Multiple Sclerosis References 2003; Authors: D
(43 References)
D'Agati, V. (2003). "Pathologic classification of focal segmental glomerulosclerosis." Semin Nephrol 23(2): 117-34.
Focal segmental glomerulosclerosis (FSGS) is defined as a clinical-pathologic syndrome manifesting proteinuria and focal and segmental glomerular sclerosis with foot process effacement. The pathologic approach to the classification of FSGS is complicated by the existence of primary (idiopathic) forms and multiple subcategories with etiologic associations, including human immunodeficiency virus (HIV)-associated nephropathy, heroin nephropathy, familial forms, drug toxicities, and a large group of secondary FSGS mediated by structural-functional adaptations to glomerular hyperfiltration. A number of morphologic variants of primary and secondary focal sclerosis are now recognized, including FSGS not otherwise specified (NOS), perihilar, cellular, tip, and collapsing variants. The defining features of these morphologic variants and of the major subcategories of FSGS are discussed with emphasis on distinguishing light microscopic patterns and clinical-pathologic correlations.
D'Ambrosio, D., P. Panina-Bordignon, et al. (2003). "Chemokine receptors in inflammation: an overview." J Immunol Methods 273(1-2): 3-13.
Chemokine receptors play a key role in directing the migration of inflammatory cells into various injured or infected organs. However, migration of inflammatory cells into tissues can in itself be a cause and amplifier of tissue damage and disease, particularly in chronic autoimmune or allergic disorders. On this basis, much effort is currently devoted at the identification of molecular signals regulating the recruitment of inflammatory cells into tissues and at developing novel strategies to inhibit discrete pathways in this process. Great progress has recently been made in identification of a number of chemokine receptors involved in the process of leukocyte migration. The challenge is now to elucidate the specific contribution and involvement of the different receptors in distinct inflammatory processes and diseases and to prove that interference with any of these pathways may lead to development of novel therapeutics.
Dalton, C. M., P. A. Brex, et al. (2003). "New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes." Ann Neurol 53(5): 673-6.
In clinically isolated syndromes, the new McDonald criteria for multiple sclerosis diagnosis require new gadolinium-enhancing lesions for dissemination in time at a 3-month follow-up magnetic resonance imaging scan. In a cohort of 56 patients, these criteria were specific (95%) but less sensitive (58%) for clinically definite multiple sclerosis at 3 years. If new T2 lesions were allowed as an alternative for dissemination in time, sensitivity increased (74%) with maintained specificity (92%), enabling an accurate diagnosis of multiple sclerosis in more patients.
Dalton, C. C. and L. N. Gottlieb (2003). "The concept of readiness to change." J Adv Nurs 42(2): 108-17.
AIM: Readiness is associated with change, yet there is little understanding of this construct. The purpose of this study was to examine readiness; its referents, associated factors and the resulting consequences. METHODS: In the course of nursing five clients living with multiple sclerosis over a 7-month period using a Reflective Practice Model, data were systematically gathered using open-ended and then more focused questioning. Data collected during 42 client encounters (28 face-to-face encounters; 14 telephone contacts) were analysed using Chinn and Kramer's concept analysis technique. Findings. The concept of readiness was inductively derived. Readiness is both a state and a process. Before clients can create change they need to become ready to change. A number of factors trigger readiness. These include when: (a) clients perceive that a health concern is not going to resolve, (b) a change in a client's physical condition takes on new significance, (c) clients feel better able to manage their stress, (d) clients have sufficient energy, (e) clients perceive that they have adequate support in undertaking change. When one or more of these factors is present clients become ready to consider change. The process of readiness involves recognizing the need to change, weighing the costs and benefits and, when benefits outweigh costs, planning for change. The desire to change and to take action determines clients' degree of readiness. When they experience a high degree of readiness they report less anger, less depression, and view their condition in a more positive light. In contrast, when they experience a low degree of readiness they report feeling depressed, afraid and vulnerable in the face of change. CONCLUSION: Nursing has an important role to play in creating conditions to support change. To fulfil this role, nurses need to be able to assess readiness for change and the factors that enable it and then to intervene in ways that facilitate readiness.
Daly, C. and B. J. Rollins (2003). "Monocyte Chemoattractant Protein-1 (CCL2) in Inflammatory Disease and Adaptive Immunity: Therapeutic Opportunities and Controversies." Microcirculation 10(3-4): 247-57.
Monocyte chemoattractant protein (MCP)-1 (CCL2) specifically attracts monocytes and memory T cells. Its expression occurs in a variety of diseases characterized by mononuclear cell infiltration, and there is substantial biological and genetic evidence for its essential role in atherosclerosis and multiple sclerosis. Despite intensive screening, there are as yet no small-molecule antagonists of the receptor of MCP-1/CCL2, CCR2. However, biological agents, including antibodies and inhibitory peptides, have been developed and may be useful for these indications. Recent evidence from genetically modified mice indicates that MCP-1 and CCR2 have unanticipated effects on T helper (Th) cell development. However, unlike the identical phenotypes of MCP-1/CCL2(-/-) and CCR2(-/-) mice in inflammatory diseases, the phenotypes of these mice are disparate in adaptive immunity: MCP-1 stimulates Th2 polarization, whereas CCR2 activation stimulates Th1 polarization. This presents both a challenge and an opportunity for targeting the MCP-1/CCL2/CCR2 axis in disease.Microcirculation (2003) 10, 247-257. doi:10.1038/sj.mn.7800190
Danilov, A. I., M. Andersson, et al. (2003). "Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis." J Neuroimmunol 136(1-2): 112-8.
Nitric oxide (NO) is formed as a consequence of induction of the iNOS enzyme during inflammatory disorders. To investigate NO production in multiple sclerosis (MS), we determined the concentrations of its oxidation products (NOx) in the cerebrospinal fluid (CSF) and plasma of 61 MS patients. The patients were divided into three groups on the basis of their clinical disease activity. The total levels of NOx in CSF were significantly increased in all MS groups as compared to healthy controls and tension headache patients. CSF nitrite correlated with clinical disease activity. At exacerbation, the CSF nitrite levels exceed the plasma level. This suggests that clinical disease activity is due to a CNS inflammatory response, which is more intense and qualitatively different from that during clinical stable phases. This study supports NO involvement in the pathogenesis of MS and determination of nitrite levels may be useful a surrogate marker for disease activity.
Das, U. N. (2003). "Is there a role for saturated and long-chain fatty acids in multiple sclerosis?" Nutrition 19(2): 163-6.
Dasgupta, S., M. Jana, et al. (2003). "Role of very-late antigen-4 (VLA-4) in myelin basic protein-primed T cell contact-induced expression of proinflammatory cytokines in microglial cells." J Biol Chem 278(25): 22424-31.
The presence of neuroantigen-primed T cells recognizing self-myelin antigens within the CNS is necessary for the development of demyelinating autoimmune disease like multiple sclerosis. This study was undertaken to investigate the role of myelin basic protein (MBP)-primed T cells in the expression of proinflammatory cytokines in microglial cells. MBP-primed T cells alone induced specifically the microglial expression of interleukin (IL)-1beta, IL-1alpha tumor necrosis factor alpha, and IL-6, proinflammatory cytokines that are primarily involved in the pathogenesis of MS. This induction was primarily dependent on the contact between MBP-primed T cells and microglia. The activation of microglial NF-kappaB and CCAAT/enhancer-binding protein beta (C/EBPbeta) by MBP-primed T cell contact and inhibition of contact-mediated microglial expression of proinflammatory cytokines by dominant-negative mutants of p65 and C/EBPbeta suggest that MBP-primed T cells induce microglial expression of cytokines through the activation of NF-kappaB and C/EBPbeta. In addition, we show that MBP-primed T cells express very late antigen-4 (VLA-4), and functional blocking antibodies to alpha4 chain of VLA-4 (CD49d) inhibited the ability of MBP-primed T cells to induce microglial proinflammatory cytokines. Interestingly, the blocking of VLA-4 impaired the ability of MBP-primed T cells to induce microglial activation of only C/EBPbeta but not that of NF-kappaB. This study illustrates a novel role of VLA-4 in regulating neuroantigen-primed T cell-induced activation of microglia through C/EBPbeta
Dasgupta, S., Y. Zhou, et al. (2003). "Sodium phenylacetate inhibits adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice at multiple steps." J Immunol 170(7): 3874-82.
Experimental allergic encephalomyelitis (EAE) is the animal model for multiple sclerosis. The present study underlines the importance of sodium phenylacetate (NaPA), a drug approved for urea cycle disorders, in inhibiting the disease process of adoptively transferred EAE in female SJL/J mice at multiple steps. Myelin basic protein (MBP)-primed T cells alone induced the expression of NO synthase (iNOS) and the activation of NF-kappaB in mouse microglial cells through cell-cell contact. However, pretreatment of MBP-primed T cells with NaPA markedly inhibited its ability to induce microglial expression of iNOS and activation of NF-kappaB. Consistently, adoptive transfer of MBP-primed T cells, but not that of NaPA-pretreated MBP-primed T cells, induced the clinical symptoms of EAE in female SJL/J mice. Furthermore, MBP-primed T cells isolated from NaPA-treated donor mice were also less efficient than MBP-primed T cells isolated from normal donor mice in inducing iNOS in microglial cells and transferring EAE to recipient mice. Interestingly, clinical symptoms of EAE were much less in mice receiving NaPA through drinking water than those without NaPA. Similar to NaPA, sodium phenylbutyrate, a chemically synthesized precursor of NaPA, also inhibited the disease process of EAE. Histological and immunocytochemical analysis showed that NaPA inhibited EAE-induced spinal cord mononuclear cell invasion and normalized iNOS, nitrotyrosine, and p65 (the RelA subunit of NF-kappaB) expression within the spinal cord. Taken together, our results raise the possibility that NaPA or sodium phenylbutyrate taken through drinking water or milk may reduce the observed neuroinflammation and disease process in multiple sclerosis patients.
DasGupta, R. and C. J. Fowler (2003). "Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies." Drugs 63(2): 153-66.
Although patients with multiple sclerosis (MS) are likely to have problems with bladder, bowel and sexual function, these problems have often been neglected in the past. Bladder dysfunction produces symptoms of urgency, frequency and urge incontinence (due to bladder overactivity and incomplete emptying), and is found in up to 75% of patients with MS. The mainstay of drug treatment for neurogenic bladder overactivity is anticholinergic medication, although intravesical treatments have also been proposed, such as the vanilloids and botulinum toxin, as well as sublingual cannibanoids. There has been much progress with pro-erectile agents in recent years, notably the use of sildenafil citrate, which has been shown to be particularly efficacious in these patients. Other agents include apomorphine hydrochloride and newer phosphodiesterase 5 inhibitors; however, the efficacy of these drugs in patients with MS remains to be proven. Research in female sexual dysfunction is also progressing, although this aspect of patient well being has only recently been addressed; the reported development of a classification system for the condition is likely to help categorise future treatments. Unlike bladder and sexual dysfunction, there have been rather limited advances in the treatment of faecal incontinence and constipation specifically for patients with MS, despite a prevalence of up to 50%. This review highlights the strategies for these types dysfunction commonly seen in patients with MS, with report of recent pharmacological developments.
Davies, G. R., A. Ramani, et al. (2003). "Preliminary magnetic resonance study of the macromolecular proton fraction in white matter: a potential marker of myelin?" Mult Scler 9(3): 246-9.
We report on a new quantitative magnetization transfer (MT) technique that allows for the in vivo estimation of the macromolecular proton fraction (f) and the bound pool T2 relaxation time (T2b), whilst permitting whole brain coverage. In this pilot study, five subjects with multiple sclerosis (MS) and five healthy controls were studied. Both f and T2b were significantly different between MS lesions and normal control white matter (WM). Relationships between f and T1 relaxation time [Spearmans rank correlation coefficient (r(s)) = -0.97, P < 0.001] and f and the magnetization transfer ratio (MTR; r(s) = 0.80, P < 0.001) were observed. Compared with MTR, f and T2b have the potential advantage of relative independence from MT acquisition protocol while offering more pathologically specific information. In particular, f may provide a more direct indication of myelin content in WM.
Davies, G., G. Keir, et al. (2003). "The clinical significance of an intrathecal monoclonal immunoglobulin band: a follow-up study." Neurology 60(7): 1163-6.
BACKGROUND: Intrathecal oligoclonal band synthesis occurs in 95% of patients with clinically definite MS but may also occur in the context of CNS infection and other inflammatory conditions. By contrast, the significance of an intrathecal synthesis of a monoclonal band remains uncertain. Previously, an association between a single intrathecal band and CNS lymphoma has been reported but a relationship has also been shown with diagnoses more usually associated with an oligoclonal pattern. At present, it is not known whether a single band will convert to an oligoclonal response with time. METHODS: Data were obtained from patients who had CSF and serum analyzed by isoelectric focusing (IEF) at the authors' institutions over a 6-year period. Clinical details were acquired for those who underwent repeat lumbar puncture after an initial CSF examination revealed an intrathecal monoclonal immunoglobulin G band. RESULTS: Of the 31 patients identified as having an initial intrathecal monoclonal band, clinical details were available for 27. Of those, 9 were found on subsequent lumbar puncture to have developed an intrathecal oligoclonal response. CONCLUSIONS: Among those subjects who developed oligoclonal bands, there was a propensity for either a diagnosis of MS or clinically isolated syndromes due to demyelination. In the 18 subjects who either reverted to having normal CSF IEF or continued to exhibit only the monoclonal band, no cases of MS were encountered. Importantly, one of these had cerebral lymphoma.
Davis, D. P. and A. Marino (2003). "Acute cerebellar ataxia in a toddler: case report and literature review." J Emerg Med 24(3): 281-4.
Acute cerebellar ataxia (ACA) is an inflammatory CNS disease that is characterized by rapid onset of ataxia in a child under 6 years of age. Symptoms typically occur in association with a relatively benign viral illness and have been reported after vaccination as well. Immunological studies suggest that both involve autoimmune destruction of axon tracts, with pathological and radiographic evidence of a link with multiple sclerosis. The emergency approach should be focused on excluding more significant illnesses, such as meningitis or an intracranial mass lesion. Here we present a case of a young girl with ACA and review the relevant literature.
Dawson, J., W. Miltz, et al. (2003). "Targeting monocyte chemoattractant protein-1 signalling in disease." Expert Opin Ther Targets 7(1): 35-48.
Monocyte chemoattractant protein-1 (MCP-1) has been implicated in many inflammatory and autoimmune diseases. The G-protein-coupled receptor CCR-2B is probably the most important MCP-1 receptor in vivo, and loss of MCP-1 effector function alone is sufficient to impair monocytic trafficking in inflammation models. MCP-1 signalling appears to be a relevant target, especially in rheumatoid arthritis (RA). In RA patients, MCP-1 is produced by synovial cells and infiltrating monocytes, plasma MCP-1 concentrations correlate with swollen joint count, and elevated serum MCP-1 concentrations were found in juvenile RA in patients with active disease. Modulation of MCP-1 signalling in experimental RA showed beneficial effects on inflammation and joint destruction. With respect to chronic neuroinflammation, a critical role for MCP-1 has been established in animal models for multiple sclerosis. In acute neuroinflammation, experimental evidence for a detrimental role of MCP-1 in stroke and excitotoxic injury has been found. Several selective small molecular weight CCR-2B antagonists and MCP-1-blocking antibodies have been described. The proof for the validity of targeting MCP-1 signalling in disease, however, has yet to be established in clinical trials.
De Andres, C. (2003). "[The interest of multiple sclerosis attacks. Physiopathology and therapy]." Rev Neurol 36(11): 1058-64.
AIMS. To review the clinical concept of an attack, the physiopathological mechanisms underlying the symptoms of the attack, in the recovery phase, and those corresponding to the progressive or degenerative phase of the disease. DEVELOPMENT. Although they do not explain the exact mechanisms responsible for the onset of the attack or the processes that account for the clinical and pathological heterogeneity, most research studies suggest that the lesions produced in multiple sclerosis are the consequence of complex immunological interactions that take place mostly in the white matter of the central nervous system. These lesions affect, to variable extents, the myelin and the axon. We survey how these events are reflected in the images obtained by magnetic resonance. Clinical observations have shown that, in some patients, infections and hormones can exert an influence on the activity of the disease. Recovery, in the initial stages at least, would be produced by the action of poorly understood mechanisms that limit inflammation, and by local or cortical neuroplasticity or repair processes. Finally, we discuss the mechanisms behind the action of corticoids that justify their use when treating these attacks. CONCLUSION. A more thorough understanding of these events opens up the way to providing better therapy in the future.
De Keyser, J., E. Zeinstra, et al. (2003). "Are astrocytes central players in the pathophysiology of multiple sclerosis?" Arch Neurol 60(1): 132-6.
An interaction between antimyelin T cells and antigen-presenting glial cells is a crucial step in the cascade of immune events that lead to the inflammatory lesions in multiple sclerosis (MS). One of the most debated and controversial issues is whether microglial cells or astrocytes are the key players in initiating the (auto)immune reactions in the central nervous system in MS. Many investigators consider microglia to be the responsible intrinsic immunoeffector cells. In this review, we speculate that in MS astrocytes may serve as primary (facultative) antigen-presenting cells due to a failure of noradrenergic suppression of class II major histocompatibility complex molecules, which is caused by a loss of beta(2)-adrenergic receptors. If this hypothesis is correct, pharmacologic suppression of the antigen-presenting capacities of astrocytes may be a potential therapy for MS.
De Stefano, N., P. M. Matthews, et al. (2003). "Evidence of early cortical atrophy in MS: relevance to white matter changes and disability." Neurology 60(7): 1157-62.
OBJECTIVE: To assess cortical gray matter (GM) changes in MS and establish their relevance to clinical disability and to inflammatory changes of white matter (WM) in patients with the relapsing-remitting (RR) and primary progressive (PP) forms of the disease. METHODS: Conventional MRI examinations were obtained in patients with definite MS who had either the RR or the PP form of the disease. An automated analysis tool was used with conventional T1-weighted MR images to obtain total and cortical brain volumes normalized for head size. Total brain lesion load was estimated on conventional proton density and T2-weighted MR images. The relationship between volumetric MR measures and scores of clinical disability was assessed. RESULTS: Normalized cortical volumes (NCV) were lower for both RR and PP MS patients than for normal control subjects (p < 0.001) but were similar between the two patient groups (p > 0.5). NCV decreases in both patients groups were detected even in those patients with short disease duration (<5 years; p < 0.001 in RR MS and p < 0.05 in PP MS) and minimal brain lesion volume (<5 mL; p < 0.0001 in RR MS and p < 0.005 in PP MS). Measures of NCV in individual patients were negatively correlated with T2-weighted lesion volume (r = -0.47, p < 0.001) and disease duration (r = -0.25, p < 0.05) only in the patients with RR MS. NCV correlated with Expanded Disability Status Scale scores across all of the patients, but the strength of the correlation was stronger (p < 0.05) for PP (r = -0.64, p < 0.0001) than for RR (r = -0.27, p = 0.04) MS patients. CONCLUSIONS: These data confirm substantial neocortical volume loss in MS patients and suggest that neocortical GM pathology may occur early in the course of the disease in both RR and PP MS patients and contribute significantly to neurologic impairment. Although a proportion of this neocortical pathology may be secondary to WM inflammation, the extent of the changes suggests that, especially in patients with PP MS, an independent neurodegenerative process also is active.
Debruyne, J. C., J. Versijpt, et al. (2003). "PET visualization of microglia in multiple sclerosis patients using [11C]PK11195." Eur J Neurol 10(3): 257-64.
Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up-regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno-pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium-lesions was significantly increased compared with normal white matter. Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation. However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation. During disease progression, an increase of normal-appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS.
Dedrick, R. L., S. Bodary, et al. (2003). "Adhesion molecules as therapeutic targets for autoimmune diseases and transplant rejection." Expert Opin Biol Ther 3(1): 85-95.
Inflammatory disorders such as autoimmune diseases and graft rejection are mediated by activated leukocytes, particularly T lymphocytes, which penetrate the inflamed tissue and perpetuate or amplify the immune reaction. In an unstimulated state, leukocytes do not readily adhere to the vascular endothelium. However, inflammatory signals induce the expression of proteins on the endothelial cell surface that promote the adhesion and extravasation of activated immune cells from the circulation into the underlying tissues. Key among these molecules are P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the endothelial cells, and their respective counter receptors, P-selectin glycoprotein ligand-1 (PSGL-1), leukocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4), on the leukocytes. In vitro blockade of these molecules inhibits the adhesion of leukocytes. In many cases there is attenuation of leukocyte activation as well. Adhesion blockade in animal models prevents or ameliorates graft rejection and disease severity in autoimmune models. Clinical studies with humanised monoclonal antibodies which interfere with LFA-1/ICAM-1 or VLA-4/VCAM-1 interactions have shown significant efficacy and good safety profiles in autoimmune disease, including psoriasis, multiple sclerosis and inflammatory bowel disease. Thus, adhesion blockade is emerging as a useful therapeutic strategy in several inflammatory settings.
Dehmeshki, J., D. T. Chard, et al. (2003). "The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study." J Neurol 250(1): 67-74.
BACKGROUND: In 10-15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. METHODS: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75% probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). RESULTS: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = -0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = -0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. CONCLUSIONS: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted.
Delgado, M., C. Abad, et al. (2003). "PACAP in immunity and inflammation." Ann N Y Acad Sci 992: 141-57.
The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the VIP/secretin/glucagon family of peptides, produced by the lymphoid cells, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, PACAP has been clearly identified as a potent anti-inflammatory factor that exerts its function by regulating the production of both anti- and proinflammatory mediators. In this sense, PACAP prevents death by septic shock, an acute inflammatory disease with a high mortality. In addition, PACAP regulates the expression of costimulatory molecules, inasmuch as this related to the modulation in the shift from Th1 towards Th2 differentiation. We recently reported that PACAP prevents the deleterious effects of arthritis by downregulating both inflammatory and autoimmune components of the disease. Therefore, PACAP and analogs have been proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, arthritis, multiple sclerosis, Crohn's disease, or autoimmune diabetes.
Denkinger, C. M., M. Denkinger, et al. (2003). "In vivo blockade of macrophage migration inhibitory factor ameliorates acute experimental autoimmune encephalomyelitis by impairing the homing of encephalitogenic T cells to the central nervous system." J Immunol 170(3): 1274-82.
Macrophage migration inhibitory factor (MIF) is a cytokine that plays a critical role in the regulation of macrophage effector functions and T cell activation. However, its role in the pathogenesis of T cell-mediated autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), has remained unresolved. In this study, we report that anti-MIF Ab treatment of SJL mice with acute EAE improved the disease severity and accelerated the recovery. Furthermore, the anti-MIF treatment impaired the homing of neuroantigen-reactive pathogenic T cells to the CNS in a VCAM-1-dependent fashion. Interestingly, MIF blockade also decreased the clonal size of the neuroantigen-specific Th1 cells and increased their activation threshold. Taken together, the results demonstrate an important role for MIF in the pathogenesis of EAE/multiple sclerosis and suggest that MIF blockade may be a promising new strategy for the treatment of multiple sclerosis.
Derk, C. T. and S. A. Jimenez (2003). "Systemic sclerosis: current views of its pathogenesis." Autoimmun Rev 2(4): 181-91.
Systemic sclerosis (SSc) is an autoimmune disorder of unknown etiology characterized by severe and often progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immune abnormalities. Clinically, SSc is very heterogeneous, encompassing a spectrum ranging from mild limited forms of skin sclerosis with minimal internal organ involvement to severe skin and multiple internal organ fibrosis. Mortality and morbidity in SSc are very high and are directly related to the extent of the fibrotic and microvascular alterations. A better understanding of the pathogenesis of this incurable disorder will help to better target and design effective therapy in the future.
DeStefano, F., T. Verstraeten, et al. (2003). "Vaccinations and risk of central nervous system demyelinating diseases in adults." Arch Neurol 60(4): 504-9.
BACKGROUND: Several case reports of the onset or exacerbation of multiple sclerosis or other demyelinating conditions shortly after vaccination have suggested that vaccines may increase the risk of demyelinating diseases. OBJECTIVE: To evaluate the association between vaccination and onset of multiple sclerosis or optic neuritis. DESIGN: Case-control study involving cases of multiple sclerosis or optic neuritis among adults 18 to 49 years of age. Data on vaccinations and other risk factors were obtained from computerized and paper medical records and from telephone interviews. SETTING: Three health maintenance organizations. PARTICIPANTS: Four hundred forty case subjects and 950 control subjects matched on health maintenance organization, sex, and date of birth. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Onset of first symptoms of demyelinating disease at any time after vaccination and during specified intervals after vaccination (<1 year, 1-5 years, and >5 years). RESULTS: Cases and controls had similar vaccination histories. The odds ratios (95% confidence intervals), adjusted for potential confounding variables, of the associations between ever having been vaccinated and risk of demyelinating disease (multiple sclerosis and optic neuritis combined) were 0.9 (0.6-1.5) for hepatitis B vaccine; 0.6 (0.4-0.8) for tetanus vaccination; 0.8 (0.6-1.2) for influenza vaccine; 0.8 (0.5-1.5) for measles, mumps, rubella vaccine; 0.9 (0.5-1.4) for measles vaccine; and 0.7 (0.4-1.0) for rubella vaccine. The results were similar when multiple sclerosis and optic neuritis were analyzed separately. There was no increased risk according to timing of vaccination. CONCLUSION: Vaccination against hepatitis B, influenza, tetanus, measles, or rubella is not associated with an increased risk of multiple sclerosis or optic neuritis.
Devendra, D. and G. S. Eisenbarth (2003). "17. Immunologic endocrine disorders." J Allergy Clin Immunol 111(2 Suppl): S624-36.
Immune-mediated tissue destruction or disregulation is the cause of multiple common, as well as rare, endocrine disorders including type 1 diabetes, Graves' disease, Hashimoto thyroiditis, and Addison's disease. Each of these disorders can be divided into a series of stages beginning with genetic susceptibility, environmental triggering events, and active autoimmunity, followed by metabolic abnormalities with overt disease. Common genetic susceptibility is suggested by the clustering of a series of disorders in the same individual and his or her family. A major portion of the genetic susceptibility lies in the HLA region, but for several disorders, mutation of transcription factors underlies disease susceptibility (eg, X-linked polyendocrinopathy, immune deficiency and diarrhea, and autoimmune polyendocrine syndrome type 1). With improving immunogenetic and pathogenic understanding, type 1A diabetes is now predictable, and excellent autoantibody screening assays are available. This knowledge, combined with studies in animal models, has led to trials for the prevention of diabetes. In addition, aberrant immunologic reactions (eg, insulin autoantibodies after insulin therapy, Graves' disease after monoclonal anti-T-cell therapy in multiple sclerosis) can complicate standard and experimental therapies. We therefore believe that an understanding of the immunogenetics and immunopathogenesis of endocrine disorders can aid in the prevention of morbidity and mortality for these related diseases.
Devlin, N., J. Appleby, et al. (2003). "Patients' views of explicit rationing: what are the implications for health service decision-making?" J Health Serv Res Policy 8(3): 183-6.
Patient groups in England and Wales have expressed concerns about the decision-making processes of the National Institute for Clinical Excellence (NICE), the body responsible for explicit rationing. Five key issues were identified by the Multiple Sclerosis Society regarding NICE appraisals and guidance: they focus too narrowly on costs to the National Health Service; quality-adjusted life-years are an inadequate measure of health gain, particularly for long-term conditions; NICE takes too conservative a view of long-term benefits; NICE's cost-effectiveness threshold is inappropriate; and NICE evaluations fail to capture patients' personal experiences of their condition and treatments. We question the veracity of some of these arguments and, where appropriate, suggest ways in which NICE's processes might be strengthened.
Dharmasaroja, P. (2003). "Specificity of autoantibodies to epitopes of myelin proteins in multiple sclerosis." J Neurol Sci 206(1): 7-16.
An autoimmune response to one or more myelin-protein components is thought to be part of the pathogenesis of multiple sclerosis (MS). The immunodominant-autoantibody epitope may be localized on a linear peptide segment, on a conformation-sensitive epitope, or on an epitope resulting from post-translational modifications. Primary, secondary, and tertiary structures of myelin proteins may determine the specific site for binding of autoantibodies. A myelin protein-specific autoantibody can bind to either a linear or conformational epitope, whereas all of the T cell epitopes are linear. At present, the conformational epitopes of myelin proteins have not been identified; most of the methods used to identify the myelin-protein epitopes corresponding to the pathogenesis of multiple sclerosis are involved in the linear epitope mapping. Polymorphism or mutations may cause inappropriate expression of the myelin proteins with alterations to their linear and/or conformational epitopes, and make them susceptible to autoantibody binding, especially if these changes occur at the surface of the protein. This review focuses on the specificity of autoantibodies to the epitopes of myelin proteins and correlates this to the structures of proteins. Factors that influence the expression of myelin-protein epitopes such as the alpha-helical or beta-sheet structure of the protein, the tri-proline site, and the post-translational modifications as well as physicochemical properties of amino acid changed are included.
Dhib-Jalbut, S., M. Chen, et al. (2003). "Glatiramer acetate-reactive peripheral blood mononuclear cells respond to multiple myelin antigens with a Th2-biased phenotype." J Neuroimmunol 140(1-2): 163-71.
One favored mechanism of action of glatiramer acetate (GA) in multiple sclerosis (MS) involves the induction of GA-reactive Th2 cells that are believed to enter the central nervous system and mediate bystander suppression in response to cross-reactive myelin antigens. To test this hypothesis, we examined the proliferative response and cytokine release from peripheral blood mononuclear cells (PBMCs) of 12 MS patients treated with GA, in response to 16 myelin peptides that were previously described as immunodominant or encephalitogenic and a tetanus peptide as a control antigen. Interferon-gamma (IFN-gamma) and IL-5 (markers of Th1 and Th2 responses, respectively) were assayed by enzyme-linked immunosorbent assay (ELISA). GA-stimulated PBMCs from 9 of 12 patients (75%) proliferated to one or more myelin peptides. Among the 16 peptides tested, GA-stimulated PBMCs from the majority of the patients proliferated in response to MOG(21-44). PBMCs from two thirds of the patients produced IL-5 in response to myelin peptides, while half of them produced IFN-gamma. Th1/Th0/Th2 cytokine phenotypes demonstrated that responses from 10 of 12 patients were either Th0- or Th2-biased. Responses from two patients were Th1-biased. Conversely, some myelin-specific T-cell lines (TCLs) responded to GA by proliferation (3 of 21 TCLs), IL-5 release (11 of 21 TCLs), and IFN-gamma release (3 of 21 TCLs). These results indicate that GA-reactive TCLs can respond to a spectrum of myelin peptides in a Th2-biased fashion, which is consistent with the concept of bystander suppression. Furthermore, some myelin-specific TCLs are able to recognize GA, with a tendency to produce more IL-5 than IFN-gamma, which would suggest a systemic modulatory effect of the drug.
Dhib-Jalbut, S. (2003). "Glatiramer acetate (Copaxone(R)) therapy for multiple sclerosis." Pharmacol Ther 98(2): 245-55.
Glatiramer acetate (GA) (Copaxone(R)) is a worldwide-approved drug for the treatment of relapsing multiple sclerosis (MS), an autoimmune disease of the CNS. The drug is a synthetic copolymer with an amino acid composition based on the structure of myelin basic protein, one of the autoantigens implicated in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE). Developed initially as a "tool" to study EAE, the drug unexpectedly inhibited disease and was subsequently developed for the treatment of MS. The drug has been shown in controlled clinical trials to significantly reduce relapse rate and progression of disability in MS with long-term efficacy, remarkable safety, and tolerability. Efficacy as measured by magnetic resonance imaging parallels its clinical benefits as manifested by a reduction in gadolinium-enhancing lesions and brain atrophy. The mechanism of action of the drug in humans is believed to involve the induction of glatiramer-reactive regulatory cells, including CD4+ and CD8+ T-cells. Glatiramer-reactive Th2 cells are believed to enter the brain and, through cross-reactivity with myelin antigens, produce bystander suppression, antiinflammatory effects, and neuroprotection.
Di Legge, S., M. C. Piattella, et al. (2003). "Longitudinal evaluation of depression and anxiety in patients with clinically isolated syndrome at high risk of developing early multiple sclerosis." Mult Scler 9(3): 302-6.
We investigated the relationship between emotional changes, brain lesion burden and development of multiple sclerosis (MS). Thirty-seven consecutive patients with clinically isolated syndrome (CIS) were prospectively assessed with the Expanded Disability Status Scale (EDSS), the 21-item Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI) and gadolinium enhanced (Gd+) MRI scans. BDI and STAI were also administered to 36 age-matched controls. Conversion to MS was defined as the occurrence of a clinical relapse. CIS patients were more likely to endorse symptoms of anxiety and depression than controls. Baseline scores for depression and anxiety did not correlate with the total lesion load (i.e., volume of Gd+, T2 and T1 lesions) and the number of Gd+ lesions during the first six months of follow-up. A positive correlation was found between severity of depressive scores and the lesion load in the right temporal region (P = 0.005). After 33+/-6 months of the study entry, patients who had a clinical relapse were more frequently depressed (P = 0.001) than those relapse free. Emotional disturbances are frequently observed in CIS patients and show a tendency towards a normalization in relapse-free patients. The increased rate of depressive symptoms observed in patients who developed MS seems to result from a combination of psychological and organic features. The lesion load in the right temporal region is confirmed as a key area for developing depressive symptoms, even in the early phase of the disease.
Dianzani, U., A. Chiocchetti, et al. (2003). "Role of inherited defects decreasing Fas function in autoimmunity." Life Sci 72(25): 2803-24.
Fas is a death receptor belonging to the TNFR superfamily and induces cell apoptosis by both activating a caspase cascade and altering mitochondria. In the immune system, Fas is involved in the switching-off of the immune responses and cell mediated cytotoxicity. In humans, genetic defects decreasing Fas function cause the Autoimmune Lymphoproliferative Syndrome (ALPS) where autoimmunities are associated with accumulation of polyclonal lymphocytes in the secondary lymphoid tissues and expansion of T cells lacking both CD4 and CD8 (DN cells). Expansion of DN cells is absent in an ALPS variant, named Dianzani's Autoimmune Lymphoproliferative Disease (DALD). The observation that DALD patients' families display increased frequency of autoimmune diseases different from ALPS suggests that defects of Fas function may also play a role in development of "common" autoimmune diseases. This possibility is supported by detection of defective Fas function in substantial proportions of patients with the multiple autoimmune syndrome or aggressive forms of type 1 diabetes or multiple sclerosis. This article reviews data suggesting that development of autoimmune/lymphoproliferative patterns may involve several alterations hitting the Fas system, but might also involve alterations in other systems contributing to the switching-off or proliferation of lymphocytes.
Diaz-Arrastia, R., Y. Gong, et al. (2003). "Increased risk of late posttraumatic seizures associated with inheritance of APOE epsilon4 allele." Arch Neurol 60(6): 818-22.
BACKGROUND: Late posttraumatic seizures are a common complication of moderate and severe traumatic brain injury. Inheritance of the apolipoprotein E (APOE) epsilon4 allele is associated with increased risk of Alzheimer disease, progression to disability in multiple sclerosis, and poor outcome after traumatic brain injury. OBJECTIVE: To determine whether inheritance of APOE epsilon4 is associated with increased risk of developing late posttraumatic seizures. DESIGN: Prospective study. SETTING: Neurosurgical service at an urban level I trauma center.Patients Patients admitted with a diagnosis of moderate and severe traumatic brain injury were enrolled. METHODS: Six months after injury, patients were contacted to determine functional outcome (according to the Glasgow Outcome Scale-Expanded [GOS-E]) and the presence of late posttraumatic seizures. Genotype at the APOE locus was determined by restriction fragment length polymorphism analysis. RESULTS: DNA and outcome information was obtained from 106 subjects. Six months after injury, 31 (29%) had a poor outcome (GOS-E score, 1-4), 47 (44%) had an intermediate outcome (GOS-E score, 5-6), and 28 (26%) had a favorable outcome (GOS-E score, 7-8). Twenty-one patients (20%) had at least 1 late posttraumatic seizure. The relative risk of late posttraumatic seizures for patients with the epsilon4 allele was 2.41 (95% confidence interval, 1.15-5.07; P =.03). In this cohort, inheritance of APOE epsilon4 was not associated with an unfavorable GOS-E score 6 (P =.47). CONCLUSIONS: Inheritance of the APOE epsilon4 allele is associated with increased risk of late posttraumatic seizures. In this cohort, this risk appears to be independent of an effect of epsilon4 on functional outcome. A better understanding of the molecular role of APOE in neurodegenerative diseases may be helpful in developing antiepileptogenic therapies.
Dieckmann, K., R. Potter, et al. (2003). "Does bulky disease at diagnosis influence outcome in childhood Hodgkin's disease and require higher radiation doses? Results from the German-Austrian Pediatric Multicenter Trial DAL-HD-90." Int J Radiat Oncol Biol Phys 56(3): 644-52.
PURPOSE: The identification of risk factors is required for risk-adapted treatment strategies in the treatment of Hodgkin's disease. To assess the influence of bulky disease at diagnosis as compared with other risk factors on event-free survival (EFS) in pediatric Hodgkin's disease such as stage, B-symptoms, number of involved lymph node regions, histology, and remission status after chemotherapy, we analyzed the outcome of 552 patients treated with a risk-adapted treatment strategy consisting of OPPA(OEPA)/COPP (vincristine, procarbazine, etoposide, prednisone, adriamycin, cyclophosphamide) and involved-field radiotherapy. METHODS AND MATERIALS: Between 1990 and 1995, 578 patients with primary Hodgkin's disease (HD) were enrolled in the German/Austrian Pediatric Hodgkin's Disease Study Group (DAL) Multicenter Study (HD-90). Patients were stratified into three treatment groups (TGs) for early, intermediate, and advanced stage. All patients received induction chemotherapy (CT) with two cycles of OEPA for boys and two cycles of OPPA for girls. Patients in TG2 and TG3 received another two or four cycles, respectively, of COPP. Chemotherapy was followed by involved-field radiotherapy. The radiation field, which was prescribed by the study center, was treated with a dose of 25 Gy/25 Gy/20 Gy (TG1/TG2/TG3), and in case of insufficient remission with a local boost of 5 Gy to 10 Gy. The following prognostic factors were analyzed with regard to their impact on EFS: bulky disease, mediastinal tumor, number of involved lymph node regions, histology, treatment group, B-symptoms, sex, age, and remission status after chemotherapy. RESULTS: Significant univariate predictive factors for the EES were: nodular sclerosis type 2 (NS2) histology (relative risk [RR] 3.43; p = 0.0002), presence of B-symptoms (RR 2.70; p = 0.0014), number of involved regions (1.55; p = 0.019), and treatment groups (RR 1.33; p = 0.017). There was a higher risk (RR 1.92; p = 0.040) for patients with bulky compared with nonbulky disease (5-year EFS 89.6%/94.6%). In the multiple regression model, only NS2 and B-symptoms remained strong predictive factors. The remission status after chemotherapy did not correlate with EFS (p = 0.66). CONCLUSION: Treatment strategies in Hodgkin's disease have an impact on different risk factors. In the risk-adapted treatment strategy of the HD-90 study, tumor burden indicated as bulky disease or as number of involved lymph nodes loses its importance, whereas NS2 histology and B-symptoms have a major impact on treatment outcome. Bulky disease at diagnosis might require higher radiation doses only in case of insufficient remission.
Diem, R., A. Tschirne, et al. (2003). "Decreased amplitudes in multiple sclerosis patients with normal visual acuity: a VEP study." J Clin Neurosci 10(1): 67-70.
Primary demyelination with relative preservation of axons is considered to be one pathological hallmark of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. However, imaging and pathomorphological studies have stimulated a recent re-emergence of interest in the axonal, neurodegenerative aspect of MS pathology. Axonal injury appears to be a key factor of disability and permanent neurological deficit in MS patients. In the present electrophysiological study, visual potentials evoked by pattern reversal (VEPs) were recorded in 25 MS patients with normal visual acuity and unimpaired visual functions. Compared to a control population, VEP amplitudes for two different spatial frequencies were significantly decreased. From this observation, we conclude that an underlying pathological process threatening axonal integrity may not be reliably reflected by clinical parameters due to the distinct ability of the visual system to compensate for axonal loss. Pattern VEP may thus serve as an objective tool to diagnose and to monitor axonal pathology in MS. Focal conduction block due to demyelination as a cause for reduced VEP amplitudes can not be fully excluded, but would appear less likely since latency prolongation in the MS group was moderate compared to controls.
Dilorenzo, T., J. Halper, et al. (2003). "Reliability and validity of the multiple sclerosis quality of life inventory in older individuals." Disabil Rehabil 25(16): 891-7.
PURPOSE: Despite the increasing number of older individuals with multiple sclerosis (MS), there is a paucity of research on this subpopulation. Health-related quality of life (HRQOL) has received extensive attention in MS; however samples tend to be young. The present study assesses the internal consistency reliability and construct validity of the MS Quality of Life Inventory (MSQLI), a widely employed measure of HRQOL, in older individuals. METHOD: Select subscales of the MSQLI and other measures of mental health and physical functioning were administered by telephone to 30 randomly selected older ( >or= 60) individuals and a gender-matched sample of younger ( < 60) individuals. Reliability estimates were calculated separately for each group. Construct (convergent) validity was assessed by examining the pattern of correlations between MSQLI subscales and measures of related constructs in the two groups. RESULTS: Reliability estimates were similar in the two groups. With few exceptions, the correlations measuring convergent validity were in the expected direction, and of considerable magnitude, in both groups. CONCLUSIONS: Results provide preliminary evidence that the MSQLI is a reliable and valid instrument for use with older individuals. The slightly different pattern of results observed in the validity analysis might be explained by an adjustment hypothesis. Future research on HRQOL in this subpopulation is encouraged.
Dimayuga, F. O., Q. Ding, et al. (2003). "The neuregulin GGF2 attenuates free radical release from activated microglial cells." J Neuroimmunol 136(1-2): 67-74.
The neuregulin glial growth factor 2 (GGF2) is a neural growth factor that is best known for its ability to promote the survival and proliferation of oligodendrocytes and Schwann cells. While it has been shown in recent years that GGF2 is effective in the treatment of autoimmune models of brain injury, it is not known if the beneficial effects of GGF2 are based in part on modulation of brain inflammation. In this report, we document the anti-inflammatory effects of recombinant human GGF2 (rhGGF2) on microglial free radical production in vitro. The presence of the neuregulin receptors ErbB2, 3, and 4 was confirmed in N9 microglial cells by Western blot analysis. Pretreatment of N9 cells with 10-100 ng/ml rhGGF2 24 h before either phorbol 12-myristate 3-acetate (PMA) or interferon gamma (IFNgamma) caused dose-dependent decreases in oxidative burst activity and nitrite release, respectively, with 50 and 100 ng/ml causing significant effects. When cells were co-treated with increasing doses of rhGGF2 and PMA or IFNgamma, only concentrations of 50 ng/ml, but not 10 or 100 ng/ml, were able to decrease oxidative burst activity and nitrite release. Finally, when microglial cell viability following treatment of cells with IFNgamma with or without rhGGF2 was evaluated, it was observed that 50 and 100 ng/ml rhGGF2 conferred significant protection against IFNgamma-induced cell death in microglial cells. Overall, these results indicate that the neuregulin rhGGF2 may have anti-inflammatory and antioxidant properties in the brain, and may also provide trophic support for brain-resident microglial cells.
Doggrell, S. A. (2003). "Is natalizumab a breakthrough in the treatment of multiple sclerosis?" Expert Opin Pharmacother 4(6): 999-1001.
In patients with either relapsing-remitting or secondary-progressive multiple sclerosis, there were fewer new lesions/patient with natalizumab (0.7 and 1.1 with natalizumab 3 and 6 mg/kg every 28 days, respectively) than in the placebo group (9.6 new lesions/patient) over 6 months. There were also fewer relapses in the natalizumab groups than the placebo group. However, there were no changes in the Expanded Disability Status Scale scores in any of the groups. Natalizumab was well-tolerated. Thus, the initial results with natalizumab treatment over 6 months in multiple sclerosis are encouraging.
Dogusan, Z., N. Martens, et al. (2003). "Effects of prolactin on cloned human T-lymphocytes." Endocrine 20(1-2): 171-6.
To evaluate the possible role of prolactin (PRL) in T-lymphocytes, we monitored gene induction in one cytotoxic T-lymphocyte (CTL) clone derived from a patient with hemochromatosis and in several T-helper clones generated from a normal donor and a patient with multiple sclerosis. The CTL clone expressed conventional PRL receptor (PRLR), and PRL induced the expression of suppressor of cytokine signaling-3 (SOCS-3) and increased the expression of SOCS-2 and cytokine-inducible src homology-2 containing protein (CIS, another member of the SOCS family). As is the case in granulocytes, expression of a conventional receptor for PRL could not be shown by polymerase chain reaction analysis on three helper clones. In addition, as in granulocytes, PRL modulated the expression of genes such as the interferon-regulatory factor-1, inducible nitric oxide synthase, CIS, and SOCS-2. These effects were also elicited with ovine PRL and could be prevented by anti-PRL antibodies. Thus, the use of clones allowed the detection of direct effects of PRL on T-cells, even when these have few or no detectable PRLR, confirming that human T-lymphocytes are targets for PRL.
Dohi, N., S. Ishikawa, et al. (2003). "Multiple sclerosis with open-ring enhancement in the cerebrum and spinal cord." Intern Med 42(3): 273-6.
A 67-year-old woman presented with open-ring enhancement on MR images in the thoracic spinal cord. Steroid therapy improved the patient's paraplegia, but six months later she developed left hemiparesis and a new open-ring enhancement appeared in the right cerebrum. Despite high-dose methylprednisolone therapy and plasmapheresis, another lesion appeared at the middle portion of the left centrum semiovale. Stereotaxic brain biopsy demonstrated active demyelination characteristics of multiple sclerosis (MS). This case indicates that openring enhancement can help differentiate MS from nondemyelinating disease, and that MS showing ring enhancement may contribute to disease severity and need more intensive immunomodulatory therapies.
Drulovic, J., D. Popadic, et al. (2003). "Decreased frequency of the tumor necrosis factor alpha -308 allele in Serbian patients with multiple sclerosis." Eur Neurol 50(1): 25-9.
Tumor necrosis factor (TNF) alpha has been considered the prototypic cytopathogenic cytokine in multiple sclerosis (MS), but recently this cytokine has been shown to possess significant anti-inflammatory and neuroprotective effects in demyelinating diseases. It has been reported that the TNFalpha -308 polymorphism influences levels of TNFalpha production, and that the rare allele, TNF2, is associated with high TNFalpha production. We investigated the TNFalpha -308 polymorphism in 143 unrelated Serbian patients with MS and 123 ethnically matched, healthy individuals using the allele-specific restriction fragment length polymorphism polymerase chain reaction technique. The frequency of the TNF2 allele was significantly decreased in MS patients (14%) in comparison with controls (24%; p = 0.044). The TNF2 allele had no influence on disease behavior, since it was not associated with the course and severity of MS in this group of patients. The result suggests that in the Serbian population polymorphism at position -308 of TNFalpha or at an adjacent locus might have a role in MS susceptibility.
Dubois, B. D., E. Keenan, et al. (2003). "Interferon beta in multiple sclerosis: experience in a British specialist multiple sclerosis centre." J Neurol Neurosurg Psychiatry 74(7): 946-9.
BACKGROUND: The efficacy of interferon beta (IFN beta) is well established in relapsing-remitting multiple sclerosis (MS). However, the use of this drug in clinical practice is complex, especially because it is only partially effective, its long term efficacy and side effects are unknown, its efficacy may be abrogated by the development of neutralising antibodies, compliance is variable, and its cost effectiveness is controversial. Objectives and Methods: Analysis of a prospectively followed up series of 101 MS patients treated with IFN beta was undertaken to: (1) monitor the outcome of IFN beta treatment in clinical practice; (2) compare the immunogenicity of the three commercial IFN beta preparations available; (3) assess the proportion of patients fulfilling the current guidelines of the Association of British Neurologists for stopping IFN beta therapy. RESULTS: During a median treatment period of 26 months (range 2-85), the relapse rate decreased by 41%. Although the reduction in the relapse rate was similar for all three commercial products, none of the Avonex treated patients were relapse free, compared with 19% of the Betaferon treated and 27% of the Rebif treated patients (p=0.02). Neutralising antibodies were not detected in Avonex treated patients (0 of 18), compared with 12 of 32 (38%) Betaferon treated and 10 of 23 (44%) Rebif treated patients (p=0.02). Forty of 101 (40%) patients satisfied the current (2001) Association of British Neurologists criteria for stopping IFN beta treatment at some stage during their treatment. CONCLUSION: IFN beta is effective in reducing the relapse rate in patients with relapsing-remitting MS in routine clinical practice. However, after a median treatment duration of 26 months, 40% of initially relapsing-remitting MS patients seem to have ongoing disease activity, presenting as disabling relapses or insidious progression.
Durelli, L., E. Verdun, et al. (2003). "Re: Vartanian T. An examination of the results of the EVIDENCE, INCOMIN, and phase III studies of interferon beta products in the treatment of multiple sclerosis. Clin Ther. 2003;25:105-118." Clin Ther 25(6): 1890-3.
Duvanel, C. B., P. Honegger, et al. (2003). "Inhibition of glial cell proinflammatory activities by peroxisome proliferator-activated receptor gamma agonist confers partial protection during antimyelin oligodendrocyte glycoprotein demyelination in vitro." J Neurosci Res 71(2): 246-55.
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a member of the nuclear hormone superfamily originally characterized as a regulator of adipocyte differentiation and lipid metabolism. In addition, PPAR-gamma has important immunomodulatory functions. If the effect of PPAR-gamma's activation in T-cell-mediated demyelination has been recently demonstrated, nothing is known about the role of PPAR-gamma in antibody-induced demyelination in the absence of T-cell interactions and monocyte/macrophage activation. Therefore, we investigated PPAR-gamma's involvement by using an in vitro model of inflammatory demyelination in three-dimensional aggregating rat brain cell cultures. We found that PPAR-gamma was not constitutively expressed in these cultures but was strongly up-regulated following demyelination mediated by antibodies directed against myelin oligodendrocyte glycoprotein (MOG) in the presence of complement. Pioglitazone, a selective PPAR-gamma agonist, partially protected aggregates from anti-MOG demyelination. Heat shock responses and the expression of the proinflammatory cytokine tumor necrosis factor-alpha were diminished by pioglitazone treatment. Therefore, pioglitazone protection seems to be linked to an inhibition of glial cell proinflammatory activities following anti-MOG induced demyelination. We show that PPAR-gamma agonists act not only on T cells but also on antibody-mediated demyelination. This may represent a significant benefit in treating multiple sclerosis patients.