Multiple Sclerosis References 2003; Authors: G
(46 References)
Gadoth, N. (2003). "Multiple sclerosis in children." Brain Dev 25(4): 229-32.
Multiple sclerosis (MS) is traditionally the domain of adult neurologists due to its characteristic presentation during early adult life. Although descriptions of infants with MS appeared in the beginning of the last century and the first autopsy was described even earlier, it was not until 1980 that childhood onset MS was recognized and subsequently well characterized. In spite of this, the awareness of pediatricians and pediatric neurologists to the occurrence of MS especially in infants and young children is still unsatisfactory. It is not infrequent that a meticulous, time consuming and costly search for metabolic and degenerative disorders other that MS is initiated before the diagnosis of MS is considered. This leads to a significant diagnostic and therapeutic delay in many young patients. Moreover, when the presentation is acute and characterized by confusion, seizures, CSF pleocytosis following a viral infection, a diagnosis of meningoencephalitis will be frequently reached. In this review, updated data on frequency, epidemiology, some special clinical and radiological features of childhood onset MS, outcome and treatment will be briefly discussed with the purpose of alerting physicians to the possibility of the occurrence of MS even in infants and young children.
Gagliardi, B. A. (2003). "The experience of sexuality for individuals living with multiple sclerosis." J Clin Nurs 12(4): 571-8.
Little is known of the experience of sexuality among people living with multiple sclerosis (MS). This Roy Adaptation Model-based study focused on identifying the experiences of sexuality reported by individuals living with MS. A qualitative, naturalistic case study method was employed. Five women and three men diagnosed with MS were interviewed by telephone three times over a period of 1 year. The telephone interview guide consisted of a series of structured questions. Analysis of the telephone interview transcripts revealed three themes. The theme, "How I Feel About My Appearance", reflected elements of the Roy model physiological, self-concept, role function and interdependence modes. The theme, "I Have Feelings About My Sexuality", reflected the self-concept and interdependence modes, and the theme, "Sexuality For Me Has Both Negative and Positive Emotions", reflected the self-concept and interdependence modes. The small sample size precludes generalization of the results to all individuals living with MS. Nurses and other health care providers need to recognize that sexuality is an important issue for individuals with MS. Researchers should continue to examine experiences of sexuality in a larger sample of individuals with MS and also should begin to examine the effects of nursing interventions, such as support groups and individual counselling, on feelings about sexuality in individuals with MS.
Galie, E., A. Pietrangeli, et al. (2003). "Demyelinating disease in monoclonal gammopathy of undetermined significance." J Exp Clin Cancer Res 22(2): 337-9.
We describe herein the case of a 57 year old man who, over the last five years, has presented ataxic and spastic gait on the right side, a reduction in fine motor movement of the fingers mainly on the right side, superficial right side brachiocrural hypoesthesia and a marked dysarthria associated with internuclear ophthalmoplegia. The neurological picture, after an initial progressive worsening which lasted some months, remained relatively stable over the years. Repeated magnetic resonance imaging (MRI) of the brain and spinal cord documented the presence of demyelinating plaques spread in the white matter of the periventricular region and the semioval centres, and a right side paramedian plaque at the C4-C5 level, none of which were in the active phase. Oligoclonal bands were revealed in the cerebrospinal fluid (CSF). Monoclonal IgM/lambda gammopathy with anti-myelin and anti-nucleo reactivity, found with serum immunofixation, were confirmed several times in successive annual controls, not associated to myeloproliferative pathology. The lack of progression in the clinical picture would seem to contradict the diagnosis of late Multiple Sclerosis. The presence of antibody activity against the myelin might support the hypothesis of a pathogenetic role of the immunoglobulins at the onset of the demyelinating disease in this patient. However, in the end, there is the possibility of casual association with a poorly functioning immune system connected to age.
Gallus, J. and V. Mathiowetz (2003). "Test-retest reliability of the Purdue Pegboard for persons with multiple sclerosis." Am J Occup Ther 57(1): 108-11.
OBJECTIVE: The Purdue Pegboard test often is used in clinical settings to evaluate changes in clients' fine motor dexterity. The purpose of this study was to determine the test-retest reliability and practice effects of the Purdue Pegboard for persons with multiple sclerosis. In addition, this study compared the reliability of one-trial administration to three-trial administration of the four subtests. METHOD: Thirty-two volunteers from a midwestern community-based maintenance rehabilitation center for persons with multiple sclerosis participated in this study. The participants were administered the four subtests of the Purdue Pegboard, three trials in a row. A second administration was completed 1 week later. Data from 25 participants were analyzed using paired t tests, Pearson product-moment correlations, and intraclass correlation coefficients. RESULTS: The test-retest reliability coefficients ranged from .85 to .90 for one-trial administration and from .92 to .96 for the sum of three trials. No significant practice effects existed except for the sum of three trials of both hands. CONCLUSION: This study suggests that the one-trial administration of the Purdue Pegboard is a sufficiently reliable assessment to use with persons with multiple sclerosis. Findings further suggest that for a person with multiple sclerosis, any changes in Purdue Pegboard scores using one-trial administration may reflect actual change in that person's dexterity, as no practice effect was demonstrated in this study.
Gambetti, P., P. Parchi, et al. (2003). "Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia." Clin Lab Med 23(1): 43-64.
Studies on hereditary CJD and FFI have contributed greatly to the understanding of all forms of prion disease. Most importantly, they have provided strong support for the prion hypothesis [2]. The linkage of pathogenic PRNP mutations to human prion disease strengthens the notion that a change in PrP conformation is a key event that triggers the development of the disease. Although hereditary CJD and FFI account for only 10% of all cases of human prion disease, they provide a unique opportunity for studying disease pathogenesis initiated by perturbation in the PrP structure. An understanding of the events that accompany a change in PrP conformation has far-reaching implications for sCJD (the most common form of the disease) and for sporadic fatal insomnia. A wealth of available evidence indicates that a common pathway in disease pathogenesis may be shared by both the sporadic and the hereditary forms of prion disease, except that the initiating events are stochastic in the former, rather than predetermined by the presence of a germ-line mutation. In addition, investigations of hereditary CJD and FFI have provided plausible mechanisms of phenotypic heterogeneity in prion disease, a phenomenon analogous to the "prion strain" diversity in animal prion disease. Although many other neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's chorea are fairly homogeneous in disease phenotype, prion disease includes many clinically and pathologically distinct disease entities. In hereditary prion disease, the disease phenotype is likely to be determined by the combined effect of pathogenic mutations, codon 129 polymorphism, and the type of PrPSc. The pathogenic mutations include point mutations that are located mostly in the central and C-terminal region of PrP, and deletion and insertion mutations that are located in the N-terminal region. It is conceivable that these distinct types of mutations may result in differential changes in conformation or stability of PrP. The codon 129 polymorphism plays a twofold role in modulating the disease outcome. On the mutant allele, it determines the basic features of the disease phenotype--as in the case of FFI and CJD178--that result respectively from the coupling of M or V at codon 129 with the D178N mutation. On the normal allele, it may modulate the severity of the phenotype. A PrPSc subtype is encoded by the PRNP haplotype, and subsequently is generated by a conformational conversion process that transforms the cellular isoform to the pathogenic protein. The site for the formation of a specific PrPSc conformer and its accumulation in different brain regions are likely to contribute to the clinical features and pathologic lesions. The phenotypic homogeneity in other neurologic diseases, including Alzheimer's disease, may be due, in part, to the lack of a powerful genetic modifier such as the codon 129 polymorphism in the PrP gene, and the lack of the ability of affected gene products such as PrP to assume multiple protein conformations. Clearly, the remaining issue in the understanding of pathogenesis of prion disease is a detailed and accurate knowledge of the in vivo processes and conditions for the formation of PrPSc that inevitably lead to the development and expression of the disease. This knowledge will enable the development of a rational and effective strategy for therapeutic intervention.
Gandelman-Marton, R., J. M. Rabey, et al. (2003). "Periodic lateralized epileptiform discharges in multiple sclerosis: a case report." J Clin Neurophysiol 20(2): 117-21.
The occurrence of epileptiform abnormalities on the EEG in patients with multiple sclerosis (MS) is rare. The following case correlates the clinical, EEG, MRI, and single photon emission computed tomographic (SPECT) findings in a patient with a long history of MS and acute onset of focal motor seizures and confusion. Two routine EEGs, brain MRI, and brain SPECT were performed. The patient was a 44-year-old woman with a long history of clinically definite MS of the relapsing-remitting and secondary progressive form with three events of focal motor seizures followed by generalized tonic-clonic seizures and postictal confusion. The first EEG done during admission showed periodic lateralized epileptiform discharges in the right temporal region. Brain MRI done several weeks later showed scattered T2 hyperintensities in several locations, including the periventricular and subcortical white matter bilaterally. Brain SPECT using Tc99-Neurolite demonstrated decreased perfusion on the right parietal and temporal lobes. This case suggests that focal motor seizures and a transient state of altered consciousness can be the result of an exacerbation of MS. The neurophysiologic expression of these clinical manifestations may present as periodic lateralized epileptiform discharges on the EEG and decreased regional perfusion on brain SPECT.
Ganor, Y., M. Besser, et al. (2003). "Human T Cells Express a Functional Ionotropic Glutamate Receptor GluR3, and Glutamate by Itself Triggers Integrin-Mediated Adhesion to Laminin and Fibronectin and Chemotactic Migration." J Immunol 170(8): 4362-72.
T cells may encounter glutamate, the major excitatory neurotransmitter in the nervous system, when patrolling the brain and in glutamate-rich peripheral organs. Moreover, glutamate levels increase in the CNS in many pathological conditions in which T cells exert either beneficial or detrimental effects. We discovered that normal human T cells, human T leukemia cells, and mouse anti-myelin basic protein T cells express high levels of glutamate ion channel receptor (ionotropic) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype 3 (GluR3). The evidence for GluR3 on T cells includes GluR3-specific RT-PCR, Western blot, immunocytochemical staining and flow cytometry. Sequencing showed that the T cell-expressed GluR3 is identical with the brain GluR3. Glutamate (10 nM), in the absence of any additional molecule, triggered T cell function: integrin-mediated T cell adhesion to laminin and fibronectin, a function normally performed by activated T cells only. The effect of glutamate was mimicked by AMPA receptor-agonists and blocked specifically by the selective receptor-antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo[f]quinoxalin-2,3-dione (NBQX), and by relevant anti-integrin mAbs. Glutamate also increased the CXCR4-mediated T cell chemotactic migration toward the key chemokine CXCL12/stromal cell-derived factor-1. GluR3 expression on normal, cancer and autoimmune-associated T cells and the ability of glutamate to directly activate T cell function could be of substantial scientific and clinical importance to normal neuroimmune dialogues and to CNS diseases and injury, and especially to: 1) T cell transmigration to the CNS and patrolling in the brain, 2) T cell-mediated multiple sclerosis, and 3) autoimmune epilepsy, as neurotoxic anti-GluR3 Abs are found and suspected to cause/potentiate seizures and neuropathology in several types of human epilepsies. Thus far, GluR3 was found only on neurons and glia cells; our results reveal a novel peripheral source of this antigenic receptor.
Garcia, D. M., S. E. Weigum, et al. (2003). "GFAP and nuclear lamins share an epitope recognized by monoclonal antibody J1-31." Brain Res 976(1): 9-21.
Monoclonal antibody J1-31 was raised against plaque materials taken from brains of patients who had suffered from multiple sclerosis (MS). Preliminary characterization of the antigen revealed it to be a protein of M(w) 68-70 kDa with both a cytoplasmic and nuclear localization. Here we report the results of isolation and peptide sequencing of the antigen from human brains, and immunocytochemical analysis of the antigen in F98 glioma cells. Purification and peptide sequencing indicate that the antibody recognizes a form of glial fibrillary acidic protein, possibly a phosphorylated variant. However, confocal immunocytochemistry and western analysis of F98 glioma cells raise the possibility that it also recognizes a phosphorylated epitope found in nuclear lamins. Analysis of the expression of the J1-31 epitope in F98 cells with respect to time in culture, cell density, and DNA synthesis showed a developmental relationship: cells that were engaged in rapid growth and DNA synthesis exhibited strong J1-31 staining in nuclei, whereas quiescent cells did not. We conclude that mAB J1-31 remains a useful antibody for studying multiple sclerosis, and is likely to prove useful in studies of the dynamics of nuclear lamins, particularly in models for wound-healing.
Garcia Merino, J. A., M. R. Blasco Quitez, et al. (2003). "[Combined therapy in multiple sclerosis]." Rev Neurol 36(6): 545-9.
INTRODUCTION. The availability of new drugs has been a significant advance in the therapy of multiple sclerosis over the last years. However, the control of the disease is far from being complete, and some patients respond poorly or not at all to the new drugs. DEVELOPMENT. The present paper reviews the approved therapies for multiple sclerosis and examines the advantages of the association of drugs, both with known and possible efficacy, as well as the theoretical basis for such associations and their possible clinical indications. Different designs for clinical trials in combination therapy are analyzed with a consideration of the current difficulties for the use of placebo in multiple sclerosis forms associated with relapses. CONCLUSIONS. The achievement of a higher efficacy than the present one is a major challenge in multiple sclerosis therapy. Combination therapy appears to be a reasonable option for that purpose.
Garcion, E., L. Sindji, et al. (2003). "Treatment of experimental autoimmune encephalomyelitis in rat by 1,25-dihydroxyvitamin D3 leads to early effects within the central nervous system." Acta Neuropathol (Berl) 105(5): 438-48.
We report here that curative treatment of the multiple sclerosis paradigm, chronic relapsing experimental autoimmune encephalomyelitis (EAE) of the Lewis rat, by 1,25-dihydroxyvitamin D(3 )(1,25-D3) leads to a rapid clinical improvement accompanied by an inhibition of CD4, MHC class II and type II nitric oxide synthase (NOS II) expression in the posterior areas of the central nervous system (CNS). In contrast, the hormone has no effect on transforming growth factor-beta1 transcripts. Computer analysis of the NOS II promoter, expressed by microglia and astrocytes, reveals consensus sequence for vitamin D receptor binding, emphasizing the idea that 1,25-D3 may regulate some aspects of EAE by acting directly on CNS constituent cells. We also demonstrate that vitamin D deprivation leads to minimal effects on the kinetic profile of EAE accompanied by a moderate exacerbation of the clinical symptoms. Interestingly, curative treatment of vitamin D-deprived rats with a non-toxic-1,25-D3 analogue (MC1288) strongly inhibited EAE symptoms, thus promulgating the potential interest of such compounds in the management of multiple sclerosis.
Garg, R. K. (2003). "Acute disseminated encephalomyelitis." Postgrad Med J 79(927): 11-7.
Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, and is characterised by multifocal white matter involvement. Diffuse neurological signs along with multifocal lesions in brain and spinal cord characterise the disease. Possibly, a T cell mediated autoimmune response to myelin basic protein, triggered by an infection or vaccination, underlies its pathogenesis. ADEM is a monophasic illness with favourable long term prognosis. The differentiation of ADEM from a first attack of multiple sclerosis has prognostic and therapeutic implications; this distinction is often difficult. Most patients with ADEM improve with methylprednisolone. If that fails immunoglobulins, plasmapheresis, or cytotoxic drugs can be given. Recent literature suggests that a significant proportion of patients with ADEM will later develop multiple sclerosis; however, follow up experience from developing countries does not support this view.
Garner, D. J. and J. J. Widrick (2003). "Cross-bridge mechanisms of muscle weakness in multiple sclerosis." Muscle Nerve 27(4): 456-64.
Vastus lateralis muscle biopsies were obtained from six individuals with multiple sclerosis (MS) having an Expanded Disability Status Score of 4.75 +/- 0.28, and from six age- and gender-matched individuals without MS. Biopsies from the MS group showed fewer fibers (31 +/- 4 vs. 46 +/- 4%) containing the type IIa myosin heavy chain (MHC) isoform exclusively. However, the percentage of fibers coexpressing type IIa and IIx MHC increased in direct proportion with MS disability status. The average unloaded shortening velocity of skinned fibers containing type I or IIa MHC did not differ between subject groups. Peak Ca(2+)-activated force was 11-13% lower in fibers from the MS group due to atrophy (type I and IIa fibers) and reduced specific force (type I fibers). Increasing intracellular inorganic phosphate (0-30 mM) or hydrogen ion (pH 7.0-6.2) reduced Ca(2+)-activated force in a manner that was independent of MS status. Thus, fibers from the MS group showed a subtle shift in fast MHC isoform coexpression and a modest reduction in cross-bridge number, density, or average force, with no change in maximal cross-bridge cycling rate or susceptibility to intracellular metabolites. These changes explain part of the muscle weakness and fatigue experienced by individuals with MS.
Gatehouse, P. D. and G. M. Bydder (2003). "Magnetic resonance imaging of short T2 components in tissue." Clin Radiol 58(1): 1-19.
The most widely used clinical magnetic resonance imaging techniques for the diagnosis of parenchymal disease employ heavily T(2)-weighted sequences to detect an increase or decrease in the signal from long T(2) components in tissue. Tissues also contain short T(2) components that are not detected or only poorly detected with conventional sequences. These components are the majority species in tendons, ligaments, menisci, periosteum, cortical bone and other related tissues, and the minority in many other tissues that have predominantly long T(2) components.The development and clinical application of techniques to detect short T(2) components are just beginning. Such techniques include magic angle imaging, as well as short echo time (TE), and ultrashort TE (Ute) pulse sequences. Magic angle imaging increases the T(2) of highly ordered, collagen-rich tissues such as tendons and ligaments so signal can be detected from them with conventional pulse sequences. Ute sequences detect short T(2) components before they have decayed, both in tissues with a majority of short T(2) components and those with a minority. In the latter case steps usually need to be taken to suppress the signal from the majority of long T(2) components. Fat suppression of different types may also be helpful. Once signal from short T(2) components has been detected, different pulse sequences can be used to determine increases or decreases in T(1) and T(2) and study contrast enhancement.Using these approaches, signals have been detected from normal tissues with a majority of short T(2) components such as tendons, ligaments, menisci, periosteum, cortical bone, dentine and enamel (the latter four tissues for the first time) as well as from the other tissues in which short T(2) components are a minority. Some diseases such as chronic fibrosis, gliosis, haemorrhage and calcification may increase the signal from short T(2) components while others such as loss of tissue, loss of order in tissue and an increase in water content may decrease them. Changes of these types have been demonstrated in tendonopathy, intervertebral disc disease, ligament injury, haemachromatosis, pituitary perivascular fibrosis, gliomas, multiple sclerosis and angiomas.Use of these techniques has reduced the limit of clinical detectability of short T(2) components by about two orders of magnitude from about 10 ms to about 100 micros. As a consequence it is now possible to study tissues that have a majority of short T(2) components with both "bright" and "dark" approaches, with the bright (high signal) approach offering options for developing tissue contrast of different types, as well as the potential for tissue characterization. In addition, tissues with a minority of short T(2) components may demonstrate changes in disease that are not apparent with conventional heavily T(2)-weighted sequences.
Gaudez, C., S. Regnier, et al. (2003). "[Livedo-like dermatitis (Nicolau's syndrome) after injection of Copolymer-1 (Glatiramer acetate)]." Rev Neurol (Paris) 159(5 Pt 1): 571-3.
We report the first case of a 33-year-old woman with multiple sclerosis, who developed a livedo-like dermatitis after injection of Copolymere-1. This disease is characterized by the development of acute violent pain during or immediately after injection, and a livedo-like plaque followed by necrosis corresponding to an arterial ischemia by vasospasm or thrombosis. Early treatment with vasoactive and anticoagulation agents is required. Surgery may be necessary.
Gaupp, S., D. Pitt, et al. (2003). "Experimental autoimmune encephalomyelitis (EAE) in CCR2(-/-) mice: susceptibility in multiple strains." Am J Pathol 162(1): 139-50.
Chemokines are low molecular weight cytokines which act as chemoattractants for infiltrating cells bearing appropriate receptors (CCR) to sites of inflammation. It has been proposed that CCR2 on monocytes is responsible for their recruitment into the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, and two previous reports have described resistance of CCR2(-/-) mice to EAE. The present study examined three different mouse strains with CCR2 deletions for susceptibility to EAE. Animals were studied up to 4 months post-sensitization and were examined by neuropathology, RNase protection assay, in situ hybridization, and in vitro assays. All three strains were found to be susceptible to EAE: C57BL/6 x J129 and Balb c strains, 100%; and C57BL/6, 67%. Unusual in CNS lesions of CCR2(-/-) mice was an overabundance of neutrophils versus monocytes in wild-type animals. An attempt of the immune system to develop compensatory mechanisms for the lack of CCR2 was evidenced by a corresponding increase in mRNA for other chemokines and CCR. Inasmuch as neutrophils replaced monocytes and led to demyelination, our findings support the concept that promiscuity of chemokines and CCR was able to surmount the deletion of CCR2, still resulting in full expression of this autoimmune disease.
Gbadamosi, J., C. Buhmann, et al. (2003). "Effects of mitoxantrone on multiple sclerosis patients' lymphocyte subpopulations and production of immunoglobulin, TNF-alpha and IL-10." Eur Neurol 49(3): 137-41.
We designed this longitudinal study to clarify the short- and long-term effects of mitoxantrone on the immune system in a subgroup of multiple sclerosis patients treated at our centre. After 14 days we found a highly significant sustained reduction of leucocytes, primarily affecting neutrophils and most lymphocyte subsets except for naive and activated T lymphocytes. The CD4/CD8 ratio and serum immmunoglobulin levels were not affected. Furthermore, whole blood-stimulated mononuclear cell IL-10 production showed a significant lower level 2 weeks treatment, whereas basal IL-10 as well as stimulated and basal TNF-alpha secretion showed no significant changes. Longitudinal data disclosed a persistent decrease of B lymphocytes, while secretion of immunoglobulins, IL-10, and TNF-alpha was not altered in the follow-up. In conclusion, we confirmed a selective short-term effect of mitoxantrone therapy on most lymphocyte subpopulations, but not on immunoglobulines or the pro- and anti-inflammatory cytokines TNF-alpha and IL-10, which do not serve as possible response markers.
Gbadamosi, J., A. Munchau, et al. (2003). "Severe heart failure in a young multiple sclerosis patient." J Neurol 250(2): 241-2.
Geschwind, D. H. (2003). "DNA microarrays: translation of the genome from laboratory to clinic." Lancet Neurol 2(5): 275-82.
As the complete sequences of human and other mammalian genomes become available we are faced with the challenge of understanding how variation in sequence and gene expression contributes to neurological and psychiatric disorders. DNA microarrays, or DNA chips, provide the means to measure simultaneously where and when thousands of genes are expressed. Microarrays are changing the way that researchers approach work at the bench and have already yielded new insights into brain tumours, multiple sclerosis, acute neurological insults such as stroke and seizures, and schizophrenia. The study of disease-related changes in gene expression is the first step in the long process in translation of genome research to the clinic. Eventually, the changes observed in microarray studies will need to be independently confirmed and we wil need to understand how gene expression changes translate into functional effects at the cellular level in the nervous system. Progress in these studies will translate into array-based disease classification schemes and help optimise therapy for individual patients based on gene expression patterns or their genetic background.
Geurts, J. J., G. Wolswijk, et al. (2003). "Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis." Brain 126(Pt 8): 1755-66.
Recent evidence supports a role for glutamate receptors in the pathophysiology of multiple sclerosis. In the present study, we have focused specifically on the expression of metabotropic glutamate receptors (mGluRs) in multiple sclerosis brain tissue. The expression of group I (mGluR1alpha and mGluR5) and group II (mGluR2/3) mGluRs was studied using immunohistochemistry in tissue from 12 multiple sclerosis cases and seven non-neurological controls. The expression patterns of both group I and II mGluRs in multiple sclerosis tissue differed significantly from those in control tissue. Strong mGluR1alpha immunoreactivity was observed in axons of the subcortical white matter, particularly in the centre of actively demyelinating lesions and in the borders of chronic active lesions. mGluR1alpha axonal immunopositivity was also found in normal appearing multiple sclerosis white matter, but axons in control white matter were generally negative. mGluR1alpha axonal labelling was associated with the presence of non-phosphorylated neurofilaments and beta-amyloid precursor protein, which are sensitive markers for axonal injury and disturbed axonal transport. Changes in mGluR immunoreactivity were also observed in glia. A diffuse increase in the expression of mGluR5 and mGluR2/3 was detected in reactive astrocytes in multiple sclerosis lesions. However, only a subpopulation of reactive astroglial cells expressed mGluR1alpha. In addition, labelling with antibodies to mGluR2/3 and, to a lesser extent labelling with antibodies to mGluR1alpha, was detected in a population of cells of the microglial/macrophage lineage that displayed a macrophage-like morphology. Our data suggest that mGluRs, like ionotropic glutamate receptors, play a role in the complex processes that are associated with the progressive brain damage in multiple sclerosis, including both glial activation and pathological changes in axons.
Gherardi, R. K. (2003). "[Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome]." Rev Neurol (Paris) 159(2): 162-4.
Macrophagic myofasciitis is a condition first reported in 1998, which cause remained obscure until 2001. Over 200 definite cases have been identified in France, and isolated cases have been recorded in other countries. The condition manifests by diffuse myalgias and chronic fatigue, forming a syndrome that meets both Center for Disease Control and Oxford criteria for the so-called chronic fatigue syndrome in about half of patients. One third of patients develop an autoimmune disease, such as multiple sclerosis. Even in the absence of overt autoimmune disease they commonly show subtle signs of chronic immune stimulation, and most of them are of the HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and rheumatoid arthritis. Macrophagic myofasciitis is characterized by a stereotyped and immunologically active lesion at deltoid muscle biopsy. Electron microscopy, microanalytical studies, experimental procedures, and an epidemiological study recently demonstrated that the lesion is due to persistence for years at site of injection of an aluminum adjuvant used in vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid. Aluminum hydroxide is known to potently stimulate the immune system and to shift immune responses towards a Th-2 profile. It is plausible that persistent systemic immune activation that fails to switch off represents the pathophysiologic basis of chronic fatigue syndrome associated with macrophagic myofasciitis, similarly to what happens in patients with post-infectious chronic fatigue and possibly idiopathic chronic fatigue syndrome. Therefore, the WHO recommended an epidemiological survey, currently conducted by the French agency AFSSAPS, aimed at substantiating the possible link between the focal macrophagic myofasciitis lesion (or previous immunization with aluminium-containing vaccines) and systemic symptoms. Interestingly, special emphasis has been put on Th-2 biased immune responses as a possible explanation of chronic fatigue and associated manifestations known as the Gulf war syndrome. Results concerning macrophagic myofasciitis may well open new avenues for etiologic investigation of this syndrome. Indeed, both type and structure of symptoms are strikingly similar in Gulf war veterans and patients with macrophagic myofasciitis. Multiple vaccinations performed over a short period of time in the Persian gulf area have been recognized as the main risk factor for Gulf War syndrome. Moreover, the war vaccine against anthrax, which is administered in a 6-shot regimen and seems to be crucially involved, is adjuvanted by aluminium hydroxide and, possibly, squalene, another Th-2 adjuvant. If safety concerns about long-term effects of aluminium hydroxide are confirmed it will become mandatory to propose novel and alternative vaccine adjuvants to rescue vaccine-based strategies and the enormous benefit for public health they provide worldwide.
Gibson, J. C. and A. O. Frank (2003). "Supporting individuals with disabling multiple sclerosis." J R Soc Med 96(5): 256-7.
Gielen, A., M. Khademi, et al. (2003). "Increased brain-derived neurotrophic factor expression in white blood cells of relapsing-remitting multiple sclerosis patients." Scand J Immunol 57(5): 493-7.
Central nervous system (CNS)-autoreactive immune responses can exert neuroprotective effects, possibly mediated via the release of neurotrophic factors from infiltrating leucocytes. Herein, we analysed neurotrophin and cytokine mRNA levels using TaqMan polymerase chain reaction in unstimulated peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients in remission and controls. We demonstrate that mRNA for brain-derived neurotrophic factor (BDNF), but not neurotrophin-3 or nerve growth factor (NGF), is readily detectable in PBMC and that levels in MS are increased by approximately 60% compared with patients with other neurological diseases or healthy subjects. These results provide additional evidence that a potentially neuroprotective facet of autoimmune inflammation is present in MS.
Giovannoni, G. and C. T. Bever, Jr. (2003). "Patients with clinically isolated syndromes suggestive of MS: does MRI allow earlier diagnosis?" Neurology 60(1): 6-7.
Gironi, M., R. Furlan, et al. (2003). "Beta endorphin concentrations in PBMC of patients with different clinical phenotypes of multiple sclerosis." J Neurol Neurosurg Psychiatry 74(4): 495-7.
The possible link between the opioid peptide beta endorphin and the heterogeneity of the clinical course of multiple sclerosis (MS) was investigated. Peripheral blood mononuclear cells (PBMC) concentrations of beta endorphin were measured in 50 patients in different phases of MS. Thirty nine patients also underwent post-contrast magnetic resonance imaging of the brain. Among MS forms, the highest beta endorphin concentrations were found in PBMC from patients with relapsing remitting MS and the lowest in patients with the progressive forms. Average beta endorphin concentrations were lower, although not significantly, in patients with than in those without magnetic resonance imaging enhanced lesions. These data suggest that beta endorphin may have a role in the downregulation of the inflammatory process.
Giuliani, F., C. G. Goodyer, et al. (2003). "Vulnerability of human neurons to T cell-mediated cytotoxicity." J Immunol 171(1): 368-79.
Axonal and neuronal loss occurs in inflammatory diseases of the CNS such as multiple sclerosis. The cause of the loss remains unclear. We report that polyclonally activated T cells align along axons and soma of cultured human neurons leading to substantial neuronal death. This occurs in an allogeneic and syngeneic manner in the absence of added Ag, requires T cells to be activated, and is mediated through cell contact-dependent mechanisms involving FasL, LFA-1, and CD40 but not MHC class I. Activated CD4(+) and CD8(+) T cell subsets are equally neuronal cytotoxic. In contrast to neurons, other CNS cell types (oligodendrocytes and astrocytes) are not killed by T cells. These results demonstrate for the first time the high and selective vulnerability of human neurons to T cells, and suggest that when enough activated T cells accumulate in the CNS, neuronal cytotoxicity can result through Ag-independent non-MHC class I mechanisms.
Giunti, D., G. Borsellino, et al. (2003). "Phenotypic and functional analysis of T cells homing into the CSF of subjects with inflammatory diseases of the CNS." J Leukoc Biol 73(5): 584-90.
The recruitment of lymphocytes across the blood brain barrier (BBB) is mediated by adhesion molecules and chemokines. The expression of activation markers and of chemokine receptors on T cells homing to the nervous system (NS) may help define their functional state. In the cerebrospinal fluid (CSF) of subjects with inflammatory neurological diseases (IND), including multiple sclerosis, we observed an increased number of T cells coexpressing CXCR3 and CCR5 as well as T cells with a CD45RO+ CCR7+ CD27+ memory phenotype. A subset of CCR7+ T cells coexpressed CXCR3 and CCR5. We also detected an increased number of interferon-gamma-producing T cells in the CSF compared with peripheral blood, mostly but not exclusively in the CD45RO+ CCR7- CD27- compartment. T helper 1 (Th1) clones, established from the CSF of individuals with IND and from a healthy subject, similarly migrated to CXCL10, CXCL12, and CCL5. CXCL10, CXCL12, and CCL19 were increased in the CSF of individuals with neuroinflammation. These findings suggest that CSF is enriched in Th1-polarized memory T cells capable of differentiating into effector cells upon antigen encounter. These cells are recruited into the CSF by inducible chemokines. Thus, CSF represents a transitional station for T cells trafficking to and from the NS.
Glabinski, A. R., B. Bielecki, et al. (2003). "Chemokine upregulation follows cytokine expression in chronic relapsing experimental autoimmune encephalomyelitis." Scand J Immunol 58(1): 81-8.
Chronic relapsing experimental autoimmune encephalomyelitis (ChREAE) is an autoimmune disease of the central nervous system (CNS) induced by CNS myelin components. In the early active stage, both ChREAE and multiple sclerosis (MS) are characterized by the presence of perivascular inflammatory cuffs disseminated in the CNS. There is growing evidence that chemoattractant cytokines (chemokines) play an important role in this process. The main goal of the present study was to analyse the hypothesis that chemokine expression in the CNS during autoimmune inflammation is regulated by proinflammatory cytokines. To address this concept, we analysed temporal relations between chemokine and cytokine expression during ChREAE. Phasic upregulation of gene expression for chemokines T-cell activation gene 3 (TCA-3)/CCL1, monocyte chemoattractant protein-1 (MCP-1)/CCL2, macrophage inflammatory protein-1 alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4, regulated on activation normal T cell expressed and secreted (RANTES)/CCL5 and MIP-2/CXCL2-3 as well as cytokines tumour necrosis factor-alpha (TNF-alpha), -beta, LT-beta, interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) in the CNS was observed during attacks of ChREAE. Expression of cytokines TNF-beta and LT-beta preceded, and the expression of TGF-beta1 followed chemokine upregulation. Our results suggest that chemokine expression during CNS autoimmune inflammation may be regulated by some proinflammatory cytokines.
Glass, W. G. and T. E. Lane (2003). "Functional expression of chemokine receptor CCR5 on CD4(+) T cells during virus-induced central nervous system disease." J Virol 77(1): 191-8.
Intracranial infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a demyelinating disease similar in pathology to the human disease multiple sclerosis (MS). CD4(+) T cells are important in amplifying demyelination by attracting macrophages into the central nervous system (CNS) following viral infection; however, the mechanisms governing the entry of these cells into the CNS are poorly understood. The role of chemokine receptor CCR5 in trafficking of virus-specific CD4(+) T cells into the CNS of MHV-infected mice was investigated. CD4(+) T cells from immunized CCR5(+/+) and CCR5(-/-) mice were expanded in the presence of the immunodominant epitope present in the MHV transmembrane (M) protein encompassing amino acids 133 to 147 (M133-147). Adoptive transfer of CCR5(+/+)-derived CD4(+) T cells to MHV-infected RAG1(-/-) mice resulted in CD4(+)-T-cell entry into the CNS and clearance of virus from the brain. These mice also displayed robust demyelination correlating with macrophage accumulation within the CNS. Conversely, CD4(+) T cells from CCR5(-/-) mice displayed an impaired ability to traffic into the CNS of MHV-infected RAG1(-/-) recipients, which correlated with increased viral titers, diminished macrophage accumulation, and limited demyelination. Analysis of chemokine receptor mRNA expression by M133-147-expanded CCR5(-/-)-derived CD4(+) T cells revealed reduced expression of CCR1, CCR2, and CXCR3, indicating that CCR5 signaling is important in increased expression of these receptors, which aid in trafficking of CD4(+) T cells into the CNS. Collectively these results demonstrate that CCR5 signaling is important to migration of CD4(+) T cells to the CNS following MHV infection.
Gniadek, P., O. Aktas, et al. (2003). "Systemic IFN-beta treatment induces apoptosis of peripheral immune cells in MS patients." J Neuroimmunol 137(1-2): 187-96.
In multiple sclerosis (MS), an impaired apoptotic deletion of activated CNS-specific immune cells, leading to their pathogenic persistence, has been suggested to maintain chronic brain inflammation. We here investigated whether interferon-beta (IFN-beta) therapy induces apoptosis of peripheral immune cells. Serial blood samples from 127 relapsing-remitting MS patients were analyzed prior to the initiation of a weekly IFN-beta 1a therapy and 4, 26, and 52 weeks thereafter. Peripheral immune cells were investigated for apoptosis and for the expression of apoptosis-regulatory genes CD95, CD95 ligand, FLIP, Bcl-2, Bcl-X(L), Bag-1, and caspase 3 by quantitative real-time PCR. Biological efficacy of IFN-beta treatment was checked by quantification of Mx expression (ELISA and real-time PCR). We found a significant increase in the apoptosis rate of immune cells in response to IFN-beta treatment, compared to baseline levels. While Bcl-2 levels were permanently and Bag-1 levels transiently elevated upon therapy, other apoptosis-regulatory genes revealed no alterations. Upregulation of Mx expression confirmed the activity of IFN-beta in vivo. These findings indicate that immunomodulatory IFN-beta therapy involves the induction of apoptotic cell death with the observed RNA upregulation of Bcl-2 family members rather reflecting a possible compensatory mechanism. The increased apoptosis susceptibility of peripheral immune cells may contribute to the known reduction of brain inflammatory lesions during IFN-beta treatment.
Goeb, J. L., A. Cailleau, et al. (2003). "Acute delirium, delusion, and depression during IFN-beta-1a therapy for multiple sclerosis: a case report." Clin Neuropharmacol 26(1): 5-7.
Adverse effects of interferon (IFN) treatment are common, and efforts to minimize these reactions are of considerable importance. IFN-beta-1a is an established therapy for patients with relapsing-remitting multiple sclerosis (MS). Its psychiatric side effects are debated and not yet fully established. The authors report here the case of a patient on IFN-beta-1a therapy for MS who developed acute delirium, delusion, and depression that ceased with treatment discontinuation. Although he had a history of recurrent major depressive disorder, his prior psychiatric illness had followed a course that was clinically independent of other signs of MS. This observation points out psychiatric vulnerability of patients taking IFN-beta-1a therapy for MS and suggests that IFN-beta-1a may induce or exacerbate preexisting psychotic symptoms.
Goertz, B., W. J. Fassbender, et al. (2003). "Vitamin D receptor genotypes are not associated with rheumatoid arthritis or biochemical parameters of bone turnover in German RA patients." Clin Exp Rheumatol 21(3): 333-9.
OBJECTIVE: Vitamin D is known to exert immunomodulatory effects. An overrepresentation of the b allele of the vitamin D receptor (VDR) has been detected in autoimmune diseases as type-1-diabetes and multiple sclerosis. VDR polymorphisms have been shown to influence bone metabolism and bone density. The aim of the present study was to examine the distribution of VDR alleles in German rheumatoid arthritis (RA) patients and their relation to bone turnover parameters. METHODS: 62 German RA patients were included and compared to 40 controls. Three VDR alleles were examined (Bsm I, Taq I and Fok I). In addition, serum intact osteocalcin (OC), parathyroid hormone, bone specific alkaline phosphatase (B-ALP), the carboxyterminal extension peptide of type I procollagen, 25-OH-vitamin D and urinary deoxypyridinoline (DPD) excretion were measured. Furthermore, C-reactive protein, erythrocyte sedimentation rate and rheumatoid factor were measured. RESULTS: We found a slightly higher frequency of the bB and tT-genotype in RA patients compared to controls, which was not statistically significant. OC and B-ALP were found to be significantly higher in RA patients with positive correlations between bone formation and resorption parameters indicating higher bone turnover in RA patients with maintained coupling. CRP in RA patients correlated with DPD and inversely with PTH. VDR genotype showed no association with bone turnover, family history or the presence of rheumatoid factor. CONCLUSIONS: Our results suggest that VDR polymorphisms do not play a major role in RA predisposition in Germans.
Gold, S. M., K. H. Schulz, et al. (2003). "Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls." J Neuroimmunol 138(1-2): 99-105.
Neurotrophins like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are thought to play an important role in neuronal repair and plasticity. Recent experimental evidence suggests neuroprotective effects of these proteins in multiple sclerosis (MS). We investigated the response of serum NGF and BDNF concentrations to standardized acute exercise in MS patients and controls. Basal NGF levels were significantly elevated in MS. Thirty minutes of moderate exercise significantly induced BDNF production in MS patients and controls, but no differential effects were seen. We conclude that moderate exercise can be used to induce neutrophin production in humans. This may mediate beneficial effects of physical exercise in MS reported recently.
Gomes, A. C., G. Jonsson, et al. (2003). "Upregulation of the apoptosis regulators cFLIP, CD95 and CD95 ligand in peripheral blood mononuclear cells in relapsing-remitting multiple sclerosis." J Neuroimmunol 135(1-2): 126-34.
Multiple sclerosis (MS) is a chronic disease involving an inflammatory reaction within the white matter of the CNS, mediated by T cells, B cells and macrophages. The pathogenesis of MS may involve impaired activation-induced cell death of activated myelin-specific mature T cells. We investigated the mRNA expression of the apoptosis mediators cellular FLICE-inhibitory protein (cFLIP), caspase-8, CD95 and CD95L in peripheral blood mononuclear cells (PB MNCs) from MS patients using real-time PCR. The overall increased expression of the four key players in the CD95 pathway in relapsing-remitting MS suggests their involvement in the inflammatory process in this disease.
Gomez, G. and M. V. Sitkovsky (2003). "Targeting G protein-coupled A2a adenosine receptors to engineer inflammation in vivo." Int J Biochem Cell Biol 35(4): 410-4.
G protein-coupled adenosine receptors are the subject of intense study as immunomodulators of inflammation especially since the recent demonstration that the A2a receptor acts to down-regulate inflammation and inhibit tissue damage in vivo [Nature 414 (6866) (2001) 916]. The adverse effects of overactive inflammation are evident in diseases e.g. sepsis, rheumatoid arthritis, and multiple sclerosis underscoring the importance of inhibiting inflammation or selectively enhancing inflammatory processes. It has been shown recently that the A2a adenosine receptor is a critical component of an endogenous "immunosuppressive loop" in which extracellular adenosine that accumulates due to local hypoxia caused by inflammatory insult signals through cAMP-elevating A2a receptors in a delayed negative feedback manner. Understanding how tissues regulate inflammation will provide the information necessary to allow for the engineering, or selective targeting, of endogenous inflammatory pathways. Recognition of A2a receptors as "natural" or endogenous brakes of inflammation provides the intellectual scaffolding needed to pursue these goals.
Gomez-Lira, M., M. Liguori, et al. (2003). "CD45 and multiple sclerosis: the exon 4 C77G polymorphism (additional studies and meta-analysis) and new markers." J Neuroimmunol 140(1-2): 216-21.
We re-evaluated the association with multiple sclerosis (MS) of the C77G splicing regulatory variation in the CD45 gene and screened for new mutations the three alternatively spliced exons (#4, 5 and 6). No association with C77G was detected in two groups of patients (total=448) and controls (total=559) from Northern and Southern Italy. When excluding the first published study indicating a positive association, a meta-analysis of the five further studies conducted to date (including the present one) led to a non-significant combined odds ratio (OR) of 1.11. None of the four newly identified nucleotide substitutions, namely C77T (Pro59Pro) in exon 4, G69C (Asp121His) in exon 5, T127A (Ile187Asn) and A138G (Thr191Ala) in exon 6, was significantly associated to MS.
Gonsette, R. E. (2003). "Mitoxantrone in progressive multiple sclerosis: when and how to treat?" J Neurol Sci 206(2): 203-8.
Mitoxantrone (MX) has been approved by the Food and Drug Administration (FDA) for the treatment of patients with worsening relapsing-remitting (RR) or secondary progressive (SP) multiple sclerosis (MS). However, indications should be refined and mitoxantrone reserved as a rescue therapy to: (1) patients in the relapsing-remitting phase with frequent and disabling exacerbations likely leading to permanent severe disability and (2) to patients in the secondary progressive phase whose disability progression rate increases by one EDSS point or more per year and who do not respond to other current therapies. An induction phase with the monthly intravenous administration of 12 mg/m(2) followed by a maintenance phase with 12 mg/m(2) every 3 months for 2 years seems the most effective and safe treatment regimen, not exceeding the maximum cumulative dose of 140 mg/m(2). Given the potent myelosuppressive activity of mitoxantrone, dosage should be carefully adapted to the body surface and hematological changes. Long-term toxicities (amenorrhoea and therapy-related leukemia) seem acceptable but a valid evaluation will need a longer follow-up in more patients. Cardiotoxicity, the major long-term toxicity, is clearly dose-dependent and is a strict treatment duration limiting factor. To reduce the risk of cardiac events, the drug should be administered by slow infusion (over 30 min). Analogs of mitoxantrone with a much lower cardiotoxicity are currently investigated in animal experimental models.
Goodin, D. S. (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1821; author reply 1823-4.
Goodman, A. D., D. J. Mock, et al. (2003). "Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions." J Infect Dis 187(9): 1365-76.
Evidence for a candidate multiple sclerosis (MS) virus, human herpesvirus 6 (HHV-6), was sought in biopsy specimens of acute lesions that presented clinically as cerebral tumors obtained from 5 patients. Histopathology, magnetic resonance imaging, and clinical course confirmed the diagnosis of MS in each case. A sensitive in situ polymerase chain reaction (ISPCR) method was used to detect HHV-6 genome, in conjunction with immunocytochemical staining (ICC) to detect viral and cellular antigens. ISPCR revealed numerous oligodendrocytes, lymphocytes, and microglia containing HHV-6 genome within all lesions, whereas ICC showed only the HHV-6 glycoprotein 116 antigen in some reactive astrocytes and microglia. High frequencies of neuroglial and inflammatory cells containing HHV-6 genome were present in acute-phase lesion tissue from patients who were free of the effects of chronic MS and had not been received immunomodulatory therapy for MS. The prevalence of HHV-6 genome-containing cells, including oligodendrocytes, in each lesion suggests that HHV-6 plays a role in the demyelinative pathogenesis of MS; the significance of the discrepant expression of viral antigens remains uncertain.
Granger, C. V., K. Wende, et al. (2003). "Use of the FIM instrument in a trial of intramuscular interferon beta-1a for disease progression in relapsing-remitting multiple sclerosis." Am J Phys Med Rehabil 82(6): 427-36.
OBJECTIVE: This study is a secondary analysis of results from the Multiple Sclerosis Collaborative Research Group multicenter trial. We investigated the effect of interferon beta-1a on disability in patients with relapsing-remitting multiple sclerosis (MS), using the FIM instrument to assess levels of decline in total, motor, and cognitive items. DESIGN: Of the 301 patients enrolled in the trial, 274 subjects with relapsing-remitting multiple sclerosis with baseline FIM and Kurtzke Expanded Disability Status Scale scores were studied in this secondary analysis. Mildly disabled patients were chosen, as indicated by a Kurtzke Expanded Disability Status Scale score of 1.0-3.5. Matched subjects were assigned to receive either interferon beta-1a or placebo. Kurtzke Expanded Disability Status Scale and FIM scores were measured serially every 6 mo. Failure was defined as a 4-point reduction in total FIM score sustained for 6 mo. Analysis was by Kaplan-Meier methodology. The Mann-Whitney test (log rank) compared mean change and Spearman's rank-correlation test determined correlation. RESULT: A significant difference in treatment groups was seen, with a FIM score decline of > or = 4 points, with placebo subjects demonstrating greater loss of function than subjects treated with interferon beta-1a. There was no statistically significant difference in total, cognitive, or motor activities, with a decline of < or = 3 points. CONCLUSION: Disability, as measured by the FIM instrument, was slowed by treatment with interferon beta-1a compared with placebo. The treatment effect determined using the FIM instrument, with its motor and cognitive components, indicates an additional level of response to therapy for mild to moderate multiple sclerosis.
Greenwood, J., C. E. Walters, et al. (2003). "Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis." Faseb J 17(8): 905-7.
Neuroinflammatory diseases, such as multiple sclerosis (MS), result from aberrant leukocyte traffic into the central nervous system (CNS). To breach the specialized blood-brain barrier, activated leukocytes interact with CNS endothelial cells (EC) and activate a CD54-mediated signaling pathway controlling the Rho GTPase. To function correctly Rho requires posttranslational prenylation, and this can be inhibited by depleting the supply of isoprenoids through inhibition of the cholesterol synthesis pathway with 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) inhibitors (statins). Here we show that treatment of brain EC in vitro with lovastatin inhibits Rho-mediated transendothelial T cell migration. This effect can be reversed by supplementation with mevalonolactone, the downstream product of HMG-CoA reductase, or by ectopic expression of myristoylated Rho, which remains active in the absence of prenylation. In a relapsing-remitting mouse model of MS, lovastatin treatment inhibited leukocyte migration into the CNS and significantly attenuated the development of both acute and relapsing clinical disease. These studies demonstrate that the indirect pharmacological inhibition of Rho proteins in brain EC by statins can inhibit a key stage in the pathogenesis of neuroinflammation, namely leukocyte migration across the blood-brain barrier. These studies demonstrate a novel effect of statins in modulating the immune response in neuroinflammtory diseases and may provide additional rationale for their use in the treatment of MS.
Groom, A. J., T. Smith, et al. (2003). "Multiple sclerosis and glutamate." Ann N Y Acad Sci 993: 229-75; discussion 287-8.
Experimental autoimmune encephalomyelitis reproduces in rodents the features of multiple sclerosis, an immune-mediated, disabling disorder of the human nervous system. No adequate therapy is available for multiple sclerosis, despite anti-inflammatory, immunosuppressive, and immunomodulatory measures. Increasingly glutamate is implicated in the pathogenesis of neurodegenerative diseases. Here we (1) review changes in the glutamatergic system in multiple sclerosis and (2) reveal the effects of glutamate AMPA antagonists in acute and chronic rodent models of multiple sclerosis. Administration of structurally diverse competitive and non-competitive AMPA antagonists reduces neurologic disability in rodents subjected to acute experimental autoimmune encephalomyelitis. In addition, AMPA antagonists are active in both the adoptive transfer and in chronic models of experimental autoimmune encephalomyelitis in rats and mice and affect both the acute and chronic relapsing phases. Moreover, short-term therapy with AMPA antagonists leads to sustained benefit well into the progressive phases. These results imply that therapeutic strategies for multiple sclerosis should be complemented by glutamate AMPA antagonists to reduce neurologic disability.
Gudiene, D. and B. Burba (2003). "[Mental disorders and their relation to brain lesion location: diagnostic problems]." Medicina (Kaunas) 39(2): 114-21.
Knowledge of symptoms of appropriate brain areas lesion helps to differ psychiatric and neurological disorders. The objective of our work was to find out the situation in scientific research about mental disorder relation to brain lesion location and to except the location of lesions, which are most complicated in differential diagnosis. We discussed the relation of most important mental disorders to brain lesion location. The study of discrete organic cerebral lesions resulting in clearly definable psychiatric disorders may provide an understanding of the underlying pathophysiological basis of these disorders. Different nervous functions need the integrational work of various brain areas. The regions differ from each other by the importance of playing part in corresponding functions. The differential problems appear because various structural brain lesions provide symptoms, similar to mental disorder symptoms. The development of mental disorders and lesion location questions are very urgent. While analyzing the location of lesion, it is important to motivate the theories of development of schizophrenia, organic depression, emotional lability and other disorders.
Guerrero, A. L., V. Bueno, et al. (2003). "[Apolipoprotein e polymorphism AS a predictor of progression of multiple sclerosis]." Neurologia 18(3): 146-8.
INTRODUCTION: During recent years, different studies have proposed that apolipoprotein E e4 can be a predictor of progression in multiple sclerosis. We aim to evaluate these findings in our country. PATIENTS AND METHODS: We studied 42 patients with relapsing remitting or secondary progressive multiple sclerosis, and a disease duration of at least 2 years. We correlated the presence or absence of e4 allele with markers of progression such as age of onset and diagnosis, disease duration, number of relapses, EDSS at 1, 2, 5 and 10 years, progression index and relapse rate. RESULTS: None of the parameters evaluated significantly correlate with e4 allele of the APOE. CONCLUSIONS: In spite of the limitation due to the small number of patients studied, we cannot confirm that APOE e4 allele is a predictor of progression of disability in multiple sclerosis.
Gulick, E. E. (2003). "Adaptation of the postpartum support questionnaire for mothers with multiple sclerosis." Res Nurs Health 26(1): 30-9.
The purposes of this study were to determine the dimensionality of the Postpartum Support Questionnaire adapted for mothers with multiple sclerosis through factor-analytic techniques and to provide construct validity for the factored dimensions. One hundred and seventy-four mothers with multiple sclerosis comprised the sample. Using a priori criteria, a three-factor structure, resulting from principal components analysis with an orthogonal rotation consisting of 24 of the 28 items, was found to best represent the dimensionality of the instrument. The three support factors-emotional, instrumental, and informational-showed acceptable coefficient alpha reliabilities at the 1-, 3-, and 6-month administrations. Evidence of construct validity was shown in that, as hypothesized, (a) mothers with comparatively lower emotional distress reported higher levels of emotional and instrumental support, and (b) mothers with one child reported receiving more informational support during the 6-month postpartum period than did mothers with more than one child. The results support the use of the 24-item Postpartum Support Questionnaire in assessing the adequacy of these specific dimensions of social support needed by mothers with multiple sclerosis during the postpartum period.
Gunnarsson, M., P. Sundstrom, et al. (2003). "Native and transformed alpha2-macroglobulin in plasma from patients with multiple sclerosis." Acta Neurol Scand 108(1): 16-21.
Multiple sclerosis (MS) is an inflammatory demyelinating disease with unknown etiology. Various proteinases have been observed in increased levels in the central nervous system of patients with MS, which may contribute to the release of immunogenic myelin components. alpha2-Macroglobulin (alpha2M) inhibits a broad spectrum of proteinases sterically, undergoing major conformational changes induced by the proteinases themselves. Moreover, alpha2M acts as a carrier of several cytokines in the systemic circulation. By use of radial immunodiffusion, we determined the total alpha2M levels in plasma from 28 MS patients and 15 control subjects [14 patients with other neurologic diseases (OND) and one healthy individual]. No significant differences in total alpha2M concentration were observed between the MS patients and the control subjects. A comparison of the degree of alpha2M transformation in MS patients with different disease courses and controls was performed, using monoclonal antibodies (mAbs) specific for binding to native and transformed alpha2M, respectively. The fractions of transformed alpha2M were significantly increased in patients with secondary or primary progressive disease course compared with the controls. No significant differences were obtained using a native-specific mAb. At least a major proportion of alpha2M from the MS patients was able to change conformation from its native to its transformed state, as demonstrated by a shift in mAb reactivity, following methylamine treatment of the plasma samples. In conclusion, the results indicate that plasma alpha2M may be inactivated at a higher degree in patients with chronic progressive MS compared with patients with OND. This may influence the levels of proteinases and cytokines in the systemic circulation and may furthermore have diagnostic implications.
Gveric, D., B. Herrera, et al. (2003). "Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors." Brain 126(Pt 7): 1590-8.
Tissue plasminogen activator (tPA), a neuronal as well as the key fibrinolytic enzyme, is found concentrated on demyelinated axons in multiple sclerosis lesions together with fibrin(ogen) deposits. The decreased tPA activity in normal-appearing white and grey matter and lesions of multiple sclerosis is reflected in diminished fibrinolysis as measured by a clot lysis assay. Nonetheless, peptide products of fibrin, including D-dimer, accumulate on demyelinated axons-the result of fibrinogen entry through a compromised blood-brain barrier (BBB). Analysis of tissue samples on reducing and non-reducing polyacrylamide gels demonstrates complexes of tPA with plasminogen activator inhibitor-1 (PAI-1) but not with neuroserpin, a tPA-specific inhibitor concentrated in grey matter. As total tPA protein remains unchanged in acute lesions and the concentration of PAI-1 rises several fold, complex formation is a probable cause of the impaired fibrinolysis. Although the tPA-plasmin cascade promotes neurodegeneration in excitotoxin-induced neuronal death, in inflammatory conditions with BBB disruption it has been demonstrated to have a protective role in removing fibrin, which exacerbates axonal injury. The impaired fibrinolytic capacity resulting from increased PAI-1 synthesis and complex formation with tPA, which is detectable prior to lesion formation, therefore has the potential to contribute to axonal damage in multiple sclerosis.