There is controversy whether determination of antibodies against myelin, myelin oligodendrocyte glycoprotein, and myelin basic protein in serum from patients with a first episode suggestive of multiple sclerosis is of prognostic value. We evaluated whether detection of antimyelin antibodies in serum indicates a worse course with earlier time to a second relapse and increased progression of disability. We conducted a prospective study at the Department of Neurology, Inselspital Bern, Switzerland from 2004 to 2008 in patients presenting with a clinically isolated syndrome (CIS) and a follow-up of at least 4 months. Antimyelin antibodies were assessed by Western blot. Results were correlated with clinical course and sex. Among 93 consecutive patients with a CIS, 74 (80%) were positive for either one or both antimyelin antibodies. A relapse occurred in 49 (53%) and the median EDSS was 2 (range 1-3.5) after a mean observation period of 20 months. Presence of antimyelin antibodies at CIS neither increased the risk for a second relapse nor for progression of disability. Stratification for gender did not reveal differences for any of the clinical surrogates. The sole determination of antimyelin antibodies in serum is of limited prognostic value for the identification of patients with different short-term course.

Chronic oxidative stress has been causally linked to several neurodegenerative disorders. As sensitivity for oxidative stress greatly differs between brain regions and neuronal cell types, specific cellular mechanisms of adaptation to chronic oxidative stress should exist. Our objective was to identify molecular mechanisms of adaptation of neuronal cells after applying chronic sublethal oxidative stress. We demonstrate that cells resistant to oxidative stress exhibit altered cholesterol and sphingomyelin metabolisms. Stress-resistant cells showed reduced levels of molecules involved in cholesterol trafficking and intracellular accumulation of cholesterol, cholesterol precursors, and metabolites. Moreover, stress-resistant cells exhibited reduced SMase activity. The altered lipid metabolism was associated with enhanced autophagy. Treatment of stress-resistant cells with neutral SMase reversed the stress-resistant phenotype, whereas it could be mimicked by treatment of neuronal cells with a specific inhibitor of neutral SMase. Analysis of hippocampal and cerebellar tissue of mouse brains revealed that the obtained cell culture data reflect the in vivo situation. Stress-resistant cells in vitro showed similar features as the less vulnerable cerebellum in mice, whereas stress-sensitive cells resembled the highly sensitive hippocampal area. These findings suggest an important role of the cell type-specific lipid profile for differential vulnerabilities of different brain areas toward chronic oxidative stress.

Beneficial effects by both interferon-P and statin treatment in patients with multiple sclerosis (MS) may be linked to interference with the Th1/Th2 cytokine balance. We determined patterns of Th1/Th2 cytokines (interleukin (IL)-1 beta, IL-2, IL-6, IL-12p70, tumor-necrosis factor(TNF)-alpha and interferon-gamma, and IL-4, IL-5 and IL-10, respectively) in the serum of patients with relapsing-remitting MS treated with 250 mu g interferon-beta 1b or with interferon-beta plus 40 mg atorvastatin.In treatment naive patients with MS, a trend for lower TNF-alpha serum levels compared to controls was detected (P = 0.08). Interferon-beta treatment increased TNF-alpha levels, while a trend for lowering of IL-5 serum levels was found (P = 0.07). Addition of atorvastatin raised IL-12p70 serum levels (P < 0.05). Mean levels of two Th2 cytokines (IL-4, IL-10) showed a non-significant increase after addition of atorvastatin.We conclude that interferon-P and atorvastatin exert divergent action on Th1/Th2 serum cytokines levels in MS. Supplemental atorvastatin might promote a Th1-type response by raising IL-12p70. Further studies are required to support a Th2 cytokine shift by atorvastatin in patients with MS. (c) 2008 Elsevier Ltd. All rights reserved.

The anti-inflammatory potential of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as reflected by modulation of C-reactive protein (CRP), might be beneficial in the treatment of patients with multiple sclerosis (MS). We evaluated serum levels of high-sensitivity (hs)-CRP in relapsing–remitting MS patients receiving interferon-β 1b and atorvastatin as add-on therapy. This study shows that interferon-β treatment is associated with increased serum levels of hs-CRP in MS patients ( P < 0.01). In contrast, when atorvastatin is added to interferon-β, hs-CRP serum levels decrease to the normal range ( P < 0.05), indicating an anti-inflammatory action of atorvastatin in MS. However, whether add-on treatment with atorvastatin modifies the course of MS remains to be investigated.

Elimination of autoreactive T cells by apoptosis is critical for restricting immune responses to self-antigens. An errant lytic interaction between the CD95 death receptor and its ligand CD95L is presumed to be involved in the pathogenesis of multiple sclerosis (MS). Statins are promising agents for the treatment of MS and were shown to modulate levels of soluble death receptors. Here, we evaluated the in vivo effects by interferon (IFN)-beta and atorvastatin on soluble CD95 (sCD95) and sCD95L in serum of patients with MS. Concentrations of sCD95 and sCD95L did not show any differences between MS and healthy control subjects. In patients with MS, treatment with IFN-beta increased serum levels of sCD95 and sCD95L significantly (P < 0.01 and P < 0.05 respectively). Addition of atorvastatin to IFN-beta did not alter serum levels of sCD95 and sCD95L significantly. Our study suggests that atorvastatin does not affect IFN-beta-induced increases of the soluble death receptors in the serum of patients with MS.

Acute partial transverse myelitis (APTM) may be the first clinical manifestation of multiple sclerosis (MS), of relapsing myelitis, or remain a monophasic event. Identification of risk factors associated with relapse or conversion to MS is important, as prognostic information might help to guide management. The objective of this study was to define clinical, laboratory and neuroimaging factors in patients with first-ever APTM that predict relapses or conversion to MS. We identified 73 patients with a first-ever APTM admitted to our institution from January 1999 to June 2005. The follow-up time ranged from 12 to 90 months (mean follow-up 46 months). Patient demographics, clinical impairment at onset and after 3 months, ancillary tests including cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), evoked potentials, recurrent and new symptoms and signs during follow-up were analysed. APTM remained a monophasic event in 35 patients (47.9%), conversion to MS occurred in 32 (43.8%) and recurred as relapsing myelitis in six patients (8.2%). According to univariate analysis, a family history of MS (P = 0.02), higher expanded disability status scale (EDSS) at onset (P = 0.03) and lesions on brain MRI (P = 0.03) were predictive factors for conversion to MS. CSF-specific oligoclonal bands (P = 0.04) or abnormal IgG-index (P = 0.04) were associated with increased risk for MS as well. In patients with a first-ever APTM, a family history of MS, high EDSS at presentation, lesions on brain MRI, CSF-specific oligoclonal bands or abnormal IgG-index may indicate an increased risk for conversion to MS.

OBJECTIVES:In patients with a clinically isolated syndrome (CIS), the time interval to convert to clinically definite multiple sclerosis (CDMS) is highly variable. Individual and geographical prognostic factors remain to be determined. Whether anti-myelin antibodies may predict the risk of conversion to CDMS in Swiss CIS patients of the canton Berne was the subject of the study.METHODS:Anti-myelin oligodendrocyte glycoprotein and anti-myelin basic protein antibodies were determined prospectively in patients admitted to our department.RESULTS:After a mean follow-up of 12 months, none of nine antibody-negative, but 22 of 30 antibody-positive patients had progressed to CDMS. Beta-Interferon treatment delayed the time to conversion from a mean of 7.4 to 10.9 months.CONCLUSIONS:In a Swiss cohort, antibody-negative CIS patients have a favorable short-term prognosis, and antibody-positive patients benefit from early treatment.

Seladin-1 (SELective Alzheimer's Disease INdicator-1) is an anti-apoptotic gene, which is down-regulated in brain regions affected by Alzheimer's disease (AD). In addition, seladin-1 catalyzes the conversion of desmosterol into cholesterol. Disruption of cholesterol homeostasis in neurons may increase cell susceptibility to toxic agents. Because the hippocampus and the subventricular zone, which are affected in AD, are the unique regions containing stem cells with neurogenic potential in the adult brain, it might be hypothesized that this multipotent cell compartment is the predominant source of seladin-1 in normal brain. In the present study, we isolated and characterized human mesenchymal stem cells (hMSC) as a model of cells with the ability to differentiate into neurons. hMSC were then differentiated toward a neuronal phenotype (hMSC-n). These cells were thoroughly characterized and proved to be neurons, as assessed by molecular and electrophysiological evaluation. Seladin-1 expression was determined and found to be significantly reduced in hMSC-n compared to undifferentiated cells. Accordingly, the total content of cholesterol was decreased after differentiation. These original results demonstrate for the first time that seladin-1 is abundantly expressed by stem cells and appear to suggest that reduced expression in AD might be due to an altered pool of multipotent cells.