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At least 757 records · Page 42Linked to original sources
PubMed1998

Pulse cyclophosphamide plus methylprednisolone induces myelin-antigen-specific IL-4-secreting T cells in multiple sclerosis patients.

Multiple sclerosis (MS) is a presumed cell-mediated Th1-type autoimmune disease. Thus therapies which decrease T cells secreting IFN-gamma production or increase IL-4 production would be expected to have an ameliorating effect on MS. We have previously reported increased anti-CD3-induced IL-4 secretion by T cells in progressive MS patients treated with cyclophosphamide plus methylprednisolone (CY/MP) which was associated with eosinophilia. To investigate whether the increased IL-4 secretion was myelin antigen specific, we generated 3990 short-term T cell lines to myelin basic protein (MBP), proteolipid protein (PLP), or tetanus toxoid (TT) from 31 progressive MS patients: 11 MS patients treated with CY/MP, 10 MS patients treated with MP alone, and 10 untreated MS patients. We found increased frequencies of both MBP- and PLP-specific IL-4-secreting T cell lines in CY/MP-treated patients compared to untreated MS patients. However, no change in the frequency of TT-specific IL-4-secreting T cells was observed. MP treatment alone did not increase the frequency of antigen-specific IL-4-secreting T cell lines. These results demonstrate immune deviation favoring Th2-type responses specific to autoantigens following pulse cyclophosphamide therapy in MS patients.

Adult↗
PubMed2006

NAD(P)H:quinone oxidoreductase 1 expression in multiple sclerosis lesions.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), marked by infiltration of monocyte-derived macrophages in the brain parenchyma. Macrophages contribute to disease pathology by secretion of inflammatory mediators, such as reactive oxygen species (ROS). ROS are involved in various processes underlying MS pathology, including monocyte migration across the blood-brain barrier, phagocytosis and degradation of myelin, axonal degeneration, and oligodendrocyte damage. High concentrations of ROS cause oxidative stress, which induces transcriptional activation of phase II detoxification enzymes, such as the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1). Since NQO1 expression may act as an indicator of oxidative stress and knowledge about the cellular distribution pattern of NQO1 in MS brains is lacking, we examined the expression of NQO1 in various well-characterized MS lesions. Here, we show for the first time that NQO1 is highly upregulated in active and chronic active MS lesions, particularly in hypertrophic astrocytes and myelin-laden macrophages. We hypothesize that increased NQO1 expression may reflect an endogenous defense response against ROS-mediated cellular toxicity. Compounds that induce the production of endogenous antioxidant enzymes, such as NQO1, may be potential targets for future treatment strategies in MS.

Adult↗
PubMed2002

Effect of interferon-beta-1b on cognitive functions in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is recognised as a central nervous system disease also affecting cognition. The rate of cognitive dysfunction in MS is in the range of 45-65% and adversely affect the quality of life. OBJECTIVE: To evaluate the effect of 1 year of treatment with interferon-beta-1b (IFNbeta-1b) on cognitive functions in patients suffering from relapsing-remitting MS. METHODS: A battery of cognitive tests was used to assess verbal learning, delayed recall, visual learning and recall, complex attention, concentration and verbal fluency at baseline and after 1 year of treatment with IFNbeta-1b. A group of 23 relapsing-remitting MS patients matched for neurological disability served as controls. RESULTS: Eighteen of 23 patients treated with IFNbeta-1b (74%) completed the study. In the IFNbeta-1b-treated group, complex attention, concentration as well as visual learning and recall improved significantly (p = 0.024, p = 0.006 and p = 0.005, respectively), while no deterioration was observed in the other dimensions. In the control group, complex attention, verbal fluency, as well as visual learning and recall deteriorated significantly (p = 0.02, p = 0.004 and p = 0.01, respectively), while no deterioration was observed in the other dimensions. CONCLUSION: Immunomodulating drugs that reduce the relapse rate and slow the disease progression also inhibit cognitive deterioration in patients with MS.

Adjuvants, Immunologic↗
PubMed2000

NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions.

Multiple sclerosis (MS) is characterized by multifocal loss of myelin, oligodendrocytes, and axons. Potential MS therapies include enhancement of remyelination by transplantation or manipulation of endogenous oligodendrocyte progenitor cells. Characteristics of endogenous oligodendrocyte progenitors in normal human brain and in MS lesions have not been studied extensively. This report describes the distribution of cells in sections from normal adult human brain and MS lesions by using antibodies directed against NG2, an integral membrane chondroitin sulfate proteoglycan expressed by oligodendrocyte progenitor cells. Stellate-shaped NG2-positive cells were detected in the white and gray matter of normal adult human brain and appeared as abundant as, but distinct from, astrocytes, oligodendrocytes, and microglia. Stellate-shaped or elongated NG2-positive cells also were detected in chronic MS lesions. A subpopulation of the elongated NG2-positive cells expressed the putative apoptotic signaling molecule p75(NTR). TUNEL-positive cells in three active, nine chronic active, and four chronic inactive lesions, however, were p75(NTR)-negative. These studies identify cells with phenotypic markers of endogenous oligodendrocyte progenitors in the mature human CNS and suggest that functional subpopulations of NG2-positive cells exist in MS lesions. Endogenous oligodendrocyte progenitor cells may represent a viable target for future therapies intended to enhance remyelination in MS patients.

Adult↗
PubMed1998

Identification of glial cell proliferation in early multiple sclerosis lesions.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which leads to destruction of myelin sheaths. The patterns of cell proliferation in the early course of the disease are largely unknown. The present study used immunohistochemical identification of proliferating glial cells in stereotactic brain biopsy material of eight patients with early chronic MS. Double-labelling with the proliferation marker MIB-1 detected proliferating oligodendrocytes (MOG), astrocytes (GFAP) and microglia/macrophages (Ki-M1P). The majority of proliferating cells were macrophages/microglia when compared with oligodendrocytes (P > 0.005) or astrocytes (P > 0.0005); only a minor proportion of microglia/macrophages, however, proliferated in situ. Astrocytic and oligodendroglial proliferation was sparse to absent and showed significant variations between different patients. There were statistically significant differences when comparing the amount of proliferation between lesions of different demyelinating activity: highest numbers of proliferating cells were found in early active lesions compared with demyelinated and early remyelinated lesions (P > 0.05) or the periplaque white matter (P > 0.01). MOG-positive oligodendrocytes proliferated occasionally in the early stages of lesion formation; this proliferation occurred in four cases but was independent of the stage of the disease. Since MOG is expressed by mature oligodendrocytes, and not by immature precursors, this might suggest a potential role for the proliferation of mature surviving oligodendrocytes with subsequent remyelination.

Adult↗
PubMed1997

Perivascular T cells express the pro-inflammatory chemokine RANTES mRNA in multiple sclerosis lesions.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), characterized by accumulation of mononuclear cells. The pathogenesis of MS is complex and probably involves soluble immune mediators, particularly cytokines, and activated memory T cells, that are thought to migrate into the CNS. During lesion formation in MS, cytokines regulate cell functions, such as cell recruitment and migration. Because the chemokine RANTES play a role in both activating and recruiting leucocytes, particularly memory T cells into inflammatory sites, the authors have assessed RANTES mRNA levels at the site of lesions. Expression levels were analysed in brain samples and compared with neurological, infectious and other controls. RANTES was expressed by activated perivascular memory T cells, predominantly located at the edge of active plaques. While RANTES mRNA was detected in all 17 MS brains analysed, it was only found in six of the 14 control patients and generally at a lower expression level. In view of the regulatory and chemotactic properties of RANTES, these results imply that RANTES in MS lesions may play an important role in the activation and/or selective accumulation of memory T cells and, thereby, in the pathogenic events associated with MS.

Adult↗
PubMed2003

Patterns of misdiagnosis of multiple sclerosis.

BACKGROUND: Multiple sclerosis is a chronic demyelinating disease of the central nervous system that presents with variable signs and symptoms. This variability in the clinical presentation may result in misdiagnosis, unnecessary referrals and misleading information to the patients. OBJECTIVES: To identify the types of misdiagnoses made on the presentation of MS. METHODS: Fifty consecutive MS patients were questioned on their early symptoms, their mental status, the disease course until the diagnosis was confirmed, and the different diagnoses they received. RESULTS: The patients had been referred to 2.2 +/- 1.3 specialists before seeing a neurologist, and learned about their disease 3.5 years after the onset of symptoms. Twenty-nine patients (58%) were initially given 41 wrong diagnoses. While the majority of women were misdiagnosed mentally, orthopedic work-up was offered to the men. Misdiagnosis of MS occurred most often in patients who presented with non-specific sensory symptoms that did not conform to a specific neurologic syndrome. The patients emphasized the fact that not knowing worsened their anxiety, whereas receiving the diagnosis enabled them to begin coping with their disease. CONCLUSIONS: MS is often overlooked when patients present with non-specific sensory complaints. The difference in type of misdiagnosis between men and women may reflect a gender-dependent bias in the way physicians interpret sensory complaints.

Adult↗
PubMed2006

Complex I deficiency in Persian multiple sclerosis patients.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by the morphological hallmarks of inflammation, demyelination and axonal loss. Until now, little attention has been paid to the contribution of mitochondrial respiratory chain enzyme activities to MS. In this study, kinetic analysis of mitochondrial respiratory chain complex I enzyme (measured as NADH-ferricyanide reductase) was performed on intact mitochondria isolated from fresh skeletal muscle in MS patients (n = 10) and control subjects (n = 11). Mitochondrial DNA common deletion and deletions were also tested in MS patients. Our findings showed that complex I activities were significantly reduced (P = 0.007) in patients compared with control. However, we could not find deletion in mtDNA of patients with MS. The presupposition of relationship between MS and mitochondrial disorders is due to predominant maternal transmission of MS in affected parent-child pairs, pathoaetiological role of respiratory chain dysfunction in multisystem disorders and important role of it in neurodegenerative disorders, a number of patients such as LHON or other mtDNA abnormality with developed neurological symptoms indistinguishable from MS and similarity of clinical symptoms in mitochondrial disorders to those of MS. This study suggested that a biochemical defect in complex I activity may be involved in pathogenesis of MS.

Adult↗
PubMed2003

Genome-wide linkage screen of a consanguineous multiple sclerosis kinship.

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.

Adolescent↗
PubMedDate not supplied

[Neurorehabilitation of multiple sclerosis].

INTRODUCTION: Multiple sclerosis (MS) is the second most important/common cause of neurological disability in young adults. Current treatment includes the new immunomodulating agents and various drugs used in symptomatic management. Neurorehabilitation (NR) complements these treatments, forms an integral therapeutic strategy and is orientated to improve the activity and participation of the patient from a biopsychosocial point of view. DEVELOPMENT: Although there is a generally favorable opinion towards NR, there is little scientifically validated evidence regarding the benefits of its use. Correct measurement of the results is essential for their interpretation in terms of efficiency and efficacy. Of the various instruments for measurement of the results of NR, there are scales which have been shown to be of satisfactory clinical usefulness and scientifically sound for use in NR programmes in MS. In spite of methodological difficulties for the design of protocols in this field, in recent years several well-designed studies (randomised, controlled, double or single blind) have shown the usefulness of NT in MS (both outpatients and inpatients and including progressive forms) since handicap has been reduced and quality of life improved. These studies refer to NR as a multidisciplinary approach (a specially trained team of professionals) with concrete objectives and established job descriptions, a suitable battery of instruments for measurement of the results, active participation of the patient and his family and correct follow-up in the community.

Adjuvants, Immunologic↗
PubMed2004

Rural-urban comparisons of nursing home residents with multiple sclerosis.

CONTEXT: Multiple sclerosis (MS) is the most common neurologic disease that disables younger adults, affecting as many as 350,000 Americans. PURPOSE: The objectives of this study are to develop profiles of nursing home residents with MS from rural areas and compare them to residents with MS who lived in urban areas, suburban areas, and large towns. METHODS: We analyzed all admission assessments for residents with MS (13,357 assessments) in the Minimum Data Set between June 23, 1998, and December 31, 2000, that also had the resident's ZIP code of primary residence before admission. FINDINGS: Urban and rural comparisons of residents with MS demonstrate a range of significant demographic differences. Significantly greater proportions of MS residents from rural areas exhibited a sense of initiative or involvement in activities of the nursing facility compared with residents with MS from urban and suburban areas. The differences in the utilization of physical and occupational therapies were striking, with MS residents from rural areas averaging significantly fewer minutes of these therapies. We also found that MS residents from rural areas averaged fewer minutes of psychological therapy in the nursing facility and also were less likely to have seen a licensed mental health specialist than MS residents from urban areas. CONCLUSIONS: Nursing home residents with MS from rural areas receive fewer therapies and less mental health care than residents with MS from other areas.

Female↗
PubMed2004

Association between Synapsin III gene promoter polymorphisms and multiple sclerosis.

Although multiple sclerosis (MS) is considered to be an inflammatory demyelinating disease, increasing evidence indicates that it is also an axonal pathology; indeed, studies of experimental allergic encephalitis showed that several neuronal proteins such as synapsins take part in the pathogenesis of the axonal dysfunction. Synapsins are a family of abundant neuron-specific phosphoproteins with crucial roles in synaptogenesis and neuronal plasticity. Distinct genes encode the three different isolated proteins (I, II and III); of interest, the gene of synapsin III (SYN3) is located in the chromosome 22q12-q13, a locus close to one of the candidate susceptibility regions (22q13.1) for MS. In the present study we selected two polymorphisms (g.-631C > G and g.-196A > G) within the SYN3 5'-promoter region because of the protein's role and genetic location; we analysed the allele and genotype distributions of these polymorphisms in a selected MS population of southern Italy. An inverse association between MS and the g-631C > G polymorphism was found; indeed, the two polymorphisms were in almost complete linkage disequilibrium and the haplotype analysis showed that the C631/A196 haplotype seemed to confer a significant protection against MS.

Adolescent↗
PubMed2003

CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions.

Multiple sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal central nervous system (CNS) damage, postulated to be mediated by CNS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to CD1a (immature DC) and CD83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No CD1a-positive cells were detected in the MS or control CNS tissue blocks investigated. CD83-positive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However; in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were CD83-positive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced chemokines.

Antigens, CD↗
PubMedDate not supplied

Adherence to disease-modifying therapy in multiple sclerosis: Part I.

Multiple sclerosis (MS) is a chronic, debilitating disease for which there is no cure. However, the recent introduction of injectable immunomodulating agents has made it possible to reduce the frequency of relapsing episodes and to possibly slow its progression. The use of these agents is recommended by the National MS Society, however, their true potential cannot be realized if patients do not accept them and healthcare professionals do not promote them. Because MS is unpredictable, and treatments can produce side effects, ensuring adherence to the recommended therapy is a complex and challenging issue. A better understanding of the obstacles to adherence, and the identification of possible solutions, should be of value to nurses, who have numerous opportunities to encourage patients to initiate and continue therapy. This article, which is in two parts, describes the particular problems of treatment adherence, and proposes that the transtheoretical model of behavior change can be useful in achieving treatment goals in MS and in other chronic disease states. This model is based upon the concept that a patient's "readiness for change" is crucial, and that attempts at intervention should be sensitive to the patient's changing conditions and state of mind. Nurses who work with patients with MS and other chronic diseases can apply the model to help their patients accept and adhere to the demands of ongoing treatment.

Chronic Disease↗
PubMed1992

Visual accommodation and sustained visual resolution in multiple sclerosis.

Many multiple sclerosis (MS) patients frequently experience transient blurring. We investigated the possibility that this symptom is due to the inability of patients to sustain an accommodative response to stimuli viewed at distances nearer than or farther from the individual tonus position of accommodation. In a group of MS patients and age-matched healthy control subjects, we measured (1) accommodative range and tonus position; (2) reaction time (RT) to detect a change in a small optotype (viewed in a Badal lens system) as a function of viewing distance; and (3) contrast sensitivity at a fixed viewing distance. MS patients did not differ significantly from healthy controls on near point, far point, pupil size, accommodative range, or tonus position measures. However, as a group, MS patients showed significantly slower RTs than controls to detect optotype changes for stimuli viewed at distances nearer to or farther from the individual tonus position of accommodation. All subjects showed significantly slower RTs to detect changes in optotypes viewed at extreme near and far optical distances compared to RTs to detect changes in stimuli viewed at the tonus position. This difference was significantly larger for MS patients than for controls. These data also suggest that dynamic dioptric factors contribute to the magnitude of contrast sensitivity deficits in this patient population and indicate that the relationship between the individual tonus accommodation position and viewing distance is an important variable in CS testing.

Accommodation, Ocular↗
PubMed2004

Inflammatory cell expression of cyclooxygenase-2 in the multiple sclerosis lesion.

Multiple sclerosis (MS) is a progressive immune-mediated disease characterized by the loss of the oligodendrocytes that constitute the myelin sheath. Recent reports show that glutamate-mediated excitotoxic death of oligodendrocytes contributes to pathogenesis in demyelinating disease. A link between the immune-mediated inflammatory response and glutamate-mediated excitotoxicity of oligodendrocytes could involve the interaction of inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Both enzymes are tightly coupled to neuronal excitotoxic death. We examined tissue from two controls and seven MS patients with chronic active lesions to determine the extent of COX-2 and iNOS expression. In contrast to the lack of expression in controls, there was a marked induction of COX-2 in all these MS lesions. COX-2 was frequently expressed in association with iNOS. COX-2 was found in areas that contained catabolites of myelin basic protein, indicating recent demyelination. COX-2 expression was found near damaged oligodendrocytes in cells that expressed the macrophage/microglia marker CD64, indicating that a substantial portion of the COX-2 in the lesions was expressed in immune-derived cells. We discuss these findings in the context of how COX-2 could be coupled with iNOS to contribute to excitotoxic death and damage of oligodendrocytes.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2026

Multiancestry genome-wide association and multiomics analyses elucidate spatiocellular features of multiple sclerosis genetics.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination disseminated in space and time. Here we performed a genome-wide association study (GWAS) using 688 MS cases and 205,199 controls from the Japanese population and identified significant associations in the major histocompatibility complex region and a population-specific risk variant in 11q24. Through cross-population GWAS meta-analyses using a total of 29,374 cases and 1,843,563 controls from 4 ancestral populations, we identified 22 novel susceptibility loci. Integration of GWAS and single-cell and single-nucleus RNA sequencing of peripheral blood mononuclear cells and subcortical lesions from patients with MS revealed enrichment of genetic risk factors for MS in CD4+ T helper cell lineage and regulatory T cells, as well as in endothelial cells. Furthermore, spatial transcriptomics of subcortical lesions demonstrated spatial and temporal heterogeneity in associations with MS genetic risk. Our study demonstrates the value of investigation of spatiocellular features of disease genetics across diverse populations and omics modalities.

Humans↗
PubMed2004

Expression of chemokine receptors CCR1 and CCR5 reflects differential activation of mononuclear phagocytes in pattern II and pattern III multiple sclerosis lesions.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. A recent study identified 4 patterns of demyelination in active MS lesions. The characteristics of pattern II lesions suggested a primary inflammatory mechanism of myelin injury, while pattern III lesions showed features consistent with dying-back oligodendrogliopathy. The recruitment, differentiation, and activation of mononuclear phagocytes are dependent on the expression of chemokine receptors. Using immunohistochemistry we quantified cellular expression of CCR1 and CCR5 in pattern II (n = 21) and pattern III (n = 17) lesion areas of differing demyelinating activity. Infiltrating monocytes in both lesion patterns co-expressed CCR1 and CCR5, suggesting conserved mechanisms of monocyte recruitment into the CNS. In pattern II lesions, the number of cells expressing CCR1 significantly decreased while CCR5 increased in late active compared with early active demyelinating regions. In striking contrast, numbers of cells expressing CCR1 and CCR5 were equal in all regions of pattern III lesions. As hypoxia-like mechanisms may play a role in pattern III lesions, we extended these studies to white matter infarcts (n = 7) in which the expression of CCR1 better resembled pattern III than pattern II lesions. As judged by mononuclear phagocyte chemokine receptor expression, there appear to be distinct tissue environments in pattern II and III MS lesions.

Adult↗