Multiple Sclerosis References 2003; Authors: M
(50 References)
Mackowiak, A., V. Jamart, et al. (2003). "[General practitioners' approach to relapsing multiple sclerosis]." Rev Neurol (Paris) 159(2): 196-8.
Management of multiple sclerosis depends on close multidisciplinary collaboration but general practitioners play a particularly important role, especially in case of relapse, due to their close relationship with the patient. The purpose of this work was to conduct a survey of general practitioners' knowledge of relapsing multiple sclerosis and ascertain their main difficulties in patient management. One hundred seventy-seven practitioners answered a written questionnaire with two headings, diagnostic criteria for relapse and therapeutic approaches. Analysis of the results showed that this common event is under recognized. While 55.9 p.cent of the general practitioners stated they diagnosed relapse by themselves, only 2.8 p.cent knew its exact definition. Differential diagnosis accounted for a large number of mistakes. Our survey also underlined the use of certain therapeutic options (low-dose oral corticosteroid therapy) for which the effectiveness has not been demonstrated. It would be important to propose specific education on relapsing multiple sclerosis for general practitioners and improve cooperation with specialists. An integrated care network might be useful.
Mahad, D. J., J. Lawry, et al. (2003). "Longitudinal study of chemokine receptor expression on peripheral lymphocytes in multiple sclerosis: CXCR3 upregulation is associated with relapse." Mult Scler 9(2): 189-98.
The interaction between chemokines and their receptors leads to selective recruitment of cells to foci of inflammation. Cross-sectional studies have reported significantly different expression of chemokine receptors CXCR3, CCR5 and CCR2 on peripheral blood lymphocytes in multiple sclerosis (MS) compared with controls. Cells expressing these receptors are likely to play a pathogenic role as suggested by studies of experimental autoimmune encephalomyelitis. Also, immunogenetic studies of nonfunctional CCR5 receptors in MS patients, due to 32delta deletion, demonstrated a delay in time to next relapse. The aims of this study were to detect any changes in the serial expression of chemokine receptors CCR2, CCR3, CCR5 and CXCR3 on peripheral blood CD4+ lymphocytes from patients with MS and to correlate the changes with relapses. Upregulation of CXCR3 expression on peripheral blood CD4+ lymphocytes was associated with all relapses and CCR5 expression was significantly affected with all relapses. Clinical recovery, with or without intravenous methylprednisolone treatment, coincided with the return of CXCR3 towards baseline in all but one case. Fluctuation in the expression of CXCR3 and CCR5 was also significantly greater in clinically stable patients with MS compared with controls, which may be due to subclinical disease activity. These findings provide further support for the view that CXCR3 and CCR5 antagonists could have a therapeutic value in MS.
Mahad, D. J. and R. M. Ransohoff (2003). "The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE)." Semin Immunol 15(1): 23-32.
Multiple sclerosis (MS) is the commonest inflammatory demyelinating disease of the human central nervous system (CNS). In MS, CNS inflammation is associated with demyelination and axonal degeneration, which leads to clinical presentation. Expression and cellular localization of CCL2/MCP-1 and CCR2 in MS have been described in the three compartments: brain, cerebrospinal fluid (CSF) and blood. Evidence from descriptive, transgenic, knockout and neutralizing studies of experimental autoimmune encephalomyelitis (EAE) points towards a nonredundant role of CCL2 and CCR2 in the recruitment of inflammatory infiltrate into the CNS. Hence, CCL2 and CCR2 may be targets for specific and effective treatment in MS.
Mahnke, K., Y. Qian, et al. (2003). "Dendritic cells, engineered to secrete a T-cell receptor mimic peptide, induce antigen-specific immunosuppression in vivo." Nat Biotechnol.
A T-cell receptor mimic peptide (TCRpep) consisting of an 8-amino-acid peptide, homologous to the transmembrane region of the T-cell receptor (TCR) alpha chain, blocks T-cell activation after systemic application. When dendritic cells (DCs) were transduced to secrete the TCRpep and injected into mice, evidence of immunosuppression was observed. In a CD8-driven allergy model, the injection of DCs transduced with the TCRpep reduced inflammation markedly and in a CD4(+) T cell-dependent model of multiple sclerosis (experimental autoimmune encephalitis, EAE), injection of TCRpep-secreting DCs abrogated EAE symptoms and prolonged survival. These effects were antigen specific, because transduced DCs that did not express the respective antigen failed to convey protection in the allergy model as well as in the EAE model. Thus these data show that DCs expressing the TCRpep are able to suppress T-cell activation and might be a useful tool for inducing antigen-specific immune suppression in vivo.
Mahon, B. D., S. A. Gordon, et al. (2003). "Cytokine profile in patients with multiple sclerosis following vitamin D supplementation." J Neuroimmunol 134(1-2): 128-32.
Multiple sclerosis (MS) patients were randomized, in a double blind design, and placed into either a vitamin D supplemented group or a placebo control group. As expected, serum 25-hydroxyvitamin D levels increased significantly following 6 month vitamin D supplementation (17+/-6 ng/ml at baseline to 28+/-8 ng/ml at 6 months). Vitamin D supplementation also significantly increased serum transforming growth factor (TGF)-beta 1 levels from 230+/-21 pg/ml at baseline to 295+/-40 pg/ml 6 months later. Placebo treatment had no effect on serum TGF-beta 1 levels. Tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-13 were not different following vitamin D supplementation. IL-2 mRNA levels decreased following vitamin D supplementation but the differences did not reach significance. Vitamin D supplementation of MS patients for 6 months was associated with increased vitamin D status and serum TGF-beta 1.
Mak, B. C., K. Takemaru, et al. (2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity." J Biol Chem 278(8): 5947-51.
Tuberous sclerosis complex (TSC) is characterized by the formation of hamartomas in multiple organs resulting from mutations in the TSC1 or TSC2 gene. Their protein products, hamartin and tuberin, respectively, form a functional complex that affects cell growth, differentiation, and proliferation. Several lines of evidence, including renal tumors derived from TSC2+/- animals, suggest that the loss or inhibition of tuberin is associated with up-regulation of cyclin D1. As cyclin D1 can be regulated through the canonical Wnt/beta-catenin signaling pathway, we hypothesize that the cell proliferative effects of hamartin and tuberin are partly mediated through beta-catenin. In this study, total beta-catenin protein levels were found to be elevated in the TSC2-related renal tumors. Ectopic expression of hamartin and wild-type tuberin, but not mutant tuberin, reduced beta-catenin steady-state levels and its half-life. The TSC1-TSC2 complex also inhibited Wnt-1 stimulated Tcf/LEF luciferase reporter activity. This inhibition was eliminated by constitutively active beta-catenin but not by Disheveled, suggesting that hamartin and tuberin function at the level of the beta-catenin degradation complex. Indeed, hamartin and tuberin co-immunoprecipitated with glycogen synthase kinase 3 beta and Axin, components of this complex in a Wnt-1-dependent manner. Our data suggest that hamartin and tuberin negatively regulate beta-catenin stability and activity by participating in the beta-catenin degradation complex.
Malamud, V., A. Vaaknin, et al. (2003). "Tryptase activates peripheral blood mononuclear cells causing the synthesis and release of TNF-alpha, IL-6 and IL-1beta: possible relevance to multiple sclerosis." J Neuroimmunol 138(1-2): 115-22.
Presence of mast cells and an increase in the concentration of their products has been reported in multiple sclerosis (MS) plaques. The most abundant secretory mediator of the human mast cell is the tetrameric protease tryptase. We demonstrate that tryptase can activate peripheral mononuclear cells (PBMCs), isolated from healthy donors as well as MS patients for the release of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1beta. Cytokine secretion was significantly higher in secondary progressive (SP) MS patients and healthy control (HC) individuals than in relapsing-remitting (RR) patients. Our findings suggest that tryptase is, most probably, an important mediator of inflammation in MS.
Marcisz, C., E. J. Kucharz, et al. (2003). "Pulmonary functional abnormalities in asymptomatic patients with systemic sclerosis." Eur J Intern Med 14(3): 162-165.
BACKGROUND: Systemic sclerosis (SSc) is a disease characterized by widespread fibrosis of the skin and multiple organs, including the lungs. This study was designed to evaluate pulmonary function in SSc patients without symptoms of lung involvement. METHODS: Spirometric measurements were done in 26 female SSC patients without symptoms of pulmonary involvement. RESULTS: Maximal voluntary ventilation was found to be decreased in half of the patients, and forced vital capacity was decreased in 23% of the patients. Forced expiratory flow rate was impaired in about half of the SSc patients, especially the flow at 50-75% of forced vital capacity. Peak expiratory flow rate was decreased in 77% of asymptomatic patients. CONCLUSIONS: A functional defect, mainly of the restrictive type, was observed in the majority of asymptomatic patients with SSc. Pulmonary function testing is recommended for all SSc patients.
Markovic, M., V. Trajkovic, et al. (2003). "Antibodies against myelin oligodendrocyte glycoprotein in the cerebrospinal fluid of multiple sclerosis patients." J Neurol Sci 211(1-2): 67-73.
Antibodies against myelin oligodendrocyte glycoprotein (MOG) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) in different animal species and are implicated in the immunopathogenesis of multiple sclerosis (MS). In order to evaluate the anti-MOG response, we have analyzed the cerebrospinal fluids (CSFs) from 44 MS patients and 51 controls, 11 with other inflammatory neurological disorders (OIND) and 40 with non-inflammatory neurological disorders (NIND). The frequency of anti-MOG antibodies positive patients in the MS group (30%) was significantly higher compared to the NIND (8%, p=0.02), but not compared to the OIND group (55%, p=0.228). Interestingly, all six patients with neurosarcoidosis had MOG-specific antibodies in their CSF. Frequency of anti-MOG antibodies was similar in patients with clinically active and stable MS (32% and 26%, respectively; p=0.921). However, in clinically active MS patients, antibody titers were higher in comparison with patients with stable disease, although the difference did not reach the level of statistical significance (p=0.06). These results further support the potential role of anti-MOG antibodies in the immunopathology of MS in the subset of patients with this disease. Furthermore, our findings suggest for the first time that anti-MOG antibodies could be an accessory diagnostic tool in neurosarcoidosis.
Marta, C. B., C. M. Taylor, et al. (2003). "Antibody cross-linking of myelin oligodendrocyte glycoprotein leads to its rapid repartitioning into detergent-insoluble fractions, and altered protein phosphorylation and cell morphology." J Neurosci 23(13): 5461-71.
Myelin oligodendrocyte glycoprotein (MOG) is, quantitatively, a relatively minor component of the myelin membrane. Nevertheless, peritoneal administration of MOG evokes potent cellular and humoral immunoreactivity, resulting in an experimental allergic encephalitis with immunopathology similar to multiple sclerosis. Moreover, antibodies against MOG cause myelin destruction in situ. Therefore, it appears that MOG-related demyelination is dependent on anti-MOG antibody, but the mechanism(s) by which it occurs is unclear. Of potential significance are observations that some proteins are selectively partitioned into specialized plasma membrane microdomains rich in glycosphingolipids and cholesterol ("lipid rafts"). In particular, during ligand or antibody cross-linking, various plasma membrane receptors undergo enhanced partitioning into rafts as an obligatory first step toward participation in early signal transduction events. In contrast to mature myelin, in oligodendrocytes (OLs) in culture MOG is not raft associated [Triton X-100 (TX-100) soluble, 4 degrees C]. However, in this study we show that antibody cross-linking (anti-MOG plus secondary antibody) of MOG on the surface of OLs results in the repartitioning of approximately 95% of MOG into the TX-100-insoluble fraction. This repartitioning of MOG is rapid (<or=1 min), antibody dose dependent, requires an intact cytoskeleton, leads to phosphorylation or dephosphorylation of tyrosine, serine, and threonine residues in specific proteins (e.g., beta-tubulin, Gbeta1-2), and invokes a rapid retraction of OL processes. After removal of the cross-linking antibodies, these events are reversed. We hypothesize that antibody-mediated repartitioning of MOG into TX-100-insoluble glycosphingolipid-cholesterol-rich microdomains initiates specific cellular signaling that could be related to initial steps of MOG-mediated demyelination.
Martinez, L., S. Rivas, et al. (2003). "Aggressive conservative treatment of esophageal perforations in children." J Pediatr Surg 38(5): 685-9.
Background/Purpose: In contrast with adult patients in whom surgical closure of the defect is preferred, nonoperative treatment has been the usual approach for esophageal perforation (EP) in children. This report aims to assess whether this strategy stands the passage of time. METHODS: We reviewed retrospectively the charts of 17 patients aged 5.3 +/- 0.9 years (mean +/- SD) treated at our institution for EP between 1991 and 2001. RESULTS: Nineteen episodes of EP were caused by stricture dilation in 9 cases, foreign body extraction in 3, and blunt trauma and sclerosis of varices in 2 cases each. The remaining child had multiple gastrointestinal perforations in the course of chemotherapy for leukemia. Vigorous treatment, consisting of nasopharyngeal aspiration, wide spectrum antibiotics, prompt drainage of effusions and either parenteral or infraesophageal nutritition, was implemented immediately after diagnosis. Perforations were closed without direct surgery in 18 of 19 episodes (16 of 17 children). One or more pleural drains were inserted in 12 cases, and pericardial drainage was required once. Seven gastrostomies, 2 jejunostomies, and one esophagostomy were performed. Several major abdominal operations were necessary to repair concomitant lesions in a child who sustained severe blunt abdominal trauma and in the patient with leukemic perforations. All patients survived, and all recovered esophageal function. However, 2 with intractable lye strictures ultimately required esophageal replacement. The only patient in whom a direct approach for esophageal necrosis due to variceal endosclerosis was unavoidable, lost her organ and had a retrosternal colonic interposition after a successful portosystemic shunt. Excluding patients with other concomitant lesions and the patient who underwent surgery, median length of stay was 11 days (range, 6 to 47). CONCLUSIONS: Prompt and aggressive nonoperative treatment of esophageal perforations in children allows survival with conservation of the organ in most cases and remains, in the authors' hands, the first therapeutic choice at this age. J Pediatr Surg 38:685-689.
Matheu, V., A. Treschow, et al. (2003). "Upregulation of B7 molecules (CD80 and CD86) and exacerbated eosinophilic pulmonary inflammatory response in mice lacking the IFN-beta gene." J Allergy Clin Immunol 111(3): 550-7.
BACKGROUND: IFN-beta has been shown to be effective as therapy for multiple sclerosis. Some reports attributed its beneficial effects to the capacity to induce a T(H)2 response. However, other studies have suggested that endogenous type I IFN might downregulate the allergic response in mice. OBJECTIVE: We sought to define the differential role of endogenous IFN-beta in controlling the development of allergic inflammation. METHODS: We assessed whether deletion of the gene encoding IFN-beta (IFNB) with knockout mice participated in the development of allergic response in ovalbumin (OVA)-sensitized and OVA-challenged mice. RESULTS: OVA-sensitized and OVA-challenged mice with lack of the IFNB gene had more severe pulmonary inflammation with increased lung local response, including IL-4, IL-5, IL-13, IgE, eosinophilia, and goblet cells, than their litter mates (IFN-beta+/-), whereas no differences were observed in regard to local levels of IFN-gamma. Moreover, systemic response with IgE production is also enhanced. Lack of IFN-beta also results in significantly higher antigen-specific T cells, with higher levels of IL-4, IL-5, and IL-13, whereas no significant differences in IFN-gamma response could be observed. We have also detected a higher ratio of CD4+/CD8+ T cells and increased expression of B7.1/B7.2 on B cells and antigen-presenting cells in IFNB knockout mice. CONCLUSIONS: These results demonstrate that IFN-beta plays an important role in immunoregulation of allergic response in mice. The stronger pulmonary inflammation could be a consequence of significantly expanded antigen-specific CD4+ T(H)2 cells as a result of efficient antigen presentation by antigen-presenting cells and hence increased production of IgE by B cells.
Mathisen, P. M. (2003). "Gene discovery and validation for neurodegenerative diseases." Drug Discov Today 8(1): 39-46.
Treatment of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis (ALS), represents a major challenge for the pharmaceutical industry. These disorders have common and unique molecular pathological characteristics that result in serious reductions in nervous-system functionality. Key to developing novel and efficacious therapeutics is the discovery of new gene targets. Genomic, proteomics and bioinformatic analyses are identifying vast amounts of genes whose expression is associated with the pathology of a specific disease. Extensive validation studies performed in parallel with drug development are crucial for the selection of appropriate target genes. This review outlines some of the current progress in gene discovery for neurodegenerative disease.
Matsumoto, Y., W. K. Yoon, et al. (2003). "Complementarity-determining region 3 spectratyping analysis of the TCR repertoire in multiple sclerosis." J Immunol 170(9): 4846-53.
Multiple sclerosis (MS) is considered to be an autoimmune disease mediated by T cells reactive with Ags in the CNS. Therefore, it has been postulated that neuroantigen-reactive T cells bearing particular types of TCRs are expanded clonally during the course of the disease. However, there is a controversy with regard to the TCR usage by T cells associated with the development of MS. By the use of complementarity-determining region 3 spectratyping analysis that is shown to be a useful tool for identification of pathogenic TCR in autoimmune disease models, we tried to demonstrate that spectratype was T cells bearing particular types of TCR are activated in MS patients. Consequently, it was found that Vbeta5.2 were often oligoclonally expanded in peripheral blood of MS patients, but not of healthy subjects. Sequence analysis of the complementarity-determining region 3 region of spectratype-derived TCR clones revealed that the predominant TCR clone was different from patient to patient, but that similar results were obtained in a patient examined at different time points. More importantly, examination of cerebrospinal fluid T cells and longitudinal studies of PBLs from selected patients revealed that Vbeta5.2 expansion was detectable in the majority of patients examined. These findings suggest that Vbeta5.2 spectratype expansion is associated with the development of MS and that TCR-based immunotherapy can be applicable to MS patients if the TCR activation pattern of each patient is determined at different stages of the disease.
May, M., M. Seehafer, et al. (2003). "[Angiomyolipoma of the kidneys as a rare cause of retroperitoneal hemorrhage. Two case reports with tuberous sclerosis Bourneville-Pringle]." Urologe A 42(5): 693-701.
Tuberous sclerosis (Bourneville-Pringle-disease, TSC) is an autosomal dominant disorder characterized by seizures, mental retardation and hamartomatous tumours in multiple organs, including subependymal giant cell astrocytomas, cardiac rhabdomyomas and renal angiomyolipomas. Recent population-based studies suggest a prevalence of 1 case per 25,000 individuals. Renal angiomyolipomas, which may be found sporadically or associated with TSC, become evident as an acute retroperitoneal haemorrhage or by symptoms of a flank mass. Ultrasound and computed tomography provide clear evidence of lipomatous formation while, in rare instances, angiography can demonstrate the existence of multiple vascular tumour compartments. In view of two cases which were admitted with the clinical picture of an acute abdomen on the basis of retroperitoneal haemorrhage, the therapeutic strategies for TSC patients with renal angiomyolipomas are discussed, paying regard to the literature in this field.
Mazzeo, L., L. Ricciardi, et al. (2003). "Severe urticaria due to recombinant interferon beta-1a." Br J Dermatol 148(1): 172.
McDonnell, G. V., J. Cabrera-Gomez, et al. (2003). "Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions: the subclinical stage of primary progressive multiple sclerosis may last 10 years." Mult Scler 9(2): 204-9.
BACKGROUND: Subclinical multiple sclerosis (MS) has been identified incidentally at autopsy; apparently unaffected individuals with an affected twin have demonstrated magnetic resonance imaging (MRI) changes consistent with MS, and 'MRI relapses' are several times more common than clinical relapses. CASE DESCRIPTION: A 39-year-old, right-handed man underwent MRI and PET scanning in 1986 as a 'normal' control in a Parkinson's disease study, where his father was the proband. MRI indicated multiple areas of abnormal signal intensity in a periventricular and grey-white matter junction distribution. Repeated clinical evaluations over the next 10 years were unchanged until 1996, when he complained of progressive weakness of the right foot and clumsiness in the right hand. MRI now indicated a further area of high signal intensity in the right posterior cord at the level of C5/C6. There was mild pyramidal distribution weakness in the right leg with an extensor plantar response on the same side. Over the next five years there has been mild progression in weakness and fatigue and intermittent Lhermitte's phenomenon. At no stage has there been a history of relapse, cerebrospinal fluid examination was normal and evoked responses (visual and somatosensory) are normal. CONCLUSION: This case demonstrates the phenomenon of subclinical MS, unusually supported by prolonged clinical and MRI follow-up. The patient eventually became symptomatic nine years after MRI diagnosis and is following a primary progressive course. Although MRI is known to be sensitive in identifying subclinical 'attacks', the pattern illustrated here may actually be quite typical of primary progressive MS and is compatible with the later onset seen in this subgroup of patients.
McGuire, T. R., P. Gwilt, et al. (2003). "High-dose cyclophosphamide in multiple sclerosis patients undergoing autologous stem cell transplantation." Int Immunopharmacol 3(2): 279-83.
High-dose cyclophosphamide (CTX) is commonly used in preparation for autologous and allogeneic stem cell transplantation. CTX is a pro-drug, which undergoes complex oxidative metabolism with the metabolites being eliminated both renally and hepatically. In the following study, we evaluated the pharmacokinetic characteristics of high-dose CTX in three patients undergoing autologous stem cell transplantation for multiple sclerosis. The plasma concentration-time profiles for CTX and its hydroxy-metabolite were similar in multiple sclerosis patients to those reported in cancer patients undergoing stem cell transplantation. There was an increase in drug clearance after the second CTX dose indicating that the drug induced its own metabolism consistent with reports in other populations receiving high-dose CTX. One of the three patients cleared the drug slowly but this was not associated with greater toxicity. The patient with the slow clearance value and therefore highest drug exposure had stable disability scores at 2 years posttransplant compared with baseline values taken prior to transplantation. In conclusion, in this small case series, there was no indication that CTX metabolism was different than that in other populations undergoing transplantation.
McKeown, L. P., A. P. Porter-Armstrong, et al. (2003). "The needs and experiences of caregivers of individuals with multiple sclerosis: a systematic review." Clin Rehabil 17(3): 234-48.
PRIMARY OBJECTIVE: To appraise recent studies regarding the needs and experiences of caregivers of individuals with multiple sclerosis (MS). DESIGN: The following computerized databases were searched: CINAHL, BIDS IBSS, ASSIA, MEDLINE, PSYCHINFO, British Nursing Index, ISI Web of Science, Zetoc, AMED (1990-April 2002). The computer-based search was supplemented by manual searches of the reference lists of all retrieved studies and review articles. Inclusion and exclusion criteria were formulated. RESULTS: Twenty-four studies from across the world that met the inclusion criteria were reviewed. The majority of studies were descriptive in nature. The studies covered a variety of topics, including how carers assist people with MS, the effect of providing care on a carer's physical and psychological well-being, social life, financial situation and overall quality of life, and how carers cope with the stresses of providing care. CONCLUSIONS: Providing care for a person with MS has a major impact on all areas of the caregiver's life. Perceived social support has been shown to have a beneficial impact on the caregiver. Limitations in design and variation in methodology of studies limits the generalizability of findings. There is a need for further research, in particular the development of reliable and valid disease-specific caregiver assessment instruments.
McLeod, B. C. (2003). "Plasmapheresis in multiple sclerosis." J Clin Apheresis 18(2): 72-4.
Meager, A., M. Wadhwa, et al. (2003). "Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis." Clin Exp Immunol 132(1): 128-36.
We have screened for spontaneous anticytokine autoantibodies in patients with infections, neoplasms and autoimmune diseases, because of their increasingly reported co-occurrence. We tested for both binding and neutralizing autoantibodies to a range of human cytokines, including interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, interferon-alpha2 (IFN-alpha2), IFN-omega, IFN-beta, IFN-gamma, tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta-1 (TGF-beta1) and granulocyte-macrophage colony stimulating factor (GM-CSF), in plasmas or sera. With two notable exceptions described below, we found only occasional, mostly low-titre, non-neutralizing antibodies, mainly to GM-CSF; also to IL-10 in pemphigoid. Strikingly, however, high-titre, mainly IgG, autoantibodies to IFN-alpha2, IFN-omega and IL-12 were common at diagnosis in patients with late-onset myasthenia gravis (LOMG+), thymoma (T) but no MG (TMG-) and especially with both thymoma and MG together (TMG+). The antibodies recognized other closely related type I IFN-alpha subtypes, but rarely the distantly related type I IFN-beta, and never (detectably) the unrelated type II IFN-gamma. Antibodies to IL-12 showed a similar distribution to those against IFN-alpha2, although prevalences were slightly lower; correlations between individual titres against each were so modest that they appear to be entirely different specificities. Neither showed any obvious correlations with clinical parameters including thymoma histology and HLA type, but they did increase sharply if the tumours recurred. These antibodies neutralized their respective cytokine in bioassays in vitro; although they persisted for years severe infections were surprisingly uncommon, despite the immunosuppressive therapy also used in most cases. These findings must hold valuable clues to autoimmunizing mechanisms in paraneoplastic autoimmunity.
Medana, I. M. and M. M. Esiri (2003). "Axonal damage: a key predictor of outcome in human CNS diseases." Brain 126(Pt 3): 515-30.
Axonal damage has recently been recognized to be a key predictor of outcome in a number of diverse human CNS diseases, including head and spinal cord trauma, metabolic encephalopathies, multiple sclerosis and other white-matter diseases (acute haemorrhagic leucoencephalitis, leucodystrophies and central pontine myelinolysis), infections [malaria, acquired immunodeficiency syndrome (AIDS) and infection with human lymphotropic virus type 1 (HTLV-I) causing HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP)] and subcortical ischaemic damage. The evidence for axonal damage and, where available, its correlation with neurological outcome in each of these conditions is reviewed. We consider the possible pathogenetic mechanisms involved and how increasing understanding of these may lead to more effective therapeutic or preventive interventions.
Mehta, P. D., B. A. Patrick, et al. (2003). "Detection of apolipoprotein E phenotype in unconcentrated cerebrospinal fluid." J Clin Lab Anal 17(1): 18-21.
We developed a simple method to detect apolipoprotein E (Apo E) polymorphism distribution in approximately 20 microL of unconcentrated cerebrospinal fluid (CSF). A combination of isoelectric focusing in 3 M urea gel and immunoblotting was employed. Apo E phenotypes were identified in CSF samples from 45 patients with probable Alzheimer disease (AD), 15 with multiple sclerosis (MS), and 25 with other neurological diseases (OND). When the data were compared with a set of matched plasma samples, the results were identical. The method is useful for Apo E phenotyping from fresh or frozen unconcentrated CSF, when blood or plasma is not available.
Melhem, E. R., E. H. Herskovits, et al. (2003). "Defining thresholds for changes in size of simulated T2-hyperintense brain lesions on the basis of qualitative comparisons." AJR Am J Roentgenol 180(1): 65-9.
OBJECTIVE: Our purpose was to define thresholds below which trained reviewers cannot detect changes in the size of T2-hyperintense brain lesions. MATERIALS AND METHODS: We generated T2-weighted brain MR images (TR/TE, 4000/80) with simulated hyperintense lesions derived from a real multiple sclerosis plaque. The size of the original multiple sclerosis lesion was varied by scaling up or down the lesion using a bicubic interpolation method. Three hundred seventy-eight composite images, in which two T2-weighted images containing lesions were paired, were presented to three equally trained neuroradiologists to define thresholds below which changes in original lesion size could not be detected. Stepwise logistic regression was used to evaluate the dependency of size thresholds on the original size of the lesion. RESULTS: Thresholds ranged from a 5% to 15% increase in the original lesion diameter. For increases greater than 15%, all three reviewers detected the change in lesion size irrespective of the diameter of the original lesion. There was a dependency of the threshold on the diameter of the original lesion (p = 0.02). CONCLUSION: Using an MR simulator, we can define thresholds below which changes in original lesion size cannot be reliably detected. These results may guide the design of clinical trials that rely on trained reviewers to assess change in lesion burden.
Mellai, M., M. Giordano, et al. (2003). "Prolactin and prolactin receptor gene polymorphisms in multiple sclerosis and systemic lupus erythematosus." Hum Immunol 64(2): 274-84.
Genes encoding for prolactin (PRL) and its receptor (PRLR) are possible candidates for multiple sclerosis (MS) and systemic lupus erythematosus (SLE) susceptibility. In fact: (1) a prolactin secretion dysfunction has been described in several autoimmune diseases including SLE and MS and their animal models; (2) both PRL and PRLR are structurally related to members of the cytokine/hematopoietin family and have a role in the regulation of the immune response; and (3) both PRL and PRLR genes map in genomic regions that showed linkage with autoimmunity. Prolactin maps on chromosome 6p, about 11-kb telomeric to HLA-DRB1 and PRLR in 5p12-13, which revealed evidence of linkage with MS in different populations. To evaluate a possible role of these two genes in SLE and MS we performed an association study of 19 PRL and PRLR single nucleotide polymorphisms (SNPs). These were directly searched by DHPLC in a panel of SLE and MS patients and selected from databases and the literature. The SNP allele frequencies were determined on patient and control DNA pools by primer-extension genotyping and HPLC analysis. Moreover a panel of HLA typed SLE and control individuals were individually genotyped for the PRL G-1149T polymorphism previously described to be associated with SLE. No statistically significant difference in the allele distribution was observed for any of the tested variations.
Melo, T. M., C. Larsen, et al. (2003). "Manganese, Copper, and Zinc in Cerebrospinal Fluid from Patients with Multiple Sclerosis." Biol Trace Elem Res 93(1-3): 1-8.
The concentrations of manganese, copper, and zinc in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) and patients with no known neurological disease (control group) were measured. Manganese and copper levels were determined by two different analytical methods: atomic absorption spectrometry (AAS) and high-resolution inductively coupled plasma-mass spectrometry (HR-ICP-MS), whereas zinc levels were determined by HR-ICP-MS only. Manganese levels (mean+/-SEM) were significantly decreased in the CSF of MS patients (1.07+/-0.13 &mgr;g/L, ICP-MS; 1.08+/-0.11 &mgr;g/L, AAS) compared to the levels in the control group (1.78+/-0.26 &mgr;g/L, ICP-MS; 1.51+/-0.17 &mgr;g/L, AAS). Copper levels were significantly elevated in the CSF of MS patients (10.90+/-1.11 &mgr;g/L; ICP-MS, 11.53+/-0.83 &mgr;g/L, AAS) compared to the levels in the control group (8.67+/-0.49 &mgr;g/L, ICP-MS; 9.10+/-0.62 &mgr;g/L, AAS). There were no significant differences between the CSF zinc levels of MS and control patients. The physiological basis for the differences in manganese and copper concentrations between MS patients and controls is unknown, but could be related to alterations in the manganese- containing enzyme glutamine synthetase and the copper-containing enzyme cytochrome oxidase.
Mennel, E. A. and S. D. John (2003). "Osteosclerotic metaphyseal dysplasia: a skeletal dysplasia that may mimic lead poisoning in a child with hypotonia and seizures." Pediatr Radiol 33(1): 11-4.
We report the case of a 23-month-old male with hypotonia, developmental delay, and complex seizures. Radiographs revealed profound sclerosis of the metaphyses and epiphyses of the long and short bones in the extremities, with a unique pattern of distribution. Sclerosis also involved the anterior ribs, iliac crests, talus, and calcaneus. The skull and vertebral bodies appeared unaffected. Blood lead levels were normal. We believe that this constellation of clinical and radiographic abnormalities closely resembles osteosclerotic metaphyseal dysplasia (OMD) due to an autosomal recessive defect. Characteristic skeletal findings were instrumental in determining the diagnosis. OMD is a very rare sclerosing bone disorder, first described in 1993. The syndrome is characterized clinically by developmental delay of a progressive nature, hypotonia, elevated alkaline phosphatase, and late-onset spastic paraplegia. We encountered a young child with these neurologic symptoms who displayed sclerotic metaphyseal changes on hand radiographs obtained to determine the bone age. Lead poisoning, a known cause of metaphyseal sclerosis, was initially suspected. Careful analysis of the metaphyseal bone changes helped to distinguish this bone dysplasia from lead poisoning and other causes of metaphyseal sclerosis.
Merkelbach, S., J. Konig, et al. (2003). "Personality traits in multiple sclerosis (MS) patients with and without fatigue experience." Acta Neurol Scand 107(3): 195-201.
OBJECTIVES: To determine the impact of personality characteristics on feelings of fatigue in multiple sclerosis (MS) patients and to compare the results with the impact of bodily impairment. PATIENTS AND METHODS: Eighty patients with definite MS (mean age 38.5 +/- 9.0 years, 62 females) were surveyed using questionnaires assessing fatigue experience and personality traits (German Freiburg Personality Inventory-Revised; FPI-R) and by clinical examination assessing the Expanded Disability Status Scale. RESULTS: Increased levels of "neuroticism", and "excitability" and decreased levels of "extraversion" were found to relate independent of fatigue scores (0.21 < beta < 0.52; 0.05 < P < 0.0001). The impact of these personality traits on fatigue (partial R2 ranging up to 0.32; 0.02 < P < 0.0001) was much higher than the impact of physical impairment (partial R2 ranging up to 0.04; not significant). CONCLUSION: Our results support a psychological model of fatigue in MS. FPI-R-items over-weighted somatic sources of the fatigue syndrome in MS and may specifically relate to fatigue experience in chronical disorders.
Mevellec, E., D. Lamotte, et al. (2003). "[Relationship between gait speed and strength parameters in multiple sclerosis]." Ann Readapt Med Phys 46(2): 85-90.
INTRODUCTION: Recent studies have focused on correlation between strength and gait parameters in hemiplegia, suggesting the interest for strength training in patients with central nervous system lesions. The aim of this study was to evaluate this correlation in multiple sclerosis (MS) patients with special regard to the different clinical forms including proprioceptive loss or cerebellar ataxia. PATIENTS AND METHOD: Gait speed and muscular function were performed in 27 patients with moderate affected gait (EDDS < 6). Gait speed was evaluated with Locometre and peak-torques of quadriceps and hamstrings were evaluated with isokinetic dynamometer. Patients were separated in three groups related to their deficiency: spastic group (8 patients), spastic with proprioceptive loss (12 patients) and spastic with cerebellar ataxia (7 patients). Gait parameters were evaluated in 10 healthy subjects as control group. RESULTS: Gait speeds (spontaneous and maximal) and peak torques of quadriceps and hamstring were similar in the three groups. In the whole patients group, gait speed was reduced and related to hamstring peak torque (r = 0.56 at spontaneous speed and 0.51 at high speed) but not with quadriceps peak torque. Patients with proprioceptive loss exhibited not only a higher correlation between gait speed and hamstring torque (r = 0.76 and 0.65 respectively) than other patients but also with quadriceps torque (r = 0.66 and 0.59 respectively) when patients in other groups did not. CONCLUSION: As it was previously pointed out in hemiplegic patients, MS patients exhibit some correlation between gait speed and muscle strength, mainly with hamstrings. These correlations can change in special sensory conditions suggesting that patients with sensory loss use different muscular strategies to maintain gait speed. Strength training may therefore be discussed in MS including specific modalities as a function of clinical parameters.
Milicevic, I., S. Pekovic, et al. (2003). "Ribavirin reduces clinical signs and pathological changes of experimental autoimmune encephalomyelitis in Dark Agouti rats." J Neurosci Res 72(2): 268-78.
The effect of ribavirin on development of experimental autoimmune encephalomyelitis (EAE) was investigated. The disease was induced in genetically susceptible Dark Agouti rats with syngeneic spinal cord homogenate in complete Freund's adjuvant (SCH-CFA). Depending on the amount of mycobacteria in CFA, the animals developed either moderate or severe EAE. Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was applied i.p. at a daily dosage of 30 mg/kg in two treatment protocols: from the start of immunization (preventive treatment) or from the onset of the first EAE signs after the induction (therapeutic treatment). Signs of EAE began between 7 and 9 days after induction and peaked at days 11-13. In moderate EAE (mean maximal severity score 3.33 +/- 0.21), the recovery was completed by days 23-26, whereas, in severe EAE (mean maximal severity score 4.5 +/- 0.23), obvious recovery was not detected. Preventive ribavirin treatment significantly decreased clinical signs after both moderate (score 1.75 +/- 0.25, P < 0.05) and severe (score 3.62 +/- 0.31, P < 0.015) immunization. Also, disease manifestations were reduced by therapeutic treatment of ribavirin (mean maximal severity score 2.5 +/- 0.2 vs. 3.33 +/- 0.21 in controls, P < 0.005) but less so in comparison with preventive treatment. Analysis of the effects of ribavirin on histopathologic changes in the spinal cord tissue revealed a reduction of mononuclear cell infiltrates, composed of T cells and macrophages/microglia, and the absence of demyelination, which were pronounced in control EAE animals. Beneficial effects of preventive and therapeutic treatment with ribavirin on development of EAE suggest this nucleoside analogue as a useful candidate for therapy in multiple sclerosis.
Miller, D. M., R. A. Rudick, et al. (2003). "Factors that predict health-related quality of life in patients with relapsing-remitting multiple sclerosis." Mult Scler 9(1): 1-5.
Health-Related Quality of Life (HRQoL) research is gaining acceptance in the field of multiple sclerosis (MS). Little is known about what precipitates quality of life change. It was hypothesized that physical aspects of quality of life decline with worsening objective disease measures and psychosocial aspects remain relatively stable regardless of change in objective measures. These assumptions are tested using data from a Phase 3 study of relapsing-remitting MS patients treated with interferon beta-1a and reassessed approximately eight years after study initiation. The Sickness Impact Profile (SIP) questionnaire is the generic quality of life measure used in this study. Three summary scores of the SIP (Physical, Psychosocial, and Total scores), Expanded Disability Status Scores, Multiple Sclerosis Functional Composite, and Brain Parenchymal Fraction were determined at baseline, year 2, and after an average of 8.1 years from study entry. SIP data collected during a clinic visit were available from 137 of the original 172 participants. All objective indicators worsened by follow-up. SIP Physical and Total scores significantly worsened from baseline to follow-up. SIP Psychosocial showed nonsignificant worsening. Regression analysis indicated that final measures of SIP Physical and Total scores were most strongly associated with change in objective measures and follow-up SIP Psychosocial was most strongly related to earlier scores on the same measure.
Miller, A., G. Eninia, et al. (2003). "[Adhesive molecules as immunologic markers of activity of multiple sclerosis]." Zh Nevrol Psikhiatr Im S S Korsakova 103(1): 35-8.
The correlations between concentrations of the adhesive circulating molecules cICAM-1 and cVCAM-1 in the peripheral blood of patients with relapses-remitting multiple sclerosis (RRMS) in different clinical phases and magnetic resonance imaging (MRI) activity are presented. The patients in clinically active phase with Gd-enhancing lesions had elevated blood levels of cICAM-1. However, 5 patients without Gd-enhancing lesions exhibited elevated cICAM-1 and cVCAM-1 levels in active phase comparing to those in remission stage that indicate a high level of sensibility of these immunologic parameters.
Miller, D. H., O. A. Khan, et al. (2003). "A controlled trial of natalizumab for relapsing multiple sclerosis." N Engl J Med 348(1): 15-23.
BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
Minagar, A., D. Ostanin, et al. (2003). "Serum from patients with multiple sclerosis downregulates occludin and VE-cadherin expression in cultured endothelial cells." Mult Scler 9(3): 235-8.
Disruption of the blood brain barrier (BBB) and transendothelial migration of inflammatory cells are crucial steps in the development of demyelinating lesions in multiple sclerosis (MS). Occludin and vascular endothelial-cadherin (VE-cadherin) are two major components of the tight junctions (TJs) in the brain microvasculature that help to create the BBB. In the present study, we investigated the effect of serum from MS patients on the expression of these two junctional markers and on the endothelial integrity. Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured endothelial cells, and the expression of occludin and VE-cadherin was measured by immunoblotting. Serum from MS patients in exacerbation significantly reduced the expression of occludin and VE-cadherin compared with patients in remission and normal controls. This disintegrating effect was more pronounced for occludin than for VE-cadherin. We assume that the elevation in cytokines or other serum-soluble factors in MS patients in exacerbation likely provokes downregulation of occludin and VE-cadherin. This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition.
Miscio, G., G. Guastamacchia, et al. (2003). "Are the neurophysiological techniques useful for the diagnosis of diaphragmatic impairment in multiple sclerosis (MS)?" Clin Neurophysiol 114(1): 147-53.
OBJECTIVE: To characterize cortico-diaphragmatic pathway involvement in multiple sclerosis (MS) by means of transcranial magnetic stimulation (TMS), and verify its clinical impact. METHODS: TMS from diaphragm (Dia), and abductor digiti minimi (AbdV degrees ) was performed in 26 MS patients. Phrenic nerve (PN) conduction study was also performed. Expanded disability status scale (EDSS) and fatigue descriptive scale (FDS) were measured. Forced vital capacity (FVC), forced expiratory volume at the first second (FEV1), peak expiratory flow (PEF) were tested: the predicted percentage value (% pred) was considered. RESULTS: Cortical motor evoked potential (Cx-MEP) latency and central motor conduction time (CMCT) were prolonged, respectively, in 31 and 23% of patients from Dia, in 76 and 79% from AbdV degrees. PN-compound motor action potential (CMAP) was normal. EDSS correlated to Cx-MEP from AbdV degrees (P<0.01), and PN-CMAP amplitude (P<0.05), FEV1 % pred (P<0.01), PEF % pred (P<0.01). PN-CMAP amplitude correlated to FVC % pred P=0.05, FEV1 % pred P<0.01, PEF % pred P<0.01. Fatigue was related to AbdV degrees Cx-MEP and CMCT (P<0.05 and P<0.01). CONCLUSIONS: Cortico-diaphragmatic pathway is impaired only in a minority of MS patients. Lack of correlation between TMS findings from Dia and respiratory tests argues against its routinary use to detect subclinical respiratory alterations. Fatigue seems to be related to the motor impairment rather than to respiratory distress.
Miwa, H., Y. Kajimoto, et al. (2003). "T2-low signal intensity in the cortex in multiple system atrophy." J Neurol Sci 211(1-2): 85-8.
To determine the clinical significance of T2-low signal intensity in the cortex of patients presenting parkinsonism, T2-weighted magnetic resonance (MR) images of the cortex of patients with multiple system atrophy (MSA), Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and compared with those of patients with amyotrophic lateral sclerosis (ALS) and age-matched normal controls. The MR images were gathered and presented randomly to three neurologists who were blind to information on the patients. There was a significant increase in the frequency of T2-low signal intensity in the cortex of patients with ALS and MSA. Particularly in those with MSA, the T2-low signal intensity was observed not only in the motor cortex but also in the frontal association cortex. The cortical T2-low signal intensity in MSA might reflect the spread of degenerative processes in the cortex.
Mizuno, T., J. Kawanokuchi, et al. (2003). "Production and neuroprotective functions of fractalkine in the central nervous system." Brain Res 979(1-2): 65-70.
The CX3C-chemokine, fractalkine is reportedly to be expressed in the central nervous system, and up-regulated in certain pathological conditions, such as HIV encephalopathy and multiple sclerosis. In the present study, we examined the production of fractalkine and the expression of its receptor, CX3CR1 in murine glial and neuronal cell in vitro, and investigated its neuroprotective functions. Both fractalkine and CX3CR1 were expressed constitutively in neurons, microglia, and astrocytes. Neither the production of fractalkine nor its receptor expression was up-regulated by lipopolysaccharide (LPS), as measured by mRNA expression and protein synthesis. Fractalkine dose-dependently suppressed the production of nitric oxide (NO), interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha with activated microglia. It also significantly suppressed neuronal cell death induced by microglia activated with LPS and interferon-gamma, in a dose-dependent manner. These results suggest the possible functions of fractalkine as an intrinsic inhibitor against neurotoxicity by activated microglia.
Modin, H., T. Masterman, et al. (2003). "Genome-wide linkage screen of a consanguineous multiple sclerosis kinship." Mult Scler 9(2): 128-34.
Multiple sclerosis (MS), like Alzheimer's disease (AD) and Parkinson's disease (PD), is a common neurological disorder thought to be caused by the interaction of several genes with unknown environmental factors. In both AD and PD the identification of disease forms inherited in a classic Mendelian fashion has helped investigators elucidate pathogenetic mechanisms. In this study a whole-genome screen, with an average of 608 successful genotypes per person, was performed on nine members of a consanguineous family: the index case, three of her siblings and her daughter, all of whom have been diagnosed with definite MS; as well as the parents of the index case (first cousins), one of her five healthy siblings and her husband (who is also her first cousin). Nonparametric linkage analysis was performed on genotyping data. Based on the presence of consanguinity, the a priori hypothesis was that the disease is transmitted in an autosomal recessive fashion in the pedigree. Linkage analysis revealed a suggestive logarithm of odds (LOD) score of 2.29 on the long arm of chromosome 9. Four of five affected family members were identically homozygous for a haplotype under this peak, spanning approximately 43 cM, while the fifth affected subject and all unaffected family members were heterozygous for the haplotype.
Mogenet, I., E. Simiand-Erdociain, et al. (2003). "Acute myelogenous leukemia following mitoxantrone treatment for multiple sclerosis." Ann Pharmacother 37(5): 747-8.
Mohamed, A., A. Shoker, et al. (2003). "Improvement of experimental allergic encephalomyelitis (EAE) by thymoquinone; an oxidative stress inhibitor." Biomed Sci Instrum 39: 440-5.
Experimental Allergic Encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system that is widely accepted as an animal model for the human multiple sclerosis. Oxidative stress appears to play a role in the onset and progression of EAE. We reasoned that decreasing oxidative stress might ameliorate symptoms and signs of EAE. Thymoquinone is reported to inhibit oxidative stress. One way of decreasing oxidative stress is to induce glutathione (GSH). We tested the impact of Thymoquinone (1 mg/kg, injected at tail vein) in our EAE model. We induced (EAE) in female Lewis rats using myelin basic protein emulsified with complete Freund's adjuvant. 24 animals were placed into three groups: A) Rats with EAE B) EAE rats with concomitant five day injection of Thymoquinone days 1-5, C) EAE rats with five doses of Thymoquinone injected at day 12-17. Twenty-eight days later, animals were sacrificed; spinal cord tissues collected for glutathione (GSH). RESULTS: 63% of animals in group "A" developed hind limb weakness and/or paralysis while 37% developed mild tail weakness, perivascular inflammation and low spinal cord GSH level. 25% of animals in group "B" exhibited mild tail and hind limb weakness and 75% animals had no symptoms, no perivascular inflammation and high spinal cord GSH level. 63% of animals of group "C" showed improving symptoms following Thymoquinone injections, no perivascular inflammation and higher GSH level while 37% of animals showed no symptoms prior and post Thymoquinone injections. Clinical symptoms correlated well with perivascular inflammation and GSH level. Animals received Thymoquinone at day 12-17 had higher GSH level, no perivascular inflammation and no symptoms compared with other groups. CONCLUSION: Thymoquinone inhibited oxidative stress which leads into improvement in our EAE animals. Thymoquinone may have a role in treatment of Multiple Sclerosis.
Mokhtarian, F., C. M. Huan, et al. (2003). "Semliki Forest virus-induced demyelination and remyelination--involvement of B cells and anti-myelin antibodies." J Neuroimmunol 137(1-2): 19-31.
Semliki Forest virus (SFV) infection induces a demyelinating encephalomyelitis in the central nervous system (CNS) of mice and serves as a model for multiple sclerosis (MS). This study investigated CNS immune responses at different stages of infection and during SFV-induced demyelination and remyelination. Following the initial CNS inflammation, pathology and viral clearance on days 6-10 post-infection (pi), primary demyelination was observed in cerebellar, brainstem and corpus collosal white matter by days 15-21 pi, with plasma cells and microglia as main participants, and this was followed by remyelination. By day 35 pi, the tissue appeared almost normal. Fluorescent antibody cell sorter (FACS) analysis showed that brain CD8(+) T cells increased during the initial inflammatory response and gradually decreased thereafter. Brain B cell (B220(+)CD19(+)) numbers did not change significantly during the course of infection; however, from days 14 to 35 pi, they matured and produced antibodies to viral and myelin proteins (and peptides) during the period of demyelination and remyelination. The proportion of CD3(-)B220(-)CD11b(+) cells also progressively increased throughout the periods of de- and remyelination. Our results suggest that CD8(+) T cells are involved in the initial destruction of CNS tissue during the first weeks of SFV infection, while B cells, antibodies and microglia may contribute to the myelin pathology seen after recovery.
Molina-Monasterios, M. C. and H. Molina-Abecia (2003). "[Nasu Hakola disease: a report of the first two cases in Bolivia]." Rev Neurol 36(9): 837-40.
INTRODUCTION: Nasu Hakola disease (NHD) is a progressive dementia that presents accompanied by bone cysts and, at random, epilepsy. It is an autosomal recessive hereditary disease and its genetic defect is located at the 19q13.1 chromosome. The genetic mutation was identified at DAP 12. It appears that DAP 12 is expressed in the microglial activation and the differentiation of macrophages in the central nervous system and, at the same time, in the osteoclasts in charge of bone remodelling. This double character consisting of dementia and bone cysts, which contain triglycerides and thin PAS positive membranes in a bone with cortical erosion and medullary hypoplasia, enables us to differentiate this disease from other frontotemporal neurodegenerative disorders, such as Pick s disease. At the same time this also allows it to be distinguished from multiple sclerosis, metachromatic leukodystrophy, Marchafava Bignami disease, and prion diseases (such as new variant Creutzfeldt Jakob). CASE REPORTS: In this paper we describe two cases of NHD, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, in which progressive dementia, bone cysts and epilepsy were identified. Serious brain atrophy was found and confirmed by imaging studies and brain biopsies, which were also used to rule out other degenerative diseases of the frontal lobe, as well as Creutzfeldt Jakob disease. CONCLUSIONS: Both cases meet all the necessary criteria to satisfy a diagnosis of NHD. This is a hereditary, little known disease whose genetic alterations (i.e. mutations) are still in need of further study. It mainly affects males, who suffer the onset of dementia in their thirties. The neurological disorders constitute a frontal syndrome, due to predominant prefrontal involvement, and they occur in the dorsolateral area, with disorders affecting the executive and planning functions; in the orbitofrontal area, which is reflected in social maladjustment and clear obsessive compulsive traits; and also in the medial or cingulate area, which manifests itself as apathy and lack of motivation. When dealing with this disease, in addition to symptomatic therapy, genetic counselling is also important.
Monge-Argiles, J. A., F. Palacios-Ortega, et al. (2003). "Sympathetic dysfunction is related to the clinical activity of multiple sclerosis." Mult Scler 9(2): 216; author reply 215.
Mpofu, S. and R. J. Moots (2003). "A case of multiple sclerosis associated with rheumatoid arthritis and positive anticardiolipin antibodies." Ann Rheum Dis 62(4): 376.
Munger, K. L., R. W. Peeling, et al. (2003). "Infection with Chlamydia pneumoniae and risk of multiple sclerosis." Epidemiology 14(2): 141-7.
BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent for multiple sclerosis (MS), but results of previous studies are conflicting. METHODS: Using a nested case-control design, we examined the association between Cpn infection and MS in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) cohorts. Among 32,826 women in the NHS and 29,722 women in the NHS II with blood samples, 141 incident cases of definite or probable MS were documented. Each case was matched to two healthy controls on year of birth and NHS cohort. Serum samples were tested for the presence of Cpn-specific immunoglobin G antibodies using microimmunofluorescence. RESULTS: Cpn immunoglobin G seropositivity was positively associated with risk of MS (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.1-2.7). This association did not change after adjusting for age at blood collection, ancestry, latitude of residence at birth, and smoking (OR = 1.9; CI = 1.1-3.1). Seropositivity for Cpn was only moderately associated with risk of relapsing-remitting MS (OR = 1.7; CI = 0.9-3.2), but it was strongly associated with risk of progressive MS (OR = 7.3; CI = 1.4-37.2). Geometric mean titers of Cpn-specific immunoglobin G antibody were similar in women with relapsing-remitting MS as compared with matched controls (44 vs 39), but they were elevated in women with progressive MS (99 vs 40). CONCLUSIONS: These results support a positive association between Cpn infection and progressive MS.
Muraro, P. A., R. C. Ingoni, et al. (2003). "Hematopoietic stem cell transplantation for multiple sclerosis: current status and future challenges." Curr Opin Neurol 16(3): 299-305.
PURPOSE OF REVIEW: This article reviews recent advances in clinical trials of hematopoietic stem cell transplantation as a therapy for multiple sclerosis, and progress in exploring the potential for neural repair of hematopoietic-derived precursors. RECENT FINDINGS: Important recent findings are that hematopoietic stem cell transplantation can completely suppress the inflammatory component of multiple sclerosis, hematopoietic stem cells can migrate into the central nervous systems of rodents and humans, and can differentiate into cells expressing neural and glial markers. Hematopoietic stem cells also have neural and myelin repair potential. The heterogeneity of transplant regimens, the selection of patients at different stages of disease in clinical trials, and the limited duration of follow-up all currently preclude the evaluation of the long-term clinical benefits of hematopoietic stem cell transplantation for multiple sclerosis. SUMMARY: Hematopoietic stem cell transplantation is an experimental treatment that shows strong effects on the inflammatory component of multiple sclerosis. On the basis of experience acquired from initial pilot studies, controlled clinical trials are now being designed to verify long-term clinical efficacy. Selecting patients at high risk in the earlier stages of the disease that is dominated by inflammation, and monitoring objectively disease activity by magnetic resonance imaging will be critically important in these studies. Recent advances on the migratory potential and on the differentiation plasticity of hematopoietic stem cells have opened new opportunities for remyelination and axonal repair strategies for multiple sclerosis.
Muraro, P. A., K. P. Wandinger, et al. (2003). "Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders." Brain 126(Pt 1): 20-31.
T cells recognizing self or microbial antigens may trigger or reactivate immune-mediated diseases. Monitoring the frequency of specific T cell clonotypes to assess a possible link with the course of disease has been a difficult task with currently available technology. Our goal was to track individual candidate pathogenic T cell clones, selected on the basis of previous extensive studies from patients with immune-mediated disorders of the CNS, including multiple sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and chronic Lyme neuroborreliosis. We developed and applied a highly specific and sensitive technique to track single CD4(+) and CD8(+) T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time reverse transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and CSF during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. By integrating clonotype tracking with direct visualization of antigen-specific staining, we showed that a single T cell clone contributed substantially to the overall recognition of the viral peptide/MHC complex in a patient with HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further elucidation of the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses in neurological disorders.
Murphy, C. B., S. A. Hashimoto, et al. (2003). "Clinical exacerbation of multiple sclerosis following radiotherapy." Arch Neurol 60(2): 273-5.
BACKGROUND: Radiation of the central nervous system in patients with demyelinating disease may have deleterious effects. OBJECTIVE: To describe a 30-year-old woman with multiple sclerosis who developed an attack of demyelination 2 months following radiotherapy for a parotid malignancy. RESULTS: Magnetic resonance imaging demonstrated new hyperintense lesions that corresponded to both the localization of the patient's symptoms and to the area defined by the 50% isodose radiation field. CONCLUSION: Radiation treatment likely triggered an exacerbation of multiple sclerosis.
Mycko, M. P., R. Papoian, et al. (2003). "cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity." Brain 126(Pt 5): 1048-57.
cDNA microarray analysis of the regions of pathologically proven different activity of multiple sclerosis lesions was performed. Major differences in gene expression (DGE) occurred between the lesion margin and lesion centre in active lesions studied (57 and 69 genes differentially expressed, respectively), whereas the margins and centres of silent lesions showed markedly reduced heterogeneity (only 11 and two genes differentially expressed, respectively). To compare differences between chronic active and silent lesions, we performed DGE comparison of the pooled data from both types of lesions. The major DGE occurred at the lesion margin, 156 (26; 5%), the greater number representing upregulated genes at the margin of active lesions (15%). Fourteen genes were found to be significantly upregulated in marginal versus central zones in active lesions examined. These genes comprised predominantly inflammation/immune-related factors. We also performed DGE analysis of pooled genes upregulated at the margin of active lesions and found that among the 50 genes showing differences, nine out of 14 were identified in the previous analysis of overlapping differentially expressed genes. Thus this microarray analysis has identified a novel set of genes associated with lesion activity in multiple sclerosis, many of them not previously linked with the disease.
Myers, J. A., K. M. McPherson, et al. (2003). "Duration of condition is unrelated to health-state valuation on the EuroQoL." Clin Rehabil 17(2): 209-15.
OBJECTIVE: To determine whether health valuations, such as those used in economic evaluation, are affected by duration of a health condition. People with disabling health conditions tend to value health more highly than members of the general population, and one explanation for this is that over time their experience of living with a disabling illness changes the way in which they value health. If this is so, a relationship between the duration of an individual's disabling health condition and the valuation they assign to their health-state might reasonably be expected. DESIGN: A postal survey using the EuroQoL (EQ-5D) instrument to collect descriptions and valuations for health from people who reported a diagnosis of either stroke or multiple sclerosis. Contact with participants was made through national support organizations and questionnaires were returned by mail. RESULTS: Eight hundred and ninety-four people completed the survey. One hundred (11 %) had one health-state indicating moderate problems in all five dimensions of the EQ-5D descriptive profile. For people with this health-state, analysis of covariance showed no relationship between valuation of health-state and time from onset of illness (F = 0.38, p = 0.54). This finding applied irrespective of the diagnosis, and for some other less frequently reported health-states. CONCLUSION: Clinical experience suggests that over time people adapt to long-term disability. However we found no evidence to support the proposition that higher health-state valuations by people with disabling conditions are explained by the actual duration of their condition.