Mostert JP, Ramsaransing GS, Heersema DJ, Heerings M, Wilczak N, De Keyser J
J Neurol Sci 2005 Apr 15;231(1-2):41-4
Academisch Ziekenhuis Groningen, Department of Neurology, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
A number of studies found that patients with Multiple Sclerosis (MS) have low Serum levels of Uric Acid. It is unclear whether this represents a primary deficit or secondary effect.
Uric Acid is a scavenger of Peroxynitrite, which is the product of Nitric Oxide (NO) and Superoxide.
Because Peripheral Blood Leukocyte NO production and NO metabolites in Serum are raised in MS patients, associations might be expected between Serum Uric Acid levels and Peripheral NO production.
Serum levels of Uric Acid and NO production by Peripheral Blood Leukocytes were measured in 60 patients with MS without a relapse in the past 3 months, and 30 age- and sex-matched healthy controls.
Uric Acid was determined with the uricase PAP method, and NO production was assayed by measuring Nitrite concentration in supernatants of lysed Leukocytes.
Serum Uric Acid levels were not different between MS patients and controls. Compared to controls, patients with MS had significantly higher Peripheral Blood Leukocytes Nitrite concentrations (p < 0.001).
There was no correlation between Leukocyte Nitrite concentration and Serum Uric Acid levels.
Our findings suggest that in MS patients there is no primary deficit in Serum Uric Acid. NO production by Peripheral Blood Leukocytes is increased, but there is no association with Serum Uric Acid levels.
Sisto D, Trojano M, Vetrugno M, Trabucco T, Iliceto G, Sborgia C
Invest Ophthalmol Vis Sci 2005 Apr;46(4):1264-8
University of Bari, Departments of Ophthalmology and Otorhinolaringology and Psychiatric Sciences, Bari, Italy
To evaluate the effectiveness of Visual Evoked Potentials (VEPs), Frequency-Doubling Perimetry (FDP), Standard Achromatic Perimetry (SAP), Contrast Sensitivity (CS) test, and Magnetic Resonance Imaging (MRI), isolated or in combination, in detecting Subclinical Impairment of Visual function in Multiple Sclerosis (MS).
Twenty-two eyes of 11 patients affected by Clinically Definite MS, without a history of Optic Neuritis and asymptomatic for visual disturbances, underwent full Ophthalmic Examination and, in addition, VEPs, FDP, SAP, CS, and MRI.
Abnormal results were taken to be as follows:
- VEPs, a P100 latency >115 ms
- FDP, abnormal Mean Deviation (MD) or pattern SD (PSD)
- SAP, abnormal MD or PSD; for CS, abnormal CS at one spatial frequency, at least
- MRI, evidence of at least one DeMyelinating plaque along the Visual Pathway
VEPs showed abnormal results in 12 eyes (54.4%), FDP in 11 (50%), SAP in 14 (63.6%), CS in 17 (77.1%), and MRI in 16 (72.7%). In only two (9.1%) eyes of the same patient was no abnormality found.
No single test detected all the abnormal eyes. Four (18.2%) eyes had pure Optic Nerve involvement and the remaining 16 (72.7%) had both Pre- and PostChiasmal involvement.
In patients affected by Clinically Definite MS without history of Optic Neuritis and no Visual symptoms, there is a large prevalence of Visual Pathway involvement that can be diagnosed only by performing multiple tests.
The comparison of the tests is also useful to detect the presence of multiple lesions in the same patient.
Hafler DA, Slavik JM, Anderson DE, O'connor KC, De Jager P, Baecher-Allan C
Immunol Rev 2005 Apr;204:208-31
Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Multiple Sclerosis (MS) is a complex genetic disease associated with inflammation in the Central Nervous System (CNS) White Matter and is thought to be mediated by AutoImmune processes.
Clonal expansion of B-Cells, their AntiBody products, and T-Cells, hallmarks of inflammation in the CNS, are found in MS.
The association of the disease with Major HistoCompatibility Genes, the inflammatory White Matter infiltrates, similarities with animal models.
And the observation that MS can be treated with ImmunoModulatory and ImmunoSuppressive Therapies support the hypothesis that AutoImmunity plays a major role in the disease pathology.
This review discusses the ImmunoPathology of MS with particular focus given to regulatory T-Cells and the role of B-Cells and AntiBodies, ImmunoModulatory Therapeutics, and finally new directions in MS research.
Particularly new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA Haplotypes, RNA expression, and protein structures.
That will allow the generation of a new series of hypotheses that can be tested to develop better understandings and therapies for this disease.
Leptin Increase In Multiple Sclerosis Associates With Reduced Number Of CD4+CD25+ Regulatory T-Cells
Matarese G, Carrieri PB, La Cava A, Perna F, Sanna V, De Rosa V, Aufiero D, Fontana S, Zappacosta S
Proc Natl Acad Sci USA 2005 Mar 23
Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Naples, Italy; Dipartimenti di Biologia e Patologia Cellulare e Molecolare, Scienze Neurologiche, and Medicina Clinica e Sperimantale, Universita di Napoli "Federico II", 80131 Naples, Italy
We analyzed the Serum and CerebroSpinal Fluid (CSF) Leptin secretion and the interaction between Serum Leptin and CD4+CD25+ regulatory T-Cells (TRegs) in naive-to-therapy Relapsing/Remitting Multiple Sclerosis (RRMS) patients.
Leptin production was significantly increased in both Serum and CSF of RRMS patients and correlated with IFN- secretion in the CSF.
T-Cell lines against human Myelin Basic Protein (hMBP) produced ImmunoReactive Leptin and up-regulated the expression of the Leptin Receptor (ObR) after activation with hMBP.
Treatment with either AntiLeptin or AntiLeptin-Receptor Neutralizing AntiBodies inhibited in vitro proliferation in response to hMBP.
Interestingly, in the RRMS patients, an inverse correlation between Serum Leptin and percentage of circulating TRegs was also observed.
To better analyze the finding, we enumerated TRegs in Leptin-deficient (ob/ob) and Leptin-Receptor-deficient (db/db) mice and observed the significant increase in TRegs.
Moreover, treatment of WT mice with soluble ObR fusion protein (ObR:Fc) increased the percentage of TRegs and ameliorated the clinical course and progression of disease in ProteoLipid Protein Peptide (PLP139-151)-induced Relapsing-Experimental Autoimmune Encephalomyelitis (R-EAE), an animal model of RRMS.
These findings show an inverse relationship between Leptin secretion and the frequency of TRegs in RRMS and may have implications for the pathogenesis of and therapy for Multiple Sclerosis.
Low-Contrast Letter Acuity Testing Captures Visual Dysfunction In Patients With Multiple Sclerosis
Baier ML, Cutter GR, Rudick RA, Miller D, Cohen JA, Weinstock-Guttman B, Mass M, Balcer LJ
Neurology 2005 Mar 22;64(6):992-5
Cooper Institute, Center for Research Methodology and Biometrics, 14023 Denver West Parkway, 100, Golden, CO 80401, USA
To evaluate concurrent and predictive validity for Low-Contrast Letter Acuity (L-CLA) testing as a candidate Visual Component for the Multiple Sclerosis Functional Composite (MSFC).
L-CLA testing was conducted in two MS patient cohorts. In the MSFC Validation Study, 137 participants from a Phase III trial of Inteferon-beta-1a (Avonex) for Relapsing/Remitting MS were followed.
A second cohort included 65 patients with Secondary/Progressive MS who participated in a substudy of the International MS Secondary Progressive Avonex Controlled Trial (IMPACT).
The total number of letters read correctly at four contrast levels (100, 5, 1.25, and 0.6%) was correlated with Expanded Disability Status Scale (EDSS), MSFC, Sickness Impact Profile, Multiple Sclerosis Quality of Life Inventory, and Brain Parenchymal Fraction (BPF), as determined by MRI.
Low- and high-contrast letter Acuity Scores correlated with BPF at follow-up in the MSFC Validation Study (5%: r = 0.40, p < 0.0001; 100%: r = 0.31, p = 0.0002).
L-CLA also correlated with EDSS (5%: r = -0.35, p < 0.0001; 1.25%: r = -0.26, p = 0.0003) and MSFC (5%: r = 0.47, p < 0.0001; 1.25%: r = 0.45, p < 0.0001).
In the IMPACT Substudy, change in L-CLA scores from baseline to year 1 predicted subsequent change in the EDSS from year 1 to 2 at the 5% (p = 0.0142) and the 1.25% (p = 0.0038) contrast levels, after adjusting for change in MSFC scores from baseline to year 1.
Low-Contrast Letter Acuity (L-CLA) scores demonstrate concurrent and predictive validity in patients with Relapsing/Remitting and Secondary/Progressive Multiple Sclerosis (MS).
L-CLA testing provides additional information relevant to the MS disease process that is not entirely captured by the Multiple Sclerosis Functional Composite.
Treatment With Laquinimod Reduces Development Of Active MRI Lesions In Relapsing MS
Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T
Laquinimod in Relapsing MS Study Group
Neurology 2005 Mar 22;64(6):987-91
VU Medical Centre, Department of Neurology, Amsterdam, The Netherlands
Laquinimod is a novel ImmunoModulatory substance developed as an orally available disease modifying treatment in Multiple Sclerosis (MS).
The purpose of this study was to evaluate safety, tolerability, and efficacy on MRI lesions of two different doses of Laquinimod compared with placebo in patients with Relapsing MS.
In this multicenter, double-blind, randomized trial, patients with Relapsing MS received 0.1 mg or 0.3 mg Laquinimod or placebo as three daily tablets for 24 weeks.
Gadolinium-enhanced Brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment.
The primary efficacy variable was the cumulative number of active lesions over 24 weeks. Safety measures included adverse events, physical examination, and laboratory variables.
Of 256 screened patients, 209 were randomized (67 to 74 patients per group) in 20 centers.
There was a significant difference between Laquinimod 0.3 mg and placebo for the primary outcome measure (mean cumulative number of active lesions reduced by 44%).
In the subgroup of patients with at least one active lesion at baseline the reduction was slightly more pronounced (52%).
No differences with respect to clinical variables (relapses, disability) were found. The safety profile was favorable; there were no clinical signs of undesired inflammatory manifestations.
Oral Laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in Relapsing Multiple Sclerosis.
Ephrin A Receptors And Ligands In Lesions And Normal-Appearing White Matter In Multiple Sclerosis
Brain Pathol 2005 Jan;15(1):35-45
Veterans Affairs Health Care System, Laboratory Service, Palo Alto, California 94304, USA
Complexes of the Tyrosine Kinase Ephrin Ligands (Ephrins) and their Receptors (Ephs) provide critical cell recognition signals in CNS development.
Complementary Ephrin/Eph expression gradients present topographic guidance cues that may either stimulate or repulse Axon growth.
Some Ephrin/Ephs are upregulated in adult CNS injury models. To assess their involvement in Multiple Sclerosis (MS), Ephrin A1-5 and Eph A1-8 expression was analyzed in CNS tissues using ImmunoHistoChemistry.
Control samples showed distinct expression patterns for each Ephrin/Eph on different cell types.
PeriVascular MonoNuclear Inflammatory Cells, reactive Astrocytes and Macrophages expressed Ephrin A1-4, Eph A1, -A3, -A4, -A6 and -A7 in active MS lesions.
Axonal Ephrin A1 and Eph A3, -A4, and -A7 expression was increased in active lesions and was greater in Normal-Appearing White Matter (NAWM) adjacent to active lesions than within or adjacent to chronic MS lesions, in ContraLateral NAWM, or in control samples.
As in development, therefore, there are temporally dynamic, lesion-associated Axonal Ephrin/Eph A expression gradients in the CNS of MS patients.
These results indicate that Ephrin/Eph As are useful cell markers in human CNS tissue samples. They likely are involved in the ImmunoPathogenesis of active lesions and in NeuroDegeneration in MS NAWM; and they represent potential therapeutic targets in MS.