 1212.
Narayana, K. M., R. Agrawal, et al. (2003). "Recurrent anterior uveitis and healed retinal vasculitis associated with multiple sclerosis." Indian J Ophthalmol 51(1): 77-9.
We describe the occurrence of anterior uveitis with healed retinal vasculitis in an Asian-Indian woman. She had features of anterior uveitis and healed retinal vasculitis. This rare disease in India may be associated with intraocular inflammation.
Nash, R. A., J. D. Bowen, et al. (2003). "High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis." Blood.
Twenty-six patients were enrolled in a pilot study of high-dose immunosuppressive therapy (HDIT) for severe multiple sclerosis (MS). Median baseline Expanded Disability Status Scale (EDSS) was 7.0 (5.0-8.0). HDIT consisted of total body irradiation, cyclophosphamide and antithymocyte globulin (ATG) and was followed by transplantation of autologous, G-CSF-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were eight infectious events of the lower urinary tract. One patient died from EBV-PTLD associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever +/- rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurological symptoms. Two significant adverse neurologic events occurred, including a flare of MS during mobilization and an episode of irreversible neurological deterioration after HDIT associated with fever. With a median follow-up of 24 (3-36) months, the Kaplan-Meier estimate of progression (>/=1.0 points EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. Four patients developed new enhancing lesions on magnetic resonance imaging of the brain after HDIT. The estimate of survival at 3 years was 91%. Important clinical issues in the use of HDIT and stem cell transplantation for MS were identified; however, modifications of the initial approaches appear to reduce treatment risks. This was a heterogeneous high-risk group, and a phase III study is planned to fully assess efficacy.
Nayak, S., R. J. Matheis, et al. (2003). "Use of unconventional therapies by individuals with multiple sclerosis." Clin Rehabil 17(2): 181-91.
OBJECTIVE: To examine the prevalence and patterns of use of complementary and alternative medicine (CAM) among individuals with multiple sclerosis (MS) in the USA and to explore the reasons for use, symptoms treated and perceived effectiveness of these therapies. METHODS: Surveys were mailed to the entire mailing list of the MS Foundation, constituting 11,600 individuals with MS or their family members; 3,140 adults with MS returned surveys, yielding a response rate of 27.1%. RESULTS: More than half of the responding sample (57.1%) had used at least one CAM modality. The longer that people had MS and the less satisfied they were with conventional health care the more likely they were to use CAM therapies. The most common reasons for using CAMs were the desire to use holistic health care (i.e., treatments that recognized the interrelatedness of mind, body and spirit) and dissatisfaction with conventional medicine. Ingested herbs were the most frequently used CAM modalities (26.6%), followed by chiropractic manipulation (25.5%), massage (23.3%) and acupuncture (19.9%). Women were 25% more likely than men and whites were 30% more likely than non-whites to use CAM therapies. There was no significant relationship between the frequency of use and the reported efficacy of the CAM techniques (r = 0.17, p > 0.10). CONCLUSIONS: The prevalence of CAM use in this population warrants more research on the efficacy and safety of these therapies, especially those with high usage or high efficacy ratings, such as herbs, chiropractic manipulation and massage, but for which there is little or no research evidence for efficacy or safety.
Nejentsev, S., M. Laaksonen, et al. (2003). "Intercellular adhesion molecule-1 K469E polymorphism: study of association with multiple sclerosis." Hum Immunol 64(3): 345-9.
Intercellular adhesion molecule-1 (ICAM-1) is involved in the pathogenesis of multiple sclerosis (MS), whereas sequence variations in the ICAM-1 gene could potentially be responsible for the genetic susceptibility to MS. We studied an association of MS with the 13,848A>G (K469E) polymorphism of the ICAM-1 gene in Finnish and Spanish cases and controls and affected families. An increased risk for the AA (Lys(469)/Lys(469)) genotype was found in both populations. The effect observed was found to be strongest among the HLA-DQB1*0602-positive subjects, which implies genetic heterogeneity of MS. Meta-analysis of all published datasets supports increased risk of MS for the ICAM-1 Lys(469) homozygotes (relative risk = 1.3, p = 0.002).
Nelissen, I., E. Martens, et al. (2003). "Gelatinase B/matrix metalloproteinase-9 cleaves interferon-beta and is a target for immunotherapy." Brain 126(Pt 6): 1371-81.
Parenteral administration of interferon (IFN)-beta is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of gelatinase B, also called matrix metalloproteinase (MMP) 9. Gelatinase B is capable of destroying the blood-brain barrier, and of cleaving myelin basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and being a therapeutic target in multiple sclerosis. Here we demonstrate that gelatinase B proteolytically cleaves IFN-beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline minocycline, which has a known blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhibitors prevent the in vitro degradation of IFN-beta by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-beta has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-beta may reduce the side-effects of treatment with IFN-beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
Neri, M. T. and T. Kroll (2003). "Understanding the consequences of access barriers to health care: experiences of adults with disabilities." Disabil Rehabil 25(2): 85-96.
PURPOSE: The study explores: (1) the scope and nature of the consequences that adults with disabilities perceive as the result of inappropriate access to health care services; (2) the variability of these consequences by demographic attributes such as disability type, gender, and health insurance type; and (3) the inter-relatedness and multidimensionality of these consequences. METHODS: Qualitative, semi-structured, in-depth interviews were administered over the telephone to 30 participants with spinal cord injury, cerebral palsy, or multiple sclerosis as part of a nation-wide study on access and utilisation in the USA. Interviews were transcribed and coded for analysis using the qualitative analysis program, NVivo. RESULTS: Consequences were grouped into one of five categories: social, psychological, physical, economic and independence issues. Responses differed slightly with regard to disability type, gender and health insurance type. There was substantial overlap among consequence categories. For most respondents, negative consequences were not limited to just one area--frequently, one consequence triggered others. CONCLUSIONS: Health insurers and providers need a better understanding of the multiple consequences of access barriers. Based on this knowledge, detrimental and costly effects of inappropriate service delivery could be more effectively prevented. Implications for health care services and policy are discussed.
Neuhaus, O., J. J. Archelos, et al. (2003). "Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection." Trends Pharmacol Sci 24(3): 131-8.
Multiple sclerosis (MS) is the most common disabling neurological disease of young adulthood. Following advances in the understanding of the immunological mechanisms that underlie the pathogenesis of MS, a growing arsenal of immunomodulatory agents is available. Two classes of immunomodulators are approved for long-term treatment of MS, the efficacy of several promising new concepts is being tested in clinical trials and classical immunosuppressive agents used in MS treatment have been shown to exert specific, immunomodulatory effects. Furthermore, two recent observations have changed our basic understanding of the pathogenesis of MS. First, immune cells in MS lesions have neuroprotective activity, which indicates a beneficial role of neuroinflammation. Second, there is evidence that axonal loss, rather than demyelination, underlies the progression of MS and, hence, constitutes a therapeutic target.
Neumann, H. (2003). "Molecular mechanisms of axonal damage in inflammatory central nervous system diseases." Curr Opin Neurol 16(3): 267-73.
PURPOSE OF REVIEW: Axonal dysfunction and damage is an early pathological sign of autoimmune central nervous system disease, viral and bacterial infections, and brain trauma. Axonal injury has attracted considerable interest during the past few years because the degree of axonal damage appears to determine long-term clinical outcome. RECENT FINDINGS: Advanced magnetic resonance spectroscopic imaging techniques have suggested that axonal loss and dysfunction is responsible for the persistent neurological deficits that occur in patients with multiple sclerosis. Histopathological methods have shown that axonal damage is defined primarily by dysfunction of axonal transport, and finally by complete transection and degeneration of axons. Recent studies have demonstrated that the extent of axonal damage in the primary demyelinating lesion of multiple sclerosis patients is associated with the number of activated microglia/macrophages and cytotoxic CD8+ T lymphocytes. In addition, diffuse axonal dysfunction independent of demyelination develops in normal appearing white matter, possibly due to indirect effects of inflammation. SUMMARY: The fact that axonal damage in response to overt inflammatory reactions may occur gradually, leaving a window for therapeutical intervention, has important clinical implications. Determination of the exact molecular mechanism might help in finding new therapies for inflammatory axonal damage.
Nguyen, L. T., M. Ramanathan, et al. (2003). "Sex differences in in vitro pro-inflammatory cytokine production from peripheral blood of multiple sclerosis patients." J Neurol Sci 209(1-2): 93-9.
We compared the patterns of the pro-inflammatory cytokines, interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory cytokines, interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta) from peripheral blood of male and female patients with relapsing-remitting (RR) and secondary progressive (SP) forms of multiple sclerosis (MS). The relationships between pro-inflammatory cytokines and disability (expanded disability status scale, EDSS) were also examined.Peripheral blood anti-coagulated with heparin was obtained from 47 MS patients (30 women and 17 men) and activated with phorbol-12-myristate 13 acetate (PMA) and ionomycin in the presence of brefeldin A and stained for flow cytometry with fluorescently labeled antibodies against intracellular IFN-gamma, TNF-alpha, IL-2, IL-4 and IL-10. The T cells were delineated with peridinin chlorophyll protein (Per-CP) labeled anti-CD3 antibody. The stained samples were analyzed on a flow cytometer to assess the intracellular pro-inflammatory cytokine patterns. The levels of interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta) were measured in plasma using enzyme-linked immunoassay.The percentage of TNF-alpha-producing CD3 positive cells was significantly higher (P=0.045) in men (mean+/-S.D., 39+/-13%) than in women (mean+/-S.D., 29+/-13%) RR-MS patients. The percentage of CD3 positive cells producing IFN-gamma was significantly correlated with EDSS in females but not in males (Spearman rank correlation r(S)=0.49, P=0.018). The secretion of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha, is influenced by gender in MS patients and may contribute to the sexual dimorphism of MS.
Nicholas, R. S., J. Partridge, et al. (2003). "The role of the PTPRC (CD45) mutation in the development of multiple sclerosis in the North West region of the United Kingdom." J Neurol Neurosurg Psychiatry 74(7): 944-5.
BACKGROUND: A point mutation in protein tyrosine phosphatase receptor, type c polypeptide (PTPRC) has been associated with familial multiple sclerosis. This CG mutation at position 77 of exon 4 results in altered expression of CD45 isoforms on immune cells. OBJECTIVE: To study the incidence of PTPRC mutations in subjects with multiple sclerosis in the North West region of the United Kingdom. METHODS: Affected and unaffected subjects from five pedigrees with familial multiple sclerosis, 330 non-familial cases of multiple sclerosis, and 197 controls were studied. Genomic DNA was amplified using CD45IE34 and CD45IE44 primers, digested with Mspl, and run on an agarose gel. Polymerase chain reaction products were sequenced to exclude any other mutations. RESULTS: No PTPRC exon 4 genomic mutations were seen in any of the five families. In the non-familial cases the incidence of mutation was 4.1% in 197 controls and 5.1% in 330 multiple sclerosis patients. No significant association was found in this study with this mutation and disease susceptibility, sex, or an extended disability scale score of < 5.5. CONCLUSIONS: This candidate does not appear to influence the development of familial multiple sclerosis in this population. The negative result could arise from a type II error owing to the number of families and non-familial cases screened. Alternatively it might suggest that the contribution of the PTPRC mutation depends upon the genetic background.
Nicot, A., P. V. Ratnakar, et al. (2003). "Regulation of gene expression in experimental autoimmune encephalomyelitis indicates early neuronal dysfunction." Brain 126(Pt 2): 398-412.
Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Whereas oligodendrocytes have been considered the primary neural cell type most affected, recent evidence indicates that axonal and neuronal degeneration also occurs in both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model reproducing many features of multiple sclerosis. The molecular mechanisms underlying neuronal deficits in multiple sclerosis and EAE remain elusive. To address this issue, we have analysed the expression of genes encoding proteins that play critical roles in ion homeostasis, exocytosis, mitochondrial function and impulse conduction in the Lewis rat lumbar spinal cord during the clinical course of acute EAE. Transcript and protein levels of plasma membrane Ca(2+) ATPase 2 (PMCA2), an essential ion pump expressed exclusively in grey matter and involved in Ca(2+) extrusion, synapsin IIa and syntaxin 1B, important regulators of vesicular exocytosis, were dramatically decreased coincident with the onset of clinical symptoms. In contrast, changes in the expression of several other ion pumps, vesicular proteins, mitochondrial enzymes and sodium channels occurred at more advanced disease stages. Moreover, exposure of spinal cord slice cultures to kainic acid significantly reduced PMCA2 mRNA levels. Taken together, our findings suggest that glutamate, which recently has been implicated in EAE pathogenesis, suppresses neuronal PMCA2 expression leading to Ca(2+) dyshomeostasis at initial clinical phases. Consequently, perturbations in Ca(2+) balance and neurotransmitter exocytosis may partially underlie aberrant neuronal function and communication at onset of symptoms. Altered mitochondrial function and impulse conduction may exacerbate neurological deficits at subsequent disease stages.
Niederwieser, G., W. Buchinger, et al. (2003). "Prevalence of autoimmune thyroiditis and non-immune thyroid disease in multiple sclerosis." J Neurol 250(6): 672-5.
Since multiple sclerosis (MS) and autoimmune thyroiditis (AIT) are presumed to be of autoimmune origin the correlation of these two diseases is of special interest. The aim of this study was to determine whether there are differences in the prevalence of thyroid disease with special emphasis on AIT compared with MS and normal subjects and whether the presence of thyroid disease correlates with disability, disease course, age, and disease duration. 353 consecutive patients with clinically definite MS, without interferon-beta treatment and 308 patients with low back pain or headache were extensively examined for the presence of non-immune or autoimmune thyroid disease. We found a significantly higher prevalence of AIT in male MS patients (9.4 %) than in male controls (1.9 %; p = 0.03). The prevalence of AIT in female MS patients (8.7 %) did not differ from female controls (9.2 %). Hypothyroidism, caused by AIT in almost all cases, showed a tendency to be more severe and more often present in patients with MS. There was no association between relapsing-remitting and secondary progressive disease course of MS and the prevalence of AIT. MS patients with AIT were significantly older but did not differ in disease duration and expanded disability status scale (EDSS). Further studies are warranted, to see if there is a difference in sex-hormone levels between MS patients with and without AIT and healthy controls. Longitudinal studies comparing MS patients with or without AIT could show whether there is an influence of AIT on the disease course or progression.
Niino, M., S. Kikuchi, et al. (2003). "Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients." J Neuroimmunol 136(1-2): 125-9.
Osteopontin (OPN) exhibits pleiotropic functions and abundant transcripts for OPN are present in brains of patients with multiple sclerosis (MS). The aim of this study was to investigate the role of OPN genes in the pathogenesis of MS. Polymorphisms at the 8090th, 9250th and 9583rd positions in OPN were detected by PCR-RFLP from DNAs of 116 MS Japanese patients and 124 healthy controls. The C/C genotype at the 8090th position in exon 6 was more prevalent in MS than in control (p<0.0001), and C allele was more prevalent in MS than in control (p<0.0001, OR=2.57, 95% CI=1.65-4.00). For the 9583rd position polymorphism in exon 7, patients with G/G genotype (age; 32.1+/-12.5 years, mean+/-S.D.) showed a later disease onset than G/A (age; 25.9+/-7.8 years, p=0.01) and A/A (age; 25.2+/-8.9 years, p=0.01) genotypes. There were no significant correlations between OPN gene polymorphisms and disease progression. Our results suggest that the 8090th polymorphism might be associated with susceptibility to MS, while the 9583rd polymorphism might be associated with age of onset of MS.
Nilsson, F. M., L. V. Kessing, et al. (2003). "Affective disorders in neurological diseases: a case register-based study." Acta Psychiatr Scand 108(1): 41-50.
OBJECTIVE: To investigate the temporal relationships between a range of neurological diseases and affective disorders. METHOD: Data derived from linkage of the Danish Psychiatric Central Register and the Danish National Hospital Register. Seven cohorts with neurological index diagnoses and two control group diagnoses were followed for up to 21 years. The incidences of affective disorders in the different groups were compared with the control groups, using competing risks to consider the risk of affective disorder and the risk of death in the same analysis. RESULTS: We found an increased incidence of affective disorders in dementia, Parkinson's disease, epilepsy, stroke and intracerebral haemorrhage compared with control groups. The association was found to be the strongest for dementia and Parkinson's disease. In hospitalized patients, with incident multiple sclerosis, the incidence of affective disorder was lower than the incidence in the control groups. CONCLUSION: In neurological diseases there seems to be an increased incidence of affective disorders. The elevated incidence was found to be particularly high for dementia and Parkinson's disease (neurodegenerative diseases).
Nortvedt, M. W. and T. Riise (2003). "The use of quality of life measures in multiple sclerosis research." Mult Scler 9(1): 63-72.
Quality of life research contributes knowledge essential to the health and healthcare of multiple sclerosis (MS) patients. This article reviews 83 MS studies in English that have presented data on quality of life. The studies may be classified into three categories, according to the application and the main focus: 1) evaluating the development and validity of quality of life questionnaires and clinical scales (n = 27); 2) evaluating factors that might influence the quality of life or comparing the quality of life among various groups (n = 37); and 3) using quality of life questionnaires as outcome measures in medical trials and other interventions (n = 19). The studies have shown that quality of life questionnaires more broadly measure the impact of MS than do the most frequently used measures of disease activity and effects. Using quality of life measures provides additional information in evaluating the effects of treatment and in studying the development of the disease. Such information is crucial in planning interventions for MS patients. A challenge in this field is to improve the study designs, including reaching some agreement on how to measure the quality of life.
Noseworthy, J. H. (2003). "Management of multiple sclerosis: current trials and future options." Curr Opin Neurol 16(3): 289-97.
PURPOSE OF THE REVIEW: The present review of multiple sclerosis (MS) therapeutic trials published in 2002 is intended to assist the reader in understanding the most current advances in the care of their patients. RECENT FINDINGS: A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of patients with MS. Several short-term studies in relapsing/remitting MS have demonstrated that it is possible to complete head-to-head comparison trials of active agents in MS (e.g. without a placebo control group). The findings of these trials remain open to interpretation and have generated considerable controversy, as expected. A phase 3 trial [the International MS Secondary Progressive Avonex Controlled Trial (IMPACT)] became the fourth study of the beta interferons (interferon-beta-1a, in this case) to demonstrate a partial effect on disease activity in secondary progressive MS. Two trials demonstrated apparent partial efficacy for the anthrecenedione mitoxantrone in active and progressive MS. Disappointing results were announced for a number of large pivotal trials, although those results have not yet been published (e.g. oral glatiramer acetate in relapsing/remitting MS, glatiramer acetate in primary progressive MS, and intravenous immunoglobulin in secondary progressive MS). SUMMARY: The MS research community needs to determine how best to address two key unanswered questions. Is late clinical deterioration often or invariably tied to the initial inflammatory/demyelinating phase of the disease? What is the optimal research design to address whether current and future experimental strategies affect the later phases of MS (e.g. does early treatment delay or prevent clinical disability)?
Noseworthy, J. H. (2003). "Treatment of multiple sclerosis and related disorders: what's new in the past 2 years?" Clin Neuropharmacol 26(1): 28-37.
Noseworthy, J., L. Kappos, et al. (2003). "Competing interests in multiple sclerosis research." Lancet 361(9354): 350-1.
Nowak, J., D. Januszkiewicz, et al. (2003). "Multiple sclerosis-associated virus-related pol sequences found both in multiple sclerosis and healthy donors are more frequently expressed in multiple sclerosis patients." J Neurovirol 9(1): 112-7.
In the etiopathogenesis of multiple sclerosis (MS), both genetic and environmental factors play an important role. Among environmental factors, viral infections are most likely connected with the etiology of MS. There are many evidence suggesting possible involvement of retroviruses in the development of autoimmune diseases including MS. Multiple sclerosis-associated retrovirus (MSRV) seems to be the important candidate for viral etiology of MS. The aim of the study was to analyze MSRV pol sequences in patients with MS. As control, groups of myasthenia gravis, Parkinson's disease, and migraine patients, and healthy individuals have been studied. The MSRV pol sequences have been analyzed in RNA isolated from the serum and in DNA and RNA of peripheral blood lymphocytes from untreated MS patients and control groups. The MSRV pol sequences have been detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and PCR technique, using specific oligonucleotide primers. In the serum RNA (cDNA), MSRV pol sequences have been identified in 31/32 MS patients. MSRV pol sequences were detected in serum cDNA of 9/17 myasthenia gravis patients, 7/16 Parkinson's disease patients, 10/21 migraine patients, and 13/27 healthy individuals. MSRV pol sequences were observed also in RNA from lymphocytes of all MS patients, 12/17 myasthenia gravis patients, 9/16 Parkinson's disease patients, 14/21 migraine patients, and 18/27 healthy donors. In the DNA from peripheral blood lymphocytes of all studied patients and healthy individuals, MSRV pol sequences have been found. The observed pattern of fiber-fluorescence in situ hybridization (FISH) signals suggests the presence of multiple copies of MSRV pol sequences, most likely tandemly dispersed in the genome. It can be concluded that MSRV pol sequences are endogenous, widespread in lymphocytes DNA, and transcribed into RNA of MS patients as well as of other studied patients and healthy individuals. However, more frequent expression of MSRV sequences detected in lymphocytes RNA (cDNA), as well as their presence in higher frequency in the serum of MS patients, may suggest the involvement of MSRV in the etiopathogenesis on MS.
Nyul, L. G., J. K. Udupa, et al. (2003). "Incorporating a measure of local scale in voxel-based 3-D image registration." IEEE Trans Med Imaging 22(2): 228-37.
We present a new class of approaches for rigid-body registration and their evaluation in studying multiple sclerosis (MS) via multiprotocol magnetic resonance imaging (MRI). Three pairs of rigid-body registration algorithms were implemented, using cross-correlation and mutual information (MI), operating on original gray-level images, and utilizing the intermediate images resulting from our new scale-based method. In the scale image, every voxel has the local "scale" value assigned to it, defined as the radius of the largest ball centered at the voxel with homogeneous intensities. Three-dimensional image data of the head were acquired from ten MS patients for each of six MRI protocols. Images in some of the protocols were acquired in registration. The registered pairs were used as ground truth. Accuracy and consistency of the six registration methods were measured within and between protocols for known amounts of misregistrations. Our analysis indicates that there is no "best" method. For medium misregistration, the method using MI, for small add large misregistration the method using normalized cross-correlation performs best. For high-resolution data the correlation method and for low-resolution data the MI method, both using the original gray-level images, are the most consistent. We have previously demonstrated the use of local scale information in fuzzy connectedness segmentation and image filtering. Scale may also have potential for image registration as suggested by this work.
O'Connor, K. C., T. Chitnis, et al. (2003). "Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions." J Neuroimmunol 136(1-2): 140-8.
The presence of autoantibodies to the immunodominant antigen, myelin basic protein (MBP), in the serum and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) has been poorly characterized. Many studies report detectable levels of autoantibodies to myelin basic protein though other studies, using similar techniques, report their absence. We compared a solution-phase assay that has detected clinically relevant autoantibodies in diabetes and other autoimmune diseases to solid phase assays similar to those used in previous reports. The solution-phase assay consistently measured autoantibodies to MBP in serum from human subjects with Semple rabies vaccine (SRV)-induced demyelinating disease and from MBP-immunized animals. A solid phase assay detected MBP autoantibodies in the serum of a fraction of patients with MS. Autoantibodies capable of binding to MBP in the solution-phase were not detected in the CSF or serum of patients with MS. Additional solution-phase measurements revealed that anti-MBP antibodies from individuals with SRV-induced demyelinating disease demonstrated a binding affinity profile consistent with that of polyclonal antibodies with a range of affinities from low to high. In contrast, antibodies to MBP in the serum of MS patients detected by ELISA did not bind soluble MBP in the same assay. These results indicate that the humoral response in patients with MS does not include moderate- or high-affinity autoantibodies to MBP.
O'Donovan, M. (2003). "Infection and multiple sclerosis." J Neurol Neurosurg Psychiatry 74(5): 693.
Offit, P. A. and C. J. Hackett (2003). "Addressing parents' concerns: do vaccines cause allergic or autoimmune diseases?" Pediatrics 111(3): 653-9.
Anecdotal case reports and uncontrolled observational studies in the medical literature claim that vaccines cause chronic diseases such as asthma, multiple sclerosis, chronic arthritis, and diabetes. Several biological mechanisms have been proposed to explain how vaccines might cause allergic or autoimmune diseases. For example, allergic diseases might be caused by prevention of early childhood infections (the "hygiene hypothesis"), causing a prolongation of immunoglobulin E-promoting T-helper cell type 2-type responses. However, vaccines do not prevent most common childhood infections, and large well-controlled epidemiologic studies do not support the hypothesis that vaccines cause allergies. Autoimmune diseases might occur after immunization because proteins on microbial pathogens are similar to human proteins ("molecular mimicry") and could induce immune responses that damage human cells. However, wild-type viruses and bacteria are much better adapted to growth in humans than vaccines and much more likely to stimulate potentially damaging self-reactive lymphocytes. Consistent with critical differences between natural infection and immunization, well-controlled epidemiologic studies do not support the hypothesis that vaccines cause autoimmunity. Flaws in proposed biological mechanisms that explain how vaccines might cause chronic diseases are consistent with the findings of many well-controlled large epidemiologic studies that fail to show a causal relationship.
Oikonen, M., M. Laaksonen, et al. (2003). "Ambient air quality and occurrence of multiple sclerosis relapse." Neuroepidemiology 22(1): 95-9.
Infectious viruses and bacteria can trigger multiple sclerosis (MS) exacerbations. Seasonally changing concentrations of ambient air pollutants are known to predispose to transmissible infections, to induce systemic immune responses and to enhance existing peripheral inflammation. Ambient air quality and monthly MS relapse occurrence in south-western Finland were compared by multivariate logistic regression. The odds ratio of the risk of a relapse onset was over fourfold (4.143, p < 0.001) when the concentration of inhalable particulate matter (PM(10)) was at the highest quartile. Inhalable airborne particulate matter concentrations were connected to relapse occurrence. Poor air quality may enhance the seasonal changes in MS relapse occurrence by an increased susceptibility to transmissible infections.
Okafor, M. C. (2003). "Thalidomide for erythema nodosum leprosum and other applications." Pharmacotherapy 23(4): 481-93.
Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.
Oliveira, E. M., A. Bar-Or, et al. (2003). "CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls." J Autoimmun 20(1): 71-81.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, thought to be mediated in part by an autoimmune response of T cells to protein components of the myelin sheath. The reaction of nai;ve T cells against these antigens requires co-stimulation through CD28. However, the proliferative response of peripheral blood mononuclear cells isolated from patients with MS and stimulated with myelin basic protein (MBP) has been shown to be relatively independent of B7-CD28 co-stimulation, suggesting that dysregulation of co-stimulatory pathways may be involved in the pathogenesis of MS. Here, the role of CTLA-4 engagement was investigated. As expected, blocking CTLA-4-mediated signaling during stimulation of MBP-reactive T cells from healthy controls enhanced the proliferative and cytokine responses. In contrast, CTLA-4 blockade had less effect in patients with MS, suggesting that at least two regulatory mechanisms may be impaired in these individuals. Understanding how co-stimulatory signals may be dysregulated in patients with MS is important at a time when targeting of these pathways is being developed.
Olsson, T. (2003). "[Humanized antibodies against an adhesion molecule block the CNS inflammation in multiple sclerosis]." Lakartidningen 100(19): 1705.
Ooka, S., T. Matsui, et al. (2003). "Autoantibodies to low-density-lipoprotein-receptor-related protein 2 (LRP2) in systemic autoimmune diseases." Arthritis Res Ther 5(3): R174-80.
We previously reported that autoantibodies (autoAbs) to the main epitope on CD69 reacted to its homologous amino acid sequence in low-density-lipoprotein-receptor-related protein 2 (LPR2), a multiligand receptor for protein reabsorption. In this study, we have investigated the prevalence, autoepitope distribution, and clinical significance of the autoAbs to LRP2 in patients with systemic autoimmune diseases. Using six recombinant proteins (F2-F7) for LRP2 and one for CD69, we detected autoAbs to LRP2 in sera of patients with rheumatoid arthritis (RA), systemic lupus erythematosus, Behcet's disease, systemic sclerosis, and osteoarthritis and then mapped autoepitopes by Western blotting. The autoAbs to LRP2 were detected in 87% of the patients with rheumatoid arthritis, 40% of those with systemic lupus erythematosus, 35% of those with systemic sclerosis, 15% of those with osteoarthritis, and 3% of those with Behcet's disease. Multiple epitopes on LRP2 were recognized by most of the anti-LRP2+ serum samples. All of the tested anti-CD69 autoAb+ samples reacted to LRP2-F3 containing the homologous sequence to the main epitope of CD69; however, only 38% of the anti-LRP2-F3+ samples reacted to CD69. Clinically, the existence of the autoAbs to LRP2-F4, -F5, and -F6 correlated with the presence of proteinuria in RA. This study revealed that LRP2 is a major autoantigen in RA. The autoAbs to LRP2 are probably produced by the antigen-driven mechanism and the autoimmunity to LRP2 may spread to include CD69. The anti-LRP2 autoAbs may play pathological roles by inhibiting the reabsorbing function of LRP2.
Optic Neuritis Study, G. (2003). "High- and Low-Risk Profiles for the Development of Multiple Sclerosis Within 10 Years After Optic Neuritis: Experience of the Optic Neuritis Treatment Trial." Arch Ophthalmol 121(7): 944-949.
OBJECTIVE: To identify factors associated with a high and low risk of developing multiple sclerosis after an initial episode of optic neuritis. METHODS: Three hundred eighty-eight patients who experienced acute optic neuritis between July 1, 1988, and June 30, 1991, were followed up prospectively for the development of multiple sclerosis. Consenting patients were reassessed after 10 to 13 years. RESULTS: The 10-year risk of multiple sclerosis was 38% (95% confidence interval, 33%-43%). Patients (160) who had 1 or more typical lesions on the baseline magnetic resonance imaging (MRI) scan of the brain had a 56% risk; those with no lesions (191) had a 22% risk (P<.001, log rank test). Among the patients who had no lesions on MRI, male gender and optic disc swelling were associated with a lower risk of multiple sclerosis, as was the presence of the following atypical features for optic neuritis: no light perception vision; absence of pain; and ophthalmoscopic findings of severe optic disc edema, peripapillary hemorrhages, or retinal exudates. CONCLUSIONS: The 10-year risk of multiple sclerosis following an initial episode of acute optic neuritis is significantly higher if there is a single brain MRI lesion; higher numbers of lesions do not appreciably increase that risk. However, even when brain lesions are seen on MRI, more than 40% of the patients will not develop clinical multiple sclerosis after 10 years. In the absence of MRI lesions, certain demographic and clinical features seem to predict a very low likelihood of developing multiple sclerosis. This natural history information is a critical input for estimating a patient's 10-year multiple sclerosis risk and for weighing the benefit of initiating prophylactic treatment at the time of optic neuritis or other initial demyelinating events in the central nervous system.
Ostenfeld, T. and C. N. Svendsen (2003). "Recent advances in stem cell neurobiology." Adv Tech Stand Neurosurg 28: 3-89.
1. Neural stem cells can be cultured from the CNS of different mammalian species at many stages of development. They have an extensive capacity for self-renewal and will proliferate ex vivo in response to mitogenic growth factors or following genetic modification with immortalising oncogenes. Neural stem cells are multipotent since their differentiating progeny will give rise to the principal cellular phenotypes comprising the mature CNS: neurons, astrocytes and oligodendrocytes. 2. Neural stem cells can also be derived from more primitive embryonic stem (ES) cells cultured from the blastocyst. ES cells are considered to be pluripotent since they can give rise to the full cellular spectrum and will, therefore, contribute to all three of the embryonic germ layers: endoderm, mesoderm and ectoderm. However, pluripotent cells have also been derived from germ cells and teratocarcinomas (embryonal carcinomas) and their progeny may also give rise to the multiple cellular phenotypes contributing to the CNS. In a recent development, ES cells have also been isolated and grown from human blastocysts, thus raising the possibility of growing autologous stem cells when combined with nuclear transfer technology. 3. There is now an emerging recognition that the adult mammalian brain, including that of primates and humans, harbours stem cell populations suggesting the existence of a previously unrecognised neural plasticity to the mature CNS, and thereby raising the possibility of promoting endogenous neural reconstruction. 4. Such reports have fuelled expectations for the clinical exploitation of neural stem cells in cell replacement or recruitment strategies for the treatment of a variety of human neurological conditions including Parkinson's disease (PD), Huntington's disease, multiple sclerosis and ischaemic brain injury. Owing to their migratory capacity within the CNS, neural stem cells may also find potential clinical application as cellular vectors for widespread gene delivery and the expression of therapeutic proteins. In this regard, they may be eminently suitable for the correction of genetically-determined CNS disorders and in the management of certain tumors responsive to cytokines. Since large numbers of stem cells can be generated efficiently in culture, they may obviate some of the technical and ethical limitations associated with the use of fresh (primary) embryonic neural tissue in current transplantation strategies. 5. While considerable recent progress has been made in terms of developing new techniques allowing for the long-term culture of human stem cells, the successful clinical application of these cells is presently limited by our understanding of both (i) the intrinsic and extrinsic regulators of stem cell proliferation and (ii) those factors controlling cell lineage determination and differentiation. Although such cells may also provide accessible model systems for studying neural development, progress in the field has been further limited by the lack of suitable markers needed for the identification and selection of cells within proliferating heterogeneous populations of precursor cells. There is a further need to distinguish between the committed fate (defined during normal development) and the potential specification (implying flexibility of fate through manipulation of its environment) of stem cells undergoing differentiation. 6. With these challenges lying ahead, it is the opinion of the authors that stem-cell therapy is likely to remain within the experimental arena for the foreseeable future. In this regard, few (if any) of the in vivo studies employing neural stem cell grafts have shown convincingly that behavioural recovery can be achieved in the various model paradigms. Moreover, issues relating to the quality control of cultured cells and their safety following transplantation have only begun to be addressed. 7. While on the one hand cell biotechnologists have been quick to realise the potential commercial value, human stem cell research and its clinical applications has been the subject of intense ethical and legislative considerations. The present chapter aims to review some recent aspects of stem cell research applicable to developmental neurobiology and the potential applications in clinical neuroscience.
Otomo, A., S. Hadano, et al. (2003). "ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics." Hum Mol Genet 12(14): 1671-1687.
ALS2 mutations account for a number of recessive motor neuron diseases including forms of amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. Although computational predictions suggest that ALS2 encodes a protein containing multiple guanine nucleotide exchange factor (GEF) domains [RCC1-like domain (RLD), the Dbl homology and pleckstrin homology (DH/PH), and the vacuolar protein sorting 9 (VPS9)], the functions of the ALS2 protein have not been revealed as yet. Here we show that the ALS2 protein specifically binds to small GTPase Rab5 and functions as a GEF for Rab5. Ectopically expressed ALS2 protein localizes with Rab5 and early endosome antigen-1 (EEA1) onto early endosomal compartments and stimulates the enlargement of endosomes in cultured cortical neurons. The carboxy-terminus of ALS2 protein carrying a VPS9 domain mediates not only the activation of Rab5 via a guanine-nucleotide exchanging reaction but also the endosomal localization of the ALS2 protein, while the amino-terminal half containing RLD acts suppressive in its membranous localization. Further, the DH/PH domain in the middle portion of ALS2 protein enhances the VPS9 domain-mediated endosome fusions. Taken together, the ALS2 protein as a novel Rab5-GEF, ALS2rab5GEF seems to be implicated in the endosomal dynamics in vivo. Notably, a feature common to eight reported ALS2 mutations among motor neuron diseases is the loss of VPS9 domain, resulting in the failure of Rab5 activation. Thus, a perturbation of endosomal dynamics caused by loss of ALS2 rab5GEF activity might underlie neuronal dysfunction and degeneration in a number of motor neuron diseases.
Owen, W. E. and W. L. Roberts (2003). "Performance characteristics of four immunonephelometric assays for the quantitative determination of IgA and IgM in cerebrospinal fluid." Am J Clin Pathol 119(5): 689-93.
Measurement of IgA and IgM in cerebrospinal fluid (CSF) can be useful in the diagnosis of multiple sclerosis and other central nervous system disorders. The Dade Behring (Deerfield, IL) N Latex IgA and N Latex IgM tests on the BN II System and Beckman Coulter (Brea, CA) low-concentration IgA and IgM tests on the IMMAGE Immunochemistry System were evaluated for linearity, imprecision, method comparison, and reference interval verification. Both IgA methods were linear from 1.4 to at least 50 mg/L. Both IgM methods were linear from 0.14 to more than 6 mg/L. The total imprecision of the BN II IgA and IgM methods and the IMMAGE IgA method was less than 10%. The imprecision of the IMMAGE IgM method was 10.2% at 0.49 mg/L and less than 5% at higher IgM concentrations. Method comparison studies indicated that IgA and IgM methods on both instruments showed good comparability. Reference interval studies demonstrated that both methods had similar reference intervals that agreed with published values of less than 6 mg/L for IgA and less than 1.3 mg/L for IgM. Methods for quantifying IgA and IgM in CSF on the BN II and IMMAGE nephelometers perform well and give comparable results.
Owens, T. (2003). "The enigma of multiple sclerosis: inflammation and neurodegeneration cause heterogeneous dysfunction and damage." Curr Opin Neurol 16(3): 259-65.
PURPOSE OF REVIEW: The demyelinating disease multiple sclerosis has an autoimmune inflammatory component, which has dominated the description of multiple sclerosis. A degenerative component to multiple sclerosis was always apparent, but was underappreciated until recently. Recent work has brought axonal pathology and brain atrophy into new focus. The purpose of this review is to highlight the relative roles played by the inflammatory and degenerative processes in multiple sclerosis pathology. RECENT FINDINGS: In the past year reports have been published to show that early disability and disease progression correlate with axonal damage, and that brain atrophy resulting from axonal loss is a feature of early multiple sclerosis, and is not restricted to the secondary progressive forms of the disease. Inflammatory mediators (CD8 T cells and antibodies) are implicated in axonal damage, and treatment with steroids or anti-inflammatory therapies reduce brain atrophy, pointing to the involvement of the inflammatory response in the initiation of degeneration. Reduced regenerative capability also contributes to degeneration, and inflammatory responses are shown to inhibit the growth and migration of precursor cells for oligodendrocytes. SUMMARY: Oligodendrocyte precursors are abundant in multiple sclerosis lesions, but fail to remyelinate. Oligodendrocyte growth and regeneration are probably compromised by the action of growth inhibitory signals and lack of growth stimuli. Inflammatory cells and mediators induce axonal loss as well as demyelination. The degenerative response is therefore an integral and early component of multiple sclerosis.
Ozakbas, S., E. Idiman, et al. (2003). "Childhood and juvenile onset multiple sclerosis: clinical and paraclinical features." Brain Dev 25(4): 233-6.
It is well known that multiple sclerosis (MS) is a demyelinating disease of the central nervous system that mostly starts in the second to third decade. In the present study, we reviewed our own observations of the clinical and paraclinical features in the 36 of 890 (4.04%) MS patients whose symptoms started before 16 years of age. The average age at onset of the disease in these 36 patients was 12.9 years. In 18 patients, the disease onset was monosymptomatic. Diplopia and sensory disturbances were the most common initial manifestations and occurred in 27.7% of cases. Twenty-one patients (59%) had a relapsing and 11 patients (30.5%) had a secondary progressive course. On the last evaluation, the EDSS score was above 5 in 11 patients and it was below 5 in 21 patients. As a result of this study, we concluded that childhood onset MS does not significantly differ from that it has been typically seen in adults in terms of major clinical manifestations and course of disease.
Ozaki, I., C. Suzuki, et al. (2003). "Multiple sclerosis manifesting as a Brown-Sequard syndrome." Eur J Neurol 10(2): 190-1.