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Multiple Sclerosis References 2003; Authors: B

(72 References)

Babcock, A. and T. Owens (2003). "Chemokines in experimental autoimmune encephalomyelitis and multiple sclerosis." Adv Exp Med Biol 520: 120-32.

Back, T., R. Mockel, et al. (2003). "Combined MR measurements of magnetization transfer, tissue diffusion and proton spectroscopy. A feasibility study with neurological cases." Neurol Res 25(3): 292-300.

            Magnetic resonance imaging (MRI) of diffusion and magnetization transfer was combined with 1H-spectroscopic imaging (CSI) to evaluate the clinical potential of in-vivo profiles of various brain pathologies. Ten patients (multiple sclerosis, cerebrovascular disease, leukodystrophy, Alzheimer dementia) and five healthy volunteers were investigated with diffusion-weighted MRI, magnetization transfer imaging, and CSI. Proton spectra were analyzed as ratios of NAA/Cr and Cho/Cr calculated from the peak areas of N-acetylaspartate (NAA), (phospho)-creatine (Cr) and choline (Cho). The apparent diffusion coefficient (ADC) and the magnetization transfer ratio (MTR) were determined in identical voxels to ensure identical partial volume effects compared to CSI. Compared to MTR and ADC assessments, the lower spatial resolution of CSI clearly indicates a hindrance at 1.5 T. In most demyelinating lesions, NAA/Cr reduction paralleled attenuated MTRs and elevated ADCs. By contrast, in acute stroke and some acute MS lesions the ADC was reduced, while MTR and NAA/Cr were also decreased. In Alzheimer's dementia, ADC was increased, MTR unchanged and Cho/Cr increased. In a case of leukodystrophy, ADC was pronouncedly increased, MTR and NAA/Cr both reduced, and Cho/Cr normal. Combined measurements of ADC, MTR and CSI are feasible and provide differential in-vivo information on various brain pathologies.

Bagaeva, L. V., L. P. Williams, et al. (2003). "IL-12 dependent/IFN gamma independent expression of CCR5 by myelin-reactive T cells correlates with encephalitogenicity." J Neuroimmunol 137(1-2): 109-16.

            Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease with similarities to multiple sclerosis (MS). It is induced in mice by the transfer of myelin-reactive T cells. Here we demonstrate that IL-12 stimulates myelin-reactive T cells to up-regulate the beta-chemokine receptor, CCR5, in correlation with the acquisition of central nervous system-infiltrating and encephalitogenic properties. These effects of IL-12 are IFN gamma-independent. The CCR5 ligands, RANTES and MIP-1 alpha, are expressed in the spinal cords of mice at EAE onset. Our results suggest that reagents that block CCR5/beta-chemokine interactions and/or antagonize IL-12 might be useful for treatment of autoimmune demyelination.

Bagnato, F. and C. Pozzilli (2003). "Pharmacological methods to overcome IFN-beta antibody formation in the treatment of multiple sclerosis." Expert Opin Investig Drugs 12(7): 1153-63.

            Diminished efficacy in terms of clinical relapses and lesion load on magnetic resonance images for patients developing neutralising antibodies (NAbs) to recombinant IFN-beta may be found in multiple sclerosis. NAbs become detectable over the first few years of therapy, disappearing during the treatment course in some patients and persisting longer in some others. Therefore, the administration of concomitant therapies to recombinant IFNbeta to prevent the formation of NAbs could be indicated mainly in the latter group of patients at the early stage of the treatment. Among those therapies, steroids meet the best criteria in terms of either safety or impact on the development of NAbs, at the present time.

Bagnato, F., N. Jeffries, et al. (2003). "Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years." Brain 126(Pt 8): 1782-9.

            T1 black holes (BHs) on MRIs may represent either areas of oedema or axonal loss in patients with multiple sclerosis. BHs begin as contrast enhancing lesions (CELs) and evolve differently from patient to patient, and within the same patient over time. We analysed BHs formation over a 4-year period. Forty-eight monthly MRIs of nine non-treated multiple sclerosis patients were evaluated for numbers of CELs and BHs. A BH was defined as a hypointense lesion on a T1 pre-constrast image that coincided with a region of high signal intensity on the T2-weighted images. A BH was considered as acute (ABH) when it occurred coincidently with the presence of enhancement and as persisting (PBH) when present after the cessation of enhancement. The present study aimed to analyse: (i) the incidence of CELs and new PBHs, and the accumulation of PBHs; (ii) the relationship between the quantity of the CELs in a given month and the likelihood of accumulating PBHs in the subsequent month; and (iii) the relationship between the duration of CELs and PBHs. Pitman's correlation test evaluated the effect of time on either the increase of CELs and new PBHs or the accumulation of PBHs, while a multiple logistic regression analysis evaluated the relationship between progression of time and CELs, and the increase of PBHs in a multivariate model. The relationship between the enhancing lesions duration and the PBHs duration, or the time to revert back to an isointense lesion was analysed using Kaplan-Meier survival models. PBHs accumulated (P < 0.001) in all patients, but the formation of new PBHs increased in four patients (P </= 0.007) in conjunction with an increase in either the quantity of CELs (P < 0.001, for two patients) or the proportion of CELs turning into PBHs (P </= 0.02, for two patients). Logistic regression analysis showed that neither progression of time nor the number of CELs in a given month were able to predict the probability of increasing the number of PBHs in the subsequent month in any patient. Out of 397 ABHs, 55.7% evolved to a PBH. The duration of PBHs correlated with the duration of enhancement. PBHs preceded by CELs observable on a single MRI persisted for a shorter time (P < 0.002) than those preceded by CELs visible on >/=2 monthly MRIs. The formation of a new PBH was found to be related to CELs activity; however, duration of PBHs is most likely a consequence of the duration of the enhancement.

Bagnato, F. and J. A. Frank (2003). "The role of nonconventional magnetic resonance imaging techniques in demyelinating disorders." Curr Neurol Neurosci Rep 3(3): 238-45.

            The use of nonconventional magnetic resonance imaging techniques (eg, magnetization transfer, magnetic resonance spectroscopy, and diffusion weighted imaging) allows for an accurate characterization of lesions as compared with conventional or standard approaches in demyelinating diseases. Magnetization transfer, magnetic resonance spectroscopy, and diffusion weighted imaging have revolutionized our understanding of demyelinating diseases because these techniques have been used to identify pathologic changes of normal-appearing brain tissue and characterize the differences in lesions. Metrics derived from these methods correlate with clinical disability and provide more accurate tools for monitoring disease activity and treatment effect over time. Quantitative T1 and T2 relaxation time maps provide additional information on demyelinating diseases, allowing for the evaluation of myelin water and distribution of water within tissues. Finally, the measurement of central nervous system atrophy has become a valuable element in determining the course of multiple sclerosis.

Baker, D., P. Adamson, et al. (2003). "Potential of statins for the treatment of multiple sclerosis." Lancet Neurol 2(1): 9-10.

Baker, D., G. Pryce, et al. (2003). "The therapeutic potential of cannabis." Lancet Neurol 2(5): 291-8.

            Research of the cannabinoid system has many similarities with that of the opioid system. In both instances, studies into drug-producing plants led to the discovery of an endogenous control system with a central role in neurobiology. Few compounds have had as much positive press from patients as those of the cannabinoid system. While these claims are investigated in disorders such as multiple sclerosis spasticity and pain, basic research is discovering interesting members of this family of compounds that have previously unknown qualities, the most notable of which is the capacity for neuroprotection. Large randomised clinical trials of the better known compounds are in progress. Even if the results of these studies are not as positive as many expect them to be, that we are only just beginning to appreciate the huge therapeutic potential of this family of compounds is clear.

Baker, D. and D. J. Hankey (2003). "Gene therapy in autoimmune, demyelinating disease of the central nervous system." Gene Ther 10(10): 844-53.

            Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), where suspected autoimmune attack causes nerve demyelination and progressive neurodegeneration and should benefit from both anti-inflammatory and neuroprotective strategies. Although neuroprotection strategies are relatively unexplored in MS, systemic delivery of anti-inflammatory agents to people with MS has so far been relatively disappointing. This is most probably because of the limited capacity of these molecules to enter the target tissue, because of exclusion by the blood-brain barrier. The complex natural history of MS also means that any therapeutic agents will have to be administered long-term. Gene therapy offers the possibility of site-directed, long-term expression, and is currently being preclinically investigated in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. While some immune effects may be targeted in the periphery using DNA vaccination, strategies both viral and nonviral are being developed to target agents into the CNS either via direct delivery or using the trafficking properties of cell-carrier systems. Targeting of leucocyte activation, cytokines and nerve growth factors have shown some promising benefit in animal EAE systems, the challenge will be their application in clinical use.

Baker, D. and G. Pryce (2003). "The therapeutic potential of cannabis in multiple sclerosis." Expert Opin Investig Drugs 12(4): 561-7.

            There has been renewed interest in the therapeutic applications of cannabis, and people, particularly those with multiple sclerosis, claim that it may offer benefit in symptom control. Cannabis exerts many of its effects because it taps into an endogenous cannabinoid system. Recent advances have begun to shine light on the biology of this system and may support some of the anecdotal medical claims. The problem with cannabis as a drug is that both the positive and negative aspects are largely the work of the same receptor. However, it may be possible to avoid these through modulation of the endogenous system. Cannabinoids provide a novel therapeutic target, not only for controlling symptoms, but also slowing disease progression through inhibition of neurodegeneration, which is the cause of accumulating irreversible disability.

Bakshi, R. (2003). "Fatigue associated with multiple sclerosis: diagnosis, impact and management." Mult Scler 9(3): 219-27.

            In patients with multiple sclerosis (MS) fatigue is the most common symptom and one of the most disabling features. As many as 40% have described it as the single most disabling symptom--a higher percentage than weakness, spasticity, motor problems, or bowel or bladder problems. The etiology and pathophysiology of MS-related fatigue remain unknown. Studies have failed to demonstrate an association between MS-related fatigue and the level of disability, clinical disease subtype, or gender, although recent data show an association between MS-related fatigue and depression and quality of life. Imaging studies using positron emission tomography suggest that fatigue in MS is related to hypometabolism of specific brain areas, including the frontal and subcortical circuits. The impact of fatigue on patient functioning and quality of life clearly warrants intervention. In addition to nonpharmacologic measures, such as exercise and energy conservation strategies, several pharmacologic agents have been evaluated for their ability to reduce MS-related fatigue, including amantadine, central nervous system stimulants (pemoline), and the novel wake-promoting agent modafinil.

Barca, O., S. Ferre, et al. (2003). "Interferon beta promotes survival in primary astrocytes through phosphatidylinositol 3-kinase." J Neuroimmunol 139(1-2): 155-9.

            Although interferon-beta (IFN-beta) has been demonstrated to be effective in the treatment of multiple sclerosis (MS) patients, the mechanism(s) underlying its beneficial effects has not been uncovered yet. Until now, most of the effort in the study of the relevant mechanisms of IFN-beta has dealt with its ability to modulate the immune response. Only recently, it has been proposed that the beneficial effects of IFN-beta in MS patients could depend on its ability to modulate astrocyte function. In the present work, we have found that IFN-beta treatment promotes the survival of astrocytes through stimulation of the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway. We propose that the beneficial effects of IFN-beta in MS therapy may depend, at least in part, on its capacity to protect astrocytes against the apoptotic cell death that occurs in the early steps of the pathogenesis of MS.

Barcellos, L. F., J. R. Oksenberg, et al. (2003). "HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course." Am J Hum Genet 72(3): 710-6.

            Models of disease susceptibility in multiple sclerosis (MS) often assume a dominant action for the HLA-DRB1*1501 allele and its associated haplotype (DRB1*1501-DQB1*0602 or DR2). A robust and phenotypically well-characterized MS data set was used to explore this model in more detail. A dose effect of HLA-DR2 haplotypes on MS susceptibility was revealed. This observation suggests that, in addition to the role of HLA-DR2 in MS, two copies of a susceptibility haplotype further increase disease risk. Second, we report that DR2 haplotypes modify disease expression. There is a paucity of benign MS and an increase of severe MS in individuals homozygous for DR2. Concepts of the molecular mechanisms that underlie linkage and association of the human leukocyte antigen (HLA) region to MS need to be revised to accommodate these data.

Barkhof, F., M. Rocca, et al. (2003). "Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon beta1a." Ann Neurol 53(6): 718-24.

            In the recently proposed diagnostic criteria for multiple sclerosis (MS) by McDonald, the modified magnetic resonance imaging (MRI) Barkhof criteria have been incorporated. We examined the validity of this implementation in the Early Treatment of MS study, a randomized, double-blind, placebo-controlled study of 22 microg interferon beta1a given subcutaneously once weekly in 309 patients with a first episode consistent with demyelinating disease (and abnormal MRI). Conversion to clinically definite MS (CDMS) within 2 years of follow-up, as evidenced by a new clinical episode, occurred in 41% of patients (independent of treatment) with gadolinium enhancement or nine or more T2 lesions versus 11% of those without either finding (p = 0.017); similarly, proportions converting were 44% versus 31% for infratentorial lesions (p = 0.026), 40% versus 35% for juxtacortical lesions (p = 0.413), and 41% versus 17% for three or more periventricular lesions (p = 0.034). The rate of conversion to CDMS based on the number of modified Barkhof criteria was 22% for two or fewer positive criteria, increasing to 47% with four positive criteria. For a cutoff of three positive criteria, the hazard ratio for time to CDMS was 2.3 (95% confidence interval, 1.17-4.55; p = 0.016). Treatment effect seemed more evident as the number of positive criteria increased, and the number of patients needed to avoid one patient converting to CDMS decreased from 50 in patients with one or two positive criteria to 5.6 in patients with four positive criteria. However, the study was not powered to detect statistically significant treatment by variable interaction, and this remains an important issue for further study.

Barnes, M. P., R. M. Kent, et al. (2003). "Spasticity in multiple sclerosis." Neurorehabil Neural Repair 17(1): 66-70.

            The objective of this article is to establish the prevalence of spasticity in a random selection of people with multiple sclerosis (MS) in the city of Newcastle upon Tyne in the Northeast of England. A secondary aim was to assess the adequacy of current pharmacological intervention for spasticity and assess the relationship between spasticity and overall disability. The study design was a simple comparison that examined differences in functional independence in 2 random groups of people with MS subdivided by the presence of clinically significant spasticity. A total of 68 adults with a diagnosis of clinically definite MS were included in the study. Their level of functional independence was assessed using the Newcastle Independence Assessment Form (NIAF), the Functional Independence Measure (FIM), and the Kurtzke Extended Disability Status Scale (EDSS). Spasticity was assessed using the Modified Ashworth Scale. A subjective analysis was made of the appropriateness of oral antispastic medication by a rehabilitation physician. Thirty-two people (47%) had clinically significant spasticity (Modified Ashworth Score of 2, 3, or 4). Seventy-eight percent of the population were receiving some oral antispastic medication, but 50% were deemed to require some drug adjustment or additional treatment. Individuals with spasticity were found to have significantly higher levels of disability than those who had no spasticity or clinically insignificant spasticity. This study has confirmed that spasticity is highly prevalent in the MS population and is significantly associated with a reduced level of functional independence. Treatment of spasticity is suboptimal in a large proportion of the population, and the need for further information and education to health professionals and to people with MS is highlighted.

Barnett, M. H., D. B. Williams, et al. (2003). "Progressive increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 35-year study." J Neurol Sci 213(1-2): 1-6.

            The prevalence of multiple sclerosis (MS) in Newcastle, Australia increased significantly between 1961 and 1981 and the incidence of the disease also increased between the decades 1950-1959 and 1971-1981. The present study sought to determine whether there has been a further increase in the frequency of MS in the subsequent 15 years, and to examine the potential factors underlying this change. The incidence, prevalence and clinical profile of multiple sclerosis were therefore re-examined in Newcastle, Australia in 1996 using comparable diagnostic criteria and methods to those employed in studies in the same region in 1961 and 1981. There has been a significant progressive increase in prevalence from 19.6 to 59.1 per 100,000 population and a significant increase in incidence from 1.2 to 2.4 per 100,000 population from 1961 to 1996. The most pronounced increase in prevalence was in females and in the age-group over 60 years, and there was also an increased incidence in females aged 20-29 years. There was little change in the age of disease onset, but duration of disease in females had increased substantially. The significant increase in prevalence is attributed to increased incidence, particularly in females; and to increased survival. Although such trends in prevalence have been observed in the Northern Hemisphere, this is the first such study in the Southern Hemisphere to show a longitudinal increase in prevalence and incidence over a period of this duration.

Bashir, K. and R. A. Kaslow (2003). "Chlamydia pneumoniae and multiple sclerosis: the latest etiologic candidate." Epidemiology 14(2): 133-4.

Bates, I. R., J. M. Boggs, et al. (2003). "Membrane anchoring and charge effects in the interaction of myelin basic protein (MBP) with lipid bilayers studied by site-directed spin labeling." J Biol Chem.

            Myelin basic protein (MBP) maintains the compaction of the myelin sheath in the central nervous system by anchoring the cytoplasmic face of the two apposing bilayers, and may also play a role in signal transduction. Site-directed spin labeling was done at 8 matching sites in each of two recombinant murine MBPs, qC1 (charge +19) and qC8 charge (+13), which respectively emulate the native form of the protein (C1) and a post-translationally modified form (C8) that is increased in multiple sclerosis (MS). When interacting with large unilamellar vesicles, most spin-labeled sites in qC8 were more mobile than those in qC1. Depth measurement via continuous wave power saturation indicated that the N-terminal and C-terminal sites in qC1 were located below the plane of the phospholipid headgroups. In qC8, the C-terminal domain dissociated from the membrane, suggesting a means by which the exposure of natural C8 to cytosolic enzymes and ligands might increase in vivo in MS. The importance of two FF pairs in MBP to its interactions with lipids was investigated by separately mutating each pair to AA. The mobility at F42A-F43A and especially F86A-F87A increased significantly. Depth measurements and helical wheel analysis indicated that the F86-F87 region could form a surface-seeking amphipathic alpha-helix.

Batocchi, A. P., M. Rotondi, et al. (2003). "Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta." J Neuroimmunol 139(1-2): 150-4.

            The role of leptin was investigated in relapsing-remitting multiple sclerosis (MS). Control and MS patients showed comparable baseline serum leptin levels. During the first year of IFNbeta-1a treatment, leptin significantly decreased since 2 months after starting therapy in 11 patients who had no relapses. A significant decrease in IL12/IL10 ratio was observed in this group of patients only after 1 year of treatment. An increase of leptin was observed before the first clinical exacerbation in 13 relapsing patients. Leptin may play a pathogenic role in MS and can be a useful marker of disease activity and response to therapy.

Battistini, L., L. Piccio, et al. (2003). "CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1." Blood 101(12): 4775-82.

            Multiple sclerosis (MS) is considered an autoimmune inflammatory disease of the central nervous system. Under physiologic conditions, we compared the adhesiveness of CD4+ and CD8+ lymphocytes from nontreated patients with acute, relapsing-remitting multiple sclerosis (RRMS) and from healthy donors. We show that in patients with RRMS CD8+, but not with RRMS CD4+, T cells display increased rolling and arrest in inflamed murine brain venules. Moreover, CD8+, but not CD4+, lymphocytes from MS patients show increased rolling on P-selectin in vitro. Anti-P-selectin glycoprotein ligand-1 (PSGL-1) antibodies dramatically block the recruitment of CD8+ cells in brain vessels of patients with MS, suggesting that PSGL-1 represents a novel pharmaceutical target that may be exploited to block the selective entrance of CD8+ cells during early inflammation. Vascular cell adhesion molecule-1 (VCAM-1), but not PSGL-1, is critical for the adhesion of CD4+ cells in MS patients, highlighting a fundamental dichotomy in the mechanisms governing the recruitment of lymphocyte subsets in RRMS. Importantly, 7-color fluorescence-activated cell sorter (FACS) analysis, together with functional data, indicates that a large fraction of CD8+ cells from MS patients display the characteristics of memory-effector phenotype. In conclusion, our results show that CD8+, but not CD4+, T cells from patients with RRMS in the acute phase of the disease display increased ability to be recruited in inflamed brain venules.

Baumhackl, U., C. Franta, et al. (2003). "A controlled trial of tick-borne encephalitis vaccination in patients with multiple sclerosis." Vaccine 21 Suppl 1: S56-61.

            The aim of this study was to investigate a possible link between a single vaccination against tick-borne encephalitis (TBE) and the appearance of one or more new cerebral lesions in magnetic resonance imaging (MRI) and/or a clinical relapse of MS. Fifteen MS patients with documented history of MS relapses living in a TBE endemic area were matched with 15 patients selected from a patient database containing 500 cases of MS. Three patients in each group were unvaccinated while all others had basic immunisation and regular booster vaccinations. Patients of the vaccination group received a single dose (3.3 microg) of a TBE vaccine. TBE antibodies were detected by ELISA and confirmed by neutralisation test. MRI was used as marker for disease activity and progression in addition to the clinical neurological examination. No association was seen between TBE vaccination and MRI detected disease activity, clinical relapse or disease progression of MS.

Bazzi, C., C. Petrini, et al. (2003). "Fractional excretion of IgG predicts renal outcome and response to therapy in primary focal segmental glomerulosclerosis: a pilot study." Am J Kidney Dis 41(2): 328-35.

            BACKGROUND: Prolonged treatment with steroids and/or cyclophosphamide improves the prognosis of primary focal segmental glomerulosclerosis (FSGS). In nephrotic patients, no clinical or histological feature predicts responsiveness to therapy. METHODS: In 50 patients with FSGS, fractional excretion (FE) of immunoglobulin G (IgG), albumin, transferrin, and alpha(1)-microglobulin (alpha(1)m) was calculated. The aim of the study is to assess whether FE IgG and FE alpha(1)m: (1) correlate with histological lesions, (2) predict outcome, and (3) may be useful to guide therapy. RESULTS: The association of FE IgG with percentage of glomeruli with segmental sclerosis was at the limit of significance (P = 0.01). FE alpha(1)m was associated with extent of tubulointerstitial damage (P = 0.008). By multiple regression analysis, FE alpha(1)m was dependent on FE IgG (R(2) = 0.76; P = 0.000). The predictive value of proteinuric variables on outcome was evaluated in 29 patients with nephrotic syndrome and baseline normal renal function (serum creatinine level, 1.04 +/- 0.22 mg/dL [92 +/- 19 micromol/L]; follow-up, 50 +/- 33 months); remission rates were 91% and 0% in patients with FE IgG less than versus greater than 0.140 (P = 0.0009). By multiple logistic regression analysis, only FE IgG was associated with remission (P = 0.043). Proteinuria less than versus greater than 7.5 g/d of protein predicted end-stage renal failure (0% versus 36%; P = 0.004); the predictive value of FE IgG less than versus greater than 0.140 was higher (0% versus 71%; P = 0.0000). Patients with FE IgG less than 0.025 were responsive to steroids alone (70%) or steroids and cyclophosphamide (20%); patients with FE IgG greater than 0.025 and less than 0.140 were responsive to steroids alone (20%) or steroids and cyclophosphamide (80%); and 100% of patients with FE IgG greater than 0.140 were unresponsive to therapy (P = 0.000). CONCLUSION: In FSGS, FE IgG is at the limit of statistically significant association with segmental sclerosis, and FE alpha(1)m is associated with extent of tubulointerstitial damage. FE IgG shows the best predictive value for remission, progression, and response to therapy and may be useful to guide treatment. Am J Kidney Dis 41:328-335.

Beatty, W. W., D. M. Orbelo, et al. (2003). "Comprehension of affective prosody in multiple sclerosis." Mult Scler 9(2): 148-53.

            Deficits in cognition have been repeatedly documented in patients with multiple sclerosis (MS), but their ability to comprehend emotional information has received little study. Forty-seven patients with MS and 19 demographic controls received the comprehension portion of the Aprosodia Battery, which is known to be sensitive to the impairments of patients with strokes and other neurological conditions. Patients also received tests of hearing, verbal comprehension and naming, a short cognitive battery, and the Beck Depression Inventory. Patients with MS were impaired in identifying emotional states from prosodic cues. The magnitude of the deficits was greatest for patients with severe physical disability and under test conditions of limited prosodic information. Correlational analyses suggested that the patients' difficulties in comprehending affective prosodic information were not secondary to hearing loss, aphasic deficits, cognitive impairment, or depression. For some patients with MS, deficits in comprehending emotional information may contribute to their difficulties in maintaining effective social interactions.

Becanovic, K., E. Wallstrom, et al. (2003). "New loci regulating rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis." J Immunol 170(2): 1062-9.

            Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4, 10, 15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 x PVG.1AV1) male/female F(2) population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1(av1) MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae16 on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms.

Beck, R., H. Wiendl, et al. (2003). "Human herpesvirus 6 in serum and spinal fluid of patients with multiple sclerosis?" Arch Neurol 60(4): 639; author reply 639-40.

Becker, H., F. Chochon, et al. (2003). "[Report of the 55th meeting of the American Academy of Neurology. Honolulu, March 29-April 6, 2003]." Rev Neurol (Paris) 159(4): 470-86.

Bedinghaus, J. M. (2003). "A piece of my mind. Family history." Jama 289(2): 142.

Bee, Y. S., M. C. Lin, et al. (2003). "Optic neuritis: clinical analysis of 27 cases." Kaohsiung J Med Sci 19(3): 105-12.

            We retrospectively reviewed 27 cases diagnosed as idiopathic optic neuritis between 1992 and 2001 at Kaohsiung Veterans General Hospital to assess the clinical features, visual prognosis, neuroimaging, laboratory studies, and development of multiple sclerosis in Chinese patients with optic neuritis. Patient age ranged from 13 to 54 years (mean, 35.8 +/- 11.3 years). Five cases presented as bilateral optic neuritis and 22 as unilateral. Visual function improved gradually from 2 weeks after treatment. Twelve (44.4%) cases showed disc swelling and ocular pain was also noted in 44.4% of patients. All cases that underwent visual field and visual evoked potential tests showed abnormality in lesion eyes. Of the 23 cases that underwent neuroimaging studies, including computerized tomography (17 patients) and magnetic resonance imaging (6 patients), 10 revealed optic nerve thickening. Four cases (14.8%) developed multiple sclerosis during follow-up (mean, 4.3 years). The incidence of disc swelling was higher than that reported by the Optic Neuritis Treatment Trial, but the incidence of initial ocular pain, the presence of periventricular plaques, and the development of multiple sclerosis were lower in our study. The unilateral group had significantly better visual outcome than the bilateral group.

Beeton, C., H. Wulff, et al. (2003). "A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes." J Biol Chem 278(11): 9928-37.

            T lymphocytes with unusually high expression of the voltage-gated Kv1.3 channel (Kv1.3(high) cells) have been implicated in the pathogenesis of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. We have developed a fluoresceinated analog of ShK (ShK-F6CA), the most potent known inhibitor of Kv1.3, for detection of Kv1.3(high) cells by flow cytometry. ShK-F6CA blocked Kv1.3 at picomolar concentrations with a Hill coefficient of 1 and exhibited >80-fold specificity for Kv1.3 over Kv1.1 and other K(V) channels. In flow cytometry experiments, ShK-F6CA specifically stained Kv1.3-expressing cells with a detection limit of approximately 600 channels per cell. Rat and human T cells that had been repeatedly stimulated 7-10 times with antigen were readily distinguished on the basis of their high levels of Kv1.3 channels (>600 channels/cell) and ShK-F6CA staining from resting T cells or cells that had undergone 1-3 rounds of activation. Functional Kv1.3 expression levels increased substantially in a myelin-specific rat T cell line following myelin antigen stimulation, peaking at 15-20 h and then declining to baseline over the next 7 days, in parallel with the acquisition and loss of encephalitogenicity. Both calcium- and protein kinase C-dependent pathways were required for the antigen-induced Kv1.3 up-regulation. ShK-F6CA might be useful for rapid and quantitative detection of Kv1.3(high) expressing cells in normal and diseased tissues, and to visualize the distribution of functional channels in intact cells.

Ben-Hur, T., O. Einstein, et al. (2003). "Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis." Glia 41(1): 73-80.

            Transplanted neural precursor cells remyelinate efficiently acutely demyelinated focal lesions. However, the clinical value of cell transplantation in a chronic, multifocal disease like multiple sclerosis will depend on the ability of transplanted cells to migrate to the multiple disease foci in the brain. Here, we expanded newborn rat neural precursor cells in spheres and transplanted them intracerebroventricularly or intrathecally in rats. The cells were labeled by the nuclear fluorescent dye Hoechst or by incubation with BrdU to enable their identification at 2 days and 2 weeks after transplantation, respectively. Spheres consisted of PSA-NCAM(+), nestin(+), NG2(-) undifferentiated precursor cells that differentiated in vitro into astrocytes, oligodendrocytes, and neurons. Spheres that were transplanted into intact rats remained mostly in the ventricles or in the spinal subarachnoid space. Following transplantation at peak of experimental autoimmune encephalomyelitis, cells migrated into the brain or spinal cord parenchyma, exclusively into inflamed white matter but not into adjacent gray matter regions. After 2 weeks, many transplanted cells had migrated into distant white matter tracts and acquired specific markers of the astroglial and oligodendroglial lineages. Thus, the inflammatory process may attract targeted migration of transplanted precursor cells into the brain parenchyma.

Benatru, I., P. Terraux, et al. (2003). "[Gustatory disorders during multiple sclerosis relapse]." Rev Neurol (Paris) 159(3): 287-92.

            Gustatory dysfunction is a known but uncommon element in the course of multiple sclerosis. Gustatory dysfunction has been described during the chronic progressive phase and during the relapse phase. We report five patients with clinically definite multiple sclerosis who developed transient gustatory disorders during the relapse phase of their disease. Agueusia occurred as one of the first symptoms in three patients, revealing the disease. Symptoms generally improved with remission or corticosteroid administration. These disorders are due to demyelinating lesions of the gustatory pathways in the thalamus or brainstem. MRI studies were not performed during the relapse phase and no clinical neuroimaging correlations could be established. Agueusia may be accompanied by olfactory dysfunction which is due to plaque demyelinization of the olfactory pathways, particularly in the temporal and inferior frontal lobes. Taste anomalies can also be observed in other diseases, including systemic diseases such as sarcoidosis or Sjogren's syndrome. Drug-induced gustatory disorders are also reported.

Benedict, R. H., F. Munschauer, et al. (2003). "Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire." Mult Scler 9(1): 95-101.

            Since there is a need for cost-effective screening techniques to identify neuropsychological impairment in multiple sclerosis (MS) patients, and because existing methods require cognitive testing with subsequent interpretation by a neuropsychologist, a brief self-report procedure was developed to screen for neuropsychological impairment in MS. In the first phase of the study, a pool of 80 items was generated based on a literature review and consultation with healthcare professionals. The set was reduced to 15 via Rasch analysis. Using these items, a brief (five minute) MS Neuropsychological Screening Questionnaire (MSNQ), including patient- and informant-report forms, was composed. In phase II, 50 MS patients and their caregivers completed the MSNQ. A comprehensive neuropsychological test battery was also administered. Analyses covered the reliability of the MSNQ and correlations between both patient- and informant-report scores and objective neuropsychological testing. Cronbach's alpha coefficients were 0.93 and 0.94 for the patient- and informant-report forms, respectively, and both forms of the test were strongly correlated with a more general cognitive complaints questionnaire. The patient MSNQ form correlated significantly with measures of depression but not with objective tests of cognitive function. In contrast, the informant form was correlated with patient cognitive performance but not depression. A cut-off score of 27 on the informant form of the MSNQ optimally separated patients based on a neuropsychological summary score encompassing measures of processing speed and memory. There were two false-negatives and one false-positive, giving the test a sensitivity of 0.83 and a specificity of 0.97. It is concluded, therefore, that this self-administered neuropsychological screening test is reliable and predicts neuropsychological impairment in MS patients with a reasonable degree of accuracy.

Benito-Leon, J. and P. Martinez-Martin (2003). "[Health-related quality of life in multiple sclerosis]." Neurologia 18(4): 210-7.

            The clinical scales used to assess disease severity in multiple sclerosis (MS) patients share a common feature: assessment is made and interpreted by neurologists, and, therefore, someone other than the patient. Furthermore, these scales do not assess the health factors that are important components of patient's experienced quality of life. Health-related quality of life (HRQoL) instruments include several domains, which are regarded by patients as being more important determinants of their overall health states. In fact, HRQoL measurements in MS are becoming important in assessing the effect of treatment and progression of the disease. This article will provide a review of the most significant studies on HRQoL in MS. Neurologia 2003;18(4):210-217

Benjamins, J. A., L. Nedelkoska, et al. (2003). "Protection of mature oligodendrocytes by inhibitors of caspases and calpains." Neurochem Res 28(1): 143-52.

            Mature mouse oligodendrocytes (OLs) are susceptible to death in demyelinating diseases such as multiple sclerosis and in brain injury following neurotrauma, ischemia, or stroke. To understand mechanisms leading to death of mature OLs and develop strategies for protection, we utilized cultures of mature mouse OLs to investigate the role of caspases and calpains in OL cell death mediated by different mechanisms. The agents used were (i) staurosporine, which induces apoptotic death via inhibition of protein kinases; (ii) kainate, which activates non-NMDA glutamate receptors; (iii) thapsigargin, which releases intracellular calcium stores; and (iv) SNAP, which releases active NO species and causes necrotic cell death. Inhibitors blocking primary effector caspases (including caspase 3), the FAS (death receptor)-mediated initiator caspases (including caspase 8), and stress-induced caspases (including caspase 9), were tested for their protective effects. Inhibition of caspases 3, 8, and 9 each robustly protected OLs following insult with staurosporine, thapsigargin, or kainate when added at optimal times. The time of addition of the inhibitors for maximal protection varied with the agent, from 1 h of preincubation before addition of staurosporine to 6 h after addition of kainate. Much less protection was seen for the NO generator SNAP under any condition. The role of calcium in OL death in each model was investigated by chelating extracellular Ca++ with EGTA, and by inhibiting the Ca++-activated calpain proteases. Calcium chelation did not protect against staurosporine, but decreased OL death initiated by kainate, thapsigargin, or NO. The calpain inhibitors PD150606 and calpain inhibitor I protected from cell death initiated by staurosporine, kainate, and thapsigargin, but not from cell death initiated by the NO donor SNAP.

Benz, M. S., J. S. Glaser, et al. (2003). "Progressive outer retinal necrosis in immunocompetent patients treated initially for optic neuropathy with systemic corticosteroids." Am J Ophthalmol 135(4): 551-3.

            PURPOSE: To report two cases of progressive outer retinal necrosis occurring in immunocompetent individuals after treatment with corticosteroids for presumed optic neuropathy. DESIGN: Observational case report. SETTING: University-based tertiary eye hospital. METHODS: Retrospective review of existing clinical records. RESULTS: Two patients were treated empirically with systemic corticosteroids for suspected inflammatory papillopathy. Subsequently, both were diagnosed with necrotizing herpetic retinitis with features of progressive outer retinal necrosis. Anterior chamber paracentesis confirmed varicella-zoster infection. Both patients were human immunodeficiency virus negative; one patient with rheumatoid arthritis was taking etanercept. Both became completely blind in one eye despite intensive treatment with antiviral medication intravenously and intravitreally. CONCLUSIONS: Progressive outer retinal necrosis is not confined to patients with underlying severe immunodeficiency, such as acquired immune deficiency syndrome. Initial treatment of acute, unexplained vision loss with systemic corticosteroids may lead to catastrophic visual loss in patients with evolving necrotizing herpetic retinopathy.

Berger, T., P. Rubner, et al. (2003). "Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event." N Engl J Med 349(2): 139-45.

            BACKGROUND: Most patients with multiple sclerosis initially present with a clinically isolated syndrome. Despite the fact that clinically definite multiple sclerosis will develop in up to 80 percent of these patients, the course of the disease is unpredictable at its onset and requires long-term observation or repeated magnetic resonance imaging (MRI). We investigated whether the presence of serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome predicts the interval to conversion to clinically definite multiple sclerosis. METHODS: A total of 103 patients with a clinically isolated syndrome, positive findings on cerebral MRI, and oligoclonal bands in the cerebrospinal fluid were studied. At base line, serum samples were collected to test for anti-MOG and anti-MBP antibodies with Western blot analysis, and the lesions detected by cerebral MRI were quantified. Neurologic examinations for relapse or disease progression (defined as conversion to clinically definite multiple sclerosis) were performed at base line and subsequently every three months. RESULTS: Patients with anti-MOG and anti-MBP antibodies had relapses more often and earlier than patients without these antibodies. Only 9 of 39 antibody-seronegative patients (23 percent) had a relapse, and the mean (+/-SD) time to relapse was 45.1+/-13.7 months. In contrast, 21 of 22 patients (95 percent) with antibodies against both MOG and MBP had a relapse within a mean of 7.5+/-4.4 months, and 35 of 42 patients (83 percent) with only anti-MOG antibodies had a relapse within 14.6+/-9.6 months (P<0.001 for both comparisons with antibody-seronegative patients). The adjusted hazard ratio for the development of clinically definite multiple sclerosis was 76.5 (95 percent confidence interval, 20.6 to 284.6) among the patients who were seropositive for both antibodies and 31.6 (95 percent confidence interval, 9.5 to 104.5) among the patients who were seropositive only for anti-MOG antibodies, as compared with the seronegative patients. CONCLUSIONS: Analysis of antibodies against MOG and MBP in patients with a clinically isolated syndrome is a rapid, inexpensive, and precise method for the prediction of early conversion to clinically definite multiple sclerosis. This finding may be important for the counseling and care of patients with a first demyelinating event suggestive of multiple sclerosis.

Bermel, R. A., J. Sharma, et al. (2003). "A semiautomated measure of whole-brain atrophy in multiple sclerosis." J Neurol Sci 208(1-2): 57-65.

            Brain atrophy is a proposed MRI marker of irreversible pathologic damage in multiple sclerosis (MS). The brain parenchymal fraction (BPF) is the ratio of brain parenchymal volume to the total volume within the surface contour. We developed a semiautomated measure of BPF using commercially available edge-finding and thresholding software (30-min analysis time per patient). We measured BPF in 78 patients with MS and 17 healthy controls. BPF was lower in a cohort of patients with MS (n=50) (0.843+/-0.042, range 0.743-0.906) age-matched to controls (0.877+/-0.020, range 0.835-0.901) (p<0.001). BPF correlated inversely with third ventricular width (r=-0.785, p<0.001), and total T1 hypointense lesion volume (r=-0.347, p=0.011), but not with total T2 hyperintense lesion volume (r=-0.213, p=0.13). BPF correlated negatively with expanded disability status scale (EDSS) score (r=-0.391, p=0.0006) and disease duration (r=-0.281, p=0.01). Stepwise regression compared the relative abilities of MRI variables to predict clinical data. By regression of age, BPF, third ventricular width, T2 lesions, and T1 lesions, BPF was the best predictor of disability score (R(2)=0.204, p<0.001). Third ventricular width was the best predictor of disease duration (R(2)=0.316, p<0.001). None of the MRI variables differed between relapsing-remitting (RR) (n=60) and secondary progressive (SP) (n=18) disease course (p>0.05). The intrarater, interrater, and scan-rescan BPF variability (COV) was 0.31%, 0.34%, and 0.41% and the accuracy against a phantom was 99.1%. We conclude that whole-brain atrophy in MS can be reliably and readily quantified by a semiautomated approach. Longitudinal studies are warranted to determine if this method provides a sensitive biologic marker of the MS disease process.

Bermel, R. A., M. D. Innus, et al. (2003). "Selective caudate atrophy in multiple sclerosis: a 3D MRI parcellation study." Neuroreport 14(3): 335-9.

            Deep gray matter damage may be an important component of the multiple sclerosis (MS) disease process. We tested whether caudate atrophy occurs in MS, and whether it correlates with conventional MRI or clinical markers of disease progression. Caudate nuclei of 24 MS patients and 10 age-matched healthy controls were traced, normalized, reconstructed and visualized from MRI scans. Normalized bicaudate volume was 19% lower in MS controls ( p< 0.001), an effect that persisted after adjusting for whole-brain atrophy ( p< 0.008). Caudate volume did not correlate with disease duration, physical disability score, whole-brain atrophy, or total T2 hyperintense or T1 hypointense lesion load (all p > 0.05). We conclude that selective caudate atrophy is associated with MS and may occur through direct mechanisms.

Besler, H. T. and S. Comoglu (2003). "Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis." Nutr Neurosci 6(3): 189-96.

            Free radical-mediated peroxidation of biological molecules, especially of lipids, is implicated in the pathogenesis of a number of diseases like multiple sclerosis. Low concentration of antioxidant vitamins: beta carotene, retinol, alpha tocopherol and ascorbic acid have been observed in serum or cerebrospinal fluid of multiple sclerosis patients. On the basis of these observations, we studied the potential lipoprotein oxidation and total antioxidant capacity in the pathogenesis of multiple sclerosis. Lipoprotein oxidizability for plasma in vitro, serum levels of autoantibodies against oxidized low-density lipoproteins, plasma total homocysteine levels with vitamin B12 and folate, and plasma total antioxidant capacity were measured in twenty four patients with multiple sclerosis and twenty four healthy sex- and age-matched person as control. In multiple sclerosis patients during an attack, a significant increase in both in vitro lipid oxidizability for plasma and in the levels of autoantibodies against oxidized low-density lipoproteins, and a strong decrease in plasma total antioxidant capacity were detected. Plasma total homocysteine levels were significantly higher in multiple sclerosis patients whose plasma vitamin B12 and folate levels were lower but not statistically significant, than controls. The present study indicates that lipoprotein oxidation may be important factor in the course of multiple sclerosis and in vitro measurements of plasma oxidation kinetics as an indication for lipoprotein oxidation might be useful as an additional tool for the clinical diagnosis of multiple sclerosis.

Bettelli, E., M. Pagany, et al. (2003). "Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis." J Exp Med 197(9): 1073-81.

            Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis. The relationship of optic neuritis to MS is not well understood. We have generated novel T cell receptor (TCR) transgenic mice specific for myelin oligodendrocyte glycoprotein (MOG). MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent. A large proportion (>30%) of MOG-specific TCR transgenic mice spontaneously develop isolated optic neuritis without any clinical nor histological evidence of experimental autoimmune encephalomyelitis (EAE). Optic neuritis without EAE could also be induced in these mice by sensitization with suboptimal doses of MOG. The predilection of these mice to develop optic neuritis is associated with higher expression of MOG in the optic nerve than in the spinal cord. These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.

Bilinska, M., I. Frydecka, et al. (2003). "Fas expression on T cells and sFas in relapsing-remitting multiple sclerosis." Acta Neurol Scand 107(6): 387-93.

            OBJECTIVES: To investigate the proportions of peripheral blood CD4+/Fas+ and CD8+/Fas+ cells and serum sFas levels in relapsing-remitting multiple sclerosis (RRMS) patients with relapses (active RRMS), those without relapses (stable RRMS), and controls over 1 year. MATERIAL AND METHODS: Sixteen RRMS patients and 10 controls were tested monthly. Cells were analyzed by dual immunofluorescence and the sFas levels by ELISA. There were 14 relapses which occurred 1223 days after the last control visits. The measurements performed at these visits in the active RRMS patients were considered as relapse-related, while the rest were regarded as relapse-unrelated. RESULTS: In active RRMS patients the median of CD4+ Fas+ to total CD4+ and CD8+ Fas+ to total CD8+ from relapse-related measurements were higher than the median from relapse-unrelated measurements (P=0.003, 0.004, respectively). The median of CD4+ Fas+ to total CD4+ from relapse-unrelated measurements in active RRMS was higher compared with stable RRMS (P = 0.005) and controls (P = 0.004). The sFas level from relapse-unrelated measurements was also higher in active RRMS than in stable RRMS (P = 0.04) and in controls (P = 0.004). CONCLUSIONS: We suggest that increased expression of Fas antigen on CD4+ subset and increased serum sFas level are valuable markers of clinical activity in MS.

Bingham, S. C. and P. W. Beatty (2003). "Rates of access to assistive equipment and medical rehabilitation services among people with disabilities." Disabil Rehabil 25(9): 487-90.

            PURPOSE: To determine rates of access to assistive equipment and medical rehabilitation services among people with disabilities in the US, and to determine whether health plan type is associated with rates of access to these health services. METHOD: Results were derived from a nationwide US survey sample of people with cerebral palsy, multiple sclerosis or spinal cord injury. Analyses were restricted to working-age adults (n=500). Need for, and receipt of (1) assistive equipment in the last 12 months, and (2) rehabilitative services in the last 3 months, was determined. RESULTS: Over half of the sample indicated a need for assistive equipment in the last 12 months. Nearly a third of those who indicated a need did not receive assistive equipment every time it was needed. Forty per cent of the sample indicated a need for rehabilitative services in the last 3 months, and over half of those indicating a need did not receive rehabilitative services every time they were needed. Access rates did not differ appreciably between respondents covered by managed care and fee-for-service health plans. CONCLUSION: Emphasis in healthcare for people with disabilities should shift from traditional acute healthcare models that focus on functional restoration, to preventive services, and maintenance of function, health and independence.

Birnboim, S. (2003). "The automatic and controlled information-processing dissociation: is it still relevant?" Neuropsychol Rev 13(1): 19-31.

            The purpose of this paper is to examine the "dual-process" information-processing model of Schneider and Shiffrin (Schneider, W., and Shiffrin, R. M., Psychol. Rev. 84: 1-66, 1977; see also Shiffrin, R. M., and Schneider, W., Psychol. Rev. 84: 127-190, 1977) in light of the research data that have accumulated since the model was introduced more than 20 years ago. First, a brief introduction of the basic model of automatic and controlled information processing will be given. Second, some alternatives to the basic model that were developed over the last two decades will be reviewed. Third, data from neuropsychology and cognitive neuroscience that have a bearing upon this framework will be considered. Finally, some comments on the current usefulness of the dual-process framework for neuropsychological research will be offered.

Bjartmar, C. and B. D. Trapp (2003). "Axonal degeneration and progressive neurologic disability in multiple sclerosis." Neurotox Res 5(1-2): 157-64.

            Accumulating data support axonal degeneration as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). The extent of axonal injury correlates with the degree of inflammation in active MS lesions and occurs at early stages of disease, indicating that inflammatory demyelination is an important factor behind axon pathology at the relapsing-remitting stage of MS. Axonal loss from disease onset can remain clinically silent for many years, and permanent neurological disability develops when a threshold of axonal loss is reached and the CNS compensatory resources are exhausted. Lack of myelin-derived trophic support due to long term demyelination may cause continuous axonal degeneration in chronic inactive lesions at the secondary-progressive stage of MS. Axonal pathology is not limited to demyelinated lesions, but also extends into normal appearing white matter. The concept of MS as a neurodegenerative disorder has important clinical implications: First, proactive anti-inflammatory and immunomodulatory treatment should prevent or delay chronic disability since inflammation influences axonal injury. Second, the pathophysiological mechanisms underlying axonal degeneration in MS need to be clarified in order to develop novel neuroprotective therapeutics. Finally, surrogate markers of axonal pathology, such as N-acetyl aspartate, can be used to monitor axonal dysfunction, axonal loss and treatment efficiency in patients with MS.

Bjartmar, C., J. R. Wujek, et al. (2003). "Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease." J Neurol Sci 206(2): 165-71.

            Axonal degeneration has been identified as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory demyelination influences axon pathology during relapsing-remitting MS (RR-MS). This axonal loss remains clinically silent for many years, and irreversible neurological disability develops when a threshold of axonal loss is reached and compensatory CNS resources are exhausted. Experimental support for this view-the axonal hypothesis-is provided by data from various animal models with primary myelin or axonal pathology, and from pathological or magnetic resonance studies on MS patients. In mice with experimental autoimmune encephalomyelitis (EAE), 15-30% of spinal cord axons can be lost before permanent ambulatory impairment occurs. During secondary progressive MS (SP-MS), chronically demyelinated axons may degenerate due to lack of myelin-derived trophic support. In addition, we hypothesize that reduced trophic support from damaged targets or degeneration of efferent fibers may trigger preprogrammed neurodegenerative mechanisms. The concept of MS as an inflammatory neurodegenerative disease has important clinical implications regarding therapeutic approaches, monitoring of patients, and the development of neuroprotective treatment strategies.

Blanco, Y., J. Yague, et al. (2003). "No association of inducible nitric oxide synthase gene ( NOS2A) to multiple sclerosis." J Neurol 250(5): 598-600.

            Nitric oxide (NO) is a nonspecific inflammatory mediator that has been involved in the pathogenesis of multiple sclerosis (MS). The influence of the promoter polymorphism of inducible NO synthase gene ( NOS2A) on susceptibility and outcome was studied in 140 MS Spanish patients and 147 healthy controls matched for sex, age, and ethnicity. No association was found between MS susceptibility, course or outcome of the disease, and NOS2A polymorphisms.

Blom, T., A. Franzen, et al. (2003). "Comment on "The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease"." Science 299(5614): 1845; author reply 1845.

Bobholz, J. A. and S. M. Rao (2003). "Cognitive dysfunction in multiple sclerosis: a review of recent developments." Curr Opin Neurol 16(3): 283-8.

            PURPOSE OF REVIEW: Nearly half of all patients diagnosed with multiple sclerosis will develop cognitive dysfunction, a symptom associated with significant decline in activities of daily living. The purpose of this review is to discuss recent literature investigating issues related to cognitive dysfunction in multiple sclerosis. RECENT FINDINGS: Recent studies, examined in this review, have provided increased understanding regarding specific cognitive processes affected in multiple sclerosis, as well as a characterization of its natural history. Studies have also continued to emphasize the extent to which cognitive deficits in the condition are associated with decline in daily living skills. Recent concerns regarding driving performance have been documented among cognitively impaired individuals. Studies have also examined correlates of cognitive dysfunction, with particular emphasis on neuroimaging techniques reflecting disease activity or lesion burden. With increased understanding of neurobiological correlates of cognitive deficits, investigators have begun to examine potential treatments for managing cognitive dysfunction. SUMMARY: This area of research has suggested that disease modifying medications can have an impact on magnetic resonance imaging disease activity by altering the cerebral demyelinating process resulting in a slower decline in cognitive functions over time and improved activities of daily living for patients with multiple sclerosis.

Bode, R. K., J. S. Lai, et al. (2003). "Issues in the development of an item bank." Arch Phys Med Rehabil 84(4 Suppl 2): S52-60.

            OBJECTIVE: To describe and illustrate 2 issues involved in the development of an item bank that can be used to improve measurement across settings and over time. DESIGN: Secondary (psychometric) analysis of data collected on existing quality of life (QOL) instruments. SETTING: Five cancer clinics in hospital settings in various parts of the United States; 523 solo or group practices in 3 major US cities; and an inpatient rehabilitation hospital in a large metropolitan area. PARTICIPANTS: Illustration 1: 399 persons being treated for or having a history of cancer, 170 persons being treated for human immunodeficiency virus (HIV), 328 persons with stroke assessed during and after acute rehabilitation, and 433 persons being treated for multiple sclerosis. Illustration 2: 1714 persons with cancer and/or HIV participating in a large-scale multisite study, 3429 persons with prevalent treatable chronic health conditions, and 125 persons with stage IV metastatic breast cancer. INTERVENTIONS: Not applicable. Main Outcomes Measures: QOL as measured by 10 different instruments. RESULTS: The illustrations show that (1). core items, which functioned similarly across 4 diagnostic groups, can be identified and used to construct instruments measuring physical function that are tailored to each of these groups, and (2). items from 3 separate datasets can be linked to create a dataset that can serve as an initial pain item bank. CONCLUSION: The methodology exists to develop item banks to develop better measures of QOL.

Boeije, H. R., M. S. Duijnstee, et al. (2003). "Continuation of caregiving among partners who give total care to spouses with multiple sclerosis." Health Soc Care Community 11(3): 242-52.

            As is expressed in the term 'caregiving career', caregiving is a dynamic phenomenon. The present study addresses the total care phase in which spouses give direct and ongoing personal care to their partners with multiple sclerosis (MS). The dyadic nature of caregiving is stressed by examining the roles which both spouses play in establishing a commitment that results in the continuation of caregiving. For this purpose, 17 couples facing MS were selected in the Netherlands and Belgium. Ten females and seven males were disabled, and all were living with partners who provided a full range of care. Both partners were interviewed separately about their motivation to give care, dependency on help, the continuation of caregiving and their relationship. The analysis consisted of fragmenting and connecting the data, and involved close reading and constant comparison. The present findings support those previous studies, i.e. that continuation of caregiving is the result of an interchange between the partners. The commitment that is established can be expressed in terms of inevitability, shared misfortune, reciprocity and the desire to prevent admission to a nursing home. Three aspects appear to contribute to the creation of commitment and the ensuing continuation of caregiving: namely, marital loyalty, and the arbitrariness of the disease and its serious nature. For community care, it is important to consider the negotiations between partners and the impact of caregiving on their relationship.

Bolviken, B., E. G. Celius, et al. (2003). "Radon: a possible risk factor in multiple sclerosis." Neuroepidemiology 22(1): 87-94.

            Ecological studies in Norway, using a method for spatially moving bivariate correlation analysis, show that south of 65 degrees N, there are significant positive correlations (p < 0.01) for rates of multiple sclerosis (MS) versus contents of radon (Rn) in indoor air, and significant negative correlations for MS rates versus fallout of magnesium (Mg) and amounts of precipitation. Based on these data, we propose the hypothesis that the content of Rn in inhaled air is a risk factor in MS. The release of harmful Rn levels to the air may be influenced by (1) the levels of exchangeable Mg in soil, which may affect the soil content of the Rn precursor radium (Ra), and (2) the amounts of precipitation through its effects on soil moisture, which is one of the factors controlling Rn emanation from the soil. This hypothesis agrees with several of the known epidemiological characteristics of MS.

Borchmann, P. and M. Reiser (2003). "Pixantrone (Novuspharma)." IDrugs 6(5): 486-90.

            Novuspharma is developing pixantrone, a second-generation, well-tolerated anthracenedione analog, for the potential treatment of lymphoma and multiple sclerosis.

Bosch, X. (2003). "Spanish centre for rehabilitation of multiple sclerosis to be built." Lancet Neurol 2(7): 391.

Boven, L. A., N. Vergnolle, et al. (2003). "Up-regulation of proteinase-activated receptor 1 expression in astrocytes during HIV encephalitis." J Immunol 170(5): 2638-46.

            Proteinase-activated receptor 1 (PAR-1) is a G protein-coupled receptor that is activated by thrombin and is implicated in the pathogenesis of inflammation. Although PAR-1 is expressed on immunocompetent cells within the brain such as astrocytes, little is known about its role in the pathogenesis of inflammatory brain diseases. Herein, we investigated PAR-1 regulation of brain inflammation by stimulating human astrocytic cells with thrombin or the selective PAR-1-activating peptide. Activated cells expressed significantly increased levels of IL-1 beta, inducible NO synthase, and PAR-1 mRNA. Moreover, supernatants of these same cells were neurotoxic, which was inhibited by an N-methyl-D-aspartate receptor antagonist. Striatal implantation of the PAR-1-activating peptide significantly induced brain inflammation and neurobehavioral deficits in mice compared with mice implanted with the control peptide or saline. Since HIV-related neurological disease is predicated on brain inflammation and neuronal injury, the expression of PAR-1 in HIV encephalitis (HIVE) was investigated. Immunohistochemical analysis revealed that PAR-1 and (pro)-thrombin protein expression was low in control brains, but intense immunoreactivity was observed on astrocytes in HIVE brains. Similarly, PAR-1 and thrombin mRNA levels were significantly increased in HIVE brains compared with control and multiple sclerosis brains. These data indicated that activation and up-regulation of PAR-1 probably contribute to brain inflammation and neuronal damage during HIV-1 infection, thus providing new therapeutic targets for the treatment of HIV-related neurodegeneration.

Bowen, J. D., K. Maravilla, et al. (2003). "Open-label study of pirfenidone in patients with progressive forms of multiple sclerosis." Mult Scler 9(3): 280-3.

            BACKGROUND: Pirfenidone is an oral medication with a number of actions affecting the immune system. It has been proposed as a possible treatment for multiple sclerosis (MS). METHODS: An early-phase study of progressive forms of MS was conducted. Pirfenidone was slowly titrated to 2400 mg/day. Safety, clinical, quality-of-life, and magnetic resonance image (MRI) outcomes were measured. RESULTS: Twenty people were enrolled (13 with secondary progressive and seven with primary progressive MS). The mean age was 47.7 years; the mean Expanded Disability Status Scale (EDSS) was 5.15; 75% were female. Eighteen patients achieved the full dose, although five additional patients eventually had to decrease the dose, primarily because of nausea. The Neurologic Rating Scale showed a slight worsening, from 69.8+/-8.4 at baseline to 71.8+/-8.9 at one year (P = 0.03). Other clinical outcomes remained stable, including the EDSS, ambulation index, and nine-hole peg test. The Short-Form Health Survey (SF-36) quality-of-life measure remained unchanged. Comparisons of MRI scans at baseline and one year found that 715 plaques were unchanged, six were better, and 10 were worse. Three patients had plaques that improved and two patients had plaques that were worse. There were eight gadolinium-enhancing lesions on the baseline scans and 14 on the one-year scans. CONCLUSIONS: Pirfenidone was well tolerated in patients with MS. Patients with primary progressive or secondary progressive MS tolerated the medication and remained clinically stable during the one year of follow up. Placebo-controlled blinded studies are needed to determine clinical effectiveness.

Bowling, A. C. and T. M. Stewart (2003). "Current Complementary and Alternative Therapies for Multiple Sclerosis." Curr Treat Options Neurol 5(1): 55-68.

            The use of complementary and alternative medicine (CAM) appears to be high in the general population and in patients with multiple sclerosis (MS). There are no diets or dietary supplements that are definitely effective in altering the disease course in MS. However, diets and dietary supplements that increase the intake of polyunsaturated fatty acids may produce mildly beneficial effects. Because these approaches are not definitely effective, they may be of limited interest to physicians and other conventional health providers. In contrast, for patients with MS, these interventions may be of considerable interest, because they may be mildly effective and are inexpensive and relatively safe. Vitamin D, ginkgo biloba, cannabinoids, and Padma 28 produce immunomodulatory actions and therapeutic effects in experimental autoimmune encephalomyelitis. However, for these compounds, there are not enough clinical trial data or safety information to support their use as disease-modifying therapies. The role of antioxidant compounds in MS is unclear. There is no evidence that vitamin B(12) supplementation or gluten-free diets are effective MS therapies. Conventional health providers can play an important role in the care of MS patients by being open to discuss CAM therapies and by providing objective MS-relevant CAM information.

Boyd, J. G., V. Skihar, et al. (2003). "Olfactory ensheathing cells: Historical perspective and therapeutic potential." Anat Rec 271B(1): 49-60.

            Olfactory ensheathing cells (OECs) are the glial cells that ensheath the axons of the first cranial nerve. They are attracting increasing attention from neuroscientists as potential therapeutic agents for use in the repair of spinal cord injury and as a source of myelinating glia for use in remyelinating axons in demyelinating diseases such as multiple sclerosis. This review mainly addresses the cell biological aspects of OECs pertinent to addressing two questions. Namely, where do OECs fit into the groupings of central nervous system (CNS)/peripheral nervous system (PNS) glial cells and should OECs be viewed as a clinically relevant alternative to Schwann cells in the treatment of spinal cord injury? The evidence indicates that OECs are indeed a clinically relevant alternative to Schwann cells. However, much more work needs to be done before we can even come close to answering the first question as to the lineage and functional relationship of OECs to the other types of CNS and PNS glial cells. Anat Rec (Part B: New Anat) 271B:49-60, 2003. Copyright 2003 Wiley-Liss, Inc.

Bozzao, A., R. Floris, et al. (2003). "Cerebrospinal fluid changes after intravenous injection of gadolinium chelate: assessment by FLAIR MR imaging." Eur Radiol 13(3): 592-7.

            Fluid-attenuated inversion recovery (FLAIR) sequence is currently used in clinical practice. Some reports emphasize the possibility that, in pathologic conditions, intravenous injection of gadolinium chelates may lead to an increased signal inside the cerebrospinal fluid (CSF). The aim of this study was to evaluate the presence of CSF signal changes in pathologic conditions causing blood-brain barrier disruption or neovascularization when imaging is performed after intravenous injection of gadolinium. We obtained FLAIR sequences after gadolinium injection from 33 patients affected by different intracranial pathologies and 10 control subjects. Patients were affected by ischemic stroke in the subacute phase, from 2 to 7 days from onset of symptoms (12 patients), meningiomas (8 patients), high-grade gliomas (5 patients), previous surgical procedures for intra-axial neoplasms (5 patients), and multiple sclerosis with active plaques (3 patients). Magnetic resonance imaging was performed in patients and controls using a 1.5-T magnet, using T2- and T1-weighted FLAIR sequences. The FLAIR sequence was acquired before and 1-3 h after injection of a standard dose of gadolinium. In those patients affected by ischemic lesions, FLAIR sequences were repeated the next days and 3-4 days later. The CSF signal was visually evaluated by two readers and scored from 0 to 3 depending by the degree of enhancement. The location of CSF signal changes (close to the lesion, hemispheric, or diffuse) was also considered. The CSF signal was markedly increased after 3 h from intravenous injection of gadolinium in all the patients with stroke, in those with previous surgery, and in those with high-grade gliomas whose neoplasm's surface was in contact with the subarachnoid spaces (SAS) or ventricles; a strong enhancement was also evident inside the necrotic component of the tumor. The CSF changes were more evident close to the pathology and/or in the hemisphere involved by the pathology. Moderate CSF enhancement was observed in the SAS close to meningiomas. No signal changes were evident in all the others. In those patients with stroke imaged in the following days, CSF signal showed to be diffuse to both hemispheres the next day and returned to normal values within 2 days. In patients affected by pathologies with blood-brain barrier breakdown or neovascularization close the SAS or the ventricles, CSF changes, related to gadolinium leakage, are likely when FLAIR sequences are acquired 2-24 h after i.v. injection of the contrast. This pattern should be known in order to differentiate it from that of subarachnoid hemorrhage.

Bradbury, J. (2003). "Wrong cytokine backed in multiple-sclerosis model." Lancet Neurol 2(4): 203.

Breij, E. C., W. L. van der Pol, et al. (2003). "No association of FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb polymorphisms with MS." J Neuroimmunol 140(1-2): 210-5.

            Anti-myelin IgGs occur in the cerebrospinal fluid (CSF) and serum of multiple sclerosis (MS) patients, and can induce inflammatory effector functions in leukocytes by crosslinking IgG receptors (FcgammaR). The efficiency of FcgammaR-mediated inflammatory processes is affected by functional polymorphisms of three Fcgamma receptors (FcgammaRIIa, FcgammaRIIIa, FcgammaRIIIb).The relevance of FcgammaR polymorphisms in MS was evaluated by studying the distribution of FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb genotypes in 432 MS patients and 515 healthy controls. No significant differences were found between MS patients and controls, or between subgroups of patients. We conclude that Fcgamma receptor polymorphisms influence neither susceptibility nor clinical disease course of MS.

Breithaupt, C., A. Schubart, et al. (2003). "Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein." Proc Natl Acad Sci U S A.

            Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis of demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the surface of CNS myelin. Here we present the crystal structures of the extracellular domain of MOG (MOG(Igd)) at 1.45-A resolution and the complex of MOG(Igd) with the antigen-binding fragment (Fab) of the MOG-specific demyelinating monoclonal antibody 8-18C5 at 3.0-A resolution. MOG(Igd) adopts an IgV like fold with the A'GFCC'C" sheet harboring a cavity similar to the one used by the costimulatory molecule B7-2 to bind its ligand CTLA4. The antibody 8-18C5 binds to three loops located at the membrane-distal side of MOG with a surprisingly dominant contribution made by MOG residues 101-108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R(101)DHSYQEE(108) is unique for MOG, whereas large parts of the remaining sequence are conserved in potentially tolerogenic MOG homologues expressed outside the immuno-privileged environment of the CNS. Strikingly, the only sequence identical to DHSYQEE was found in a Chlamydia trachomatis protein of unknown function, raising the possibility that Chlamydia infections may play a role in the MOG-specific autoimmune response in man. Our data provide the structural basis for the development of diagnostic and therapeutic strategies targeting the pathogenic autoantibody response to MOG.

Brooke, H. (2003). "How I coped with....nursing and MS. Interview by David Crouch." Nurs Times 99(17): 38-9.

Brostrom, S., J. L. Frederiksen, et al. (2003). "Motor evoked potentials from the pelvic floor in patients with multiple sclerosis." J Neurol Neurosurg Psychiatry 74(4): 498-500.

            The use of motor evoked potentials (MEPs) to study the integrity of pelvic floor motor innervation is poorly described in the literature. This study evaluated the clinical use of pelvic floor MEPs in 16 women with multiple sclerosis. Lower urinary tract dysfunction was assessed with urodynamic investigations. Transcutaneous magnetic stimulation was applied over the motor cortex and spinal roots, and MEPs were recorded from the puborectalis, the external urethral sphincter, and the abductor hallucis muscles. In many patients, responses from the pelvic floor muscles could not be evoked, and central motor conduction times for the puborectalis motor pathways could only be calculated in 56%. There was a poor correlation of abnormal conduction to lower urinary tract dysfunction. It is concluded, that unevokable responses from pelvic floor muscles in a patient with multiple sclerosis should be interpreted with care, and that pelvic floor MEPs have a limited clinical value in the investigation of suspected demyelinating disease.

Brown, J. S. (2003). "Correlation of mollicutes and their viruses with multiple sclerosis and other demyelinating diseases." Med Hypotheses 60(2): 298-303.

            To identify infectious diseases likely involved in MS, the author previously correlated the geographical distribution of MS with the global distribution of tick-borne diseases. Tick-borne infectious agents include mollicutes or mycoplasmas. The current paper reviews evidence that mollicutes, especially spiroplasmas, or their viruses could be the initial exposure that causes MS. Mollicute infections, including the effects of their toxins, can be treated or prevented with gold salts or tetracyclines. If further research recommended by this review finds a role of mycoplasmas in MS, treatment of MS with gold with tetracycline should be evaluated.

Bruck, W., T. Kuhlmann, et al. (2003). "Remyelination in multiple sclerosis." J Neurol Sci 206(2): 181-5.

            Remyelination in multiple sclerosis (MS) lesions has been described in several studies. It depends on the presence of myelinating oligodendrocytes and a functional interaction between these myelinating cells and axons. The imaging signal of remyelination in magnetic resonance imaging or spectroscopy is not yet defined. The present review will focus on the morphological appearance of remyelinating MS lesions, their correlation with oligodendrocyte pathology, and possible markers for remyelination in imaging.

Buchanan, R. J., S. Wang, et al. (2003). "Gender analyses of nursing home residents with multiple sclerosis." J Gend Specif Med 6(2): 35-46.

            OBJECTIVE: To present gender comparisons of residents with multiple sclerosis (MS) at admission to nursing facilities, including demographic characteristics, health measures, and treatments. METHODS: We analyzed 13,998 admission assessments in the Minimum Data Set for residents with MS recorded between June 23, 1998 and December 31, 2000. RESULTS: Although both male and female residents with MS tended to have severe disability, there were significant gender differences in measures of activities of daily living (ADL) dependency and disability, with males slightly more likely to exhibit total ADL dependence and greater loss of voluntary movement. Females with MS tended to have significantly better cognitive performance and better communication abilities than males with MS. There were significant gender differences in pain symptoms among residents, with one-third of females and one-fifth of males experiencing daily pain. Depression was the most common comorbidity among residents with MS, with females significantly more likely to have this diagnosis. Although females with MS were slightly more likely to have depression or anxiety disorder, males with MS were slightly more likely to receive mental health services. CONCLUSIONS: These analyses demonstrate that many nursing facilities need to improve pain management and mental health care provided to residents with MS, especially to females.

Buchanan, R. J., S. Wang, et al. (2003). "Analyses of nursing home residents with multiple sclerosis and depression using the Minimum Data Set." Mult Scler 9(2): 171-88.

            Depression is the most common psychiatric condition among people with multiple sclerosis (MS). A total of 14009 people with MS at admission to a nursing facility were analyzed using the Minimum Data Set and 36% also had depression. This study developed profiles of nursing home residents with MS who also had depression and compared them with other residents with MS. MS residents with depression were significantly more likely to be female and younger than other MS residents, with significant racial differences as well. MS residents with depression were significantly more likely than other MS residents to have a history of mental health conditions, exhibit mood indicators, and have unsettled relationships. Both groups of MS residents had high levels of physical disability, although MS residents with depression tended to be slightly less disabled. MS residents with depression were more likely than other MS residents to experience daily pain and more likely to have the diseases common to all residents with MS. This research found that most MS residents with depression did not receive mental health services, demonstrating that nursing facilities must improve the mental healthcare provided to residents with MS with depression.

Bunin, A. and A. A. Iakovlev (2003). "[Pathology of the lateral geniculate body and visual function]." Vestn Oftalmol 119(1): 46-9.

Burt, R. K., B. A. Cohen, et al. (2003). "Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of intense immune suppression to prevent disease progression in patients with high disability scores." Blood.

            Twenty-one patients with rapidly progressive multiple sclerosis (MS) were treated on a phase I/II study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no one year mortality. Following transplant, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pre transplant EDSS </= 6.0. In 8 of 12 patients with high pre transplant disability scores (EDSS > 6.0), progressive neurologic disability as defined by at least a 1 point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. Two patients with a pre-transplant EDSS of 7.0 and 8.0 died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression and hematopoietic stem cell transplantation (HSCT) is not effective for patients with progressive disease and high pre-transplant disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. In specific, more patients and longer follow-up would be required in patients with an EDSS </= 6.0 before drawing conclusions on this subgroup.

Burton, C. and R. Kaczmarski (2003). "Oxidative haemolysis secondary to high-dose vitamins in a woman with glucose-6-phosphate dehydrogenase deficiency." Br J Haematol 121(2): 201.

Busche, K. D., J. D. Fisk, et al. (2003). "Short term predictors of unemployment in multiple sclerosis patients." Can J Neurol Sci 30(2): 137-42.

            BACKGROUND: Unemployment is common in people with multiple sclerosis (MS) and is associated with loss of income and impaired health related quality of life. This study determined variables associated with unemployment and risk factors for the development of unemployment in people with MS. METHODS: Ninety-six patients who were under age 65 and participated in two previous studies to measure economic costs and health related quality of life in MS were included. The baseline employment rate and variables associated with unemployment at baseline were determined. The ability of these variables to predict unemployment over the next two and a half years was then evaluated. RESULTS: At baseline 50.1% (50/96) of participants were employed. Two and a half years later only 40.6% (39/96) remained employed. This represents loss of employment for 22.0% (11/50) of those originally employed. Factors associated with unemployment at baseline included greater disability, progressive disease course, longer disease duration, and older age. Risk factors for loss of employment over the next 2.5 years included greater disability and older age. CONCLUSIONS: This study confirms the low employment rate among people with MS and confirms the association of several previously-reported factors with greater risk of unemployment. It is also the first study to confirm that some of these factors also increase the risk of future unemployment. People with MS who are over age 39 or have moderate disability and are still employed can now be identified as at risk for becoming unemployed over the next 2.5 years. They should be considered for interventions to maintain employment or to lessen the impact of unemployment.

Butterfield, R. J., R. J. Roper, et al. (2003). "Sex-Specific Quantitative Trait Loci Govern Susceptibility to Theiler's Murine Encephalomyelitis Virus-Induced Demyelination." Genetics 163(3): 1041-6.

            Susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination (TMEVD), a mouse model for multiple sclerosis (MS), is genetically controlled. Through a mouse-human comparative mapping approach, identification of candidate susceptibility loci for MS based on the location of TMEVD susceptibility loci may be possible. Composite interval mapping (CIM) identified quantitative trait loci (QTL) controlling TMEVD severity in male and female backcross populations derived from susceptible DBA/2J and resistant BALBc/ByJ mice. We report QTL on chromosomes 1, 5, 15, and 16 affecting male mice. In addition, we identified two QTL in female mice located on chromosome 1. Our results support the existence of three linked sex-specific QTL on chromosome 1 with opposing effects on the severity of the clinical signs of TMEV-induced disease in male and female mice.

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