Multiple Sclerosis References 2003; Authors: S
(78 References)
Sadallah, S., C. Hess, et al. (2003). "Autoantibodies against complement receptor 1 (CD35) in SLE, liver cirrhosis and HIV-infected patients." Clin Exp Immunol 131(1): 174-81.
The acquired loss of CR1 (CD35) on erythrocytes in specific autoimmune diseases and chronic infections may be due to autoAb against CR1. An ELISA using rCR1 was established to measure antiCR1 IgG autoAb. Plasma containing alloAb to polymorphism on CR1 (Knops blood group Ab) reacted strongly against rCR1 and were used as positive controls. AntiCR1 Ab was found in 3/90 (3.5%) plasma samples from healthy blood donors. The binding of these Ab was not inhibited by high salt concentrations. AntiCR1 Ab were present in the IgG fractions of plasma, and they bound to rCR1 on Western Blot. Affinity chromatography on rCR1-sepharose depleted the plasma of antiCR1, and the acid-eluted fractions contained the antiCR1 Ab. An increased frequency of antiCR1 autoAb was found in patients with SLE (36/78; 46%), liver cirrhosis (15/41; 36%), HIV infection (23/76; 30%) (all P < 0.0001), and in patients with anticardiolipin Ab (4/21; 19%, P < 0.01) multiple sclerosis (7/50; 14%, P < 0.02), and myeloma (autoAb (8/56; 14%, P < 0.02), but not in those with acute poststreptococcal glomerulonephritis (1:32; 3%). Because C1q binds to CR1, antiC1q Ab were analysed in the same patients. There was no correlation between levels of antiC1q and antiCR1 autoAb. In HIV patients, levels of antiCR1 did not correlate with low CR1 levels expressed on erythrocytes or soluble CR1 in plasma. The binding of antiCR1 autoAb to rCR1 fixed on ELISA plates was not inhibited by soluble rCR1 or by human erythrocyte CR1, in contrast to alloAb and one SLE serum, which induced partial blockade. Thus, antiCR1 autoAb recognize mostly CR1 epitope(s) not present on the native molecule, suggesting that they are not directly involved in the loss of CR1. Rather antiCR1 autoAb might indicate a specific immune response to denatured CR1.
Saeki, T. and A. Naya (2003). "CCR1 chemokine receptor antagonist." Curr Pharm Des 9(15): 1201-8.
The selective accumulation and activation of leukocytes in inflamed tissues contributes to the pathogenesis of inflammatory and autoimmune diseases such as infection, rheumatoid arthritis, allergic asthma, atopic dermatitis, and multiple sclerosis. A substantial body of reports suggests that chemokines and their receptors, which belong to a family of seven transmembrane G-protein coupled receptors (GPCR), may be involved in the selective accumulation and activation of leukocytes in inflamed tissues, and in the pathogenesis of inflammatory and autoimmune diseases. One such receptor is CCR1 which is a receptor for CC chemokines, such as CCL5 (RANTES) and CCL3 (MIP-1alpha). The involvement of CCR1 in immunological diseases now is documented in several preclinical studies with CCR1 deficient mice, anti-CCR1 antibodies and CCR1 antagonists, suggesting that CCR1 may be an attractive therapeutic target for a variety of diseases. Publications and patents describing CCR1 antagonists and their pharmacological effects have recently been disclosed. This review highlights the biology and pathophysiology of CCR1, and some of its currently reported antagonists. Additionally, our approach to CCR1 drug discovery is summarized.
Sailer, M., B. Fischl, et al. (2003). "Focal thinning of the cerebral cortex in multiple sclerosis." Brain 126(Pt 8): 1734-44.
Brain atrophy as determined by quantitative MRI can be used to characterize disease progression in multiple sclerosis. Many studies have addressed white matter (WM) alterations leading to atrophy, while changes of the cerebral cortex have been studied to a lesser extent. In vivo, the cerebral cortex has been difficult to study due to its complex structure and regional variability. Measurement of cerebral cortex thickness at different disease stages may provide new insights into grey matter (GM) pathology. In the present investigation, we evaluated in vivo cortical thickness and its relationship to disability, disease duration, WM T2 hyper-intense and T1 hypo-intense lesion volumes. High-resolution MRI brain scans were obtained in 20 patients with clinically definite multiple sclerosis and 15 age-matched normal subjects. A novel method of automated surface reconstruction yielded measurements of the cortical thickness for each subject's entire brain and computed cross-subject statistics based on the cortical anatomy. Statistical thickness difference maps were generated by performing t-tests between patient and control groups and individual thickness measures were submitted to analyses of variance to investigate the relationship between cortical thickness and clinical variables. The mean overall thickness of the cortical ribbon was reduced in multiple sclerosis patients compared with controls [2.30 mm (SD 0.14) versus 2.48 mm (SD 0.11)], showing a significant main effect of group (controls versus patients). In patients, we found significant main effects for disability, disease duration, T2 and T1 lesion volumes. The visualization of statistical difference maps of the cortical GM thickness on inflated brains across the cortical surface revealed a distinct distribution of significant focal thinning of the cerebral cortex in addition to the diffuse cortical atrophy. Focal cortical thinning in frontal [2.37 mm (SD 0.17) versus 2.73 mm (SD 0.25)] and in temporal [2.65 mm (SD 0.15) versus 2.95 mm (SD 0.11)] brain regions was observed, even early in the course of the disease or in patients with mild disability. Patients with longstanding disease or severe disability, however, presented additionally with focal thinning of the motor cortex area [2.35 mm (SD 0.19) versus 2.74 mm (SD 0.15)]. We conclude that in vivo measurement of cortical thickness is feasible in patients suffering from multiple sclerosis. The data provide new insight into the cortical pathology in multiple sclerosis patients, revealing focal cortical thinning beside an overall reduction of the cortical thickness with disease progression.
Sakai, K., Y. Kitagawa, et al. (2003). "Binding of the ELAV-like protein in murine autoimmune T-cells to the nonameric AU-rich element in the 3' untranslated region of CD154 mRNA." Mol Immunol 39(14): 879-83.
The CD154 molecule is important for experimental allergic encephalomyelitis (EAE) which is mediated by autoimmune CD4(+) T-cells. Post-transcriptional instabilization/stabilization of mRNAs, which contain an adenylate uridylate rich element (ARE) in their 3' untranslated region (3'UTR), is regulated in part by binding of ARE-binding proteins to the element. We have investigated the protein which binds to the nonameric ARE in the 3'UTR of CD154 mRNA. A protein which binds to the CD154 ARE was found to exist in a extract prepared from murine autoimmune T-cells activated with myelin basic protein (MBP), and turned out to be mHuR which is a ubiquitous ELAV-like protein. It was found that mHuR was upregulated upon stimulation of the T-cells with a MBP antigen. The CD154 ARE and the ARE in the 3'UTR of tumor necrosis factor-alpha (TNF-alpha) mRNA were competed in binding to mHuR, indicating that both AREs bind to the same site on mHuR. The presence of the CD154 ARE downstream of the luciferase cDNA in a reporter plasmid decreased the translational efficiency, and co-expression of the mHuR slightly increased the translation. These results suggest the possibility that the ELAV-like protein participates in the regulation of the expression of CD154 on the autoimmune T-cells. Modification of the expression of CD154 on autoimmune T-cells by regulating the ELAV-like protein may provide effective therapy for EAE and human multiple sclerosis.
Salama, H. H., O. J. Kolar, et al. (2003). "Effects of combination therapy of beta-interferon 1a and prednisone on serum immunologic markers in patients with multiple sclerosis." Mult Scler 9(1): 28-31.
Beta-interferon (beta-IFN) has a proven treatment effect on relapsing-remitting multiple sclerosis (MS), presumably through its regulatory properties on T-cell activation and cytokine production. This paper examines whether combination therapy of beta-IFN with prednisone would enhance immunoregulatory effects of beta-IFN by measuring serum levels of selected proinflammatory cytokines and soluble T-cell activation markers associated with MS. The selected markers were analyzed in MS patients treated with beta-IFN alone (n = 22) and beta-IFN combined with a low daily dose of prednisone (n = 33), as compared with those in 27 healthy controls at baseline and at a three-month interval for one year. The study confirmed that beta-IFN treatment inhibited serum levels of tumor necrosis factor-alpha (TNFalpha) and intracellular adhesion molecule-1 (ICAM-1) in patients with MS. However, combination therapy did not significantly enhance the inhibitory effect of beta-IFN treatment on the production of TNFalpha, interleukin (IL)-12, IL-2R, and ICAM-1, while the addition of prednisone antagonized the effect of beta-IFN on up-regulation of IL-10 and soluble CD95. No difference in the occurrence of binding antibodies to beta-IFN was found between the two treatment groups. The findings are important for the understanding of the role of combination therapy in the treatment of MS.
Sanna, V., A. Di Giacomo, et al. (2003). "Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses." J Clin Invest 111(2): 241-50.
In the work presented here, we explored the influence of leptin on the kinetics of experimental autoimmune encephalomyelitis (EAE) onset, in the EAE-associated inflammatory anorexia, and in the development of pathogenic T cell responses. We found that the expression of serum leptin increased before the clinical onset of EAE in disease-susceptible C57BL/6J (H-2(b)) and SJL/J (H-2(s)) strains of mice, which are models of chronic-progressive and relapsing-remitting EAE, respectively. This increase in serum leptin correlated with disease susceptibility, reduction in food intake, and decrease in body weight. Indeed, acute starvation, which is able to prevent the increase in serum leptin, delayed disease onset and attenuated clinical symptoms by inducing a T helper 2 cytokine switch. Furthermore, immunohistochemical analysis revealed a parallel in situ production of leptin in inflammatory infiltrates and in neurons only during the acute/active phase of both chronic-progressive and relapsing-remitting EAE. We also found that leptin secretion by activated T cells sustained their proliferation in an autocrine loop, since antileptin receptor antibodies were able to inhibit the proliferative response of autoreactive T cells in vitro. Given that leptin appears to regulate EAE susceptibility, inflammatory anorexia, and pathogenic T-cell immune function, we postulate that it may offer a potential target in the treatment of multiple sclerosis.
Sardanelli, F., A. Iozzelli, et al. (2003). "Three subsequent single doses of gadolinium chelate for brain MR imaging in multiple sclerosis." AJNR Am J Neuroradiol 24(4): 658-62.
BACKGROUND AND PURPOSE: A triple-dose (TD) of gadolinium chelate is highly sensitive approach for detecting lesion activity in multiple sclerosis (MS). However, individual TD injections do not provide data on the severity of the pathologic process in a population of lesions, and its clinical use is limited by the cost-benefit considerations. Our aim was to determine whether the use of three subsequent single doses (SD) of a gadolinium chelate in brain MR imaging is useful in detecting MS lesions with different patterns of enhancement. METHODS: In 10 patients, T1-weighted spin-echo images were acquired before and after three intravenous administrations of 0.1 mmol/kg of gadodiamide. RESULTS: In all patients, SD images showed six enhancing lesions; double-dose (DD) images, 13; and TD images, 22. Differences between SD and TD and between DD and TD were significant (P <.018). Six lesions (27%) enhanced with all the three doses; seven (32%), with both DD and TD; and nine (41%), with only TD. Proportions of patients with at least one enhancing lesion were, for SD, four of 10; DD, seven of 10; and TD, nine of 10. In defining active disease in these nine patients, we needed only 19 SDs versus the 30 SDs that would have been needed if individual TD injections were used. CONCLUSION: With three subsequent SD injections, the number of enhancing lesions progressively increases. This approach allows the distinction of three levels of enhancement, and it reduces the amount of contrast agent needed to distinguish patients with active MS from those with nonactive MS.
Sastre-Garriga, J., E. Munteis, et al. (2003). "Unconventional therapy in multiple sclerosis." Mult Scler 9(3): 320-2.
BACKGROUND: The use of unconventional therapies is growing in western countries. Few studies on their frequency and rationale among multiple sclerosis (MS) patients have been carried out in Europe. OBJECTIVE: To assess the frequency of use of unconventional therapies among MS patients and to explore associated clinical variables. METHODS: Structured questionnaires were given to 380 consecutive patients seen at two hospital-based MS clinics in Barcelona. Clinical and demographical data were recorded at the same time. The questionnaire inquired about demographical features, education, income, use of unconventional therapies for MS and satisfaction with conventional medicine both in general and specifically in MS. RESULTS: The response rate was 50.78%. Forty-one per cent of patients admitted using unconventional therapies during the previous year. Low levels of satisfaction with conventional medicine in general and for MS, and higher Expanded Disability Status Scale (EDSS) scores (EDSS mean: 4.43 in users versus 3.48 in nonusers) were significantly associated with use of unconventional therapies. CONCLUSION: Use of unconventional therapies is not rare among MS patients, and it is associated with high disability levels and dissatisfaction with conventional medicine.
Sastre-Garriga, J., M. Tintore, et al. (2003). "Conversion to multiple sclerosis after a clinically isolated syndrome of the brainstem: cranial magnetic resonance imaging, cerebrospinal fluid and neurophysiological findings." Mult Scler 9(1): 39-43.
BACKGROUND AND AIM: Conversion to multiple sclerosis (MS) after optic neuritis and myelitis has been thoroughly studied; however, limited data are available regarding conversion to MS after a clinically isolated syndrome of the brainstem (CISB). The aim of this study was to investigate conversion to MS in patients with CISB. METHODS: Fifty-one patients with CISB were prospectively studied. Cranial magnetic resonance imaging (MRI), determination of oligoclonal bands (OBs) in the cerebrospinal fluid (CSF) and evoked potentials (EPs) were performed. Based on conversion to MS at follow-up, the sensitivity, specificity, accuracy and positive and negative predictive values of these tests were calculated. RESULTS: Clinically definite MS developed in 18 (35%) patients after a mean follow-up of 37 months. Paty's MRI criteria showed a sensitivity of 89%, a specificity of 52% and an accuracy of 65%; Fazekas' criteria showed a sensitivity of 89%, a specificity of 48% and an accuracy of 63%; Barkhof's criteria showed a sensitivity of 78%, a specificity of 61% and an accuracy of 67%. The presence of OBs in the CSF showed a sensitivity of 100%, a specificity of 42% and an accuracy of 63%. No differences for neurophysiological parameters were found between patients who did and those who did not convert to MS. CONCLUSION: Fulfilling Paty's, Fazekas' or Barkhof's MRI criteria and the presence of OBs in the CSF are associated with a higher risk of conversion to MS in patients with CISB. Determination of OBs in the CSF has the greatest sensitivity of all tests. Barkhof's MRI criteria have greater specificity (although less than previously published for mixed cohorts of clinically isolated syndromes) in predicting conversion to MS for CISB than either Paty's or Fazekas' criteria.
Satoh, J., M. Yukitake, et al. (2003). "Detection of the 14-3-3 protein in the cerebrospinal fluid of Japanese multiple sclerosis patients presenting with severe myelitis." J Neurol Sci 212(1-2): 11-20.
Recent studies showed that the 14-3-3 protein is detectable in the cerebrospinal fluid (CSF) of prion-unrelated neurological diseases, such as meningoencephalitis and myelitis. To investigate the possible association between the amounts of the 14-3-3 protein in the CSF and the clinical severity of multiple sclerosis (MS), its levels were determined by Western blot in the CSF of the patients with relapsing-remitting MS (RRMS) (n=10), secondary progressive MS (SPMS) (n=7), primary progressive MS (PPMS) (n=2), and non-MS inflammatory diseases of the CNS (n=5). The 14-3-3 protein was identified in seven CSF samples, including four patients with SPMS in acute relapse, one with SPMS in remission accompanied by fresh cerebral infarction, one with RRMS in acute relapse, and one with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy. The patients positive for the CSF 14-3-3 protein immunoreactivity showed more severe disability and higher levels of pleocytosis, protein, IgG, beta2-microglobulin, and neuron-specific enolase in the CSF, compared with those negative for its immunoreactivity. Four of these patients exhibited extensive lesions distributed along multiple vertebral segments in the spinal cord on MRI. In contrast, none of the MS patients without an extensive involvement of the spinal cord showed the CSF 14-3-3 protein immunoreactivity. These results suggest that detection of the 14-3-3 protein in the CSF provides a marker for severe inflammation-induced extensive damage of the central nervous system tissues responsible for poor therapeutic responses and irreversible neurological deficits in MS.
Saucedo, L. J., X. Gao, et al. (2003). "Rheb promotes cell growth as a component of the insulin/TOR signalling network." Nat Cell Biol 5(6): 566-71.
Insulin signalling is a potent inhibitor of cell growth and has been proposed to function, at least in part, through the conserved protein kinase TOR (target of rapamycin). Recent studies suggest a that the tuberous sclerosis complex Tsc1-Tsc2 may couple insulin signalling to Tor activity. However, the regulatory mechanism involved remains unclear, and additional components are most probably involved. In a screen for novel regulators of growth, we identified Rheb (Ras homologue enriched in brain), a member of the Ras superfamily of GTP-binding proteins. Increased levels of Rheb in Drosophila melanogaster promote cell growth and alter cell cycle kinetics in multiple tissues. In mitotic tissues, overexpression of Rheb accelerates passage through G1-S phase without affecting rates of cell division, whereas in endoreplicating tissues, Rheb increases DNA ploidy. Mutation of Rheb suspends larval growth and prevents progression from first to second instar. Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR. Levels of rheb mRNA are rapidly induced in response to protein starvation, and overexpressed Rheb can drive cell growth in starved animals, suggesting a role for Rheb in the nutritional control of cell growth.
Saveliev, A. N., D. R. Ivanen, et al. (2003). "Amylolytic activity of IgM and IgG antibodies from patients with multiple sclerosis." Immunol Lett 86(3): 291-7.
IgG and IgM antibodies from the sera of patients with multiple sclerosis (MS) were found to possess amylolytic activity hydrolyzing alpha-(1-->4)-glucosyl linkages of maltooligosaccharides, glycogen, and several artificial substrates. Individual IgM fractions isolated from 54 analyzed patients with the clinically definite diagnoses of MS had approximately three orders of magnitude higher specific amylolytic activity than that for healthy donors, whereas IgG from only a few patients had high amylolytic activity. Strict criteria were used to prove that the amylolytic activity of IgMs and IgGs is their intrinsic property and is not due to any enzyme contamination. Fab fragments produced from IgM and IgG fractions of the MS patients displayed the same amylolytic activity. IgMs from various patients demonstrated different modes of action in hydrolyzing maltooligosaccharides.
Savitz, S. L., S. Malhotra, et al. (2003). "Cell transplants offer promise for stroke recovery." J Cardiovasc Nurs 18(1): 57-61.
Cell transplantation is an experimental approach to restore brain function in neurodegenerative disorders such as Parkinson's and Huntington's disease. Transplantation also represents a possible strategy to repair the brain after a stroke. Various cell types are under investigation in experimental stroke studies. This review discusses the different graft sources and presents preliminary data on the transplantation of neural progenitor cells after stroke in rats. Following transplantation, progenitor cells proliferated and differentiated into all the different brain cell types, including neurons, and they repopulated the ischemic infarct. These results suggest that cell transplantation may serve as a future restorative therapy for stroke and other neurologic disorders such as Parkinson's disease, Alzheimer's disease, trauma, and multiple sclerosis.
Scarisbrick, I. A. and M. Rodriguez (2003). "Hit-Hit and hit-Run: viruses in the playing field of multiple sclerosis." Curr Neurol Neurosci Rep 3(3): 265-71.
Viruses have been major players in the search for the cause of multiple sclerosis (MS). In support of the viral theory is the predominance of CD8+ T cells and class-I major histocompatibility complex in lesions, the powerful therapeutic effects of beta interferons, the ease of inducing demyelination in experimental models following virus challenge, and the documented examples of several human demyelinating diseases conclusively demonstrated to be of viral origin. We propose two hypotheses of how viruses may cause MS. In the "Hit-Hit" hypothesis, the virus persists or may be reactivated in the central nervous system (CNS). Injury is the result of direct viral damage and by an attempt of the immune response to clear the infectious agent. In the "Hit-Run" hypothesis, virus infects the periphery but never enters the CNS. The virus sets up an abnormal immunologic milieu for subsequent autoimmunity. In both scenarios, knowing the inciting virus would be expected to eliminate disease if the population were vaccinated to prevent infection. In the treatment of patients with fully established disease, the Hit-Hit hypothesis would require that antiviral agents enter the CNS and stop replication. In the case of the Hit-Run hypothesis, treatment of patients with established disease with antiviral agents would be futile.
Schmidt, J., J. M. Metselaar, et al. (2003). "Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis." Brain 126(Pt 8): 1895-1904.
High-dose glucocorticosteroid hormones are a mainstay in the treatment of relapses in multiple sclerosis. We searched for a way to deliver ultra high doses of glucocorticosteroids to the CNS of rats with experimental autoimmune encephalomyelitis (EAE) using a novel formulation of polyethylene glycol (PEG)-coated long-circulating liposomes encapsulating prednisolone (predni solone liposomes, PL). 3H-labelled PL showed selective targeting to the inflamed CNS, where up to 4.5-fold higher radioactivity was achieved than in healthy control animals. HPLC revealed much higher and more persistent levels of prednisolone in spinal cord after PL compared with an equal dose of free prednisolone. Gold-labelled liposomes could be detected in the target tissue, mostly taken up by macrophages (Mphi), microglial cells and astrocytes. Blood-brain barrier disruption was greatly reduced by 10 mg/kg PL, which was superior to a 5-fold higher dose of free methylprednisolone (MP). PL was also superior to MP in diminishing T-cell infiltration by induction of T-cell apoptosis in spinal cord. Mphi infiltration was clearly decreased only by PL. The percentage of tumour necrosis factor-alpha (TNF-alpha)-positive T cells or Mphi was greatly reduced by PL and by MP. No adverse effects on glial cells were detected. A single injection of PL clearly ameliorated the course of adoptive transfer EAE and EAE induced by immunization. In conclusion, PL is a highly effective drug in treatment of EAE, and is superior to a 5-fold higher dose of free MP, possibly by means of drug targeting. These findings may have implications for future therapy of autoimmune disorders such as multiple sclerosis.
Schmidt, S., A. Papassotiropoulos, et al. (2003). "Investigation of a genetic variation of a variable number tandem repeat polymorphism of interleukin-6 gene in patients with multiple sclerosis." J Neurol 250(5): 607-11.
Interleukin-6 (IL-6) plays an important role in the regulation of the inflammatory response in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous reports indicated that the C allele of a variable number tandem repeat (vntr) polymorphism located in the 3'flanking region of the IL-6 gene ( IL-6) is associated with reduced activity of IL-6 in vivo. Since disease-modifying genes are likely to contribute to phenotypic differences in MS patients, we tested the hypothesis that the IL-6 C allele is associated with the clinical course of MS. The IL-6 C allele was equally distributed between 217 MS patients of German Caucasian origin and 111 age-mached healthy controls. Stratification of patients according to the course of disease revealed no significant difference of IL-6 C allele distribution between patients with primary progressive and those with either relapsing-remitting or secondary progressive MS although IL-6 C allele was more frequent in patients with RR-MS. Since IL-6 C allele has been associated with a benign course in Sardinian MS patients, we further analysed an independent sample of 125 Sardinian MS patients revealing that IL-6 C allele was much more frequent than in German MS patients. Taken together, a disease-modifying effect of IL-6 C allele could not be demonstrated in MS patients of German Caucasian descent.
Schmidt, S., G. M. Marrosu, et al. (2003). "Genetic variations and humoral immune responses to myelin oligodendroglia glycoprotein in adult phenotypes of X-linked adrenoleukodystrophy." J Neuroimmunol 135(1-2): 148-53.
The lack of phenotype/genotype association in X-linked adrenoleukodystrophy (X-ALD) has prompted the search for disease modifying factors. We previously demonstrated increased serum antibody responses against myelin oligodendrocyte glycoprotein (MOG) in various clinical phenotypes of X-ALD allowing speculations that myelin specific humoral immune responses might be involved in phenotype generation of X-ALD. In the present study, we investigated the possible association of (1) a naturally occurring variable number tandem repeat (vntr) polymorphism (C allele) in the 3' flanking region of the interleukin-6 gene (IL-6), previously demonstrated to modify the course of Alzheimer's disease, systemic lupus erythematodes and Multiple Sclerosis (MS), (2) a tetranucleotide repeat polymorphism (TAAA)(n) in the 3' flanking region of the MOG gene and (3) HLA class II alleles with adult clinical phenotypes and serum antibody responses to MOG in 70 adult X-ALD patients. HLA class II alleles, (TAAA)(n) MOG gene polymorphisms, and IL-6 C allele were not associated with clinical phenotypes. Anti-MOG antibodies were detectable in 17/54 X-ALD patients (31.5%). Anti-MOG antibodies were associated with the 226 bp (TAAA)(n) MOG gene polymorphism but not with distinct clinical phenotypes.
Schmied, M., P. W. Duda, et al. (2003). "In vitro evidence that subcutaneous administration of glatiramer acetate induces hyporesponsive T cells in patients with multiple sclerosis." Clin Immunol 106(3): 163-74.
Glatiramer acetate (GA; Copaxone) is a random sequence polypeptide used in the treatment of relapsing remitting multiple sclerosis (RR MS). We have recently demonstrated that prior to treatment, GA induces proliferation of resting T cells and is not cross-reactive with myelin antigens. Daily GA injections induce a significant loss of this GA responsiveness, which is associated with the induction of highly cross-reactive Th2-type T cells potentially capable of suppressing inflammatory responses. The mechanism of action by which GA induces T cell nonresponsiveness leading to T cell receptor degeneracy in patients with RR MS is unknown. Here, we examined the effects of daily GA administration on the induction of T cell hyporesponsiveness. The frequency of GA-reactive T cells in peripheral blood of seven patients with RR MS was measured by limiting dilution analysis prior to and during 6 months of treatment. In addition, a model in which GA-reactive T cells were stimulated in vitro was developed to better characterize the selection of T cell populations over time. In vivo treatment with GA induced a decrease in GA-reactive T cell frequencies and hyporesponsiveness of CD4(+) T cell reactivity to GA in vitro that was only partially reversed by the addition of IL-2. These data suggest that T cell peripheral tolerance to GA was achieved in vivo during treatment. Thus, our in vitro data suggest that the underlying changes in GA-reactive CD4(+) T cell reactivity could be explained by the induction of T cell anergy and clonal elimination.
Schneider-Monteiro, E. D., A. M. Lucon, et al. (2003). "Bilateral giant renal angiomyolipoma associated with hepatic lipoma in a patient with tuberous sclerosis." Rev Hosp Clin Fac Med Sao Paulo 58(2): 103-8.
OBJECTIVE: To report a case of bilateral giant renal angiomyolipoma associated with tuberous sclerosis, with successful treatment, and to review the literature concerning angiomyolipoma treatment. CASE REPORT: Patient with tuberous sclerosis and angiomyolipoma diagnosed by ultrasonography during her pregnancy. At that time, the angiomyolipoma on the right side was 9 cm in diameter. Conservative management was selected during her pregnancy. The patient returned 7 years later, with a 24.7 x 19.2 x 10.7 cm tumor on the right side and another of 13 x 11.5 x 6.5 cm on the left side, in addition to multiple small angiomyolipomas. A nephron-sparing surgery with tumoral enucleation was performed on the right side, and after 3 months, the tumor on the left side was removed. Renal function in the post-operative period was preserved, and contrast medium progression was uniform and adequate in both kidneys. CONCLUSION: We conclude that an angiomyolipoma larger than 4 cm should be removed surgically, since they have a greater growth rate and pose a risk of hemorrhage. Resection of smaller tumors is safe and has decreased morbidity. Tumoral enucleation is an effective treatment method that preserves kidney function.
Schoenian, S., I. Konig, et al. (2003). "HLA-DRB genotyping in Gilles de la Tourette patients and their parents." Am J Med Genet 119B(1): 60-4.
Gilles de la Tourette syndrome (GTS) is a common neuropsychiatric disorder of unknown cause. There is, however, growing evidence that both autoimmune and genetic factors are involved in the pathogenesis of GTS. In classical autoimmune disorders such as diabetes mellitus or multiple sclerosis, genetic susceptibility is at least in part conferred by human leucocyte antigen (HLA-) subtypes, in particular by distinct HLA-DRB alleles. We undertook modern, PCR-based HLA-DRB typing in 83 trios (affected index child and both parents) to investigate whether GTS may be associated with a particular HLA-DRB allele. The extended transmission/disequilibrium test (ETDT) was applied to analyze transmission disequilibrium for any of the 13 alleles detected. The ETDT failed to detect transmission disequilibrium for any allele at the DRB1 locus (overall allele-wise chi(2) (12) = 12.741, Monte Carlo P = 0.4998). Our results imply that the HLA-DRB locus does not confer genetic susceptibility to GTS.
Schrijver, H. M., J. van As, et al. (2003). "Interleukin (IL)-1 gene polymorphisms: relevance of disease severity associated alleles with IL-1beta and IL-1ra production in multiple sclerosis." Mediators Inflamm 12(2): 89-94.
BACKGROUND: Multiple sclerosis (MS) is an autoimmune disorder, with a considerable genetic influence on susceptibility and disease course. Cytokines play an important role in MS pathophysiology, and genes encoding various cytokines are logical candidates to assess possible associations with MS susceptibility and disease course. We previously reported an association of a combination of polymorphisms in the interleukin (IL)-1B and IL-1 receptor antagonist (IL-1RN) genes (i.e. IL-1RN allele 2+/IL-1B(+3959)allele 2-) with disease severity in MS. Extending this observation, we investigated whether IL-1beta and IL-1ra production differed depending on carriership of this gene combination. METHODS: Twenty MS patients and 20 controls were selected based upon carriership of the specific combination. In whole blood, in vitro IL-1beta and IL-1ra production was determined by enzyme-linked immunosorbent-assay after 6 and 24 h of stimulation with lipopolysaccharide. RESULTS: Carriers of the specific combination produced more IL-1ra, especially in MS patients, although not significantly. IL-1ra production was significantly higher in individuals homozygous for IL-1RN allele 2. In patients, Il-1ra production was higher and IL-1beta production lower compared with controls. In primary progressive patients, the IL-1beta /IL-1ra ratio was significantly lower than in relapsing-remitting patients. CONCLUSION: Our results suggest higher in vitro IL-1ra production in carriers of IL-1RN allele 2, with an indication of an allelic dose-effect relationship.
Schuster, B., M. Kovaleva, et al. (2003). "Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF." J Biol Chem 278(11): 9528-35.
Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotrophic lateral sclerosis. Clinical application of human CNTF, however, was prevented by high toxicity at higher dosages. Human CNTF elicits cellular responses by induction of a receptor complex consisting of the CNTF alpha-receptor (CNTFR), which is not involved in signal transduction, and the beta-receptors gp130 and leukemia inhibitory factor receptor (LIFR). Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 alpha-receptor, whereas at high concentrations, it can directly induce a signaling heterodimer of human gp130 and human LIFR in the absence of the CNTF receptor. Here, we demonstrate that human CNTF cannot directly induce a heterodimer of human gp130 and LIFR. However, human CNTF can use both the membrane-bound and the soluble human IL-6R as a substitute for its cognate alpha-receptor and thus widen the target spectrum of human CNTF. Engineering a CNTFR-specific human CNTF variant may therefore be a prerequisite to improving the safety profile of CNTF.
Schuster, B., M. Kovaleva, et al. (2003). "Signalling of human CNTF revisited: the interleukin-6 (IL-6) receptor can serve as an a-receptor for ciliary neurotrophic factor (CNTF)." J Biol Chem.
Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotropic lateral sclerosis. Clinical application of human CNTF, however, was prevented by high toxicity at higher dosages. Human CNTF elicits cellular responses by induction of a receptor complex consisting of the CNTF a-receptor (CNTFR), which is not involved in signal transduction, and the b-receptors gp130 and leukaemia inhibitory factor receptor (LIFR). Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 a-receptor, whereas at high concentrations, it can directly induce a signalling heterodimer of human gp130 and human LIFR in the absence of the CNTF receptor. Here, we demonstrate that human CNTF cannot directly induce a heterodimer of human gp130 and LIFR. However, human CNTF can use both, the membrane bound and the soluble human IL-6R, as a substitute for its cognate a-receptor and thus widen the target spectrum of human CNTF. Engineering a CNTFR specific human CNTF variant may therefore be a prerequisite to improve the safety profile of CNTF.
Schwinzer, R., T. Witte, et al. (2003). "Enhanced frequency of a PTPRC (CD45) exon A mutation (77C-->G) in systemic sclerosis." Genes Immun 4(2): 168-9.
A point mutation in exon A (C to G transversion at position 77) of human PTPRC (CD45) has recently been associated with the development of multiple sclerosis (MS) for at least a subgroup of patients. In the present report, we studied the frequency of the 77C-->G transversion in two other autoimmune diseases namely systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). The mutation was found with significantly enhanced frequency in patients suffering from SSc suggesting that PTPRC could play a role as susceptibility gene not only in MS but also in other autoimmune diseases. Further understanding of the mode of interaction of mutant PTPRC with other susceptibility genes may uncover mechanisms common in various autoimmune disorders.Genes and Immunity (2003) 4, 168-169. doi:10.1038/sj.gene.6363894
Scott, T. F., C. J. Schramke, et al. (2003). "Sample size estimates for determining treatment effects in high-risk patients with early relapsing-remitting multiple sclerosis." Mult Scler 9(3): 289-92.
BACKGROUND: Risk factors for short-term progression in early relapsing remitting MS have been identified recently. Previously we determined potential risk factors for rapid progression of early relapsing remitting MS and identified three groups of high-risk patients. These non-mutually exclusive groups of patients were drawn from a consecutively studied sample of 98 patients with newly diagnosed MS. High-risk patients had a history of either poor recovery from initial attacks, more than two attacks in the first two years of disease, or a combination of at least four other risk factors. OBJECTIVE: To determine differences in sample sizes required to show a meaningful treatment effect when using a high-risk sample versus a random sample of patients. METHODS: Power analyses were used to calculate the different sample sizes needed for hypothetical treatment trials. RESULTS: We found that substantially smaller numbers of patients should be needed to show a significant treatment effect by employing these high-risk groups of patients as compared to a random population of MS patients (e.g., 58% reduction in sample size in one model). CONCLUSION: The use of patients at higher risk of progression to perform drug treatment trials can be considered as a means to reduce the number of patients needed to show a significant treatment effect for patients with very early MS.
Scott, G. S., L. Virag, et al. (2003). "Peroxynitrite-induced oligodendrocyte toxicity is not dependent on poly(ADP-ribose) polymerase activation." Glia 41(2): 105-16.
Oligodendrocyte loss is a characteristic feature of several CNS disorders, including multiple sclerosis (MS) and spinal cord injury. However, the mechanisms responsible for oligodendrocyte destruction remain undefined. As recent studies have implicated peroxynitrite in the pathogenesis of both spinal cord injury and MS, we have examined whether peroxynitrite may mediate at least some of the oligodendrocyte damage and demyelination observed in these conditions. Primary rat oligodendrocytes were exposed to authentic peroxynitrite in vitro and assessed for cytotoxicity. Mitochondrial function, measured by the reduction of MTT to formazan, and mitochondrial membrane potential were used as indicators of cell viability. Cell death was quantitated by measuring either the release of lactate dehydrogenase from, or the uptake of propidium iodide into, damaged and dying cells. Peroxynitrite dose-dependently reduced the viability of primary oligodendrocytes and induced cell death. Furthermore, peroxynitrite significantly increased DNA strand breakage and the activity of poly(ADP-ribose) polymerase (PARP) in oligodendrocyte cultures. To identify whether PARP activation plays a role in peroxynitrite-induced oligodendrocyte toxicity, we examined the effects of the PARP inhibitors 3-aminobenzamide (3AB) and 5-iodo-6-amino-1,2-benzopyrone (INH(2)BP) on mitochondrial function and cell death in oligodendrocytes. The presence of 3AB and INH(2)BP did not protect oligodendrocytes from peroxynitrite-induced cytotoxicity. However, both compounds significantly reduced PARP activity in these cells. Primary oligodendrocytes generated from PARP-deficient mice were also highly susceptible to peroxynitrite-induced cell death. Therefore, our results show that peroxynitrite exerts cytotoxic effects on oligodendrocytes in vitro independently of PARP activation.
Seamons, A., J. Sutton, et al. (2003). "Competition between two MHC binding registers in a single peptide processed from myelin basic protein influences tolerance and susceptibility to autoimmunity." J Exp Med 197(10): 1391-7.
Experimental allergic encephalomyelitis (EAE) is an animal model for multiple sclerosis induced by stimulating myelin basic protein (MBP)-specific T cells. The MBP-specific repertoire in B10.PL mice is shaped by tolerance mechanisms that eliminate MBP121-150-specific T cells. In contrast, MBPAc1-11-specific T cells escape tolerance and constitute the encephalitogenic repertoire. To determine if this differential tolerance is caused by differences in the abundance of MBP epitopes generated by processing, MBP peptides were eluted from I-Au complexes and analyzed by mass spectrometry. Peptides were identified from both the NH2-terminal and MBP121-150 regions. Unexpectedly, MBPAc1-18 and Ac1-17, which contain the MBPAc1-11 epitope, were much more abundant than MBP121-150 peptides. The results demonstrate that competition between two I-Au binding registers, a low affinity register defined by MBPAc1-11 and a high affinity register defined by MBP5-16, prevents most of the NH2-terminal naturally processed peptides from binding in the MBPAc1-11 register. The small fraction of MBPAc1-18 bound in the MBPAc1-11 register is not sufficient to induce tolerance but provides a ligand for MBPAc1-11-specific T cells during disease. These results provide a basis for both the lack of tolerance to MBPAc1-11 and the ability of this epitope to become a target during autoimmunity.
Seeger, U., U. Klose, et al. (2003). "Parameterized evaluation of macromolecules and lipids in proton MR spectroscopy of brain diseases." Magn Reson Med 49(1): 19-28.
Short echo time (TE) proton MR spectra of the brain include signals of several metabolites as well as macromolecules. In various pathologies, such as brain tumors and multiple sclerosis (MS), the presence of mobile lipids or pathologically altered macromolecules may provide useful additional diagnostic information. A reliable quantitation of these resonances, however, is often not possible due to the lack of adequate prior knowledge. Furthermore, even if advanced fitting procedures are used, a reliable evaluation of metabolites in the presence of pathological lipids or macromolecules often fails if the latter are omitted in the spectral evaluation. In this study, a method is presented for the simultaneous evaluation of all visible components, including metabolites, lipids, and macromolecules, by the use of the fitting procedure LCModel. A standard basis set of brain metabolites was extended by inclusion of parameterized components for macromolecules and lipids that were derived from metabolite-nulled in vivo spectra of normal brain and high-grade gliomas, respectively. The improved spectral quantitation is demonstrated in glial brain tumors and MS lesions as well as in normal brain. It is pointed out that both macromolecules and lipids must be included to provide a proper spectral evaluation.
Sellebjerg, F., C. V. Jensen, et al. (2003). "Gadolinium-enhanced magnetic resonance imaging predicts response to methylprednisolone in multiple sclerosis." Mult Scler 9(1): 102-7.
Oral high-dose methylprednisolone treatment is efficacious in acute optic neuritis (ON) and attacks of multiple sclerosis (MS). The responses to treatment in subgroups of patients participating in two randomized, controlled trials were assessed. Fifty-eight patients with ON and 51 patients with attacks of MS were treated with placebo or oral methylprednisolone (500 mg daily for five days with a 10-day tapering period). A gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) scan was obtained at baseline in 66 patients, and 29 patients underwent repeated MRI studies. Seventy-four patients underwent lumbar puncture before treatment. The odds ratio (OR) of improvement after methylprednisolone treatment (a one point change in the visual function system score of the Kurtzke Expanded Disability Status Scale (EDSS) in ON or in the EDSS score in attacks of MS) was higher in patients with enhancing lesions on baseline MRI (one week: OR 15, P = 0.02; eight weeks: OR 4.6, P = 0.02). Methylprednisolone treatment suppressed Gd-enhancement after one week (P < 0.001) and three weeks (P = 0.001). Cerebrospinal fluid measures of intrathecal inflammation correlated with the area of Gd-enhancement but did not correlate as closely with the treatment response as did the results of Gd-enhanced MRI. These findings suggest that the resolution of intrathecal inflammation as assessed by Gd-enhanced MRI is a major effect of oral high-dose methylprednisolone.
Semana, G. (2003). "[Synopsis of the conferences F. Lhermitte. Immunomodulation and induction of tolerance in MS]." Rev Neurol (Paris) 159(2): 242-4.
Sena, A., R. Pedrosa, et al. (2003). "Therapeutic potential of lovastatin in multiple sclerosis." J Neurol 250(6): 754-5.
Sener, R. N. (2003). "Diffusion MR imaging of giant cell tumors in tuberous sclerosis." J Comput Assist Tomogr 27(3): 431-3.
Giant cell tumors were studied by diffusion MR imaging in three patients with tuberous sclerosis. Diffusion MR imaging was performed on a 1.5-T unit with a gradient strength of 30 mT/m. b = 1000 seconds/mm2 images, and apparent diffusion coefficient (ADC) maps were studied. ADC values were recorded from ADC maps with particular care to obtain the values from the noncalcified regions of the giant cell tumors. ADC values of the normal brain parenchyma and hamartomas were also recorded by multiple evaluations. The ADC values in all three giant cell tumors (0.78, 0.92, and 0.92 x 10-3mm2/s) were within the ranges of the normal brain parenchyma (0.62-1.04 x 10-3mm2/s), and they were prominently less than those of parenchymal hamartomas (1.18-1.86 x 10-3mm2/s). The finding of ADC values of the noncalcified portions of the giant cell tumors being identical to those of normal brain parenchyma is consistent with the presence of normal molecular motion of water, hence relatively normal tissue integrity within these tumors. This was likely a reflection of benignity of these slowly growing tumors.
Serra, A., J. Derwenskus, et al. (2003). "Role of eye movement examination and subjective visual vertical in clinical evaluation of multiple sclerosis." J Neurol 250(5): 569-75.
BACKGROUND AND PURPOSE: Modern neuroimaging has demonstrated progression of disease in multiple sclerosis (MS) that may not be detected by standard clinical protocols, prompting a search for new, sensitive tests. METHODS: In fifty patients with MS, we examined eye movements, with particular attention to the speed and accuracy of saccades, and the vestibulo-ocular reflex during small, high-speed head rotations. We also measured the subjective visual vertical (SVV), using a modified laser-pointer. Visual function was measured, and patients were graded using the Kurtzke Functional Neurological Status (FSS), and Expanded Disability Status Scale (EDSS). RESULTS: Our main finding was that patients showing abnormalities of eye movements (20/50) were more disabled than those with a normal examination (EDSS scores significantly different, p < 0.01), although the ages and duration of disease were similar in both groups. Saccadic dysmetria and internuclear ophthalmoparesis were common. SVV was abnormally large in 36 % of patients; these showed abnormal eye movements and poorer visual acuity more commonly than those with normal SVV. In patients with the largest deviations of SVV, Kurtzke FSS cerebellar functions were significantly worse (p = 0.021). CONCLUSIONS: Clinical examination of eye movements, with attention to dynamic properties of saccades and the vestibulo-ocular reflex, takes only a few minutes to perform, but may provide better information concerning the presence of brainstem and cerebellar involvement than Kurtzke protocols. Measurement of SVV is possible in the clinic and is a sensitive sign of brainstem dysfunction; our present study suggests that SVV is also affected when cerebellar circuits are involved in MS. Prospective studies are required to determine whether the development of abnormalities with ocular motor and SVV testing are predictive of disease activity and progressive disability in MS.
Sewell, D. L., E. K. Reinke, et al. (2003). "Infection with Mycobacterium bovis BCG Diverts Traffic of Myelin Oligodendroglial Glycoprotein Autoantigen-Specific T Cells Away from the Central Nervous System and Ameliorates Experimental Autoimmune Encephalomyelitis." Clin Diagn Lab Immunol 10(4): 564-72.
Infectious agents have been proposed to influence susceptibility to autoimmune diseases such as multiple sclerosis. We induced a Th1-mediated central nervous system (CNS) autoimmune disease, experimental autoimmune encephalomyelitis (EAE) in mice with an ongoing infection with Mycobacterium bovis strain bacillus Calmette-Guerin (BCG) to study this possibility. C57BL/6 mice infected with live BCG for 6 weeks were immunized with myelin oligodendroglial glycoprotein peptide (MOG(35-55)) to induce EAE. The clinical severity of EAE was reduced in BCG-infected mice in a BCG dose-dependent manner. Inflammatory-cell infiltration and demyelination of the spinal cord were significantly lessened in BCG-infected animals compared with uninfected EAE controls. ELISPOT and gamma interferon intracellular cytokine analysis of the frequency of antigen-specific CD4(+) T cells in the CNS and in BCG-induced granulomas and adoptive transfer of MOG(35-55)-specific green fluorescent protein-expressing cells into BCG-infected animals indicated that nervous tissue-specific (MOG(35-55)) CD4(+) T cells accumulate in the BCG-induced granuloma sites. These data suggest a novel mechanism for infection-mediated modulation of autoimmunity. We demonstrate that redirected trafficking of activated CNS antigen-specific CD4(+) T cells to local inflammatory sites induced by BCG infection modulates the initiation and progression of a Th1-mediated CNS autoimmune disease.
Sewell, D., Z. Qing, et al. (2003). "Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization." Int Immunol 15(1): 59-69.
Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic inflammatory demyelination of the central nervous system (CNS). The pathology of EAE involves autoimmune CD4(+) T(h)1 cells. There is a striking inverse correlation between the occurrence of parasitic and autoimmune diseases. We demonstrate that in mice with Schistosoma mansoni ova immunization, the severity of EAE is reduced as measured by decreased clinical scores and CNS cellular infiltrates. Disease suppression is associated with immune deviation in the periphery and the CNS, demonstrated by decreased IFN-gamma and increased IL-4, transforming growth factor-beta and IL-10 levels in the periphery, and increased frequency of IL-4 producing neuroantigen-specific T cells in the brain. S. mansoni helminth ova treatment influenced the course of EAE in wild-type mice, but not in STAT6-deficient animals. This indicates that STAT6 plays a critical role in regulating the ameliorating effect of S. mansoni ova treatment on the autoimmune response, and provides the direct link between helminth treatment, T(h)2 environment and improved EAE. As some intestinal helminthic infections induce minimal pathology, they might offer a safe and inexpensive therapy to prevent and/or ameliorate MS.
Shapiro, H. (2003). "Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system?" Prostaglandins Leukot Essent Fatty Acids 68(3): 219-24.
The intake of n-3 polyunsaturated fatty acids (PUFAs) in many industrialized countries is relatively low and its increased consumption has protective and modifying effects on such diverse conditions as atherosclerosis, ventricular arrhythmias, multiple sclerosis, major depression and inflammatory and autoimmune diseases. In addition, n-3 PUFAs have been shown to alleviate pain in patients with rheumatoid arthritis, inflammatory bowel disease and in a number of other painful conditions. This has been attributed to the inhibition of pro-inflammatory eicosanoid and cytokine production by peripheral tissues. n-3 PUFAs have also been shown to inhibit eicosanoid production in glial cells, block voltage-gated sodium channels (VGSCs), inhibit neuronal protein kinases and modulate gene expression. They also appear to have mood-stabilizing and sympatholytic effects. The present article explores the possibility that, based on what is known about their neural and non-neural effects, n-3 PUFAs directly attenuate the neuronal and glial processes that underlie neuropathic and inflammatory pain.
Sharief, M. K., H. Matthews, et al. (2003). "Expression ratios of the Bcl-2 family proteins and disease activity in multiple sclerosis." J Neuroimmunol 134(1-2): 158-65.
There is emerging evidence that failure of apoptosis (programmed cell death) of potentially pathogenic T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). The commitment of T lymphocytes to die is partly regulated by the Bcl-2 family proteins, which act as a checkpoint upstream of mitochondrial dysfunction. These proteins include the death antagonists Bcl-2 and Bcl-X(L), and death agonists Bax and Bad. Recent studies suggest that altered expression of Bcl-2 family proteins in T lymphocytes is involved in promoting cellular resistance to apoptosis in patients with MS. However, the relationship between these alterations in Bcl-2 proteins expression and clinical disease activity has not yet been evaluated. In this study, we analyzed the expression ratios of pro- to anti-apoptosis Bcl-2 family proteins in patients with clinically active MS and compared results to corresponding ratios in patients with stable MS and relevant control groups. We observed a significant reduction in the expression ratios of pro- to anti-apoptosis Bcl-2 members in peripheral lymphocytes from patients with active MS when compared to corresponding ratios in patients with stable MS or other controls. This imbalance in the expression ratios of pro- and anti-apoptosis proteins was functionally active in reducing cellular susceptibility to apoptosis in active MS. It also correlated with clinical features of disease activity, such as the number of gadolinium-enhancing MRI lesions and clinical relapses. Our findings indicate that dysregulated expression of Bcl-2 family proteins in peripheral lymphocytes is a feature of clinically active multiple sclerosis.
Shee, C. D. and M. Green (2003). "Non-invasive ventilation and palliation: experience in a district general hospital and a review." Palliat Med 17(1): 21-6.
Non-invasive ventilation (NIV) is increasingly being used in hospitals to treat respiratory failure. The use of NIV with palliative intent in a district general hospital is described and ten illustrative cases where NIV was used in an attempt to palliate symptoms or to 'buy time' are presented. The role of NIV in relieving symptoms in various conditions is reviewed and ethical aspects are considered. It is suggested that hospital palliative care teams will increasingly see patients treated by this technique as it becomes more widely used for exacerbations of chronic obstructive airways disease, for relief of breathlessness in the terminally ill and for buying time in patient management. Domiciliary teams will see increasing numbers of people with motor neurone disease and other conditions treated with NIV.
Shibuya, S. and Y. Wakayama (2003). "[Available laboratory tests of neurological diseases involving autoimmune]." Rinsho Byori Suppl 124: 81-5.
Shiga, Y., M. Tsutsumi, et al. (2003). "Angiomyolipoma with regional lymph node involvement: a case report and literature review." Hinyokika Kiyo 49(2): 81-6.
A 28-year-old man without tuberous sclerosis, who complained of pollakisuria, consulted to our hospital for a left renal mass. Abdominal computed tomography revealed a solid mass without a lipid component, 10 cm in diameter, in the left kidney and with regional lymphadenopathy. Renal arteriography showed a hypervascular mass, demonstrating multiple tumor stains and aneurysms. Left radical nephrectomy and perihilar lymph node dissection were performed for an anticipated diagnosis of malignant tumor in November 2001. The histopathological diagnosis was an angiomyolipoma with lymph node involvement. Immunostaining for myogen markers was positive in the renal mass and lymph node tumors. He was free from disease ten months after surgery.
Shin, T., M. Ahn, et al. (2003). "Activation of mitogen-activated protein kinases in experimental autoimmune encephalomyelitis." J Neuroimmunol 140(1-2): 118-25.
The expression of mitogen-activated protein (MAP) kinases, including extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal protein kinase (JNK), and p38, was analyzed in experimental autoimmune encephalomyelitis (EAE) in rats.Western blot analysis showed that the three MAP kinases (phosphorylated ERK (p-ERK), p-JNK, and p-p38) were increased significantly in the spinal cords of rats with EAE at the peak stage as compared with the levels in controls (p<0.05), and both p-ERK and p-JNK declined slightly in the recovery stage of EAE. Immunohistochemistry showed that p-ERK was constitutively expressed in brain cells, including astroglial cells, and showed enhanced immunoreactivity in those cells in EAE, while some T cells and macrophages were weakly immunopositive for p-ERK in EAE lesions. Both p-JNK and p-p38 were intensely immunostained in T cells in EAE lesions, while a few glial cells and astrocytes were weakly positive for both.Taking all these facts into consideration, we postulate that increased expression of the phosphorylated form of each MAP kinase plays an important role in the initiation of acute monophasic EAE. Differential expression of three MAP kinases was discerned in an animal model of human autoimmune central nervous system diseases, including multiple sclerosis.
Shinar, Y., A. Livneh, et al. (2003). "Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients." Genes Immun 4(3): 197-203.
Ancient founder mutations in the Mediterranean fever gene, MEFV, are associated with familial Mediterranean fever, a recessive, episodic, inflammatory disease. Since these mutations are reported to express with above normal levels of acute phase reactants in healthy heterozygotes we postulated that the heterozygous phenotype could aggravate the clinical expression of ongoing autoimmune diseases. This study evaluated progression to disability in relapsing-remitting multiple sclerosis (RR-MS) patients of non-Ashkenazi and Ashkenazi origin carrying an MEFV mutation, particularly the detrimental M694V, using the expanded disability status scale (EDSS). In the non-Ashkenazi patients group (n=48), carriers (n=17) presented with a two-fold higher fraction which reached EDSS=3.0 and 6.0 compared to noncarriers (n=31) despite a comparable mean of MS duration. The median time to reach EDSS=3.0 was 2 years in the carriers vs 10 years in noncarriers (P=0.007); The median time to reach EDSS=6.0 was 6 years vs 23 years, respectively (P=0.003). M694V heterozygous patients reached both EDSS milestones earlier than other patients. Progression to disability was not enhanced in Ashkenazi RR-MS carriers (n=12, noncarriers n=59). In conclusion, non-Asheknazi MS patients carrying one mutated MEFV gene, particularly M694V, expressed rapid progression to disability. The expressed mutation may increase inflammatory damage inflicted by autoimmune responses.Genes and Immunity (2003) 4, 197-203. doi:10.1038/sj.gene.6363967
Sicotte, N. L., R. R. Voskuhl, et al. (2003). "Comparison of multiple sclerosis lesions at 1.5 and 3.0 Tesla." Invest Radiol 38(7): 423-7.
OBJECTIVE: To evaluate the relative sensitivity of MR scanning for multiple sclerosis (MS) at 1.5 Tesla (T) and 3.0 T using identical acquisition conditions, as is typical of multicenter clinical trials. METHODS: Twenty-five subjects with MS were scanned at 1.5 T and 3.0 T using fast spin echo, and T(1)-weighted SPGR with and without gadolinium contrast injections. Image data, blinded to field strength, were analyzed using automated segmentation and lesion counting. RESULTS: Relative to scanning at 1.5 T, the 3.0 T scans showed a 21% increase in the number of detected contrast enhancing lesions, a 30% increase in enhancing lesion volume and a 10% increase in total lesion volume. DISCUSSION: The improved detection ability using high-field MR imaging is prominent even when sequence parameters are optimized around the midfield units. Multicenter trials using both 1.5 T and 3.0 T instruments may be affected by these sensitivity differences.
Siddiqui, M. A. and I. A. Khan (2003). "Differential electrocardiographic artifact from implanted spinal cord stimulator." Int J Cardiol 87(2-3): 307-9.
Siebert, H. and W. Bruck (2003). "The role of cytokines and adhesion molecules in axon degeneration after peripheral nerve axotomy: a study in different knockout mice." Brain Res 960(1-2): 152-6.
The loss of axons and axonal dysfunction has become of outstanding interest with respect to degenerative and inflammatory diseases of the central and peripheral nervous system. In particular in terms of demyelinating diseases such as multiple sclerosis it is important to know the mechanisms which are responsible for the degeneration and destruction of axons. Here we focused on the loss or preservation of axons after induction of Wallerian degeneration in transected mouse sciatic nerves. We examined the distal transected nerve segments of different knockout mice (ICAM-1; TNF-alpha; iNOS; IL-6) 6 days after axotomy. Despite a distinct number of invading macrophages which phagocytosed most of the myelin and axonal debris, we were able to demonstrate, that animals which are deficient for the cell adhesion molecule ICAM-1 and the cytokine TNF-alpha showed a significantly higher number of preserved axons within the degenerating distal nerve stump. Since macrophage invasion is known to be impaired in the absence of ICAM-1, these data indicate an essential role of these cells and their secreted factors, namely TNF-alpha, but not nitric oxide or IL-6 in the destruction of the axonal cytoskeleton in the peripheral nervous system.
Simpson, D., S. Noble, et al. (2003). "Spotlight on Glatiramer Acetate in Relapsing-Remitting Multiple SclerosisThis Spotlight is derived from abstract and summary text of an Adis Drug Evaluation originally published in full in CNS Drugs 2002 Dec; 16 (12): 825-850." BioDrugs 17(3): 207-10.
Glatiramer acetate (Copaxone((R))) is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS).In three randomised, double-blind trials in patients with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more effective than placebo for the primary outcome measure of each trial (mean relapse rate, proportion of relapse-free patients and number of gadolinium-enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse rate was significantly reduced at endpoint (approximately one-third less) in the two larger trials (the US pivotal trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in patients receiving glatiramer acetate compared with those receiving placebo. The rate was 78% less for glatiramer acetate than placebo patients in the pilot trial that investigated a slightly different patient population. Glatiramer acetate significantly decreased disease activity and burden of disease, as assessed in the European/Canadian study using a range of MRI measures. Patients with RRMS treated with glatiramer acetate in the US trial were significantly more likely to experience improved disability (whereas placebo recipients were more likely to experience worsening disability) and their overall disability status was significantly improved compared with placebo recipients. Data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years. Glatiramer acetate was generally well tolerated; the most commonly reported treatment-related adverse events were localised injection-site reactions and transient post-injection systemic reactions. Both reactions were generally mild and self limiting but were responsible for the majority of withdrawals from treatment (up to 6.5% and 3.5%, respectively). Glatiramer acetate is not associated with the influenza-like syndrome or neutralising antibodies that are reported in patients treated with interferon-beta for RRMS.The cost effectiveness of glatiramer acetate has yet to be definitively determined as assessment of available data is confounded by very different models, data sources and assumptions.In conclusion, glatiramer acetate has shown efficacy in well controlled clinical trials in patients with RRMS; it reduces relapse rate and decreases MRI-assessed disease activity and burden. It is generally well tolerated and is not associated with the influenza-like symptoms and formation of neutralising antibodies seen with the interferons-beta. Based on available data and current management guidelines, glatiramer acetate is a valuable first-line treatment option for patients with RRMS.
Sireci, G., F. Dieli, et al. (2003). "A Human Leucocyte Antigen-DR1 Transgene Confers Susceptibility to Experimental Allergic Encephalomyelitis Elicited by an Epitope of Myelin Basic Protein." Scand J Immunol 58(2): 188-94.
Much evidence now indicates that human leucocyte antigen (HLA) class I and class II transgenic (Tg) mice can be of value in analysing HLA-restricted presentation of T-cell epitopes relevant to experimental models of autoimmune diseases. One area where this has been applied is the characterization of myelin epitopes presented by HLA class II molecules in experimental model of multiple sclerosis (experimental allergic encephalomyelitis (EAE)). As a first step towards humanized disease models in HLA Tg mice, we have analysed immune response of lymph node cells of HLA-DR1 Tg mice immunized with the human myelin basic protein (MBP) peptides 13-33, 87-106 and 139-154 bound by HLA-DR1. We report here that HLA-DR1 Tg mice display a hierarchy of response in vivo and in vitro to MBP epitopes depending on the binding affinity to DRB*0101 molecule. In fact, the 13-33 epitope induced a strong T helper 1 (Th1) response accompanied by high T-cell precursor frequency and caused mild EAE, while the two other epitopes gave poor (139-154) or no disease (87-106), and these data correlate with in vitro Th1 response. These data could prove a useful tool in understanding the role played by different MBP epitopes in EAE.
Skundric, D. S., V. Zakarian, et al. (2003). "Distinct immune regulation of the response to H-2b restricted epitope of MOG causes relapsing-remitting EAE in H-2b/s mice." J Neuroimmunol 136(1-2): 34-45.
To find immune mechanisms underlying relapse regulation, we developed a model of relapsing-remitting experimental autoimmune encephalomyelitis (EAE) in (B6xSJL) F1 (H-2(b/s)) mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)) and compared with low/non-relapsing B6 (H-2(b)) mice.In relapsing H-2(b/s) mice, inflammatory lesions scattered throughout the white matter with extensive demyelination, consisted of CD4(+) T and B220(+) B cells with fewer Mac3(+) macrophages. Memory T cell proliferation to MOG(35-55) was significantly enhanced. Switch of macrophage chemoattractant protein-1 (MCP-1) production from GFAP(+) astrocytes to CD3(+) T cells was observed.Distinct patterns of inflammation and demyelination, MOG(35-55) memory T cell response and regulation of MCP-1 are associated with relapsing H-2(b/s) phenotype.
Skurkovich, B. and S. Skurkovich (2003). "Anti-interferon-gamma antibodies in the treatment of autoimmune diseases." Curr Opin Mol Ther 5(1): 52-7.
Interferon (IFN)-gamma is an important immune regulator in normal immunity. When IFN gamma production is disturbed, various autoimmune diseases (ADs) can develop, in which we suggest that anti-IFN gamma could have a beneficial effect. Depending on the cell type in which IFN gamma synthesis is disturbed, different clinical manifestations may result. We have also proposed to remove tumor necrosis factor (TNF)-alpha, together with certain types of IFNs, to treat various ADs and AIDS, also an autoimmune condition. Anti-IFN gamma has been tested in several T-helper cell (Th1) ADs, including rheumatoid arthritis (RA), multiple sclerosis (MS), corneal transplant rejection, uveitis, Type I diabetes, schizophrenia (anti-IFN gamma and anti-TNF alpha), and various autoimmune skin diseases (alopecia areata, psoriasis vulgaris, vitiligo, pemphigus vulgaris and epidermolysis bullosa). A strong, sometimes striking, therapeutic response followed administration of anti-IFN gamma, indicating that it may be a promising therapy for Th1 ADs.
Smit, M. J., P. Verdijk, et al. (2003). "CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3-kinase." Blood.
The chemokines CXCL9, 10 and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T-cells. These IFN-gamma induced chemokines, are thought to be crucial in directing activated T-cells to sites of inflammation. As such, they play an important role in several chronic inflammatory diseases, including ulcerative colitis, multiple sclerosis, artherosclerosis and delayed type hypersensitivity reactions of the skin. In this study, we first demonstrate that in COS-7 cells heterologously expressing CXCR3, CXCL11 is a potent activator of the pertussis toxin sensitive (PTX) p44/p42 MAPK and Akt/PI-3 kinase pathways. Next, we show that these signal transduction pathways are also operative and PTX sensitive in primary human T-cells expressing CXCR3. Importantly, abrogation of these signaling cascades by specific inhibitors did not block the migration of T-cells towards CXCR3 ligands, suggesting that MAPK and Akt activation is not crucial for CXCR3-mediated chemotaxis of T-cells. Finally, we demonstrate that CXCR3 targeting chemokines control T-cell migration via PTX sensitive, phospholipase C pathways and phosphatidylinositol kinases other than class I PI3-Kgamma.
Smith, K., C. Norwood, et al. (2003). "Do the physical and histologic features and time course in acute generalized exanthematous pustulosis reflect a pattern of cytokine dysregulation?" J Cutan Med Surg 7(1): 7-12.
BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is characterized by fever and an indurated erythematous eruption early, with the development of nonfollicular pinhead sterile pustules on an erythematous background. The eruption progresses and resolves relatively rapidly. Although drugs are believed to be the major etiologic agents, other immune modulators, including infections, heavy metals, and radiation, have been implicated. OBJECTIVE: The purpose of this study was to document underlying diseases in patients with AGEP and to determine if this data and the histologic features suggested an underlying pattern of immune dysregulation. METHODS: Twenty-one patients with new or recurrent episodes of AGEP were questioned concerning underlying diseases. The histopathologic features seen in the biopsy sections and the approximate time of biopsy during the course of their eruptions were recorded. RESULTS: Two patients had a history of psoriasis and one patient had a family history of psoriasis, two patients had diagnoses of sarcoid, two patients had inflammatory bowel disease, one had autoimmune thyroiditis, and one patient had multiple sclerosis. Biopsies done at the onset of the eruption showed marked to moderate papillary dermal edema and a mixed dermal inflammatory infiltrate. Shortly thereafter, biopsies showed spongiform pustules within the epidermis and occasional dyskeratotic cells with residual perivascular dermal edema. Although no definitive vasculitis was seen, there was leukocytoclasis within the dermal infiltrate in the majority of biopsy specimens performed more than 48 hours after the onset of the eruption. CONCLUSION: The histologic features seen in AGEP and the disease associations suggest that patients who develop this eruption may have an underlying tendency for development of a pattern of immune dysregulation characterized by a T helper-1 cytokine pattern.
Solari, A., B. Uitdehaag, et al. (2003). "Aminopyridines for symptomatic treatment in multiple sclerosis." Cochrane Database Syst Rev(2): CD001330.
BACKGROUND: The potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) increase nerve conduction in demyelinated nerve fibers, and have been proposed as a symptomatic therapy for people with multiple sclerosis (MS). OBJECTIVES: To determine the efficacy and safety of aminopyridines for neurological deficits in MS people. SEARCH STRATEGY: We searched CENTRAL (Issue 2, 2002), MEDLINE (January 1966-July 2002), EMBASE (1974-July 2002), and the Cochrane MS Group's Specialised Register. We hand searched bibliographic references from retrieved studies and recent MS symposia reports, and contacted known studies' investigators. SELECTION CRITERIA: We included trials fulfilling all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints. DATA COLLECTION AND ANALYSIS: We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from 17 full-paper studies. MAIN RESULTS: Six studies (eight publications, 198 participants, all crossover trials) were considered. Five studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. Treatment duration ranged from hours to six months. Median quality score of the studies was 3. Heterogeneity of outcome assessment and absence of information on individual study periods allowed quantitative pooling of results for few categorical variables. Of the 198 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Three studies (54 patients) assessed manual muscle testing, with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Nine out of 54 participants (17%) improved in ambulation during study treatment versus none during placebo (p<0.001). A lower EDSS score was found in 13/198 participants during study treatment (7%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in three trials assessing cognitive function. Finally, 47/136 MS people (35%) felt better when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0). REVIEWER'S CONCLUSIONS: Currently available information allows no unbiased statement about safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs (more than 300 participants). We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.
Somerset, M., T. J. Peters, et al. (2003). "Factors that contribute to quality of life outcomes prioritised by people with multiple sclerosis." Qual Life Res 12(1): 21-9.
The aim was to investigate factors associated with depression and social function, two outcomes identified as important by people with multiple sclerosis (MS) and to identify underlying dimensions of psycho-social well-being that may be useful as outcome measures. People with MS in eight randomly selected health authorities/boards in England and Scotland completed a postal questionnaire relating to preferences and needs for their health and social care, along with the Beck Depression Inventory and the SF-36. Responses to 10 of the original items were subjected to factor analysis. These and other explanatory variables were entered into multivariable regression models for the two outcomes. The factor analysis resulted in three dimensions representing different aspects of psycho-social well-being; one of these (representing autonomy) was associated with improvements in both outcomes, as was the SF-36 emotional role limitation score. Three other SF-36 dimensions and lack of contact with a health professional in the last year were related just to social function. The regression models emphasise the value of enabling autonomy and self-reliance amongst people with MS, as well as more general measures of emotional health. The present work identifies specific questions that could be used to measure pivotal aspects of an individual's psycho-social well-being. While these findings warrant replication for people with MS, they may have relevance to those with other long-term illnesses.
Sorensen, P. S. (2003). "The role of intravenous immunoglobulin in the treatment of multiple sclerosis." J Neurol Sci 206(2): 123-30.
Intravenous immunoglobulin (IVIG) has several effects on the immune system that could have a beneficial influence on disease processes in multiple sclerosis (MS). Owing to its anti-inflammatory properties, IVIG may be beneficial in the treatment of acute relapses and in prevention of new relapses. By promoting remyelination, IVIG could have a beneficial effect on disability and disease progression. Four double-blind trials in relapsing-remitting MS have demonstrated that IVIG reduces the relapse rate and the number of gadolinium enhancing lesions, and in this respect seems comparable to established therapies in relapsing-remitting MS, i.e. interferon-beta and glatiramer acetate. The doses of IVIG that have been used for treatment in relapsing-remitting have varied 10-fold, and the ideal dosage of IVIG for treating MS still needs to be determined. Three studies have been performed to assess the effect of IVIG on chronic visual impairment or established motor symptoms in MS. None of these trials could confirm that established symptoms in MS can be reversed by IVIG. In secondary progressive MS, a large randomized placebo-controlled trial has recently shown that IVIG is without beneficial effects in this phase of the disease. In conclusion, IVIG is a valuable alternative for treatment of relapsing-remitting MS in patients who do not tolerate or are unwilling to take the approved injectable medications, but additional studies are needed to establish the role of IVIG in the management of multiple sclerosis.
Spiegel, J., C. Hansen, et al. (2003). "Sensitivity of laser-evoked potentials versus somatosensory evoked potentials in patients with multiple sclerosis." Clin Neurophysiol 114(6): 992-1002.
OBJECTIVE: Somatosensory evoked potentials (SEPs) play a less important role in the diagnosis of multiple sclerosis (MS) than visually evoked potentials. Since standard SEPs only reflect the dorsal column function, we now investigated spinothalamic tract function in patients with MS using laser-evoked potentials (LEPs). METHODS: LEPs to thulium laser stimuli (3ms, 540 mJ, 5mm diameter) were recorded from 3 midline positions (Fz, Cz, Pz) in 20 patients with MS, and 6 patients with possible but unconfirmed MS. Peak latencies and peak-to-peak amplitude of the vertex potential negativity (N2) and positivity (P2) were evaluated and compared with normative values from 22 healthy control subjects. Median and tibial nerve SEPs were recorded with standard methods. Depending on the results of sensory testing, two skin areas (both hands, both feet, or one hand and foot of the same body side) were assessed in each patient. RESULTS: In group comparisons, LEPs in patients with MS were significantly delayed and reduced in amplitude compared with healthy subjects (P<0.001) or patients with suspected but unconfirmed MS (P<0.05). In intraindividual comparisons within the patients with MS, LEP amplitude was significantly lower (P<0.01) and latencies were significantly longer (N2: P<0.01; P2: P<0.05) for a clinically hypoalgesic skin area than an unaffected control area. On a single case basis, LEPs were abnormal in 12 (60%) and SEPs in 8 (40%) of the patients with MS; combined analysis of LEPs and SEPs raised sensitivity to 75% (15 patients). LEPs were also abnormal for 7 skin areas with clinically normal nociception and thermal sensitivity, indicating subclinical lesions. Standard SEPs detected subclinical lesions in 5 areas with normal tactile sensitivity. CONCLUSIONS: In patients with multiple sclerosis, spinothalamic tract function and LEPs were impaired more often than dorsal column function and SEPs. LEPs also detected subclinical lesions. Combined assessment of LEPs and SEPs can help to document dissemination of demyelinating CNS lesions and thus contribute to the diagnosis of multiple sclerosis.
Srinivasan, R., R. Henry, et al. (2003). "Standardized, reproducible, high resolution global measurements of T1 relaxation metrics in cases of multiple sclerosis." AJNR Am J Neuroradiol 24(1): 58-67.
BACKGROUND AND PURPOSE: We herein present a methodology for standardized and clinically applicable measurement of T1 relaxation maps with high resolution and volumetric coverage by using the commercially available 3D spoiled gradient-echo sequence. The reproducibility of the T1 metrics derived from these maps and their sensitivity to distinguish between control participants and patients with multiple sclerosis are evaluated. METHODS: Axial view 3D RF spoiled data sets with two flip angles were acquired at 1.5 T to generate the T1 maps, with all other imaging parameters (27/6 ms [TR/TE]; field of view, 180 x 240 x 186 mm(3); matrix, 192 x 256 x 124) kept identical between the two acquisitions. T1 maps were collected from 20 normal control participants and 32 patients with multiple sclerosis. An automated and operator-independent method was developed to segment the relaxation maps and define T1 metrics. RESULTS: We showed that the metrics derived from these maps to represent tissue characteristics were highly reproducible (coefficient of variation, approximately 1% to 4%) and were significantly different between normal control participants and patients with multiple sclerosis (P <.001) for the small cohort of patients in this study. CONCLUSION: The commercially accessible 3D spoiled gradient-echo sequence can be used to generate T1 relaxation maps with high resolution and volumetric coverage. The metrics derived from the relaxation maps are reproducible and have been shown to be sensitive to qualitative and quantitative differences between subgroups of patients with multiple sclerosis and control participants, with strong statistical significance. The use of a commercially available sequence enables the standardization and comparison of T1 metrics across different multiple sclerosis centers.
Sriram, U., L. F. Barcellos, et al. (2003). "Pharmacogenomic analysis of interferon receptor polymorphisms in multiple sclerosis." Genes Immun 4(2): 147-52.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system characterized by progressive neurological dysfunction. No curative therapy is currently available, and approximately 80-90% of afflicted individuals are ultimately disabled. Interferon beta (IFNbeta) has been shown to decrease clinical relapses, reduce brain disease activity, and possibly slow progression of disability. However, the overall effect of treatment is partial and a substantial number of patients are considered poor or nonresponders. For this report, we tested the pharmacogenomic effects of eight polymorphisms in the interferon receptor genes (IFNAR1 and IFNAR2) in a group of 147 patients undergoing open-label IFNbeta therapy. Overall, no significant differences in the distribution of responders and nonresponders, classified based on prospectively acquired primary and secondary clinical end points, were observed when stratified by any of the studied IFNAR gene polymorphisms. A trend detected with a single nucleotide polymorphism SNP 16469 (A/T) located at the third intron of the IFNAR1 gene, suggesting modest association with relapse-free status, will require confirmation in an independent data set. In addition, no significant association was observed of any of the IFNAR gene polymorphisms with susceptibility to MS, as studied by a family-based association analysis.Genes and Immunity (2003) 4, 147-152. doi:10.1038/sj.gene.6363946
Stangel, M. and D. Bernard (2003). "Polyclonal IgM influence oligodendrocyte precursor cells in mixed glial cell cultures: implications for remyelination." J Neuroimmunol 138(1-2): 25-30.
Polyclonal immunoglobulins for intravenous use (IVIg) are a potent immunomodulator and have been shown to be effective in several immune-mediated diseases. This includes inflammatory demyelinating diseases of the central nervous system (CNS) like multiple sclerosis (MS). Besides their immunomodulatory function, IVIg have been proposed to enhance remyelination based on studies in the animal model of Theiler's murine encephalomyelitis virus (TMEV). Disappointingly, recent treatment trials in patients with MS have failed to demonstrate repair of longstanding deficits. Since the clinical trials have used IVIg that contained nearly exclusively IgG, whereas the most pronounced effect in TMEV was seen with IgM, this could be a possible explanation for the negative outcome in the MS trials. Here we have examined the effects of a new polyclonal IgM preparation (IVIgM) on cultured oligodendrocyte precursor cells (OPCs). To achieve successful remyelination, OPCs proliferate, migrate, and differentiate into mature myelinating oligodendrocytes. IVIgM and commercial IVIg preparations had no influence on proliferation and differentiation of either isolated OPCs or OPCs in coculture with microglia. In contrast, IVIgM inhibited the proliferation of OPCs in mixed glial cultures containing astrocytes and microglia. This was not seen in cultures treated with IVIg, albumin, or interferon-gamma (IFN-gamma), suggesting that this is a specific effect of IVIgM. Differentiation was slightly delayed by IVIgM in mixed glial cultures, but this was not statistically significant and interferon-gamma had a similar effect. These results underline the importance of IgM in influencing OPCs and corroborate the in vivo findings that polyclonal IgM are more potent than IgG in their capacity to influence remyelination. The exact mechanism of how this modulation of OPCs is achieved remains unknown, but a complex interaction among all cells present in the CNS has to be postulated.
Staples, J. A., A. L. Ponsonby, et al. (2003). "Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence." Environ Health Perspect 111(4): 518-23.
The apparent immune-suppressive effect of ultraviolet radiation (UVR) has suggested that this environmental exposure may influence the development of immune-related disorders. Self-reported prevalence rates of type 1 diabetes mellitus, rheumatoid arthritis (RA), eczema/dermatitis, and asthma, from the 1995 Australian National Health Survey, were therefore examined by latitude and ambient level of UVR. A positive association of type 1 diabetes mellitus prevalence was found with both increasing southern latitude of residence (r = 0.77; p = 0.026) and decreasing regional annual ambient UVR (r= -0.80; p = 0.018); a 3-fold increase in prevalence from the northernmost region to the southernmost region was evident. In contrast, asthma correlated negatively with latitude (r = -0.72; p = 0.046), although the change in asthma prevalence from the north to the south of Australia was only 0.7-fold. For both RA and eczema/dermatitis, there were no statistically significant associations between latitude/UVR and disease prevalence. These ecologic data provide some support for a previously proposed beneficial effect of UVR on T-helper 1-mediated autoimmune disorders such as type 1 diabetes. The inverse association of type 1 diabetes prevalence with UVR is consistent with that previously reported for another autoimmune disease, multiple sclerosis, in Australia, and also with type 1 diabetes latitudinal gradients in the Northern Hemisphere. The finding also accords with photoimmunologic evidence of UVR-induced immunosuppression and may suggest a beneficial effect of UVR in reducing the incidence of such autoimmune conditions. In light of this study, analytic epidemiologic studies investigating risk of immune disorders in relation to personal UVR exposure in humans are required.
Steens, S. C., G. P. Bosma, et al. (2003). "A neuroimaging follow up study of a patient with juvenile central nervous system systemic lupus erythematosus." Ann Rheum Dis 62(6): 583-6.
BACKGROUND: The course of central nervous system systemic lupus erythematosus (CNS-SLE) is largely unknown. New imaging techniques are available to assist in monitoring the disease course. OBJECTIVE: To report a case of juvenile CNS-SLE, in which magnetic resonance imaging (MRI) was used to assess disease activity. CASE REPORT: A 10-year-old female patient with SLE presented with convulsions; MRI and computed tomography (CT) of the cerebrum disclosed abnormalities. Despite adequate treatment, two years later she had a generalised convulsion, and MRI showed new lesions. MR spectroscopy (MRS) indicated neuronal loss, inflammation, and metabolically compromised tissue; magnetisation transfer imaging (MTI) showed an increase in whole brain lesion load. After exclusion of a malignancy, CNS-SLE was the most likely diagnosis, and cyclophosphamide pulses were administered. Initially, multiple sclerosis (MS)-like lesions regressed, but despite maximal immunosuppressive drugs, new lesions formed and disappeared. When immunosuppressive drugs had been stopped for six months MRI showed improved lesions and MTI histograms. DISCUSSION: In this case report, the anatomical substrate, metabolic aspect, neuroimaging, and clinical course of MS-like lesions in a child with CNS-SLE are described. The way in which radiological techniques can support clinical decision making in this young patient with progressive CNS-SLE is illustrated.
Stein, R. L. (2003). "A new model for drug discovery--meeting our societal obligation." Drug Discov Today 8(6): 245-8.
The development of new models that will enable and encourage drug discovery in disease areas that are neglected by the industry is urgently needed. Here, one model is described that has been established to find treatments for neurodegenerative diseases.
Steinman, L. and S. Zamvil (2003). "Transcriptional analysis of targets in multiple sclerosis." Nat Rev Immunol 3(6): 483-92.
Large-scale analyses of messenger RNA transcripts and autoantibody responses, taken from the actual sites of disease, provide us with an unprecedented view of the complexity of autoimmunity. Despite an appreciation of the large number of pathways and pathological processes that are involved in these diseases, a few practical targets and several new strategies have emerged from these studies. This review focuses on multiple sclerosis and on the approaches that are being used to identify new targets that might be manipulated to control this disease.
Steinman, L. (2003). "Medicine: Collateral damage repaired." Nature 422(6933): 671-2.
Stenager, E., H. Bronnum-Hansen, et al. (2003). "The risk of multiple sclerosis in nurses: a population-based epidemiological study." Mult Scler 9(3): 299-301.
The incidence of multiple sclerosis (MS) in nurses during the period 1980-1996 was calculated in a nationwide study. The cohort consisted of 69,428 nurses, 2185 men and 67,243 women. Sixty (two men and 58 women) with definite MS were observed, whereas 69.3 were expected. We found no significant difference between the observed and expected number of MS cases (standardized incidence ratio = 0.87; 95% confidence interval, 0.66-1.12).
Stolz, E., C. Klotzsch, et al. (2003). "High-dose corticosteroid treatment is associated with an increased risk of developing cerebral venous thrombosis." Eur Neurol 49(4): 247-8.
Stonehouse, M., G. Gupte, et al. (2003). "Acute disseminated encephalomyelitis: recognition in the hands of general paediatricians." Arch Dis Child 88(2): 122-4.
Acute disseminated encephalomyelitis will often present to the general paediatrician as an acute polysymptomatic encephalopathy, and initially the diagnosis may not be clear. A brain MRI scan is essential in establishing the diagnosis and so enabling appropriate advice and treatment to be given. Multicentre clinical audit of outcome and controlled therapeutic trials are needed to secure an evidence base for current practice.
Striano, P., S. Striano, et al. (2003). "Epilepsia partialis continua as a first symptom of multiple sclerosis: electrophysiological study of one case." Mult Scler 9(2): 199-203.
RATIONALE: The prevalence of epilepsy in people with multiple sclerosis (MS) is higher than in the general population.