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Multiple Sclerosis Abstracts

  1. Vitamin D supplementation, 25-HydroxyVitamin D concentrations, and safety
    Am J Clin Nutr 1999 May;69(5):842-56

  2. Partial volume effects in MRI studies of Multiple Sclerosis
    Magn Reson Imaging 1999 May;17(4):593-601

  3. Regulation of inflammatory responses by Oncostatin M
    J Immunol 1999 May 1;162(9):5547-55

  4. The natural history of Multiple Sclerosis: A geographically based study. 5. The clinical features and natural history of Primary/Progressive Multiple Sclerosis
    Brain 1999 Apr;122 (Pt 4):625-39

  5. The natural history of Multiple Sclerosis: A geographically based study. 6. Applications to planning and interpretation of clinical therapeutic trials in Primary/Progressive Multiple Sclerosis
    Brain 1999 Apr;122 (Pt 4):641-7

  6. Multiple Sclerosis among utility workers
    Neurology 1999 Apr 12;52(6):1279-82

  7. Leber's Hereditary Optic Neuropathy DNA mutations in Familial Multiple Sclerosis
    Graefes Arch Clin Exp Ophthalmol 1999 Apr;237(4):348-50

  8. Binding motifs of Copolymer-1 to Multiple Sclerosis & Rheumatoid Arthritis associated HLA-DR Molecules
    J Immunol 1999 Apr 15;162(8):4697-4704


Vitamin D Supplementation: 25-HydroxyVitamin D Concentrations, & Safety

Vieth R
Am J Clin Nutr 1999 May;69(5):842-56
Univ of Toronto, Dept of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, Ontario, Canada
PMID# 10232622; UI# 99247582

For adults, the 5-microg (200 IU) Vitamin D recommended dietary allowance may prevent OsteoMalacia in the absence of sunlight.

But, more is needed to help prevent Osteoporosis and secondary HyperParaThyroidism.

Other benefits of Vitamin D supplementation are implicated Epidemiologically: prevention of some Cancers, OsteoArthritis progression, Multiple Sclerosis, and Hypertension.

Total-body Sun exposure easily provides the equivalent of 250 microg (10,000 IU) Vitamin D/d, suggesting that this is a physiologic limit.

Sailors in US submarines are deprived of environmentally acquired Vitamin D equivalent to 20-50 microg (800-2,000 IU)/d.

The assembled data from many Vitamin D supplementation studies reveal a curve for Vitamin D dose versus Serum 25-HydroxyVitamin D [25(OH)D] response that is surprisingly flat up to 250 microg (10,000 IU) Vitamin D/d.

To ensure that Serum 25(OH)D concentrations exceed 100 nmol/L, a total Vitamin D supply of 100 microg (4,000 IU)/d is required. Except in those with conditions causing hypersensitivity.

There is no evidence of adverse effects with Serum 25(OH)D concentrations > 140 nmol/L, which require a total Vitamin D supply of 250 microg (10,000 IU)/d to attain.

Published cases of Vitamin D toxicity with HyperCalcemia, for which the 25(OH)D concentration and Vitamin D dose are known, all involve intake of > or = 1,000 microg (40,000 IU)/d.

Because Vitamin D is potentially toxic, intake of > 25 microg (1,000 IU)/d has been avoided.

Even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 50 microg (2,000 IU)/d is too low by at least 5-fold.


Volume Effects In MRI Studies Of
Multiple Sclerosis

Firbank MJ, Coulthard A, Harrison RM, Williams ED
Magn Reson Imaging 1999 May;17(4):593-601
Univ, Dept of Radiology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK
PMID# 10231186; UI# 99246217

We have estimated the accuracy of volume measurements of Multiple Sclerosis (MS) lesions made using Magnetic Resonance Imaging (MRI) for lesions of comparable diameter to the image slice thickness.

We used a phantom containing objects of known volume and obtained images using a range of slice thicknesses.

Measurements on the phantom were used to assess a theoretical model, which was then employed to investigate the effects of image dimensions and geometry upon volume measurement accuracy.

We observed measured volume to be dependent upon slice thickness. Thin slices gave the most accurate estimate of volume.

As slice thickness increased relative to object diameter, the error in the volume measurement increased (to as much as 100%), the volume measured being dependent on the position of the object relative to the slice center.

Using a signal intensity threshold value of 50% to outline objects gave results closest to the actual volume.

As expected, a lower threshold value tended to give higher volume estimates (up to 100% larger), as did a semi-automated local edge detection technique.

For accurate volume measurement, the slice thickness should be no more than a fifth of anticipated object diameter. For typical MS lesions (7 mm in diameter), this implies using a 1.5-mm slice thickness.

For serial studies, a repositioning error of 1 mm could lead to differences in the volume measurement of individual lesions of up to 12% between studies for lesions of typical MS size and 5-mm slice thickness.

These results emphasize the need for accurate patient repositioning, relatively thin slices, for regular quality assurance checks to ensure that pixel size and slice position are correct and stable over time, and that lesion outlining is performed in a consistent fashion.

We would recommend the use of a 3D sequence with 1 mm cubic Voxels (volume element) for accurate measurements of MS lesions.


Oncostatin M Regulates Inflammatory Responses

Wallace PM, MacMaster JF, Rouleau KA, Brown TJ, Loy JK, Donaldson KL, Wahl AF
J Immunol 1999 May 1;162(9):5547-55
Bristol-Myers Squibb Pharmaceutical Research Institute,
Seattle, WA 98121 and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA
PMID# 10228036; UI# 99244926

Oncostatin M (OM) is a PleioTropic Cytokine produced late in the activation cycle of T-Cells and Macrophages.

In vitro it shares properties with related proteins of the IL-6 family of Cytokines; however, its in vivo properties and physiological function are as yet ill defined.

We show that administration of OM inhibited bacterial LPS-induced production of TNF-alpha and lethality in a dose-dependent manner.

Consistent with these findings, OM potently suppressed inflammation and tissue destruction in murine models of Rheumatoid Arthritis and Multiple Sclerosis.

T-Cell function and Ab production were not impaired by OM treatment. Taken together these data indicate the activities of this Cytokine in vivo are AntiInflammatory without concordant ImmunoSuppression.


The Natural History Of Multiple Sclerosis:
A Geographically Based Study. 5. The Clinical Features Of Primary/Progressive Multiple Sclerosis

Cottrell DA, Kremenchutzky M, Rice GP, Koopman WJ, Hader W, Baskerville J, Ebers GC
Brain 1999 Apr;122 (Pt 4):625-39
Dept of Clinical Neurological Sciences, Univ of Western Ontario, London, Canada
PMID# 10219776; UI# 99235182

We report a natural history study of 216 patients with Primary/Progressive (PP)-Multiple Sclerosis defined by at least 1 year of exacerbation-free progression at onset.

This represents 19.8% of a largely population-based patient cohort having a mean longitudinal follow-up of 23 years.

This subgroup of PP-Multiple Sclerosis patients had a mean age of onset of 38.5 years, with females predominating by a ratio of 1.3:1.0.

The rate of deterioration from disease onset was substantially more rapid than for Relapsing/Remitting Multiple Sclerosis, with a median time to Disability Status Score (DSS 6) and DSS 8 of 8 and 18 years, respectively.

Forty-nine percent of patients were followed through to death. Examination of the early disease course revealed two groups with adverse prognostic profiles.

  1. Firstly, a shorter time to reach DSS 3, from onset of PP-Multiple Sclerosis significantly adversely influenced time to DSS 8.

  2. Second, involvement of three or more Neurological Systems at onset resulted in a median time to DSS 10 of 13.5 years in contrast to PP-Multiple Sclerosis patients with one system involved at onset where median time to death from Multiple Sclerosis was 33.2 years.

However, age, gender and type of Neurological System involved at onset appeared to have little influence on prognosis.

Life expectancy, cause of mortality and familial history profile were similar in PP-Multiple Sclerosis and non-PP-Multiple Sclerosis (all other Multiple Sclerosis patients from the total population).

From clinical onset, rate of progression was faster in the PP-Multiple Sclerosis group than in the Secondary/Progressive (SP)-Multiple Sclerosis group.

When the rates of progression from onset of the progressive phase to DSS 6, 8 and 10 were compared, SP-Multiple Sclerosis had a more rapid progressive phase.

A substantial minority (28%) of the PP-Multiple Sclerosis cohort had a distinct relapse even decades after onset of progressive deterioration.

These studies establish natural history outcomes for the subgroup of Multiple Sclerosis patients with Primary/Progressive disease.


The Natural History of Multiple Sclerosis:
A Geographically Based Study. 6. Applications To Planning & Interpretation Of Clinical Therapeutic Trials In Primary/Progressive Multiple Sclerosis

Cottrell DA, Kremenchutzky M, Rice GP, Hader W, Baskerville J, Ebers GC
Brain 1999 Apr;122 (Pt 4):641-7
Univ of Western Ontario, Dept of Clinical Neurological Sciences, London, Canada
PMID# 10219777; UI# 99235183

The natural history of Primary/Progressive Multiple Sclerosis (PP-Multiple Sclerosis) recently has been defined in a geographically based Multiple Sclerosis population.

For a series of prognostically defined hypothetical entry criteria based upon current trends in presentation to the London Multiple Sclerosis Clinic, we determined the number of patients who would have been trial eligible.

Using 23 year mean longitudinal natural history data, we identified the observed rate of deterioration for frequently used trial endpoints.

Hypothetical entry criteria were based on the practical considerations which would attend the execution of clinical trials in Progressive Multiple Sclerosis.

We then developed a series of sample size tables giving the number of patients with PP-Multiple Sclerosis and the length of observation that would be required to detect a significant result.

(P = 0.05) for a 25, 50 and 75% decrease in the median time to progression with 80 or 90% power, with treatment efficacy based upon the ability to slow progression on the Disability Status score.

It is expected that the considerations outlined here will prove useful for both trial design and interpretation of trials in PP-Multiple Sclerosis which will require multi-center collaborative efforts.


Multiple Sclerosis Among Utility Workers

Johansen C, Koch-Henriksen N, Rasmussen S, Olsen JH
Neurology 1999 Apr 12;52(6):1279-82
The Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen
PMID# 10214760; UI# 99229573

The incidence of MS was assessed in a nationwide cohort study of 31,990 employees of Danish utility companies between 1900 and 1993.

Overall, 32 cases of MS were diagnosed, as compared with 23.7 expected from national incidence rates, to yield a standardized incidence ratio of 1.35 (95% confidence interval, 0.92 to 1.91).

We found no support for the hypothesis of an association between occupational exposure to ElectroMagnetic Fields and the risk of MS.


Leber's Hereditary Optic Neuropathy DNA Mutations In Familial Multiple Sclerosis

Mojon DS, Fujihara K, Hirano M, Miller C, Lincoff NS, Jacobs LD, Greenberg SJ
Graefes Arch Clin Exp Ophthalmol 1999 Apr;237(4):348-50
Univ of Bern, Dept of Ophthalmology, Switzerland
PMID# 10208269; UI# 99222950

Leber's Hereditary Optic Neuropathy (LHON) can be difficult to distinguish from Optic Neuritis due to Multiple Sclerosis (MS).

For several decades an association of LHON and MS has been suspected, and within the past 7 years the LHON Nucleotide (nt)-3460 and nt-11778 mtDNA mutations have been identified in several patients with MS-like phenotypes.

To further study this association, we tested 42 index patients with clinically definite, Familial MS for the LHON mtDNA mutations at nt-3460, nt-11778, and nt-14484.

No patients had a Pathogenic LHON mtDNA mutation; however, two MS patients with unilateral Optic Neuritis harbored the nt-15257 mtDNA polymorphism that was reported originally as a Pathogenic LHON mutation.

Several investigators have shown evidence that the nt-15257 mtDNA mutation is not primarily Pathogenic.

Therefore, we conclude that Pathogenic LHON mtDNA mutations are absent or rare in unselected patients with familial, Clinically Definite MS (95% confidence intervals for each of the negative mutations 0-7.0%).


Binding Motifs of Copolymer-1 To
Multiple Sclerosis & Rheumatoid Arthritis
Associated HLA-DR Molecules

Fridkis-Hareli M, Neveu JM, Robinson RA, Lane WS, Gauthier L, Wucherpfennig KW, Sela M, Strominger JL
J Immunol 1999 Apr 15;162(8):4697-4704
Harvard University, Dept of Molecular and Cellular Biology, and Microchemistry Facility, Cambridge, MA 02138; Harvard Medical School, Dana Farber Cancer Institute, Boston, MA 02115; and The Weizmann Institute of Science, Dept of Immunology, Rehovot, Israel
PMID# 10202010

Copolymer-1 (Cop-1, poly (Y, E, A, K)) is a random synthetic Amino Acids Copolymer-1 effective in the treatment of Relapsing forms of Multiple Sclerosis (MS).

Cop-1 binds promiscuously, with high affinity and in a Peptide-specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and Rheumatoid Arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules.

In the present work at least 95% of added Cop-1 could be bound to recombinant "empty" HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins.

Amino Acid composition, HPLC profiles, and sequencing patterns of Cop-1 eluted by acid extraction from HLA-DR molecules were similar to those of the unseparated Cop-1.

Protruding N-terminal ends of Cop-1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with Aminopeptidase I, followed by Elution, HPLC, and pool sequencing.

In contrast to untreated or unbound Cop-1, this material exhibited distinct motifs at some positions with increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y.

Presumably at P1 of the bound Peptide, at the third to fifth cycles, regardless of the HLA-DR molecule employed. No preference was seen at the following cycles that were mainly A.

These first pooled HLA-DR binding Epitopes provide clues to the components of Cop-1 that are biologically active in suppressing MS and possibly Rheumatoid Arthritis.

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