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Multiple Sclerosis References: 2003

(826 References)

Aarli, J. A. (2003). "Role of cytokines in neurological disorders." Curr Med Chem 10(19): 1931-7.

            The balance between cytokines with pro- and anti-inflammatory effects contributes to the course of the Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. TNFalpha seems to be an important factor in the cascade of events leading to demyelination and even axonal damage. During the acute phase, the serum concentrations of TNFalpha and IL-6 are elevated while anti-inflammatory cytokines are up-regulated in the recovery phase. Cytokines also have a key role in the pathogenesis of multiple sclerosis and most data suggest that this effect is mediated by myelin-specific CD4 T lymphocytes secreting Th type 1 cytokines. However, several different immune cells including B lymphocytes, CD8 T lymphocytes and NK T lymphocytes are also involved in the pathogenesis. Both Th1 and Th2 lymphocytes and cytokines probably participate in the development of myasthenia gravis (MG). The IFNalpha production is probably related to the severity of the disease, with clinical improvement associated with decreased production. The serum levels of IL-18 are significantly elevated in MG, with highest concentrations in patients with generalized disease. The immune system may be involved in the pathogenesis of AD by the effect of microglia, which can induce microglial activation with subsequent release of pro-inflammatory cytokines. In parkinsonism, there is evidence of chronic inflammation in the substantia nigra and striatum. Activated microglia, producing proinflammatory cytokines, surround the degenerating dopaminergic neurons and may contribute to the dopaminergic neuron loss. Studies of patients with epilepsy and animals with experimentally induced seizures indicate that cytokines may also influence the electrophysiological properties of neurons.

Aboul-Enein, F., H. Rauschka, et al. (2003). "Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases." J Neuropathol Exp Neurol 62(1): 25-33.

            Destruction of myelin and oligodendrocytes leading to the formation of large demyelinated plaques is the hallmark of multiple sclerosis (MS) pathology. In a subset of MS patients termed pattern III, actively demyelinating lesions show preferential loss of myelin-associated glycoprotein (MAG) and apoptotic-like oligodendrocyte destruction, whereas other myelin proteins remain well preserved. MAG is located in the most distal periaxonal oligodendrocyte processes and primary "dying back" oligodendrogliopathy may be the initial step of myelin degeneration in pattern III lesions. In the present study, various human white matter pathologies, including acute and chronic white matter stroke, virus encephalitis, metabolic encephalopathy, and MS were studied. In addition to a subset of MS cases, a similar pattern of demyelination was found in some cases of virus encephalitis as well as in all lesions of acute white matter stroke. Brain white matter lesions presenting with MAG loss and apoptotic-like oligodendrocyte destruction, irrespective of their primary disease cause, revealed a prominent nuclear expression of hypoxia inducible factor-1alpha in various cell types, including oligodendrocytes. Our data suggest that a hypoxia-like tissue injury may play a pathogenetic role in a subset of inflammatory demyelinating brain lesions.

Acar, G., F. Idiman, et al. (2003). "Nitric oxide as an activity marker in multiple sclerosis." J Neurol 250(5): 588-92.

            Nitric oxide (NO) molecules have one of the most important roles in the pathogenesis of multiple sclerosis (MS). It has been stated that a continuous and high concentration of NO metabolites in CSF and in the serum of MS patients in relapse may cause toxic damage to myelin and oligodendroglia. The aim of this study was to investigate whether NO is a marker of disease activity and is correlated with other disease activity markers such as active lesions on brain magnetic resonance imaging (MRI) and increased immunoglobulin G (IgG) index.Cerebrospinal fluid (CSF) and peripheral serum (PS) samples were taken from patients with definite MS (n = 24) during relapse and remission and from control subjects (n = 18). The Griess reaction was used to measure the NO metabolites, nitrite and nitrate in CSF and PS. Cranial MRI was carried out with triple dose (0,3 mmol/kg) gadolinium and the IgG index was determined.Nitrite and nitrate concentrations (NNCs) of CSF were 11.16 +/- 8.60 micromol/ml in relapse and 6.72 +/- 3.50 micromol/ml in remission, whereas in PS they were 12.89 +/- 7.62 micromol/ml during relapse and 12.35 +/- 6.62 micromol/ml during remission. In control subjects NNCs in CSF and PS were 7.42 +/- 2.81 micromol/ml and 4.37 +/- 1.63 micromol/ml respectively. NNCs in CSF during relapse period were significantly higher than those of both remission phase and control subjects (p = 0.000). Although serum NNCs did not differ in relapse and remission, they were still higher than normal controls. Validity analysis revealed that NNC measurement in CSF was 71 % specific and 66 % sensitive to disease activity. The most important result was the significant correlation of increased NNCs with the existence of active lesion in cranial MRI and an increase in IgG index (p < 0.05).In conclusion, these results add background data to assist in further outlining the possible role of NO in the pathogenesis of MS. Together with the other markers it may be used as an activity marker in relapses of MS.

Achiron, A., Y. Barak, et al. (2003). "Alfacalcidol treatment in multiple sclerosis." Clin Neuropharmacol 26(2): 53.

Achiron, A. and Y. Barak (2003). "Cognitive impairment in probable multiple sclerosis." J Neurol Neurosurg Psychiatry 74(4): 443-6.

            OBJECTIVES: To evaluate and characterise cognitive impairment in the very early stage of multiple sclerosis (MS), in which patients are still diagnosed as suffering from probable MS. METHODS: The Brief Repeatable Battery-Neuropsychological (BRB-N) that has been validated for MS patients was used. Abnormal performance was defined as one standard deviation below the mean reported for healthy age matched subjects. Neurological disability and brain magnetic resonance imaging (MRI) were performed for all patients. Correlation coefficients were calculated between disease burden variables and performance on the BRB-N. RESULTS: Sixty seven patients with probable MS were evaluated within a mean of one month of the onset of new neurological symptoms. Evidence for the presence of cognitive impairment was shown in 53.7% of patients. Verbal abilities and attention span were most frequently affected. Impairment was not correlated with neurological disability or MRI disease burden. CONCLUSION: Prevalent cognitive impairment already exists at onset of MS.

Ackerman, K. D., A. Stover, et al. (2003). "Relationship of cardiovascular reactivity, stressful life events, and multiple sclerosis disease activity." Brain Behav Immun 17(3): 141-51.

            Previous studies of stress in multiple sclerosis patients have suggested that life events may alter the onset and development of MS. However, results have been inconsistent because of infrequent monitoring and reporting bias. We followed fifty female MS patients for 1 year to determine characteristics of life events associated with MS exacerbations, and examine the influence of cardiovascular activity. Subjects completed weekly life-event checklists. The short- and long-term threat of each event was determined using the Life Events and Difficulties Schedule. Neurologic symptoms were also monitored weekly. MS exacerbations were confirmed by a neurologist blinded to psychosocial events. Cardiovascular reactivity to an acute psychological stressor was determined at study onset, and resting heart rate and blood pressure were monitored monthly. Forty-two percent of life events were associated with exacerbations in the subsequent 6 weeks. Logistic regression confirmed that exacerbations were more likely during at-risk periods following life events and were relatively independent of the threat level and type of stressor. Participants with higher cardiovascular reactivity to acute stress and higher baseline heart rate demonstrated a greater number of exacerbations and proportion of weeks ill. Using multiple regression, we found that disability level, medication usage, cardiovascular reactivity, baseline heart rate, and life event density explained approximately 30% of the variance in the proportion of weeks ill. These results are consistent with the hypothesis that stress is a potential trigger of MS disease activity and suggest that autonomic tone and stress reactivity may play a role in the development of stress-related exacerbations.

Adam, P., O. Sobek, et al. (2003). "CSF and serum orosomucoid (alpha-1-acid glycoprotein) in patients with multiple sclerosis: a comparison among particular subgroups of MS patients." Clin Chim Acta 334(1-2): 107-10.

            INTRODUCTION: To compare cerebrospinal fluid (CSF) and serum orosomucoid (alpha-1-acid glycoprotein-AAG) concentrations in various subgroups of patients with multiple sclerosis (MS). MATERIALS AND METHODS: CSF and serum AAG concentrations, AAG quotient (i.e., CSF AAG/serum AAGx10(3)) and index were determined in a group of 59 patients with clinically definite or probable MS. Patients were subdivided according to the disease form, disease severity according to an expanded disability status scale (EDSS), its treatment, disease duration and sex. RESULTS: CSF AAG was increased in 52.5% of the patients and AAG quotient even in 64.4%. An increase in the CSF AAG concentration, as well as in AAG quotient and index, appear only after several years of disease duration, while no significant correlation with age has been found. This suggests that CSF AAG changes in MS represent a secondary, unspecific phenomenon and that this protein is not relevant for the aethiopathogenesis of the disease. Nevertheless, the finding of subnormal CSF AAG levels in some MS patients in remission (never observed in those in the attack) implies the possibility that CSF AAG may be used as a "state marker" in MS. Serum AAG levels were significantly lower in secondary progressive form and in severely disabled patients. This observation suggest that serum AAG values determination might have some prognostic significance. Further studies are, however, needed. Serum AAG should be investigated in parallel with other CSF and serum protein fractions in order to establish a pannel of examinations enabling multiple statistical analyses. This approach may lead to the finding of a "complex state marker" enabling thus to evaluate more precisely disease course in individual patients and to accept appropriate therapeutic measures.

Adiga, G. U., L. Abebe, et al. (2003). "Partially successful treatment of a patient with chronic lymphocytic leukemia and Hodgkin's disease: case report and literature review." Am J Hematol 72(4): 267-73.

            Chronic lymphocytic leukemia (CLL) is rarely associated with Hodgkin's disease (HD). We report a case of nodular sclerosis HD in a patient previously diagnosed with CLL. Reed-Sternberg cells were CD15(+) and CD30(+). He was treated with dose-escalated CHOP and at relapse, mitoxantrone, vinblastine, and CCNU (MVC) with partial response to the former and complete response to the latter, although the patient died 15 months later. Data from 88 other similar cases published in the English language were analyzed. Based on the histological and clinical features at the time of transformation, these patients were divided into distinct categories for analysis. Prognosis was found to be poorer in patients with continued active CLL when compared with those with CLL in remission at the time of transformation to HD. It is suggested that these two presentations may derive from different pathogenic mechanisms.

Aggarwal, S., N. Ghilardi, et al. (2003). "Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17." J Biol Chem 278(3): 1910-4.

            Interleukin (IL)-17 is a pro-inflammatory cytokine that is produced by activated T cells. Despite increasing evidence that high levels of IL-17 are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis, and multiple sclerosis, the regulation of its expression is not well characterized. We observe that IL-17 production is increased in response to the recently described cytokine IL-23. We present evidence that murine IL-23, which is produced by activated dendritic cells, acts on memory T cells, resulting in elevated IL-17 secretion. IL-23 also induced expression of the related cytokine IL-17F. IL-23 is a heterodimeric cytokine and shares a subunit, p40, with IL-12. In contrast to IL-23, IL-12 had only marginal effects on IL-17 production. These data suggest that during a secondary immune response, IL-23 can promote an activation state with features distinct from the well characterized Th1 and Th2 profiles.

Akassoglou, K., E. Douni, et al. (2003). "Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice." Proc Natl Acad Sci U S A 100(2): 709-14.

            Tumor necrosis factor (TNF) is up-regulated in a variety of central nervous system (CNS) diseases with diverse etiology and pathologic manifestation. TNF mediates multiple biological activities through two membrane receptors, the p55 and p75 TNF receptors (TNFRs). We have shown previously that human transmembrane TNF (tmTNF)p55TNFR signaling in transgenic mice triggers oligodendrocyte apoptosis, endothelial cell activation, parenchymal inflammation, and primary demyelinating lesions similar to those of acute multiple sclerosis. To address the role of the p75TNFR in the CNS, we have generated "humanized" mice that express human tmTNF in astrocytes and a physiologically regulated human p75TNFR transgene, in the absence of the endogenous (murine) p55TNFR. Human tmTNFp75TNFR transgenic mice develop CNS vascular pathology, characterized by endothelial cell activation, meningeal inflammation, and vessel fibrosis. There is no evidence of oligodendrocyte apoptosis or primary demyelination in these mice. Late in disease, vasculitis can result in vessel occlusion and secondary, multifocal CNS ischemic injury. These results identify a proinflammatory role for the p75TNFR at the level of the CNS vascular endothelium, which correlates with the expression pattern of this receptor in the CNS, and indicate that the differential expression patterns of the two TNFRs within the CNS play a significant role in shaping the outcome of TNF signaling during neuroimmune interactions.

Aktas, O. and F. Zipp (2003). "Regulation of self-reactive T cells by human immunoglobulins--implications for multiple sclerosis therapy." Curr Pharm Des 9(3): 245-56.

            The intravenous administration of high doses of immunoglobulins pooled from the plasma of healthy donors (IVIg therapy) has beneficial effects in patients with a variety of autoimmune disorders. These clinical observations indicate that IVIg have potent antiinflammatory characteristics, and identification of the precise mode of action may open up perspectives for future therapeutic strategies. In certain tissue-specific autoimmune disorders like multiple sclerosis (MS), self-reactive T cells recognizing autoantigens play a significant role for disease pathogenesis, as these cells are able to initiate, maintain, and propagate the harmful immune attack in experimental animal models of disease. These findings render self-reactive T cells an important therapeutic target for autoimmune diseases. Here, we review the effects of IVIg on the homeostasis of T cells and discuss the possible therapeutic implications for multiple sclerosis. As supported by several experimental studies, IVIg regulate crucial steps of T cell-mediated immune responses. These effects involve the modulation of activation, proliferation, differentiation, apoptosis, and effector mechanisms of T cells. The pattern of IVIg-T cell interactions is complex, as IVIg may directly bind to regulatory structures on T cells, or modulate T cell functions indirectly via soluble or cellular components of the immune system.

Al-Shammari, S., R. F. Nelson, et al. (2003). "HHV-6 DNAaemia in patients with multiple sclerosis in Kuwait." Acta Neurol Scand 107(2): 122-4.

            OBJECTIVE: To study the presence of active human herpesvirus type-6 (HHV-6) infection indicated by the presence of HHV-6 DNA in serum (DNAaemia) in patients suffering from multiple sclerosis (MS) in Kuwait. MATERIAL AND METHODS: Sera from 24 patients with MS (18 relapsing-remitting, six secondary progressive disease), control sera from 13 patients suffering from other neurological diseases and sera from 20 healthy volunteers were examined for the presence of HHV-6 DNA by nested polymerase chain reaction (PCR) test. RESULTS: None of the MS patients, nor patient controls were positive for HHV-6 DNAaemia while, one of the normal healthy controls was positive for HHV-6 DNAaemia. CONCLUSION: HHV-6 DNAaemia, indicating active HHV-6 infection could not be demonstrated in a sample of Kuwaiti patients suffering from active clinically definite MS. There is no evidence to incriminate this virus in the pathogenesis of MS in Kuwait.

Albrecht, P. J., J. C. Murtie, et al. (2003). "Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production." Neurobiol Dis 13(2): 89-101.

            Multiple sclerosis is characterized by multiple lesions with selective loss of myelin and oligodendrocytes, leading to deficits of sensation and movement, as well as cognitive disabilities. Consequently, a major research endeavor is to identify strategies to enhance oligodendrocyte regeneration and remyelination. FGF-2 is a potent mitogen for OPCs, and it is induced in astrocytes in animal models of demyelinating diseases in conjunction with successful remyelination. However, the factors responsible for inducing FGF-2 after demyelination in astrocytes are unknown. Here we show that CNTF mRNA and protein increase coincident with spinal cord remyelination in mice recovering from MHV-induced demyelination. We identify CNTF within astrocytes surrounding and within remyelinating lesions, and show that CNTF increases FGF-2 ligand and receptor mRNAs in spinal cord after direct application. Furthermore, we show that CNTF increases FGF-2 mRNA approximately 2.5-fold in cultured mouse spinal cord astrocytes. Altogether, these results strongly implicate CNTF as an important cytokine in demyelinating disease and as an upstream regulator of FGF-2 production in astrocytes during early remyelination.

Alizadeh, M., M. C. Babron, et al. (2003). "Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients." Ann Neurol 54(1): 119-22.

            Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122

Alley, J., S. Khasabov, et al. (2003). "More severe neurologic deficits in SJL/J male than female mice following Theiler's virus-induced CNS demyelination." Exp Neurol 180(1): 14-24.

            Although multiple sclerosis (MS) is more prevalent in women than men, male MS patients develop more severe clinical symptoms and deteriorate faster than female patients. We investigated the differences in CNS demyelinating disease between SJL/J male and female mice following Theiler's murine encephalomyelitis virus (TMEV) infection. Infected female mice had consistently higher serum levels of virus-specific IgG at 14 and 21 days and and 7 months postinfection, which resulted in less infectious virus in CNS. All male mice infected for 6 to 7 months developed paralysis, with 50% displaying bilateral posterior limb paralysis, whereas 77% of age-matched female mice were paralyzed, all displaying unilateral posterior limb paralysis. Male mice infected for 6 to 7 months performed up to threefold fewer spontaneous horizontal and vertical movements (activity box test) compared to infected age-matched females. In addition, infected male mice performed the coordination and balance (Rotarod) test at 27 +/- 4% of the expected level (expressed as a percentage of that of uninfected age-matched mice), whereas infected female mice performed at 41 +/- 5% of the expected level. Male mice had a small increase in the extent of spinal cord white matter demyelination analyzed at both 45 days and between 6 and 7 months postinfection. For individual male and female mice, the extent of demyelination had a negative linear relationship with the neurologic performances. The emergence of a disease paradigm similar to MS supports using the TMEV model to investigate molecular and genetic factors responsible for the gender dimorphism in MS and other autoimmune diseases.

Alter, A., M. Duddy, et al. (2003). "Determinants of human B cell migration across brain endothelial cells." J Immunol 170(9): 4497-505.

            Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.

Alusi, S. H., S. Glickman, et al. (2003). "Target board test for the quantification of ataxia in tremulous patients." Clin Rehabil 17(2): 140-9.

            OBJECTIVE: The objective was to develop and assess the validity and reliability of a target board test (TBT) for quantifying ataxia and measuring dysmetria in the presence of tremor. DESIGN: Each subject was instructed to reach out and mark a target placed at arm's length with a pen (10 times with each hand). Ten patients performed the test twice. SETTING: A hospital-based multiple sclerosis (MS) unit. SUBJECTS: Fifty-three patients with MS and upper limb tremor/ataxia and 20 healthy control subjects. The MS patients were classified into four subgroups: MS control group (n = 13), MS tremor group (n = 9), MS dysmetria group (n = 6), MS mixed (tremor and dysmetria) group (n = 25). MAIN OUTCOME MEASURES: The main outcome measures were the average radial distance away from the target (mean R) and the mean directional error (mean V) of the 10 contact points from the target. From these a dysmetria tremor index (DTI) was calculated by dividing mean V by mean R. Also used were a dysmetria scale, a dysdiadochokinesia scale and a finger-tapping test. RESULTS: Mean R correlated significantly with dysmetria, dysdiadochokinesia, kinetic tremor and (inversely) with the finger-tapping test (all p < 0.005). The median difference between two measurements of mean R for all 10 contact points was 11.3% and 19.0% and for mean V48.3% and 63.4% and DTI 57.2% and 50.5% for the right- and left-hand sides respectively, indicating the considerable directional variability within ataxia. CONCLUSION: The TBT provides simple quantitative objective measurements of upper limb ataxia.

Alvarez-Linera, J., J. Escribano, et al. (2003). "[Hydrogen spectroscopy in neurology]." Neurologia 18(6): 324-40.

            for a long time to the research field despite its unquestionable diagnostic value. The availavility of programs able to automatically obtain a spectrum, and the current possibility of estimating easily the relationship among its different peaks, have approached this diagnostic technology to the current clinical situation. With hydrogen MRI spectroscopy (MRS) it is possible to obtain additional information which make it possible to distinguish among different neurological alterations with similar morphological appearance, such as cerebral tumors and pseudotumoral types of inflammatory processes, or tumor recurrence and radionecrosis. On other occasions, it makes it possible to detect alterations which are invisible by imaging study, such as medial temporal sclerosis, or multiple sclerosis. It is also very useful in following-up many alterations, either in their natural history, as in Alzheimers disease, or in order to monitor treatments on cerebral tumors or infectious processes. However, MRS does not often show pathognomonic patterns, so it is always recommended to consider it not just in the clinical context, but as inseparable part of an MR study, either structural or functional (diffusion, perfusion), since it is this is how it provides more useful information from a clinical point of view. Neurologia 2003;18(6):324-340

Amarenco, G., S. S. Ismael, et al. (2003). "Urodynamic effect of acute transcutaneous posterior tibial nerve stimulation in overactive bladder." J Urol 169(6): 2210-5.

            PURPOSE: Of the various treatments proposed for urge incontinence, frequency and urgency electrostimulation has been widely tested. Different techniques have been used with the necessity of surgical implantation (S3 neuromodulation or sacral root stimulation) or without requiring surgery (perineal transcutaneous electrostimulation). Recently peripheral electrical stimulation of the posterior tibial nerve was proposed for irritative symptoms in first intention or for intractable incontinence. Clinical studies have demonstrated good results and urodynamic parameters were improved after chronic treatment. However, to our knowledge no data concerning acute stimulation and immediate cystometry modifications have been reported. We verified urodynamic changes during acute posterior tibial nerve stimulation. MATERIALS AND METHODS: A total of 44 consecutive patients with urge incontinence, frequency and urgency secondary to overactive bladder were studied. There were 29 women and 15 men with a mean age +/-SD of 53.3 +/- 18.2 years. Of the patients 37 had detrusor hyperreflexia due to multiple sclerosis (13), spinal cord injury (15) or Parkinson's disease (9), and 7 had idiopathic detrusor instability. Routine cystometry at 50 ml. per minute was done to select the patients with involuntary detrusor contractions appearing before 400 ml. maximum filling volume. Repeat cystometry was performed immediately after the first study during left posterior tibial nerve stimulation using a surface self-adhesive electrode on the ankle skin behind the internal malleolus with shocks in continuous mode at 10 Hz. frequency and 200 milliseconds wide. Volume comparison was done at the first involuntary detrusor contraction and at maximum cystometric capacity. The test was considered positive if volume at the first involuntary detrusor contraction and/or at maximum cystometric capacity increased 100 ml. or 50% during stimulation in compared with standard cystometry volumes. RESULTS: Mean first involuntary detrusor contraction volume on standard cystometry was 162.9 +/- 96.4 ml. and it was 232.1 +/- 115.3 ml. during posterior tibial nerve stimulation. Mean maximum cystometric capacity on standard cystometry was 221 +/- 129.5 ml. and it was 277.4 +/- 117.9 ml. during stimulation. Posterior tibial nerve stimulation was associated with significant improvement in first involuntary detrusor contraction volume (p <0.0001) and significant improvement in maximum cystometric capacity (p <0.0001). The test was considered positive in 22 of the 44 patients. CONCLUSIONS: These results suggest an objective acute effect of posterior tibial nerve stimulation on urodynamic parameters. Improved bladder overactivity is an encouraging argument to propose posterior tibial nerve stimulation as a noninvasive treatment modality in clinical practice.

Anane, R., M. Geffard, et al. (2003). "Effects of GSM-900 microwaves on the experimental allergic encephalomyelitis (EAE) rat model of multiple sclerosis." Bioelectromagnetics 24(3): 211-3.

            The effects of acute exposure to GSM-900 microwaves (900 MHz, 217 Hz pulse modulation) on the clinical parameters of the acute experimental allergic encephalomyelitis (EAE) model in rats were investigated in two independent experiments: rats were either habituated or nonhabituated to the exposure restrainers. EAE was induced with a mixture of myelin basic protein and Mycobacterium tuberculosis. Female Lewis rats were divided into cage control, sham exposed, and two groups exposed either at 1.5 or 6.0 W/kg local specific absorption rate (SAR averaged over the brain) using a loop antenna placed over their heads. There was no effect of a 21 day exposure (2 h/day) on the onset, duration, and termination of the EAE crisis.

Ando, Y., Y. Liang, et al. (2003). "Caspase-1 and -3 mRNAs are differentially upregulated in motor neurons and glial cells in mutant SOD1 transgenic mouse spinal cord: a study using laser microdissection and real-time RT-PCR." Neurochem Res 28(6): 839-46.

            Amyotrophic lateral sclerosis is characterized by selective motor neuron degeneration. An apoptotic pathway is thought to be involved. It is difficult, however, to analyze the molecular pathogenic mechanism in single motor neurons because of complexity in the neural tissue, which consists of multiple lineages of cells neighboring motor neurons. We quantified the caspase-1 and -3 mRNA in single motor neurons and neighboring glial cells isolated from the spinal ventral horn of mutant SOD1 transgenic (Tg) mice and littermates. Motor neurons and neighboring glial cells were isolated from spinal sections by laser microdissection, and the mRNAs were quantified by RT-PCR. In the Tg mice, caspase-1 mRNA was first upregulated in motor neurons and second in glial cells. The caspase-3 mRNA was increased in motor neurons following the caspase-1 mRNA. These results indicated that caspase-1 and -3 mRNAs are differentially upregulated in motor neurons and glial cells of the Tg mice, and that mRNAs in isolated cells can be accurately assessed using our procedures.

Angelov, D. N., S. Waibel, et al. (2003). "Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis." Proc Natl Acad Sci U S A 100(8): 4790-5.

            Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu/Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 +/- 7 days (n = 15) to 263 +/- 8 days (n = 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

Anlar, O., M. Kisli, et al. (2003). "Visual evoked potentials in multiple sclerosis before and after two years of interferon therapy." Int J Neurosci 113(4): 483-9.

            Magnetic resonance imaging (MRI) is important in the diagnosis of and follow-up for the treatment of multiple sclerosis (MS); evoked potentials may be important if MRI is normal or cannot be performed. We assessed serial visual evoked potentials (VEPs) and cranial MRI in a group of clinically relapsing-remitting multiple sclerosis (N = 15) treated with interferon beta-lb (INFB-1b) and in normal subjects (N = 15). The investigations were done 1 week before INFB-lb therapy, 1 year later (N = 15), and 2 years later (N = 10). VEPs were abnormal in most of the patients; MRIs were abnormal in all patients. We used P100 latency as an electrophysiological index for the progress of illness. There were significant differences in VEPs between the beginning and ending of the interferon treatment. We concluded that VEPs would be a reliable index for following up the progress of MS under interferon therapy.

Anlar, B. (2003). "Infection and multiple sclerosis." J Neurol Neurosurg Psychiatry 74(5): 692-3.

Antel, J. P. and A. Bar-Or (2003). "Do myelin-directed antibodies predict multiple sclerosis?" N Engl J Med 349(2): 107-9.

Antonijevic, I. A. and A. Steiger (2003). "Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis." Psychoneuroendocrinology 28(6): 780-95.

            Acute exacerbations of multiple sclerosis (MS) are commonly treated with high doses of corticosteroids that can influence sleep regulation and hypothalamo-pituitary-adrenal (HPA) activity. We examined the sleep-EEG (including conventional and spectral EEG analysis) in 9 female patients with relapsing-remitting MS (and no psychiatric disorder) just prior to and on days 2 and 10 of high dose corticosteroid treatment (500 mg/day methylprednisolone given IV for 5 days, then PO taper down) and age-matched healthy female controls.Before treatment with corticosteroids, MS patients compared to controls showed few changes of the sleep EEG, namely a significant increase in slow wave sleep (SWS) and a decrease in stage 2 sleep. In contrast, on day 10, but not day 2 of treatment, MS patients showed a number of sleep-EEG changes typically observed in patients with depression, including a reduction in REM latency, an increase in REM density, a decrease in the SWS and delta sleep ratio and a decrease in sigma EEG activity. However, no concomitant effect of treatment on mood was noted.In summary, unlike acute treatment with methylprednisolone, prolonged treatment induces several changes of the sleep-EEG in MS patients, that are also observed in patients with an acute depressive episode. Further prospective studies with longer-term follow-up are needed to examine the clinical relevance of our preliminary data.

Arai, T., K. Nakahara, et al. (2003). "Age-related mitochondrial DNA deletion in human heart: its relationship with cardiovascular diseases." Aging Clin Exp Res 15(1): 1-5.

            BACKGROUND AND AIMS: Accumulation of damage to mitochondrial DNA (mtDNA) occurs in myocardial tissue with advancing age. However, despite higher incidence of cardiac diseases in the elderly, little attempt has been made to detect deletions of mtDNA in the myocardial tissue of aged individuals. The aim of the present study was to clarify the relationship between aging, mtDNA deletion and cardiovascular (CV) diseases. METHODS: We examined 163 autopsy cases, aged 60 years or older, using two different kinds of polymerase chain reaction (PCR): highly sensitive PCR to detect a common 4977-bp deletion and long-PCR for multiple deletions, which could be detected in case that deleted mtDNA accounted for more than several percents in total mtDNA. RESULTS: The common 4977-bp deletion was detected in 156 cases (95.7%), showing no significant difference among these age groups and no relation to CV diseases. By long-PCR, multiple deletions in cardiac mtDNA were found in 33 (20.2%) of 163 cases. The proportion of the mtDNA deletion in the nineties (46.2%) was significantly higher than those in the younger (15.3%, p < 0.05). Female predominance was significantly found in the group with the mtDNA deletion (p < 0.05). Multiple deletions of mtDNA were not significantly related to ischemic change, valvular diseases, left ventricular hypertrophy, congestive heart failure, coronary sclerosis, or heart weight except for right ventricular hypertrophy. CONCLUSIONS: These findings suggest that there is a close relationship between aging and deletion of mtDNA, and that the ratio of deleted mtDNA to total mtDNA increases with advancing age. Age-related deletion of mtDNA may have little influence on CV diseases except for right ventricular hypertrophy.

Araki, I., M. Matsui, et al. (2003). "Relationship of bladder dysfunction to lesion site in multiple sclerosis." J Urol 169(4): 1384-7.

            PURPOSE: We investigated the relationship of voiding dysfunction type and the lesion site in patients with multiple sclerosis. MATERIALS AND METHODS: Voiding dysfunction was evaluated in 32 patients with multiple sclerosis using the International Prostate Symptom Score and urodynamic tests. Lesion sites were determined by combined neurological examination and magnetic resonance imaging findings. RESULTS: Compared with reports from Western countries the ratio of emptying-to-filling symptoms was high in Japan. Of urinary symptoms only filling correlated with disability status and disease duration. Urinary symptoms were not related to lesion sites. Urodynamic evaluation revealed detrusor hyperreflexia in 14 of 32 patients, hyporeflexia or areflexia in 12, detrusor hyperreflexia with impaired contractile function in 4, a low compliance bladder in 1 and normal function in 1. Of 14 patients with hyperreflexia 13 had overactive sphincter concurrently. Incompetent sphincter was identified in 2 patients who had detrusor hyperreflexia with impaired contractility and in 1 with a low compliance bladder. A significant correlation was noted for a pontine lesion and detrusor hyporeflexia, and for a cervical cord lesion and detrusor-sphincter dyssynergia. CONCLUSIONS: Detrusor hyporeflexia and detrusor-sphincter dyssynergia are indicative of a pontine and cervical spinal cord lesion, respectively. Thus, the lesion site in the central nervous system may be a major determinant of the type of bladder and urethral sphincter dysfunction. The high prevalence of emptying symptoms in Japanese patients may reflect the prevalence of detrusor hyporeflexia and detrusor-sphincter dyssynergia.

Araki, M., T. Kondo, et al. (2003). "Th2 bias of CD4+ NKT cells derived from multiple sclerosis in remission." Int Immunol 15(2): 279-88.

            Although CD1d-restricted NKT cells have been implicated as a participant in the regulatory mechanism of autoimmune diseases, it remains unclear how they would regulate human autoimmune diseases such as multiple sclerosis (MS). Furthermore, although the NKT cells comprise CD4(+) and CD4(-) populations, prior studies have often represented them as simply a CD4(-) population. Given that CD4(+) and CD4(-) NKT cells may represent functionally distinct populations, it appears crucial to examine the individual NKT subset in autoimmune diseases. Here we studied the frequency and cytokine phenotypes of the CD4(+) and CD4(-) NKT cells in fresh peripheral blood mononuclear cells, and of alpha-galactosylceramide-stimulated short-term cell lines obtained during the remission or relapse phase of MS as compared with from healthy subjects (HS). Here we report that CD4(+) NKT line cells expanded from MS in remission (MS-rem) would produce a larger amount of IL-4 than those from HS or from MS in relapse (MS-rel). They were significantly biased for T(h)2 as judged by the IL-4/IFN-gamma balance. However, there was no functional bias toward T(h)1 or T(h)2 in CD4(-) NKT line cells from MS-rem due to the defects in both IFN-gamma and IL-4 production, compared with HS. Of note, although double-negative NKT cells in the periphery were greatly reduced, the reduction of CD4(+) NKT cells was only marginal, if any, in MS-rem compared with HS. The T(h)2 bias of CD4(+) NKT line cells from MS-rem may support an immunoregulatory role for the CD4(+) NKT cells in vivo.

Aranapakam, V., G. T. Grosu, et al. (2003). "Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis." J Med Chem 46(12): 2361-75.

            The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.

Arbour, N., A. Holz, et al. (2003). "A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis." J Neuroimmunol 137(1-2): 197-209.

            We used a flow cytometry assay to measure proliferation and cytokine production of self-antigen-specific T cells in individual patients during the clinical course of multiple sclerosis (MS). Myelin-associated oligodendrocytic basic protein (MOBP) was selected for proof of principles in the assay, along with myelin basic protein (MBP) to assess specific activated T cells in 10 MS patients over an 18-month period, in parallel with brain magnetic resonance imaging (MRI) scans and clinical rating scale. A positive correlation occurred between antigen-specific T cell proliferation and interferon-gamma production with clinical relapses and MRI lesion activity that was absent when the same patients were in remission.

Arevalo-Martin, A., J. M. Vela, et al. (2003). "Therapeutic action of cannabinoids in a murine model of multiple sclerosis." J Neurosci 23(7): 2511-6.

            Theiler's virus infection of the CNS induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids may act as immunosuppressive compounds that have shown therapeutic potential in chronic inflammatory disorders. Using the Theiler's murine encephalomyelitis virus model, we report here that treatment with the synthetic cannabinoids WIN 55,212-2, ACEA, and JWH-015 during established disease significantly improved the neurological deficits in a long-lasting way. At a histological level, cannabinoids reduced microglial activation, abrogated major histocompatibility complex class II antigen expression, and decreased the number of CD4+ infiltrating T cells in the spinal cord. Both recovery of motor function and diminution of inflammation paralleled extensive remyelination. Overall, the data presented may have potential therapeutic implications in demyelinating pathologies such as MS; in particular, the possible involvement of cannabinoid receptor CB2 would enable nonpsychoactive therapy suitable for long-term use.

Armutlu, K., A. Meric, et al. (2003). "The effect of transcutaneous electrical nerve stimulation on spasticity in multiple sclerosis patients: a pilot study." Neurorehabil Neural Repair 17(2): 79-82.

            The aim of this study was to examine the effects of transcutaneous electrical nerve stimulation on spasticity in patients with multiple sclerosis. The study was carried out in the Hacettepe University School of Physical Therapy and Rehabilitation. The subjects in the study were 10 clinically definite, primary and secondary progressive type multiple sclerosis outpatients with mild to moderate spasticity in the plantar flexor muscles of the ankle. Stimuli of frequency 100 Hz and pulse width 0.3 msec were used 20 minutes per day for 4 weeks. Patients were assessed by electromyography, Modified Ashworth Scale, and Ambulation Index. Electromyography was performed before and after the daily treatment of spastic muscles with transcutaneous electrical nerve stimulation in order to assess the effect on muscle relaxation. The Modified Ashworth Scale and Ambulation Index were used before and after 4 weeks' treatment. After 4 weeks of treatment, there were statistically significant reductions in spasticity of both extremities as assessed by myoelectric activity and the Modified Ashworth Scale (P < 0.05). Ambulation Index level was not improved significantly (P > 0.05).

Aronica, E., D. Troost, et al. (2003). "Expression and regulation of voltage-gated sodium channel beta1 subunit protein in human gliosis-associated pathologies." Acta Neuropathol (Berl) 105(5): 515-23.

            Auxiliary beta1 subunits of voltage-gated sodium channels (NaChs) critically regulate channel activity and may also act as cell adhesion molecules (CAMs). In a recent study we have shown that the expression of beta1 NaCh protein is increased in reactive astrocytes in a rat epilepsy model of mesial temporal lobe epilepsy. The present study was undertaken to examine whether changes of NaCh beta1 subunit protein expression are also associated with structural changes occurring in human reactive astrocytes under different pathological conditions in vivo, as well as in response to changing environmental conditions in vitro. Strong beta1 astroglial immunoreactivity was present in human brain tissue from patients with astrogliosis. The over-expression of beta1 protein in reactive glia was observed in both epilepsy-associated brain pathologies (temporal lobe epilepsy, cortical dysplasia), as well as non-epileptic (cerebral infarction, multiple sclerosis, amyotrophic lateral sclerosis, meningo-encephalitis) disorders. The up-regulation of beta1 subunit protein in astrocytes can be reproduced in vitro. beta1 protein is highly expressed in human astrocytes cultured in the presence of trophic factors, under conditions in which they show morphology similar to the morphology of cells undergoing reactive gliosis. The growth factor-induced overexpression of beta1 protein was abrogated by PD98059, which inhibits the mitogen-activated protein kinase pathway. These findings demonstrate that the expression of NaCh beta1 subunit protein in astrocytes is plastic, and indicate a novel mechanism for modulation of glial function in gliosis-associated pathologies.

Aruoma, O. I. (2003). "Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods." Mutat Res 523-524: 9-20.

            The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Downs syndrome) and aging challenges continue to emerge from difficulties associated with methods used in evaluating antioxidant actions in vivo. Our interest presently is focused on development of neurodegeneration models based on the integrity of neuronal cells in the central nervous system and how they are protected by antioxidants when challenged by neurotoxins as well as Fenton chemistry models based on the profile of polyunsaturated fatty acids (PUFAs) for the assessment of antioxidant actions in vivo. Use continues to be made of several in vitro analytical tools to characterise the antioxidant propensity of bioactive compounds in plant foods and supplements. For example, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), total oxidant scavenging capacity (TOSC), the deoxyribose assay, assays involving oxidative DNA damage, assays involving reactive nitrogen intermediates (e.g. ONOO(-)), Trolox equivalent antioxidant capacity (TEAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. There is need to agree governance on in vitro antioxidant methods based on an understanding of the mechanisms involved. Because some of the assays are done in non-physiological pH values, it is impossible to extrapolate the results to physiological environment. The consensus of opinion is that a mix of these tools should be used in assessing the antioxidant activities in vitro. The proof of bio-efficacy must emanate from application of reliable in vivo models where markers of baseline oxidative damage are examined from the standpoint of how they are affected by changes in diet or by antioxidant supplements.

Ashjazadeh, N., A. Borhani Haghighi, et al. (2003). "Neuro-Behcet's disease: a masquerader of multiple sclerosis. A prospective study of neurologic manifestations of Behcet's disease in 96 Iranian patients." Exp Mol Pathol 74(1): 17-22.

            Behcet's disease is a multisystem vasculitis. Its neurologic complications include different syndromes. The purpose of this investigation was to study the prevalence of neurologic manifestations among patients with Behcet's disease and to determine the frequency of different symptoms, signs, and syndromes in neuro-Behcet's disease. Ninety-six consecutive patients who were referred to the Behcet's Disease Clinic in Shiraz (southern Iran) were interviewed and thoroughly examined. Psychiatric evaluation, CSF analysis, electroencephalography, electrodiagnostic studies, and neuroradiologic imaging (preferably MRI) were performed in appropriate cases. Six patients (6.3%) had definite neuro-Behcet's disease. They were 4 males and 2 females (mean age 37.5 years). In 2 patients Behcet's disease had not been diagnosed before. The most frequent symptoms of neuro-Behcet's disease were headache (83.3%), paresthesia (83.3%), unsteadiness (66.7%), diplopia (66.7%), and weakness (50%). The most frequent signs were gait abnormalities (66.7%), sensory abnormalities (66.7%), ophthalmoplegia (50%), cerebellar ataxia (50%), and hemiplegia (50%). The most common syndrome was brain-stem+ type (50%). Subacute onset and relapsing-remitting course were the most common temporal patterns. Neurological manifestation is a relatively less frequent complication of Behcet's disease but it produces severe disabilities. It must be considered in differential diagnosis of multiple sclerosis.

Ashton, E. A., C. Takahashi, et al. (2003). "Accuracy and reproducibility of manual and semiautomated quantification of MS lesions by MRI." J Magn Reson Imaging 17(3): 300-8.

            PURPOSE: To evaluate the accuracy, reproducibility, and speed of two semiautomated methods for quantifying total white matter lesion burden in multiple sclerosis (MS) patients with respect to manual tracing and to other methods presented in recent literature. MATERIALS AND METHODS: Two methods involving the use of MRI for semiautomated quantification of total lesion burden in MS patients were examined. The first method, geometrically constrained region growth (GEORG), requires user specification of lesion location. The second technique, directed multispectral segmentation (DMSS), requires only the location of a single exemplar lesion. Test data sets included both clinical MS data and MS brain phantoms. RESULTS: The mean processing times were 60 minutes for manual tracing, 10 minutes for region growth, and 3 minutes for directed segmentation. Intra- and interoperator coefficients of variation (CVs) were 5.1% and 16.5% for manual tracing, 1.4% and 2.3% for region growth, and 1.5% and 5.2% for directed segmentation. The average deviations from manual tracing were 9% for region growth and 5.7% for directed segmentation. CONCLUSION: Both semiautomated methods were shown to have a significant advantage over manual tracing in terms of speed and precision. The accuracy of both methods was acceptable, given the high variability of the manual results. J. Magn. Reson. Imaging 2003;17:300-308.

Aune, T. M., K. Maas, et al. (2003). "Gene expression profiles in human autoimmune disease." Curr Pharm Des 9(23): 1905-17.

            To acquire a functional view of human autoimmunity, we compared differences in gene expression (>4000 genes) in the peripheral blood mononuclear cells of normal individuals following immunization to those in individuals with four different autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, insulin dependent diabetes mellitus, and multiple sclerosis). Each individual from all disease groups displayed a similar pattern of gene expression that was highly distinct from the gene expression pattern of the immunized group. These findings indicate that the expression pattern accompanying autoimmunity is not simply a recapitulation of the immune response to non-self. Of note, expression levels of genes that encode key proteins in several distinct apoptosis pathways were markedly reduced in all autoimmune disease groups. Taken together, these data indicate that the pattern of gene expression describes a molecular portrait of autoimmunity that is constant among individuals with autoimmune disease but is independent of the specific autoimmune disease and the clinical parameters associated with any individual autoimmune disease.

Avasarala, J. R., A. H. Cross, et al. (2003). "Comparative assessment of Yale Single Question and Beck Depression Inventory Scale in screening for depression in multiple sclerosis." Mult Scler 9(3): 307-10.

            OBJECTIVES: To examine if depression in multiple sclerosis (MS) can be accurately recognized using the Yale Single Question (YSQ) screen as compared with the Beck Depression Inventory (BDI), a 21-item self-report rating scale for depression. In addition, we sought to assess the sensitivity, specificity the positive predictive value (PPV) and the negative predictive value (NPV) of the YSQ. BACKGROUND: Depression associated with MS is a major contributor to morbidity. Screening for depression in patients with MS currently includes the BDI, which measures characteristic attitudes and symptoms of depression. However, in a busy outpatient clinic, the BDI might not be the most appropriate instrument, particularly if depression screening can be assessed accurately using simpler techniques that are easy to administer and consume less time. We compared the accuracy of the YSQ screen response against the BDI to screen for depression in MS patients, in an outpatient setting. METHODS: This is a comparative outcome study of two 'instruments' used for screening depression in MS patients in an academic outpatient setting. All patients were initially screened for depression by asking patients the YSQ--'Do you frequently feel sad or depressed?', followed by BDI administration. Depression was defined as a score of > or = 13 on the BDI. One hundred and twenty successive patients who presented to the MS clinic at Washington University School of Medicine and met the criteria for diagnosis of MS were screened for depression. All patients diagnosed as having MS, regardless of type, were included in the study. RESULTS: Of the 120 patients studied, a total of 49 of 120 were clinically depressed as defined by a BDI cut-off of > or = 13; 71 of 120 were not. The sensitivity of the YSQ was 32 of 49 = 65.3% with a 95% confidence interval (0.50, 0.78), specificity was 62 of 71 = 87.3% (0.77, 0.94), PPV was 32 of 41 = 78.0% (0.62, 0.89) and NPV was 62 of 79 = 78.5% (0.68, 0.87). Of the 49 patients depressed by BDI criteria, 17 responded 'no' to the YSQ, yielding a false-negative rate of 34.7% (0.22, 0.50). The Wilcoxon-Mann-Whitney test for difference in age among those on antidepressants compared with those who were not showed no statistical difference (P = 0.35). For patients on antidepressants, the mean BDI score was 16.0+/-8.9 (mean+/-SD) and 9.5+/-8.7 for those not on antidepressants. Differences in BDI scores among patients on antidepressants versus those who were not were statistically significant (P < 0.0001). Patients on antidepressants had significantly higher BDI scores. CONCLUSIONS: Our results show that the YSQ cannot replace the BDI as a screening instrument for depression in MS. The YSQ could not identify 34.7% of patients who were depressed by BDI criteria. However, as reported in a published study, BDI missed 30% of cases with early depression in MS when a cut-off of > or = 13 was used. The YSQ appears to be specific in ruling out depression when a patient is not depressed. MS is a chronic disease and since prevalence of depression varies, it is important to screen patients repeatedly over time so as not to miss the diagnosis. That BDI scores were higher among those taking antidepressants underscores the fact that this subset of patients need to be on medication, but the higher scores could also represent a sampling error since the duration of antidepressant use was not studied.

Avasarala, J. R., A. H. Cross, et al. (2003). "Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis." Mult Scler 9(1): 59-62.

            Mitoxantrone is a recently approved drug for patients with secondary progressive multiple sclerosis (SPMS). However, cardiac side effects limit Mitoxantrone use in SPMS and its lifetime cumulative dose should not exceed 140 mg/m2. Additionally, Mitoxantrone is contraindicated for use in SPMS patients with a baseline left ventricular ejection fraction (LVEF) of < or = 50%. The goal of this study was to monitor LVEF more frequently than ordinarily recommended since experience with Mitoxantrone use in SPMS patients is limited. An unexpected decline in LVEF in one of the SPMS patients being treated with Mitoxantrone prompted further investigation into this finding. In our clinic, 47 patients on Mitoxantrone were followed prospectively; 28 of 47 patients had received a minimum of three doses and underwent a repeat LVEF evaluation prior to their fourth dose of Mitoxantrone. Of these 28 patients, five of 28 (17.8%) had a significant decline in LVEF from baseline. It is suggested that more stringent cardiac monitoring guidelines than current Food and Drug Administration (FDA) recommendations be used to avert potential cardiac complications in SPMS patients on Mitoxantrone.

Avolio, C., M. Ruggieri, et al. (2003). "Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes." J Neuroimmunol 136(1-2): 46-53.

            In multiple sclerosis (MS), matrix metalloproteinase (MMP) activity in tissues is the result of a balance between MMPs and their tissue inhibitors (TIMPs). MMP-9 predominates in acute MS lesions and is inhibited by TIMP-1, while MMP-2 may participate in the remodeling of the extracellular matrix (ECM) such as in chronic disease and is inhibited by TIMP-2. These differences may be reflected in serum and cerebrospinal fluid (CSF). We have tried to characterize MMP-2 and MMP-9 activities, in relation to their respective TIMPs, 2 and 1, as a factor of different types of the disease, as this information was not previously clearly stated. We found the MMP-2/TIMP-2 ratio in serum to show higher values in secondary progressive (SP, p=0.02) and primary progressive (PP, p=0.01) MS than short disease duration (SDD) relapsing-remitting (RR) MS, but not different from the healthy control (HC) group. Whereas the MMP-9/TIMP-1 ratio in serum showed higher (p=0.04) values in SDD RR MS than PP but also in active patients, evaluated either clinically (p=0.006) or from the magnetic resonance imaging (MRI, p<0.05), compared to inactive disease. CSF MMP to TIMP ratios did not differ between MS subtypes, suggesting systemic rather CNS-restricted changes. These results show that an increase in MMP-2/TIMP-2 ratio marks chronic progression in MS, but it is as high as in HC, and also confirm that high MMP-9 activity characterizes short duration relapsing and active forms of the disease.

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 t