We have studied the characteristics of pH(i) regulation at different stages of rat Oligodendrocyte differentiation in Primary culture. pH(i) was measured at 37 degrees C using the pH-sensitive fluorescent probe BCECF.

In immature Oligodendrocyte Progenitor (OLP), three distinct Ionic mechanisms were involved in pH(i) regulation:
1. A Sodium-independent Cl^-/HCO^-(3) exchanger,
2. A Na⁺/H⁺ exchanger and
3. A voltage-dependent Na⁺-HCO^-(3) cotransporter.

The two latter mechanisms were also detected in more differentiated pro-Oligodendrocytes and in mature Oligodendrocytes whereas the Cl^-/HCO^-(3) exchanger was not active in these two later stages of differentiation.

The presence of this Cl^-/HCO^-(3) exchanger (that acts as a Chronic acidifying mechanism) only in immature OLP maintains in these cells a steady-state pH(i) value significantly lower than values measured in more differentiated cells.

The possible involvement of this pH(i) change in triggering cell differentiation is discussed.

Copyright 2000 Wiley-Liss, Inc.

A role for 4 Integrins in different forms of the Multiple Sclerosis-like disease Experimental AutoImmune EncephaloMyelitis (EAE) has been demonstrated.

But the individual contributions of 4ß1, 4ß7, and the related Eß7 Integrin have not been determined.

The P7 Integrins 4ß7 and Eß7 play a central role in Chronic Inflammation.

Mediating the trafficking, entry, and/or adhesion of Lymphocytes in the inflamed Pancreas and Gut, and their Ligands MAdCAM-1, VCAM-1 and E-Cadherin are expressed on Brain Endothelial Cells and/or on MicroVessels in the inflamed Central Nervous System.

Here, we show that an AntiBody directed against the beta7 subunit greatly attenuates a Non-Remitting form of EAE, induced by adoptive transfer of Myelin Oligodendrocyte Peptide (MOG35-55)-stimulated T-Cells.

Combinational treatment with both Anti-ß7 and A4 Integrin subunit AntiBodies led to more rapid and complete remission than that obtained with anti-A4 AntiBody alone, potentially implicating a role for Eß7 in disease progression.

Remission correlated with the down-regulation of the Vascular Addressins VCAM-1. MAdCAM-1, and ICAM-1 on Cerebral blood vessels.

Attenuated forms of disease were induced by adoptive transfer of either wild-type EncephalitoGenic T-Cells to beta7-deficient Gene knockout mice, or of beta7-/-EncephalitoGenic T-Cells to wild-type recipients.

The former finding indicates that beta7 + ve recruited cells contribute to disease progression.

Thus 4ß1, 4ß7, and Eß7 Integrins may all play a contributory role in the progression of Chronic forms of DeMyelinating Disease, and together with their Ligands could represent potential targets for improved treatment of some forms of Multiple Sclerosis.

PhosphoDiEsterase Inhibitors (PDEIs), when used in combination, synergistically suppress TNF- production by various cells and also suppress experimental DeMyelination at very low concentrations.

We conducted a pilot study to determine whether the combination of three PDEIs suppresses the relapse of MS at the usual therapeutic doses.

Of the 12 Relapsing/Remitting MS, the mean relapse rate/year dropped remarkably (from 3.08+/-3.32 to 0.92+/-1.86) after PDEI treatment. Seven out of 12 (58.3%) were relapse-free in the follow up period (499+/-142 days).

The combination of three PDEIs can be safe and useful strategy for the future treatment of MS.

Multiple Sclerosis (2000) 6 56 - 58

Patients suffering from Multiple Sclerosis have a high frequency of Cognitive Deficits usually attributable to DeMyelination and Axonal loss in the SubCortical White Matter.

Neurologic abnormalities referable to Cortical function are uncommon but have been described.

The present study describes three patients with Clinically Definite MS with deficits in Cognitive function referable to Cortical location.

Two of the patients underwent Positron Emission Tomography and showed profound Cortical hypometabolism adjacent to SubCortical White Matter lesions seen on MRI.

This paper points out that Neurologic deficits referable to Cortical sites may be caused by SubCortical White Matter lesions and that Cognitive Dysfunction in patients with MS may progress rapidly in the absence of motoria deficits or other evidence of clinical deterioration.

Multiple Sclerosis (2000) 6 50 - 55

Magnetic Resonance Imaging (MRI) has been used to study the history of Multiple Sclerosis (MS).

We analyze the relationship between MRI activity in the first scan compared to the subsequent five scans, and we evaluate whether a shorter observation period of 3 months may predict the subsequent 3 months.

Monthly enhanced MRI was performed in 103 Relapsing/Remitting (RR) MS patients for 6 months.

Thirty-five per cent of patients had an inactive scan on the initial examination. More than 80% of them developed MRI activity during the following 5 months.

Eighteen per cent of patients had three consecutive inactive scans; 65% of them had at least one active scan on the subsequent 3 monthly MRI's. The relationship between the first scan and all subsequent scans demonstrates a clear weakening over time.

Eighty-two per cent of patients had at least one active scan during the initial 3 consecutive months, the chance of becoming inactive decreased from 23% to 0% over the subsequent 3 months, according with the mean number of enhancing lesions during the first 3 months.

These results suggest that neither a single scan nor a short baseline of 3 months may adequately describe the natural history of disease in an individual R/R-MS patient.

Multiple Sclerosis (2000) 6 43 - 49

There are still questions regarding whether Macrophages found in MS lesions are agents of recovery or of destruction.

To address this, we examined in aggregate cultures prepared from dissociated Embryonic Spinal Cord tissue, with or without addition of exogenous Macrophages, the effect of Menadione-induced Oxidative Stress.

Similar to findings of other laboratories, we observed that in the absence of Oxidative Stress Macrophage enrichment promoted MyelinoGenesis.

In Macrophage-poor cultures, Menadione at 5 microM had very little effect upon the status of the aggregate cultures; however, increasing this to 10 and 20 microM did result in some damage to Axons and Myelin.

By contrast, in Macrophage enriched cultures, Menadione at a concentration as little as 5 microM caused the complete destruction of the aggregates.

We suggest that in Neural tissues that have sufficiently high Macrophage numbers, Oxidative Stress results in a positive Inflammatory feedback loop that results in massive tissue destruction.

We further suggest that what we see in Macrophage-enriched aggregates subjected to Oxidative Stress may represent what happens in the Marburg-type of MS lesion.

Multiple Sclerosis (2000) 6 37 - 42

The ProInflammatory Cytokine Interferon-gamma (IF-) is elevated in body fluids of Multiple Sclerosis patients but its variation range is broad. The reason for this wide scatter of IF- production is not yet known.

We looked for the relation between clinical parameters such as Disability, exacerbation frequency, disease duration, course of the disease and IF- producing blood Lymphocytes.

Forty-one consecutive, clinically stable Multiple Sclerosis patients with Primary Relapsing course of the disease and without ImmunoModulatory or ImmunoSuppressive treatment in the last 3 months were investigated for IF- in blood Lymphocytes by flow cytometry.

A significant positive correlation between IF- production and Disability (r = 0.45, P<0.01, Spearman's rho coefficient) was found. PathoPhysiological implications and therapeutical relevance of this unexpected finding are discussed.

Multiple Sclerosis (2000) 6 19 - 23

Rapid correction of Chronic Hyponatremia can cause Osmotic Brain DeMyelination in animals and humans.

Why DeMyelination develops is unknown, but Blood-Brain Barrier disruption might expose Oligodendrocytes to substances normally excluded from the Brain.

To test this hypothesis, Chronic Hyponatremia was induced and corrected using a new, reproducible rat model for producing Osmotic Brain DeMyelination.

Blood-Brain Barrier integrity was assessed by NMR imaging at either 3, 16 or 24 h during the first day of correction. DeMyelination was determined HistoPathologically 5 - 6 days later.

Of 96 rats studied, DeMyelination developed 5 - 6 days later in 37 rats, 89% of whom showed barrier disruption. In the 59 rats who did not develop DeMyelination, 45 (76%) had no Barrier disruption.

Thus, Blood-Brain Barrier disruption during the first 24 h of correction was associated with a 70% risk of developing DeMyelination. By contrast, the risk of developing subsequent DeMyelination was only 8% when the Barrier was intact.

This strong association between Barrier disruption and subsequent DeMyelination provides new insights into the role of Blood-Brain Barrier function in DeMyelinative Disorders such as the Osmotic DeMyelination Syndrome and by extension to other DeMyelinative Disorders such as Multiple Sclerosis.

Multiple Sclerosis (2000) 6 24 - 31

Objective
To assess the potential of registered volumetric MRI in measuring rates of Atrophy in MS.

Background
Pathologic and imaging studies suggest that the development of permanent Neurologic Impairment in MS is associated with Progressive Brain and Spinal Cord Atrophy.

Atrophy has been suggested as a potential marker of disease progression. Conventional Atrophy measurements requiring manual outlining are time-consuming and subject to reproducibility problems.

Registration of serial MRI may offer a useful alternative in that Cerebral losses may be measured directly from automated subtraction of Brain Volumes.

Methods
Twenty-six patients with MS and 26 age- and gender-matched controls had two volumetric Brain MR studies 1 year apart.

Baseline Brain and Ventricular volumes were measured using semiautomated techniques, and follow-up scans were registered to baseline.

Rates of Cerebral Atrophy were calculated directly from the registered scans.

Results
Baseline Brain Volumes in the MS group were smaller (mean difference 78 mL [95% CI 13 to 143; p = 0.02]) and Ventricular volumes greater (mean difference 12 mL [95% CI 6 to 18; p < 0.001]) than controls.

The rate of Cerebral Atrophy in the MS group (0.8% per year) was over twice that of controls (0.3%), and the rate of Ventricular enlargement was five times greater than the controls (1.6 versus 0.3 mL/year).

Conclusion
Progressive Cerebral Atrophy is an important feature of MS.

Registration-based measurements are sensitive and reproducible, allowing Progressive Atrophy to be detected within 1 year and may have potential as a marker of progression in monitoring therapeutic trials.

Comment in: Neurology 2000 Feb 22;54(4):782-3