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MS Abstracts 06c-2g5

  1. Gray matter pathology in Multiple Sclerosis
    J NeuroPathol Exp Neurol 2005 Dec;64(12):1101-7

  2. Prognostic factors in multidisciplinary rehabilitation treatment in Multiple Sclerosis: an outcome study
    Mult Scler 2005 Dec;11(6):719-24

  3. Conservative Bladder management in advanced Multiple Sclerosis
    Mult Scler 2005 Dec;11(6):694-9

  4. Suppression of acute Experimental Allergic Encephalomyelitis with a small molecule inhibitor of alpha4 Integrin
    Mult Scler 2005 Dec;11(6):683-90

  5. Interferon-ß-1b effects on re-enhancing lesions in patients with Multiple Sclerosis
    Mult Scler 2005 Dec;11(6):658-68

  6. Axonal metabolic recovery and potential NeuroProtective effect of Glatiramer Acetate in Relapsing/Remitting Multiple Sclerosis
    Mult Scler 2005 Dec;11(6):646-51

  7. CD26+ CD4+ T-Cell counts and attack risk in Interferon-treated Multiple Sclerosis
    Mult Scler 2005 Dec;11(6):641-5

  8. SimvaStatin affects cell motility and Actin Cytoskeleton distribution of Microglia
    Glia 2006 Jan 15;53(2):115-23

  9. Glutamate inhibition in MS: the NeuroProtective properties of Riluzole
    J Neurol Sci 2005 Jun 15;233(1-2):113-5

  10. 9-Cis-retinoic acid suppresses inflammatory responses of Microglia and Astrocytes
    J NeuroImmunol 2006 Feb;171(1-2):135-44

  11. Arvanil inhibits T-Lymphocyte activation and Ameliorates Autoimmune Encephalomyelitis
    J NeuroImmunol 2006 Feb;171(1-2):110-9

  12. Investigating the presence of Human HerpesVirus 7 and 8 in Multiple Sclerosis and normal control Brain tissue
    J Neurol Sci 2006 Jan 15;240(1-2):37-44


Gray Matter Pathology In Multiple Sclerosis

Vercellino M, Plano F, Votta B, Mutani R, Giordana MT, Cavalla P
J NeuroPathol Exp Neurol 2005 Dec;64(12):1101-7
University of Turin, Department of NeuroScience, Turin, Italy
PMID# 16319720

The aim of our study is to evaluate the extent and distribution of Gray Matter DeMyelinating lesions in Multiple Sclerosis (MS), addressing also Neuronal Loss and Synaptic loss.

Whole coronal sections of 6 MS Brains and 6 control Brains were selected. ImmunoHistoChemistry was performed for Myelin Basic Protein, NeuroFilaments, SynapTophysin, Ubiquitin, and activated Caspase-3.

Neuronal density and optical density of SynapTophysin staining were estimated in Cortical lesions and compared with those observed in corresponding areas of normal (i.e. NonDeMyelinated) Cortex in the same section.

DeMyelinating lesions were observed in the Cerebral Cortex, in the Thalamus, Basal Ganglia, and in the Hippocampus. The percentage of DeMyelinated Cortex was remarkable in 2 cases of Secondary/Progressive MS (48% and 25.5%, respectively).

Neuronal density was significantly reduced in Cortical lesions (18-23% reduction), if compared with adjacent normal Cortex, in the 2 cases showing the higher extent of Cortical DeMyelination.

In the same cases, very rare Apoptotic Neurons expressing Caspase-3 were observed in Cortical lesions and not in adjacent normal Cortex.

No significant decrease in optical density of SynapTophysin staining was observed in Cortical lesions. Gray Matter DeMyelination and Neuronal Loss could contribute to disability and Cognitive Dysfunctions in MS.


Prognostic Factors In Multidisciplinary Rehabilitation Treatment In Multiple Sclerosis: An Outcome Study

Grasso MG, Troisi E, Rizzi F, Morelli D, Paolucci S
Mult Scler 2005 Dec;11(6):719-24
Fondazione Santa Lucia-IRCCS, Rome, Italy
PMID# 16320734

The aim of this outcome study was to evaluate the effectiveness and prognostic factors of inpatient multidisciplinary rehabilitation treatment in patients with Multiple Sclerosis (MS).

We analysed 230 consecutive inpatients with MS admitted to an MS rehabilitation ward who followed an individualized, goal-oriented, multidisciplinary rehabilitation program.

Every patient was submitted to a neurological examination and evaluated by means of Kurtzke's Expanded Disability Status Scale (EDSS), with its functional systems (FS), Barthel Index (BI) and the Rivermead Mobility Index (RMI).

We observed an effectiveness (percentage of potential improvement achieved during rehabilitation) of nearly 16% on BI and 8% on RMI, corresponding to an improvement in 124 patients (54%) on BI and 113 patients (49%) on RMI.

Basal EDSS (beta = -0.32, P < 0.001), Cognitive status (beta = -0.15, P < 0.05) and disease duration (beta = -0.13, P < 0.05) were negatively associated with effectiveness of treatment on BI (adjusted R2 = 0.176).

Whereas effectiveness on RMI was correlated only with the EDSS score (beta = -0.34, P < 0.001, adjusted R2 = 0.113).

In the logistic regression analysis, the absence of severe sphincteric disturbances was correlated with the probability of improvement on BI that was nearly twice as high (OR =2.25, 95% CI 1.24-4.08) as that of other patients.

Moreover, patients without severe Cognitive deficits showed a similar probability (OR =2.37, 95% CI 1.05-5.33) of improvement on RMI.

The results of this study provide further evidence that intensive multidisciplinary rehabilitation in MS is effective in the majority of MS patients and that early treatment may favor functional recovery.


Conservative Bladder Management In Advanced Multiple Sclerosis

De Ridder D, Ost D, Van der Aa F, Stagnaro M, Beneton C, Gross-Paju K, Eelen P, Limbourg H, Harper M, Segal JC, Fowler CJ, Nordenbo A
Mult Scler 2005 Dec;11(6):694-9
University Hospitals KU Leuven, Department of Urology, Belgium
PMID# 16320730

AntiCholinergics and intermittent catheterization are the cornerstones of Bladder management in early Multiple Sclerosis (MS). In advanced MS however, Bladder management is based more on tradition than on evidence.

Nurses seem to deal with catheter problems and chronic incontinence. Despite the abundant use of indwelling catheters, there is a lack for guidelines on catheter-induced problems.

The psychosexual and social impact of Bladder problems in advanced MS is often neglected.

The international multidisciplinary special interest group on Sexual, Urological and Bowel dysfunction in MS (SUBDIMS) as a special interest group of the Rehabilitation in Multiple Sclerosis (RIMS) was confronted with a high variability in practice and a lack of guidelines.

A literature review was prepared during three multidisciplinary expert meetings. This review will be the basis of further initiatives to improve the Urological treatment of patients with advanced MS.


Suppression Of Acute Experimental Allergic Encephalomyelitis With A Small Molecule Inhibitor Of Alpha4 Integrin

Piraino PS, Yednock TA, Freedman SB, Messersmith EK, Pleiss MA, Karlik SJ
Mult Scler 2005 Dec;11(6):683-90
University of Western Ontario, Department of Physiology and Pharmacology, London, Canada
PMID# 16320728

To determine the efficacy of a small molecule inhibitor of alpha4 Integrin (CT301) at reversing the clinical, pathological and MR-detectable deficits associated with the acute phase of Experimental Allergic Encephalomyelitis (EAE).

Materials And Methods
EAE was induced in 36 female Hartley guinea pigs, and the treatment period was from day 11 to day 17 post-immunization.

Animals received either saline (n = 12), anti-alpha4 integrin AntiBody (AN100226m; n = 12) or CT301 (n = 12).

T2-weighted fast spin echo and T1-weighted pre- and post-contrast scans were performed at the beginning (day 11) and end (day 18) of the treatment period, and scored for Cerebral inflammation and Gadolinium enhancement.

T1-weighted images were further analyzed to quantify this enhancement as a measure of Blood-Brain Barrier integrity. Dissected CNS was evaluated for inflammation and DeMyelination.

CT301 successfully reversed two clinical indicators of disease over the course of the treatment period.

These animals showed decreased T2-weighted abnormalities, as well as a reduction in Gadolinium leakage on T1-weighted images.

Meningeal and perivascular inflammation was decreased by anti-alpha4 Integrin treatments.

CT301 effectively reverses the clinical, pathological and MR-detectable deficits of acute EAE, and may therefore be a promising therapeutic agent in Multiple Sclerosis (MS).


Interferon-ß-1b Effects On Re-Enhancing Lesions In Patients With Multiple Sclerosis

Gupta S, Solomon JM, Tasciyan TA, Cao MM, Stone RD, Ostuni JL, Ohayon JM, Muraro PA, Frank JA, Richert ND, McFarland HF, Bagnato F
Mult Scler 2005 Dec;11(6):658-68
National Institute of Neurological Disorders and Stroke, NIH, NeuroImmunology Branch, Bethesda, MD 20892, USA
PMID# 16320725

Interferon-ß (IFN-ß) reduces the number and load of new contrast-enhancing lesions (CELs) in patients with Multiple Sclerosis (MS).

However, the ability of IFN-ß to reduce lesion sizes and re-enhancements of pre-existing CELs has not been examined extensively.

Activity of contrast re-enhancing lesions (Re-CELs) and contrast single-enhancing lesions (S-CELs) were monitored in ten patients with Relapsing/Remitting (RR) MS.

These patients underwent monthly post-contrast Magnetic Resonance Imaging (MRIs) for an 18-month natural history phase and an 18-month therapy phase with subcutaneous IFN-ß-1b, totaling 37 images per patient.

The activity was analysed using the first image as a baseline and registering subsequent active monthly images to the baseline. There was a 76.4% reduction in the number of CELs with IFN-ß therapy.

The decrease was greater (P = 0.003) for S-CELs (82.3%) than for Re-CELs (57.4%). S-CELs showed no changes in durations of enhancement and maximal lesion sizes with treatment.

Exclusively for Re-CELs, IFN-ß-1b significantly decreased maximal lesion sizes, total number of enhancement periods and total months of enhancement.

Thus, IFN-ß appears to be effective in reducing the degree of severity of inflammation among Re-CELs, as reflected by their reduced maximal lesion sizes and durations of enhancement.


Axonal Metabolic Recovery And Potential NeuroProtective Effect Of Glatiramer Acetate In Relapsing/Remitting Multiple Sclerosis

Khan O, Shen Y, Caon C, Bao F, Ching W, Reznar M, Buccheister A, Hu J, Latif Z, Tselis A, Lisak R
Mult Scler 2005 Dec;11(6):646-51
Wayne State University School of Medicine, Department of Neurology, Multiple Sclerosis Center, Detroit, MI 48201, USA
PMID# 16320723

Glatiramer Acetate (GA) is a disease-modifying therapy for Relapsing/Remitting Multiple Sclerosis (RRMS) with several putative mechanisms of action.

Currently, there is paucity of in vivo human data linking the well-established peripheral Immunologic effects of therapy with GA to its potential effects inside the Central Nervous System (CNS).

Brain proton Magnetic Resonance Spectroscopy (MRS) allows in vivo examination of Axonal integrity by quantifying the resonance intensity of the Neuronal marker N-AcetylAspartate (NAA).

In a pilot study to investigate the effect of GA on Axonal injury, we performed combined Brain Magnetic Resonance Imaging (MRI) and MRS studies in 18 treatment naive RRMS patients initiating therapy with GA at baseline and annually for two years on therapy.

A small group of four treatment naive RRMS patients, electing to remain untreated, served as controls.

NAA/Cr was measured in a large central Brain volume of interest (VOI) as well as the Normal-Appearing White Matter (NAWM) within the VOI.

After two years, NAA/Cr in the GA-treated group increased significantly by 10.7% in the VOI (2.17 +/- 0.26 versus 1.96 +/- 0.24, P = 0.03) and by 71% in the NAWM (2.23 +/- 0.26 versus 2.08 +/- 0.31, P = 0.04).

In the untreated group, NAA/Cr decreased by 8.9% at two years in the VOI (2.01 +/- 0.16 versus 1.83 +/- 0.21, P = 0.03) and 8.2% in the NAWM (2.07 +/- 0.24 versus 1.90 +/- 0.29, P = 0.03).

Our data shows that treatment with GA leads to Axonal metabolic recovery and protection from sub-lethal Axonal injury. These results support an in situ effect of GA therapy inside the CNS and suggest potential NeuroProtective effects of GA.


CD26+ CD4+ T-Cell Counts And Attack Risk In Interferon-Treated Multiple Sclerosis

Sellebjerg F, Ross C, Koch-Henriksen N, Sorensen PS, Frederiksen JL, Bendtzen K, Sorensen TL
Mult Scler 2005 Dec;11(6):641-5
Copenhagen University Hospital, The MS Clinic, Glostrup, Denmark
PMID# 16320722

Biomarkers that allow the identification of patients with Multiple Sclerosis (MS) with an insufficient response to ImmunoModulatory treatment would be desirable, as currently available treatments are only incompletely efficacious.

Previous studies have shown that the expression of CD25, CD26 and CCR5 on T-Cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during ImmunoModulatory treatment.

In Interferon-ß (IFN-ß)-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26+ CD4+ T-Cell counts above median, and this risk was independent of the risk conferred by Neutralizing Anti-IFN-ß AntiBodies.

CD26+ CD4+ T-Cell counts may identify patients with MS at increased risk of attack during treatment with IFN-ß.


SimvaStatin Affects Cell Motility And Actin CytoSkeleton Distribution Of Microglia

Kuipers HF, Rappert AA, Mommaas AM, Van Haastert ES, Van Der Valk P, Boddeke HW, Biber KP, Van Den Elsen PJ
Glia 2006 Jan 15;53(2):115-23
Leiden University Medical Center, Department of ImmunoHematology and Blood Transfusion, Leiden, The Netherlands
PMID# 16206159

Statin treatment is proposed to be a new potential therapy for Multiple Sclerosis (MS), an Inflammatory DeMyelinating Disease of the Central Nervous System. The effects of Statin treatment on Brain cells, however, are hardly understood.

We therefore evaluated the effects of SimvaStatin treatment on the migratory capacity of Brain Microglial Cells, key elements in the pathogenesis of MS.

It is shown that exposure of human and murine Microglial Cells to SimvaStatin reduced cell surface expression of the Chemokine receptors CCR5 and CXCR3.

In addition, SimvaStatin treatment specifically abolished Chemokine-induced Microglial cell motility, altered actin CytoSkeleton distribution, and led to changes in IntraCellular vesicles.

These data clearly show that SimvaStatin inhibits several Immunological properties of Microglia, which may provide a rationale for Statin treatment in MS.

(c) 2005 Wiley-Liss, Inc.


Glutamate Inhibition In MS: The NeuroProtective Properties Of Riluzole

Killestein J, Kalkers NF, Polman CH
J Neurol Sci 2005 Jun 15;233(1-2):113-5
VU Medical Centre, Department of Neurology, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
PMID# 15949499

In addition to DeMyelination and damage to Oligodendrocytes, Axonal injury and Neuronal cell death are dominating histopathological characteristics of Multiple Sclerosis (MS).

Still little is known about the cause of the damage. ExtraCellular accumulation of Glutamate contributes to excitotoxic injury of Neurons and Glial Cells, suggesting the maintenance of subtoxic ExtraCellular Glutamate levels may be crucial.

Riluzole is a NeuroProtective agent that inhibits the release of Glutamate from Nerve Terminals and modulates Glutamate, i.e., Kainate and NMDA receptors.

It inhibits excitotoxic injury in several experimental models of NeuroDegenerative Disease. We performed a small run-in versus treatment MR-monitored pilot study in 16 Primary/Progressive MS patients.

The results suggest that Riluzole reduces the rate of Cervical Cord atrophy and the development of T1 HypoIntense lesions on Magnetic Resonance Imaging in Primary/Progressive MS. The rate of Brain Atrophy was only slightly decreased.

The results indicate an effect on mechanisms involving lesion evolution and Axonal loss, but no clear effect on new lesion formation. However, the data suffer from several limitations and must be confirmed in future trials.


9-Cis-Retinoic Acid Suppresses Inflammatory Responses Of Microglia And Astrocytes

Xu J, Drew PD
J NeuroImmunol 2006 Feb;171(1-2):135-44
University of Arkansas for Medical Sciences, Department of Neurobiology and Developmental Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA
PMID# 16303184

Retinoic Acid (RA) regulates a wide range of biologic process, including inflammation. Previously, RA was shown to inhibit the clinical signs of Experimental Autoimmune Encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS).

The current study investigated the effects of 9-cis-RA on primary mouse Microglia and Astrocytes, two cell types implicated in the pathology of MS and EAE.

The studies demonstrated that 9-cis-RA inhibited the production of Nitric Oxide (NO) as well as the pro-inflammatory Cytokines TNF-alpha, IL-1ß and IL-12 p40 by LPS-stimulated Microglia.

However, this Retinoid had no effect on IL-6 secretion and increased MCP-1 production by LPS-stimulated Microglia. In LPS-stimulated Astrocytes, 9-cis-RA inhibited NO and TNF-alpha production but had not effect on IL-1ß, IL-6 and MCP-1 secretion.

These results suggest that RA modulates EAE, at least in part, by suppressing the production of NO and specific inflammatory Cytokines from activated Glia and suggests that RA might be effective in the treatment of MS.


Arvanil Inhibits T-Lymphocyte Activation And Ameliorates Autoimmune Encephalomyelitis

Malfitano AM, Matarese G, Pisanti S, Grimaldi C, Laezza C, Bisogno T, Di Marzo V, Lechler RI, Bifulco M
J NeuroImmunol 2006 Feb;171(1-2):110-9
Universita' di Salerno, Dipartimento di Scienze Farmaceutiche, Via Ponte don Melillo 84084 Fisciano (Salerno), Italy; Department of Immunology, Hammersmith Campus, Imperial College London, UK
PMID# 16239036

This study examined the ImmunoModulatory effect of Arvanil, a synthetic Capsaicin-Anandamide hybrid. Arvanil inhibits Lymphocyte proliferation and IFN-γ production.

The phenotype of activated CD4+T-Cells treated with Arvanil shows a down-regulation of T-Cell activation markers such as CD25, HLA-DR and CD134/OX40. Arvanil and Anandamide do not induce Apoptosis on CD4+T-Cells.

Arvanil blocks the G1/S phase transition of the cell cycle in stimulated peripheral blood mononuclear cells, inducing activation of p21waf-1/cip-1 and phosphorylation of Akt/PKB.

In vivo, Arvanil ameliorates Experimental Autoimmune Encephalomyelitis in the SJL/J mouse.

Our findings have relevance for the use of Arvanil and related compounds as a novel ImmunoTherapeutic approach in the treatment of Multiple Sclerosis.


Investigating The Presence Of Human HerpesVirus 7 And 8 In Multiple Sclerosis And Normal Control Brain Tissue

Opsahl ML, Kennedy PG
J Neurol Sci 2006 Jan 15;240(1-2):37-44
University of Glasgow Department of Neurology, Division of Clinical Neurosciences, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, Scotland, UK
PMID# 16242723

Multiple Sclerosis (MS) is an important DeMyelinating disease of the Central Nervous System, the Etiology of which is thought to have a possible Viral component.

In this study we investigated the possible involvement in MS of two Herpes Viruses: the NeuroTropic Human HerpesVirus 7 (HHV-7) and the related Human HerpesVirus 8 (HHV-8).

Utilizing Fluorescent In Situ Hybridisation (FISH) techniques, we examined human post mortem tissues for the presence of immediate early and late Viral gene or protein expression in MS patient Normal-Appearing White Matter (NAWM), lesional tissue and normal control Brain samples.

HHV-7 and/or HHV-8 mRNA or protein was detected in some individuals in all three sample categories and was restricted to Oligodendrocytes, as determined by double mRNA FISH analysis or Immuno fluorescence (IF).

No samples showed evidence of Viral mRNA when subjected to RT-PCR on extracted Ribonucleic Acid. We therefore conclude that there is little evidence in our particular sample cohort to suggest involvement of either HHV-7 or HHV-8 in MS.

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